Hepatocyte transplantation

Authors:
Namita Roy-Chowdhury, PhD, FAASLD
Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 30, 2021.
INTRODUCTIONAdvances in the understanding of hepatocyte engraftment and the
remarkable proliferative potential of hepatocytes have brought liver cell transplantation
to the doorstep of application in the treatment of inherited and acquired human
diseases. Extensive animal experiments have shown that hepatocytes transplanted in
the liver or at ectopic sites survive, function, and participate in the regenerative process.
Because the host liver architecture remains intact following the integration of the
engrafted hepatocytes in the liver cords, hepatocyte transplantation is metabolically less
stressful than transplantation of the whole organ, and the consequences of graft loss
are much less severe.

Hepatocyte transplantation has many potential applications. Therapeutic genes can be

transferred into cultured hepatocytes, and the phenotypically modified cells can then be
transplanted for ex vivo gene therapy. Such gene transfer could be used to replace a
missing gene product, to prevent immune rejection, or to give the cells a proliferative
advantage. Hepatocyte transplantation does not interfere with subsequent liver
transplantation or gene therapy. Although the clinical efficacy of hepatocyte
transplantation has been demonstrated, the shortage of good quality donor livers for
hepatocyte isolation and the lack of dependable methods of cryopreservation will limit
widespread clinical application of this method until further research overcomes these
problems.

SCOPE OF HEPATOCYTE TRANSPLANTATIONPotential clinical

applications of hepatocyte transplantation are listed in (table 1).
Treatment of inherited metabolic diseases — Missing gene products can be
substituted by transplanting normal primary hepatocytes from allogeneic donors. This
simple approach holds promise for diseases such as Crigler-Najjar syndrome type 1,
urea cycle disorders, and coagulopathies, including hemophilias [1]. (See "Crigler-Najjar
syndrome" and "Inborn errors of metabolism: Classification", section on 'Urea cycle
disorders' and "Genetics of hemophilia A and B".)
Hepatocytes used for gene therapy can be derived from a separate donor (allogeneic
transplantation) or the recipient can serve as the donor, in which case the genetic defect
needs to be corrected before transplantation (autologous transplantation). An
advantage of autologous transplantation is that it does not require immunosuppression
[2-4].
Management of acute liver failure — Liver cell transplantation can assist in the
management of patients with fulminant hepatic failure [5-7]. The transplanted
1
hepatocytes can provide temporary liver support in patients awaiting the availability of a
donor liver or spontaneous recovery. In some patients, regeneration of endogenous
hepatocytes combined with the transplanted hepatocytes could possibly replace the
need for transplantation of the whole liver. Hepatocyte transplantation has been shown
to improve some biochemical parameters, such as reduction of blood ammonia levels,
as well as improvement of encephalopathy, but patient survival beyond a week without
liver transplantation has been rare [8-10]. Whether hepatocyte transplantation is
superior to the use of artificial liver assist devices for bridging to liver transplantation
remains to be determined. (See "Acute liver failure in adults: Management and
prognosis", section on 'Artificial hepatic assist devices'.)
Management of chronic liver failure — Hepatocyte transplantation can provide
metabolic support and partially restore liver function in patients with chronic liver failure
[11]. Transplanted normal hepatocytes have a survival advantage compared with the
host cells in some inherited disorders, such as hereditary tyrosinemia type I
(fumarylacetoacetate hydrolase deficiency), and could potentially repopulate the liver
over time [12]. (See "Disorders of tyrosine metabolism".)

Most patients with chronic liver failure have already established cirrhosis, and the
benefit of hepatocyte transplantation in the presence of cirrhosis has not been
established by studies performed to date.

SOURCES OF HEPATOCYTESIn animal experiments, primary hepatocytes

derived from congenic (varying in only one gene locus) or syngeneic (immunologically
compatible) strains can be transplanted without the need for immunosuppression. Such
complete tissue matching is not possible in clinical situations. As mentioned above,
when hepatocytes are used as vehicles for ex vivo gene therapy, immunosuppression
can be circumvented by isolating hepatocytes from resected liver segments and
transplanting them back to the donor after genetic manipulations. However, in most
cases, the cells are obtained from allogeneic donors and immunosuppression will be
required, unless specific tolerance to the alloantigens can be achieved (see below).
The worldwide shortage of donor organs severely limits the number of donor livers that
can be used for hepatocyte isolation. Investigators have attempted to alleviate this
shortage by transplanting hepatocytes isolated from one fragment of a donor liver to
several recipients [13]. In addition, livers explanted from patients with a monogenic
disorder at the time of liver transplantation have been used to isolate hepatocytes for
transplantation into a recipient with a different monogenic disease (domino
transplantation) [14]. The shortage of transplantable primary human hepatocytes has
led to the search for alternative sources of hepatocytes as follows:
●Immortalized hepatocytes: Hepatocytes derived from animal and human livers
have been immortalized by transferring the gene for the large T antigen of the
simian virus 40 (SV40). However, persistent expression of T antigen can
predispose to transformation by oncogenes, such as Ras. One approach involves
expression of a thermolabile mutant T antigen via retroviral vectors. The
transduced cells proliferate in vitro at permissive temperatures (33°C), but are
degraded at physiologic temperatures (37 to 39°C), thereby stopping cell growth.
In rodent models, such conditionally immortalized hepatocytes have been used to

2
provide metabolic support in acute or chronic liver failure, and for ex vivo gene
therapy [15].
●Methods utilizing the p-lox/cre recombinase system have been used to reversibly
immortalize hepatocytes [16]. Human hepatocytes, conditionally immortalized in
this manner, were used successfully to rescue rats with acute liver failure, induced
by 90 percent hepatectomy [17].
●Xenogeneic hepatocytes: Hepatocytes derived from porcine or other animal
sources could be potentially used for providing metabolic support during liver
failure [18], but major immunological hurdles remain. Another concern about these
approaches is the potential to transmit agents, such as the porcine endogenous
retroviruses, which can infect humans.
●Fetal hepatocytes: Human fetal hepatocytes have been transplanted into patients
with acute liver failure with marginal benefit. Transplantation of EpCAM+ve liver
progenitor cells isolated from human fetal liver by infusion into the hepatic artery of
patients with decompensated cirrhosis was reported to improve synthetic and
excretory functions of the liver [19].
●Hepatocytes derived from pluripotent cells: Several laboratories have developed
methods to generate hepatocyte-like cells by in vitro differentiation of human
embryonic stem cells or induced pluripotent stem cells (iPSC) produced by
reprogramming somatic cells, such as fibroblasts, blood cells, and epithelial cells
shed in the urine [20-23]. In an alternative approach, skin fibroblasts were directly
reprogrammed to hepatocyte-like cells without initial conversion to iPSCs [24,25].
Hepatocyte-like cells derived from human-induced pluripotent stem cells have
been transplanted into genetically analbuminemic rats [20], UGT1A1-deficient
jaundiced Gunn rats (model of Crigler-Najjar syndrome type 1) [26], and mice
expressing mutant human alpha-1-antitrypsin [23]. In each case, there was partial
repopulation of the liver with the human cells.
●Adult stem/progenitor cells: Cells that can self-replicate, as well as differentiate
into multiple cell types, persist in many adult tissues including the bone marrow
[27], fat, and the liver. In animal studies, transplanted bone marrow-derived cells
have been shown to give rise to hepatocytes, albeit at a very low frequency,
making it questionable whether they could be a significant source of hepatocytes
for transplantation [28]. Mesenchymal stem cells derived from human adipose
tissue [29] and mouse tail fibroblasts [30] have been differentiated into cells
exhibiting some characteristics of hepatocytes. Benefits of using such cells for the
treatment of liver-based disorders have yet to be demonstrated. Liver stem cells
derived from adult human liver and expanded in culture have been transplanted in
a child with ornithine carbamoyltransferase deficiency [31]. The procedure
resulted in partial clinical improvement, as well as reduction of blood ammonium
and urinary orotic acid levels. However, limited follow-up precluded the evaluation
of duration of clinical benefit.
●Human hepatocytes expanded by repopulation of animal liver: Transplanted
human hepatocytes proliferate extensively in the livers of immunodeficient
fumarylacetoacetate hydrolase knockout mice, replacing the majority of the mouse
hepatocytes with human hepatocytes [32]. This source of mature human

3
 hepatocytes (expanded in the liver of mice) could potentially be used for
transplantation.
SITES OF HEPATOCYTE TRANSPLANTATIONThe liver provides the most
supportive environment for engraftment and function of transplanted hepatocytes
because of the availability of nutrients and growth factors present in the portal
circulation, and interaction with other liver cells and the hepatic matrix. However, the
optimum route for hepatocyte transplantation also depends upon the specific
application.
Hepatocytes infused into the portal vein or injected into the splenic pulp travel to the
hepatic sinusoids and integrate into the liver cords [33,34]. The cells obtain polarity and
establish appropriate junctions with the neighboring hepatocytes within 24 hours.
Studies in rats, mice, and rabbits have shown that syngeneic or congenic hepatocytes
survive and function throughout the life of the host. Hepatocytes equivalent to up to one
to five percent of the liver mass could be transplanted into normal livers with only a
transient and reversible increase in the portal pressure. By contrast, hepatocyte
transplantation in cirrhotic animals results in portal hypertension and an increase in right
atrial pressure [35].

After injection into the splenic pulp, a fraction of the transplanted cells may survive in
the spleen and eventually develop liver cord-like structures, replacing up to 40 percent
of the splenic mass. Over time, bile canaliculi, sinusoids, and endothelial cells may
develop. Thus, in specific circumstances, the spleen may serve as an important site of
hepatocyte engraftment.

For inherited metabolic disorders, implantation into the liver via injection into a tributary
of the portal vein or into the splenic pulp has been most effective [36-38]. However, in
the presence of cirrhosis, the liver may not be the most desirable site for hepatocyte
transplantation. Although hepatocytes can engraft within cirrhotic nodules, the
transplanted cells may not function normally in this environment. Similarly, a liver that is
undergoing massive necrosis may not provide a hospitable environment for the
transplanted cells. In the presence of portal hypertension, a large proportion of the cells
infused into the portal vein may be translocated to the pulmonary vascular bed. In such
cases, hepatocytes have been transplanted into the spleen by injection into the splenic
pulp or infusion into the splenic artery [36,37]. More study is needed to determine if the
transplantation in the splenic artery would augment liver function in patients with liver
cirrhosis.
Other sites, such as the renal subcapsular space or subcutaneous tissue, are less
efficient. However, with further development, the peritoneal cavity could be an effective
site for transplanting hepatocytes that are encapsulated [39], attached to collagen-
coated microcarriers [40], or encased in Hydrogel-based hollow fibers [41]. Hepatocytes
cryopreserved on these carrier beads could represent a readily available source for
transplantation into the peritoneal cavity for the treatment of acute liver failure [42].
PRECLINICAL EVALUATION IN EXPERIMENTAL ANIMAL
MODELSThe efficacy of hepatocyte transplantation has been evaluated extensively in
natural mutant animals.

4
Disorders due to single gene defects — Hepatocytes have been transplanted into
Gunn rats (a model of Crigler-Najjar syndrome type 1), which have life-long
unconjugated hyperbilirubinemia due to the lack of hepatic bilirubin-UDP-
glucuronosyltransferase activity, by infusion into the portal vein, injection into the splenic
pulp, or attachment to microcarriers, followed by injection into the peritoneal cavity.
These procedures resulted in the excretion of bilirubin glucuronides in the bile and
amelioration of hyperbilirubinemia [43,44]. The metabolic defect was corrected in
subsequent studies in which the rats were first treated with liver resection and radiation,
thereby promoting the preferential repopulation of the native liver with the transplanted
hepatocytes [45]. Hepatic irradiation appears to disrupt hepatic sinusoidal endothelial
cells and inhibit the phagocytic function of Kupffer cells, thereby enhancing hepatocyte
engraftment [46].
Similarly, serum albumin levels increased after transplantation of normal hepatocytes
into Nagase analbuminemic rats [47]. Hepatocyte transplantation reduced plasma
cholesterol levels by up to 50 percent in Watanabe heritable hyperlipidemic rabbits that
lack LDL receptors (an animal model of familial hypercholesterolemia) [48]. Hepatocyte
transplantation also ameliorates the metabolic abnormality in fumarylacetoacetate
hydrolase (FAH)-deficient mice (a model of hereditary tyrosinemia 1) [12], Long-Evans
Cinnamon rats (a model of Wilson disease) [49], and mdr2 (-/-) mice (a model of
progressive familial intrahepatic cholestasis) [50]. (See "Disorders of tyrosine
metabolism", section on 'Hereditary tyrosinemia type 1' and "Wilson disease:
Epidemiology and pathogenesis" and "Inherited disorders associated with conjugated
hyperbilirubinemia", section on 'Familial hepatocellular cholestasis'.)
Acute and chronic liver failure — Transplantation of hepatocytes significantly
improved the survival of animals with acute liver failure induced by D-galactosamine or
dimethylnitrosamine administration, hepatic ischemia, or 90 percent hepatectomy
[40,51], but not in a mouse model of acute toxic liver failure [52]. Hepatocyte
transplantation reversed encephalopathy and prevented intracranial hypertension in
animals with ischemic liver failure [53]. In rats with hepatic encephalopathy caused by
end-to-side portacaval shunt, intrasplenic transplantation of hepatocytes improved the
behavior score, partially corrected amino acid imbalances, and protected the rats from
hepatic coma induced by an exogenous ammonia load [53]. In similar experiments,
transplantation of hepatocytes that had been immortalized by transfection with the
simian virus 40 T antigen was able to improve measures of liver failure and prolong
survival [54]. Hepatocyte transplantation in rats with chronic decompensated liver
cirrhosis stabilized total bilirubin and prothrombin time, improved serum albumin and
encephalopathy scores, and prolonged survival [11].
Massive repopulation of the liver — The effectiveness of hepatocyte transplantation
for inherited liver diseases depends on the number of transplanted cells persisting long-
term in the liver. The mass of transplanted hepatocytes depends on several factors:
Efficiency of initial engraftment: After hepatocyte transplantation by infusion into the
portal venous system or injection into the splenic pulp, instant blood-mediated
inflammatory reaction (IBMIR) activates thrombin, which produces fibrin clots and
activates complements, resulting in death of the injected hepatocytes and their
clearance by granulocytes, monocytes, Kupffer cells, and natural killer cells [55].
Antithrombin activator (heparin) and thrombin inhibitor (bivalirudin) inhibit IBMIR in vitro,

5
suggesting that effective inhibition of IBMIR should improve initial engraftment. After
arriving into the liver sinusoids, the liver sinusoidal endothelial cells (LSEC) pose a
barrier to integration of hepatocytes into the liver plates. Preparative X-irradiation of the
liver results in transient disruption of the LSEC, thereby enhancing initial engraftment of
transplanted hepatocytes in preclinical [46,56] and clinical studies [57].
Proliferation of transplanted hepatocytes: Following initial engraftment, proliferation of
the transplanted hepatocytes is desirable for generation of a therapeutically effective
mass. However, normal physiologic mechanisms tend to keep the total hepatocyte
mass constant, and repopulation of the liver occurs by replacement of the host liver
cells by the engrafted hepatocytes. This requires a proliferative advantage of the
transplanted cells over host hepatocytes. Such proliferative advantage exists in some
inherited liver diseases, such as the FAH-deficient mouse model of hereditary
tyrosinemia type 1 [58] and MDR3 gene knockout mouse model of progressive
intrahepatic cholestasis type 3 [59]. In these cases, markedly reduced hepatocyte life
span provides both space and stimulation for preferential proliferation of transplanted
hepatocytes, leading to massive hepatic repopulation. In a transgenic mouse model of
human alpha-1 antitrypsin disease (AAT-ZZ), transplanted normal hepatocytes were
shown to spontaneously proliferate and replace the host hepatocytes [60]. Similar to the
majority of human AAT-ZZ patients, liver injury is minimal in these mice, but the stress
of production of the misfolded protein (AAT-Z) is sufficient to provide a competitive
proliferative advantage to the engrafted normal hepatocytes. (See "Clinical
manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

Because many inherited liver disorders do not cause significant injury of host
hepatocytes, two approaches are being explored to enable hepatic repopulation by the
transplanted cells through cell competition: preparative manipulation of the host liver to
cause death or mitotic inhibition of host hepatocytes, or increasing the mitotic capacity
of donor hepatocytes.

To reduce the proliferative capacity of host hepatocytes, preparative X-irradiation has

been applied to all major lobes of the liver [45] or to a single lobe [61]. In one study that
combined stimulation of hepatocyte mitosis (eg, partial hepatectomy) and preparative
hepatic irradiation, the transplanted hepatocytes repopulated the irradiated host liver,
thereby reducing serum bilirubin to normal levels in UGT1A1-deficient jaundiced Gunn
rats [45] and normalizing urinary oxalate excretion in a mouse model of primary
hyperoxaluria [62]. Normal function and histological architecture of the liver is retained
after repopulation of the liver with the transplanted hepatocytes [45,61,62]. Techniques
for hepatic irradiation that target a portion of the liver and do not require surgery have
also been studied for the management of inherited liver diseases [56,57,63].
(See 'Clinical experience' below.)
Another approach to enable long-term hepatic repopulation involves providing
transplanted hepatocytes with pharmacologically-regulated proliferative capacity [64].
Attrition through allograft rejection: Early and delayed allograft rejection is a critical
factor that impairs the longevity and function of transplanted hepatocytes. The
mechanism of hepatocyte allograft rejection is not fully understood, and methods for
detecting organ rejection are not useful for monitoring for hepatocyte rejection.
However, in one study, the emergence of donor-specific antibodies (DSA) were found to
6
be temporally related to loss of hepatocyte allograft in a patient with phenylketonuria,
suggesting that DSA could be a sign of rejection [57].
Ex vivo gene therapy — Hepatocytes can be transduced in vitro and then transplanted
[65,66]. In one report, for example, primary hepatocytes from LDL-receptor deficient
Watanabe heritable hyperlipidemic rabbits were harvested and transduced with a
recombinant virus expressing the LDL receptor gene [65]. The transduced hepatocytes
were then transplanted back into the rabbits. Long-term expression of the transgene
was observed, and the serum cholesterol levels were reduced by 20 to 30 percent
during several months of observation. A clinical trial of this method in human subjects
with familial hypercholesterolemia resulted in modest reduction of serum LDL
cholesterol levels, which were not considered to be therapeutically useful.
At this time, several factors limit the efficiency of ex vivo gene therapy for liver diseases.
The procedure requires partial hepatectomy and, as a result, cannot be repeated easily.
The proportion of primary hepatocytes that can be established in culture and transduced
using recombinant viral vectors remains modest and variable. The number of
phenotypically corrected hepatocytes that can be harvested and engrafted after
transplantation also restricts the final metabolic impact of ex vivo gene therapy.
Solutions to these technical problems may come from improved hepatocyte culture
methods and conditional immortalization of hepatocytes [15]. However, because of the
current hurdles, ex vivo gene therapy for liver diseases is unlikely to be applied broadly
in the near future.
CLINICAL EXPERIENCEClinical outcome data for patients receiving hepatocyte
transplantation have been reported [67,68].
Metabolic disorders — Patients have undergone hepatocyte transplantation for a
variety of conditions, including alpha-1 antitrypsin deficiency, Crigler-Najjar syndrome
type 1, coagulation factor VII deficiency, glycogen storage disease types 1a and 1b,
infantile Refsum's disease, phenylketonuria, progressive familial intrahepatic
cholestasis, tyrosinemia type 1, primary hyperoxaluria type 1 and several types of urea
cycle disorders (table 2). The results have been variable because of differences in the
severity of the underlying diseases, the quality and quantity of transplanted
hepatocytes, and immune rejection of the transplants. In most instances, the study
design included orthotopic liver transplantation (OLT) or auxilliary liver transplantation
after a few months to evaluate the metabolic effect of hepatocyte transplantation.
Reports of hepatocyte transplantation for metabolic disorders have included:
●One child with the urea cycle disorder OTC received 10 billion hepatocytes.
Although some clinical improvement was seen, she died of pneumonia a short
time later.
●A newborn OTC-deficient child who received hepatocyte transplantation via the
umbilical vein had normalization of plasma ammonia and glutamine levels on a
normal diet without phenylbutyrate/phenylacetate therapy. However, following
repeated transplantation from multiple donors, the cells appeared to be rejected,
possibly because of inadequate immunosuppression [69].
●Transplantation of 240 million viable cryopreserved hepatocytes per kilogram
over 16 weeks in a 14-month-old boy with OTC deficiency resulted in significant
decrease in mean blood ammonia levels and increase in blood urea levels. This

7
 permitted eventual elective OLT, demonstrating the value of hepatocyte
transplantation for bridging to OLT [70].
●One study reported significant reduction in blood ammonia concentration and
improved urea production for up to 11 months in a 2.5-month-old child with
carbamoyl phosphate synthetase I deficiency, after transplantation of 1.4 ×
109 cryopreserved hepatocytes [13].
●In a patient with argininosuccinate lyase deficiency, who received multiple
hepatocyte transplantation over a five-month period, sustained engraftment was
demonstrated for up to 15 months, along with restitution of argininosuccinate
metabolism to 3 percent of normal, permitting significant psychomotor catch-up
[71].
●One 18-week-old child received hepatocyte transplantation for alpha-1 antitrypsin
deficiency, but the patient had to be subsequently treated with orthotopic liver
transplantation as the liver biopsy of the patient at the time of cell transplantation
revealed cirrhosis [72].
●The long-term therapeutic benefit of hepatocyte transplantation was
demonstrated unequivocally in a 10-year-old patient with Crigler-Najjar syndrome
type 1 who received 7.5 billion hepatocytes via a percutaneous portal vein
catheter [73]. Duodenal bile samples collected at various time points up to two
years showed the excretion of significant amounts of bilirubin monoglucuronide
and diglucuronide, demonstrating function of the engrafted hepatocytes in vivo.
Hepatic bilirubin-UDP-glucuronosyltransferase activity was also detected on liver
biopsy specimens (5.5 percent of the normal compared with 0.4 percent before
treatment). Serum bilirubin declined from a pretreatment average of 27 mg/dL to
around 11 to 13 mg/dL, and the phototherapy could be reduced from 12 to 6 hours
per day.
Analysis of the world-wide experience in hepatocyte transplantation for inherited
metabolic liver diseases (table 2) led to the following conclusions:
●Hepatocyte transplantation exhibits beneficial metabolic effects in the absence of
established cirrhosis of the liver.
●Although hepatocyte transplantation improves the metabolic state and the clinical
condition in many liver-based inherited metabolic disorders, none of these
disorders have been fully cured to date. Also, if the host liver is not manipulated
pretransplant, the engrafted hepatocytes do not tend to survive and function
beyond a few months to a few years. Most patients have required subsequent liver
transplantation for various reasons.
●Hepatocyte transplantation has been particularly useful as a "bridge" to
subsequent liver transplantation in newborns or infants with life-threatening
metabolic emergencies. For example, several infants with urea cycle disorders
showed significant metabolic improvement, permitting them to grow until liver
transplantation could be performed safely [74].
Liver failure — While the efficacy of transplanted cells can be best evaluated in the
treatment of inherited metabolic disorders, the greatest need for hepatocyte
transplantation is for acute and chronic liver failure. In an early study, hepatocytes were
injected into the spleen of several patients with chronic hepatitis and cirrhosis [37].
Epidermal growth factor was injected into the splenic artery to stimulate hepatocyte

8
proliferation. The transplanted hepatocytes were detected in 88 percent of patients 1 to
11 months after transplantation, although the metabolic benefit was not clear.
Another group injected 5 billion pooled human fetal (24- to 34-week gestation)
hepatocytes into the peritoneal cavity of patients with fulminant hepatic failure (FHF) of
less than two weeks in duration and grade III to IV encephalopathy [9]. More patients
who received the transplanted cells survived (48 versus 33 percent), but the difference
was not statistically significant because of the small number of patients. Best results
were obtained when the transplantation was performed during earlier stages of liver
failure. In the survivors, plasma ammonia and serum bilirubin levels decreased in 48
hours after hepatocyte transplantation.
In the United States, hepatocyte transplantation has been performed in an effort to
"bridge" patients awaiting OLT for FHF or chronic liver failure with acute
decompensation (table 3 and table 4). Following transplantation by infusion into the
splenic artery, 66 percent of patients with FHF survived long enough to receive OLT
[10]. In the patients with chronic failure with acute decompensation, only one of four
survived long enough to receive OLT. In the transplant recipients, there was
improvement in plasma ammonia levels, grade of encephalopathy, cerebral perfusion
pressure, and prothrombin time, but the differences from the values observed in
controls were not statistically significant. Because most survivors had received OLT, it is
difficult to be sure whether hepatocyte transplantation provided a significant clinical
benefit. However, in one 37-year-old woman with hepatitis B virus-induced liver failure,
there was sufficient recovery after hepatocyte transplantation to permit discharge from
the hospital without OLT.
Ex vivo gene therapy — Ex vivo gene therapy has been performed in patients with
familial hypercholesterolemia (LDL receptor deficiency). Hepatocytes were isolated by
collagenase perfusion of resected liver segments from patients. The cells were
transduced with LDL receptor gene in culture using retroviral vectors, and were
transplanted back into the donors. Although persistence of the transgene expression
was demonstrated [65], the serum cholesterol reduction was modest and probably not
therapeutically beneficial [75].
BARRIERS AND ADDITIONAL RESEARCHAs discussed above, the major
barrier to extensive clinical application of hepatocyte transplantation is the shortage of
donor organs for hepatocyte isolation. Hepatocytes are usually obtained from donor
organs that have been rejected for transplantation because of extensive steatosis. Cells
obtained from these livers are of variable viability and their survival after
cryopreservation is unpredictable. The best quality hepatocytes are obtained from
segmental transplants or reduced liver grafts, which have the shortest duration of cold-
ischemia.
Although the experience is limited, it appears that repeated cell transplantation from
multiple donors may increase the possibility of allograft rejection. Development of
reliable methods of cryopreservation of human hepatocytes will be needed for repeated
transplantation of hepatocytes obtained from a single donor. A study in fumaryl
acetoacetate dehydrogenase-(FAH) deficient mice (model of hereditary tyrosinemia)
demonstrated that adult human hepatocytes, like adult rodent hepatocytes, retain the
capacity to proliferate extensively and massively repopulate the liver [76]. In some
disorders, such as the classic form of alpha1 antitrypsin (AAT) deficiency, accumulation
9
of the mutant AAT-Z protein in hepatocytes causes a stress in the host liver that
promotes spontaneous repopulation by transplanted normal hepatocytes [60]. However,
in a majority of liver-based inherited metabolic disorders, the longevity and regenerative
capacity of host hepatocytes remains normal. In these cases, an alternative solution
could be to prepare the host liver to promote repopulation by a relatively small number
of transplanted hepatocytes. The use of preparative irradiation of the host liver [7,61,77]
or treatment of the host with drugs (eg, retrorsine) that suppress host hepatocyte
proliferation [78] have been evaluated in preclinical studies for enhancing the
engraftment and preferential proliferation of the transplanted cells.
Alternative sources of hepatocytes are also being explored. Research on culture and
transplantation of fetal hepatocytes is in its infancy, but offers great possibilities. As
mentioned above, conditionally immortalized human hepatocytes, from which the
immortalizing gene (eg, SV40 large T antigen) can be deleted prior to transplantation,
have been developed and are being evaluated [15]. Transplantation of hepatocytes
from xenogeneic sources is also being explored, although major immunological barriers
and the risk of infection of human tissues by known or unknown animal viruses are
important concerns. A novel potential source of human hepatocytes is an animal liver
repopulated by human hepatocytes. This has been achieved by transplanting human
hepatocytes serially into FAH-deficient, immunodeficient mice. Human hepatocytes
isolated from the repopulated mouse livers have been successfully transplanted into the
livers of immunodeficient animals [76].
A noninvasive method to measure the mass of engrafted cells could greatly facilitate the
follow-up and optimization of hepatocyte transplantation methods. One way to
accomplish this is to mark cells genetically before transplantation. Luciferase-based
optical imaging, which is effective in mouse experiments, is not applicable to humans
because of the greater thickness of the abdominal wall. However, magnetic resonance
imaging methods are being developed for three-dimensional quantification of
transplanted hepatocytes using genetic marking with creatine kinase, which is not
normally expressed in hepatocytes [79].
Hepatocyte transplantation would be much more useful and attractive if the need for
immunosuppression could be circumvented. For this purpose, the immune response of
the host to specific alloantigens could be abrogated by interference with costimulation
between antigen-presenting cells and cytotoxic lymphocytes, at the time of hepatocyte
transplantation, by the administration of CTLA4-Ig alone, or in combination with an anti-
CD40 antibody. CTLA4-Ig could also be expressed in vivo by gene transfer for this
purpose [80,81]. As an alternative, immunomodulatory genes could be transduced into
the donor hepatocytes before transplantation [3]. Some studies in rodents showed that
ex vivo transduction with some viral genes can protect transplanted liver cells from
allograft rejection [82]. In addition, when allogeneic hepatocytes are used, developing
methods for detecting early allograft rejection is important, so that measures to prevent
graft loss could be initiated.
SUMMARY
●Hepatocyte transplantation has many potential clinical applications including
treatment of inherited metabolic diseases and management of acute and chronic
liver failure. (See 'Scope of hepatocyte transplantation' above.)

10
●When hepatocytes are used as vehicles for ex vivo gene therapy,
immunosuppression can be circumvented by isolating hepatocytes from resected
liver segments and transplanting them back to the donor after genetic
manipulations. However, in most cases, the cells are obtained from allogeneic
donors and immunosuppression will usually be required. (See 'Sources of
hepatocytes' above.)
●The liver provides the most supportive environment for engraftment and function
of transplanted hepatocytes because of the availability of nutrients and growth
factors present in the portal circulation and interaction with other liver cells and the
hepatic matrix. Hepatocytes infused into the portal vein or injected into the splenic
pulp travel to the hepatic sinusoids and integrate into the liver cords. (See 'Sites of
hepatocyte transplantation' above.)
●The major barrier to extensive clinical application of hepatocyte transplantation is
the shortage of donor organs for hepatocyte isolation. Hepatocyte transplantation
would also be much more useful and attractive if the need for immunosuppression
could be circumvented. (See 'Barriers and additional research' above.)

11
Living donor liver transplantation in adults
Authors:
Scott J Cotler, MD
Kristina Lemon, MD, FRCSC
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 11, 2021.
INTRODUCTIONThe scarcity of donor organs has been a limiting factor in liver
transplantation. As an example, in 2018 in the United States, there were over
14,000 individuals on the waiting list for liver transplantation. Approximately 7000
liver transplantation candidates will wait for >1 year for a transplant, and many
patients will die waiting for an organ. Living donor liver transplantation (LDLT) is
one approach that has been used to expand organ availability. Adult-to-adult LDLT
has been performed in the United States for over twenty years, and over 4500
patients have received a living donor liver transplant [1].

This topic will review evaluation of the living liver donor candidate, surgical
technique for the recipient operation, and outcomes of LDLT. Other issues
regarding liver transplantation, such as pretransplantation evaluation of the
recipient candidate and selection of organs from deceased donors are discussed
separately:

●(See "Liver transplantation in adults: Patient selection and

pretransplantation evaluation".)
●(See "Liver transplantation in adults: Deceased donor evaluation and
selection".)

Medical care of the liver transplant recipient is discussed separately:

●(See "Liver transplantation in adults: Long-term management of transplant

recipients".)
●(See "Liver transplantation in adults: Overview of immunosuppression".)
●(See "Infectious complications in liver transplantation".)
Perioperative anesthesia management for patients undergoing liver
transplantation is discussed separately. (See "Liver transplantation: Anesthetic
management".)
12
An overview of hepatic resection and specific resection techniques are discussed
separately. (See "Overview of hepatic resection" and "Open hepatic resection
techniques".)
EVALUATION OF THE LIVING LIVER DONOR CANDIDATEEvaluating
and selecting an adult liver donor is a comprehensive process that includes a
medical and psychosocial assessment in addition to an assessment by an
Independent Living Donor Advocate (ILDA). The decision to accept a liver donor is
determined by a multidisciplinary team (eg, transplant surgery, transplant
hepatology, mental health clinician, ILDA) and is informed by establishing that:
●The donor is medically fit to undergo donor hepatectomy
●There are no active psychosocial issues that would preclude donation
●The donor liver is suitable based on criteria such as ABO compatibility, liver
size, and liver anatomy for the designated recipient
Each liver transplant center has developed specific protocols for donor evaluation
and selection based on their experience and the population of donor candidates
that they serve. Based on the comprehensive evaluation, a donor candidate may
be accepted or declined. The Organ Procurement and Transplantation Network
(OPTN) has defined a number of absolute contraindications to liver donation, while
there is variability among centers concerning relative contraindications for liver
donation. (See 'Contraindications to liver donation' below.) The OPTN guidance can
be found here [2].
Blood typing and crossmatch — For adults who wish to be a liver donor, the
evaluation of a living liver donor candidate begins with an assessment of the
donor and recipient blood groups and crossmatch compatibility, which are the
criteria for biologic compatibility of the donor and recipient [3,4]. ABO typing is
performed on two separate occasions.
Medical evaluation — After a living donor candidate is screened for blood type
and crossmatch compatibility with the designated recipient, a comprehensive
medical evaluation of the donor is performed with the following goals (table 1):
●Ensure that the donor is in good health and has normal liver function and
structure
●Ensure that the donor is not a risk to the recipient with respect to disease
transmission
●Ensure that the donor liver is suitable for the intended recipient based on
liver size and anatomy
Less than half of the candidates who complete the evaluation process will be
accepted for liver donation. In a study including 1011 donor candidates in the
Adult-to-Adult Living Donor Liver Transplantation Cohort, 405 donor candidates
(40 percent) were accepted for donation [5]. Donor characteristics that were
13
associated with acceptance included younger age, lower body mass index, and
biologic or spousal relationship to the recipient.
History and physical examination — The medical evaluation consists of a history
and physical examination and an assessment for pre-existing conditions such as
viral hepatitis, nonalcoholic fatty liver disease, cardiovascular disease, malignancy,
and bleeding disorders. The evaluation also includes confirming that donors have
had age- and sex-appropriate cancer screening. Preventive care in adults is
discussed separately. (See "Overview of preventive care in adults", section on
'Cancer screening'.)
Laboratory and screening tests — Laboratory testing is performed primarily to
assess liver function, to screen for infections (eg, viral hepatitis), and to screen for
diseases affecting the liver (eg, hereditary hemochromatosis). A chest radiograph
is also routinely obtained. The pre-anesthesia evaluation for noncardiac surgery is
discussed separately. (See "Preanesthesia evaluation for noncardiac surgery",
section on 'Preoperative testing'.)
An electrocardiogram is performed for all donors. If there are abnormalities or if
the donor has risk factors for coronary artery disease (eg, family history of cardiac
disease), further cardiac testing such as echocardiogram is typically performed
along with cardiology consultation. (See "Overview of established risk factors for
cardiovascular disease".)
The evaluation of cardiac risk prior to noncardiac surgery is discussed separately.
(See "Evaluation of cardiac risk prior to noncardiac surgery".)
The use of liver biopsy is center-specific and is not needed for most donor
candidates because computed tomography (CT) or magnetic resonance imaging
(MRI) can identify hepatic steatosis that would result in excluding the donor
candidate [6]. Liver biopsy has been performed at some centers for potential
donors with elevated liver biochemical tests and/or mild hepatic steatosis on
imaging [6,7]. (See 'Advanced imaging' below.)
Advanced imaging — Advanced imaging of the donor serves to determine if the
donor liver is suitable for the designated recipient and includes the following
studies, alone or in combination, according to the transplant center’s protocol:
●Triple phase CT of the liver with liver volumetrics and 3D reconstruction –
This CT is performed to delineate the arterial and venous anatomy of the
donor liver. Additionally, volumetrics and 3D reconstructions are completed
to assist the surgical team in determining if the liver is an appropriate size
match and which donor lobe is preferred based on anatomic fit. Donation is
contraindicated when the expected donor remnant liver is <30 percent of
native liver volume. (See 'Surgical technique' below.)

14
 In addition, advanced imaging of the donor liver can identify hepatic
steatosis that would typically eliminate the potential donor as a candidate.
(See 'Laboratory and screening tests' above.)
Contrast-enhanced MRI of the liver is another option for evaluation of hepatic
steatosis, liver size, and vascular anatomy.
●Magnetic resonance cholangiopancreatography (MRCP) – MRCP is
performed to assess anatomy of the biliary tree to help plan the surgical
approach and determine if right or left liver lobe donation is preferred. In
addition, most centers perform intra-operative cholangiography to delineate
biliary anatomy prior to transection of the biliary ducts.
Psychosocial evaluation — The OPTN mandates performance of a psychosocial
evaluation by a clinician with expertise in mental health (eg, psychiatrist,
psychologist, Master's-prepared social worker) prior to donation, including
documentation of the following [8]:
●Screening for any psychosocial issues, including mental health issues, that
might complicate the living donor's recovery and could be identified as risks
for poor psychosocial outcome. The donation process can be a
psychologically stressful event for the donor, and review of the donor's social
supports and coping skills is an important aspect of this process.
●Screening for behaviors that may increase risk for disease transmission as
defined by the United States Public Health Service Guideline [9].
●A review of the living donor's history of smoking, alcohol, and drug use,
including past or present substance abuse disorder.
●Establishing that the living donor understands the medical and psychosocial
risks for both the living donor and the recipient. Most transplant centers
require that donors and their caregivers attend an education session
detailing the risks and benefits of live liver donation.
●An assessment of whether the decision to donate is free of inducement,
coercion, and other undue pressure by exploring the reasons for donating
and the nature of the donor's relationship, if any, to the transplant candidate.
Some centers evaluate unrelated, altruistic donors.
●An assessment of the living donor's ability to make an informed decision
and the ability to cope with major surgery and related stress. This includes
evaluating whether the donor has a realistic plan for donation and recovery,
which includes social, emotional, and financial support.
●An assessment of the living donor's ability to provide informed consent, to
contemplate the risks of donation and to decline participation, if desired.
●A review of the living donor's occupation, employment status, health
insurance status, living arrangements, and social support. Establishing

15
 adequate support for donors during their postoperative recovery includes
identifying caregivers for the liver donor and for the transplant recipient. The
donor cannot serve as primary caregiver for the transplant recipient.
●Establishing that that the living donor understands the potential financial
implications of living donation.

Some elements of the psychosocial evaluation (eg, documenting history of

smoking or alcohol use) are also performed by the clinician performing the
medical evaluation.

Independent Living Donor Advocate (ILDA) — The OPTN policy requires that

living donor recovery hospitals must designate and provide each donor candidate
with an ILDA (ie, one person or a team with a key contact) who is not involved with
the recipient evaluation and is independent of the decision to transplant the
potential recipient. The ILDA must have adequate qualification and training
requirements regarding knowledge of living organ donation, transplantation,
medical ethics, informed consent, and the potential impact of family or other
external pressure on the living donor's decision about whether to donate. To fulfill
the OPTN requirements, the ILDA must do the following [10] (see "Kidney
transplantation in adults: Evaluation of the living kidney donor candidate", section
on 'Donor evaluation'):
●Function independently from the transplant candidate's team.
●Advocate for the rights of the living donor.
●Review whether the living donor has received information on each of the
following areas: informed consent, the evaluation process, the surgical
procedure, medical and psychosocial risks, and follow-up requirements.
●Assist the donor in obtaining additional information from other health care
professionals as needed.
CONTRAINDICATIONS TO LIVER DONATIONExclusion criteria for live
liver donation are informed by the Organ Procurement and Transplantation
Network (OPTN) and each transplant center's policy. While variability exists among
centers, common contraindications to living donation include [8,11]:
●Age <18 years.
●Age >60 years – The upper age limit for donors varies depending on the
specific program requirements and donor availability. A study comparing
outcomes by donor age (≥50 versus <50 years, range 20 to 63 years) found no
significant difference in complications based upon donor age [12]. In another
study including 378 liver donors, no significant difference in outcomes based
on donor age (50 to 60 years versus <50 years) was reported [13].

16
 ●Inability to provide informed consent (eg, lack of decision-making capacity)
(see "Informed procedural consent").
●Body mass index (BMI) ≥30 to 35 kg/m2 – Most centers use a BMI threshold
of ≥30 to 35 kg/m2 to exclude potential donors because of the risk of hepatic
steatosis and surgical complications [14-17].
●Active malignancy or incompletely treated malignancy.
●Evidence of active symptomatic infection (see "Evaluation for infection
before solid organ transplantation").
●HIV infection – Unless the requirements for variance are met according to
the OPTN Policy 15.7 (Open Variance for the Recovery and Transplantation of
Organs from HIV Positive Donors).
●Hepatitis C virus ribonucleic acid positivity.
●Hepatitis B virus surface antigen positivity.
●History of hypercoagulable disorder (see "Overview of the causes of venous
thrombosis", section on 'Inherited thrombophilia').
●Active psychiatric conditions requiring treatment before donation, including
evidence of suicidality.
●The following alpha-1 antitrypsin phenotypes: ZZ, Z-null, null-null, and S-null
(see "Clinical manifestations, diagnosis, and natural history of alpha-1
antitrypsin deficiency", section on 'Background').
●Expected donor remnant volume <30 percent of native liver volume.
●Prior living liver donation.
●High suspicion of donor coercion.
●High suspicion of illegal financial exchange between the donor and the
recipient.
ANESTHESIA MANAGEMENTPerioperative anesthesia management for
patients undergoing liver transplantation is discussed separately. (See "Liver
transplantation: Anesthetic management" and "Anesthesia for the patient with
liver disease", section on 'Anesthesia for hepatic resection'.)
For living liver donors, initiating an enhanced recovery after surgery (ERAS)
protocol during the pre-operative period may facilitate pain management, and
ERAS is discussed separately. (See "Anesthetic management for enhanced recovery
after major surgery (ERAS) in adults".)
SURGICAL TECHNIQUE
General principles — In addition to medical and psychosocial evaluation, the
surgical team evaluates the donor and reviews the results of laboratory testing
and imaging. The decision to accept a liver donor is informed by the donor's liver
size and appearance and the recipient's weight:

17
 ●Donor liver size – The donor must have sufficient liver size to allow for
donation of adequate volume of liver to the recipient while maintaining an
adequate size of the future liver remnant (FLR). Resecting <70 percent of
donor liver volume is generally acceptable; thus the FLR will consist of ≥30
percent of original liver volume [18].
●Graft weight to recipient weight ratio – Determining a minimum allograft
size that will provide the recipient with adequate liver function is based on
the recipient's weight. The ratio of allograft weight to recipient weight is used
to determine the minimum allograft size. A graft weight to recipient weight
(GW:RW) ratio of >0.8 has been associated with safety and adequate liver
function for the recipient, although donor livers with lower GW:RW ratios
have been used successfully in selected cases. (See 'Recipient
outcomes' below.)

If these criteria cannot be met by the donor/recipient pair, the donor is declined to
ensure the safety of both the donor and the recipient.

Donor hepatectomy — The left or right lobe of the liver can be used for
transplantation depending upon anatomic considerations, the volume of the
donor liver, and the size of the recipient. (See 'General principles' above.)
An overview of hepatic resection and specific resection techniques (eg, left
hemihepatectomy, right hemihepatectomy) are discussed separately.
(See "Overview of hepatic resection" and "Open hepatic resection techniques".)
Recipient operation
Recipient hepatectomy — The first portion of the recipient operation is the
recipient hepatectomy which can often be the most challenging part of the
transplant due to portal hypertension, liver size, and adhesions from previous
surgeries or episodes of spontaneous bacterial peritonitis. Portal venous bypass
has been commonly used to ensure that there is adequate drainage of the portal
venous system during hepatectomy and during implantation of the allograft prior
to reperfusion.

Another important aspect of the recipient operation is maintaining the length of

the recipient's portal structures by dividing the hepatic artery, portal vein, and bile
duct as close to the liver as possible and ideally above their respective bifurcations.

Preparing the liver allograft for implantation — The approach to preparing the

liver allograft for implantation varies among liver transplantation centers and
according to surgical team preference; however, common techniques include:

18
 ●Reconstruction of the hepatic veins – Cadaveric donor vein is typically used
to reconstruct the hepatic veins to optimize venous outflow. All middle
hepatic vein branches >5 mm in diameter are reconstructed in order to
maximize venous outflow of the graft. This is more commonly performed
with a right lobe donor graft than with a left lobe graft. A venous patch is also
often used to widen and lengthen the right or left hepatic vein.
●Preparation for bile duct anastomosis – For transplant centers that typically
connect the donor bile ducts to the recipient common bile duct, multiple
donor ducts may need to be brought together into one common duct before
implanting the allograft. However, for centers that typically perform Roux-en-
Y hepaticojejunostomy reconstruction, combining donor bile ducts may not
be necessary (figure 1). For some donor livers with multiple ducts, a
combination of these two techniques may also be used.
Implantation — The process of implanting of the donor allograft can be divided
into the following steps:
●Venous outflow – The first step in implantation of the graft is
reconstruction of the venous outflow. This can be accomplished with one or
two maneuvers, depending on the size and anatomy of the graft. The first
maneuver is reconstructing the main outflow (right hepatic vein or
left/middle hepatic vein confluence), typically in an end-to-side fashion to the
recipient vena cava. To maximize venous outflow, some right lobe grafts
require a second maneuver that is usually performed after reperfusion. This
maneuver involves the construction of a venous jump graft created on the
back table to drain the graft's large middle hepatic vein branches to the
recipient hepatic vein.
●Portal vein inflow – The second step in implantation is the creation of the
portal vein anastomosis. This is typically performed with an end-to-end
anastomosis. Once the portal vein anastomosis has been completed, the
allograft is re-perfused.
●Arterial inflow – Following reperfusion, the arterial anastomosis is created,
usually in an end-to-end fashion.
●Biliary reconstruction – The last anastomosis that is performed is the
biliary anastomosis, which can be done as a Roux-en-Y hepaticojejunostomy,
or as an end-to-end anastomosis to the recipient common bile duct, or a
combination of both methods.
The specific approach for biliary reconstruction is based on surgeon
preference, the size of the bile ducts, and the number of donor ducts. For
example, in a situation where there is a size mismatch between the donor
and recipient duct or ducts, a hepaticojejunostomy may be preferred.

19
 ●Inflow modulation – The last major step of allograft implantation is
assessing portal and arterial vascular supply to the allograft. Portal and
arterial flows are measured, and if hepatic arterial flow is low, the
measurements are repeated after test clamping the splenic artery. If hepatic
arterial flow improves with this maneuver, the splenic artery can be ligated to
provide long-term improvement. This approach leverages the hepatic arterial
buffer response to decrease portal inflow and subsequently upregulate
arterial inflow.
RECIPIENT OUTCOMES
Survival — Multiple case series have demonstrated favorable results with adult
LDLT [19-26]. One multicenter report summarized outcomes of 385 LDLT
performed at nine centers (the Adult-to-Adult Living Donor Liver Transplantation
Cohort [A2ALL] consortium) [27]. 90-day and one-year graft survival rates were 87
and 81 percent, respectively. Graft failure within 90 days occurred in 51 transplant
recipients (13 percent), primarily because of vascular thrombosis, primary non-
function, and sepsis. Older recipient age and length of cold ischemia time were
predictors of graft failure. In a follow-up study of 67 non-A2ALL transplant centers
including 1664 transplants, outcomes were not significantly different in the non-
A2ALL centers compared with the A2ALL study sites, suggesting that the results of
the A2ALL consortium are generalizable within the United States [28].
Data comparing outcomes of LDLT with deceased donor transplantation are
mixed, although some studies have suggested a survival benefit for LDLT [1,26]. In
a single center study including 245 patients who received LDLT and 592 patients
who received deceased donor transplants, LDLT was associated with higher rates
of patient survival at three years compared with deceased donor (86 versus 80
percent) [26]. However, these outcomes may not have been directly comparable
since most recipients who received a live donor graft had less severe liver disease
(ie, lower the Model for End-stage Liver Disease [MELD] score) than patients who
received a deceased donor graft. (See "Model for End-stage Liver Disease (MELD)".)
Long-term survival rates were examined in a report from the A2ALL consortium
[29]. The study included 963 patients who received LDLT and 464 patients with
deceased donor transplants, and after adjusting for confounders such as MELD
score, the 10-year survival rates were not significantly different for LDLT compared
with deceased donor transplant.
Adverse events — Data have suggested a higher overall complication rate for
recipients of LDLT than deceased donor recipients [1,30,31]. Specific recipient
complications include:
●Early allograft dysfunction – Early allograft dysfunction has been defined on
the basis of post-operative day 7 laboratories (total bilirubin >10 mg/dl or INR
20
 >1.6) in the absence of technical complications [32,33]. Early allograft
dysfunction has been associated with a graft weight to-recipient body weight
ratio of less than 0.8 [33]. In an analysis of two observational cohorts
including a total of 631 LDLT recipients, early allograft dysfunction developed
in 16 to 19 percent of recipients. In addition, early allograft dysfunction was
associated with higher rates of graft failure at 90 days (24 versus 5 percent).
Risk factors for early allograft dysfunction included graft type (left lobe graft),
size (lower graft weight), severity of recipient disease (MELD score), and
higher portal reperfusion pressure [33].
●Vascular complications – Vascular complications such as hepatic artery
thrombosis or portal vein thrombosis have been reported more frequently
for living donor grafts than for deceased donor grafts. In a study from the
A2ALL consortium including 384 LDLT recipients and 216 deceased donor
recipients, LDLT was associated with higher overall rates of hepatic artery
thrombosis (7 versus 2 percent) and portal vein thrombosis (3 versus 0
percent) compared with deceased donor recipients [34].
●Biliary complications – Outcome data from A2ALL consortium and other
transplant centers have reported biliary complication rates ranging from 5 to
40 percent [26,30,31]. Bile leak was the most commonly reported
complication and often occurs from the cut surface of the liver.
●Other complications – For recipients of LDLT, having a biologically-related
liver donor has been associated with lower risk of acute rejection. (See "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft", section on 'Epidemiology'.)
DONOR OUTCOMES
General recovery and liver regeneration — While liver donors are at risk for
complications of donor hepatectomy, most donors do very well and have an
uneventful recovery. The typical length of stay in the hospital after donor
hepatectomy is usually four to seven days. Most donors are absent from work for a
minimum of two months (or longer if their occupation involves manual labor).
Most liver regeneration occurs within the first two weeks after donation, and
studies on postoperative imaging have shown that the donor liver remnant
returns to a size ranging from 84 to 92 percent of its original volume by six months
[25,35,36]. Additionally, data have suggested that most laboratory abnormalities
(eg, liver biochemical and function tests) have returned to baseline by three
months after donation [25].
Adverse events — Data from the Adult-to-Adult Living Donor Liver
Transplantation Cohort consortium on liver donor outcomes have reported an
overall complication rate of 24 percent [1]. Most events were Clavien-Dindo grade
21
1 (minor) or grade 2 (table 2), while approximately 1 percent of donors developed
complications that were classified as grade 3 or higher [26].
Commonly-reported short-term complications have included bile leaks, surgical
site infections, and urinary tract infections, while long-term complications included
incisional hernias. However, most postsurgical complications resolved by one year
after donation [1]. Risk factors for complications were blood transfusion
requirement, intra-operative hypotension (ie, systolic blood pressure <100 mmHg),
higher body weight, older donor age, and male sex [1].
Reported rates of donor mortality and of donor liver failure requiring liver
transplantation have been 0.4 percent and 0.04 percent, respectively [37-39].
Other outcomes — Most donors have reported that they felt positively about their
donation, while some donors (<10 percent) had experienced psychosocial distress
following donation [40-43]. In a study of 271 living donors that assessed changes
in their interpersonal relationships after donation, most donors reported an
improved relationship with the recipient [41].
SPECIAL POPULATIONS
Pediatric living donor liver transplantation — The scarcity of appropriate-sized
deceased donor organs for infants and children awaiting liver transplantation
served as the impetus for advances in segmental liver transplantation. Surgical
techniques developed for graft reduction and liver splitting were applied to living
donors to achieve successful pediatric LDLT using the left lateral segment or left
lobe of the liver [44]. With increased experience, LDLT has become a successful
method of transplantation in children [45-49]. (See "Acute liver failure in children:
Management, complications, and outcomes", section on 'Liver transplant'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Evaluating and selecting a liver donor is a comprehensive process that
includes a medical and psychosocial assessment in addition to designating an
Independent Living Donor Advocate (ILDA) (table 1). The decision to accept a
liver donor is determined by a multidisciplinary team and is informed by
establishing that (see 'Evaluation of the living liver donor candidate' above):
•The donor is medically fit to undergo donor hepatectomy
•There are no active psychosocial issues that would preclude donation
•The donor liver is suitable based on criteria such as ABO compatibility,
liver size, and liver anatomy for the designated recipient
●The Organ Procurement Transplantation Network (OPTN) policy requires
that living donor recovery hospitals must designate and provide each donor
22
candidate with an ILDA who is not involved with the recipient evaluation and
is independent of the decision to transplant the potential recipient.
(See 'Independent Living Donor Advocate (ILDA)' above.)
●The OPTN has defined a number of absolute contraindications to liver
donation (eg, active malignancy, donor coercion, inability to provide informed
consent), while there is variability among centers concerning relative
contraindications for liver donation. (See 'Contraindications to liver
donation' above.)
●The decision to accept a liver donor is also informed by the donor's liver size
and appearance and the recipient's weight (see 'Surgical technique' above):
•Donor liver size – Resecting <70 percent of donor liver volume is
generally acceptable; thus the future liver remnant will consist of ≥30
percent of original liver volume. The donor must have sufficient liver size
to allow for donation of adequate volume of liver to the recipient while
maintaining an adequate size of the future liver remnant.
•Graft weight to recipient weight ratio – The ratio of graft weight to
recipient weight is used to determine the minimum allograft size. A graft
weight to recipient weight (GW:RW) ratio of >0.8 has been associated with
safety and adequate liver function for the recipient.
●For individuals who undergo donor hepatectomy, most liver regeneration
occurs within the first two weeks after donation, and studies on
postoperative imaging have shown that the donor liver remnant returns to
most of its original volume by six months. (See 'General recovery and liver
regeneration' above.)
●For individuals who undergo donor hepatectomy, commonly-reported short-
term complications have included bile leaks, surgical site infections, and
urinary tract infections, while long-term complications included incisional
hernias. However, most postsurgical complications have resolved within one
year after donation. (See 'Adverse events' above.)

23
Evaluation of the potential deceased organ donor
(adult)
Authors:
Gary F Marklin, MD
Ron Shapiro, MD
Section Editors:
Daniel C Brennan, MD, FACP
Elbert P Trulock, MD
Deputy Editor:
Albert Q Lam, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: May 19, 2021.
INTRODUCTIONOrgan transplantation remains the best therapeutic option for
many patients with end-stage organ failure. As of April 2021, there were 107,388
patients on the United Network for Organ Sharing (UNOS) waiting list for an organ
transplant in the United States, but there were only 39,036 transplants performed
in 2020, and 6508 patients died while waiting for a transplant [1]. There were
12,588 deceased donors that yielded 33,310 transplanted organs, averaging 2.65
organs per deceased donor. There is a marked imbalance between the supply and
demand for organs, with a severe scarcity of deceased organ donors. Thus, it is
imperative that critical care clinicians identify each potential organ donor,
ultimately saving additional lives through transplantation.

This topic will review the evaluation of the adult patient for potential deceased
organ donation. Management of the deceased adult organ donor and evaluation
and management of the potential deceased pediatric organ donor are discussed
separately:

●(See "Management of the deceased organ donor".)

●(See "Assessment of the pediatric patient for potential organ donation".)
●(See "Management of the potential pediatric organ donor".)

TYPES OF DECEASED ORGAN DONORSSixty-eight percent of organ donors

in the United States are deceased, and 75 percent of those are deceased by
neurologic criteria, also referred to as brain death (donation after neurologic
determination of death [DNDD]), with the remaining organ donors being deceased
by circulatory death (donation after circulatory determination of death [DCDD]) [1].

24
Donation after neurologic determination of death (DNDD) — Most (85 to 90
percent) organs from deceased donors are procured after declaration of death by
neurologic criteria, also known as "brain death." Brain death is the complete and
irreversible cessation of cerebral and brainstem function. Brain death is a relatively
uncommon event, occurring in approximately 1 percent of all deaths [2]. The three
most common causes of brain death are trauma, cerebrovascular accident, and
anoxia, with the incidence of anoxic brain death increasing, in part due to
nonmedical drug overdose [1]. The diagnosis of brain death is usually established
by neurologic examination at the bed side, although ancillary tests may be
required when clinical criteria cannot be applied. (See "Diagnosis of brain death".)
The concept of brain death was first reported in 1959, when two French
neurologists described 23 ventilated patients with "coma dépassé" or "irretrievable
coma" with absent motor and brainstem reflexes and apnea when disconnected
from the ventilator [3]. Subsequently in 1968, an ad hoc committee at Harvard
Medical School defined brain death as the state of irreversible coma characterized
by unresponsiveness and lack of receptivity, absence of spontaneous movement
and breathing, absence of brainstem reflexes, and a flat or isoelectric
electroencephalogram (EEG) [4]. This was the first report to suggest that a patient
could be diagnosed as brain dead and still have a heartbeat. This led to the
Uniform Determination of Death Act (UDDA) in 1980, which defined death in an
individual who has sustained either irreversible cessation of circulatory and
respiratory functions or irreversible cessation of all functions of the entire brain,
including the brain stem [5].
Brain death is associated with significant pathophysiological abnormalities that
can threaten organ viability. These issues and their management are discussed
separately. (See "Management of the potential pediatric organ donor", section on
'Pathophysiologic consequences of neurologic death' and "Management of the
deceased organ donor", section on 'Steps to optimize organ function'.)
In spite of the multitude of possible insults to the organs after brain death, organ
donation from a brain-dead donor has the advantage of shorter warm ischemic
time, since there is blood flow to the organ up to the time of aortic cross-clamping
in the operating room. In general, DNDD organs have less initial graft dysfunction
than DCDD organs, but overall graft survival is equivalent [6].
Donation after circulatory determination of death (DCDD) — Because of the
severe shortage of donated organs and the limited number of brain-dead donors,
another option for organ donation is donation after circulatory determination of
death (DCDD; also known as donation after cardiac death [DCD] or non-heart-
beating donation [NHBD]). Circulatory death can occur under different
circumstances that can lead to organ donation. In 1995, an international workshop

25
on non-heart-beating donors in Maastricht (Netherlands) devised a four-category
classification for DCDD (table 1). This was subsequently revised to the modified
Maastricht classification of DCDD that allowed subclassification due to location of
cardiac arrest (in or out of the hospital) (table 2). In the United States, Maastricht
category III (controlled withdrawal of life support) is the most common scenario
for organ donation after circulatory death. Category II (uncontrolled cardiac arrest
with unsuccessful resuscitation) is used much less frequently in the United States
but is used more commonly in Europe [7]. An international collaborative has
provided a statement to expand controlled DCDD in the world to offer more
patients the opportunity of organ donation and to help countries progress toward
self-sufficiency in organ transplantation [8].
A number of mechanically ventilated patients suffer either significant neurologic
injuries but do not progress to brain death (eg, stroke) or suffer severe critical
illnesses (eg, cardiac arrest, multiple trauma), with no hope for survival. When it is
apparent that the patient is not going to survive, and after end-of-life discussions
with the clinicians, the family may decide to withdraw life-sustaining therapies and
treat the patient with comfort measures only. After the family has made the
decision to withdraw treatment, and if the patient is deemed to be a potential
donor, then the family may be approached for authorization for organ donation.
The decision to withdraw treatment must be made separately and independently
from any discussion about organ donation, to avoid possible conflict of interest
that the family may perceive [9]. After authorization is obtained, a plan is made for
the controlled withdrawal of life support (Maastricht category III). A surgical team
from the transplant center needs to arrive prior to extubation. Extubation from
mechanical ventilation can occur in the operating room, perioperative area, or
intensive care unit (ICU) depending upon the hospital's facilities and policy.
Extubation and administration of intravenous (IV) medications for comfort are
performed by hospital staff under the supervision of the hospital clinician. The
transplant surgical team is prohibited from being in the room, involved in the
comfort treatment of the patient, and involved in the declaration of death [10].
If the patient expires in the allotted time, usually 60 minutes from withdrawal of
ventilatory support, and is declared dead by cardiorespiratory criteria (permanent
absence of respiration, circulation, and responsiveness) by the attending clinician,
a mandatory waiting period of at least two minutes and not more than five
minutes is observed for autoresuscitation [11]. After the waiting period, the organs
are procured expeditiously. If the patient does not expire in the allotted time, the
patient is no longer considered a potential donor; they are returned to the ICU,
and comfort care is continued. (See "Management of the deceased organ donor",

26
section on 'Donation after circulatory determination of death' and 'Circulatory
death' below.)
Although kidneys are transplanted most frequently after DCDD, liver, pancreas,
and lungs may also be procured. Cardiac transplantation after DCDD has been
performed in Australia and the United Kingdom since 2015 and has been
performed in adults in the United States since 2019 [12,13]. There are two
strategies for reperfusion of the asystolic DCDD heart, including direct
procurement and normothermic ex-vivo machine perfusion and thoracoabdominal
normothermic regional perfusion in situ with exclusion of the cerebral vasculature.
Both of these techniques are described in detail in the International Society of
Heart and Lung Transplantation's consensus statement on heart and lung
procurement [14].
RESPONSIBILITIES OF THE CLINICIAN
Identification of the potential organ donor — Identification of the potential
deceased organ donor is the initial step in the organ donation process. A potential
organ donor is typically a mechanically ventilated intensive care unit (ICU) patient
with severe brain injury. Although the primary goal of the critical care clinician is to
stabilize and aggressively treat the severely injured patient, unfortunately for
some patients, the injury is so severe that the patient progresses to brain death. It
is at this time that the clinician must realize that the patient has the potential to
save multiple other patients' lives with organ donation. The focus of the clinician
needs to shift from aggressive care to declaring the patient dead by neurologic
criteria, compassionately informing and explaining to the grieving family that their
loved one has died, and continuing supportive treatment of the patient to preserve
the possibility of organ donation. Organ donation may provide the only solace to a
distraught family coping with the tragic loss of a loved one [15]. Thus, every effort
should be made to identify each potential organ donor, to allow emotional closure
for the family and to avoid additional lives being lost on the transplant waiting list.
(See 'Referral to the organ procurement organization (OPO)' below.)
There are no universally accepted criteria or definitions for potential deceased
organ donors. The following are commonly used clinical criteria (or "triggers") that
should prompt a referral from the hospital to the local organ procurement
organization (OPO) [16]:
●Any mechanically ventilated patient with one or more of the following:
•Glasgow Coma Scale score <5 without sedation (table 3)
•Brain death examinations being considered
•Withdrawal of life support being considered
•Do-not-resuscitate or comfort care being considered
•The family brings up the topic of organ donation
27
Referral to the organ procurement organization (OPO) — Once a patient has
been identified as a potential deceased organ donor (see 'Identification of the
potential organ donor' above), the clinician or other hospital representative must
alert the local OPO about the potential referral. A list of local OPOs is available on
the Internet.
To avoid missing the opportunity for donation, the Centers for Medicare and
Medicaid Services (CMS) have instituted federal regulations requiring all hospitals
to establish a relationship with an OPO and to notify the local OPO of all imminent
deaths in a timely manner (within one hour) so the OPO can assess the patient's
potential for organ donation [17]. Early and timely referrals to the OPO allow for
the evaluation of the medical, legal, and behavioral suitability for organ donation
prior to discussions with the family about extubation or the withdrawal of life-
sustaining therapy. CMS regulations stipulate that all potential donors should be
referred to the OPO and that the OPO should determine suitability for organ
donation, rather than the hospital ruling out a patient as a potential donor [17].
Importantly, the OPO should be contacted prior to any mention of donation to the
patient's family. (See 'Responsibilities of the organ procurement organization
(OPO)' below.)

When notifying the OPO of a potential donor referral, the clinician should have the
patient's chart available and should be prepared to provide the following
information:

●Patient's name, age, date of birth, sex, race, and medical record number
●Patient's admitting diagnosis
●Ventilator status of the patient
●Neurologic status of the patient
●Plan for brain death testing
●Patient's current vital signs, labs, and medications
●Patient's past medical history
●Family's understanding of the patient's event/status
A representative of the OPO will typically perform an initial screen on the
telephone to determine if the patient has any immediate contraindications to
donation (see 'Initial donor screening' below). If there are no contraindications, an
OPO coordinator will travel to the hospital to obtain authorization for donation,
evaluate the patient for donor suitability, and coordinate the organ donation
process. The clinician and hospital staff work in cooperation with the OPO
coordinator to help facilitate this process. This may involve several meetings
("huddles") in which the OPO coordinator, clinician, and hospital staff come
together to establish a plan, outline individual responsibilities, and discuss
28
communication with the patient's family or next of kin (NOK). (See 'Responsibilities
of the organ procurement organization (OPO)' below.)
Family communication — The clinician's responsibility is to keep the family
informed of the patient's clinical status, prognosis, and pertinent test results (eg,
results of computed tomography [CT] of the head); answer their questions; and
provide compassionate care. They should avoid bringing up the topic of organ
donation. Any questions that the family has about organ donation should be
deferred to the OPO.
Determination/declaration of death — Determination and declaration of death
are the responsibilities of the clinician and are required before the surgical
removal of organs for transplantation. Determination of death differs for
neurologic death (brain death) and circulatory death. Once death has been
determined, the clinician informs the patient's family or NOK that the patient is
deceased and documents a death note stating that the examination has been
performed.
Brain death — The clinician is responsible for determining and declaring the
diagnosis of brain death according to state law and institutional policy.
Importantly, the clinician who declares brain death cannot be the clinician who
recovers the donated organs from the patient. Documentation of brain death
should include the date and time of death, and results of the clinical examination,
apnea test, and any ancillary testing. Most hospitals have an established brain
death policy to ensure that documentation and determination of brain death have
been properly performed. The clinician should refer to his or her respective
hospital's brain death policy to determine appropriate institutional practice.
Suggested guidelines are available for assisting the clinician in determining brain
death [18]. A large, multidisciplinary, international panel has formulated a
consensus statement of recommendations on the determination of brain death,
which represents the most current and extensive review of the data (The World
Brain Death Project) [19]. A discussion of the clinical criteria and ancillary tests
used to establish the diagnosis of brain death is presented separately:
●(See "Diagnosis of brain death", section on 'Diagnosis: Clinical criteria'.)
●(See "Diagnosis of brain death", section on 'Ancillary tests'.)
Circulatory death — The clinician is responsible for determining and declaring the
diagnosis of circulatory death. Once the patient's family has made the decision to
withdraw life-sustaining treatments and the OPO coordinator (or another
designated requestor) has obtained authorization for organ donation, a plan is
made for withdrawal of life support. The clinician and hospital staff are responsible
for extubation and administration of intravenous (IV) medications for comfort and
sedation as appropriate. Full disclosure to the family regarding any medications

29
and/or interventions that are solely for the organ donation process (eg, heparin,
bronchoscopy) is necessary, and informed consent is required. A surgical team
from the transplant center must arrive prior to extubation of the patient.
Extubation from mechanical ventilation can occur in the operating room,
perioperative area, or ICU depending upon the hospital's facilities and policy.
Importantly, the transplant surgical team cannot be allowed in the room and
should not be involved in the comfort treatment of the patient or the declaration
of death. (See "Withholding and withdrawing ventilatory support in adults in the
intensive care unit".)
Following withdrawal of life support, the patient is observed until circulatory
function ceases. Determination of circulatory death is based upon
cardiorespiratory criteria (permanent absence of respiration, circulation, and
responsiveness). The declaration of cardiac death is based upon permanent loss of
circulation (absent pulse pressure on an arterial line) and not cardiac electrical
activity (ie, asystole). In a patient with pulseless electrical activity, waiting for
asystole to occur adds unnecessary warm ischemic time to the organs [9,20]. Most
hospital protocols mandate that if circulatory arrest does not occur within 60 to
90 minutes from withdrawal of ventilator support, the patient should be returned
to the ICU and organ procurement is aborted. If the patient expires in the allotted
time, the clinician documents the date and time of death in the patient's medical
record. After the determination of death, a mandatory waiting period of at least
two minutes and not more than five minutes is observed for autoresuscitation
(ie, return of spontaneous circulation) [9,11,20,21]. After the waiting period, the
organs are then procured by the surgical team. If lungs are being procured, the
donor is reintubated and the lungs inflated with either continuous positive airway
pressure (CPAP) or mechanical ventilation.
Predicting time of death after withdrawal of life support — From the
perspective of the transplant team, the awaiting recipient, the potential donor
family, and the hospital resources utilized, it would be advantageous to predict
which patients will or will not expire in the 60 minutes after withdrawal of care
[16]. Several studies have developed and evaluated criteria to predict the likelihood
of death after extubation [22-27]. As examples:
●In one study of 43 patients, the University of Wisconsin Donation after
Cardiac Death Evaluation Tool, which assigns scores to clinical parameters
observed during a 10 minute spontaneous breathing trial, correctly predicted
the likelihood of death within 60 minutes with a rate of 84 percent [22].
●A prospective study of 533 patients evaluated the utility of the United
Network for Organ Sharing (UNOS) donation after circulatory determination
of death (DCDD) consensus committee criteria for prediction of death within

30
 60 minutes after withdrawal of life-sustaining treatment (table 4) [23]. A total
of 29, 52, 65, and 82 percent of patients with 0, 1, 2, and 3 UNOS DCDD
criteria, respectively, died within 60 minutes of withdrawal of life support.
●Another prospective study of 178 patients examined the utility of a
predictive score for cardiac death in patients in a coma with irreversible brain
injury (DCD-N score) based upon four clinical parameters (corneal reflex,
cough reflex, best motor response, and oxygenation index) [24]. A DCD-N
score of 3 or more had a sensitivity of 72 percent and specificity of 78 percent
for predicting death within 60 minutes of withdrawal of life-sustaining
treatment.
The clinical judgment of the intensivist has been found to predict death within 60
and 120 minutes with a sensitivity of 73 and 89 percent, respectively, and a
specificity of 56 and 25 percent, respectively [25]. Other factors that may predict
death after withdrawal of life support include controlled mechanical ventilation
[25], mean arterial pressure [26], age, fraction of inspired oxygen (FiO2), and mode
of ventilation [27].
With each DCDD case, the benefit of recovering an organ must be weighed against
the cost of an unsuccessful attempt. A consensus statement by the Society of
Critical Care Medicine/American College of Chest Physicians/Association of Organ
Procurement Organization (AOPO) regarding DCDD stated, "In order to maximize
the potential of adult DCD donors, an increase in the number of unsuccessful
cases must be acceptable" [16]. Since it is difficult to predict which patients will
protect their airway after extubation, and the best predictive tools are inaccurate
30 percent of the time, some OPOs are not using any predictive tools but rather
pursuing DCDD if the patient has an organ that is deemed transplantable. Our
OPO uses this strategy and recovers organs on average from 65 percent of DCDD
patients, which is comparable to using the predictive tools.
Optimization of organ function — Optimal donor management is essential in
both the ICU and in the operating room to maximize the function of transplanted
organs, as well as the quality of life and survival benefits conveyed to the
recipients. Specific details regarding the management of the potential deceased
organ donor prior to organ procurement are discussed separately.
(See "Management of the deceased organ donor".)
For donation after neurologic determination of death (DNDD) donors, once brain
death has been declared and consent for donation has been obtained, the OPO is
responsible for medical management of the donor until the time of organ
procurement (see 'Coordination of donor management' below). Nursing care
continues to be provided by the hospital staff in collaboration with the OPO

31
coordinator. By contrast, DCDD donors remain under the care of the clinician and
all care is directed by the clinician until the time of organ procurement.
RESPONSIBILITIES OF THE ORGAN PROCUREMENT
ORGANIZATION (OPO)The Organ Procurement and Transplantation Network
(OPTN), which is responsible for organ allocation and policy development, is
comprised of 57 organ procurement organizations (OPOs), over 250 transplant
centers, and 156 histocompatibility laboratories. Each OPO has a federally
assigned geographic region, or donation service area (DSA), and is responsible for
identifying potential donors, obtaining authorization, managing the donor to
optimize organ function, allocating organs, and preserving all organs in their
assigned area [28]. The OPO collaborates with the donor hospital's medical staff to
achieve these goals. The transplant centers are responsible for registering
recipients on the United Network for Organ Sharing (UNOS) waitlist, reviewing and
accepting organ offers, and procuring and transplanting the organs. The OPO also
works closely with the transplant centers during the allocation process to facilitate
placement of the organs with recipients according to organ-specific allocation
schemes, arrange the procurement of operating room time, and label and package
the organs for transportation.
Initial donor screening — The organ donor referral from a hospital will be initially
screened to exclude obvious patients who cannot be donors. Common screening
questions include:
●What is the age of the patient?
●Is the patient currently on a ventilator?
●Does the patient have an active malignancy or a history of malignancy?
●Are brain death examinations planned?
●Is the family ready to withdraw support?
Immediate contraindications to donation — The following patient
characteristics are generally considered to be absolute contraindications to
deceased organ donation:
●Age >80 years
●Not on a ventilator
●History of active metastatic cancer
●History of active hematologic malignancy
●History of active melanoma
●History of Creutzfeldt-Jakob disease
All other patients are evaluated on an individual basis, as discussed below.
(See 'Evaluation of donor suitability' below.)
Authorization for organ donation — Before any organ donation can proceed
there must be authorization for the organ procurement. There are two different
32
systems of authorization. The authorization can be active, in which the donor
(premortem authorization) or next of kin (NOK) must consent to organ donation
upon the donor's death ("opt-in system"). The other option is when the legislature
of a country has stipulated that all citizens are automatically consented (presumed
consent) for organ donation upon their death, unless they object and refuse
donation ("opt-out system"). The United States has an opt-in system, but many
countries in Europe have an opt-out system. Although it would seem logical that
an opt-out system would have higher organ donation rates, one study showed no
significant difference in deceased donors per million population (20.3 versus 15.4)
or in total solid organs transplanted per million population (63.6 versus 61.7)
between opt-out and opt-in countries, respectively [29].
Since 1998, the Centers for Medicare and Medicaid Services (CMS) has required
that authorization for organ donation must be performed by a "designated
requestor," which is defined as either an OPO staff member or a hospital staff
member who has been trained by the OPO to be qualified to request authorization
for donation [17]. Authorization for organ donation should not be obtained by the
clinician caring for the patient, unless the patient is a "designated requestor."
Several studies have shown increased authorization rates when the family is
approached by trained OPO personnel, who can spend time with the family in a
quiet setting to explain the donation process [30-38].
The Uniform Anatomical Gift Act (UAGA) was first enacted in 1968 to permit
individuals older than 18 years to donate their organs and tissues after death. In
2006, the UAGA was revised to simplify the consent process, enabling individuals
to consent to organ donation by expressing their wish when obtaining a driver's
license, joining a state or national registry of organ donors, or by writing their wish
in a will or other advance directive. This "First Person Authorization" (FPA) of an
adult for organ donation via one of these three methods is legally binding
and cannot be revoked by family or NOK.
OPOs have access to all donor registries when notified of a potential donor. The
OPO coordinator notifies the family of the potential donor's registry status during
the initial conversation regarding donation options. A patient on the registry has
already provided authorization for donation, and no additional consent or
authorization is needed from the family. The only exception to this is a patient
under 18 years of age who signed up on the registry upon obtaining a driver's
license; such a patient is considered to be a minor, and the legal parent or
guardian can rescind authorization. If the patient is not on the registry,
authorization for donation must be obtained from the NOK as defined by the state
of residence. Given the many different religious, cultural, ethnic, and emotional
views that the donor's family may have, the OPO representative must approach

33
the donor family with sensitivity and discretion. The OPO coordinator must explain
in detail the options for donation to the NOK to obtain informed authorization.
CMS has specified a list of requirements that the OPO must perform to obtain
authorization (table 5) [39]. The family's knowledge of the patient's prior decision
about donation is significantly associated with the family's willingness to donate
[33,40,41].
The optimal timing of the approach for consent has not been clearly defined. Some
studies have found increased authorization rates when the request for organ
donation was separated by time and personnel, or "decoupled" from the time the
family was informed of the diagnosis of brain death [34,42], although another
study found conflicting results [43]. In our OPO experience, approaching the family
at a separate time, by an experienced OPO staff member, increases the likelihood
of donation. This separation between declaring the patient brain dead and making
an approach allows families to dissociate their feelings about the clinician's efforts
to save their loved one from the OPO's request to offer the chance of life to a
waiting recipient. If the clinician caring for the patient wishes to be involved in the
organ donation discussion, the clinician should collaborate with the OPO staff and
approach the family jointly at an appropriate time [44].
Evaluation of donor suitability — The OPO coordinator is responsible for
determining suitability of the donor for transplantation. This requires a thorough
review of the patient's medical record to identify any medical condition that would
preclude organ donation or be transmissible to the recipient. The OPTN has
mandated certain tasks that the OPO must perform on every organ donor.
Medical and social history — The OPO coordinator reviews the patient's medical
chart for any history of malignancy, active infection, or other diseases that may
affect transplanted organ function, such as diabetes or hypertension. The OPO
coordinator also obtains a detailed medical and social history from the patient's
family or NOK, if available, including a history of smoking, alcohol consumption,
and use of nonprescription drugs. The patient's travel history should also be
reviewed, particularly to endemic areas of transmissible parasites
(eg, Strongyloides) and viruses (eg, Zika).
To reduce the risk of viral transmission of HIV, hepatitis B virus (HBV), and hepatitis
C virus (HCV) through organ transplantation, the United States Public Health
Service (USPHS) developed and revised a set of criteria (table 6) to identify donors
who have risk factors for acute HIV, HBV, and HCV infection [45]. These risk criteria
include donor behavioral characteristics that could place the potential recipient at
increased risk of viral disease transmission and do not refer to the quality of the
organ. In obtaining the donor's medical, social, and sexual history from the
medical record and from available family or friends, the OPO coordinator must

34
also determine if the donor meets any of these risk criteria within the past 30 days.
If the donor meets any of the criteria, or if the donor's history cannot be
ascertained, the donor is considered to be at risk for acute HIV, HBV, or HCV
infection, and the transplant surgeons and recipients must verify that they have
been informed of the risk prior to accepting organs from these donors. Such
organs are more likely to be discarded, despite the fact that recipient and graft
survival of these organs are generally comparable with that of organs from donors
without risk of HIV, HBV, and HCV infection [46]. In accepting an organ with risk for
HIV, HBV, and HCV, the surgeon and recipient must weigh the small risk of donor-
derived infection with the risk of death on the waiting list. (See 'Infection' below.)
The concept of donors at risk for acute HIV, HBV, or HCV was developed to identify
donors at risk of recent viral infection who might have false-negative serologic
testing for these viruses. False-negative testing can occur when patients are tested
during the "serologic window period" between the time of acute infection and the
formation of antibodies detectable by serologic testing. To decrease the chance of
viral transmission during the serologic window period, OPTN policy requires
nucleic acid amplification testing (NAT) for HIV, HBV, and HCV on all donors. The
NAT window period is much shorter than the antibody (serologic) window, and
NAT becomes positive within days of infection (11 to 13 days for HIV, three to five
days for HCV, and 20 to 22 days for HBV) [47]. For most exposures, NAT testing
decreases the risk of infection during the serologic window period by
approximately 10-fold. Thus, the goal is to identify donors with negative serology
and negative NAT testing for HIV, HBV, and HCV who are at higher risk for recent
acquisition of the viruses and could inadvertently transmit the infection to the
recipient. The risk of infection during the NAT window period is extremely low if
the risk behavior occurred more than three weeks prior to the NAT testing.
(See 'Infectious disease testing' below.)
The risk of viral transmission varies widely among the increased-risk behaviors.
Donors with intravenous (IV) drug use carry the highest risk of HCV transmission
during the NAT window period of 0.32 percent, while donors with a history of
incarceration have a very low rate of 0.008 percent. The risk of HIV transmission
with a negative NAT is <0.1 percent regardless of the behavior [48,49].
Malignancy — In general, a history of past or current malignancy in the potential
donor is not an absolute contraindication to organ donation. When a donor
presents with an active or prior history of malignancy, the final decision about
organ suitability rests with the transplant team and potential recipient. The risk of
cancer transmission from the donor to the recipient must be weighed against the
risk of the recipient not receiving an organ. If death of the recipient is imminent
without a transplant, then accepting a low risk of malignancy transmission may be

35
reasonable. The recipient must be fully aware of the risk and provide informed
consent to proceed with transplantation [50].
Reported rates of donor-derived tumor transmission to organ recipients are highly
variable, ranging from 0 to 42 percent, depending upon the source of the data
[50]. Much of these data have come from the Israel Penn International Transplant
Tumor Registry, which has followed organ recipients from donors with known
malignancies for over 40 years. The data were obtained from voluntary reporting
of index cases, and therefore, may be prone to overestimation [51]. UNOS has also
collected outcome data on recipients from donors with active or previous
malignancies since 1996, but reporting the data was not mandated by the OPTN
policy until 2005, and therefore, earlier data may be prone to underestimation. In
2008, the Ad Hoc Disease Transmission Advisory Committee of OPTN formed a
subcommittee to examine the donor-related malignancy transmission data and
evaluate the risk of developing a malignancy in the recipient. They defined six risk
categories (none, minimal, low, intermediate, high, and unknown) for donor-
related tumor transmission with recommended clinical use and suggested risk
categorization for specific tumor types (table 7) [52]:
●Malignancies not involving the central nervous system (CNS) – Patients
with metastatic cancer, choriocarcinoma, melanoma, lung cancer, or breast
cancer (stage >0) have a high rate of transmission and are a contraindication
for organ donation. In addition, patients with a history of aggressive tumors
with the potential for late metastases, such as melanoma, leukemia,
lymphoma, breast, and colon cancer, are considered high risk for
transmission and are a contraindication for organ donation [53].
Nonmelanoma skin cancer without metastases, in situ carcinomas, and some
small thyroid carcinomas have a minimal risk of transmission. A kidney with a
completely resected, small, solitary, well-differentiated renal cell carcinoma
may be usable for transplantation [52]. In general, patients with a history of a
treated malignancy and patients who are disease free for more than five
years, with a high probability of cure, may be considered for organ donation.
●CNS malignancies – Primary CNS malignancies are generally considered to
have a low rate of metastasis, and patients with nonmetastatic primary CNS
malignancies can be considered for organ donation. Tumor transmission
rates are highly variable, depending upon the source of the data, and range
from 0 to 23 percent [16]. Violation of the blood-brain barrier, other than with
an uncomplicated biopsy, may increase the risk of tumor transmission. In one
study of 62 recipients of organs from donors with an active CNS malignancy,
the overall rate of tumor transmission was 23 percent [54]. Risk factors for
tumor transmission included high-grade tumors, the presence of a

36
 ventriculoperitoneal or ventriculoatrial shunt, previous craniotomy, and
systemic chemotherapy. Patients with one or more of these risk factors had a
higher risk of tumor transmission compared with those who had no risk
factors (53 versus 7 percent).
Metastases to the brain can be misdiagnosed as primary CNS tumors or
intracranial hemorrhage, and transplantation of organs from these donors
has a poor prognosis for the recipients. In a study of 42 recipients of organs
from patients with misdiagnosed primary CNS tumors, 74 percent developed
a donor-derived malignancy and 64 percent developed metastatic disease;
the five-year survival rate was 32 percent [55]. Thus, in donors who present
with unexplained intracranial hemorrhage or a suspected primary CNS
neoplasm without a biopsy, an evaluation for metastatic disease should be
considered.
Infection — Organ donors are typically in the intensive care unit (ICU) and
frequently have community-acquired or nosocomial infections. The risk of
transmitting an infection to a potential recipient must be considered before organ
procurement.
●Bacteremia/bacterial sepsis – In general, bacterial donor infections that
are treated with appropriate antibiotics are not a contraindication to organ
donation. If a potential donor is found to be bacteremic, appropriate
antibiotic therapy should be administered as soon as possible. In some cases,
delaying organ procurement until the donor has received antibiotics for at
least 48 hours may be reasonable.
Multiple studies have demonstrated very low rates (0 to 8 percent) of donor-
derived infections in the recipient [56-59]. In these studies, appropriate
antibiotics were administered to the donors before organ procurement and
continued in the recipient for four to seven days. In one report, no adverse
outcomes in terms of survival and graft function were observed in the
recipients of bacteremic donors [57].
●Meningitis – Bacterial meningitis, treated with appropriate antibiotic
therapy, is not a contraindication to organ donation. Several studies have
reported successful organ retrieval from donors with documented or
assumed bacterial meningitis who were treated with appropriate antibiotics
prior to organ procurement, with no transmission of infection to the recipient
and no reduction in patient survival [60-63]. There are no guidelines for the
optimal duration of donor antibiotic treatment before organ procurement,
but some experts suggest treating for 24 to 48 hours. The organ recipient
should also be treated with the same antibiotic regimen for 5 to 10 days.

37
 Patients with viral or parasitic encephalitis should not be considered for
organ donation [64]. Donor-to-recipient transmission has been reported for
West Nile virus, rabies virus [65], lymphocytic choriomeningitis virus [66],
and Balamuthia mandrillaris  with very poor recipient outcomes.
●HIV, hepatitis B, and hepatitis C – The use of organs from donors who are
HIV-infected is contraindicated for HIV-uninfected recipients due to the risk
of viral transmission [16]. Transplantation of organs from HIV-infected
donors into HIV-infected recipients has been reported, but this practice
remains experimental. A National Institutes of Health (NIH)-sponsored,
multicenter study of kidney and liver transplantation from HIV-infected
donors to HIV-infected recipients under a research protocol is underway.
Patients who are seronegative for HIV but meet risk behavioral criteria (table
6) for HIV infection should not be excluded as organ donors, but the
transplant team and potential recipient must be notified:
•(See "Kidney transplantation in adults: Kidney transplantation in patients
with HIV", section on 'Donors with HIV'.)
•(See "Lung transplantation: Deceased donor evaluation", section on
'Donor infection'.)
The use of organs from donors infected with HBV and/or HCV is not
contraindicated, but the suitability of such organs depends upon several
factors, including the serologic status of both the donor and the recipient.
The risk of viral transmission from a donor who tests positive for anti-
hepatitis B core (anti-HBc) antibody, but negative for HBV DNA and hepatitis
B surface antigen (HBsAg), is low. These issues are discussed in more detail
elsewhere:
•(See "Kidney transplantation in adults: Hepatitis B virus infection in
kidney transplant recipients", section on 'Suitable donors' and "Kidney
transplantation in adults: Hepatitis B virus infection in kidney transplant
recipients", section on 'Considerations for donor selection'.)
•(See "Liver transplantation in adults: Deceased donor evaluation and
selection", section on 'Hepatitis B virus-positive donors'.)
•(See "Kidney transplantation in adults: Hepatitis C virus infection in
kidney donors", section on 'Approach to the use of kidneys from donors
with HCV infection'.)
•(See "Liver transplantation in adults: Deceased donor evaluation and
selection", section on 'Hepatitis C virus-positive donors'.)
•(See "Lung transplantation: Deceased donor evaluation", section on
'Donor infection'.)
Laboratory testing and procedures

38
Routine blood and urine tests — The following laboratory tests are performed on
all deceased donors:
●Complete blood count
●Serum electrolytes, blood urea nitrogen (BUN), and creatinine
●Liver function tests
●Urinalysis
●Arterial blood gas (ABG)
●Prothrombin time (PT)/international normalized ratio (INR) and activated
partial thromboplastin time (aPTT)
●Blood, sputum, and urine cultures

Laboratory tests are repeated depending upon the clinical condition of the donor.
The OPTN requires certain laboratory tests to be performed within a certain time
frame prior to organ offers. As examples, a urinalysis is required within 24 hours of
cross-clamping, an ABG and a chest radiograph are required within two to three
hours of lung offers, and liver function tests are required within 12 hours of liver
offers. Blood for serologic testing for HIV, HCV, and HBV must be drawn within 96
hours of procurement. A plasma and serum sample must be drawn within 24
hours of procurement and stored frozen for 10 years. This sample is used to detect
donor-derived infections and diseases retrospectively should they occur in the
recipient.

ABO blood typing — ABO blood typing must be performed on two different blood
samples, drawn at separate times, with congruent results. ABO subtyping must be
performed on all donors with blood type A to determine if the blood type is non-
A1, since blood type A, non-A1 donors (eg, blood type A2) can be used for low titer
blood type B recipients. ABO subtyping can only be reported if there is congruence
between the two samples. The blood type must be verified by two qualified health
care professionals, with source documentation, and reported to UNOS prior to the
match run.
Histocompatibility testing — All deceased donors must have human leukocyte
antigen (HLA) typing of antigens A, B, Bw4, Bw6, C, DR, DR51/52/53, DQA1, DQB1,
and DPB1. Many OPOs send the donor's blood samples to a reference lab for HLA
typing. However, if the donor is at an academic hospital or transplant center, HLA
testing is typically performed at the institution's tissue typing laboratory. The
results must be available before any kidney or pancreas is offered to the
transplant centers on the match run. The HLA results must be available before
final acceptance of an offer for heart or lung donors, if required by the transplant
program. The OPO provides donor blood or lymph nodes to the transplant centers
for direct crossmatching for kidney donation. (See "Kidney transplantation in
39
adults: Overview of HLA sensitization and crossmatch testing", section on 'HLA
typing'.)
Infectious disease testing — All organ donors are tested for various infectious
diseases that can be transmitted to a recipient. Infectious disease testing
requirements include the following:
●HIV antibody (anti-HIV) donor screening test or HIV antigen/antibody
(Ag/Ab) combination test
●HIV RNA nucleic acid amplification test (NAT)
●Hepatitis B surface antigen (HBsAg) donor screening test
●Hepatitis B core antibody (anti-HBc) donor screening test
●Hepatitis B DNA NAT
●Hepatitis C virus antibody (anti-HCV) donor screening test
●Hepatitis C RNA NAT
●Cytomegalovirus antibody (anti-CMV) donor screening or diagnostic test
●Epstein-Barr virus antibody (anti-EBV) donor screening or diagnostic test
●Syphilis donor screening or diagnostic test
●Toxoplasma immunoglobulin G (IgG) antibody test

The donor specimen should be collected within 96 hours before organ

procurement with the result available at the time of procurement. To ensure
accuracy, infectious disease serologic testing should be performed on donor blood
that is not hemodiluted. Hemodilution may occur with hemorrhage, massive blood
product transfusions, or shock resuscitated with large volumes of IV crystalloid
and colloidal fluids. The OPO must document all blood products, colloids, and
crystalloids that the donor received during the hospitalization. Hemodilution is
determined by a US Food and Drug Administration (FDA) hemodilution calculation.
If the donor's blood sample is determined to be hemodiluted, then a
pretransfusion blood sample should be utilized, if available, for repeat testing.

Additional organ-specific testing — Depending upon the organs available for

donation, additional testing may be required:
●Echocardiography is required for potential heart donors; a cardiac
catheterization may be required for older heart donors (>40 years) or those
with significant risk factors for coronary heart disease.
●Fiberoptic bronchoscopy is required for potential lung donors. Computed
tomography (CT) of the chest is also frequently requested.
●A percutaneous liver biopsy may be requested for liver donors with obesity,
positive testing for HCV, or history of alcoholism.
Allocation of organs — The donor's medical history, physical examination, and all
testing results are uploaded into DonorNet, a UNOS-based computer program that
40
will allow a match run with patients on the waiting lists to be generated for each
organ. The match run provides a sequential list of potential recipients for each
organ, based upon OPTN allocation policy for that specific organ. A tenet of OPTN
allocation policy is that organ offers are not biased by race, ethnicity, sex, religion,
political influence, national origin, financial status, or geographic location. Prior to
2017, the allocation schemes gave priority to local transplant centers in the OPO's
DSA, with the intent to decrease cold ischemic time. This policy was legally
challenged on the basis of geographic disparity, and now all organs are allocated
on concentric circles of specified miles (250, 500, 1000) from the donor hospital
("continuous distribution"). The policy is intended to provide an equitable
distribution of organs to those recipients most in need. Each organ has a unique
algorithm that is followed to generate the match run. The OPO must follow the
rank order of the match run in making organ offers to the transplant program.
Each transplant center has one hour to open the electronic offer and to respond to
the offer by accepting or declining the organ. After the organs have been
allocated, an operating room-procurement time is arranged. (See "Kidney
transplantation in adults: Organ sharing", section on 'National deceased-donor
kidney allocation policy'.)
Coordination of donor management — The evaluation and management of an
organ donor traditionally occurs in the donor's hospital. The OPO uses the donor
hospital's ICU, nursing staff, ancillary services, and operating room for
procurement of organs. The time from declaration of brain death to organ
procurement is typically between 24 and 72 hours, depending upon the number of
organs procured.
Alternatively, donor management and organ procurement can take place at a
dedicated organ recovery center that is independent of any hospital or transplant
center [67,68]. These OPO-based organ recovery centers are typically equipped
with an ICU, laboratory, portable radiograph equipment, computed tomography
(CT) scanner, cardiac catheterization lab, and organ and tissue surgical suites. After
authorization for organ donation is obtained, the OPO transfers the donor from
the hospital to the recovery center by ambulance or plane, and diagnostic testing
and management of the donor occurs in the recovery center under the supervision
of a medical director. After allocation of the organs, the transplant surgeons travel
to the recovery center and procure the organs in the surgical suite. This model for
organ recovery has been shown to decrease surgeons' time and air travel, cold
ischemic time, and cost, while increasing organ yield [69-71]. One study showed
that the lung donation rate increased from 20 to 34 percent with a donor lung
management protocol at a specialized donor recovery center [72]. Other studies
have demonstrated the specialized donor recovery center to be less costly and

41
more effective, particularly for thoracic organ donors [73], and to be an ideal
setting for organ donor management research studies [74]. Additional benefits of
an OPO-based facility include appropriate surgical equipment, operating room
staff familiar with organ procurement, and favorable operating room time,
allowing the surgeons to operate during the day rather than at night. As of 2021,
approximately 15 percent of United States OPOs have a functioning organ
recovery center, which is either independent or associated with a hospital.
STRATEGIES TO EXPAND THE DONOR ORGAN SUPPLYAs outcomes
have continued to improve after solid organ transplantation, the demand has
remained consistently higher than the supply of transplantable organs. Several
approaches have been developed to address this need:
●Hepatitis C-positive donors – The advent of direct-acting antivirals (DAAs)
has revolutionized the therapy for hepatitis C virus (HCV) and enabled the
safe transplantation of HCV-positive hearts, lungs [75,76], kidneys, and livers
into HCV-positive and HCV-negative recipients. The use of HCV-positive donor
organs is discussed in more detail elsewhere. (See "Kidney transplantation in
adults: Hepatitis C virus infection in kidney donors" and "Hepatitis C virus
infection in liver transplant candidates and recipients".)
●HIV-positive donors – HIV-positive patients with an undetectable viral load
and a CD4 count >200 have been able to undergo kidney and liver
transplantation successfully. Historically, the donors were always HIV
negative. However, transplantation of HIV-positive, deceased-donor kidneys
into HIV-positive recipients has been reported to be safe and effective. A
more detailed discussion of kidney transplantation in HIV-infected individuals
is presented separately. (See "Kidney transplantation in adults: Kidney
transplantation in patients with HIV".)
●HLA-incompatible donors – Advances in human leukocyte antigen (HLA)
desensitization strategies have enabled the transplantation of kidneys into
HLA-incompatible recipients. This is discussed in more detail elsewhere.
(See "Kidney transplantation in adults: HLA desensitization".)
●Normothermic ex vivo perfusion – Standard approaches to organ
preservation have included cold storage for kidneys, pancreases, livers,
hearts, and lungs as well as cold pulsatile preservation for kidneys.
Normothermic ex vivo perfusion, while not yet the routine standard of care,
has been described for clinical lung, liver, and kidney transplantation and has
shown promising results. (See "Lung transplantation: Donor lung
procurement and preservation", section on 'Normothermic ex-vivo perfusion
(after cold static preservation)' and "Liver transplantation in adults: Deceased
donor evaluation and selection", section on 'Machine liver perfusion'.)
42
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Kidney transplantation" and "Society
guideline links: Management of potential deceased organ donors".)
SUMMARY AND RECOMMENDATIONS
●Organ transplantation remains the best therapeutic option for many
patients with end-stage organ failure. However, there is a marked imbalance
between the supply and demand for organs, with a severe scarcity of
deceased organ donors. Thus, it is imperative that critical care clinicians
identify each potential organ donor, ultimately saving additional lives
through transplantation. (See 'Introduction' above.)
●Sixty-eight percent of organ donors are deceased, and 75 percent of those
are deceased by neurologic criteria, also referred to as brain death (donation
after neurologic determination of death [DNDD]), with the remaining organ
donors being deceased by circulatory death (donation after circulatory
determination of death [DCDD]). (See 'Types of deceased organ
donors' above.)
●In the evaluation of the potential deceased organ donor, responsibilities of
the clinician include the following:
•Identification of the potential deceased organ donor – This is the
initial step in the organ donation process. There are no universally
accepted criteria or definitions for potential deceased organ donors.
Commonly used clinical criteria (or "triggers") that should prompt a
referral from the hospital to the local organ procurement organization
(OPO) include any mechanically ventilated patient with one or more of the
following (see 'Identification of the potential organ donor' above):
-Glasgow Coma Scale score <5 without sedation (table 3)
-Brain death examinations being considered
-Withdrawal of life support being considered
-Do-not-resuscitate or comfort care being considered
-The family brings up the topic of organ donation
•Referral to the OPO – Once a patient has been identified as a potential
deceased organ donor, the clinician or a hospital representative must
alert the local OPO about the potential referral. A list of local OPOs is
available on the Internet. The Centers for Medicare and Medicaid Services
(CMS) have instituted federal regulations requiring all hospitals to notify
the local OPO of all imminent deaths in a timely manner (within one
hour) so the OPO can assess the patient's potential for organ donation.

43
 Importantly, the OPO should be contacted prior to any mention of
donation to the patient's family. (See 'Referral to the organ procurement
organization (OPO)' above.)
•Family communication – The clinician's responsibility is to keep the
family informed of the patient's deteriorating clinical status, poor
prognosis, and pertinent test results; answer their questions; and provide
compassionate care. They should avoid bringing up the topic of organ
donation. Any questions that the family has about organ donation should
be deferred to the OPO. (See 'Family communication' above.)
•Determination/declaration of death – Determination and declaration of
death are the responsibilities of the clinician and are required before the
surgical removal of organs for transplantation. Determination of death
differs for neurologic death (brain death) and circulatory death. Once
death has been determined, the clinician informs the patient's family or
next of kin (NOK) that the patient is deceased and documents a death
note stating that the examination has been performed.
(See 'Determination/declaration of death' above.)
•Optimization of organ function – Optimal donor management is
essential in both the intensive care unit (ICU) and in the operating room to
maximize the function of transplanted organs, as well as the quality of life
and survival benefits conveyed to the recipients. For DNDD donors, once
brain death has been declared and consent for donation has been
obtained, the OPO is responsible for medical management of the donor
until the time of organ procurement. Nursing care continues to be
provided by the hospital staff in collaboration with the OPO coordinator.
By contrast, DCDD donors remain under the care of the clinician and all
care is directed by the clinician until the time of organ procurement.
(See 'Optimization of organ function' above.)
●In the evaluation of the potential deceased organ donor, the responsibilities
of the OPO are to identify potential donors, obtain authorization for
donation, manage the donor to optimize organ function, allocate organs, and
preserve all organs in their assigned donation service area (DSA) [28]. The
OPO collaborates with the donor hospital's medical staff to achieve these
goals. The OPO also works closely with the transplant centers during the
allocation process to facilitate acceptance of the organs, arrange
procurement operating room time, and label and package the organs for
transportation. (See 'Responsibilities of the organ procurement organization
(OPO)' above.)

44
Liver transplantation in adults: Clinical
manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft
Author:
K Rajender Reddy, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Feb 12, 2021.
INTRODUCTIONAcute liver allograft rejection is an important cause of allograft
dysfunction. Acute rejection episodes can have an impact on long-term graft
survival, even among patients who recover. The use of potent immunosuppressive
agents for induction and maintenance therapy for liver transplantation has
reduced the incidence of acute rejection, which is defined as liver allograft
dysfunction associated with specific pathologic changes in the graft.
Acute rejection can be categorized into T cell-mediated (cellular) rejection (TCMR)
and antibody-mediated (previously known as humoral) rejection. However,
antibody-mediated rejection rarely occurs in liver transplantation recipients, while
acute TCMR has been commonly reported [1].
This topic will review the clinical manifestations and diagnosis of acute TCMR.
Treatment of acute TCMR and a review of transplantation immunobiology are
discussed separately. (See "Liver transplantation in adults: Treatment of acute T
cell-mediated (cellular) rejection of the liver allograft" and "Transplantation
immunobiology".)
The approach to immunosuppression following liver transplantation is discussed
separately. (See "Liver transplantation in adults: Overview of
immunosuppression".)
Long-term management of liver transplantation recipients and nonimmunologic
complications of transplantation are discussed separately. (See "Liver
transplantation in adults: Long-term management of transplant
recipients" and "Infectious complications in liver transplantation".)
EPIDEMIOLOGY
Incidence — With the availability of calcineurin inhibitors and antiproliferative
agents, acute T-cell mediated (cellular) rejection (TCMR) has been reported in
45
approximately 10 to 30 percent of liver transplantation recipients [2-6]. As an
example, in a study of two large cohorts of liver transplant recipients, at least one
biopsy-proven acute rejection episode occurred in 27 percent of transplant
recipients in the Adult-to-Adult Living Donor Liver Transplantation (A2ALL) cohort
and in 16 percent of transplant recipients in Scientific Registry of Transplant
Recipients (SRTR) cohort [2].
Risk factors — Risk factors for developing acute TCMR can be broadly classified as
the following [7]:
●Recipient-related factors – Etiology of underlying liver disease has been
associated with risk of developing acute TCMR. In a study of two large
cohorts of liver transplant recipients (the A2ALL and SRTR database), risk of
rejection was higher for recipients with primary biliary cholangitis (hazard
ratio [HR] 2.10, 95% CI 1.31-3.36, and HR 1.37, 95% CI 1.22-1.53, respectively)
or hepatitis C virus infection (HR 2.22, 95% CI 1.57-3.16 and HR 1.11, 95% CI
1.05-1.18, respectively) [2]. Other risk factors for acute TCMR have included
recipient age >55 years, cytomegalovirus infection, and subtherapeutic levels
of cyclosporine or tacrolimus (for acute rejection occurring more than 180
days posttransplant) [2,8-11].
●Preservation-related factors – Prolonged cold ischemic time has been
associated with risk of developing acute TCMR [10].
●Transplant-related factors – Transplant-related risk factors include
sensitization (ie, presence of donor-specific human leukocyte antigen [HLA]
alloantibodies) and fewer HLA-DR matches [8,11].
Protective factors — For recipients of living donor liver transplantation, having a
biologically-related liver donor was associated with lower risk of acute rejection. In
the A2ALL and SRTR cohorts, liver transplantation from a biologically related donor
was associated with lower risk of acute rejection compared with a non-biologically
related donor (HR 0.57, 95% CI 0.43-0.76, and HR 0.78, 95% CI 0.66-0.91,
respectively) [2].
CLINICAL FEATURES
Clinical presentation and timing — Most episodes of acute T-cell mediated
(cellular) rejection (TCMR) occur within three to six months after liver
transplantation, although some episodes occur beyond six months [12,13]. In
addition, acute rejection after 12 months post-transplant is typically related to
medication noncompliance, reduction in immunosuppression, or other factors
interfering with calcineurin inhibitor trough levels (eg, drug-drug interaction).
Most patients who have acute TCMR are asymptomatic. However, some patients
present with fever, malaise, abdominal pain, hepatosplenomegaly, and rarely,
increasing ascites. Because most patients are asymptomatic, acute TCMR is
46
suspected primarily by an increase in liver biochemical tests [14]. (See 'When to
suspect acute rejection' below.)
Laboratory manifestations — Patients with acute TCMR present with abnormal
liver biochemical tests which may include elevations of any of the following: serum
aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase
[AST]), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin
levels. (See 'When to suspect acute rejection' below.)
Imaging features — Imaging findings in patients with acute TCMR (eg, liver
allograft enlargement) are not specific for the diagnosis, and imaging studies are
generally performed to exclude other causes of elevated liver biochemical tests
and allograft dysfunction (eg, biliary complications). (See "Liver transplantation in
adults: Endoscopic management of biliary complications".)
DIAGNOSTIC EVALUATION
When to suspect acute rejection — Acute T-cell mediated (cellular) rejection
(TCMR) is suspected in liver transplantation recipients who have elevations in at
least one liver biochemical test within six months after transplant. Liver
biochemical tests include serum aminotransferases (ALT, AST), alkaline
phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin levels.
However, abnormalities in liver biochemical tests are not specific for distinguishing
acute TCMR from other causes of liver allograft dysfunction and do not correlate
with the severity of the rejection episode [14,15].

For patients with suspected acute TCMR, further evaluation is typically performed
within one week and includes:

●Liver allograft biopsy (see 'Assessing liver histology' below)

●Liver ultrasound with Doppler study to exclude biliary strictures or vascular
thrombosis (hepatic artery and portal vein). We routinely obtain both a
Doppler ultrasound and a liver allograft biopsy on the same day.
For patients with biliary tract abnormalities on ultrasound, further imaging
with magnetic resonance cholangiopancreatography, endoscopic retrograde
cholangiopancreatography, or percutaneous transhepatic cholangiography is
typically performed. (See "Liver transplantation in adults: Endoscopic
management of biliary complications".)

Liver transplant recipients with suspected acute TCMR require care and input from
a multidisciplinary team including specialists from transplant hepatology,
transplant surgery, and pathology.

Establishing the diagnosis

47
Assessing liver histology — The diagnosis of acute TCMR is made by examining
liver allograft histology. The liver biopsy specimen is used for grading the severity
of rejection and excluding other causes of elevated liver biochemical tests.
(See 'Defining severity of rejection' below.)
Patient preparation for and complications of percutaneous liver biopsy are
discussed separately. (See "Approach to liver biopsy".)
Acute TCMR occurs due to recipient T-cells that react to donor histocompatibility
antigens present within donor tissue [16]. The pathologic changes that occur in the
liver allograft in the setting of acute TCMR include (picture 1A-C) [12,17]:
●Portal inflammation – Portal inflammation consists of a mixed inflammatory
infiltrate (predominately mononuclear activated lymphocytes, but may also
contain neutrophils and eosinophils).
●Bile duct inflammation or damage – Bile duct inflammation or damage is
characterized by nonsuppurative cholangitis involving bile duct epithelium.
The affected ducts are infiltrated by inflammatory cells and may show
changes ranging from mildly reactive to degenerative changes or focal
luminal disruption. The inflammatory process may occur between epithelial
cells, inside the basement membrane, or even within the lumen.
●Venous endothelial inflammation – Venous endothelial inflammation (ie,
endotheliitis) involving the portal veins or terminal hepatic venules is often
seen in patients with acute TCMR. Endotheliitis is characterized by the
attachment of lymphocytes and other immunocytes to the luminal surface of
the endothelium. The inflammatory process may affect only a small segment
of the cross-section of the vessel. Lymphocytes also aggregate under the
damaged endothelium, which is then lifted from the basement membrane.
The adequacy of a biopsy specimen is ultimately left to the judgment of the
pathologist. Liver allograft biopsy technique typically includes performing two
passes with the biopsy needle to obtain samples that each have a minimum of five
portal triads [18]. (See "Interpretation of nontargeted liver biopsy findings in
adults", section on 'General principles'.)
Defining severity of rejection — A classification system for acute TCMR was
developed by a panel of expert hepatologists who agreed on a nomenclature and
histopathologic criteria for grading acute rejection (ie, Banff classification) [12].
After assessing the allograft biopsy specimen for histologic evidence of acute
TCMR, three specific features (portal inflammation, bile duct inflammation, and
venous endothelial inflammation) are more critically evaluated and scored on a
scale from zero to three. Thus, a maximum score of nine is possible, and the sum
of scores from each category is called the rejection activity index (RAI) [12].

48
Rejection severity is determined by RAI values (table 1). Mild rejection has been
regarded as RAI ≤4, although the classification of RAI values has varied among
studies [12-14,17,19-23].
Although management of patients with histologic evidence of acute TCMR is
guided by severity of rejection, a higher RAI has not been correlated with failure to
respond to antirejection treatment. In a study of 231 patients with acute TCMR
confirmed by histology, higher RAI scores were not associated with inadequate
response to glucocorticoid therapy [19].
DIFFERENTIAL DIAGNOSISThe differential diagnosis of elevated liver
biochemical tests in liver transplantation recipients includes other causes of
allograft dysfunction such as ischemic reperfusion injury, vascular thrombosis,
biliary strictures, infection, and recurrence of primary liver disease. Occasionally,
more than one disorder may occur in transplant recipients, and thus, features of
both disorders may be found on liver allograft biopsy.
Timing of the clinical presentation may help to narrow the potential causes of
elevated liver biochemical tests in transplant recipients. During the first few days
and up to one month after transplantation, elevated liver tests may reflect surgical
complications or issues such as hepatic artery thrombosis, ischemic reperfusion
injury, biliary anastomotic leakage or stricture, primary graft nonfunction, or
consequences of hemodynamic instability. Imaging (eg, Doppler ultrasonography)
and liver biopsy are typically obtained to differentiate these disorders from acute
TCMR. (See 'Diagnostic evaluation' above.)

Elevated liver biochemical tests and allograft dysfunction that occur within the first
month following transplant may be caused by:

●Ischemic reperfusion injury – Abnormalities in liver biochemical tests in the

immediate post-transplantation period (<4 weeks) may reflect graft injury
that usually manifests with elevation of the alkaline phosphatase and GGT,
without an increase in total bilirubin [14]. By contrast, elevation of
aminotransferases (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]) together with rising bilirubin level and/or GGT
should raise concern for acute T-cell mediated (cellular) rejection (TCMR).
●Prolonged intrahepatic cholestasis – Prolonged intrahepatic cholestasis (ie,
duration >1 week) typically presents in the initial posttransplantation period
and is marked by elevations in total bilirubin and alkaline phosphatase in the
absence of extrahepatic biliary obstruction on imaging [24,25]. On liver
allograft biopsy, portal tract and bile duct inflammation is often accompanied
by bile duct plugging and bile staining within the hepatocytes [26].

49
 Subcellular organelle damage produced by cold ischemia may play an
etiologic role, leading to bile flow dysfunction [27].
●Cyclosporine toxicity – Cyclosporine toxicity is a potential cause of liver
allograft dysfunction; however, cyclosporine is infrequently used for
immunosuppression for liver transplant recipients. For patients who take
cyclosporine, toxicity should be suspected when elevated liver biochemical
tests are seen in conjunction with elevations in serum creatinine.
(See "Cyclosporine and tacrolimus nephrotoxicity".)
●Antibody-mediated rejection – Antibody-mediated rejection is an infrequent
cause of allograft injury and loss after ABO-compatible liver transplantation
that can mimic or overlap with acute TCMR. Proposed features of antibody-
mediated rejection in patients following liver transplantation include donor-
specific human leukocyte antigen (HLA) alloantibodies in serum,
microvascular endothelial cell injury on biopsy, and linear C4d positivity in
liver sinusoids, in the absence of other causes of liver injury [17,28,29].
●Recurrent hepatitis C virus (HCV) infection – Some histologic features, such
as bile duct injury and portal lymphocytic infiltration, are found in both
recurrent HCV infection and acute TCMR. However, the availability of safe and
highly effective therapy with direct acting antivirals has revolutionized the
approach to HCV management in liver transplant candidates and recipients.
The diagnosis and management of recurrent HCV infection following liver
transplantation is discussed separately. (See "Hepatitis C virus infection in
liver transplant candidates and recipients".)
●Massive hemorrhagic necrosis – A very rare complication after liver
transplantation is acute graft necrosis and failure in the absence of vascular
obstruction. Histologic features include widespread hemorrhage and
infarction. This syndrome has been described as massive hemorrhagic
necrosis [30].
●Graft-versus-host disease – Graft-versus-host disease (GVHD) after liver
transplantation has been rarely reported but usually presents within the first
month after transplantation [31]. Common clinical features have included
skin rash, diarrhea, and cytopenia. The diagnosis can be made on
rectosigmoid biopsies showing histologic features of increased crypt
epithelial apoptosis, crypt loss, and neutrophilic infiltration. A biopsy of the
skin rash can also be used to evaluate for GVHD. (See "Cutaneous
manifestations of graft-versus-host disease (GVHD)".)
Causes of liver allograft dysfunction that are typically seen later in the post-
transplantation period (ie, after six months) include infections (eg,
cytomegalovirus, Epstein-Barr virus) and recurrence of primary liver disease (eg,

50
primary biliary cholangitis). (See "Infectious complications in liver
transplantation".)
Recurrence of nonviral chronic liver disease (eg, primary biliary cholangitis,
primary sclerosing cholangitis) typically occurs >1 year following liver
transplantation. (See "Liver transplantation in primary biliary cholangitis".)
Recurrent viral hepatitis (eg, hepatitis B virus infection) may occur at any time after
transplant. (See "Liver transplantation for chronic hepatitis B virus infection".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Acute liver allograft rejection is an important cause of allograft dysfunction.
Acute rejection episodes can have an impact on long-term graft survival, even
among patients who recover. The use of potent immunosuppressive agents
for induction and maintenance therapy for liver transplantation has reduced
the incidence of acute rejection, which is defined as liver allograft dysfunction
associated with specific pathologic changes in the graft.
(See 'Introduction' above.)
●With the availability of calcineurin inhibitors and antiproliferative agents,
acute T-cell mediated (cellular) rejection (TCMR) has been reported in
approximately 10 to 30 percent of liver transplantation recipients.
(See 'Incidence' above.)
●Most liver transplant recipients with acute TCMR are asymptomatic and
present with elevated liver biochemical tests within three to six months
following transplantation. (See 'Clinical features' above.)
●Acute TCMR is suspected in liver transplantation recipients who have
elevations in at least one liver biochemical test within six months after
transplant. Liver biochemical tests include serum aminotransferases (ALT,
AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and
bilirubin levels. (See 'When to suspect acute rejection' above.)
Patients with suspected acute TCMR are evaluated with liver allograft biopsy
and liver ultrasound with Doppler study.
●The diagnosis of acute TCMR is made by examining liver allograft for
histologic evidence of acute rejection. The liver biopsy specimen is also used
for grading the severity of rejection and excluding other causes of elevated
liver biochemical tests. The pathologic changes that occur in the liver
allograft include portal inflammation, bile duct inflammation and damage,
and venous endothelial inflammation. (See 'Assessing liver histology' above.)

51
●For patients with acute TCMR of the liver allograft, rejection severity is
determined by the rejection activity index (RAI) (table 1). (See 'Defining
severity of rejection' above and "Liver transplantation in adults: Treatment of
acute T cell-mediated (cellular) rejection of the liver allograft".)
●Long-term management of liver transplantation recipients and
nonimmunologic complications of transplantation are discussed separately.
(See "Liver transplantation in adults: Long-term management of transplant
recipients" and "Infectious complications in liver transplantation".)

52
Liver transplantation in adults: Deceased donor
evaluation and selection
Author:
Scott J Cotler, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 19, 2021.
INTRODUCTIONThe shortage of available donor organs is the major limiting
factor in liver transplantation. Optimal deceased donors are generally young,
previously healthy persons who develop a fatal brain injury due to causes such as
head trauma, intracerebral hemorrhage, or anoxia. The relative paucity of donor
organs has led transplant centers to consider organs from marginal donors.

This topic will review the selection process for deceased donors and examine
donor characteristics associated with recipient outcomes. Patient selection for liver
transplantation and for living donor liver transplantation is discussed elsewhere.

●(See "Liver transplantation in adults: Patient selection and

pretransplantation evaluation".)
●(See "Living donor liver transplantation in adults".)

DONOR EVALUATION
Donation after brain death — The United Network for Organ Sharing (UNOS)
provides minimum guidelines for organ procurement. The initial evaluation is
typically performed by the local organ procurement organization (OPO). The OPO
representative verifies that the prospective donor meets the criteria for brain
death. Consent for donation is obtained from the potential donor's next of kin.
ABO blood type, height, weight, and chest circumference are obtained because
recipient matching is based upon blood type and donor organ size.
Potential donors with contraindications to donation are excluded. These include
nonhepatic malignancy (other than primary brain tumor without
ventriculoperitoneal shunt). Previously, anti-human immunodeficiency virus (HIV)
seropositivity was an absolute contraindication to donation in the United States.
The ban was in part due to concern that transplanting HIV-positive organs into
patients with HIV that was well controlled could result in the transfer of resistant
53
HIV to the recipient. However, in 2013, a law was passed that ended a ban on
transplanting organs from donors with HIV into HIV-positive recipients because of
better HIV therapy as well as high waiting list mortality rates for patients with HIV
[1]. Although septicemia is usually considered a contraindication to donation,
organs from bacteremic donors have been used successfully. A large retrospective
study, for example, showed similar 30-day graft and patient survival in recipients
of organs from bacteremic and nonbacteremic donors [2].
The OPO representative obtains a medical history, evaluates for a history of
substance or alcohol use disorder, and performs a physical examination.
Laboratory testing generally includes ABO blood type, complete blood count (CBC),
chemistries, prothrombin time (PT), activated partial thromboplastin time (PTT),
hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antigen (HBc), anti-
hepatitis C virus (HCV), anti-HIV, venereal disease research laboratory (VDRL) or
rapid plasma reagin (RPR), and anti-cytomegalovirus (CMV). Blood and urine
cultures are performed if the prospective donor was hospitalized for more than 72
hours. OPOs obtain nucleic acid testing (NAT) for HIV and HCV in all increased risk
donors to shorten the window period between acquisition of infection and
detection by ELISA in order to reduce the risk of transmission to the recipient [3].
Ultrasound imaging or liver biopsy is performed if needed.

The local OPO is responsible for donor maintenance until the time of procurement.
Vital signs, intake, and output are monitored. Fluids and vasopressors are given as
needed to achieve hemodynamic stability. Antibiotics are provided if necessary.

Living donors — This topic is discussed in detail elsewhere. (See "Living donor

liver transplantation in adults", section on 'Evaluation of the living liver donor
candidate'.)
DONOR FACTORS IMPACTING RECIPIENT OUTCOMEMultiple donor
and transplant-related characteristics associated with recipient outcomes have
been evaluated [4-13]. Comparisons among these studies can be difficult since
variable clinical endpoints have been measured, recipients had different forms of
underlying liver disease, and because donors are often selected based upon
recipient characteristics. Clinical endpoints frequently include the following
measures:
●Initial graft function
●Primary nonfunction (PNF, ie, graft failure in the immediate postoperative
period)
●Graft survival
●Patient survival

54
Donor factors that have been associated with adverse outcomes include advanced
donor age, donor sex or donor-recipient sex mismatch, moderate to marked
hepatic steatosis, and donor hypernatremia.

Strategies used to increase available donor livers may affect outcomes. These
strategies include adult living donor liver transplantation, donation after
circulatory death, the use of hepatitis C virus (HCV)-positive donors for HCV-
infected recipients, and use of hepatitis B surface antigen (HBsAg)-positive donors
for hepatitis B virus (HBV)-positive and anti-hepatitis B core antigen (HBc)-positive
recipients. (See "Living donor liver transplantation in adults" and "Hepatitis C virus
infection in liver transplant candidates and recipients".).

Although donor characteristics and technical factors will be discussed individually,

a combination of risk factors may interact to affect outcomes in individual patients.

Older age — The use of livers from older donors is now a common practice [14].
However, livers from older donors can have more initial dysfunction due to
ischemic or preservation injury, and in recipients with hepatitis C virus (HCV)
infection, there is an association of donor age with the development of severe
recurrent HCV. Delayed nonfunction may occur, necessitating retransplantation.
Use of organs felt to be of good quality on careful inspection [15] and minimizing
cold ischemia time [16,17] may help to maximize outcomes when livers are used
from older donors.
Several studies have evaluated the relationship between donor age and recipient
outcomes, although data are mixed [4,6-8,15,16,18-22]. An illustrative report
included 772 patients who underwent liver transplantation at three centers [15].
Older donors were defined as those aged 50 years and older. Laboratory
parameters including alanine aminotransferase (ALT), aspartate aminotransferase
(AST), bilirubin, and prothrombin time were higher in recipients with older donors
during the first week after transplantation. More importantly, graft survival was
reduced at three months in recipients of livers from older donors and this
difference persisted to 24 months post-transplant. In multivariate analysis
controlling for donor and recipient factors, reduced graft survival was identified
only for older donors when the allograft was rated to be poor or fair in quality by
the surgeon at the time of harvest. Similar results have been reported in several
other series, although the exact donor age associated with worsening outcomes
has varied.
Other studies suggest that acceptable outcomes can be achieved with older
donors [7,8,16,22-24]. Limiting cold ischemia time and degree of steatosis were
hypothesized to be important in optimizing the results of transplantation from
55
older donors. In a study using the UNOS database, the five-year cumulative
mortality rates were lower for transplant candidates who accepted a liver from an
older donor (≥70 years old) compared with matched controls who declined the
same offer (23 versus 41 percent) [22].
Prior to the availability of highly effective direct antiviral agents for HCV infection,
the use of livers from older donors was a particular concern for recipients with
HCV. A single-center study of 124 liver transplants showed that donor age >60
years was associated with the development of severe recurrent HCV and provided
an optimal age cutoff to predict an increased risk of HCV-related graft loss [25].
Hepatic steatosis — Donor livers that appear fatty on inspection are biopsied for
histologic determination of fat content. Severe macrovesicular steatosis is
associated with primary nonfunction [12,26-31]. Outcomes are more variable when
organs with moderate steatosis are used. Illustrative studies have shown the
following:
●One study, which analyzed 158 donor liver biopsies, found that moderate
fatty change (defined as 30 to 60 percent fat content) was associated with the
development of early graft dysfunction [28].
●Another report that categorized donor steatosis as mild (<30 percent),
moderate (30 to 60 percent), and massive (>60 percent) found an increased
frequency of early graft dysfunction and PNF when donor organs had
moderate or massive steatosis [29]. Compared with patients who received
livers with mild steatosis, graft survival at one month was slightly lower in
those who received livers with moderate steatosis and substantially reduced
in those given grafts with massive steatosis.
●A report of 225 consecutive transplants showed that while ≥30 percent
donor steatosis was associated with early graft dysfunction, five-year graft
survival was similar between patients who received grafts with <30 or >30
percent steatosis [32].
●A retrospective review of the United Network for Organ Sharing Standard
Transplant Analysis and Research files examined 5051 liver transplants [33].
At one year, 864 (17 percent) of the grafts had failed. The study found that on
multivariable analysis, donor livers with greater than 30 percent
macrovesicular steatosis had an increased risk of graft loss (relative risk 1.71).
Many transplant centers try to avoid using organs with more than 40 percent
fatty infiltration and refuse organs with more than 50 percent fat content
[34].
Hypernatremia — Worse outcomes have been reported in liver transplant
recipients who receive grafts from donors with hypernatremia. Donor
hypernatremia may be a surrogate marker for other factors affecting graft

56
function, including prolonged donor intensive care stay, excessive saline infusion,
and negative water balance resulting from aggressive treatment of cerebral
edema, and reduced antidiuretic hormone secretion after brain death. In two
reports, the rate of graft loss within one month of transplantation was increased
when the donor plasma sodium level exceeded 155 mmol/L [35,36]. Other
investigators observed a direct relationship between donor serum sodium levels
and degree of early graft dysfunction [37]. Most respondents to a survey of the
South-Eastern Organ Procurement Foundation liver transplant centers indicated
that the maximum donor serum sodium level that they would accept was 160 to
170 mEq/L [34].
Hemodynamic instability — Hepatic blood flow decreases with periods of
hypotension and the use of high doses of vasopressors predisposing to ischemic
liver injury. Early graft dysfunction was observed when donors had hypotension
refractory to dopamine levels exceeding 15 mcg/kg/min [38]. However, the use of
high doses of dopamine was not associated with graft dysfunction when the
donor's blood pressure was maintained above 90 mmHg.
Donor-recipient mismatch
Sex — Transplantation of livers from female donors was associated with worse
outcomes in many, but not all, series [39-42]. Some studies suggest that sex-
mismatched transplants in which the liver from a female donor is given to a male
recipient may be particularly problematic. As an example, a retrospective
evaluation of 994 liver transplants performed over 10 years showed significantly
lower graft and patient survival for transplantation of female donors into male
recipients compared with other donor-recipient combinations (approximately 56
versus 75 percent two-year graft survival) [40].
A further study of 462 liver transplants with 1.1 to 2.6 years of follow-up found that
graft survival was superior with male donors relative to female donors when
controlling for other factors [39]. The poorest results were observed with the use
of female donors over age 60. A study of pediatric liver transplant patients also
documented superior one and five-year graft and patient survival for male-male
donor-recipient pairs compared to males who received livers from female donors
[41]. The organ allocation system does not take the donor's or recipient's sex into
account in distributing livers since other considerations are more important.
ABO compatibility — Livers are routinely matched by ABO blood type (ABO
identical), although mismatched organs have been used in extreme circumstances.
Mismatched organs may either be ABO compatible (eg, an organ from a donor
who is type O going to a recipient who is type B) or ABO incompatible (eg, an
organ from an donor who is type A going to a recipient who is type B). A
retrospective study of 234 liver transplants found that two-year graft survival was

57
30 percent in 17 ABO-incompatible emergency transplants compared with 76
percent in 55 ABO-compatible emergency transplants and 80 percent in 162 ABO-
compatible elective transplants [43]. Compared with ABO-compatible transplants,
humoral rejection, acute cellular rejection, arterial thrombosis, and biliary
complications were more common in ABO-incompatible recipients. These data
suggest that ABO incompatibility (and not a need for emergency transplantation)
was the major reason for graft loss, although the urgent nature of the transplant
and severe illness likely had a role as well. Registry data from Europe showed that
the risk of mortality was increased nearly two times in recipients of ABO-
incompatible livers [44]. However, good outcomes have been reported among
recipients with blood type O who receive an organ from a donor with blood type
A2 with overall and graft survival rates that are similar to those seen when a
recipient with blood type O receives an ABO-compatible organ [45].
Many centers use ABO-incompatible livers in emergency situations such as
fulminant hepatic failure when an ABO-identical or compatible organ is
unavailable, with the understanding that retransplantation will be required in
some patients. In such cases, perioperative plasmapheresis, intensive induction
immunosuppression, and prostaglandin E1 administration may reduce the
development of severe acute rejection [46,47].
There have also been successful elective transplantations of ABO-incompatible
organs from living donors. In a series of 22 recipients of ABO-incompatible organs,
overall patient and graft survival were 100 percent after a mean follow-up of 10
months (range 3 to 21 months) [48]. All of the patients received rituximab two
weeks prior to transplantation and also underwent plasma exchange with blood
group AB fresh frozen plasma every other day prior to transplantation. Plasma
exchange transfusion was continued until the IgM and IgG isoagglutinin titers that
corresponded to the donor ABO blood group were ≤1:8. During the first two weeks
following transplantation, plasma exchange transfusion was repeated if the titers
were >1:32.
TECHNICAL FACTORS
Cold ischemia time — Prolonged cold ischemia time (ie, greater than 12 hours)
may impact donor organ viability and graft survival. Donor livers are typically
preserved in University of Wisconsin storage solution cooled to 0 to 4º C after
harvesting. Cold preservation leads to liver injury over time, and the duration of
cold ischemia time (CIT) affects recipient outcomes.
Early studies showed that CIT exceeding 18 to 20 hours was associated with
increased rates of early graft dysfunction, PNF [28], and need for retransplantation
within 14 days [49]. Subsequent reports showed a benefit for maintaining CIT less
than 12 hours. Better initial graft function, reduced frequency of PNF, and superior
58
graft and patient survival were observed with CIT less than 12 hours in an analysis
that excluded emergency transplantation [50]. Data from a large European registry
indicated that the risk of recipient mortality was stable for CIT up to 12 hours and
increased with longer preservation times [44]. In multivariate analysis, there was a
negative interaction between CIT exceeding 12 hours and recipient age greater
than or equal to 60 years, and CIT exceeding 12 hours and status as a previous
transplant recipient with graft failure.
Other studies found that CIT exceeding 12 hours was associated with an increased
rate of biliary complications, such as intrahepatic strictures [51]. Most centers try
to limit CIT to less than 12 hours, particularly in the presence of other donor or
recipient characteristics that can adversely affect transplant outcomes.
RISK ASSESSMENT INDICES
Donor risk index — Data from over 20,000 liver transplants were used to develop
a predictive model comprised of donor factors known at the time an organ is
offered to quantify the risk of graft failure, and this model is known as the donor
risk index [52]. The parameters most strongly associated with graft loss include
increasing donor age, donation after cardiac death, and use of split/partial grafts.
Other risk factors include African American donors, shorter donors, death due to
cerebrovascular accident, and causes of brain death other than trauma or anoxia.
Eurotransplant donor risk assessment — Analysis of 4701 deceased donors from
Eurotransplant and the European Transplant Registry identified risk factors for
graft loss in first time recipients who received a deceased donor liver [53]. Cold
ischemia time, highest serum sodium level, cause of donor death, gamma-
glutamyl transferase (GGT) level, and female donor sex were predictors of graft
loss at three months. In addition, cold ischemia time, GGT, and cause of donor
death were associated with 12-month graft loss. The data were used to construct
nomograms to allow for rapid assessment of the complex interaction among risk
factors in a given donor. When the donor risk index was applied to the dataset,
there was limited agreement with the Eurotransplant nomogram (kappa = 0.23).
The area under the receiver operating characteristic curve for both predictors was
relatively low, indicating the difficulty in defining criteria for extended donors.
APPROACHES TO EXPAND DONOR LIVER SUPPLY
Donation after circulatory death — Patients with an irreversible, catastrophic
illness may serve as non-heart-beating donors after withdrawal of care in a
controlled hospital setting and after achieving set criteria for cardiac death [54,55].
Such donation is referred to as "donation after circulatory death" (DCD). In the
United States, life support is usually withdrawn in the operating room. The patient
is observed until the time of death, which is declared by a clinician who is not part
of the transplant team. After a waiting period that is generally in the range of five
59
minutes, organ retrieval is initiated with femoral artery cannulation and infusion of
cold University of Wisconsin storage solution. Warm ischemia time includes the
interval between withdrawal from life support and infusion of University of
Wisconsin solution [54].

Use of DCD donor livers could provide a substantial number of needed organs.
Outcomes for recipients of DCD donor livers include:

●Patient and graft survival — Studies comparing recipients of organs from

DCD donors with standard brain-dead deceased donors have been variable,
with some showing similar outcomes, while others suggest decreased graft
and patient survival following receipt of a DCD donor organ [54-59]. However,
many of the studies are limited by the fact that they were not randomized,
potentially leading to disparate outcomes that were not the result of the type
of donor organ. One series looked at 2572 liver transplantations, 352 of
which were from DCD donors [59]. Compared with recipients of standard
brain-dead deceased donor organs, recipients of DCD donor organs had
higher three-year graft loss (27 versus 18 percent) and higher three-year
mortality (19 versus 14 percent). Another retrospective series with 200 liver
transplantations from DCD donors and 1828 liver transplantations from
brain-dead deceased donors did not find any significant differences in graft
or patient survival between the groups at one, three, or five years [58].
Donor factors associated with graft failure have included indicators of
prolonged warm ischemia time, such as a mean arterial pressure lower than
60 mmHg for more than 20 minutes after the withdrawal of life support and
longer cold ischemia times (>6 hours in one study) [58,60]. The use of DCD
liver grafts with moderate macrosteatosis (30 to 60 percent) was associated
with adverse outcomes including primary non-function and early allograft
dysfunction [61].
Many centers avoid using DCD livers from older donors (eg, donor age >50
years). However, a study from the UK transplant registry of experienced
centers using careful selection of donors and recipients showed no
significant differences in 5-year graft survival between DCD donor age >70
years compared with donor age <70 years [62].
Recipient factors associated with reduced DCD graft survival reflected
severity of illness, functional reserve, and complexity of the operation. As an
example, recipient factors included in the UK-DCD risk score were age >60
years, MELD score >25, and retransplantation [63]. The UK-DCD risk score
was developed to match DCD donors and recipients to optimize outcomes
[58,60].
60
 ●Biliary complications — The use of DCD donors is associated with an
increased risk of ischemic cholangiopathy, manifested by diffuse
nonanastomotic biliary strictures in the absence of hepatic artery thrombosis.
Ischemia-reperfusion injury can cause bile duct injury and subsequent
fibrotic narrowing and scarring of the biliary tree after transplantation
[64,65]. Indicators of prolonged functional warm ischemia time (eg, longer
asystole to cross clamp time) are associated with biliary complications [66].
Single-center studies from transplantation programs that are experienced in
the use of DCD livers have reported ischemic cholangiopathy in
approximately five percent of recipients of DCD liver grafts [67,68]. However,
prior studies including recipients of DCD donor livers reported higher rates of
post-transplant biliary complications that ranged from 12 to 60 percent
[57,58,69].
Strategies to expand the use of DCD donor livers while minimizing the risk of
ischemic cholangiopathy for recipients of such liver grafts include an organ
preservation technique using hypothermic oxygenated machine perfusion
[70,71]. In a randomized trial of 156 patients who were transplanted with a
DCD liver graft, conventional cold storage followed by hypothermic machine
perfusion of the liver graft prior to implantation resulted in a lower risk of
nonanastomotic biliary strictures within six months after transplant
compared with cold storage alone (6 versus 18 percent; risk ratio 0.36, 95% CI
0.14-0.94) [70]. In addition, patients in the machine-perfusion group had
lower rates of endoscopic or percutaneous interventions for nonanastomotic
biliary strictures (4 versus 14 percent), although statistical analysis was not
provided. Notably, the rate of ischemic cholangiopathy in the hypothermic
machine perfusion group (6 percent) was similar to rates reported in some
studies of DCD donor livers without machine perfusion [67,68,72]. Additional
trials are needed to assess the short- and long-term impact of novel
preservation techniques such as hypothermic machine perfusion on
outcomes for recipients of DCD donor livers. (See 'Machine liver
perfusion' below.)
Hepatitis C virus-positive donors — Given the high success rate of direct-acting
antiviral (DAA) therapy and limited supply of donor livers, use of livers from HCV-
viremic donors for HCV-positive recipients is common. Increasing evidence has
suggested that using organs from HCV viremic donors for HCV-negative recipients
followed by DAA treatment in the early post-transplant period is an overall
effective and safe strategy [73,74]. Outcomes in recipients of HCV-positive liver
grafts are discussed separately. (See "Hepatitis C virus infection in liver transplant
candidates and recipients".)

61
Hepatitis B virus-positive donors — Transplantation of organs from donors with
serologic markers for past HBV infection has the potential to increase the donor
pool, particularly in regions where HBV carriers are frequent (such as the
Mediterranean region and Asia). It is generally recommended that grafts from
hepatitis B core antibody (anti-HBc)-positive donors should be offered to hepatitis
B surface antigen (HBsAg)-positive recipients, although recipients who lack HBV
markers may also be eligible provided that they receive antiviral prophylaxis post-
transplantation. Antiviral prophylaxis for reducing the risk of donor-related HBV
transmission to the recipient is discussed separately. (See "Liver transplantation
for chronic hepatitis B virus infection".)
More controversial is the use of livers from donors who are HBsAg-positive.
Transplantation of such grafts has been described [75,76] but should probably not
be offered to patients who are HBsAg-negative or to recipients who have
concurrent HDV infection since such patients may develop severe HDV-related
disease after transplant [77].
Machine liver perfusion — Both hypothermic machine perfusion and
normothermic ex-vivo liver evaluation are being studied as techniques to expand
the donor pool by limiting the deleterious effects of cold ischemia on extended
criteria grafts such as DCD liver grafts and livers with steatosis [70,78-81]:
●Hypothermic oxygenated machine perfusion – Hypothermic machine
perfusion has been studied as a method to improve outcomes with use of
extended criteria donors and may protect against ischemic cholangiopathy in
DCD livers [70,78]. (See 'Donation after circulatory death' above.)
●Normothermic ex-vivo liver perfusion – Preliminary data have demonstrated
that normothermic ex-vivo liver perfusion allows for assessment of graft
function including metabolic and perfusion parameters and bile flow prior to
implantation [79,80,82,83]. Use of a normothermic ex-vivo circuit has the
potential to predict graft viability in an effort to minimize primary graft
nonfunction with use of extended criteria donor livers.
SPLIT-LIVER TRANSPLANTATIONSplitting livers into right and left lobes for
transplantation has been investigated as a way to increase the supply of donor
organs. Studies have looked at allocating the split organ to an adult and a pediatric
recipient or to two adults.
A working group appointed by the American Society of Transplant Surgeons and
the American Society of Transplantation has advocated the institution of a national
policy for splitting appropriate donor livers into left lateral and extended right
grafts for transplantation into a pediatric and an adult recipient, respectively [84].
Many suitable livers are reduced in size for pediatric transplantation, and are not
split with an adult recipient. According to the analysis of the working group,
62
approximately 20 percent of donors could be split, increasing the total number of
liver transplant recipients in the United States by up to 1000 annually. Outcomes of
in situ liver splitting for adult/child pairs have been comparable to whole graft
transplantation.
In a study of 106 split liver transplantations, adult 1-, 5-, and 10-year survival rates
were 93, 77, and 73 percent, respectively, with graft survival rates of 89, 76, and 65
percent, respectively [85]. For children, 1-, 5-, and 10-year survival rates were 84,
75, and 69 percent, respectively, with graft survival rates of 77, 63, and 57 percent,
respectively.
Splitting the organ between two adults was examined in a retrospective study of
42 patients who received split liver transplantations [86]. One lobe of the liver went
to the patient on the waiting list with the same blood type and the highest Model
for End-stage Liver Disease score, provided the graft-recipient weight ratio (GRWR)
for one of the lobes was at least 0.8 percent. The second lobe went to a recipient
with the same blood type in whom the GRWR was 0.8 percent or more. The three-
month, one-year, three-year, and five-year survival rates were 76, 71, 69, and 69
percent, respectively. Survival rates were similar to those seen in patients who
received living donor transplantations during the same period.
EXTENDED CRITERIA LIVER GRAFT OUTCOMESThe use of marginal or
extended criteria liver grafts may lower the risk of mortality on the liver transplant
waiting list without impacting patient or graft survival. In an 18-year study of over
2000 liver transplant recipients from a single transplant program, there was no
significant difference in rates of one- three- and five-year patient survival for
patients receiving marginal liver grafts compared with those receiving standard
grafts during the second nine year period [87]. Marginal liver grafts included those
with any of the following characteristics:
●Liver donor age >70 years (see 'Older age' above)
●Livers discarded regionally and shared nationally
●Livers from HCV-positive donors  
●Livers with cold ischemia time >12 hours (see 'Cold ischemia time' above)
●Livers from donation after circulatory death donors (see 'Donation after
circulatory death' above)
●Livers with >30 percent steatosis (see 'Hepatic steatosis' above)
●Livers split between two recipients (see 'Split-liver transplantation' above)

The mortality rate for patients who were waitlisted at the transplant program
using marginal liver grafts was lower compared with the national waitlist mortality
rate (19 versus 24 percent).

63
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●The United Network for Organ Sharing provides minimum guidelines for
organ procurement. The initial evaluation is typically performed by the local
organ procurement organization (OPO). The OPO representative verifies that
the prospective donor meets the criteria for brain death. Consent for
donation is obtained from the potential donor's next of kin. (See 'Donation
after brain death' above.)
●Donor characteristics that are associated with an adverse effect on graft
function and/or graft survival include "donation after circulatory death"
(DCD), advanced donor age, moderate to marked hepatic steatosis, and
donor hypernatremia. (See 'Donor factors impacting recipient
outcome' above.)
●The number and severity of donor risk factors is considered in evaluating
prospective donors and risk assessment indices have been developed.
(See 'Risk assessment indices' above.)
●A shortage of donor livers has led to alternative approaches such as the use
of DCD donors and hepatitis C virus (HCV)-positive donors to increase the
donor organ supply. (See "Hepatitis C virus infection in liver transplant
candidates and recipients".)
Strategies such as hypothermic machine perfusion of DCD donor livers are
being studied to expand the donor supply while minimizing the risk of
recipient complications (eg, ischemic cholangiopathy). (See 'Approaches to
expand donor liver supply' above.)
●Judicious use of extended criteria liver grafts may lower the risk of mortality
for patients on the liver transplant waiting list without impacting patient
survival or graft function or survival. (See 'Extended criteria liver graft
outcomes' above.)

64
Liver transplantation in adults: Endoscopic
management of biliary complications
Authors:
Andrés Cárdenas, MD, PhD, MMSc, AGAF, FAASLD
Karen L Krok, MD
Paul J Thuluvath, MBBS, MD, FRCP
Section Editor:
Douglas G Adler, MD, FACG, AGAF, FASGE
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 21, 2021.
INTRODUCTIONLiver transplantation (LT) is performed for some patients with
decompensated cirrhosis, hepatocellular carcinoma, and/or acute liver failure.
Biliary tract complications such as biliary strictures and bile leaks may contribute
to patient morbidity and limited graft survival. Most biliary complications can be
managed with interventional endoscopic retrograde cholangiography (ERC) for LT
recipients with duct-to-duct biliary anastomosis. Some LT recipients with Roux-en-Y
anastomosis can also be managed endoscopically. (See "ERCP in patients with
Roux-en-Y anatomy".)

This topic will discuss endoscopic management of biliary complications related to

LT. Medical care of the LT recipient is discussed separately:

●(See "Liver transplantation in adults: Long-term management of transplant

recipients".)
●(See "Liver transplantation in adults: Overview of immunosuppression".)
●(See "Infectious complications in liver transplantation".)
An overview of endoscopic retrograde cholangiopancreatography (ERCP) is
discussed separately. (See "Overview of endoscopic retrograde
cholangiopancreatography (ERCP) in adults".)
INCIDENCE AND RISK FACTORSThe estimated incidence of biliary
complications related to LT ranges from 10 to 15 percent in recipients of deceased
donor livers and from 15 to 30 percent in recipients of living donor livers [1-5]. Risk
factors for biliary complications after LT include (table 1) [2,6-18]:
●Donor-related factors – Transplanted liver from a living donor (rather than
deceased donor) or a donation after cardiac death donor; older age of donor;

65
 high donor body mass index; macrovesicular graft steatosis >25 percent [19-
21] (see 'Special populations' below).
●Recipient-related factors – History of primary sclerosing cholangitis,
cytomegalovirus infection.
●Vascular factors – Hepatic artery thrombosis, hepatic artery stenosis.
●Surgical/technical factors – Excessive dissection of periductal tissue during
procurement of the liver graft, excessive use of electrocautery for control of
biliary ductal bleeding, tension at the anastomosis, small bile duct diameter
of the graft, mismatched size between donor and recipient bile ducts,
ischemia/reperfusion injury, prolonged cold and/or warm ischemia times.
●Postoperative factors – Bile leak (via local inflammation and fibrosis)
(see 'Bile leaks' below).
●Other factors – ABO incompatibility.
Whether the type of biliary reconstruction (duct-to-duct
choledochocholedochostomy or Roux-en-Y choledochojejunostomy) increases the
risk of biliary complications is uncertain [22-25]. However, duct-to-duct
anastomosis facilitates endoscopic access to the biliary tree and preserves the
sphincter of Oddi, which in theory avoids reflux of luminal contents into the bile
duct [7]. (See "ERCP in patients with Roux-en-Y anatomy".)
Historically, T-tube placement was associated with biliary complications, but T-
tubes are rarely used in most centers that perform liver transplantation [26-28].
EVALUATION
When to suspect a biliary complication — The clinical presentation of biliary
complications varies among LT recipients. At one extreme, some patients have
asymptomatic elevations in liver enzymes, primarily in a cholestatic pattern
(disproportionate elevation of the alkaline phosphatase compared with the
aminotransferases) but without abdominal pain, pruritus, or jaundice.
(See "Approach to the patient with abnormal liver biochemical and function tests",
section on 'Patterns of liver test abnormalities'.)
However, other patients may present with fever, right upper quadrant abdominal
pain, and/or jaundice. Occasionally, other symptoms such as anorexia and pruritus
are reported. For patients with a bile leak, exposure of the peritoneum to bile
usually results in abdominal pain. However, some patients with bile leak do not
have abdominal pain, possibly because of immunosuppression and hepatic
denervation [6,7,25]. (See 'Bile leaks' below.)
The evaluation of other suspected hepatobiliary complications following liver
transplantation (eg, acute T-cell mediated rejection) is discussed separately.
(See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute
T-cell mediated (cellular) rejection of the liver allograft", section on 'Diagnostic
66
evaluation' and "Liver transplantation in adults: Long-term management of
transplant recipients", section on 'Hepatobiliary complications'.)
Initial testing — For patients suspected of having a biliary complication based on
symptoms and/or elevated liver enzymes, the evaluation begins with a
transabdominal liver ultrasound with a Doppler study of the hepatic vessels.
Further testing is informed by ultrasound findings:
●Biliary abnormality – If liver ultrasound demonstrates features of bile duct
obstruction (eg, biliary ductal dilation) or a fluid collection suggestive of a bile
leak, a cholangiogram is usually obtained to confirm the diagnosis, further
define the complication, and perform an intervention if needed (eg, biliary
stent placement) [1,6,7,18,25,29]. For patients with suspected biliary
obstruction, the approach to care is outlined in the algorithm (algorithm 1).  
Selecting a method for cholangiogram is determined by the type of biliary
reconstruction, the likelihood of therapeutic intervention, and the available
expertise. For patients with suspected biliary complication based on
symptoms, laboratory studies, and ultrasound findings (eg, dilated bile duct),
endoscopic retrograde cholangiography (ERC) or percutaneous transhepatic
cholangiography (PTC) is typically performed. For patients with duct-to-duct
anastomosis, we proceed with ERC for diagnostic confirmation and
therapeutic intervention [30]. We generally reserve PTC for patients in whom
ERC was unsuccessful and for some patients with a Roux-en-Y
choledochojejunostomy. In high-volume centers with experienced advanced
endoscopists, ERC can be successfully performed in some patients with a
Roux-en-Y choledochojejunostomy with a variable stiffness pediatric
colonoscope or with deep small bowel enteroscopy [31-33]. Methods for
performing ERC in patients with Roux-en-Y anatomy are discussed separately.
(See "ERCP in patients with Roux-en-Y anatomy".)
The evaluation of biliary complications in the LT recipient often includes
performing ERC that is simultaneously diagnostic and therapeutic, although
in the nontransplant setting, ERC is usually reserved for therapeutic
indications. (See "Overview of endoscopic retrograde
cholangiopancreatography (ERCP) in adults", section on 'Indications'.)
●Vascular abnormality – If a vascular abnormality such as hepatic artery
stenosis or occlusion is suspected by Doppler study, a computed tomography
scan with angiogram is obtained to confirm the diagnosis [34-36].
●No biliary or vascular abnormality – Transabdominal ultrasound may not
be sufficiently sensitive to detect biliary obstruction (sensitivity of ultrasound,
38 to 66 percent) [10,37,38]. Thus, a normal appearing biliary tree should not
preclude further evaluation when a biliary tract complication is suspected.

67
 For such patients, magnetic resonance cholangiopancreatography (MRCP) is
obtained before proceeding with an invasive cholangiogram (ERC or PTC)
(image 1) [39].
MRCP is also an option for patients in whom ERC and/or PTC cannot be
performed. As examples, ERC may be unsuccessful in patients with Roux-en-Y
choledochojejunostomy and a long Roux limb, and PTC may not be feasible in
patients without dilated biliary ducts. (See "Percutaneous transhepatic
cholangiography".)  
MRCP is a reliable, noninvasive technique for detecting biliary complications after
LT. A meta-analysis found that MRCP had a sensitivity of 96 percent and a
specificity of 94 percent for diagnosing biliary obstruction [39]. In a study including
165 LT recipients with suspected biliary complication, performing ERC when there
was evidence of bile duct obstruction or bile leak on advanced imaging, laboratory
tests, or liver biopsy was associated with higher rates of a high-yield endoscopic
procedure (ie, one in which a clinically important intervention was needed)
compared with diagnostic ERC (ie, performing ERC without preprocedure
advanced imaging such as MRCP) (90 versus 66 percent) [40]. Rates of serious
complications were not significantly different between the groups.
Subsequent testing — For patients with a suspected biliary complication but
without evidence of biliary abnormality on transabdominal ultrasound and MRCP,
liver biopsy is often performed to exclude acute T-cell mediated rejection (TCMR)
or other causes of elevated liver enzymes (eg, recurrence of primary disease). It is
important to exclude biliary obstruction with imaging (eg, ultrasound or MRCP)
prior to liver biopsy because performing liver biopsy in the setting of biliary
obstruction may increase the risk of biopsy-related complications such as bile leak
and peritonitis [41]. (See 'Initial testing' above and "Approach to liver biopsy",
section on 'Complications'.)
The clinical features and diagnosis of acute TCMR in the LT recipient are discussed
in more detail separately. (See "Liver transplantation in adults: Clinical
manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the
liver allograft".)
BILIARY STRICTURES
Incidence and risk factors — Biliary strictures account for approximately 40
percent of all biliary complications after LT, and they have been classified as
anastomotic or non-anastomotic strictures [7]. In a systematic review of 61 studies
including over 14,000 liver transplantations, the overall incidence of biliary
stricture was 13 percent (ie, 12 percent reported among deceased donor recipients
and 19 percent among living donor recipients) [42].

68
Strictures that occur early after LT (eg, within two months after transplantation)
are often related to technical problems during surgery, whereas nonearly
strictures are mainly due to vascular insufficiency, ischemia, and problems with
healing and fibrosis [7,38]. In addition, approximately 20 percent of postoperative
bile leaks progress to biliary strictures [15,43]. (See 'Bile leaks' below.)
Whether the type of biliary reconstruction (duct-to-duct anastomosis or Roux-en-Y
choledochojejunostomy) is a risk factor for biliary strictures has been uncertain
[18,44,45]. (See 'Incidence and risk factors' above.)
Anastomotic strictures
Clinical features — The majority of anastomotic biliary strictures (ABS) develop
between 2 to 12 months after LT [46]. ABS have been defined as being located
within 5 to 10 mm of the biliary anastomosis and are usually isolated [47]. On
cholangiogram, the stricture typically appears as a thin narrowing in the area of
the biliary anastomosis (image 2A-C).
In some patients, a transient narrowing of the anastomosis may become evident
within one to two months after LT due to postoperative edema and inflammation
[25]. This postoperative narrowing is not a true stricture and does not require
endoscopic intervention unless liver biochemistries are elevated and a biliary
complication is suspected. (See 'When to suspect a biliary complication' above.)
Initial intervention
Goals — The goals of endoscopic intervention are to increase the diameter of the
ABS as demonstrated on cholangiography, to improve flow of bile through the
anastomosis, and to resolve symptoms and laboratory abnormalities associated
with cholestasis (eg, jaundice, cholangitis, elevated liver enzymes) [48].
Frequency and number of endoscopic sessions — The total number of
endoscopic sessions required for stricture resolution usually depends on timing of
stricture development:
●Early stricture (within two months after LT) – Early strictures generally
respond to one session of endoscopic balloon dilation and/or plastic stent
placement. For most patients, the stricture will resolve within three months,
and the anastomosis will remain patent without further intervention.
●Late stricture (≥2 months after LT) – Most patients with late ABS require
periodic endoscopic retrograde cholangiography (ERC) sessions (every three
months) with balloon dilation and long-term stenting (ie, 6 to 12 months).
Stents are usually exchanged at three-month intervals to avoid increased risk
of stent occlusion and bacterial cholangitis. Most patients require several
endoscopic interventions (ie, generally ranging from three to five endoscopic
procedures) [46,49-62].

69
Technique — During the initial endoscopic session, we perform the following
interventions (see "Overview of endoscopic retrograde cholangiopancreatography
(ERCP) in adults" and "Endoscopic biliary sphincterotomy"):
●Place a guidewire across the stricture
●Perform biliary sphincterotomy to facilitate stent placement
●Dilate the stricture using balloons with diameters ranging from 6 to 8 mm
●Place one to three plastic stents (size range: 7 to 11.5 Fr) in a parallel fashion
across the stricture

After the index procedure, ERC is repeated in approximately three months for the
following interventions: the previously-placed stents are removed, the stricture is
examined and dilated if needed, and new stents are replaced across the stricture if
they are still warranted. An increasing number of stents are generally used at each
subsequent endoscopic session to achieve stricture resolution.

Outcomes — Endoscopic therapy with plastic stent placement has been associated

with long-term stricture resolution for most patients with ABS [46,55,58,59,61-64].
In a systematic review of eight studies including 440 patients with ABS, endoscopic
therapy with placement of multiple plastic stents for 12 months or longer was
associated with stricture resolution rates of 97 percent, with a stricture recurrence
rate of 2 percent after mean follow-up ranging from 11 to 40 months [49,59,64].
Most patients with stricture recurrence were successfully managed with
endoscopic therapy with repeat plastic stenting. In a subsequent study including
56 patients with ABS, a course of endoscopic therapy with plastic stenting that
required a median of four ERCs was associated with a stricture resolution rate of
98 percent [63]. ERC-related adverse events occurred in three of 56 patients (5
percent). After a median follow-up of nearly six years after stent removal, three of
50 patients (6 percent) had recurrent ABS. All three patients were successfully
treated with endoscopic therapy and were asymptomatic after further median
follow-up of nearly six years.
Strategies to reduce the number of stent exchanges have included a multi-stenting
technique with stent exchange for selected indications (eg, biliary obstruction). In a
study of 83 patients with ABS who had ERC with stenting, a maximum of nine
plastic stents were placed during the index procedure [64]. ERC was repeated if
biliary obstruction developed, if two or fewer stents remained, or after one year if
three or more stents were in place. This approach was associated with stricture
resolution rate of 94 percent, while four patients (6 percent) required surgery
(hepaticojejunostomy). After a median follow-up of 11 months, two patients (3
percent) required repeat ERC for recurrent ABS.

70
Subsequent intervention — For patients who do not respond to ERC-guided
stricture dilation and plastic stenting or who have recurrent ABS after responding
to an initial course of endoscopic therapy, subsequent options include:
●Repeat course of endoscopic therapy – Repeat endoscopic therapy with
plastic stent placement has been associated with long-term success. In a
study of 24 patients with recurrent ABS related to liver transplantation, 20
patients (83 percent) had long-term resolution of the stricture following at
least one additional course of endoscopic therapy [65].
●Covered self-expandable metal stent (SEMS) placement – Temporary
placement (approximately 4 to 12 months) of covered SEMS is an option for
patients who do not respond to plastic stent placement. Use of covered SEMS
requires fewer stent exchanges than plastic stents; however, data on the risk
of stent migration and other outcomes have been mixed [59,66-68]. In a
systematic review of four trials including 205 patients with ABS after liver
transplantation, there were no significant differences in rates of stricture
resolution, stricture recurrence, and overall adverse events in patients
treated with covered SEMS compared with plastic stents [68]. In another
systematic review of 10 studies including 200 patients with ABS, covered
SEMS placement was associated with stricture resolution rates of 82 percent
as initial therapy and 78 percent as subsequent therapy when the stenting
duration was three months or longer [59]. However, the stent migration rate
was 16 percent. In a subsequent study including 41 patients who were
followed for five years after either removal of covered SEMS or observed
stent migration, rates for remaining stent-free at five years were 49 percent
overall and 61 percent among 31 patients with over four months of covered
SEMS indwelling time [67]. In 28 patients with stricture resolution after SEMS
removal or observed migration after a median of five months stent
indwelling time, the rate of no stricture recurrence at five years was 72
percent. Serious adverse events were reported in 16 patients (39 percent),
and the most commonly reported event was cholangitis.
●Non-endoscopic interventions – Endoscopic therapy for ABS may be
unsuccessful due to any of the following:
•For some patients with fibrotic and/or angulated ABS, the guidewire
cannot be placed across the stricture during ERC, a step that is necessary
prior to dilation and stent placement [51,53,55,69,70]. Some patients
require surgery for definitive therapy [71].
•For patients with Roux-en-Y choledochojejunostomy, ERC may be
unsuccessful, despite use of small bowel enteroscopy or other advanced
endoscopic approaches. In such patients, percutaneous transhepatic

71
 cholangiography (PTC) and stricture dilation can be performed by
interventional radiology, followed by placement of a percutaneous
transhepatic catheter [72]. (See "ERCP in patients with Roux-en-Y
anatomy".)

Surgical revision may ultimately be required in patients with strictures that are
refractory to endoscopic and/or percutaneous treatment. A Roux-en-Y
choledochojejunostomy is usually performed in patients with duct-to-duct
anastomosis. For patients who already have a Roux-en-Y anastomosis,
repositioning the bile duct of the graft to a well-vascularized area may be required.

Monitoring after endoscopic therapy — After stricture resolution, we monitor

patients periodically with liver enzymes (aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase, and total bilirubin) (eg, every one to three
months). If liver enzymes are elevated over baseline values, magnetic resonance
cholangiography is obtained for further evaluation. Patients with ABS require long-
term surveillance and clinical follow-up since strictures may recur. Based on clinical
observation and experience, risk factors for recurrence include initial presentation
>6 months after LT and very tight strictures.
Nonanastomotic strictures
Incidence and etiology — Non-anastomotic biliary strictures (NABS) account for
10 to 25 percent of all stricture complications after LT, with a reported incidence
ranging from 0.5 to 10 percent [22,24,29,50,73-75].  
NABS result mainly from hepatic artery thrombosis or other forms of ischemia.
Less commonly, they can be due to recurrence of the underlying disease such as
primary sclerosing cholangitis. Impaired blood supply may cause injury to the
peribiliary glands and vascular plexus. Damage to these structures has been
associated with the development of NABS after transplantation [76]. NABS are
more common when donor organs have been retrieved after cardiac death.
(See "Liver transplantation in adults: Deceased donor evaluation and selection",
section on 'Donation after circulatory death'.)
Clinical features
●Timing – NABS usually develop within three to six months after LT, although
they can present up to one year following surgery [50,74].
●Location and appearance – NABS appear as an irregularity or narrowing of
the lumen of the intra- or extrahepatic duct, and NABS have been defined as
being located at least 1 cm proximal to the anastomosis [47,77]. There may
be multiple strictures involving the hilum of the liver and intrahepatic ducts,
causing a cholangiographic appearance that resembles primary sclerosing
cholangitis. Biliary sludge can accumulate proximal to the strictures, leading
72
 to the formation of casts [78]. This may predispose the patient to develop
recurrent episodes of cholangitis. (See 'Bile duct casts' below.)
Management — Endoscopic therapy for NABS typically consists of ERC and
stricture dilation with a 4 to 6 mm balloon, followed by sphincterotomy and
placement of plastic stents (size range: 10 to 11.5 Fr). Plastic stents are replaced
every three months for approximately 6 to 12 months, and usually these strictures
may require prolonged treatment including balloon dilatations and removals of
casts and debris [50].
NABS are often challenging to treat because they may be multiple, diffuse, and/or
involving small intrahepatic ducts that may be difficult to reach endoscopically
[47]. Approximately 50 percent of patients have a long-term response to
endoscopic therapy with stricture dilation and stent placement [1,50,78-81]. Some
patients may require other interventions for treating NABS such as PTC or surgical
revision (eg, conversion of duct-to-duct anastomosis to hepaticojejunostomy).
However, up to 50 percent of patients experience progressive disease despite
endoscopic therapy, leading to retransplantation or death [6,50,74,78]. Diffuse
intrahepatic bile duct strictures have been associated with increased risk of poor
graft survival and in many instances will require retransplantation for patients who
are suitable candidates. (See "Liver transplantation in adults: Patient selection and
pretransplantation evaluation".)
As an example, in a study including 81 patients with NABS, 28 patients (35 percent)
underwent interventional treatment (ERC, PTC, or surgery) [78]. Intervention was
associated with improvement in liver enzymes; however, other outcomes were not
reported for this subgroup of patients. Among 59 patients with NABS and
radiologic follow up after a median of nearly two years, 28 patients (42 percent)
had progressive biliary abnormalities on cholangiography [78]. Cirrhosis or
advanced fibrosis developed in 23 patients (28 percent). Although graft survival
was compromised (73 percent at five years), patient survival was not affected.
Thirteen patients (16 percent) underwent liver retransplantation.
BILE LEAKS
Incidence and etiology — Bile leaks may originate from the anastomosis, the
cystic duct, or from the cut surface of the liver (for recipients of a living donor liver)
(image 3). Bile leaks are often related to technical issues such as lack of perfusion
from the hepatic artery and tension at the anastomosis [48]. In a systematic review
of 61 studies, bile leak rates for recipients of deceased donor liver transplantation
were 7.8 percent and for recipients of living donor liver transplantation (LDLT)
were 9.5 percent [82].
Bile leak following liver transplant is a risk factor for developing biliary strictures
and thus requires prompt intervention [9].
73
Clinical features and diagnosis — Most bile leaks develop within four weeks after
LT and usually occur at the anastomotic site. Bile leaks are suspected in patients
with abdominal pain, peritonitis, and/or jaundice.
The diagnosis of a bile leak can usually be confirmed with a transabdominal
ultrasound that demonstrates a fluid collection. Magnetic resonance
cholangiopancreatography (MRCP) can also detect a bile leak if transabdominal
ultrasound is nondiagnostic. Hepatobiliary scintigraphy scanning, which has a
sensitivity of approximately 50 percent and a specificity of approximately 80
percent, may also be useful for evaluating suspected bile leaks when other
imaging studies are equivocal [83].
Management — The goal of endoscopic therapy is to eliminate the transpapillary
pressure gradient, thereby permitting preferential transpapillary bile flow rather
than extravasation at the site of the leak.

Endoscopic management of bile leaks is informed by the type of biliary

anastomosis and severity of the bile leak (eg, size of fluid collection):

●Patients with duct-to-duct anastomosis – For recipients with duct-to-duct

anastomosis and bile leak, ERC-guided placement of a plastic, transpapillary
biliary stent, with or without biliary sphincterotomy is performed because this
approach is effective for resolving most bile leaks [1,84-86]. The duration of
plastic stenting is approximately two months because of the potential risk of
delayed healing related to immunosuppression [6]. Stent exchange is
required only if recurrent biliary obstruction is suspected (eg, jaundice,
elevated liver enzymes). After two months of stenting, most leaks have
healed, and the stent is removed endoscopically.
However, short-duration stenting (two to three weeks) is preferred by some
advanced endoscopists. In our experience, stent removal in two to three
weeks may be too early in some patients, particularly those who are on
multiple immunosuppressive agents. Nevertheless, removing the stent in
four to six weeks may be reasonable for patients with complete resolution of
symptoms and who are not receiving glucocorticoids.
For some patients with small or low-grade leaks (ie, a leak that requires near
complete intrahepatic filling to demonstrate contrast extravasation), some
advanced endoscopists perform ERC with biliary sphincterotomy alone rather
than ERC with stent placement. However, published data supporting this
approach are lacking. In a study including 80 patients with bile leaks, ERC
with plastic stent placement (with or without sphincterotomy) was associated
with higher rates of bile leak resolution compared with sphincterotomy alone
(94 versus 58 percent) [87]. Endoscopic approaches to managing bile leaks in
74
 the nontransplant setting are discussed separately. (See "Endoscopic
management of complications from laparoscopic cholecystectomy", section
on 'Bile leak'.)
Endoscopic therapy has been effective for managing bile leaks related to LT
[1,6,49,84,85,87]. In a systematic review of 34 studies including 370 LT
recipients with bile leak who were treated with endoscopic biliary stent
placement, 278 patients (82 percent) had complete resolution of the bile leak
[85].
●Patients with Roux-en-Y anatomy – For recipients with Roux-en-Y
hepaticojejunostomy, anastomotic bile leaks are less common. However, for
such patients with a bile leak, ERC is often not feasible due to anatomic
difficulties in reaching the biliary anastomosis. Management usually involves
percutaneous internal to external drainage. Bile leaks in patients with Roux-
en-Y anatomy may require surgical management if less invasive methods for
diverting bile flow are not successful. (See "ERCP in patients with Roux-en-Y
anatomy".)
●Patients with a T-tube – For patients undergoing LT, most centers no
longer use T-tubes (ie, a T-shaped draining tube that is inserted into the
common bile duct and exits through the abdominal wall to the skin surface in
the right upper quadrant). (See "Surgical common bile duct exploration",
section on 'T-tube placement'.)
However, for recipients with a T-tube, small anastomotic leaks can be
diagnosed with a T-tube cholangiogram and managed by leaving the tube
open to drainage without further intervention.
Following removal of a T-tube, some patients will develop a bile leak that
results from delay in T-tube tract maturation due to immunosuppression. A
bile leak should be suspected in patients who develop abdominal pain when
the T-tube is removed.
ERC (with or without sphincterotomy) with placement of biliary stent may be
indicated for such patients, particularly in patients with abdominal pain. An
alternative approach consisting of medical management with analgesics and
observation for up to one week is also reasonable. If symptoms persist,
management with ERC and placement of transpapillary biliary stents is
indicated [1,6,29,49,88]. Surgery or a percutaneous transhepatic approach is
reserved for patients in whom ERC is unsuccessful.
BILE DUCT FILLING DEFECTSFilling defects in the bile duct after LT can be
due to gallstones, sludge, blood clots, casts, and/or migrated stents; most defects
are caused by stones [1]. Reported rates of bile duct filling defects have ranged
from 2 to 10 percent [24,49,86,89]. The potential mechanisms related to the
75
formation of stones, sludge, and casts include bile duct stricture and/or
obstruction, prolonged warm and cold ischemia times, and bacterial infection
[6,25,90,91].
Bile duct stones — Stones usually develop late (>1 year) after LT (image 4). As an
example, in one series of 37 LT recipients with biliary stones, bile duct stones were
identified at a median of 19 months after LT [49]. Following ERC with stone
extraction, the stone recurrence rate was 17 percent after median of six months.
For most patients with biliary stones, one ERC session with biliary sphincterotomy
is effective for clearing the bile duct; however, for some patients, two or more
endoscopic sessions may be required [49,89].
Endoscopic management of bile duct stones and sludge is similar to the
nontransplant setting, and is discussed in more detail separately.
(See "Choledocholithiasis: Clinical manifestations, diagnosis, and management",
section on 'Subsequent evaluation and management' and "Endoscopic
management of bile duct stones: Standard techniques and mechanical
lithotripsy".)
Bile duct casts — Bile duct casts are usually related to ischemic injury (eg, hepatic
artery thrombosis) or diffuse stricture formation in the hilum of the liver graft [92].
Clearance of casts may be difficult to achieve with endoscopic methods. In one
series, combined endoscopic and percutaneous methods were able to successfully
clear the casts in 60 percent of patients [92]. Various combinations of endoscopic
methods including sphincterotomy, balloon and basket extraction, stent
placement, and lithotripsy are often necessary, and many patients will ultimately
require management with percutaneous intervention.

Patients with Roux-en-Y choledochojejunostomy and bile duct stones are typically
managed with percutaneous drainage.

Biliary cast syndrome is an uncommon complication of LT that is characterized by

biliary casts and debris causing biliary obstruction and cholangitis after LT. In two
case series including a total of 1242 LT recipients, reported rates of biliary cast
syndrome were 3 percent [93,94]. The etiology of biliary cast syndrome is not well
understood. Associated risk factors include hepatic artery stenosis and biliary
strictures. Biliary cast syndrome has been associated with limited graft survival.
Several endoscopic interventions have been described with variable success, and
some patients have undergone retransplantation [93].
OTHER COMPLICATIONSOther complications of liver transplantation that
involve the biliary tree include:
●Biloma – In patients with bile duct necrosis secondary to hepatic artery
thrombosis, bilomas can occur due to bile duct rupture and extravasation of
76
 bile into the hepatic parenchyma or the abdominal cavity. Most bilomas occur
in the perihepatic area, outside of the liver. If the biloma occurs in the hepatic
parenchyma and communicates with the biliary tree, it may resolve
spontaneously or, in some cases, be managed with endoscopy and
transpapillary stent placement. However, in this setting, the role of
endoscopy is more diagnostic than therapeutic, as disrupted bile ducts may
not completely communicate with the extrahepatic ducts.
Large bilomas not communicating with the extrahepatic bile ducts are
managed with percutaneous drainage and antibiotics. Surgery is indicated
when the bile leak cannot be effectively controlled with nonsurgical methods.
(See "Endoscopic management of complications from laparoscopic
cholecystectomy", section on 'Biloma'.)
●Sphincter of Oddi dysfunction – Sphincter of Oddi dysfunction (SOD) has
been described in 1 to 7 percent of LT recipients [22,49,84,95,96]. The
pathogenesis is unclear; one hypothesis is that denervation of the common
bile duct in the ampullary region (secondary to surgical intervention) leads to
the development of a hypertonic sphincter, causing dilated ducts and
cholestasis [7,90]. Data have suggested that papillary stenosis and functional
biliary sphincter disorders (as defined by Rome IV criteria) are uncommon in
LT recipients [97,98].
SOD is suspected in patients with cholestasis and a uniformly dilated bile duct
without filling defects; abdominal pain is not usually present. In most studies,
the diagnosis of SOD was based upon clinical suspicion and the response to
biliary sphincterotomy. Other causes of cholestasis or elevated liver enzymes
(eg, acute T-cell mediated rejection) should be excluded. (See "Clinical
manifestations and diagnosis of sphincter of Oddi dysfunction" and "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft", section on 'Diagnostic
evaluation'.)
Management of SOD in LT recipients is similar to the nontransplant setting
(ie, biliary sphincterotomy), and this is discussed separately [95].
(See "Treatment of sphincter of Oddi dysfunction".)
SPECIAL POPULATIONS
Recipients of living donor liver transplantation — Biliary complications after
living donor liver transplantation (LDLT) may be related to surgical factors (multiple
and/or small caliber ducts used for anastomosis, type of reconstruction) and non-
surgical factors (older donor age) [99-103]. (See "Living donor liver transplantation
in adults", section on 'Recipient outcomes'.)

77
For LDLT, many transplantation centers perform duct-to-duct anastomosis rather
than Roux-en-Y choledochojejunostomy because duct-to-duct anastomosis has the
potential advantage of a shorter operation time, no contamination by bowel
contents, and a preserved sphincter of Oddi [20]. However, data have suggested
that the risk of biliary stricture was lower with Roux-en-Y anatomy. In a meta-
analysis of six studies including 1286 recipients of LDLT, 260 patients (20 percent)
developed anastomotic biliary stricture and 118 patients (9 percent) had bile leak.
Roux-en-Y choledochojejunostomy was associated with a lower risk of anastomotic
biliary stricture (ABS) compared with duct-to-duct anastomosis (odds ratio 0.45,
95% CI 0.31–0.64) [104]. Rates of bile leak were not significantly different between
groups.
Management of biliary strictures in recipients of living donor livers is similar to
recipients of deceased donor livers and typically consists of ERC with balloon
dilation and plastic stent placement for patients with duct-to-duct anastomosis.
Reported rates of stricture resolution with this approach have ranged from 50 to
79 percent [58,105-107]. For patients who do not respond to endoscopic therapy or
for those with Roux-en-Y anatomy, percutaneous transhepatic biliary drainage
with stricture dilation is an alternative option [108]. As an example, in a study of
110 patients with LDLT and duct-to-duct anastomosis, 38 patients (35 percent)
developed an anastomotic stricture, and ERC was attempted as initial therapy in all
patients [58]. Thirty-two patients (84 percent) were managed with endoscopic
therapy alone, while six patients required a combination of percutaneous
transhepatic cholangiography initially to cross the stricture, followed by
endoscopic therapy. A median of four endoscopic sessions were required for
stricture resolution. For most patients, strictures remained patent during an
average follow up of 70 months, while eight patients (21 percent) had recurrent
stricture after initial treatment success. All patients with stricture recurrence were
successfully retreated with endoscopic therapy. (See 'Biliary strictures' above.)
Use of covered self-expandable metal stents (SEMS) has been reported as an
alternative for managing biliary complications in LDLT recipients. In a small cohort
of 13 LDLT recipients with biliary strictures with median follow up of 15 months,
covered SEMS placement was associated with stricture resolution rate of 92
percent [109].
Living liver donors — Living liver donors may experience biliary complications
following donor hepatectomy. Data from the Adult-to-Adult Living Donor Liver
Transplantation Cohort consortium on liver donor outcomes included two studies
with total of 1133 liver donors. The reported rate for overall biliary complications
was 10 percent and for bile leak was 9 percent [110-112]. Biliary complications in
liver donors are seen more often with right lobe donation than with left lobe

78
donation, and the management is similar to that described for liver
transplantation recipients. (See "Living donor liver transplantation in adults".)
ENDOSCOPY-RELATED COMPLICATIONSThe risks of advanced
endoscopic interventions are generally regarded as similar for LT transplant
recipients and nontransplant patients. For LT recipients, the estimated overall
complication rates of up to 9 percent have been reported [1,113]. The most
common complications are pancreatitis, cholangitis, and sphincterotomy-related
bleeding. Complications of endoscopic retrograde cholangiopancreatography are
discussed in more detail separately:
●(See "Overview of endoscopic retrograde cholangiopancreatography (ERCP)
in adults", section on 'Complications'.)
●(See "Post-endoscopic retrograde cholangiopancreatography (ERCP)
pancreatitis".)
●(See "Post-endoscopic retrograde cholangiopancreatography (ERCP) septic
complications".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Incidence and risk factors – The estimated incidence of biliary
complications related to LT ranges from 10 to 15 percent in recipients of
deceased donor livers and from 15 to 30 percent in recipients of living donor
livers. Risk factors for biliary complications are listed in the table (table 1).
(See 'Incidence and risk factors' above.)
●Evaluation – Biliary complications after LT are suspected in recipients with
elevations in liver enzymes, primarily in a cholestatic pattern (ie,
disproportionate elevation of alkaline phosphatase compared with
aminotransferases) with or without symptoms (eg, fever, right upper
quadrant abdominal pain, jaundice). For such patients, the evaluation begins
with a transabdominal liver ultrasound with a Doppler study, and further
testing is informed by ultrasound findings. (See 'Evaluation' above.)
For patients with suspected biliary obstruction, the approach to care is
outlined in the algorithm (algorithm 1).
●Anastomotic biliary strictures – For most patients with anastomotic biliary
stricture (ABS) and duct-to-duct anastomosis, we suggest ERC-guided
intervention rather than percutaneous transhepatic cholangiography (PTC)-
guided intervention or surgery (Grade 2C). An ERC-guided approach with
stent placement has been associated with long-term stricture resolution.
(See 'Biliary strictures' above.)
79
ERC-guided intervention typically includes biliary sphincterotomy, stricture
dilation, and plastic stent placement. PTC is reserved for patients in whom
ERC is unsuccessful or for some patients with Roux-en-Y
choledochojejunostomy. (See "ERCP in patients with Roux-en-Y anatomy".)
ERC with routine plastic stent exchange is performed approximately every
three months for a total stent indwelling time of 6 to 12 months. Most
patients will require a total of three to five endoscopic sessions. After
stricture resolution, we monitor patients with liver enzymes every one to
three months and obtain imaging (eg, magnetic resonance cholangiogram
[MRC]) when there is a rise in liver enzymes over baseline values.
●Nonanastomotic biliary strictures – For most patients with non-
anastomotic biliary strictures (NABS) for which endoscopic therapy would be
feasible, we suggest ERC-guided balloon dilatation and plastic stent
placement rather than PTC-guided or surgical intervention (Grade 2C).
However, NABS are challenging to treat endoscopically, and some patients
will require PTC-guided intervention, surgical revision, or retransplantation if
progressive disease with diffuse biliary stricturing develops.
(See 'Nonanastomotic strictures' above.)
●Bile leak – For most patients with duct-to-duct anastomosis complicated by
a bile leak after LT, we suggest ERC-guided intervention rather than PTC-
guided intervention or surgery (Grade 2C). An ERC-guided approach has
been effective for resolving bile leaks.
We perform ERC with placement of a transpapillary plastic stent, with or
without biliary sphincterotomy. Stents generally remain in place for
approximately two months to allow for healing of the ductal defect. ERC is
then repeated to confirm that the bile leak has resolved and to remove the
stents. (See 'Bile leaks' above.)
●Endoscopy-related complications – The risks of endoscopy-related
complications for LT recipients are similar to those reported the
nontransplant setting. The most common complications are pancreatitis,
cholangitis, and sphincterotomy-related bleeding:
•(See "Overview of endoscopic retrograde cholangiopancreatography
(ERCP) in adults", section on 'Complications'.)
•(See "Post-endoscopic retrograde cholangiopancreatography (ERCP)
pancreatitis".)
•(See "Post-endoscopic retrograde cholangiopancreatography (ERCP)
septic complications".)

80
Liver transplantation in adults: Long-term
management of transplant recipients
Authors:
Paul J Gaglio, MD
Scott J Cotler, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 18, 2021.
INTRODUCTIONLiver transplantation is the treatment of choice for
appropriately selected patients with end-stage liver disease. With improved long-
term survival, more patients are being cared for outside of a transplant center,
requiring more widespread familiarity with the complications seen in this patient
population. Several medical problems are routinely encountered by clinicians
caring for patients after liver transplantation. These include:
●Acute or chronic rejection.
●Complications of immunosuppression including hypertension, renal
insufficiency, infection, malignancy, a variety of dermatologic conditions, and
metabolic diseases such as diabetes mellitus, obesity, hyperlipidemia, and
bone disease.
●Biliary complications.
●Recurrence of the primary liver disease.
This topic will review the general management of patients following liver
transplantation and the nonimmunologic complications of liver transplantation.
Acute and chronic rejection, infectious complications of liver transplantation,
recurrent hepatitis, and recurrent hepatocellular carcinoma are discussed in detail
elsewhere. (See "Liver transplantation in adults: Clinical manifestations and
diagnosis of acute T-cell mediated (cellular) rejection of the liver
allograft" and "Infectious complications in liver transplantation" and "Hepatitis C
virus infection in liver transplant candidates and recipients" and "Liver
transplantation for chronic hepatitis B virus infection" and "Liver transplantation
for hepatocellular carcinoma".)
ROLE OF THE PRIMARY CARE CLINICIANImmediately following liver
transplantation, patients are managed by transplant surgeons and/or transplant
hepatologists. However, after several months, the general medical care of a liver
81
transplant recipient is often transferred back to the patient's primary care clinician
[1]. While practices vary in different transplant centers, the transplant center
typically continues to manage the administration of immunosuppressive agents, to
treat recurrent liver disease, and to manage biliary complications. In addition, the
transplant center may also manage some of the complications of
immunosuppression, such as renal disease. The patient's other medical issues,
including other complications of immunosuppression, are often managed by the
primary care clinician.
PREVENTIVE MEDICINEGeneral health maintenance for liver transplant
recipients is similar to that for the general population (see "Overview of preventive
care in adults"). However, certain disorders require more intensive screening
because they are more common following liver transplantation (eg, hypertension,
diabetes, dyslipidemia, renal disease, and malignancy). In addition, because there
are numerous drugs that interact with immunosuppressive agents, at each visit
patients should be asked about any new medications or supplements they are
taking (including over-the-counter medications) and be reminded not to start any
new medications or supplements without first talking to their clinicians (table 1).
(See 'Immunosuppression' below.)
Screening for nonmalignant disease — Our approach to screening for
nonmalignant diseases in liver transplant recipients includes:
●General assessment: Annual history and physical examination, annual
dental evaluations in addition to routine (twice-yearly) cleanings.
●Hypertension: For the first six months following transplantation, self-
monitoring every week and blood pressure monitoring by a healthcare
provider every month. In patients without hypertension after six months,
blood pressure monitoring by a healthcare provider every six months.
(See "Overview of hypertension in adults", section on 'Diagnosis'.)
●Diabetes mellitus: Screening every six months (typically with either a fasting
plasma glucose or a hemoglobin A1C), and, in patients with diabetes, an
annual eye examination. (See "Screening for type 2 diabetes mellitus", section
on 'A suggested approach'.)
●Dyslipidemia: Annual fasting lipid profile. (See "Measurement of blood lipids
and lipoproteins".)
●Cardiovascular disease: We generally perform stress testing every five years
in patients with risk factors for coronary artery disease and more frequently
in patients with preexisting coronary artery disease. However, not all
insurance covers cardiovascular disease screening in this setting, which may
influence whether testing is performed. Exercise stress testing is preferred
for those who are able to do the test. For those unable to do exercise stress
82
 testing, adenosine and dobutamine stress tests are alternatives. (See "Stress
testing for the diagnosis of obstructive coronary heart disease".)
●Renal disease: During the first year, urinalysis, microalbumin, and
determination of the creatinine/glomerular filtration rate every two to three
months. After the first year, we measure creatinine/glomerular filtration rate
every three to six months. (See "Diagnostic approach to adult patients with
subacute kidney injury in an outpatient setting", section on 'Evaluation'.)
●Metabolic bone disease: Bone mineral density measurement prior to
transplantation and every other year after transplantation. (See "Overview of
dual-energy x-ray absorptiometry".)
Screening for malignancies — Both skin cancer and non-skin malignancies are
more common following liver transplantation when compared to the general
public. As a result, we perform intensive screening in this population. (See 'De
novo malignancy' below.)
Immunizations — Immunizations recommended for patients receiving solid
organ transplantations include vaccinations for influenza, pneumonia, and
hepatitis A and B virus. In addition, the recombinant zoster vaccine (RZV) can be
given posttransplantation (table 2).
Because immunosuppression can affect the patient's ability to mount an immune
response to vaccinations, it is recommended that many of the vaccinations (eg,
hepatitis A and B vaccines) be administered prior to transplantation when possible.
In addition, live virus vaccinations should be avoided. The role of immunizations in
patients undergoing solid organ transplantation is discussed in detail elsewhere.
(See "Immunizations in solid organ transplant candidates and recipients".)
Physical activity — Increasing physical activity provides a potential means to
reduce metabolic complications after liver transplantation. In a prospective study,
lack of physical exercise was associated with abdominal obesity in liver transplant
recipients [2]. Another study showed a reduction in percent body fat in liver
transplant patients who participated in a structured 12-week exercise program [3].
A retrospective analysis of patients greater than one-year post-transplant found an
inverse association between exercise intensity and metabolic syndrome [4].
(See 'Metabolic syndrome' below.)
Recommendations regarding alcohol consumption — All patients should be
advised to avoid alcohol consumption following liver transplantation. Patients who
consume excessive alcohol following liver transplantation have lower survival rates
than those who do not, regardless of the indication for liver transplantation. In a
study of 441 patients who underwent liver transplantation for various indications,
the five-year survival rates for those with and without sustained excessive alcohol

83
consumption (>20 g/day for females and >30 g/day for males (figure 1)) were 49
and 75 percent, respectively [5].
In particular, it is recommended that patients with alcoholic liver disease abstain
from alcohol completely [6]. Prevention and management of recurrent alcohol use
in patients with alcoholic liver disease is presented separately. (See "Liver
transplantation for alcoholic liver disease", section on 'Recurrent harmful alcohol
use'.)

Studies have not addressed whether light to moderate alcohol consumption

following liver transplantation for non-alcohol-related indications is safe. As a
result, we take a conservative approach and suggest that patients abstain from
alcohol following liver transplantation.

IMMUNOSUPPRESSIONMost transplant centers use either two or three

agents to prevent allograft rejection in the immediate post-transplantation period
(table 3). This typically involves a combination of a glucocorticoid such
as prednisone, a calcineurin inhibitor (CNI) such as tacrolimus or cyclosporine, and
a third agent such as mycophenolate mofetil. Once patients achieve adequate liver
function and are free from rejection for six months, ongoing immunosuppression
can often be with monotherapy, typically a CNI. Some centers
use sirolimus or everolimus as part of a calcineurin inhibitor sparing regimen in
selected patients after the immediate post-transplant period. Mycophenolate
mofetil may be continued in patients at increased risk for acute or chronic
rejection. (See "Liver transplantation in adults: Overview of immunosuppression".)
All immunosuppressive agents have undesired effects, the spectrum of which vary
and in some cases overlap (table 3). Common side effects include hypertension,
diabetes mellitus, and renal dysfunction. In addition, there are numerous
medications that may interact with immunosuppressive agents, leading to
changes in the serum concentrations of the immunosuppressants (table 1). In
order to decrease the risk of graft rejection or toxicity due to drug interactions,
potential interactions should be reviewed prior to starting any new medications or
supplements. If there are any concerns about the safety of a given medication or
supplement, they should be discussed with the patient's transplant center prior to
initiation.
The approach to immunosuppression and issues related to acute and chronic
rejection following liver transplantation are discussed in detail elsewhere.
(See "Liver transplantation in adults: Overview of immunosuppression" and "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft" and "Liver transplantation in
adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)
84
COMPLICATIONS OF IMMUNOSUPPRESSION
Infections — The leading cause of mortality following liver transplantation is
infection. In one autopsy series, infections accounted for 64 percent of 321 deaths
[7]. Serious infections occur most frequently within the first three months post-
transplantation, which is the time of greatest immunosuppression [7,8]. However,
patients with poor graft function who require increased levels of
immunosuppression to treat recurrent cellular rejection or chronic rejection
continue to be at risk for opportunistic infections [9]. A variety of pathogens can
cause infections post-transplantation, including bacteria, fungi, and viruses (figure
2). (See "Infectious complications in liver transplantation".)
Liver transplant recipients who develop a fever or other signs of infection require
urgent evaluation because even common infections, such as pharyngitis or urinary
tract infections, can rapidly progress to sepsis with multiorgan failure [1]. In
addition, patients with signs of sepsis should be transferred to a transplant center
whenever possible. (See "Sepsis syndromes in adults: Epidemiology, definitions,
clinical presentation, diagnosis, and prognosis", section on 'Definitions'.)
Our approach to patients with a fever following liver transplantation begins with a
thorough history and physical examination (table 4). Laboratory and radiographic
evaluation consists of complete blood count, comprehensive metabolic panel,
urinalysis, urine culture, sputum Gram stain, blood cultures, and chest radiograph.
Abnormalities on chest radiograph or persistent pulmonary symptoms are
evaluated by chest computed tomography (CT) and/or bronchoscopy, and
abdominal symptoms are evaluated by expanded abdominal imaging such as CT
or magnetic resonance imaging with magnetic resonance
cholangiopancreatography (MRCP).

Other testing is based upon the clinical setting:

●Patients with arthralgia, fever, and leukopenia, recent treatment for

rejection, or those within 90 days of transplant are tested for
cytomegalovirus (CMV) by quantitative polymerase chain reaction.
(See "Overview of diagnostic tests for cytomegalovirus infection".)
●An abdominal ultrasound with Doppler examination is performed in patients
with cholestatic laboratory abnormalities or known biliary disease to evaluate
for evidence of biliary obstruction and for hepatic artery thrombosis. We
proceed to an MRCP or endoscopic retrograde cholangiopancreatography
when there is clinical suspicion of a biliary stricture. (See "Liver
transplantation in adults: Endoscopic management of biliary complications",
section on 'Evaluation' and "Acute cholangitis: Clinical manifestations,
diagnosis, and management", section on 'Diagnostic approach'.)
85
 ●A CT scan of the head and a lumbar puncture for patients presenting with
headache and fever without an identified source for the fever, since
meningeal signs are frequently absent in immunosuppressed transplant
patients with meningitis. (See "Clinical features and diagnosis of acute
bacterial meningitis in adults".)
If a source of infection is identified, appropriate treatment should be initiated
immediately and antibiotic choice may be guided by the patient's previous
microbiologic culture and sensitivity data. (See "Infectious complications in liver
transplantation", section on 'Time course of infections' and "Infection in the solid
organ transplant recipient", section on 'Evaluation and management'.)  

However, not all fevers in transplant recipients are due to infection. Graft rejection
or the development of malignancy should also be considered. Liver biopsy is
indicated if the above studies fail to identify a source for the fever.

Metabolic syndrome — The metabolic syndrome is common among patients who

have undergone liver transplantation [10]. It is defined by a combination of
hypertension, insulin resistance/diabetes, dyslipidemia, and obesity (table 5). Liver
transplant recipients may meet criteria for the metabolic syndrome prior to
transplantation, in which case immunosuppressive medications can exacerbate
the problem. In addition, many patients will develop the metabolic syndrome de
novo. A study of 252 liver transplant patients found that 52 percent had metabolic
syndrome following transplantation, compared with only 5 percent prior to
transplantation [11]. A second study with 455 liver transplant recipients found that
the rate of obesity increased from 24 percent four months after transplantation to
41 percent three years after transplantation [12].
Immunosuppressant use is associated with all aspects of the metabolic syndrome
(table 3):
●Hypertension: Glucocorticoids, cyclosporine, tacrolimus
●Diabetes mellitus: Glucocorticoids, tacrolimus >cyclosporine
●Obesity: Glucocorticoids, cyclosporine
●Dyslipidemia: Glucocorticoids, sirolimus, cyclosporine >tacrolimus
It is important to recognize and treat the components of the metabolic syndrome
because it is strongly associated with increased morbidity and mortality in liver
transplant recipients [13]. (See "Metabolic syndrome (insulin resistance syndrome
or syndrome X)".)
Hypertension — Approximately 65 to 70 percent of liver transplant recipients
develop hypertension following transplantation [14-16]. In addition, some patients
lose the normal circadian blood pressure patterns and develop nocturnal
hypertension [17]. Because hypertension is common post-transplantation, we
86
suggest that for the first six months following transplantation, the patient's blood
pressure be assessed at home with self-monitoring every week and by a
healthcare provider every month. In patients without hypertension after six
months, blood pressure monitoring should be performed by a healthcare provider
every six months. (See "Overview of hypertension in adults", section on
'Diagnosis'.)
The cause of hypertension is multifactorial but is mostly related to the use of
calcineurin inhibitors (CNIs; eg, cyclosporine or tacrolimus) and glucocorticoids
[18]. CNIs act by increasing both systemic vascular resistance and renal vascular
resistance (primarily affecting the afferent arterioles) [19]. How this occurs is
incompletely understood, but increased release of vasoconstrictors, particularly
endothelin, has been thought to play an important role. (See "Pharmacology of
cyclosporine and tacrolimus", section on 'Hypertension' and "Kidney
transplantation in adults: Hypertension after kidney transplantation".)
By comparison, glucocorticoids are usually not a major risk factor for chronic
hypertension in transplant recipients because of rapid dose reduction. However,
they may play a contributory role, and gradual withdrawal of glucocorticoid
therapy results in a fall in blood pressure in most patients. (See "Major side effects
of systemic glucocorticoids".)
There are conflicting data concerning the frequency of hypertension induced
by tacrolimus compared with cyclosporine. Two long-term trials, the European
FK506 Multicentre Liver Study Group and the US Multicenter FK506 Liver Study
Group, found no difference in the frequency of hypertension between the two
drugs [20,21]. By comparison, other trials in liver transplant recipients have found
a lower incidence of late-onset hypertension with tacrolimus [22,23]. A meta-
analysis of randomized trials in heart transplant recipients included eight studies
that compared tacrolimus and cyclosporine with regard to hypertension [24].
Patients who received tacrolimus were at decreased risk for developing
hypertension compared with patients who received cyclosporine (relative risk 0.80;
95% CI 0.69-0.93). A lesser degree of weight gain and lower doses
of prednisone used with tacrolimus may have been contributing factors [22].
Because of inconclusive data among liver transplant recipients, switching from
cyclosporine to tacrolimus solely for treating hypertension is not recommended.
(See "Pharmacology of cyclosporine and tacrolimus" and "Cyclosporine and
tacrolimus nephrotoxicity".)
Most transplant centers approach hypertension with a stepwise approach,
including limiting salt intake, assessing CNI serum levels, and modulating CNI dose
if the level is inappropriately elevated. If antihypertensive medications are
required, we suggest initiating therapy with a calcium channel blocker since part of

87
the mechanism of hypertension is thought to be due to renal arteriolar
vasoconstriction (table 6). Amlodipine, felodipine, and nicardipine are preferred as
first-line agents since they are long-acting, minimally interact with CNIs, and have
limited side effects. First-generation calcium channel blockers
(eg, nifedipine or verapamil) may inhibit cytochrome P450, increasing CNI levels,
and should be avoided.
Up to 30 percent of patients will require more than one agent to control their
blood pressure [25]. If calcium channel blockers are not effective or are not
tolerated, we suggest the addition or substitution of a cardioselective beta blocker
such as metoprolol or atenolol (nonselective beta blockers may decrease portal
blood flow). An angiotensin-converting enzyme (ACE) inhibitor or angtioensin-2
receptor blocker (ARB) can also be used in patients with difficult-to-control
hypertension. ACE inhibitors and ARBs are preferred in patients with diabetes [26].
However, ACE inhibitors and ARBs may induce hyperkalemia in patients taking
CNIs, and the potential risks with ACE inhibitors/ARBs are discussed in more detail
separately. (See "Moderately increased albuminuria (microalbuminuria) in type 2
diabetes mellitus", section on 'ACE inhibitors and ARBs' and "Kidney
transplantation in adults: Hypertension after kidney transplantation", section on
'Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and
other agents'.)
Diuretics are not used as primary therapy for hypertension due to concerns
related to the potential to exacerbate electrolyte disturbances and dyslipidemias
induced by CNIs but sometimes are used in combination with other agents.
(See "Pharmacology of cyclosporine and tacrolimus", section on 'Hypertension'.)
A goal blood pressure of less than 125 to 130/<80 mmHg is reasonable for liver
transplant recipients since most have multiple risk factors for cardiovascular
disease (eg, diabetes, obesity, dyslipidemia). (See "Treatment of hypertension in
patients with diabetes mellitus".)
Diabetes mellitus — Glucocorticoids, cyclosporine, tacrolimus, and weight gain
predispose to the development of diabetes following liver transplantation. The risk
also appears to be increased in patients transplanted for hepatitis C virus [27,28].
To screen for diabetes, we obtain fasting plasma glucose levels or hemoglobin A1C
every six months. We also obtain annual eye examinations in patients with
diabetes mellitus. (See "Screening for type 2 diabetes mellitus".)
Patients who are diabetic prior to transplantation frequently require insulin
following transplantation. In addition, 5 to 30 percent of recipients develop de
novo diabetes [14,29-35]. A meta-analysis that included 16 studies with 3813 liver
transplant recipients found that the risk of developing de novo insulin-requiring
diabetes was significantly higher among patients treated

88
with tacrolimus compared with those treated with cyclosporine (relative risk 1.38;
95% CI 1.01-1.86) [36]. (See "Kidney transplantation in adults: Posttransplantation
diabetes mellitus".)
The development of diabetes does not adversely affect survival in the first year
following transplantation, but it is associated with decreased survival after 5 to 10
years [37-39]. This was illustrated in a series in which 26 of 497 liver transplant
recipients (5 percent) who developed diabetes mellitus post-transplantation were
compared with matched nondiabetic post-transplantation controls [37]. The total
number of days in the hospital, graft survival, renal function, and the type and
number of infections were similar between the groups during the subsequent 12
months. However, increased 10-year mortality related to infection was reported in
a cohort of liver transplant recipients with sustained new-onset diabetes compared
with a group of patients with established diabetes pretransplant, transient post-
transplantation diabetes, or without diabetes [38]. Similarly, in a database study
that looked at more than 35,000 patients who received a liver transplant and had
at least five years of follow-up, development of diabetes mellitus post-transplant
was associated with increased mortality (adjusted odds ratio 1.06; 95% CI 1.02-
1.11) [39].
The lack of deleterious effects of diabetes in the first year is important clinically
because diet, weight loss, and tapering of immunosuppressant medications
results in amelioration or resolution of de novo diabetes in many patients. In one
series of 88 patients who were not diabetic prior to liver transplantation, the
prevalence of diabetes fell from 27 percent at one year to 7 percent at three years,
in association with a reduction in the mean daily prednisone dose from 13 to 2 mg
[29]. Furthermore, some patients who remain diabetic on low doses of
glucocorticoids become euglycemic after prednisone withdrawal [40].
Treatment of diabetes post-transplantation includes standard medical and
nutritional therapy, including limiting caloric intake, an appropriate diet with
weight loss, and the initiation of pharmacologic agents for treatment of diabetes
[41] (see "Initial management of hyperglycemia in adults with type 2 diabetes
mellitus"). In the peri- and early postoperative period, insulin is generally required.
In addition, modulating immunosuppression, including lowering or stopping
glucocorticoids, may be of benefit. As steroids are tapered, treatment with lifestyle
modification with or without oral hypoglycemic medications may be possible.
Finally, switching from tacrolimus to cyclosporine in patients with difficult-to-
control diabetes following liver transplantation is also an option [42]. (See "General
principles of insulin therapy in diabetes mellitus".)
Obesity — Patients with end-stage liver disease frequently have a compromised
nutritional status. Despite this, over one-third of patients are obese [43,44].

89
Following transplantation, improved health and treatment with glucocorticoids
or cyclosporine predispose to weight gain. Approximately one-third of patients
who are normal weight at the time of transplantation will become obese following
transplantation [14,44-46]. Body weight tends to increase during the first two years
after transplantation and then stabilizes. As an example, in one series of 774
patients, mean body mass index increased from 24.8 kg/m2 at baseline to 27.0
kg/m2 at year 1, to 28.1 kg/m2 at year 2; there was very little change with
subsequent observations [45]. (See "Obesity in adults: Prevalence, screening, and
evaluation", section on 'BMI-based classifications'.)
The dose of prednisone has been identified as an independent predictor of the
development of obesity [45]. However, once obesity is established, tapering of
prednisone may not lead to weight loss [14]. In addition, patients treated
with cyclosporine are more likely to have weight gain than those who
receive tacrolimus (46 versus 27 percent in one study) [47].
Overweight liver transplant recipients may have great difficulty losing weight.
Excessive weight gain often leads to reduced physical activity, which predisposes
to further weight gain and a sedentary lifestyle. Thus, prevention of excessive
weight gain through patient education, nutritional counseling, and an exercise
program is important for reducing post-transplantation morbidity. (See "Obesity in
adults: Behavioral therapy".)
Treatment of obesity includes caloric restriction, encouraging exercise, and
tapering steroids, with an initial goal of losing one to two pounds per week [1]. If
those measures fail to result in adequate weight loss, additional treatment options
include switching from cyclosporine to tacrolimus and possibly bariatric surgery
[13,48]. Small studies have shown potential for pretransplantation sleeve
gastrectomy in patients with obesity and low MELD scores [49] and for sleeve
gastrectomy at the time of transplantation [50,51], or in the post-transplant period
[52-54]. For example, for patients who had failed a weight loss program, sleeve
gastrectomy at the time of liver transplantation was effective in achieving weight
loss and reducing metabolic complications post-transplant [50]. In a follow-up
report, weight loss and metabolic improvement persisted for >3 years after
combined sleeve gastrectomy and liver transplantation [51].
However, a history of bariatric surgery (particularly Roux-en-Y gastric bypass) was
correlated with adverse outcomes for patients on the liver transplant waiting list.
In a study of 78 patients with a history of bariatric surgery (Roux-en-Y gastric
bypass in most patients) prior to liver transplantation, bariatric surgery was
associated with higher rates of removal from the transplant waiting list or
mortality compared with controls matched for age and liver disease severity (33
versus 10 percent) [55]. In addition, Roux-en-Y gastric bypass may impair access to

90
the biliary tree (which may be required if biliary complications develop post-
transplant) and decreases intestinal drug absorption, which could affect
immunosuppression levels. For these reasons, sleeve gastrectomy is preferred for
liver transplant candidates and recipients who are candidates for a surgical weight
loss intervention. (See "Bariatric operations for management of obesity:
Indications and preoperative preparation" and "Liver transplantation in adults:
Endoscopic management of biliary complications".)
Dyslipidemia — Dyslipidemia is common after liver transplantation, and patients
should have a fasting lipid profile obtained annually [56]. Hypercholesterolemia
develops in 16 to 43 percent of patients and hypertriglyceridemia in 40 to 47
percent; reduced serum HDL-cholesterol is also common [57,58].
Hypertriglyceridemia usually develops within the first month post-transplantation
and then remains stable throughout the first year. By comparison, serum
cholesterol increases gradually and plateaus at six months [58]. Patients with
elevated pretransplantation cholesterol levels are most likely to develop
hypercholesterolemia following transplantation [58]. (See "Measurement of blood
lipids and lipoproteins".)
The hyperlipidemia observed in liver transplant recipients is mostly related to the
side effects of glucocorticoids, cyclosporine, and tacrolimus. Immunosuppression
consisting of tacrolimus monotherapy with early glucocorticoid withdrawal, which
is common at many centers, has been associated with lower rates of
hypercholesterolemia and hypertriglyceridemia at six months post-transplantation
compared with dual therapy with tacrolimus and glucocorticoids [59].
Furthermore, tacrolimus appears to have a less prominent effect on lipids than
cyclosporine [60]. (See "Kidney transplantation in adults: Lipid abnormalities after
kidney transplantation".)
Treatment begins with dietary modification and, if possible, reducing the dose of
or discontinuing glucocorticoids [40]. Another option is
substituting tacrolimus for cyclosporine. In one study of renal transplant
recipients, 53 patients with serum cholesterol concentrations greater than 240
mg/dL (6.2 mmol/L) were randomized to either the continuation of maintenance
cyclosporine or conversion to tacrolimus [61]. Substitution with tacrolimus resulted
in significant reductions in total and LDL-cholesterol levels (by 16 and 25 percent,
respectively) at six-month follow-up, but no change in renal function or glycemic
control.
Dyslipidemia improves in many patients over time if the maintenance dose
of tacrolimus or cyclosporine is low. Thus, medical therapy is rarely indicated early
in the course when steroid doses are relatively high. Treatment is indicated in
patients whose dyslipidemia does not improve with steroid withdrawal. Treatment

91
is similar to treatment in nontransplant recipients. However, treatment is
complicated by interactions of the drugs used to treat dyslipidemia with
immunosuppressive agents (table 1). These interactions can lead to alterations in
immunosuppressant levels and/or increased toxicities, including rhabdomyolysis.
Thus, agents to treat dyslipidemia must be chosen carefully based upon the
patient's immunosuppressive regimen, and immunosuppressant levels should be
monitored if interactions are anticipated (table 7).
Most patients are treated with a statin. Pravastatin and fluvastatin are preferred
due to decreased interactions with immunosuppressants (table 7). The goals of
treatment depend upon whether the patient has a history of cardiovascular
disease or other risk factors for cardiovascular disease. (See "Management of
elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of
cardiovascular disease" and "Hypertriglyceridemia in adults:
Management" and "Management of low density lipoprotein cholesterol (LDL-C) in
the secondary prevention of cardiovascular disease".)
Ezetimibe has also been studied alone or as an adjunct to a statin in liver and
kidney transplant recipients. It has been shown to reduce LDL levels with generally
stable levels of immunosuppression and a low risk of serious side effects.
However, there have been reports of myalgia, rhabdomyolysis, hepatitis, acute
pancreatitis, and thrombocytopenia [62-64]. In addition, studies in patients outside
of the transplant setting have failed to show convincing evidence of clinical
benefits from ezetimibe. (See "Statins: Actions, side effects, and
administration" and "Low-density lipoprotein cholesterol lowering with drugs
other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)
We avoid treatment with cholestyramine because it can raise triglyceride levels
and may significantly impair the absorption of medications, including calcineurin
inhibitors. We also avoid nicotinic acid because it can decrease glucose tolerance
and raise uric acid levels, leading to symptomatic gout in some patients. (See "Low-
density lipoprotein cholesterol lowering with drugs other than statins and PCSK9
inhibitors", section on 'Nicotinic acid (niacin)' and "Low-density lipoprotein
cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section
on 'Bile acid sequestrants'.)
Cardiovascular risk — Because of the high rates of hypertension, diabetes,
obesity, and dyslipidemia following liver transplantation, it is not surprising that
coronary heart disease is also common. A meta-analysis that included 4792
patients following liver transplantation with 28,783 person-years of follow-up
found that the 10-year risk of cardiovascular events was 14 percent and was
particularly high among those with the metabolic syndrome [65]. Factors that have
been associated with cardiovascular events include older age at transplantation,

92
male sex, post-transplantation diabetes, post-transplantation hypertension,
history of coronary artery disease, history of nonalcoholic steatohepatitis, and use
of mycophenolate mofetil (MMF) [12,66,67].  
Liver transplant recipients have a greater risk of cardiovascular death and ischemic
events than age- and sex-matched nontransplanted patients [65]. As an example,
one study compared 1312 liver transplant recipients with age- and sex-matched
controls [68]. The relative risk of death due to cardiovascular disease in liver
transplant recipients was 2.6 (95% CI 1.5-4.0) compared with controls. When
excluding infection, recurrent disease, graft loss due to technical complications,
and de novo malignancy, coronary heart disease represents the most common
cause of death following liver transplantation [69]:
●In a report that described the cause of death in 299 adult liver transplant
recipients who lived for more than three years, 8 out of 38 deaths (21
percent) were due to cardiovascular complications [70].
●Similarly, in a study of 433 patients who survived at least one year after liver
transplantation, cardiovascular events accounted for 18 of 43 non-graft
related deaths (42 percent) [71].
●A study from the Netherlands evaluated cardiovascular morbidity in 37 liver
transplant recipients who survived more than 15 years post-transplantation
[72]. Cardiovascular events including myocardial infarction, angina,
claudication, and transient ischemic attacks occurred in 19 percent of
patients.
As in any patient with cardiovascular disease, modification of risk factors both
before and after liver transplantation is essential to maximize outcomes. Thus,
treatment and prevention of obesity, hyperlipidemia, diabetes, and hypertension
are priorities. At present, no clear guidelines exist related to invasive modalities
(coronary angiography) or noninvasive modalities (cardiac stress testing) to assess
cardiac function and coronary artery patency following liver transplantation. Our
approach is to consider performing exercise or adenosine or dobutamine stress
testing every three to five years in patients with risk factors for coronary artery
disease.
Acute and chronic renal disease — Acute and chronic kidney injuries are
common in liver transplantation. For the first year following transplantation, we
screen patients every two to three months with a urinalysis (including
microalbumin assessment) and determination of the creatinine/glomerular
filtration rate (GFR). After the first year, we measure creatinine/GFR every three to
six months. (See "Diagnostic approach to adult patients with subacute kidney
injury in an outpatient setting", section on 'Evaluation'.)

93
The best data on the incidence of chronic kidney disease come from a cohort study
of almost 37,000 liver transplant recipients who were followed for a median of 36
months [73]. The incidence of chronic kidney disease (defined as an estimated GFR
<30 mL/min per 1.73 m2) was 14 percent at three years and 18 percent at five years
(figure 3). Risk factors for chronic renal failure included calcineurin inhibitor (CNI)
therapy (given in at least 89 percent), older age, lower pretransplant GFR, female
sex, postoperative acute renal failure, baseline diabetes and hypertension,
hepatitis C virus infection, and transplantation before 1998.
Another study evaluated changes in kidney function in 432 patients maintained
on tacrolimus who were followed for a mean of 3.7 years [74]. Estimated GFR
declined ≥30 percent after transplant in 36 percent of patients. Following a decline
during the first six months post-transplantation, mean GFR remained stable for the
duration of follow-up.
The cause of kidney injury is multifactorial. Important contributing factors are
preexisting chronic kidney disease, renal failure prior to liver transplantation,
acute tubular necrosis around the time of transplantation, hypertension, diabetes
mellitus, and CNI toxicity. CNI-related acute renal failure is due to renal
vasoconstriction and improves with dose reduction. Chronic renal disease can also
be induced by these drugs, warranting continued monitoring of the plasma
creatinine concentration and urinalysis. There are conflicting data about whether
chronic nephrotoxicity in liver transplant recipients is more common
with cyclosporine or tacrolimus [20,21,73]. (See "Cyclosporine and tacrolimus
nephrotoxicity" and "Kidney function and non-kidney solid organ transplantation".)
Attempts to prevent or reverse CNI-related chronic kidney disease have been
largely unsuccessful [75]. Several renal-sparing strategies have been proposed,
including reduction or complete withdrawal of the CNI and use of antibody
induction therapy to delay initiation of CNI-based therapy [76,77]. (See "Kidney
function and non-kidney solid organ transplantation" and "Liver transplantation in
adults: Overview of immunosuppression", section on 'Antibody therapy'.)
A reduction in the dose of the CNI does not typically improve renal function, but
may minimize disease progression. Since cyclosporine and tacrolimus appear to be
associated with similar degrees of nephrotoxicity, substituting one agent for the
other is unlikely to improve renal function and is not recommended [20,21,78].
However, substitution with mycophenolate mofetil (MMF), or a mammalian
(mechanistic) target of rapamycin (m-TOR) inhibitor (eg, everolimus, sirolimus) in
patients who do not have proteinuria is an option since these agents are
associated with a lower risk of renal injury. This strategy may result in a significant
decrease in serum creatinine values, particularly when used prior to irreversible
renal impairment [79,80]. A multicenter open-label trial utilizing early introduction

94
of everolimus with reduced tacrolimus levels revealed improved renal function at
two years post-liver transplantation compared with tacrolimus alone [81]. An
improvement in renal function was also observed in a retrospective study that
examined 157 liver transplantation recipients with renal impairment who were
converted to everolimus [82]. The mean glomerular filtration rate increased by
10.9 mL/min/1.73 m2 at three months after conversion, and by 6.8 mL/min/1.73
m2 at six months after conversion. However, immunosuppression with MMF,
sirolimus, everolimus monotherapy may be associated with an increased risk of
acute rejection, requiring vigilance to recognize and appropriately treat this
complication. (See "Pharmacology of mammalian (mechanistic) target of
rapamycin (mTOR) inhibitors".)
It has been suggested that calcium channel blockers might offer long-term
protection against cyclosporine nephrotoxicity because they block CNI-induced
renal vasoconstriction. However, the bulk of evidence suggests that this is not the
case [83], probably because interstitial fibrosis and tubular injury (rather than
transient renal vasoconstriction) appears to be responsible for chronic
nephrotoxicity due to CNIs. (See "Cyclosporine and tacrolimus nephrotoxicity",
section on 'Calcium channel blockers'.)
Care should be taken to avoid exposing patients to additional causes of renal
injury. Nonsteroidal antiinflammatory drugs can precipitate renal failure in
patients receiving CNIs, while other drugs, such as aminoglycoside antibiotics,
amphotericin B, and trimethoprim-sulfamethoxazole, can produce renal failure by
other mechanisms. Hypertension and diabetes should also be adequately
controlled. (See 'Hypertension' above and 'Diabetes mellitus' above.)
Metabolic bone disease — Bone loss is an important source of morbidity in liver
transplant recipients (figure 4), and we assess bone mineral density prior to
transplantation and every other year after transplantation to assess for osteopenia
or osteoporosis. The majority of bone loss and fractures occur within the first six
months following transplantation, and fractures often involve the spine [84].
Patients transplanted for cholestatic liver disease are particularly vulnerable to the
development of bone loss before and after liver transplantation. (See "Evaluation
and treatment of low bone mass in primary biliary cholangitis (primary biliary
cirrhosis)" and "Primary sclerosing cholangitis in adults: Clinical manifestations and
diagnosis", section on 'Metabolic bone disease' and "Osteoporosis after solid
organ or stem cell transplantation", section on 'Pretransplantation evaluation'.)
Osteopenia following transplantation mostly results from the use of
glucocorticoids, although animal studies suggest
that cyclosporine and tacrolimus also increase bone resorption. Other contributing
factors may include immobility, hypogonadism, and certain chronic liver diseases

95
(eg, primary biliary cirrhosis or autoimmune hepatitis treated with glucocorticoids,
alcohol-related liver disease). Treatment of patients with osteoporosis is often with
a bisphosphonate. Osteoporosis following solid organ transplantation is discussed
in detail elsewhere. (See "Osteoporosis after solid organ or stem cell
transplantation".)
De novo malignancy — The incidence of malignancy is increased in liver
transplant recipients [85]. Because of the increased risk, we pursue more intensive
screening than is done in the general population. (See 'Screening and
prevention' below.)
Incidence of de novo malignancy — Both skin cancer and non-skin malignancies
are more common in liver transplant recipients than in the general population,
with skin cancers being the most common malignancies seen [86].
(See "Malignancy after solid organ transplantation" and "Epidemiology and risk
factors for skin cancer in solid organ transplant recipients".)
In a systematic review that included nine studies with a minimum of 400 patients
each, the rates of de novo malignancy in patients following liver transplantation
were [87]:
●Skin cancer: 0.9 to 3.2 percent, mean time to diagnosis of 36 to 50 months
●Post-transplant lymphoproliferative disorder: 0.9 to 2.6 percent, mean time
to diagnosis of 26 to 32 months
●Colorectal cancer: 0 to 0.6 percent, mean time to diagnosis of 16 to 51
months
●Head and neck cancer: 0.1 to 5 percent, mean time to diagnosis of 34 to 61
months
●Lung cancer: 1 to 1.2 percent, mean time to diagnosis of 42 to 50 months
●Breast cancer: 0.2 to 0.7 percent, mean time to diagnosis of 41 to 124
months
●Cervical, uterine, or ovarian cancer: 0 to 1.5 percent, mean time to diagnosis
of 1 to 59 months
●Prostate cancer: 0 to 0.3 percent, mean time to diagnosis of 6 to 18 months
●Bladder or renal cancer: 0 to 0.4 percent, mean time to diagnosis of 20 to 55
months
An analysis of a United States national database published after the systematic
review included 798 liver transplant recipients and identified 171 adult patients
who developed 271 de novo malignancies [85]. Most were skin-related, whereas 29
were hematologic and 95 were solid-organ cancers. (See "Overview of
dermatologic problems following liver transplantation".)

96
The probability of developing any non-skin malignancy varied according to the
underlying diagnosis. It was highest in patients with primary sclerosing cholangitis
(22 percent at 10 years) and alcohol-related liver disease (18 percent at 10 years),
and was about 10 percent for all other diagnoses. The risk increased with
advancing age and with smoking.

Other studies have demonstrated an association of specific cancers with particular

underlying liver diseases. Examples include:

●Primary sclerosing cholangitis and ulcerative colitis with colon cancer [88].
(See "Primary sclerosing cholangitis: Inflammatory bowel disease and
colorectal cancer".)
●Recurrent viral hepatitis with hepatocellular carcinoma. (See "Epidemiology
and risk factors for hepatocellular carcinoma".)
●Alcoholic cirrhosis with oropharyngeal and esophageal squamous cell
carcinoma [89,90].
Screening and prevention — Because of the increased risk of cancer in liver
transplant recipients, studies have looked at the role of intensive screening [91-
93]. One study included 779 patients who underwent liver transplantation between
1982 and 2007 [91]. The patients were managed at a center that started to employ
intensive cancer screening in 2002. Prior to 2002, the screening regimen included
annual chest radiographs and abdominal ultrasounds. Urological screenings and
mammographies were performed based upon standard screening
recommendations for the general public. In addition, chest and abdominal
computed tomography (CT) scans were performed in patients with a history of
malignancy prior to transplantation.

Starting in 2002, their screening regimen changed to include:

●Annual chest CT scan

●Annual abdominal CT
●Annual urologic evaluation including measurement of prostate specific
antigen (PSA) in males
●Annual cervical Papanicolaou (Pap) smear in females
●Annual mammogram in females
●Annual dermatologic screening
●Colonoscopy three years after liver transplantation unless indicated sooner
because of a history of an adenoma or inflammatory bowel disease, followed
by colonoscopy every five years

97
Between 1982 and 2001, 24 malignancies were detected in 490 patients (5
percent), and all 21 non-skin cancer malignancies were diagnosed due to
symptomatic disease. Between 2002 and 2007, 81 malignancies were detected in
625 patients (13 percent), and 19 of 66 non-skin cancer malignancies (29 percent)
were diagnosed by screening. In addition, the cancers were diagnosed at earlier
stages compared with the earlier time period. Survival among patients diagnosed
with a malignancy during intensive surveillance was 3.3 years after diagnosis,
which was significantly longer than patients during the earlier time period (1.2
years). In addition, overall survival following liver transplantation was longer
among patients undergoing intensive surveillance (11.3 versus 3.1 years).
However, it should be noted that there is a potential for lead-time bias when
comparing survival among patients who underwent intensive surveillance and
those who did not. In addition, other aspects of patient care may have also
changed between the two time periods, so factors other than surveillance may
have contributed to the increased survival. (See "Evidence-based approach to
prevention", section on 'Lead-time bias'.)

Our approach to intensive screening is as follows:

●Annual physical examination including examination of the oropharynx and a

full body dermatologic examination.
●Some centers perform annual rectal exam and prostate-specific antigen
(PSA) in men.
●Annual Pap smear and mammography in women.
●Surveillance for hepatocellular carcinoma with annual magnetic resonance
imaging and/or abdominal ultrasound every six months with alpha-
fetoprotein (AFP) measurements in patients with recurrent viral hepatitis who
progress to bridging fibrosis or cirrhosis, and in patients who were
transplanted for hepatocellular carcinoma or were found to have
hepatocellular carcinoma in their explanted liver.
●We follow the Multi-Society Task Force of Colorectal Cancer guidelines for
colonoscopy for colorectal cancer screening, surveillance after screening and
polypectomy, and for more frequent screening (every one to two years) in
patients with ulcerative colitis or Crohn disease [94].
•(See "Screening for colorectal cancer: Strategies in patients at average
risk".)
•(See "Screening for colorectal cancer in patients with a family history of
colorectal cancer or advanced polyp", section on 'Screening approach'.)
•(See "Surveillance and management of dysplasia in patients with
inflammatory bowel disease".)
98
 •(See "Overview of colon polyps".)
●There are no national guidelines related to screening for head, neck, or
esophageal neoplasia. We generally do not pursue routine screening for
these cancers. However, for patients at high risk for one of these cancers (eg,
patients who have a history of smoking and alcohol abuse), the need for
periodic evaluation by an ear, nose, and throat surgeon and/or an upper
endoscopy is individualized, depending on the patient's specific risk factors.

We do not obtain routine screening of the chest or abdominal imaging (with the
exception of screening for hepatocellular carcinoma, described above).

In addition to screening, patients should be instructed to use high sun protection

factor sunblock. Cigarette smokers should be counseled to quit and preferably
should do so prior to transplantation. (See "Selection of sunscreen and sun-
protective measures" and "Overview of smoking cessation management in
adults".)
Neurologic events — Neurologic complications, such as vascular damage,
infections, immunosuppressive-associated leukoencephalopathy, and metabolic
abnormalities, occur in 16 to 80 percent of liver transplant recipients [95-100].
Clinical symptoms are usually mild, but major neurologic sequelae are observed in
some patients.
The development of serious neurologic events in the first month post-
transplantation was evaluated in a series of 168 liver transplant recipients [99]. The
most common events consisted of encephalopathy (19 percent) and seizures (5
percent). Less common complications included ischemia with seizures (related to
heparin-induced thrombocytopenia), osmotic demyelination syndrome (formerly
called central pontine myelinolysis), stroke, and posterior leukoencephalopathy
syndrome. (See "Osmotic demyelination syndrome (ODS) and overly rapid
correction of hyponatremia" and "Reversible posterior leukoencephalopathy
syndrome" and "Hyponatremia in patients with cirrhosis".)
With inclusion of serum sodium as a factor in the Mayo End-Stage Liver Disease
(MELD) score, some patients undergoing liver transplantation may be at increased
risk for osmotic demyelination syndrome if they undergo transplantation with a
baseline serum sodium of <125 mEq/L [101]. In a study of over 1200 patients who
underwent liver transplantation, osmotic demyelination syndrome was diagnosed
by neuroimaging in 11 patients (0.9 percent) [102].
Central nervous system (CNS) complications have been identified less frequently in
patients receiving immunosuppressive regimens aimed at maintaining low blood
levels of tacrolimus [100]. In a study of 395 such patients, major neurologic

99
symptoms or complications were noted in 64 patients (16 percent). None of the
complications were caused by infections. Complications included:
●Tacrolimus-related leukoencephalopathy – 0.8 percent
●Cerebrovascular disease – 4 percent
●Osmotic demyelination syndrome – 0.5 percent
●CNS symptoms with no identified cause – 11 percent

Pretransplant variables associated with an increased risk of CNS complications

included the presence of portosystemic encephalopathy, higher peak serum
bilirubin levels, and lower serum cholesterol levels.

Hearing impairment — At least one report suggested that hearing impairment

may be common following transplantation [103]. The most common hearing
complaints in a survey of 521 transplant recipients were hearing loss (52 percent),
tinnitus (38 percent), and otalgia (30 percent). An association with tacrolimus-
based immunosuppression was suggested in one analysis [104].
Hyperuricemia and gout — Hyperuricemia is common in liver transplant
recipients, although clinical evidence of gout occurs in only a small proportion of
cases. Both cyclosporine and tacrolimus can decrease uric acid excretion.
●An analysis of 134 consecutive liver transplant patients found that 47
percent had hyperuricemia and 6 percent developed gout a mean of 25
months post-transplantation [105]. The incidence of hyperuricemia and gout
was similar between patients receiving cyclosporine and tacrolimus.
●A study of 75 liver transplant recipients identified hyperuricemia in 86
percent, whereas gout developed in only 2.6 percent of cases [106].
Asymptomatic hyperuricemia is not treated in liver transplant recipients since the
development of gout is uncommon. If gout does develop, treatment of the acute
attack is similar to the approach used in renal transplant recipients. The acute
attack is typically treated with colchicine. Treatment with prednisone can be
considered as a second-line therapy. Nonsteroidal antiinflammatory medications
should be avoided since they can worsen renal function. Maintenance therapy is
often with allopurinol, though in patients receiving azathioprine rather than the
more commonly utilized antimetabolite, mycophenolic acid, the combination of
azathioprine and allopurinol can lead to myelosuppression, therefore, dose
adjustments and close monitoring are required. In addition, switching from
azathioprine to mycophenolic acid is an option. (See "Kidney transplantation in
adults: Hyperuricemia and gout in kidney transplant recipients".)
Dermatologic complications — A variety of dermatologic conditions have been
described following liver transplantation, including infections, drug-induced
lesions, and conditions related to the underlying liver disease. The dermatologic
100
complications of liver transplantation are discussed in detail separately.
(See "Overview of dermatologic problems following liver transplantation".)
HEPATOBILIARY COMPLICATIONSHepatobiliary complications following
liver transplantation include acute and chronic rejection, biliary complications, and
recurrence of the primary liver disease.
Acute and chronic rejection — Issues related to acute and chronic rejection
following liver transplantation are discussed in detail elsewhere. (See "Liver
transplantation in adults: Overview of immunosuppression" and "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft" and "Liver transplantation in
adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)
Biliary complications — The most common biliary complications following liver
transplantation are leaks and strictures [107,108]. The approach to patients with
biliary complications is presented separately. (See "Liver transplantation in adults:
Endoscopic management of biliary complications".)
Recurrence of primary liver disease — A major challenge for many patients
following liver transplantation is recurrence of the primary disease that caused the
original liver injury. Diseases that do not recur following liver transplantation
include congenital anatomic anomalies (biliary atresia, polycystic liver disease,
Caroli disease, Alagille syndrome, congenital hepatic fibrosis), metabolic diseases
(Wilson disease, alpha-1 antitrypsin deficiency), and acute hepatic insults (drug-
induced liver failure), provided the source of injury is removed. However, all other
causes of liver disease, including hepatitis B and C virus infection, primary biliary
cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, nonalcoholic
fatty liver disease, hemochromatosis, alcohol-associated liver disease, and
hepatocellular carcinoma may recur after liver transplantation and can be
associated with graft injury and failure.
The disorders most commonly associated with recurrence include hepatitis B virus
(HBV) and hepatitis C virus (HCV). Fortunately, recurrence of HBV after liver
transplantation can be prevented by administering hepatitis B immune globulin at
the time of transplantation and at regular intervals thereafter in combination with
antivirals such as tenofovir or entecavir. Strategies to minimize or eliminate the
use of hepatitis B immune globulin are evolving, including the use of entecavir or
tenofovir. (See "Liver transplantation for chronic hepatitis B virus infection",
section on 'Management of recurrent HBV infection'.)
By contrast, HCV recurrence following liver transplantation has been a significant
source of morbidity and mortality. HCV viremia and histologic injury following
transplantation is essentially universal. The management of HCV recurrence after

101
liver transplantation is presented separately. (See "Hepatitis C virus infection in
liver transplant candidates and recipients".)
Recurrences of other diseases following liver transplantation are discussed
elsewhere. (See "Liver transplantation in primary biliary cholangitis", section on
'Recurrence of PBC in the transplanted liver' and "Primary sclerosing cholangitis in
adults: Management", section on 'Liver transplantation' and "Liver transplantation
for alcoholic liver disease" and "Liver transplantation for hepatocellular
carcinoma" and 'Preventive medicine' above and "Autoimmune hepatitis:
Treatment", section on 'Need for liver transplantation'.)
ADDITIONAL ISSUESPatients with end-stage liver disease may struggle with
fatigue and sexual dysfunction, problems that can also be seen following liver
transplantation. In addition, many female patients regain fertility following
transplantation, so issues surrounding pregnancy also need to be addressed.
Fatigue — Fatigue is a major problem after liver transplantation. One of the most
detailed studies included 96 transplant recipients who were followed for up to 15
years [109]. Sixty-six percent of patients reported fatigue, while 44 percent
reported severe fatigue based upon validated quality of life instruments. A
decrease in health-related quality of life correlated with the severity of fatigue.
Fatigue did not appear to improve with time. Structured exercise programs might
benefit patients with fatigue. In a study of 18 liver transplant recipients who
experienced fatigue, a 12-week program of exercise training and physical activity
counseling improved fatigue and aerobic capacity [2].
Sexual dysfunction — Sexual dysfunction is common before liver transplantation
and often continues afterward [110,111]. (See "Evaluation of male sexual
dysfunction" and "Overview of sexual dysfunction in females: Epidemiology, risk
factors, and evaluation".)
Pregnancy — Amenorrhea and decreased fertility are common among female
patients with end-stage liver disease [112]. However, premenopausal women often
regain reproductive function following liver transplantation. It is important to
avoid the use of potentially teratogenic immunosuppressive agents in female
patients of child-bearing potential who wish to become pregnant. In this
circumstance, we recommend conversion from mycophenolic acid to azathioprine,
with follow-up at both the liver transplant center and with an obstetrician who
manages high-risk pregnancies if the patient becomes pregnant. The approach to
pregnancy in women with preexisting liver disease, including those who have
undergone liver transplantation, is discussed in detail elsewhere. (See "Pregnancy
in women with pre-existing chronic liver disease", section on 'Liver
transplantation'.)

102
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here is the patient education article that is relevant to this topic. We encourage
you to print or e-mail this topic to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

●Basics topic (see "Patient education: Liver transplant (The Basics)").

SUMMARY AND RECOMMENDATIONS
●Many patients are managed by primary care clinicians following liver
transplantation. However, issues related to immunosuppression (including
infections, organ rejection, and renal disease) and biliary complications are
typically managed by a transplant hepatologist and/or surgeon. (See 'Role of
the primary care clinician' above.)
●Numerous drugs interact with immunosuppressive agents, so patients
should be asked about any new medications or supplements they are taking
(including over-the-counter medications) and be reminded not to start any
new medications or supplements without first speaking with their clinicians
(table 1). (See 'Immunosuppression' above.)
●Several medical problems in addition to rejection are common following
transplantation, many of which are the result of, or are made worse by,
immunosuppression (table 3). In addition to the standard treatments used in
the non-transplantation population, the treatment of many of these
problems may include changes in the patient's immunosuppressive regimen.
Common problems include:
•Infections (see 'Infections' above).
•Hypertension (see 'Hypertension' above).
•Diabetes (see 'Diabetes mellitus' above).
103
 •Obesity (see 'Obesity' above).
•Dyslipidemia (see 'Dyslipidemia' above).
•Renal disease (see 'Acute and chronic renal disease' above).
•Metabolic bone disease (see 'Metabolic bone disease' above).
•Malignancy (see 'De novo malignancy' above).
●We suggest the following screening tests for nonmalignant disease in liver
transplant recipients (Grade 2C) (see 'Screening for nonmalignant
disease' above):
•General assessment: Annual history and physical examination, annual
dental evaluations in addition to routine (twice-yearly) cleanings.
•Hypertension: For the first six months following transplantation, self-
monitoring every week and blood pressure monitoring by a healthcare
provider every month. In patients without hypertension after six months,
blood pressure monitoring by a healthcare provider every six months.
(See "Overview of hypertension in adults", section on 'Diagnosis'.)
•Diabetes mellitus: Screening every six months (typically with either a
fasting plasma glucose or a hemoglobin A1C) and, in patients with
diabetes, an annual eye examination to look for diabetic changes.
(See "Screening for type 2 diabetes mellitus", section on 'A suggested
approach'.)
•Dyslipidemia: Annual fasting lipid profile. (See "Measurement of blood
lipids and lipoproteins".)
•Cardiovascular disease: We generally perform stress testing every three
to five years in patients with risk factors for coronary artery disease.
However, not all insurance covers cardiovascular disease screening in this
setting, which may influence whether testing is performed. Exercise stress
testing is preferred for those who are able to do the test. For those unable
to do exercise stress testing, adenosine and dobutamine stress tests are
alternatives. (See "Stress testing for the diagnosis of obstructive coronary
heart disease".)
•Renal disease: During the first year, we obtain urinalysis, microalbumin,
and creatinine/glomerular filtration rate every two to three months. After
the first year, we measure creatinine/glomerular filtration rate every three
to six months. (See "Diagnostic approach to adult patients with subacute
kidney injury in an outpatient setting", section on 'Evaluation'.)
•Metabolic bone disease: Bone mineral density measurement prior to
transplantation and every other year after transplantation. (See "Overview
of dual-energy x-ray absorptiometry".)

104
●We suggest the following screening tests for malignant disease in liver
transplant recipients (Grade 2C) (see 'Screening for malignancies' above):
•Annual physical examination including examination of the oropharynx
and a full body dermatologic examination.
•Some centers perform an annual rectal exam and prostate-specific
antigen (PSA) in male patients.
•Annual Papanicolaou smear and mammography in female patients.
•Surveillance for hepatocellular carcinoma with annual magnetic
resonance imaging and/or abdominal ultrasound every six months with
alpha-fetoprotein measurement in patients with recurrent viral hepatitis
who progress to bridging fibrosis or cirrhosis and in patients who were
transplanted for hepatocellular carcinoma or were found to have
hepatocellular carcinoma in their explanted liver.
•We follow the Multi-Society Task Force of Colorectal Cancer guidelines for
colonoscopy for colorectal cancer screening, surveillance after screening
and polypectomy, and for more frequent screening (every one to two
years) in patients with ulcerative colitis or Crohn disease.
•We generally do not pursue routine screening for head, neck, or
esophageal neoplasia. However, for patients at high risk for one of these
cancers (eg, patients who have a history of smoking and alcohol abuse),
the need for periodic evaluation by an ear, nose, and throat surgeon
and/or an upper endoscopy is individualized, depending on the patient's
specific risk factors.
●Patients receiving solid organ transplantations should be vaccinated for,
among other things, influenza, pneumonia, and hepatitis A and B virus (table
2). (See "Immunizations in solid organ transplant candidates and recipients".)
●Infection is the leading cause of mortality following liver transplantation and
patients who develop a fever or other signs of infection require urgent
evaluation because even common infections can rapidly progress to sepsis
with multiorgan failure (table 4). (See 'Infections' above.)

105
Liver transplantation in adults: Overview of
immunosuppression
Author:
John M Vierling, MD, FACP
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 24, 2021.
INTRODUCTIONIn 1994, the US Multicenter FK506 Liver Study Group
published a paper comparing cyclosporine and tacrolimus for immunosuppression
after liver transplantation [1]. The study was a landmark in the evolution of liver
transplantation. First, the introduction stated that rejection remained an important
cause of graft loss and death. Second, the paper reported that survival with
cyclosporine and tacrolimus was similar but that tacrolimus was associated with
fewer episodes of steroid-resistant rejection. Third, it reported that tacrolimus was
associated with excess adverse events, including nephrotoxicity and neurotoxicity.
Liver transplantation has evolved substantially since that publication, and we have
addressed many of the issues outlined in the 1994 study. Acute rejection is usually
easy to manage, and we now try to balance the risk of rejection with the risk of
drug toxicity. Our focus has shifted to avoiding the long-term complications of
immunosuppression and recurrent liver disease. Tacrolimus has become first-line
immunosuppression in most liver transplant programs, and a number of
supplemental drugs allow us to customize immunosuppression.
This topic will provide an overview of the drugs used for immunosuppression
following liver transplantation. The diagnosis and treatment of acute T-cell
mediated (cellular) rejection are discussed elsewhere. (See "Liver transplantation in
adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular)
rejection of the liver allograft" and "Liver transplantation in adults: Treatment of
acute T cell-mediated (cellular) rejection of the liver allograft".)
IMMUNOBIOLOGY OF ACUTE REJECTIONOrgan rejection is a multistep
process that includes alloantigen recognition, lymphocyte activation, clonal
expansion, and graft inflammation (figure 1 and figure 2).
Signal I: Alloantigen recognition — Alloantigen recognition requires
presentation of a foreign alloantigen along with a host major histocompatibility

106
complex (MHC) molecule. Presentation is done by an antigen-presenting cell (APC).
The antigen, bound to an MHC molecule, binds to the T-cell receptor. This is the
first of three signals that are required for T-cell maturation and can be aborted by
antilymphocyte antibodies. (See 'Antibody therapy' below.)
Signal II: Lymphocyte activation (costimulation) — T-cell activation requires
costimulation, a process in which a number of ligands on the APC bind to a variety
of T-cell receptors, including CD28, CD154, CD2, CD11a, and CD54. The T-cell
receptor complex is internalized and binds to immunophilin. Immunophilin
stimulates calcineurin, which activates nuclear factor of T-cell activation (NFAT) by
removing pyrophosphate. The activated NFAT then translocates to the nucleus
where it drives interleukin (IL)-2 transcription. Two immunophilin targets,
cyclophilin and FK-binding protein, are targets of cyclosporine and tacrolimus,
respectively. Both agents block calcineurin and are known collectively as
calcineurin inhibitors. (See 'Tacrolimus' below and 'Cyclosporine' below.)
Signal III: Clonal expansion — Newly synthesized IL-2 is secreted by T cells and
binds to IL-2 receptors (IL-2R) on the cell surface in an autocrine fashion,
stimulating a burst of cell proliferation. Basiliximab and daclizumab, both
monoclonal antibodies against the IL-2 receptor, block this signal. Sirolimus, which
binds to the downstream mechanistic target of rapamycin (mTOR), also acts at this
step. Finally, the proliferation burst can be inhibited at the level of DNA synthesis
by azathioprine and mycophenolate mofetil. (See 'Basiliximab' below
and 'Sirolimus' below and 'Inhibitors of purine and pyrimidine synthesis' below.)
Inflammation — T-cell proliferation is associated with cell-mediated cytotoxicity
and secretion of cytokines, chemokines, and adhesion molecules. The secreted
mediators recruit additional inflammatory cells to the graft. The result is an
inflammatory milieu with additional toxic and vasoactive mediators. Control of this
step is possible with glucocorticoids and antilymphocyte antibodies.
(See 'Glucocorticoids' below and 'Antibody therapy' below.)
DRUG INTERACTIONSA major issue with the immunosuppressive agents
used for liver transplant recipients (particularly calcineurin inhibitors and
mechanistic target of rapamycin inhibitors) is their extensive metabolism by
CYP3A4. This creates the potential for drug-drug interactions that may produce
toxicity or dangerously low levels of immunosuppressive agents, leading to an
increased risk of rejection. As examples, antifungal agents, some antibiotics, and
many of the drugs used in the treatment of HIV inhibit CYP3A4. (See "Kidney
transplantation in adults: Kidney transplantation in patients with HIV".)
A knowledge of the common interfering compounds is essential and drug levels
must be monitored closely when these compounds are used (table 1).
GLUCOCORTICOIDS
107
Approach to therapy — Glucocorticoids suppress antibody and complement
binding, upregulate interleukin (IL)-10 expression, and downregulate IL-2, IL-6, and
interferon-gamma synthesis by T cells [2-4]. They have traditionally been the
cornerstone of immunosuppression, and they remain the first line of initial therapy
and treatment of acute allograft rejection in many centers. (See "Liver
transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of
the liver allograft".)
Four steroid formulations are used commonly in
transplantation: hydrocortisone, prednisone, prednisolone,
and methylprednisolone. These drugs have different relative potencies (table 2).
Steroid use varies among transplant centers, and there is no agreement on an
ideal protocol. The protocol at Baylor College of Medicine is shown in the table
(table 3). Another common regimen is a 1 gram bolus of methylprednisolone
during the anhepatic phase, followed by 20 mg/day intravenously. Once the
patient is able to take oral medications, he/she is switched to prednisone 20
mg/day. Tapering to zero is usually achieved over three to six months, although
some centers leave patients on 5 mg/day indefinitely.
Steroids are associated with a number of side effects including diabetes, fluid
retention, hypertension, emotional lability, hyperlipidemia, cosmetic changes
(acne, buffalo hump, etc), poor wound healing, susceptibility to infection, visual
changes, cataracts, and osteopenia, and they may cause adrenal suppression that
may persist up to the time of weaning [5].
In addition to the side effects, steroid therapy increases hepatitis C virus (HCV)
replication. The basis of this increase is controversial. Steroids may drive
replication directly, and/or they may permit more effective replication through
immunosuppression. In vitro studies using a replicon system (which avoids the
effect of the immune system) have yielded conflicting results [6,7]. The controversy
about steroid avoidance and tapering in HCV-infected patients is discussed below,
but it is mostly of historical interest with the availability of potent direct acting
antiviral agents. (See 'Patients with HCV infection' below.)
Given the problems with glucocorticoids, many centers try to wean from steroids
as early as possible. This must be done cautiously since rapid steroid withdrawal
can precipitate a flare of an underlying condition (eg, autoimmune hepatitis,
inflammatory bowel disease, or hepatitis) or an episode of rejection. A meta-
analysis looked at 16 randomized trials that compared postoperative
glucocorticoid avoidance or withdrawal with glucocorticoid-containing
immunosuppression [8]. There were no differences detected in mortality, graft
loss, or infection rates when postoperative glucocorticoid avoidance or withdrawal
was compared with glucocorticoid-containing immunosuppression. However,

108
acute rejection and glucocorticoid-resistant rejection were more common with
glucocorticoid avoidance or withdrawal (relative risk [RR] 1.33, 95% CI 1.08 to 1.64,
and RR 2.14, 95% CI 1.13 to 4.02, respectively). Diabetes mellitus and hypertension
occurred less often with glucocorticoid avoidance or withdrawal (RR 0.81, 95% CI
0.66 to 0.99 and RR 0.76, 95% CI 0.65 to 0.90, respectively). However, all of the
studies included in the analysis were at high risk of bias.
A possible alternative to traditional glucocorticoids is budesonide. Budesonide is a
glucocorticoid with reduced systemic effects because of high first-pass hepatic
metabolism. Budesonide is used commonly to treat inflammatory bowel disease
and has proven effective in the management of autoimmune hepatitis [9]. Its use
in liver transplantation is attractive because of the high frequency of post-
transplant diabetes, especially in patients transplanted for hepatitis C virus. One
study reported three post-orthotopic liver transplant (OLT) patients treated with
budesonide with apparent success [10]. In a single-center study including 20 post-
OLT patients and 20 matched controls who were treated with glucocorticoids for
12 weeks in addition to calcineurin inhibitors and mycophenolate mofetil,
budesonide was associated with lower infection rates compared
with prednisone (30 versus 0 percent); however, rates of acute cellular rejection
and new onset diabetes were not significantly different between the groups [11].
Further studies using budesonide for immunosuppressive therapy are needed to
validate these findings.
Patients with HCV infection — A great deal of literature had been devoted to
optimizing immunosuppression for patients who were transplanted for HCV-
related liver disease [12-22]. However, the availability of safe and effective HCV
therapy with direct-acting antivirals has revolutionized the approach to HCV
management in liver transplant candidates and recipients. Many patients are
successfully treated for HCV infection before liver transplantation. Management of
HCV infection in liver transplant candidates and recipients is discussed separately.
(See "Hepatitis C virus infection in liver transplant candidates and recipients".)
CALCINEURIN INHIBITORSThe early challenges to successful liver
transplantation included surgical technique, organ preservation, and
immunosuppression. As surgical technique improved, the need for better
immunosuppression became more obvious. A report published in 1980 described
one-year survival of only 26 percent [23]. The introduction of the calcineurin
inhibitor (CNI) cyclosporine A the following year marked a turning point in liver
transplantation [24,25].
Cyclosporine — Cyclosporine, a peptide derived from the fungus Cylindrocarpon
lucidum, is a potent immunosuppressive agent [26]. It inhibits T-cell activation by
binding intracellular cyclophilin, thus reducing calcineurin activation. Without
109
calcineurin, the nuclear factor of activated T cells (NFAT) does not translocate to
the nucleus, and interleukin (IL)-2 production (along with a number of other genes)
is shut down. The result is a markedly diminished T-cell response to class I and
class II antigens, and a significant reduction in the rejection cascade.
The impact of cyclosporine was illustrated in an early report in which one- and five-
year survival rates with "conventional" immunosuppression
(azathioprine plus prednisone) were 33 and 20 percent, respectively, while the
survival rates with cyclosporine plus prednisone were 70 and 63 percent,
respectively [27]. Cyclosporine subsequently became first-line therapy, and the
first 1000 cases done at the University of Pittsburgh were described in a report in
1988 [28].
Cyclosporine was initially formulated as Sandimmune, a corn oil-based preparation
with inconsistent absorption, especially in the absence of bile flow. Accurate
dosing was difficult, and serum drug levels varied with meals. In addition, any
change in bile flow (eg, with rejection episodes or biliary complications) caused a
change in cyclosporine absorption. This is clearly a problem after liver
transplantation, so the nonaqueous, microemulsified version (Neoral) has become
the preferred formulation.
Cyclosporine can be administered intravenously, although it is usually given orally
as a tablet or an oral suspension (table 4). The intravenous dose is approximately
30 percent of the oral dose because of improved bioavailability, and because it is
given as a continuous infusion. All of the comments below regarding oral
administration are based on the Neoral formulation of cyclosporine.
After oral administration, cyclosporine is variably absorbed in the jejunum and
enters the lymphatic system. Peak blood levels are achieved in two to four hours,
and the drug is widely distributed with highest concentrations in adipose,
pancreatic, adrenal, renal, and hepatic tissues. The average half-life is 15 hours but
ranges widely (10 to 40 hours). Cyclosporine is cleared in the bile after extensive
metabolism in the liver by CYP3A4. The metabolites have little immunosuppressive
activity. CYP3A4 activity (and, therefore, blood cyclosporine levels) depends upon
genetic and environmental factors including gene polymorphisms, graft function,
hepatitis C virus (HCV) replication, and certain foods and drugs (table 1).
Cyclosporine levels should be monitored frequently in the peritransplant period
(typically daily), with decreasing frequency as graft function stabilizes and rejection
becomes less of a threat. Patients who are stable can be monitored monthly, but
levels should be checked more frequently if they develop an acute illness or start
taking a potentially interfering drug. Several drugs commonly affect CNI levels.
The goal therapeutic level of cyclosporine is usually 200 to 250 ng/mL in the first

110
three months after transplantation, but is typically tapered to 80 to 120 ng/mL by
12 months.
Cyclosporine levels should be monitored closely, and patients should be monitored
for renal toxicity, hypertension, hyperkalemia, and hypomagnesemia. Potassium-
sparing diuretics and potentially nephrotoxic drugs should be avoided if possible.
Neurologic toxicity may include altered mental status, polyneuropathy, dysarthria,
myoclonus, seizures, hallucinations, and cortical blindness [29]. Other common
problems include hyperlipidemia, gingival hyperplasia, and hirsutism.
(See "Pharmacology of cyclosporine and tacrolimus".)
Tacrolimus — In an update on liver transplantation in 1988, the University of
Pittsburgh group reported that phase 1 trials of FK506 (tacrolimus) had recently
begun [30]. A year later, the same group described use of FK506 as salvage
therapy in patients who had failed cyclosporine [31]. Within approximately five
years, tacrolimus would overtake cyclosporine as the mainstay in liver
transplantation.
Tacrolimus (Prograf) is a macrolide compound originally isolated
from Streptomyces tsukubaensis. It inhibits IL-2 and interferon-gamma production
and is 100 times more potent than cyclosporine. Oral bioavailability is variable (5 to
67 percent), and an oral dose of 0.15 mg/kg results in a peak concentration of 0.4
to 3.7 ng/mL. Like cyclosporine, tacrolimus is metabolized in the liver via CYP3A4
and is not removed by dialysis.
Cyclosporine versus tacrolimus — By the mid-1990s, most centers agreed
that tacrolimus was associated with superior graft and patient survival. A criticism
of the early studies was their use of oil-based cyclosporine, raising the question of
bioavailability versus efficacy. A landmark study greatly influenced thinking on the
subject [32]. The authors compared the efficacy of tacrolimus versus
microemulsified cyclosporine in 606 patients undergoing first orthotopic liver
transplant using a composite primary endpoint of death, retransplantation, or
"treatment failure for immunological reasons (TFIR)." The study was an open-label,
randomized design, and all patients received
concomitant prednisolone and azathioprine. TFIR was defined as biopsy-proven
rejection requiring a change from protocol immunosuppression including more
than one cycle of increased steroid or any increased immunosuppression,
including antilymphocyte preparation or investigational drug. The justification for
using TFIR as an endpoint was to avoid the distorting effect of tacrolimus rescue in
patients who were failing cyclosporine therapy. The groups were well matched for
diagnosis, age, gender, blood group, cold ischemia time, and intraoperative blood
use.

111
Both treatment regimens were effective, but tacrolimus was superior with regard
to the composite endpoint and for patient and graft survival (figure 3). In addition,
more patients in the tacrolimus group survived without an episode of significant
rejection.
The results of the study were updated with a two-year extension of the
randomization protocol [33]. Tacrolimus remained superior for the composite
endpoint (RR 0.79; 95% CI 0.60-0.95), although the individual endpoints of freedom
from death or retransplantation were no longer statistically significant.
Significantly more patients randomized to tacrolimus were alive with their original
graft and on their assigned medication compared with the cyclosporine group (62
versus 42 percent). Six patients were switched from tacrolimus to cyclosporine,
while 17 were switched from cyclosporine to tacrolimus (five for graft rejection not
meeting endpoint criteria).
Multiple subsequent studies have been performed; the superiority
of tacrolimus over cyclosporine was confirmed in a meta-analysis of 16
randomized clinical trials [34,35]. Tacrolimus was superior when analyzed for
survival, graft loss, acute rejection, and steroid-resistant rejection in the first year
(table 5). The incidence of lymphoproliferative disease was similar for the two
groups, and de novo diabetes mellitus was more common in the tacrolimus group.
More patients stopped cyclosporine than tacrolimus. The authors estimated that
treating 100 patients with tacrolimus versus cyclosporine would avoid rejection,
steroid-resistant rejection, graft loss, and death in nine, seven, five, and two
patients, respectively, but that four additional patients would develop diabetes.
Tacrolimus dosing — Tacrolimus dosing should be individualized. We usually start
with a low dose (0.5 to 1 mg every 12 hours) on postoperative day 1, and aim for a
level of 7 to 10 ng/mL by the end of the first week. We use lower dosing, often with
the addition of an auxiliary agent like mycophenolate mofetil (MMF) or a
monoclonal antibody in patients with preoperative renal impairment. It is
important to attain adequate tacrolimus levels quickly. In a study of 493 liver
transplantation recipients who were treated with tacrolimus as their primary
immunosuppression, patients with trough tacrolimus levels >7 ng/mL at the time
of a protocol liver biopsy (mean 6 days after transplantation) had lower rates of
moderate or severe rejection compared with those who had lower levels (24 versus
41 percent) [36]. In addition, patients with mean levels between 7 and 10 ng/mL
within 15 days after liver transplantation had lower rates of graft loss during
follow-up compared with patients who had trough levels <7 ng/mL or 10 to 15
ng/mL (relative risks of 2.32 and 2.17, respectively). These findings suggest that in
the early post-transplantation period, a tacrolimus level between 7 and 10 ng/mL

112
is associated with improved outcomes. However, it must be kept in mind that
because the study was not a randomized trial, it is at risk for bias and confounding.

A level of 6 ng/mL is usually satisfactory after six months, and maintenance at a

level of 4 to 6 ng/mL is common beyond one year. We aim for higher levels in
patients who are transplanted for autoimmune liver diseases, including primary
biliary cholangitis (PBC) and primary sclerosing cholangitis. Patients transplanted
for alcohol-associated liver disease or hemochromatosis usually tolerate low levels
of CNIs after their initial recovery. With improved survival, our goal is to use as
little immunosuppression as possible to minimize the known long-term
complications of these drugs, including renal insufficiency and post-transplant
lymphoproliferative disorders (PTLD).

Calcineurin inhibitors and renal failure — CNI-induced renal failure is a serious

problem after orthotopic liver transplant (OLT) [37]. The problem has been
exacerbated by the switch to a MELD-based organ allocation system, which is
weighted towards higher serum creatinine. (See "Model for End-stage Liver
Disease (MELD)".)
A number of strategies, including switching to mammalian (mechanistic) target of
rapamycin (mTOR) inhibitors or using alternative supplemental
immunosuppressive agents, have been tried. A retrospective analysis of patients
who received either dual therapy with a CNI and a steroid (n = 3884) or triple
therapy with a CNI, steroid, and MMF (n = 4946 patients) found that triple therapy
was associated with a 6 percent lower adjusted risk of progressive renal disease as
well as lower risk of death [38]. Progressive renal disease was defined as a 25
percent decline in estimated glomerular filtration rate (eGFR) based on the
Modification of Diet in Renal Disease (MDRD) study formula. The authors
hypothesized that MMF improved renal function by lowering CNI dosing and via a
direct nephroprotective effect.
A prospective, multicenter trial compared standard dose tacrolimus to low dose
and delayed tacrolimus with the primary endpoint of a change in eGFR (Cockroft-
Gault formula) at 52 weeks [39]. Patients were divided into three groups:
●Group A (n = 183): standard-dose tacrolimus (target trough >10 ng/mL) and
steroids
●Group B (n = 70): MMF 2 g/day, low-dose tacrolimus (target trough 8 ng/mL),
and steroids
●Group C (n = 172): daclizumab induction, MMF, reduced-
dose tacrolimus delayed until the fifth day post-transplant, and steroids

113
The eGFR decreased by 23.6, 21.2, and 13.6 mL/min in groups A, B, and C,
respectively (A versus C, p = 0.012; A versus B, p = 0.199).

Hemodialysis was required more frequently in group A compared with group C (10
versus 4 percent). Biopsy-proven acute rejection rates were 28, 29, and 19 percent,
respectively. Patient and graft survival were similar among the groups. This study
suggests that the kidney is particularly vulnerable to injury in the immediate post-
OLT period. Delayed CNI dosing reduced, but did not eliminate, renal injury.

Patients with HCV infection — The availability of highly effective antiviral agents

(DAAs) has greatly simplified post-OLT HCV therapy. Antiviral agents may interfere
with drug metabolism because of effects on CYP3A4 and/or P-glycoprotein (gp)
[40-45]. In addition, the rate of calcineurin inhibitor clearance may increase with a
declining viral load. For these reasons, calcineurin inhibitor levels should be
monitored closely after starting DAAs. (See "Hepatitis C virus infection in liver
transplant candidates and recipients", section on 'Interactions with
immunosuppressive agents'.)
Drug interactions can also be checked through the Lexicomp drug
interactions program included with UpToDate.
Summary on the role of calcineurin
inhibitors — Cyclosporine and tacrolimus are potent immunosuppressive agents.
Their availability has allowed us to shift our focus from acute cellular rejection and
short-term post-transplant survival to long-term management of complications.
They have similar adverse effects including nephrotoxicity, neurotoxicity, and
electrolyte abnormalities, and both can be monitored with drug levels.
Tacrolimus is superior in terms of preventing acute rejection, steroid-resistant
rejection, graft loss, and postoperative death. These findings have made
tacrolimus first line therapy in most liver transplant centers despite its higher
association with post-transplant diabetes mellitus. Diabetes is a significant concern
since it will probably contribute to the progressive renal failure that may be seen in
long-term survivors.

The concept is that significant immunosuppression is needed in the immediate

post-transplant period. Beyond this period, the complications of excessive
immunosuppression outweigh the ever decreasing risk of organ rejection. With
careful monitoring, low doses of immunosuppression are usually well tolerated.

INHIBITORS OF MAMMALIAN (MECHANISTIC) TARGET OF

RAPAMYCIN (MTOR)
114
Sirolimus — Sirolimus (Rapamune), a macrolide antibiotic produced
by Streptomyces hygroscopicus, is a potent immunosuppressive agent approved by
the US Food and Drug Administration (FDA) for renal transplantation in 1999 [46].
It is structurally similar to tacrolimus and binds the same target (FK-binding
protein) but does not inhibit calcineurin. Instead, it blocks the transduction signal
from the IL-2 receptor, thus inhibiting T- and B-cell proliferation. Its advantage
over the calcineurin inhibitors (CNIs) is its freedom from nephrotoxicity and
neurotoxicity. However, side effects of sirolimus have relegated it to the status of
an important second-line drug. (See 'Side effects' below.)
The effectiveness of sirolimus was illustrated in an early report of its use in 15
patients undergoing liver transplantation [47]. Sirolimus was used as a single
agent or as part of dual (sirolimus and cyclosporine) or triple therapy (sirolimus,
cyclosporine, and prednisolone). Rejection was seen more commonly with
monotherapy, rarely with dual therapy, and not at all with triple therapy. In
addition, all patients were on sirolimus monotherapy by three months. Only 3 of
the 15 patients discontinued sirolimus: one for hyperlipidemia, one for taste
perversion, and one for Pneumocystis pneumonia.
Although sirolimus binds its target (FK-binding protein) with higher affinity
than tacrolimus, the two drugs act synergistically, rather than competitively, to
prevent rejection. This led to speculation that a low-dose combination strategy
might reduce the incidence of tacrolimus-associated problems. In a study of 56
patients on this combination, patient and graft survival at 23 months were 93 and
91 percent, respectively [48]. One case of hepatic artery thrombosis was observed
in this series.
Sirolimus may be especially useful as a substitute in cases of CNI-intolerance
(primarily renal failure and neurotoxicity) [49-51]. However, its benefits in renal
failure remain unsettled. While retrospective analyses did not show improved
renal function in patients switched to sirolimus [52-54], a small randomized
controlled trial showed improvement [51]. In the randomized trial, transplant
recipients with underlying renal disease were switched to sirolimus at least six
months after liver transplant. The glomerular filtration rate improved within three
months. However, long-term outcomes were not reported, and two patients in the
sirolimus arm developed acute rejection.
A retrospective analysis showed no benefit for renal function when patients with
chronic renal insufficiency were switched from CNIs to sirolimus [54]. This study
suggests that renal dysfunction from CNIs becomes irreversible at some point, and
highlights the importance of CNI optimization. Similarly, another study showed
that early conversion (less than 90 days) to sirolimus was associated with improved
renal function, while late conversion was of limited benefit [55].

115
A systematic review that included 11 studies found a small (3.4 mL/min),
nonsignificant increase in glomerular filtration rate after one year of sirolimus use
in patients who received sirolimus as primary immunosuppression due to renal
insufficiency or who were switched to sirolimus from another regimen due to
nephrotoxicity [56]. However, sirolimus use was associated with higher rates of
infection, rash, ulcers, and discontinuation of therapy. Sirolimus was not
associated with an increased risk of graft failure or death, though the data
reporting for these outcomes were incomplete.

Larger trials with longer follow-up are needed to settle the issue and to determine
whether the potential improvement in renal function outweighs a possible
increased risk of rejection.

Sirolimus has also been proposed as a better choice for patients with

hepatocellular carcinoma because of its antiproliferative activity [57-59]. This
benefit has yet to be proven in prospective trials. Finally, although not supported
by publications, many transplant centers find that sirolimus is inadequate as
monotherapy and routinely add a second agent when switching from a CNI for any
reason.
Side effects — Side effects of sirolimus reported in the postoperative period
include hepatic artery thrombosis, delayed wound healing, and incisional hernias,
while chronic use has been associated with hyperlipidemia, bone marrow
suppression, mouth ulcers, skin rashes, albuminuria, and pneumonia. These risks
are difficult to quantify because the incidence (and even the presence) of side
effects varies widely by report. In 2008, the FDA updated the labeling of sirolimus
to include a boxed warning stating that the use of sirolimus was associated with
excess mortality, graft loss, and hepatic artery thrombosis following liver
transplantation, and that its use de novo in liver transplantation recipients was not
recommended [60].
As an example, one report showed that sirolimus was more likely to cause
hyperlipidemia when administered with cyclosporine than with tacrolimus (30
versus 6 percent for hypercholesterolemia, 33 versus 3 percent for
hypertriglyceridemia) [61]. Similar results in another retrospective trial suggested
that the combination of sirolimus with tacrolimus is associated with minimal
elevation of triglycerides [62]. These contrast with a study that reported a 49
percent incidence of hyperlipidemia in patients switched from a CNI to sirolimus
monotherapy [63].
Another retrospective study compared 170 patients treated with sirolimus as initial
therapy compared with 180 historic controls [64]. No significant differences in
wound complications (12 versus 14 percent) or hepatic artery complications (5
116
versus 8 percent) were seen [64]. Finally, a large retrospective study found
complications that included edema, dermatitis, oral ulcers, joint pains, pleural
effusions, hepatic artery thrombosis (two patients), and one wound dehiscence
[65]. The results reported in the above studies have not been validated in
prospective studies.
An open-label randomized trial found that patients who were switched from a CNI
to sirolimus had increased rates of acute rejection but similar mortality at 12
months [66].
Everolimus — Because prolonged use of calcineurin inhibitors (CNI), such
as tacrolimus, is associated with renal disease, everolimus (EVR) has been studied
as an alternative for long term immunosuppression. The FDA recommends that
both mTORs, everolimus and sirolimus, not be used earlier than 30 days after liver
transplantation because of an increased risk of hepatic artery thrombosis in the
early post-transplantation period [67]. (See 'Sirolimus' above.).
The initial immunosuppressive regimen after transplantation and optimal timing
of withdrawal of CNI is not clear [68]. Three trials of post-transplant regimens
including EVR compared with standard CNI therapy have generally shown benefit
in renal function parameters for the EVR groups but its efficacy compared with
standard CNI therapy needs further study [68-70]. (See 'Calcineurin inhibitors and
renal failure' above.)
●In a trial of 188 liver transplant recipients, all of whom initially
received basiliximab induction therapy and enteric
coated mycophenolate sodium (with or without steroids), renal function was
better after 24 weeks in patients receiving EVR and tacrolimus (EVR+TAC)
while tapering tacrolimus (TAC) with discontinuation by week 16, compared
with patients receiving continuous TAC (mean eGFR 95.8 versus 76.0 mL/min)
[68]. Rates of treatment failure (defined as biopsy-proven acute rejection,
graft loss or death) at 24 weeks were not significantly different between the
EVR+TAC and the TAC groups.
●In a trial of 303 liver transplant recipients with GFR >50 mL/min who
received basiliximab induction therapy followed by CNI (with or without
steroids) for four weeks post-transplantation and who then continued CNI or
were converted to EVR, the mean calculated GFR (Cockroft-Gault) at 11
months showed no difference between regimens (-2.9 mL/min in favor of
EVR, 95% CI [-10.65 to 4.81]) [69]. The difference in GFR was significant if the
Modification of Diet in Renal Disease formula was used (-7.8 mL/min in favor
of EVR; 95% CI: -14.366 to -1.191). Rates of mortality and biopsy-proven acute
rejection were similar in both groups. (See "Assessment of kidney function",
section on 'Assessment of GFR'.)

117
 ●In an open-label trial, liver transplantation recipients received standard
immunosuppression with steroids and TAC for 30±5 days and were then
randomly assigned 1:1:1 to one of three groups: EVR, everolimus with
reduced dose tacrolimus (EVR+TAC), or standard dose tacrolimus (TAC) [70].
Because a high rate of acute rejection was observed in the tacrolimus
elimination arm, recruitment to this group was suspended. Patients after this
point were assigned to receive EVR+TAC or TAC. The final study included 719
patients. The primary endpoint, which was the treatment failure rate (ie,
treated biopsy-proven acute rejection, graft loss, or death at 12 months after
transplantation), occurred in 45 of 231 (19.5 percent) EVR recipients, in 15 of
245 (6.5 percent) EVR+TAC recipients, and in 23 of 243 (9.5 percent) TAC
recipients. The change in adjusted GFR from randomization to month 12 was
superior in the EVR+TAC group compared with TAC alone, with a difference of
8.5 mL/min (97.5% CI 3.7-13.3).
Everolimus is the hydroxyethyl derivative of sirolimus. The mechanism of action of
EVR is via inhibition of mammalian target of rapamycin (mTOR), similar to sirolimus
[71]. Everolimus is rapidly absorbed and reaches a peak concentration within one
to two hours if given on an empty stomach [72]. Fatty foods retard absorption. It
has higher oral availability and lower plasma binding than sirolimus and a mean
elimination half-life of 30±11 hours. A starting dose of 0.75 mg twice daily with a
target trough level of 3 to 8 ng/mL is standard [73]. Metabolism is via CYP3A4, 3A5,
and 2C8, and interactions with azoles, macrolides, antiepileptic agents, antiviral
agents, and grapefruit juice are known. The clearance of everolimus is about 20
percent higher in Black patients.
Side effects — Side effects of everolimus seem to be dose related and are similar
to those seen for sirolimus, [72] and may include anemia, peripheral edema,
elevations in serum creatinine when used with full dose CNIs, diarrhea, nausea,
urinary tract infections, and hyperlipidemia. Mouth ulcers were not seen in heart
and kidney transplantation trials, but they were reported in the liver
transplantation trials.
INHIBITORS OF PURINE AND PYRIMIDINE SYNTHESISThe major
antimetabolite drugs are prodrugs of mycophenolic acid (MPA), a purine synthesis
inhibitor, and azathioprine.
The original drugs in this class, cyclophosphamide (Cytoxan)
and azathioprine (Imuran), are rarely used in transplantation in the United States,
although a multicenter study suggested that azathioprine is used routinely in the
United Kingdom [19]. While mycophenolate mofetil (MMF) has become more
popular than the other agents, clear evidence of superiority is lacking [74].
Azathioprine is sometimes substituted for MMF in women who are pregnant or of
118
childbearing age due to increased safety experience with it in pregnancy. MMF is
pregnancy class D.
Mycophenolate mofetil and mycophenolate sodium — MPA is produced by
several species of the fungus Penicillium. MPA is poorly absorbed, but two orally
available prodrugs are available in the United States: the 2-morpholinoethyl
ester, mycophenolate mofetil (MMF, CellCept), and mycophenolate sodium
(Myfortic). Both drugs are converted to MPA and eliminated predominantly via
glucuronidation and urinary excretion [75].
MPA inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the
formation of guanosine monophosphate (GMP). Cells depleted of GMP cannot
synthesize guanine triphosphate (GTP) or deoxy guanine triphosphate (d-GTP) and
therefore cannot replicate. Most mammalian cells are able to maintain GMP levels
through the purine salvage pathway. However, lymphocytes lack a key enzyme of
the guanine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase),
and cannot overcome the MPA-induced block. As a result, MPA selectively inhibits
the proliferation of both B and T lymphocytes [75].
Reports on the use of MMF in liver transplantation began to appear in the late
1990s [76-78]. MMF does not cause neurotoxicity or nephrotoxicity, and is widely
used as a calcineurin inhibitor (CNI)- or steroid-sparing agent. The most common
side effects are bone marrow suppression and gastrointestinal complaints,
including abdominal pain, ileus, nausea, vomiting, and oral ulceration. These
symptoms are usually dose-related and improve with temporary or permanent
dose reduction. Usual dosing is 1 g twice daily. Patients may tolerate the drug
better if it is initially dosed at 500 mg twice daily or 500 mg four times daily.
Myfortic (mycophenolate sodium) is formulated as 360 mg tablets and is typically
given as two tablets (720 mg) orally every 12 hours. Food may interfere with
absorption of the drugs, so they should be taken one hour before or two hours
after meals.
The role of MMF is similar to that of sirolimus in that it is used to reduce or
discontinue CNI dosing in order to treat side effects. Studies suggest MMF
monotherapy may be effective in certain situations long after liver transplantation:
●A randomized trial assigned 150 patients who had received a liver
transplantation and were maintained on a CNI to either continued therapy
with a CNI or to MMF monotherapy [79]. The mean time between liver
transplantation and study enrollment was 4.9 years for patients assigned to
continued CNI therapy, and 5.7 years for those assigned to MMF. After five
years of follow-up, there were no significant differences between those who
continued on a CNI and those who were switched to MMF with regard to
chronic rejection or patient survival (0 versus 0 percent and 94 versus 90

119
 percent, respectively). There was a trend toward lower acute rejection rates in
the CNI group (3 versus 11 percent, p = 0.055). All patients with acute
rejection were successfully treated with steroid-pulse therapy. Among
patients with renal insufficiency, renal function improved in those switched to
MMF. There were no significant differences between the groups with regard
to malignancy rates or to adverse cardiovascular, gastrointestinal, or
neurologic events.
●In a prospective open-label study, 19 patients at the University of
Washington were switched from azathioprine to MMF with cyclosporine,
which was then tapered [80]. After five years, seven patients remained off
cyclosporine, and six patients were on MMF monotherapy. Serum creatinine
in the seven patients off cyclosporine decreased significantly (from 2.2 to 1.9
mg/dL), while creatinine clearance increased significantly (from 38 to 47
mL/min). Control of arterial hypertension also improved. MMF appeared to
be well tolerated, although six patients required dose reductions.
The added immunosuppression of MMF may also allow for the early
discontinuation or avoidance of steroids [81].
Azathioprine — Azathioprine is a prodrug of 6-mercaptopurine, which is further
metabolized into 6-thioguanine (6-TG) nucleotides that inhibit purine synthesis. By
preventing the de novo synthesis of purines, and thus interfering with RNA and
DNA synthesis, azathioprine inhibits the replication of T and B cells. Azathioprine is
typically given at a dose of 1.5 to 2.0 mg/kg daily, up to a maximum dose of 200
mg daily [82]. Assessing thiopurine methyltransferase metabolite (TPMT) enzyme
activity and measuring levels of 6-TG can help optimize dosing of azathioprine.
(See "Thiopurines: Pretreatment testing and approach to therapeutic drug
monitoring for adults with inflammatory bowel disease".)
Side effects of azathioprine include bone marrow suppression, nausea, vomiting,
pancreatitis, hepatotoxicity, and neoplasia. (See "Pharmacology and side effects of
azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)
ANTIBODY THERAPYBecause T and B cells express specific antigens on their
cell surfaces, antibodies to these markers can be used to deplete populations of
cells. The initial concept of lymphoid depletion by thoracic duct fistula [83] gave
way to the more elegant method of antithymocyte globulin preparations, now
refined to include humanized antibodies and monoclonal antibodies against
specific cell surface proteins such as the interleukin (IL)-2 receptor [84].
These agents are not used routinely in liver transplantation, but have an important
role in treating steroid-resistant rejection and as calcineurin inhibitor (CNI)-sparing
agents in the immediate post-transplant period. Antibody therapy may also permit
steroid free immunosuppression regimens if needed. We generally use antibody
120
preparations in the rare case of steroid-resistant rejection and in situations where
we wish to minimize CNI dosing, such as in patients with pretransplant renal
failure. (See "Liver transplantation in adults: Treatment of acute T cell-mediated
(cellular) rejection of the liver allograft", section on 'Therapy for nonresponders'.)
Polyclonal antibodies — Antithymocyte globulin (ATG, thymoglobulin) and
antilymphocyte globulin (ALG) are prepared by immunizing animals against mixed
populations of thymocytes. The resulting preparations have antibodies to multiple
T-cell antigens including CD2, CD3, CD4, and CD8. They are administered via a
central line and result in profound lymphopenia by complement-mediated cell lysis
and uptake of opsonized cells. Repopulation occurs within 3 to 10 days.
Polyclonal antibodies have been used for induction of immunosuppression or
treatment of steroid-resistant rejection [15,85-87]. A review of the Scientific
Registry of Transplant Recipient (SRTR) data between 1993 and 2003 showed that
antibodies were used commonly in kidney, kidney/pancreas, and intestinal
transplants, but uncommonly (<20 percent) in liver transplantation [88]. The
authors also noted a shift from muromonab-CD3 and horse ATG to rabbit ATG and
anti-IL-2 receptor antagonists.
In addition, a large series examined the efficacy of rabbit ATG following liver
transplantation [87]. The series included 500 patients who received a single dose
of solumedrol followed by ATG induction. Patients also
received mycophenolate mofetil and tacrolimus or sirolimus. The tacrolimus or
sirolimus was weaned after three months. After one year, patient and graft
survival rates were 93 and 90 percent, respectively. Rejection occurred in 114
patients (23 percent) and 33 patients required glucocorticoids (7 percent).
Complications with these agents include fever, chills, rash, anemia,
thrombocytopenia, serum sickness, and nephritis. Although our personal
preference is to use monoclonal antibodies when necessary, some reports suggest
that polyclonal antibodies are still in use in pediatric and adult patients undergoing
liver transplantation [89,90].
Monoclonal antibodies
Basiliximab — Basiliximab (Simulect) and daclizumab (Zenapax) are humanized
monoclonal antibodies against the IL-2 receptor. Blockade of the IL-2 receptor
prevents T-cell proliferation. The chimeric structure makes both preparations less
immunogenic than muromonab-CD3 (OKT3, no longer available), and they have
longer half-lives and are better tolerated. Basiliximab, for example, has an
elimination half-life of 4.1±2.1 days, and complete saturation of interleukin-2
receptor alpha-chain was maintained as long as serum concentrations exceeded
0.1 microgram/mL [91]. The mean duration of receptor saturation was 23 +/- 7

121
days after transplantation (range of 13 to 41 days). The half-life may be decreased
by the presence of bleeding or ascites.
Similar efficacy has been demonstrated with daclizumab dosed at 2 mg/kg on
post-orthotopic liver transplant (OLT) days 1 and 3, and 1 mg/kg on day 8 [92].
CD25 suppression was confirmed through day 30, and maximal effects were noted
with a daclizumab concentration of at least 5 micrograms/mL. Similarly, a
nonrandomized study of daclizumab 2 mg/kg before engraftment and 1 mg/kg on
day 5 post-OLT resulted in a much lower rejection rate in the first six months (18
versus 40 percent), marked improvement in renal function, and no increase in
cytomegalovirus (CMV) or infectious complications when compared with a control
group treated with standard immunosuppression [93].
However, daclizumab was removed from the market in 2018 due to safety
concerns following several reports of inflammatory encephalitis and
meningoencephalitis [94,95].
Antibodies can be used to reduce CNI use in patients with pre-OLT renal disease
[96] or to minimize steroid use [22,97]. In one report with median follow-up of 22
months, basiliximab controlled steroid-resistant rejection after OLT in five out of
seven children [98].
Few controlled trials have compared contemporary immunosuppressive regimens
involving these agents. One randomized multicenter study
compared tacrolimus plus steroids (T+S; 347 patients) to a steroid-free tacrolimus
plus daclizumab group (T+D; 351 patients) [99]. The incidence of biopsy-confirmed
glucocorticoid-resistant acute rejection was higher in the T+S group (6 versus 3
percent), although graft and patient survival were comparable. The overall adverse
event profiles were similar, but the incidences of diabetes mellitus (15 versus 6
percent) and CMV infection (12 versus 5 percent) were significantly higher in the
T+S group. Mean cholesterol levels increased by 16 percent in the T+S group, but
were unchanged in the T+D group.
INVESTIGATIONAL AGENTS
Belatacept (LEA29Y) — Belatacept is a high affinity fusion protein that binds
CD80/86 on antigen-presenting cells (APCs). This prevents binding of CD80/86 to
CD28 on the T cell (signal II in Figure 1) (figure 1), and blocks the costimulatory
pathway [100]. The drug is given as a monthly infusion and may permit
immunosuppression without nephrotoxicity. Several reports confirm its
effectiveness in renal transplantation [101-103], but an increased rate of post-
transplant lymphoproliferative disorder (especially involving the central nervous
system [104]) has confined its use to Epstein-Barr virus-positive recipients. We are
unaware of belatacept use in liver transplantation.

122
Efalizumab — This is a humanized monoclonal antibody against leukocyte
function-associated antigen-1 (LFA-1; CD11a). LFA-1 plays multiple roles in
rejection, including cell migration, cell adhesion, and stabilization of the APC-T-cell
complex. An open-label trial of efalizumab with lower doses of standard
immunosuppression suggested that the drug was effective, but associated with an
11 percent incidence of PTLD [101]. The role of this potent compound in liver
transplantation has yet to be determined.
A few other agents, including alefacept and a Janus tyrosine kinase 3 inhibitor, are
in early testing in renal transplantation [105].
Alemtuzumab — Alemtuzumab is a humanized monoclonal, complement-fixing,
anti-CD52 antibody. CD52 is expressed on the surface of B lymphocytes, T
lymphocytes, macrophages, monocytes, and eosinophils. Through complement
activation, alemtuzumab leads to profound lymphocyte depletion. It is approved
by the US Food and Drug Administration for the treatment of chronic B-cell
lymphocytic leukemia, but it has also been used for immunosuppression following
solid organ transplantation. In liver transplantation, alemtuzumab has been
proposed as a method to decrease steroid and calcineurin inhibitor use [16].
However, concern about profound immunosuppression with attendant infectious
complications and PTLD have reduced enthusiasm for alemtuzumab [106-108],
although one review supports further studies [109].
IMMUNOSUPPRESSION MANAGEMENT IN PATIENTS
UNDERGOING NON-TRANSPLANT SURGERYPatients should continue to
take their immunosuppressive medication around the time of surgery, although
the route of administration may need to be changed if the patient cannot tolerate
oral medication. Intravenous administration of calcineurin inhibitors (CNIs) is
associated with a higher risk of nephrotoxicity and should be avoided if possible.
In addition, clinicians should be careful to check for potential drug interactions
with medications used around the time of surgery (eg, antimicrobials or
antifungals). The patient's transplant hepatologist should be consulted prior to
making any changes to the immunosuppression regimen. (See 'Drug
interactions' above.)

In patients receiving glucocorticoids, additional perioperative glucocorticoid

coverage should be considered for patients likely to have suppression of their
hypothalamic-pituitary-adrenal axis (eg, those on long-term, higher dose
glucocorticoids). Stress dose steroids are rarely necessary.

STOPPING IMMUNOSUPPRESSIONSome patients will develop

immunologic tolerance following liver transplantation and may be able to stop

123
taking immunosuppressants [110]. However, because of the risk of graft rejection
and because it is not yet clear which patients are good candidates for stopping
immunosuppression, additional studies are needed before recommending
attempts at stopping immunosuppression. We have seen a number of fatal
rejections in patients who stopped immunosuppression without medical
supervision, including patients many years post-orthotopic liver transplant. We
therefore never recommend stopping all immunosuppression.
Discontinuing immunosuppression was examined in a study of 24 patients without
active viral hepatitis or autoimmune disease who had side effects from
immunosuppression or who were at high risk for developing de novo malignancy
[111]. The patients underwent gradual reduction of their immunosuppression.
Patients who had normal liver function tests following withdrawal of
immunosuppression were considered to be tolerant. After a median of 14 months,
15 patients (63 percent) were tolerant. The remaining nine patients could not have
their immunosuppression completely withdrawn because of abnormal liver tests.
In these patients, immunosuppression was increased with normalization of liver
function in seven patients. The remaining two patients underwent liver biopsy.
One had mild chronic rejection, and one had acute rejection that was treated with
glucocorticoids. A longer median interval between transplantation and inclusion in
the study was associated with tolerance (156 months for patients who developed
immunotolerance versus 71 months for those who did not).
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Organ rejection is a multistep process that includes alloantigen recognition,
lymphocyte activation, clonal expansion, and graft inflammation.
(See 'Immunobiology of acute rejection' above.)
●Tacrolimus remains the mainstay of immunosuppression in many centers.
(See 'Tacrolimus' above.)
●For patients with pretransplant renal failure in whom we wish to minimize
the use of calcineurin inhibitors (CNI), we generally use antibody
preparations in the immediate post-transplant period along with delayed
calcineurin inhibitors. (See 'Antibody therapy' above and 'Calcineurin
inhibitors' above.)
●Slowly worsening renal disease in the late post-orthotopic liver transplant
period can be managed by reducing the CNI dose, with the addition of MMF,
or by switching to sirolimus or everolimus. (See 'Inhibitors of mammalian
(mechanistic) target of rapamycin (mTOR)' above.)
124
●Some patients will develop immunologic tolerance following liver
transplantation and may be able to stop taking immunosuppressants.
However, because of the risk of irreversible graft rejection, and because we
have no tools to assess which patients are good candidates for stopping
immunosuppression, we never recommend complete cessation of
immunosuppression. (See 'Stopping immunosuppression' above.)

125
Liver transplantation in adults: Patient selection
and pretransplantation evaluation
Authors:
Lorna M Dove, MD, MPH
Robert S Brown, Jr, MD, MPH
Section Editor:
Keith D Lindor, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Mar 26, 2021.
INTRODUCTIONLiver transplantation is an important treatment option for
patients with acute liver failure, end-stage liver disease, and primary hepatic
malignancy, though it is not the initial or primary treatment modality for most liver
diseases.

Transplantation infrequently cures the underlying disease; recurrent liver disease

after transplantation occurs in 0 to 100 percent of patients, depending on the
disease for which transplantation was performed. Thus, the decision to list a
patient for transplantation is a risk-benefit analysis in which the inherent risks of
surgery, recurrent disease, and long-term immunosuppression must be weighed
against the potential benefits of transplantation. These benefits differ for each
patient but include improvements in survival, prevention of long-term
complications, and better health-related quality of life. In most cases, the risks
associated with recurrent disease do not outweigh the benefits of liver
transplantation.

This topic will review the selection of patients for liver transplantation and the
pretransplantation evaluation. Other issues related to liver transplantation
including donor selection, living donor liver transplantation, immunosuppression
following liver transplantation, and the medical management of patients who have
undergone liver transplantation are discussed elsewhere. (See "Liver
transplantation in adults: Deceased donor evaluation and selection" and "Living
donor liver transplantation in adults" and "Liver transplantation in adults:
Overview of immunosuppression" and "Liver transplantation in adults: Long-term
management of transplant recipients".)

126
The American Association for the Study of Liver Diseases and the American Society
of Transplantation have developed guidelines regarding the indications for liver
transplantation and the evaluation of patients being considered for liver
transplantation [1]. The discussion that follows is generally consistent with those
guidelines.
FREQUENCY OF LIVER TRANSPLANTATION BY UNDERLYING
LIVER DISEASEAccording to the United Network for Organ Sharing/Organ
Procurement and Transplantation Network registry, hepatocellular carcinoma and
hepatitis C virus cirrhosis have been the most common diseases leading to liver
transplantation, although increasing numbers of patients with alcoholic cirrhosis
and nonalcoholic steatohepatitis are receiving transplants [2,3]. For additional
information, see optn.transplant.hrsa.gov/data/view-data-reports.
INDICATIONS
Acute liver failure — Patients with acute liver failure are given the highest priority
for liver transplantation (United Network for Organ Sharing [UNOS] status 1). In
the absence of liver transplantation, patients with acute liver failure will either
have a complete recovery of liver function or will die [4]. However, because it can
be difficult to predict whether a given patient will recover, patients with acute liver
failure should be referred to a liver transplantation center as soon as possible.
(See "Acute liver failure in adults: Management and prognosis", section on 'Liver
transplantation'.)
Acute liver failure is defined by the development of severe acute liver injury with
encephalopathy and impaired synthetic function (international normalized ratio
[INR] of ≥1.5) in a patient without cirrhosis or preexisting liver disease. While the
time course that differentiates acute liver failure from chronic liver failure varies
between reports, a commonly used cutoff is an illness duration of <26 weeks.
While there are numerous causes of acute liver failure (table 1), viral and drug-
induced hepatitis are the most common causes of acute liver failure in adults.
(See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
Cirrhosis — The presence of cirrhosis alone is not sufficient to warrant
transplantation. Transplantation is generally considered when a patient has
suffered either a complication of portal hypertension or a manifestation of
compromised hepatic function [1]. Variceal hemorrhage, ascites, and
encephalopathy are the primary manifestations of end-stage liver disease and are
designated as markers of decompensation. The onset of decompensation is
associated with significantly impaired survival. Another complication of cirrhosis is
the development of hepatorenal syndrome, which is an ominous marker and
signals the need for immediate transplantation evaluation. (See "Cirrhosis in
adults: Overview of complications, general management, and prognosis".)
127
Patients with cirrhosis are typically candidates for liver transplantation once their
biologic Model for End-stage Liver Disease (MELD) score is ≥15 (MELD-Na score).
However, some patients with Child B cirrhosis (table 2) with portal hypertension
but a low MELD score may be candidates for liver transplantation. The
transplantation evaluation is typically started once a patient has a MELD score >10.
This permits the patient to meet the transplantation team prior to the
development of end-stage liver disease and ensures adequate time for the patient
to complete the pretransplantation evaluation. If patients are referred for
evaluation once end-stage liver disease has developed, there may not be adequate
time for education, and the patient may have impaired mental status from
underlying encephalopathy. (See "Model for End-stage Liver Disease (MELD)",
section on 'Prioritization for liver transplantation based on MELD score'.)
Patients may also qualify for liver transplantation if they have a complication or
condition that qualifies for standard MELD exception points. Exception points are
awarded because there are some conditions associated with chronic liver disease
that may result in impaired survival but are not directly accounted for in the MELD
scoring system. Conditions that qualify for MELD exception points include
(see "Model for End-stage Liver Disease (MELD)", section on 'Standard MELD
exceptions in liver transplantation'):
●Hepatocellular carcinoma
●Hepatopulmonary syndrome
●Portopulmonary hypertension (provided the mean arterial pressure can be
maintained at <35 mmHg with treatment)
●Familial amyloid polyneuropathy
●Primary hyperoxaluria
●Cystic fibrosis
●Hilar cholangiocarcinoma (provided the liver transplantation center has a
UNOS-approved protocol detailing the work-up and management of patients
with cholangiocarcinoma undergoing transplantation)
●Hepatic artery thrombosis (occurring within 14 days of liver transplantation
but not meeting criteria for status 1A)
Finally, patients may have complicating medical conditions that are related to their
liver disease but that do not qualify for standard MELD exception points. Such
patients can be considered for liver transplantation if their clinicians believe that
the biologic MELD score does not adequately reflect a patient's true liver-related
morbidity and mortality or if the complications are severely impairing the patient's
quality of life. Some of these complications include (see "Model for End-stage Liver
Disease (MELD)", section on 'Petitioning for additional MELD points'):

128
 ●Recurrent cholangitis in patients with primary sclerosing cholangitis who are
on antibiotic suppressive therapy or require repeated biliary interventions
●Refractory ascites
●Refractory hepatic encephalopathy
●Refractory variceal hemorrhage
●Portal hypertensive gastropathy leading to chronic blood loss
●Intractable pruritus in a patient with primary biliary cirrhosis
Liver neoplasms — Patients with some primary liver neoplasms may be
candidates for liver transplantation, provided the neoplasms meet specific criteria
(eg, for patients with hepatocellular carcinoma [HCC], a single lesion ≤5 cm or up
to three separate lesions all <3 cm, no evidence of gross vascular invasion, and no
regional nodal or distant metastases). In addition, there may be a role for liver
transplantation in patients with neuroendocrine tumors that have metastasized to
the liver, but experience in this setting is limited [5]. (See "Metastatic
gastroenteropancreatic neuroendocrine tumors: Local options to control tumor
growth and symptoms of hormone hypersecretion", section on 'Liver
transplantation'.)
Some of the liver neoplasms that have been treated with liver transplantation
include [5]:
●HCC (including fibrolamellar HCC) (see "Liver transplantation for
hepatocellular carcinoma" and "Epidemiology, clinical manifestations,
diagnosis, and treatment of fibrolamellar carcinoma", section on 'Liver
transplantation')
●Epithelioid hemangioendothelioma [6-8]
●Large hepatic adenomas (see "Hepatocellular adenoma")
Metabolic disorders — Several liver-based metabolic conditions with systemic
manifestations may be treated with liver transplantation. In some cases (eg, alpha-
1 antitrypsin deficiency and Wilson disease), patients are cured of the underlying
disease with liver transplantation, though some clinical manifestations may not be
reversible.

Liver-based metabolic conditions that have been treated with liver transplantation
include:

●Familial amyloid polyneuropathy (qualifies for standard MELD exception

points) [9-11].
●Primary hyperoxaluria (qualifies for standard MELD exception points)
(see "Primary hyperoxaluria", section on 'Transplantation').
●Cystic fibrosis (qualifies for standard MELD exception points) (see "Cystic
fibrosis: Hepatobiliary disease", section on 'Management').
129
 ●Alpha-1 antitrypsin deficiency [12,13].
●Some forms of glycogen storage disease (type I and type IV) (see "Glucose-6-
phosphatase deficiency (glycogen storage disease I, von Gierke disease)",
section on 'Liver transplantation' and "Glycogen branching enzyme deficiency
(glycogen storage disease IV, Andersen disease)", section on 'Treatment').
●Tyrosinemia (see "Disorders of tyrosine metabolism", section on 'Liver
transplantation').
●Hemochromatosis [14,15].
●Wilson disease (see "Wilson disease: Treatment and prognosis", section on
'Liver transplantation').
●Acute intermittent porphyria (see "Acute intermittent porphyria:
Management", section on 'Liver transplantation').

In the case of alpha-1 antitrypsin deficiency, cystic fibrosis, tyrosinemia,

hemochromatosis, and Wilson disease, liver transplantation is usually reserved for
patients who have developed end-stage liver disease or HCC.

CONTRAINDICATIONSAlthough organ allocation is centralized, criteria and

contraindications to listing for liver transplantation are often transplantation
center-specific. General contraindications adopted by most centers include [1]:
●Cardiopulmonary disease that cannot be corrected and is a prohibitive risk
for surgery
●Acquired immunodeficiency syndrome (AIDS)
●Malignancy outside of the liver not meeting oncologic criteria for cure
●Hepatocellular carcinoma with metastatic spread
●Intrahepatic cholangiocarcinoma
●Hemangiosarcoma
●Anatomic abnormalities that preclude liver transplantation
●Uncontrolled sepsis
●Acute liver failure with a sustained intracranial pressure >50 mmHg or a
cerebral perfusion pressure <40 mmHg
●Persistent nonadherence with medical care
●Lack of adequate social support
For patients with alcohol-associated liver disease, many programs require a
minimum period of abstinence of six months, participation in a structured
rehabilitation and abstinence program, and adequate social support to help
maintain sobriety. However, it has been suggested that the six-month period of
abstinence be reconsidered in patients with severe alcoholic hepatitis and that
methods to identify transplant candidates who are at low risk of relapse are
needed. Pretransplant management and post-transplant outcomes for patients
130
with alcohol-associated liver disease are discussed in more detail separately.
(See "Liver transplantation for alcoholic liver disease" and "Management and
prognosis of alcoholic hepatitis", section on 'Liver transplantation'.)
Advanced age and human immunodeficiency virus (HIV) (but not AIDS) are
examples of relative contraindications that are site-specific and are often decided
on a case-by-case basis. Liver transplantation can be performed in those older
than 65 years of age, provided that there has been a comprehensive evaluation for
comorbidities [16].
Many transplantation centers in the United States and Europe perform liver
transplantation for patients with HIV [17-24]. Early studies have suggested
favorable outcomes for patients who were not coinfected with hepatitis C virus
(HCV) [25-27]. Initial studies on the efficacy of direct-acting antiviral therapy in
coinfected patients are promising; therefore, we anticipate that further study will
demonstrate similar post-transplant survival rates for HIV/HCV-coinfected patients
compared with HCV-monoinfected patients [28,29]. We list patients with HIV for
transplantation if they meet other criteria. We do not exclude patients with HCV
coinfection because antiviral therapy for HCV improves outcomes following
transplantation. (See "Hepatitis C virus infection in liver transplant candidates and
recipients".) In addition to the standard pretransplantation counseling, patients
with HIV have the option of receiving an organ from an HIV-infected donor,
according to the HIV Organ Policy Equity Act, enacted in 2013 [30]. (See "Kidney
transplantation in adults: Kidney transplantation in patients with HIV", section on
'Donors with HIV'.)
Society guidelines suggest that class 3 obesity (body mass index [BMI] ≥40) is a
relative contraindication to liver transplant [1]. However, the available data are not
conclusive as to whether patients with increased BMI and/or metabolic syndrome
have worse outcomes following transplantation [31,32]. Whether all patients with
high BMI should be excluded from transplantation and what cutoff should be used
(BMI >40, >50) remains controversial, and some centers will perform a gastric
sleeve before or at the time of transplantation [33].
PRETRANSPLANTATION EVALUATIONThe goal of the pretransplantation
evaluation is to assess the patient's ability to tolerate the stress of surgery,
immunosuppression, and the demands of post-transplantation care. Thus, each
patient undergoes an extensive cardiopulmonary evaluation, screening for occult
infection or cancer, and psychosocial evaluation (table 3). Specific testing varies
depending on the patient's age, medical history, and transplantation center
practice. In addition, while a certain battery of tests may initiate the work-up, more
testing may be indicated if the initial test results are abnormal or if the patient has

131
signs or symptoms of a significant comorbid illness that is not evaluated as part of
the initial evaluation.
Laboratory testing — Laboratory tests that should be obtained in patients being
evaluated for liver transplantation include:
●ABO-Rh blood typing
●Liver biochemical and function tests (alanine aminotransferase, aspartate
aminotransferase, alkaline phosphatase, bilirubin, international normalized
ratio [INR])
●Complete blood count with differential
●Creatinine clearance
●Serum sodium
●Serum alpha-fetoprotein
●Calcium and vitamin D levels
●Serologies for cytomegalovirus, Epstein-Barr virus, varicella, human
immunodeficiency virus, hepatitis A, hepatitis B, hepatitis C, rapid plasma
reagin (RPR)
●Urinalysis
●Urine drug screen
Cardiopulmonary evaluation — The cardiopulmonary evaluation is designed to
evaluate for coronary artery disease, valvular heart disease, cardiomyopathy,
obstructive or restrictive lung disease, hepatopulmonary syndrome, and
pulmonary hypertension [1,34-36]. There are some nuances in cardiac evaluation
(reduced afterload, hyperdynamic circulation, etc.) that need to be taken into
account in patients with cirrhosis to ensure that the work-up is appropriately
vigorous. Some findings discovered during initial testing may permanently
preclude transplantation, whereas others may need to be treated or corrected
prior to surgery.

We obtain noninvasive cardiac testing for all patients over 40 years of age and for
those younger than 40 years if there are multiple risk factors for coronary artery
disease. We obtain pulse oximetry and an arterial blood gas in all patients. We also
perform pulmonary function testing in all patients who are able to undergo the
testing. In patients who are unable to undergo testing, pulmonary function is
assessed based on the patient's history, physical exam, arterial blood gas, and
chest imaging.

Morbidity and mortality from liver transplantation are increased in patients with
coronary artery disease [37] or those with severe hypoxemia and elevated mean
pulmonary artery pressure measurements [38,39]. However, the risk of poor
outcomes does not appear to be increased in patients with mild to moderate
132
pulmonary hypertension (pulmonary artery systolic pressure between 40 and 59
mmHg) [40]. (See "Liver transplantation in adults: Long-term management of
transplant recipients", section on 'Cardiovascular risk' and "Management of cardiac
risk for noncardiac surgery".)
Electrocardiogram — We obtain an electrocardiogram to look for signs of cardiac
arrhythmias, conduction defects, signs of prior cardiac ischemia, or chamber
enlargement/hypertrophy. (See "ECG tutorial: Basic principles of ECG analysis".)
Cardiac stress testing — To screen for coronary artery disease, we obtain
noninvasive cardiac testing for all patients over 40 years of age and for those
younger than 40 years if there are multiple risk factors for coronary artery disease.
(See "Stress testing for the diagnosis of obstructive coronary heart disease".)

However, the ideal evaluation of coronary artery disease prior to liver

transplantation is unclear:

●The American Heart Association and the American College of Cardiology

Foundation has suggested noninvasive stress testing in liver transplantation
candidates with no active cardiac conditions if there are multiple (three or
more) risk factors for coronary artery disease present (eg, diabetes, prior
cardiovascular disease, left ventricular hypertrophy, age greater than 60
years, smoking, hypertension, or dyslipidemia) [41]. (See "Overview of
established risk factors for cardiovascular disease", section on 'Established
risk factors for atherosclerotic CVD'.)
●The American Association for the Study of Liver Diseases and the American
Society of Transplantation has recommended noninvasive cardiac testing
(either exercise stress testing or pharmacologic stress testing) for all adults
being evaluated for liver transplantation [1].
●Some cardiologists have recommended that patients with known coronary
artery disease, diabetes mellitus, or more than two cardiovascular risk factors
undergo coronary angiography to assess the extent and severity of coronary
artery disease [42].
Another method that is being studied for pretransplant evaluation is submaximal
cardiopulmonary exercise testing. One study found that the calculated anaerobic
threshold (which corresponds with cardiorespiratory reserve) predicted post-
transplantation mortality [43]. Survivors of liver transplantation had higher mean
anaerobic thresholds than patients who did not survive (12.0 versus 8.4
mL/min/kg). This method of pretransplantation evaluation is not in widespread
use. (See "Cardiopulmonary exercise testing in cardiovascular disease", section on
'Ventilatory anaerobic threshold determination'.)

133
If initial noninvasive testing is abnormal, cardiac catheterization is indicated. If
clinically significant coronary artery stenoses are present, patients should be
evaluated for revascularization prior to transplantation. (See "Percutaneous
coronary intervention of specific coronary lesions" and "Left main coronary artery
disease" and "Management of significant proximal left anterior descending
coronary artery disease".)
Echocardiography — We obtain transthoracic contrast-enhanced
echocardiography to look for evidence of valvular heart disease, portopulmonary
hypertension, or decreased cardiac function, which may be a result of cirrhotic
cardiomyopathy. (See "Definition and classification of the cardiomyopathies",
section on 'Cirrhotic cardiomyopathy' and "Portopulmonary hypertension".)
Contrast-enhanced echocardiography is also part of the evaluation of patients with
suspected hepatopulmonary syndrome. (See 'Pulse oximetry' below.)
Portopulmonary hypertension refers to pulmonary arterial hypertension that is
associated with portal hypertension. Symptoms and signs of pulmonary
hypertension (PH) may be difficult to recognize because they are nonspecific.
Initially, patients present with fatigue, exertional dyspnea and a loud pulmonic
component of the second heart sound. If the echocardiography suggests PH,
additional testing is required to confirm the diagnosis and to rule out other causes
of PH. (See "Portopulmonary hypertension", section on 'Diagnostic evaluation'.)
Pulse oximetry — Patients should undergo pulse oximetry to screen for
hepatopulmonary syndrome. Hepatopulmonary syndrome is considered present
when the following triad exists:
●Liver disease
●Impaired oxygenation
●Intrapulmonary vascular abnormalities, referred to as intrapulmonary
vascular dilatations
The presence of hepatopulmonary syndrome worsens the prognosis of patients
with cirrhosis. As a result, patients with hepatopulmonary syndrome receive
standard Model for End-stage Liver Disease (MELD) exception points. If the oxygen
saturation on pulse oximetry is low (<96 percent [44]), patients should have a
blood gas obtained while breathing room air and undergo transthoracic contrast-
enhanced echocardiography. Testing should also be obtained to rule out
alternative causes for a low oxygen saturation. Testing to rule out other causes
includes a chest radiograph, pulmonary function tests, and chest computed
tomography (CT). (See "Hepatopulmonary syndrome in adults: Prevalence, causes,
clinical manifestations, and diagnosis", section on 'Diagnostic
evaluation' and "Model for End-stage Liver Disease (MELD)", section on 'Standard
MELD exceptions in liver transplantation'.)

134
We also perform an arterial blood gas in patients with normal pulse oximetry to
calculate their age-adjusted alveolar-arterial gradient (calculator 1).
Additional testing for pulmonary disease — The role of pulmonary function
testing with diffusing capacity of the lungs for carbon monoxide to look for
evidence of hepatopulmonary syndrome or primary lung disease is controversial,
and there is wide variation in practice. Some transplantation centers perform such
testing in all transplant candidates, while others restrict testing to patients with
symptoms, smoking history, or prior known lung disease. Similarly, the use of
chest radiography and chest CT scan to look for signs of pulmonary disease is
variable. (See "Overview of pulmonary function testing in adults", section on
'Pulmonary function tests'.)
Cancer screening — Cancer screening should include abdominal CT scanning or
magnetic resonance imaging (MRI) to look for hepatocellular carcinoma (HCC) and
a skin examination to look for evidence of skin cancer. Colorectal cancer screening
is indicated for patients who are ≥50 years of age (or younger for selected patients
such as those with family history of colon cancer in a first-degree relative or those
with primary sclerosing cholangitis). The approach to colon cancer screening is
discussed separately. (See "Screening for colorectal cancer: Strategies in patients
at average risk" and "Screening for colorectal cancer in patients with a family
history of colorectal cancer or advanced polyp".)
Screening for cervical cancer, breast cancer, and prostate cancer should be
obtained when indicated based on the patient's sex and age. (See "Screening for
cervical cancer in resource-rich settings" and "Screening for breast cancer:
Strategies and recommendations" and "Screening for prostate cancer".)
Infectious disease evaluation and vaccinations — In addition to obtaining
serologies for several viral infections, the infectious disease evaluation should
include skin testing or interferon-gamma release assay for tuberculosis. If positive,
treatment may be initiated prior to transplantation or deferred until after
transplantation, depending on the clinical assessment of the patient (eg, treatment
should be initiated prior to transplantation if the patient has any signs or
symptoms of tuberculosis). Similarly, any required dental extractions should be
carried out prior to transplantation. Patients from endemic areas should be
screened for coccidiomycosis or strongyloides (table 4). (See "Infectious
complications in liver transplantation".)
Several vaccinations are recommended prior to liver transplantation including
COVID-19 [45], hepatitis A, hepatitis B, pneumococcus, influenza, diphtheria,
pertussis, and tetanus. Immunizations in solid organ transplantation candidates
are discussed in detail elsewhere. (See "Immunizations in solid organ transplant
candidates and recipients".)

135
Hepatic imaging and HCC staging — Hepatic imaging should be obtained to
assess the vasculature (to ensure there are no anatomic barriers to
transplantation) and, in the case of HCC, for tumor staging. This is typically done
with multiphase contrast-enhanced CT scanning or contrast-enhanced MRI. If
cross-sectional imaging cannot be obtained, the hepatic vasculature can be
assessed with transabdominal ultrasonography with Doppler imaging or contrast-
enhanced ultrasonography (where available). (See "Staging and prognostic factors
in hepatocellular carcinoma", section on 'Staging and prognostic scoring
systems' and "Contrast-enhanced ultrasound for the evaluation of liver lesions",
section on 'Liver transplantation'.)
Upper endoscopy — Upper endoscopy should be performed in patients with
cirrhosis or portal hypertension to evaluate for varices. (See "Primary and pre-
primary prophylaxis against variceal hemorrhage in patients with cirrhosis",
section on 'Screening for varices'.)
Bone density testing — Patients should be screened for osteoporosis with bone
density testing. If osteoporosis is present, treatment should be initiated prior to
transplantation. Oral bisphosphonates should be used with caution in patients
with esophageal varices, and patients should be aware of the importance of taking
the drugs as instructed (eg, sitting upright for at least 30 minutes after taking the
drug). Patients who are osteopenic should receive calcium and vitamin D
supplementation. (See "Overview of the management of osteoporosis in
postmenopausal women", section on 'Choice of drug' and "Overview of the
management of osteoporosis in postmenopausal women", section on
'Calcium/vitamin D'.)
Psychosocial evaluation and education — In addition to a standard medical
evaluation, initial assessment should include an educational session discussing the
risks and benefits of transplantation, including the potential for poor outcomes. A
psychological evaluation and assessment of the patient's social supports is
another key part of the evaluation.
The purpose of this assessment is to identify issues that may impair a successful
outcome after transplantation. These potential problems include a lack of insight
into the nature of the transplantation procedure, post-transplantation care, and
substance use disorders. The assessment includes education of the family and/or
the patient's support network. The ability to comply with complex medical and
behavioral regimens is crucial after any organ transplantation procedure.
Recipients must be able to incorporate complicated medication regimens, follow-
up appointments, and frequent laboratory visits into their lives. Making spouses,
friends, and family aware of these requirements encourages patient compliance

136
and may improve long-term success. (See "Screening for unhealthy use of alcohol
and other drugs in primary care".)
In patients with a history of a substance use disorder (drugs or alcohol), treatment
should be provided prior to transplantation in an effort to increase the likelihood
of success after transplantation. The treatment requirements vary among different
transplantation centers but often include participation in a structured
rehabilitation and abstinence program, adequate social support to help maintain
sobriety, and a minimum period of sobriety prior to listing for transplantation.
(See "Liver transplantation for alcoholic liver disease".)
CANDIDATES FOR LIVING DONOR LIVER TRANSPLANTATIONLiving
donor liver transplantation (LDLT) in adults was initiated in response to the
growing shortage of organs from deceased donors [46]. Recipients considered for
LDLT should fulfill the same minimal listing criteria established for deceased donor
liver transplantation. The goal is to avoid premature transplantation. The optimal
Model for End-stage Liver Disease (MELD) score at which patients should undergo
LDLT has yet to be determined [47]. The optimal MELD score is one that identifies
the recipient when the chance of liver disease-related mortality is greater than the
chance of mortality from surgical complications.
Evaluation of the adult living liver donor candidate, surgical technique, and
outcomes of LDLT are discussed separately. (See "Living donor liver
transplantation in adults".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

137
 ●Basics topic (see "Patient education: Liver transplant (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications for liver transplantation include acute liver failure, cirrhosis with
complications, some liver neoplasms, and liver-based metabolic conditions
with systemic manifestations. (See 'Indications' above.)
•Patients with acute liver failure are given the highest priority for liver
transplantation and should be referred to a liver transplantation center
for evaluation as soon as possible. (See 'Acute liver failure' above.)
•Patients with cirrhosis are typically candidates for liver transplantation
once their biologic Model for End-stage Liver Disease (MELD) score is ≥15
(MELD-Na score). However, the transplantation evaluation is typically
started once a patient has a MELD score >10. This permits the patient to
meet the transplantation team prior to developing end-stage liver disease
and ensures adequate time for the patient to complete the
pretransplantation evaluation. (See 'Cirrhosis' above.)
Patients with cirrhosis may also qualify for liver transplantation if they
have a complication that qualifies for standard MELD exception points
including hepatocellular carcinoma (HCC), hepatopulmonary syndrome,
and portopulmonary hypertension. (See "Model for End-stage Liver
Disease (MELD)", section on 'Standard MELD exceptions in liver
transplantation'.)
Finally, patients with cirrhosis may be considered for liver transplantation
if they have other complications related to cirrhosis such as refractory
ascites, though they do not receive standard MELD exception points.
(See "Model for End-stage Liver Disease (MELD)", section on 'Petitioning
for additional MELD points'.)
•Patients with some primary liver neoplasms (eg, HCC) may be candidates
for liver transplantation, provided the neoplasms meet specific criteria. In
addition, there may be a role for liver transplantation in patients with
neuroendocrine tumors that have metastasized to the liver, but
experience in this setting is limited. (See 'Liver neoplasms' above.)
•Liver-based metabolic conditions with systemic manifestations that may
be treated with liver transplantation include familial amyloid
polyneuropathy, primary hyperoxaluria, and cystic fibrosis. (See 'Metabolic
disorders' above.)
●Contraindications to liver transplantation include cardiopulmonary disease
that cannot be corrected and is a prohibitive risk for surgery, malignancy
outside of the liver not meeting oncologic criteria for cure, metastatic HCC,

138
intrahepatic cholangiocarcinoma, persistent nonadherence with medical
care, and lack of adequate social support. (See 'Contraindications' above.)
●The goal of the pretransplantation evaluation is to assess the patient's ability
to tolerate the stress of surgery, immunosuppression, and the demands of
post-transplantation care. Thus, each patient undergoes an extensive
cardiopulmonary evaluation, screening for occult infection or cancer, and
psychosocial evaluation (table 3). (See 'Pretransplantation evaluation' above.)

139
Liver transplantation in adults: Treatment of
acute T cell-mediated (cellular) rejection of the
liver allograft
Author:
Scott J Cotler, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Feb 22, 2021.
INTRODUCTIONThe use of potent immunosuppressive agents for induction
and maintenance therapy for liver transplantation has reduced the incidence of
acute rejection, which is defined as liver allograft dysfunction associated with
specific pathologic changes in the graft. With use of immunosuppression
protocols, acute T cell-mediated (cellular) rejection (TCMR) occurs in approximately
10 to 30 percent of liver transplantation recipients [1-4].

Acute rejection can be broadly categorized into TCMR and antibody-mediated

(previously known as humoral) rejection (AMR). A liver allograft biopsy is required
to establish the diagnosis and determine the severity of rejection in order to guide
treatment.

The focus of this topic is treatment of acute TCMR of the liver allograft. The clinical
features and diagnostic evaluation of patients with suspected acute TCMR are
discussed separately. (See "Liver transplantation in adults: Clinical manifestations
and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)
The approach to immunosuppression following liver transplantation is discussed
separately. (See "Liver transplantation in adults: Overview of
immunosuppression".)
Infectious complications in liver transplant recipients are discussed separately.
(See "Infectious complications in liver transplantation".)
PRETREATMENT EVALUATIONTherapy for patients with acute TCMR of the
liver allograft is guided by pretreatment evaluation, which excludes other causes
of graft dysfunction and determines the severity of rejection. The diagnostic
evaluation typically includes the following tests (see "Liver transplantation in

140
adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular)
rejection of the liver allograft", section on 'Diagnostic evaluation'):
●Liver biochemical tests (alanine aminotransferase [ALT], aspartate
aminotransferase [AST], alkaline phosphatase, and total bilirubin).
●Drug concentration levels for patients on tacrolimus or cyclosporine.
●Laboratory tests to exclude infection for patients with suspected infection
(eg, cytomegalovirus [CMV] antigen). (See "Infectious complications in liver
transplantation".)
●Liver ultrasound with Doppler study to exclude hepatic artery or portal vein
thrombosis or signs of biliary obstruction.
●Biopsy of liver allograft to determine rejection severity and to assess for
other conditions (eg, ischemic injury, biliary abnormality, drug-induced liver
injury, viral infection such as CMV, recurrence of primary liver disease,
antibody-mediated rejection [AMR]). (See 'Defining severity of
rejection' below.)
AMR is a less common cause of allograft injury and loss after ABO-compatible liver
transplantation that can mimic or overlap with acute TCMR. The differential
diagnosis of acute TCMR of the liver allograft is discussed in more detail
separately. (See "Liver transplantation in adults: Clinical manifestations and
diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section
on 'Differential diagnosis'.)
MANAGEMENT
Goals of therapy — Treatment goals for patients with acute TCMR include:
●Improving liver biochemical tests and liver histology
●Preventing chronic rejection
●Avoiding adverse impact on long-term graft survival [5]
Measures for all patients
Optimizing baseline immunosuppression — For all patients with histologic
evidence of acute TCMR of the liver allograft, the baseline maintenance
immunosuppressive regimen is assessed and optimized, while the specific
approach depends on the patient's drug regimen and baseline kidney function.
(See 'Defining severity of rejection' below.)

Options for optimizing immunosuppression are the following:

●Tacrolimus – For patients on tacrolimus as part of their baseline regimen,

the dose is often adjusted to target a higher drug level. For example, for
patients with a tacrolimus level in the 3 to 5 ng/ml range, the dose might be
increased to achieve tacrolimus levels in the 5 to 7 ng/mL range provided
that the patient has no or only mild chronic kidney disease at baseline
141
(estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2) and does
not develop calcineurin-related nephrotoxicity. Acute and chronic
nephrotoxicity related to tacrolimus are discussed separately.
(See "Cyclosporine and tacrolimus nephrotoxicity".)
Tacrolimus is used for primary immunosuppression at most liver
transplantation centers; however, patients with acute TCMR who are being
treated with cyclosporine may be switched to tacrolimus. Indirect evidence
has suggested that switching from cyclosporine to tacrolimus may provide
benefit for some patients with acute rejection [6,7]. In a series of 18 patients
with acute TCMR refractory to initial therapy with either glucocorticoids or
muromonab-CD3 (OKT3, no longer available), conversion to tacrolimus was
associated with liver biochemical and histologic improvement in 10 patients
(56 percent) [7].
Tacrolimus dosing, adverse effects, and efficacy as primary
immunosuppression are discussed separately. (See "Liver transplantation in
adults: Overview of immunosuppression", section on 'Calcineurin inhibitors'.)
●Mycophenolate – For patients on mycophenolate, the dose may be
increased.
For patients who are not receiving an antimetabolite agent as part of the
baseline immunosuppressive regimen, mycophenolate may be added.
Antimetabolite agents interfere with the synthesis of nucleic acids and inhibit
the proliferation of both T and B lymphocytes. Mycophenolate mofetil (MMF)
or enteric-coated mycophenolate sodium (EC-MPS) is the antimetabolic agent
used for most liver and kidney transplant recipients in the United
States; azathioprine is occasionally used. (See "Kidney transplantation in
adults: Maintenance immunosuppressive therapy".)
The recommended dose of MMF is 2 g daily by mouth in two divided doses.
Adverse effects of mycophenolate include gastrointestinal symptoms (ie
diarrhea, nausea, anorexia) and dose-related bone marrow suppression.
Initiating MMF at a reduced dose (ie, 500 mg twice daily) and then titrating
the dose upward may improve tolerability.
EC-MPS, an enteric-coated formulation of mycophenolate, was developed to
try to improve the upper gastrointestinal tolerability of mycophenolate.
However, EC-MPS and MMF doses are not equivalent. The dosing range for
mycophenolate sodium is 360 to 720 mg orally twice daily. For specific dosing
information, refer to the Lexicomp drug database and the drug label, while
dosing conversion is also discussed separately. (See "Kidney transplantation
in adults: Maintenance immunosuppressive therapy", section on
'Mycophenolate mofetil versus mycophenolate sodium'.)

142
 The use of MMF has been associated with improvement in liver biochemical
tests and histology for liver transplantation recipients with acute rejection [8-
11]. In an observational study of 47 patients with acute rejection refractory to
glucocorticoids, adding MMF to the existing drug regimen
(ie tacrolimus or cyclosporine) was associated with normalization of liver
biochemical tests in 38 patients (81 percent) [10].
Defining severity of rejection — A classification system for acute TCMR was
developed by a panel of expert hepatologists who agreed on a nomenclature and
histopathologic criteria for grading acute rejection (ie, Banff classification) [12].The
management of patients with histologic evidence of acute TCMR is guided by
histopathologic severity of rejection. (See 'Pretreatment evaluation' above
and "Liver transplantation in adults: Clinical manifestations and diagnosis of acute
T-cell mediated (cellular) rejection of the liver allograft", section on 'Establishing
the diagnosis'.)
Three specific histologic features associated with acute TCMR are (table 1):
●Mixed portal inflammatory infiltrate
●Bile duct epithelial inflammation and damage
●Venous endothelial inflammation
Each of these parameters is given a score, and the sum of the scores is called the
rejection activity index (RAI) [12,13]. Rejection severity is determined by RAI values.
Mild rejection has been regarded as RAI ≤4, while classification of RAI values has
varied among studies [12-19]. (See 'Patients with RAI ≤4' below and 'Patients with
RAI ≥5' below.)
Patients with RAI ≤4 — Initial treatment for patients with mild acute TCMR based
on histologic evidence (ie, rejection activity index [RAI] ≤4) typically includes
optimizing the baseline immunosuppressive regimen (algorithm 1). However, the
specific approach depends on the patient's existing immunosuppressive
medications. (See 'Measures for all patients' above.)
Monitoring laboratory testing is required after augmenting the baseline
immunosuppressive regimen. We obtain liver biochemical tests (ie alanine
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase,
and total bilirubin) weekly after adjusting immunosuppressive medications. For
patients who do not have improvement in liver biochemical tests within four weeks
or who have increasing elevations in liver tests, we generally repeat the biopsy of
the liver allograft to reassess rejection severity. Patients without histologic
improvement or with histologic progression after optimizing immunosuppression
are regarded as having moderate to severe rejection and are typically treated with
glucocorticoids. (See 'Patients with RAI ≥5' below.)

143
Patients with histologic improvement or resolution are continued on maintenance
immunosuppression. (See "Liver transplantation in adults: Overview of
immunosuppression".)
Patients with RAI ≥5
Initial therapy — For patients with biopsy-proven moderate to severe acute TCMR
(ie, RAI ≥5), initial therapy consists of high-dose glucocorticoids
(eg, methylprednisolone) followed by a glucocorticoid taper, in addition to
optimizing the maintenance immunosuppression regimen (algorithm 1) [14,20,21].
(See "Liver transplantation in adults: Overview of immunosuppression".)
Methylprednisolone dosing varies among liver transplantation centers. We
administer methylprednisolone in a daily bolus dose of 500 mg or 1000 mg
intravenously for one to three days. A typical oral glucocorticoid taper would be to
start prednisone 40 to 80 mg daily and to gradually reduce the dose over four
weeks until a maintenance dose is reached (eg, prednisone 5 mg daily) or
prednisone is discontinued.
For most patients with acute TCMR, biochemical response (ie improvement of liver
biochemical tests) to initial glucocorticoid therapy (in addition to optimizing the
baseline immunosuppressive regimen) typically occurs within three to five days.
For patients who do not have biochemical improvement within five days, biopsy of
the liver allograft is repeated. If histology is consistent with acute TCMR, we
typically give a second course of bolus methylprednisolone. For patients without a
biochemical response within five days, subsequent pharmacologic options include
antithymocyte globulin (ATG).
For patients who do not respond to initial bolus glucocorticoid therapy and who
have biopsy-confirmed acute TCMR, some liver transplantation centers do not give
a second course of bolus methylprednisolone and proceed to subsequent therapy
(eg, ATG). (See 'Therapy for nonresponders' below.)
While most patients respond to glucocorticoid therapy, few high-quality studies
have compared the efficacy of various glucocorticoid regimens for the treatment
of acute TCMR [22]. In a trial including 38 patients with acute TCMR of the liver
allograft, methylprednisolone (1 g bolus intravenously) followed by a six day
glucocorticoid taper (ie from 200 mg daily to 20 mg daily) resulted in higher rates
of histologic resolution of acute rejection compared with methylprednisolone 1 g
boluses given for three consecutive days (83 versus 50 percent) [22]. In addition,
infection rates were lower in patients given a single methylprednisolone dose
followed by prednisone taper (55 versus 90 percent).
Managing glucorticoid-related toxicity — The major complication of
glucocorticoids is increased susceptibility to infection, especially oral candidiasis,
cytomegalovirus (CMV), Aspergillus, Pneumocystis jirovecii (previously referred to

144
as P. carinii), and bacterial pathogens [22]. Other potential problems include
hyperglycemia, hypertension, peptic ulcer disease, and psychiatric disturbances
including euphoria and depression.
For patients with acute TCMR who are treated with high-dose glucocorticoids, our
approach to managing treatment-related toxicity includes (see "Major side effects
of systemic glucocorticoids"):
●During the glucocorticoid bolus therapy phase of treatment:
•Blood glucose levels are monitored daily.
•For ulcer prophylaxis, a proton pump inhibitor is given daily and is
continued during the glucocorticoid taper. (See "Peptic ulcer disease:
Treatment and secondary prevention", section on 'Maintenance
antisecretory therapy'.)
●For all patients treated with high-dose glucocorticoids, antimicrobial and
antiviral prophylaxis includes:
•CMV polymerase chain reaction (PCR) testing is performed monthly for
three months, and for high-risk recipients (ie, donor CMV
positive/recipient CMV negative), CMV prophylaxis is given for three
months. The approach to CMV prophylaxis in the liver transplant recipient
is discussed separately:
-(See "Infectious complications in liver transplantation", section on
'Cytomegalovirus'.)
-(See "Prophylaxis of infections in solid organ transplantation",
section on 'Cytomegalovirus'.)
-(See "Approach to the diagnosis of cytomegalovirus infection".)
•For  P. jirovecii  prophylaxis, trimethoprim-sulfamethoxazole is given for
three months. Prevention of P. jirovecii  pneumonia is discussed
separately. (See "Infectious complications in liver transplantation", section
on 'Antibacterial and Pneumocystis prophylaxis' and "Prophylaxis of
infections in solid organ transplantation", section on 'Pneumocystis
pneumonia'.)
Therapy for nonresponders — While most patients with acute TCMR rejection
respond to optimizing baseline immunosuppression and glucocorticoid therapy,
some patients do not respond to initial antirejection treatment [20,23].
Therapeutic options such as ATG have been used to treat patients with
glucocorticoid-refractory rejection.
Antithymocyte globulin — ATG is an option for patients with glucocorticoid-
refractory acute TCMR that has been confirmed with biopsy of the liver allograft.
ATG is a polyclonal immune globulin that induces T lymphocyte depletion in the
peripheral blood primarily by complement-dependent cell lysis [24]. ATG also
145
contains some B cell-specific antibodies that inhibit B cell proliferation and induce
B cell apoptosis.
Prior to initiating ATG, we obtain quantitative PCR testing for CMV and Epstein-Barr
virus (EBV). The risk of and monitoring for viral infections in transplant recipients
are discussed separately. (See "Infectious complications in liver
transplantation" and "Infection in the solid organ transplant recipient", section on
'CMV and EBV' and "Overview of diagnostic tests for cytomegalovirus infection".)
ATG is typically administered at a dose of 1.5 mg/kg daily intravenously for five to
seven days. The ATG dose is titrated to achieve an absolute lymphocyte count ≤200
cells/microL. Prior to the first two doses of ATG, patients receive preinfusion
therapy with a glucocorticoid
(methylprednisolone or hydrocortisone), diphenhydramine, and acetaminophen to
minimize infusion reactions. In addition, some patients receive preinfusion therapy
prior to the subsequent doses of ATG. (See "Heart transplantation in adults:
Treatment of acute allograft rejection", section on 'Antithymocyte globulin'.)

Liver biochemical tests are obtained daily to assess response to therapy, while
white blood cell, absolute lymphocyte, and platelet counts are obtained daily to
monitor for adverse effects.

Patients with glucocorticoid-refractory acute TCMR continue antimicrobial and

antiviral prophylaxis that was initiated during glucocorticoid bolus therapy.
(See 'Initial therapy' above.)
Limited data have suggested that ATG therapy was associated with histologic
improvement in patients with glucocorticoid-refractory acute rejection of the liver
allograft [20,25,26]. In a case series of 20 patients who had 21 episodes of acute
TCMR, ATG therapy was associated with histologic improvement or resolution by
day seven for 18 patients (90 percent) [20]. Three-year graft and patient survival
rates were 60 and 65 percent, respectively.
Other pharmacologic options — Basiliximab is a monoclonal antibody that binds
to the interleukin-2 (IL-2) receptor on T cells, and it has been used as induction
immunosuppressive therapy after liver transplantation [27]. Basiliximab blocks IL-
2-mediated T cell proliferation, and thus inhibits the T cell response to alloantigens
that produces allograft damage in patients with acute TCMR. (See "Liver
transplantation in adults: Overview of immunosuppression", section on
'Monoclonal antibodies'.)
Limited data have suggested that IL-2 antibody therapy was associated with
resolution of acute TCMR in some patients who did not respond to glucocorticoid
therapy [28-30]. In a study including 16 patients with glucocorticoid-resistant acute
TCMR, IL-2 receptor antibody therapy (ie basiliximab or daclizumab [no longer
146
available]) was associated with resolution of glucocorticoid-refractory rejection in
12 patients (75 percent) [29]. Of the remaining four patients, two developed
chronic rejection, one required repeat liver transplantation, and one died with
graft failure.
Repeat liver transplantation — Approximately five percent of liver
transplantation recipients who develop acute TCMR progress to chronic rejection
despite antirejection therapy [20] (see 'Outcomes' below). Some patients with
chronic rejection may require retransplantation, and management of such patients
requires a multidisciplinary approach (transplant hepatology, transplant surgery,
pharmacy). Adjusting immunosuppression for patients with chronic rejection
during the perioperative period is individualized, and the goal is to reduce the risk
of infectious complications. (See "Infectious complications in liver
transplantation".)
OUTCOMESData have suggested that up to 4 percent of liver transplantation
recipients develop chronic rejection [31,32]. The risk of chronic rejection appears
to be increased in patients who have had repeated episodes of acute TCMR [33].
Data on the long-term impact of acute TCMR have been mixed [34-37]. Older
studies suggested that early acute rejection (ie within three months of liver
transplantation) did not adversely affect graft or patient outcomes [34-36].
However, data from two large cohorts of liver transplant recipients (Adult to Adult
Living Donor Liver Transplantation [A2ALL] and Scientific Registry of Transplant
Recipients [SRTR] cohorts) showed that acute rejection within six months
posttransplant was associated with higher risk of graft failure (hazard ratio [HR]
1.91, 95% CI 1.21-3.01; and HR 1.77, 95% CI 1.63-1.92, respectively) and death (HR
1.86, 95% CI 1-3.47, and HR 1.66, 95% CI 1.52-1.83, respectively) [37]. (See "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft", section on 'Epidemiology'.)
The impact of successfully treating acute TCMR on graft outcomes has not been
well studied. Greater histologic severity of acute TCMR, later onset of rejection (>3
months posttransplant), and lack of response to antirejection therapy have been
associated with worse graft outcomes (eg, progression to chronic rejection, graft
loss) [37-39].
SPECIAL POPULATIONS
Patients with subclinical rejection — Subclinical acute TCMR rejection of the liver
allograft is detected in patients with histologic evidence of acute rejection on
biopsy without elevated liver biochemical tests (eg, aspartate aminotransferase
[AST], alanine aminotransferase [ALT]). However, subclinical acute rejection is
rarely recognized because protocol biopsies in the absence of abnormal liver
biochemical tests are not routinely performed at most transplantation centers. The
147
use of protocol biopsies is generally restricted to patients undergoing
investigational immunosuppressive treatments, and whether antirejection therapy
improves outcomes for patients with subclinical rejection is uncertain. Older data
have suggested that patients with subclinical rejection may experience histologic
improvement without modifying immunosuppression and that such subclinical
immune activation might be beneficial for inducing a degree of tolerance [5,39].
Patients with hepatitis C virus infection — Management of acute TCMR in
patients with hepatitis C virus (HCV) infection has required special attention
because some histologic features, such as bile duct injury and portal lymphocytic
inflammation, are found in both acute TCMR and recurrent HCV infection
(see "Hepatitis C virus infection in liver transplant candidates and recipients",
section on 'Evaluation of HCV infection post-transplant'). Thus, differentiating acute
rejection in the setting of HCV infection from HCV infection alone can be difficult
on histologic grounds. (See "Liver transplantation in adults: Clinical manifestations
and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft",
section on 'Establishing the diagnosis'.)
During the era of peginterferon therapy for HCV infection, glucocorticoid or T cell
depletion therapies were associated with more severe histologic HCV recurrence,
accelerated progression to fibrosis, and increased mortality [40-44]. However, the
availability of safe and effective HCV therapy with direct-acting antivirals has
revolutionized the approach to HCV management in liver transplant candidates
and recipients [45,46]. Thus, the need to differentiate HCV recurrence from acute
TCMR is uncommon because many patients are successfully treated for HCV
infection before liver transplantation, and those who are not treated
pretransplantation often receive antiviral therapy early post-transplantation.
Patients with autoimmune liver disease — Autoimmune liver disease has been
associated with an increased risk of glucocorticoid-refractory acute rejection. In a
study of 413 living donor liver transplant recipients, autoimmune liver disease was
associated with higher rates of glucocorticoid-refractory acute TCMR compared
with recipients with other causes of liver disease (53 versus 40 percent) [4]. In
addition, autoimmune liver disease was associated with increased risk of acute
TCMR (odds ratio [OR] 2.61; 95% CI 1.48-4.60). (See "Autoimmune hepatitis:
Treatment", section on 'Prognosis'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Theuse of potent immunosuppressive agents for induction and
maintenance therapy following liver transplantation has reduced the
148
incidence of acute T cell-mediated (cellular) rejection (TCMR), which is defined
as liver allograft dysfunction associated with specific histologic changes in the
graft. With use of immunosuppression protocols, acute TCMR occurs in
approximately 10 to 30 percent of liver transplantation recipients.
(See 'Introduction' above.)
●For patients with acute TCMR, the goals of treatment are (see 'Goals of
therapy' above):
•Improving liver biochemical tests and liver histology
•Preventing chronic rejection
•Avoiding adverse impact on long-term graft and patient survival
●For all patients with histologic evidence of acute TCMR of the liver allograft,
the baseline immunosuppressive regimen is optimized, while the specific
approach depends on the patient's existing regimen and baseline kidney
function. For example, higher levels of tacrolimus may be targeted or an
antimetabolite (mycophenolate) may be added to the baseline drug regimen.
(See 'Optimizing baseline immunosuppression' above.)
●The management of patients with histologic evidence of acute TCMR is
guided by histopathologic severity of rejection and the rejection activity index
(RAI) (table 1). Mild rejection has been regarded as RAI ≤4, while classification
of RAI values has varied among studies. (See 'Defining severity of
rejection' above.)
●For patients with biopsy-proven moderate to severe acute TCMR (ie, RAI ≥5),
we suggest glucocorticoid therapy in addition to optimizing baseline
immunosuppression (Grade 2C). We typically
administer methylprednisolone in a daily bolus dose of 500 mg or 1000 mg
intravenously for one to three days, followed by a gradual prednisone taper
(algorithm 1). (See 'Patients with RAI ≥5' above.)
●For all patients treated with high-dose glucocorticoids, antimicrobial and
antiviral prophylaxis includes (see 'Managing glucorticoid-related
toxicity' above and "Prophylaxis of infections in solid organ transplantation"):
•Cytomegalovirus (CMV) polymerase chain reaction (PCR) testing is
performed monthly for three months, and for high-risk recipients (ie,
donor CMV positive/recipient CMV negative) CMV prophylaxis is given for
three months.
•For  P. jirovecii  prophylaxis, trimethoprim-sulfamethoxazole is given for
three months.
The indications for and duration of antimicrobial and antiviral prophylaxis for
liver transplant recipients are discussed in more detail separately.
(See "Infectious complications in liver transplantation".)

149
●The impact of successfully treating acute TCMR on graft outcomes has not
been well studied. Greater histologic severity of acute TCMR, later onset of
rejection (>3 months posttransplant), and lack of response to antirejection
therapy have been associated with worse graft outcomes (eg, progression to
chronic rejection, graft loss). (See 'Outcomes' above.)

150
Osteoporosis after solid organ or stem cell
transplantation
Authors:
Elizabeth Shane, MD
Harold N Rosen, MD
Section Editor:
Peter J Snyder, MD
Deputy Editor:
Jean E Mulder, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 14, 2021.
INTRODUCTIONTransplantation has become an established therapy for end-
stage kidney, heart, lung, and liver diseases, as well as for several hematologic
disorders. Improved survival of transplant recipients has raised awareness of post-
transplant complications, such as osteoporosis. Post-transplant osteoporosis and
fracture occur in a substantial proportion of patients.
The pathogenesis, clinical manifestations, and management of bone loss after
solid organ (with the exception of renal transplant) or stem cell transplantation will
be reviewed here. Management of bone loss after renal transplantation is
discussed elsewhere. (See "Kidney transplantation in adults: Bone disease after
kidney transplantation" and "Kidney transplantation in adults: Persistent
hyperparathyroidism after kidney transplantation".)
EPIDEMIOLOGY AND RISK FACTORS
Incidence — Osteoporosis and fracture frequently occur after solid organ or
hematopoietic transplantation [1]. In the past, fracture incidence rates ranging
from 10 to 65 percent were reported (eg, 10 to 36 percent after heart
transplantation and 24 to 65 percent after liver transplantation) [2-5]. In some
[6,7], but not all [8], subsequent studies, the reported rate of post-transplant
fracture was lower than in the 1990s, possibly due to increased recognition of the
problem, which has resulted in changes in immunosuppressive regimens (eg,
reduction in dose and duration of glucocorticoids), earlier treatment for
osteoporosis, and improvement in pre- and post-transplantation nutrition.
Risk factors — Transplant-related osteoporosis and fracture are due to both pre-
and post-transplant factors (table 1).
Pretransplant risk factors — Many patients undergoing transplantation already
have low bone mineral density (BMD) [9]. The mechanism appears to vary with the
underlying disease:
151
 ●In patients with severe heart failure (New York Heart Association [NYHA]
classes III and IV) who are candidates for cardiac transplantation, chronic
kidney disease, vitamin D deficiency, secondary hyperparathyroidism,
hypogonadism, chronic use of heparin and/or loop diuretics, and reduced
physical activity may contribute to low BMD [10].
●In patients with primary biliary cholangitis, a toxin or toxins retained
because of cholestasis may inhibit normal osteoblast function, causing a low-
turnover form of osteoporosis (see "Evaluation and treatment of low bone
mass in primary biliary cholangitis (primary biliary cirrhosis)"). In patients
with cirrhosis due to other etiologies, excessive alcohol use, vitamin D
deficiency, hypogonadism, and glucocorticoid use increase the risk of
osteoporosis [11].
●In patients with chronic lung disease, preexisting glucocorticoid therapy
appears to be the primary risk factor for bone loss [12]. Other risk factors
include low body weight, smoking, physical inactivity, and vitamin D
deficiency. In patients with cystic fibrosis, additional risk factors are
hypogonadism, malnutrition, and malabsorption. (See "Clinical features and
evaluation of glucocorticoid-induced osteoporosis" and "Cystic fibrosis:
Clinical manifestations and diagnosis", section on 'Musculoskeletal
disorders'.)
Post-transplant risk factors — Patients lose bone rapidly after solid organ [13-16]
and hematopoietic cell [17,18] transplantation (table 1). The bone loss is most
rapid in the first three to six months after transplantation with subsequent slowing
thereafter, the latter likely due to a reduction in glucocorticoid
and cyclosporine dose and resolution of pretransplant conditions, such as
hyperbilirubinemia, that were deleterious to skeletal health. Rates of bone loss
during the first year after heart [19,20] and liver [21] transplant are lower in recent
years than they were in the 1990s and early 2000s. (See 'Incidence' above.)
A large proportion of post-transplant fractures occur during the brief phase of
rapid bone loss that occurs in the first six months after transplantation (figure 1)
[2,4,5,16,22]. The fracture rate is highest in patients with low pretransplant bone
mass who lose bone rapidly; however, a substantial proportion of men with
normal BMD before transplant may still fracture [4], and BMD changes do not
always predict fracture risk [2]. In a multivariate analysis of a nested case-control
study of transplant recipients (kidney, liver, lung, and heart), a history of
hyperthyroidism, pretransplant diabetes, fracture, or corticosteroid use, as well as
current exposure to antidepressants, narcotics, sirolimus, and loop diuretics were
significant risk factors for post-transplant fracture [23]. Use of bisphosphonates

152
or calcitonin was also a predictor of fracture, likely indicating the presence of
pretransplant osteoporosis.
The incidence of fracture falls as bone loss slows 6 to 24 months after
transplantation. Studies of up to three to four years duration show that lumbar
spine (LS) BMD begins to recover during the second half of the first year for liver
transplant recipients, and during the second and third years for heart transplant
recipients and often returns to baseline, whereas femoral neck (FN) BMD remains
below baseline levels [2,13,17,24,25]. As examples:
●In a prospective study of 280 patients undergoing allogeneic hematopoietic
stem cell transplant, LS and FN BMD decreased by 5.8 and 8.5 percent,
respectively, in the first year after transplant [17]. Although LS BMD returned
to baseline during the four-year study, FN BMD did not recover completely.
●In a retrospective study of 201 liver transplant recipients transplanted
between 2001 and 2011, T-scores declined significantly at the LS and FN six
months after liver transplantation, but increased thereafter at the LS,
reaching pretransplantation values at two years and remaining stable
thereafter [2]. FN T-scores remained consistently lower than
pretransplantation values. The prevalence of vertebral fractures increased
from 56 percent at screening to 71 percent at one year after transplantation,
with a fracture incidence of 34 percent. BMD changes did not predict fracture
risk.
Effects of immunosuppressive regimens — Immunosuppressive drugs,
particularly glucocorticoids, contribute to post-transplant bone loss and fracture.
Glucocorticoids are administered in large doses initially and then tapered over
time; dose increases for episodes of rejection or graft versus host disease are not
uncommon. The doses of glucocorticoids used in modern-day transplantation,
however, are much lower and tapered more rapidly than in the past [16].
The predominant effect of glucocorticoids on the skeleton is reduced bone
formation. The decline in bone formation may be mediated by direct inhibition of
osteoblast proliferation and by increased apoptosis of osteoblasts and mature
osteocytes. Glucocorticoids also increase bone resorption by increasing
osteoclastogenesis. In addition, glucocorticoids decrease secretion of androgens
and estrogens, primarily mediated by inhibition of gonadotropin secretion, and
increase secretion of parathyroid hormone (PTH). The etiology of glucocorticoid-
induced osteoporosis is reviewed in detail separately. (See "Clinical features and
evaluation of glucocorticoid-induced osteoporosis".)
Calcineurin inhibitors (cyclosporine and tacrolimus) may also contribute to post-
transplant bone loss. There is some evidence that cyclosporine may increase bone
turnover in humans. However, the effect of cyclosporine on bone metabolism in

153
humans is less clear, being confounded by the presence of other illnesses or drugs
that affect bone, particularly glucocorticoids (see "Drugs that affect bone
metabolism", section on 'Cyclosporine'). Tacrolimus appears to have less adverse
effect on bone than cyclosporine [26], and mycophenolate mofetil, rapamycin,
and azathioprine have shown no effects on bone volume in a rat model [27].
PRETRANSPLANTATION EVALUATIONPrior to transplantation, we
suggest the following initial evaluation in all patients:
●Bone mineral density (BMD, dual-energy x-ray absorptiometry [DXA]) of the
hip or spine
●Spine radiographs, or vertebral fracture analysis (VFA) by DXA, to screen for
vertebral fractures
●Serum 25-hydroxyvitamin D
Although bone loss slows or reverses after the first 6 to 12 months, prevention of
that early phase of bone loss is desirable, given the evidence for high fracture
rates, particularly during the first post-transplant year. Because low bone mass is
common in adult patients awaiting transplant and low pretransplant BMD and
fractures are risk factors for post-transplant fracture, measurement of BMD and
screening for prevalent vertebral fractures prior to transplantation is widely
recommended [3,16,18,27].
Prevalent vertebral fractures may be detected before transplantation even in
patients with relatively normal BMD and are likely to increase the risk of incident
vertebral fractures after transplantation. Vitamin D deficiency is very common in
recent transplant recipients [28,29] and patients awaiting organ transplantation.
●Osteoporosis – Patients who have a history of fracture, a prevalent vertebral
fracture, or osteoporosis on BMD (T-score ≤-2.5) before transplantation
should be evaluated for secondary causes (table 2 and table 3). (See "Clinical
manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal
women", section on 'Evaluation' and "Clinical manifestations, diagnosis, and
evaluation of osteoporosis in men", section on 'Evaluation'.)
When a secondary cause (eg, vitamin D deficiency) is identified, appropriate
treatment is recommended prior to transplant if possible. In addition to the
treatment of secondary causes of osteoporosis, some patients may benefit
from additional osteoporosis therapy, such as bisphosphonates, while
awaiting transplant, particularly those with prevalent vertebral fractures or a
history of other osteoporotic fractures (wrist, humerus, pelvis, hip, etc).
(See 'Patients with osteoporosis prior to transplantation' below and "Vitamin
D deficiency in adults: Definition, clinical manifestations, and
treatment" and "Overview of the management of osteoporosis in
postmenopausal women" and "Treatment of osteoporosis in men".)
154
 ●Osteoporosis absent – Patients without osteoporosis on BMD, without
prevalent vertebral fractures, and without history of fragility fracture can
defer medical therapy until after transplant, when renal function is stabilized.
(See 'Candidates for medical therapy' below.)
MANAGEMENT
General recommendations — The same measures used to prevent or treat
osteoporosis in the general population apply to transplant recipients. General
recommendations that apply to all patients, regardless of the pretransplant bone
mineral density (BMD) measurement, include the following:
●Counseling to stop smoking, mobilization soon after transplantation, and
prevention of falls.
●Calcium intake, prior to transplantation, of approximately 1000 mg/day
(from food sources and supplements) and vitamin D intake of 800
international units/day (20 micrograms/day). Higher vitamin D doses should
be given if the patient is overtly vitamin D deficient (eg, 25-hydroxyvitamin D
level less than 20 ng/mL [50 nmol/L]). Calcium and vitamin D, alone and in
combination, do not prevent transplantation-related bone loss. However, it is
established medical practice to ensure that patients are calcium and vitamin
D replete when receiving pharmacologic therapy for osteoporosis and the
vast majority of randomized trials assessing antiresorptive therapy, such as
bisphosphonates, have been carried out in the setting of concomitant
calcium and vitamin D repletion. (See 'Choice of initial medical
therapy' below.)
●Use of the lowest prednisone dose compatible with graft survival. However,
bone loss has occurred in patients given prednisone in doses as low as 5 to
10 mg/day. (See "Clinical features and evaluation of glucocorticoid-induced
osteoporosis".)
●Regular weightbearing exercise (30 minutes, three times per week)
(see "Overview of the management of osteoporosis in postmenopausal
women", section on 'Exercise'). Trials in cardiac transplant recipients suggest
that resistance exercise training may be beneficial after transplantation
[30,31]. In these trials, six months of resistance exercise training (including
lumbar extension exercise and variable resistance exercises with a
specialized fitness equipment) restored BMD toward pretransplantation
values. However, these studies included a very small number of participants
and may not be generalizable to all transplant recipients.
Prevention of post-transplantation osteoporosis
Candidates for medical therapy — Although there is some lack of consensus
about which patients should receive therapy to prevent bone loss and fractures,
155
we suggest preventive medical therapy for all patients undergoing heart, liver, or
lung transplantation or stem cell transplantation. We base our suggestion on
studies showing that the most rapid bone loss occurs immediately after transplant;
that fractures are common during the first post-transplant year, even in patients
who do not have pretransplant osteoporosis by dual-energy x-ray absorptiometry
(DXA); and that there is overlap in pretransplant BMD values between those who
do and do not fracture [4,5]. In addition, most transplant patients receive
glucocorticoid doses in excess of 7.5 mg daily for three to six months after
transplantation [16,27]. The duration of preventive therapy for transplant
recipients may be as short as one year [32], which reduces concerns about adverse
effects and cost of long-term bisphosphonate therapy. We initiate preventive
medical therapy as soon as renal function is stabilized after heart, liver, or lung
transplantation or stem cell transplantation, continue it for the first 12 months,
and then reevaluate. (See 'Choice of initial medical therapy' below and 'Duration of
therapy' below.)
An alternative approach suggested by some specialists is to individualize
preventive medical treatment, targeting patients with clinical risk factors for
fracture (eg, age ≥65 years, previous fragility fracture, BMD T-score ≤-1.5).
However, there is less evidence to support this approach, in part because patient
recruitment in randomized trials of bisphosphonates for the prevention of
transplantation-related osteoporosis was not based upon a particular BMD T-score
criterion or clinical risk factor (other than transplantation) (see 'Efficacy' below).
Thus, it is difficult to determine the best candidates for preventive therapy.
The optimal approach to the prevention of bone loss and fractures among renal
transplant recipients is reviewed separately. (See "Kidney transplantation in adults:
Bone disease after kidney transplantation", section on 'Prevention of
osteoporosis'.)
Choice of initial medical therapy — Bisphosphonates are considered the medical
therapy of choice for the prevention of transplantation-related bone loss.
Bisphosphonates should be used with caution in premenopausal women,
however, because of insufficient information on the potential for harm to the fetus
in women who become pregnant while receiving or shortly after discontinuing
bisphosphonates. If bisphosphonates are contraindicated or not
tolerated, calcitriol or estradiol/progesterone therapy (in women with
hypogonadism) are alternatives. Treatment with calcitriol requires monitoring of
serum and urinary calcium levels, making it less convenient than bisphosphonates
in this setting. (See 'Calcitriol' below.)
Bisphosphonates and calcitriol appear to prevent fractures. In a meta-analysis of
11 trials (780 patients) evaluating treatment with bisphosphonates (nine trials) or

156
vitamin D analogs (two trials) versus placebo or no treatment after solid organ
(liver, heart, kidney) transplantation, there was a significant reduction in the
number of patients with fractures one year post-transplantation (26 versus 51,
odds ratio [OR] 0.50, 95% CI 0.29-0.83) [33]. There was also a reduction in the total
number of fractures (38 versus 89, OR 0.37, 95% CI 0.22-0.60) and the number of
vertebral fractures (29 versus 78, OR 0.24, 95% CI 0.07-0.78). Overall, the number
of fracture events was small, limiting the precision of the meta-analysis.
(See 'Efficacy' below and 'Calcitriol' below.)
Choice of bisphosphonate — Either oral or intravenous bisphosphonates can be
administered. We favor intravenous zoledronic acid over oral bisphosphonates for
patients at high risk of fracture, such as those with pretransplant osteoporosis,
prior vertebral or other fragility fracture, pretransplant T-scores below -1.5, and
those who find the weekly dosing schedule and requirement for post-alendronate
fasting too burdensome, especially since post-transplant patients must take many
oral medications.
There are few data to support the use of one bisphosphonate over another. Many
of the trials used intravenous bisphosphonates due to ease of administration. In
one of the only head-to-head trials comparing an intravenous bisphosphonate
(zoledronic acid, single 5 mg infusion) with oral alendronate (70 mg weekly), both
drugs were similarly effective in preventing bone loss at the hip with no difference
in heart or liver transplant recipients [20]. In contrast, lumbar spine (LS) BMD
declined significantly in the alendronate group and increased (2 percent from
baseline) in the zoledronic acid group.
Dosing — The contraindications, dosing, prescribing instructions, and adverse
effects of bisphosphonates are reviewed in detail elsewhere. (See "Bisphosphonate
therapy for the treatment of osteoporosis", section on 'Practical management
issues' and "Risks of bisphosphonate therapy in patients with
osteoporosis" and "Bisphosphonate therapy for the treatment of osteoporosis",
section on 'Contraindications to bisphosphonates'.)
Efficacy — Bisphosphonates attenuate glucocorticoid-induced bone loss, and they
are frequently used for the prevention and treatment of osteoporosis in patients
taking glucocorticoids (see "Prevention and treatment of glucocorticoid-induced
osteoporosis", section on 'Bisphosphonates'). Because post-transplant bone loss is
highly associated with glucocorticoid treatment, bisphosphonates are also
frequently used for the prevention of post-transplantation bone loss.
A number of trials and a meta-analysis have demonstrated that bisphosphonates
are very effective for prevention of bone loss after solid organ or stem cell
transplant [19,21,34-43].

157
As examples:

●In a study of 99 patients receiving stem cell transplantation, patients were

randomly assigned to receive calcium (1000 mg/day) and vitamin D (800
international units/day) or the same calcium-vitamin D regimen
plus pamidronate (60 mg intravenously six times over the first post-
transplant year). Treatment with pamidronate prevented LS bone loss (0
percent in the pamidronate group versus -2.9 percent in the calcium group),
and attenuated hip bone loss (-5.5 and -7.8 percent in the pamidronate and
calcium-vitamin D groups, respectively) [35].
●In a trial of 62 adults undergoing liver transplantation who were randomly
assigned to receive infusions of zoledronic acid (4 mg) or placebo within
seven days of transplantation and 3, 6, 9, and 12 months later, the zoledronic
acid group lost significantly less bone at the hip at all time points [21]. In the
spine, the zoledronic acid group lost less bone at three months, but the
difference between the two groups was no longer significant at 12 months,
because of improvements between 3 and 12 months in the placebo group.
Zoledronic acid sometimes caused postinfusion hypocalcemia and temporary
secondary hyperparathyroidism.
●In a trial of 98 patients receiving a liver transplant, subjects randomly
assigned to alendronate (70 mg weekly) versus no alendronate had
significant increases in LS (5.1 and 8.9 percent) and femoral neck (FN; 4.3 and
8.7 percent) BMD at 12 and 24 months, respectively, compared with the
control group [37]. All subjects received calcium (1000 mg daily)
and calcitriol (0.5 mcg daily).
In addition to preventing bone loss, bisphosphonates appear to prevent fracture
[44]. A meta-analysis of nine trials evaluating treatment with bisphosphonates
versus control (placebo or no treatment) on fracture outcomes after solid organ
(liver, heart, kidney) transplantation showed a reduction in the proportion of
patients with fracture after treatment with bisphosphonates (OR 0.53, 95% CI 0.30-
0.91) [33]. The reduction in vertebral fractures did not reach statistical significance
(OR 0.34, 95% CI 0.09-1.24). Only two of the trials in the meta-analysis were
designed to explore fracture as a primary outcome [41,42].
In the majority of trials, individuals with serum creatinine concentrations above
the upper limits of normal were excluded from participation. In general, there are
limited data on the level of renal impairment at which bisphosphonate use should
be avoided. This topic is reviewed elsewhere. (See "Bisphosphonate therapy for the
treatment of osteoporosis", section on 'Use in chronic kidney

158
disease' and "Osteoporosis in patients with chronic kidney disease: Diagnosis and
evaluation".)
Contraindications/intolerance to bisphosphonates — If bisphosphonates are
contraindicated or not tolerated, calcitriol or estradiol/progesterone therapy (in
women with hypogonadism) are alternatives. Men with symptomatic
hypogonadism should receive testosterone replacement therapy. (See "Treatment
of osteoporosis in men", section on 'Hypogonadism' and 'Hormone replacement
therapy' below and "Bisphosphonate therapy for the treatment of osteoporosis",
section on 'Contraindications to bisphosphonates'.)
Calcitriol
●Efficacy – Calcitriol is also effective in preventing post-transplantation bone
loss [19,45,46]. As an example, in one trial, 149 heart transplant recipients
were randomly assigned to alendronate (10 mg orally daily) or calcitriol (0.25
micrograms orally twice daily) [19]. Treatment was initiated within one month
after transplantation; all patients also received calcium (945 mg daily) and
vitamin D (1000 international units daily). Study participants were compared
with a prospectively recruited reference group of 27 patients who declined to
participate in the randomized trial.
At one year, the decrease in BMD was less marked for
the alendronate and calcitriol groups than for the reference group in both
the LS (0.7 and 1.6 versus 3.2 percent) and the FN (1.7 and 2.1 versus 6.2
percent). There was a trend toward fewer vertebral fractures with
alendronate and calcitriol (6.8 and 3.6 versus 13.6 percent in the reference
group). Hypercalciuria developed in significantly more patients treated with
calcitriol than with alendronate (27 versus 7 percent).
In the meta-analysis described above, evaluating treatment with
bisphosphonates (nine trials) or vitamin D analogs (two trials) versus placebo
or no treatment after solid organ (liver, heart, kidney) transplantation, there
was a significant reduction in the number of patients with fractures one year
post-transplantation [33]. (See 'Choice of initial medical therapy' above.)
●Dosing and monitoring – A typical initial dose of calcitriol is 0.25
micrograms twice daily. Serum calcium levels should be monitored as part of
the usual post-transplantation biochemistry panel. If hypercalcemia develops,
calcium supplements should be discontinued. If hypercalcemia persists, the
calcitriol dose can be reduced to 0.25 mcg once daily, and if hypercalcemia is
still present, calcitriol should be discontinued. Patients with persistent
hypercalcemia after calcium supplements and calcitriol are discontinued
require further evaluation to determine the etiology. (See "Diagnostic
approach to hypercalcemia".)

159
Hormone replacement therapy — Estradiol/progesterone replacement is an
alternative option for prevention of post-transplantation bone loss in hypogonadal
premenopausal women. Men with symptomatic hypogonadism should
receive testosterone replacement therapy (if not contraindicated). Hypogonadal
men and women who are at high risk for fracture may require additional
pharmacologic therapy. The diagnosis of hypogonadism and details of therapy are
discussed elsewhere. (See "Clinical features and diagnosis of male
hypogonadism" and "Testosterone treatment of male hypogonadism", section on
'Appropriate candidates' and "Evaluation and management of secondary
amenorrhea".)
Estrogen-progestin therapy is no longer a first-line approach for the treatment of
osteoporosis in postmenopausal women, because of increased risk of breast
cancer, stroke, venous thromboembolism, and perhaps coronary disease
(although the risk-benefit profile in the unopposed estrogen trial was different).
(See "Menopausal hormone therapy: Benefits and risks" and "Menopausal
hormone therapy in the prevention and treatment of osteoporosis".)
Many premenopausal women and men undergoing solid organ transplantation
have temporary hypogonadism, most often related to the effects of
glucocorticoids and chronic illness [47,48]. In some cases (eg, chemotherapy
and/or radiation therapy for hematopoietic stem cell transplantation),
hypogonadism is permanent [49]. In men and women undergoing
transplantation, testosterone and estrogen-progestin replacement, respectively,
have been shown to slow bone loss [35,50-52]. (See "Evaluation and treatment of
premenopausal osteoporosis", section on 'Estrogen' and "Treatment of
osteoporosis in men", section on 'Candidates for therapy' and "Treatment of
osteoporosis in men", section on 'Hypogonadism'.)
Other — Denosumab, a potent inhibitor of bone resorption approved for
treatment of postmenopausal osteoporosis, has been evaluated in renal
transplant recipients, and more recently in a diverse group of 63 long-term
transplant recipients that included 14 who had received liver transplants [53], but
no studies of denosumab for prevention of bone loss during the first year after
heart, liver, lung, or marrow transplant patients have been reported. (See "Kidney
transplantation in adults: Bone disease after kidney transplantation", section on
'Denosumab'.)
The concern about using denosumab to prevent transplantation osteoporosis is
that treatment is often temporary during the period of use of high glucocorticoid
doses, and in postmenopausal women, there is an increased risk of bone loss and
vertebral fractures, particularly multiple vertebral fractures, after stopping
denosumab. If denosumab is discontinued, administering an alternative therapy

160
(typically a bisphosphonate) to prevent rapid bone loss and vertebral fracture is
advised. This issue is discussed in detail elsewhere. (See "Denosumab for
osteoporosis", section on 'Increased fracture risk after stopping'.)
Although recombinant human parathyroid hormone (rPTH, teriparatide) has been
shown to improve BMD in patients with glucocorticoid-induced osteoporosis, there
are few studies evaluating parathyroid hormone (PTH) for the prevention of post-
transplant osteoporosis (particularly non-kidney transplantation). (See "Prevention
and treatment of glucocorticoid-induced osteoporosis", section on 'Parathyroid
hormone' and "Kidney transplantation in adults: Bone disease after kidney
transplantation", section on 'Teriparatide'.)
Duration of therapy — We typically continue therapy for 12 months and then
reevaluate. If BMD is stable during the first year after transplantation and
glucocorticoids have been withdrawn completely or reduced to doses <5 mg/day,
we typically stop bisphosphonate therapy.
There are few data to guide duration of therapy in transplant recipients. Given that
LS BMD begins to recover in many patients within 12 months of transplant, long-
term treatment may be unnecessary. In some patients, 12 months of therapy may
be adequate [32]. Treatment duration should be based upon patient factors, such
as ability to withdraw glucocorticoids, presence of other risk factors for low bone
mass and fracture, and BMD measurements. (See "Osteoporotic fracture risk
assessment", section on 'Clinical risk factor assessment'.)
Monitoring — Monitoring the response to therapy is important for identifying
patients who may be able to discontinue therapy and for patients who are not
responding to therapy. While there are a number of approaches to monitoring
therapy, there is no consensus on the optimal approach. In the majority of
patients, we suggest BMD measurements prior to and one year after
transplantation, at a minimum.
In patients who require continued glucocorticoid therapy (eg, prednisone at ≥5 mg
daily), or in those with T-scores below -2.5, continuation of bisphosphonates
should be considered, with BMD measurements every one to two years. In
patients who have successfully tapered off glucocorticoid therapy, we suggest
annual BMD measurements for two years after transplantation with less frequent
monitoring (every two to three years) thereafter.
Treatment of osteoporosis
Patients with osteoporosis prior to transplantation — The treatment of
patients who are diagnosed with osteoporosis prior to transplantation is similar to
the treatment of osteoporosis in patients who are not transplant recipients.
●When a secondary cause (eg, vitamin D deficiency) is identified, it should be
treated, if possible.

161
 ●For men and postmenopausal women with pretransplantation osteoporosis
(T-score ≤-2.5, a prevalent vertebral fracture or prior fragility fracture, or a
high risk of fracture by the Fracture Risk Assessment Tool [FRAX]), we suggest
bisphosphonates as the first-line medical therapy.
●In contrast, medical therapy needs to be individualized in premenopausal
women because of insufficient information on the potential for harm to the
fetus in women who become pregnant while currently or recently receiving
bisphosphonates (although this is rarely a problem in the immediate post-
transplant period). However, for premenopausal women with fractures or
accelerated bone loss who do not need estrogen replacement therapy
because they have normal menstrual function, bisphosphonates are
generally the drugs of choice.
Initial and subsequent treatment of patients with osteoporosis is reviewed
separately. (See "Overview of the management of osteoporosis in postmenopausal
women" and "Treatment of osteoporosis in men" and "Evaluation and treatment of
premenopausal osteoporosis".)
Patients with osteoporosis after transplantation — Although
bisphosphonates, calcitriol, and, in select patients, hormone replacement therapy
are efficacious in preventing bone loss at the time of transplantation, many
patients are not evaluated for osteoporosis nor do they receive preventive therapy.
Low bone mass and osteoporosis are commonly found in patients with a history of
transplantation months or years in the past.
For those who remain on glucocorticoids, their treatment is similar to the
treatment of osteoporosis in patients on glucocorticoids. (See "Prevention and
treatment of glucocorticoid-induced osteoporosis".)
Bisphosphonates are efficacious in patients with persistent osteoporosis years
after transplantation [54-56]. (See "Bisphosphonate therapy for the treatment of
osteoporosis".)
rPTH has not been studied in the population receiving transplants other than
kidney. Patients who have received total body irradiation during hematopoietic
stem cell transplantation, who have primary or secondary elevations in PTH, or
other hypercalcemic disorders are not candidates for rPTH therapy.
(See "Parathyroid hormone/parathyroid hormone-related protein analog for
osteoporosis".)
In one small study that included a few liver transplant recipients, denosumab was
associated with a significant increase in BMD [53]. Denosumab should not be given
to patients with preexisting hypocalcemia until it is corrected. PTH and denosumab
for the treatment of osteoporosis are reviewed separately. (See "Denosumab for
osteoporosis".)

162
SUMMARY AND RECOMMENDATIONS
●Osteoporosis and fracture frequently occur after solid organ or
hematopoietic transplantation, though rates may be lower than in the past.
The etiology is multifactorial (table 1). (See 'Epidemiology and risk
factors' above.)
●In patients undergoing organ or hematopoietic transplantation, we suggest
measurement of pretransplant bone mineral density (BMD), assessment for
prevalent vertebral fractures by spine radiographs or vertebral fracture
assessment (VFA) by dual-energy x-ray absorptiometry (DXA), and
measurement of serum 25-hydroxyvitamin D. (See 'Pretransplantation
evaluation' above.)
●Patients with low pretransplant BMD (T-score ≤-2.5), a prevalent vertebral
fracture, or a prior fragility fracture should be evaluated for secondary causes
of bone loss (table 2 and table 3). (See 'Pretransplantation evaluation' above
and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in
postmenopausal women", section on 'Evaluation' and "Clinical
manifestations, diagnosis, and evaluation of osteoporosis in men", section on
'Evaluation'.)
●General measures to improve skeletal health in transplant recipients include
reducing the dose of glucocorticoids as soon as possible, smoking cessation,
exercise, supplementation with calcium and vitamin D, and regular
weightbearing exercise. (See 'General recommendations' above.)
●We suggest osteoporosis preventive therapy for all patients undergoing
heart, liver, or lung transplantation or stem cell transplantation (Grade 2B).
An alternative approach suggested by some specialists is to treat patients
with clinical risk factors for fracture (age ≥65 years, previous fragility fracture)
or BMD T-score ≤-1.5. (See 'Candidates for medical therapy' above.)
●For the prevention of post-transplant osteoporosis in men and
postmenopausal women, we suggest bisphosphonates, rather
than calcitriol (Grade 2B). Either oral or intravenous bisphosphonates can be
administered as both have been shown to be effective in this setting. We
favor intravenous zoledronic acid for patients at high risk for fracture (eg,
osteoporosis at baseline, prevalent or prior vertebral or other fragility
fracture, T-scores below -1.5 prior to beginning glucocorticoids) and for those
who find the weekly dosing schedule of alendronate too burdensome.
Prevention therapy should be initiated after transplant when renal function is
stabilized. (See 'Choice of initial medical therapy' above.)
Bisphosphonates should be used with caution in premenopausal women
because of insufficient information on the potential for harm to the fetus in
163
women who become pregnant while currently or recently receiving
bisphosphonates (see "Evaluation and treatment of premenopausal
osteoporosis", section on 'Glucocorticoids'). Calcitriol or hormone
replacement therapy (in hypogonadal women) are alternative prevention
options.
●For all patients who have pretransplantation osteoporosis (T-score ≤-2.5) or
a fragility fracture, we recommend medical therapy (Grade 1B). For men and
postmenopausal women, we suggest bisphosphonates as the first-line
medical therapy (Grade 2B). (See 'Patients with osteoporosis prior to
transplantation' above and "Overview of the management of osteoporosis in
postmenopausal women" and "Bisphosphonate therapy for the treatment of
osteoporosis" and "Treatment of osteoporosis in men".)
In contrast, medical therapy needs to be individualized in premenopausal
women because of insufficient information on the potential for harm to the
fetus in women who become pregnant while currently or recently receiving
bisphosphonates (although this is rarely a problem in the immediate post-
transplant period). However, for premenopausal women with fractures or
accelerated bone loss who do not need estrogen replacement therapy
because they have normal menstrual function, bisphosphonates are
generally the drugs of choice. (See "Evaluation and treatment of
premenopausal osteoporosis", section on 'Bisphosphonates'.)
●There is no consensus on the optimal strategy for monitoring patients on
therapy. However, we typically measure BMD one year after transplantation
and periodically thereafter, depending upon individual patient
characteristics. (See 'Monitoring' above.)

164
Overview of dermatologic problems following
liver transplantation
Authors:
Jean-François Dufour, MD
Patrick Antony Oberholzer, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Feb 19, 2020.
INTRODUCTIONLiver transplantation recipients, like other solid organ
transplantation recipients, have an increased risk of dermatologic problems due to
their long-term immunosuppression and benefit from pre-and post-
transplantation screenings, and management by a dermatologist and
dermatologic care should be integrated into the comprehensive, multidisciplinary
care of liver transplantation recipients [1,2]. Cutaneous findings include aesthetic
alterations, infections, precancerous lesions, and malignancies. The severity of skin
alterations ranges from benign, unpleasant changes to life-threatening conditions
[3-5]. In addition to skin cancer diagnosis and management, visits with a
dermatologist serve to educate and improve the patient's sun-protection behavior.
Among all solid organ transplantations, liver transplantation requires the least
amount of immunosuppression, sometimes even permitting its complete
cessation [6]. As a result, patients who have undergone liver transplantation tend
to have fewer dermatologic complications compared with other solid organ
transplantation recipients [7]. However, due to the large volume of the liver,
patients undergoing liver transplantation receive more donor lymphocytes than
kidney, heart, or lung transplantation recipients. Because of the
immunosuppression, the transplanted lymphocytes proliferate and rarely trigger
graft-versus-host-disease [8,9].
This topic will provide an overview of dermatologic disorders that may be seen
following liver transplantation. A detailed discussion of skin cancer following solid
organ transplantation and the general management of patients following liver
transplantation are discussed separately. (See "Malignancy after solid organ
transplantation" and "Prevention and management of skin cancer in solid organ
transplant recipients" and "Liver transplantation in adults: Long-term management
of transplant recipients".)
165
EFFECT OF TRANSPLANTATION ON PREEXISTING DERMATOLOGIC
DISORDERSPatients undergoing liver transplantation may have preexisting
dermatologic disorders that are subsequently affected by transplantation. In many
cases, the disorders improve either as a result of removal of the diseased liver or
because of the immunosuppression patients receive.
Dermatologic manifestations of liver disease — In patients with dermatologic
lesions related to cirrhosis or associated with specific forms of liver disease,
transplantation often leads to improvement in the dermatologic findings (table 1).
Most of the non-specific mucocutaneous lesions linked to cirrhosis, such as palmar
erythema, spider nevi, and pruritus, disappear in the weeks following the liver
transplantation [10], though skin pigmentation, clubbing, and fingernail changes
[11] may take several months to regress. Dupuytren's contractures are usually
irreversible (picture 1). (See "Cirrhosis in adults: Etiologies, clinical manifestations,
and diagnosis", section on 'Physical examination'.)
Specific forms of liver disease may also be associated with dermatologic
manifestations (table 1). Although the clinical courses of these disorders after liver
transplantation have not been well described, the available data suggest that
many of these conditions improve. Examples include:
●Autoimmune hepatitis: Alopecia [12] and vitiligo (picture 2) [13].
●Chronic cholestatic liver disease: Xanthomas and xanthelasmas (picture 3)
[14] (see "Clinical manifestations, diagnosis, and prognosis of primary biliary
cholangitis (primary biliary cirrhosis)", section on 'Physical examination').
●Hepatitis C: Cryoglobulinemia, porphyria cutanea tarda (picture 4),
leukocytoclastic vasculitis (picture 5), and lichen planus (picture 6) [15].
Coexisting dermatologic disorders — Patients with liver disease may have
dermatologic disorders that are not the result of their liver disease, such as
psoriasis and atopic dermatitis. There may be shared risk factors for dermatologic
disorders and liver disease (eg, alcohol use is a risk factor for psoriasis and
alcoholic liver disease [16,17]). In addition, the treatment of the dermatologic
disorder could be associated with hepatotoxicity (eg, methotrexate [18,19]). In
some cases, the immunosuppressive agents used following liver transplantation,
such as glucocorticoids and calcineurin inhibitors, may also lead to improvement
in dermatologic disorders. However, rapid tapering of immunosuppression could
lead to exacerbations of dermatologic disorders. (See "Treatment of psoriasis in
adults" and "Treatment of atopic dermatitis (eczema)".)
Previously treated skin cancer — Patients undergoing liver transplantation may
have a history of treated skin cancer. While a history of treated skin cancer is not
an absolute contraindication to transplantation, if a patient develops a recurrence
of the cancer, a reduction in immunosuppression may be needed, increasing the
166
risk of graft rejection [20]. (See "Prevention and management of skin cancer in
solid organ transplant recipients" and "Liver transplantation in adults: Patient
selection and pretransplantation evaluation", section on 'Contraindications'.)
DERMATOLOGIC COMPLICATIONS AFTER LIVER
TRANSPLANTATIONNew dermatologic lesions may develop following liver
transplantation, often related to the patient's immunosuppression
[21,22]. Dermatologic complications include cosmetic side effects of
immunosuppressive therapy (table 2), skin infections (table 3 and table 4 and table
5), skin cancer (table 6), and graft-versus-host disease (table 7).

The following questions may be helpful to estimate a patient's risk for

dermatologic complications following liver transplantation:

●Were there pretransplantation dermatologic problems?

●Is his/her skin sensitive to light?
●What is his/her exposure to sunlight (professional, non-professional)?
●What is his/her contact with animals?
●Are serologies for herpes simplex I, herpes simplex II, herpes virus 8,
hepatitis C virus, or syphilis positive?
●What is the degree of immunosuppression?
●What is the length of the follow-up since the liver transplantation?
Cosmetic problems and side effects of immunosuppressive therapy — Many of
the immunosuppressive drugs used in the transplantation setting have been
associated with mucocutaneous complications, such as acne, cushingoid
appearance, and gingival hyperplasia (table 2). The complexity of
immunosuppressive regimens often makes it difficult to identify a specific drug as
the cause of a dermatologic complication.
Dermatologic infections — Dermatologic infections after liver transplantation can
be challenging [4]. Dermatologic infections may be due to bacteria [23] (table 3),
mycobacteria (table 3), viruses (table 4), or fungi (table 5), and often involve several
infectious agents, such as skin coinfection with herpes virus and cytomegalovirus.
Another frequently seen problem is the development of warts due to
papillomavirus infection. (See "Infection in the solid organ transplant recipient".)
In the transplantation setting, some of these skin lesions lose their characteristic
macroscopic appearance, making the diagnosis more difficult than in the non-
transplantation setting. As a result, systematic microbiologic and histologic tests
should not be delayed. Common bacterial and viral infections predominate early
(less than three months) after transplantation, while rarer bacteria and
opportunistic agents, such as fungi (picture 7), are seen later [24-27].

167
Skin cancer — Skin cancers, including squamous cell carcinoma (the most
common form) (picture 8), basal cell carcinoma (picture 9), melanoma (picture 10)
[28,29] and Merkel cell carcinoma (picture 11 and picture 12 and picture 13), are
important dermatologic complications of liver transplantation (table 6) [30-37].
Skin cancer is more commonly seen in patients who have undergone liver
transplantation than in patients with other immunosuppressed states [6].
Additionally, squamous cell carcinomas tend to be more aggressive in organ
transplant recipients compared to the general population [38]. The relatively high
incidence of skin cancer is principally due to the effects of three factors:
●Immunosuppression (table 8 and table 9)
●Exposure to sunlight
●Infection with human papilloma virus
The diagnosis and management of skin cancer following solid organ
transplantation are discussed in detail elsewhere. (See "Epidemiology and risk
factors for skin cancer in solid organ transplant recipients" and "Prevention and
management of skin cancer in solid organ transplant recipients" and "Malignancy
after solid organ transplantation" and "Liver transplantation in adults: Long-term
management of transplant recipients", section on 'De novo malignancy'.)
Miscellaneous — A variety of uncommon skin disorders may also be seen
following liver transplantation (table 7) [3,39-49]. These include:
●Graft-versus-host disease (picture 14 and picture 15) because the donor liver
contains a large number of lymphocytes (see "Clinical manifestations,
diagnosis, and grading of acute graft-versus-host disease", section on 'Skin')
●Cutaneous calcinosis
●Erythema elevatum diutinum (picture 16 and picture 17) (see "Erythema
elevatum diutinum")
●Photosensitivity due to pseudoporphyria, transitory porphyrinemia (picture
18)
●Porokeratosis (picture 19 and picture 20) (see "Porokeratosis", section on
'Clinical presentation')
●Immune thrombocytopenia (also called idiopathic thrombocytopenic
purpura) (picture 21) (see "Immune thrombocytopenia (ITP) in adults: Clinical
manifestations and diagnosis")
●Granuloma annulare (picture 22) (see "Granuloma annulare: Epidemiology,
clinical manifestations, and diagnosis", section on 'Clinical features')
PREVENTION AND MANAGEMENTPrevention of dermatologic
complications following liver transplantation focuses primarily on skin cancer
prevention. After liver transplantation, patients should protect themselves from
sunlight. We recommend patients wear sun protective clothing and use
168
sunscreens with a sun protection factor (SPF) of 30 or higher, though data are
lacking with regard to the minimal SPF patients should use. It is important that the
sunscreen chosen protects against the entire spectrum of ultraviolet radiation
(UVA and UVB). The sunscreen should be applied 30 minutes before sun exposure
and should be reapplied at least every two hours. (See "Selection of sunscreen and
sun-protective measures" and "Prevention and management of skin cancer in solid
organ transplant recipients", section on 'Sun protection'.)
Chemoprevention for squamous cell carcinoma (SCC) of the skin is discussed
separately. (See "Prevention and management of skin cancer in solid organ
transplant recipients", section on 'Chemoprevention for SCC'.)
The skin of patients after transplantation should be examined completely and
systematically, including the oral, genital, and anal areas [50]. Regular systematic
examination of the skin is needed to discover and treat precancerous lesions, such
as actinic keratosis (picture 23), verrucae (picture 24), and oral leukoplakia (picture
25). Any suspicious lesions should be examined by a dermatologist.
(See "Prevention and management of skin cancer in solid organ transplant
recipients", section on 'Post-transplantation surveillance' and "Prevention and
management of skin cancer in solid organ transplant recipients", section on
'Follow-up'.)
The early recognition of cutaneous diseases after liver transplantation permits
treatment during the mild stages and alerts the transplantation hepatologist that a
reduction in the level of immunosuppression may be needed. A declining incidence
of keratinocyte carcinoma has been observed following the implementation of
routine, periodic dermatologic screening for organ transplant recipients
[35,51,52].
Adequate management of the cosmetic consequences of the immunosuppressive
regimen, such as hypertrichosis and sebaceous hyperplasia (table 2), enhances the
adherence of patients to treatment and their trust in the clinician. In some cases,
changing the immunosuppressive regimen may improve dermatologic
complications following solid organ transplantation. As an example, in renal
transplantation recipients, conversion from calcineurin inhibitors (eg, cyclosporine)
to tacrolimus has been shown to improve hypertrichosis [53]. Also, inhibitors of
the mechanistic target of rapamycin (mTOR) kinase have been shown to slow down
cutaneous carcinogenesis [54,55] compared with cyclosporine, but they can have
multiple side effects such as impaired wound healing [56,57], rashes, and acne.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
169
●Patients undergoing liver transplantation may have preexisting
dermatologic disorders that are subsequently affected by transplantation.
(See 'Effect of transplantation on preexisting dermatologic disorders' above.)
•In patients with dermatologic lesions related to cirrhosis or associated
with specific forms of liver disease, transplantation often leads to
improvement in the dermatologic findings (table 1). Most of the non-
specific mucocutaneous lesions linked to liver cirrhosis, such as palmar
erythema, spider nevi, and pruritus, disappear in the weeks following the
liver transplantation, though skin pigmentation, clubbing, and fingernail
changes may take several months to regress. Dupuytren's contractures
are usually irreversible. (See 'Dermatologic manifestations of liver
disease' above.)
•Patients with liver disease may have dermatologic disorders that are not
the result of their liver disease, such as psoriasis and atopic dermatitis. In
some cases, the immunosuppressive agents used following liver
transplantation, such as glucocorticoids and calcineurin inhibitors, may
also lead to improvement in dermatologic disorders. However, rapid
tapering of immunosuppression could lead to exacerbations of
dermatologic disorders. (See 'Coexisting dermatologic disorders' above.)
•Patients undergoing liver transplantation may have a history of treated
skin cancer. While a history of treated skin cancer is not an absolute
contraindication to transplantation, if a patient develops a recurrence, a
reduction in immunosuppression may be needed, increasing the risk of
graft rejection. (See 'Previously treated skin cancer' above.)
●New dermatologic lesions may develop following liver transplantation, often
related to the patient's immunosuppression. (See 'Dermatologic
complications after liver transplantation' above.)
These include:
•Side effects of immunosuppressive therapy, such as acne, hypertrichosis,
cushingoid appearance, and immune thrombocytopenia (table 2).
(See 'Cosmetic problems and side effects of immunosuppressive
therapy' above.)
•Skin infections due to bacteria, viruses, and/or fungi (table 3 and table
4 and table 5). The infections often involve several infectious agents.
Common bacterial and viral infections predominate early (less than three
months) after transplantation, while rarer bacteria and opportunistic
agents, such as fungi, are seen later. (See 'Dermatologic
infections' above.)

170
 •Skin cancer, particularly squamous cell carcinoma (table 6 and table 8).
(See 'Skin cancer' above.)
•Graft-versus-host disease (table 7). (See 'Miscellaneous' above.)
●Prevention of dermatologic complications following liver transplantation
focuses primarily on skin cancer prevention. After liver transplantation,
patients should protect themselves from sunlight with sun protective clothing
and sunscreens with a sun protective factor (SPF) of 30 or higher. In addition,
patients' skin should be examined completely and systematically, including
the oral, genital, and anal areas. (See "Prevention and management of skin
cancer in solid organ transplant recipients", section on 'Sun
protection' and "Prevention and management of skin cancer in solid organ
transplant recipients", section on 'Post-transplantation surveillance'.)
●The early recognition of cutaneous diseases after liver transplantation
permits treatment during the mild stages and alerts the transplantation
hepatologist that a reduction in the level of immunosuppression may be
needed. In some cases, changing the immunosuppressive regimen may
improve dermatologic complications following solid organ transplantation.
(See 'Prevention and management' above.)

171
Pharmacology of cyclosporine and tacrolimus
Authors:
Karen Hardinger, PharmD, BCPS
Colm C Magee, MD, MPH, FRCPI
Section Editors:
Daniel E Furst, MD
Daniel C Brennan, MD, FACP
Deputy Editor:
Albert Q Lam, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 03, 2021.
INTRODUCTIONCyclosporine and tacrolimus selectively inhibit calcineurin,
thereby impairing the transcription of interleukin (IL)-2 and several other cytokines
in T lymphocytes. Calcineurin inhibitors have been mainstays of
immunosuppression in solid organ transplantation for over three decades.
Cyclosporine and tacrolimus are occasionally used in the treatment of various
immune-mediated diseases. However, concerns about their long-term toxicity
(especially kidney dysfunction and hypertension) and the availability of newer
biologic agents have restricted the use of cyclosporine and tacrolimus to patients
who have not responded to conventional treatment. The kidney toxicity of these
agents is reviewed in detail separately. (See "Cyclosporine and tacrolimus
nephrotoxicity".)
The pharmacology of cyclosporine and tacrolimus is reviewed here. The efficacy
and use of these agents in specific conditions, including organ transplantation and
immune-mediated diseases, are discussed separately in the topic reviews
addressing the treatment of each disorder. (See appropriate topic reviews.)
MECHANISM OF ACTIONCyclosporine is a lipophilic cyclic peptide of 11
amino acids, while tacrolimus is a macrolide antibiotic. Both drugs have been
isolated from fungi and possess similar suppressive effects on cell-mediated and
humoral immune responses.
Both drugs bind with high affinity to a family of cytoplasmic proteins present in
most cells: cyclophilins for cyclosporine and FK-binding proteins for tacrolimus.
The drug-receptor complex specifically and competitively binds to and inhibits
calcineurin, a calcium- and calmodulin-dependent phosphatase [1-4]. This process
inhibits the translocation of a family of transcription factors (NF-AT), leading to
reduced transcriptional activation of cytokine genes for interleukin (IL)-2, tumor
necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-

172
stimulating factor, and interferon-gamma [1,2,5,6]. Ultimately, proliferation of T
lymphocytes is reduced.
Cyclosporine and tacrolimus act primarily on T helper cells, although some
inhibition of T suppressor and T cytotoxic cells may also occur. Cyclosporine also
increases the expression of transforming growth factor (TGF)-beta, which may be
an important mechanism by which it causes kidney fibrosis [7,8]. Unlike some
other immunosuppressive agents, such as azathioprine and the alkylating agents,
cyclosporine and tacrolimus do not cause clinically significant myelosuppression
[9].
FORMULATIONSOral, intravenous, and ophthalmic formulations
of cyclosporine are available (table 1). Oral, intravenous, and topical formulations
of tacrolimus are available. The intravenous forms of both drugs should be used
only if enteral administration is not possible, because there is the potential for
greater toxicity with intravenous administration. Generic forms of cyclosporine
and tacrolimus are available in many countries, including the United States. In
general, patients stabilized on one preparation should not be switched to another,
because there are concerns about differences in pharmacokinetics. If a conversion
between preparations is necessary, monitoring trough concentrations should be
performed until the results are stable [10]. (See 'Switching formulations' below.)
Cyclosporine — Oral, intravenous, and ophthalmic formulations
of cyclosporine are available.
Cyclosporine is available in nonmodified and modified formulations. Nonmodified
oral cyclosporine depends upon bile for absorption and has erratic gastrointestinal
absorption patterns. Modified cyclosporine, a microemulsion formulation, does
not depend upon bile salts for absorption and exhibits increased bioavailability
and more consistent absorption.
Nonmodified — Liquid cyclosporine is available in capsules, oral solution, and
concentrate for injection:
●Liquid-filled capsules of 25 mg and 100 mg are stored at less than 86°F
(30°C) but not frozen.
●The oral solution of 100 mg/mL in 50 mL bottles remains stable for two
months after opening if stored in the original container at less than 86°F
(30°C) but does not require refrigeration and should not be frozen.
●Concentrate for injection of 50 mg/mL in 5 mL ampules should be stored at
less than 86°F (30°C) and protected from light and freezing. Dilutions in 5
percent glucose or normal saline are stable for 24 hours. Substantial
amounts of cyclosporine may be lost during intravenous administration
through plastic tubing. Polyoxyethylated castor oil that is contained in the
concentration for intravenous cyclosporine infusion can cause phthalate
173
 stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus,
when intravenous nonmodified cyclosporine is administered, PVC-free
intravenous fluid containers and tubing should be used.
Modified — Capsules and solution are for oral use; no parenteral formulation is
available. Patients who need an intravenous formulation should be
prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine
modified capsules or the equivalent generic product are preferred due to superior
pharmacokinetic profile compared with the nonmodified formulation:
●Capsules of 25 mg and 100 mg should be stored at 68 to 77°F (20 to 25°C);
some generic formulations are available in a 50 mg capsule.
●The oral solution of 100 mg/mL is available in 50 mL bottles, which remains
stable for two months after opening if stored in the original container at 68 to
77°F (20 to 25°C).
Ophthalmic emulsion — An ophthalmic emulsion of 0.05 percent is available in
single vials of 0.4 mL and stored at 59 to 77°F (15 to 25°C).
Tacrolimus — Oral, intravenous, and topical formulations of tacrolimus are
available.
●Tacrolimus immediate-release capsules of 0.5 mg, 1 mg, and 5 mg are
stored at 59 to 86°F (15 to 30°C).
●Extended-release capsules (Astagraf XL) of 0.5 mg, 1 mg, and 5 mg are
stored at 59 to 86°F (15 to 30°C). They should not be crushed or chewed.
●Extended-release tablets (Envarsus XR) of 0.75 mg, 1 mg, and 4 mg are
stored at 59 to 86°F (15 to 30°C). They should not be crushed or chewed.
●Tacrolimus concentrate for injection of 5 mg/mL in 1 mL ampules is stored
at 41 to 77°F (5 to 25°C) and is stable for 24 hours in plastic syringes at 75°F
(24°C). When diluted in glucose or saline solutions, it remains stable for 24
hours in glass, but not PVC, containers.
●Tacrolimus ointment of 0.03 and 0.1% in 30 g and 60 g tubes are stored at
41 to 77°F (5 to 25°C).
●Tacrolimus granules of 0.2 and 1 mg unit-dose packets are stored at 68 to
77°F (20 to 25°C). Tubing, syringes, and other equipment (cups) containing
PVC should not be used to prepare or administer tacrolimus products. The
suspension should be given immediately after preparation and not stored.
There are two extended-release formulations of tacrolimus designed for once-daily
administration. Their mechanisms of prolonged release and pharmacokinetic
profiles differ; therefore, the two are not interchangeable. The extended-release
tacrolimus capsule (Astagraf XL) is a modified-release formulation that allows slow
release of the drug by controlling water penetration and forming a protective
polymer gel layer around tacrolimus [11]. The extended-release

174
tacrolimus tablet (Envarsus XR) uses a drug-delivery technology that improves the
bioavailability of drugs with low water solubility [12].
Extended-release tacrolimus capsules (Astagraf XL) are not approved in liver
transplantation due to an increase in mortality in female liver transplant recipients
[13]. Extended-release tacrolimus tablets (Envarsus XR) are only approved in
kidney transplant patients converted from immediate-release tacrolimus.
Short courses of sublingual tacrolimus have been used as an alternative to
intravenous tacrolimus when enteral administration is not possible [14].
DOSE AND ADMINISTRATION
Administration
●Cyclosporine – Cyclosporine should be administered at a consistent time of
the day (at 12-hour intervals), and with a consistent relation to meals, in order
to decrease the intra-individual blood concentration variations.
Cyclosporine nonmodified oral solution should be mixed with milk, chocolate
milk, or orange juice at room temperature. Cyclosporine modified oral
solution should be mixed with water, orange juice, or apple juice.
Both cyclosporine solutions may adhere to plastic and therefore should not
be mixed in a plastic cup or with plastic utensils. If a dose is missed, patients
should take it as soon as possible, ideally within four hours. They should not
double the next dose.
●Tacrolimus – Tacrolimus immediate-release should be administered at a
consistent time of the day (at 12-hour intervals) and preferably on an empty
stomach. The extended-release products should be taken at the same time of
the day, preferably in the morning. Patients should not chew, divide, or crush
the tablets.
If an immediate-release tacrolimus dose is missed, patients should take it as
soon as possible, ideally within four hours.
For the extended-release product, if a dose is missed, patients should take it
as soon as possible within 14 to 15 hours after missing the dose. After the 14-
to 15-hour timeframe, patients should wait until the usual scheduled time to
take the next daily dose. Patients should not double the next dose. Patients
should avoid alcoholic beverages while taking the extended-release product.
Consumption of alcohol may increase the release rate of tacrolimus and/or
adversely alter the pharmacokinetic properties and the effectiveness and
safety of the extended-release product [15].
For the granules, tubing, syringes, and other equipment (cups) containing
PVC should not be used to prepare or administer tacrolimus products [16]. To
prepare the dose, patients should empty the entire contents of each granules
packet into a glass cup. The granules should then be mixed with 1 to 2
175
 tablespoons (15 to 30 mL) of room temperature drinking water. The granules
will not completely dissolve. The suspension should be taken immediately
after preparation. The cup or non-PVC syringe should be rinsed with the
same quantity of water (15 to 30 mL) and given to the patient to ensure that
all of the medication is taken. Wearing disposable gloves is recommended
during dilution of the injection or when preparing the oral suspension in the
hospital and when wiping any spills. Inhalation or direct contact with skin or
mucous membranes of the powder or granules should be avoided. If such
contact occurs, the skin should be washed thoroughly with soap and water; if
ocular contact occurs, eyes should be rinsed with water. In case a spill occurs,
the surface should be wiped with a wet paper towel. Granules should not be
sprinkled on food.
Dose — The dose and target concentrations of cyclosporine and tacrolimus vary
with the disease being treated. The doses used in patients with solid organ
transplants are discussed below. Other diseases are discussed elsewhere in the
appropriate topic reviews.
Initial doses of calcineurin inhibitors should be determined by taking into account
drug interactions, diet, time after transplantation, pharmacokinetics, presence of
infection, drug toxicity, and/or rejection. Drug concentration monitoring should
occur after the initial doses are given. (See 'Drug monitoring' below.)
Most centers start calcineurin inhibitor therapy just before transplantation or
within the first 24 hours of transplantation (see "Kidney transplantation in adults:
Induction immunosuppressive therapy"). Some centers delay the introduction of a
calcineurin inhibitor until the serum creatinine has decreased by 50 percent from
the pretransplant value or the patient has significant urine output. However, there
is little evidence that delayed, rather than immediate, initiation of a calcineurin
inhibitor results in lower rates of delayed graft function [17,18].
In addition, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines
recommend that administration of calcineurin inhibitors should not be delayed
until the onset of graft function [19].
●Cyclosporine modified – For nonautoimmune disease, cyclosporine
modified is initially dosed at 4 to 10 mg/kg/day orally in two divided doses.
Most clinicians start at the lower end of the dosing range and make
adjustments based upon drug concentrations. The first dose may be
administered within 24 hours of transplantation. In newly transplanted
patients, the initial dose of cyclosporine modified is the same as the initial
dose of cyclosporine nonmodified, although cyclosporine modified is
preferred.

176
 ●Tacrolimus – Tacrolimus is typically dosed at 0.1 to 0.2 mg/kg/day orally in
two divided doses. Most clinicians start at the lower end of the dosing range
and make adjustments based upon drug concentrations. The product
information recommends the following for tacrolimus initiation [16]:
•At 0.1 mg/kg/day in kidney transplant recipients who also
receive mycophenolate mofetil plus an interleukin (IL)-2 receptor
antagonist
•At 0.2 mg/kg/day in kidney transplant recipients treated
with azathioprine rather than mycophenolate mofetil
•At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients
•At 0.075 mg/kg/day in adult heart and lung transplant recipients
●Extended-release tacrolimus products – In patients
receiving mycophenolate mofetil, glucocorticoids, and basiliximab induction,
extended-release tacrolimus capsules (Astagraf XL) should be given at a dose
of 0.15 to 0.2 mg/kg/day prior to reperfusion or within 48 hours of the
completion of the transplant procedure. In patients treated with
mycophenolate mofetil and glucocorticoids without basiliximab induction,
extended-release tacrolimus capsules should be given as a single dose of 0.1
mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at least 4 hours
after the preoperative dose, and within 12 hours after reperfusion, then 0.2
mg/kg daily [13]. The recommended starting dose of extended-release
tacrolimus tablets (Envarsus) in de novo kidney transplant patients is 0.14
mg/kg/day with antibody induction [20].
Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is
complicated by the narrow margin between adequate immunosuppression and
toxicity. Whole blood should be used as a sample for both drugs. A variety of
assays are available, and clinicians should become familiar with the one used in
their local laboratory.
Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose
(C2), or abbreviated area under the time concentration curve (AUC) [19]. Although
monitoring of C0 is common practice, there is a poor correlation with safety,
efficacy, and drug exposure using this strategy. Some centers use C2 monitoring
among kidney transplant recipients since these concentrations may correlate more
closely with exposure, and higher C2 concentrations have been associated with
decreased acute rejection rates in the first year [21-23]. In one study of liver
transplant patients, C2 was more closely associated with the first four-hour post-
dose cyclosporine exposure (AUC0-4) than C0 [24]. C2 monitoring may be more
accurate but is often more difficult and less convenient for the patient. Most
centers monitor either C0 or C2 concentrations but not both. In rare

177
circumstances, assessing both may be beneficial in a patient with absorption
issues.
Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations
for the immediate-release and extended-release preparations, respectively [19].
Blood concentrations should be checked two to three days after
starting cyclosporine or tacrolimus and after any dose change. Typically, after
transplant, concentrations are measured every one or two days while hospitalized.
After discharge, levels should be measured once or twice weekly for the first
month, then weekly until three months posttransplantation, then every two weeks
until six months posttransplant, and then monthly. Some stable, low-risk patients
may have concentrations monitored every two to three months. However, if drugs
that affect cyclosporine or tacrolimus metabolism are added or withdrawn, more
frequent measurement of trough concentrations will be required (see 'Food and
drug interactions' below). Tacrolimus and cyclosporine reach steady-state
concentrations after four to six doses.
Target concentrations — Target concentrations
for cyclosporine and tacrolimus vary depending upon which disease is being
treated. These recommendations are presented elsewhere:
●In kidney transplant recipients (see "Kidney transplantation in adults:
Maintenance immunosuppressive therapy")
●In lung transplant recipients (see "Maintenance immunosuppression
following lung transplantation", section on 'Calcineurin inhibitors')
●In liver transplant recipients (see "Liver transplantation in adults: Overview
of immunosuppression", section on 'Calcineurin inhibitors')
●In heart transplant recipients (see "Heart transplantation in adults: Induction
and maintenance of immunosuppressive therapy", section on 'Calcineurin
inhibitors')
●In hematopoietic cell transplant recipients (see "Prevention of acute graft-
versus-host disease", section on 'Calcineurin-inhibitor-based
therapy' and "Treatment of acute graft-versus-host disease")
●In glomerular diseases (see "Steroid-resistant idiopathic nephrotic syndrome
in children: Management", section on 'Calcineurin
inhibitors' and "Membranous nephropathy: Treatment and prognosis",
section on 'Calcineurin inhibitors' and "Treatment of idiopathic nephrotic
syndrome in children" and "Minimal change disease: Treatment in adults",
section on 'Glucocorticoid-sparing regimens' and "Focal segmental
glomerulosclerosis: Treatment and prognosis", section on 'Calcineurin
inhibitors as alternative initial therapy')

178
 ●In inflammatory bowel diseases (see "Management of the hospitalized adult
patient with severe ulcerative colitis")
●In autoimmune diseases (see "Chronic immunosuppressive therapy for
myasthenia gravis", section on 'Glucocorticoid-sparing therapy')
Dose adjustments — In clinical practice, dose adjustments are made in small
increments with subsequent drug concentration monitoring. If
a cyclosporine concentration is high, then the dose of cyclosporine may be
lowered by 25 to 50 mg per dose. If the concentration is low, then the dose may be
increased by 25 to 50 mg per dose. For tacrolimus, dose adjustments are typically
0.5 to 1 mg per dose. If a drug concentration is supratherapeutic (eg, C0 >400
ng/mL for cyclosporine or >20 ng/mL for tacrolimus), then the dose may be held
until the concentration returns to the therapeutic range. It is important to
determine whether the concentration was obtained correctly before making any
dose adjustments. Tacrolimus and cyclosporine reach steady-state concentrations
after four to six doses, and therefore, dose adjustments can be assessed via drug
concentration monitoring two to three days after an adjustment. In addition,
safety and efficacy should be monitored after adjustments.
Optimal dosing and concentrations may be affected by several factors including
pharmacokinetic factors, presence of infection, drug toxicity, and/or rejection
(table 2) (see "Kidney transplantation in adults: Maintenance immunosuppressive
therapy" and "Kidney transplantation in adults: Treatment of acute T cell-mediated
(cellular) rejection of the renal allograft"). Testing for polymorphisms of the
multidrug resistance-1 (P-glycoprotein) and CYP3A5 genes may aid in the dosing of
calcineurin inhibitors [25-30], but large, well-designed trials are needed to
determine if testing improves outcomes and is cost effective.
Switching formulations — When switching formulations of products, drug
concentrations should be closely monitored for several weeks. The frequency of
monitoring should depend upon several factors (table 2), as well as how far the
patient is from transplant. In a stable patient who is more than six months
posttransplant, we monitor drug concentrations weekly for two to three weeks.
The dose should subsequently be adjusted to attain the preconversion blood
concentration. In addition, safety and efficacy should be monitored after
conversion.
●Cyclosporine
•Oral to intravenous administration – For patients unable to take
oral cyclosporine, the intravenous dose should equal one-third of the oral
dose. Intravenous administration should occur over at least two to six
hours twice daily in a well-hydrated patient to avoid nephrotoxicity.

179
 •Nonmodified to modified formulation – In general, modified formulations
of cyclosporine lead to higher area under the time concentration curve
(AUC) than nonmodified preparations. Thus, patients stabilized on either
form should generally not be switched from one to the other. If patients
are switched, a 1:1 ratio is recommended when converting from the
nonmodified to the modified formulation.
•Cyclosporine to tacrolimus – Clinicians use a 40:1 ratio when converting
from cyclosporine to tacrolimus. As an example, if a patient takes 125 mg
of modified cyclosporine twice daily (250 mg/day), then a tacrolimus dose
of 3 mg twice daily (6 mg/day) would be appropriate.
●Tacrolimus
•Oral to intravenous administration – For patients unable to take
oral tacrolimus, the intravenous dose should equal one-third to one-fifth
of the oral daily dose and should be given as a continuous 24-hour
infusion.
•Immediate-release to extended-release capsules – A 1:1 conversion from
immediate-release tacrolimus to extended-release tacrolimus capsules
(Astagraf XL) has been proven equivalent. The ratio of exposure (AUC0-24)
of extended-release tacrolimus capsules to immediate-release tacrolimus
twice daily is approximately 90 percent across various conversion studies
in kidney, liver, and heart transplant recipients; however, in liver
transplant patients, the extended-release tacrolimus capsule AUC was
significantly lower in the early posttransplant period compared with that
of tacrolimus twice daily [29,31-36].
•Immediate-release to extended-release tablets – Eighty percent of the
total daily dose of immediate-release tacrolimus should be used when
converting to extended-release tablets (Envarsus XR) [37].
•Oral immediate-release to sublingual immediate-release tacrolimus – To
convert from oral tacrolimus to sublingual tacrolimus, the oral tacrolimus
dose should be decreased by 50 percent [14,38].
•Granules – To convert from granules to capsules or from capsules to
granules, the total daily dose should remain the same [16].
PHARMACOKINETICS
Absorption — Oral cyclosporine and tacrolimus are only partially absorbed with
large inter- and intra-individual variability. Cyclosporine and tacrolimus are
absorbed in the small intestine, and peak blood concentrations occur after one to
eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent
for tacrolimus) as a result of poor absorption, partial metabolism by enzymes in
the bowel mucosa, and first-pass hepatic metabolism [39,40]. In general, modified
180
formulations of cyclosporine lead to higher area under the time concentration
curve (AUC) than the nonmodified preparations.
In healthy volunteers, the oral bioavailability of extended-
release tacrolimus tablets was approximately 50 percent higher as compared with
tacrolimus immediate-release at steady state [37]. Both extended-release
tacrolimus products exhibit chronopharmacokinetic effects; evening
administration, compared with morning dosing, results in a 15 percent lower AUC
for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-
release tacrolimus capsules [13,37]. Thus, both products should be taken
consistently every morning.
Pharmacokinetic trials comparing extended-release tacrolimus formulations with
immediate-release tacrolimus have demonstrated a decreased maximum
concentration (Cmax) and delayed time to maximum concentration with extended-
release formulations. However, extended-release tacrolimus tablets have an AUC0-
24 (area under the time concentration curve from 0 to 24 hours) that is
comparable with that of immediate-release tacrolimus; extended-release
tacrolimus capsules have an AUC0-24 that is higher than that of immediate-release
tacrolimus [13,37].
The absorption and metabolism of calcineurin inhibitors may vary with race and
ethnicity. As an example, the mean tacrolimus exposure after a single 5 mg oral
dose in healthy Hispanic and African-American individuals was 18 and 39 percent
less, respectively, than in White individuals [41]. Similar results have been seen
with the extended-release products [13,37]. Such variation may be related to
differences in the frequency of polymorphisms in the CYP3A5  gene among African-
American, Hispanic, and White transplant recipients [42-44].
The absorption of cyclosporine, but not tacrolimus, is dependent upon bile salts.
Thus, cyclosporine modified or tacrolimus may be preferable in patients with
biliary diversion or cholestasis. Cyclosporine modified absorption is decreased
modestly when ingested with a fatty meal (table 3). Similarly, tacrolimus
absorption is decreased if administered after a fatty meal and should be taken on
an empty stomach, if possible [45].
Patients receiving long-term cyclosporine ophthalmic emulsion of 0.05 percent had
no detectable blood cyclosporine concentrations, indicating no significant systemic
absorption [46].
Topical tacrolimus is minimally absorbed in patients with normal skin, but clinically
significant absorption has been reported when used in patients with skin disease
[47].
Distribution — Cyclosporine and tacrolimus are lipophilic and undergo extensive
body distribution. In the blood, most of the absorbed amount of each drug is

181
taken up by erythrocytes. In the plasma, cyclosporine binds mainly to lipoproteins,
whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid
glycoprotein. The plasma protein binding of tacrolimus is approximately 99
percent and is independent of concentration over a range of 5 to 50 ng/mL.
The highest tissue cyclosporine concentration is achieved in the thymus, spleen,
lymph nodes, bone marrow, liver, pancreas, kidney, adrenal glands, lung, and
skin. Tacrolimus accumulates mainly in the lung, spleen, heart, kidney, and
pancreas.
Cyclosporine penetrates well into synovial fluid but does not cross the blood-brain
barrier. Both drugs cross the placenta and appear to some extent in breast milk,
but actual toxicity in breastfed infants appears to be rare [48]. Some centers
measure cyclosporine and/or tacrolimus blood concentrations in breastfed infants
to confirm that these are low.
Metabolism — Cyclosporine and tacrolimus are extensively metabolized by
cytochrome P-450 CYP3A enzymes in the liver. There is also some metabolism in
the gut mucosa. The most active cyclosporine metabolites have only 10 to 20
percent of the drug's immunosuppressive activity. By comparison, one of the
metabolites of tacrolimus possesses equal immunosuppressive potency to the
parent drug.
Elimination — Cyclosporine and tacrolimus are excreted in the bile. The
elimination half-life can vary significantly among patients, especially with
cyclosporine nonmodified, but is approximately 19 hours for cyclosporine modified
and 12 hours for immediate-release tacrolimus. The elimination half-life of
extended-release tacrolimus tablets after oral administration of 2 mg once daily
for 10 days was 31±8 hours in healthy subjects [37]. The elimination half-life of
extended-release tacrolimus capsules after oral administration of 4 mg capsules
daily for 10 days was 38±3 hours in healthy subjects [13]. Cyclosporine metabolism
is age dependent, with a 1.5- to 2.5-fold increase in half-life in adults compared
with children. Liver dysfunction prolongs the half-life of both cyclosporine and
tacrolimus [49,50].
Food and drug interactions
●Food interactions – The presence, composition, and timing of food may
affect the absorption of many of the immunosuppressive drugs (table 3).
Because the avoidance of food at the time of medication administration is not
always practical, many clinicians recommend that patients be consistent and
always take their medication in the same manner, whether it is with or
without food.
A group of active chemical compounds in grapefruit, known as the
furanocoumarins, are potent inhibitors of cytochrome P-450 3A4 enzyme.

182
Grapefruit or grapefruit juice can result in an increase in systemic exposure
to cyclosporine or tacrolimus. It is important to educate patients about the
interaction between grapefruit/grapefruit juice and their immunosuppressive
agents. Patients should be counseled to completely avoid grapefruit and
grapefruit juice when being treated with cyclosporine or tacrolimus. In
patients who refuse to avoid grapefruit and grapefruit juice, more frequent
monitoring of blood cyclosporine or tacrolimus concentrations is required.
●Drug interactions – There are multiple interactions between calcineurin
inhibitors and commonly used medications. General principles of these drug
interactions are reviewed here. More detailed discussions of drug
interactions are found elsewhere.
•Since cyclosporine and tacrolimus are substrates for cytochrome P-450
3A4/5 (CYP3A4/5) enzymes, any drug that is metabolized by these
enzymes or that affects metabolism by these enzymes can potentially
interact with calcineurin inhibitors. A common example is the prescribing
of macrolides for respiratory tract infections: acute
cyclosporine/tacrolimus toxicity may occur. These interactions are
discussed in detail separately on the drug information topics for
cyclosporine and tacrolimus (table 4 and table 5 and table 6). (See "Kidney
transplantation in adults: Maintenance immunosuppressive therapy".)
If a patient cannot avoid a strong inhibitor/inducer of CYP3A4/5, then drug
concentrations and toxicities must be closely monitored. Limited data are
available regarding precise dose adjustments when inhibitors of CYP3A4/5
are coadministered with cyclosporine and tacrolimus.
•Clinicians may take advantage of cytochrome drug interaction to lower
the dose of the calcineurin inhibitor or enhance the drug concentration.
The effects of diltiazem and ketoconazole on cyclosporine metabolism
have led to their use in transplant recipients as a method of lowering the
total cyclosporine dose and, therefore, the cost of cyclosporine therapy.
(See "Kidney transplantation in adults: Maintenance immunosuppressive
therapy".)
•Drugs that affect gastrointestinal motility or emptying (eg, prokinetic
agents) may adversely affect absorption of calcineurin inhibitors.
Laxatives, for example, can reduce
oral cyclosporine and tacrolimus absorption by accelerating their passage
through the intestine. By contrast, narcotics may prolong transit time in
the intestine, increasing the time for absorption.
•Concomitant administration of cyclosporine or tacrolimus with other
potentially nephrotoxic drugs (eg, nonsteroidal antiinflammatory drugs)

183
 should be avoided because increased toxicity may result. Since calcineurin
inhibitors may produce or worsen hyperkalemia, serum potassium levels
should be monitored closely in patients concomitantly taking drugs that
may increase potassium (eg, amiloride, triamterene, and spironolactone).
(See "Cyclosporine and tacrolimus nephrotoxicity".)
•Divalent cations may influence the absorption of tacrolimus. In a single-
dose, crossover study in healthy volunteers, coadministration of
tacrolimus and aluminum hydroxide-magnesium hydroxide resulted in a
21 percent increase in the mean tacrolimus area under the curve (AUC)
and a 10 percent decrease in the mean tacrolimus Cmax relative to
tacrolimus administration alone [16]. However, in another study, patients
did not require tacrolimus dose adjustment when magnesium/aluminum
was prescribed with tacrolimus therapy [51]. To minimize these potential
interactions, magnesium- and aluminum-containing products should not
be administered within two hours of tacrolimus products, and tacrolimus
drug concentrations should be closely monitored.
•Cyclosporine is a substrate and inhibitor of P-glycoprotein [52,53]. In vitro
data suggest that tacrolimus is neither a substrate nor an inhibitor of P-
glycoprotein [54]. Cyclosporine can enhance the efficacy of some
chemotherapy agents by inhibiting P-glycoprotein and reducing the efflux
of drug out of the tumor cell. Additionally, carvedilol inhibits P-
glycoprotein and may increase the blood concentrations of cyclosporine
[55].
•Several antiviral medications are being evaluated or have already been
approved for treatment of coronavirus disease 2019 (COVID-19). Clinicians
should be aware that these medications could interact
with cyclosporine or tacrolimus, and if these immunosuppressants are
continued during COVID-19 infection, their levels should be frequently
monitored. (See "COVID-19: Issues related to solid organ transplantation",
section on 'Drug-drug interactions'.)
For additional information on drug interactions, use the Lexicomp drug
interactions program provided by UpToDate.
SIDE EFFECTSThe side effects of cyclosporine and tacrolimus are generally
similar. When used for the treatment of autoimmune disorders, the frequency and
severity of side effects are lower compared with those seen in transplant
recipients. This observation is explained by the lower doses used and the option to
decrease the dose or discontinue the medication when toxicity appears in patients
with autoimmune disorders; these options may not be available in transplant
recipients.
184
Nephrotoxicity — Nephrotoxicity is a significant adverse effect of both
drugs. Cyclosporine and tacrolimus nephrotoxicity is manifested as an acute
increase in plasma creatinine, which is largely reversible after reducing the dose,
or as chronic occasionally progressive kidney disease, which is usually irreversible.
Other kidney effects of cyclosporine include tubular dysfunction and, rarely, a
thrombotic microangiopathy (TMA). (See "Cyclosporine and tacrolimus
nephrotoxicity".)
Hypertension — Hypertension, caused by renal vasoconstriction and sodium
retention, generally develops within the first few weeks of therapy. Stimulation of
the renal sodium chloride cotransporter is a potential mechanism by which
calcineurin inhibitors may mediate this effect [56]. The blood pressure elevation
usually responds to dose reduction, but antihypertensive medications may be
required. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Kidney
transplantation in adults: Hypertension after kidney transplantation", section on
'Patient is taking a calcineurin inhibitor'.)
Calcium channel blockers are usually considered the drugs of choice if
antihypertensive therapy is needed in the setting of cyclosporine therapy. As noted
above, diltiazem also impairs cyclosporine metabolism, thereby allowing a lower
dose to be given. Initiation of diltiazem should prompt immediate reduction in the
dose of cyclosporine or tacrolimus and careful monitoring of blood concentrations.
Diltiazem also reverses the acute vasoconstriction induced by cyclosporine; there
is, however, no convincing evidence that this prevents chronic cyclosporine
nephrotoxicity. (See "Cyclosporine and tacrolimus nephrotoxicity", section on
'Prevention of chronic calcineurin inhibitor nephrotoxicity'.)
Neurotoxicity — Neurotoxicity associated with cyclosporine and tacrolimus may
manifest as follows [57-62]:
●Mild tremor is common with both cyclosporine and tacrolimus use,
occurring in 35 to 55 percent of patients [59,60]. It may improve despite
continued therapy.
●Rarely, patients develop severe headache, visual abnormalities, and
seizures. This syndrome is associated with acute hypertension and resembles
hypertensive encephalopathy [57]. Posterior leukoencephalopathy is usually
seen on brain imaging [62]. (See "Reversible posterior leukoencephalopathy
syndrome".)
●Akinetic mutism, encephalopathy, seizures, focal neurologic abnormalities,
and even coma have been reported with intravenous tacrolimus [58].
●A calcineurin-inhibitor pain syndrome has been reported with
both cyclosporine and tacrolimus [63]. This syndrome is characterized by
symmetrical pain in the lower limbs, usually involving the bones of the feet,

185
 ankles, and knees. Magnetic resonance imaging (MRI) may show marrow
edema. Symptoms usually improve with cessation of the drug and/or use of
calcium channel blockers.
The neurologic side effects are usually reversible following a change from
intravenous to an oral preparation, lowering of the drug dose, or drug
discontinuation [57,58,61]. They are generally more common with tacrolimus than
with cyclosporine [59,60].
Metabolic abnormalities — Cyclosporine and tacrolimus have been associated
with the following metabolic abnormalities:
●Glucose intolerance and diabetes mellitus (see "Kidney transplantation in
adults: Posttransplantation diabetes mellitus")
●Hyperlipidemia (see "Heart transplantation: Lipid abnormalities after
transplantation" and "Kidney transplantation in adults: Lipid abnormalities
after kidney transplantation")
●Hyperuricemia and gout (see "Kidney transplantation in adults:
Hyperuricemia and gout in kidney transplant recipients")
●Hyperkalemia (see "Cyclosporine and tacrolimus nephrotoxicity", section on
'Hyperkalemia')
●Hypomagnesemia (see "Cyclosporine and tacrolimus nephrotoxicity",
section on 'Hypomagnesemia')
Cyclosporine may also contribute to bone loss after organ transplantation [64]; this
effect may be due to the induction of high bone turnover. (See "Drugs that affect
bone metabolism" and "Kidney transplantation in adults: Bone disease after kidney
transplantation", section on 'Pathogenesis and risk factors'.)
Infections — Bacterial, viral (most often, cytomegalovirus [CMV]), and fungal
infections often develop in transplant recipients receiving combined
immunosuppressive therapy. In a large trial of liver transplant recipients
comparing the efficacy and safety of cyclosporine- and tacrolimus-based
immunosuppressive regimens, infection, sepsis, and CMV disease occurred in
approximately 40, 20, and 15 to 25 percent of patients, respectively [59].
Infection in the solid organ transplant recipient is discussed in more detail
elsewhere. (See "Infection in the solid organ transplant recipient".)
Risk of malignancy — Both cyclosporine and tacrolimus are associated with an
increased risk of squamous cell skin cancer and benign or malignant
lymphoproliferative disorders. Spontaneous regression of lymphoma may occur if
the drug is discontinued early. (See "Malignancy after solid organ
transplantation".)
The overall level of immunosuppression appears to be the principal factor that
increases the risk of posttransplant malignancy. However, evidence from animal

186
models suggests that cyclosporine itself may promote cancer progression,
principally via the production of transforming growth factor (TGF)-beta. In vitro,
cyclosporine treatment of a normally noninvasive adenocarcinoma cell line
induced an invasive phenotype; in addition, cyclosporine promoted tumor growth
in immunodeficient animals [65]. Both the in vitro and in vivo changes were
prevented by the administration of anti-TGF-beta antibodies.
Pregnancy and lactation — The effects of cyclosporine on pregnancy and
lactation are discussed in more detail elsewhere. (See "Safety of rheumatic disease
medication use during pregnancy and lactation", section on
'Cyclosporine' and "Safety of rheumatic disease medication use during pregnancy
and lactation", section on 'Tacrolimus' and "Kidney transplantation in adults:
Sexual and reproductive health after kidney transplantation", section on
'Management of immunosuppression'.)
Other side effects — Other side effects associated with the use
of cyclosporine and tacrolimus include the following:
●Gastrointestinal – Gastrointestinal side effects include anorexia, nausea,
vomiting, diarrhea, and abdominal discomfort. These symptoms are more
frequent with tacrolimus (72 versus 47 percent for cyclosporine in one report)
[60]. Elevated serum aminotransferase levels with mild hyperbilirubinemia
may also occur; if present, this abnormality is reversible with dose reduction
or discontinuation of the drug [66].
●Cosmetic – Gingival hyperplasia and hirsutism occur
with cyclosporine therapy [67,68] but not with tacrolimus. Poor dental
hygiene, higher doses of cyclosporine, and concomitant use
of nifedipine appear to be the principal risks [69]. Case reports suggest that
the gingival hyperplasia can be effectively treated with a two-week course
of metronidazole (750 mg three times daily) while cyclosporine is continued
[70,71]. It is not clear whether metronidazole acts in this setting via its
antibacterial activity or via another mechanism. Treatment
with azithromycin (500 mg/day for three consecutive days) may also be
effective, particularly among those with mild or early disease [72]. In the
transplant setting, the substitution of cyclosporine with tacrolimus was found
to significantly ameliorate gingival hyperplasia without increasing the risk of
renal allograft dysfunction or rejection [73].
An increasingly recognized complication of immunosuppressive therapy in
transplant recipients is alopecia, a finding attributed, in one study, to the use
of tacrolimus [74]. At one transplant center, alopecia was noted in 3 to 6
percent of recipients receiving this agent [75]. Higher doses were associated

187
 with an increased risk. Another study reported an incidence of 30 percent
among kidney-pancreas recipients who received tacrolimus [76].
CONTRAINDICATIONSHypersensitivity to cyclosporine, tacrolimus, or
polyoxyl castor oil products (used as solvents for injection preparation of both
drugs) is a contraindication to their use. The following conditions are generally
accepted contraindications to the use of cyclosporine or tacrolimus:
●Concurrent malignancy (except for nonmelanoma skin carcinoma)
●Uncontrolled hypertension
●Uncontrolled infections
●Hypersensitivity

INFORMATION FOR PATIENTSUpToDate offers two types of patient

education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Disease-modifying

antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the
Basics)" and "Patient education: Heart transplantation (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Formulations – Cyclosporine and tacrolimus are immunosuppressive
agents occasionally used in the treatment of various immune-mediated
diseases and more commonly used to prevent rejection in solid organ
transplantation; the drugs are available in oral, intravenous, ophthalmic, and
topical formulations (table 1). (See 'Formulations' above.)
●Mechanism of action – Cyclosporine and tacrolimus reduce T cell activation
through the inhibition of calcineurin after forming complexes in the
cytoplasm with cyclophilins and FK-binding proteins, respectively. Calcineurin
inhibition results in reduced transcription of early cytokine genes, including

188
those for interleukin (IL)-2, tumor necrosis factor (TNF), and several others.
(See 'Mechanism of action' above.)
●Dose and administration – The dose, route, formulation, and drug
concentrations of calcineurin inhibitors depend upon several factors. Routine
blood monitoring is recommended. Many factors should be considered when
making dose adjustments to calcineurin inhibitors. (See 'Dose and
administration' above.)
●Pharmacokinetics
•Oral cyclosporine and tacrolimus are only partially absorbed, with large
inter- and intra-individual variability. The oral bioavailability is limited for
both drugs due to poor absorption, partial metabolism by enzymes in the
bowel mucosa, and first-pass hepatic metabolism. The drugs are lipophilic
and undergo extensive body distribution. Cyclosporine does not cross the
blood-brain barrier. (See 'Absorption' above and 'Distribution' above.)
•Cyclosporine and tacrolimus are metabolized by hepatic cytochrome P-
450 3A enzymes in the liver and are excreted into the bile. Liver
dysfunction prolongs the half-life of both agents. A variety of important
drug interactions with drugs that either affect or are metabolized by these
enzymes can occur (table 4 and table 5 and table 6). Details about specific
interactions are available by using the Lexi-Interact program included with
UpToDate. (See 'Metabolism' above and 'Elimination' above and 'Food and
drug interactions' above.)
●Side effects – The side effects of cyclosporine and tacrolimus are similar.
Nephrotoxicity is the most common and clinically significant adverse effect of
both drugs. Hypertension, caused by renal vasoconstriction and sodium
retention, is also common and generally develops within the first few weeks
of therapy. Other potential adverse effects include neurotoxicity, metabolic
abnormalities, infections, and an increased risk of malignancy.
Contraindications to use depend upon the presence of various comorbidities
or hypersensitivity to the agents. (See 'Side effects' above and "Cyclosporine
and tacrolimus nephrotoxicity" and 'Contraindications' above.)

189
COVID-19: Issues related to solid organ
transplantation
Authors:
Ajit P Limaye, MD, FACP, FIDSA
Karen Hardinger, PharmD, BCPS
Section Editors:
Daniel C Brennan, MD, FACP
Emily A Blumberg, MD
Deputy Editors:
Albert Q Lam, MD
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 21, 2021.
What's New
Neutralization of SARS-CoV-2 variants in transplant recipients after three
doses of mRNA vaccine (December 2021)
In transplant recipients, administration of a third COVID-19 mRNA vaccine dose
has been shown to improve the immune response without causing short-term
adverse events; however, data on vaccine immunogenicity against SARS-CoV-
2 variants are limited. In a secondary analysis of a recent randomized trial, sera
obtained from participants after receipt of the third vaccine dose had greater
ability to neutralize wild-type SARS-CoV-2 and Alpha, Beta, and Delta variants when
compared with sera obtained after the second dose and sera from participants
who received placebo [1]. The third dose was well tolerated; no cases of rejection
were reported, and graft function remained stable in all patients for three months
after the third dose. These findings support administering a three-dose primary
vaccine series among transplant recipients and other immunocompromised
patients. (See "COVID-19: Issues related to solid organ transplantation", section on
'Vaccination'.)
Read more

INTRODUCTIONSolid organ transplant recipients may be at increased risk for

COVID-19 because they are immunosuppressed and are less likely to mount
effective immune responses to vaccination.

This topic reviews aspects of COVID-19 that are specific to solid organ
transplantation, including screening prior to transplantation, distinct clinical

190
features, managing immunosuppression, and important drug interactions. Other
aspects of COVID-19 care are discussed separately:

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)
●(See "COVID-19: Management in hospitalized adults".)
●(See "COVID-19: Management of the intubated adult".)
●(See "COVID-19: Issues related to acute kidney injury, glomerular disease,
and hypertension".)
●(See "COVID-19: Arrhythmias and conduction system disease".)
●(See "COVID-19: Anesthetic concerns, including airway management and
infection control".)
●(See "COVID-19: Outpatient evaluation and management of acute illness in
adults".)
●(See "COVID-19: Vaccines to prevent SARS-CoV-2 infection".)
●(See "COVID-19: Infection prevention for persons with SARS-CoV-2
infection".)
●(See "COVID-19: Hypercoagulability".)
●(See "COVID-19: Extracorporeal membrane oxygenation (ECMO)".)
●(Related Pathway(s): COVID-19: Initial telephone triage of adult outpatients.)

RISK OF TRANSMISSION
Potential for donor-derived infection — Donor-derived SARS-CoV-2 infection has
been reported with lung transplantation [1]. Data from case series have shown
that transplantation of nonrespiratory organs from SARS-CoV-2-infected donors
can be successfully performed [1-3].
Bloodborne transmission has not been reported and is not expected; both the
frequency of SARS-CoV-2 viremia and its magnitude are low [4-7]. (See "Blood
donor screening: Medical history", section on 'Active or prior infection'.)
Posttransplantation risk — It is not known whether solid organ transplant
recipients are at higher risk for acquiring SARS-CoV-2 infection than the general
population. However, chronic immunosuppression may lower the infectious dose
needed to cause COVID-19 and impair adequate immune control once infection is
established.

Like other immunosuppressed persons, solid organ transplant recipients may shed
greater amounts of virus for longer durations than otherwise healthy hosts. Thus,
they may be more likely to spread infection to others. Further data is needed to
confirm these theories and to quantify viral dynamics and transmission risks in the
solid organ transplant population.

191
DEFERRAL OF NONURGENT TRANSPLANTATIONTo minimize the risk
of infection and conserve hospital resources, elective transplantation (eg, living-
donor kidney transplantation) and nonurgent, deceased-donor transplantation are
being deferred at some transplant centers where the community prevalence of
COVID-19 is high and/or where resources (personnel, hospital or intensive care
unit [ICU] beds, operating rooms, other equipment) are limited [8-12].
Life-saving transplantation continues to be performed, and the Centers for
Medicare & Medicaid Services have classified organ transplantation as a tier 3b
activity: Do not delay, on the basis of assessment of the potential risks compared
with known benefits [13]. The risk-benefit ratio for delaying elective
transplantation during the pandemic is not clear. Limited data suggest that
patients who are waitlisted for kidney transplantation had a higher risk of
hospitalization and death compared with patients who were transplanted [14].
Modelling data provide further support for kidney transplantation during the
pandemic, at least for select populations [15].
PRETRANSPLANTATION SCREENINGAll organ donors and potential
recipients should be screened for COVID-19 prior to organ procurement. This is
necessary to prevent initiation of potent induction immunosuppression in the
context of active infection and for the safety of the organ transplant recipients
(who are typically potently immunosuppressed in the immediate posttransplant
period) and the organ procurement team.
Reverse-transcriptase polymerase chain reaction (RT-PCR; primarily used to detect
active infection) is the main assay used for screening. The utility of serology
(primarily used to detect past infection) for pretransplant screening has not been
established. However, once the performance characteristics of serology are better
established among solid organ transplant recipients, serologies may become a
helpful adjunct assay. (See "COVID-19: Diagnosis", section on 'Specific diagnostic
techniques'.)
Donor screening — All donors should be screened for COVID-19 [16]. We
generally perform a careful history, obtain chest imaging, and perform
microbiologic testing. In all cases the decision to proceed to transplantation
should take into account the urgency of the transplant and the risk and benefits in
each individual. General principles adapted from the American Society of
Transplantation (AST) guidelines and Organ Procurement and Transplantation
Network (OPTN) on SARS-CoV-2 donor evaluation and testing are below [17,18]:
●Living donors
•Self-quarantine for 14 days prior to donation should be considered to
reduce the risk of SARS-CoV-2 infection.

192
 •At the time of donation, donors should be screening for symptoms and
potential exposures. Chest imaging and nucleic acid amplification testing
(NAAT) for SARS-CoV-2 from a respiratory tract sample should be
performed within 72 hours of donation (ideally as close as possible to the
time of donation).
●Deceased donors
•Screening should include assessing for past COVID-19 exposures and
their dates.
•NAAT for SARS-CoV-2 should be performed on nasopharyngeal samples
from deceased donors within 72 hours and, ideally, as close as possible to
organ recovery. When lungs are recovered for transplantation, NAAT for
SARS-CoV-2 should be performed on both nasopharyngeal and lower
respiratory tract samples.
Donors who have known or suspected active COVID-19 based on history and/or
testing have generally been deferred. For donors with resolved COVID-19 who test
positive, the decision to proceed to transplantation should be on a case-by-case
basis and take into account the urgency of transplantation and the risk of recipient
mortality if transmission occurs. In general, for donors who recovered from
COVID-19 21 to 90 days prior to donation, the likelihood of transmission via
transplantation is low and a positive NAAT is not thought to reflect
active/transmissible virus. For those who more recently recovered or who have no
clear history of COVID-19, the safety of organ donation is not known. Similarly, for
donors who have been exposed but test negative, the safety of donation is not
known. In all cases, consultation with an infectious disease expert can help with
test interpretation and risk-benefit analysis [17]. The OPTN has provided
a summary of the evidence to help guide decision-making.
Candidate screening — All potential organ transplant recipients should be
screened for COVID-19 by history, chest imaging, and microbiologic testing prior
to transplantation. Although data are lacking, COVID-19 can be asymptomatic, and
there is concern that the intense immunosuppression given at the time of
transplantation could result in rapidly progressive and potentially fatal COVID-19:
●All potential organ recipients should be screened for COVID-19 prior to
transplantation. At most transplant centers this includes NAAT of an upper
respiratory tract specimen (eg, nasopharyngeal swab), a thorough symptom
and exposure history, and chest imaging. A chest radiograph is usually
sufficient for patients who lack respiratory symptoms, however, for those
with respiratory symptoms (even if minor), computed tomography (CT) of the
chest is appropriate.

193
 ●Candidates with active COVID-19 and/or signs or symptoms of other
respiratory illnesses should generally be deferred for transplantation.
For patients with active COVID-19 and patients who screen positive, the optimal
deferral period is not known. The AST suggests waiting until all symptoms have
resolved and at least two NAATs for SARS-CoV-2 have been negative [16]. As with
any transplantation, the risk of transplantation must be balanced with the risk of
not transplanting a patient with acute or recent COVID-19.
PREVENTION
General measures — Preventive measures for organ transplant recipients are
similar to those defined for the general population. However, we continue to
advise vaccinated transplant recipients to maintain personal measures to minimize
exposure to SARS-CoV-2 (eg, masking, distancing, avoiding crowds when possible),
because early data suggest that vaccine response is suboptimal. (See "COVID-19:
Epidemiology, virology, and prevention", section on 'Prevention'.)
One additional consideration is that solid organ transplant recipients who have
COVID-19 may shed greater amounts of virus for longer durations than
nonimmunosuppressed patients [19,20]. Thus, a longer duration of isolation
and/or testing may be needed to document viral clearance to help reduce the
likelihood of spreading the infection to others. (See "COVID-19: Infection
prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention
in the home setting' and "COVID-19: Infection prevention for persons with SARS-
CoV-2 infection", section on 'Discontinuation of precautions'.)
Vaccination — All transplant recipients are eligible for vaccination, unless
contraindicated (eg, hypersensitivity to the vaccine or its components). Although
the immunogenicity and efficacy of COVID-19 vaccines are lower in solid organ
transplant recipients than the general population [21], the benefit from
vaccination outweighs risk for most patients. Solid organ transplant recipients
should continue to adhere to protective measures (such as masking and social
distancing) despite vaccination, based upon data suggesting a suboptimal immune
response among transplant recipients [22-26] and studies suggesting lower
efficacy against severe disease [27,28].
●Timing – The ideal timing of vaccination in the posttransplantation setting is
not known. In all cases, we weigh the likelihood of contracting COVID-19
(based on community prevalence) against the probability of developing a
protective immune response to vaccination.
•When possible, we delay vaccination for at least one month from the time
of transplantation and for at least three months after use of T cell-
depleting agents (eg, anti-thymocyte globulin) or specific B cell-depletion
agents (eg, rituximab) [29].
194
 •For patients who are transplanted between vaccine doses, we delay the
second dose until at least one month after transplantation (if induction did
not include a T or B cell-depleting agent) and for three months when a T
or B cell-depleting agent was used for induction.
These recommendations are consistent with expert guidance from
International Society for Heart and Lung Transplantation (ISHLT) [29]; the
American Society of Transplantation (AST) also recommends vaccinating at
least two weeks before transplantation but does not specify whether
vaccination should be delayed when T or B cell-depleting agents are used
[30].
●Dose and interval – Data suggest that the humoral immune response to
COVID-19 vaccination is impaired in solid organ transplant recipients [22-
24,26]. Several studies have found that the antibody response to a two-dose
mRNA vaccine is substantially lower in solid organ transplant recipients when
compared with the general population [22,23,26,31]. Poor immune response
was associated with the use of antimetabolite immunosuppression in one
study [23].
Administering a third dose to solid organ transplant recipients is associated
with improved immunogenicity in a significant number of individuals and
appears to be safe. The US Food and Drug Administration (FDA) approved
third doses of mRNA COVID-19 vaccine for many immunosuppressed
patients, including solid organ transplant recipients. Guidance from the
Advisory Committee on Immunization Practices recommended
administration of the same mRNA vaccine used in the primary series
whenever possible; the vaccine should be given a minimum of 28 days after
the second dose. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection",
section on 'Immunocompromised individuals'.)
Administration of a third dose of the mRNA vaccine to transplant recipients
has been shown to improve the immune response without causing short-
term, serious adverse events in randomized trials and cases series [32-37]. In
one trial of 120 solid organ transplant recipients who had received two doses
of an mRNA vaccine, patients were randomly assigned to either a third dose
of mRNA vaccine or saline placebo two months after the second dose of
vaccine (dosing schedule: 0, 1, and 3 months) [34]. Baseline anti-receptor-
binding domain (anti-RBD) antibody levels and neutralizing antibody levels
were similar between the two groups. At month 4, a serologic response
(arbitrarily defined as an anti-RBD antibody level ≥100 U/mL) was present in
55 percent of patients in the vaccine group compared with 18 percent in the
placebo group. Local and systemic events were more common after a third

195
 dose of vaccine than after a dose of placebo, but there were no serious
events or cases of acute rejection.
In a secondary analysis of this trial, sera obtained from participants after receipt of
the third vaccine dose had greater ability to neutralize wild-type SARS-CoV-2 and
Alpha, Beta, and Delta variants when compared with sera obtained after the
second dose and sera from participants who received placebo [38]. After receipt of
the second dose, the proportions of patients with positive neutralization for wild-
type virus and the Alpha, Beta, and Delta variants were 40 of 117 (34 percent), 17
of 117 (15 percent), 15 of 117 (13 percent), and 21 of 117 (18 percent), respectively;
following receipt of the third dose, proportions rose to 71, 55, 34, and 43 percent,
respectively. The third dose was generally well tolerated; no cases of rejection
were reported and graft function remained stable in all patients for three months
following receipt of the third dose.
●Booster doses – Because of the possibility of waning immunity and
decreased efficacy against more virulent variants, the FDA and the Centers
for Disease Control and Prevention (CDC) have approved a booster dose for
all adults 18 years or older, regardless of the vaccine received.
Booster doses in the general population are a distinct issue from
administering a third dose of an mRNA vaccine for the primary series in solid
organ transplant recipients. Solid organ transplant recipients who received
three doses of a primary mRNA vaccine series may also receive a booster
dose six months later. However, there are no available data on the efficacy of
booster doses in solid organ transplant recipients.
Further details on the indications and approach to booster vaccinations are
discussed separately. (See "COVID-19: Vaccines to prevent SARS-CoV-2
infection", section on 'Role of booster vaccinations/waning efficacy'.)
●Immunosuppression and vaccine response – The optimal approach to
managing immunosuppression around the time of vaccination is not known,
and approaches vary among experts:
•For transplant recipients outside of the early posttransplantation period,
there are insufficient data to guide modifications of immunosuppression
in anticipation of, or preparation for, vaccination, and society guidelines
do not recommend routine modification of immunosuppression [39].
However, some experts favor holding the antimetabolite around the time
of vaccination to maximize the likelihood of developing protective
immunity; there is no specific evidence to guide how best to adjust
immunosuppression with respect to timing, duration, or specific
medication adjustment. A clinical trial evaluating the effects of

196
 immunosuppression reduction on vaccine response is in progress
(NCT05060991).
•For those receiving B or T cell-depleting therapy for rejection or other
indications, we may delay vaccination for one to three months depending
on the agent used.
Available studies have not reported an increased rate of acute allograft
rejection with vaccination, but longer-term follow-up and assessment of
donor-specific antibodies are needed.
All available COVID-19 vaccines are inactivated (non-live), and no formulation
is preferred over another for transplant recipients. Most other considerations
(eg, intervals between vaccination, lack of need for serologic testing) are
similar to those for the general population. (See "COVID-19: Vaccines to
prevent SARS-CoV-2 infection".)
●Breakthrough infections after vaccination – Breakthrough infections
among vaccinated solid organ transplant patients, including cases requiring
hospitalization and mechanical ventilation, have been reported [40-45].
Although the overall incidence of breakthrough infections among vaccinated
transplant patients is low, it appears to be greater than that among
vaccinated individuals in the general population. (See "COVID-19: Vaccines to
prevent SARS-CoV-2 infection", section on 'Breakthrough infections after
vaccination'.)
Postexposure prophylaxis — Solid organ transplant recipients who have had
close contact with an individual with SARS-CoV-2 infection or who are at high risk
of exposure to individuals with infection in an institutional setting are eligible for
prophylactic monoclonal antibody treatment (eg, casirivimab-
imdevimab; bamlanivimab-etesevimab). Because of their immunosuppressed
state, we typically refer all exposed organ transplant recipients for postexposure
prophylaxis, when available. (See "COVID-19: Epidemiology, virology, and
prevention", section on 'Post-exposure prophylaxis for select individuals'.)
ACTIVE COVID-19 IN SOLID ORGAN TRANSPLANT RECIPIENTS
Clinical presentation
Clinical features — Clinical features of COVID-19 among solid organ transplant
recipients are variable and similar to those in immunocompetent patients.
However, fever appears to be less common, possibly as a consequence of the
effects of immunosuppressive therapy on the systemic inflammatory response [46-
50]. As an example, in two case series of solid organ transplant recipients in New
York City, fever was a presenting symptom in only 58 to 70 percent [47,48].
Lymphopenia is also common and may be more profound than in nontransplant
patients with COVID-19 [48,50].
197
Severity of illness — It is unclear if solid organ transplant recipients have a higher
risk of severe disease compared with nontransplant patients if infected with SARS-
CoV-2. Many solid organ transplant recipients have medical comorbidities (eg,
hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease)
that have been associated with more severe COVID-19 disease and mortality,
which makes the attributable impact of solid organ transplantation on disease
severity difficult to assess.
While some studies have suggested higher morbidity in solid organ transplant
recipients [47,48,50-59], this has not been corroborated across studies [55,60-65].
A multicenter cohort study, comparing 2307 solid organ transplant recipients with
COVID-19 with 231,047 propensity-matched nontransplant controls, found similar
rates of mechanical ventilation and death between groups, although rates of
hospitalization and acute kidney injury were higher in the solid organ transplant
group [64]. Another study that compared 45 solid organ transplant recipients to
2427 nontransplant patients admitted within the same hospital system found that
despite having a higher risk profile, solid organ transplant recipients had a faster
decline in disease severity over time [65].
Risk factors for severe COVID-19 are discussed in detail elsewhere. (See "COVID-19:
Clinical features", section on 'Risk factors for severe illness'.)
Effect of immunosuppression — The impact of immunosuppression in the solid
organ transplant population on COVID-19 disease severity remains unclear. The
pathogenesis of COVID-19 appears to represent an interplay between direct virally
mediated injury and the associated host response, with experimental data
suggesting that a dysregulated and hyperintense immune response may mediate
more severe disease [66]. Since immunosuppressive agents modulate several
aspects of the host immune response, the severity of COVID-19 could potentially
be affected by the type, combinations, and intensity of immunosuppression. As an
example, certain immunosuppressive medications can either directly (eg,
lymphocyte-depleting antibodies) or indirectly (eg, antimetabolites) cause
lymphopenia, which is a reported risk factor for severe COVID-19 illness. Specific
agents that have been independently associated with decreased immune
responses to vaccines (eg, mammalian [mechanistic] target of rapamycin [mTOR]
inhibitors, mycophenolate) could theoretically impair the ability to develop an
adequate immune response to natural infection. Conversely, some experimental
data suggest that mTOR inhibitors may have some biological activity against SARS-
CoV-2 [67]. Additional studies are required to determine the impact of specific
immunosuppressive agents on the course of COVID-19.
Diagnosis — Criteria for testing for COVID-19 in solid organ transplant recipients
are similar to those for the general population. However, clinicians should have a

198
higher index of suspicion of infection, as is generally recommended for
immunosuppressed individuals (table 1):
●For solid organ transplant recipients with suspected COVID-19 who are
hospitalized, testing is recommended.
●For solid organ transplant recipients with mild symptoms, optimal practice is
not defined. While some favor testing all such patients based upon the
potential for rapid disease progression and early treatment, others favor
making a clinical diagnosis and monitoring the patient at home. Thus, the
decision is often individualized based upon local COVID-19 prevalence,
available resources, and patient-provider preference. (See "COVID-19:
Outpatient evaluation and management of acute illness in adults", section on
'Monoclonal antibodies'.)
●Routine screening of asymptomatic solid organ transplant recipients is not
recommended.
Specific testing and screening methods are discussed separately. (See "COVID-19:
Diagnosis", section on 'Clinical suspicion' and "COVID-19: Infection prevention for
persons with SARS-CoV-2 infection".)
Management
General considerations — The approach to the management of acute COVID-19
in solid organ transplant recipients is similar to that for nontransplant patients;
however, because of their immunosuppressed status the threshold to treat with
monoclonal antibodies is lower.

These issues are discussed in more detail separately:

●(See "COVID-19: Outpatient evaluation and management of acute illness in

adults".)
●(See "COVID-19: Management in hospitalized adults".)
●(See "COVID-19: Clinical manifestations and diagnosis in children".)
●(See "COVID-19: Management of the intubated adult".)
Adjusting immunosuppression — Adjustments to the immunosuppressive
regimen are necessarily individualized, based upon disease severity, the specific
regimen used, type of organ transplanted, time posttransplant, and the risk of
acute allograft rejection [47,50,55,68-70].

Although the optimal approach is not defined, we usually reduce

immunosuppression in patients with moderate to severe COVID-19 (eg, those
requiring hospitalization):

199
 ●As a first step, we often reduce or hold the antimetabolite
(eg, mycophenolate mofetil/sodium), particularly for patients with
lymphopenia (eg, absolute lymphocyte count <700 cells/mL).
●We generally continue the calcineurin inhibitor (CNI) because CNIs inhibit
interleukin (IL) 6 and IL-1 pathways; these cytokines may contribute to the
development of the severe, dysregulated immune response seen in some
patients with severe COVID-19.
In all cases the decision to reduce immunosuppression must be carefully weighed
against the risk for acute rejection, particularly in transplant recipients who
generally require high levels of maintenance immunosuppression (eg, lung or
heart recipients). Data supporting our approach and any other are limited to
observational studies [47,48,50,55,71,72].
There are also concerns that COVID-19 itself may increase the risk for acute
rejection and that an overly intense inflammatory host immune response might
contribute to overall disease severity. Thus, attenuating the immune response by
maintaining low-dose immunosuppression could theoretically be beneficial. In
addition, experimental data suggest that certain immunosuppressive agents such
as mTOR inhibitors may have some biological activity against SARS-CoV-2 [67].
Additional studies are required to confirm these findings.

Additional guidance on adjusting immunosuppression in transplant recipients with

active infection can be found in the following topic reviews:

●(See "Kidney transplantation in adults: Maintenance immunosuppressive

therapy", section on 'Patients who develop an infection'.)
●(See "Maintenance immunosuppression following lung transplantation",
section on 'Monitoring and adjusting maintenance therapy'.)
●(See "COVID-19: Evaluation and management of cardiac disease in adults",
section on 'Cardiac transplantation'.)
Recommendations from specific medical societies are listed separately.
(See 'Society guideline links' below.)
Drug-drug interactions — Several new antiviral medications are being evaluated
or have already been approved for treatment of COVID-19 (see "COVID-19:
Management in hospitalized adults", section on 'Specific treatments'). Clinicians
should be aware that these medications have potential drug-drug interactions with
immunosuppressive medications that are commonly used among solid organ
transplant recipients (such as CNIs) (table 2). If these immunosuppressive agents
are continued during COVID-19 infection, their blood levels should be frequently
monitored [73].

200
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The

Basics)" and "Patient education: COVID-19 vaccines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Challenges for organ transplantation – COVID-19 poses challenges for
individual solid organ transplant candidates and recipients, as well as the
process of organ transplantation. (See 'Introduction' above.)
●Risk of transmission – Donor-derived SARS-CoV-2 infection has been
reported through lung transplantation but not via non-lung transplantation.
(See 'Potential for donor-derived infection' above.)
●Screening before transplantation – Because of this risk and the potential
for transmitting SARS-CoV-2 to health care providers, all solid organ donor
and transplant candidates should be screened for COVID-19 by history, chest
imaging, and microbiologic testing. (See 'Pretransplantation
screening' above.)
●Posttransplant risk – Posttransplantation, solid organ transplant recipients
may be at increased risk for acquisition of COVID-19 because they are
immunocompromised, although this association has not been studied.
(See 'Posttransplantation risk' above.)
●Clinical manifestations – The clinical manifestations of COVID-19 in solid
organ transplant recipients are variable and generally similar to those
observed in nonimmunocompromised patients. However, fever appears to

201
be less common. Whether the disease course is more severe is not known.
(See 'Clinical presentation' above and 'Severity of illness' above.)
●Diagnosis – The approach to diagnosis is similar to that for the general
population. Because signs and symptoms of COVID-19 may be subtle in
transplant recipients and disease progression can be rapid, some clinicians
have a lower threshold for evaluating and testing transplant recipients.
(See 'Diagnosis' above.)
●Management approach – The approach to management (eg, use of
antivirals, supportive care) is also similar to that for the general population,
although the threshold for monoclonal antibody use is lower. Careful
attention should be paid to potential drug-drug interactions and effects on
the immunosuppressive regimen. (See 'General considerations' above
and 'Drug-drug interactions' above.)
●Adjusting immunosuppression – Adjustments to the immunosuppressive
regimen are necessarily individualized, based upon disease severity, the
specific regimen used, type of organ transplant, time posttransplant, and the
risk of acute allograft rejection. Some organ transplant recipients recover
without reduction in immunosuppression, which carries the risk of rejection
and immune reconstitution. Conversely, continued immunosuppression may
enhance the risk of uncontrolled infection. (See 'Adjusting
immunosuppression' above.)
●Vaccination – All transplant recipients are eligible for vaccination, unless
contraindicated (eg, hypersensitivity to the vaccine or its components). The
ideal timing in the posttransplantation setting is uncertain, and our approach
is discussed above. Because early data suggest that vaccine response is
suboptimal, we continue to advise that vaccinated transplant recipients
maintain personal measures to minimize exposure to SARS-CoV-2 (eg,
masking, distancing, avoiding crowds when possible).
(See 'Vaccination' above and 'General measures' above.)

202
Evaluation for infection before solid organ
transplantation
Author:
Jay A Fishman, MD
Section Editor:
Emily A Blumberg, MD
Deputy Editor:
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 22, 2020.
INTRODUCTIONSolid organ transplantation is the therapy of choice for a
variety of types of organ failure. Two major complications, infection and
malignancy, are the result of the life-long immunosuppression needed to maintain
allograft function. The pretransplant evaluation identifies opportunities to assess
the risks for common post-transplant infections and to develop individualized
preventative strategies including treatment of existing infections, prophylaxis, and
vaccination. Thus, the evaluation focuses on exposure history, prior infections,
serologic testing for distant exposures, cultures to identify colonization patterns,
and administration of vaccines [1].
The components of the pretransplant evaluation will be reviewed here. The
infections that follow solid organ transplantation are discussed separately.
(See "Infection in the solid organ transplant recipient" and "Prophylaxis of
infections in solid organ transplantation" and "Nontuberculous mycobacterial
infections in solid organ transplant candidates and recipients" and "Tuberculosis in
solid organ transplant candidates and recipients" and "Infectious complications in
liver transplantation" and "Bacterial infections following lung
transplantation" and "Fungal infections following lung
transplantation" and "Prevention of cytomegalovirus infection in lung transplant
recipients" and "Clinical manifestations, diagnosis, and treatment of
cytomegalovirus infection in lung transplant recipients" and "Kidney
transplantation in adults: Clinical manifestations, diagnosis, and management of
cytomegalovirus disease in kidney transplant recipients".)
CAUSES OF INFECTIONThe organisms commonly associated with post-
transplant infection are the result of reactivation of latent infection carried by the
donor organ or the recipient and/or following new exposures in the community or
in the hospital [1-3]. Latent infection refers to organisms residing in a suppressed

203
state in the recipient or in the donor tissue. Cytomegalovirus, Epstein-Barr
virus, Toxoplasma gondii, Strongyloides stercoralis, and Trypanosoma cruzi are
examples of organisms that can exist in the normal host and are, in general,
controlled by the host immune system. The risk for reactivation (replication) of any
latent infection is related to the nature and intensity of the immune suppression
following transplantation.

Established infection is difficult to treat in the immunocompromised transplant

recipient. Significant antimicrobial toxicities are common, often due to diminished
renal or hepatic function and drug interactions. Thus, a pretransplant evaluation
for infection is central to care and should be comprehensive. The evaluation is
aimed at identifying and treating any active infection prior to transplantation,
identifying latent infections and developing a prophylactic strategy to prevent
reactivation following transplant, and identifying pertinent colonization with
multidrug-resistant organisms (MDRO) and developing appropriate perioperative
antibiotic management plans based on this knowledge.

Colonizing organisms are potential pathogens in the setting of immune

suppression or acutely in the postoperative setting if acquired from the
environment via vascular access catheters, endotracheal tubes, anastomotic leaks,
fluid collections, or open surgical wounds [4-6]. Infections, when they occur, may
manifest well after transplantation. Colonizing organisms may include
antimicrobial-resistant organisms such as Pseudomonas
aeruginosa, Aspergillus species, Stenotrophomonas maltophilia, Burkholderia cepacia,
methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.
Colonization with such resistant pathogens is common with:
●Multiple prior hospitalizations
●Multiple exposures to broad-spectrum antimicrobial agents
●Cystic fibrosis or other forms of chronic lung disease
●Cardiomyopathy with heart failure
●Cirrhosis often with ascites
●Those awaiting organ replacement with chronic organ dysfunction
MDRO including carbapenem-resistant Klebsiella pneumoniae and other gram-
negative bacilli are increasingly common in solid organ transplant recipients
[7,8]. The identification of such potential pathogens prior to transplantation allows
perioperative prophylaxis and/or appropriate antimicrobial therapy if infection
occurs. There is no consensus regarding optimal approaches to screening for
MDRO prior to transplantation. Antimicrobial therapy should be based on in vitro
susceptibility data and accompanied by debridement of foci of infections, such as
infected hematoma or other fluid collections.
204
CLINICAL EVALUATIONThe clinical evaluation of a patient prior to solid
organ transplantation should focus on exposure history, history of prior infections,
cultures for colonization, serologies for more distant exposures, and
administration of vaccines [1].
History — Important elements of the pretransplant historical evaluation include:
●Travel to or residence in areas of the world with unique endemic infections
(eg, S.
stercoralis, Trypanosoma  spp, Schistosoma  spp, Leishmania  spp, Histoplasma
capsulatum, Coccidioides  spp, Paracoccidioides  spp, Brucella  spp, hepatitis
viruses, mycobacteria infections)
●Travel to or residence in areas with outbreaks of infection (eg, West Nile
Virus, Zika virus, coronavirus disease 2019 [COVID-19], flooding after
hurricanes)
●Animal exposures including cats, dogs, rodents, or birds
●Dietary exposures including well water, unpasteurized dairy products, or
imported cheeses (eg, Cryptosporidium or Listeria monocytogenes)
●Employment and hobbies including exposures to soil, birds, and toxins
(endemic fungi, nontuberculous mycobacteria)
●Potential or known exposure to tuberculosis (TB) and/or prior testing for TB
●Risk factors for HIV infection and other sexually transmitted infections
●Potential or known exposure to hepatitis viruses
●Presence of prosthetic material (eg, prosthetic joint, central venous
catheters, pacemakers)
●Other active infections, prior infections, and conditions that may predispose
to infection (eg, urinary tract infections, vesicoureteral reflux, herpes simplex
infections, shingles, recurrent respiratory tract infections, diverticulitis,
cholecystitis, hepatitis, peritonitis, tick
bites, Salmonella or Toxoplasma  infections)
●Surgical history (eg, splenectomy, sinus surgery, portasystemic shunting)
●Cardiac valvular abnormalities or vascular defects (aneurysms) or clots
●Malignancies, particularly those infectious in origin which can reactivate
post-transplant (eg, anogenital carcinoma due to papilloma virus,
nasopharyngeal carcinoma, or Burkitt lymphoma associated with Epstein-
Barr virus)
●Drug and alcohol use
●Vaccination history
History-taking on immunosuppressive medication use should be thorough. Use of
immunosuppressive therapies in the pretransplant period can increase the risk
of Pneumocystis jirovecii pneumonia, reactivation of TB, histoplasmosis,
205
cryptococcosis, or toxoplasmosis in the early post-transplant period. In addition, a
history of recent immunosuppressive regimens such as glucocorticoids for
systemic lupus erythematosus, T cell or B cell depletion and immune modulators
("biologics") for rheumatologic disease or inflammatory bowel disease, or past
treatment for malignancy can alter the choice and intensity of both prophylactic
and immunosuppressive regimens after transplantation.

A careful review of systems should also be performed to uncover current occult

infection or colonization. All prior infections should be documented, including the
antimicrobial susceptibility pattern of organisms previously isolated and any
treatments received. In some cases, transplant candidates with recurrent
infections such as cholecystitis, sinusitis, diverticulitis, and pyelonephritis may
need to have these conditions resolved prior to transplantation.

Laboratory testing — Laboratory testing for evidence of past infectious

exposures or active infections is performed to determine the risk for infection in
the transplant recipient [1-3,7,9,10]. Some tests are suggested for all patients,
whereas others are useful in selected patients with suggestive epidemiologic risk
factors (table 1).

Serologic testing is used as an indicator of prior infections. Antibody-based tests

(serologic tests) should not, in general, be used for the diagnosis of active
infections since there may be a delay between pathogen exposure and
seroconversion ("window period"). Nucleic acid tests (NATs) are used to detect and
measure active infections in organ donors or recipients and generally will be
positive earlier in infection compared with serologic assays.

Screening for cytomegalovirus, herpes simplex virus, varicella zoster virus,

toxoplasmosis, histoplasmosis, and Chagas disease are used as guides for
prophylactic strategies after transplantation rather than for pretransplant
therapies. EBV serologies are useful in stratifying the risk for post-transplant
lymphoproliferative disorders, particularly among pediatric recipients and those
treated with belatacept who are at higher risk. (See "Kidney transplantation in
adults: Clinical manifestations, diagnosis, and management of cytomegalovirus
disease in kidney transplant recipients" and "Treatment and prevention of post-
transplant lymphoproliferative disorders".)
Histoplasma and Coccidioides antibodies are insensitive for detecting latent
infections. Therefore, negative serologies do not rule out latent infections with
these pathogens. The risk of infection should be assessed for each patient based
upon exposure history, reports of prior consistent symptomatic infections (eg,

206
Valley fever), and findings of healed granulomas (eg, in the lungs and/or hilar
lymph nodes), which suggest latent infection.
Viral load testing should be obtained for HIV, hepatitis B virus, and hepatitis C virus
in infected candidates. Routine peritransplant prophylaxis for hepatitis B is
advocated for unvaccinated liver transplant recipients with active infections.
Decisions regarding the timing of HCV therapy should be individualized based on
disease activity and likely waiting time for liver transplantation. (See "Prophylaxis
of infections in solid organ transplantation" and "Kidney transplantation in adults:
Hepatitis B virus infection in kidney transplant recipients" and "Hepatitis B virus
reactivation associated with immunosuppressive therapy" and "Patient evaluation
and selection for antiviral therapy for chronic hepatitis C virus
infection" and "Hepatitis C virus infection in liver transplant candidates and
recipients".)
Particular note must be made of TB testing and of the pretransplant treatment of
patients with positive serologies for Strongyloides. In endemic regions and in the
appropriate season, donors and recipients may be screened for exposure to West
Nile virus, Chagas disease, Zika virus, or other unique pathogens (table 1).
(See "Tuberculosis in solid organ transplant candidates and recipients".)
Human T lymphotropic virus (HTLV)-1 may cause spastic paraparesis/myelopathy
or adult T cell leukemia/lymphoma. HTLV-2, which is endemic in regions including
the Caribbean and parts of Asia and Africa, is less clearly associated with these
diseases and has been difficult to distinguish serologically from HTLV-1. As a result
of the low rate of infection in the United States and poor testing options,
mandatory screening for HTLV-1/-2 was discontinued in the United States in 2009
[11]. Rarely, donor-transmitted HTLV-1 infection has been identified with
significant adverse outcomes in some individuals. HTLV-1 and -2 may be
distinguished from one another using Western blot or nucleic acid testing.
(See "Infection in the solid organ transplant recipient", section on 'HIV, HTLV, and
hepatitis viruses'.)
Vaccinations — Prevention of infection through immunization is of paramount
importance to the increasing population of solid organ transplant recipients.
Confirmation of vaccine status for hepatitis B virus, measles-mumps-rubella,
hepatitis A virus, human papillomavirus, pneumococcus, and tetanus-diphtheria
and pertussis should be obtained. However, many immunocompromised patients
are often unable to mount protective immune responses to vaccines. Live virus
vaccines should be administered in advance of transplantation as
immunosuppression may result in unchecked proliferation of attenuated vaccine
strains and is generally avoided in solid organ transplant recipients. For these
reasons, it is optimal to immunize patients prior to transplantation. Vaccine

207
recommendations for solid organ transplant candidates and recipients are
discussed in detail separately. (See "Immunizations in solid organ transplant
candidates and recipients".)
Testing for latent tuberculosis — The incidence of TB in solid organ transplant
recipients is 20 to 74 times higher than in the general population [12-16]. The vast
majority of cases are due to reactivation disease, although transmission via a
transplanted organ has been described [17].
There are two available tests that can be used to screen for latent TB,
the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). Both
tests are less sensitive in immunocompromised individuals. The frequency of
indeterminate IGRAs is highest in liver transplant candidates. The IGRA is more
often positive in renal transplant candidates than is the TST and has a greater
association with risk factors for TB [18-21]. The predictive value in transplantation
requires further study.

Radiographic changes on chest films can also be suggestive of prior exposure to

TB.

Indications for prophylaxis include:

●Untreated LTBI (eg, positive TST or IGRA without evidence of active TB)
or LTBI without documentation of adequate therapy
●A history of TB contact before transplantation
●Recipients of transplants from donors with a history of untreated TB

Patients who have completed a course of adequate therapy for TB do not need
repeat prophylaxis unless they subsequently have one of the last two indications
above.

Screening and treatment of latent TB in solid organ transplant candidates and

recipients are discussed in detail separately. (See "Tuberculosis in solid organ
transplant candidates and recipients".)
Active infections in the transplant candidate — Active bacterial and fungal
infections must be eliminated or controlled, whenever possible, prior to
transplantation. Even asymptomatic infections can evolve into overwhelming
sepsis following transplantation. As an example, lung transplant candidates with
cystic fibrosis will generally be colonized with organisms such as P.
aeruginosa, S. aureus, and B. cepacia  that are resistant to antimicrobial agents.
Since manipulation of the infected lung tissue during transplantation theoretically
could disseminate infection, perioperative bactericidal and fungicidal therapies are
208
employed. B. cenocepacia appears to be a particularly virulent genomovar of B.
cepacia. Management of lung transplant candidates and recipients who are
colonized with this organism is discussed in greater detail separately.
(See "Bacterial infections following lung transplantation", section on 'Burkholderia
cepacia'.)

Sterilization is often not feasible for colonized lungs, hepatic abscesses, or bile
leaks. Infection must be controlled to the degree possible prior to transplant
surgery. Proceeding to transplant in the setting of active infection requires
thorough consideration of the risks and benefits of transplantation. Prior to or at
the time of "activation" of the candidate on the transplant waiting list, the status of
any active or pertinent past infections should be documented, including plans for
reimaging with interventional sampling to assure drainage and sterilization of
infected fluids or repeat respiratory cultures.

As noted above, patients with an anatomic predisposition to infections, such as

cholecystitis, diverticulitis, or recurrent aspiration (in lung transplant recipients),
may benefit from pre-emptive surgery prior to transplantation. Patients with a
history of recurrent sinusitis should be evaluated prior to transplantation for sinus
infection by computed tomography and by an otolaryngologist, who can obtain
culture specimens from deep tissue and/or perform a drainage procedure, if
needed. As an additional example, patients with
recurrent Clostridioides difficile  infection may benefit from fecal transplantation
prior to solid organ transplantation [22,23].
Whenever possible, all intravenous or urinary catheters should be removed as
soon as is possible but certainly discontinued prior to transplantation. Exceptions
include hemodialysis or peritoneal dialysis catheters in the nonbacteremic patient
and intra-aortic balloon pumps. However, these should be removed, if possible, at
the time of transplantation. In patients with liver failure awaiting transplantation,
elective intubation may be performed to prevent aspiration. Baseline sputum
cultures should be obtained (to document colonizing organisms) and active
infections treated when possible. Antimicrobial prophylaxis against spontaneous
bacterial peritonitis, generally with a fluoroquinolone agent, may be useful in
patients with ascites after documentation of negative cultures [1,2].
(See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)
Coronavirus disease 2019 — Organ donors and recipients require careful
assessment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the
virus that causes coronavirus disease 2019 (COVID-19), prior to transplantation
[24,25]. Although the concern is theoretical, induction and maintenance
immunosuppression could potentially lead to more severe infection. In addition,
209
COVID-19 can induce a profound systemic inflammatory response, which could
enhance the risk of graft rejection.
●Organ donors should be screened for COVID-19 prior to organ procurement.
This is necessary for the safety of organ procurement teams as well as for the
organ recipients. Donors with known exposures to individuals infected with
COVID-19 should be declined. Protocols for screening for lung donors likely
differ among institutions but often include screening from multiple sites. For
example, screening by nasopharyngeal swab may be performed first and, if
negative, followed by bronchoalveolar lavage sampling.
●Potential organ recipients should be screened for COVID-19 prior to
transplantation. Individuals with symptoms of respiratory viral illness should
be deferred for transplantation.
Testing methods for COVID-19 are discussed separately. (See "COVID-19:
Diagnosis", section on 'Diagnostic approach'.)
Perioperative prophylaxis — In the absence of specific data about colonization or
infection due to resistant organisms in an individual patient, standard
perioperative antimicrobial prophylaxis is administered for solid organ
transplantation [26]. Regimens including vancomycin (except in cardiac transplant
recipients) or clindamycin should be avoided whenever possible, to decrease the
risk of colonization with vancomycin-resistant organisms and the latter to lessen
the chance of developing diarrhea due to C. difficile postoperatively.
Generally, 24 hours or less of a first-generation cephalosporin provides adequate
protection for renal transplantation in the absence of specific microbiologic data
that would require broader coverage. In hepatic transplantation, coverage is
generally employed for biliary and bowel flora including enterococci and anaerobic
organisms, in addition to antifungal prophylaxis. Perioperative antifungal
prophylaxis with azole or echinocandin agents should be considered for patients
with specific risk factors, including those requiring a Roux-en-Y loop, reoperation,
and renal replacement therapy or for pancreas transplant recipients based upon
the higher incidence of candidal infection in these hosts. Many centers with a
significant rate of infection due to Aspergillus after liver or lung transplantation use
perioperative prophylaxis with a lipid formulation of amphotericin B, inhaled
amphotericin products (for lung transplant recipients), or later-generation azoles
(voriconazole, posaconazole). The azole antifungals have significant effects on the
metabolism of calcineurin inhibitors and sirolimus; dose adjustments must be
made during and after such therapies [27].
More detailed recommendations for the use of perioperative prophylaxis are
presented separately. (See "Prophylaxis of infections in solid organ
transplantation", section on 'Peritransplantation prophylaxis'.)

210
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Infections in solid organ transplant
recipients".)
SUMMARY AND RECOMMENDATIONS
●The organisms most commonly associated with post-transplant infection are
the result of reactivation of latent infection carried by the donor organ or the
recipient or are due to exposures in the community or in the hospital.
(See 'Causes of infection' above.)
●Latent infection refers to organisms residing in a suppressed state in the
recipient or in the donor tissue. Cytomegalovirus, Epstein-Barr
virus, Toxoplasma gondii, Strongyloides stercoralis, and Trypanosoma cruzi are
examples of organisms that can exist in the normal host and are, in general,
controlled by the host immune system. These pathogens may cause life-
threatening infection in the immunocompromised host. The risk for
reactivation of any latent infection is related to the nature and intensity of the
immune suppression following transplantation. (See 'Causes of
infection' above.)
●Colonizing organisms may include antimicrobial-resistant organisms
including methicillin-resistant Staphylococcus aureus, vancomycin-resistant
enterococci, carbapenem-resistant Klebsiella pneumoniae, Pseudomonas
aeruginosa, Aspergillus species, Stenotrophomonas maltophilia, and others.
Multidrug-resistant organisms are important pathogens in transplantation.
These organisms are potential pathogens in the setting of
immunosuppression or acutely in the postoperative setting. (See 'Causes of
infection' above.)
●The pretransplant evaluation is central to the prevention of postoperative
infection. The clinical evaluation of a patient prior to solid organ
transplantation should focus on history of prior infections and relevant
exposures, cultures for colonization, serologies for more distant exposures,
and administration of vaccines. (See 'Clinical evaluation' above.)
●History-taking should be comprehensive and detailed in order to uncover
exposures to organisms that may be of importance in the
immunocompromised host (eg, travel and residence history, pets,
occupational and recreational exposures, high-risk behaviors). In addition, a
careful review of systems may uncover current occult infection or
colonization. (See 'History' above.)
●Laboratory testing for evidence of past infectious exposures is performed to
detect asymptomatic infection in the transplant candidate. Some tests are
211
suggested for all patients, whereas others are useful in selected patients with
epidemiologic risk factors (table 1). Serologic testing is used as an indicator of
significant past exposures; screening for cytomegalovirus, herpes simplex
virus, varicella zoster virus, hepatitis viruses, HIV, and toxoplasmosis are used
as guides for prophylactic strategies after transplantation. (See 'Laboratory
testing' above.)
●It is optimal to immunize patients prior to transplantation. Vaccine
recommendations for solid organ transplant candidates and recipients are
discussed in detail separately. (See "Immunizations in solid organ transplant
candidates and recipients".)
●Perioperative antimicrobial prophylaxis is used to prevent infection in the
early post-transplant period. (See 'Perioperative prophylaxis' above
and "Prophylaxis of infections in solid organ transplantation", section on
'Peritransplantation prophylaxis'.)

212
Immunizations in solid organ transplant
candidates and recipients
Authors:
Camille N Kotton, MD
Patricia L Hibberd, MD, PhD
Section Editor:
Emily A Blumberg, MD
Deputy Editors:
Milana Bogorodskaya, MD
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 18, 2021.
INTRODUCTIONPrevention of infection is of paramount importance to the
increasing population of solid organ transplant recipients. Infection in these
patients results in substantial morbidity and mortality, and antimicrobial therapy is
often less effective than in the immunocompetent host. Although immunization
appears to be an obvious way to prevent infection, immunocompromised patients
are less likely to mount protective immune responses following vaccination. While
concern has been raised that vaccination might trigger rejection, there does not
appear to be a causal association between vaccination and organ rejection.
Immunization with live virus vaccines is generally avoided in solid organ transplant
recipients as it may result in adverse events from proliferation of attenuated
vaccine strains.
Our approach to immunizing patients who are awaiting or have undergone solid
organ transplantation will be reviewed here. Issues related to immunizations in
patients who have had hematopoietic cell transplants, who have undergone
chemotherapy for treatment of hematologic malignancies or solid tumors, who
have HIV infection, patients with impaired splenic function, and in healthy adults
are discussed separately. (See "Immunizations in hematopoietic cell transplant
candidates and recipients" and "Immunizations in adults with
cancer" and "Immunizations in patients with HIV" and "Standard immunizations
for nonpregnant adults" and "Prevention of infection in patients with impaired
splenic function".)
IMMUNOGENICITYThe risk of acquiring infection and the inability to prevent
infection by immunization are directly related to the patient's "net state of
immunosuppression." The greater the degree of immunosuppression, the less
likely the patient is to respond to immunization. Factors contributing to
213
immunosuppression in solid organ transplant recipients include the underlying
disease (eg, renal or hepatic insufficiency), the post-transplant immunosuppressive
regimen, the presence of allograft rejection, advanced age, and other
comorbidities (eg, diabetes mellitus, asplenia).
Although vaccination is likely to provide benefit to the immunocompromised
patient, an adequate vaccine response cannot be assumed [1-3]. Protection of the
immunocompromised patient may require the use of vaccines and/or passive
immunization (ie, intravenous immunoglobulin) as well as adjunctive measures,
such as antiviral drug prophylaxis after influenza exposure.
While concern has been raised that vaccination might trigger rejection, numerous
trials have shown no causal association between vaccination and organ rejection
[4].
TIMING OF IMMUNIZATIONS
Pretransplant — Prior to transplantation, we review each patient's vaccination
and exposure history in detail and administer any indicated vaccinations (table 1)
[1,5] (see "Evaluation for infection before solid organ transplantation"). A
programmatic approach to pretransplant vaccination has been shown to be
beneficial and conveys better protection against infection [6]. Many transplant
programs have initiated routine pretransplant vaccination programs. In general,
updating pneumococcal, influenza, and tetanus immunizations, along with
serology-based vaccine recommendations against measles, mumps,
varicella/shingles, hepatitis B virus, and hepatitis A virus, are key interventions.
Standard vaccines for children are summarized in the following figures (figure
1B and figure 1A). Standard vaccines for adults with medical conditions are
summarized in the following figure (figure 1C). (See "Standard immunizations for
nonpregnant adults" and "Immunizations in patients with end-stage kidney
disease" and "Immunizations for patients with chronic liver disease" and "Standard
immunizations for children and adolescents: Overview", section on 'Routine
schedule'.)
The pretransplant period is an important window of opportunity. Although vaccine
responses may be diminished in some patients during this period, vaccine
responses are generally even more attenuated post-transplantation when the
patient is immunosuppressed [1-3]. Since vaccine immunogenicity is often
diminished in the setting of organ failure, transplant candidates should be
immunized as early in the course of their disease as possible [7]. In addition, live
virus vaccines (eg, measles, mumps, rubella, varicella, zoster-vaccine live, and the
intranasal influenza vaccine) are usually avoided post-transplantation. The
Infectious Diseases Society of America recommends waiting a minimum of four

214
weeks between live virus vaccine administration and subsequent transplantation
[5].
Post-transplant — Optimal timing is important in maximizing the response to
immunization following solid organ transplantation. It is common to wait at least 3
and often up to 12 months after transplantation before giving vaccines, once
maintenance immunosuppression levels have been attained [5,7]. An exception is
that during influenza outbreaks, it is reasonable to give the inactivated influenza
vaccine as early as one month following transplantation [5]; most programs give
influenza vaccine starting three months after transplant. Although there had been
some concern about vaccine safety after transplant, multiple studies have shown
that inactivated vaccines are safe and not associated with organ rejection following
transplantation [8-14]. Live vaccines are generally contraindicated post-
transplantation when patients are immunosuppressed.

The timing of vaccination may need to be modified when immunomodulatory

treatment is given for rejection (eg, anti-CD20 antibodies, antithymocyte globulin).
While specific timing will vary based on individual circumstance, we generally try to
vaccinate when the effect of any immunosuppressive agents is at its nadir in order
to maximize the likelihood of developing a protective immune response. We often
avoid vaccination, other than seasonal influenza, for six months following
treatment for rejection.

INACTIVATED VACCINES
Influenza — Annual administration of an inactivated seasonal influenza vaccine is
indicated for all transplant candidates and recipients, including during the first
year following transplantation [7]. When vaccinating, we generally prefer the high-
dose influenza vaccine for adults because it increases the likelihood of developing
a more robust immune response [15,16]; however, using the standard-dose
vaccine is also reasonable.
We typically resume vaccinations for influenza approximately three to six months
after transplantation, once maintenance immunosuppression levels have been
attained. In the United States, the Centers for Medicare and Medicaid Services
have recommended that all patients, including transplant recipients, be
immunized prior to discharge from the hospital. This may result in some patients
being immunized very early following transplantation and in suboptimal immune
responses to the vaccine. Revaccination of such patients three to six months
following transplantation can be considered if there is still influenza activity.
(See 'Timing of immunizations' above.)
Influenza is a common infection in solid organ transplant recipients and is
associated with high morbidity and mortality [17]. In addition to the usual
215
complications of influenza (eg, pneumonia), influenza infection may also be
associated with rejection in solid organ transplant recipients [18]. Although the
immune response to influenza vaccines is less robust and more heterogenous in
solid organ transplant recipients when compared with healthy individuals,
vaccination is still effective in preventing and reducing the severity of influenza
infection [8,13,19-24]. As an example, in an observational study of lung transplant
recipients who received one or two doses of an adjuvanted monovalent 2009 to
2010 pandemic H1N1 influenza vaccine versus no vaccine, documented influenza
infection occurred in 2 of 148 vaccinated patients (1.3 percent) compared with 5 of
20 unvaccinated patients (25 percent) [25]. The degree of protection from
vaccination likely varies based on circulating influenza strains, the intensity of the
post-transplant immunosuppressive regimen, and time since transplantation
[3,13,26,27].
Several strategies have been employed to augment vaccine immunogenicity in
solid organ transplant recipients [28]. Among them, use of a high-dose inactivated
influenza vaccine appears most efficacious. As an example, in one randomized trial
evaluating 172 solid organ transplant recipients, seroconversion rates and
postimmunization antibody titers were significantly higher among solid organ
transplant recipients who were vaccinated with a high-dose influenza vaccine
when compared with a standard-dose vaccine [15]. While rejection rates did not
differ between groups, the study was not powered for this outcome. Booster
dosing may also improve immunogenicity, though results among studies have
varied [22,28,29]. Intradermal vaccination and adjuvanted standard-dose
vaccination have not been shown to improve immunogenicity.
Use of inactivated influenza vaccines is generally considered safe following solid
organ transplantation. While there is a theoretical concern that vaccination may
trigger organ rejection [30,31], this association has not been reported in clinical
trials [9,28,32-34]. By contrast, in a retrospective cohort study of 51,730 adult renal
transplant recipients receiving Medicare, influenza vaccination during the first year
after transplantation was associated with lower risk of subsequent allograft loss
and death [14]. Like all live virus vaccines, the live attenuated influenza vaccine is
contraindicated in solid organ transplant recipients. (See 'Live virus
vaccines' below.)
Although vaccination against seasonal influenza appears effective and safe,
protection is incomplete. Solid organ transplant recipients exposed to influenza or
those who have inadvertently received a live formulation of the influenza vaccine
are candidates for antiviral prophylaxis (see "Prevention of seasonal influenza with
antiviral drugs in adults"). Transplant recipients who develop influenza are

216
candidates for antiviral treatment, regardless of vaccine status. (See "Seasonal
influenza in adults: Treatment".)
Pneumococcus — All adult solid organ transplant candidates and recipients in the
United States should be vaccinated against pneumococcus with both the 23-valent
polysaccharide pneumococcal vaccine (PPSV23) and the 13-valent pneumococcal
conjugate vaccine (PCV13) (table 2) [35]. In general, PCV13 should be given first
and at least eight weeks prior to PPSV23. However, the specific vaccine schedule
varies based on whether either vaccine has been given previously (algorithm 1).
Pneumococcal vaccination in adults is discussed in greater detail separately.
(See "Pneumococcal vaccination in adults".)
Pediatric solid organ transplant candidates and recipients should also be
vaccinated against pneumococcus [36-38]. The following tables and algorithms
summarize the recommendations for vaccination against pneumococcus in high-
risk children (table 3A-B and algorithm 2A-B). (See "Pneumococcal vaccination in
children", section on 'Conjugate vaccines'.)
Pneumococcal conjugate vaccines that contain a different number of serotypes
(eg, the 10-valent pneumococcal conjugate vaccine [PCV10]) are used in some
countries in Europe and elsewhere; patients should be vaccinated against
pneumococcus according to their national guidelines. (See "Pneumococcal
vaccination in children", section on 'Conjugate vaccines'.)
Several small cohort studies have evaluated the immune response to
pneumococcal vaccination in solid organ transplant recipients [39-43]. In most,
organ transplant recipients developed measurable serologic responses to
vaccination, but responses were lesser than those in immunocompetent patients.
As an example, in one study, immunization with PPSV23 one year after heart
transplantation was successful (defined as protective titers of >300 units/mL to
eight of nine selected serotypes) in 75 to 100 percent of recipients [39]. However,
only 50 percent of the transplant recipients developed protective levels to
pneumococcal serotype 3, compared with a 91 percent response rate in healthy
individuals. In trials comparing the 7-valent pneumococcal conjugate vaccine
(PCV7) with PPSV23 in renal transplant recipients, there was no difference in
immunogenicity between the vaccines [40,41]. Antibody response rates to each
individual serotype were poor eight weeks following administration of each
vaccine (13 to 40 percent with PPSV23, 17 to 50 percent with PCV7) [40]. Among
patients who had adequate responses eight weeks following vaccination,
responses to each serotype persisted in only 42 to 85 percent of individuals at
three years [41].
Hepatitis B — Hepatitis B virus vaccination is indicated for all anti-hepatitis B
surface antigen (anti-HBs)-negative solid organ transplant candidates [5]. For

217
adults on hemodialysis, we give a high-dose vaccine series (ie, 40 mcg of hepatitis
B surface antigen [HBsAg] for Recombivax HB or Engerix-B). For others (including
those with cirrhosis), there is no clear consensus on whether the high-dose or
standard-dose vaccine or the CpG-adjuvanted recombinant vaccine series should
be given and any vaccine can be used. Because transplant recipients may not
mount an adequate antibody response to vaccination, we check an anti-HBs titer
following vaccination [44-47]. If a titer of ≥10 milli-international units/mL is not
attained, revaccination is indicated. The complete high-dose vaccine series can be
repeated; alternatively, one additional dose can be given and titers rechecked.
Another alternative for revaccination is to give the CpG-adjuvanted recombinant
hepatitis B vaccine; however, some experts have concerns about adjuvants in
organ transplant recipients as they could alter immunotolerance of the
transplanted organ. (See "Hepatitis B virus immunization in adults", section on
'Patients on dialysis and immunocompromised hosts'.)
Since a transplant candidate may be offered an organ from a HBsAg-negative, core
antibody-positive ("core-positive") donor, the vaccine series should be completed
prior to transplantation whenever possible [48]. The response to hepatitis B
vaccine administration after transplantation varies greatly, with ranges reported
from 17 to 89 percent [49-51]. Unfortunately, titers decline more rapidly than
usual, even in those who develop protective levels of antibody [49,52], and booster
doses produce suboptimal responses [49]. These results underscore the value of
pretransplant immunization, ideally done prior to the onset of advanced renal or
liver failure. (See "Hepatitis B virus immunization in adults", section on
'Postvaccination testing'.)
The management of patients with chronic hepatitis B infection who undergo liver
transplantation and of HBsAg-negative transplant recipients who receive a liver
from a hepatitis B core antibody (anti-HBc)-positive donor is discussed in detail
separately. (See "Liver transplantation for chronic hepatitis B virus infection".)
Hepatitis A — Hepatitis A vaccine is indicated for all adult liver transplant
candidates and recipients because of their increased risk of fulminant hepatic
failure from hepatitis A virus (HAV) [53-55]. Hepatitis A vaccination is also indicated
for all pediatric solid organ transplant candidates and recipients ≥12 months of
age [5,7] and all nonliver solid organ transplant recipients who have additional risk
factors for HAV transmission (eg, clotting factor disorder, travel to or residence in
regions where hepatitis A virus is endemic) [7]. Monitoring titers is indicated only
for individuals with an ongoing risk of exposure, such as planned travel to an
endemic area [5].
Patients should be vaccinated as early as possible after the diagnosis of chronic
liver disease because advanced liver failure blunts the immune response to the

218
vaccine [56]. Several observational studies suggest that receipt of a complete
vaccine series prior to solid organ transplantation engenders better immunity than
when vaccines are given post-transplantation [57-60]. The duration of both natural
immunity and vaccine-induced immunity is also reduced post-transplantation
[57,61,62]. In one study of liver transplant recipients who acquired natural
hepatitis A infection prior to transplantation, 4 of 22 patients (18 percent) and 7 of
24 patients (29 percent) became seronegative one and two years after
transplantation, respectively [61]. While combination vaccine with both hepatitis A
and B (Twinrix) may be efficient, some studies have shown that the combination
vaccine is less immunogenic compared with monovalent vaccines [63].
Additional detail on hepatitis A vaccination is provided separately. (See "Hepatitis A
virus infection: Treatment and prevention", section on 'Vaccination'.)
Human papillomavirus — Female solid organ transplant recipients with human
papillomavirus (HPV) infection are at 20- to 100-fold increased risk of cervical
intraepithelial neoplasia, and both male and female recipients are at risk for other
anogenital cancers [30,64,65]. We recommend vaccinating solid organ candidates
who have an indication for HPV vaccination [7,65]. (See "Human papillomavirus
vaccination", section on 'Indications and age range'.)
Vaccination should be given prior to transplantation when possible. If all doses are
not given prior to transplantation, the additional doses can be given beginning
three to six months following transplantation. There are few data on the
immunogenicity of the HPV vaccination in solid organ transplant recipients, but it
should be safe to administer following transplantation since it is not a live vaccine.
In one study, the quadrivalent HPV virus-like particle vaccine demonstrated poor
immunogenicity in solid organ transplant recipients, with responses ranging from
53 to 68 percent against the four types included in the vaccine [66]. Factors
associated with reduced immunogenicity included vaccination early after
transplant, having a lung transplant, and having higher tacrolimus levels. At 12
months, there were significant declines in antibody titers to all four HPV types,
although the number of patients who remained seropositive did not differ
significantly. We suggest giving the HPV vaccine at least to unvaccinated solid
organ transplant candidates and recipients who fit within the vaccination
recommendations described above [7].
There may be a role for HPV vaccine in male transplant recipients and female
transplant recipients outside the age-based indications to prevent anogenital
warts, anal cancer, and HPV-associated skin cancers [65]. We anticipate that there
will be a future recommendation to broaden the indications for use of the HPV
vaccine in transplant recipients, pending reporting of results of an ongoing study

219
of the safety and efficacy of HPV in solid organ transplant recipients up to age 35
years.
Additional detail on HPV vaccination is provided separately. (See "Human
papillomavirus vaccination".)
Meningococcus — The incidence of meningococcal disease after solid organ
transplantation is unknown, and there is no information on the efficacy of
meningococcal vaccines in patients with renal or liver failure or in solid organ
transplant recipients. The quadrivalent meningococcal and serogroup B vaccines
should be administered to solid organ transplant recipients and candidates who
have a specific risk factor for invasive meningococcal infection (eg, asplenia, use
of eculizumab) (table 4) [7,67].
A special transplant-related indication would be for those transplant recipients
who are likely to receive or who have been given the terminal complement
pathway inhibitor eculizumab. Guidelines suggest that for patients who will be
starting eculizumab, when possible, vaccination should be completed at least two
weeks in advance in order to provide adequate time for an immune response [7].
Many clinicians would still give antibiotic prophylaxis even after appropriate
vaccination, as not all strains are covered and the immune response may not be as
robust as needed.
Available formulations for quadrivalent meningococcal conjugate vaccine in the
United States include Menactra, MenQuadfi, and Menveo. In addition, there are
two serogroup B meningococcal vaccines (Trumenba, MenB-FHbp; Bexsero, MenB-
4C) that have been approved for use in the United States. We generally vaccinate
solid organ transplant recipients with specific indications, although the efficacy of
these vaccines is not well studied in this population. Recommendations for
vaccination are discussed separately. (See "Meningococcal vaccination in children
and adults", section on 'Indications and schedules in the United States'.)
Haemophilus influenzae — Pediatric solid organ transplant recipients should
receive the Haemophilus influenzae type b (Hib) conjugate vaccine according to the
routine schedule for children (figure 1B and figure 1A). Hib titers should be
checked at least four weeks after vaccine administration if serologic testing is
available; a titer >0.15 mg/L is considered protective in the general population [7].
(See "Prevention of Haemophilus influenzae type b infection", section on 'Routine
schedule'.)
Among adults, Hib is generally only recommended for individuals with impaired
splenic function and following stem cell transplantation. (See "Prevention of
infection in patients with impaired splenic function", section on
'Vaccinations' and "Immunizations in hematopoietic cell transplant candidates and
recipients", section on 'Haemophilus influenzae'.)

220
Tetanus, diphtheria, and pertussis — The tetanus, diphtheria, pertussis (Tdap),
the diphtheria, tetanus, pertussis (DTaP), and the tetanus, diphtheria (Td) vaccines
should be given per the same indications and schedules as the general population
(figure 1A-C).
Like other inactivated vaccines, these vaccines can be safely given post-
transplantation when needed [30,68,69]. Observational data suggest that there is
no increased risk of rejection following vaccination. However, the immune
response to these vaccines may be blunted [68-71]. The American Society of
Transplantation guidelines recommend monitoring tetanus titers in pediatric (but
not adult) solid organ transplant candidates and recipients a minimum of four
weeks following vaccination [7]. (See "Diphtheria, tetanus, and pertussis
immunization in children 7 through 18 years of age" and "Diphtheria, tetanus, and
pertussis immunization in children 6 weeks through 6 years of age", section on
'Schedules' and "Tetanus-diphtheria toxoid vaccination in adults".)
COVID-19 vaccine — SOT candidates and recipients are eligible for coronavirus
disease 2019 (COVID-19) vaccination. This is discussed in detail elsewhere.
(See "COVID-19: Vaccines to prevent SARS-CoV-2 infection" and "COVID-19: Issues
related to solid organ transplantation", section on 'Vaccination'.)
ZOSTER VACCINESThere are two vaccine formulations available for the
prevention of herpes zoster: the recombinant (nonlive) glycoprotein E vaccine
(recombinant zoster vaccine [RZV]; sold as Shingrix) and the live attenuated
vaccine (zoster vaccine live [ZVL]; no longer available in the United States) [72].
●Pretransplantation – We recommend vaccination against herpes zoster
(shingles) for solid organ transplant candidates who are ≥50 years old. This
recommendation is consistent with the US Advisory Committee on
Immunization Practices (ACIP) [73]. Although the US Food and Drug
Administration has approved RZV for immunocompromised individuals who
are ≥18 years old [74], further recommendations from ACIP are pending. Like
other vaccines, zoster vaccination should ideally be given before
transplantation to help ensure maximal immune response.
For pretransplantation vaccination, we recommend RZV over ZVL when
feasible, although specific circumstances (vaccine availability, timing of
transplant) may impact the selection.
RZV requires two doses spaced at least four weeks apart followed by a two-
week interval prior to transplantation to ensure maximal immune response.
In addition, the recombinant vaccine contains a novel adjuvant and is
associated with high reactogenicity rates in healthy adults, leading to the
concern that it could potentiate rejection if given near the time of
transplantation.
221
 ZVL can be used in situations where RZV is not available or timing of
transplantation does not allow a complete series of RZV as outlined above.
ZVL is administered as a single dose and should be given at least four weeks
prior to transplantation.
The RZV appears to be more effective than ZVL in the general health
population and is not associated with a risk of disseminated disease. In a
systematic network meta-analysis of randomized trials of healthy adults 60
years or older, ZVL was approximately half as effective in preventing zoster
infection compared with RZV [75]. The efficacy of ZVL in preventing herpes
zoster (shingles) following transplantation is unknown [30,76].
●Post-transplantation – The varicella-zoster vaccine (Zostavax)
is contraindicated in solid organ transplant recipients post-transplantation
because it is a live virus vaccine [7,76].
For solid organ transplant recipients who were not vaccinated prior to
transplant, we decide whether to give RZV on a case-by-case basis. In
general, we administer RZV to those aged ≥50 years at low risk for rejection
(eg, a stable kidney transplant recipient on low-dose immunosuppression)
[72,77].
This approach is consistent with American Society of Transplantation
Infectious Disease Community of Practice guidelines and supported by a
randomized trial [7,78]. In this trial, 264 adult renal transplant recipients aged
≥18 years (without a history of underlying autoimmune disease or prior graft
loss) received either RZV or placebo 4 to 18 months post-transplantation.
Vaccination boosted cellular and humoral immune responses when
compared with placebo. Although local adverse events (eg, injection site
reactions) occurred more frequently with RZV, serious adverse events
(including rejection) did not differ between groups over a 12-month period.
Small, observational studies have also demonstrated efficacy and safety of
RZV in other solid organ transplant recipients [79].
Additional detail on the vaccination of the prevention of herpes zoster is provided
separately. (See "Vaccination for the prevention of shingles (herpes zoster)".)
LIVE VIRUS VACCINESThe Infectious Diseases Society of America (IDSA)
recommends waiting a minimum of four weeks between live virus vaccine
administration and solid organ transplantation [5]. Live organism vaccines are
generally avoided following solid organ transplantation (or in those candidates
who are immunosuppressed before transplant) given the potential for active
infection. A list of live vaccines is provided in the following table (table 5).
The following caveats should be noted regarding the administration of live virus
vaccines prior to transplantation [7]:
222
 ●The measles, mumps, and rubella (MMR) vaccine and the varicella
vaccine can be administered on the same day, but if they are not given on the
same day, the second live vaccine should be administered at least 28 days
after the first.
●Live vaccines can interfere with the response to the tuberculin skin
test (TST). A TST can be placed the same day as a live vaccine is given, but if it
is not done on the same day, it should be delayed for four to six weeks. An
alternative to the TST is the interferon-gamma release assay for tuberculosis,
which may have higher sensitivity in patients with end-stage organ disease
[80,81]. (See "Tuberculosis in solid organ transplant candidates and
recipients", section on 'Screening'.)
●Intravenous immunoglobulin (IVIG) and antibodies transferred with blood
products can bind vaccine and interfere with the immune response to live
virus vaccines. Thus, administering MMR vaccine as well as the varicella
vaccine should be delayed after receipt of IVIG and other blood products
(table 6). Delay is not needed before the administration of inactivated
vaccines (eg, recombinant zoster vaccine). (See "Overview of intravenous
immune globulin (IVIG) therapy", section on 'Vaccination of patients receiving
IVIG'.)
Measles, mumps, and rubella — Measles, mumps, and rubella infections are rare
after solid organ transplantation, but the potential severity of these diseases is
well recognized for nonimmunized individuals. All children should ideally receive a
two-dose series of the MMR vaccine, with at least four weeks between doses [7]. In
one study of children who were on dialysis when they received the MMR vaccine,
70, 50, and 80 percent developed protective titers against measles, mumps, and
rubella, respectively, but only 30 percent were protected against all three
infections [82]. Every effort should be made to immunize such transplant
candidates at least one month prior to transplantation [5,38]. We suggest checking
antibody titers after immunization prior to transplantation because of the
variability in the vaccine response.
In order to immunize pediatric solid organ transplant candidates younger than
one year of age prior to transplantation, the American Society of Transplantation
(AST) and the IDSA state that the MMR vaccine can be given as early as six months
of age in infants not receiving immunosuppression, although the vaccine is most
effective after one year of age when maternal antibodies have waned [5,7]. Data
suggest excellent immunogenicity in those infants with chronic renal failure
and/or receiving peritoneal dialysis [83]. If transplantation has not occurred by one
year of age, a second dose should be given, provided that a minimum of four
weeks has elapsed since the previous dose. At least four weeks should elapse

223
between live virus vaccine administration and transplantation. Several caveats are
reviewed above. (See 'Live virus vaccines' above.)
Based upon the severe complications related to measles infection in transplant
recipients and the experience of administering MMR in HIV-infected children [84],
some transplant centers have started to use MMR after solid organ transplantation
for children or others who have not completed the recommended series of MMR
[85], primarily in those on low-dose immunosuppression [86]. However, this
practice is not widespread and safety data are limited [87]. In one study, 7 of 17
seronegative pediatric liver transplant recipients developed protective titers
against measles after immunization, and none developed clinical measles [88]. In
another study, 44 pediatric liver transplant recipients who were ≥1 year post-
transplantation on low-dose immunosuppression with lymphocyte counts ≥0.75
G/L were given MMR vaccine without any serious adverse events [86]. Vaccination
was given a median of 6.3 years post-transplantation, and seroprotection was
achieved in most patients following 1 to 3 doses of MMR. However, these limited
data are inadequate to support a recommendation for post-transplant
immunization with MMR in nonimmune individuals. Guidelines from the AST
Infectious Diseases Community of Practice state "MMR and varicella vaccination
are generally contraindicated post-transplant but may be administered in carefully
selected patients with appropriate education and close follow-up" [7].

Nonimmune adult solid organ transplant candidates should receive MMR

vaccination prior to transplantation. The optimal approach is not known. Some
experts give a total of two MMR doses prior to transplantation while others give a
single dose and test for a protective serologic response ≥4 weeks later. If
seroconversion has not occurred, a second dose can be given prior to
transplantation, if time permits. A key caveat is that the MMR is a live vaccine,
which must be given at least four weeks prior to vaccination.

Nonimmune solid organ transplant recipients and those who are severely
immunocompromised who have been exposed to measles should receive
postexposure prophylaxis with intravenous immune globulin. (See "Measles,
mumps, and rubella immunization in adults", section on 'Postexposure
prophylaxis'.)
Varicella — Given the risk of severe varicella infection (chickenpox) in nonimmune
solid organ transplant recipients, we suggest immunization with the varicella
vaccine at least four weeks prior to transplantation [5]. Because patients with end-
stage organ disease have reduced seroconversion rates of approximately 60
percent to varicella vaccination [89-92], it is particularly important for such patients
to receive two doses of the varicella vaccine, if feasible, with a minimum interval of
224
four weeks between doses for individuals aged ≥13 years and a minimum interval
of three months for individuals aged 1 to 12 years [5,76]. (See "Vaccination for the
prevention of chickenpox (primary varicella infection)", section on 'Schedules in the
United States'.)
Maternal antibodies interfere with the response to varicella vaccination, and the
vaccine is most effective after one year of age when maternal antibodies have
waned [7]. Infants awaiting transplantation may receive the vaccine as early as six
months of age [5]. Varicella antibodies should be checked four weeks after the
second dose of vaccine has been given [7]. If seroconversion does not occur, an
additional dose can be given if time permits. Those who do not seroconvert are
candidates for postexposure prophylaxis, should an exposure occur following
transplantation. (See 'Postexposure prophylaxis' below.)
A potential concern for patients high on the waiting list is the possibility that
transplantation could occur shortly after vaccination, subjecting a recently
vaccinated patient to high-dose immunosuppression and the risk of proliferation
of the attenuated strain. As noted above, transplant candidates should be
vaccinated at least four weeks prior to transplant [5]. If transplantation is urgently
indicated in a patient who has received the varicella vaccine within the previous
month, peri- and post-transplant prophylaxis with intravenous acyclovir or
oral valacyclovir or famciclovir should be given.
If the varicella vaccine is not administered pretransplant, we recommend against
administration post-transplant in the majority of patients due to concern for
disseminated varicella-zoster virus (VZV) infection. An exception is varicella-
nonimmune pediatric renal or liver transplant recipients who are receiving
minimal or no immunosuppression and who have had no recent allograft
rejection; the IDSA has endorsed varicella vaccination post-transplant in this group
of patients [5]. When indicated, the varicella vaccine should be given as the single
antigen preparation rather than as part of the combined measles, mumps, rubella,
and varicella vaccine.
Prior to widespread vaccination, varicella-zoster infection (chickenpox) occurred in
up to 2 percent of pediatric renal transplant recipients in the first year after
transplantation and was associated with significant morbidity and mortality [93].
Although adults are rarely susceptible to varicella, morbidity and mortality is high
in those who acquire primary infection after transplantation. The recombinant
shingles vaccine (Shingrix) is not studied or licensed for prevention of varicella in
nonimmune subjects.
Preliminary data are encouraging regarding the efficacy of varicella immunization
for stable patients after liver, kidney, and intestinal transplantation [94-96]. As an
example, in one study, 16 VZV-naïve pediatric renal and liver transplant recipients

225
were immunized with the varicella vaccine during the late post-transplant period
(range eight months to six years) [95]. Evidence of humoral immunity developed in
13 of 15 patients (87 percent) and cell-mediated immunity developed in 12 of 14
patients (86 percent). Following vaccination, four patients had fever and four
developed vesicular rashes, three of whom received acyclovir. Subsequent VZV
exposures in four patients, one of whom received varicella-zoster immune
globulin, did not result in VZV infection. Case reports of disseminated VZV have
been described following varicella vaccination in solid organ transplant recipients
[97,98]; one case was proven to be caused by the vaccine strain [97].
Rotavirus — Rotavirus infection can lead to significant morbidity among solid
organ transplant recipients and is particularly prevalent among pediatric solid
organ transplant recipients [99]. Age-appropriate rotavirus vaccination is
recommended for pediatric solid organ transplant candidates prior to
transplantation but is not recommended following transplantation because it is a
live vaccine [7]. Good infection control practices, including hand hygiene (especially
after diaper changes), are recommended for immunocompromised household
members of a recently vaccinated infant. (See "Rotavirus vaccines for infants",
section on 'Schedule'.)
POSTEXPOSURE PROPHYLAXISPostexposure prophylaxis (PEP) may be
warranted for selected immunocompromised patients who have been exposed to
certain pathogens, including varicella-zoster virus (VZV), influenza virus, hepatitis B
virus, measles virus, meningococcus, rabies virus, and tetanus. Although the
decision to use PEP is usually individualized based on the type of exposure, timing
of the exposure, and degree of immunosuppression, it is often prudent to provide
PEP for patients who have not been vaccinated against the pathogen to which they
were exposed and/or for those who are severely immunocompromised.
Varicella exposure — For nonimmune solid organ transplant recipients who have
been exposed to a patient with VZV (varicella or herpes zoster) infection, we
recommend prophylaxis with VariZIG and/or antiviral therapy. Solid organ
transplant recipients with immunity to VZV (VZV IgG positive) do not require VZV
prophylaxis following exposure to a patient with VZV infection.
In the outpatient environment, significant exposure is defined as exposure to a
household contact or nontransient face-to-face contact indoors with a playmate or
other contact [7,100]. In the hospital environment, significant exposure is defined
as exposure in the same two- to four-bed room, face-to-face contact with an
infectious staff member or patient, or a visit by a person deemed contagious. All
transplant recipients should be monitored carefully after exposure, even if VariZIG
or antiviral therapy is administered.

226
VariZIG is a purified human varicella-zoster immunoglobulin preparation [76,101].
When postexposure prophylaxis is indicated, VariZIG should be offered as soon as
possible, but it may be given for up to 10 days following exposure.
Immunoprophylaxis alone does not prevent all cases of varicella in
immunocompromised patients, but it lessens the severity of infection [7]. For high-
risk patients who have additional exposures to varicella-zoster virus ≥3 weeks after
initial VariZIG administration, another dose of VariZIG should be considered.
(See "Post-exposure prophylaxis against varicella-zoster virus infection".)
Use of antiviral agents (ie, acyclovir, famciclovir, valacyclovir) as postexposure
prophylaxis has not been evaluated in randomized trials in immunocompromised
patients, but it should be considered as adjunctive therapy in patients receiving
immunoprophylaxis or in patients who were unable to receive immunoprophylaxis
within 10 days following exposure. Although either oral acyclovir or valacyclovir
can be used for postexposure prophylaxis, we prefer valacyclovir (1 g orally three
times daily) given its superior bioavailability. The optimal prophylactic regimen is
not known, and approaches vary among experts [76,100]. We typically give
antiviral prophylaxis from days 3 to 28 after known exposure for patients who
have been given immunoprophylaxis. The antiviral is started on day 3 following
exposure because of the theoretical concern that VariZIG might prolong VZV's
incubation period [102,103]. For patients who have not received
immunoprophylaxis, we treat for 22 days following exposure.
All patients who have been exposed should also be monitored closely for any sign
of active infection; intravenous acyclovir should be started immediately should this
occur [104].
Other exposures — Other PEP regimens vary based on the pathogen and may
include antimicrobial prophylaxis, vaccination, and/or passive immunization (ie,
generic or pathogen-specific immune globulin). For immunocompromised
patients, live vaccines recommended in some PEP regimens may need to be
replaced or supplemented with immunoglobulin administration.

Specific PEP indications and recommendations are discussed separately for each
pathogen:

●(See "Prevention of seasonal influenza with antiviral drugs in adults".)

●(See "Management of nonoccupational exposures to HIV and hepatitis B and
C in adults", section on 'Exposure to hepatitis B virus'.)
●(See "Measles, mumps, and rubella immunization in adults", section on
'Postexposure prophylaxis'.)
●(See "Treatment and prevention of meningococcal infection", section on
'Antimicrobial chemoprophylaxis'.)
227
 ●(See "Rabies immune globulin and vaccine", section on 'Post-exposure
prophylaxis'.)
●(See "Infectious complications of puncture wounds".)

HEALTH CARE WORKERS AND CLOSE CONTACTSHealth care workers

and close contacts (eg, family members) of solid organ transplant recipients
should receive all recommended immunizations [5,7]. In particular, such
individuals should be immunized against influenza annually, but they should also
receive other indicated vaccines, including COVID-19. The following figures
summarize routine vaccine recommendations for children (figure 1B and figure
1A), healthy adults (figure 2), and adults with medical conditions (figure 1C).
(See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children:
Prevention with vaccines" and "Standard immunizations for nonpregnant
adults" and "Immunizations for health care providers" and "Standard
immunizations for children and adolescents: Overview", section on 'Routine
schedule' and "COVID-19: Vaccines to prevent SARS-CoV-2 infection".)
With the exception of the smallpox vaccine and oral polio virus vaccines, there is
little to no risk of transmission of vaccine viruses from vaccine recipients to their
close contacts [7]. Nevertheless, health care workers and close contacts of solid
organ transplant recipients should receive inactivated vaccines, when possible.
●Influenza – The American Society of Transplantation (AST) favors the use of
the inactivated influenza vaccine (IIV) for contacts of solid organ transplant
recipients; they state that if the live attenuated influenza vaccine (LAIV) is the
only available option, it can be given, but vaccine recipients should wash their
hands frequently for two weeks following vaccination [7]. We agree with this
approach. In contrast, the Infectious Diseases Society of America (IDSA)
recommend either IIV or LAIV for contacts of solid organ transplant
recipients; LAIV can be used in healthy nonpregnant individuals between 2
and 49 years of age [5]. (See "Seasonal influenza vaccination in
adults" and "Seasonal influenza in children: Prevention with vaccines".)
●MMR – Nonimmune household and close contacts of solid organ transplant
recipients should be immunized against measles, mumps, and rubella (MMR)
to prevent transmission of wild-type viruses to transplant recipients [5,7,38].
(See "Measles, mumps, and rubella immunization in adults" and "Measles,
mumps, and rubella immunization in infants, children, and adolescents",
section on 'Measles, mumps, and rubella disease'.)
●Varicella – The use of the varicella vaccine in household contacts of
transplant recipients has been the subject of much discussion. The American
Academy of Pediatrics (AAP) recommends use of the varicella vaccine in
household contacts but cautions that vaccinees who develop a rash should
228
 avoid contact with transplant recipients for the duration of the rash [100].
The AST and IDSA guidelines also support this view and recommend that
close contacts and family members aged 12 months or older should be
vaccinated against varicella if they have never received the vaccination, have
no history of varicella or herpes zoster, and have no contraindications to
vaccination [5,7]. Transplant recipients should be isolated from vaccine
recipients who develop a rash. If isolation is not possible, then the
nonvaricella-immune transplant recipient should be monitored for the
development of a rash, and antiviral therapy (eg, valacyclovir or famciclovir)
should be started in the unlikely event that a rash suggestive of varicella
develops. (See "Vaccination for the prevention of chickenpox (primary
varicella infection)", section on 'Contacts of immunocompromised hosts'.)
Similarly, the zoster vaccine should be administered to household contacts
who have an indication to receive it. We generally prefer to use
the recombinant zoster vaccine (RZV) for household contacts of solid organ
transplant recipients rather than the live zoster virus vaccine because there is
not risk of transmission of vaccine stain virus with RZV.
●Rotavirus – Rotavirus vaccines are given routinely to healthy infants and
pose a theoretical risk of transmission since live virus may be shed in stool for
two to four weeks following vaccination [5,105-107]. Highly
immunocompromised patients (eg, solid organ transplant recipients within
the first two months following transplantation) should avoid handling the
diapers of infants who have received the rotavirus vaccine for four weeks
following vaccination [5]. In addition, good handwashing practices should be
adhered to among those who change the diapers of infants who received the
rotavirus vaccine [7]. (See "Rotavirus vaccines for infants".)
Pets should also receive routine vaccines, including the live intranasal
canine Bordetella bronchiseptica  vaccine [7]. Transplant recipients should not be in
the same room when this is administered, to avoid potential illness from this live
attenuated vaccine [108].
LIVING DONORSLiving donors should be vaccinated according to
recommendations for healthy individuals issued by the United States Advisory
Committee on Immunization Practices (or, for those outside the United States,
other national guidelines) [5]. Influenza vaccination is particularly important when
transplantation occurs during influenza season. (See "Standard immunizations for
nonpregnant adults".)
Live virus vaccines should be avoided within four weeks of organ donation (table 5)
[5]. Vaccination of donors for the potential benefit of the recipient is not
recommended.
229
IMMUNIZATIONS IN TRAVELERSImmunizations in travelers are discussed
separately. The use of the different vaccines must be considered in relation to the
issues described above. (See "Travel advice for immunocompromised hosts",
section on 'Routine vaccines' and "Travel advice for immunocompromised hosts",
section on 'Travel vaccines'.)
GUIDELINESIn 2019, the American Society of Transplantation (AST) updated the
guidelines for vaccination of pediatric and adult solid organ transplant candidates
and recipients as well as health care workers, household contacts, and other close
contacts of these patients [7]. In 2013, the Infectious Diseases Society of America
(IDSA) published guidelines for vaccination of immunocompromised hosts,
including solid organ transplant recipients [5]. The United States Advisory
Committee on Immunization Practices (ACIP) also includes immunocompromised
hosts in their recommendations (figure 1C) [109].
Our recommendations are generally in keeping with the AST guidelines, the IDSA
guidelines, and the ACIP recommendations. Clinicians in other countries should
consider referring to their national guidelines for recommendations regarding
immunization of solid organ transplant candidates and recipients. (See 'Society
guideline links' below.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Immunizations in solid organ transplant
recipients".)
SUMMARY AND RECOMMENDATIONS
●Vaccine-preventable infections, such as influenza and pneumococcal
disease, cause substantial morbidity and mortality in solid organ transplant
recipients. Thus, vaccination is an important part of care.
(See 'Introduction' above.)
●Prior to transplantation, we review each patient's vaccination and exposure
history in detail and administer any needed vaccinations (table 1).
(See 'Pretransplant' above and "Evaluation for infection before solid organ
transplantation".)
●Vaccines should be administered as early in the pretransplant period as
possible when the likelihood of developing a protective immune response is
highest and when live vaccines can be given safely. Live vaccines should be
given at least four weeks prior to transplantation in immunocompetent
patients. With rare exception, live vaccines are contraindicated in
immunocompromised patients and post-transplantation. (See 'Timing of
immunizations' above and 'Live virus vaccines' above.)

230
●Post-transplantation, inactivated vaccines are considered safe, although
their efficacy may be diminished. To maximize immune response, we
generally wait at least 3 months and often up to 12 months to give any
needed inactivated (nonlive) vaccines. However, during influenza outbreaks,
the inactivated influenza virus can be given as early as one month post-
transplantation. (See 'Post-transplant' above.)
●Vaccination against seasonal influenza virus should be given annually both
pre- and post-transplantation. Post-transplantation, we suggest using the
high-dose influenza vaccine for adults because it augments immune
response and does not appear to increase the likelihood of rejection (Grade
2B). However, using the standard-dose vaccine is also reasonable.
(See 'Influenza' above.)
●We recommend that solid organ transplant candidates and recipients be
vaccinated against pneumococcus with both the pneumococcal conjugate
vaccine (PCV13) and the pneumococcal polysaccharide vaccine (PPSV23) if
they have not received these vaccines previously (Grade 1B).
(See 'Pneumococcus' above.)
●The hepatitis B virus vaccine series should be given to solid organ transplant
candidates and recipients who are nonimmune to the virus based on
serologic testing. Like the hepatitis A virus (HAV) vaccines, vaccination is
particularly important for liver transplant candidates and recipients who are
at increased risk of fulminant hepatic failure from these viruses. The HAV
vaccine is also indicated for most pediatric solid organ transplant recipients
and all nonliver solid organ transplant recipients with specific risk factors (eg,
travel to or residence in a HAV-endemic area). (See 'Hepatitis B' above
and 'Hepatitis A' above.)
●Vaccination against herpes zoster (shingles) is indicated for solid organ
transplant candidates who are ≥50 years old. Vaccination should ideally be
given pretransplantation when either the recombinant formulation or the live
attenuated zoster vaccine can be used. The risk-benefit ratio of using the
recombinant vaccine, which contains a novel adjuvant, post-transplantation is
unclear. We generally decide whether to give the vaccine on case-by-case
basis, favoring vaccination in organ transplant recipients who are at low risk
for rejection. (See 'Zoster vaccines' above.)
●SOT candidates and recipients are eligible for coronavirus disease 2019
(COVID-19) vaccination. Although the immunogenicity and efficacy of COVID-
19 vaccines are uncertain in patients receiving immunosuppressive and
immunomodulatory agents, the potential for benefit from vaccination likely
outweighs these uncertainties. (See "COVID-19: Vaccines to prevent SARS-

231
CoV-2 infection" and "COVID-19: Issues related to solid organ
transplantation", section on 'Vaccination'.)
●Additional vaccines may be needed for patients based on age, vaccination
history, or other specific risk factors (eg, meningococcal vaccination for
patients receiving eculizumab). (See 'Human papillomavirus' above
and 'Haemophilus influenzae' above and 'Tetanus, diphtheria, and
pertussis' above and 'Live virus vaccines' above and 'Meningococcus' above.)
●Following exposure to certain pathogens (eg, varicella-zoster virus, measles
virus, or hepatitis B virus), passive immunization (eg, administration of
immunoglobulin) and/or postexposure antimicrobial prophylaxis may be
warranted for severely immunocompromised patients and/or for those who
have not been vaccinated against these pathogens. (See 'Postexposure
prophylaxis' above.)
●We advise that close contacts of solid organ transplant candidates receive all
recommended immunizations. When possible, live virus vaccines should be
given prior to transplantation and/or the start of immunosuppression.
(See 'Health care workers and close contacts' above.)

232
Infection in the solid organ transplant recipient
Author:
Jay A Fishman, MD
Section Editor:
Emily A Blumberg, MD
Deputy Editor:
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Apr 22, 2020.
INTRODUCTIONSolid organ transplantation has increased worldwide since the
first successful human kidney transplant was performed in 1954. As
immunosuppressive agents and graft survival have improved, infection and
malignancy have become the main barriers to disease-free survival after organ
transplantation. Due to the growing population of immunosuppressed patients
with improved survival and with use of improved diagnostic tools, an increased
incidence and spectrum of opportunistic infections has been observed [1-4].
The risks of infection and an overview of specific infections in the solid organ
transplant recipient will be reviewed here. The pretransplant evaluation for solid
organ and hematopoietic cell transplant (HCT) recipients, prophylaxis of infections
in solid organ transplant and HCT recipients, and an overview of infections
following HCT are discussed separately. (See "Evaluation for infection before solid
organ transplantation" and "Evaluation for infection before hematopoietic cell
transplantation" and "Prophylaxis of infections in solid organ
transplantation" and "Prevention of infections in hematopoietic cell transplant
recipients" and "Overview of infections following hematopoietic cell
transplantation".)
GENERAL PRINCIPLESWhen a transplant recipient presents with an infectious
syndrome, early, specific diagnosis and rapid, aggressive treatment are essential
to optimal clinical outcomes.
●Potential etiologies of infection in these patients are diverse, including
common community-acquired bacterial and viral diseases and uncommon
opportunistic infections of clinical significance only in immunocompromised
hosts [1-3]. Pulmonary processes can progress rapidly and may constitute
medical emergencies [1]. These include infections due to Pneumocystis
jirovecii (formerly P. carinii), Nocardia asteroides, Aspergillus  spp, Cryptococcus
neoformans, cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza,
respiratory syncytial virus (RSV), and Legionella  spp.
233
 ●Inflammatory responses associated with microbial invasion are impaired by
immunosuppressive therapy, which results in diminished symptoms and
muted clinical and radiologic findings. Fever is neither a sensitive nor a
specific predictor of infection; up to 40 percent of infections cause no fever
(especially fungal infections) and up to 22 percent of fevers are noninfectious
in origin [5]. Infections are often advanced (ie, disseminated) at the time of
clinical presentation.
●Serologic testing is not generally useful for the diagnosis of acute infection
in the immunocompromised host because seroconversion is often delayed or
may not occur. Serologic assays may be used to identify latent infections and
distant exposures as a basis for prophylaxis. Microbiologic cultures are
supplemented by antigen-based tests (eg, enzyme-linked immunosorbent
assays [ELISAs]) or nucleic acid-based tests (NAT), such as polymerase chain
reaction for specific diagnoses.
●Altered anatomy following transplant surgery may change the physical
findings associated with infection. Diagnosis often requires anatomic data
from imaging such as computed tomography (CT) scans or magnetic
resonance imaging (MRI).
●Tissue biopsies with histopathology and microbiology are often needed to
make a specific microbiologic diagnosis in transplant recipients. Such clinical
samples must be obtained early in the clinical course to enhance the chance
for successful therapy, to minimize side effects of therapy, and before the
patient's illness progresses to a point where such procedures can no longer
be performed.
●The choice of antimicrobial regimens is often more complex than in other
patients due to the urgency of therapy and the frequency of drug toxicities
and drug interactions.
●Antimicrobial resistance is increased in immunocompromised hosts and
should be considered in the choice of antimicrobial regimens.
●Surgical intervention is often necessary to cure localized infections (ie,
debridement); antimicrobial agents alone are frequently inadequate.
●Drug levels provide only crude means of monitoring immunosuppressive
regimens, and patients are often more or less immunosuppressed than
anticipated. Side effects of these regimens are also common; some side
effects may mimic infection. Immune function assays are under development
to guide management [6].
For these reasons, the central focus must be on disease prevention, including drug
therapy and vaccination. This requires stratification of the risk for various
infections. (See "Prophylaxis of infections in solid organ

234
transplantation" and "Immunizations in solid organ transplant candidates and
recipients" and "Evaluation for infection before solid organ transplantation".)
Bacteremia is more common in solid organ transplant recipients than in other
hosts and usually occurs in association with urinary tract or other focal infections.
In a case-control study, the mortality rate due to bacteremic sepsis appeared to be
lower in solid organ transplant recipients compared with nontransplant patients at
28 days (hazard ratio [HR] 0.22, 95% CI 0.09-0.54) and at 90 days (HR 0.43, 95% CI
0.20-0.89) [7]. In a retrospective cohort study of patients with sepsis, solid organ
transplant recipients had a lower rate of mortality than nontransplant patients [8].
The association was seen in all types of transplant recipients except lung
transplant recipients, who had a higher rate of mortality, and heart transplant
recipients, in whom there was no difference. It is postulated that the lower rate of
mortality in solid organ transplant recipients may be due to the fact that the
immunosuppression associated with transplantation may blunt the inflammatory
response to infection and/or that these patients may receive more aggressive
management.
RISK OF INFECTION FOLLOWING TRANSPLANTATIONThe risk of
infection in the organ transplant patient is determined by the synergy between
two factors: the epidemiologic exposures of the individual and the "net state of
immunosuppression," which is a conceptual measure of all of the factors that
contribute to the individual's susceptibility (or resistance) to infection [1,4,9,10].
Epidemiologic exposures — To adequately assess epidemiologic exposures, the
clinician must take a detailed history of potential encounters with a variety of
pathogens, even if the exposure was relatively remote. Latent pathogens are often
activated in the setting of immune suppression. The epidemiologic exposures of
importance to an individual will vary based upon the nature of the immune
deficits. Most transplant patients have multiple deficits. Thus, bacterial and fungal
pathogens are more important in the setting of neutropenia, while viral (eg,
cytomegalovirus [CMV]) and intracellular (eg, tuberculosis [TB]) infections are more
common with T cell immune deficits. Strongyloides stercoralis may reactivate many
years following transplantation [1,11]. (See "Evaluation for infection before solid
organ transplantation".)
Community-acquired pathogens — The transplant recipient can have contact
with potential pathogens within the community. These organisms include common
respiratory viruses (influenza, parainfluenza, respiratory syncytial [RSV] virus,
adenovirus, and human metapneumovirus) and bacterial, viral, and parasitic
gastrointestinal pathogens that may produce more persistent infections in these
hosts (eg, with norovirus). Common bacterial pathogens include Streptococcus
pneumoniae, Mycoplasma, Legionella, Listeria monocytogenes, and Salmonella.
235
Vaccinations for pneumococcus and influenza virus are encouraged but may have
reduced efficacy in immunocompromised individuals. (See "Immunizations in solid
organ transplant candidates and recipients".)
In the appropriate geographic regions, endemic fungi (Histoplasma
capsulatum, Coccidioides  spp, Paracoccidioides spp, Blastomyces
dermatitidis, Cryptococcus gattii) and common environmental pathogens
(eg, Cryptococcus neoformans, Aspergillus  spp, Cryptosporidia  spp) will be observed.
Thus, while specific infectious exposures within the community will vary based
upon such factors as geography and socioeconomic status, the general dictum
that "common things occur commonly" applies to transplant recipients. The
severity and duration of infection and the frequency of multiple simultaneous
processes are features that differentiate the transplant recipient from the normal
host.
Reactivation of infections — Reactivated infection may be derived from the
organ donor or the recipient. Common viral infections that frequently reactivate
following transplantation include herpes simplex virus (HSV), CMV, varicella-zoster
virus (VZV; shingles), hepatitis B (HBV) and hepatitis C (HCV), papillomavirus, and
BK polyomavirus. Some exposures may have occurred many years before
transplantation including geographically restricted systemic mycoses (eg,
histoplasmosis, coccidioidomycosis, blastomycosis), Mycobacterium
tuberculosis, Strongyloides stercoralis, Leishmania  spp, or Trypanosoma cruzi  [10-14].
An important goal of the pretransplant evaluation is to identify such latent
infections so as to develop a preventive strategy for each. (See "Evaluation for
infection before solid organ transplantation".)
Nosocomial infections — Transplant recipients are vulnerable to nosocomial
infections, especially in the early post-transplant (ie, postsurgical) period,
particularly those with prolonged hospitalizations or who require mechanical
ventilation. Common pathogens include:
●Legionella spp and other gram-negative bacilli such as Pseudomonas
aeruginosa and multidrug-resistant organisms
●Gram-positive organisms, particularly antimicrobial-resistant species such as
vancomycin-resistant enterococci (VRE) and methicillin-
resistant Staphylococcus aureus (MRSA) [15]
●Fungi such as Aspergillus spp and non-albicans or azole-
resistant Candida species (table 1) [16]
●Clostridioides difficile colitis [17-19]
●Nontuberculous mycobacteria in surgical wounds [20,21]

236
When the air, food, equipment, or potable water supply either in the hospital or
the home are contaminated with these pathogens, clusters of infection can occur.

Coronavirus disease 2019 — Although the clinical manifestations and outcomes

of coronavirus disease 2019 (COVID-19) in solid organ transplant recipients are not
yet well characterized, several important aspects of care can be defined [22]:
●Individuals can be infected without known epidemiologic exposures.
●Clinical variability is marked. Fever, cough, shortness of breath, myalgias,
and sputum production are common; however, fever may be absent, and, in
some patients, gastrointestinal symptoms (diarrhea, nausea, and vomiting)
predominate.
●Leukopenia and lymphopenia tend to be profound in transplant recipients.
●The systemic inflammatory response to COVID-19 is variably affected by
transplant immunosuppression. While inflammatory markers are often
elevated, immunosuppressive medication might blunt their rise. Thus, serial
measurements may have better prognostic value than single measurements.
●Renal function is commonly impaired in all kidney transplant recipients. This
may reflect rejection following reduction in immunosuppression, drug
interactions with calcineurin inhibitors, dehydration, or deposition of viral
antigen in the kidney [23].
●Patients with dyspnea and documented COVID-19 may have clear chest
radiographs but abnormal chest computed tomography scans with bilateral
patchy infiltrates and/or ground-glass opacities.
●Coinfection of COVID-19 with other respiratory viruses, with Pneumocystis
jirovecii, with cytomegalovirus, and with bacterial pathogens has been
observed, but this does not appear to be common.
●Donor-derived infection from infected donors to immunosuppressed
recipients is not yet described. However, the lungs, heart, and kidneys can all
be involved in COVID-19, suggesting that transmission from a transplant
donor is possible. Thus, both organ donors and recipients should be
screened prior to transplant [24,25].
The care of solid organ transplant patients with COVID-19, particularly adjustment
of the immunosuppressive regimen, is necessarily individualized. As with other
infections, immunosuppression in the absence of effective antiviral therapy carries
the risk of uncontrolled infection. However, reduction of immunosuppression
carries the risk of rejection and some transplant recipients have recovered from
COVID-19 without adjustment of their immunosuppressive regimens. (See "COVID-
19: Issues related to solid organ transplantation", section on 'Management'.)

237
Donor-derived infections — Unanticipated infections that are derived from donor
organs and activated in the recipient are among the most important exposures in
transplantation [26-30]. Some of these infections are latent, while others are the
result of bad timing (unappreciated active infection in the donor at the time of
transplantation). The efficiency of the transmission of infectious diseases is
enhanced in immunosuppressed transplant recipients. In immunosuppressed
hosts, classic signs of infections (eg, leukocytosis, erythema) may be replaced by
nonspecific signs (eg, altered mental status, elevation of blood liver function tests,
wound dehiscence, unexplained hypotension). As an example, in
immunosuppressed hosts, the transmission of bloodborne or organ-derived
infection due to West Nile virus more often manifests as neurologic disease with
poor clinical outcomes than in immunocompetent hosts [31]. Clusters of infection
associated with organ transplantation have also included M.
tuberculosis, Candida and Aspergillus  (and other fungal) species, HSV, human
herpes virus 8, lymphocytic choriomeningitis virus (LCMV) [32-35], rabies virus [36-
38], Trypanosoma cruzi (causing Chagas disease), Balamuthia mandrillaris  [39-
42], Encephalitozoon cuniculi (causing microsporidiosis) [43], HIV, and HCV.
Both living and deceased organ donors are screened to avoid transmission of
certain infections to transplant recipients (table 2). Nonetheless, transmission of
infection from donor to recipient may still occur (table 3). The data supporting
transmission of the individual infections are discussed separately in the
appropriate topic reviews for each infection. Organ donor screening requirements
for HIV, HCV, and HBV have been established [44].

Several types of donor infection merit special attention: bloodstream infection,

unexpected infections that are accelerated by immunosuppression, and a number
of specific infections.

Bloodstream infection — Some donors may have active infection at the time of

procurement. Certain pathogens (eg, staphylococci,
pneumococcus, Candida, Salmonella, Escherichia coli) may "stick" to anastomotic
sites (vascular, urinary, biliary, tracheal) and produce fever, bloodstream
infections, or mycotic aneurysms. Proof of adequate therapy for such infections
must be established prior to accepting organs for transplantation.
Unexpected infections accelerated by immunosuppression — Other donor-
derived infections may be unusual (eg, West Nile virus, leishmaniasis, rabies,
LCMV, Chagas disease, HIV, HSV) and may cause clinical syndromes that are
accelerated by immune suppression.
As an example, LCMV occurred in the recipients of solid organ transplants from
three different donors [32,33]. In the investigation of the first two clusters, LCMV
238
was identified in tissues in all organ transplant recipients from both investigations
[32]. The isolates from each investigation were identical to each other but distinct
between the two outbreaks. In contrast, the common donors had no clinical or
laboratory evidence of infection, although the donor from the 2005 cluster had a
history of exposure to a pet hamster. Seven of eight transplant recipients died; one
survivor was treated with ribavirin and decreasing doses of immunosuppressants.
An epidemiologic investigation, using phylogenetic analysis of virus sequences,
eventually traced the origin of these infections to an animal distribution center in
Ohio [34].
Three patients in Australia who received a kidney or liver from a single donor died
of a febrile illness with associated encephalopathy four to six weeks after
transplantation [45]. High-throughput RNA sequencing from the allografts of two
of the patients revealed an arenavirus that is related to LCMV. These results were
confirmed by immunohistochemical analysis of allograft tissue as well as
immunoglobulin (Ig)M and IgG antiviral antibodies from the serum of the donor.
In addition, polymerase chain reaction revealed the presence of the virus in the
kidneys, liver, blood, and cerebrospinal fluid of the recipients. The donor had just
returned home from a three-month visit to rural areas of the former Yugoslavia.
CMV and EBV — Common viral infections such as those due to cytomegalovirus
(CMV) and Epstein-Barr virus (EBV) are associated with particular syndromes and
morbidity in the immunocompromised population. The greatest risk for invasive
infection is seen in recipients who are seronegative (immunologically naïve) and
receive infected grafts from seropositive donors (latent viral infection). This risk
constitutes the rationale for anti-CMV prophylaxis and EBV monitoring in organ
recipients. (See "Kidney transplantation in adults: Clinical manifestations,
diagnosis, and management of cytomegalovirus disease in kidney transplant
recipients" and "Infectious complications in liver transplantation" and "Prevention
of cytomegalovirus infection in lung transplant recipients" and "Approach to the
diagnosis of cytomegalovirus infection".)
Tuberculosis and histoplasmosis — Late, latent infections including tuberculosis
and histoplasmosis may activate many years after transplantation. Early
emergence of tuberculosis in recipients has also been described after receiving
organs from a donor with undiagnosed active infection [46].
Mycobacterial infection may be more difficult to treat after transplantation
because of interactions between the antimicrobial agents used to treat infection
(eg, rifampin, streptomycin, isoniazid) and immunosuppressive drugs [47].
The evaluation and management of tuberculosis in solid organ transplant
recipients is discussed in detail separately. (See "Tuberculosis in solid organ
transplant candidates and recipients".)

239
HIV, HTLV, and hepatitis viruses — In 2007, four recipients of organs from a
single donor, who had died from trauma, were infected with both HIV and
hepatitis C [48]. The donor had presumably been infected during the weeks prior
to death since the antibody tests for these viruses were negative during the
pretransplant donor screening. Subsequent cases of unexpected donor-derived
HIV, HCV infections, as well as HBV infections, have been reported [44,49,50].
Transmission of these viruses typically occurs from high-risk donors with recently
acquired infections (eg, during the "window period" prior to seroconversion).
The likelihood of tissue donors having viremia due to hepatitis B, hepatitis C, HIV,
and human T lymphotropic virus (HTLV) was evaluated in 11,391 tissue donors to
five tissue banks in the United States [51]. The estimated probability of viremia at
the time of donation that would be undetected by screening with current serologic
methods (because of the window period for infection) was 1 in 34,000 for hepatitis
B, 1 in 42,000 for hepatitis C, 1 in 55,000 for HIV, and 1 in 128,000 for HTLV. The
use of NAT allows detection of viral nucleic acids prior to seroconversion and
shortens the window period. NAT was estimated to reduce the probabilities of
viremia to 1 in 100,000 for hepatitis B, 1 in 421,000 for hepatitis C, and 1 in 173,000
for HIV. However, no available assays can completely exclude the risk of infectious
transmissions, especially in the limited time available for deceased donor
screening prior to transplantation [30].
The availability of directly acting antiviral agents (DAA) for HCV infection and highly
active antiviral therapies for HIV infection have had a major impact on organ
utilization. Organ transplantation from HIV-infected individuals to HIV-infected
recipients can be performed safely by transplant teams experienced in HIV
management. Organs from HCV-infected donors have been used in both HCV-
infected and uninfected recipients with subsequent or preemptive DAA therapy
[52-57]. In a prospective study of 44 HCV-uninfected heart and/or lung transplant
recipients who received an organ from an HCV-infected donor,
preemptive sofosbuvir-velpatasvir given for four weeks prevented the
development of HCV infection in the recipients for the six-month follow-up period
in all patients [55]. High rates of sustained virologic response with preemptive DAA
use have also been reported in previous case series, one with a 12-month follow-
up period [52-54,56].
Donor-derived HTLV infections with subsequent development of cutaneous T cell
lymphoma [58] and, rarely, HTLV-I associated myelopathy/tropical spastic
paraparesis have also been reported. Serologic screening of organ donors for
HTLV is no longer required in the United States. This is discussed in detail
separately. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and
epidemiology", section on 'Tissue donation'.)

240
Net state of immunosuppression — The net state of immunosuppression is a
conceptual assessment of the factors contributing to the risk for infection in an
individual [59-65]:
●Type, dose, duration, and temporal sequence of immunosuppressive
therapies (table 4)
●Underlying diseases or comorbid conditions
●Presence of devitalized tissues or fluid collections
●Invasive devices such as vascular access or urinary catheters, surgical drains,
and ventricular assist devices
●Other host factors affecting immune function including neutropenia,
hypogammaglobulinemia, and metabolic problems (eg, protein-calorie
malnutrition, uremia, diabetes)
●Concomitant infection with immunomodulating viruses including CMV, EBV,
human herpesvirus (HHV)-6 and -7, HBV, and HCV

The sum of any congenital, acquired, metabolic, operative, and transplant-related

factors is the patient's "net state of immune suppression." Multiple factors are
usually present in each host. The identification and correction of any modifiable
risk factor is essential for the prevention and treatment of infection.

Immune competence may be measured crudely using cell counts, the frequency
and severity of common infections (eg, herpes simplex virus), or the presence of
circulating viruses. Nonspecific assays have been introduced to assess
susceptibility to infection. Some are based in the production of intracellular ATP in
response to mitogenic stimulation [66]. These assays are more useful in measuring
the risk of infection than rejection. However, they have not yet been well validated
prospectively for the ability to predict the risk for infection in individual transplant
recipients. Advances in the assessment of T and B cell responses to specific
pathogens, such as cytomegalovirus, have been achieved using cell sorting
technologies that measure the level of immune responses committed to specific
pathogens [67-69].
TIMING OF INFECTION POST-TRANSPLANTATIONImmunosuppressive
regimens vary among centers, with the organ transplanted, and the patient
population. As an example, "induction" using T-lymphocyte depletion may be
applied to renal transplantation from deceased donors but might not be used for
living related donor transplants. Lung recipients or human leukocyte
antigen (HLA)-mismatched transplants may receive intensified
immunosuppression including glucocorticoid therapy or plasmapheresis. For
maintenance immunosuppression, most recipients receive a relatively standard
combination of agents. (See "Kidney transplantation in adults: Induction
241
immunosuppressive therapy" and "Kidney transplantation in adults: Maintenance
immunosuppressive therapy" and "Maintenance immunosuppression following
lung transplantation".)
Based on this background, the post-transplant course can be roughly divided into
three time periods related to the risks of infection by specific pathogens: the early
period post-transplant (first month), an intermediate period (one to six months),
and more than six months (figure 1) [1,3]. This timetable is useful in three ways:
●In developing a differential diagnosis for the individual transplant recipient
with clinical signs of infection
●As a clue to the presence of excessive environmental hazards (nosocomial,
community, or individual)
●As a guide to the design of preventive antimicrobial strategies
Alterations in the type or intensity of immune suppression alters the risk of
infection (table 4) and the differential diagnosis of infectious syndromes (table 3).
First month after transplantation — In the first month post-transplant, there are
two major causes of infection in all forms of solid organ transplantation: pre-
existing infection from either the donor or recipient and infectious complications
of the transplant surgery and hospitalization. The major effects of exogenous
immunosuppression are not yet evident. Exceptions include those patients who
receive immunosuppression prior to transplantation (eg, for autoimmune
hepatitis) and individuals with underlying immunodeficiencies.
Donor-derived infections — The risk for infections acquired with the allograft is
discussed above (table 3) [26-28,70]. Recognition of donor organ-derived bacterial
and fungal infections has increased with the transmission of antimicrobial-
resistant strains including vancomycin-resistant enterococci, methicillin-resistant
staphylococci, carbapenem- and multidrug-resistant gram-negative bacteria, and
fluconazole-resistant Candida  species [71]. Graft-associated viral infections
(lymphocytic choriomeningitis virus, West Nile virus, rabies, HIV) and parasitic
infections (toxoplasmosis, Chagas disease, Balamuthia mandrillaris) are uncommon
but may be amplified in the immunosuppressed host. Endemic infections (eg,
histoplasmosis or tuberculosis) should be considered in the differential diagnosis
of post-transplant infection or unusual clinical syndromes (eg, encephalitis,
hepatitis). (See 'Donor-derived infections' above.)
Recurrent infection — Infection may have been present in the donor organ or in
the recipient prior to transplantation. An important component of the
pretransplant evaluation is to recognize and treat such infections, if possible.
(See "Evaluation for infection before solid organ transplantation".)
Some common viral infections (eg, hepatitis B virus [HBV], hepatitis C virus [HCV])
may re-emerge early after transplantation. Recipient-derived tuberculosis,

242
nontuberculous mycobacteria, histoplasmosis, or toxoplasmosis tends to emerge
more than a month after transplantation [72]. Reactivation of Strongyloides may be
accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia [11].
Infectious complications related to surgery — Solid organ transplant recipients
develop many common postoperative complications, such as aspiration
pneumonitis, surgical site (wound) infections, catheter-related bloodstream
infections, urinary tract infection, or pulmonary embolus [73]. Transplant
recipients are also at unique risk for superinfection of ischemic or injured graft
tissues (eg, anastomotic suture lines) or of fluid collections (eg, hematomas,
lymphoceles, pleural effusions, urinomas). These patients are at increased risk for
infection associated with indwelling vascular access catheters, urinary catheters,
and surgical drains.
The organisms responsible for such postoperative complications are often the
bacteria and fungi that have colonized the recipient or donor (eg, the lungs and/or
sinuses in cystic fibrosis) prior to transplantation or the local flora of the hospital.
Colonization acquired prior to transplantation may include relatively resistant
nosocomial pathogens (eg, vancomycin-resistant enterococcus) and pathogens
such as Aspergillus spp that are resistant to the usual agents used for surgical
prophylaxis. Patients receiving antimicrobial agents are at increased risk for C.
difficile colitis.
Transplant patients at increased risk for nosocomial infection are those requiring
prolonged ventilatory support or those with diminished lung function, persistent
ascites, stents of the urinary tract or biliary ducts, or with intravascular clot or
ischemic graft tissue [63,74]. Individuals with delayed graft function or who require
early re-exploration or retransplantation are also at increased risk for infection,
notably with fungi or bacteria with antimicrobial resistance.
1 to 6 months after transplantation — In the period one to six months post-
transplant, the nature of common infections changes. The effect of
immunosuppression is often maximal, and patients are at greatest risk for the
development of opportunistic infections. However, residual problems from the
perioperative period can persist. There is significant geographic and institutional
variation in the occurrence of opportunistic infections during the first six months
post transplantation. This reflects local epidemiology, varying immunosuppressive
strategies, and the specific antimicrobial prophylaxis used in the post-transplant
period. Prevention of common infections observed during this period is the basis
of prophylactic antimicrobial strategies. Prophylaxis delays but does not eliminate
the risk for infections that may occur in the months following cessation of
prophylaxis. (See "Prophylaxis of infections in solid organ transplantation".)

243
Major infections due to opportunistic pathogens include:

●Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP). (See "Fungal

infections following lung transplantation", section on 'Pneumocystis
jirovecii'.)
●Viral pathogens, particularly cytomegalovirus (CMV) and the other herpes
viruses (ie, Epstein-Barr virus [EBV], human herpesvirus [HHV]-6, -7, and -8
[Kaposi's sarcoma-associated herpesvirus (KSHV)]) (table 5). HBV and HCV
infections may emerge if untreated. BK polyomavirus is particularly
important in kidney recipients. Community-acquired respiratory viruses are
important in this population (influenza, parainfluenza, respiratory syncytial
virus [RSV], adenovirus, metapneumovirus).
●Latent infections, such as the protozoal diseases including strongyloidiasis,
toxoplasmosis, Chagas disease, and, less commonly, leishmaniasis
[10,61,62,75-77].
●The geographic or endemic fungal infections caused by Histoplasma
capsulatum, Coccidioides  spp, Paracoccidioides spp, and,
rarely, Cryptococcus  spp or  Blastomyces dermatitidis. (See "Fungal infections
following lung transplantation".)
●Tuberculosis and, increasingly, nontuberculous mycobacteria [78].
(See "Tuberculosis in solid organ transplant candidates and
recipients" and "Nontuberculous mycobacterial infections in solid organ
transplant candidates and recipients".)
●Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses
(CMV, norovirus) may be associated with persistent diarrhea [79].
More than 6 to 12 months after transplantation — Six to 12 months or longer
post-transplant, most patients are receiving stable and reduced levels of
immunosuppression. These patients are subject to community-acquired
pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other
common pathogens.
"Late CMV" may emerge in patients who received prophylaxis for the first three to
six months [80-82]. New strategies are emerging to prevent late infections
including extending prophylaxis or monitoring of either pathogen-specific immune
function or global immune function as a guide to infectious risk [6,68]. CMV
infection may also develop in patients treated for graft rejection.
Patients who have less than adequate graft function may require higher-than-
usual immunosuppressive therapy. As a result, they represent a subgroup of
transplant patients at highest risk for opportunistic infections including PCP,
cryptococcosis, and nocardiosis. They are also at risk for severe illness from

244
community-acquired infections due to influenza or Listeria monocytogenes.
Prolonged antimicrobial prophylaxis may be indicated for this subgroup of
patients. This group of patients may also suffer less common infections in the late
transplant period with atypical clinical presentations. These infections include the
molds or Nocardia species, unusual viruses (eg, JC virus-associated progressive
multifocal encephalopathy) or virus-associated malignancies: post-transplant
lymphoproliferative disorder (PTLD) or squamous cell cancers of the skin or
anogenital region. (See "Prophylaxis of infections in solid organ transplantation".)
VIRUSES AS COPATHOGENSViruses, particularly cytomegalovirus (CMV),
serve as important cofactors for many opportunistic infections [1,59,60]. The
potential effects of viral infection are diverse and apply not only to CMV but also to
hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), and
probably to other common viruses such as respiratory syncytial virus (RSV), human
herpesvirus (HHV)-6, and adenovirus (table 6). Viruses contribute to a variety of
processes post transplantation (table 5) [1,60,63,83-85].
Direct effects — "Direct effects" include virus-specific clinical syndromes such as
fever and neutropenia (CMV), pneumonitis (respiratory viruses), hepatitis (HCV,
HBV), gastritis, esophagitis, colitis (CMV), cholangitis (varicella-zoster virus [VZV]),
encephalitis (herpes simplex virus [HSV], JC virus), pancreatitis, myocarditis, and
retinitis. Less common syndromes include adrenalitis with adrenal insufficiency
(CMV) or meningoencephalitis due to CMV vasculitis.
Indirect effects — "Indirect effects" are generally immune effects including:
●Immune suppression and predisposition to opportunistic infection
(eg, Aspergillus  after CMV infection or RSV pneumonia, Pneumocystis after
CMV infection). Thus, CMV coinfection has been implicated in the accelerated
course of HCV infection with cirrhosis and graft loss and of EBV with
increased risk for post-transplant lymphoproliferative disorder (PTLD; usually
B cell lymphoma).
●Graft rejection that is thought to be mediated by proinflammatory cytokine
release and/or upregulation of histocompatibility antigens or adhesion
proteins in the setting of CMV reactivation [83,86,87]. Graft rejection may
necessitate an increase in the immunosuppressive regimen and an increased
risk for opportunistic infection.
●Oncogenesis – Many viruses predispose to cancer (HCV, EBV) or to cellular
proliferation (CMV and accelerated atherogenesis, BK polyomavirus, and
ureteric smooth muscle cell proliferation).
Specific viral pathogens — The spectrum of viral infections in the transplant
recipient is broad (table 5):

245
●The BK polyomavirus has been associated with infection of renal allografts
with hemorrhagic cystitis, asymptomatic viruria, interstitial nephritis, ureteric
obstruction, and rising creatinine values in renal transplant recipients [88-91].
(See "Overview of JC polyomavirus, BK polyomavirus, and other polyomavirus
infections".)
●Adenovirus may cause a similar hemorrhagic cystitis syndrome, hepatitis (in
liver recipients), or pneumonia diagnosed by culture or antigen detection or
molecular testing. (See "Pathogenesis, epidemiology, and clinical
manifestations of adenovirus infection".)
●HHV-6, -7, and -8 have also been identified in transplant recipients [92]
(see "Virology, pathogenesis, and epidemiology of human herpesvirus 6
infection" and "Human herpesvirus 7 infection" and "Disease associations of
human herpesvirus 8 infection"). HHV-6 has been implicated as a cofactor in
CMV infection (and vice versa) or may cause leukopenia and fever as part of a
viral syndrome. The role of HHV-7 remains to be clarified.
●EBV, VZV, and HSV are often activated during this one to six month period.
EBV may be associated with the development of B cell non-Hodgkin
lymphoma, particularly in seronegative recipients of seropositive organs.
However, some cases of T cell, NK cell, and non-EBV-related PTLD have been
described (see "Treatment and prevention of post-transplant
lymphoproliferative disorders"). Herpes zoster (shingles) may occur;
occasionally, patients present with cholangitis due to VZV. Human
papillomavirus (HPV) is associated with anogenital and squamous cell
cancers.
●Parvovirus B19 may also present in this time period with anemia
unresponsive to erythropoietin or with myocarditis [93]. Parvovirus B19 has
also been associated with chronic allograft injury in renal transplant
recipients [94].
●Respiratory viruses remain important community-acquired pathogens,
particularly in the lung transplant recipient [95]. Infections with these latter
viruses predispose the patient to the development of bacterial infections and
graft rejection. (See "Viral infections following lung transplantation".)
●Viruses that have been reported rarely in solid organ transplant recipients
include human T lymphotropic virus, hepatitis E virus, rabies virus,
lymphocytic choriomeningitis virus, measles, mumps, dengue, orf, and
human coronaviruses HKU1 and NL63 [96]. Most of these were infections
derived from asymptomatic organ donors.

246
EVALUATION AND MANAGEMENTThe pursuit of diagnostic testing and
the management of infection in a transplant recipient must be guided by a
number of principles:
●These hosts generally have fewer clinical manifestations of infection and few
or no findings by conventional radiography. Thus, more sensitive imaging
techniques such as computed tomographic (CT) scans and magnetic
resonance imaging (MRI) are essential for assessing the presence and nature
of infectious and malignant processes.
●The "gold standard" for diagnosis is specific microbiology and/or tissue
histology. No radiologic finding is sufficiently diagnostic to obviate the need
for clinical samples. Multiple simultaneous infections are common. Thus,
invasive procedures that provide tissues or fluids for culture and histology
must be employed as a routine component of the initial evaluation of
transplant recipients with infectious syndromes. Patients failing to respond to
appropriate therapy may also need invasive diagnostic procedures.
●Serologic tests, which indicate past exposure to certain pathogens, are
useful in the pretransplant setting to assess risk for relapse of latent disease
but are not generally useful after transplantation. Patients, especially those
receiving immunosuppressive therapies, do not reliably develop antibodies
quickly enough during an active infection to enable a serologic diagnosis.
Thus, quantitative tests that directly detect the protein products or nucleic
acids of the organisms such as sandwich enzyme linked immunosorbent
assays (ELISA), direct immunofluorescence, or quantitative molecular assays
(nucleic acid tests [NATs]) should be utilized.
●Transplant recipients are often colonized and thus are particularly
vulnerable to organisms resistant to antimicrobial agents either from the
hospital environment or through induction of antibiotic resistance in their
flora during therapy (eg, inducible beta-lactamases). Sites at risk for infection
with resistant organisms (eg, ascites, blood clots, drains, lungs) can be
sampled so that information is available to guide empiric therapy at times of
clinical deterioration.
●When undrained fluid collections, blood, or devitalized tissues are present,
antimicrobial therapy alone is often inadequate. Antibiotics, used in lieu of
definitive drainage or debridement, merely delay clinical deterioration and
promote the acquisition of resistant microorganisms. Early and aggressive
surgical debridement of such collections is essential for successful care.
●Some components of the immunosuppressive regimen may be modified
during acute infection to elicit an improved host response. This must be done

247
 with caution since reductions in immunosuppression may provoke immune
reconstitution syndromes or allograft rejection.
Infectious disease consultation improves outcomes in solid organ transplant
recipients. As an example, in a study of solid organ transplant recipients admitted
with an infection, infectious disease consultation was associated with reduced 28-
day mortality (hazard ratio 0.33) and 30-day rehospitalization rates (17 versus 24
percent) [97]. The median length of stay and hospitalization costs did not differ
between patients who received an early infectious disease consultation (<48 hours)
and those who did not.
The evaluation for infection prior to solid organ transplantation is discussed
separately. (See "Evaluation for infection before solid organ transplantation".)
FUTURE DIRECTIONSMany important hurdles remain to be overcome in the
diagnosis and treatment of infections to enhance the safety and success of solid
organ transplantation. The initiation of a diagnostic evaluation for infection
frequently begins when clinical symptoms become manifest. That is often late in
the course of the disease in immunocompromised patients. Further, specific
microbiologic diagnoses are needed to avoid unnecessary toxicities associated
with therapy. Thus, invasive diagnostic procedures are often required to make an
accurate microbiologic diagnosis [98-100].

More advanced, quantitative laboratory assays utilizing molecular techniques or

antigen detection are integral components of transplant care. Such tests may be
prohibitively costly for routine use. Rapid, quantitative, cost-effective assays that
do not depend upon invasive procedures are needed for the routine monitoring of
transplant patients for infections and for graft rejection. Assays measuring
pathogen-specific immunity are increasingly used to guide prophylactic strategies;
global measures of immune function are not yet in routine clinical use. Such tests
would allow the clinician to individualize prophylactic antimicrobial regimens and
minimize drug-associated toxicity.

The evolution of pathogens (bacteria, viruses, fungi) with resistance to common

antimicrobial agents and the incidence of drug toxicity and allergy have limited the
available antimicrobial strategies for transplant recipients. The introduction of new
therapies (eg, directly acting antivirals for hepatitis C virus and highly active
antiviral therapy for HIV) have dramatically altered clinical practice. New
antimicrobial agents are needed for prophylaxis and therapy.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
248
separately. (See "Society guideline links: Infections in solid organ transplant
recipients" and "Society guideline links: Urinary tract infections in solid organ
transplant recipients".)
SUMMARY
●The risk of infection in the organ transplant patient is determined by the
synergy between two factors: the epidemiologic exposures of the individual
and the "net state of immunosuppression," which is a conceptual measure of
all of the factors that contribute to the individual's susceptibility (or
resistance) to infection. (See 'Risk of infection following
transplantation' above and 'Epidemiologic exposures' above and 'Net state of
immunosuppression' above.)
●Dividing the post-transplant course into three time periods related to the
risks of infection by specific pathogens is a useful starting point for
differential diagnosis of infectious syndromes: the early period post-
transplant (first month), an intermediate period (1 to 6 months), and more
than 6 to 12 months (figure 1). The timing of the presentation of infectious
processes will be altered (delayed) by the deployment of antimicrobial
prophylaxis and individual risk factors. Prophylaxis may result in the delayed
presentation of infection (eg, "late cytomegalovirus [CMV] infection").
(See 'Timing of infection post-transplantation' above.)
•In the first month post-transplant, the major causes of infection in all
forms of solid organ transplantation include infection derived from either
the donor or recipient and infectious complications of the transplant
surgery and hospitalization. (See 'First month after
transplantation' above.)
•The period 1 to 6 months post-transplant is the period when patients
suffer the greatest impact of immunosuppression and are at the greatest
risk for the development of opportunistic infections. Virally mediated
infections are common. Patterns are altered by prophylaxis. (See '1 to 6
months after transplantation' above.)
•Six to 12 months or longer post-transplant, most patients are receiving
stable and reduced levels of immunosuppression. These patients are
subject to community-acquired infections, including pneumonias due to
respiratory viruses, the pneumococcus, Legionella, or other common
pathogens. (See 'More than 6 to 12 months after transplantation' above.)
●Viruses, particularly CMV, serve as important cofactors to many
opportunistic infections. The potential effects of viral infection are diverse
and apply not only to CMV but also to hepatitis B virus (HBV), hepatitis C virus
(HCV), Epstein-Barr virus (EBV), and probably to other common viruses such
249
as respiratory syncytial virus (RSV), human herpesvirus (HHV)-6, and
adenovirus (table 6). (See 'Viruses as copathogens' above.)
●The pursuit of diagnostic testing and the management of infection in a
transplant recipient must be guided by a number of principles:
•These hosts may have nonspecific clinical manifestations of infection and
few or no findings by conventional radiography. Thus, more sensitive
imaging techniques such as computed tomographic (CT) scans and
magnetic resonance imaging (MRI) are necessary.
•Specific microbiologic diagnoses are important to avoid drug toxicities
and interactions and to enhance care. Tests that detect pathogen-specific
proteins or nucleic acids are important to transplant management.
•Serologic tests, which indicate past exposure to pathogens, are useful in
the pretransplant setting to assess the presence of latent disease but are
not generally useful for acute diagnosis after transplantation.
•Transplant recipients are often colonized by organisms resistant to
antimicrobial agents from the hospital environment or selected during
antimicrobial therapy.
•When undrained fluid collections, blood, or devitalized tissues are
present, antimicrobial therapy alone is inadequate. Early and aggressive
surgical debridement of such collections is essential for successful care.
(See 'Evaluation and management' above.)

250
Infectious complications in liver transplantation
Authors:
Nina M Clark, MD
Scott J Cotler, MD
Section Editors:
Emily A Blumberg, MD
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 02, 2021.
INTRODUCTIONInfectious complications are major sources of morbidity and
mortality in liver transplant recipients.
The specific factors (preoperative and postoperative) that increase the risk for
infection in liver transplant recipients will be reviewed here. The most common
pathogens responsible for infection at three key time points (the first month after
transplant, months 1 through 6, and after the initial six months) will also be
discussed. Other issues related to liver transplantation and infections in solid
organ transplant recipients are presented separately. (See "Infection in the solid
organ transplant recipient" and "Evaluation for infection before solid organ
transplantation" and "Prophylaxis of infections in solid organ transplantation".)
EPIDEMIOLOGYDespite advances in liver transplantation, morbidity and
mortality due to infectious complications remain major problems. In many centers,
infection is the most frequent cause of death following liver transplantation,
particularly in the first year after transplant [1], even though deaths related to
infectious diseases in nontransplant settings have steadily decreased. In an
autopsy series, for example, infections were the cause of death in 64 percent of
321 transplant patients who died between 1982 and 1997 [2]. The most common
types of infection were bacterial (48 percent), fungal (22 percent), and viral (12
percent). In another report, up to two-thirds of all liver transplant patients had at
least one episode of infection [3]. Other series have observed infection rates of 1 to
2.5 episodes per patient [4-6]. Infection is the most common cause of fever in liver
transplant recipients [7].
GENERAL PRINCIPLESSeveral principles of infection in solid organ transplant
recipients are important to recognize [8,9]:
●Signs and symptoms of infection are often attenuated in the setting of
immunosuppression, and infection may be more difficult to diagnose.
251
 ●Noninfectious causes of fever may mimic infection (eg, allograft rejection,
medications).
●The variety of possible pathogens is quite broad but is influenced by the
timing of infection in relation to transplantation.
●Antimicrobial agents used to treat infections can have important drug
interactions with immunosuppressive medications.
●Infection may be more severe and progress more rapidly compared with
immunocompetent hosts.
●Infection risk is determined by a patient's "net state of immunosuppression"
[8], a balance contributed to by factors such as the dose, type, and duration
of immunosuppressive therapy, the presence of indwelling devices such as
catheters, nutritional status, metabolic conditions, certain
immunomodulating viral infections, graft function, and underlying diseases.
(See "Infection in the solid organ transplant recipient", section on 'Net state
of immunosuppression'.)
RISK FACTORSIdentification of risk factors for infection before transplantation
permits the optimal use of strategies for preventing infections in the post-
transplant setting. Although the ability to accurately predict a patient's risk of
infection after transplantation remains limited, there are some risk factors that can
be modified when recognized, such as the cytomegalovirus (CMV) serostatus of the
transplant donor and recipient. (See 'Herpesviruses' below.)
One important risk factor is the presence of a latent or unrecognized infection in
either the transplant donor or recipient. Such infections may reactivate and cause
significant morbidity after the introduction of immunosuppressive therapy. As a
result, potential transplant donors and recipients are routinely screened for
infections such as those due to CMV and other herpesviruses, tuberculosis,
hepatitis B and C, syphilis, and human immunodeficiency virus (table 1). This is
discussed in detail separately. (See "Evaluation for infection before solid organ
transplantation".)
Infection in the donor that is active at the time of organ procurement may also be
transferred to the recipient [9]. For example, bacteremic donors have transmitted
bloodstream infection to transplant recipients despite administration of
appropriate antimicrobial prophylaxis, and liver transplant recipients may be at
increased risk for donor-derived bacteremias [10]. (See "Infection in the solid
organ transplant recipient", section on 'Donor-derived infections'.)
Pretransplant colonization of liver transplant recipients with organisms such as
methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-
resistant Enterococcus (VRE) can lead to post-transplant infection with these
organisms and increased mortality [11-15]. However, MRSA and VRE colonization
252
are not contraindications to transplantation [16]. An increased prevalence of
multidrug-resistant gram-negative bacilli (eg, extended-spectrum beta-lactamase-
producing Enterobacteriaceae, including Escherichia coli and Klebsiella pneumoniae;
carbapenem-resistant Enterobacteriaceae) has been observed not only in the
general population but also in solid organ transplant recipients [17]. Transplant
recipients often have several risk factors for acquisition of resistant bacteria, such
as prior antimicrobials, devices, exposure to the health care environment, and
underlying illness [18].
Various other risk factors for infection after liver transplantation have been
reported. Many are related to surgical complications of the transplant operation
[3]. As an example, in a series of 101 patients, risk factors for infection included a
prolonged operative time (>12 hours) and reoperation [19]. Two pretransplant
variables were predictive of infection; a serum alanine aminotransferase
concentration above 60 international units/L was associated with an increased risk
of all types of infection, and a T helper/suppressor ratio ≤2.8 was associated with
an increased risk of viral and fungal infections [19].
In other reports, the risk of bacterial infections was increased in patients who had
undergone Roux-en-Y biliary anastomosis rather than
choledochocholedochostomy, had multiple abdominal surgeries, or had CMV
infection in the postoperative period [3,20]. Similar risk factors have been
identified for post-transplant fungal infections [3,21-23]. Graft dysfunction and pre-
existing critical illness also confer an increased risk for post-transplant infection
[9].
CMV infection increases the risk of other infections, which may in part be due to
the immunomodulatory effects of this virus [3,8,20]. Patients who develop
rejection or who have poor graft function after transplant are also at increased risk
of infection, at least in part because they receive a more aggressive
immunosuppressive regimen.
PREVENTIONIn addition to screening potential liver donors and recipients for
infection as noted above, there are some general approaches to the prevention of
infections in liver transplant patients. These include vaccination, the universal
administration of prophylactic antimicrobials to patients at increased risk for
specific infections (both perioperative surgical prophylaxis and post-transplant
prophylaxis), and pre-emptive therapy [8]. "Targeted prophylaxis" and "educated
avoidance" are additional approaches [9]. Preventive strategies are discussed in
further detail below.
Vaccination — Patients awaiting liver transplantation should receive appropriate
vaccinations before transplantation since antirejection immunosuppressive
medications may prevent optimal responses to vaccination post-transplantation
253
[24]. Although efficacy is decreased after transplantation, particularly in the first
few months after transplant or during other periods of intensified
immunosuppression [25], certain vaccines such as pneumococcal and influenza
vaccines should be repeated after transplantation in an attempt to lower the risk
for these diseases. As a general rule, live vaccines should be avoided in transplant
recipients due to the risk of disseminated disease. (See "Immunizations in solid
organ transplant candidates and recipients" and "Immunizations for patients with
chronic liver disease" and "COVID-19: Issues related to solid organ
transplantation", section on 'Vaccination'.)
Antibacterial and Pneumocystis prophylaxis — The rate of surgical site infection
(SSI) is higher in liver transplant recipients compared with other solid organ
transplant types and can cause considerable morbidity [26]. Antibiotics are
administered at transplantation in an attempt to prevent SSIs, including wound
and intra-abdominal infection, although they do not provide complete protection
[27]. Skin and intestinal flora are common SSI pathogens, and it is important to
recognize local epidemiologic patterns and recent colonizing or infecting
organisms in the transplant recipient and donor when choosing antibiotics for
prophylaxis. The use of antibacterial agents around the time of transplantation is
discussed separately. (See "Prophylaxis of infections in solid organ
transplantation", section on 'Antibacterial prophylaxis'.)
In patients without sulfonamide allergy, trimethoprim-sulfamethoxazole is
generally administered for 6 to 12 months after liver transplantation [28], primarily
to reduce the risk of Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP), but
it also helps to prevent infections with Listeria monocytogenes, Nocardia
asteroides, Toxoplasma gondii, and many common urinary, respiratory, and
gastrointestinal bacterial pathogens [8,28-30]. One single-strength tablet taken
daily or one double-strength tablet taken three times weekly are appropriate
doses for PCP prevention. Optimal dosing of trimethoprim-sulfamethoxazole for
the prevention of other pathogens is not well established. Routine use of
trimethoprim-sulfamethoxazole prophylaxis has virtually eliminated PCP infection
in the post-transplant setting in comparison with a 10 to 12 percent incidence in
earlier series [29]. (See "Treatment and prevention of Pneumocystis pneumonia in
patients without HIV".)
In patients who are intolerant of trimethoprim-sulfamethoxazole, second-line PCP
prophylaxis agents can be used, including dapsone, aerosolized pentamidine,
or atovaquone. However, these medications do not provide the broad-spectrum
activity that trimethoprim-sulfamethoxazole does against pathogens other than
PCP [28].

254
The most common adverse effect of trimethoprim-sulfamethoxazole is allergy.
Myelosuppression can also occur, but it is uncommon at the doses used for
prophylaxis. Oral trimethoprim-sulfamethoxazole in combination
with cyclosporine can affect tubular secretion of creatinine and increase serum
creatinine levels without necessarily decreasing renal function [31]. In higher
doses (such as those needed to treat PCP), it can also exacerbate the
nephrotoxicity of cyclosporine or tacrolimus. Rarely, it may cause hyperkalemia.
Herpesviruses — Cytomegalovirus (CMV) remains the most important viral
infection in liver transplant recipients. CMV infection, the presence of the virus in
blood, tissue, or body fluids, should be distinguished from CMV disease, which is
CMV infection accompanied by signs and symptoms of CMV
[32]. Ganciclovir and valganciclovir have been incorporated into strategies
designed to prevent CMV disease in patients at risk of CMV reactivation [33-35]. As
a result, the incidence of CMV disease in the post-transplant setting has declined
[36,37].
Other herpesviruses including herpes simplex virus (HSV) types 1 and 2 and
varicella-zoster virus (VZV) can be significant pathogens after transplantation.
Without prophylaxis, approximately 50 percent of patients with HSV will have a
recurrence [38]. Antiviral agents used to prevent CMV infection also have activity
against HSV and VZV but do not have clinical benefit against other herpes viruses
such as Epstein-Barr virus and human herpes virus 6. (See "Treatment of genital
herpes simplex virus infection" and "Vaccination for the prevention of shingles
(herpes zoster)".)
Prophylactic and pre-emptive CMV therapy — Patients at greatest risk of
cytomegalovirus (CMV) infection and disease are those without pre-existing
immunity. As a result, liver transplant recipients who are seronegative for CMV and
receive an organ from a CMV-seropositive donor (D+/R-) have the highest risk for
developing CMV disease, while CMV-seropositive recipients (R+) have a modest
risk, and CMV D-/R- recipients have the lowest risk [39,40].
(See 'Cytomegalovirus' below.)
CMV not only has direct effects on tissues that it infects but also has indirect
effects resulting from its ability to modulate the immune system [41]. CMV
infection is associated with an increased risk of bacteremia and invasive fungal
infections and an almost fourfold increase in the risk of death within one year of
transplantation [42-44]. In addition, CMV infection has been associated with an
accelerated course of hepatitis C virus recurrence and allograft loss after liver
transplantation [45,46]. Thus, strategies to reduce the risk of CMV reactivation can
also reduce the risk of related infections [42].

255
Several studies have described varied approaches to prevention including
prophylaxis and pre-emptive therapy [47-51]. CMV prophylaxis refers to giving an
anti-CMV drug to those at increased risk of CMV reactivation (eg, CMV D+/R-,
D+/R+, D-/R+), while pre-emptive therapy refers to giving an anti-CMV drug only
when there is evidence of CMV replication (eg, by detection of CMV nucleic acids in
serum via polymerase chain reaction or CMV antigenemia). Both strategies have
been shown to reduce the risk of CMV disease in solid organ transplant recipients
[52-54]. In one randomized trial evaluating over 200 CMV seronegative liver
transplant recipients, the incidence of CMV disease over a 12-month period was
reduced by 10 percent (95% CI 0.5 versus 19.6 percent) when comparing pre-
emptive therapy with continuous antiviral prophylaxis [54]. However, there was no
difference in the incidence of allograft rejection, opportunistic infections,
neutropenia, or mortality with preemptive therapy when compared with
continuous prophylaxis. Further study is needed to determine if these results are
reproducible and generalizable, and transplant centers need to consider the
findings in the context of the resources and logistics required for weekly CMV
monitoring to day 100 after transplant.
Valganciclovir, a valyl-ester prodrug of oral ganciclovir, has a bioavailability of
nearly 70 percent (compared with 7 percent for oral ganciclovir) and at doses of
900 mg daily produces serum ganciclovir levels that are similar to those measured
with intravenous (IV) administration of ganciclovir administered at 5 mg/kg daily.
(See "Kidney transplantation in adults: Clinical manifestations, diagnosis, and
management of cytomegalovirus disease in kidney transplant recipients", section
on 'Antiviral therapy'.)
Although valganciclovir has been approved by the US Food and Drug
Administration (FDA) for the prevention of CMV reactivation in renal, lung, and
pancreas transplant recipients, it was not approved for liver transplant recipients
because a clinical trial showed an increased incidence of CMV disease compared
with those who received oral ganciclovir in patients who had undergone liver
transplantation [37,41]. Despite concerns raised by this trial, valganciclovir is used
widely among liver transplant recipients because its bioavailability and ease of
administration make it a more attractive option than the intravenous formulation
of ganciclovir [55]. Oral ganciclovir is no longer manufactured in the United States.
Universal CMV prophylaxis has additional benefits
since ganciclovir and valganciclovir are active against other herpesviruses
including VZV and HSV [8]. The use of CMV prophylaxis also reduces the risk of
other infections and complications by reducing infections that occur more
commonly in patients with CMV reactivation [52]. As an example, in a retrospective
study of 192 liver transplant recipients, there was a significant reduction of

256
bacteremia in patients who had received greater than 14 days of CMV prophylaxis
[42]. In addition, CMV prophylaxis reduced the risk of biopsy-proven rejection in
liver transplant recipients [56]. In a large retrospective multicenter cohort of more
than 7000 hospitalized liver transplant recipients, sepsis diagnosed >100 days after
transplant was associated with prior CMV disease [57].
We recommend either CMV prophylaxis or pre-emptive monitoring in CMV D+/R-
and CMV R+ liver transplant recipients, depending on the capacity of the transplant
center to perform pre-emptive monitoring. These recommendations are in
accordance with the 2019 American Society of Transplantation (AST) guidelines on
the management of cytomegalovirus in solid organ transplantation [58]. The 2018
international consensus guidelines on the management of cytomegalovirus in
solid organ transplantation also state that either universal prophylaxis or
preemptive therapy is acceptable for D+/R- and R+ liver transplant recipients [40].
The choice of drug and duration of prophylaxis vary among transplant centers, but
most centers use antiviral CMV prophylaxis for three to six months after transplant
and during intensification of immunosuppression for rejection [8]. Approaches for
the prevention of CMV disease in other types of solid organ transplantation are
discussed separately. (See "Kidney transplantation in adults: Clinical
manifestations, diagnosis, and management of cytomegalovirus disease in kidney
transplant recipients" and "Prevention of cytomegalovirus infection in lung
transplant recipients".)
It is important to note that patients who complete CMV prophylaxis after
transplantation are at risk for late-onset CMV disease, which may be associated
with graft loss and increased mortality [57,59]. In the retrospective study noted
above involving hospitalized liver transplant recipients, late-onset CMV disease
occurring >100 days after transplant was more common than early-onset CMV
disease (4.3 versus 2 percent) and was associated with death [57]. Late-onset CMV
disease is relatively uncommon in patients who are managed with pre-emptive
CMV therapy [58]. A "hybrid strategy" of prophylaxis followed by pre-emptive
monitoring after prophylaxis is complete has been investigated and is employed at
some centers [40,58]. However, in a study of 71 high-risk (CMV D+/R-) solid organ
transplant recipients, weekly virologic monitoring of patients who completed
prophylaxis was ineffective at predicting CMV disease [60]. Pre-emptive therapy
was successfully used in only 3 of 19 (16 percent) viremic patients, with no
progression to CMV disease. The remaining patients with detectable viremia
cleared low-level viremia spontaneously (3 patients; 16 percent) or had CMV
disease (13 patients; 68 percent), either at the first detection of viremia or before
pre-emptive therapy initiation because of rapid viral load doubling. Adequate data
are lacking for this type of monitoring strategy [40,58].

257
In patients who do not receive CMV prophylaxis, an antiviral with activity against
HSV and VZV (acyclovir, valacyclovir, famciclovir) should be given for at least the
first month after transplantation and during periods of intensified
immunosuppression (treatment of graft rejection) [61].
Fungal infection — Candida is the predominant fungal infection encountered
after liver transplantation, with a shift toward infection due to non-
albicans Candida spp [62]. Both Candida and Aspergillus infections occur in patients
with certain risk factors, which are discussed below.
The 2019 AST candidiasis guidelines recommend Candida prophylaxis for adult
liver transplant recipients with one or more of the following risk factors [63]:
●Prolonged or repeat operation
●Retransplantation
●Renal failure requiring dialysis
●High transfusion requirement (ie, transfusion of ≥40 units of cellular blood
products including platelets, packed red blood cells, and auto transfusion)
●Choledochojejunostomy
●Candida colonization during the perioperative period
It is unclear if there is additive risk for candidiasis when more than one risk factor
is present [63], but targeted prophylaxis for individuals with at least one risk factor
for invasive candidiasis appears effective [64]. Fluconazole 400 mg orally (or IV if
the patient is not taking oral medications) daily is appropriate for many patients,
but an echinocandin (micafungin, caspofungin, anidulafungin) or a lipid
formulation of amphotericin B 3 to 5 mg/kg IV daily should be used if there is a
high rate of non-albicans Candida infections or intolerance to fluconazole. The
duration of Candida prophylaxis should be one to four weeks or for as long as risk
factors persist.
The subgroup of liver transplant recipients who would benefit from anti-
Aspergillus prophylaxis has not been fully delineated, but risk factors
for Aspergillus infection after liver transplantation include fulminant hepatic failure,
reoperation, retransplantation, post-transplant renal or hepatic failure, concurrent
cytomegalovirus infection, hepatitis C infection, and high-dose glucocorticoids [65].
The 2019 AST guidelines on invasive aspergillosis in solid organ transplant
recipients recommend targeted prophylaxis in liver transplant recipients with any
of the following risk factors [66]:
●Retransplantation
●Renal failure requiring dialysis within 7 days of transplantation
●Reoperation involving the thoracic or intra-abdominal cavity
An echinocandin (micafungin, caspofungin, anidulafungin) or voriconazole for 14
to 21 days is recommended in this setting, although a lipid formulation of

258
amphotericin B at a dose of 3 to 5 mg/kg can be considered [66]. We believe that a
decision on whether to give prophylaxis against Aspergillus should be made on a
case-by-case basis and should take into account the epidemiology of invasive
fungal infections in the transplant center caring for the patient. In addition,
because azoles interact with many immunosuppressive medications
(eg, tacrolimus, cyclosporine, sirolimus), dose adjustments and careful monitoring
of drug levels is typically needed when using these agents concurrently. In the
2016 Infectious Diseases Society of America aspergillosis guidelines [65], no
specific antifungal agents are recommended for Aspergillus prophylaxis in non-
lung solid organ transplant recipients.
The role of prophylaxis for fungal infections in liver transplantation has been
studied in small randomized trials, and prophylaxis has demonstrated some
efficacy for fungal-related outcomes, although it has not been associated with
overall survival benefit [67-70]. An observational, single-center study found that
prophylactic use of amphotericin B products (amphotericin B
deoxycholate and liposomal amphotericin B) in high-risk patients significantly
reduced the incidence of fungal infections and reduced overall costs [71].
However, this study has been criticized because a number of Candida "infections"
that were diagnosed in the no-prophylaxis group likely represented colonization
rather than true infection [72]. A meta-analysis of 10 randomized trials of
antifungal prophylaxis in 1106 liver transplant recipients revealed that antifungal
prophylaxis did not reduce total mortality, although fluconazole prophylaxis
decreased invasive fungal infections by 75 percent [73]. In a subsequent open-
label randomized trial that compared micafungin with center-specific standard
care (fluconazole, liposomal amphotericin B, caspofungin) in high-risk liver
transplant recipients, similar rates of clinical success (defined as absence of
proven/probable invasive fungal infection and no need for additional antifungals)
were observed with micafungin and standard care (98.6 versus 99.3 percent) [64].
A better understanding of the optimal selection of patients at increased risk of
fungal infection, antifungal agent, dose, and length of treatment will require
additional studies.
The use of antifungal agents around the time of transplantation is discussed in
greater detail separately. (See "Prophylaxis of infections in solid organ
transplantation", section on 'Antifungal prophylaxis'.)
Tuberculosis — A systematic review of seven studies estimated that, compared
with the general population, liver transplant recipients have an 18-fold increase in
the prevalence of active Myobacterium tuberculosis infection and a fourfold increase
in the case-fatality rate [74]. It is optimal to treat latent tuberculosis prior to
transplantation, and daily rifampin for four months has become a preferred

259
regimen over isoniazid for treatment of latent tuberculosis [75]. It is challenging to
use isoniazid in liver transplant candidates due to the risk of hepatotoxicity,
although this agent has been used with very close monitoring of liver function
tests [76-79]. Some experts favor beginning latent tuberculosis therapy after
transplantation once liver function has normalized, in which case isoniazid would
be preferred due to the significant drug-drug interactions between rifampin and
standard immunosuppressive medications such as calcineurin inhibitors. A trial of
nine months of levofloxacin prophylaxis in transplant candidates was discontinued
due to a high rate of tenosynovitis (18.2 percent) [80]. (See "Tuberculosis in solid
organ transplant candidates and recipients", section on 'Treatment of latent
tuberculosis' and "Treatment of latent tuberculosis infection in HIV-uninfected
nonpregnant adults".)
Targeted prophylaxis — Immune-monitoring tests that assess an individual's risk
for infection may be useful in guiding prophylaxis and/or adjusting
immunosuppression [40,81,82]. For example, the QuantiFERON-CMV assay (which
is not FDA approved in the United States) measures interferon-gamma secretion in
response to CMV-specific peptides and has been shown in liver transplant
recipients to correlate with risk of CMV viremia [82]. There is also a CMV T cell
immunity panel, which measures CMV-specific CD4+ and CD8+ responses via
intracellular cytokine staining and flow cytometry after stimulation of whole blood
with CMV antigens [83]. The ImmuKnow assay measures adenosine triphosphate
production in response to immune cell stimulation; however, its clinical usefulness
for predicting infection is not well established [81].
Educated avoidance — Transplant recipients should be instructed on practices
that can minimize exposure to infectious pathogens that may be encountered in
daily life [84]. Such recommendations should include hand and respiratory
hygiene, ways to prevent food- and waterborne infections, how to decrease
infection risks during travel, and precautions for pet owners or those coming in
contact with animals.
TIME COURSE OF INFECTIONSThe risk of infection and types of infections
encountered differ based upon the timing after transplantation, although with
changes in immunosuppressive agents over time and the institution of prophylaxis
for various infections, the timeline of infection has been altered [8,9].
Nevertheless, most postoperative infections can be grouped into three major
periods: transplant to one month, one month to six months, and after six months
(figure 1). (See "Infection in the solid organ transplant recipient", section on 'Risk of
infection following transplantation'.)
Transplant to one month — Infections occurring immediately following
transplantation are often similar to those seen in immunocompetent hosts
260
following surgery. Bacterial infections predominate; they usually have a
nosocomial source, such as indwelling stents, central vascular access sites, and
external drainage catheters, or are related to foreign bodies, necrotic tissue, or
prolonged endobronchial intubation [29]. In addition, donor-derived infections
may present in the initial month after transplant and should be considered if there
are unexplained syndromes consistent with infection [9].
The two major sites of infection during this time period are the abdomen and the
lungs, both of which may be associated with bacteremia [19,85].
●Abdominal abscesses and infections of the peritoneum can result from
operative complications including biliary leaks or hematomas, with the
predominant pathogens being enteric organisms [3,4].
●Intrahepatic abscesses may manifest as the result of hepatic artery
thrombosis or bile duct ischemia occurring in the perioperative period.
●Cholangitis may occur after biliary tract obstruction.
●Wound infections are common [3,27].
Nosocomial pneumonias are particularly frequent in patients who require
prolonged mechanical ventilation. Pseudomonas
aeruginosa and Enterobacter species may be recovered from bronchoalveolar
lavage specimens. Other common bacterial pathogens associated with pneumonia
include S. aureus, K. pneumoniae, Stenotrophomonas maltophilia, and Citrobacter
freundii [4]. (See "Epidemiology of pulmonary infections in immunocompromised
patients" and "Epidemiology, pathogenesis, microbiology, and diagnosis of
hospital-acquired and ventilator-associated pneumonia in adults".)
Clostridioides difficile colitis can also occur, particularly in the early period following
transplantation and in patients requiring prolonged hospitalization. In fact, liver
transplantation has been identified as a significant risk factor for C.
difficile acquisition in the hospital [86]. (See "Clostridioides difficile infection in
adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides
difficile infection in adults: Clinical manifestations and
diagnosis" and "Clostridioides difficile infection in adults: Treatment and
prevention".)
The incidence of C. difficile colitis was noted to be 8 percent in a series of 467 liver
transplant recipients followed from 5 to 1999 days after transplantation, with more
than half of these cases occurring in the first month post-transplant [87]. Another
study confirmed the early onset of C. difficile colitis after liver transplantation (41
percent occurred within one week after transplant); the majority of patients did not
have fever or leukocytosis [88]. The intense immunosuppression and frequent
exposure to antimicrobial agents that occur shortly after transplantation likely
contribute to the increased risk for C. difficile infection in this period. Gastric acid

261
suppression, hypogammaglobulinemia, intra-abdominal hemorrhage, systemic
infection, and biliary complications may be additional risk factors [87,89,90].
However, it has not been demonstrated that organ transplant recipients with C.
difficile infection are necessarily at higher risk for severe disease or death
[87,88,91].
Infection is often suspected when patients develop a fever. However, as
mentioned above, fever is not always present and, when present, it may also be
due to noninfectious causes, such as malignancy, rejection, transfusion reactions,
medications, or adrenal insufficiency. In the series mentioned above, noninfectious
etiologies accounted for 22 percent of febrile episodes in liver transplant recipients
[7].

If a bacterial infection is suspected in a liver transplant recipient, empiric broad-

spectrum antibiotics should be initiated until the specific bacterium and its
sensitivities can be identified. Antibiotic regimens used for empiric therapy in the
early posttransplantation period should provide coverage for gram-positive cocci,
gram-negative bacilli, and anaerobes; while awaiting microbiologic test results,
coverage should include agents that treat resistant organisms that have already
been documented in the patient. In addition, it is important to consider local
hospital epidemiology and resistance patterns in the selection of empiric
antimicrobial coverage.

Aminoglycosides are usually avoided in solid organ transplant recipients due to

their nephrotoxicity, particularly in combination with calcineurin inhibitors. In
recent years, there has been a shift toward gram-negative organisms, and
particularly multidrug-resistant organisms, causing a higher proportion of
infections [17]. An analysis of 233 patients transplanted between 1989 and 2003
found that gram-negative infections accounted for 52 percent of bacteremias from
1998 to 2003, compared with 25 percent of bacteremias from 1989 to 1993 [85].
The three most common organisms isolated in bacteremic patients were
methicillin-resistant S. aureus (MRSA), K. pneumoniae, and Pseudomonas aeruginosa.
Candida is also an important pathogen during the first month after
transplantation. The bloodstream, surgical wounds, and the urinary tract are
common sites for primary infection, which may then disseminate
[62]. Candida infections may also manifest as esophagitis and superficial infections
of the skin (folliculitis) or oral cavity [4]. (See "Biology of Candida infections".)
Any candidemia should be treated, since fungemia is associated with high
mortality [62]. In addition, as noted above, a greater proportion of
invasive Candida infections among liver transplant recipients in recent years has
been due to non-albicans  Candida spp, a finding that has significant implications
262
for outcome and treatment as these organisms have been associated with higher
mortality and may be less susceptible to fluconazole than C. albicans [62].
(See "Management of candidemia and invasive candidiasis in adults".)
Except for herpes simplex virus (HSV) and unusual situations like donor-
transmitted viral illnesses such as that due to West Nile virus [92], viral infections
are uncommon during the first month following transplantation. Without
prophylaxis, reactivation of HSV occurs in approximately 50 percent of patients
who are seropositive prior to transplant, usually as genital or oral ulcers [93].
One to six months — Opportunistic infections tend to occur one to six months
after transplant due to the cumulative effect of relatively high-dose
immunosuppression.
Cytomegalovirus — Cytomegalovirus (CMV) is one of the most common
pathogens causing disease during this period [41]. In the absence of prophylaxis,
CMV reactivation occurs in approximately 50 to 60 percent of patients; 20 to 30
percent of these will develop CMV-related disease such as pneumonitis, enteritis,
or hepatitis [3]. As noted above, the timeline of infections following transplantation
has been altered due to prophylactic therapies. In many cases, primary CMV
infection is merely delayed rather than prevented and often occurs after
prophylaxis has been stopped [57,94].
Liver transplant recipients who were initially seronegative for CMV but received a
graft from a CMV-positive donor are at greatest risk for CMV disease, similar to the
observations with other organ transplants. (See "Kidney transplantation in adults:
Clinical manifestations, diagnosis, and management of cytomegalovirus disease in
kidney transplant recipients".)
Approximately 40 to 60 percent of healthy adults are seropositive for CMV and,
following liver transplantation, these patients can experience reactivation of latent
virus leading to CMV disease. Antithymocyte globulin and retransplantation are
additional risk factors for CMV reactivation in the post-transplant period [3,33]. The
lowest risk is present in a seronegative recipient who receives a liver from a
seronegative donor [33,38].
CMV disease can present with a variety of symptoms, the most common of which
are fever, leukopenia, thrombocytopenia, malaise, and arthralgias [95]. Less
frequent manifestations include pneumonia, gastroenteritis, hepatitis,
encephalitis, and retinitis.
CMV may also affect the allograft. CMV hepatitis may be difficult to distinguish
from graft rejection, which is also common during this period. A liver biopsy is
helpful in this setting. Findings on liver biopsy suggesting CMV disease include the
presence of viral inclusions associated with a mononuclear cell infiltrate and

263
microabscesses. Although somewhat controversial, CMV has also been implicated
as a risk factor for ductopenic (ie, chronic) rejection [96].
Of the various methods that have been developed to diagnose CMV infection
(serologic testing, histopathology, and shell vial assays), assays that allow for rapid
identification and quantification of CMV have proven to be most valuable in the
post-transplant setting. These include the CMV antigenemia test and the
polymerase chain reaction (PCR) of the blood. (See "Overview of diagnostic tests
for cytomegalovirus infection".)
The CMV antigenemia assay incorporates antibodies directed at the pp65 matrix
protein of the CMV virus. This test can be obtained relatively quickly, and
immunostaining of the antibodies permits quantification of the virus. The CMV PCR
is done by DNA amplification and is the most sensitive assay. The PCR test also
allows for the quantification of viral load. In one study, renal transplant recipients
with symptomatic CMV infection had higher CMV DNA loads than those without
CMV disease; patients with primary CMV infection or reinfection also had higher
peak viral loads than those with endogenous reactivation of CMV [97]. In another
study, the initial CMV viral load and the rate of increase of virus in the blood
correlated with the risk of developing CMV disease in liver, renal, and bone
marrow transplant recipients [98].
Either CMV PCR or the CMV antigenemia assay should be used if tissue pathology
is not available and CMV infection is suspected. They also allow for the monitoring
of viral loads once anti-CMV therapy is instituted. Patients with
"compartmentalized" CMV (eg, enteritis or retinitis) may not have detectable CMV
viremia, and therefore additional diagnostic procedures may be necessary [8,99].
Other viruses — Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), respiratory
syncytial virus (RSV), human herpesvirus 6 (HHV-6), influenza, and adenovirus may
also occur during the period of one to six months following transplant. Of these,
EBV is the most important because of its potential to cause post-transplant
lymphoproliferative disease (PTLD). Respiratory viruses (such as RSV,
parainfluenza, influenza, and adenovirus) were uncommon in one prospective
series of adult liver transplant recipients [100]. However, the study employed
direct immunofluorescence and cell culture to identify viruses, techniques that are
less sensitive than the PCR assays now commonly used to diagnose viral infections
in the respiratory tract.
EBV replication can be detected in approximately 20 to 30 percent of transplant
recipients and in approximately 80 percent of patients receiving antithymocyte
globulin and high doses of immunosuppressants [29]. EBV infection has a wide
range of clinical manifestations including a benign mononucleosis-like syndrome,
but the most serious complication of EBV is PTLD [8]. A major risk factor for PTLD is

264
primary EBV infection after transplant, which occurs when an EBV-seronegative
recipient receives an organ from a seropositive donor. (See "Treatment and
prevention of post-transplant lymphoproliferative disorders".)
HHV-6 is the cause of roseola infantum in childhood and has become appreciated
as a potential viral pathogen in several series of liver transplant recipients
[7,101,102]. The virus, like other herpesviruses, remains latent after initial infection
and can reactivate during times of immunosuppression. Detection of HHV-6 post-
transplant has been associated with fever, rash, cytopenias, interstitial
pneumonitis, and hepatitis. However, it remains unclear whether HHV-6 causes
these syndromes by directly damaging tissues or via immunomodulatory effects
that enhance CMV reactivation, infection by other pathogens, or allograft
dysfunction [102,103]. In one report, two patients with HHV-6 infection, without
concomitant CMV infection, had significant graft dysfunction [101]. When
reactivation occurs, it typically arises approximately 2 to 6 weeks post-
transplantation. However, the degree to which HHV-6 reactivation causes disease
after liver transplantation is not firmly established. As an example, in one trial, 129
liver transplant recipients were randomized to routine monitoring for HHV-6
reactivation by PCR versus usual care. Among monitored patients, 36 percent
developed HHV-6 viremia but none were symptomatic. Thus, we do not routinely
monitor for HHV-6 reactivation [104]. (See "Clinical manifestations, diagnosis, and
treatment of human herpesvirus 6 infection in adults".)
Aspergillus species — As noted above, most fungal infections following liver
transplantation are caused by Candida spp, but Aspergillus infections can also
occur. In one series, Aspergillus accounted for about 15 to 20 percent of all fungal
infections [105]. A shift in the timing of onset of invasive aspergillosis (IA) in liver
transplant recipients has been observed; a study comparing cohorts of patients
with IA between 1990 and 1995 and between 1998 and 2001 found that 55 percent
of infections in the later cohort compared with 23 percent of those in the earlier
cohort occurred at least 90 days after transplantation [106]. One potential
explanation is that CMV prophylaxis may lead to a delay in IA infections, since CMV
reactivation is a risk factor for invasive fungal infections [107].
The most common site of aspergillosis is the lung, although it may disseminate to
other sites including the central nervous system (CNS). It is the most common
cause of CNS infection in liver transplant recipients, accounting for 55 percent of
brain abscesses in one series [108]. Mortality of aspergillosis in early series of liver
transplant recipients approached 100 percent [109], but more recent data suggest
the outcomes may be improving [106,110]. (See "Epidemiology and clinical
manifestations of invasive aspergillosis" and "Treatment and prevention of
invasive aspergillosis".)

265
Other opportunistic pathogens — Infection due
to Nocardia, Listeria, Cryptococcus, and M. tuberculosis can be seen during this time
period. The risk for tuberculosis among solid organ transplant recipients is much
higher than that of the general population, and the post-transplant incidence
worldwide ranges from 0.3 to 15 percent, depending upon the country [111]. The
disease is presumed to be largely related to reactivation of latent infection,
although new infections may also occur in transplant recipients residing in
endemic countries. Tuberculosis can have serious consequences when it occurs in
the post-transplant setting. Disseminated infection is common in transplant
recipients and is associated with a high mortality rate (29 percent in a review of
499 patients) [111].
After six months — Opportunistic infections are uncommon beyond six months
post-transplant in patients who have good graft function since
immunosuppression has generally been tapered to a maintenance regimen. These
patients usually develop the same types of community-acquired infections seen in
the general population, although at an increased rate [8]. Transplant recipients
may be more susceptible to some pathogens such as Legionella  [112] and may
experience more severe manifestations of certain infections such as West Nile
virus infection [113].
On the other hand, patients with impaired graft function or those receiving higher
levels of immunosuppressive medications are at risk for the infections typically
encountered during the period of one to six months after transplant. One of these
is Cryptococcus neoformans, which usually causes meningitis. (See "Clinical
manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in
HIV-seronegative patients".)
Patients on chronic immunosuppression often initially have only subtle findings of
infection due to attenuation of inflammatory responses by immunosuppressants,
but this may be followed by a precipitous decline in status and severe
manifestations of infection. Respiratory infections due to pathogens such
as Streptococcus pneumoniae and Haemophilus influenzae can be life-threatening if
not promptly treated. Patients who have chronic rejection are also more
susceptible to chronic viral infections, possibly from the increased
immunosuppressive regimens.
Chronic or recurrent viral infections including those due to EBV, CMV, hepatitis B
(HBV), hepatitis C (HCV), and potentially human herpesviruses 6 and 7 also can lead
to complications in the late post-transplant period. As an example, CMV infection
can be persistent or occur following prophylaxis discontinuation or following
treatment for allograft rejection, with manifestations as described above. In
addition, the immunomodulatory effects of CMV and other viruses may increase

266
the risk of opportunistic infections such as P. jirovecii (formerly P. carinii)
pneumonia (PCP) and invasive aspergillosis. As mentioned above, CMV infection
has also been associated with ductopenic rejection [96].
Chronic viral infections can also produce damage to the liver allograft (HBV and
HCV) or cause secondary tumors during this period, including post-transplant
lymphoproliferative disease due to EBV and hepatocellular carcinoma due to HBV
or HCV [38]. Hepatitis E virus (HEV) can also cause chronic hepatitis in liver
transplant recipients and should be considered in patients with unexplained liver
enzyme elevations [114]. (See "Epidemiology and risk factors for hepatocellular
carcinoma" and "Hepatitis E virus infection".)
The endemic fungi, including Histoplasma capsulatum (most often occurring in the
Ohio River Valley), Coccidioides immitis (most often occurring in the southwestern
United States), and Blastomyces dermatitidis (most often occurring in the central
and southeastern United States), may also be seen in the late post-transplant
period. In two series, the median time from transplant to symptoms from
histoplasmosis was approximately 11 months [115,116]. Endemic fungal infections
may represent reactivation of disease or new infection. Listeriosis has been noted
in patients on chronic immunosuppression. It is usually associated with meningitis
but can also cause hepatitis and bacteremia. Transmission of Listeria is usually
through contaminated dairy products. The stable low incidence of Listeria can be
partially attributed to some protection from trimethoprim-
sulfamethoxazole prophylaxis for PCP [117]. (See "Clinical manifestations and
diagnosis of Listeria monocytogenes infection" and "Treatment and prevention of
Listeria monocytogenes infection".)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of
coronavirus disease 2019 (COVID-19), can cause severe respiratory infection in
liver transplant recipients as well as liver dysfunction [118]. Liver donors and
recipients are tested for COVID-19 prior to transplantation [119].
An international multicenter registry study compared the outcomes of SARS-CoV-2
infection between 151 liver transplant recipients and 627 patients without a liver
transplant [120]. In a propensity score-matched analysis adjusting for
comorbidities, liver transplantation was not associated with a higher rate of SARS-
CoV-2-related mortality and there were no liver-related deaths in the transplant
group. Liver transplant recipients had a higher rate of mechanical ventilation.
The neutralizing antibody response to the Pfizer-BioNTech BNT162b2 SARS-CoV-2
vaccine was measured 10 to 20 days after the second dose of the vaccine in 80
liver transplant recipients and compared with 25 healthy controls [121]. Only 47.5
percent of liver transplant recipients developed protective levels of SARS-CoV-2
S1/S2 immunoglobulin G antibodies and mean titers were about one-half the

267
levels of the control group. Older age and immunosuppression including receipt of
high-dose prednisone within 12 months, mycophenolate, and triple drug
immunosuppression were associated with failure to achieve a protective antibody
response.
Liver transplant recipients should be counseled about taking precautions against
contracting COVID-19 and liver transplant candidates and recipients should be
vaccinated against SARS-CoV-2. (See "COVID-19: Issues related to solid organ
transplantation" and "Society guideline links: COVID-19 – Solid organ
transplantation".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Infections in solid organ transplant
recipients" and "Society guideline links: COVID-19 – Index of guideline topics".)
SUMMARY AND RECOMMENDATIONS
●Despite advances in liver transplantation, morbidity and mortality due to
infectious complications remains a major problem. In many centers, infection
is the most frequent cause of death following liver transplantation even
though deaths related to infectious diseases in nontransplant settings have
steadily decreased. (See 'Epidemiology' above.)
●Identification of risk factors for infection before transplantation permits the
optimal use of strategies for preventing infections in the post-transplant
setting. However, there is currently no single test that can accurately predict
a patient's risk of infection after transplantation. (See 'Risk factors' above.)
●In addition to screening potential liver donors and recipients for infection,
there are several approaches to the prevention of infections in liver
transplant patients. These include vaccination, the administration of
prophylactic antimicrobials to patients at increased risk for specific infections,
pre-emptive therapy, targeted prophylaxis, and educated avoidance.
(See 'Prevention' above.)
●We recommend that trimethoprim-sulfamethoxazole (TMP-SMX) be
administered after liver transplantation to reduce the risk of Pneumocystis
jirovecii (formerly P. carinii) pneumonia (PCP). It is generally administered for
6 to 12 months. In addition to preventing PCP, TMP-SMX also helps prevent
infections with organisms including Listeria monocytogenes, Nocardia
asteroides, Toxoplasma gondii, and many common urinary, respiratory, and
gastrointestinal bacterial pathogens. However, the optimal dosing for
prevention of infections other than PCP is unclear. (See 'Antibacterial and
Pneumocystis prophylaxis' above.)

268
●Cytomegalovirus (CMV) remains the most important viral infection in liver
transplant recipients. Ganciclovir and valganciclovir have been incorporated
into strategies designed to prevent CMV disease in patients at risk of CMV
reactivation. (See 'Herpesviruses' above.)
●We recommend either universal prophylaxis or pre-emptive monitoring with
CMV polymerase chain reaction or antigenemia in all CMV donor-
seropositive/recipient-seronegative (D+/R-) and R+ solid organ transplant
recipients. The choice of drug and duration of prophylaxis vary among
transplant centers, but most centers use antiviral CMV prophylaxis for three
to six months after transplant and during intensification of
immunosuppression for rejection. (See 'Herpesviruses' above.)
●In patients who do not receive CMV prophylaxis, we recommend that an
antiviral with activity against herpes simplex virus and varicella-zoster virus
(acyclovir, valacyclovir, famciclovir) be given during at least the first month
after transplantation and during periods of intensified immunosuppression
(treatment of graft rejection). Prophylaxis can also be considered for other
"stresses" (eg, concomitant infection or surgery). (See 'Prophylactic and pre-
emptive CMV therapy' above.)
●Candida is the predominant fungal infection encountered after liver
transplantation, with a shift toward infection due to non-
albicans Candida spp. Aspergillus infections in patients with certain risk
factors. While antifungal prophylaxis is commonly used in liver transplant
recipients, the optimal patient population, dose, and duration of prophylaxis
remain to be defined. (See 'Fungal infection' above.)
●The risk of infection and types of infections differ based upon the time after
transplantation, although, with changes in immunosuppressive agents over
time and the institution of prophylaxis for various infections, the timeline of
infection has been altered to some extent. Nevertheless, most postoperative
infections can be grouped into three major periods: transplant to one month,
one month to six months, and after six months. (See 'Time course of
infections' above.)
●Infections occurring immediately following transplantation are similar to
those seen in immunocompetent hosts following surgery, such as wound
infections, pneumonia, and infections resulting from technical issues.
(See 'Transplant to one month' above.)
●Opportunistic infections tend to occur one to six months after transplant
due to the cumulative effect of relatively high-dose immunosuppression.
(See 'One to six months' above.)

269
●Opportunistic infections are uncommon beyond six months post-transplant
in patients who have good graft function since immunosuppression has
generally been tapered. These patients usually develop the same types of
community-acquired infections seen in the general population (although at
an increased rate and, in some cases, with greater severity). An exception is
certain viral infections; CMV infection may occur in the setting of recently
discontinued CMV prophylaxis, and hepatitis B and hepatitis C infections can
cause complications during this period. (See 'After six months' above.)

270
Prophylaxis of infections in solid organ
transplantation
Authors:
Jay A Fishman, MD
Barbara D Alexander, MD, MHS
Section Editor:
Emily A Blumberg, MD
Deputy Editor:
Sheila Bond, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Aug 19, 2020.
INTRODUCTIONSolid organ transplant recipients are considered to be at "high
risk" for developing infection; individual risk is determined by a relationship
between the epidemiologic exposures of the individual and the patient's "net state
of immunosuppression" [1,2]. The successful prevention of infection in the solid
organ transplant recipient requires an understanding of these factors in order to
develop a preventive strategy adapted for each individual. (See "Evaluation for
infection before solid organ transplantation" and "Infection in the solid organ
transplant recipient".)
Epidemiologic exposures may have occurred many years before transplantation or
at any point following the transplant procedure. The range of pathogens to which
patients are exposed has increased as transplantation has become available to a
broader range of individuals with more varied epidemiologic exposures and as
transplant recipients survive longer, remaining on lifelong immunosuppression.
Thus, clinicians must obtain a detailed history of encounters with potential
pathogens, even if the exposure was relatively remote [3,4].

The use of antimicrobial agents for prophylaxis varies by the disease being
targeted for prevention and the nature of the recipient's risks. Strategies include
universal prophylaxis and pre-emptive therapy:

●Universal prophylaxis involves giving an antimicrobial agent to all patients

considered to be at increased risk for infection during a defined period. For
example, in many programs trimethoprim-sulfamethoxazole (TMP-SMX) is
given to all transplant recipients who do not have sulfa allergies for the
prevention of Pneumocystis pneumonia which occurs in up to 10 percent of
organ recipients; TMP/SMX also helps prevent infections with other

271
 pathogens, including Listeria monocytogenes and Toxoplasma gondii [5,6].
(See 'Pneumocystis pneumonia' below.)
●Pre-emptive therapy involves using sensitive assays (eg, antigen detection
or molecular assays) to monitor patients at predefined intervals to detect
infection (eg, cytomegalovirus [CMV] DNA in the blood or DNAemia) before
infection progresses to invasive disease. A positive assay triggers the
initiation of antimicrobial therapy, a reduction in the intensity of
immunosuppression, and/or intensified monitoring. Pre-emptive therapy
incurs extra costs for monitoring and coordination of outpatient care as well
as clinical effects of episodes of viremia but reduces drug exposures and
avoids some of the costs and toxicities of prophylactic antiviral therapy.
●Hybrid approaches that include some period of prophylaxis and
subsequent monitoring are also common for individuals at increased risk for
infection or who are unable to comply with monitoring or intolerant of
prophylaxis. Thus, following T cell-depleting antibody-induction therapies,
many recipients receive some period of antiviral prophylaxis for CMV
followed by a period of monitoring. This approach may be employed for the
CMV seronegative organ recipient who receives an organ from a seropositive
donor (D+/R-) or the seropositive recipient (R+).
PRETRANSPLANT PROPHYLAXISBefore transplantation, it is important to
establish the patient's immunization history, travel history, and prior infectious
exposures to design an appropriate preventive strategy.
Laboratory testing — Laboratory testing for evidence of past infectious
exposures is performed to detect asymptomatic infection in the transplant
candidate. Some tests are recommended for all patients, while others are useful in
selected patients with suggestive epidemiologic risk factors (table 1).
(See "Evaluation for infection before solid organ transplantation".)
Serologic testing is used as an indicator of significant past exposures, and, in some
cases (eg, cytomegalovirus serostatus), the results are used to guide prophylactic
strategies after transplantation. In other cases, the results are used to guide
pretransplant immunizations or therapy. These issues are discussed in detail
separately. (See "Evaluation for infection before solid organ transplantation",
section on 'Laboratory testing' and "Immunizations in solid organ transplant
candidates and recipients".)
During the coronavirus disease 2019 (COVID-19) pandemic, routine screening of
organ donors and recipients for severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) is recommended. In candidates for transplantation, COVID-19
infection and viral shedding must be resolved in advance of organ transplantation.
Each center will determine a protocol for such potential recipients. Assays used in
272
viral diagnosis and serologic tests for the detection of prior infection are discussed
elsewhere. (See "COVID-19: Issues related to solid organ transplantation", section
on 'Pretransplantation screening'.)
Immunizations — Prevention of infection through immunization is of paramount
importance to the increasing population of solid organ transplant recipients [7,8].
Optimally, transplant candidates should be immunized before transplantation
because they are less likely to mount a protective immune response once
immunosuppressed following transplantation. Immunization with live virus
vaccines is generally avoided post-transplant as it may result in unchecked
proliferation of attenuated vaccine strains. The safety and efficacy of these
vaccines in selected transplant recipients is understudy [9]. (See "Immunizations in
solid organ transplant candidates and recipients".)
Vaccine recommendations for solid organ transplant candidates and recipients are
discussed in detail separately. (See "Immunizations in solid organ transplant
candidates and recipients".)
Screening for latent tuberculosis — In one compilation of published cases, the
incidence of tuberculosis (TB) in transplant recipients worldwide ranged from 0.35
to 15 percent, which reflected an 8- to 100-fold increased incidence over the
general population in the represented countries [10,11]. Reactivation of latent
disease following immunosuppression is thought to be the dominant factor in the
pathogenesis of infection in these hosts, although transmission with the allograft,
nosocomial transmission, and community-acquired TB have been documented in
solid organ transplant recipients.
Given the high morbidity associated with TB in the post-transplant setting, all
patients listed for organ transplantation should undergo tuberculin skin testing
(TST) or TB interferon-gamma release assays [4,10-14]. In addition to TST, baseline
chest radiographs should be obtained for anyone with epidemiologic history
suggestive of exposure to TB. For patients with uremia, liver failure, and for those
who have received corticosteroids or other immunosuppressive therapies, TST
must be interpreted according to the more sensitive standards developed for
patients with HIV infection.
T cell-based interferon-gamma release assays, such as the QuantiFERON Gold TB
(QFT-G) assay, are a useful alternative to TST with a high degree of concordance
between TSTs and the QFT-G assay [15,16]. Although some studies have suggested
that QFT-G correlates better with the risk of TB in immunocompromised patients
than the TST, data remain limited [15], and false-negative results have been
reported for both tests [17]. In a study of liver transplant candidates,
indeterminate QFT-G results were more likely in those with more advanced liver
disease [16]. (See "Tuberculosis in solid organ transplant candidates and

273
recipients", section on 'Screening' and "Use of interferon-gamma release assays
for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults".)

Pretransplant antituberculous prophylaxis or therapy should be provided for solid

organ transplant candidates with the following specific indications:

●Tuberculin reactivity of ≥5 mm before transplantation

●History of tuberculin reactivity without adequate prophylaxis
●Recent conversion of TST to positive
●Radiographic evidence of old TB without prior prophylaxis; a chest
computed tomographic scan should be performed in these patients to look
for disseminated disease and to serve as a baseline study
●History of inadequately treated TB
●Close contact with an individual with active pulmonary TB
●Receipt of an allograft from a donor with a history of untreated TB

The risk of infection relates to the intensity and temporal proximity of exposure.
Individuals from endemic regions for TB with positive skin tests or radiologic
evidence of prior disease merit therapy. Individuals with prior Bacille Calmette-
Guérin therapy should be followed expectantly without therapy unless prior
disease or recent exposure is suspected.

If possible, therapy should be provided prior to transplantation. Patients may

receive one of a variety of regimens for the treatment of latent TB infection [18].
The routine use of antituberculous prophylaxis after transplantation remains
controversial but is generally provided to anyone with high risk of active infection.
Treatment after transplantation is frequently compromised by drug toxicities and
interactions with immunosuppressive
therapies. Isoniazid or pyrazinamide hepatotoxicity, for example, may be
intolerable after liver transplantation. Rifampin will significantly reduce the serum
level of calcineurin inhibitors and of glucocorticoids, effects that persist for several
weeks after cessation of therapy. This observation suggests that treatment
regimens that include rifampin should be completed two to four weeks before
transplantation, whenever possible. Regimens that include the fluoroquinolones
and rifabutin are available as alternative treatments for latent TB in organ
transplant recipients; drug interactions may still occur with these alternative
regimens.
The evaluation and management of TB in lung transplant candidates and
recipients are discussed in detail separately. (See "Tuberculosis in solid organ
transplant candidates and recipients".)

274
Microbial colonization — Assessment of microbial colonization patterns can also
be used to guide peritransplant prophylaxis for bacteria (eg, methicillin-
resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, carbapenem-
resistant Enterobacteriaceae) [19]. Available microbiologic data should be
reviewed prior to transplant. Some data may be available from prior microbiologic
evaluations (eg, microbiology from bronchoscopic evaluations) or prior infections
(eg, Clostridioides [formerly Clostridium]  difficile colitis). Individuals with active
chronic infections should have infecting organisms identified and susceptibility
testing performed prior to transplantation to help guide peritransplant
prophylaxis. (See 'Peritransplantation prophylaxis' below.)
Treatment of active or recurrent infections — Because infections are more
difficult to treat following transplantation when patients are immunosuppressed,
any active infection identified prior to transplantation should be treated when
possible. Similarly, patients with recurrent infection or anatomic predispositions to
infection may require additional care prior to transplantation.
As examples, patients with recurrent C. difficile  infection may benefit from fecal
transplantation [20-22]; patients with diverticulitis may benefit from pre-emptive
surgery prior to transplantation. (See "Evaluation for infection before solid organ
transplantation", section on 'Active infections in the transplant candidate'.)
PERITRANSPLANTATION PROPHYLAXISAs with nontransplant surgeries,
solid organ transplant recipients are vulnerable to infectious complications of the
surgical procedure, most commonly bacterial and fungal infections. Accordingly,
perioperative antimicrobial prophylaxis should be used in accord with institutional
protocols. Specific prophylactic regimens are tailored to the organ transplanted
and individualized based on the recipient's unique risks.
Antibacterial prophylaxis — Standard surgical antibiotic prophylaxis is
recommended for all organ transplant procedures. The unique technical features
of transplantation (vascular, ureteric, tracheal, biliary anastomoses) predispose to
leaks (hematoma, bile leak, lymphocele), which are common sites of infection. As
an example, the risk of peritoneal soilage is great in individuals undergoing liver
transplantation with Roux-en-Y biliary drainage. Other risk factors for bacterial
infections after liver transplantation include large-volume blood transfusions,
treatment of graft rejection with glucocorticoids, and cytomegalovirus (CMV)
infection [23,24]. If the patient is colonized with methicillin-resistant S.
aureus  (MRSA) or vancomycin-resistant Enterococcus  (VRE), perioperative
prophylaxis should be expanded to cover the resistant organisms. Active infections
must be eradicated or controlled prior to transplantation.
Pretransplant colonization with multidrug-resistant organisms (MDRO), such as
MDRO gram-negative bacteria, MRSA, and VRE, is associated with higher rates of
275
peritransplant infections and recurrent infections [25,26]. In endemic areas, a 3 to
10 percent incidence of carbapenem-resistant Klebsiella pneumonia infection is
reported in liver, kidney, lung, or heart recipients [25]. Carbapenem-resistant
Enterobacteriaceae (CRE) carry a mortality rate of up to 40 percent once
established in organ recipients [27]. Many bacterial infections in lung transplant
recipients involve the lower respiratory tract (bronchitis and pneumonia) and occur
in the first two weeks post-transplant. Patients with chronic bronchiectasis and
those with cystic fibrosis, who are colonized with resistant gram-negative bacteria
including Pseudomonas and Burkholderia  species, present a dilemma with regard
to increased risk of lung transplantation. Some centers consider colonization
with Burkholderia cenocepacia [28] or pan-resistant Pseudomonas  species a
contraindication to transplantation.
No consensus exists for the management of patients colonized with these gram-
negative organisms during the peritransplant period. Decolonization strategies
have proven effective in preventing infections in some studies [29-32].
Peritransplant prophylaxis for MDRO merits study. Each transplant center typically
develops antibiotic prophylaxis protocols based upon the susceptibility patterns of
the organisms most frequently recovered at that center. Prophylactic regimens are
then individualized on the basis of both recipient colonization patterns and those
isolated from the donor lungs. Serial microbiology data post-transplantation are
used to refine therapy.
Infections of ventricular-assist devices and chest tubes are often due to gram-
positive organisms (staphylococci, enterococci) or yeasts, which should be
identified, and susceptibility testing used to guide therapy prior to and through
transplantation. Drains and vascular access catheters must be removed as quickly
as is feasible. Broad-spectrum antimicrobial prophylaxis (including antifungal
agents) is generally reserved for the perioperative management of intestinal and
pancreas transplants; routine use of broad-spectrum antimicrobial therapy
increases the risk of C. difficile colitis and superinfection with resistant fungal
organisms.
In addition, if the organ donor is known to be colonized or infected with potential
pathogens including MDRO such as CRE, prophylaxis should be expanded in the
recipient to avoid postoperative infections [25,26]. Often, donor data become
available only after implantation, and adjustments should be considered if there is
evidence of donor bloodstream infection or infection involving the transplanted
organ.
Antifungal prophylaxis — The incidence of invasive fungal infections (IFIs)
following solid organ transplantation ranges from 3 to 42 percent and varies with
the organ being transplanted and the epidemiology at individual centers. In

276
general, incidence tends to be highest in lung and liver transplant recipients and
lowest in cardiac and renal transplant recipients [33].
Candida and Aspergillus species are the leading causative agents, with the median
time to onset following transplantation depending on the type of transplant [34-
38]. These infections are associated with high overall mortality rates [39-45]. As an
example, a multicenter retrospective study of 1963 cardiac, heart-lung, and lung
transplant recipients in Italy reported fungal infections in 51 patients (2.6 percent)
occurring at a median of 58 days post-transplantation
[46]. Aspergillus and Candida spp accounted for 64 and 23 percent of the cases,
respectively, with mortality rates of 29 and 33 percent, respectively.
Generally, transplant centers develop institution-specific strategies for the
prevention of fungal infections based on the incidence and nature of fungal
infections observed at their institutions. Data support the use of prophylaxis
for Aspergillus in liver and lung transplant recipients and for Candida species in
liver, bowel, and pancreas transplant recipients [47-53]. (See "Fungal infections
following lung transplantation".)
Targeted antifungal prophylaxis — Given the potential for toxicities of antifungal
agents and the risk for emergence of resistance, strategies for antifungal
prophylaxis should not be universal but instead targeted toward patients with
increased risks for IFI. Targeted antifungal prophylaxis is effective for high-risk
lung, pancreas, and liver transplant recipients, including those with known fungal
colonization and those at increased risk for IFIs due to technical complications
following surgery [47-53]. In liver recipients, risk factors for IFI and criteria for
antifungal prophylaxis vary among studies but generally include:
●Renal replacement therapy and hepatic dysfunction
●Bile leaks [47]
●Living donor transplantation
●Large blood transfusion requirements
●Prolonged intensive care unit (ICU) stays
●CMV infection [37,54]
●Additional surgery post-transplant including laparotomy and
retransplantation
●Known fungal colonization pretransplant
●Broad-spectrum antimicrobial use
●Prolonged use of total parenteral nutrition
There are few data available on the impact of pretransplant treatment on post-
transplant risk for IFI [55,56]. In general, lung transplant recipients receive
antifungal prophylaxis because of their overall high risk of IFIs [33]. Major risk
factors for IFI in lung recipients include cystic fibrosis (in the recipient), mold

277
colonization, acute and/or chronic graft rejection, CMV infection,
hypogammaglobulinemia, primary graft dysfunction, and airway stenting.
(See "Fungal infections following lung transplantation".)
In pancreas transplantation, the risk of contamination (at procurement) or
anastomotic leaks at exocrine drainage sites create the need for some period of
anti-Candida prophylaxis using echinocandin or fluconazole [57,58].
In endemic regions, long-term antifungal prophylaxis may be given to some solid-
organ transplant recipients to prevent the reactivation of pulmonary and
extrapulmonary disease due to Coccidioides immitis and Coccidioides
posadasii, Histoplasma capsulatum, and Cryptococcus neoformans. However, clinical
trials supporting the routine use of antifungal prophylaxis outside of lung
transplantation and in regions or institutions with high intrinsic rates of fungal
infection are lacking.
In programs with a high incidence of infection due to Aspergillus, Histoplasma,
or Candida species, both epidemiologic protection (eg, high-efficiency particulate
air filtered air supply within the hospital) and antifungal prophylaxis (as
appropriate to the common isolates) may be utilized [59-62]. (See 'Choice of
regimen' below and "Infectious complications in liver transplantation" and "Fungal
infections following lung transplantation".)
The approaches to antifungal prophylaxis discussed above are generally similar to
available clinical practice guidelines [33,63,64]. The 2016 Infectious Diseases
Society of America and 2019 American Society of Transplantation guidelines
recommend targeted prophylaxis for individuals at increased risk
for Aspergillus  infection, such as all lung transplant recipients and selected
recipients of other organs who are deemed to be at increased risk based upon
institutional epidemiology and individual risk factors [64,65]. The 2015
International Society for Heart and Lung Transplantation guidelines for lung
transplantation recommend antimold prophylaxis in lung recipients with a history
of mold colonization in donor or recipient (up to 76 percent of patients with cystic
fibrosis and 21 to 40 percent for other patients) or other factors outlined above
[33]. The 2019 American Society of Transplantation guidelines for the management
of candidiasis in solid organ transplant recipients recommend fluconazole (400 mg
daily) OR a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously daily) as
postoperative antifungal prophylaxis for liver, pancreas, and small bowel
transplant recipients at high risk of IFIs [66]. The echinocandins
(anidulafungin, micafungin) also appear to be effective for antifungal prophylaxis
in solid organ transplant recipients [58,67], and, unlike amphotericin B, are not
nephrotoxic. Echinocandins are a reasonable choice for antifungal prophylaxis.

278
Weekly administration of a lipid formulation of intravenous amphotericin B or
reduced-dose lipid amphotericin B may also be an option [68].
Choice of regimen — None of the available antifungal agents are ideal for all
indications for post-transplant prophylaxis. In addition to the organ being
transplanted, the selection of a specific antifungal agent should take into account
the epidemiology of fungal infections at the transplant center, the potential for
drug interactions (both at the initiation and cessation of therapy) with the
immunosuppressive regimen, and the side effect profiles of the drugs, particularly
hepatotoxicity with azoles. Gaps in antifungal coverage should be noted for the
echinocandins and azoles. Echinocandins have no activity against Mucorales molds
or Cryptococcus  species; fluconazole, itraconazole, and voriconazole have no
activity against Mucorales molds. Lower-risk patients at centers without significant
incidence of IFI may use fluconazole or echinocandins perioperatively [48-52].
Specific antifungal prophylaxis recommendations for lung and liver transplant
recipients are discussed in detail separately. (See "Fungal infections following lung
transplantation" and "Infectious complications in liver transplantation", section on
'Fungal infection'.)
Antifungal agents — Agents used for antifungal prophylaxis include the
following:
●Fluconazole – Fluconazole appears to be safe and has not been associated
with hepatotoxicity following liver transplantation; it can be used as
prophylaxis against susceptible Candida  species and reduces invasive
infections in such patients [53,69].
Fluconazole does not have activity against filamentous fungi. In addition,
some Candida species are intrinsically resistant (ie, Candida krusei) while
others have relatively high minimum inhibitory concentrations (ie, Candida
glabrata) to the drug. Drug interactions with calcineurin inhibitors are
variable but will increase these drug levels in most patients. Similarly, serum
calcineurin inhibitor levels will fall when prophylaxis is discontinued; dose
readjustment is essential to prevent graft rejection.
●Itraconazole – Itraconazole capsules have poor oral bioavailability and
should not be relied upon in the critically ill patient after transplantation. The
itraconazole suspension has better oral bioavailability, but trials to date have
failed to demonstrate the efficacy of the oral solution for the prevention of
invasive aspergillosis [70]. Some centers continue to use itraconazole for the
prevention of fungal infection after lung transplantation [33].
Intraconazole levels should be obtained to assure absorption. Efficacy of the
intravenous formulation as prophylaxis awaits testing in clinical trials.

279
Significant drug interactions with calcineurin inhibitors result in levels
increased two- to fourfold over baseline.
●Voriconazole – Voriconazole was approved by the US Food and Drug
Administration (FDA) for the treatment of aspergillosis, scedosporiosis, and
fusariosis in 2002. This azole offers broader filamentous mold activity than
either fluconazole or itraconazole but has no activity against the agents of
mucormycosis. However, no multicenter trial examining the prophylactic use
of voriconazole in the solid organ transplant population has been performed
to date. Drug levels should be obtained to assure absorption. As with the
other azoles, voriconazole is a significant inhibitor of the cytochrome P450
enzymes. Of particular note, coadministration of voriconazole
and sirolimus is contraindicated due to these interactions [71]. Significant
drug interactions with calcineurin inhibitors result in levels three- to fivefold
over baseline in most patients. Adverse effects associated with voriconazole
use include dose-related hepatoxicity, QT prolongation, and increased rates
of skin cancers in immunosuppressed patients [72]. (See "Pharmacology of
azoles", section on 'Selected clinical effects'.)
●Posaconazole – Posaconazole was approved for prophylaxis in high-risk
hematopoietic cell transplantation recipients and is used for antimold
prophylaxis in lung recipients at some centers. Optimal use for therapy and
prophylaxis is solid organ transplantation is not yet well defined. QT
prolongation may be significant. Drug levels should be obtained to assure
absorption.
●Isavuconazole – Isavuconazole is a triazole antifungal that was approved in
2015 for the treatment of invasive aspergillosis and invasive mucormycosis
[73]. This agent is used for antimold prophylaxis in lung recipients at some
centers. Like posaconazole, optimal use in therapy and prophylaxis in solid
organ transplantation have not yet been defined. QT prolongation may be
less likely to occur with this agent. Drug levels should be obtained to assure
absorption.
●Amphotericin B – Lipid formulations of amphotericin B are used at a
number of centers for the prevention of fungal infections but may be
associated with nephrotoxicity, notably in individuals receiving calcineurin
inhibitors or with diminished renal function at baseline. Several studies have
demonstrated the failure of low-dose regimens as prophylaxis for invasive
aspergillosis [74,75], and such therapies should be used with caution.
Studies evaluating aerosolized amphotericin B (including lipid formulations)
for Aspergillus prophylaxis in lung transplant recipients have demonstrated

280
 efficacy for short-term prophylaxis [76-80]. (See "Fungal infections following
lung transplantation".)
●Echinocandins – There are three FDA-approved echinocandins with similar
spectra of antifungal activity (caspofungin, micafungin, and anidulafungin). In
an open-label randomized trial that compared micafungin with center-
specific standard care (fluconazole, liposomal amphotericin B, caspofungin)
in high-risk liver transplant recipients, similar rates of clinical success (defined
as absence of proven/probable IFI and no need for additional antifungals)
were observed with micafungin and standard care (98.6 versus 99.3 percent)
[67]. In another study in which anidulafungin was compared with fluconazole
in high-risk liver transplant recipients, the overall rate of IFIs was similar in
both groups (5 versus 8 percent) [58]. There was a trend toward a reduction
in Aspergillus colonization or infection in the anidulafungin group compared
with the fluconazole group (3 versus 9 percent). These agents are not
inducers or inhibitors of the cytochrome P450 enzymes. In patients with mild
and moderate hepatic impairment, caspofungin area under the curve (AUC) is
increased about 20 and 75 percent, respectively; there is no clinical
experience with this agent in patients with severe hepatic
insufficiency. Cyclosporine moderately increases the AUC of caspofungin and
elevations in hepatic transaminases were noted in healthy subjects when the
drugs were administered concomitantly. In liver transplant recipients,
caspofungin may increase transaminase levels with or without
coadministration of calcineurin inhibitors [81]. These drugs are available in
intravenous formulations only.
The pharmacology of these antifungal agents is discussed in greater detail
separately. (See "Pharmacology of azoles" and "Pharmacology of amphotericin
B" and "Pharmacology of echinocandins".)
POST-TRANSPLANT PROPHYLAXISFollowing transplantation, recipients
are vulnerable to nosocomial infections, especially in the early post-transplant
period. Patients with prolonged hospitalizations or who require mechanical
ventilation are at particularly high risk. The infections commonly encountered in
the first month after transplantation are caused by the nosocomial pathogens that
infect other complex postoperative patients. Ninety-five percent of these infections
are due to bacterial and fungal agents. However, the difficulty in eradication of
such infections is increased in the immunocompromised host.
Pneumocystis pneumonia — Pneumocystis jirovecii (formerly Pneumocystis carinii)
is a ubiquitous organism and common fungus that is a well-known cause of
pulmonary disease in the immunocompromised host [6]. Prior to the use
of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, the incidence of
281
infection was 10 to 15 percent in most programs and was reported to be as high as
70 to 88 percent in the lung transplant population [41,82]. The effectiveness of
prophylaxis against Pneumocystis  pneumonia (PCP) has virtually eliminated the
organism as a cause of significant morbidity in solid organ transplantation [83].
(See "Treatment and prevention of Pneumocystis pneumonia in patients without
HIV".)
The usual dose of TMP-SMX is one single-strength tablet a day or one double-
strength tablet three to seven times a week. The distinct advantages of TMP-SMX
prophylaxis include low cost, low toxicity in most individuals, and efficacy in the
prevention of many common urinary, respiratory, and gastrointestinal infections
as well as most, but not all, infections due to Toxoplasma, Listeria species,
and Isospora belli. TMP-SMX may also provide some degree of protection against
infection with Nocardia spp, although breakthrough infections have been reported.
As an example, in a case-control study of solid organ transplant recipients with
nocardiosis, 24 (69 percent) of 35 case patients were receiving TMP-SMX for PCP
prophylaxis [84]. Successful prevention of infections other than PCP requires daily
dosing.
Prophylaxis should be continued for six months to one year; many renal and liver
programs use less. Extending the duration of PCP prophylaxis beyond one year
may be warranted for lung transplant recipients, for patients receiving continued
higher degrees of immunosuppression, or for those with persistent infections,
such as CMV reactivation or recurrent respiratory infections [85]. Programs with an
increased incidence or clusters of PCP may want to extend routine prophylaxis.
Daily TMP-SMX is preferred for PCP prophylaxis because of its broad antimicrobial
protection (including Toxoplasma, Listeria, and many Nocardia species), ease of
administration, low cost, and tolerability [86]. Thus, another agent (daily
fluoroquinolone) must be added to atovaquone for antibacterial activity when
desired (eg, for urinary tract infection prophylaxis in a renal transplant recipient).
This may be of greatest importance in renal and lung transplant recipients where
the early incidence of postoperative bacterial infections is high.
History of "allergy" to TMP-SMX may be misleading, and allergy testing is often
worthwhile. Sulfonamide hypersensitivity is occasionally reported as a basis for
renal or liver toxicity [87,88]. Patients with true hypersensitivity reactions to sulfa-
containing medications may be given dapsone, inhaled pentamidine,
or atovaquone as alternatives for PCP prophylaxis [83]. Atovaquone dosage should
be 1500 mg by mouth once daily, as solid organ transplant recipients receiving
lower doses have been documented to have breakthrough infection [83,89]. We
generally advise patients to take atovaquone with fatty foods (eg, milk) to increase
its absorption.

282
Toxoplasmosis — Toxoplasmosis is an uncommon but highly morbid infection
after transplantation. Given that cysts of T. gondii are commonly found in muscle
tissues (as well as brain and phagocytic cells), the greatest risk for toxoplasmosis
occurs after cardiac transplantation. The highest-risk group for symptomatic
reactivation disease occurs in seronegative recipients of heart transplants from
seropositive donors; the risk in this group in the absence of prophylaxis is
approximately 50 to 75 percent [3]. Toxoplasma infection presents most often as
myocarditis or cardiomyopathy but also as brain abscess, pneumonitis, empyema,
or disseminated infection. Disease may occur at any time post-transplantation,
with a median time to presentation of two months; up to 10 percent have
reactivation in the first post-transplant month [90]. Although uncommon,
toxoplasmosis has also been transmitted by liver, kidney, and lung
transplantation. Organ-transmitted disease is generally more severe than that due
to reactivation of latent infection in the recipient. The risk of disease reactivation
appears to be increased by use of lymphocyte-depleting induction therapy [91].
Prevention of toxoplasmosis has not been well studied. In general, seronegative
recipients of seropositive cardiac transplants receive at least six weeks to six
months of prophylaxis, although lifetime prophylaxis is preferred at many centers
[92]. One retrospective study suggests that TMP-SMX at a dose of one double-
strength tablet three times per week is sufficient for
both Pneumocystis and Toxoplasma prevention in cardiac transplant recipients [93].
Other centers use lower-dose regimens or add pyrimethamine to TMP-SMX in
high-risk (donor Toxoplasma seropositive and recipient seronegative) combinations
[94,95]. Lower-dose regimens provide less effective protection in such
combinations, notably in seronegative cardiac transplant recipients from endemic
regions (eg, France, the Caribbean islands) [3]. The risk of disease in seropositive
recipients of heart transplants from seropositive donors is uncertain, but lifetime
prophylaxis with at least one single-strength tablet of TMP-SMX daily may be
beneficial.
Most alternative regimens (sulfadiazine, dapsone, atovaquone, clindamycin in
combination with pyrimethamine or primaquine) have not been well studied in
high-risk transplant populations. Atovaquone or dapsone alone have been
effective for prevention of Pneumocystis and Toxoplasma. Breakthrough infections
have been observed with dapsone at doses of 50 mg daily, and 100 mg doses may
be preferred; testing for glucose-6-phosphate dehydrogenase deficiency is
required [3]. The clindamycin-pyrimethamine regimen has also been used
successfully as an alternative for those intolerant of TMP-SMX.
Streptococcus pneumoniae — Immunocompromised individuals have a high
incidence of infection due to Streptococcus pneumoniae with diminished

283
susceptibility to penicillin; many of these isolates are also resistant to TMP-SMX.
Thus, transplant candidates should receive the pneumococcal vaccines prior to the
transplant surgery unless they were vaccinated previously based upon the
underlying illness, such as chronic pulmonary disease. Both the 13-valent
pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal
polysaccharide vaccine (PPSV23) are indicated for such individuals. Specific
recommendations for pneumococcal vaccination in solid organ transplant
candidates and recipients are discussed in greater detail separately.
(See "Immunizations in solid organ transplant candidates and recipients", section
on 'Pneumococcus'.)
All solid organ transplant recipients should receive a second dose of PPSV23 ≥5
years after the first whether initial vaccination occurred before or after the
transplant procedure [7,96]. The need for subsequent revaccination with PPSV23 is
discussed separately. (See "Pneumococcal vaccination in adults", section on
'Revaccination' and "Immunizations in solid organ transplant candidates and
recipients", section on 'Pneumococcus'.)
Viral infections — Viral infections are among the most common complications of
immune suppression after solid organ transplantation. The use of antiviral agents
should be linked to the intensity of immune suppression and to the risk of the
individual for disease.
Influenza — Vaccination remains the primary method of preventing and
controlling influenza and continual changes in viral antigens necessitates annual
revision and administration of the influenza vaccine [97,98]. The
intramuscular inactivated influenza vaccine should be given to solid organ
transplant recipients. The intranasal live-attenuated influenza vaccine
should not be given to solid organ transplant recipients. (See "Seasonal influenza
vaccination in adults" and "Immunizations in solid organ transplant candidates
and recipients", section on 'Influenza'.)
Antiviral prophylaxis is indicated under certain circumstances, such as in solid
organ transplant recipients who have been exposed to an individual with
suspected or confirmed influenza infection. Specific recommendations regarding
antiviral prophylaxis are reviewed elsewhere. (See "Prevention of seasonal
influenza with antiviral drugs in adults".)
Cytomegalovirus — Cytomegalovirus (CMV) is the most common opportunistic
pathogen following solid organ transplantation and is an important cause of
morbidity and mortality. CMV may be acquired from the donated allograft, blood
products transfused from a seropositive donor, or reactivation of endogenous
virus. Once CMV infection is acquired, it persists as a latent infection for the
lifetime of the host.

284
Most CMV disease occurs between one and four months after transplantation in
the absence of antiviral prophylaxis. Increasingly, CMV disease is recognized later,
in the period following cessation of prophylaxis. Patients at highest risk for CMV
disease are those who are seronegative for CMV (immunologically naive) and
receive an allograft from a seropositive donor (D+/R-) and those with latent CMV
infection who require treatment with antilymphocyte antibodies as a part of
induction therapy or for graft rejection. Asymptomatic infection is common in both
the D+/R- combination and seropositive recipients [99].
Universal prophylaxis with valganciclovir or ganciclovir is a common approach to
prevention of CMV reactivation in at-risk patients (eg, CMV-seropositive recipients
and recipients with CMV-seropositive donors, notably after T-lymphocyte
depletion). The duration of antiviral therapy generally ranges from 3 to 12 months
and often depends on the type of organ transplanted, the specific risk status of
patient, and individual institutional practice [100,101]. Letermovir prophylaxis,
while useful in other populations, has not yet proven useful in organ
transplantation [99,102]. Some transplant centers prefer to use a pre-emptive
approach (eg, routine CMV viral load monitoring within initiation of treatment
when reactivation becomes evident) for specific patient populations; this approach
may be as effective as universal prophylaxis [100]. (See "Kidney transplantation in
adults: Clinical manifestations, diagnosis, and management of cytomegalovirus
disease in kidney transplant recipients" and "Prevention of cytomegalovirus
infection in lung transplant recipients" and "Infectious complications in liver
transplantation" and "Infectious complications in liver transplantation", section on
'Cytomegalovirus'.)
The efficacy of targeted anti-CMV prophylaxis in patients at highest risk for CMV
reactivation (ie, CMV-seronegative recipients with CMV-seropositive donors) is well
documented [99,103,104]. A systematic review of 19 randomized controlled trials
of CMV prophylaxis in 1981 solid organ transplant recipients demonstrated the
following [103]:
●Compared with placebo, prophylaxis with acyclovir, ganciclovir,
or valacyclovir significantly reduced the risks of CMV disease (relative risk
0.42, 95% CI 0.34-0.52), CMV infection (relative risk 0.61, CI 0.48-0.77), and all-
cause mortality (relative risk 0.63, CI 0.43-0.92). The reduction in mortality
was primarily due to lower mortality from CMV disease.
●For CMV-related disease and mortality, the relative benefits of ganciclovir,
high-dose acyclovir, and valacyclovir were consistent across recipients of
heart, kidney, and liver transplants and occurred in both CMV-positive and
CMV-negative recipients of seropositive organs. These results were
irrespective of the type of immunosuppression given. No conclusions could

285
 be drawn for CMV-negative recipients of CMV-negative organs (D-/R-).
Patients considered at lower risk for CMV infection (D-/R-) receive antiviral
prophylaxis for herpes simplex virus and varicella-zoster virus with acyclovir,
valacyclovir, or famciclovir.
●In the subset of direct comparison treatment trials, ganciclovir was more
effective than acyclovir; high-dose valganciclovir and intravenous ganciclovir
were as effective as oral ganciclovir.
A subsequent meta-analysis of 17 universal prophylaxis trials and 9 pre-emption
trials demonstrated that both prophylaxis strategies were equally effective in
reducing the incidence of CMV disease [105]. However, only universal prophylaxis
affected patient survival and reduced graft rejection and reduced the incidence of
post-transplant opportunistic infections and post-transplant lymphoproliferative
disorder (PTLD) [104,105].
Oral valganciclovir and intravenous ganciclovir treatment are associated with
similar long-term outcomes in solid organ transplant recipients with CMV
syndrome and tissue-invasive CMV disease based on randomized trials in adult
renal, liver, heart, and lung transplant recipients [106,107]. Thus, these are the
preferred drugs for CMV prophylaxis. High-dose
oral acyclovir and valacyclovir have also been used successfully in some centers.
However, the oral bioavailability of these drugs and efficacy data supporting their
use are limited.
Issues related to CMV prophylaxis in specific transplant settings are discussed
separately. (See "Kidney transplantation in adults: Clinical manifestations,
diagnosis, and management of cytomegalovirus disease in kidney transplant
recipients" and "Prevention of cytomegalovirus infection in lung transplant
recipients" and "Infectious complications in liver transplantation", section on
'Cytomegalovirus'.)
Epstein-Barr virus — Epstein-Barr virus (EBV) is associated with PTLD. PTLD occurs
in approximately 1 percent of transplants and ranges in severity from "benign"
polyclonal lymphocytosis to highly malignant lymphomas. The optimal strategy for
the prevention of PTLD has not been established, although lesser degrees of
immunosuppression appear to lower the risk. Excess rates of PTLD have been
observed with belatacept maintenance immunosuppression, notably in EBV
seronegative recipients and children. Routine monitoring should be performed for
higher risk patients (D+/R- for EBV and all children). (See "Treatment and
prevention of post-transplant lymphoproliferative disorders".)
Herpes simplex and varicella-zoster — Patients who are not receiving CMV
prophylaxis (ie, patients who are seronegative for CMV and received an allograft
from a CMV-seronegative donor) should receive prophylaxis against herpes

286
simplex virus and varicella-zoster virus during the first three to six months after
transplantation and during periods of lymphodepletion for treatment of rejection.
Herpes zoster vaccination is recommended pretransplant, notably in those at
greatest risk for zoster and for post-herpetic neuralgia. A new adjuvanted subunit
vaccine is under study for use in transplant recipients. (See "Vaccination for the
prevention of shingles (herpes zoster)" and "Immunizations in solid organ
transplant candidates and recipients".)
Hepatitis B virus — The hepatitis B virus vaccine is recommended for all
individuals prior to transplantation. Accelerated schedules for vaccination have
been developed for healthy travelers but do not appear to produce an adequate
immune response in transplant candidates [108,109]. (See "Immunizations in solid
organ transplant candidates and recipients", section on 'Hepatitis B'.)
Among infected patients, hepatitis B virus (HBV) can be reactivated after
transplantation. Immunosuppression can amplify HBV DNA, and steroid therapy
may have a direct stimulatory effect on an enhancer region of the viral genome
[110,111]. This issue is particularly important in two settings: liver transplant
recipients, in whom the graft is the primary site of HBV infection, and in renal
transplant recipients, since many chronic dialysis patients are hepatitis B surface
antigen (HBsAg) positive.
●Among liver transplant recipients, preventive therapy is given to reduce the
risk of reinfection of the graft. Ideally, HBV-infected recipients should be on a
nucleotide analogue reverse-transcriptase inhibitor with an undetectable or
unquantifiable viral load prior to transplant. (See "Liver transplantation for
chronic hepatitis B virus infection".)
●If the patient is on tenofovir or entecavir prior to transplantation and has
experienced effective HBV suppression, the pretransplant antiviral agent
should be continued after transplantation. If the recipient
is lamivudine experienced, tenofovir should be used due to the high rate of
entecavir resistance in lamivudine-experienced patients.
●For patients with renal insufficiency, entecavir is generally preferred over
tenofovir. Concerns among renal transplant recipients are deterioration of
the liver and worse renal allograft survival. (See "Kidney transplantation in
adults: Hepatitis B virus infection in kidney transplant recipients".)
Another potential problem related to transplantation is transmission of HBV from
the transplanted organ. This has occurred in HBsAg-positive donors and in livers
from donors with documented anti-hepatitis B core antibody. A review from the
National Institute of Diabetes and Digestive and Kidney Diseases Liver
Transplantation Database identified 23 liver transplants from isolated anti-
hepatitis B core antigen (anti-HBc)-positive donors [112]. Eighteen developed HBV

287
infection compared with only 3 of 651 from anti-HBc-negative donors. (See "Liver
transplantation for chronic hepatitis B virus infection".)
The situation is quite different when kidneys from anti-HBc-positive donors are
used. Transmission of HBV is uncommon in this setting, and these donor organs
are frequently transplanted to expand the pool of available kidneys, hearts, and
lungs [113]. Recipients should be immunized against HBV prior to their use.

Given the availability of vaccination and effective therapies for HBV,

transplantation of organs from HBV-infected donors may be considered on an
individual basis. These donors are generally not viremic but are anti-HB core
antibody positive.

OTHER CONSIDERATIONS
Hepatitis C virus — With the approval of interferon-free, direct-acting antiviral
drug regimens (DAA) for treatment of hepatitis C virus (HCV), transplant physicians
have greater flexibility in the timing of treatment of hepatitis C-infected patients
before or after solid organ transplantation [114-117]. Use of HCV-seropositive
donor organs to expand the donor pool is common; use of HCV-viremic donors is
increasing, including in uninfected recipients. Decisions regarding the timing of
DAA therapy relate to the status and progression of the disease in the individual,
financial considerations, and any potential effect of improved clinical status and
Model for End-Stage Liver Disease (MELD) score on transplant listing [118].
(See "Overview of the management of chronic hepatitis C virus infection".)
HIV — HIV infection of recipients is not a contraindication to solid organ
transplantation and outcomes are excellent [119,120]. Increasingly, HIV-infected
individuals are considered as donors for HIV-infected recipients, generally under
research protocols. The care of HIV-infected and coinfected recipients (eg, HIV and
HCV infected) requires expertise in the management of drug interactions among
the drugs required for maintenance of immunosuppression and antiviral therapy
in the post-transplant period. In general, stable antiretroviral regimens with
omission of protease inhibitors is preferred to limit interactions with the
calcineurin inhibitors [119]. The optimal immunosuppressive regimens for
maintenance therapy are under investigation. (See "Kidney transplantation in
adults: Kidney transplantation in patients with HIV" and "Overview of antiretroviral
agents used to treat HIV".)
Severe acute respiratory syndrome coronavirus 2 — Issue related to
coronavirus disease 2019in solid-organ transplantation are discussed separately.
(See "COVID-19: Issues related to solid organ transplantation".)

288
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Infections in solid organ transplant
recipients".)
SUMMARY AND RECOMMENDATIONS
●Solid organ transplant recipients are at "high risk" for developing infection;
individual risk is determined by a relationship between the epidemiologic
exposures of the individual and the patient's "net state of
immunosuppression." (See 'Introduction' above.)
●Before transplantation, it is important to establish the patient's
immunization history, travel history, and prior infectious exposures to design
an appropriate preventative strategy. Evaluation typically focuses on
laboratory testing for past infectious exposures (table 1), screening for latent
tuberculosis, reviewing microbiologic records, and administering vaccines
when appropriate. (See 'Pretransplant prophylaxis' above.)
●Because infections are more difficult to treat following transplantation when
patients are immunosuppressed, any active infection identified prior to
transplantation should be treated when possible. Surgical or other
procedures may also be warranted for those with recurrent infections or
anatomic predispositions to infections. (See 'Treatment of active or recurrent
infections' above.)
●At the time of transplantation, solid organ transplant recipients are
vulnerable to infectious complications of the surgical procedure, most
commonly bacterial and fungal infections. Peritransplantation prophylaxis is
typically tailored according to the organ transplanted and may need to be
further individualized based on the recipient's unique risks.
(See 'Peritransplantation prophylaxis' above.)
●Following transplantation, prophylactic strategies vary by the specific
disease being prevented and the nature of the recipient's risks. Strategies
include universal, targeted, and pre-emptive prophylaxis
(see 'Introduction' above and 'Post-transplant prophylaxis' above):
•Trimethoprim-sulfamethoxazole (TMP-SMX) is given universally to all
transplant recipients who do not have sulfa allergies for the prevention
of Pneumocystis pneumonia. TMP-SMX also protects against Listeria
monocytogenes, Toxoplasma gondii, and other potential pathogens,
although efficacy against pathogens other than Pneumocystis varies with
dose. (See 'Pneumocystis pneumonia' above.)
•Antifungal and antiviral prophylaxis is individualized (targeted) to
patients considered at the greatest risk. In programs with a high incidence
289
of infection due to Aspergillus, Histoplasma, or Candida species, both
epidemiologic protection (eg, high-efficiency particulate air filtered air
supply within the hospital) and antifungal prophylaxis (as appropriate to
the isolates) may be utilized. (See 'Antifungal prophylaxis' above.)
•Universal prophylaxis with valganciclovir or ganciclovir is typically given
to patients at greatest risk for cytomegalovirus (CMV) reactivation (eg,
seropositive recipients and those with seropositive donors). The duration
of therapy often depends on the type of organ transplanted, the risk
status of the patient, and individual institutional practice. Some transplant
centers prefer to use a pre-emptive approach (eg, routine CMV viral load
monitoring within initiation of treatment when reactivation becomes
evident) for specific patient populations. (See 'Cytomegalovirus' above.)
•Patients who are not receiving CMV prophylaxis should receive
prophylaxis against herpes simplex virus and varicella-zoster virus during
the first three to six months after transplantation and during periods of
intensification of immunosuppression for treatment of rejection.
(See 'Herpes simplex and varicella-zoster' above.)
•Because there is no effective antiviral prophylactic therapy for Epstein-
Barr virus (EBV) reactivation, high-risk patients (eg, all children and EBV-
seronegative recipients who receive organs from seropositive donors)
should be monitored for reactivation at routine intervals and evaluated
for evidence of post-transplant lymphoproliferative disease if reactivation
occurs. (See 'Epstein-Barr virus' above.)
•Vaccination remains the primary method for preventing influenza
(inactivated influenza vaccine), pneumococcal, and hepatitis B infections.
Live vaccines should generally be avoided in immunosuppressed hosts.
For patients with known hepatitis B infections, preventive treatment
options are available. (See 'Hepatitis B virus' above.)

290
Acute liver failure in adults: Etiology, clinical
manifestations, and diagnosis
Authors:
Eric Goldberg, MD
Sanjiv Chopra, MD, MACP
Jonah N Rubin, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 09, 2020.
INTRODUCTIONAcute liver failure is characterized by acute liver injury, hepatic
encephalopathy, and an elevated prothrombin time/international normalized ratio
(INR). It has also been referred to as fulminant hepatic failure, acute hepatic
necrosis, fulminant hepatic necrosis, and fulminant hepatitis. Untreated, the
prognosis is poor, so timely recognition and management of patients with acute
liver failure is crucial [1]. Whenever possible, patients with acute liver failure should
be managed in an intensive care unit at a liver transplantation center.
This topic will review the etiology, clinical manifestations, and diagnosis of acute
liver failure in adults. The prognosis and management of patients with acute liver
failure is discussed separately. (See "Acute liver failure in adults: Management and
prognosis".)
The discussion that follows is consistent with society guidelines from The American
Association for the Study of Liver Diseases (AASLD) and European Association for
the Study of the Liver (EASL) for the management of acute liver failure [2,3].
DEFINITIONSAcute liver failure refers to the development of severe acute liver
injury with encephalopathy and impaired synthetic function (INR of ≥1.5) in a
patient without cirrhosis or preexisting liver disease [2-4]. While the time course
that differentiates acute liver failure from chronic liver failure varies among
reports, a commonly used cutoff is an illness duration of <26 weeks.
Acute liver failure may also be diagnosed in patients with previously undiagnosed
Wilson disease, vertically acquired hepatitis B virus, or autoimmune hepatitis, in
whom underlying cirrhosis may be present, provided the disease has been
recognized for <26 weeks. On the other hand, patients with acute severe alcoholic
hepatitis, even if recognized for <26 weeks, are considered to have acute-on-
chronic liver failure since most have a long history of heavy drinking. The approach
291
to such patients is discussed elsewhere. (See "Management and prognosis of
alcoholic hepatitis".)
Acute liver failure can be subcategorized based upon how long the patient has
been ill and various cutoffs have been used. We classify acute liver failure as
hyperacute (<7 days), acute (7 to 21 days), or subacute (>21 days and <26 weeks).
In patients with hyperacute or acute liver failure, cerebral edema is common,
whereas it is rare in subacute liver failure [5]. On the other hand, renal failure and
portal hypertension are more frequently observed in patients with subacute liver
failure. These subcategories have been associated with prognosis, but the
associations reflect the underlying causes, which are the true determinants of
prognosis. As an example, patients with hyperacute liver failure tend to have a
better prognosis than those with subacute liver failure. The better prognosis is
related to the fact that these patients often have acetaminophen toxicity or
ischemic hepatopathy, diagnoses associated with a better prognosis than many of
the disorders that may result in subacute liver failure, such as Wilson disease [2].
ETIOLOGYAcute liver failure can result from a wide variety of causes, including
(table 1 and table 2) [2,6]:
●Acetaminophen (paracetamol)
●Idiosyncratic drug reactions
●Viral hepatitis
●Alcoholic hepatitis (in which case it is considered to be acute-on-chronic liver
failure) (see 'Definitions' above)
●Autoimmune hepatitis
●Wilson disease
●Ischemic hepatopathy
●Budd-Chiari syndrome
●Veno-occlusive disease
●Acute fatty liver of pregnancy/HELLP (hemolysis, elevated liver enzymes, low
platelets) syndrome
●Malignant infiltration (most often breast cancer, small cell lung cancer,
lymphoma, melanoma, or myeloma)
●Partial hepatectomy
●Toxin exposure, including mushroom poisoning
●Sepsis
●Heat stroke
●Hemophagocytic lymphohistiocytosis (primarily a disorder of children) [7]
Viral and drug-induced hepatitis are the most common causes of acute liver failure
in adults. Drug-induced liver injury is the most common cause of acute liver failure

292
in Australia, Europe, the United Kingdom, and the United States, whereas in Asia
and Africa, viral hepatitis predominates [3,8,9]:
●In the United States, the US Acute Liver Failure Study Group collected data
on 1147 cases of acute liver failure from 23 sites between 1998 and 2007 [1].
The most common causes of acute liver failure
were acetaminophen overdose (46 percent), indeterminate (14 percent),
idiosyncratic drug reactions (12 percent), hepatitis B virus (7 percent), and
hepatitis A virus (3 percent).
●Among 856 patients with acute liver failure in Japan between 1998 and 2006,
51 percent of cases were due to viral hepatitis (42 percent hepatitis B), and 10
percent were due to drugs (including acetaminophen) [10].
Viral hepatitis — Several viruses have been associated with acute liver failure,
including hepatitis A, B, C, D, and E. In addition, acute liver failure can be seen with
herpes simplex virus, varicella zoster virus, Epstein-Barr virus, adenovirus, and
cytomegalovirus [1,8].
Acute liver failure is estimated to develop in 0.35 percent of patients with hepatitis
A and in 0.1 to 0.5 percent of patients with acute hepatitis B [11]. However, the
incidence of acute liver failure from hepatitis B may be underestimated. Precore or
pre-S mutant hepatitis B viruses that are able to produce infection but do not
produce hepatitis B e antigen (precore mutants) or surface antigen (pre-S mutants)
may be difficult to diagnose by routine serology. Thus, liver failure in such patients
may be erroneously attributed to cryptogenic causes [12]. This was illustrated in a
study in which evidence of hepatitis B infection was detected by polymerase chain
reaction (PCR) in 6 of 17 patients (35 percent) who underwent liver transplantation
for what was initially thought to be non-A, non-B hepatitis [13]. (See "Hepatitis A
virus infection in adults: Epidemiology, clinical manifestations, and
diagnosis" and "Hepatitis B virus: Clinical manifestations and natural history",
section on 'Acute hepatitis' and "Clinical significance and molecular characteristics
of common hepatitis B virus variants".)
In addition to acute hepatitis B, acute liver failure may also develop in patients who
are receiving chemotherapy or immunosuppression and have reactivation of
previously inactive hepatitis B, highlighting the importance of screening these
patients for prior hepatitis B exposure. (See "Hepatitis B virus reactivation
associated with immunosuppressive therapy".)
Hepatitis C virus alone does not appear to be a significant cause of acute liver
failure in the absence of coinfection with hepatitis B. In a study of 109 patients with
acute hepatitis C, acute liver failure developed in 11 (10 percent), 9 of whom had
concurrent hepatitis B infection [14]. (See "Clinical manifestations and natural
history of chronic hepatitis C virus infection".)

293
Infection with hepatitis D virus can lead to acute liver failure in patients with
hepatitis B virus infection. A patient may either acquire both viruses at the same
time (coinfection) or acquire hepatitis D in the setting of preexisting chronic
hepatitis B (superinfection). The risk of acute liver failure appears to be higher
among patients who are coinfected than in those with hepatitis D superinfection
or with acute hepatitis B alone. (See "Pathogenesis, epidemiology, natural history,
and clinical manifestations of hepatitis D virus infection".)
Hepatitis E virus is a significant cause of liver failure in countries where it is
endemic, such as Russia, Pakistan, Mexico, and India. Overall, the case-fatality rate
for hepatitis E is 0.5 to 3 percent. However, among women who are pregnant, the
mortality rate increases to 15 to 25 percent. (See "Hepatitis E virus infection",
section on 'Acute hepatitis E' and "Overview of coincident acute hepatobiliary
disease in pregnant women", section on 'Hepatitis E virus'.)
Acute liver failure is a rare complication of HSV infection. Both HSV-1 and HSV-2
have been implicated as etiologic agents. Those at risk include neonates, patients
taking steroids, HIV-infected patients, those with cancer or myelodysplastic
syndromes, and pregnant women. HSV hepatitis has also been reported as an
early cause of death after liver transplantation with concomitant lung and
gastrointestinal involvement. HSV-related hepatitis has also been reported rarely
in immunocompetent hosts. (See "Epidemiology, clinical manifestations, and
diagnosis of herpes simplex virus type 1 infection", section on 'Hepatitis'.)
Immunocompromised patients, such as transplant recipients and HIV-infected
individuals with advanced disease, are at increased risk for developing complicated
herpes zoster infections including acute liver failure. Hepatic involvement may
occasionally develop in the absence of coincident rash. (See "Epidemiology, clinical
manifestations, and diagnosis of herpes zoster", section on 'Special considerations
in immunocompromised hosts'.)
Epstein-Barr virus can affect virtually any organ system and has been associated
with hepatitis and cholestasis. While rare, fatal cases of hepatitis have been
described. (See "Infectious mononucleosis", section on 'Other'.)
The more common gastrointestinal manifestation of adenovirus is an acute
diarrheal illness. However, hepatitis is a well-described complication of adenovirus
infection in immunocompromised hosts, especially with subgroup C type 5.
(See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus
infection", section on 'Gastrointestinal system'.)
Liver function abnormalities are frequently encountered in patients with
symptomatic cytomegalovirus infection. Subclinical transaminitis is the most
common finding in immunocompetent patients, but occasionally, patients present
with more significant laboratory abnormalities or signs of hepatic dysfunction.

294
(See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus
infection in immunocompetent adults", section on 'Hepatic manifestations'.)
Acetaminophen and other hepatotoxins — Acetaminophen is the most common
toxin associated with acute liver failure in the United States and other developed
countries (table 2) [15]. The hepatotoxicity is dose-dependent and rarely occurs at
therapeutic doses (up to four grams per day in a patient without preexisting liver
disease). (See "Acetaminophen (paracetamol) poisoning in adults:
Pathophysiology, presentation, and evaluation" and "Acetaminophen
(paracetamol) poisoning in adults: Treatment".)
Most cases occur after ingestion of large doses in an attempt to commit suicide. In
addition, some patients unknowingly take large amounts of acetaminophen when
multiple acetaminophen-containing medications are taken together or if
acetaminophen-containing medications are not taken as directed (a "therapeutic
misadventure"). Acute liver failure can also result from normally therapeutic doses
in patients who have underlying liver disease (particularly with ongoing alcohol
use, which induces the cytochrome P450 system) or who are taking medications
known to induce the cytochrome P450 system (particularly CYP2E1), such as
anticonvulsants (figure 1). The dosing and safety of acetaminophen for pain
management in patients with cirrhosis are discussed separately.
(See "Management of pain in patients with advanced chronic liver disease or
cirrhosis", section on 'Acetaminophen (paracetamol)'.)
Other toxins associated with acute liver failure include mushroom poisoning (most
often Amanita phalloides) and carbon tetrachloride. (See "Amatoxin-containing
mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis,
and treatment" and "Acute hydrocarbon exposure: Clinical toxicity, evaluation, and
diagnosis", section on 'Pathophysiology'.)
Idiosyncratic drug reactions — Unlike acute liver failure due to acetaminophen,
which is dose-related, acute liver failure due to idiosyncratic drug reactions is dose-
independent. Drug-induced liver injury (DILI) usually occurs within six months of
drug initiation [2]. Drugs commonly implicated in cases of DILI include antibiotics,
nonsteroidal anti-inflammatory drugs, and anticonvulsants (table 2). Herbal
medications and dietary supplements have also been associated with acute liver
failure. (See "Drug-induced liver injury" and "Hepatotoxicity due to herbal
medications and dietary supplements".)
Hypoperfusion — Hypoperfusion of the liver can result in ischemic hepatitis and
acute liver failure. Hypoperfusion may result from systemic hypotension due to
causes such as cardiac dysfunction, sepsis, or drugs. Hypoperfusion of the liver
may also be seen with Budd-Chiari syndrome (hepatic vein thrombosis), veno-
occlusive disease, or the use of vasoconstricting drugs such as cocaine and

295
methamphetamine. (See "Ischemic hepatitis, hepatic infarction, and ischemic
cholangiopathy" and "Budd-Chiari syndrome: Epidemiology, clinical
manifestations, and diagnosis" and "Hepatic sinusoidal obstruction syndrome
(veno-occlusive disease) in adults".)
CLINICAL MANIFESTATIONSBy definition, patients with acute liver failure
have severe acute liver injury (demonstrated by liver test abnormalities) with signs
of hepatic encephalopathy and a prolonged prothrombin time (INR ≥1.5). Other
clinical manifestations may include jaundice, hepatomegaly, and right upper
quadrant tenderness.
Symptoms — Many of the initial symptoms in patients with acute liver failure are
nonspecific [16]. They include:
●Fatigue/malaise
●Lethargy
●Anorexia
●Nausea and/or vomiting
●Right upper quadrant pain
●Pruritus
●Jaundice
●Abdominal distension from ascites

As the liver failure progresses, patients who were initially anicteric may develop
jaundice, and those with subtle mental status changes (eg, lethargy, difficulty
sleeping) may become confused or eventually comatose.

Physical examination findings

Neurologic examination — The presence of hepatic encephalopathy is one of the
defining characteristics of acute liver failure. Findings in patients with hepatic
encephalopathy are variable, ranging from changes in behavior to coma. Hepatic
encephalopathy is graded from I to IV (table 3 and figure 2) (see "Hepatic
encephalopathy in adults: Clinical manifestations and diagnosis"):
●Grade I: Changes in behavior, mild confusion, slurred speech, disordered
sleep, including sleep reversal
●Grade II: Lethargy, moderate confusion
●Grade III: Marked confusion (stupor), incoherent speech, sleeping but wakes
with stimulation
●Grade IV: Coma, unresponsive to pain
Patients with grade I encephalopathy may have mild asterixis, whereas
pronounced asterixis is typically seen in patients with grade II or III
encephalopathy [15]. Asterixis is typically absent in patients with grade IV

296
encephalopathy, who instead may demonstrate decorticate or decerebrate
posturing.
Cerebral edema may develop in patients with acute liver failure leading to
increased intracranial pressure [15]. Cerebral edema is uncommon in patients with
grade I or II encephalopathy, but it is present in 25 to 35 percent of those with
grade III encephalopathy and in approximately 75 percent of those with grade IV
encephalopathy [16,17]. Pupillary changes are one sign of increased intracranial
pressure. The pupils may progress from having a normal response (typical with
grade I encephalopathy), to being hyperresponsive (grade II to III
encephalopathy), to being slowly responsive (grade III to IV encephalopathy). As
the coma worsens, the pupils may become fixed and dilated (a sign typically
associated with brainstem herniation).
Other clinical features of increased intracranial pressure can include systemic
hypertension, bradycardia, respiratory depression (Cushing's triad), seizures, and
abnormal brain stem reflexes (eg, oculocephalic reflex, corneal reflex, jaw reflex,
cough response to tracheobronchial suctioning). (See "Evaluation and
management of elevated intracranial pressure in adults", section on 'Clinical
manifestations'.)
Seizure activity in patients with acute liver failure is common, but may be difficult
to detect if patients are intubated and receiving paralytics. In the control arm of
one trial, 7 of 22 patients (32 percent) had subclinical seizure activity detected by
electroencephalogram [18].
Other physical examination findings — Other findings on physical examination
in patients with acute liver failure may include:
●Jaundice, which is a common finding in patients with acute liver failure but
may be absent early in the course of acetaminophen poisoning or herpes
simplex virus infection [2]
●Vesicular skin lesions suggestive of herpes simplex virus (present in 30 to 50
percent of patients with acute liver failure due to herpes simplex virus) [2,19]
●Fever in patients with herpes simplex virus (reported in 82 percent of
patients in one review) [19]
●Right upper quadrant tenderness and hepatomegaly
●Ascites
●Signs of intravascular volume depletion, such as orthostatic hypotension
Laboratory test abnormalities — Laboratory test abnormalities typically seen in
patients with acute liver failure include:
●Prolonged prothrombin time, resulting in an INR ≥1.5 (this finding is part of
the definition of acute liver failure and thus must be present); hemostasis
when measured by thromboelastography is normal [20,21].

297
 ●Elevated aminotransferase levels (often markedly elevated).
●Elevated bilirubin level.
●Low platelet count (≤150,000/mm3), but this is variable and has been
associated with portal hypertension (see "Hemostatic abnormalities in
patients with liver disease", section on 'Physiologic effects of hepatic
dysfunction')
Decreasing aminotransferase levels may indicate spontaneous recovery but could
also signal worsening of the liver failure with loss of hepatocyte mass. In patients
who are improving, the bilirubin and prothrombin time/INR will decline, whereas
in those with worsening liver failure, the bilirubin and prothrombin time/INR will
continue to rise. Because of the prognostic importance of the prothrombin
time/INR, it is recommended that products such as plasma only be used when
there is a clear indication [2]. In addition, despite an abnormal INR, patients may
not be hypocoagulable. In a study of 20 patients with acute liver failure,
thromboelastography suggested a hypocoagulable state in 20 percent, normal
coagulation in 45 percent, and a hypercoagulable state in 35 percent [22].
(See "Acute liver failure in adults: Management and prognosis", section on
'Bleeding prevention' and "Hemostatic abnormalities in patients with liver
disease", section on 'Bleeding' and "Hemostatic abnormalities in patients with liver
disease", section on 'Invasive procedures'.)
Other laboratory findings that may be seen in patients with acute liver failure
include [15]:
●Hemolytic anemia
●Elevated serum creatinine and blood urea nitrogen
●Elevated amylase and lipase
●Hypoglycemia
●Hypophosphatemia
●Hypomagnesemia
●Hypokalemia
●Acidosis or alkalosis
●Elevated ammonia level
●Elevated lactate dehydrogenase (LDH) level
Acute kidney injury complicates acute liver failure in approximately 30 to 70
percent of patients [17,23-25]. The frequency of renal injury is higher (up to 75
percent) for etiologies of acute liver failure that are known to independently
damage the kidneys, such as acetaminophen intoxication [12,25,26]. In one series
of 1604 patients with acute liver failure, some degree of acute kidney injury
developed in 70 percent of the patients, with 30 percent receiving renal
replacement therapy [25].

298
The pathogenesis of renal injury in patients with acute liver failure is incompletely
understood, but may be related to systemic and intrarenal hemodynamic changes
similar to those seen in hepatorenal syndrome. The clinical picture is similar in that
the urine sodium concentration and fractional excretion are very low in the
absence of diuretic therapy or tubular injury (as might be induced
by acetaminophen), and the urine sediment shows few or no cells or casts in the
absence of marked hyperbilirubinemia. The blood urea nitrogen concentration
may not be a sensitive test to follow renal function in patients with acute liver
failure since hepatic production of urea is decreased. (See "Hepatorenal
syndrome".)
Laboratory findings associated with specific diagnoses — Laboratory test
findings often vary depending upon the specific cause of acute liver failure.
Patterns seen on laboratory testing may suggest a diagnosis, but additional
history, laboratory and imaging testing is required prior to making a diagnosis.
These patterns should not be used to rule in or rule out a given diagnosis.
(See 'Diagnosis' below.)
Some patterns that may be seen include [2]:
●Acetaminophen: Very high aminotransferase levels (>3500 international
units/L), low bilirubin, high INR (see "Acetaminophen (paracetamol) poisoning
in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical
manifestations')
●Ischemic hepatic injury: Very high aminotransferase levels (25 to 250 times
the upper limit of normal), elevated serum LDH levels (see "Ischemic
hepatitis, hepatic infarction, and ischemic cholangiopathy", section on
'Clinical manifestations')
●Hepatitis B virus: Aminotransferase levels of to 1000 to 2000 international
units/L are common, alanine aminotransferase (ALT) level that is higher than
the aspartate aminotransferase (AST) level (see "Hepatitis B virus: Clinical
manifestations and natural history", section on 'Acute hepatitis')
●Wilson disease: Coombs-negative hemolytic anemia, aminotransferase
levels <2000 international units/L, AST to ALT ratio of >2, normal or markedly
subnormal alkaline phosphatase (<40 international units/L), alkaline
phosphatase (international units/L) to total bilirubin (mg/dL) ratio <4, rapidly
progressive renal failure, low uric acid levels (see "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'Acute hepatitis
and acute liver failure')
●Acute fatty liver of pregnancy/HELLP syndrome: Aminotransferase levels
<1000 international units/L, elevated bilirubin, low platelet count (see "HELLP

299
 syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Acute
fatty liver of pregnancy")
●Herpes simplex virus: Markedly elevated transaminases, leukopenia, low
bilirubin
●Reye syndrome, valproate toxicity, or tetracycline toxicity: Minor to
moderate elevations in aminotransferase and bilirubin levels [15]
Imaging and other studies — Abdominal computed tomography (CT) in a patient
with acute liver failure often reveals a liver that appears less dense than skeletal
muscle [27]. Other findings may include heterogenous liver parenchyma,
hepatomegaly, ascites, evidence of malignant infiltration, and evidence of hepatic
vein occlusion. Cirrhosis may be present in patients with acute liver failure due to
Wilson disease, vertically transmitted hepatitis B, or autoimmune hepatitis and
may result in a nodular-appearing liver on imaging. However, a massively necrotic
liver may also appear nodular due to parenchymal collapse [28]. However, because
of the risk of renal failure with the intravenous contrast used for CT, ultrasound
with Doppler imaging is often the preferred initial modality for the evaluation of
acute liver failure. (See 'Imaging studies' below.)
Neuroimaging (head CT or magnetic resonance imaging) in patients with acute
liver failure may reveal evidence of cerebral edema, including a decrease in the
size of the ventricles, flattening of cerebral convolutions, and attenuation of the
signal intensity of brain parenchyma [29]. An electroencephalogram may reveal
seizure activity, even in the absence of clinical signs of seizures [18].
Pulmonary edema and pulmonary infections develop in approximately 30 percent
of patients with acute liver failure and may be seen on chest radiographs [17].
(See "Clinical evaluation and diagnostic testing for community-acquired
pneumonia in adults", section on 'Chest imaging' and "Clinical manifestations and
evaluation of edema in adults", section on 'Isolated pulmonary edema'.)
DIAGNOSIS
Diagnosing acute liver failure — Acute liver failure should be in the differential
diagnosis of patients with the recent onset (<26 weeks) of mental status changes,
jaundice, or right upper quadrant pain. It should also be considered in patients
with nonspecific symptoms such as nausea, vomiting, and malaise. The evaluation
of such patients should include serum liver tests (aspartate aminotransferase
[AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl
transpeptidase [GGT], total and direct bilirubin, albumin). If the liver tests are
abnormal, the patient's prothrombin time/INR should also be measured.
(See 'Symptoms' above.)

Acute liver failure is diagnosed by demonstrating all of the following:

300
 ●Elevated aminotransferases (often with abnormal bilirubin and alkaline
phosphatase levels) (see 'Laboratory test abnormalities' above)
●Hepatic encephalopathy (see 'Neurologic examination' above)
●Prolonged prothrombin time (INR ≥1.5) (see 'Laboratory test
abnormalities' above)
Determining the cause of acute liver failure — A cause for acute liver failure can
be established in approximately 60 to 80 percent of patients [5]. Identifying the
underlying cause of the liver failure is important because it influences the
approach to management and provides prognostic information. A diagnosis is
typically made with a combination of history taking, laboratory tests, and imaging
studies. If the initial evaluation fails to identify an etiology, a liver biopsy may be
required.
Empiric therapy is often started along with the diagnostic workup if a particular
cause is likely based upon history or examination findings. This is especially true in
patients with suspected acetaminophen-associated acute liver failure since the
treatment, N-acetylcysteine (NAC), significantly improves outcomes if started early
and has few side effects. NAC has also been used for patients with non-
acetaminophen induced liver failure. Once the cause of the liver failure is
confirmed, therapy can be adjusted as needed. (See 'Laboratory findings
associated with specific diagnoses' above and "Acute liver failure in adults:
Management and prognosis", section on 'Treatment of the underlying cause'.)
Timing of the evaluation — The evaluation of a patient diagnosed with acute liver
failure should begin immediately to identify the cause of the acute liver failure and
institute empiric therapy as indicated. This is crucial because in some cases, early
diagnosis and treatment may improve the patient's prognosis. In addition, timely
evaluation is required to identify patients who may require urgent evaluation for
liver transplantation. (See "Acute liver failure in adults: Management and
prognosis", section on 'Treatment of the underlying cause'.)
The initial transplantation evaluation should not be delayed for patients who are
being transferred to a liver transplant center. Instead, the diagnostic evaluation
should be initiated at the facility where the patient presents, with results
communicated to the transplant center as they become available. Laboratory tests
and abdominal imaging should be ordered as soon as acute liver failure is
recognized and should not be delayed while the history and physical examination
are being performed. Likewise, because patients with grade I or II encephalopathy
may progress to higher grade encephalopathy and lose their ability to
communicate, a history should be obtained as soon as possible from such
patients. In addition, patient transfer should not be delayed because test results

301
are still pending, because some patients (particularly those with cerebral edema)
will quickly become too unstable.
History — A thorough history may identify potential causes for a patient's acute
liver failure, but in patients with severe encephalopathy, the history may be limited
or unavailable. In some cases, the patient's family may be able to provide useful
information, even if the patient is not able to.

Patients and/or their families should be asked about:

●Timing of symptom onset (eg, malaise, nausea, vomiting, jaundice, mental

status changes).
●History of alcohol use.
●History of prior episodes of jaundice.
●Medication use, including all medications used, the amounts ingested, and
the durations of use. Medication use is not limited to prescription
medications, but also includes over-the-counter medications, herbal and
dietary supplements, and illicit drug use.
●Risk factors for intentional drug overdose, such as a history of depression or
prior suicide attempts.
●Toxin exposure, including occupational toxin exposures or wild mushroom
ingestion.
●Risk factors for acute viral hepatitis, including travel to areas endemic for
hepatitis A or E, intravenous drug use, occupational exposure, sexual
exposure, chronic or inactive hepatitis B infection, history of blood
transfusion, and immunosuppression.
●Risk factors for hepatic ischemia, including hypotension, cardiac failure, a
hypercoagulable disorder, oral contraceptive use, or malignancy.
●Family history of liver disease such as Wilson disease.

In patients who develop acute liver failure while hospitalized, the patient's records
should be reviewed for possible causes including medications the patient has
received (including anesthetics and immunosuppressants) and episodes of
hypotension or cardiac dysfunction.

Physical examination — Physical examination findings may help identify a cause

of a patient's acute liver failure, but in many cases the findings, such as jaundice or
hepatomegaly, are nonspecific. The physical examination may also help identify
complications of acute liver failure, such as cerebral edema and infection.
(See 'Physical examination findings' above.)

302
All patients should have a routine physical examination, including a complete skin
examination. In addition, patients suspected of having Wilson disease should
undergo an ocular slit-lamp examination. (See "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'When to consider
Wilson disease'.)

Physical examination findings that may point to a specific cause of acute liver
failure include:

●Vesicular skin lesions (herpes simplex virus)

●Kayser-Fleisher rings (Wilson disease) (picture 1)
●Features of preeclampsia, such as hypertension (HELLP syndrome) (table
4 and table 5)
Laboratory evaluation — An extensive laboratory evaluation is required in
patients with acute liver failure to determine the cause, assess the severity, and
prepare for possible liver transplantation. Because patients with acute liver failure
may decompensate rapidly, testing should not be delayed. (See 'Timing of the
evaluation' above.)
Laboratory tests that should be obtained at presentation include [2]:
●Prothrombin time/INR
●Serum chemistries (sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, creatinine, glucose, calcium, magnesium, phosphate, lactate
dehydrogenase)
●Liver blood tests (AST, ALT, alkaline phosphatase, GGT, total and direct
bilirubin, albumin)
●Complete blood count with differential
●Acetaminophen level
●Blood and urine toxicology screen
●Viral hepatitis serologies (anti-hepatitis A IgM, hepatitis B surface antigen,
anti-hepatitis B core IgM, anti-hepatitis C virus antibodies, hepatitis C RNA,
herpes simplex virus type 1 and type 2 DNA polymerase chain reaction (PCR),
varicella zoster virus DNA PCR, Epstein-Barr virus (EBV) DNA PCR, anti-viral
capsid antigen IgM, anti-viral capsid antigen IgG, anti-EBV nuclear antigen,
cytomegalovirus (CMV) DNA PCR, anti-CMV virus antibodies; anti-hepatitis E
IgM in women who are pregnant)
●Serum pregnancy test in women of childbearing potential who are not
already known to be pregnant
●Autoimmune markers (antinuclear antibody, antismooth muscle antibody,
anti-liver/kidney microsomal antibody type 1, anti-liver soluble antigen,
immunoglobulin levels)
303
 ●Arterial blood gas
●Arterial lactate
●Arterial ammonia
●Blood type and screen
●Serologic testing for HIV
●Amylase and lipase

Additional tests that are indicated in specific circumstances include:

●Ceruloplasmin level in patients suspected of having Wilson disease.

However, serum ceruloplasmin may be normal or elevated in the setting of
acute liver failure, so if there is significant concern for Wilson disease, a liver
biopsy may be required. However, since most patients with acute liver failure
due to Wilson disease will need emergent liver transplantation, liver biopsies
are usually not necessary if the liver failure is due to Wilson disease, and
transplantation should not be delayed in order to obtain biopsies.
(See "Wilson disease: Clinical manifestations, diagnosis, and natural history",
section on 'Diagnosis'.)
We obtain testing for Wilson disease in patients with acute liver failure who
are under the age of 40 years or who have any of the following:
•A Coombs-negative hemolytic anemia
•Neurologic symptoms prior to the onset of acute liver failure
•Kayser-Fleisher rings
•A ratio of AST to ALT of greater than two
•A normal or subnormal alkaline phosphatase
•A ratio of alkaline phosphatase (international units/L) to total bilirubin
(mg/dL) of less than four
●Anti-hepatitis D virus antibodies in patients with acute or chronic hepatitis B.
(See "Diagnosis of hepatitis D virus infection", section on 'Diagnosis of HDV
infection'.)
●Anti-hepatitis E virus antibodies for patients with travel to endemic areas
such as Russia, Pakistan, Mexico, India, or Africa. (See "Hepatitis E virus
infection", section on 'Diagnosis'.)
●Urinalysis to look for proteinuria in women who are pregnant.
Imaging studies — Imaging with abdominal Doppler ultrasonography should be
obtained to look for evidence of Budd-Chiari syndrome, portal hypertension,
hepatic steatosis, hepatic congestion, and underlying cirrhosis. Ultrasonography is
readily available, inexpensive, and noninvasive. Hepatic imaging may also reveal
evidence of malignant infiltration. As noted above, a massively necrotic liver may
appear nodular and does not necessarily indicate underlying cirrhosis. (See "Budd-
304
Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis", section on
'Diagnosis' and 'Imaging and other studies' above.)
Alternatives to ultrasound included abdominal computed tomography (CT)
scanning, venography, or magnetic resonance imaging and venography
(MRI/MRV). In addition to being able to detect Budd-Chiari syndrome, CT and MRI
are more sensitive than ultrasound for diagnosing hepatic malignancies. However,
prior to obtaining a CT scan, venogram, or MRI/MRV, the risk of renal injury
associated with the contrast agents (contrast-induced nephropathy with iodinated
contrast agents and nephrogenic systemic fibrosis with gadolinium) should be
weighed against the need for the examination, especially since patients with acute
liver failure may also have renal failure. We reserve the use of these imaging
techniques to patients with a negative ultrasound in whom the suspicion for Budd-
Chiari syndrome or malignancy remains high. For patients who are being
considered for liver transplantation, contrast-enhanced, cross-sectional imaging
with either a CT scan or an MRI of the liver is performed to assess for thrombosis
or malignancy. (See "Contrast-associated and contrast-induced acute kidney injury:
Clinical features, diagnosis, and management" and "Patient evaluation before
gadolinium contrast administration for magnetic resonance imaging", section on
'Approach to preventing nephrogenic systemic fibrosis'.)
An echocardiogram to look for cardiac dysfunction should be considered in
patients suspected of having acute hepatic ischemia without a known cause (eg, in
a patient with markedly elevated transaminases without a cause identified from
the patient's history, laboratory examination, or abdominal imaging). Additionally,
patients who are being considered for liver transplantation should undergo
institution-specific protocols for pre-transplant cardiac evaluation. (See "Liver
transplantation in adults: Patient selection and pretransplantation evaluation",
section on 'Cardiopulmonary evaluation'.)
Liver biopsy — If laboratory and imaging tests fail to identify an etiology, a liver
biopsy may aid with the diagnosis. A transjugular approach is preferred in the
setting of acute liver failure because of concerns over bleeding. Portal pressure
measurements can help determine the chronicity of the patient's underlying
disease. Our practice is to obtain a liver biopsy in patients with acute liver failure of
indeterminate etiology who are hemodynamically stable with low bleeding risk.
However, if the patient has progressed to the point of requiring liver
transplantation, histologic evaluation can instead be performed on the explanted
liver. (See "Transjugular liver biopsy".)

Prior to a proceeding with a liver biopsy, we obtain contrast-enhanced, cross-

sectional liver imaging (MRI or computed tomography scan) to exclude

305
malignancy. If malignancy is identified on imaging, a discussion with the
institution's multidisciplinary hepatobiliary tumor board takes place to assess if
liver biopsy is necessary for guiding further management. Liver biopsy may help
with the diagnosis of:

●Malignant infiltration.
●Autoimmune hepatitis. (See "Overview of autoimmune hepatitis", section on
'Histology'.)
●Wilson disease. (See "Wilson disease: Diagnostic tests", section on 'Liver
biopsy'.)
●Hepatitis due to herpes simplex virus.
●Acute fatty liver of pregnancy. However, because liver biopsy is invasive, it
should be approached with caution during pregnancy and reserved for cases
in which a diagnosis of acute fatty liver of pregnancy is in doubt and the
appropriate treatment (delivery) is being delayed. (See "Acute fatty liver of
pregnancy", section on 'Histologic findings'.)
DIFFERENTIAL DIAGNOSISThe primary entity in the differential diagnosis of
acute liver failure is severe acute hepatitis. Patients with severe acute hepatitis
have jaundice and coagulopathy but lack signs of hepatic encephalopathy.
Distinguishing the two is important because patients with severe acute hepatitis
generally have a good prognosis, whereas those who progress to acute liver
failure have a high mortality rate and often require liver transplantation [15].
Differentiating severe acute hepatitis from acute liver failure in a patient with
Wilson disease may be difficult because neurologic Wilson disease may be
confused with hepatic encephalopathy. Features that suggest neurologic Wilson
disease rather than hepatic encephalopathy include the presence of dysarthria,
dystonia, tremors, or parkinsonism. In addition, neurologic symptoms in a patient
with Wilson disease may have been present prior to the onset of the hepatic
manifestations. (See "Wilson disease: Clinical manifestations, diagnosis, and
natural history", section on 'Neurologic manifestations'.)
Patients with severe acute alcoholic hepatitis may present with liver failure that
appears to have developed over the course of weeks to months [30]. However,
patients with alcoholic hepatitis typically have a history of heavy drinking for many
years and are thus thought to have acute-on-chronic liver failure [31].
Differentiating alcoholic hepatitis from acute liver failure is important because the
two entities are managed differently (eg, there is a role for corticosteroids in the
treatment of alcoholic hepatitis, but not in acute liver failure). (See "Management
of alcohol-associated steatosis and alcohol-associated cirrhosis".)

306
Alcoholic hepatitis should be considered in patients with a history of heavy alcohol
use or who have an aspartate aminotransferase to alanine aminotransferase ratio
of approximately 2:1. However, a history of heavy alcohol use does not exclude
other causes of acute liver failure (and in the case of acetaminophen toxicity may
predispose to it), so a patient presenting with acute liver failure in the setting of
heavy alcohol use still requires a thorough evaluation. (See "Alcoholic hepatitis:
Clinical manifestations and diagnosis", section on 'Introduction'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Acute liver failure".)
SUMMARY AND RECOMMENDATIONS
●Acute liver failure refers to the development of severe acute liver injury with
encephalopathy and impaired synthetic function (international normalized
ratio [INR] of ≥1.5) in a patient without cirrhosis or preexisting liver disease.
While the time course that differentiates acute liver failure from chronic liver
failure varies between reports, a commonly used cutoff is an illness duration
of <26 weeks. (See 'Definitions' above.)
●Acute liver failure can result from a wide variety of causes, including (table
1 and table 2) [2,15] (see 'Etiology' above):
•Acetaminophen (paracetamol)
•Idiosyncratic drug reactions
•Viral hepatitis
•Autoimmune hepatitis
•Wilson disease
•Ischemic hepatopathy
•Budd-Chiari syndrome
•Veno-occlusive disease
•Acute fatty liver of pregnancy/HELLP (hemolysis, elevated liver enzymes,
low platelets) syndrome
•Malignant infiltration
•Partial hepatectomy
•Mushroom poisoning
•Sepsis
•Heat stroke
●Viral and drug-induced hepatitis are the most common causes of acute liver
failure in adults. (See 'Etiology' above.)
●Clinical manifestations of acute liver failure in addition to hepatic
encephalopathy, abnormal liver blood tests, and an INR ≥1.5 (all of which are
required for the diagnosis), may include jaundice, hepatomegaly, right upper
307
quadrant tenderness, and thrombocytopenia. (See 'Clinical
manifestations' above.)
●Determining the etiology of acute liver failure requires a combination of
history taking, laboratory tests, and imaging studies. If the initial evaluation
fails to identify an etiology, a liver biopsy may be required.
(See 'Diagnosis' above.)
Because patients may decompensate rapidly, the initial evaluation should be
broad, even in patients with a presumed cause for their acute liver failure. A
broad evaluation is required to identify a cause of the acute liver failure and
to prepare for possible liver transplantation.
●Laboratory tests that should be obtained at presentation include
(see 'Laboratory evaluation' above):
•Prothrombin time/INR.
•Serum chemistries (sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, creatinine, glucose, calcium, magnesium, phosphate, lactate
dehydrogenase).
•Liver blood tests (AST, ALT, alkaline phosphatase, GGT, total and direct
bilirubin, albumin).
•Complete blood count with differential.
•Acetaminophen level.
•Blood and urine toxicology screen.
•Viral hepatitis serologies (anti-hepatitis A IgM, hepatitis B surface
antigen, anti-hepatitis B core IgM, anti-hepatitis C virus antibodies,
hepatitis C RNA, herpes simplex virus type 1 and type 2 DNA polymerase
chain reaction (PCR), varicella zoster virus DNA PCR, Epstein-Barr virus
[EBV] DNA PCR, anti-viral capsid antigen IgM, antiviral capsid antigen IgG,
anti-EBV nuclear antigen, cytomegalovirus [CMV] DNA PCR, anti-CMV virus
antibodies; antihepatitis E IgM in women who are pregnant).
•Serum pregnancy test in women of childbearing potential who are not
already known to be pregnant.
•Autoimmune markers (antinuclear antibody, antismooth muscle
antibody, anti-liver/kidney microsomal antibody type 1, anti-liver soluble
antigen, immunoglobulin levels).
•Arterial blood gas.
•Arterial lactate.
•Arterial ammonia.
•Blood type and screen.
•Serologic testing for HIV.
•Amylase and lipase.
308
●Additional laboratory tests that are indicated in specific circumstances
include:
•Ceruloplasmin level in patients suspected of having Wilson disease.
However, serum ceruloplasmin may be normal or elevated in the setting
of acute liver failure, so if there is significant concern for Wilson disease, a
liver biopsy may be required. (See "Wilson disease: Clinical manifestations,
diagnosis, and natural history", section on 'Diagnosis'.)
•Anti-hepatitis D virus antibodies in patients with acute or chronic
hepatitis B. (See "Diagnosis of hepatitis D virus infection", section on
'Diagnosis of HDV infection'.)
•Anti-hepatitis E virus antibodies for pregnant patients or patients with
travel to endemic areas such as Russia, Pakistan, Mexico, Africa, or India.
(See "Hepatitis E virus infection", section on 'Diagnosis'.)
•Urinalysis to look for proteinuria in women who are pregnant.
●Imaging with abdominal Doppler ultrasonography, computed tomography
(CT) scanning, venography, or magnetic resonance imaging and venography
(MRI/MRV) should be obtained to look for evidence of Budd-Chiari syndrome.
Hepatic imaging may also reveal evidence of malignant infiltration. However,
CT scanning, venography, and MRI/MRV should be used with caution because
the contrast agents used are associated with renal injury. We reserve the use
of CT, venography, and MRI/MRV for patients with a negative ultrasound in
whom the suspicion for Budd-Chiari syndrome or malignancy remains high.
In addition, for patients who are being considered for liver transplantation,
contrast-enhanced, cross-sectional imaging with either a CT scan or an MRI of
the liver is performed to assess for thrombosis and malignancy.
(See 'Imaging studies' above.)

309
Liver transplantation for alcoholic liver disease
Author:
Scott L Friedman, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 19, 2020.
INTRODUCTIONHistorically, physicians were reluctant to offer liver
transplantation to patients with alcoholic liver disease. However, in appropriately
selected patients, it is clear that transplantation offers an excellent survival
advantage similar to that for other disease indications. Prior reluctance stemmed
from the perception that the disease was self-inflicted and from concern regarding
the risk of alcohol-related damage to sites outside the liver [1,2]. There was also
concern that relapse and medication noncompliance would lead to graft failure.
Alcoholic cirrhosis was responsible for 21 percent of all orthotopic liver transplants
in 2015 in the United States, according to the Organ Procurement and
Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR)
report [3]. Liver transplantation appears to be cost-effective for alcoholic liver
disease, albeit possibly less so than for transplantation for some indications such
as primary biliary cholangitis and primary sclerosing cholangitis [1,4,5].

This topic will review liver transplantation for alcoholic liver disease. The diagnosis
and treatment of alcohol use disorder and the pathogenesis, diagnosis, and
treatment of alcoholic liver disease are discussed separately.

●(See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis,

clinical manifestations, course, assessment, and diagnosis".)
●(See "Approach to treating alcohol use disorder".)
●(See "Pathogenesis of alcohol-associated liver disease".)
●(See "Clinical manifestations and diagnosis of alcohol-associated fatty liver
disease and cirrhosis".)
●(See "Management of alcohol-associated steatosis and alcohol-associated
cirrhosis".)
The allocation of donor livers by the Model for End-stage Liver disease (MELD) is
also discussed separately. (See "Model for End-stage Liver Disease (MELD)".)

310
DEFINING ALCOHOL USE AFTER TRANSPLANTATIONWhile abstinence
is the expectation both before and after liver transplantation, there is a range of
patterns of alcohol use. Quantification of alcohol consumption after liver
transplantation is not standardized, although several terms are used to describe
alcohol use:
●Abstinence – No alcohol use.
●Slips – Occasional consumption of limited amounts of alcohol with
immediate measures to re-establish abstinence [6].
●Harmful and excessive drinking – Referred to as relapses and defined as
more than 40 g alcohol per day; four or more drinks in one day; or drinking
for at least four consecutive days [6,7].
The Diagnostic and Statistical Manual of Mental Disorders Version V (DSM-5)
criteria for the diagnosis of alcohol use disorder are discussed separately.
(See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical
manifestations, course, assessment, and diagnosis", section on 'Diagnosis'.)
PRE-TRANSPLANT MANAGEMENT
Timing of referral — Early referral for transplantation is an important
determinant of success, and we recommend that patients with alcoholic liver
disease who are transplant candidates are referred for transplantation evaluation.
With progressively longer waiting times until a suitable donor liver is available,
delayed referral may prevent the patient from surviving the evaluation and waiting
period [8,9].
The presence of cirrhosis alone is not sufficient to warrant transplantation.
Transplantation is generally considered when a patient has suffered either a
complication of portal hypertension or a manifestation of compromised hepatic
function. The indications for liver transplantation are discussed separately.
(See "Liver transplantation in adults: Patient selection and pretransplantation
evaluation", section on 'Indications'.)
Early referral for liver transplantation is not always accomplished, in part because
of active drinking or a perception among referring clinicians that liver
transplantation is not a viable option. However, it is unclear how often patients
who are transplant candidates are not being referred for evaluation [1]. In a study
of nearly 200 potential liver transplantation candidates according to the American
Association for the study of Liver Diseases (AASLD) guidelines, patients with
alcoholic liver disease were less likely to receive counseling regarding liver
transplantation compared with patients with cirrhosis of another etiology (OR 0.10,
95% CI 0.02-0.57) [10]. In this cohort, 41 patients with cirrhosis (21 percent) were
referred for transplant evaluation and the most common reason for not referring
patients was active alcohol use.
311
Overall risk of alcohol relapse — In appropriately selected patients, the alcohol
relapse rate after transplantation generally ranges from 10 to 30 percent [11-17].
In two studies of over 600 patients, 5 percent of patients resumed excessive
drinking [18,19]. However, there are conflicting data on whether such patients can
be identified with accuracy in advance.
Two groups have proposed multivariate models to better predict alcohol relapse
after transplant, incorporating readily definable behaviors and psychosocial
factors [7,20]. Further studies are needed to establish their validity.
Risk factors for alcohol relapse — There are several patient-related factors that
affect the likelihood that alcohol use will be resumed following transplantation:
●Social factors – Lack of social support is a risk factor for alcohol relapse
[12,13,20,21].
●Psychiatric disorder – Current or previous psychiatric illness is a risk factor
for alcohol relapse after liver transplantation; assessment for comorbid
psychiatric condition may help identify at-risk patients [7,20-22].
In a study of 387 patients who underwent liver transplantation for alcoholic
liver disease, patients with psychiatric illness (ie, anxiety or depressive
disorder) were more likely to resume harmful alcohol use (ie, >40 g per day)
after transplantation (OR 7.8, 95% CI 3.1-20) [7].
●Family history of alcohol dependence – Family history of alcohol
dependence correlated with risk of alcohol relapse in one meta-analysis, but
the strength of the correlation was modest [13].
●Noncompliance – In a study of 195 patients with alcoholic liver disease who
underwent liver transplantation, noncompliance with office visits after
transplantation was a nonsignificant risk factor for alcohol relapse (OR 4.36,
95% 0.92-15.43) [23,24].
●Hepatitis C infection – Liver disease due to both alcohol and hepatitis C is
not uncommon, but the presence of hepatitis C does not result in greater risk
of alcohol relapse following transplantation. In a study of 167 post-transplant
patients with a history of either alcoholic liver disease alone or hepatitis C
and alcoholic liver disease, there was no significant difference in alcohol
relapse rates (18 versus 8 percent) [25].
●Younger age – Younger age is not consistently associated with a higher rate
of alcohol relapse [11,12,17,26].
●Duration of abstinence pre-transplant – Longer periods of abstinence pre-
transplant appear to be associated with lower risks of alcohol relapse.
(See 'Pre-transplant abstinence and monitoring' below.)
A score incorporating several factors (age at liver transplantation, nonalcohol-
related criminal history, pre-transplantation alcohol abstinence, and number of

312
drinks per day) has been developed and has shown promise for identifying
patients at increased risk for alcohol relapse [27].
Pre-transplant abstinence and monitoring
Six-month rule — Six months of abstinence is a requirement prior to placement
on the transplantation waiting list at many programs for two reasons [28]:
●To identify patients who are at risk for relapse
●To allow time for liver recovery from ongoing alcohol-related injury
The six-month rule affects the eligibility of patients with alcoholic liver disease for
transplantation. Some transplantation programs and society guidelines suggest
that no absolute interval of abstinence is required because some patients who are
otherwise suitable candidates will not survive a period of six months. (See 'Patients
with severe alcoholic hepatitis' below.)
Based on the available studies, it is unclear whether the six-month abstinence
requirement significantly reduces the rate of relapse after transplantation or
improves outcomes [7,11,20,29,30].  While the six-month abstinence requirement
is somewhat arbitrary, some [7,29,31] but not all [11,20,30] studies have found that
longer duration of abstinence before transplant is associated with lower alcohol
relapse rates after transplant. For example, in one study, for every month of pre-
transplantation abstinence, there was a 5 percent decrease in the adjusted relapse
rate [31].
In addition, patient-reported alcohol use may not be accurate. In a study of 40
patients with alcoholic liver disease who were referred for liver transplant
evaluation, urine toxicological screening was positive for any substance in 15
patients (38 percent) and for alcohol in eight patients (20 percent) [32]. However,
only 3 percent of the patients admitted to using alcohol.
Alcohol treatment program — In addition to adhering to the six-month rule,
some transplant centers require that patients enroll in a substance abuse
treatment program such as Alcoholics Anonymous. In a study of 118 patients who
underwent liver transplantation, participation in a substance abuse treatment
program both before and after liver transplantation lowered the post-transplant
alcohol relapse rate compared with those who only participated in a treatment
program before transplant or those who received no treatment (16 percent versus
45 and 41 percent, respectively) [33].
Monitoring for alcohol use — We monitor patients with alcoholic liver disease for
alcohol use both prior to and following liver transplantation by clinical interview
and by testing of urine ethyl glucuronide (uEtG) during outpatient visits and
randomly, if needed. Urine ethyl glucuronide can be detected for up to 80 hours
after complete ethanol elimination from the body and after consumption of less
than 5 g of ethanol, and has low false positive rates [34,35]. In one study of 121

313
patients with alcoholic liver disease who were either candidates for or recipients of
liver transplantation, alcohol consumption was detected by clinical interview (using
a validated screening tool) or by patient response to abnormal tests (ie, urine or
blood markers of alcohol use) in 31 percent of patients [36]. Urine ethyl
glucuronide was the strongest marker of alcohol consumption (OR 415, 95% CI 51
to >1000).
Additional methods for monitoring patients for alcohol use include assessment of
blood or breathalyzer alcohol levels [37-39]. The available data suggest that the
serum marker phosphatidylethanol is more sensitive for detecting chronic alcohol
use compared with other blood tests (eg, carbohydrate deficient transferrin)
[40,41].
Some centers randomly check blood alcohol levels in patients on the transplant
waiting list. In a study of 134 such patients in whom alcohol use was defined as a
positive blood alcohol level, self-reported alcohol use or refusal to check a blood
alcohol level within 12 hours of the request, alcohol use was less likely in patients
with a higher number of random blood alcohol level checks (RR 0.63, 95% CI 0.52-
0.76) and with a longer duration of prelisting abstinence (RR 0.88, 95% 0.83-0.94)
[42]. This study did not address whether this practice reduced post-transplant
alcohol relapse.
Carbohydrate deficient transferrin is a laboratory test that is elevated in the setting
of sustained heavy alcohol use (ie, six standard drinks for two weeks or more), but
it can also be elevated in patients with advanced liver disease who are abstinent.
Thus, carbohydrate deficient transferrin levels should be interpreted with caution.
(See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical
manifestations, course, assessment, and diagnosis", section on 'Laboratory
evaluation'.)
Smoking cessation — Smoking remains an independent and significant risk factor
for post-transplant morbidity and mortality [43,44]. Long-term follow-up of
patients who have undergone liver transplantation for alcoholic liver disease has
shown an increased rate of lung, liver, and oropharyngeal cancer compared to
patients transplanted for other indications [45,46]. It is likely that this association is
due to the relatively high prevalence of smoking in this population combined with
the impact of immunosuppression on tumor surveillance. Moreover, long-term
morbidity and mortality are also linked to continued smoking, which accelerates
cardiovascular and cancer risk [1].
Increasing emphasis or insistence on enrollment of patients into smoking
cessation programs has been advocated to reduce morbidity post-transplantation
[47,48]. (See "Overview of smoking cessation management in adults".)

314
Some authorities have advocated removing patients from the transplant waiting
list who continue to smoke despite these interventions. Roughly 20 percent of
transplant centers report that they will refuse to list patients due to smoking [49].
One report found that up to 40 percent of patients who had undergone
transplantation for alcoholic liver disease resumed smoking early in the post-
transplant course, underscoring the need for continued counseling and
monitoring after transplantation [50].
Other goals of pre-transplant evaluation — The goal of the pre-transplantation
evaluation is to assess the patient's ability to tolerate the stress of surgery,
immunosuppression, and the demands of post-transplantation care. The details of
the extensive cardiopulmonary, psychosocial and screening evaluation are
discussed separately. (See "Liver transplantation in adults: Patient selection and
pretransplantation evaluation", section on 'Pretransplantation evaluation'.)
PATIENTS WITH SEVERE ALCOHOLIC HEPATITISLiver transplantation
may be the only treatment option for patients with severe alcoholic hepatitis who
do not respond to glucocorticoids, and transplantation has been life-saving for
some patients [51-53]. The number of patients undergoing liver transplantation for
acute alcoholic hepatitis has been steadily increasing in the United States, with
marked geographic variation because a limited number of centers perform
transplantation for this indication [51,54,55]. Patients who are transplanted for
acute alcoholic hepatitis are generally younger, have higher MELD Scores, and are
more frequently on renal dialysis compared with patients transplanted for other
indications [55]. (See "Management and prognosis of alcoholic hepatitis", section
on 'Liver transplantation'.)
It has been suggested that the six-month period of abstinence be reconsidered in
patients with severe alcoholic hepatitis and that methods to identify transplant
candidates who are at low risk of relapse are needed [56]. While recurrent harmful
alcohol use is associated with post-transplant morbidity, the risk for alcohol
relapse is not well defined and may be similar to patients who complete a six-
month period of abstinence prior to transplantation [57].
In general, patients who have alcoholic hepatitis are rarely transplanted because
the diagnosis of alcoholic hepatitis implies recent harmful alcohol use, and
because some patients will improve without transplantation. In principle, the
chronic inflammatory state associated with alcoholic hepatitis has the potential to
increase perioperative complications, although most studies found that long-term
morbidity is related primarily to recurrent alcohol abuse rather than acute
complications of transplantation [5,7,12,58]. (See "Alcoholic hepatitis: Clinical
manifestations and diagnosis".)

315
The outcome of liver transplantation in patients with acute alcoholic hepatitis is
discussed separately. (See "Management and prognosis of alcoholic hepatitis",
section on 'Liver transplantation'.)
POST-TRANSPLANT OUTCOMES
Management — The general management of patients following liver
transplantation including the approach to immunosuppression and its
complications, preventative medicine, and diagnosis and treatment of acute
cellular rejection are discussed separately:
●(See "Liver transplantation in adults: Long-term management of transplant
recipients".)
●(See "Liver transplantation in adults: Overview of immunosuppression".)
●(See "Liver transplantation in adults: Clinical manifestations and diagnosis of
acute T-cell mediated (cellular) rejection of the liver allograft".)
●(See "Liver transplantation in adults: Treatment of acute T cell-mediated
(cellular) rejection of the liver allograft".)
Mortality and graft survival — Short term patient and graft survival rates
following liver transplantation for alcoholic liver disease are similar to rates
following transplantation for nonalcohol-related diagnoses; however, the 10-year
patient and graft survival rates are lower for patients with alcoholic liver disease
[59-62]. In a cohort study of the United Network of Organ Sharing database
including 9438 patients with alcohol-associated liver disease who were
transplanted, the following outcomes were reported [62]:
●Patient survival – Patient survival rates at one year and at five years were
similar for patients with alcoholic liver disease compared with patients with
nonalcohol-associated disease (one year: 91 versus 90 percent; five years: 79
versus 80 percent). However, patient survival rates at 10 years were lower for
patients with alcoholic liver disease compared with those with a nonalcohol-
related diagnosis (63 versus 68 percent).
●Graft survival – Graft survival rates at one and at five years were similar for
patients with alcoholic liver disease compared with patients with nonalcohol-
associated disease (one year: 91 versus 89 percent; five years: 79 versus 80
percent). However, graft survival rates at 10 years were lower for patients
with alcoholic liver disease compared with those with a nonalcohol-related
diagnosis (60 versus 63 percent).
The increase in mortality at 10 years after liver transplant in patients with alcoholic
liver disease suggests the need for long-term follow-up studies to identify risk
factors for mortality, so that patient selection for transplantation and post-
transplant care can be optimized for long-term survival [62]. (See "Liver
transplantation in adults: Long-term management of transplant recipients".)
316
Recurrent harmful alcohol use — Despite comprehensive pre-transplant
evaluation and adherence to the six-month rule by most centers, some patients
will resume alcohol use following liver transplantation. (See 'Overall risk of alcohol
relapse' above.)
A model has been developed to identify individuals who drink heavily and are at
high risk for liver disease progression that incorporates patient sex, baseline
fibrosis levels, onset of heavy drinking, amount of alcohol intake, and body mass
index [63].
Complications — Graft rejection, graft loss and recurrent alcoholic liver disease
are potential complications of alcohol relapse after liver transplantation [22].
Excessive drinking after liver transplantation may be associated with rapidly
progressive liver injury, allograft failure, and fatal alcoholic hepatitis [19,64-66]. In
a study of 300 patients with alcoholic liver disease who underwent transplantation,
patients who relapsed were more likely to develop steatohepatitis (OR 6.2, 95% CI
1.7-22.7) and advanced (stage three or higher) fibrosis (OR 23.2, 95% CI 3.1-177.3)
compared with those who maintained abstinence [19]. In another study, 128 of
712 patients who underwent liver transplantation for alcoholic cirrhosis had a
severe alcoholic relapse [16]. Among the patients with a severe relapse, 41 (32
percent) developed recurrent alcoholic cirrhosis after a median of 5.1 years.
Survival at 10 and 15 years was lower among patients with severe alcoholic relapse
compared with those who did not have a severe relapse (50 versus 70 percent at
10 years and 21 versus 41 percent at 15 years). A separate report also suggested
impaired survival after 10 years in patients who resumed drinking, possibly
because of an increased risk of death from cancer and cardiovascular events [67].
However, in one study, alcohol use in the immediate pre-transplant period was not
associated with lower long-term survival [68].

The continued use of alcohol by patients after liver transplantation may also
increase the likelihood that they will be lost to follow-up, leading to an
underestimate of the impact of alcohol use on outcomes.

Monitoring — We monitor patients with a history of alcoholic liver disease for

recurrent alcohol use following liver transplantation by clinical interview and by
testing of urine ethyl glucuronide (uEtG) at each follow-up outpatient visit and
randomly, if needed. (See 'Monitoring for alcohol use' above.)
Prevention and treatment — Patients with either alcoholic liver disease who did
not complete an alcohol treatment program prior to liver transplantation or with
acute severe alcoholic hepatitis are required to sign a patient contract prior to
transplantation. They also must complete an alcohol treatment program when

317
medically appropriate following transplantation (usually three to six months
postoperatively).
Few studies have addressed the utility of post-liver transplantation alcohol
treatment programs in preventing relapse. In a study of 103 patients with alcoholic
liver disease who underwent transplantation, participation in an alcohol treatment
program resulted in lower rates of any alcohol use during a four-year follow-up
period (22 versus 48 percent) [17]. In the United Kingdom, all patients who
undergo transplantation for alcoholic liver disease are followed by an addiction
treatment psychiatrist [69,70]. Such a program is recommended but not
mandatory in the United States.
Psychosocial and pharmacologic treatment of alcohol use disorder are discussed
separately. (See "Approach to treating alcohol use disorder" and "Alcohol use
disorder: Psychosocial treatment".)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Alcoholic cirrhosis was responsible for 21 percent of all orthotopic liver
transplants in 2015 in the United States, according to the Organ Procurement
and Transplantation Network/Scientific Registry of Transplant Recipients
(OPTN/SRTR) report. (See 'Introduction' above.)
●Transplantation is an appropriate treatment option for some patients with
alcoholic liver disease and is generally considered when a patient has
suffered either a complication of portal hypertension or a manifestation of
compromised hepatic function. Such patients should be referred for
transplantation as early referral is an important determinant of success.
(See 'Timing of referral' above.)
●Abstinence is an expectation for patients on the transplant waiting list. Most
studies suggest that longer durations of abstinence pre-transplantation are
associated with reduced rates of relapse after transplant; six-month
abstinence is a common requirement in many centers. In addition, other
centers monitor patients for alcohol use and/or require that patients
participate in an alcohol treatment program. The efficacy of these measures
in preventing alcohol relapse after transplantation and improving other
outcomes is uncertain.  (See 'Pre-transplant abstinence and
monitoring' above.)
●One- and five-year patient and graft survival rates following liver
transplantation for alcoholic liver disease are similar to rates following
transplantation for nonalcohol-related diagnoses. However, 10-year patient
318
and graft survival rates are lower for patients with alcoholic liver disease,
while the cause for this is not well-defined. (See 'Mortality and graft
survival' above.)
●Alcohol relapse after transplantation occurs in 10 to 30 percent of patients
and has been associated with increased risk of graft rejection, graft loss, and
recurrent alcoholic liver disease as well as decreased survival. The accuracy of
predictors of relapse is incompletely understood but, poor social support, a
family history of alcohol dependence, and pre-transplantation abstinence of
≤6 months are some of the predictors that may be important. (See 'Risk
factors for alcohol relapse' above and 'Recurrent harmful alcohol use' above.)
●We suggest that patients with a history of alcoholic liver disease participate
in an alcohol treatment program following liver transplantation.
(See 'Prevention and treatment' above.)
●Smoking is a significant risk factor for post-transplant morbidity and
mortality. We suggest that patients with alcoholic liver disease who smoke
undergo counseling and treatment for smoking cessation (Grade 2B).
(See 'Smoking cessation' above.)
●Liver transplantation may be an option for patients with severe alcoholic
hepatitis who do not respond to glucocorticoids. It has been suggested that
the six-month period of abstinence be reconsidered in patients with severe
alcoholic hepatitis and that methods to identify transplant candidates who
are at low risk of relapse are needed. (See 'Patients with severe alcoholic
hepatitis' above.)

319
Liver transplantation in primary biliary
cholangitis
Authors:
Steven Flamm, MD
Fredric D Gordon, MD
Raoul Poupon, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Oct 07, 2020.
INTRODUCTIONLiver transplantation can be successful in treating end-stage
liver disease from primary biliary cholangitis (PBC; previously referred to as
primary biliary cirrhosis). The total number of transplants performed for PBC has
been declining slightly, possibly reflecting benefits of early treatment [1].
Nevertheless, transplantation remains an important option in patients with
progressive disease despite medical therapy. In the United States, the average age
of patients undergoing transplantation for PBC is in the range of 53 to 55 years [1].
This topic will review issues related to patient selection for liver transplantation,
the timing of transplantation, and transplantation outcomes in patients with PBC.
Other issues related to the pathogenesis, clinical manifestations, diagnosis, and
treatment of PBC are discussed elsewhere. (See "Clinical manifestations, diagnosis,
and prognosis of primary biliary cholangitis (primary biliary
cirrhosis)" and "Overview of the management of primary biliary
cholangitis" and "Pathogenesis of primary biliary cholangitis (primary biliary
cirrhosis)".)
OPTIMAL TIME FOR TRANSPLANTATIONAn important issue is to
determine the optimal time to perform a liver transplantation. Many groups have
developed models that use clinical variables to estimate patient survival. Three
types of models have been developed: one based upon initial data on entry into
the study; one that uses both initial and follow-up data; and one that is based on
response to treatment. The Mayo model (table 1), which uses data from the initial
evaluation, is most widely used, but because of individual patient variation, it does
not replace the input of an experienced clinician [2,3]. The Mayo model can predict
short- and long-term survival using current laboratory and clinical data. This tool
can be used to anticipate liver failure, allowing the clinician to refer the patient for
320
transplantation in a timely manner. Although these models are specific to survival
in PBC, the MELD score is used to prioritize patients for transplantation and is
often used to determine when to refer patients for transplant evaluation.
(See "Model for End-stage Liver Disease (MELD)".)

In addition to considering the MELD score and Mayo model, we suggest that
patients with PBC be referred for transplantation evaluation if one or more of the
following is present:

●The plasma bilirubin concentration is greater than 5 mg/dL (85.5

micromol/L) and is increasing
●The serum albumin concentration is below 2.8 g/dL (28 g/L) and is
decreasing
●Signs of decompensation or portal hypertension develop, such as ascites,
variceal bleeding, coagulopathy malnutrition, or encephalopathy
●The patient has intractable pruritus
●The patient has recurrent, debilitating, nontraumatic bone fractures
Models based upon initial data — Some prognostic models are based on clinical
features including physical examination findings, laboratory data, and liver biopsy
because these characteristics have predictive value [2,4-7]. Additional factors that
have been found to correlate with prognosis are age, plasma bilirubin and albumin
concentrations, hepatomegaly, and the presence of cholestasis, portal fibrosis, or
cirrhosis on biopsy [4,5].
A model developed at the Mayo Clinic does not require liver biopsy [2,6]. Survival
could be predicted from the patient's age, plasma bilirubin and albumin
concentrations, the prothrombin time, and the presence of edema (table 1).

These models are all based upon data obtained at a fixed time point and do not
consider more dynamic data such as changes over time or the response to
therapy. Models that incorporate these elements would likely more accurately
reflect disease progression in individual patients.

Models based upon initial and follow-up data — Two time-dependent predictive

models have been developed that use readily available markers and follow-up data
to predict survival [8]. These models therefore permit a change in the patient's
condition to provide an updated prognosis. One uses the plasma albumin and
bilirubin concentrations, the presence of ascites, a history of gastrointestinal
bleeding, and age as important variables. The second uses the same variables and
adds plasma immunoglobulin measurements and the presence of cirrhosis and
central cholestasis on biopsy.

321
Both models were validated and were more accurate than the time-fixed models in
predicting survival, particularly in the short term. They suggest that liver
transplantation be undertaken when the estimated six-month survival is less than
80 percent. Six months is used as the cut-off since this is the time when survival
after transplantation becomes better than survival without transplantation
(assuming that an organ is available for transplantation within six months) (figure
1) [3].
Models based on treatment response — Prognostic models that incorporate
data from patients on ursodeoxycholic acid (UDCA) have been developed and may
be used to identify high risk patients who may benefit from closer monitoring or
second line therapies [9,10]. For example, a risk score to predict transplant-free
survival uses clinical and biochemical variables obtained after one year of UDCA
therapy [9]. Another model, the UK-Primary biliary cholangitis risk score for
predicting end stage liver disease, contains both baseline variables (ie, albumin
and platelet count) and variables after 12 months of UDCA therapy (ie, bilirubin,
transaminases and alkaline phosphatase) [10].
OUTCOME AFTER LIVER TRANSPLANTATIONExcellent short- and long-
term survival rates have been described following transplantation for PBC, and
one-year survival rates of 90 to 95 percent are common at many medical centers
[11,12]. In a multicenter study including 785 patients, survival rates at 5-, 10-, and
20-years were 90, 81, and 53 percent, respectively [11].
These results are significantly better than the predicted survival in
nontransplanted patients derived from the models described above. A survival
benefit has been demonstrated as early as three months after transplantation. As
an example, one study monitored 161 patients with PBC after liver transplantation
and compared the results to a simulated group of patients with the same
diagnosis who were managed without transplantation [3]. The three-month
survival in this group was significantly higher than the predicted values in
nontransplanted patients. The two-year survival was also higher with
transplantation (74 versus 31 percent), a benefit that was seen in patients from all
pretransplant risk groups (figure 1).
Although all patients with PBC benefit from liver transplantation, those who are
chronically ill and malnourished prior to surgery do not do as well as those with
less severe disease [3]. The Mayo model (table 1) can help to identify high-risk
patients. Unfortunately, the shortage of donor organs often limits transplantation
to patients with advanced disease (and thus higher MELD scores), except for those
with a suitable living donor. (See 'Models based upon initial data' above
and "Model for End-stage Liver Disease (MELD)" and "Living donor liver
transplantation in adults".)
322
As with transplantation for other liver diseases, a very small proportion of patients
with PBC require a second transplantation, less than 2 percent in our experience.
While recurrent PBC is not uncommon, in one series of patients with recurrent PBC
following liver transplantation, only 5 percent lost their grafts [13]. Most second
transplants occur within the first month due to problems such as primary liver
nonfunction, hepatic artery thrombosis, chronic rejection, acute rejection, and
portal vein thrombosis, problems common to liver transplantation in general. This
is an important issue because of the shortage in donor organs. (See 'Rate of
recurrence' below.)
Effect of transplantation on symptoms — Resolution of symptoms related to
PBC occurs at variable rates. Pruritus and complications of end-stage liver disease,
such as encephalopathy, variceal bleeding, and hepatorenal syndrome are usually
promptly reversed after transplantation. (See "Pruritus associated with
cholestasis".)
Jaundice and ascites resolve somewhat more slowly, over a period of days to a few
months. Splenomegaly usually persists, although the enlarged spleen may
decrease slightly in size. Skin xanthomas also resolve within a few weeks.
(See "Hypercholesterolemia in primary biliary cholangitis (primary biliary
cirrhosis)".)
By contrast, it may take 12 to 18 months before improvement is seen in hepatic
osteodystrophy, despite vitamin D and calcium supplementation. As a result, bone
disease is a possible source of long-term morbidity (due to vertebral compression
fractures, pain, opioid dependence, and immobility) despite successful liver
transplantation. (See "Evaluation and treatment of low bone mass in primary
biliary cholangitis (primary biliary cirrhosis)".)
Fatigue may improve in some patients following liver transplantation. In a study
that analyzed 31 patients who received a liver transplantation for PBC, 89 percent
of patients had moderate or severe fatigue prior to transplantation. Two years
following transplantation, 44 percent reported moderate or severe fatigue [14]. By
contrast, in a study of 351 women and 29 men who underwent liver
transplantation and equal numbers of matched controls, fatigue did not improve
following transplantation in women and was worse following transplantation in
men [15].
Recurrence of PBC in the transplanted liver — It is now generally accepted that
PBC can recur following liver transplantation, although there was much initial
debate [16-22].
Rate of recurrence — A precise estimate of the recurrence rate is uncertain since
not all studies have used uniform criteria for defining recurrent PBC, and studies
have had variable follow-up [11,16,23,24]. Two of the largest series with the

323
longest follow-up (in which the diagnosis of recurrent PBC was based upon
histologic features) probably represent the best available estimates [11,25]. In a
multicenter cohort study of 571 patients who had liver transplantation for PBC and
underwent at least one follow-up liver biopsy, the rates of PBC recurrence at 5 and
10 years were 18 and 31 percent, respectively [25]. In another multicenter study
including 785 patients, the rate of PBC recurrence at 5 and 10 years was 22 and 36
percent, respectively [11].
Impact on outcomes — Data have suggested that recurrence has been associated
with a negative impact on graft and patient survival [11,22,26]. In a cohort study of
571 patients who had liver transplantation for PBC and had at least one follow-up
liver biopsy, recurrence was associated with higher risk of graft loss (hazard ratio
[HR] 1.96, 95% CI 1.45-2.65) and patient mortality (HR 1.93, 95% CI 1.42-2.63)
compared with no recurrence [25].
Risk factors — The following factors are associated with increased risk for PBC
recurrence after liver transplantation:
●Younger age at diagnosis or at transplantation – Younger age at
diagnosis or at liver transplantation increases the risk of recurrence [11,27].
In a study of 785 patients with PBC, patients who were ≤50 years old at PBC
diagnosis or were ≤60 years old at liver transplantation were more likely to
have recurrence after transplantation (HR 1.79, 95% CI 1.36-2.36 and HR 1.39,
95% CI 1.02-1.90, respectively) [11].
●Elevation in alkaline phosphatase – Elevated alkaline phosphatase levels
(beyond the upper limit of normal) at six and 12 months after liver
transplantation have been associated with increased risk of recurrence [11].
●Use of tacrolimus, sirolimus or mycophenolate mofetil
– Immunosuppression with tacrolimus, sirolimus or mycophenolate mofetil
has been associated with a higher risk of recurrence [11,23,26].
Prevention — Strategies to prevent PBC recurrence include using ursodeoxycholic
acid (UDCA) following liver transplantation and an immunosuppressive regimen
containing cyclosporine (rather than tacrolimus) [24-26]. For most patients, we
typically start UDCA (10 to 15 mg/kg/day in two divided doses) within two weeks
following transplantation.
Data on the use of UDCA for preventing recurrence have been limited to
observational studies but have suggested that UDCA was associated with better
outcomes. In a cohort study including 780 patients who underwent liver
transplantation for PBC and were followed for a median of 11 years, use of UDCA
was associated with lower risk of histologic recurrence (adjusted HR [aHR] 0.41,
95% CI 0.28-0.61) and graft loss (aHR 0.33, 95% CI 0.13-0.82) compared with no
UDCA [25]. In addition, UDCA was associated with lower risk of liver-related death

324
(aHR 0.46, 95% CI 0.22-98) and all-cause mortality (aHR 0.69, 95% 0.49-0.96). In a
smaller retrospective series of 90 patients who underwent liver transplantation for
PBC, 19 patients (21 percent) received preventive UDCA (10 to 15 mg/kg/day) [24].
The use of UDCA was associated with a decreased risk of histologic recurrence
(adjusted HR 0.32, 95% CI 0.11-0.91). The rates of recurrence for those who
received UDCA were 11, 21, and 40 percent at 5, 10, and 15 years, respectively,
whereas the recurrence rates for those who did not receive UDCA were 32, 53, and
70 percent, respectively.
The use of cyclosporine may have a protective effect, although the data are mixed
[11,25,26,28]. Preliminary data have suggested that combining an
immunosuppressive regimen containing cyclosporine with preventive UDCA has
been associated with a complementary protective effect. In a cohort study
including 780 patients who underwent liver transplantation for PBC and were
followed for a median of 11 years, UDCA combined with cyclosporine was
associated with lower risk of histologic recurrence compared with use of either
agent alone (aHR 0.47, 95% CI 0.34-0.66) [25].
Diagnosis — The diagnosis of recurrent PBC must be based upon histologic rather
than serologic or biochemical findings. The following criteria have been proposed
[29,30]:
●Transplantation for PBC, and
●Persistence of antimitochondrial antibodies, and
●Liver histology showing the characteristic portal tract lesions (mononuclear
inflammatory infiltrate, formation of lymphoid aggregates, epithelioid
granulomas, bile duct damage). Definite recurrent PBC is present when three
of the four portal tract lesions are present, whereas probable recurrence is
diagnosed when two are present.
A cholestatic pattern of liver biochemical abnormalities is neither sensitive nor
specific for recurrence. Cholestasis can arise from multiple causes in the transplant
setting and not all patients with well documented histologic recurrence have
cholestasis [31].
Similarly, the presence of antimitochondrial antibodies does not establish that
recurrence is present or will develop. Antimitochondrial antibodies persist in most
patients following transplantation, usually with a small and transient fall in their
titer [32,33].
Treatment — There are limited data to guide treatment of recurrent disease,
although treatment with UDCA is reasonable. UDCA appears to improve
biochemical tests [30], but its effect on the natural history of recurrent PBC is
uncertain. UDCA was not associated with improved patient and graft survival

325
compared with untreated patients in a retrospective study involving 52 patients
with recurrent PBC [22].
Recurrent disease in patients with PBC following liver transplantation is not an
indication for treatment with obeticholic acid. (See "Overview of the management
of primary biliary cholangitis", section on 'Subsequent therapy'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Primary biliary cholangitis" and "Society
guideline links: Liver transplantation".)
INFORMATION FOR PATIENTSUpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

●Basics topic (see "Patient education: Primary biliary cholangitis (primary

biliary cirrhosis) (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Liver transplantation in primary biliary cholangitis (PBC) is prioritized using
the Model for End-stage Liver Disease (MELD) score. (See "Model for End-
stage Liver Disease (MELD)".)
●In addition to considering the MELD score, we suggest that patients with
PBC be referred for liver transplantation evaluation if one or more of the
following is present (see 'Optimal time for transplantation' above):
•The plasma bilirubin concentration is greater than 5 mg/dL (85.5
micromol/L) and is increasing
•The serum albumin concentration is below 2.8 g/dL (28 g/L) and is
decreasing
•Signs of decompensation or portal hypertension develop, such as ascites,
variceal bleeding, coagulopathy, malnutrition, or encephalopathy

326
 •The patient has intractable pruritus
•The patient has recurrent, debilitating, nontraumatic bone fractures
●Excellent short- and long-term survival have been described following liver
transplantation for PBC, and one-year survival rates of 90 to 95 percent are
common at many medical centers. (See 'Outcome after liver
transplantation' above.)
●Resolution of symptoms related to PBC occurs at variable rates following
liver transplantation. (See 'Effect of transplantation on symptoms' above.)
●Recurrent PBC after liver transplantation has been described in up to 36
percent of patients after 10 years of follow-up. Data have suggested that
recurrence of disease was associated with a negative impact on graft and
patient survival. (See 'Recurrence of PBC in the transplanted liver' above.)
●For most patients who undergo liver transplantation for PBC, we suggest
therapy with ursodeoxycholic acid (UDCA) to prevent histologic recurrence
rather than no pharmacologic intervention (Grade 2B). We typically use
UDCA, 10 to 15 mg/kg/day, in two divided doses.

327
Acute liver failure in adults: Etiology, clinical
manifestations, and diagnosis
Authors:
Eric Goldberg, MD
Sanjiv Chopra, MD, MACP
Jonah N Rubin, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 09, 2020.
INTRODUCTIONAcute liver failure is characterized by acute liver injury, hepatic
encephalopathy, and an elevated prothrombin time/international normalized ratio
(INR). It has also been referred to as fulminant hepatic failure, acute hepatic
necrosis, fulminant hepatic necrosis, and fulminant hepatitis. Untreated, the
prognosis is poor, so timely recognition and management of patients with acute
liver failure is crucial [1]. Whenever possible, patients with acute liver failure should
be managed in an intensive care unit at a liver transplantation center.
This topic will review the etiology, clinical manifestations, and diagnosis of acute
liver failure in adults. The prognosis and management of patients with acute liver
failure is discussed separately. (See "Acute liver failure in adults: Management and
prognosis".)
The discussion that follows is consistent with society guidelines from The American
Association for the Study of Liver Diseases (AASLD) and European Association for
the Study of the Liver (EASL) for the management of acute liver failure [2,3].
DEFINITIONSAcute liver failure refers to the development of severe acute liver
injury with encephalopathy and impaired synthetic function (INR of ≥1.5) in a
patient without cirrhosis or preexisting liver disease [2-4]. While the time course
that differentiates acute liver failure from chronic liver failure varies among
reports, a commonly used cutoff is an illness duration of <26 weeks.
Acute liver failure may also be diagnosed in patients with previously undiagnosed
Wilson disease, vertically acquired hepatitis B virus, or autoimmune hepatitis, in
whom underlying cirrhosis may be present, provided the disease has been
recognized for <26 weeks. On the other hand, patients with acute severe alcoholic
hepatitis, even if recognized for <26 weeks, are considered to have acute-on-
chronic liver failure since most have a long history of heavy drinking. The approach
328
to such patients is discussed elsewhere. (See "Management and prognosis of
alcoholic hepatitis".)
Acute liver failure can be subcategorized based upon how long the patient has
been ill and various cutoffs have been used. We classify acute liver failure as
hyperacute (<7 days), acute (7 to 21 days), or subacute (>21 days and <26 weeks).
In patients with hyperacute or acute liver failure, cerebral edema is common,
whereas it is rare in subacute liver failure [5]. On the other hand, renal failure and
portal hypertension are more frequently observed in patients with subacute liver
failure. These subcategories have been associated with prognosis, but the
associations reflect the underlying causes, which are the true determinants of
prognosis. As an example, patients with hyperacute liver failure tend to have a
better prognosis than those with subacute liver failure. The better prognosis is
related to the fact that these patients often have acetaminophen toxicity or
ischemic hepatopathy, diagnoses associated with a better prognosis than many of
the disorders that may result in subacute liver failure, such as Wilson disease [2].
ETIOLOGYAcute liver failure can result from a wide variety of causes, including
(table 1 and table 2) [2,6]:
●Acetaminophen (paracetamol)
●Idiosyncratic drug reactions
●Viral hepatitis
●Alcoholic hepatitis (in which case it is considered to be acute-on-chronic liver
failure) (see 'Definitions' above)
●Autoimmune hepatitis
●Wilson disease
●Ischemic hepatopathy
●Budd-Chiari syndrome
●Veno-occlusive disease
●Acute fatty liver of pregnancy/HELLP (hemolysis, elevated liver enzymes, low
platelets) syndrome
●Malignant infiltration (most often breast cancer, small cell lung cancer,
lymphoma, melanoma, or myeloma)
●Partial hepatectomy
●Toxin exposure, including mushroom poisoning
●Sepsis
●Heat stroke
●Hemophagocytic lymphohistiocytosis (primarily a disorder of children) [7]
Viral and drug-induced hepatitis are the most common causes of acute liver failure
in adults. Drug-induced liver injury is the most common cause of acute liver failure

329
in Australia, Europe, the United Kingdom, and the United States, whereas in Asia
and Africa, viral hepatitis predominates [3,8,9]:
●In the United States, the US Acute Liver Failure Study Group collected data
on 1147 cases of acute liver failure from 23 sites between 1998 and 2007 [1].
The most common causes of acute liver failure
were acetaminophen overdose (46 percent), indeterminate (14 percent),
idiosyncratic drug reactions (12 percent), hepatitis B virus (7 percent), and
hepatitis A virus (3 percent).
●Among 856 patients with acute liver failure in Japan between 1998 and 2006,
51 percent of cases were due to viral hepatitis (42 percent hepatitis B), and 10
percent were due to drugs (including acetaminophen) [10].
Viral hepatitis — Several viruses have been associated with acute liver failure,
including hepatitis A, B, C, D, and E. In addition, acute liver failure can be seen with
herpes simplex virus, varicella zoster virus, Epstein-Barr virus, adenovirus, and
cytomegalovirus [1,8].
Acute liver failure is estimated to develop in 0.35 percent of patients with hepatitis
A and in 0.1 to 0.5 percent of patients with acute hepatitis B [11]. However, the
incidence of acute liver failure from hepatitis B may be underestimated. Precore or
pre-S mutant hepatitis B viruses that are able to produce infection but do not
produce hepatitis B e antigen (precore mutants) or surface antigen (pre-S mutants)
may be difficult to diagnose by routine serology. Thus, liver failure in such patients
may be erroneously attributed to cryptogenic causes [12]. This was illustrated in a
study in which evidence of hepatitis B infection was detected by polymerase chain
reaction (PCR) in 6 of 17 patients (35 percent) who underwent liver transplantation
for what was initially thought to be non-A, non-B hepatitis [13]. (See "Hepatitis A
virus infection in adults: Epidemiology, clinical manifestations, and
diagnosis" and "Hepatitis B virus: Clinical manifestations and natural history",
section on 'Acute hepatitis' and "Clinical significance and molecular characteristics
of common hepatitis B virus variants".)
In addition to acute hepatitis B, acute liver failure may also develop in patients who
are receiving chemotherapy or immunosuppression and have reactivation of
previously inactive hepatitis B, highlighting the importance of screening these
patients for prior hepatitis B exposure. (See "Hepatitis B virus reactivation
associated with immunosuppressive therapy".)
Hepatitis C virus alone does not appear to be a significant cause of acute liver
failure in the absence of coinfection with hepatitis B. In a study of 109 patients with
acute hepatitis C, acute liver failure developed in 11 (10 percent), 9 of whom had
concurrent hepatitis B infection [14]. (See "Clinical manifestations and natural
history of chronic hepatitis C virus infection".)

330
Infection with hepatitis D virus can lead to acute liver failure in patients with
hepatitis B virus infection. A patient may either acquire both viruses at the same
time (coinfection) or acquire hepatitis D in the setting of preexisting chronic
hepatitis B (superinfection). The risk of acute liver failure appears to be higher
among patients who are coinfected than in those with hepatitis D superinfection
or with acute hepatitis B alone. (See "Pathogenesis, epidemiology, natural history,
and clinical manifestations of hepatitis D virus infection".)
Hepatitis E virus is a significant cause of liver failure in countries where it is
endemic, such as Russia, Pakistan, Mexico, and India. Overall, the case-fatality rate
for hepatitis E is 0.5 to 3 percent. However, among women who are pregnant, the
mortality rate increases to 15 to 25 percent. (See "Hepatitis E virus infection",
section on 'Acute hepatitis E' and "Overview of coincident acute hepatobiliary
disease in pregnant women", section on 'Hepatitis E virus'.)
Acute liver failure is a rare complication of HSV infection. Both HSV-1 and HSV-2
have been implicated as etiologic agents. Those at risk include neonates, patients
taking steroids, HIV-infected patients, those with cancer or myelodysplastic
syndromes, and pregnant women. HSV hepatitis has also been reported as an
early cause of death after liver transplantation with concomitant lung and
gastrointestinal involvement. HSV-related hepatitis has also been reported rarely
in immunocompetent hosts. (See "Epidemiology, clinical manifestations, and
diagnosis of herpes simplex virus type 1 infection", section on 'Hepatitis'.)
Immunocompromised patients, such as transplant recipients and HIV-infected
individuals with advanced disease, are at increased risk for developing complicated
herpes zoster infections including acute liver failure. Hepatic involvement may
occasionally develop in the absence of coincident rash. (See "Epidemiology, clinical
manifestations, and diagnosis of herpes zoster", section on 'Special considerations
in immunocompromised hosts'.)
Epstein-Barr virus can affect virtually any organ system and has been associated
with hepatitis and cholestasis. While rare, fatal cases of hepatitis have been
described. (See "Infectious mononucleosis", section on 'Other'.)
The more common gastrointestinal manifestation of adenovirus is an acute
diarrheal illness. However, hepatitis is a well-described complication of adenovirus
infection in immunocompromised hosts, especially with subgroup C type 5.
(See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus
infection", section on 'Gastrointestinal system'.)
Liver function abnormalities are frequently encountered in patients with
symptomatic cytomegalovirus infection. Subclinical transaminitis is the most
common finding in immunocompetent patients, but occasionally, patients present
with more significant laboratory abnormalities or signs of hepatic dysfunction.

331
(See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus
infection in immunocompetent adults", section on 'Hepatic manifestations'.)
Acetaminophen and other hepatotoxins — Acetaminophen is the most common
toxin associated with acute liver failure in the United States and other developed
countries (table 2) [15]. The hepatotoxicity is dose-dependent and rarely occurs at
therapeutic doses (up to four grams per day in a patient without preexisting liver
disease). (See "Acetaminophen (paracetamol) poisoning in adults:
Pathophysiology, presentation, and evaluation" and "Acetaminophen
(paracetamol) poisoning in adults: Treatment".)
Most cases occur after ingestion of large doses in an attempt to commit suicide. In
addition, some patients unknowingly take large amounts of acetaminophen when
multiple acetaminophen-containing medications are taken together or if
acetaminophen-containing medications are not taken as directed (a "therapeutic
misadventure"). Acute liver failure can also result from normally therapeutic doses
in patients who have underlying liver disease (particularly with ongoing alcohol
use, which induces the cytochrome P450 system) or who are taking medications
known to induce the cytochrome P450 system (particularly CYP2E1), such as
anticonvulsants (figure 1). The dosing and safety of acetaminophen for pain
management in patients with cirrhosis are discussed separately.
(See "Management of pain in patients with advanced chronic liver disease or
cirrhosis", section on 'Acetaminophen (paracetamol)'.)
Other toxins associated with acute liver failure include mushroom poisoning (most
often Amanita phalloides) and carbon tetrachloride. (See "Amatoxin-containing
mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis,
and treatment" and "Acute hydrocarbon exposure: Clinical toxicity, evaluation, and
diagnosis", section on 'Pathophysiology'.)
Idiosyncratic drug reactions — Unlike acute liver failure due to acetaminophen,
which is dose-related, acute liver failure due to idiosyncratic drug reactions is dose-
independent. Drug-induced liver injury (DILI) usually occurs within six months of
drug initiation [2]. Drugs commonly implicated in cases of DILI include antibiotics,
nonsteroidal anti-inflammatory drugs, and anticonvulsants (table 2). Herbal
medications and dietary supplements have also been associated with acute liver
failure. (See "Drug-induced liver injury" and "Hepatotoxicity due to herbal
medications and dietary supplements".)
Hypoperfusion — Hypoperfusion of the liver can result in ischemic hepatitis and
acute liver failure. Hypoperfusion may result from systemic hypotension due to
causes such as cardiac dysfunction, sepsis, or drugs. Hypoperfusion of the liver
may also be seen with Budd-Chiari syndrome (hepatic vein thrombosis), veno-
occlusive disease, or the use of vasoconstricting drugs such as cocaine and

332
methamphetamine. (See "Ischemic hepatitis, hepatic infarction, and ischemic
cholangiopathy" and "Budd-Chiari syndrome: Epidemiology, clinical
manifestations, and diagnosis" and "Hepatic sinusoidal obstruction syndrome
(veno-occlusive disease) in adults".)
CLINICAL MANIFESTATIONSBy definition, patients with acute liver failure
have severe acute liver injury (demonstrated by liver test abnormalities) with signs
of hepatic encephalopathy and a prolonged prothrombin time (INR ≥1.5). Other
clinical manifestations may include jaundice, hepatomegaly, and right upper
quadrant tenderness.
Symptoms — Many of the initial symptoms in patients with acute liver failure are
nonspecific [16]. They include:
●Fatigue/malaise
●Lethargy
●Anorexia
●Nausea and/or vomiting
●Right upper quadrant pain
●Pruritus
●Jaundice
●Abdominal distension from ascites

As the liver failure progresses, patients who were initially anicteric may develop
jaundice, and those with subtle mental status changes (eg, lethargy, difficulty
sleeping) may become confused or eventually comatose.

Physical examination findings

Neurologic examination — The presence of hepatic encephalopathy is one of the
defining characteristics of acute liver failure. Findings in patients with hepatic
encephalopathy are variable, ranging from changes in behavior to coma. Hepatic
encephalopathy is graded from I to IV (table 3 and figure 2) (see "Hepatic
encephalopathy in adults: Clinical manifestations and diagnosis"):
●Grade I: Changes in behavior, mild confusion, slurred speech, disordered
sleep, including sleep reversal
●Grade II: Lethargy, moderate confusion
●Grade III: Marked confusion (stupor), incoherent speech, sleeping but wakes
with stimulation
●Grade IV: Coma, unresponsive to pain
Patients with grade I encephalopathy may have mild asterixis, whereas
pronounced asterixis is typically seen in patients with grade II or III
encephalopathy [15]. Asterixis is typically absent in patients with grade IV

333
encephalopathy, who instead may demonstrate decorticate or decerebrate
posturing.
Cerebral edema may develop in patients with acute liver failure leading to
increased intracranial pressure [15]. Cerebral edema is uncommon in patients with
grade I or II encephalopathy, but it is present in 25 to 35 percent of those with
grade III encephalopathy and in approximately 75 percent of those with grade IV
encephalopathy [16,17]. Pupillary changes are one sign of increased intracranial
pressure. The pupils may progress from having a normal response (typical with
grade I encephalopathy), to being hyperresponsive (grade II to III
encephalopathy), to being slowly responsive (grade III to IV encephalopathy). As
the coma worsens, the pupils may become fixed and dilated (a sign typically
associated with brainstem herniation).
Other clinical features of increased intracranial pressure can include systemic
hypertension, bradycardia, respiratory depression (Cushing's triad), seizures, and
abnormal brain stem reflexes (eg, oculocephalic reflex, corneal reflex, jaw reflex,
cough response to tracheobronchial suctioning). (See "Evaluation and
management of elevated intracranial pressure in adults", section on 'Clinical
manifestations'.)
Seizure activity in patients with acute liver failure is common, but may be difficult
to detect if patients are intubated and receiving paralytics. In the control arm of
one trial, 7 of 22 patients (32 percent) had subclinical seizure activity detected by
electroencephalogram [18].
Other physical examination findings — Other findings on physical examination
in patients with acute liver failure may include:
●Jaundice, which is a common finding in patients with acute liver failure but
may be absent early in the course of acetaminophen poisoning or herpes
simplex virus infection [2]
●Vesicular skin lesions suggestive of herpes simplex virus (present in 30 to 50
percent of patients with acute liver failure due to herpes simplex virus) [2,19]
●Fever in patients with herpes simplex virus (reported in 82 percent of
patients in one review) [19]
●Right upper quadrant tenderness and hepatomegaly
●Ascites
●Signs of intravascular volume depletion, such as orthostatic hypotension
Laboratory test abnormalities — Laboratory test abnormalities typically seen in
patients with acute liver failure include:
●Prolonged prothrombin time, resulting in an INR ≥1.5 (this finding is part of
the definition of acute liver failure and thus must be present); hemostasis
when measured by thromboelastography is normal [20,21].

334
 ●Elevated aminotransferase levels (often markedly elevated).
●Elevated bilirubin level.
●Low platelet count (≤150,000/mm3), but this is variable and has been
associated with portal hypertension (see "Hemostatic abnormalities in
patients with liver disease", section on 'Physiologic effects of hepatic
dysfunction')
Decreasing aminotransferase levels may indicate spontaneous recovery but could
also signal worsening of the liver failure with loss of hepatocyte mass. In patients
who are improving, the bilirubin and prothrombin time/INR will decline, whereas
in those with worsening liver failure, the bilirubin and prothrombin time/INR will
continue to rise. Because of the prognostic importance of the prothrombin
time/INR, it is recommended that products such as plasma only be used when
there is a clear indication [2]. In addition, despite an abnormal INR, patients may
not be hypocoagulable. In a study of 20 patients with acute liver failure,
thromboelastography suggested a hypocoagulable state in 20 percent, normal
coagulation in 45 percent, and a hypercoagulable state in 35 percent [22].
(See "Acute liver failure in adults: Management and prognosis", section on
'Bleeding prevention' and "Hemostatic abnormalities in patients with liver
disease", section on 'Bleeding' and "Hemostatic abnormalities in patients with liver
disease", section on 'Invasive procedures'.)
Other laboratory findings that may be seen in patients with acute liver failure
include [15]:
●Hemolytic anemia
●Elevated serum creatinine and blood urea nitrogen
●Elevated amylase and lipase
●Hypoglycemia
●Hypophosphatemia
●Hypomagnesemia
●Hypokalemia
●Acidosis or alkalosis
●Elevated ammonia level
●Elevated lactate dehydrogenase (LDH) level
Acute kidney injury complicates acute liver failure in approximately 30 to 70
percent of patients [17,23-25]. The frequency of renal injury is higher (up to 75
percent) for etiologies of acute liver failure that are known to independently
damage the kidneys, such as acetaminophen intoxication [12,25,26]. In one series
of 1604 patients with acute liver failure, some degree of acute kidney injury
developed in 70 percent of the patients, with 30 percent receiving renal
replacement therapy [25].

335
The pathogenesis of renal injury in patients with acute liver failure is incompletely
understood, but may be related to systemic and intrarenal hemodynamic changes
similar to those seen in hepatorenal syndrome. The clinical picture is similar in that
the urine sodium concentration and fractional excretion are very low in the
absence of diuretic therapy or tubular injury (as might be induced
by acetaminophen), and the urine sediment shows few or no cells or casts in the
absence of marked hyperbilirubinemia. The blood urea nitrogen concentration
may not be a sensitive test to follow renal function in patients with acute liver
failure since hepatic production of urea is decreased. (See "Hepatorenal
syndrome".)
Laboratory findings associated with specific diagnoses — Laboratory test
findings often vary depending upon the specific cause of acute liver failure.
Patterns seen on laboratory testing may suggest a diagnosis, but additional
history, laboratory and imaging testing is required prior to making a diagnosis.
These patterns should not be used to rule in or rule out a given diagnosis.
(See 'Diagnosis' below.)
Some patterns that may be seen include [2]:
●Acetaminophen: Very high aminotransferase levels (>3500 international
units/L), low bilirubin, high INR (see "Acetaminophen (paracetamol) poisoning
in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical
manifestations')
●Ischemic hepatic injury: Very high aminotransferase levels (25 to 250 times
the upper limit of normal), elevated serum LDH levels (see "Ischemic
hepatitis, hepatic infarction, and ischemic cholangiopathy", section on
'Clinical manifestations')
●Hepatitis B virus: Aminotransferase levels of to 1000 to 2000 international
units/L are common, alanine aminotransferase (ALT) level that is higher than
the aspartate aminotransferase (AST) level (see "Hepatitis B virus: Clinical
manifestations and natural history", section on 'Acute hepatitis')
●Wilson disease: Coombs-negative hemolytic anemia, aminotransferase
levels <2000 international units/L, AST to ALT ratio of >2, normal or markedly
subnormal alkaline phosphatase (<40 international units/L), alkaline
phosphatase (international units/L) to total bilirubin (mg/dL) ratio <4, rapidly
progressive renal failure, low uric acid levels (see "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'Acute hepatitis
and acute liver failure')
●Acute fatty liver of pregnancy/HELLP syndrome: Aminotransferase levels
<1000 international units/L, elevated bilirubin, low platelet count (see "HELLP

336
 syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Acute
fatty liver of pregnancy")
●Herpes simplex virus: Markedly elevated transaminases, leukopenia, low
bilirubin
●Reye syndrome, valproate toxicity, or tetracycline toxicity: Minor to
moderate elevations in aminotransferase and bilirubin levels [15]
Imaging and other studies — Abdominal computed tomography (CT) in a patient
with acute liver failure often reveals a liver that appears less dense than skeletal
muscle [27]. Other findings may include heterogenous liver parenchyma,
hepatomegaly, ascites, evidence of malignant infiltration, and evidence of hepatic
vein occlusion. Cirrhosis may be present in patients with acute liver failure due to
Wilson disease, vertically transmitted hepatitis B, or autoimmune hepatitis and
may result in a nodular-appearing liver on imaging. However, a massively necrotic
liver may also appear nodular due to parenchymal collapse [28]. However, because
of the risk of renal failure with the intravenous contrast used for CT, ultrasound
with Doppler imaging is often the preferred initial modality for the evaluation of
acute liver failure. (See 'Imaging studies' below.)
Neuroimaging (head CT or magnetic resonance imaging) in patients with acute
liver failure may reveal evidence of cerebral edema, including a decrease in the
size of the ventricles, flattening of cerebral convolutions, and attenuation of the
signal intensity of brain parenchyma [29]. An electroencephalogram may reveal
seizure activity, even in the absence of clinical signs of seizures [18].
Pulmonary edema and pulmonary infections develop in approximately 30 percent
of patients with acute liver failure and may be seen on chest radiographs [17].
(See "Clinical evaluation and diagnostic testing for community-acquired
pneumonia in adults", section on 'Chest imaging' and "Clinical manifestations and
evaluation of edema in adults", section on 'Isolated pulmonary edema'.)
DIAGNOSIS
Diagnosing acute liver failure — Acute liver failure should be in the differential
diagnosis of patients with the recent onset (<26 weeks) of mental status changes,
jaundice, or right upper quadrant pain. It should also be considered in patients
with nonspecific symptoms such as nausea, vomiting, and malaise. The evaluation
of such patients should include serum liver tests (aspartate aminotransferase
[AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl
transpeptidase [GGT], total and direct bilirubin, albumin). If the liver tests are
abnormal, the patient's prothrombin time/INR should also be measured.
(See 'Symptoms' above.)

Acute liver failure is diagnosed by demonstrating all of the following:

337
 ●Elevated aminotransferases (often with abnormal bilirubin and alkaline
phosphatase levels) (see 'Laboratory test abnormalities' above)
●Hepatic encephalopathy (see 'Neurologic examination' above)
●Prolonged prothrombin time (INR ≥1.5) (see 'Laboratory test
abnormalities' above)
Determining the cause of acute liver failure — A cause for acute liver failure can
be established in approximately 60 to 80 percent of patients [5]. Identifying the
underlying cause of the liver failure is important because it influences the
approach to management and provides prognostic information. A diagnosis is
typically made with a combination of history taking, laboratory tests, and imaging
studies. If the initial evaluation fails to identify an etiology, a liver biopsy may be
required.
Empiric therapy is often started along with the diagnostic workup if a particular
cause is likely based upon history or examination findings. This is especially true in
patients with suspected acetaminophen-associated acute liver failure since the
treatment, N-acetylcysteine (NAC), significantly improves outcomes if started early
and has few side effects. NAC has also been used for patients with non-
acetaminophen induced liver failure. Once the cause of the liver failure is
confirmed, therapy can be adjusted as needed. (See 'Laboratory findings
associated with specific diagnoses' above and "Acute liver failure in adults:
Management and prognosis", section on 'Treatment of the underlying cause'.)
Timing of the evaluation — The evaluation of a patient diagnosed with acute liver
failure should begin immediately to identify the cause of the acute liver failure and
institute empiric therapy as indicated. This is crucial because in some cases, early
diagnosis and treatment may improve the patient's prognosis. In addition, timely
evaluation is required to identify patients who may require urgent evaluation for
liver transplantation. (See "Acute liver failure in adults: Management and
prognosis", section on 'Treatment of the underlying cause'.)
The initial transplantation evaluation should not be delayed for patients who are
being transferred to a liver transplant center. Instead, the diagnostic evaluation
should be initiated at the facility where the patient presents, with results
communicated to the transplant center as they become available. Laboratory tests
and abdominal imaging should be ordered as soon as acute liver failure is
recognized and should not be delayed while the history and physical examination
are being performed. Likewise, because patients with grade I or II encephalopathy
may progress to higher grade encephalopathy and lose their ability to
communicate, a history should be obtained as soon as possible from such
patients. In addition, patient transfer should not be delayed because test results

338
are still pending, because some patients (particularly those with cerebral edema)
will quickly become too unstable.
History — A thorough history may identify potential causes for a patient's acute
liver failure, but in patients with severe encephalopathy, the history may be limited
or unavailable. In some cases, the patient's family may be able to provide useful
information, even if the patient is not able to.

Patients and/or their families should be asked about:

●Timing of symptom onset (eg, malaise, nausea, vomiting, jaundice, mental

status changes).
●History of alcohol use.
●History of prior episodes of jaundice.
●Medication use, including all medications used, the amounts ingested, and
the durations of use. Medication use is not limited to prescription
medications, but also includes over-the-counter medications, herbal and
dietary supplements, and illicit drug use.
●Risk factors for intentional drug overdose, such as a history of depression or
prior suicide attempts.
●Toxin exposure, including occupational toxin exposures or wild mushroom
ingestion.
●Risk factors for acute viral hepatitis, including travel to areas endemic for
hepatitis A or E, intravenous drug use, occupational exposure, sexual
exposure, chronic or inactive hepatitis B infection, history of blood
transfusion, and immunosuppression.
●Risk factors for hepatic ischemia, including hypotension, cardiac failure, a
hypercoagulable disorder, oral contraceptive use, or malignancy.
●Family history of liver disease such as Wilson disease.

In patients who develop acute liver failure while hospitalized, the patient's records
should be reviewed for possible causes including medications the patient has
received (including anesthetics and immunosuppressants) and episodes of
hypotension or cardiac dysfunction.

Physical examination — Physical examination findings may help identify a cause

of a patient's acute liver failure, but in many cases the findings, such as jaundice or
hepatomegaly, are nonspecific. The physical examination may also help identify
complications of acute liver failure, such as cerebral edema and infection.
(See 'Physical examination findings' above.)

339
All patients should have a routine physical examination, including a complete skin
examination. In addition, patients suspected of having Wilson disease should
undergo an ocular slit-lamp examination. (See "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'When to consider
Wilson disease'.)

Physical examination findings that may point to a specific cause of acute liver
failure include:

●Vesicular skin lesions (herpes simplex virus)

●Kayser-Fleisher rings (Wilson disease) (picture 1)
●Features of preeclampsia, such as hypertension (HELLP syndrome) (table
4 and table 5)
Laboratory evaluation — An extensive laboratory evaluation is required in
patients with acute liver failure to determine the cause, assess the severity, and
prepare for possible liver transplantation. Because patients with acute liver failure
may decompensate rapidly, testing should not be delayed. (See 'Timing of the
evaluation' above.)
Laboratory tests that should be obtained at presentation include [2]:
●Prothrombin time/INR
●Serum chemistries (sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, creatinine, glucose, calcium, magnesium, phosphate, lactate
dehydrogenase)
●Liver blood tests (AST, ALT, alkaline phosphatase, GGT, total and direct
bilirubin, albumin)
●Complete blood count with differential
●Acetaminophen level
●Blood and urine toxicology screen
●Viral hepatitis serologies (anti-hepatitis A IgM, hepatitis B surface antigen,
anti-hepatitis B core IgM, anti-hepatitis C virus antibodies, hepatitis C RNA,
herpes simplex virus type 1 and type 2 DNA polymerase chain reaction (PCR),
varicella zoster virus DNA PCR, Epstein-Barr virus (EBV) DNA PCR, anti-viral
capsid antigen IgM, anti-viral capsid antigen IgG, anti-EBV nuclear antigen,
cytomegalovirus (CMV) DNA PCR, anti-CMV virus antibodies; anti-hepatitis E
IgM in women who are pregnant)
●Serum pregnancy test in women of childbearing potential who are not
already known to be pregnant
●Autoimmune markers (antinuclear antibody, antismooth muscle antibody,
anti-liver/kidney microsomal antibody type 1, anti-liver soluble antigen,
immunoglobulin levels)
340
 ●Arterial blood gas
●Arterial lactate
●Arterial ammonia
●Blood type and screen
●Serologic testing for HIV
●Amylase and lipase

Additional tests that are indicated in specific circumstances include:

●Ceruloplasmin level in patients suspected of having Wilson disease.

However, serum ceruloplasmin may be normal or elevated in the setting of
acute liver failure, so if there is significant concern for Wilson disease, a liver
biopsy may be required. However, since most patients with acute liver failure
due to Wilson disease will need emergent liver transplantation, liver biopsies
are usually not necessary if the liver failure is due to Wilson disease, and
transplantation should not be delayed in order to obtain biopsies.
(See "Wilson disease: Clinical manifestations, diagnosis, and natural history",
section on 'Diagnosis'.)
We obtain testing for Wilson disease in patients with acute liver failure who
are under the age of 40 years or who have any of the following:
•A Coombs-negative hemolytic anemia
•Neurologic symptoms prior to the onset of acute liver failure
•Kayser-Fleisher rings
•A ratio of AST to ALT of greater than two
•A normal or subnormal alkaline phosphatase
•A ratio of alkaline phosphatase (international units/L) to total bilirubin
(mg/dL) of less than four
●Anti-hepatitis D virus antibodies in patients with acute or chronic hepatitis B.
(See "Diagnosis of hepatitis D virus infection", section on 'Diagnosis of HDV
infection'.)
●Anti-hepatitis E virus antibodies for patients with travel to endemic areas
such as Russia, Pakistan, Mexico, India, or Africa. (See "Hepatitis E virus
infection", section on 'Diagnosis'.)
●Urinalysis to look for proteinuria in women who are pregnant.
Imaging studies — Imaging with abdominal Doppler ultrasonography should be
obtained to look for evidence of Budd-Chiari syndrome, portal hypertension,
hepatic steatosis, hepatic congestion, and underlying cirrhosis. Ultrasonography is
readily available, inexpensive, and noninvasive. Hepatic imaging may also reveal
evidence of malignant infiltration. As noted above, a massively necrotic liver may
appear nodular and does not necessarily indicate underlying cirrhosis. (See "Budd-
341
Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis", section on
'Diagnosis' and 'Imaging and other studies' above.)
Alternatives to ultrasound included abdominal computed tomography (CT)
scanning, venography, or magnetic resonance imaging and venography
(MRI/MRV). In addition to being able to detect Budd-Chiari syndrome, CT and MRI
are more sensitive than ultrasound for diagnosing hepatic malignancies. However,
prior to obtaining a CT scan, venogram, or MRI/MRV, the risk of renal injury
associated with the contrast agents (contrast-induced nephropathy with iodinated
contrast agents and nephrogenic systemic fibrosis with gadolinium) should be
weighed against the need for the examination, especially since patients with acute
liver failure may also have renal failure. We reserve the use of these imaging
techniques to patients with a negative ultrasound in whom the suspicion for Budd-
Chiari syndrome or malignancy remains high. For patients who are being
considered for liver transplantation, contrast-enhanced, cross-sectional imaging
with either a CT scan or an MRI of the liver is performed to assess for thrombosis
or malignancy. (See "Contrast-associated and contrast-induced acute kidney injury:
Clinical features, diagnosis, and management" and "Patient evaluation before
gadolinium contrast administration for magnetic resonance imaging", section on
'Approach to preventing nephrogenic systemic fibrosis'.)
An echocardiogram to look for cardiac dysfunction should be considered in
patients suspected of having acute hepatic ischemia without a known cause (eg, in
a patient with markedly elevated transaminases without a cause identified from
the patient's history, laboratory examination, or abdominal imaging). Additionally,
patients who are being considered for liver transplantation should undergo
institution-specific protocols for pre-transplant cardiac evaluation. (See "Liver
transplantation in adults: Patient selection and pretransplantation evaluation",
section on 'Cardiopulmonary evaluation'.)
Liver biopsy — If laboratory and imaging tests fail to identify an etiology, a liver
biopsy may aid with the diagnosis. A transjugular approach is preferred in the
setting of acute liver failure because of concerns over bleeding. Portal pressure
measurements can help determine the chronicity of the patient's underlying
disease. Our practice is to obtain a liver biopsy in patients with acute liver failure of
indeterminate etiology who are hemodynamically stable with low bleeding risk.
However, if the patient has progressed to the point of requiring liver
transplantation, histologic evaluation can instead be performed on the explanted
liver. (See "Transjugular liver biopsy".)

Prior to a proceeding with a liver biopsy, we obtain contrast-enhanced, cross-

sectional liver imaging (MRI or computed tomography scan) to exclude

342
malignancy. If malignancy is identified on imaging, a discussion with the
institution's multidisciplinary hepatobiliary tumor board takes place to assess if
liver biopsy is necessary for guiding further management. Liver biopsy may help
with the diagnosis of:

●Malignant infiltration.
●Autoimmune hepatitis. (See "Overview of autoimmune hepatitis", section on
'Histology'.)
●Wilson disease. (See "Wilson disease: Diagnostic tests", section on 'Liver
biopsy'.)
●Hepatitis due to herpes simplex virus.
●Acute fatty liver of pregnancy. However, because liver biopsy is invasive, it
should be approached with caution during pregnancy and reserved for cases
in which a diagnosis of acute fatty liver of pregnancy is in doubt and the
appropriate treatment (delivery) is being delayed. (See "Acute fatty liver of
pregnancy", section on 'Histologic findings'.)
DIFFERENTIAL DIAGNOSISThe primary entity in the differential diagnosis of
acute liver failure is severe acute hepatitis. Patients with severe acute hepatitis
have jaundice and coagulopathy but lack signs of hepatic encephalopathy.
Distinguishing the two is important because patients with severe acute hepatitis
generally have a good prognosis, whereas those who progress to acute liver
failure have a high mortality rate and often require liver transplantation [15].
Differentiating severe acute hepatitis from acute liver failure in a patient with
Wilson disease may be difficult because neurologic Wilson disease may be
confused with hepatic encephalopathy. Features that suggest neurologic Wilson
disease rather than hepatic encephalopathy include the presence of dysarthria,
dystonia, tremors, or parkinsonism. In addition, neurologic symptoms in a patient
with Wilson disease may have been present prior to the onset of the hepatic
manifestations. (See "Wilson disease: Clinical manifestations, diagnosis, and
natural history", section on 'Neurologic manifestations'.)
Patients with severe acute alcoholic hepatitis may present with liver failure that
appears to have developed over the course of weeks to months [30]. However,
patients with alcoholic hepatitis typically have a history of heavy drinking for many
years and are thus thought to have acute-on-chronic liver failure [31].
Differentiating alcoholic hepatitis from acute liver failure is important because the
two entities are managed differently (eg, there is a role for corticosteroids in the
treatment of alcoholic hepatitis, but not in acute liver failure). (See "Management
of alcohol-associated steatosis and alcohol-associated cirrhosis".)

343
Alcoholic hepatitis should be considered in patients with a history of heavy alcohol
use or who have an aspartate aminotransferase to alanine aminotransferase ratio
of approximately 2:1. However, a history of heavy alcohol use does not exclude
other causes of acute liver failure (and in the case of acetaminophen toxicity may
predispose to it), so a patient presenting with acute liver failure in the setting of
heavy alcohol use still requires a thorough evaluation. (See "Alcoholic hepatitis:
Clinical manifestations and diagnosis", section on 'Introduction'.)
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Acute liver failure".)
SUMMARY AND RECOMMENDATIONS
●Acute liver failure refers to the development of severe acute liver injury with
encephalopathy and impaired synthetic function (international normalized
ratio [INR] of ≥1.5) in a patient without cirrhosis or preexisting liver disease.
While the time course that differentiates acute liver failure from chronic liver
failure varies between reports, a commonly used cutoff is an illness duration
of <26 weeks. (See 'Definitions' above.)
●Acute liver failure can result from a wide variety of causes, including (table
1 and table 2) [2,15] (see 'Etiology' above):
•Acetaminophen (paracetamol)
•Idiosyncratic drug reactions
•Viral hepatitis
•Autoimmune hepatitis
•Wilson disease
•Ischemic hepatopathy
•Budd-Chiari syndrome
•Veno-occlusive disease
•Acute fatty liver of pregnancy/HELLP (hemolysis, elevated liver enzymes,
low platelets) syndrome
•Malignant infiltration
•Partial hepatectomy
•Mushroom poisoning
•Sepsis
•Heat stroke
●Viral and drug-induced hepatitis are the most common causes of acute liver
failure in adults. (See 'Etiology' above.)
●Clinical manifestations of acute liver failure in addition to hepatic
encephalopathy, abnormal liver blood tests, and an INR ≥1.5 (all of which are
required for the diagnosis), may include jaundice, hepatomegaly, right upper
344
quadrant tenderness, and thrombocytopenia. (See 'Clinical
manifestations' above.)
●Determining the etiology of acute liver failure requires a combination of
history taking, laboratory tests, and imaging studies. If the initial evaluation
fails to identify an etiology, a liver biopsy may be required.
(See 'Diagnosis' above.)
Because patients may decompensate rapidly, the initial evaluation should be
broad, even in patients with a presumed cause for their acute liver failure. A
broad evaluation is required to identify a cause of the acute liver failure and
to prepare for possible liver transplantation.
●Laboratory tests that should be obtained at presentation include
(see 'Laboratory evaluation' above):
•Prothrombin time/INR.
•Serum chemistries (sodium, potassium, chloride, bicarbonate, blood urea
nitrogen, creatinine, glucose, calcium, magnesium, phosphate, lactate
dehydrogenase).
•Liver blood tests (AST, ALT, alkaline phosphatase, GGT, total and direct
bilirubin, albumin).
•Complete blood count with differential.
•Acetaminophen level.
•Blood and urine toxicology screen.
•Viral hepatitis serologies (anti-hepatitis A IgM, hepatitis B surface
antigen, anti-hepatitis B core IgM, anti-hepatitis C virus antibodies,
hepatitis C RNA, herpes simplex virus type 1 and type 2 DNA polymerase
chain reaction (PCR), varicella zoster virus DNA PCR, Epstein-Barr virus
[EBV] DNA PCR, anti-viral capsid antigen IgM, antiviral capsid antigen IgG,
anti-EBV nuclear antigen, cytomegalovirus [CMV] DNA PCR, anti-CMV virus
antibodies; antihepatitis E IgM in women who are pregnant).
•Serum pregnancy test in women of childbearing potential who are not
already known to be pregnant.
•Autoimmune markers (antinuclear antibody, antismooth muscle
antibody, anti-liver/kidney microsomal antibody type 1, anti-liver soluble
antigen, immunoglobulin levels).
•Arterial blood gas.
•Arterial lactate.
•Arterial ammonia.
•Blood type and screen.
•Serologic testing for HIV.
•Amylase and lipase.
345
●Additional laboratory tests that are indicated in specific circumstances
include:
•Ceruloplasmin level in patients suspected of having Wilson disease.
However, serum ceruloplasmin may be normal or elevated in the setting
of acute liver failure, so if there is significant concern for Wilson disease, a
liver biopsy may be required. (See "Wilson disease: Clinical manifestations,
diagnosis, and natural history", section on 'Diagnosis'.)
•Anti-hepatitis D virus antibodies in patients with acute or chronic
hepatitis B. (See "Diagnosis of hepatitis D virus infection", section on
'Diagnosis of HDV infection'.)
•Anti-hepatitis E virus antibodies for pregnant patients or patients with
travel to endemic areas such as Russia, Pakistan, Mexico, Africa, or India.
(See "Hepatitis E virus infection", section on 'Diagnosis'.)
•Urinalysis to look for proteinuria in women who are pregnant.
●Imaging with abdominal Doppler ultrasonography, computed tomography
(CT) scanning, venography, or magnetic resonance imaging and venography
(MRI/MRV) should be obtained to look for evidence of Budd-Chiari syndrome.
Hepatic imaging may also reveal evidence of malignant infiltration. However,
CT scanning, venography, and MRI/MRV should be used with caution because
the contrast agents used are associated with renal injury. We reserve the use
of CT, venography, and MRI/MRV for patients with a negative ultrasound in
whom the suspicion for Budd-Chiari syndrome or malignancy remains high.
In addition, for patients who are being considered for liver transplantation,
contrast-enhanced, cross-sectional imaging with either a CT scan or an MRI of
the liver is performed to assess for thrombosis and malignancy.
(See 'Imaging studies' above.)

346
Hepatitis C virus infection in liver transplant
candidates and recipients
Authors:
Elizabeth C Verna, MD, MSc
Robert S Brown, Jr, MD, MPH
Section Editor:
Adrian M Di Bisceglie, MD
Deputy Editors:
Allyson Bloom, MD
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Dec 14, 2021.
INTRODUCTIONHepatitis C virus (HCV) infection causes approximately 40
percent of all chronic liver disease in the United States. While HCV-associated
cirrhosis is one of the most common indications for liver transplantation among
adults [1,2], the proportion of transplant waitlist additions for HCV-associated
disease in the United States has declined since the introduction of interferon-free,
direct-acting antiviral (DAA) therapy [3]. If not treated pretransplant, HCV
reinfection of the transplanted liver is near universal and, without effective
antiviral treatment post-transplant, can be a major cause of graft failure.
The major issues related to HCV infection in liver transplant candidates and
recipients will be reviewed here. Similar problems arise in patients with HCV who
undergo other forms of organ transplantation. (See "Kidney transplantation in
adults: Hepatitis C infection in kidney transplant candidates and recipients".)
The natural history and treatment of HCV infection, as well as the selection of
patients for liver transplantation, are discussed elsewhere. (See "Clinical
manifestations and natural history of chronic hepatitis C virus
infection" and "Overview of the management of chronic hepatitis C virus
infection" and "Treatment regimens for chronic hepatitis C virus genotype 1
infection in adults" and "Treatment regimens for chronic hepatitis C virus
genotypes 2 and 3 infection in adults" and "Liver transplantation in adults: Patient
selection and pretransplantation evaluation".)
POST-TRANSPLANT CLINICAL COURSE
Graft reinfection post-transplant — For patients with HCV viremia at the time of
transplant, recurrence of HCV infection following liver transplantation is universal
[4,5]. Sequencing studies have confirmed that reinfection is with the same viral
strain circulating prior to transplant.
347
Among individuals with pre-existing HCV infection, infection of the transplanted
liver occurs during reperfusion of the allograft in the operating room, since
patients remain viremic at the time of transplantation in the absence of antiviral
therapy. Although viral levels decline in the first days after removal of the infected
liver, they rebound and reach pretransplant levels within 72 hours [6]. Once the
graft has been infected, serum HCV RNA levels increase from 4- to 100-fold
following liver transplantation [7]. Peripheral monocytes may also harbor virus and
act as a source for reinfection of the donor liver [8].
Progression of liver disease post-transplant — With the efficacy and increasing
use of direct-acting antiviral (DAA) therapy before and after transplant, significant
HCV-related progression of liver disease post-transplant should be extremely rare.
Without successful antiviral therapy, the clinical course of HCV-associated liver
disease following liver transplantation is variable, as in the pretransplant setting;
the course is overall accelerated compared with the nontransplant natural history.
About 20 to 40 percent of post-transplant patients who have not been cured of
HCV infection develop progressive histologic damage, with 10 to 20 percent
developing cirrhosis in as little as five years post-transplant, and 5 to 10 percent
will develop a severe form of recurrence known as fibrosing cholestatic HCV [5,9-
16].
The risk factors leading to these variable patterns of recurrence in individual
patients are not well understood. Although several risk factors have been
identified, none have permitted clinically important intervention [17-25].
Risk factors for progressive disease — Variables that influence the progression
of untreated HCV-associated liver disease following orthotopic liver
transplantation (OLT) are incompletely understood, but donor characteristics
(donor type, age), recipient characteristics (demographics, immune status, and
immunosuppressive regimen), and disease characteristics (viral genotype, viral
load, and the inflammatory grade of the explanted liver) may be important [7,9-
12,26-34].
In particular, the donor characteristic that most strongly predicts outcome in HCV-
viremic liver transplant recipients is donor age. Although grafts from donors aged
60 to 80 years function without a survival disadvantage in patients without HCV
infection [35], liver disease related to HCV recurrence may be more severe when
older donors are used [34,36-40]. This diminished graft survival may even be seen
with donors in their fourth and fifth decades, and the mechanism of interaction is
unknown.
Overall post-transplant prognosis — Five-year survival after transplantation for
HCV-associated liver disease is approximately 60 to 80 percent in series performed
prior to the widespread availability of DAA agents, which is comparable to

348
transplants performed for alcohol-associated liver disease and better than historic
rates for hepatitis B virus infection, hemochromatosis, or cancer
[10,12,14,22,31,41,42]. Nevertheless, overall survival has historically been lower in
HCV-viremic recipients compared with recipients without HCV infection [40,43].
Recurrent HCV-related graft failure was the leading cause of death in these
patients, though hepatocellular carcinoma is also an important predictor of five-
year patient or graft survival [12].
The impact of more effective antiviral therapy with DAA regimens is discussed
elsewhere. (See 'Benefits' below.)
DECIDING TO TREAT BEFORE OR AFTER TRANSPLANTThe availability
of safe and highly effective HCV therapy with direct-acting antivirals (DAAs) has
revolutionized the approach to HCV management in liver transplant candidates
and recipients. A major focus of management is determining the optimal timing of
therapy relative to transplantation. Antiviral therapy of liver transplant candidates,
particularly those who have advanced cirrhosis, should be administered at
transplant centers with appropriate expertise.
Considerations — Deciding whether to treat HCV infection prior to transplant or
defer therapy until after transplantation is a key management issue for liver
transplant candidates. Although cure of HCV infection prior to transplantation
prevents reinfection of the allograft and can improve survival on the transplant
waiting list in some patients with HCV-related decompensated cirrhosis,
pretransplant antiviral therapy may not be the optimal strategy for selected
transplant candidates. Although data informing the decision are limited, the
relative benefits of pre- versus post-transplant therapy depend on several factors:
●Likelihood of meaningful clinical response to pretransplant therapy –
Sustained virologic response (SVR) following antiviral therapy can lead to
stabilization or improvement in liver function in a majority of patients with
decompensated cirrhosis (Childs-Pugh class B and C) [44,45]. As an example,
in a trial of sofosbuvir-velpatasvir, among 27 patients with decompensated
cirrhosis and a baseline Model for End-Stage Liver Disease (MELD) score ≥15,
81 percent had improvement, 11 percent had no change, and 7 percent had
worsening of the MELD score at 12 weeks post-antiviral therapy [46]. In
addition, observational studies have reported that 17 to 33 percent of
patients on the transplant waiting list could achieve sufficient clinical
improvement with successful antiviral treatment to be removed from the list
[47-50].
However, while some improvement in MELD score is common with antiviral
therapy, many patients have only modest decreases (eg, 1 to 3 MELD points)
that do not correspond to substantial clinical improvements. Furthermore,
349
whether improvements in MELD are sustained in the long term is uncertain.
In a study of real-world data from patients with cirrhosis and MELD score ≥10
who underwent antiviral therapy, there was almost no change in median
MELD scores from pretreatment values compared with follow-up at a median
of four years [51]. It is possible that modest decreases in MELD without
resolution of clinical symptoms could inadvertently disadvantage the patient
in terms of transplant priority, thus delaying transplant (sometimes referred
to as "MELD purgatory"). Thus, it may be overall beneficial to defer treatment
until after transplant for selected patients.
The clinical features that predict which patients would benefit meaningfully
from pretransplant therapy have not been well established. In observational
studies, relatively low baseline MELD score (eg, <16), low baseline Child-Pugh
score, and the absence of significant complications of portal hypertension
including encephalopathy have been associated with meaningful clinical
improvement with antiviral therapy [47-50].
Further attempts have been made to identify a specific MELD score under
which pretransplant treatment is associated with an overall survival benefit.
As an example, in one simulation model based on data from two randomized
treatment trials (of ledipasvir-sofosbuvir plus ribavirin in patients with Child-
Pugh class B and C cirrhosis) and data on organ allocation and outcomes
from the United Network for Organ Sharing (UNOS), pretransplant antiviral
therapy was associated with a survival benefit for patients with a MELD score
of 23 to 27, depending on the UNOS region [52]. However, this study was
limited by the lack of treatment efficacy data among patients with MELD
scores >20 and the lack of sufficient data on risk of disease progression
following SVR.
●Expected virologic response to therapy – Patients with Child-Pugh class C
cirrhosis have lower SVR rates with antiviral therapy than patients with less
advanced disease. Furthermore, if such patients are treated prior to
transplant and fail therapy, there is a risk of resultant resistance associated
mutations that make selection of a post-transplant antiviral regimen more
complicated. Thus, for such patients, deferring therapy until after transplant
could maximize the likelihood of treatment success.
Among patients with cirrhosis, HCC is also associated with lower SVR rates
[51,53,54]; however, antiviral treatment is still successful in the majority of
patients with HCC. Thus, in the absence of severe decompensation or short
time to transplantation, the likelihood of SVR and its attendant benefits (eg,
stabilization of clinical status and prevention of allograft reinfection) are

350
 sufficiently high to warrant treatment before transplant in most patients with
HCC.
●Access to transplant – As above, if patients have a reduction in MELD score
after SVR but symptoms of liver disease do not improve, their access to
transplant may be decreased due to the decline in their MELD score ("MELD
purgatory"). This potential outcome must be a consideration in deciding
when to treat patients who do not have alternative access strategies, such as
a living donor or MELD exception points.
Utilization of livers from HCV-viremic donors had traditionally reduced
waiting time and improved access to transplant for HCV-viremic patients on
the liver transplant waiting list. However, as use of HCV-viremic donors
among HCV-negative recipients has become more widespread, deferring
treatment to facilitate use of an HCV-viremic donor organ is less likely to
impact access to transplant. (See 'Use of grafts from HCV-viremic
donors' below.)
●Treatment options – Several HCV treatment regimens are contraindicated
for patients with Child-Pugh class B or C cirrhosis, and such patients thus
have fewer options to select among. Thus, deferring therapy until after
transplant, with the resultant improvement in organ function, will allow for
more treatment options. This may be of particular importance in patients
with prior treatment failure.
Approach — The decision to treat HCV infection before or after liver transplant
should be individualized and take into account the patient's short-term prognosis,
the likelihood of a successful and clinically meaningful response to therapy, access
to transplant, and comorbidities [55]. (See 'Considerations' above.)

Taking into account all of these factors, we generally suggest pretransplant

antiviral therapy for:

●Patients with Child-Pugh A or B cirrhosis and MELD score <20. Such patients
are likely to have virologic and clinically meaningful response to antiviral
therapy and could potentially achieve long-term, transplant-free survival with
antiviral therapy. However, the MELD threshold under which this is most
likely to occur is uncertain, so a score of 20 should not be considered an
absolute cut-off.
●Patients with access to transplant through living donation or MELD
exception points (when the expected waiting time is less than one year). This
includes patients with compensated cirrhosis and hepatocellular carcinoma
(HCC)-related MELD exception points, who are likely to have improved clinical

351
 stability with SVR but are less likely to be disadvantaged by HCV clearance
(since they have access to transplant through exception points).

Waiting to treat in the post-transplant setting may be a reasonable option for:

●Patients with advanced disease with severe portal hypertension or high

MELD (eg, MELD >27). These patients are unlikely to improve with antiviral
therapy to an extent that would preclude the need for transplant, and
deferring therapy could maximize access to transplant and the likelihood of
treatment response. In addition, transplant should not be delayed in this
group to complete HCV therapy.
Our approach is largely consistent with a consensus statement from the
International Liver Transplantation Society [56]. Specifically, that statement
suggests:
●Pretransplant antiviral therapy for patients with:
•Compensated cirrhosis and HCC
•Decompensated cirrhosis but no HCC when the MELD score is relatively
low (eg, <20) and there are no other conditions such as severe portal
hypertension that warrant prompt transplantation
•Decompensated cirrhosis and HCC when expected wait time for
transplantation is more than three to six months
●Defer antiviral therapy until post-transplant for patients with:
•Advanced decompensated cirrhosis with an anticipated wait time less
than three months
•Decompensated cirrhosis and HCC with an anticipated wait time less than
three to six months
●An individualized decision for patients with decompensated cirrhosis who do
not fit into the groups above
PRETRANSPLANT ANTIVIRAL THERAPYIn general, regimen selection for
patients with chronic HCV infection depends on genotype, presence of cirrhosis,
degree of hepatic dysfunction, treatment history, and comorbidities. In particular,
for patients with decompensated cirrhosis, protease inhibitor-based regimens are
contraindicated and should not be used. Although interferon-based regimens are
not recommended for any HCV-infected patients when DAA regimens are
available, they should especially be avoided in patients with decompensated
cirrhosis because of the risk of exacerbated liver disease and death as well as very
low rates of response.
Regimen selection by genotype is discussed elsewhere. (See "Treatment regimens
for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment
regimens for chronic hepatitis C virus genotypes 2 and 3 infection in
352
adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and
6 infection in adults".)
The concept of using DAA regimens specifically for pretransplant treatment to
prevent reinfection of the graft was first illustrated in an open-label study in which
61 patients on the liver transplant waitlist with Child A cirrhosis, biologic MELD
score <22, and hepatocellular carcinoma (who were thus listed with standard
MELD exception points) were treated with sofosbuvir and weight-
based ribavirin for up to 48 weeks prior to transplantation [57]. Of the 46 who
underwent liver transplantation, 43 had undetectable viral loads at the time of
transplantation, and 70 percent of them maintained a virologic response rate 12
weeks after transplantation. Recurrence (seen in 23 percent) was inversely related
to the number of days that HCV RNA was undetectable prior to transplantation.
This specific regimen is no longer recommended because of the more potent
combinations available.
Subsequent studies have demonstrated efficacy and safety of other DAA
combinations in patients with decompensated cirrhosis, including ledipasvir-
sofosbuvir [44,58,59], sofosbuvir-velpatasvir [46],
and sofosbuvir plus daclatasvir [60], each with or without ribavirin for 12 or 24
weeks. Sustained virologic response (SVR) rates are quite high (83 to 96 percent)
among patients with CTP class B cirrhosis but appear to be lower in patients with
more advanced Child-Pugh class C disease (56 to 87 percent).
USE OF GRAFTS FROM HCV-VIREMIC DONORS
Outcomes
In HCV-viremic recipients — Given the high success rate of direct-acting antiviral
(DAA) therapy and lack of sufficient liver allograft supply, use of livers from
hepatitis C virus (HCV)-viremic donors for HCV-viremic recipients with subsequent
DAA therapy is common. As an example, in the United States, the proportion of
HCV-seropositive recipients who received a liver from a donor with chronic HCV
infection increased from 7 to 17 percent between 2010 and 2015 [61].
Use of livers from HCV-viremic donors had previously decreased wait time for HCV-
viremic recipients, but since such organs are now more commonly allocated for
recipients without HCV infection as well, the wait-time advantage has decreased.
Nevertheless, livers from HCV-viremic donors could be of relatively high quality, as
they are often of relatively young age; the average age of HCV-viremic donors
declined from 47 to 35 years between 2012 and 2016, coincident with a rise in
deceased donor organs available due to overdose-related death [62].
Even prior to the widespread availability of DAAs, there did not appear to be a
survival difference among HCV-viremic recipients who received a liver from an
HCV-viremic versus nonviremic donor, although age and fibrosis stage of the
353
donor were important considerations [63-67]. In one multicenter retrospective
study with detailed biopsy data, overall survival was similar between patients who
received livers from donors with or without HCV infection, but the risk of advanced
fibrosis was significantly higher with grafts from HCV-viremic donors, especially
from a donor older than 65 years [65]. When DAA therapy is given in the early
post-transplant period, development of recurrent fibrosis is not a significant
concern.
In recipients without HCV infection — Historically, organs from HCV-viremic
donors were only used for recipients without HCV infection in urgent situations
[56]. However, with the advent of highly effective DAA therapy, including
pangenotypic regimens and effective salvage regimens for those who fail initial
therapy, the use of livers from HCV-viremic donors for recipients without HCV
infection followed by prompt DAA therapy has become more common [68,69]. In
the United States, the number of such transplants increased 35-fold, from 8 in
2016 to 280 in 2019 [70].
Increasing evidence suggests that using organs from HCV-viremic donors is an
overall effective and safe strategy in select HCV-negative recipients [67]. However,
published cohorts describing this strategy for liver transplantation, specifically,
have been relatively small:
●In one report of 10 HCV-negative recipients of livers from HCV-viremic
donors, 100 percent achieved sustained virologic response (SVR) post-
transplant with 12 to 24 weeks of therapy, with a median time from
transplant to treatment of 43 days [71]. With a median 380 days of follow-up,
there were no cases of graft loss.
●In another series of 9 HCV-negative recipients of livers from HCV-viremic
donors, all patients achieved SVR with 12 weeks of glecaprevir-pibrentasvir,
which was initiated within five days of transplant [72]. There were no deaths
after a median of 46 weeks of follow-up.
●In another trial of HCV-negative recipients of livers (n = 13) or kidneys (n =
11), all achieved SVR with 12 weeks of sofosbuvir-velpatasvir, which was
initiated once viremia was confirmed and the patient was clinically stable, a
median of seven days after liver transplant [73].
In addition, in a retrospective study of deceased donor liver transplantations in the
United States from 2008 to 2018, the two-year graft survival rates among HCV-
negative recipients were similar whether they received a liver from an HCV-viremic
donor (n = 87) or an HCV-nonviremic donor (n = 11,270, 86 versus 88 percent) [67].
One modeling study suggested that accepting any liver for transplantation (from
either an HCV-viremic or nonviremic donor) rather than only those from
nonviremic donors was associated with increased life expectancy among HCV-

354
negative recipients with a Model for End-Stage Liver Disease (MELD) score ≥20
[52].
The feasibility of this approach has also been demonstrated among kidney
transplant recipients. (See "Kidney transplantation in adults: Hepatitis C virus
infection in kidney donors", section on 'Approach to the use of kidneys from
donors with HCV infection'.)
Treatment approach for recipients of HCV-viremic donors — The risks and
uncertainties of using livers from HCV-viremic donors followed by antiviral therapy
should be discussed in detail with potential recipients, and adequate access to DAA
therapy following transplantation should be ensured [74-76]. The optimal
approach to timing of antiviral treatment and regimen selection for recipients of
livers from HCV-viremic donors is uncertain.
●Regimen selection – In general, we agree with joint guidelines from the
American Association for the Study of Liver Diseases (AASLD) and Infectious
Diseases Society of America (IDSA) that recommend pangenotypic regimens
(glecaprevir-pibrentasvir or sofosbuvir-velpatasvir) as first-line treatment [69].
In contrast with other organs from HCV-viremic donors, short durations of
HCV therapy should not be used in recipients of livers from HCV-viremic
donors because of the large reservoir of HCV in the transplanted organ. The
specific regimens are discussed below. (See 'Post-transplant regimen
selection' below.)
●Timing of treatment – We also agree with guidelines that suggest early
treatment, defined as starting within the first month after transplant, and
preferably within the first week, once the patient is clinically stable [77].
Randomized trials have not been performed to support a particular timeline.
However, in most published reports of using livers from HCV-viremic donors,
antiviral treatment is generally initiated once the recipient has confirmed
viremia following transplant and has achieved clinical stability; in some cases,
these criteria were met within a week of transplantation [71-73]. Early
treatment is favored because of the potential risk of severe complications,
such as fibrosing cholestatic HCV, a severe form of recurrent HCV.
(See 'Progression of liver disease post-transplant' above.)
The limited evidence supporting this approach is discussed elsewhere (see 'In
recipients without HCV infection' above). The risk of immunologic complications
(eg, rejection) in recipients of livers from HCV-viremic donors treated with DAA
therapy requires further study [69,73].
EVALUATION OF HCV INFECTION POST-TRANSPLANT
Assessment of HCV recurrence — Hepatitis C virus (HCV) reinfection of the graft
is detected by testing for HCV RNA. While there is no clear recommendation in
355
terms of timing of this testing, we recommend testing viral load and confirming
the HCV genotype when the patient is stable enough post-transplant to consider
initiating antiviral therapy. (See 'Timing' below.)
Staging of recurrent disease — Stage of liver disease (ie, presence or absence of
significant fibrosis or cirrhosis) may inform antiviral regimen selection (see 'Post-
transplant regimen selection' below) and other management considerations. For
routine assessment of post-treatment fibrosis stage, noninvasive measures of
fibrosis are adequate, as in the non-transplant setting. We use transient
elastography, since serum markers of fibrosis have not been well studied or
validated in the post-transplant setting.
Elastography, whether done as vibration-controlled transient elastography (VCTE;
eg, Fibroscan), ultrasound-based shear wave, or magnetic resonance
elastography, all appear to be relatively accurate measure of fibrosis stage in
transplant patients. For example, in a systematic review that pooled five studies of
patients with recurrent HCV infection post-transplant, the sensitivity and specificity
of ultrasound-based elastography for significant fibrosis were both 83 percent and
for cirrhosis were 98 and 84 percent, respectively [78]. (See "Noninvasive
assessment of hepatic fibrosis: Ultrasound-based elastography".)
Serum markers have also been evaluated in the transplant population, although
do not appear to be as accurate as ultrasound-based elastography [79,80].
(See "Noninvasive assessment of hepatic fibrosis: Overview of serologic and
radiographic tests".)
Prior to the availability of effective post-transplant treatment, many centers
performed routine liver biopsies to risk stratify patients for treatment. This
practice is now uncommon, and liver biopsy is generally reserved for patients with
evidence of liver injury (eg, aminotransferase elevation) in whom other causes,
including acute T cell-mediated (cellular) rejection (TCMR), are a concern. After the
early post-transplant period (ie, three to six months), however, rejection is
uncommon, and antiviral treatment for HCV infection may be undertaken
empirically in the setting of abnormal liver biochemical tests instead of pursuing
biopsy, since the likelihood that HCV is the cause is extremely high. (See "Liver
transplantation in adults: Clinical manifestations and diagnosis of acute T-cell
mediated (cellular) rejection of the liver allograft".)

Biopsy findings related to HCV infection are typically mild and nonspecific,
particularly with early recurrence. They include periportal inflammation, lobular
ballooning of hepatocytes, acidophilic bodies, or lobular apoptosis. Some of these
features are also seen in acute TCMR. Particular features supportive of recurrent
HCV are lobular activity, interface hepatitis, piecemeal necrosis, and lymphocyte

356
predominance or lymphoid follicles. Features that are more suggestive of rejection
include a mixed cellular infiltrate (eosinophils, polymorphonuclear cells, and
lymphocytes) confined to the portal triad, bile duct damage, and endotheliitis.
Nevertheless, differentiating rejection in the setting of HCV infection from HCV
infection alone can be difficult on pathologic grounds.

POST-TRANSPLANT ANTIVIRAL THERAPY

Benefits — All liver transplant recipients with HCV viremia should be treated.
Patients who achieve sustained virologic response (SVR) with treatment post-
transplant have lower rates of liver fibrosis progression and lower mortality rates
compared to those who fail therapy [81,82]. Accordingly, the short-term post-
transplant survival for HCV-associated liver disease has increased with increased
use of highly effective direct-acting antiviral (DAA) therapy [83,84]. As an example,
in a report of the United Network for Organ Sharing (UNOS) database, one-year
post-transplant survival rates from the "DAA era" (transplanted in 2014 and 2015)
were higher than from the "pre-DAA era" (transplanted in 2011 and 2012) (91.9
versus 89.8 percent) [83]. In addition, in a multivariable analysis, transplantation
during the DAA era was associated with a 34 percent reduction in one-year post-
liver transplant patient mortality, and post-transplant survival was similar or better
among patients transplanted for HCV-associated liver disease compared with
other indications.
The general benefits of SVR are discussed in detail elsewhere. (See "Patient
evaluation and selection for antiviral therapy for chronic hepatitis C virus
infection", section on 'Rationale for treatment'.)
Although studies evaluating the impact of interferon-based therapy had failed to
show differences in outcomes with early antiviral therapy post-transplant
compared with no treatment or treatment only after the development of
significant fibrosis [85,86], this is likely related to the low rates of SVR achieved
with such regimens.
Timing — The optimal timing of post-transplant treatment is uncertain, and the
decision must be made on an individual basis. Our approach is to treat patients as
soon as possible once they are clinically stable following transplant. In particular,
we prioritize treatment within the first month to prevent the risks of complications
including fibrosing cholestatic HCV. (See 'Progression of liver disease post-
transplant' above.)
Post-transplant regimen selection — Antiviral therapy should be administered at
centers with experience in managing post-transplantation patients. DAA
combination options for liver transplant recipients are more limited than in the
general population due to drug-drug interactions (see 'Interactions with

357
immunosuppressive agents' below), and fewer regimens have been formally
studied in post-transplant patients. Details on the optimal regimen choice and
durations are also evolving, as data informing these remain relatively limited.
As in the non-transplant setting, regimen options depend on the HCV genotype,
the presence of cirrhosis, drug-drug interactions, and comorbidities. Overall, our
suggestions are generally consistent with recommendations in the
joint guidelines from the American Association for the Study of Liver Diseases and
the Infectious Diseases Society of America (AASLD/IDSA) [77]. Selection among the
options for each patient population should also be informed by the potential for
drug interactions, in particular with immunosuppressant medications.
(See 'Patients without decompensated cirrhosis' below and 'Patients with
decompensated cirrhosis' below.)
The doses for the individual DAA agents used post-transplant do not differ from
those in the non-transplant setting and are discussed elsewhere (see "Direct-acting
antivirals for the treatment of hepatitis C virus infection"). When ribavirin is used,
the doses will be specified for the particular regimen (either low dose starting at
600 mg daily and increasing as tolerated or weight-based dosing at 1000 mg daily
for patients <75 kg or 1200 mg daily for patients ≥75 kg). The dosing of ribavirin
should also take into account the patient's creatinine clearance and hemoglobin
level.

Peginterferon-based regimens are not recommended because of the toxicity, the

overall poor response rates (in the absence of a DAA), and the risk of rejection.

Patients without decompensated cirrhosis — For HCV-infected liver transplant

recipients who do not have cirrhosis or have compensated cirrhosis, we suggest:
●Glecaprevir-pibrentasvir for 12 weeks
●Sofosbuvir-velpatasvir for 12 weeks
These are preferred options for any genotype. For patients with genotype 1, 4, 5,
or 6 infection, ledipasvir-sofosbuvir plus weight-based ribavirin (1000 mg daily for
patients <75 kg or 1200 mg daily for patients ≥75 kg) for 12 weeks is an alternative
option.

These regimens have well-documented safety and efficacy in the post-transplant

population.

For patients without cirrhosis:

●Glecaprevir-pibrentasvir: In an open-label trial of 100 transplant recipients

(80 were liver) with HCV infection of all genotypes and without cirrhosis,
358
 glecaprevir-pibrentasvir resulted in an SVR rate of 98 percent [87]. High SVR
rates were observed in both treatment-naïve and interferon-experienced
patients. The regimen was well tolerated; there was one mild liver transplant
rejection, which was thought unrelated to antiviral therapy.
●Sofosbuvir-velpatasvir: In an open-label trial that included 65 liver transplant
recipients with genotypes 1 through 4 infection and without cirrhosis,
sofosbuvir-velpatasvir resulted in an SVR rate of 97 percent [88]. No patients
experienced acute rejection, and the few serious adverse events were
deemed unrelated to therapy.
●Ledipasvir-sofosbuvir plus ribavirin: In two large trials (SOLAR-1 and SOLAR-
2, which respectively included 111 and 101 genotype 1- or 4-infected patients
without cirrhosis), ledipasvir-sofosbuvir plus weight-based ribavirin for 12
weeks resulted in SVR rates in 96 and 93 percent [44,58]. The regimen was
well tolerated. Large observational studies have also supported the high
efficacy and safety of ledipasvir-sofosbuvir in the liver transplant population;
in these studies, ribavirin was not associated with a higher SVR rate, but it is
unknown if unmeasured confounders impact the comparison [89-91]. Graft
rejection was rare in these studies. Efficacy in genotypes 5 and 6 is
extrapolated from studies in the non-transplant population. This regimen is
not used for genotype 2 or 3.
One large observational study has suggested that ribavirin is not necessary in
this population. Among approximately 500 post-transplant patients who were
treated with sofosbuvir plus an NS5A inhibitor (ledipasvir or daclatasvir) with
or without ribavirin for 12 to 24 weeks, SVR rates were 95 to 98 percent
among the approximately 400 who did not receive ribavirin and were not
different with the addition of ribavirin [92]. Nevertheless, pending further
data, we continue to use ribavirin, if tolerated, with sofosbuvir-ledipasvir and
sofosbuvir plus daclatasvir, since this is how the regimens were evaluated in
the above prospective trials.

For patients with compensated cirrhosis:

●Sofosbuvir-velpatasvir: In an open-label trial that included 14 liver transplant

recipients with genotypes 1 through 4 infection and cirrhosis, sofosbuvir-
velpatasvir resulted in an SVR rate of 93 percent [88]. No patients
experienced acute rejection, and the few serious adverse events were
deemed unrelated to therapy.
●Ledipasvir-sofosbuvir plus ribavirin: In two large trials (SOLAR-1 and SOLAR-
2, which respectively included 51 and 58 genotype 1- or 4-infected patients
with compensated cirrhosis [Child-Pugh class A]), ledipasvir-sofosbuvir plus
359
 weight-based ribavirin for 12 weeks resulted in SVR rates in 96 and 100
percent [44,58]. The regimen was well tolerated. As in patients without
cirrhosis, large observational studies have also supported the high efficacy
and safety of ledipasvir-sofosbuvir in the liver transplant population [89,90].
Graft rejection was rare in these studies. Efficacy in genotypes 5 and 6 is
extrapolated from studies in the non-transplant population. This regimen is
not used for genotypes 2 or 3.
One large observational study suggested that ribavirin was not associated
with improved SVR rates when added to sofosbuvir plus an NS5A inhibitor
(ledipasvir or daclatasvir), but the majority of patients in that study did not
have cirrhosis [92]. We continue to use ribavirin, if tolerated, with sofosbuvir-
ledipasvir and sofosbuvir plus daclatasvir, since this is how the regimens
were evaluated in the above prospective trials, but not with sofosbuvir-
velpatasvir (or glecaprevir-pibrentasvir).
Patients with decompensated cirrhosis — Antiviral treatment of post-transplant
patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or
gastroesophageal variceal hemorrhage; Child-Pugh class B or C) should only be
undertaken by or in close consultation with an expert in the management of such
patients. The main options for treatment-naïve patients include sofosbuvir-
velpatasvir plus low-dose ribavirin (600 mg daily with increase to 1000 mg as
tolerated) for 12 weeks or, for patients with genotypes 1, 4, 5, and 6
infection, ledipasvir-sofosbuvir plus low-dose ribavirin (600 mg daily with increase
to 1000 mg as tolerated) for 12 weeks.
Several antiviral regimens that contain a protease inhibitor are contraindicated in
patients with Child-Pugh classes B and C cirrhosis. These include glecaprevir-
pibrentasvir, elbasvir-grazoprevir, and sofosbuvir-velpatasvir-voxilaprevir.
Interactions with immunosuppressive agents — The immunosuppressive
regimen that an individual patient is on may limit the selection of the antiviral
agent or need to be modified.
In general, DAA regimens that contain a protease inhibitor have the potential to
increase drug levels of calcineurin inhibitors (cyclosporine and, to a lesser
extent, tacrolimus) and inhibitors of mammalian target of rapamycin
(mTOR; sirolimus and everolimus); some combinations are not recommended,
whereas other combinations warrant close monitoring of immunosuppressive
drug levels. Specific potential drug interactions are listed in the table (table 1).
Drug interactions can also be checked through the Lexicomp drug
interactions program included with UpToDate.
INVESTIGATIONAL THERAPIESPreliminary evidence suggests that antiviral
treatment initiated around the time of transplantation can prevent reinfection of
360
the new graft. In an open-label study, 16 patients with chronic HCV undergoing
their first liver transplantation received a single dose of ledipasvir-sofosbuvir the
day they arrived at the hospital for transplantation and once daily for four weeks
postoperatively [93]. The sustained virologic response rate 12 weeks after
completion of treatment was 88 percent (95% CI 62-98). In one patient with a
virologic relapse by four weeks post-treatment, a sustained virologic response was
achieved after retreatment with 12 weeks of ledipasvir–sofosbuvir. Additional
studies are needed to evaluate this approach.

Unlike hepatitis B virus, no effective immunoglobulin prophylaxis agents are

approved to prevent reinfection of the graft at the time of transplantation. Further,
such strategies are not needed given the high success with direct-acting antivirals
for HCV with a finite duration of therapy.

RETRANSPLANTATIONDisease recurrence may ultimately lead to graft failure

and the need for retransplantation. Indications and contraindications for
retransplantation remain unclear, and practices vary widely among institutions.
Historically, the prognosis for such patients has been poor (similar to
retransplantation for other indications) [94-102]. This was illustrated in a
multicenter study that compared survival following retransplantation in patients
with recurrent HCV with survival following retransplantation for other disorders
[103]. The one-year (69 versus 73 percent) and three-year (49 versus 55 percent)
survival rates were similar in the HCV and non-HCV groups. Model for End-Stage
Liver Disease (MELD) scores were not predictive of survival. Many patients were
not considered eligible for retransplantation and died from recurrent disease.

With the rapidly changing field of HCV treatment and likely improved safety and
efficacy of pre- and post-transplant HCV treatment, transplantation outcomes in
patients with advanced recurrent disease are likely to improve, and the need for
retransplantation in this setting will hopefully diminish over time.

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Hepatitis C infection in solid organ
transplant candidates and recipients" and "Society guideline links: Liver
transplantation".)
SUMMARY AND RECOMMENDATIONS
●Impact of DAA therapy – Hepatitis C virus (HCV)-associated cirrhosis has
been a common indication for liver transplantation, but the introduction of
well-tolerated, highly effective direct-acting antiviral (DAA) therapy for HCV is
361
reducing the need for liver transplantation in such patients and has
revolutionized the approach to management of transplant candidates and
recipients. Successful antiviral treatment of liver transplant recipients with
HCV infection reduces progression of liver fibrosis and mortality post-
transplant. (See 'Introduction' above and 'Post-transplant clinical
course' above and 'Benefits' above.)
●Deciding to treat before or after transplant – If not treated pretransplant,
HCV reinfection of the transplanted liver is near universal and can be a major
cause of graft failure without effective antiviral treatment post-transplant.
However, pretransplant antiviral therapy is not the optimal treatment
strategy for certain patients, and the decision to treat before or after
transplant should be individualized, taking into account the short-term
prognosis, the likelihood of meaningful response to therapy, access to
transplant, and other comorbidities. (See 'Considerations' above.)
In general, we suggest pretransplant antiviral therapy for patients with Child-
Pugh score A or B and Model for End-Stage Liver Disease (MELD) score <20 or
access to transplant through living donation or MELD exception points (when
the expected waiting time is less than one year) (Grade 2C). We suggest
deferring antiviral therapy until after transplantation for those with severe
portal hypertension or high MELD (eg, MELD >27) or with decompensated
cirrhosis and severe renal impairment (estimated glomerular filtration rate
[eGFR] <30 mL/min) (Grade 2C). Data informing the optimal approach are
limited. (See 'Approach' above.)
●Regimen selection for pretransplant antiviral treatment – Pretransplant
regimen selection depends on genotype, presence of cirrhosis, degree of
hepatic dysfunction, treatment history, and comorbidities. In particular, for
patients with decompensated cirrhosis, protease inhibitor-based regimens
are contraindicated. Regimen selection by genotype is discussed elsewhere.
(See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in
adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2
and 3 infection in adults" and "Treatment regimens for chronic hepatitis C
virus genotypes 4, 5, and 6 infection in adults".)
●Use of livers from HCV-viremic donors – With the advent of highly effective
antiviral therapy, including pangenotypic regimens and effective salvage
regimens for those who fail initial therapy, allocating livers from HCV-viremic
donors for HCV-negative recipients, in addition to HCV-viremic recipients,
with subsequent DAA therapy has become more common. Limited evidence
from small cohorts suggest this is a safe and effective strategy. (See 'Use of
grafts from HCV-viremic donors' above.)

362
●Post-transplant evaluation for HCV – The diagnosis of recurrent HCV
infection is based upon the detection of HCV RNA. We also perform genotype
testing. Among patients with prolonged post-transplant viremia, we use
transient elastography to assess fibrosis stage. (See 'Evaluation of HCV
infection post-transplant' above.)
●Post-transplant antiviral treatment – We recommend that all liver
transplant recipients with HCV viremia undergo antiviral therapy (Grade 1B).
Antiviral therapy should be administered at centers with experience in
managing post-transplantation patients. We aim to initiate antiviral therapy
as soon as possible once the patient is clinically stable following transplant,
ideally within the first month.
There are fewer data on the use of combination DAA regimens in liver
transplant recipients than in the general population. Regimen selection
depends on genotype and presence of decompensated cirrhosis. (See 'Post-
transplant regimen selection' above.)
•For patients without cirrhosis or with compensated cirrhosis, we
suggest glecaprevir-pibrentasvir for 12 weeks or sofosbuvir-velpatasvir for
12 weeks (Grade 2C). For patients with genotype 1, 4, 5, or 6
infection, ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks is
an alternative option.
•Antiviral treatment of post-transplant patients with decompensated
cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal
hemorrhage; Child-Pugh class B or C) should only be undertaken by or in
close consultation with an expert in the management of such patients.
Regimens containing protease inhibitors (eg, glecaprevir-pibrentasvir)
should not be used in decompensated cirrhosis.
•The immunosuppressive regimen that an individual patient is on may
limit the selection of the antiviral agent or need to be modified during
antiviral therapy (table 1).

363
Kidney transplantation in adults: Kidney
transplantation in patients with HIV
Authors:
Deirdre Sawinski, MD, FAST
Pablo Tebas, MD
Section Editors:
Daniel C Brennan, MD, FACP
Paul E Sax, MD
Christophe Legendre, MD
Deputy Editors:
Albert Q Lam, MD
Jennifer Mitty, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 30, 2021.
INTRODUCTIONKidney transplantation is accepted as the ideal therapy for
end-stage kidney disease (ESKD). Human immunodeficiency virus (HIV) infection
was traditionally considered an absolute contraindication for transplantation
because of the concern that immunosuppression would accelerate HIV disease
progression, resulting in increased mortality and a "waste" of organs [1].
Since potent antiretroviral therapy (ART) became widely available in 1996 [2], the
prognosis of patients with HIV infection has dramatically improved. There have
been significant decreases in morbidity and mortality, and, for many individuals
with well-controlled viral replication, HIV is now a chronic, manageable disease
[3,4].

Improvements in the long-term prognosis of those with HIV infection and studies
demonstrating good outcomes with kidney transplantation have prompted many
transplant programs to reevaluate their policies regarding the exclusion of
patients with HIV infection. A review of the issues surrounding kidney
transplantation inpatients with HIV is presented here.

An overview of kidney disease in patients with HIV and a discussion of HIV-

associated nephropathy (HIVAN) are presented elsewhere:

●(See "Overview of kidney disease in patients with HIV".)

●(See "HIV-associated nephropathy (HIVAN)".)

EPIDEMIOLOGY AND OUTCOMES

364
Patient and graft survival
Pre-ART era — Prior to the introduction of potent antiretroviral therapy (ART),
kidney transplantation was associated with poor patient and allograft outcomes in
patients with HIV [5]. In many patients, HIV infection was only diagnosed
retrospectively or acquired peritransplant by transfusion or transplantation with
infected organs. The improvement in patient survival with ART called into question
the previous policy of systematically denying transplantation to individuals with
HIV [1,6].
Transplantation in the ART era — Several studies have demonstrated
comparable patient and graft outcomes between HIV-infected and HIV-uninfected
patients who underwent kidney transplantation after the introduction of potent
antiretroviral therapy (ART) [7-19]. As an example, a prospective, nonrandomized
trial examined outcomes of kidney transplantation in 150 recipients with HIV who
had CD4 counts of ≥200 cells/microL and undetectable HIV RNA levels between
November 2003 and June 2009 [17]. Patient survival at one and three years was 95
and 88 percent, respectively; allograft survival was 90 and 74 percent, respectively.
These survival rates fell in between those for recipients older than 65 years of age
and those for all kidney transplant recipients, as reported by the Scientific Registry
of Transplant Recipients (SRTR). At a median follow-up of four years, patient and
allograft survival remained stable at 89 and 69 percent [19].
However, outcomes appear to be poorer among transplant recipients who are
coinfected with HIV and hepatitis C virus (HCV) [6-8]. As an example, in a
retrospective analysis of United Network for Organ Sharing (UNOS) data that
compared outcomes for 492 HIV-infected recipients and 147 HIV/HCV-coinfected
recipients, there was no significant difference in patient or allograft survival
between HIV-monoinfected recipients and an uninfected reference group [9].
However, an increased risk of mortality (hazard ratio [HR] 2.26, 95% CI 1.45-3.52)
and graft loss (HR 2.59, 95% CI 1.60-4.19) was observed in the HIV/HCV-coinfected
cohort.
The impact of new therapies for HCV on posttransplantation outcomes for
coinfected patients has yet to be determined, although limited data suggest a
beneficial effect of HCV treatment on outcomes [20]. A discussion of kidney
transplant in HCV-infected patients is found elsewhere. (See "Kidney
transplantation in adults: Hepatitis C infection in kidney transplant candidates and
recipients".)
In patients with HIV and end-stage kidney disease (ESKD), kidney transplantation
has been associated with a survival benefit over chronic dialysis. In a study of 1431
kidney transplant candidates with HIV, the risk of mortality at five years was
significantly lower among those who underwent kidney transplantation compared

365
with those who remained on dialysis (adjust relative risk [aRR] 0.21, 95% CI 0.10-
0.42), and a survival benefit was achieved at 194 days posttransplant [21]. Among
patients coinfected with HCV, kidney transplant was also associated with a lower
risk of death compared with dialysis, although the survival benefit was not
achieved until 392 days posttransplant. While kidney transplantation has become
more common among patients with HIV, the burden of ESKD remains high among
individuals with HIV despite ART, and they are less likely to achieve transplantation
than their uninfected counterparts [22].
Risk of rejection — Kidney transplant recipients with HIV have a high frequency of
rejection. In a large, multicenter trial, one- and three-year rejection rates were 31
and 41 percent, respectively, compared with an expected one-year rejection rate of
12 percent, as reported by SRTR for all kidney transplant recipients [17]. At
European transplant centers, where most patients are induced with interleukin
(IL)-2 receptor antibodies, one-year, acute rejection rates among recipients with
HIV have ranged from 15 to 44 percent [23-25].
The higher rate of rejection in recipients with HIV is likely multifactorial. Drug-drug
interactions between calcineurin inhibitors (CNIs) and protease inhibitors (PIs) can
lead to subtherapeutic exposure to immunosuppressive agents. Patients on a CNI
and PI require nonstandard dosing schedules (ie, every other or every third day),
which can make patient adherence difficult. Furthermore, concomitant
administration of a PI and CNI results in a 40 percent lower area under the curve
(AUC) for CNI exposure at the same CNI target level, leading clinicians to
systematically underdose patients taking both medications. In light of these
challenges, many transplant professionals seek to transition patients off PI-based
regimens whenever possible in favor of integrase inhibitor-based regimens, which
avoid these drug-drug interactions and permit standard immunosuppression
dosing (see "Overview of antiretroviral agents used to treat HIV", section on
'Integrase strand transfer inhibitors (INSTIs)'). Additionally, given concerns about
overimmunosuppression, many patients with HIV are given IL-2 receptor antibody
induction rather than lymphocyte-depleting agents, and this may also increase
their acute rejection risk. (See "Kidney transplantation in adults: Induction
immunosuppressive therapy", section on 'Recipients with HIV'.)
Malignancy — Kidney transplant patients are at increased risk for the
development of malignancy [26]. (See "Malignancy after solid organ
transplantation" and "Epidemiology and risk factors for skin cancer in solid organ
transplant recipients".)
Limited evidence suggests that HIV infection does not increase the risk for
posttransplant malignancy. In one large, multicenter trial of 150 transplant
recipients with HIV, only 13 (8.7 percent) developed cancer [27]. The most common

366
malignancy was skin cancer, and in 3.5 years of follow-up, there were three cancer-
related deaths.
Infection risk — Nonopportunistic infections are common in kidney transplant
recipients with HIV and mirror the trend seen in HIV-negative kidney transplant
recipients [28]. In one study, one-half of recipients were hospitalized within the
first six months posttransplant for infection [19]. HCV coinfection and induction
with antithymocyte globulin (ATG) increased the risk of posttransplant infection.
The most common etiologies were bacterial infections of the blood, urinary
system, or respiratory tract. Another study using SRTR data linked to Medicare
claims found no difference in posttransplant infection rates between different
types of induction [29].
ELIGIBILITY CRITERIAKidney transplantation is now accepted as "standard of
care" for HIV-positive patients with end-stage kidney disease (ESKD); however, the
majority of these transplants continue to be performed at large, academic medical
centers with robust transplant infectious disease support.
Kidney transplant candidates with HIV must meet center-specific, general
transplant candidate selection criteria in addition to HIV-specific criteria
(see "Kidney transplantation in adults: Evaluation of the potential kidney transplant
recipient"). There are no established HIV-specific selection criteria for recipients,
but most centers follow the patient selection criteria set forth in a National
Institutes of Health (NIH) multicenter trial [17], which specified that patients must
have an undetectable viral load and a CD4 count of >200 cells/microL on a stable
antiretroviral therapy (ART) regimen for at least six months. These criteria do not
exclude patients who have an isolated, low-level, detectable HIV RNA below 200
copies/mL (referred to as a viral blip). (See "Patient monitoring during HIV
antiretroviral therapy".)
Opportunistic infections (OIs) are no longer a cause for exclusion, but patients with
a history of Kaposi sarcoma, central nervous system (CNS) lymphoma, or
progressive multifocal leukoencephalopathy should be considered on a case-by-
case basis and may not be considered candidates at many centers. Patients who
are coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV) require
hepatology evaluation and an assessment of liver fibrosis. (See "Kidney
transplantation in adults: Hepatitis C infection in kidney transplant candidates and
recipients", section on 'HCV evaluation of transplant candidates' and "Kidney
transplantation in adults: Hepatitis B virus infection in kidney transplant
recipients", section on 'Pretransplantation assessment of HBV status'.)
PRETRANSPLANT EVALUATIONIn general, the pretransplant evaluation of
individuals with HIV is similar to that of individuals without HIV. This includes
screening for latent tuberculosis by tuberculin skin test (TST) or interferon-gamma
367
release assay and updating vaccinations. (See "Kidney transplantation in adults:
Evaluation of the potential kidney transplant recipient" and "Immunizations in
solid organ transplant candidates and recipients".)
In addition, the pretransplant evaluation includes obtaining an HIV viral load, CD4
count, and detailed HIV medication history. Candidates with HIV should be
evaluated for potential drug interactions between the patient's antiretroviral
therapy (ART) and planned immunosuppressive agents [30]. If possible, the ART
regimen should be switched to a regimen that does not include a protease
inhibitor or cobicistat because of their profound effects of the CYP3A4 system. In
general, integrase inhibitor-based regimens that include dolutegravir or
bictegravir are preferred. This is discussed in more detail elsewhere in this topic.
(See 'Management of antiretroviral therapy' below.)
PHARMACOLOGIC MANAGEMENTPharmacologic management in kidney
transplant recipients with HIV involves the administration of immunosuppression
in combination with potent antiretroviral therapy (ART).
Management of immunosuppression
Induction therapy — Options for induction immunosuppression therapy in kidney
transplant recipients with HIV include rabbit antithymocyte globulin (rATG)-
Thymoglobulin, interleukin (IL)-2 receptor antibodies, glucocorticoids,
and alemtuzumab, with the majority of transplant centers in the United States
using either rATG-Thymoglobulin or IL-2 receptor antibodies. The use of induction
immunosuppression in kidney transplant recipients with HIV is discussed in more
detail elsewhere. (See "Kidney transplantation in adults: Induction
immunosuppressive therapy", section on 'Recipients with HIV'.)
Maintenance therapy — In kidney transplant recipients with HIV, we, and most
centers transplanting recipients with HIV, administer triple immunosuppression
therapy as an initial maintenance regimen. This typically includes all of the
following:
●A calcineurin inhibitor (CNI; eg, tacrolimus)
●An antimetabolite (eg, mycophenolate)
●Prednisone
Such a regimen is similar to that used in HIV-uninfected transplant recipients.
(See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Although cyclosporine may have some antiviral effects in vitro
[31,32], tacrolimus is the preferred CNI in transplant recipients with HIV. In an
observational cohort study of 78 kidney transplant patients with HIV induced with
IL-2 receptor antibodies, use of tacrolimus as part of maintenance
immunosuppression was associated with a lower incidence of acute rejection
compared with cyclosporine (21 versus 58 percent, respectively) [25].
368
Posttransplant tacrolimus target levels may vary by transplant center and depend
upon the induction agent used, degree of allosensitization, and time
posttransplant. (See "Kidney transplantation in adults: Maintenance
immunosuppressive therapy", section on 'Target levels for calcineurin inhibitors'.)
Although the use of glucocorticoid-sparing regimens in kidney transplant
recipients with HIV has also been reported [33,34], we do not routinely discontinue
glucocorticoids in our patients. In addition, we do not routinely use mammalian
(mechanistic) target of rapamycin (mTOR) inhibitors (eg, sirolimus) as maintenance
immunosuppression in transplant patients with HIV. Although one secondary
analysis of data from a large, nonrandomized trial of kidney transplant recipients
with HIV found that maintenance immunosuppression that included sirolimus, but
not tacrolimus, was associated with lower posttransplant proviral DNA levels [35],
other studies in transplant recipients with HIV have shown that use of sirolimus
was associated with a significantly higher risk of acute rejection (adjusted hazard
ratio [aHR] 2.15, 95% CI 1.20-3.87) [36].
Management of antiretroviral therapy — Patients being considered for
transplant must be virologically suppressed on a stable ART regimen. The main
considerations about ART in a potential kidney transplant recipient are toxicities
and drug interactions. Thus, the patient's regimen may need to be modified.
Consultation with an HIV medicine expert is recommended before switching
regimens.

Potential modifications include:

●Nucleos(t)ide (NRTI) combination – For patients receiving a tenofovir-

containing regimen, the provider must decide which formulation of tenofovir
to use. There are two formulations of tenofovir, tenofovir disoproxil
fumarate (TDF) and tenofovir alafenamide (TAF). There is more clinical
experience with TDF; however, TAF has less kidney and bone toxicity.
•For patients with an estimated glomerular filtration rate (eGFR) >15
mL/min/1.73 m2, we prefer TAF plus emtricitabine (FTC). For those with an
eGFR >30 mL/min/1.73 m2, the coformulated tablet of TAF-FTC can be
used. For those with an eGFR between 15 and 30 mL/min/1.73 m2, TAF and
FTC (or the closely related agent lamivudine [3TC]) must be given
separately and the dose of FTC or 3TC adjusted according to kidney
function.
•For patients with an eGFR of <15 mL/min/1.73 m2, including those on
dialysis, we typically administer TDF plus either FTC or 3TC; all of these
agents must be adjusted according to kidney function. After
transplantation, and when the eGFR is >15 mL/min/1.73 m2, the
369
 nucleoside regimen can be switched to TAF-FTC as described above.
However, in the pretransplant setting, TDF is still used in patients with an
eGFR <15 mL/min/1.73 m2 and in those on dialysis, given the paucity of
data using TAF in this setting.
If TDF or TAF cannot be used (eg, adverse reaction or concerns about
toxicities such as osteoporosis with TDF), an alternative option is abacavir (no
renal adjustment necessary) and dose-adjusted FTC or 3TC; however, the
patient must first be tested for HLA-B5701 as abacavir is contraindicated in
patients who are HLA-B5701 positive.
●Choice of third agent – Some patients will have virologic suppression on an
initial regimen that includes an NRTI combination with a protease inhibitor
(PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) as the third
agent. Both PIs and NNRTIs are associated with an increased risk of drug
interactions (see 'Drug interactions' below). In addition, among kidney
transplant recipients with HIV, the use of PI-based regimens has been
associated with a higher risk of allograft loss (particularly in the first year
after transplantation) and death compared with the use of non-PI-based
regimens [37]. Thus, in kidney transplant candidates with HIV who are on a
PI, we generally convert to an integrase strand transfer inhibitor (INSTI)-
based regimen prior to transplantation.
Patients who are virologically suppressed on their initial regimen can usually
continue their NRTI combination and have the third agent switched to an
INSTI since preexisting integrase resistance is very rare [38]. INSTIs are
generally preferred as the third agent because they are less likely to result in
drug interactions.
For most patients, we prefer dolutegravir as the INSTI; however, raltegravir is
an acceptable alternative if drug interactions or cost preclude the use of
dolutegravir. We typically avoid elvitegravir because it is only available in a
coformulated tablet that is not suitable for patients with end-stage kidney
disease (ESKD). In addition, there is an increased risk of drug interactions
with elvitegravir because it requires cobicistat as a boosting agent.
Bictegravir is available as a single tablet combination with emtricitabine and
TAF and can be used in patients with an eGFR >30 mL/min/1.73 m2 when the
kidney function has stabilized after the transplant; however, experience with
this agent is limited in the transplant population. Special considerations
regarding the use INSTIs in persons of childbearing potential are discussed
elsewhere. (See "HIV and women".)
The approach to antiretroviral treatment in patients who have drug-resistant
virus can be complicated in the transplant setting since a PI, which puts

370
 patients at increased risk for drug interactions, is often used. A more detailed
discussion of how to select a regimen for patients with drug-resistant virus is
found elsewhere. (See "Selecting an antiretroviral regimen for treatment-
experienced patients with HIV who are failing therapy".)
Drug interactions — PIs require dosing with a boosting agent,
like ritonavir or cobicistat. Ritonavir is a potent inhibitor of the cytochrome P450
system, the main metabolic pathway for CNIs [39-41]. Thus, PIs can significantly
reduce metabolism and increase the blood levels of CNIs (table 1 and table
2 and table 3) [42]. In addition, the PI atazanavir should be used with caution
because the use of proton pump inhibitors, which are frequently used in
transplantation, interferes with its absorption.
Cobicistat is another potent CYP3A4 antagonist that, like ritonavir, can be used to
boost PIs and the integrase inhibitor elvitegravir. Patients concomitantly receiving
CNIs and a PI or cobicistat will require significant dose adjustments in the CNI. For
patients on cyclosporine, a typical dose would be 25 mg every 24 to 48 hours,
while those on tacrolimus-based regimens may require 0.5 to 1 mg every five to
eight days [43,44].
By contrast, NNRTIs are inducers of cytochrome P450 and can lead to low levels of
CNIs when the drugs are coadministered; however, the potency of this effect
varies among members of the NNRTI class. Patients taking an NNRTI and CNI
together usually require a 1.5- to 2-fold increase in CNI dose to achieve target
trough levels [45].
Maraviroc, an entry inhibitor, also interacts with ritonavir and should be used
cautiously in patients receiving PIs. However, it is neither an inhibitor nor inducer
of CYP3A4, and, therefore, it does not affect CNI levels. There is an ongoing multi-
center trial investigating the adjuvant use of maraviroc to mediate the elevated
acute rejection risk observed in this patient population; however, a separate
single-center report did not demonstrate a benefit on acute rejection rates [46].
Raltegravir, dolutegravir, and bictegravir have a low potential for interactions with
other antiretrovirals or other drugs used for the management of transplants and
are preferentially used in transplant recipients. Elvitegravir, an integrase inhibitor,
is always used in combination with cobicistat, and the expected interactions should
be similar to any regimen that includes ritonavir.
MONITORING AFTER TRANSPLANTATION
Kidney allograft function — Kidney transplant patients with HIV should receive
the same routine posttransplant monitoring as recipients without HIV. From a
laboratory perspective, this will involve serial chemistry panels to monitor kidney
function and electrolytes; complete blood count to assess leukocytes, hemoglobin,
and platelet counts; and measurement of calcineurin inhibitor (CNI) trough levels.
371
However, in patients taking antiretroviral therapy (ART) regimens that do not
permit standard CNI dosing, it is reasonable to obtain these laboratory tests more
frequently than the usual standard of care. (See "Kidney transplantation in adults:
Overview of care of the adult kidney transplant recipient", section on 'Routine
follow-up and laboratory monitoring'.)
HIV viral control — Regular monitoring of the HIV viral load and CD4 count is
recommended after kidney transplantation at one month and then every three
months posttransplant; this is particularly important if the ART was modified in the
period after the transplantation. More detailed discussions of patient monitoring
and the evaluation of a patient with a detectable viral load on therapy are
presented elsewhere. (See "Evaluation of the treatment-experienced patient failing
HIV therapy" and "Patient monitoring during HIV antiretroviral therapy".)
PROPHYLAXIS AFTER TRANSPLANTATIONLike other solid organ
recipients, kidney transplant recipients with HIV require prophylaxis against the
most common posttransplant opportunistic infections (OIs),
namely Pneumocystis pneumonia, cytomegalovirus (CMV), and fungal infections.
Antimicrobial prophylaxis is also recommended for all patients with latent
tuberculosis who were not treated prior to transplant. Prophylaxis against
toxoplasmosis is provided by the use of trimethoprim-sulfamethoxazole (TMP-
SMX). This agent also provides prophylaxis against urinary tract infections.
The optimal duration of TMP-SMX prophylaxis in transplant recipients with HIV
varies by institution. Some centers continue lifelong TMP-SMX based upon the
protocols used in the National Institutes of Health (NIH) trial [17], whereas others
administer TMP-SMX for a shorter duration, depending in part upon the CD4 count
[47-50].
For patients who have a sulfa allergy, options include atovaquone or dapsone.
Patients receiving dapsone should be assessed for glucose-6-phosphate
dehydrogenase (G6PD) deficiency. In addition, dapsone is a sulfone, and, although
it is usually tolerated by persons who have adverse reactions to TMP-SMX, it may
be prudent to avoid dapsone in patients who have had serious reactions to TMP-
SMX (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis, rash with fever
and systemic symptoms, serum sickness, or hemolytic anemia). (See "Sulfonamide
allergy in HIV-uninfected patients", section on 'Cross-reactivity'.)
POSTTRANSPLANTATION COMPLICATIONS
HIV infection of the allograft — HIV may be capable of infecting kidney allografts
even in patients with undetectable viral loads and on antiretroviral therapy (ART).
This was shown in a French study of 19 patients with HIV who had no evidence of
HIV viremia at the time of transplantation [51]. Using in situ hybridization, HIV RNA
was demonstrated in 13 patients in either podocytes or tubular cells on protocol
372
biopsies obtained at 3 and 12 months after transplantation. In five patients with
infected podocytes, there was histologic evidence of focal and segmental
glomerulosclerosis and early-onset, nephrotic-range proteinuria with a decline in
kidney function. Patients with tubular infection had a more benign course; only
one patient in this group developed end-stage kidney disease (ESKD). No
association was seen with viral tropism (CXCR4 versus CCR5) or apolipoprotein L1
(APOL1) genotype. A quantitative polymerase chain reaction (PCR) assay for HIV
RNA and DNA in the urine has been developed to identify patients with infected
allografts, but this remains experimental. This phenomenon has not been
observed in other, larger studies [17,52,53].
Opportunistic infections — Infections are more likely related to the
posttransplant immunosuppressive state, rather than to the HIV infection, since all
transplant programs require full control of viral replication and a CD4 count of
>200 cells/microL prior to transplantation for kidney transplants. (See 'Eligibility
criteria' above.)
Prophylaxis against opportunistic infections (OIs) is indicated for this patient
population after transplantation [54]. (See 'Prophylaxis after
transplantation' above.)
Delayed graft function — Delayed graft function (DGF) is defined as the
requirement for dialysis in the first week after transplant and is a risk factor for
graft loss in both recipients with and without HIV [55]. An analysis of the United
Network for Organ Sharing (UNOS) database confirmed the high rates of DGF in
recipients with HIV (42.5 percent) as well as its negative impact on allograft
survival (hazard ratio [HR] 1.86, 95% CI 1.27-2.73) [56].
Retransplantation — Patients whose first allograft fails can be considered for
retransplantation; second kidney transplants now comprise 13.1 percent of the
general waiting list [57]. One study [58] examined outcomes for 22 patients with
HIV who were retransplanted, compared with 4127 HIV-negative matched controls.
Unfortunately, in this analysis, patients with HIV who had a second transplant had
a 3.1-fold higher risk of death and a 1.96-fold increased risk of allograft loss,
questioning the utility of the practice.
SPECIAL CONSIDERATIONS
Donors with HIV — The National Organ Transplantation Act, passed in 1984,
specifically forbid organ donation by persons with HIV. However, as the transplant
waitlist has grown, outstripping the available supply of organs, there has been
renewed interest in use of donors with HIV infection.
The most extensive experience with the use of HIV-positive-to-HIV-positive
transplants comes from South Africa [52,53,59]. In this case series, 51 patients with
HIV underwent transplantation with kidneys from deceased donors who tested
373
positive for HIV using a fourth-generation enzyme-linked immunosorbent assay
(ELISA) [59]. To be eligible, transplant recipients had to have received antiretroviral
therapy (ART) for at least three months, have a CD4 T cell count of ≥200
cells/microL, and have an undetectable HIV RNA level. Potential recipients were
excluded who had any history of previous opportunistic infections (OIs), except
treated pulmonary tuberculosis.

The deceased donors had received either no or only first-line ART and had
undetectable HIV viral loads. Potential donors were excluded if they had severe
sepsis, active tuberculosis, stage 4 HIV disease (ie, acquired immunodeficiency
syndrome [AIDS]), abnormal kidney function, or proteinuria. All had normal kidney
biopsies at the time of transplantation.

Patient survival was 87, 87, and 84 percent at one, three, and five years,
respectively. Death-censored graft survival was 96, 93, and 79 percent at one,
three, and five years, respectively. Acute rejection was 25, 39, and 44 percent at
one, three, and five years, respectively. The HIV viral load remained suppressed in
all patients. However, low levels of donor HIV were detected in one recipient,
raising the possibility of superinfection.

In the United States, Congress passed the HIV Organ Policy Equity (HOPE) Act in
2013, which permits research in the area of HIV-positive-to-HIV-positive
transplantation. The first transplantation from a donor with HIV to a recipient with
HIV was performed in March of 2016 at Johns Hopkins [60-62], and since then,
several deceased, HIV-positive donor kidney transplantations have been
performed. In a multicenter pilot study that compared outcomes of 25 recipients
of an HIV-positive donor kidney with those of 50 recipients of an HIV-negative
donor kidney, one-year patient and graft survival were comparable between the
groups [63]. However, there was a trend toward higher rates of acute rejection
among recipients of HIV-positive donor kidneys (50 versus 29 percent). In March
2019 Johns Hopkins performed the first living-donor, HIV-positive kidney
transplantation under the HOPE Act, but concerns regarding the safety of the
practice, given the risk of kidney disease associated with HIV infection, remain.
Selection criteria for donors with HIV were published by the Department of Health
and Human Services in November 2015 [64]. While the overall number of HIV-
positive donors procured in the United States has not yet approached prior
estimates [65], an unanticipated benefit of the HOPE Act has been the utilization of
donors with false-positive HIV testing results [66,67]. Recipients of donors with HIV

374
have the same HIV-specific selection criteria as those receiving HIV-negative
transplants. (See 'Eligibility criteria' above.)

Deceased donors with HIV do not have a CD4 count or HIV viral load requirement
but must have no evidence of invasive opportunistic complications of HIV infection,
and a preimplantation donor kidney biopsy must be performed.

Living donation of organs from individuals with HIV is permitted under the HOPE
Act. Potential living donors must meet center-specific, living-donor criteria and, in
addition, must have a CD4 count of >500 cells/microL, an HIV viral load <20
copies/mL (the level of detection by most available assays), and no prior history of
invasive OIs. All potential donors must undergo a kidney biopsy prior to donation.

There are also eligibility criteria for centers wishing to perform HIV-positive-to-HIV-
positive transplants; they must first have demonstrated experience with HIV-
negative to HIV-positive transplantation, have infectious disease programmatic
support, have established standard operating procedures for the safe handling of
organs from individuals with HIV, have a biohazard plan in place to prevent
inadvertent disease transmission, have institutional review board approval, and
have an approved variance from the United Network for Organ Sharing (UNOS).

One important concern regarding the use of donors infected with HIV for
transplantation has been the potential transmission of virus from the donor. Use
of deep phenotyping has demonstrated that donor-derived virus can be detected
in recipients of HIV-positive organs, but so far the presence of donor viral strains
has only been transient and has not impacted recipient HIV viral control [59,68].
Coinfection with HBV or HCV — Due to shared transmission routes, many
patients with HIV are coinfected with hepatitis B virus (HBV) and/or hepatitis C
virus (HCV). For those who are not coinfected with HBV or HCV, routine screening
for these viruses pre- and posttransplantation is indicated [69], as discussed
elsewhere. (See "Kidney transplantation in adults: Evaluation of the potential
kidney transplant recipient", section on 'Initial screening studies' and "Kidney
transplantation in adults: Overview of care of the adult kidney transplant
recipient", section on 'Screening'.)
HBV infection — Patients with HIV undergoing kidney transplantation who also
have chronic or resolved hepatitis B virus (HBV) should be treated with a tenofovir-
containing ART regimen. Tenofovir is considered a first-line agent for the
treatment of HBV and can also prevent reactivation in the setting of
immunosuppressive therapy. Both tenofovir formulations (tenofovir disoproxil
375
fumarate [TDF] and tenofovir alafenamide [TAF]) are equally effective in
maintaining HBV suppression, but TAF may be preferred in the posttransplant
setting because it is less nephrotoxic. More detailed discussions of the
management of patients with HBV infection, including those who cannot take
tenofovir, are discussed elsewhere. (See 'Management of antiretroviral
therapy' above and "Treatment of chronic hepatitis B in patients with
HIV" and "Hepatitis B virus reactivation associated with immunosuppressive
therapy".)
HCV infection — Outcomes for HIV/hepatitis C virus (HCV)-coinfected kidney
transplant recipients have been inferior to those with HIV infection alone across
several large registry studies [7-9] with an approximately 1.4-fold increased risk of
death. (See 'Transplantation in the ART era' above.)
Since the clinical availability of direct-acting antivirals (DAAs) for the treatment of
HCV, there has been optimism that clearance of HCV infection will improve
outcomes for this population [70-74], but this has not been prospectively studied
in coinfected HIV/HCV transplant recipients. In one case report of six HIV/HCV-
coinfected kidney transplant recipients treated with ledipasvir-sofosbuvir, 100
percent of patients achieved a sustained viral response at 12 weeks after
completion of therapy, and HCV treatment was well tolerated
[75]. Tacrolimus dosing needed adjustment during and after therapy, but no
changes to antiretroviral regimens were required. One small study demonstrated
improved patient and allograft survival in HIV/HCV coinfected recipients who were
treated posttransplantation with DAAs [20], but this beneficial effect remains to be
demonstrated in larger patient cohorts.

ART should not be interrupted to facilitate HCV treatment but, in some cases, may
need to be modified. Treatment of HCV in HIV/HCV-coinfected kidney transplant
recipients should be coordinated with a transplant infectious disease clinician.

Detailed discussions of the management of HIV/HCV coinfected patients and the

management of HCV-infected patients undergoing transplant are found
elsewhere. (See "Treatment of chronic hepatitis C virus infection in the patient with
HIV" and "Kidney transplantation in adults: Hepatitis C infection in kidney
transplant candidates and recipients".)
FUTURE DIRECTIONSThere is interest in the use of maraviroc, a CC
chemokine receptor 5 (CCR5) inhibitor, to improve survival in kidney transplant
recipients with HIV. CCR5 is a coreceptor of HIV-1. (See "Overview of antiretroviral
agents used to treat HIV", section on 'Entry inhibitors' and "Transplantation
immunobiology".)

376
Approximately 1 percent of White individuals are homozygous carriers of an allele
of the gene for CCR5 with a 32-base-pair deletion (CCR5del32), which leads to an
inactive receptor [76]. Individuals with CCR5del32 are highly resistant to infection
with HIV-1 [77,78]. Other studies have also demonstrated that individuals that are
homozygous for this gene have a lower risk of asthma, rheumatoid arthritis, and
multiple sclerosis [79-81]. They may also have superior allograft survival after
transplantation.
The relationship between kidney allograft survival and CCR5 genotype was
evaluated in one study [82]. Among 1227 kidney transplant recipients, 21 were
homozygous for CCR5del32, and 248 were heterozygous for CCR5del32. Allograft
survival was superior in individuals who were homozygous for CCR5del32 (hazard
ratio [HR] 0.367, 95% CI 0.157-0.859). The exact mechanism of this improved
survival is unknown. (See "Kidney transplantation in adults: Risk factors for graft
failure", section on 'Gene polymorphisms'.)
Given these findings, a clinical trial (NCT02741323) evaluating the effects
of maraviroc is in progress.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Solid organ transplantation in individuals
with HIV".)
SUMMARY AND RECOMMENDATIONS
●General principles – Human immunodeficiency virus (HIV) infection was
traditionally considered an absolute contraindication for transplantation
because of the concern that immunosuppression would accelerate HIV
disease progression, resulting in increased mortality and a "waste" of organs.
However, improvements in the long-term prognosis of those with HIV
infection and studies demonstrating good outcomes with kidney
transplantation have prompted many transplant programs to reevaluate
their policies regarding the exclusion of patients with HIV infection.
(See 'Introduction' above.)
●Epidemiology and outcomes – Since the introduction of potent
antiretroviral therapy (ART), several studies have demonstrated comparable
patient and graft outcomes in patients with and without HIV who underwent
kidney transplantation. However, outcomes appear to be poorer among
transplant recipients who are coinfected with HIV and hepatitis C virus (HCV).
In addition, transplant recipients with HIV are at an increased risk of rejection
and malignancy posttransplant. (See 'Epidemiology and outcomes' above.)
●Eligibility criteria – Kidney transplantation is now accepted as "standard of
care" for patients with HIV and end-stage kidney disease (ESKD); however, the
377
majority of these transplants continue to be performed at large, academic
medical centers with robust transplant infectious disease support. Kidney
transplant candidates with HIV must meet center-specific, general transplant
candidate-selection criteria in addition to HIV-specific criteria. There are no
established HIV-specific selection criteria for recipients, but most centers
follow the patient-selection criteria set forth in a National Institutes of Health
(NIH) multicenter trial, which specified that patients must have a viral load
below the limit of detection and a CD4 count of >200 cells/microL on a stable
ART regimen for at least six months. History of treated opportunistic
infections (OIs) is not a cause for exclusion, but patients with a history of
Kaposi sarcoma, central nervous system (CNS) lymphoma, or progressive
multifocal leukoencephalopathy should be considered on a case-by-case
basis and may not be considered candidates at many centers. Patients who
are coinfected with HCV or hepatitis B virus (HBV) require hepatology
evaluation and an assessment of liver fibrosis. (See 'Eligibility criteria' above.)
●Pharmacologic management – Pharmacologic management in kidney
transplant recipients with HIV involves the administration of
immunosuppression in combination with potent ART:
•Options for induction immunosuppression therapy include rabbit
antithymocyte globulin (rATG)-Thymoglobulin, interleukin (IL)-2 receptor
antibodies, glucocorticoids, and alemtuzumab, with the majority of
transplant centers in the United States using either rATG-Thymoglobulin
or IL-2 receptor antibodies. (See 'Induction therapy' above.)
•In kidney transplant recipients with HIV, most centers administer triple
immunosuppression therapy as an initial maintenance regimen. This
typically includes a calcineurin inhibitor (CNI; eg, tacrolimus), an
antimetabolite (eg, mycophenolate), and prednisone. Such a regimen is
similar to that used in HIV-negative transplant recipients.
(See 'Maintenance therapy' above.)
•Patients being considered for transplant must be virologically suppressed
on a stable ART regimen. The main considerations about ART in a
potential kidney transplant recipient are toxicities and drug interactions.
Thus, the patient's regimen may need to be modified. (See 'Management
of antiretroviral therapy' above.)
●Monitoring after transplantation – Kidney transplant patients with HIV
should receive the same routine, posttransplant monitoring as HIV-negative
recipients. From a laboratory perspective, this will involve serial chemistry
panels to monitor kidney function and electrolytes; complete blood count to
assess leukocytes, hemoglobin, and platelet counts; and measurement of CNI

378
trough levels. In patients taking ART regimens that do not permit standard
CNI dosing, it is reasonable to obtain these laboratory tests more frequently
than the usual standard of care. Regular monitoring of the HIV viral load and
CD4 count is recommended after kidney transplantation at one month and
then every three months posttransplant; this is particularly important if the
ART was modified in the period after the transplantation. (See 'Monitoring
after transplantation' above.)
●Prophylaxis after transplantation – Kidney transplant recipients with HIV
require prophylaxis against the most common posttransplant OIs,
namely Pneumocystis pneumonia, cytomegalovirus (CMV), and fungal
infections. Antimicrobial prophylaxis is also recommended for all patients
with latent tuberculosis who were not treated prior to transplantation.
(See 'Prophylaxis after transplantation' above.)

379
Liver transplantation for chronic hepatitis B virus
infection
Author:
Anna SF Lok, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 09, 2020.
INTRODUCTIONDespite advances in treatment of chronic hepatitis B virus
(HBV) infection, liver transplantation remains the only hope for many patients with
end-stage liver disease due to HBV. In a study of the natural history of HBV-related
cirrhosis in the pre-nucleos(t)ide analogue era, the five-year survival was 71
percent for the entire group of patients, but only 14 percent for those with
decompensated disease (figure 1) [1].
The initial results with liver transplantation for chronic hepatitis B in the 1980s
were disappointing, with graft reinfection rates approaching 80 to 100 percent [2-
4]. In many patients, reinfection was associated with severe and rapidly
progressive liver disease, resulting in two-year graft and patient survival of 50
percent compared to 80 percent in those transplanted for other types of chronic
liver disease [5]. With these poor results and limited supply of donor organs, many
centers and third-party payers abandoned liver transplantation for patients with
chronic hepatitis B [6].
Since the late 1980s, the introduction of effective measures to prevent and treat
reinfection using strategies involving hepatitis B immune globulin (HBIG) and
subsequently nucleos(t)ide analogues have significantly improved the outcome of
liver transplantation [7-10]. The overall survival of patients transplanted for HBV-
related cirrhosis exceeds 85 percent at one year and 75 percent at five years [7,10-
14]. Furthermore, rates of transplantation for HBV-related end-stage liver disease
have dropped substantially, with a 24 percent decrease in liver transplantation
waiting list registrations since 2010 [15,16].
HBV REINFECTION AFTER LIVER TRANSPLANTATIONThe high rate of
hepatitis B virus (HBV) reinfection after liver transplantation is probably due to
enhanced virus replication resulting from immunosuppression and direct
stimulatory effects of steroid therapy on the glucocorticoid-responsive enhancer

380
region of the HBV genome [17,18]. Extrahepatic reservoirs of HBV, such as
peripheral blood mononuclear cells, spleen, and other organs, may also contribute
to graft reinfection [19].
Risk factors for reinfection — Patients with HBV-related cirrhosis who are eligible
for transplantation can be conceptually divided into those with high versus low risk
of reinfection.
●High-risk patients include patients with cirrhosis who are hepatitis B e
antigen (HBeAg) positive or HBeAg negative but with high serum HBV DNA
levels, and patients with antiviral drug-resistance prior to transplant [19-21].
●Low-risk patients include patients with fulminant HBV, coinfection with HDV,
and patients with cirrhosis and low serum HBV DNA levels either
spontaneously or as a result of nucleos(t)ide analogue therapy [13].
The cutoff for high versus low HBV DNA levels in the transplant setting has not
been determined. One study of 177 patients reported that HBV recurrence
occurred in 50, 7.5, and 0 percent of patients whose serum HBV DNA at the time of
transplant were higher than 100,000, 200 to 100,000, and less than 200 copies/mL,
respectively [21]. The authors concluded that serum HBV DNA higher than 5
log10 copies/mL at the time of transplant was associated with significantly higher
risk of HBV recurrence.
It should be emphasized that this study included patients transplanted between
1990 and 2002 when hepatitis B immune globulin (HBIG) monotherapy and
subsequently combination of hepatitis B immune globulin (HBIG)
and lamivudine were the only prophylactic therapies available, and HBV recurrence
rate in the high-risk group was 50 percent [21]. The authors concluded that serum
HBV DNA higher than 100,000 copies/mL (~20,000 IU/mL) at the time of transplant
was associated with significantly higher risk of HBV recurrence.
De novo HBV infection/reactivation — The risk of a hepatitis B surface antigen
(HBsAg)-negative recipient acquiring HBV infection following liver transplantation
from a hepatitis B core antibody (anti-HBc)-positive donor is generally low, but
rates as high as 80 percent have been reported [22,23].
The risk of acquiring HBV infection may be higher from donors who are HBsAg
negative but anti-HBc positive [24,25]. One of the largest studies to address this
issue found that hepatitis B (HBsAg-positive hepatitis) developed in 18 of 23 (78
percent) recipients of liver transplants from anti-HBc-positive donors, compared
with only 3 of 651 (0.5 percent) recipients of livers from anti-HBc-negative donors
[26]. The HBV infection was mild in most cases; 50 percent of patients had normal
serum aminotransferases, while 85 percent had no or only mild inflammatory
activity on liver biopsy one year after transplantation. Nevertheless, liver

381
transplantation from an anti-HBc-positive donor was associated with a decreased
four-year survival.
A second study looked at 64 patients who were anti-HBc negative and received a
liver from a donor who was HBsAg negative but anti-HBc positive [27]. De novo
HBV infection developed in nine patients (14 percent). De novo HBV infection was
not associated with an increased risk of death or graft rejection at one and five
years, and no graft loss or death was attributed to de novo HBV infection.
Eliminating livers from anti-HBc-positive individuals could result in a significant
reduction in the potential donor pool, particularly in countries where HBV infection
is endemic. Optimal strategies to prevent de novo infection in this setting have not
been established. Reserving livers that are anti-HBc positive for recipients with
chronic hepatitis B is one potential approach, since such patients will be receiving
hepatitis B antiviral prophylaxis [26,28]. Recipients who have hepatitis B surface
antibody (anti-HBs) and/or anti-HBc at the time of transplantation are also less
likely to develop de novo infection after receiving a graft from an anti-HBc-positive
donor [22,24-26,29-34]. The lowest risk of de novo infection is in recipients who are
anti-HBs and anti-HBc positive. Intermediate risk is seen in recipients who are anti-
HBs positive and anti-HBc negative (mean 21 percent) or are anti-HBs negative and
anti-HBc positive (mean 12 percent). The highest risk is seen in patients who are
both anti-HBs and anti-HBc negative (mean 76 percent).
Various prophylactic regimens have been reported to prevent de novo HBV
infection when livers from HBsAg negative, anti-HBc-positive donors are
transplanted into HBsAg-negative recipients. Many were based upon regimens
that included lamivudine monotherapy [35]. However, most studies involved small
numbers of patients with short duration of follow-up. In a systematic review
looking at patients who received livers from donors who were HBsAg negative and
anti-HBc positive, the rate of de novo HBV infection in 110 patients given
lamivudine prophylaxis was 3.6 percent after a mean follow-up of 25 months
[36]. Entecavir and tenofovir, which are associated with lower rates of drug
resistance, may be more appropriate as life-long treatment will be required [37].
HBIG prophylaxis has been studied for recipients who are HBsAg negative. One
study included 56 HBsAg-negative patients who received livers from HBsAg
negative, anti-HBc-positive donors [38]. HBV infection occurred in 8 of 45 (18
percent) recipients who received prophylaxis compared with 7 of 11 (64 percent)
recipients who did not. The rate of infection was highest among HBV-seronegative
patients who did not receive prophylaxis (five of five patients) and was
intermediate among HBV-immune recipients (two of six patients; 33 percent). HBV-
seronegative patients who received prophylaxis also had an intermediate rate of
infection (6 of 19; 32 percent). Recipients who were HBV-immune and received

382
prophylaxis had low rates of infection (2 of 26; 8 percent). These data confirm a
high rate of transmission of HBV infection from liver grafts of HBsAg negative,
anti-HBc-positive donors. The low efficacy of HBIG in preventing HBV transmission
is not surprising because HBIG is not effective in inhibiting HBV replication in the
liver.
HBIG prophylaxis has also been combined with lamivudine with improved results
compared with HBIG monotherapy. A systematic review examined patients who
received livers from donors who were HBsAg negative and anti-HBc positive. The
rate of de novo HBV infection in the 73 patients who received HBIG and lamivudine
prophylaxis was 3.6 percent after a mean follow-up of 31 months [36]. However,
the de novo infection rate for combination therapy with HBIG and lamivudine was
similar to that seen for lamivudine monotherapy (2.7 percent), suggesting that the
addition of HBIG to the regimen does not provide any added benefit.
De novo HBV infection has also been reported after liver transplantation from
donors who are serologically negative for HBV markers [22,39,40]. These donors
are thought to have occult HBV infection because of the presence of HBV DNA in
their sera or liver tissue. Although the risk of reactivation appears to be low [40],
routine HBV vaccination prior to liver transplantation may prevent this problem
and should be recommended to all liver transplant candidates. Unfortunately, the
success of hepatitis B vaccination in this group of older individuals with poor
immune response secondary to cirrhosis has been disappointing. (See "Hepatitis B
virus immunization in adults".)
Reactivation of HBV replication has also been reported in recipients who are
HBsAg negative, anti-HBc positive pretransplant, and received liver grafts from
donors who are HBsAg and anti-HBc negative. In one study of 22 patients, HBV
DNA was detected in the liver in five (23 percent) HBsAg-negative, anti-HBc-positive
patients pretransplant, and in two of these five patients post-transplant [41].
However, none of the patients became HBsAg positive or developed clinical
hepatitis post-transplant. These data have not been confirmed by other studies,
and there is no evidence that prophylactic antiviral therapy is necessary in this
setting.
Transplantation of livers from HBsAg positive donors is not recommended because
of the high risk of transmitting infection even if the recipient has immunity to HBV.
However, in countries where HBV infection is prevalent, livers from HBsAg positive
donors have been used in emergency situations, including some cases where the
recipient is HBsAg negative [42,43]. For recipients of HBsAg positive livers, a
nucleos(t)ide analogue has been given indefinitely to prevent HBV reinfection. In
some reports, biopsy of the donor liver was performed to exclude
moderate/severe inflammation or fibrosis and to exclude HDV infection. Although

383
the reported outcomes were generally favorable, the number of HBsAg negative
recipients was small and publication bias cannot be ruled out. Furthermore, some
studies reported higher rates of HBV reinfection for recipients of HBsAg positive
livers compared with HBsAg negative livers [43].
Diagnosis and clinical course — HBV reinfection has traditionally been diagnosed
by the reappearance of HBsAg in the serum. Most reinfected patients are also
HBeAg positive and have high levels of circulating HBV DNA [44].
Immunohistochemical staining of liver biopsies for HBsAg and hepatitis B core
antigen (HBcAg) usually shows intense staining.
Studies using PCR assays have demonstrated that HBV DNA can be detected in
serum prior to the reappearance of HBsAg or elevation of aminotransferases [45].
Conversely, studies in which a nucleos(t)ide analogue without HBIG is used to
prevent HBV reinfection found that some patients remained HBsAg positive but
had undetectable HBV DNA in serum [46]. These findings suggest the need to re-
examine the definition of HBV reinfection and the criteria for initiating rescue
therapy.
Reinfection is almost always accompanied by recurrent liver disease, which is often
severe and rapidly progressive [2-5]. If untreated, cirrhosis occurs within one to
two years of reinfection.
An unusual form of liver disease with severe cholestasis and rapidly progressive
liver failure (picture 1) [44,47,48], termed fibrosing cholestatic hepatitis,
characterized by prominent cholestasis and extensive fibrosis, was observed in the
1990s. Liver injury in this condition is believed to be a result of direct cytopathic
effects of HBV since liver biopsies usually show very high levels of both HBsAg and
HBcAg expression. This condition is rarely seen now as a result of early diagnosis
of HBV reinfection and availability of effective antiviral therapies.
Some patients have detectable levels of HBV DNA in liver or peripheral blood
mononuclear cells when tested by sensitive PCR assays but remain HBsAg negative
[49-53]. Most of these patients do not have clinical or histologic evidence of
recurrent hepatitis B. Whether these patients will eventually develop overt
reinfection and recurrent liver disease remains to be determined. These
observations underscore the importance of continuous prophylaxis.
PREVENTION OF HBV REINFECTIONPrevention of hepatitis B virus (HBV)
reinfection includes use of antiviral therapy pre-transplant and continuation of
antiviral therapy with or without hepatitis B immune globulin (HBIG) post-
transplant. This strategy has led to a reduction in HBV reinfection rate to less than
10 percent.
Goal — The ideal goal of antiviral therapy in patients awaiting liver transplantation
is to reverse cirrhosis complications and the need for liver transplant. However,
384
liver failure may continue to progress since clinical improvement takes three to six
months and hepatocellular carcinoma (HCC) can still develop in patients who have
clinical improvement. In patients who present late, the goal is to achieve viral
suppression, thereby stabilizing liver disease, allowing the patient to receive a liver
transplant, and (in those who proceed to transplant) decreasing the risk of HBV
reinfection.
Choice and timing of therapy — Antiviral therapy should be started as soon as
possible in patients with HBV-related decompensated cirrhosis and detectable
serum HBV DNA, regardless of HBV DNA and alanine aminotransferase levels.
Although early studies used lamivudine, the high rate of drug resistance and the
need for life-long treatment make this a suboptimal therapy.
Entecavir is attractive as a first-line antiviral agent in nucleoside-naïve transplant
patients because it is more potent, has a low rate of drug resistance, and is not
associated with nephrotoxicity (figure 2) [46]. (See "Entecavir in the treatment of
chronic hepatitis B virus infection".). Lactic acidosis in patients with severe liver
dysfunction had been reported in case series, but the incidence is unclear, and in
some cases, other factors such as sepsis may be contributory [54,55]. One series
compared six patients with decompensated cirrhosis receiving entecavir with six
patients with non-HBV-related decompensated cirrhosis who were not receiving
entecavir. Among the patients receiving entecavir, lactic acidosis was seen in one
patient who was suffering from septic shock. No lactic acidosis was seen among
the patients not receiving entecavir. Lactic acidosis may be a class effect of
nucleos(t)ide analogues.
Entecavir has been compared with other agents in studies of patients with
decompensated cirrhosis who have not yet undergone liver transplantation. In a
trial with 191 patients with chronic HBV and decompensated cirrhosis, patients
were assigned to treatment with entecavir or adefovir [56]. Entecavir was superior
to adefovir with regard to viral suppression to less than 300 copies/mL
(approximately 60 international units/mL) at weeks 24 and 48 (49 versus 16
percent and 57 versus 20 percent, respectively). An improvement in the Child-Pugh
score of two or more points was seen in 35 percent of patients receiving entecavir
and 27 percent of patients receiving adefovir. The mean decreases in Model for
End-stage Liver Disease (MELD) score from baseline were 2.6 and 1.7, respectively.
The rate of serious adverse events was consistent with advanced liver disease and
was similar between those treated with entecavir and adefovir (69 versus 66
percent). There was no significant difference between those treated with entecavir
and adefovir with regard to HCC development (12 versus 20 percent) or mortality
(23 versus 33 percent). Seven percent of patients treated with entecavir

385
discontinued the medication due to an adverse event, compared with six percent
of those treated with adefovir.
Another trial assigned 112 patients with HBV and decompensated cirrhosis to
treatment with entecavir, tenofovir, or tenofovir-emtricitabine and found results
with entecavir to be similar to those with the other treatments [57]. Viral
suppression to less than 400 copies/mL (approximately 80 international units/mL)
at 48 weeks was seen in 73, 71, and 88 percent of patients, respectively, a decrease
in Child-Pugh score of at least two points was seen in 42, 26, and 48 percent,
respectively, and all groups had a median decrease of two points from the baseline
MELD score. Treatment was discontinued due to a treatment-related adverse
event in 9, 7, and 4 percent of patients, respectively, with a mortality rate at the
end of the 48-week study of 9, 4, and 4 percent, respectively.
Many experts have recommended de novo combination therapy, but data in
support of this approach are not available and it is unclear if combination therapy
is superior to monotherapy with drugs that have a high genetic barrier to
resistance such as entecavir or tenofovir. In a report of a study comparing
entecavir monotherapy with entecavir plus tenofovir combination therapy in 379
nucleos(t)ide-naïve patients with compensated liver disease, there was no
advantage of de novo combination therapy over monotherapy with regard to viral
suppression, except in patients who were hepatitis B e antigen (HBeAg)-positive
and had very high HBV DNA levels (>108 international unit/mL) [58].
Adefovir is associated with a lower rate of drug resistance than lamivudine, but
nephrotoxicity has been observed in up to 20 percent of pre- and post-liver
transplant patients [59,60]. While many factors, such as hepatorenal syndrome
and concomitant nephrotoxic medications, may contribute to impaired renal
function, adefovir is not an ideal first-line antiviral in transplant patients because of
its weak antiviral activity and a high rate of primary nonresponse, which is likely to
be higher in patients who require dose reductions due to renal insufficiency.
(See "Tenofovir and adefovir for the treatment of chronic HBV infection", section
on 'Adefovir'.) 
Tenofovir can be substituted for adefovir. The advantage of tenofovir over adefovir
is the increased potency resulting in a lower rate of primary nonresponse, and to
date there has been no confirmed case of drug resistance. Tenofovir is preferred
to entecavir in patients with lamivudine resistance or prior exposure to other HBV
nucleos(t)ide analogues and undocumented response. Studies have shown that
tenofovir monotherapy is as effective as combination therapy with tenofovir
and emtricitabine in patients with prior lamivudine or adefovir resistance [61-63].
(See "Tenofovir and adefovir for the treatment of chronic HBV infection".)

386
One concern about the use of tenofovir disoproxil fumarate (tenofovir DF) is the
risk of nephrotoxicity since renal impairment is common in patients with
decompensated cirrhosis and in liver transplant recipients. Tenofovir
alafenamide (tenofovir AF), is a newer formulation of tenofovir with better uptake
in the liver, less systemic exposure, and lower risk of renal and bone adverse
effects, however, data in patients with liver transplantation are not yet available.
Data on telbivudine in this setting are limited, but given the high rate of drug
resistance, it is not an ideal treatment and we do not use it. (See "Hepatitis B virus:
Overview of management", section on 'Nucleos(t)ide analogs'.)
Interferon should not be used in decompensated cirrhosis due to frequent and
serious side effects [64-67]. (See "Pegylated interferon for treatment of chronic
hepatitis B virus infection".)
Monitoring — Close monitoring of serum HBV DNA levels is critical to assess
response and to detect virologic breakthrough so rescue therapy can be initiated
promptly. Virologic breakthrough secondary to drug resistance can be associated
with hepatitis flares, worsening liver failure and death, and HBV reinfection post-
transplant. Patients who are deemed not to require antiviral therapy at
presentation (of note, all patients with decompensated HBV cirrhosis should be
placed on antiviral therapy unless HBV DNA is not detected, in which case other
causes of liver disease should be evaluated) should also be monitored as HBV DNA
may become detectable or increase to higher levels during follow-up. Antiviral
drug resistance is extremely rare in patients who are nucleos(t)ide-naïve and
started on entecavir or tenofovir de novo. If HBV DNA levels increase during
therapy, these patients should be evaluated and counseled about medication
adherence. Drug resistance should be confirmed prior to switching therapy.
Prophylactic therapies post-transplant — Antiviral therapy should be initiated in
the rare patient who is not on treatment at the time of transplant, and continued
indefinitely in all patients post-transplant.
Antiviral strategies — With the availability of multiple nucleos(t)ides, the role of
HBIG is evolving. HBIG immunoprophylaxis alone has been less successful in
preventing reinfection in patients with detectable HBV DNA (and particularly those
with a viral load greater than 100,000 copies/mL or roughly 20,000 international
units/mL) or HBeAg pretransplant [9,21,68]. Antiviral therapy with nucleos(t)ide
analogues before transplant decreases the risk of reinfection by decreasing the
amount of circulating virus at the time of transplant and by prolonging the half-life
of HBIG [69].
While many transplant centers still administer HBIG during the early post-
transplant period, the dose and duration of HBIG varies markedly across
transplant centers. At our center, HBIG dose regimen is tailored according to the

387
predicted risk of reinfection. High-risk patients receive intravenous HBIG during
the first year, and then HBIG is stopped. Low-risk patients, those with undetectable
HBV DNA at transplant either in the absence of antiviral therapy or while
receiving entecavir or tenofovir (drugs associated with very low risk of resistance)
and no evidence of HDV infection do not receive HBIG [45,70,71]. Other centers
have evaluated the replacement of HBIG using HBV vaccines or combination
therapy with lamivudine and adefovir [72]. Adefovir is a weak antiviral with
moderate risk of drug resistance and is now replaced by tenofovir.
Nucleos(t)ide analogues without HBIG have been used as monotherapy or in
combination post-transplant and this approach may suffice in preventing
recurrent hepatitis B in patients with low or undetectable HBV DNA at transplant
(figure 2):
●In a study of 80 patients who all received entecavir monotherapy as
prophylaxis, 21 patients (26 percent) had complete viral suppression at the
time of transplantation [46]. After a median follow-up of 26 months post-
transplant, 18 patients (23 percent) were HBsAg positive, but 17 of those
patients had undetectable HBV DNA.
●A second study examined 362 patients who received lamivudine, entecavir,
or combination therapy (most often lamivudine and adefovir, many of these
patients had prior lamivudine resistance) for prophylaxis [73]. The overall
HBV reinfection rates were 5 percent at one year, 10 percent at three years,
13 percent at five years, and 16 percent at eight years. When examined by
the specific treatment, the reinfection rate at three years was 17 percent for
lamivudine, 0 percent for entecavir, and 7 percent for combination therapy.
●A third study included 75 patients who received a living related donor liver
transplantation and had an HBV DNA level at the time of transplantation
≤2000 international unit/mL [74]. The patients received antiviral therapy but
no HBIG. All patients were HBV-DNA negative three months after
transplantation. Sixty-six patients cleared HBsAg. Cumulative probabilities of
clearing HBsAg were 90 and 92 percent at one and two years post-transplant,
respectively. All nine patients who remained HBsAg positive had undetectable
HBV DNA at last follow-up. HBV DNA reappeared in six patients (8 percent),
five of whom had stopped taking oral antivirals and one of whom developed
resistance to entecavir. After changing the antiviral regimen, all six patients
again became HBV-DNA negative.
●A fourth study included 265 patients, 99 with undetectable HBV DNA, 90 with
HBV DNA ≤10,000 IU/mL, and 64 with HBV DNA >10,000 IU/mL at transplant.
All patients received entecavir monotherapy with no HBIG and were followed
for a median of 59 months. Two hundred forty two patients (92 percent)

388
 cleared HBsAg. Fourteen were persistently HBsAg positive but none had
detectable HBV DNA in serum. Cumulative rates of HBsAg clearance at one
and five years were 90 percent and 95 percent, respectively. All patients
including those who remained HBsAg positive had undetectable HBV DNA in
serum [75].
Hepatitis B immune globulin — HBIG immunoprophylaxis is based upon the
rationale that administered antibody to HBsAg (anti-HBs) will bind to and
neutralize circulating virions, thereby preventing graft infection. Anti-HBs also
undergoes endocytosis by hepatocytes, interacting with HBsAg within the cells,
and decreasing HBsAg secretion [76]. Several studies demonstrated a reduction in
reinfection and improved patient and graft survival with strategies involving
prophylaxis with HBIG (figure 3) [9,20,77-81]. As a result, long-term, high-dose
HBIG became the standard prophylaxis for HBV reinfection in most transplant
centers prior to the availability of effective antiviral therapy. With the introduction
of effective antiviral therapy, HBIG can often be discontinued after one year in
patients at high risk of reinfection, and may not be necessary in patients who are
at low risk.
Patients who are regarded as high risk for HBV reinfection include those with
detectable HBV DNA, with confirmed antiviral drug resistance, or with
hepatocellular carcinoma (HCC) at the time of liver transplant. Patients at high risk
for HBV reinfection are given prophylaxis with combination of HBIG plus
nucleos(t)ide analogue (entecavir or tenofovir DF) for 6 to 12 months and indefinite
nucleos(t)ide analogue monotherapy thereafter.
For patients transplanted for HBV/HDV coinfection, HBIG combined with a
nucleos(t)ide analogue is used for prophylaxis because there is no effective
treatment for recurrent HDV infection. However, patients who are transplanted for
HBV/HDV coinfection generally have low risk of reinfection [82]. (See "Liver
transplantation in adults: Prevention and management of hepatitis D virus
recurrence after liver transplantation".) .
Dose regimen — HBIG is a polyclonal preparation of human anti-HBs purified
from pooled donor plasma. It is usually given intravenously as a 10,000
international unit bolus dose during the anhepatic phase followed by daily doses
during the first week. Subsequent doses are either given monthly or in accordance
with anti-HBs titers. A trough anti-HBs titer of at least 100 international unit/L is
thought to be protective [83]. However, some studies have suggested that the rate
of reinfection can be reduced further in patients with anti-HBs titers consistently
above 500 international unit/L [20,50]. We use a fixed-dose schedule that routinely
results in anti-HBs titers of >500 international unit/L during the first year post-
transplant in patients who have high risks for reinfection.

389
Anti-HBs titers vary not only from patient to patient but also within the same
patient even when HBIG is administered as fixed doses [20,50]. Serum HBV DNA
level at the time of transplant is an important predictor of the half-life of HBIG [69].
Combined with other antiviral agents — Low-dose or limited duration HBIG
appears as effective as long-term high-dose intravenous HBIG in the era of potent
nucleos(t)ide analogues and availability of rescue therapies. A meta-analysis of two
prospective and four retrospective studies where HBIG alone had been compared
with HBIG plus lamivudine concluded that combination therapy was associated
with a significantly lower rate of HBV-related deaths and all-cause mortality [84]. In
addition, a systematic review of 46 studies found that patients treated with a
combination of HBIG plus adefovir (with or without lamivudine) had a lower
recurrence rate than patients treated with HBIG plus lamivudine (2.0 versus 6.1
percent) [85].

Other studies have evaluated strategies involving low-dose HBIG with nucleos(t)ide
analogues to reduce the high costs associated with HBIG:

●One retrospective study evaluated the risk of HBV recurrence in 42 HBsAg

positive patients with pretransplant HBV DNA levels less than 100
international unit/mL who received a short course of HBIG (5000
international unit intravenously in the anhepatic phase and then daily for five
days) in addition to antiviral therapy (tenofovir, entecavir or
tenofovir/emtricitabine), which was continued indefinitely [86]. The one-,
three-, and five-year HBsAg recurrence rate was 2.9 percent (95% CI 0.4-19.1
percent) for all time points.
●In a study of 147 patients who received low-dose HBIG intramuscularly (400
to 800 international unit daily for one week then monthly)
plus lamivudine (100 mg daily) following liver transplantation, patient survival
was 92 percent at one year and 88 percent at five years [87]. The risk of HBV
recurrence was 1 percent at one year and 4 percent at five years. A higher
HBV DNA titer at baseline was associated with an increased risk of
recurrence.
●In a study of 187 patients, HBV recurrence rates were examined in patients
who received various HBIG regimens [70]. HBIG was given to 183 patients (98
percent), and 185 patients (99 percent) received at least one nucleos(t)ide
analogue. The most common HBIG regimen was low-dose intramuscular
injection (39 percent), followed by high-dose intravenous HBIG (25 percent),
low-dose intravenous HBIG (21 percent), and finite duration of HBIG (12
percent; median duration 12 months). Overall, HBV recurrence was seen in 13
patients (7 percent).
390
Data have suggested that entecavir or tenofovir monotherapy was effective for
preventing HBV reactivation and that HBIG can be safely withdrawn one year after
transplantation [75,88]. In an observational study including 69 patients who had
liver transplantation for HBV monoinfection and were initially given HBIG alone or
HBIG in combination with nucleos(t)ide analogues, HBIG was systematically
withdrawn, and patients were followed for a median of 69 months [88]. The
nucleos(t)ide analogue (entecavir or tenofovir DF) was continued (or added if it had
not been started previously), while patients who had initially
received lamivudine plus adefovir/tenofovir were switched to tenofovir DF alone.
Following HBIG withdrawal, six patients (9 percent) became HBsAg positive (after a
median duration of 18 months), but all six patients had undetectable HBV DNA and
stable graft function during 30 additional months of follow-up. HBsAg detection
was transient in three patients and at low levels in the remaining three patients.  
Side effects — The available formulations with lower protein concentrations rarely
cause immune-mediated reactions and premedication is frequently not necessary.

HBIG preparations available for use in the United States do not contain thimerosal.

Cost and supply — Protocols that use high-dose intravenous HBIG as described

above are expensive (total charges of $80,000 to $200,000 in the first year,
including the costs of intravenous infusion sets and monitoring). In addition, the
supply of HBIG is unreliable [20]. To reduce the costs of HBIG therapy, attempts
have been made to increase the interval between intravenous HBIG dosing,
substitute maintenance intravenous HBIG with intramuscular administration of 5
mL (approximately 1000 units) HBIG, or to discontinue HBIG after the most
vulnerable period.
Novel formulations of HBIG are being tested that appear to have longer lasting
levels of circulating antibodies, and thus may require less frequent administration
and thereby reduce costs [89]. The half-life of one of these preparations (OMRI-
Hep-B) was significantly longer than standard therapy (22 versus 13 days) in a
study involving 15 patients in which the two preparations were directly compared
[89]. Further studies are needed to confirm these results.
Monoclonal anti-HBs — Results of early studies with monoclonal anti-HBs were
unsatisfactory, with a high rate of breakthrough infection [90,91]. Several new
formulations of humanized monoclonal anti-HBs are in clinical testing.
HBIG-induced escape mutants — Reinfection in patients receiving maintenance
HBIG immunoprophylaxis may be due to inadequate dosing or to the emergence
of mutant virus that can escape neutralization [92-95]. Most of the mutations
involve substitutions of one or more amino acids in the predominant epitope of

391
HBsAg, the "a" determinant. Some of these mutations result in decreased binding
to anti-HBs and may therefore escape neutralization by HBIG.
In one report, there was a significant correlation between the development of "a"
determinant mutations and the duration of HBIG therapy; cessation of HBIG
resulted in reversion to pretransplantation sequences in most instances [94]. In a
second study, variants with amino acid changes at residue 144 or 145 were most
common; patients infected with these variants had adverse clinical outcomes
compared to those who received high dose long-term HBIG but were not infected
with these mutant virus (graft failure in 44 and 23 percent, respectively) [95]. These
findings underscore the need for combination prophylaxis.

HBIG escape mutants are rare in patients who receive combination prophylaxis
with HBIG and nucleos(t)ides.

Hepatitis B vaccination — Active immunization using standard hepatitis B

vaccines has been studied to reduce the need for life-long HBIG prophylaxis. Most
studies have focused on low risk patients who are more than one to two years
post-transplant. The results of the first study were encouraging, but subsequent
studies found that response rates were variable and often poor (8 to 80 percent),
and anti-HBs titers achieved in the responders were low despite the use of higher
doses and multiple courses of vaccine [96-100]. More recent studies using new
vaccines and adjuvants have been more encouraging but these data need to be
confirmed [101].
MANAGEMENT OF RECURRENT HBV INFECTIONThe choice of
treatment for recurrent hepatitis B (HBV) depends upon prior prophylactic therapy.
When possible, antiviral resistance mutation testing should be performed to guide
the selection of nucleos(t)ide analogues.
●Rare patients who received no prophylaxis or hepatitis B immune
globulin (HBIG) should be treated with entecavir or tenofovir. Entecavir may
be preferred because of the lower rate of drug resistance and lack of
nephrotoxicity.
●Patients who received lamivudine prophylaxis are most likely to have
developed resistance to lamivudine and will require treatment with tenofovir
disoproxil fumarate (tenofovir DF), which is effective against lamivudine
resistant HBV.
●Patients who received adefovir as initial prophylaxis and developed
resistance to adefovir require the addition of entecavir or a change to
tenofovir.
●Patients who received adefovir as rescue therapy for lamivudine resistance
should undergo resistance mutation testing, if possible, to guide the
392
 selection of treatment. Most patients will likely require the combination of
tenofovir and entecavir, though some studies suggest that tenofovir alone
might suffice.
Interferon alfa — The experience with interferon has been disappointing. No
consistent effect on HBV replication or liver disease has been demonstrated [102].
In addition, side effects such as neutropenia are frequent and there are concerns
about interferon-induced rejection. Transplant recipients are immunosuppressed
and have higher viral loads, factors that probably explain the lack of response to
interferon.
Lamivudine — Lamivudine is well tolerated and can inhibit HBV replication and
improve liver disease in these patients [45,103-106]. As in the nontransplant
setting, a problem with lamivudine is the development of resistance, and it should
no longer be used in the transplant setting [104,105].
Several case reports found that patients with recurrent hepatitis B due to
combination of lamivudine and HBIG-resistant mutations run a more severe
course. In vitro studies showed that combination of these mutations had
enhanced HBV replication in the presence of lamivudine [107].
Adefovir — Adefovir is effective in suppressing HBV DNA replication and in
improving or stabilizing liver disease in patients with recurrent hepatitis B
and lamivudine resistance. Because of its potential for nephrotoxicity and weak
antiviral effects, it should not be used in the transplant setting. (See "Tenofovir and
adefovir for the treatment of chronic HBV infection", section on 'Adefovir'.)
Entecavir — Entecavir-resistant mutations are more likely to be selected in the
presence of lamivudine-resistant mutations. Entecavir should not be used in
patients with lamivudine-resistant HBV (see "Entecavir in the treatment of chronic
hepatitis B virus infection"). Because of its potent antiviral effects, low rate of drug
resistance, and lack of nephrotoxicity, entecavir is an ideal antiviral agent in
nucleoside-naïve patients.
Telbivudine — Data on use of telbivudine in the transplant setting are limited.
Based on experience in nontransplant patients, telbivudine should not be used as
monotherapy because of the high risk of drug resistance.
Tenofovir — Because of the potential for nephrotoxicity, tenofovir DF is not an
ideal drug in the transplant setting in nucleoside-naïve patients, but tenofovir DF,
alone or in combination with a
nucleoside, lamivudine, emtricitabine, telbivudine or entecavir, is recommended
for patients with lamivudine resistance or prior nucleoside exposure. Tenofovir
alafenamide (tenofovir AF) has less renal toxicity and is an alternative to tenofovir
DF in patients with (or at high risk for) renal impairment, although data in the
transplant setting are limited.

393
Reduction of immunosuppression — Immunosuppressive therapy such
as prednisone and cyclosporine increases serum HBV DNA levels. Several studies
have suggested that rapid withdrawal of prednisone may improve the long-term
course of patients with recurrent HBV infection [108,109]. As a result, many centers
now withdraw steroid therapy after three to six months in patients transplanted
for hepatitis B. Whether cyclosporine or tacrolimus (FK506) immunosuppression is
preferable in HBsAg-positive transplant recipients remains unclear [17].
TREATMENT OF PATIENTS COINFECTED WITH HIVOutcomes of liver
transplantation for selected patients with HIV and hepatitis B virus (HBV)
coinfection have been favorable [110]. Patients who are coinfected with HBV and
HIV may have lamivudine resistance if lamivudine was used as part of a
combination regimen to treat HIV infection. The choice of medications used to
prevent or treat HBV recurrence in patients who are coinfected with HBV should
take into account the medications' activity against both HBV and HIV and the
results of antiviral resistance mutation testing of those with prior treatment.
(See "Treatment of chronic hepatitis B in patients with HIV", section on 'Approach
to treatment'.)
RETRANSPLANTATIONThe experience with retransplantation for HBV-related
graft failure has been poor [3,9,111]. However, with the availability of multiple
antiviral agents, the need for retransplantation for recurrent hepatitis B has
diminished markedly. Prudent use of antiviral therapy, close monitoring for drug
resistance, and addition of salvage therapy should prevent graft failure and the
need for retransplantation.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Combination of hepatitis B immune globulin (HBIG) and antiviral therapy
has reduced recurrent hepatitis B virus (HBV) to less than 10 percent, with
resultant improvement in patient and graft survival. With the availability of
antiviral therapies that have lower rates of drug resistance and are effective
against lamivudine (LAM)-resistant HBV, reinfection rate has continued to
decrease.
●Patients with HBV-related cirrhosis who are eligible for transplantation
should be started on antiviral therapy with a nucleos(t)ide analogue as soon
as possible. Entecavir is preferred for patients who are nucleoside naïve or
who had prior treatment with adefovir, while tenofovir is preferred for

394
patients who had prior treatment with lamivudine or telbivudine. (See 'Choice
and timing of therapy' above.)
●Entecavir or tenofovir should be continued post-transplant. Patients with
undetectable HBV DNA at the time of transplant may not require HBIG post-
transplant, while a short course of HBIG is warranted in patients with
detectable HBV DNA at the time of transplant.
●The choice of treatment for recurrent hepatitis B following liver
transplantation depends upon prior prophylactic therapy and presence of
drug-resistant mutants (see 'Management of recurrent HBV infection' above):
•We suggest that patients who received no prophylaxis or HBIG only be
treated with tenofovir or entecavir (Grade 2C).
•Patients who received nucleos(t)ide analogue prophylaxis should be
tested for antiviral drug resistance mutation to guide the choice of rescue
therapy. In general, combination therapy is recommended, and most
patients will need a combination of tenofovir with entecavir.

395
Overview of intestinal and multivisceral
transplantation
Authors:
Farrukh A Khan, MD, FACS
Gennaro Selvaggi, MD
Section Editor:
Robert S Brown, Jr, MD, MPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Sep 16, 2020.
INTRODUCTIONIntestinal transplantation (ITx) has evolved into an established
therapeutic modality in the management of patients with irreversible intestinal
failure (IF). It is performed mainly in patients with short bowel syndrome, with
multivisceral transplantation reserved for those patients who develop end-stage
liver disease as a result of intestinal failure-associated liver disease. Primary
indications for intestinal transplant include depletion of central venous access
sites, multiple episodes of catheter-related sepsis, electrolyte disturbance,
dehydration, and progressive cholestatic liver failure. Additional indications for
intestinal and multivisceral transplant include diffuse portomesenteric thrombosis,
malignancies limited to the abdominal compartment, and congenital motility and
absorption disorders of the intestine.
The number of patients who undergo ITx is much lower than other forms of organ
transplantation, and there are fewer centers that perform it. The Intestinal
Transplant Registry (an international registry for intestinal transplant centers)
reported in 2016 that 3194 patients (including 1731 children) had received an
intestinal transplant [1]. The Organ Procurement and Transplantation
Network reported that in the United States between 1990 and 2019, a total of 3099
ITx were performed [2]. The number of ITx in the United States was highest in
2007 (198 transplants); however, the annual number of ITx has been declining,
from approximately 140 transplants annually between 2014 and 2016 to 81
transplants in 2019 [2].
This topic provides an overview of intestinal and multivisceral transplantation. The
American Gastroenterological Association (AGA) guideline for short bowel
syndrome and ITx [3], as well as other AGA guidelines, can be accessed through
the AGA website.

396
INDICATIONSIntestinal transplantation (ITx) has been performed in children
with a variety of causes of short bowel syndrome (SBS) including congenital
anomalies, necrotizing enterocolitis, intestinal atresia, mid-gut volvulus,
gastroschisis, and motility disorders (table 1 and figure 1). In adults, ITx has been
performed mainly in those with SBS related to Crohn disease, mesenteric
thrombosis, trauma, and desmoid tumors (table 1 and figure 2) [4-6].
In both children and adults, ITx is usually considered in patients who develop
serious complications related to chronic parenteral nutrition, such as when:
●More than one-half of the sites typically used for parenteral nutrition (PN; ie,
jugular, subclavian, and iliac veins) become inaccessible due to thrombosis
[7].
●Catheter-related sepsis has resulted in repeated episodes of disseminated
infections and/or repeated bacteremia.
●Patients have developed cholestatic liver disease attributable to PN (such
patients may also require liver transplantation). A large database study found
that patients with PN-related liver disease who underwent combined liver
and intestinal transplantation had significantly worse outcomes than patients
who underwent isolated ITx [8]. This prompted a change in the organ
allocation system so that donor organs from throughout the United States
(rather than just organs donated within the patient's geographic region)
could be offered to patients who require combined liver and intestine grafts
in order to minimize their risk of death on the transplant list.

ITx is also performed in patients who do not have SBS but have other causes of
intestinal failure. These include dysmotility disorders (such as generalized
Hirschsprung's disease, megacystis microcolon, intestinal pseudo obstruction),
genetic intestinal disorders of the mucosal cells (such as microvillus inclusion
disease and tufting enteropathy), disease with a high potential for malignant
degeneration (such as familial adenomatous polyposis), neoplastic tumors of the
gastrointestinal tract and pancreas that are limited to the abdominal cavity (eg,
neuroendocrine tumors), and radiation-induced bowel injury.

Another indication for multivisceral transplantation of the liver, stomach, pancreas,

and small and large intestine is the development of diffuse porto-mesenteric
venous thrombosis [9].
Consensus criteria — The American Society of Transplantation and the Centers
for Medicare and Medicaid Services initially recommended intestinal
transplantation under the following conditions [10,11]:
(1) Failure of home parenteral nutrition:
●Impending or overt liver failure
397
 ●Thrombosis of ≥2 central veins
●Two or more episodes per year of systemic sepsis, particularly those
requiring hospitalization with shock and fungemia
●Frequent episodes of dehydration

(2) High risk of death

(3) Severe SBS (gastrotomy, duodenostomy, residual small bowel <10 cm in infants
and <20 cm in adults)

(4) Frequent hospitalization, narcotic dependency, or pseudo-obstruction

(5) Unwillingness to accept long-term home parenteral nutrition

The appropriateness of these criteria was confirmed in at least one study that
evaluated survival based upon them [12].
A subsequent consensus paper has summarized the indications for placement on
the intestine transplant waiting list (table 1) [13].
CONTRAINDICATIONSThe contraindications to ITx are similar to those for
liver and other solid organ transplantation. The presence of active infection,
aggressive or metastatic malignancy, multisystem organ failure, cerebral edema,
and advanced human immune deficiency virus infection are absolute
contraindications for ITx [14].
PRETRANSPLANT RECIPIENT EVALUATIONMost patients with intestinal
failure have an extensive medical history and are either home or hospital bound
when they are referred for intestinal transplantation (ITx). The concept of an
intestinal failure team/center has emerged, and intestinal rehabilitation has
become an important first step in the pretransplant evaluation. The intestinal
failure team may use several strategies for disease management (eg, meeting
nutritional requirements, optimizing use of parenteral nutrition, gut rehabilitation
surgery, and, if the patients fails to respond, intestinal transplant) [15].
Transplant evaluation is then performed by a multidisciplinary team that includes a
transplant clinician, hepatologist/gastroenterologist, social worker, financial
coordinator, pharmacist, infectious disease specialist, cardiologist, nutritionist, and
psychologist [16,17].
The past medical and surgical histories and prior endoscopic and radiologic
evaluations are reviewed in detail (table 2). A liver biopsy is performed in patients
with suspected liver disease, although it may be deferred in those with clinical
features of advanced liver disease [18]. Ultrasound of the liver and central veins is
obtained to assess the vasculature. The use of magnetic resonance venography
398
has been proposed as a more comprehensive method to assess central venous
access in pediatric patients with intestinal failure [19].

Serological studies include testing for cytomegalovirus, Epstein Barr virus, human
immune deficiency virus (HIV), hepatitis B virus, and hepatitis C virus. Blood typing
human leukocyte antigen (HLA) is performed for crossmatching purpose.
Evaluation for hypercoagulability is obtained in patients with history of mesenteric
vessel thrombosis.

Part of the outcome of the evaluation is to determine whether the patients should
undergo ITx alone, or combined ITx and liver or multivisceral transplantation.
Combined ITx and liver transplantation may be required in those with IF and end-
stage liver disease, while a multivisceral transplant may be required in those with
IF and the presence of neuropathy or extensive mesenteric thrombosis. Intestinal
transplantation without liver transplantation may be feasible in some patients with
mild to moderate portal fibrosis and liver dysfunction; improvement in liver
histology following intestinal transplantation has been described in such patients
[20].
WAIT LISTIn the United States, where the most intestinal transplantations are
performed, the number of patients on the ITx waiting list has been decreasing,
most likely due to the advances made in intestinal rehabilitation [21]. The number
of patients who are listed for intestine transplantation alone are not significantly
different from the number of patients who are listed for combined liver-intestine
transplant. Additionally, the proportion of adult patients listed for ITx in 2017 was
44 percent, while pediatric patients represented 56 percent of patients on the wait
list [21].
The median time to transplantation among the patients on the waiting list has
decreased over time. For patients listed in 2016 to 2017, median time to transplant
was only 5.2 months for adults and 8.2 months for pediatric recipients [22]. The
pretransplant mortality rate in 2016 and 2017 was 7.9 per 100 waitlist-years for
adults and 3.7 per 100 waitlist-years for children [22].  
DONOR SELECTION/OPERATIONHemodynamically stable donors after
brain death who have no intestinal pathology represent the majority of donors.
Cytomegalovirus (CMV)-positive donors are preferred for CMV-positive recipients
[23].

The donor procurement operation is similar to other solid abdominal organ

procurement procedures. A long midline or cruciate incision from suprasternal
notch to pubic symphysis is made, and the gross anatomy is reviewed with

399
particular attention given to variations in the vascular anatomy of the liver. A
biopsy of the liver is performed if there is obvious fatty change.

The organs are harvested and generally preserved in either University of

Wisconsin solution (UW solution) or histidine-tryptophane-ketoglutarate solution
[24]. Cold ischemia time is kept to a minimum by coordinating timing of the donor
operation with the recipient patient's surgery team.
The intestinal graft is prepared at the back table. The type of graft is based upon
the requirements and condition of the recipient [25].
Anesthesia — The principles of anesthesia are similar to those for liver
transplantation. However, as noted above, patients with intestinal failure (IF) often
have limited vascular access. As a result, assistance from an interventional
radiologist may be required to assure adequate venous access. Transesophageal
Doppler ultrasound can also be helpful to monitor cardiac status of the recipient if
a Swan-Ganz catheter cannot be positioned or if the patient does not have
adequate venous access to allow for it [24]. (See "Liver transplantation: Anesthetic
management".)
General surgical principles — The recipient operation is started when the donor
organs are harvested and deemed satisfactory. The incisions are planned carefully,
keeping in mind the presence of the stomas and creation of new stomas. The
recipient inflow and outflow vessels are dissected. If an interposition vascular graft
is needed (such as aortic graft or venous mesenteric graft), it is placed in the
recipient before the new graft is brought to the front table.
General surgery principles are followed for restoration of intestinal continuity, with
two layer visceral anastomosis. The intestinal anastomosis is usually constructed in
side-to-side fashion to overcome any size discrepancy between the graft and the
recipient intestine. A feeding jejunostomy or gastrostomy is occasionally created.
The distal end of the graft can be brought out as a standard end ileostomy or a
loop ileostomy to allow surveillance endoscopy and monitor for rejection. Liver
graft cholecystectomy is performed routinely. Nissen fundoplication and
pyloroplasty are performed if the stomach is included in the multivisceral graft.
There is an increased trend towards utilization of the donor colon within the
allograft since there has been no observed risk of increased postoperative
complications [26]. In some patients, intestinal transplantation can be performed
without creation of a stoma [27].
Isolated intestinal transplantation — Isolated intestinal transplantation is
performed in patients who have only isolated IF and no associated liver disease
(figure 3). The arterial inflow can be either from the native superior mesenteric
artery, but is usually created with an interposition graft from the recipient

400
infrarenal aorta; venous outflow is to the native superior mesenteric vein or, in
patients with compromised mesenteric venous return venous outflow is drained to
the inferior vena cava (systemic drainage). The portal vein outflow is preferred due
to the concept of hepatotrophic factors providing insulin-like factors for continued
optimal hepatocyte function.
Liver-intestinal transplantation — Liver-intestinal transplantation (L-ITx) is
considered in recipients who have irreversible IF and end-stage liver disease (ESLD)
(figure 4).
In small children, the procedure may be modified to include the duodenum and a
rim of pancreas to avoid the need for biliary reconstruction. Inclusion of the
pancreas (total) has not increased complication rates [28].
There are some data to suggest that inclusion of the liver helps to confer
immunologic tolerance to the small bowel grafts [29,30]. However, the degree of
benefit (and shortage of organs) does not appear to justify routine use of such an
approach. As a result, a liver transplant is generally reserved for patients who have
ESLD.
Multivisceral transplantation — Multivisceral transplantation (MVTx) includes the
stomach, duodenum, pancreas, small intestine, and liver (figure 5). A modified
multivisceral transplant excludes the liver, if the recipient liver is normal. Kidney
transplant is occasionally included if the recipient has end-stage kidney disease.
Inclusion of the spleen has been proposed as a possible means to reduce the
incidence of post-transplant lymphoproliferative disorder, but data are limited
[31].
Bone marrow infusion — Infusion of donor bone marrow has been proposed as a
means to induce immunologic tolerance [4,24,32]. The approaches used include a
single infusion within 12 hours of revascularization of the allograft or two to five
infusions of donor cells in equally divided doses. However, long-term results have
not unequivocally shown advantages in terms of decreasing rejection episodes. As
a result, most centers do not use this approach.
Loss of domain/abdominal wall transplantation — The abdominal wall closure
is quite difficult in some recipients of ITx due to multiple surgical operations,
recurrent infections, scar tissue formation, and a contracted abdominal cavity. In
difficult cases, the closure is obtained with temporary mesh or Gore-Tex grafts. In
some cases plastic surgical procedures are required such as rotation flaps to
secure the closure of the abdominal wall. Case series have also described
abdominal wall transplantation [33]. The blood supply is based upon inferior
epigastric vessels left in continuity with the donor femoral and iliac vessels. In a
series of nine such patients, six patients survived with five intact abdominal walls

401
[33]. There were two mild rejection episodes and no episodes of graft versus host
disease.
LIVING-RELATED TRANSPLANTATIONIntestinal transplantation from live
donors has been proposed as a means to increase the pool of donor organs and
thereby reduce waiting time and wait list morbidity and mortality [34,35]. In
addition, living donor transplantation can be performed electively, which may
provide an immunologic advantage. Forty-four such procedures have been
performed in the last 20 years in the United States, and a similar number have
been performed worldwide [36].
During procurement, the donor intestine is measured from the ligament of Treitz
to the ileocecal valve. A segment of terminal ileum (200 cm for adult recipients and
150 to 180 cm for pediatric recipients) is harvested 20 cm proximal to the ileocecal
valve. The donor is left with at least 60 percent of the small intestine.
(See "Pathophysiology of short bowel syndrome", section on 'Ileal resection'.)
One of the largest series described 11 recipients who received 12 living-related
donor intestinal transplantation [35]. Three-year patient and graft survival were 82
and 75 percent, respectively.
IMMUNOSUPPRESSIONSuccessful intestinal transplantation would not have
been possible without significant advances in the field of immunosuppression. Due
to its high antigenic potential, intestinal grafts vigorously reject if inadequate
immunosuppression is given, especially during the first year after transplant. The
earliest attempts (in the 1960s) failed due to lack of adequate immunosuppressive
agents. Success improved dramatically after the introduction of cyclosporine in the
1980s and, most notably, tacrolimus (TAC) in the 1990s.
Most centers use an induction regimen that includes antilymphocyte
(thymoglobulin or ATGAM) or anti-IL-2 receptor antibodies (Simulect), with baseline
immunosuppression consisting of a combination of TAC, with or without
glucocorticoids. Initially, TAC is administered intravenously and switched to an oral
dose as soon as the intestine resumes normal function. The 12-hour target trough
level for TAC is 15 to 20 ng/mL in the first 90 days of the transplant [17,24,37].
Induction protocols used by most transplant centers have helped to reduce TAC
trough levels to 5 to 10 ng/mL after 90 days [38].

Optimal strategies to use immunosuppressive agents are being studied and are
evolving. Thus, several immunosuppressant agents and regimens are being used.
Other agents commonly utilized are:

●Mycophenolate mofetil, which has helped reduce dose-related toxicity of

calcineurin agents such as cyclosporine and TAC [24].

402
 ●mTOR inhibitors such as sirolimus or everolimus, which have the advantage
of a low incidence of nephrotoxicity [32].
●Glucocorticoids are used commonly. A bolus is given at the time of
transplantation with a taper for five days to a maintenance dose.
Glucocorticoids are not typically used as maintenance beyond the first three
months post-transplant in patients who receive induction therapy with
thymoglobulin.

For maintenance therapy, most transplant centers use a regimen of TAC and
mTOR inhibitors as a strategy to reduce the risk of rejection while avoiding chronic
glucocorticoid use.

ASSESSMENT OF INTESTINAL FUNCTIONIntestinal function can be

monitored using the d-xylose absorption test [39]. Impaired absorption in the early
transplant period may be seen with rejection, cytomegalovirus enteritis, or renal
dysfunction. Other tests of intestinal function include fecal fat determination.
Intestinal function may be reflected less directly by tolerance to oral feeding, the
ability to taper parenteral nutrition, and serial monitoring of
serum tacrolimus levels. (See "Approach to the adult patient with suspected
malabsorption".)
NUTRITIONParenteral nutrition (PN) is continued postoperatively until intestinal
motility returns to normal, as assessed by bowel sounds and stoma output [24].
Once anastomotic integrity is established, enteral feeds are initiated in the form of
an elemental diet through a feeding tube. The enteral feeds are advanced
gradually as tolerated.

PN is usually tapered in four to six weeks once the intestine is able to meet full
caloric needs of the recipient. Some patients lack appetite. In particular, children
who have been on long-term PN may have food aversion and need speech therapy
to help learn how to eat again. Many patients will also continue to require
supplemental intravenous fluids and electrolytes due to stoma loss during the first
post-transplant year.

In a study that included 177 surviving recipients of intestinal and multivisceral

transplantations, 160 (90 percent) achieved nutritional autonomy and were able to
take an unrestricted oral diet without the need for intravenous nutrition or fluid
supplementation after a mean follow-up of 9.4 years [40].
POSTOPERATIVE COMPLICATIONS
Technical complications — A variety of technical complications can occur,
including bleeding, thrombosis, and anastomotic leaks. Such complications can
403
lead to serious morbidity and mortality. The rate of such complications has varied
across reports, but is probably in the range of 10 to 15 percent, although much
higher rates have been reported [41]. In an illustrative series, 18 of 39 patients (45
percent) required emergency surgery after intestinal transplantation (ITx) [42].
Three (8 percent) developed duodenal stump leak resulting in one death, five (13
percent) developed spontaneous small bowel perforation resulting in two deaths,
and three (8 percent) needed emergency laparotomy for abdominal compartment
syndrome, resulting in two deaths. In another series, technical complications,
including intestinal anastomotic leak, hepatic artery thrombosis, and biliary
anastomotic leak, led to graft loss in 4 of 35 recipients (11 percent) [43]. In other
series, the overall incidence of technical complications is described as
approximately 9 percent.
Infectious complications — Infectious complications (particularly bacterial
infections) are common after ITx and remain the leading cause of death. The most
common include intra-abdominal or catheter-related sepsis, or sepsis related to
bacterial translocation from the graft.
Treatment is directed at the underlying cause of infection and may include, in
addition to broad-spectrum antibiotics, removal of the implicated catheter,
treatment for cytomegalovirus (CMV) infection, or intravenous administration of
immunoglobulins if serum levels of IgG are below normal. (See "Infection in the
solid organ transplant recipient".)
Prophylaxis against infection is also routinely given: trimethoprim-
sulfamethoxazole for Pneumocystis jirovecii (formerly Pneumocystis carinii)
infection; fluconazole for fungal prophylaxis; intravenous ganciclovir or
oral valganciclovir for CMV prophylaxis. (See "Prophylaxis of infections in solid
organ transplantation".)
Post-transplant lymphoproliferative disease — Post-transplant
lymphoproliferative disease (PTLD) develops in up to 30 percent of ITx recipients
and is usually associated with Epstein-Barr virus. Treatment principles include a
substantial decrease in the immunosuppression regimen and antiviral therapy.
Standard chemotherapeutic regimens, such as CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP
are also widely utilized in PTLD patients after ITx. (See "Treatment and prevention
of post-transplant lymphoproliferative disorders".)
Graft-versus-host disease — Graft-versus-host disease (GVHD) has been reported
with all types of organ transplantation. Transplantation of the small bowel was
considered to be particularly vulnerable to GVHD since the small intestine contains
a large reservoir of lymphocytes, including the Peyer's patches, lamina propria,
and large number of mesenteric lymph nodes. The incidence of GVHD after

404
intestinal transplant is approximately 7 to 9 percent, but its severity varies among
published series, with low morbidity and mortality in one series [44] and high
mortality (up to 72 percent) in another series [43].
The main targets of GVHD are skin, liver, lung, bone marrow, and gastrointestinal
tract. The presentation is usually with a skin rash, mouth or tongue lesions,
diarrhea, gastrointestinal ulcerations, liver dysfunction, and bone marrow
suppression [44]. (See "Clinical manifestations, diagnosis, and grading of acute
graft-versus-host disease".)
ACUTE REJECTIONThe incidence of severe acute cellular rejection (referred to
as "exfoliative" rejection in reference to the associated loss of intestinal villi) is high
in intestinal transplantation (ITx) compared with other organs, although progress
has been made. The incidence of any type of rejection was about 85 percent
during the 1990 to 1994 period and 67 percent during the 1995 to 2001 period
[23,32]. Mortality associated with severe rejection is approximately 25 to 45
percent at six months [31]. Graft loss occurs in most patients with severe rejection
despite aggressive immunosuppressive therapy [31,45,46].
Clinical manifestations — Patients with acute rejection usually present with
increased stoma output, fever, abdominal pain, distension, and ileus. Acute
rejection also predisposes to sepsis from bacterial translocation and fungal
infections.
Diagnosis — The diagnosis is made pathologically from specimens obtained
during endoscopy. The histologic features of small intestine rejection include a
mixed but mostly mononuclear infiltrate with activated lymphocytes, crypt injury,
inflammation, and increased crypt cell apoptosis [47]. The rejection is graded as
indeterminate (Grade IND), mild (Grade 1), moderate (Grade 2), or severe (Grade 3)
depending upon the extent of the mucosal injury and the degree of inflammatory
infiltrate and apoptosis (picture 1A-C) [45].

The ability to diagnose rejection in its earliest stages provides the opportunity to
intervene before irreversible complications develop. In the early postoperative
period, serial endoscopies through the stoma with intestinal biopsies are
commonly used for graft surveillance, since the highest number of rejections is
observed within the first month post-transplant. In many centers, serial endoscopy
and biopsy are performed twice a week for the first month. After the first month,
endoscopies are performed less frequently. After the ileostomy is closed,
endoscopies are performed only if indicated by clinical signs or symptoms.

Another approach that has been suggested is zoom magnification endoscopy (up
to 100-fold magnification), which may reveal suggestive early mucosal changes
that may not be visible with standard endoscopy. These include erythema, villous
405
congestion, and blunted and shortened villi [48-50]. In one series of adults with
clinical features suggestive of acute rejection, the sensitivity and specificity of
these findings compared with histology were 45 and 98 percent, respectively [49].
Similar test characteristics were described in children included in the study.
Serum citrulline and fecal calprotectin have emerged as useful studies when acute
rejection is suspected [51-53]. Serum citrulline level is a marker of acute rejection
and correlates with the severity of acute rejection after a minimum of three
months following pediatric intestinal/multivisceral transplants. Citrulline levels are
inversely proportional to the severity of acute rejection. For example, a citrulline
threshold level of >20 micromol/L (for any type of ACR) and threshold of >10
micromol/L (for moderate or severe ACR) were associated with negative predictive
values of 95 to 99 percent, respectively [51].
Acute rejection has been associated with high stool calprotectin levels. In a study
analyzing stool calprotectin measurements from 68 patients, calprotectin levels
were higher in patients with acute rejection compared with patients with viral
enteritis or normal small bowel biopsies (198 mg/kg versus 7 and 19 mg/kg,
respectively). Receiver operator characteristics have suggested the optimal cut-off
level to distinguish rejection from other diagnoses is 92 mg/kg with specificity of
77 percent and sensitivity of 83 percent [52].
Treatment — The mainstay of treatment for mild rejection typically involves bolus
doses of glucocorticoids and intensification of the baseline immunosuppressive
regimen. Anti T-cell antibodies may be used in steroid-resistant rejection.
Moderate and severe rejection episodes are treated with anti-lymphocyte
antibodies (thymoglobulin or Atgam), as well as supplemental immunotherapy
treatments such as vedolizumab, eculizumab, and bortezomib [54,55].
Unfortunately, more intensive immunosuppression increases the risk of
opportunistic infections, including cytomegalovirus and Epstein-Barr virus (which
increases the risk of post-transplant lymphoproliferative disorder).
Prevention — There have been efforts to reduce rates of rejection by irradiating
donor grafts (ex vivo), infusing donor bone marrow, or by leukocyte depletion
prior to transplant. In one report, for example, 15 ITx grafts were irradiated ex vivo
and recipients also received a single bone marrow infusion [56]. Outcomes were
compared with five recipients who served as controls. The incidence of rejection
was much lower in the irradiated group (7 versus 80 percent). However, this
approach is not used routinely because of the risk of radiation-induced small
bowel injury. (See 'Bone marrow infusion' above.)

Most anti-rejection protocols include induction immunosuppression with

antilymphocyte agents such as thymoglobulin, given in the peri-operative period,

406
in conjunction with a short course of glucocorticoids, and calcineurin inhibitors
plus mTOR inhibitors as maintenance therapy.

The inclusion of a liver may help to protect from rejection of the intestinal graft.
(See 'Liver-intestinal transplantation' above.)
Antibody-mediated rejection — Increasing evidence has pointed to the
development of donor-specific antibodies (DSA) after intestinal transplantation as
one of the factors that can increase the risk of developing acute and chronic
rejection [57]. DSA levels can be monitored, and they may correlate with biopsy
findings to confirm antibody-mediated rejection [58].
CHRONIC REJECTION AND GRAFT FAILUREChronic rejection is observed
in approximately 8 percent of patients undergoing intestinal transplantation (ITx).
Factors associated with chronic rejection include isolated ITx compared with small
bowel-liver grafts, acute rejection within the first month, increased number and
higher grade of acute rejection episodes, older recipient age, not being from a
White population, and White donor to non-White recipient transplantation
[32,59,60].
Patients usually present with poor oral intake and lack of appetite, chronic
diarrhea or intestinal obstruction due to strictures that are caused by the process
of chronic rejection. The diagnosis is not typically established by intestinal biopsy
since the chronic rejection process involves the submucosa and muscularis
mucosa. Imaging with small bowel series or magnetic resonance enterography
can show strictures when obstruction is the presenting symptom. Intestinal
function tests (eg, d-Xylose absorption test) can suggest the diagnosis even before
it becomes clinically evident and may be performed as part of a surveillance
program [24]. A definitive diagnosis is made with full-thickness biopsy of the
allograft, usually after allograft removal. Characteristic findings include
obliteration of submucosal vessels and fibrosis of the allograft. (See "Approach to
the adult patient with suspected malabsorption", section on 'Other infrequently
performed tests'.)
OUTCOMES
Quality of life — There are limited data assessing quality of life in recipients of
intestinal transplants. In a study of 29 children, quality of life scores were similar to
age-matched controls one year after transplant [61]. However, the assessment of
quality of life differed when reported by parents. Parents more frequently
reported decreased general health and physical functioning in intestinal transplant
recipients. In other studies, quality of life after ITx appeared to be better than or
equal to quality of life on PN [62].

407
In a study that included 76 adult recipients of intestinal and multivisceral
transplantations, there was improvement in many psychosocial and emotional
quality of life domains following transplantation, including anxiety,
cognitive/emotional ability, coping skills, sleep pattern, impulsiveness/control,
social support, and leisure/recreation [40]. On the other hand, depression and
financial obligations were worse after transplantation.
Graft and patient survival — The outcomes in patients undergoing ITx has
improved significantly compared with early efforts, with improvements in
immunosuppression and early detection and treatment of rejection. Graft survival
for adult and pediatric patients is similar. As reported by the 2018 Annual Report
by the Organ Procurement and Transplantation Network, one-year graft survival
for all recipients of an intestinal graft (for the period of 2016 to 2017) was
approximately 78 percent, while five-year graft survival for patients transplanted
between 2012 and 2013 was 55 percent [63]. Patient survival depends on the type
of graft: it was lowest for adult recipients of combined liver-intestine (67 percent at
one year and 49 percent at five years) and highest for isolated intestine pediatric
recipients (89 percent at one year and 76 percent at five years) [21,63,64]. Similarly,
in an earlier comprehensive report from the largest series of intestinal transplants,
one- and five-year patient survival rates were 92 and 70 percent, respectively [65].
However, overall patient survival at 10 and 15 years was only 42 and 35 percent,
respectively. Thus, short- and medium-term graft and patient survival were
encouraging, but the long-term results have been disappointing.
Various predictors of graft and patient survival have been proposed. Graft and
patient survival were related to the type of immunosuppression, whereas graft
survival was lower with retransplantation and varied across centers [66]. However,
the most important predictor appeared to be the recipients' status: Homebound
recipients had a 68 percent survival, whereas hospitalized patients had a 42
percent survival at two years. These measures undoubtedly reflected the severity
of underlying disease and comorbidities.
FUTURE DEVELOPMENTSThe future of intestinal transplantation (ITx) is
promising despite its obvious challenges. The surgical technique has been
standardized, and the immunosuppression regimens are improving. Efforts are
focusing on improving immunosuppression protocols including methods to
promote tolerance.

As more patients survive beyond the first several years after transplant, future
challenges focus on the recognition and prevention of both short-term
complications (eg, acute rejection) and long-term complications (eg, chronic renal
failure, post-transplant lymphoproliferative disease, chronic rejection). Early

408
recognition and treatment of acute rejection to prevent graft loss and associated
complications of opportunistic infections and post-transplant lymphoproliferative
disease remain a priority. Development of a clinical noninvasive marker for
detection of acute rejection in ITx has been challenging.

The shortage of appropriate deceased donors contributes to significant wait list

mortality, which needs to be overcome, possibly with the increased use of live
donors. (See 'Living-related transplantation' above.)
SUMMARY AND RECOMMENDATIONS
●Intestinal transplantation (ITx) has established itself as a therapeutic
modality for patients with intestinal failure. (See 'Indications' above.)
●ITx is performed mainly in patients with short-bowel syndrome who have
developed serious complications from parenteral nutrition (PN).
●Potential candidates should be referred to transplant centers accredited for
ITx. (See 'Pretransplant recipient evaluation' above.)
●Long-term outcomes have improved, but remain worse than for other forms
of solid-organ transplantation. (See 'Graft and patient survival' above.)
●Quality of life after ITx appears to be better than or equal to quality of life on
long-term PN. (See 'Quality of life' above.)

409