Transplantation: Table 11-1

Chapter
11 TRANSPLANTATION
INTRODUCTION 321 POST-TRANSPLANT COMPLICA- RECURRENT DISEASES 342
TIMEFRAME OF PATHOLOGIC TIONS 333 Viral Hepatitis (HBV and HCV) 342
CHANGES 321 Bile Duct Strictures 333 Primary Biliary Cirrhosis 346
PRESERVATION (HARVESTING, Hepatic Artery Thrombosis 334 Primary Sclerosing Cholangitis 347
REPERFUSION) INJURY 322 POST-TRANSPLANT OPPORTUNISTIC Autoimmune Hepatitis 348
INFECTIONS 336 Alcoholic Liver Disease 349
ACUTE GRAFT FAILURE (PRIMARY
Bacterial, Fungal Infections 336 DE NOVO LIVER DISEASE 350
NONFUNCTION) 324
Cytomegalovirus 337 HEPATIC CHANGES AFTER BONE
REJECTION 325
Hyperacute (Humoral) Rejection 325 Herpes Simplex Virus 339 MARROW TRANSPLANTS: GRAFT
Acute (Cellular) Rejection 326 POST-TRANSPLANT LYMPHOPRO- VERSUS HOST DISEASE 351
Chronic (Ductopenic) Rejection 330 LIFERATIVE DISORDER, PTLD (EBV-
AND NON–EBV-RELATED) 340
INTRODUCTION and immunosuppression is withdrawn completely in a

small proportion of patients).
1. Liver transplantation is currently standard treatment of 6. The assessment of patients after liver transplantation is a
liver replacement for acute liver failure, for end-stage liver complex process where several parameters are evaluated.
disease due to a variety of disorders, and for certain meta- A thorough understanding is essential of the pretrans-
bolic and neoplastic liver diseases. plant disease and management, details of the procedure
2. The most common indication for liver transplantation in and potential for related complications, immunosup-
the United States is chronic hepatitis C-related cirrhosis pressive regimens and side effects, expected postopera-
with or without concomitant alcoholic liver disease. tive events and complications, and conditions that could
3. Indications for hepatic transplantation in a large series impair organ function and lead to graft failure. Evalua-
of patients from the United Network for Organ Shar- tion of the liver abnormalities following transplantation
ing (UNOS) (1987-1998) and from the European Liver requires, in addition, knowledge of the liver histology,
Transplant Registry (1988-2001) are listed in Table 11-1. the assessment of patency of the hepatic artery (and less
4. Optimization of the patient prior to liver transplant is criti- commonly the portal vein, since thrombosis of the portal
cal for the successful outcome after transplantation. The vein is rare), and the assessment of the biliary anastomo-
donor organ should be optimal for normal functioning after ses with absence of bile duct obstruction, all of which are
engraftment. Factors such as fatty change of hepatocytes critical for early diagnosis and treatment. Thus, a global
that is greater than 40% of the liver cell volume, prolonged evaluation is necessary at every event during the postop-
hypotension, use of pressors prior to harvest, prolonged erative course and subsequent follow-up.
cold ischemia time, older age donor, or the background of
prior substance use in the donor may lead to less optimal
functioning of the organ and increase the risk of primary TIMEFRAME OF PATHOLOGIC CHANGES
nonfunction. Note that the organ can be preserved in Uni-
versity of Wisconsin solution for up to 24 hours; however, (Fig. 11-1)
it is preferable that the engraftment occurs within 14 hours. 1. The incidence of various morphologic features seen in
5. The procedure involves anastomoses of the hepatic vein the liver correlate in many ways with the timeframe post-
at its confluence with the inferior vena cava, and anas- transplant. For example, recurrent disease is quite uncom-
tomoses of the portal vein, hepatic artery, and bile duct mon within the first week after transplant, and humoral
(either duct-to-duct or donor duct to Roux-en-Y recipi- rejection is uncommon months to years later.
ent jejunostomy). At reperfusion of the liver, normal- 2. Biopsy, sometimes with frozen section, of the intended
ization of the color and consistency, and the immediate implanted liver at time of procurement (time 0) to assess
secretion of normal appearing bile, portend a good out- the degree (if any) of fatty change, fibrosis and inflam-
come. Immunosuppression is begun immediately in the mation, is often necessary in the acceptance or rejection
operating suite at engraftment and continues indefinitely of donor livers. It is also not uncommon to see in biop-
thereafter (unless tolerance develops after several years sies performed at the end of the transplant procedure
321
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322 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Table 11-1 Liver Disease in Transplant Recipients

UNOS EUROPEAN LIVER
DATABASE TRANSPLANT
(24,900 REGISTRY
PATIENTS) (39,196 PATIENTS)
(1987-1998)* (1988-2001)**
LIVER DISEASE (PERCENTAGE) (PERCENTAGE)
Cirrhosis
Chronic hepatitis C 20.7 15.2
Chronic hepatitis B 5.5 6.1
Alcoholic 17.1 17.7
Alcoholic + chronic 4.4
hepatitis C
Autoimmune hepatitis 4.8 2.5
Cirrhosis of other causes 10.9 5.8
(includes “cryptogenic”)
Cholestatic liver diseases
Figure 11-1 Postperfusion injury. In the immediate post-transplant
Primary biliary cirrhosis 9.3 7.5 period at the end of the surgical procedure (“time 0”), the liver may
Primary sclerosing 8.7 4.4 show variable degrees of perivenular hemorrhage with neutrophilic
cholangitis clusters. This feature may also occur in the non-transplant setting
after prolonged abdominal surgery (“surgical hepatitis,” see Fig.
Fulminant hepatitis 6.2 9.5
1-29), is a reversible process, and should not be confused with true
Congenital biliary diseases 6.0 sepsis-induced microabscess formation (see Fig. 7-2).
Hepatic malignancies 3.8 10.5
Metabolic diseases 3.7 6.1
Other 4.7 4.3 Table 11-2 Time Post-Transplant and Allograft
*Data from Keeffe EB. Selection of patients for liver transplantation. In: Maddrey Pathology
WC, Schiff ER, Sorrell MF, (eds): Transplantation of the Liver, 3rd ed, pp 5-34.
Philadelphia: Lippincott Williams, 2001; and Seaberg EC, et al: Liver transplanta-
Post-perfusion (“time zero”) • Steatosis
tion in the United States from 1987-1998: Updated results from the Pitt-UNOS Early (hours to first week) • Hyperacute (humoral) rejection
liver transplant registry. In: Cecka JM, Terasaki PI (eds): Clinical Transplants 1998, • Acute graft failure
pp 17-37. Los Angeles: UCLA Tissue Typing Laboratory, 1999. • Acute cellular rejection
**Data from Adam R, McMaster P, O’Grady, JG, et al: Evolution of liver transplan-
• Harvesting (preservation) injury
tation in Europe: Report of the European Liver Transplant Registry. Liver Transpl
2003;9:1231-1243. Delayed (3 weeks to 3 • CMV and other systemic infections
months) • Acute and/or chronic rejection
• Graft ischemia
• Biliary tract obstruction (strictures)
Late (>6 months) • Recurrent viral hepatitis (B and C)
• Recurrent disease, other (PBC, PSC)
post-perfusion biopsies) neutrophilic clusters due to sur- • De novo disease
gical manipulation of the liver (“surgical hepatitis”; see • Chronic ductopenic rejection
Figs. 1-29 and 11-1). • Post-transplant lymphoproliferative
disease (PTLD)
3. Importantly, however, many exceptions occur. For
instance, a patient who has inadvertently stopped tak-
ing anti-rejection medications years after transplant may
develop acute rejection. In addition, certain liver diseases
such as viral hepatitis can recur as early as one month
post-transplant.
4. Table 11-2 shows a summary of likely changes seen at
various times after transplantation. It is important to note
that many of these complications such as acute rejection
can occur at any time post-transplant.
PRESERVATION (HARVESTING, REPERFUSION)

INJURY
(Figs. 11-2 through 11-4)
Major morphologic features

1. Ballooning of hepatocytes with focal liver cell necrosis
and mild lobular inflammation in the perivenular and
midzones is present to variable degrees. Figure 11-2 Preservation (harvesting, reperfusion) injury. The
2. Cholestasis is often seen in the perivenular zone. perivenular hepatocytes show hydropic ballooning change.
Chapter 11 / Transplantation 323
A B
Figure 11-3 Preservation (harvesting, reperfusion) injury. A, In severe preservation injury, liver cell necrosis and dropout may occur, with
congestion and acute hemorrhage in the perivenular zone. B, The perivenular hepatocytes have undergone necrosis and have dropped out,
with red blood cells taking their place in the hepatic cords.
6. Portal tracts may show a mild lymphocytic infiltrate, but

are often uninvolved with normal interlobular bile ducts.
Differential diagnosis
1. Bile duct obstruction: When the cholestasis is severe and
is associated with cholangiolar proliferation, the features
may mimic bile duct obstruction; however, the interlobu-
lar bile ducts are normal in preservation injury, without
bile duct dilatation, periductal edema, significant bile
duct proliferation, or acute cholangitis, these features
characteristic of bile duct obstruction.
2. Bacterial sepsis: Perivenular and midzonal ballooning
change and cholestasis may be seen in instances of sec-
ondary bacterial infections, especially within the first few
weeks after transplantation. Cholangiolar proliferation
with acute cholangiolitis may also occur in sepsis and is
morphologically similar to that seen in severe harvest-
Figure 11-4 Preservation (harvesting, reperfusion) injury. A “func-
ing injury. The presence of lobular acute inflammation
tional” cholestasis may also be seen and is most prominent in the with microabscess formation (CMV negative) and acute
perivenular and mid-zones. inflammation of the interlobular bile ducts (acute chol-
angitis) is most indicative of sepsis. Of note is that both
sepsis and harvesting injury as well as bile duct stricture
may all occur during this same timeframe, making the
Other features overall diagnosis more complex.
1. In the more severe cases, the liver cell ballooning may
be diffuse. In addition, perivenular liver cell necrosis and Clinical and biologic behavior
dropout may also occur in severe cases, associated with 1. Preservation injury is a benign condition and is observed
perivenular congestion and acute hemorrhage. frequently soon after liver transplantation.
2. Mild perivenular inflammation can sometimes be seen, 2. In every patient following transplantation, elevation of
without definite endothelial inflammation. serum transaminases, alkaline phosphatase and serum
3. Red blood cell extravasation into the hepatic cords in bilirubin of varying levels is observed over the first week
these zones may be apparent, with adjacent dilated following engraftment. Persistent elevation of serum
sinusoids. bilirubin and alkaline phosphatase with mild or modest
4. Cholangiolar proliferation and ectasia may be seen in elevations of serum transaminases while all other func-
the cases where the cholestasis is panlobular, these chol- tions of the liver are improving suggests preservation or
angioles sometimes containing bile and surrounded by reperfusion injury.
neutrophils. 3. The pathogenesis is considered to be due to a variety
5. In some instances, the cholestasis is more prominent, of factors such as duration of cold and warm ischemia,
with the hydropic ballooning changes less striking to degree of reperfusion injury, and the state of the donor
absent (functional cholestasis). liver (extent of fatty change).
4. Patients recover function fully over 1 to 2 weeks with

declining serum bilirubin, alkaline phosphatase and
serum transaminases. Rarely the serum bilirubin may
remain elevated for several weeks.
5. The exclusion of acute rejection by liver histology, and the
exclusion of portal venous or hepatic artery thrombosis or
bile duct obstruction on ultrasound and Doppler studies
confirms the diagnosis.
Treatment and prognosis

1. Recovery is the rule in the vast majority of cases, with no
long term sequelae. There is no specific therapy.
2. Infrequently graft failure may occur when factors such as
prolonged warm or cold ischemia are present.
ACUTE GRAFT FAILURE (PRIMARY NONFUNCTION)

Figure 11-5 Acute graft failure (primary nonfunction). The cut
(Figs. 11-5 through 11-7) section of liver with graft failure shows extensive “nutmeg”-type
necrosis involving the central areas of the lobules. The parenchyma
in these areas of necrosis are green due to extensive cholestasis.
1. Extensive coagulation necrosis with variable acute hemor-
rhage is seen in the perivenular and midzones, often asso-
ciated with bridging necrosis from one lobule to the next.
Other features
1. Neutrophils may be seen adjacent to the areas of necrosis.
2. In the severe cases, panlobular necrosis may occur.
3. Cholestasis may be present in the areas of viable
hepatocytes.
4. The portal tracts may exhibit a mild mixed inflam-
matory infiltrate with variable edema, but the bile
ducts and hepatic arteries and arterioles are usually
unremarkable.
1. Hyperacute (humoral) rejection: Although coagulative
necrosis is a common finding in hyperacute (humoral)
rejection, the small hepatic arteries and arterioles dem- Figure 11-6 Acute graft failure (primary nonfunction). The paren-
onstrate occlusion by fibrin with severe necrotizing chyma shows extensive coagulative necrosis which oftentimes is
endothelial damage in humoral rejection. In addition, panlobular. The portal tract shows a mild mixed inflammatory infil-
immunoglobulins may be demonstrated within the arter- trate and edema.
ies, veins and portal capillaries in humoral rejection by
immunoperoxidase stains, these features not present in
primary nonfunction.
2. Other causes of coagulative necrosis: Severe hypoxia and
vascular thrombosis may cause similar changes. Morpho-
logically, both the small arteries and arterioles and portal
vein are patent in primary nonfunction, with no evidence
of vascular inflammation. Although these patients may
be hypotensive, the associated clinical presentation with
fibrinolysis and absence of bile production helps confirm
the diagnosis of primary nonfunction.
Clinical and biologic behavior

1. The optimal function of the allograft is manifested
by the appearance of deeply pigmented bile at the
time of engraftment or subsequently noted through a
bile drainage catheter, and the spontaneous improve-
ment in coagulopathy. Renal function will improve Figure 11-7 Acute graft failure (primary nonfunction). The paren-
and patients are successfully extubated within 12 to chyma on high power shows extensive coagulative necrosis of all
48 hours. hepatocytes.
2. The development of minimal bile output or the drain-

age of pale or depigmented bile is indicative of acute
allograft dysfunction (primary nonfunction). Serum
transaminases continue to remain elevated (>500 to
2000 IU/L), serum bilirubin remains elevated and coag-
ulopathy is persistent. The mental status is impaired
with inability to extubate the patient from the venti-
lator, and renal function deteriorates with low urinary
output, progressing to renal failure requiring hemodi-
alysis. Hypothermia, hypoglycemia, metabolic and lactic
acidosis, and elevations of serum lactate dehydrogenase
are observed which collectively support the diagnosis
of acute graft failure. These abnormalities are observed
immediately and within the first week following liver
transplant.
3. Ultrasound of the liver demonstrates no obstruction of Figure 11-8 Hyperacute (humoral) rejection. The small hepatic
the bile duct or thrombosis of the portal vein and hepatic artery shows a recent intraluminal fibrin thrombus. A mild lympho-
cytic inflammatory infiltrate is seen surrounding the vessel. (Cour-
artery tesy AJ Demetris, University of Pittsburgh Medical Center.)
4. Acute graft failure may result from technically inadequate
revascularization but is commonly associated with donor
characteristics of obesity, antemortem hypoxia and hypo-
tension, and hepatic steatosis. In general, when the degree
of fat in the implanted liver exceeds 60% of the liver cell
volume, the incidence of graft failure substantially rises.
In implantation of liver segments from living-related
donors, however, graft nonfunction can occur when the
degree of fat is substantially less than with cadaveric liv-
ers. Preservation factors such as prolonged warm or cold
ischemia times may also play a part in the cause of graft
failure.

1. Treatment is supportive. Recovery is indicated by nor-
malization of mental and renal function with improve-
ment in liver tests and restoration of bile to normal color
and consistency.
2. Milder forms of graft failure referred to as initial poor Figure 11-9 Hyperacute (humoral) rejection. The small artery
function may be treated with infusion of prostaglandin E1. branches within this portal tract show IgM deposition along the ves-
The exact mechanism of action is not known. sel walls (immunoperoxidase stain for IgM). (Courtesy AJ Demetris,
3. If recovery of graft function does not occur, mortality is University of Pittsburgh Medical Center.)
100% unless retransplantation occurs, which must be per-
formed expeditiously.
REJECTION
1. Liver allograft rejection is mediated by the immune

response of the recipient to allogeneic antigens expressed
by the donor liver. Multiple immunologic mechanisms
participate in the alloimmune reaction.
2. Clinically there are three types of rejection:
a. Hyperacute (humoral) rejection, which is relatively
uncommon.
b. Acute (cellular) rejection, commonly occurring during
the first few months after transplantation.
c. Chronic (ductopenic) rejection, a manifestation of bile
duct loss.
Hyperacute (Humoral) Rejection Figure 11-10 Hyperacute (humoral) rejection. Extensive coagula-
tive necrosis and hepatic infarction is seen secondary to intravascu-
(Figs. 11-8 through 11-10) lar thrombosis and occlusion of the small hepatic artery branches.
Major morphologic features flow and culminate in hemorrhagic necrosis of hepato-

1. Coagulative necrosis and acute hemorrhage are present, cytes leading to liver failure.
most prominent within the perivenular and midzones but 3. The diagnosis rests on early graft failure with no other
often involving the entire lobule. distinctive explanation, consistent microscopic features
by both light and immunofluorescence, the presence of
Other features a presensitized state in the recipient, and the presence of
1. Fibrin deposition with neutrophils and platelet aggre- preformed donor-specific antibodies in the recipient.
gates are seen in the very early stages within the sinusoids, 4. Since preformed antibodies are frequently seen in the
hepatic arterioles, and portal venules. recipient, it is surprising that hyperacute rejection is not
2. Numerous neutrophils may be seen in the sinusoids more frequent. This may be due to the fact that there is a
adjacent to resultant ischemic necrosis as the disease dual blood supply to the liver (via the hepatic artery and
progresses. portal vein). In addition, the antibodies directed toward
3. Cholestasis is often present and is most accentuated HLA class I antigens on the endothelium of the donor
amidst the adjacent viable liver cells. liver may be neutralized by high circulating soluble HLA
4. The viable hepatocytes can show variable hydropic bal- class I antigens immediately after reperfusion.
looning change 5. The clinical course of these patients after transplant is
5. Necrotizing endothelial damage and denudation occurs manifest by poor graft function, encephalopathy and
predominantly involving medium-sized (>120 μm in renal failure. Serum transaminases and serum bilirubin
diameter) arteries, with neutrophilic infiltration, fibrin levels are markedly elevated, prothrombin time is pro-
thrombi and partial vascular occlusion occurring. Fibrin longed and serum albumin is decreased.
thrombi may also be seen within portal venules and ter-
minal hepatic venules and veins. Treatment and prognosis
1. Retransplantation is the only option and is life saving.
Special stains
1. Phosphotungstic-acid-hematoxylin (PTAH): The fibrin
thrombi within vessels can best be appreciated. Acute (Cellular) Rejection
Immunohistochemistry (Figs. 11-11 through 11-15)

1. IgM, IgG, C1q, C3, C4, C4d, fibrinogen: Deposits in arter-
ies, veins and portal capillaries may be identified. Major morphologic features
The following triad of histologic changes may be seen to
Differential diagnosis variable degrees, depending on the severity of the rejection:
1. Ischemic necrosis secondary to severe hypotension, hepatic 1. Mixed portal inflammatory infiltrates
artery thrombosis: Coagulative ischemic changes within a. Activated lymphocytes (immunocytes, immunoblasts),
the lobules due to poor perfusion from various causes eosinophils, occasional plasma cells, histiocytes, and
such as hypotension and hepatic artery occlusion are sim- neutrophils are present and are usually confined to the
ilar to those seen in hyperacute rejection. The presence of portal tracts (except in severe cases, where periportal
small vessel thrombosis with immunoglobulin deposition spillover may occur).
is characteristic of hyperacute rejection. The clinical set- 2. Venous endothelial inflammation (endothelialitis)
ting without associated hypotension is also characteristic. a. Lymphocytes and immunocytes attach to the endothe-
In addition, with hepatic artery thrombosis, panlobular lium of portal and terminal hepatic venules, involving
ischemic necrosis with hepatic infarction rather than a part or all of the intravascular luminal lining.
zonal necrosis is common. b. Subendothelial infiltration of these mononuclear cells
2. Primary nonfunction: Severe perivenular and midzonal is often seen. In severe rejection, the inflammatory cells
coagulative necrosis is seen in both primary nonfunction also involve the perivenular sinusoids and may be associ-
and hyperacute humoral rejection. The absence of primary ated with perivenular ischemic necrosis of hepatocytes.
vascular involvement favors primary nonfunction. c. Arterioles may be involved in severe cases.
3. Nonsuppurative cholangitis, destructive or nondestructive
Clinical and biologic behavior a. Interlobular bile ducts are surrounded and invaded
1. Hyperacute (humoral) rejection is an infrequent compli- by lymphocytes, immunocytes and neutrophils, with
cation that occurs within hours or days following liver the biliary epithelium showing variable cytoplasmic
transplantation. vacuolization and nuclear pyknosis, dependent on the
2. It is mediated by preformed recipient antibodies that bind rejection severity.
to allogeneic epitopes on donor endothelial cells. These
preformed antibodies recognize both carbohydrate and Other features
peptide components of glycosylated proteins on the 1. Cholestasis, mild mononuclear inflammatory infiltrates,
endothelial cells. Binding of immunoglobulins results in and rare apoptosis may be present within the lobules.
a cascade of events that include complement activation, 2. W hen perivenular necrosis and lobular collapse are pres-
induction of endothelial cell expression of adhesion mole- ent in severe cases, sinusoidal congestion with acute hem-
cules for neutrophil binding, activation of the coagulation orrhage may occur. In addition, red blood cells may be
cascade, and production of vasoactive peptides. These seen infiltrating into the hepatic cords (red blood cell
events destroy sinusoidal endothelial cells, obstruct blood extravasation).
A B
Figure 11-11 Acute (cellular) rejection. These (A) low- and (B) high-power images show a portal tract with a marked mixed inflammatory infil-
trate consisting of lymphocytes, immunoblasts, and numerous eosinophils. Lymphocytes and immunoblasts can be seen hugging up against
and infiltrating beneath the endothelium of the portal venule (endothelialitis). An interlobular bile duct, best seen at the left of the field on the
higher-power image, is surrounded and infiltrated by some lymphocytes and neutrophils.
grades individually the degree of portal inflammation, duct

damage, and endothelial inflammation, each on a scale of 0
through 3, with a total score ranging from 0 (no rejection)
to 9 (severe rejection). For example, a biopsy showing portal
rejection infiltrates involving only a minority of portal tracts,
with the portal infiltrate mostly lymphocytic (score = 1),
bile duct damage involving a minority of ducts (score = 1),
and endothelial damage involving only some portal venules
(score = 1), would be graded as mild (RAI = 3 of 9). Table
11-3 outlines the criteria in acute rejection grading.
1. Acute viral hepatitis (hepatotropic viruses): Patients may
clinically present with an acute hepatitis-like picture,
with moderately or markedly elevated aminotransferases.
Biopsy in acute rejection does not exhibit the degree of
liver cell injury and lobular inflammation seen in acute
Figure 11-12 Acute (cellular) rejection. The portal tract shows a strik- viral hepatitis. In addition, in acute viral hepatitis the por-
ing infiltration by eosinophils. Interlobular bile ducts show cytologic
atypia and are surrounded and focally infiltrated by inflammatory cells.
tal inflammation is chiefly lymphocytic and not mixed,
without appreciable duct injury and with absence of vas-
3. In some cases perivenular inflammation with endothe- cular inflammation.
lialitis may occur in the absence of corresponding portal 2. CMV hepatitis: Portal lymphocytic infiltrates are seen in
tract changes of rejection. CMV hepatitis without a mixed inflammatory infiltrate,
Note: The above histologic changes are characteristic find- the latter a characteristic finding for acute rejection. In
ings of acute rejection in the early post-transplant setting addition, nuclear and/or cytoplasmic CMV inclusions,
(weeks to months); however, acute rejection in allografts which are often associated with microabscess formation
over one year post-transplant may in fact show only mild in the transplant setting, are characteristic for CMV
nonspecific changes, such as mild portal and lobular inflam- hepatitis and not a feature of acute rejection. These viral
mation, and may histologically resemble a chronic hepatitis- inclusions can also be seen within Kupffer cells and portal
like reaction. In these instances, other causes such as disease bile duct epithelium, and can be confirmed as CMV by
recurrence, drug-induced injury, and superinfection must immunoperoxidase stains as well.
be ruled out before a diagnosis of possible rejection can be 3. Epstein Barr Virus (EBV) infection: Also termed post-
made; unfortunately, in some instances this exclusion process transplant lymphoproliferative disorder, this infectious
may not confidently be possible. process is characterized by a marked portal infiltrate by
atypical lymphocytes, the infiltrate also seen within the
Grading of acute rejection (Banff Criteria) lobules and sinusoids. A mixed inflammatory infiltrate
Liver allograft pathology for acute cellular rejection is characteristic of acute rejection is not present. The diag-
graded by use of the Banff scoring system, and is subdivided nosis of EBV infection can be confirmed by in situ hybrid-
into the global assessment of mild to severe rejection, followed ization (demonstration of the EBER-1 gene), which
by a numerical score (rejection activity index, RAI). This score shows positive staining within portal lymphocytes.
A B
Figure 11-13 Acute (cellular) rejection. The portal tract in these (A) low- and (B) high-power images shows a marked mixed inflammatory
infiltrate with numerous eosinophils. Lymphocytes are seen hugging up against the endothelium of the portal venule. The interlobular bile duct
shows mild hydropic change, with a few lymphocytes beneath the duct basement membrane.
A B
Figure 11-14 Acute (cellular) rejection. A and B,The interlobular bile ducts in these two images show considerable cytologic distortion,
with irregularly arranged nuclei and inflammatory cells abutting up against and focally infiltrating into the duct walls. The portal tract shows a
prominent mixed inflammatory infiltrate including numerous immunoblasts.
4. Drug toxicity: Patients on post-transplant immunosup-

pressive treatment may exhibit variable degrees of liver
cell necrosis and occasionally cholestasis not attributable
to the more common causes such as rejection, biliary
strictures or recurrent disease. Destructive inflamma-
tory duct lesions and endothelial inflammation, features
characteristic of acute rejection, are rarely seen in drug-
induced injury.
5. Native liver disease recurrence: Transplanted livers may
often develop portal and lobular inflammation that rep-
resent recurrent disease (e.g., chronic viral hepatitis). The
portal inflammation in recurrent viral hepatitis is chiefly
lymphocytic, usually without appreciable duct injury and
without endothelialitis. Although certain recurrent dis-
eases may show a mixed portal infiltrate as well as duct
injury (e.g., portal lymphocytes, plasma cells and eosino-
Figure 11-15 Acute (cellular) rejection. The terminal hepatic venule phils, nonsuppurative cholangitis in recurrent primary
shows numerous lymphocytes up against and infiltrating through
the disrupted endothelium (endothelialitis). The inflammation has
biliary cirrhosis), endothelialitis is not a feature of disease
also extended into the perivenular zone, with damage and focal recurrence, although recurrent HCV can at time show
dropout of hepatocytes. mild focal perivenular inflammation. In addition, the
Table 11-3 Grading of acute allograft rejection
GLOBAL ASSESSMENT
SUBJECTIVE GRADE CRITERIA
Indeterminate (borderline, insufficient Portal inflammatory infiltrates that fail to meet the criteria for the diagnosis of acute rejection
for a diagnosis of acute rejection)
Mild Rejection infiltrates in a minority of the triads that are mild and confined to the portal spaces
Moderate Rejection infiltrates expanding most or all of the portal tracts
Severe As above, with spillover of inflammatory cells into the periportal areas, with moderate to severe perivenu-
lar inflammation that extends into the hepatic parenchyma and is associated with perivenular liver cell
necrosis
REJECTION ACTIVITY INDEX (RAI)
PORTAL INFLAMMATION
1 Mostly lymphocytic inflammation involving but not expanding a minority of the portal triads
2 Expansion of most or all of the portal tracts by a mixed inflammatory infiltrate containing lymphocytes
with occasional blasts, neutrophils, and eosinophils
3 Marked expansion of most or all of the portal tracts by a mixed infiltrate containing numerous immuno-
blasts and eosinophils, with spillover of the cells into the periportal region
BILE DUCT INFLAMMATION/DAMAGE
1 A minority of the ducts are surrounded and infiltrated by inflammatory cells and show only mild reactive
changes (e.g., increased nuclear/cytoplasmic ratio)
2 Most or all of the ducts are infiltrated by inflammatory cells; more than an occasional duct shows degen-
erative changes (nuclear pleomorphism, disordered polarity, cytoplasmic vacuolization)
3 As above, with most or all of the ducts showing degenerative changes or focal luminal disruption
VENOUS ENDOTHELIAL INFLAMMATION
1 Subendothelial lymphocytic infiltration involving a minority of the portal and/or hepatic venules
2 Subendothelial lymphocytic infiltration involving most or all of the portal and/or hepatic venules
3 As above, with moderate to severe perivenular inflammation that extends into the perivenular regions,
associated with perivenular liver cell necrosis
From Demetris AJ, Batts KP, Dhillon AP, et al: Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658-663.
presence of granulomas, seen in many cases of recurrent 2. Patients may present with fever, right upper quadrant and
primary biliary cirrhosis, is not a feature of acute rejection. back pain, anorexia, ascites, and decreased bile output and
Recurrent disease can also be confirmed in disorders where bile pigment (from drainage catheter).
immunoperoxidase markers are available (e.g., recurrent 3. Elevations in serum transaminases, bilirubin and alkaline
HBV infection with nuclear and cytoplasmic staining for phosphatase activity occur, with variable levels depending
the hepatitis B core and surface antigens, respectively). on the severity. Bilirubin levels may be normal early in the
6. Other causes of perivenular inflammation (central perivenu- course of acute rejection.
litis): A number of inflammatory processes besides acute 4. The diagnosis is made by exclusion of bile leak, biliary stric-
cellular rejection may cause a perivenular inflammation tures with duct dilatation, and thrombosis of the hepatic
and include ischemia (preservation injury, vascular occlu- artery on ultrasound examination. Liver biopsy confirms
sion), chronic ductopenic rejection, recurrent viral hepatitis the diagnosis and grades the severity of acute rejection, but
(especially HCV), autoimmune hepatitis, EBV infection, may not be necessary in the early postoperative period.
veno-occlusive disease, secondary syphilis, and certain 5. The “vanishing bile duct syndrome,” an irreversible type
drugs (e.g., azathioprine, busulfan). Clinical correlation is of acute rejection that occurs in a small percentage of
then necessary in consideration of these possibilities. patients, presents within the first 100 days of transplant
Note: Concurrent post-transplant disorders (e.g., acute rejec- and is characterized by spiking fever, lethargy, jaundice,
tion in a patient with recurrent viral hepatitis) unfortu- pruritus, dark urine, light stools, and ascites. The patient
nately may be seen, making definitive pathologic diagnoses rapidly deteriorates, necessitating retransplantation. The
sometimes quite difficult. Correlation with laboratory tests speed of deterioration is somewhat unique for this type
including hepatitis and autoimmune serologies, imaging, of rejection, the morphologic changes revealing marked
timeframe post-transplant, and clinical presentations are destruction of the interlobular bile ducts (see Chronic
therefore quite important in arriving at the best possibilities [ductopenic] rejection).
in biopsy signouts. 6. Extrahepatic complications of acute rejection serious
enough to be life threatening or necessitate retransplan-
Clinical and biologic behavior tation include pulmonary infections, disseminated intra-
1. Despite induction immunosuppressive therapy, about vascular coagulation, bile leaks or stricture at the site of
40% to 60% of recipients will experience one or more the duct-to-duct anastomosis, intra-abdominal abscess
acute rejection episodes, usually encountered early in the formation or peritonitis, renal failure, wound complica-
postoperative period. tions, and cardiac and neurologic abnormalities.
7. There are three stages in the pathophysiologic mecha- e nhanced by cytokines released from the activated
nisms of acute cellular rejection*: T cells, resulting in the cleaving and disassembly of
a. Presentation of allograft antigens to the host: Allograft the cellular structure with eventual cell death.
antigens are recognized by the host T cells via interac-
tion of the T-cell receptor (TCR) and particularly the Treatment and prognosis
CD4 antigen on the surface of the host lymphocytes 1. Standard treatment of acute cellular rejection is an intra-
with the MHC molecules expressed on the surface of venous bolus dose of corticosteroids (usually 1 g in proven
the graft cells. This interaction involves many compo- moderate or severe cases) and rapid tapering of dosage
nents that include adhesive molecules (promote strong over a few days with maintenance of adequate levels
adhesion between graft cells and binding T-cells) and of other immunosuppressive drugs such as tacrolimus,
co-stimulatory cells (e.g., CD28 and B7 that are neces- cyclosporine, or sirolimus.
sary for T-cell activation). 2. In milder forms, increase in dose of immunosuppressive
b. T-cell activation and cytokine release: Once there is drugs and corticosteroids (without the bolus and taper
binding of the T-cell receptor with the MHC anti- regimen) is tried.
gens, a cascade of intracellular signaling occurs with 3. The response to treatment is generally good with reso-
production and release of cytokines (e.g., interleukins, lution of injury and improvement in liver tests. Less
interferon, monocyte chemotactic protein) that have a frequently, treatment with monoclonal antibody or anti-
variety of pro-inflammatory effects including the gen- lymphocyte globulin (OKT3) is necessary.
eration of cytotoxic T lymphocytes, activation of mac-
rophages, and up-regulation of co-stimulatory cells.
c. Effector mechanisms in cell-mediated injury: The cytotoxic Chronic (Ductopenic) Rejection
T lymphocyte then mediate cell damage, with a mixed
population of CD4 and CD8 lymphocytes seen in vary- (Figs. 11-16 through 11-21)
ing proportions, the CD8 responsible for damage to bile
duct epithelium, endothelial cells, and to some extent the Major morphologic features
hepatocytes in the perivenular zone. The CD8 T-cell– 1. Interlobular bile ducts show considerable cytologic atypia
mediated damage occurs by way of two pathways: including irregularly spaced hyperchromatic and pyknotic
i. Synthesis and secretion of cytolytic granules (perforin, nuclei, and flattened to irregular eosinophilic cytoplasm,
granzymes, granulysin): After T-cell binding with without inflammatory cells oriented to the ducts (early
the target cell, these granules are released and fuse reversible stage).
with the cell membrane, causing membrane pores, 2. Eventually the bile ducts become depleted in the majority
further influx of the cytolytic proteins, and acti- of portal tracts (advanced irreversible stage).
vation of caspases with resultant apoptosis of the 3. Subendothelial intraluminal foam cells develop within
target cell. small and medium-sized hepatic arteries (obliterative
ii. Expression of Fas ligand (FasL): The ligand binds to vasculopathy).
the Fas, located on the surface of the hepatocytes,
bile ducts, and endothelial target cells, which is Other features
1. Although small interlobular bile ducts are usually involved,
*Hubscher SG, Portmann BC. Transplantation pathology. In: Burt AD,
medium-sized and larger ducts can also be affected, best
Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver. 5th appreciated in explanted livers (obtained from retransplant).
ed. London: Churchill-Livingstone; 2007: 815-879. 2. With time depletion of hepatic arterioles may also occur.
A B
Figure 11-16 Chronic (ductopenic) rejection (early). Both images show interlobular bile ducts in the early stage of chronic rejection.
A, The duct epithelium is markedly eosinophilic, with cytoplasmic damage and focal detachment from the duct basement membrane. There
is marked distortion and irregularity of the nuclei. B, The interlobular bile duct shows considerable nuclear irregularity, with focal loss of nuclei
and considerable cytoplasmic damage and loss. Note also that there is only a mild portal inflammatory infiltrate in both examples, without
these inflammatory cells oriented to the damaged ducts.
A B
Figure 11-17 Chronic (ductopenic) rejection (late). A and B, Both portal tracts show total loss of the interlobular bile ducts, with scanty
to absent portal lymphocytic infiltrates. Small arterioles are seen; however, in some instances of late chronic rejection there also may be a
decrease in arterioles.
A B
Figure 11-18 Chronic (ductopenic) rejection. A and B, Both images show small hepatic arteries almost totally occluded by foamy histiocytes
(obliterative vasculopathy).
A B
Figure 11-19 Chronic (ductopenic) rejection. A, The lumen of this hepatic artery segment is almost totally occluded by foamy histiocytes
(obliterative vasculopathy). B, This medium-sized hepatic artery shows infiltration by foamy histiocytes. Prominent fibrointimal thickening of
the intima is also present.
Figure 11-20 Chronic (ductopenic) rejection. Perivenular fibrosis Figure 11-21 Chronic (ductopenic) rejection. Clusters of foamy his-
and cholestasis is present. tiocytes are often present scattered within the hepatic lobule.
3. Perivenular ballooning of hepatocytes is often seen, with of these liver diseases may eventually progress to a biliary
associated cholestasis. In severe cases the cholestasis may cirrhosis. Adenovirus infection in the pediatric population
become diffuse. can also rarely be associated with duct injury and even-
4. Fibrosis and sclerosis of portal and terminal hepatic tual duct loss; however, characteristic nuclear inclusions
venules, with variable perivenular fibrosis, may occur. (smudge cells) are also present with this infection, and rarely
5. Occasionally a bridging fibrosis may be seen between ter- a severe confluent parenchymal necrosis may also occur.
minal hepatic venules. Biliary cirrhosis has been reported Chronic rejection, however, is associated with mild por-
but is quite uncommon. tal fibrosis, with occasional bridging fibrosis seen between
6. Variable lymphocytic infiltrates can also be seen within terminal hepatic venules, without cirrhosis (rare cases
the intima in affected vessels. reported) or significant lobular inflammation or necrosis.
7. Aggregates of foam cells can be identified within the In addition, portal inflammation diminishes as duct loss
sinusoids. develops, with most portal tracts showing virtually no por-
8. With time the foam cells in the arteries are replaced by tal inflammation at the time of late stage chronic rejection.
intraluminal myofibroblasts (fibromyointimal prolifera- 2. Drug-induced liver injury (e.g., chlorpromazine, chlor-
tion) with considerable intraluminal narrowing. propamide; see Table 5-11): Certain drugs are associated
9. Portal tracts show only a mild lymphocytic infiltrate. with bile duct injury and ductopenia. Correlation with
When duct loss is complete, portal tracts become devoid the timeframe of initiation of the drug and the onset of
of inflammatory cells. abnormal liver tests is important. In drug-induced duct
Note: Both duct loss and obliterative vasculopathy are com- injury, after the drug is discontinued, the vast majority of
ponents of chronic rejection, and it is likely that duct loss in cases will show eventual resolution of the duct damage;
many cases may be due to duct ischemia secondary to the if the etiology is chronic rejection, however, duct damage
vasculopathy; however, studies have shown that duct loss can will persist with eventual bile duct loss.
occur without evidence of vasculopathy in 14% of cases, and 3. Bile duct ischemia from hepatic artery thrombosis: Bile duct
vasculopathy can be seen without evidence of duct loss in ischemia with eventual bile duct loss can also occur in partial
15% of cases. or total hepatic artery occlusion from hepatic artery throm-
bosis. The liver injury in this setting is acute and severe
Grading of chronic rejection (Banff criteria) due to coexisting ischemic necrosis of the parenchyma, and
1. Liver allograft pathology for chronic ductopenic rejection arteriography confirms the appropriate diagnosis.
is graded by use of the Banff scoring system and is subdi-
vided into early and late chronic rejection. Unlike acute Clinical and biologic behavior
rejection, no numerical scoring system is used. A sum- 1. Chronic rejection is usually seen within a few weeks to 6
mary of the criteria are listed in Table 11-4. months, and in rare instances many years post-transplant,
and is characterized by the unrelenting and gradual loss of
Differential diagnosis bile ducts associated with progressive foamy arteriopathy.
1. Recurrent and infectious disorders associated with duct loss: 2. Chronic rejection was seen in 11.3% cases in earlier stud-
A number of recurrent liver diseases post-transplant are ies, but now the rate is 1.3% and will continue to decrease
associated with ductopenia (e.g., primary biliary cirrhosis secondary to improvement in immunosuppressive drugs
and primary sclerosing cholangitis). These conditions are and improved extra-corporeal graft preservation.
associated with prominent portal lymphocytic infiltrates 3. Chronic rejection occurs in two ways:
and in some instances (e.g., primary biliary cirrhosis) a. Acute rejection that does not respond to anti-rejection
numerous portal plasma cells, with the majority having medications, with persistent duct damage and eventual
some degree of portal fibrosis as well. In addition, many duct loss.
Table 11-4 Grading of Chronic Allograft Rejection

HISTOPATHOLOGIC STRUCTURES EARLY CHRONIC REJECTION LATE CHRONIC REJECTION
Small bile ducts (<60 μm) • Eosinophilic transformation of the cytoplasm • Small bile duct loss in >50% of portal tracts
• Increased nuclear: cytoplasmic ratio • Mural fibrosis and inflammation of large bile ducts
• Nuclear hyperchromasia
• Uneven nuclear spacing
• D ucts only partially lined by biliary epithelial cells
• Bile duct loss in <50% of portal tracts
Terminal hepatic venules, • Mild perivenular fibrosis • Severe perivenular fibrosis with focal central-to-
perivenular zone hepatocytes • Mild perivenular necrosis, liver cell swelling and central bridging
dropout • Hepatocyte swelling and dropout with cholestasis
Hepatic artery/arterioles • Mild subintimal, adventitial and focal medial foam • Advanced foam cell obliterative arteriopathy
cell accumulation • Loss of small portal hepatic artery/arterioles involv-
• Occasional loss of small portal hepatic artery/arte- ing >25% of portal tracts
rioles involving <25% of portal tracts
Other • “ Transition” hepatitis with spotty necrosis • Sinusoidal foam cell deposition
• Marked cholestasis
Data from Demetris A, et al. Update of the International Banff schema for liver allograft rejection: working recommendations for the histopathologic staging and reporting of
chronic rejection. Hepatology 2000;31:792-799.
b. Vasculopathy with extensive subintimal foam cell depo-

sition and fibrointimal thickening, with resultant
impaired blood supply and ischemia to the duct epi-
thelium and eventual duct loss. Of note is that isch-
emia can also affect the small hepatic arterioles which
can decrease in number as well.
4. Patients generally do not have any symptoms early in the
course of the disease, with the diagnosis suspected when
there is persistent elevation in serum alkaline phosphatase
activity and mild elevations of serum transaminases not
explained by other causes (e.g., viral hepatitis, drug effect,
biliary tract obstruction or strictures). In advanced stages
hyperbilirubinemia with jaundice evolve.
5. Ultrasound or computed tomography scans are usually
normal and do not demonstrate abnormalities of the
biliary system or occlusion of the hepatic artery or portal
vein.
6. The diagnosis is established when the typical features are Figure 11-22 Bile duct stricture. Proliferation and ectasia of the
interlobular bile ducts and cholangioles are present.
observed on liver biopsy.
Treatment and prognosis Other features

1. An increase in immunosuppressive therapy is sometimes 1. The parenchyma often shows perivenular cholestasis,
effective; however, in well established cases the disease sometimes associated with liver cell ballooning, with
progresses inexorably to require retransplantation, par- minimal to absent lobular necroinflammatory change.
ticularly when a lack of response is noted with increases 2. The larger hilar ducts often show variable fibrosis, focal
in the immunosuppressive regimen. mucosal sloughing, acute and chronic inflammation, and
sometimes biliary sludge within the lumen.
3. With time the portal tracts may exhibit fibrosis of a bili-
POST-TRANSPLANT COMPLICATIONS ary type if the stricture is not alleviated.
Bile Duct Strictures Differential diagnosis

1. Functional cholestasis (harvesting injury): Perivenular cho-
(Figs. 11-22 through 11-24) lestasis is common in harvesting injury. When severe, the
cholestasis may be panlobular, associated with prolifera-
Major morphologic features tion and ectasia of the cholangioles. Neutrophils can also
1. Proliferation and ectasia of the interlobular bile ducts at times be present surrounding and invading these chol-
are seen, sometimes associated with periductal edema, angioles; however, the interlobular bile ducts in functional
mild periductal fibrosis, and cholangiolar (ductular) cholestasis are normal, without ectasia, proliferation, or
proliferation. acute cholangitis.
2. Neutrophils may be seen surrounding and some- 2. Acute cellular rejection: In some instances, neutrophils can
times infiltrating into the interlobular bile ducts (acute be seen within interlobular bile ducts in acute rejection
cholangitis). with or without associated cholestasis; however, bile duct
Figure 11-23 Bile duct stricture. This interlobular bile duct shows Figure 11-24 Bile duct stricture. The parenchyma shows variable
mild periductal fibrosis and edema. hydropic change and prominent cholestasis.
proliferation and ectasia are minimal to absent in acute 3. Early recognition and reoperation will result in a success-
rejection, and the additional mixed cellular infiltrates ful outcome without long term sequelae. In extensive dis-
including eosinophils and immunoblasts as well as endo- ease, retransplantation may be necessary.
thelial inflammation strongly point to acute rejection
Clinical and biologic behavior Hepatic Artery Thrombosis

1. Bile duct complications are considered the Achilles
heel of the liver transplant procedure. Duct-to-duct cho- (Figs. 11-25 through 11-28)
ledochocholedochostomy with or without T-tube stent and
Roux-en-Y choledochojejunostomy are the two most com- Major morphologic features
mon types of biliary reconstruction performed at liver 1. The major hepatic artery or its large tributaries shows
transplantation. The frequency of biliary tract problems thrombosis of most or all of the vascular lumen, with vari-
has now decreased from 50% to 20% with better surgical able degrees of organization over time.
techniques and early recognition and treatment of these 2. The hilar and large intrahepatic bile ducts may show par-
entities. tial to extensive ischemic necrosis with extravasation of
2. Anastomotic leak is usually manifested by the appearance bile into the duct wall.
of bile in the abdominal drainage or suspected when an 3. Coagulative necrosis of the hepatocytes is present and
unexplained rise in serum bilirubin occurs during the first involves the perivenular and midzones; in severe cases,
several weeks after transplantation. Minimal well-drained panlobular necrosis and infarction can occur.
leaks will close spontaneously but more extensive bile
collections require open drainage to create a controlled Other features
fistula, or even resection and reanastomosis. Obstruction 1. In the more severe cases, portal and lobular abscesses can
of the anastomotic site occurs in the later postoperative form.
period. 2. Secondary bile duct strictures can also occur with time.
3. Patients may be asymptomatic or may present with fever, 3. Bile lakes may form adjacent to the damaged ducts.
leukocytosis, pain in the right upper quadrant, ileus, or 4. Smaller interlobular bile ducts may exhibit with time vari-
jaundice. Elevation in serum bilirubin, alkaline phospha- able and often severe cytologic atypia, with duct necrosis
tase activity, and γ-glutamyl transpeptidase out of propor- and eventual duct loss. Acute neutrophilic infiltration of
tion to serum transaminases, or the sudden unexplained the duct epithelium (ischemic cholangitis) can also occur.
rise in serum bilirubin, are clues to the diagnosis.
4. Ultrasound of the biliary tract usually confirms the diag- Differential diagnosis
nosis. In some cases, the findings on liver biopsy direct the 1. Acute graft failure (primary nonfunction): Severe coagula-
investigation of the biliary tract, and further evaluation tive necrosis is also seen within the parenchyma in pri-
with magnetic resonance cholangiography, endoscopic mary nonfunction; however, the interlobular bile ducts
retrograde cholangiopancreaticography or percutane- are normal in this disorder, compared to severe duct dam-
ous transhepatic cholangiography may be necessary for age in hepatic artery thrombosis.
diagnosis. 2. Hyperacute (humoral) rejection: Severe coagulative necrosis
is seen in hyperacute rejection. Acute inflammation of the
Treatment and prognosis hepatic arterioles and small arteries is present in humoral
1. With mild strictures, stenting or dilation is sufficient. rejection but not in hepatic artery thrombosis, which instead
2. In bile leaks or with significant strictures, reoperation and involves the large hepatic artery and its major branches
revision of the anastomosis is often necessary. without an accompanying inflammatory infiltrate.
Figure 11-25 Hepatic artery thrombosis. The main hilar bile duct
has undergone necrosis due to thrombosis of the hepatic artery,
with resultant extravasation and leakage of bile from the necrotic Figure 11-26 Hepatic artery thrombosis. The main hepatic artery
duct (biloma). (Courtesy AJ Demetris, University of Pittsburgh Med- shows a recent thrombus that occludes the vast majority of the
ical Center.) lumen in this section taken from a failed allograft.
A B
Figure 11-27 Hepatic artery thrombosis. A, The common hepatic bile duct immediately adjacent to the thrombosed hepatic artery in Fig.
11-26 shows extensive ischemic necrosis, with extravasation of the bile into the necrotic duct wall. B, The medium-power image shows the
extravasated bile, with total ischemic necrosis of the duct mucosa.
Clinical and biologic behavior b. Relapsing bacteremia and fever due to focal abscesses
1. Hepatic artery thrombosis occurs in 2% to 10% of adult or bilomas and associated biliary strictures.
liver recipients and as high as 30% in pediatric recipients. c. Necrosis of the extrahepatic biliary system resulting in
2. Risk factors are classified as surgical and medical: bile leaks and peritonitis (due to the fact that the donor
a. Surgical factors include poor inflow due to atherosclero- bile duct receives its blood supply from the hepatic artery).
sis, arterial size (<3 mm in diameter), presence of com- d. Normal or mild elevations in liver tests in the first post-
plex hepatic artery anatomy for reconstruction, split or operative week associated with acute metabolic acido-
reduced size liver transplants requiring use of arterial sis in a small number of patients (especially infants).
grafts, and technical factors such as tension, intimal 4. Late hepatic artery thrombosis may develop many years
dissection, poor placed sutures and stenosis. post-transplant as a result of vascular stenosis or intimal
b. Medical factors include graft rejection with endothelial- hyperplasia. Hepatic artery blood flow may be sustained
itis, decreased vascular flow, presence of local infection by collateralization of vessels.
near the arterial anastomosis, and degree of coagula- 5. The presence of bacteremia or abscess formation several
tion and anticoagulation (in patients with prothrom- years following liver transplant should raise the possibility
botic states such as Budd-Chiari syndrome). of ischemia from hepatic artery occlusion.
3. Hepatic artery thrombosis presents in one of four clinical 6. The diagnosis of hepatic artery thrombosis is usually con-
patterns: firmed by ultrasound Doppler studies. In situations where
a. Fulminant hepatic necrosis with markedly elevated the ultrasound findings do not corroborate the clinical
serum transaminases, associated metabolic acidosis, picture, arteriography should be performed since viability
hypoglycemia, coagulopathy, encephalopathy, and of the graft depends on the early restoration of hepatic
renal failure, and appears as acute graft failure. arterial flow.
A
Figure 11-28 Hepatic artery thrombosis. Diffuse ischemic coagula-
tive necrosis and infarction of the parenchyma is present.

1. Operative thrombectomy and revision of arterial anasto-
mosis or angiographic lysis of thrombosis can be offered
to restore hepatic arterial blood flow.
2. Retransplantation may be necessary, especially in the
acute fulminant form and when attempts to restore flow
by angiographic and surgical means have failed
POST-TRANSPLANT OPPORTUNISTIC
INFECTIONS
Bacterial, Fungal Infections B

Figure 11-29 Bacterial infections. A and B, Marked ductular (chol-
(Fig. 11-29) angiolar) proliferation and ectasia, with prominent bile plugs within
the dilated cholangioles, are seen. Neutrophils can also be identified
Major morphologic features intermixed with these ductules on the higher-power image.
1. Mixed portal inflammatory infiltrates with a neutrophilic
predominance occurs.
2. Proliferation and ectasia of cholangioles is common, Differential diagnosis
often associated with luminal bile plugs and acute 1. Bile duct obstruction: Although sepsis is uncommonly
cholangiolitis. associated with acute inflammation of interlobular bile
3. Cholestasis may also be seen in the perivenular and mid- ducts (acute cholangitis), sometimes in severe cases this
zonal regions in severe cases. finding can be seen in sepsis, mimicking features that are
present in bile duct obstruction. In addition, bile duct
Other features obstruction that is untreated can also lead to an ascend-
1. The interlobular bile ducts are often normal; however, in ing cholangitis and resultant sepsis. Periportal bile plugs
severe cases of sepsis an acute cholangitis can also be seen. within cholangioles are not typical for bile duct obstruc-
2. Lobular inflammation is present and consists of lympho- tion but are more common in sepsis. Ultrasound or other
cytes as well as neutrophils. imaging of the biliary tract (e.g., endoscopic retrograde
3. In untreated cases, microabscesses (CMV negative) may cholangiopancreatography) is often necessary for a defin-
occur. itive diagnosis.
4. In fungal infections, the most common being Aspergillus 2. Bile duct ischemia: Ischemic necrosis of large hilar as
and Candida, the organisms are usually easily identifiable well as interlobar and septal bile ducts causes duct
in areas of necrosis and abscess formation destruction, oftentimes associated with reactive ductu-
lar changes within the distal smaller portal tracts that
Special stains mimic sepsis (bile ductular proliferation with bile plugs
1. Gram stain: The microorganisms can sometimes be dem- within cholangioles). Causes of ischemia such as hepatic
onstrated in the areas of necrosis, especially in instances artery thrombosis should hence be excluded by imaging
of abscess formation. techniques.
2. PAS, Gomori methenamine silver (GMS): Fungal organisms, 3. CMV infection: Microabscesses, which can sometimes be
both yeast, hyphae and pseudohyphae are highlighted. seen in severe sepsis, are often present in CMV infection
A B
Figure 11-30 Cytomegalovirus. A and B, Microabscesses are often seen in association with post-transplant CMV infection. The intranuclear
inclusions are quite prominent.
post-transplant. Distinctive nuclear and sometimes cyto-

plasmic inclusions can be seen in the cells containing the
CMV. Immunoperoxidase stain can be helpful in con-
firming the diagnosis of CMV infection, although hema-
toxylin-eosin stain is usually diagnostic.

1. More than 90% of the bacterial infections that occur
in the first month after liver transplantation are due to
technical problems relating to the operation itself or to
the management of devices such as endotracheal tubes,
drains, catheters and vascular access devices in the post-
operative period.
2. Bacterial infections are identified from cultures of blood,
urine and body fluids when tested in the course of work
up for fever or leukocytosis. There are no specific liver test
derangements related to bacterial infection.
Figure 11-31 Cytomegalovirus. CMV inclusions may also be seen Treatment and prognosis
within bile duct epithelium.
1. Appropriate antibiotic therapy and modification of the
degree of immunosuppression is the approach.
Cytomegalovirus

1. Clusters of neutrophils are seen (microabscesses) pre-
dominantly within the parenchyma, without any zonal
preference.
2. Distinct basophilic nuclear inclusions are present within
the hepatocytes that are surrounded by the neutrophils.
Other features
1. The inclusions, although most often present within
the hepatocytes, can also be seen within Kupffer cells,
sinusoidal and vascular endothelial cells, and bile duct
epithelium.
2. Cytoplasmic inclusions may also be seen within the infected
Figure 11-32 Cytomegalovirus. Epithelioid granulomas may occur cell, and are usually composed of multiple small baso-
although less frequently than microabscess formation. philic granules rather than a single distinct inclusion.
A B
Figure 11-33 Cytomegalovirus. A, CMV inclusions are present within bile duct epithelium, endothelial cells, and portal macrophages. B, CMV
nuclear inclusions may also occur within hepatocytes in the absence of an inflammatory infiltrate. In these instances, the inclusions appear
as ground glass–type nuclear changes and may at times be difficult to appreciate on hematoxylin-eosin stain alone (immunoperoxidase stains
for CMV).
3. Epithelioid granulomas can also be seen within the lob- correct diagnosis may rest on the clinical setting, posi-
ules and are occasionally associated with the same type of tive blood cultures and blood CMV DNA, and positive
viral inclusions. cultures of the liver tissue. In addition, the presence of
4. The parenchyma otherwise shows focal mononuclear CMV inclusions on immunoperoxidase stain in areas
necroinflammatory change and mild Kupffer cell away from the granulomas also aids in the diagnosis of
hyperplasia. CMV infection.
5. Portal tracts exhibit a mild to moderate lymphocytic infil- 3. Adenovirus infection: This opportunistic infection which
trate, with mild bile ductular proliferation. usually occurs in pediatric transplant patients may be
associated with foci of liver cell necrosis, cellular debris,
Immunohistochemistry and neutrophilic infiltrates, the latter in some instances
1. CMV: Positive staining confirms the presence of the resembling the microabscesses seen in CMV infection. In
inclusions as CMV. severe cases, however, severe confluent liver cell necro-
Note: In most instances, routine hematoxylin-eosin stain sis with hemorrhage can occur. The nuclear inclusions of
demonstrates the inclusions and is appropriate for diagnosis, adenovirus, when present, differ from those seen in CMV
whereby immunoperoxidase stains are not necessary; how- in that the nuclei have a basophilic intensity (smudge
ever, CMV infection can also occur without an accompa- cells) rather than the distinct inclusion bodies of CMV.
nying inflammatory exudate, and can hence be missed on Immunoperoxidase stains will confirm the presence of
routine histologic examination. In this instance, immuno- adenovirus.
peroxidase stains are most helpful in early detection of the
virus. Clinical and biologic behavior
1. Cytomegalovirus (CMV) commonly infects humans
Differential diagnosis (see Chapter 2, “Cytomegalovirus”) and is one of the most
1. Microabscess formation of other causes: Neutrophilic clusters important opportunistic infections in the immunosup-
may be seen without viral inclusions in post-transplant pressed patients. CMV infections with and without overt
liver biopsies and do not represent CMV infection. Usu- disease occur in about 50% to 70% of all transplant recipi-
ally but not always these microabscesses are quite small ents. CMV has immunomodulatory effects causing rejec-
and less numerous compared to those seen in CMV infection and superinfection.
tion. Various causes include ischemia, bile duct obstruc- 2. The infection may be primary when a seronegative recipi-
tion, and various infectious conditions of bacterial, viral ent receives a seropositive organ, or may be secondary due
and fungal etiology. In some instances, no known cause to reactivation of a latent infection in a seropositive recip-
can be identified. It is important in these cases to assess ient. A variant of primary infection of the graft occurs
whether CMV inclusions are indeed present within these when a seronegative donor organ is engrafted in a sero-
microabscesses on deeper histologic sections. positive recipient.
2. Granulomas of other causes: Post-transplant biopsies may 3. The risk of CMV infection increases when high doses of
sometimes demonstrate the presence of epithelioid immunosuppressive drugs are used, as in the treatment of
granulomas without microabscess formation. In these acute cellular rejection with high dose corticosteroid and
instances the granulomas are usually but not always sec- calcineurin inhibitors, or following therapy with mono-
ondary to infection by other opportunistic microorgan- clonal antibody (OKT3).
isms, although the possibility of recurrent disease such 4. CMV infection occurs on average 5 to 7 weeks (range
as primary biliary cirrhosis must also be excluded in 3 weeks to 4 months) after transplantation, and clini-
the appropriate setting. CMV, however, may elicit only cally presents with gastrointestinal symptoms such
the formation of epithelioid granulomas, whereby the as ulceration, hemorrhagic proctocolitis, perforation,
pseudotumors in the antrum and ileocecal area, pneu-

matosis intestinalis, as well hepatobiliary tract signs such
as cholangitis, papillary stenosis, acalculous cholecystitis,
and hepatitis (approximately 12% incidence).
5. Patients present with fever, abdominal pain, diarrhea,
hematochezia, hematemesis, anorexia, and weight loss.
6. L eukopenia and mild to moderate increases in serum
transaminases and alkaline phosphatase activity are
common features. Serum bilirubin levels are rarely
elevated.
7. The diagnosis is best established by biopsy and demon-
stration of viral inclusions in the tissues. Serologic and
virologic tests are not specific for invasive disease. PCR
assays for CMV in the tissues are not superior to histo-
logic demonstration of CMV.

1. Ganciclovir is a virustatic agent that is effective in most Figure 11-34 Herpesvirus. Distinct Cowdry type B nuclear inclusions
(basophilic with a peripheral rim of finely granular chromatin) are
cases. seen in many of these periportal hepatocytes.
2. In the rare case of disseminated disease or due to resis-
tance to ganciclovir, foscarnet can be used. Differential diagnosis
3. Preemptive or prophylactic regimens have been offered to Although there are a number of causes of a coagulative-type
patients but it is not clear if these approaches are conclu- necrosis in the non-transplant setting and include ischemia
sively beneficial. secondary to hypotension, drug-induced (e.g., acetamino-
4. Reduction in the immunosuppression is a prerequisite for phen), and vasculitis, in post-transplant patients the differ-
good outcome with antiviral therapy. ential is more limited, especially in certain viral infections
where inclusions are more often identified. “Herpes simplex
virus” is also discussion in Chapter 2.
Herpes Simplex Virus 1. Adenovirus, varicella zoster: Coagulative confluent necro-
sis can be seen with these two viral infections post-trans-
(Fig. 11-34) plant. The nuclear inclusions in adenovirus infection
are intensely basophilic (“smudge” cells), with immuno-
Major morphologic features peroxidase stains confirmatory. In addition, the use of
1. Coagulative-type necrosis is present, is often confluent, monoclonal antibodies against the varicella zoster gp1
and is usually associated with a minimal inflammatory glycoprotein also aids in the differential diagnosis.
infiltrate.
2. Intranuclear inclusions are identified in liver cells located Clinical and biologic behavior
at the border of the necrotic and viable regions, and are of 1. Herpes simplex virus, most notably human herpesvirus-6
two types: (HHV-6) and human herpesvirus-7 (HHV-7), are ubiqui-
a. Large and eosinophilic, with a peripherally located tous in the human population and may cause a spectrum of
“clear” space or halo (Cowdry type A). disease in the transplant recipient varying from fever, skin
b. Basophilic, filling up the entire nucleus, with a periph- rash, pneumonia, gastrointestinal symptoms (ulceration of
eral rim of finely granular chromatin (Cowdry type B). the oral mucosa, esophagus, stomach, duodenojejunal or
colonic mucosa; stomatitis, dysphagia, bleeding and diarrhea)
Other features to hepatitis, the latter rare (incidence 0.01%) that develops
1. The portal tracts usually exhibit nonspecific mild portal usually within the first 2 to 3 weeks after transplantation.
lymphocytic infiltrates, or may be devoid of inflammatory 2. The recognition and treatment of early lesions, especially
cells. Bile ducts are not affected. vesicular lesions in the lips and mouth and subsequent
2. Neutrophils and macrophages are often interspersed apthous ulcers, are critical to preventing progression
amongst the necrotic hepatocytes. of infection. Investigation of dysphagia, diarrhea, and
3. Acute hemorrhage may be present in the areas of necrosis bleeding, especially in patients who receive high doses of
as well. immunosuppressive drugs or recent OKT3 therapy, will
allow early diagnosis.
Special stains 3. Disseminated herpes infection or fulminant hepatitis
1. Feulgen reaction: Positive nuclear staining is noted when is rare and is seen in patients who are critically ill prior
the nucleus is filled with viral DNA (Cowdry type B), to transplant who receive prolonged and high doses of
but is negative when the virus has entered the liver cell immunosuppression.
cytoplasm (Cowdry type A).
Immunohistochemistry 1. Treatment with acyclovir is effective. In some patients
1. HSV-1 and HSV-2 antigens: Intranuclear as well as cyto- with severe infection, ganciclovir may also be tried. Rarely
plasmic staining of cells containing the inclusions is with infections resistant to these commonly used antiviral
diagnostic. drugs, foscarnet may be worthwhile.
A B
Figure 11-35 Post-transplant lymphoproliferative disorder. A, The portal tract shows a moderate infiltrate by lymphocytes and plasma cells.
B, EBER-1 DNA probe staining EBV-infected lymphocytes in the same biopsy is seen. (From Markin RS, Wright TL: Post-transplant Epstein-
Barr virus (EBV) lymphoproliferative disorder. In: Clinical and Pathological Correlations in Liver Disease: Approaching the Next Millennium,
1998. American Association for the Study of Liver Disease, with permission from AASLD.)
A B
Figure 11-36 Post-transplant lymphoproliferative disorder. These (A) low- and (B) medium-power images show marked expansion of the
portal tract by a prominent infiltrate of monomorphic-appearing lympho-plasma cells. Immunoperoxidase stains showed these infiltrates to be
predominantly polyclonal B cells.
POST-TRANSPLANT LYMPHOPROLIFERATIVE variable cytologic atypia, and with various numbers of

DISORDER, PTLD (EBV- AND NON–EBV- plasma cells and immunoblasts; numerous mitoses also
RELATED) may occur.
3. Progression to a monoclonal cell population (non-Hodg-
(Figs. 11-35 through 11-37) kin’s lymphoma) may occur.
Major morphologic features Other features

1. Lymphocytic and plasma cell infiltrates are seen within 1. Lobular necroinflammatory change is seen, with associ-
the portal tracts that often expand the portal structures in ated sinusoidal lymphocytosis to variable degrees.
early stage disease. 2. Intralobular masses of both polyclonal and mononuclear
2. The infiltrates are initially polymorphic, with prominence cells can occur, both microscopic and larger (detectable
of cleaved and noncleaved polyclonal B-cells showing on imaging).
A B
Figure 11-37 Post-transplant lymphoproliferative disorder. A, The liver biopsy shows portal tracts markedly expanded by lymphocytes and
plasma cells. B, At autopsy the same patient had multiple distinct nodules within the liver which are composed of lymphocytes similar to those
seen in the biopsy. The lymphocytes in this case were of a polyclonal B-cell origin. This particular case was EBV negative.
Immunohistochemistry and molecular techniques a feature not typically present in EBV-related infections.
1. CD3 (T-cells); CD20, kappa, lambda (B-cells): EBV infec- Confirmation with immunoperoxidase and molecular
tion post-transplant is a T-cell mediated proliferation of techniques may be important in some cases.
B lymphocytes. These stains show that in the early stages, Note: In some instances, a small number of EBV-infected
the portal infiltrates are composed of polyclonal B cells, lymphocytes may be seen in various other inflammatory
often with some associated T cells as well. The B-cell processes post-transplant such as rejection. In addition,
population can increase and eventually compose the vast EBER-positive lymphocytes can also be seen in non-
majority of the portal tract infiltrates. Associated nodal transplant inflammatory disorders, such as primary biliary
and extranodal lymphocytic proliferative responses may cirrhosis, sclerosing cholangitis, α1-antitrypsin deficiency,
occur at this point. A monoclonal B-cell population can and autoimmune hepatitis, most likely due to the fact that
eventually develop when immunosuppressive therapy is liver diseases in general have some degree of immunosup-
continued. pressive effect, evidenced by increased susceptibility of these
2. Latent membrane proteins (LMP), Epstein-Barr nuclear- patients in developing infections. Importantly, the presence
associated antigen (EBNA): EBV-encoded proteins are of these occasional cells in the post-transplant setting does
demonstrated within portal lymphocytes. not seem to predict progression to true lymphoproliferative
3. Epstein-Barr virus-encoded small RNA (by the EBER-1 disease.
gene): EBV genome sequence is confirmed within portal
lymphocytes by this molecular technique. Clinical and biologic behavior
Note: The prevalence of EBV-related infection varies from 1. Epstein-Barr virus (EBV) hepatitis is an uncommon
one center to another. Overall, EBV-negative PTLD is not problem following liver transplantation, the incidence in
uncommon. liver recipients about 2% to 3% with a slightly higher fre-
quency in pediatric recipients. It usually occurs within 6
Differential diagnosis months after transplantation and may follow an episode
1. Viral hepatitis, either acquired or recurrent: In post-trans- of rejection or occur de novo.
plant patients who develop viral hepatitis from the 2. Mild increases in serum transaminases are noted, with
hepatotropic viruses, the portal infiltrates are chiefly lym- EBV suspected when viral hepatitis, rejection, and CMV
phocytic and may be numerous. The atypical lympho- can be excluded. In de novo cases, fever, lymphadenopa-
cytes which are seen in EBV-related infection are absent thy, pharyngitis, and leukopenia with monocytosis may
in viral hepatitis. The lymphocytic infiltrate is chiefly be present.
T-cells in viral hepatitis as opposed to a predominant 3. More importantly, EBV plays an important part in the
B-cell population in EBV- and non–EBV-related PTLD. development of post-transplant lymphoproliferative disease
Serologic confirmation of a viral (non-EBV) etiology is (PTLD), whereby an infiltrative B cell population of lym-
necessary. Immunoperoxidase and molecular techniques phocytes can progress to lymphoma and be highly lethal.
may also be required in some cases to confirm or rule out PTLD can also, however, occur in some EBV-negative
EBV-related infection. patients.
2. Acute cellular rejection: The portal inflammatory com- 4. Risk factors for PTLD include primary EBV infection,
ponent in mild acute rejection is most often predomi- excessive immunosuppression (especially OKT3 or anti-
nantly lymphocytic; however, activated lymphocytes with thymocyte globulin with high dose tacrolimus or cyclo-
immunoblasts and not atypical lymphocytes are seen in sporine), and preceding symptomatic CMV disease.
these portal tracts. Neutrophils and eosinophils are also 5. The clinical presentation of PTLD is broad, with fever,
seen in acute rejection when the rejection is more severe, hepatitis (characterize by unexplained elevations of serum
transaminases, alkaline phosphatase activity and mild

increases in serum bilirubin), aseptic meningitis, lymph-
adenopathy, gastrointestinal ulceration, mass lesions pre-
senting with bleeding, and infiltrative lesions in other
organs (e.g., lung) often occurring. Infiltration of the
allograft can also mimic rejection.

1. The priority of management is reduction or temporary
cessation of immunosuppression if this is possible.
2. High-dose acyclovir, ganciclovir or the newer antiviral
agents (e.g., valciclovir) has been effective, particularly in
children with nodal disease where approximately a 30%
response rate has been noted.
3. Less certain are responses of patients with PTLD to che-
motherapy against lymphoma, radiation therapy, inter-
feron combined with antiviral therapy, or monoclonal
anti-B cell antibody therapy. Figure 11-38 Recurrent HBV. The portal tract exhibits a prominent
infiltrate by mature lymphocytes. An interlobular bile duct in the cen-
ter of the portal tract shows no duct damage, and no endothelial
inflammation is seen, ruling out coexisting acute rejection.
RECURRENT DISEASES
1. The incidence of recurrence of the native liver disease

after transplantation is dependent on the type of acute or
end-stage disease necessitating transplant. For example,
virtually all cases of hepatitis C eventually recur, while
drug-induced fulminant hepatic failure does not.
2. In some disorders such as alcoholic liver disease, social
aspects such as noncompliance play a major role. Addi-
tionally the pathophysiologic disease mechanisms, espe-
cially in those disorders having an autoimmune etiology
(e.g., primary biliary cirrhosis with nonsuppurative duct
injury, autoimmune hepatitis with duct damage), have
some similarity in both rejection and disease recurrence.
In fact, distinguishing disease recurrence from rejection
may oftentimes be quite difficult on morphologic grounds
alone.
3. The liver diseases described below are examples of some
of the major diseases requiring transplant where disease
recurrence is known or suspect. A more detailed discus- Figure 11-39 Recurrent HBV. The parenchyma exhibits diffuse
sion of these native hepatic disorders in general can be hydropic and necroinflammatory changes.
found under the appropriate headings in other chapters.
Viral Hepatitis (HBV and HCV)

Disease recurrence can be subdivided into two basic types:
1. Typical viral hepatitis
a. Portal lymphocytic infiltrates are seen, with various
degrees of periportal interface inflammatory activity.
b. Lobular necroinflammatory change is present, the
inflammatory component chiefly lymphocytic.
c. Different morphologic changes are also seen particular
to the individual hepatotropic virus:
i. HCV: Portal lymphoid aggregates and follicles,
focal duct damage, and mild fatty change often
occur.
ii. HBV: “Ground glass” cells and sometimes mild Figure 11-40 Recurrent HBV. Numerous ground glass cells are seen
fatty change may be seen. within the lobule.
A B
Figure 11-41 Recurrent HBV. The liver cell cytoplasm stains positively for HBsAg (A) while there is intense nuclear and some cytoplasmic
staining for HBcAg (B) (immunoperoxidase stains for HBV).
2. At other times, early recurrent hepatitis may show

prominent portal inflammation and diffuse lobu-
lar necroinflammatory change. In addition, recurrent
disease at any time may show severe lobular necro-
inflammatory changes with confluent necrosis, a fea-
ture uncommonly seen in non-transplant chronic viral
hepatitis.
3. Perivenular accentuation of the necroinflammatory
change may sometimes be seen, often associated with peri-
venular hydropic change and ballooning of hepatocytes.
4. A granulomatous response to bile ducts with duct destruc-
tion, and a granulomatous hepatitis, have been reported
in recurrent HCV infection.
5. Usually histologic evidence of recurrent hepatitis is
apparent on biopsy material by 1 year in the majority of
patients with recurrent HCV.
6. With time, as in non-transplant cases, portal fibrosis
Figure 11-42 Fibrosing cholestatic hepatitis secondary to recur- occurs, with eventual progression to cirrhosis. In general,
rent HBV. There is portal and periportal intrasinusoidal collagen the timeframe of progression of the fibrosis is sometimes
deposition in this variant of recurrent HBV (trichrome).
more striking post-transplant (10% to 30% of patients
cirrhotic within 5 years, with cirrhosis rarely occurring
within 2 years) than in the non-transplant setting (cir-
2. Fibrosing cholestatic hepatitis (fibroviral hepatitis) rhosis developing in 10% to 20% of patients over 20 to 30
a. Portal expansion with periportal and intrasinusoidal years).
collagen deposition, bile ductular proliferation, but
minimal portal inflammation is seen. Special stains
b. Prominent ballooning change of liver cells occurs, with 1. Masson trichrome: The portal and periportal sinusoidal
associated cholestasis but mild lobular inflammation. fibrosis can best be appreciated with this stain for col-
c. Variable but sometimes prominent fatty change (ste- lagen, and is useful in staging the degree of fibrosis. In
atoviral) may occur. addition, the intrasinusoidal collagen deposition seen in
d. In severe cases, bridging and multiacinar necrosis is fibrosing cholestatic hepatitis can be accentuated.
seen, leading to graft failure.
Note: Although fibrosing cholestatic hepatitis is seen in both Immunohistochemistry
recurrent HBV and HCV reinfection, it is more common in 1. HBsAg, HBcAg, HCV: In recurrent HBV, these markers
the former. are positive. At first, staining may be focal and mild;
however, with time a diffuse both cytoplasmic (sAg)
Other features and nuclear (cAg) staining pattern may be seen. Addi-
1. In early stages of disease recurrence, portal and lobular tionally, in fibrosing cholestatic hepatitis, there is char-
inflammation may be quite minimal, yet apoptotic cells at acteristically diffuse strong nuclear HBcAg staining
the same time may be numerous. Additionally, sometimes (indicative of striking viral replication). HCV staining
only mild portal and lobular inflammation occurs that is also is seen but is not helpful in correlating with disease
not specific for recurrent disease. activity.
A B
Figure 11-43 Fibrosing cholestatic hepatitis secondary to recurrent HBV. A, The slightly fibrotic portal tract shows only a mild lymphocytic
infiltrate with normal interlobular bile ducts and mild cholangiolar proliferation, while the parenchyma shows marked hydropic change of the
hepatocytes. B, The liver cells on higher power show hydropic ballooning change with intracellular bile. No necroinflammatory change is seen.
Figure 11-44 Recurrent HCV. The portal tract shows a prominent Figure 11-45 Recurrent HCV. Mild periportal interface inflammatory
infiltrate by small mature lymphocytes. A benign lymphoid aggre- activity is seen.
gate is present, a feature often seen in chronic HCV infection.
A B
Figure 11-46 Recurrent HCV. A, The perivenular and midzones show slightly hydropic hepatocytes with mild necroinflammatory change. The
golden granular pigment in the hepatocytes in this example represents both intracellular bile and lipochrome. B, Lobular mononuclear inflam-
matory infiltrates, focal necrosis, and apoptosis are present.
Figure 11-47 Recurrent HCV. Scattered apoptotic cells are present Figure 11-48 Recurrent HCV. Mild macrovesicular fatty change is
with variable hydropic change of the hepatocytes but with no inflam- present. The portal tract in the corner of the field shows only a mild
matory infiltrate, a feature that can be seen in the early stages of lymphocytic infiltrate.
recurrent HCV.
Table 11-5 Differential Diagnosis of Recurrent Hepatitis C versus Acute Cellular Rejection
RECURRENT HCV ACUTE CELLULAR REJECTION

Portal, periportal Portal lymphocytic infiltrates are seen, sometimes with Often a portal mixed inflammatory infiltrate is seen, with
inflammation associated lymphoid aggregates and follicles with or activated lymphocytes, eosinophils and neutrophils; how-
without germinal centers; periportal interface inflammatory ever, in severe rejection, periportal spillover of inflamma-
activity is often present, dependent on the disease severity. tory cells may also occur but is not a common finding.
Bile duct damage Lymphocytes may surround and sometimes infiltrate Bile duct damage and infiltration by lymphocytes are
into bile duct epithelium, the ducts often present within common and sometimes striking.
lymphoid follicles; however, severe duct destructive changes
are not frequent.
Bile duct loss Duct depletion does not occur. Duct loss may occur with progression to chronic
rejection.
Fibrosis With disease progression, portal fibrosis occurs, with even- Portal fibrosis is not a feature.
tual bridging fibrosis and the development of cirrhosis.
Endothelial inflammation Although lymphocytes may abut against portal and termi- Subendothelial localization of lymphocytes
nal hepatic venules, subendothelial infiltration by lympho- (endothelialitis) is a feature.
cytes does not occur, or at most is focal and mild.
Lobular inflammation, Variable degrees of necroinflammatory change are charac- Lobular inflammation may occur but is not prominent,
apoptosis teristic, often with apoptotic cells easily demonstrable. with apoptotic cells sometimes seen but infrequent.
Fatty change Mild fatty change is usually seen in recurrent HCV and Fatty change is infrequent.
sometimes in recurrent HBV.
C4d immunoperoxidase Infrequent. May be positive in one-third to two-thirds of cases
staining of portal
capillaries*
*Although C4d is a marker of the activated complement cascade and is positive in portal capillaries in humoral rejection, it also may stain positive in acute rejection as well.
Therefore, taken in conjunction with other histologic features, this stain can be helpful in differentiating rejection from recurrent disease.
Differential diagnosis infrequently occur when both rejection and disease recur-
1. Acute cellular rejection: In many cases it may be very dif- rence are present in the same biopsy. At that time it is often
ficult to distinguish between acute rejection and recurrent left to the clinician to treat the disease most affecting liver
hepatitis, especially recurrent HCV. In recurrent HBV, function.
available immunoperoxidase stains for the core and sur-
face antigens are helpful, but difficulty often still remains Clinical and biologic behavior
when recurrent disease and rejection are both present. 1. Recurrent HBV
Table 11-5 is useful in comparing rejection features with a. Recurrent HBV infection before present treatment
recurrent hepatitis C. Many of these features, such as strategies was a significant cause of liver disease after
periportal inflammation and lobular necroinflammatory organ transplantation. The natural course of HBV
change, also apply to HBV recurrence as well. infection in transplant recipients is different from the
Note: Distinguishing rejection from any disease recur- normal population, with the effect of immunosuppres-
rence may oftentimes have useful differentiating morpho- sion having a negative impact on rate of natural clear-
logic features; however, complications in diagnosis not ance, disease progression, and survival.
b. An accelerated course may be seen in some patients c. Patients present with elevated serum transaminases
after liver transplantation. In untreated patients, HBV and alkaline phosphatase activity. Rarely is the serum
recurrence is greater than 80% leading to progressive bilirubin elevated. Fibrosing cholestatic hepatitis (FCH)
disease and death in about 70% of patients. In this also has been reported with hepatitis C following liver
setting patients present with elevated serum trans- transplantation with characteristics similar to HBV
aminases and in the rare Fibrosing Cholestatic hepatitis related FCH.
(FCH), serum transaminases are mildly elevated but d. The progression of the disease to cirrhosis occurs in
serum bilirubin and alkaline phosphatase levels are less than 50% of recipients over a 5-year period. The
significantly increased. Patients progress rapidly to cumulative 5 year survival in patients transplanted for
liver failure and death unless retransplantation is per- HCV is similar to those transplanted for non–HCV-
formed. The pathogenesis of FCH is considered to be related disease, thus justifying transplantation in this
a cytotoxic effect of the hepatotrophic viruses caused disease.
by extraordinarily high levels of virus.
c. The pretransplantation HBV replicative state is impor- Treatment and prognosis
tant in predicting viral recurrence. Patients with posi- 1. HBV: Administration of HBIG intravenously (10,000
tive HBV-DNA and HBeAg have an 83% recurrence U) during the anhepatic phase and daily for 6 days post-
rate compared to 58% recurrence rate if HBV-DNA transplant, followed by monthly doses indefinitely, is the
levels are low and anti-HBe is positive. Recurrence rate rule. The addition of lamivudine has reduced the recur-
is lower in patients transplanted for fulminant hepatitis rence rate to ≤10%. The risk of lamivudine resistant HBV
B presumably related to the development of immunity mutant is not common; however, in these cases adefovir
at the time of transplantation. Patients co-infected dipivoxil has been shown to be effective. The prognosis is
with HBV and the delta (HDV) virus have better excellent for patients with HBV infection who are treated
results, probably because HDV is associated with a prior to transplant and who are compliant with the cur-
nonreplicative phase of HBV. rently accepted post-transplant regimen.
d. The current strategy of infusing hepatitis B immuno- 2. HCV: Once recurrent hepatitis C is confirmed by viro-
globulin (HBIG) with or without lamivudine has dra- logic and histologic methods, treatment with antiviral
matically reduced the recurrence rate to 10% or less. therapy using pegylated interferon and ribavirin appears
FCH is rarely encountered. to be beneficial in at least 50% of treated patients, lead-
2. Recurrent HCV ing to sustained viral response in about 30%; however,
a. HCV-associated cirrhosis and complications are the this data is preliminary. The side effects of therapy and
commonest indication for liver transplantation in the the careful monitoring for complications are critical.
United States. HCV recurs in almost all patients fol- The previously held view that antiviral therapy increases
lowing transplantation and the immunosuppressive frequency of rejection in these patients does not appear
therapy has been shown to increase HCV viral rep- valid.
lication by an average of almost 16 fold compared to
pretransplant levels.
b. The risk of HCV recurrence with hepatitis increases Primary Biliary Cirrhosis
following treatment for acute rejection, since very high
levels of virus are encountered in this setting. (Fig. 11-49)
A B
Figure 11-49 Recurrent primary biliary cirrhosis. Both of these images are taken from the same biopsy in a patient who was transplanted
for end-stage primary biliary cirrhosis. A, The portal tract is expanded by a mixed inflammatory infiltrate consisting of lymphocytes and plasma
cells, with numerous epithelioid macrophages encircling the interlobular bile duct. The duct shows variable nuclear irregularity and slightly
hydropic cytoplasmic changes. B, An epithelioid granuloma surrounded by lymphocytes and some plasma cells is seen at the edge of a portal
tract in a different field.
Major morphologic features granulomas, characteristic of primary biliary cirrhosis,

1. Bile ducts are surrounded by granulomatous epithelioid are not present, and instead poorly defined inflamma-
cells, with associated nonsuppurative destructive duct tory aggregates (“granulomatous” changes) occur. Special
damage. stains for microorganisms are warranted to rule out an
2. Epithelioid granulomas are also seen, predominantly infectious process.
within portal tracts, but at times also within the lobules. 3. Chronic (ductopenic) rejection: In chronic rejection, duct loss
eventually occurs and may resemble the portal changes
Other features seen in recurrent primary biliary cirrhosis; however, portal
1. Portal plasma cell infiltrates may be present and are often fibrosis is absent to minimal and portal lymphocytic infil-
prominent, these cells sometimes surrounding the granu- trates are minimal at best in chronic rejection, while fibro-
lomatous process. sis, in some cases with bridging, along with prominent
2. Periportal interface inflammatory activity can be seen to portal inflammatory infiltrates, are seen in recurrent pri-
variable degrees but is usually uncommon. mary biliary cirrhosis with associated duct loss. In addi-
3. Progression to portal biliary fibrosis with duct loss, and tion, granulomas are not a feature of chronic rejection.
eventual biliary cirrhosis, may occur with time in a small
minority of patients. Clinical and biologic behavior
1. Recurrence of primary biliary cirrhosis is a controversial
Special stains issue but it is clear that it does infrequently recur. The
1. Orcein: Increase in copper-binding protein, seen as black frequency varies from 8% to 15% and is confirmed histo-
granules in periportal hepatocytes, may occur with time. logically with the characteristic features not seen in other
2. Rubeanic acid, rhodanine: These stains for copper may diseases, including chronic rejection. Antimitochondrial
show some degree of accumulation within the peripor- antibody is seen in about 40% of patients following trans-
tal hepatocytes in the advanced stage disease, the copper plantation in a small cohort of patients.
staining black-green (rubeanic) or red (rhodanine). 2. Patients are usually asymptomatic and biopsy is done for
3. Masson trichrome: The portal biliary fibrosis can best be evaluating elevation of alkaline phosphatase activity and
appreciated. to ensure the absence of chronic rejection. Careful inter-
pretation of the biopsy is important since chronic rejec-
Differential diagnosis tion, chronic bile duct obstruction from stricture, or some
1. Acute cellular rejection: Portal inflammatory infiltrates disorders that have bile duct changes on biopsy such as
including lymphocytes and plasma cells, and associated hepatitis C, CMV, and primary sclerosing cholangitis
duct damage and inflammation, are features of both recur- need to be satisfactorily excluded.
rent primary biliary cirrhosis and acute cellular rejection.
In rejection, however, neutrophils can play a role and even Treatment and prognosis
be seen within bile duct epithelium and lumen, a feature 1. The course of patients with recurrent disease is benign
not typically seen in primary biliary cirrhosis. The presence with satisfactory outcomes at least for the first decade
of duct injury and portal granulomas are a clue to a diagno- after liver transplantation.
sis of recurrent primary biliary cirrhosis, while the presence
of endothelialitis points towards rejection as the cause.
2. Other causes of granulomas: In the post-transplant set- Primary Sclerosing Cholangitis
ting, infections such as tuberculosis and fungi may
elicit a granulomatous process. Usually, true epithelioid (Fig. 11-50)
A B
Figure 11-50 Recurrent primary sclerosing cholangitis. A, Two medium-sized interlobular bile ducts show striking periductal fibrosis. B, High
power shows numerous lymphocytes circling and infiltrating into the duct wall itself. The diagnosis rests on classical imaging studies, with
other common causes of post-transplant biliary strictures ruled out.
Major morphologic features present in chronic rejection, and is not a distinctive fea-
1. Interlobular bile ducts show a prominent fibro-obliter- ture of the ischemic process.
ative “onion-skin” destructive cholangitis, with variable
lymphocytic infiltrates into the duct epithelium. Clinical and biologic behavior
2. Eventual interlobular bile duct loss occurs. 1. The recurrence of primary sclerosing cholangitis is often
suspected but difficult to prove. Patients may present with
Other features increases in serum alkaline phosphatase activity, mild or
1. In early stages, bile duct and ductular proliferation is seen, modest increases in serum transaminases, or rarely with
with variable degrees of ductular atypia. mild increases in serum bilirubin.
2. Portal lymphocytic infiltrates, sometimes associated with 2. Liver biopsy may demonstrate nonspecific changes and
mild periportal interface inflammatory activity, are pres- may miss the typical lesion. The diagnosis rests on dem-
ent to variable degrees. onstration of classic strictures and dilatation on ERCP
3. Portal fibrosis occurs, with eventual progression to a bili- with exclusion of other biliary tract abnormalities such as
ary cirrhosis. biliary strictures (at the surgical anastamotic sites), recur-
rent cholangitis, bile duct ischemia, CMV or HCV infec-
Special stains tion, and chronic rejection.
1. Orcein: Increase in copper-binding protein, seen as black
granules in periportal hepatocytes, may occur with time. Treatment and prognosis
2. Rubeanic acid, rhodanine: These stains for copper may 1. The course of patients with proven recurrent primary
show some degree of accumulation within the peripor- sclerosing cholangitis is uncertain since there is not a
tal hepatocytes in the advanced stage disease, the copper large experience or long term follow up at this time.
staining black-green (rubeanic) or red (rhodanine).
3. Masson trichrome: The portal biliary fibrosis can best be
seen. Autoimmune Hepatitis
Differential diagnosis (Fig. 11-51)

1. Bile duct obstruction: Bile duct proliferation and periductal
fibrosis are features of bile duct obstruction due to stric- Major morphologic features
ture, and are also present in recurrent primary sclerosing 1. Portal inflammation is seen consisting of lymphocytes
cholangitis. The prominent onion-skinning periductal and numerous plasma cells, often with associated peri-
fibrosis and eventual duct loss seen in primary sclerosing portal interface inflammatory activity.
cholangitis are not features of bile duct obstruction. 2. Lobular necroinflammatory change is present and at times
2. Chronic rejection, ischemic bile duct damage: Ischemic is prominent, the inflammatory component consisting of
changes to the biliary tree secondary to compromise of lymphocytes and numerous plasma cells, sometimes with
the arterial blood flow from vascular foam cell deposition associated perivenular accentuation of the inflammation
and luminal narrowing in chronic rejection may second- process.
arily cause damage and eventual loss of the interlobular
bile ducts. Other causes of vascular compromise such as Other features
hepatic artery strictures may also contribute to bile duct 1. In severe cases, perivenular confluent necrosis may occur.
loss. Periductal onion-skinning fibrosis, however, charac- 2. Interlobular bile duct damage may be seen at times
teristic of recurrent primary sclerosing cholangitis, is not (“autoimmune cholangitis”).
A B
Figure 11-51 Recurrent autoimmune hepatitis. A, Architectural distortion by portal bridging fibrosis is seen. The portal tracts show a pre-
dominantly mononuclear inflammatory infiltrate consisting of lymphocytes and plasma cells. B, Higher power shows portal lymphocytes and
numerous plasma cells, with mild interface hepatitis (“piecemeal” necrosis).
3. The perivenular inflammation may also directly involve Treatment and prognosis
the endothelium (endothelialitis). 1. The reintroduction of corticosteroid therapy or increase
4. Portal fibrosis eventually occurs in nontreated patients, in the transplant immunosuppressive regimen results in
and may eventually lead to cirrhosis. improvement in the majority of patients with this disease
recurrence.
Special stains
1. Masson trichrome: The portal fibrosis can best be
appreciated. Alcoholic Liver Disease
Differential diagnosis (Fig. 11-52)
1. Acute cellular rejection: Some degree of portal plasma cell
infiltrates is often present in acute rejection, and infre- Major morphologic features
quently the plasma cells may be moderate in number. In 1. Fatty change, most often of a macrovesicular type, is pres-
addition, duct damage may be seen in autoimmune hepa- ent and in some instances may be diffuse.
titis itself; however, portal fibrosis and periportal inflam- 2. Variable portal, periportal, and perivenular fibrosis are
matory activity are not features of acute rejection, yet are often seen.
commonly seen in recurrent autoimmune disease.
Note: Autoimmune hepatitis can occur in allografts as an Other features
acquired (de novo) process and is sometimes precipitated by 1. In the active drinker, liver cell ballooning with Mallory
chronic viral hepatitis due to HCV infection. The histologic body formation and neutrophilic lobular inflammation
features of the acquired disease are similar to that seen in may also be present at times.
recurrent autoimmune hepatitis. 2. Eventual progression to bridging fibrosis and cirrhosis
will occur in the patient who does not abstain.
1. In patients transplanted for autoimmune hepatitis, cessa- Special stains
tion or reduction in immunosuppressive drugs may lead 1. Masson trichrome: The portal and sinusoidal fibrosis can
to the development of increased serum transaminases, best be appreciated.
serum bilirubin, and elaboration of autoantibodies.
2. Histologic recurrence post-transplant is seen in about Differential diagnosis
25% of patients with pretransplant autoimmune cirrhosis. 1. Fatty change from other causes: Patients post-transplant
Liver biopsy and histology demonstrate typical features are often placed on steroid therapy, which itself may
of autoimmune hepatitis, with a characteristic plasma cell be associated with fatty change. In addition, acquired
infiltrate and substantial lobular inflammation and necro- adult onset diabetes post-transplant may also contribute
sis. The occurrence rate of de novo autoimmune hepatitis to the degree of fat. Usually the fat associated with ste-
is not known. roid use is only mild, while that in the alcoholic is more
3. A generally held view in the transplant community is marked. The fat seen in acquired diabetes may at times
that patients with cirrhosis due to an autoimmune etiol- be prominent, however, making distinction between the
ogy tend to have more frequent episodes of acute cellular two diseases somewhat difficult; in these instances clini-
rejection with tapering of the immunosuppressive regi- cal information, especially from family members as to
men and require an average higher dose of maintenance the patient’s possible use of alcohol, would be of major
immunosuppressive medications. importance.
A B
Figure 11-52 Recurrent alcoholic liver disease. A, Fatty change, focal neutrophilic infiltrates, and occasional Mallory bodies are evident. B,
Prominent perivenular sinusoidal fibrosis is seen on this trichrome stain, a characteristic finding in alcoholic liver disease.
Clinical and biologic behavior DE NOVO LIVER DISEASE

1. Chronic alcoholics with cirrhosis must show abstinence
for at least 6 months before qualifying as a liver trans- (Figs. 11-53 through 11-55)
plant candidate; unfortunately, many recipients return to 1. Acquired liver diseases outside of those seen from trans-
some degree of drinking after transplantation, with the plant complications (e.g., biliary tract disorders due to
recidivism rate ranging from 10% to 25% within 3 years duct strictures) may occur, although specific diseases such
of transplant. Various published series also show the per- as viral hepatitis are quite unusual due to appropriate
cent relapse to range from 7% to 95%. donor selection and post-transplant patient treatment.
2. The morphologic features of recurrent disease are similar 2. Liver disease, however, may occur due to activation of latent
to those seen in the non-transplant setting, with the most viruses during immunosuppressive therapy (e.g., acquired
common feature being macrovesicular steatosis; however, hepatitis due to HBV, less commonly due to HCV).
the recurrence of true alcoholic hepatitis is not common, 3. In addition, de novo autoimmune hepatitis may also rarely
estimated at 10% of nonabstinent patients. occur (3% to 5% of transplants) and usually affects chil-
dren more than adults. Autoimmune hepatitis can also be
Treatment and prognosis triggered by chronic viral hepatitis due to HCV and is felt
1. Discontinuance of alcohol use will prevent further pro- by some not to be a true autoimmune hepatitis but rather
gression of the disease in all patients. a variant of acute rejection.
A B
Figure 11-53 Acquired autoimmune hepatitis. A, Periportal interface inflammatory activity is seen, many of the inflammatory cells consisting
of plasma cells which are often arranged in clusters. B, The parenchyma exhibits diffuse necroinflammatory change with occasional plasma
cell aggregates.
A B
Figure 11-54 Acquired autoimmune hepatitis (triggered by HCV infection). Autoimmune hepatitis can also develop in allografts as an
acquired process that sometimes is precipitated by hepatitis C infection, an example of which is shown in these two images. A, Prominent
portal lymphocytes and plasma cells are seen, with marked periportal interface inflammatory activity (“piecemeal” necrosis). B, The perivenu-
lar and midzones show striking confluent necrosis with prominent plasma cell infiltrates.
A B
Figure 11-55 Acquired hepatitis due to HBV infection. A, Occasional hepatocytes exhibit a ground-glass appearance. B, Immunoperoxi-
dase stain shows those ground glass cells to contain the hepatitis B surface antigen. This patient was HBc antibody positive without clinical
evidence of chronic HBV at the time of the transplant for alcoholic cirrhosis.
A B
Figure 11-56 Graft-versus-host disease. A and B, Both of these portal tracts show a mild predominantly lymphocytic infiltrate. The interlobular
bile ducts show considerable cytologic atypia, with cytoplasmic hydropic change and vacuolization. The nuclei show prominent irregularity
and focal pyknosis.
4. Usually the histologic changes are similar to those seen in Major morphologic features
known recurrent disease, with treatment modalities also 1. Portal tracts initially exhibit a prominent lymphocytic
usually the same. infiltrate.
5. Although it is not uncommon for post-transplant liver 2. Nonsuppurative destructive and degenerative changes to
biopsies to show only mild nonspecific changes not the interlobular bile ducts are seen, consisting of cyto-
related to rejection or disease recurrence, sometimes a plasmic vacuolization, acidophilic necrosis and individ-
chronic hepatitis with portal fibrosis and periportal and ual duct epithelial cell dropout, hyperchromasia of duct
intralobular inflammation can occur for no known rea- nuclei, and distortion of duct size and shape.
son. With time, these cases can also progress to bridging 3. Veno-occlusive changes with fibrous obliteration of the ter-
fibrosis and rarely to cirrhosis. minal hepatic venules may occur.
6. W hen all other causes including drug-induced injury can
be excluded, it is possible that the inflammation may at Other features
least in part be related to an atypical form of rejection. 1. Variable degrees of mild macrovesicular fatty change may
be present.
2. Cholestasis may be seen.
HEPATIC CHANGES AFTER BONE MARROW 3. Variable lobular necroinflammatory change and spotty
TRANSPLANTS: GRAFT VERSUS HOST DISEASE necrosis are frequent but are relatively mild; however, a
hepatitis-like reaction with perivenular necrosis can at
(Fig. 11-56) times occur.
4. Endothelialitis may be seen involving portal and/or ter- 3. Patients present with a desquamative skin rash, diarrhea,
minal hepatic venules but is usually not prominent. and fever. Jaundice occurs in 50% of cases. Mortality
5. Portal macrophages and Kupffer cells, and in many is high (60% to 70%) in patients undergoing relatively
instances periportal hepatocytes, may accumulate hemo- severe reactions.
siderin (due to numerous blood transfusions in these 4. Liver tests show mild to modest increases in serum trans-
patients). aminases with marked increases in serum bilirubin and
6. Long-term disease may exhibit total duct loss with little alkaline phosphatase activity. As the disease progresses,
if any portal inflammatory infiltrates. In some cases, a symptoms worsen and serum bilirubin and alkaline phos-
portal fibrosis of a biliary type, and even a biliary cirrho- phatase activity continue to rise.
sis, may occur. 5. The risk of developing chronic GVHD rises following
the development of acute GVHD and with increasing
Special stains age of the transplant recipient. Chronic GVHD (>100
1. Prussian blue: Positive staining of hemosiderin granules days post-transplant) is characterized by severe wasting,
is seen within Kupffer cells, portal macrophages, and in skin involvement and salivary gland injury (Sjögren-like
some cases periportal hepatocytes. syndrome).
6. Veno-occlusive disease, seen in up to 20% of the cases, is
Differential diagnosis related in part to pretransplant chemotherapy (e.g., mito-
1. Complications of bone marrow transplant: Common prob- mycin C) and/or radiotherapy and possible contribution
lems relate to the patients’ underlying disease that neces- by the hepatitis C virus.
sitated bone marrow transplant, as well as complications
of chemotherapy (especially veno-occlusive disease) and Treatment and prognosis
superimposed sepsis in an immunocompromised host. 1. Optimal immunosuppressive therapy is important to
The combination of degenerative duct lesions, mild por- prevent the development of GVHD. Increased doses
tal and lobular mononuclear inflammatory changes, and of immunosuppression (corticosteroids with tacrolimus
“endothelialitis” are features most characteristic of graft or cyclosporine or addition of antithymocyte globulin)
versus host disease. are helpful in mitigating the disease. In some instances,
methotrexate has been added to the regimen. In severe
Clinical and biologic behavior cases the use of monoclonal IL-2 receptor drugs may
1. Graft versus host disease (GVHD) is induced by immuno- be beneficial. In chronic GVHD, thalidomide has been
logically competent T cells of donor origin that result in used.
damage to recipient organs. The clinical importance of 2. The prognosis is good in patients who respond to ther-
GVHD is dependent on the amount of lymphoid tissue apy. Progression of the disease with the development of
in the transplanted organ. Thus GVHD is more common portal hypertension and ascites is rare. With progressive
in bone marrow and small intestinal transplantation. The disease unresponsive to treatment, transplantation may be
risk and severity of this condition is also directly related necessary.
to the degree of genetic mismatch between donor and
recipient. The graft-versus-host reaction most commonly
attacks skin, the gastrointestinal tract, and liver. REFERENCES
2. Approximately 70% of grafted patients will develop
GVHD either alone or complicated with infection, the The complete reference list is available online at www.
acute reaction seen 5 to 50 days post-transplant. expertconsult.com.

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Transplantation: Table 11-1

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Chapter

INTRODUCTION and immunosuppression is withdrawn completely in a

Table 11-1 Liver Disease in Transplant Recipients

PRESERVATION (HARVESTING, REPERFUSION)

Major morphologic features

6. Portal tracts may show a mild lymphocytic infiltrate, but

4. Patients recover function fully over 1 to 2 weeks with

Treatment and prognosis

ACUTE GRAFT FAILURE (PRIMARY NONFUNCTION)

Clinical and biologic behavior

2. The development of minimal bile output or the drain-

Treatment and prognosis

1. Liver allograft rejection is mediated by the immune

Major morphologic features flow and culminate in hemorrhagic necrosis of hepato-

Immunohistochemistry (Figs. 11-11 through 11-15)

grades individually the degree of portal inflammation, duct

4. Drug toxicity: Patients on post-transplant immunosup-

Table 11-3 Grading of acute allograft rejection

Table 11-4 Grading of Chronic Allograft Rejection

b. Vasculopathy with extensive subintimal foam cell depo-

Treatment and prognosis Other features

Bile Duct Strictures Differential diagnosis

Clinical and biologic behavior Hepatic Artery Thrombosis

Treatment and prognosis

Bacterial, Fungal Infections B

post-transplant. Distinctive nuclear and sometimes cyto-

Clinical and biologic behavior

(Figs. 11-30 through 11-33)

Major morphologic features

pseudotumors in the antrum and ileocecal area, pneu-

Treatment and prognosis

POST-TRANSPLANT LYMPHOPROLIFERATIVE variable cytologic atypia, and with various numbers of

Major morphologic features Other features

transaminases, alkaline phosphatase activity and mild

Treatment and prognosis

1. The incidence of recurrence of the native liver disease

Viral Hepatitis (HBV and HCV)

(Figs. 11-38 through 11-48)

Major morphologic features

2. At other times, early recurrent hepatitis may show

RECURRENT HCV ACUTE CELLULAR REJECTION

Major morphologic features granulomas, characteristic of primary biliary cirrhosis,

Differential diagnosis (Fig. 11-51)

Clinical and biologic behavior DE NOVO LIVER DISEASE

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6. Portal tracts may show a mild lymphocytic infiltrate, but

4. Patients recover function fully over 1 to 2 weeks with

2. The development of minimal bile output or the drain-

1. Liver allograft rejection is mediated by the immune

4. Drug toxicity: Patients on post-transplant immunosup-

b. Vasculopathy with extensive subintimal foam cell depo-

1. The incidence of recurrence of the native liver disease

2. At other times, early recurrent hepatitis may show