REVIEW

The Liver in Systemic Disease:

Sepsis and Critical Illness
William Bernal, M.D., F.R.C.P.

NORMAL PHYSIOLOGICAL RESPONSE
Critical illness, and particularly severe sepsis, induces
profound changes in the function of the normal liver. The
balance of hepatic metabolic activity may be shifted rap-
idly in response to systemic inflammation with an ‘‘acute
phase reaction (APR).’’ This results in a series of phenom-
ena that includes complex changes in circulating and func-
tional levels of immunological, transport, and coagulation
proteins. Further, complex changes in specific hepatocellu-
lar processes occur, particularly in relation to hepatobiliary
transport pathways, with practical consequence both to
prognostic assessment and to therapeutic interventions.
The liver plays a central role in the systemic response
to critical illness both through the clearance of patho-
genic microorganisms and toxins from the circulation
and through the APR and release of liver-derived cyto-
kines, inflammatory mediators, and coagulation cascade
components.1,2 These mediators and bacterial or endo-
toxin ‘‘spillover’’ from impaired hepatic clearance may
have important systemic effects and contribute to the
pathogenesis of multiple organ failure.2
The evolution of new hepatic dysfunction in the setting
of critical illness is of great prognostic importance. By exam-
ple, jaundice is seen in approximately 10% of critically ill
patients early after intensive therapy unit admission, and it
is a specific and independent risk factor for death
(Figure 1).3 Many factors may contribute to the develop-
ment of liver dysfunction (LD) in this setting, acting either in
isolation or in concert, but using clinical presentation and

Abbreviations: APR, acute phase reaction; AST, aspartate aminotransferase; BILI, bilirubin; BSEP, bile salt export pump; CI, confi-
dence interval; CLD, cholestatic liver dysfunction; HH, hypoxic or ischemic hepatitis; ICU, intensive care unit; INR, international nor-
malized ratio; j, 30 patients who developed bilirubin greater than 3 mg/dL; LD, liver dysfunction; MDR, multidrug resistance
protein; MRP, multidrug resistance–associated protein; nj, 67 patients who did not develop bilirubin greater than 3 mg/dL; NTCP,
high-affinity Na1-dependent bile acid transporter; OATP, organic anion transporting polypeptide.
From the Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, London, United Kingdom.
Potential conflict of interest: Nothing to report.
Received 12 December 2015; accepted 10 February 2016

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C 2016 by the American Association for the Study of Liver Diseases
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88 | CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
REVIEW
FIG 1 Adjusted risk for hospital mortality stratified by maximum
bilirubin level within 48 hours of ICU admission. n 5 38,036 first
ICU admissions. Exclusion of patients with acute or acute-on-
chronic liver disease and adjustment for age, sex, primary diagno-
sis, and nonhepatic organ dysfunction. Abbreviation: CI, confi-
dence interval. Adapted with permission from Critical Care
Medicine.3 Copyright 2007, Society of Critical Care Medicine.
FIG 2 Laboratory parameters during the course of hypoxic hep-
atitis. Abbreviations: AST, aspartate aminotransferase; BILI, biliru-
bin; INR, international normalized ratio; j, 30 patients who
developed bilirubin greater than 3 mg/dL; nj, 67 patients who did
not develop bilirubin greater than 3 mg/dL. Adapted with permis-
sion from Hepatology.5 Copyright 2012, American Association
for the Study of Liver Diseases.
standard laboratory measures, patients with novel hepatic
dysfunction in the setting of critical illness can be broadly
classified into two categories, Hypoxic (or ischemic) Hepati-
tis and Cholestatic Liver Dysfunction.
HYPOXIC OR ISCHEMIC HEPATITIS
The high metabolic activity of the liver and its complex
vascular supply render it at risk for injury from hemody-
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Sepsis and Critical Illness Bernal
FIG 3 Factors that contribute to the development of hypoxic
hepatitis.
namic insults, and ‘‘hypoxic’’ or ‘‘ischemic hepatitis’’ (HH)
results from hepatocellular necrosis provoked by acute
cellular hypoxia resulting from impaired hepatic oxygen
delivery. The prevalence of HH in hospital admissions is
approximately 1 in 1000, but is probably at least an
order of magnitude more common in intensive care unit
(ICU) admissions. Diagnostic criteria vary but have
included the triad of an appropriate clinical setting of
cardiac, respiratory, or circulatory failure, an abrupt
increase in serum transaminases reaching at least 203
the upper limit of normal and with exclusion of other
causes of acute liver cell necrosis, particularly viral or
drug-induced liver injury.4 Major elevation of transami-
nases is usually of very short duration and is followed by
coagulopathy, reflecting transient hepatic synthetic com-
promise; significant jaundice follows in a minority of
patients and is associated with increased risk for compli-
cations and death (Figure 2).5 Liver biopsy is seldom
required or performed but typically shows extensive cen-
trilobular necrosis, reflecting the sensitivity of ‘‘zone 3’’
hepatocytes to ischemic insults.
Heart failure, respiratory failure, and septic shock are
responsible for more than 90% of cases of HH, with
these factors acting alone or in combination in individual
patients (Figure 3). Compromise of cardiac output result-
ing from acute cardiac events such as myocardial infarc-
tion, dysrhythmia, or tamponade may reduce blood flow
and oxygen delivery to the liver, with an important role
now also recognized from passive congestion of the liver
from right-heart failure. The latter may occur in the set-
ting of severe pulmonary disease where concurrent
hypoxemia may also contribute. Sepsis and the evoked
inflammatory response play an important permissive role
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FIG 4 Source and causative agent of infection in 141 consequ-
tive patients without preexsiting liver diseases admitted to inten-
sive care according to presence or absence of development of
LD. LD defined as serum bilirubin 2 mg/L lasting at least 48
hours. *P < 0.05. Adapted with permission from Intensive Care
Medicine.7 Copyright 2006, European Society of Intensive Care
Medicine and the European Society of Paediatric and Neonatal
Intensive Care.
in the development of HH through the development of
hepatic ‘‘dysoxia’’ and impairment of hepatic cellular
respiratory function oxygen utilization and microcircula-
tory changes.4
Effective management of HH depends on its early rec-
ognition, which may be confounded by the absence of a
classical ‘‘shock state,’’ and addressing the causative fac-
tors. In the ICU setting, this frequently involves assess-
ment and monitoring of cardiac function through
invasive or noninvasive means. Prognosis is variable
dependent on the trigger(s) of HH development,
although death seldom results from liver failure alone
but rather from multiple organ failure.
CHOLESTATIC LIVER DYSFUNCTION
Cholestatic liver dysfunction (CLD) typically has a more
insidious onset than HH, manifest in a critically ill patient
usually days after ICU admission with progressive eleva-
tion of bilirubin, alkaline phosphatase, and gamma-gluta-
myltransferase.6 Investigation is hampered by a lack of
universally accepted diagnostic criteria, but in clinical prac-
tice a bilirubin level of more than 2 to 3 mg/dL and alka-
line phosphatase and gamma-glutamyltransferase of two
to three times normal may be accepted. Overt mechanical
obstruction of bile ducts is seldom the cause, although bil-
iary ‘‘sludge’’ may be observed on hepatic imaging. CLD
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Sepsis and Critical Illness Bernal
FIG 5 Schematic representation of hepatobiliary transport sys-
tem in health and in critical illness. In normal conditions, uptake
of bile acids from the blood into the hepatocyte via the high-
affinity Na1-dependent bile acid transporter (NTCP) and the less
specific organic anion transporting polypeptide (OATP). Excretion
into the bile canaliculus at the apical surface of the hepatocyte is
mainly through the bile salt export pump (BSEP) with less specific
transporters that include those from the multidrug resistance--
associated protein (MRP) and the multidrug resistance protein
(MDR) families. Export transporters MRP3 and MRP4 are also
expressed at low levels on the basolateral membrane and
transport bile acids to the systemic circulation. In animal models
and critically ill humans, NTCP and to a lesser degree OATP are
downregulated and uptake of bile acids into the hepatocyte
declines. Bilirubin may still enter the cell via OATP for conjuga-
tion. BSEP is markedly downregulated, and MRP2, MDR1, and
MDR2 are expressed at increased levels, favoring excretion of
xenobiotic toxic compounds into the bile. On the basolateral
membrane, MRP3 and MRP4 upregulation occurs in response to
cholestasis and inflammation, shifting transport of bile acids into
the blood. Adapted with permission from Intensive Care Medi-
cine.8 Copyright 2016, European Society of Intensive Care Medi-
cine and the European Society of Paediatric and Neonatal
Intensive Care.
is thought to result from critical illness–induced alteration
of hepatobiliary transport mechanisms. Clinical risk factors
for its development include sepsis (Figure 4), both through
endotoxemia and the evoked inflammatory cytokine
response, parenteral nutrition and hyperglycemia, and
super-added drug-induced cholestasis.6,7
A complex series of hepatobiliary transporter proteins
exists to take up biliary components from the blood, traf-
fic them through the hepatocyte, and secrete them into
the bile canaliculi. This tightly regulated process is
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REVIEW
markedly altered in critical illness where uptake trans-
porters on the basolateral surface of the hepatocyte are
downregulated and alternate export transport proteins
upregulated, while transport proteins located on the api-
cal canalicular surface are downregulated.8 The net
effect of these changes is reflected by increasing circulat-
ing levels of conjugated bile acids and bilirubin (Figure
5). It is not clear whether this represents an adaptive or
maladaptive response as moderate elevations of conju-
gated bilirubin may have beneficial antioxidative or cyto-
protective effects, and bile acids may modulate
fundamental aspects of energy and metabolic activity
and contribute to the stress response by inhibiting corti-
sol breakdown. Conversely, detrimental effects may
include modulation of intestinal flora and increase release
of endotoxin to the systemic circulation and impairment
of xenobiotic excretion with clinically important effects
upon drug metabolism and handling.8
Although N-acetylcysteine and ursodeoxycholic acid
are often administered, no specific intervention of proven
benefit exists for the treatment of CLD. Management
rather seeks to exclude mechanical obstruction and to
remove or ameliorate the insults that may be responsible.
Sepsis is treated effectively, secondary drug-induced
insults minimized, and where possible the enteral rather
than parenteral route is chosen for nutritional support.
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Sepsis and Critical Illness Bernal
CORRESPONDENCE
William Bernal, Liver Intensive Therapy Unit, Institute of Liver Studies,
Kings College Hospital, London SE5 9RS, United Kingdom. E-mail:
william.bernal@kcl.ac.uk
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