REVIEW

Sepsis-Induced CholestasisNisha Chand and Arun J. Sanyal

Jaundice and hepatic dysfunction frequently accom-pany a variety of bacterial infections. The relationshipbetween sepsis and jaundice, particularly in a pediat-

ric population, was reported as early as 1837.1 Jaundicemay result either directly from bacterial products or as aconsequence of the host’s response to infection. Fre-quently, both factors contribute to the development ofjaundice. In addition, specific infections that target theliver may cause jaundice because of the liver injury asso-ciated with hepatic infection. Although jaundice may bean isolated abnormality, it is often associated with featuresof cholestasis. In critically ill patients, the development ofjaundice and/or cholestasis complicates the clinical pic-ture and poses a clinical challenge both in diagnostic eval-uation and in management. In this article, we review thecurrent concepts about the pathogenesis of jaundice andcholestasis with infection, their clinical presentation anddiagnostic assessment, and the optimal management ofthese clinical problems.

Epidemiologic ConsiderationsJaundice is a well-known complication of sepsis or ex-

trabacterial infection. Sepsis and bacterial infection areresponsible for up to 20% of cases of jaundice in patientsof all ages in a community hospital setting.2 The inci-dence of jaundice in newborns and early infants variesbetween 20% and 60%.3 There are no data from large-scale prospective studies on the incidence of hyperbiliru-binemia in adults with sepsis. Several small retrospective

studies have reported widely varying numbers, from 0.6%to 54%. This variability probably reflects both the report-ing bias and the populations of subjects studied (Table1).4,5 Sepsis is more likely to manifest with jaundice ininfants and children than in adults. In this population,males have a higher incidence of jaundice. However, inadults, no gender predilection has been reported.

Jaundice has been associated with infections caused byseveral organisms including aerobic and anaerobic gram-negative and gram-positive bacteria. Gram-negative bac-teria cause most of these cases. The primary site ofinfection is most often intraabdominal, but infection ofvarious other sites such as urinary tract infection, pneu-monia, endocarditis, and meningitis have been associatedwith this complication.4,6,7 Other specific infectionsknown to cause jaundice are infections of the hepatobili-ary tree, clostridial infection, typhoid fever, and legio-nella.

Although jaundice can occur in isolation in patientswith septicemia, it is frequently associated with other el-ements of cholestasis. Because the principal clinical man-ifestation of cholestasis is also jaundice, the publishedliterature has primarily focused on the syndrome of jaun-dice, and the exact incidence of cholestasis with jaundiceversus isolated jaundice remains unclear.

PathophysiologyThe pathogenesis of jaundice in systemic infections

is multifactorial. The development of jaundice mayoccur from an aberration in the processing of bilirubinby hepatocytes or from other effects on the liver thatlead to the accumulation of bilirubin in the body. Suchprocesses include increased bilirubin load from hemo-lysis, hepatocellular injury, and cholestasis from theseptic state and from various drugs used for the treat-ment of sepsis. The molecular and biochemical mech-anisms by which jaundice develops in subjects withsepsis is best considered in the context of normal bili-rubin metabolism.

Normal Bilirubin MetabolismBilirubin is the end product of the breakdown of the

heme moiety of hemoproteins. In humans, 4 mg of bili-rubin is formed daily from the degradation of hemopro-teins, 80% of which is derived from hemoglobin.8

Unconjugated bilirubin is a highly hydrophobic moleculeand circulates tightly but reversibly bound to albumin in

Abbreviations: AHA, autoimmune hemolytic anemia; BSEP, bile salt exportpump; BSP, tetrabromosulfophthalein; cMOAT, multispecific organic anion trans-porter; DIC, disseminated intravascular coagulation; IL, interleukin; KCs, Kupffercells; LPS, lipopolysaccharide; MRP2, multidrug-resistance-associated protein; NO,nitric oxide; NTCP, sodium-dependent taurocholate cotransporter; OATP, organicanion transport protein; RBC, red blood cells; RES, reticuloendothelial system;SLCT, sulfolithocholyltaurine; TNF, tumor necrosis factor.

From the Division of Gastroenterology, Hepatology and Nutrition, Departmentof Internal Medicine, Virginia Commonwealth University Medical Center, Rich-mond, VA.

Received May 28, 2006; accepted October 16, 2006.Address reprint requests to: Dr. Arun J. Sanyal, Professor of Medicine, Pharma-

cology and Pathology, Virginia Commonwealth University Medical Center, MCVBox 980341, Richmond, VA 23298-0341. E-mail: ajsanyal@hsc.vcu.edu; fax:804-828-4945.

Copyright © 2006 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21480Potential conflict of interest: Dr. Sanyal received grants from Sanofi-Aventis and

Debiorision.

230

plasma. Figure 1 shows normal bilirubin metabolism atthe hepatocyte. Bilirubin dissociates from albumin at thesinusoidal, basolateral membranes of hepatocytes and istaken up inside in a carrier-mediated process that requiresinorganic anions such as Cl�.6,9,10 Organic anion trans-port proteins (OATPs) are on the basolateral membranesof hepatocytes.11 Their role in bilirubin transport has stillnot been directly established, but bilirubin is a presumedsubstrate of OATPs.12

Following uptake into a hepatocyte, bilirubin isbound by a group of cytosolic proteins (mainly gluta-thione S-transferases, GST) that prevent its effluxfrom the cell. Within a hepatocyte, bilirubin is conju-

gated to monoglucuronides and diglucuronides by theenzyme uridine diphosphate-glucuronosyltrans-ferase.13 Conjugation of bilirubin converts it from ahighly hydrophobic molecule to a relatively hydro-philic molecule that can be excreted into bile.6,9 Bili-rubin glucuronides are excreted into bile against a steepconcentration gradient by a canalicular membrane pro-tein, the canalicular multispecific organic anion trans-porter (cMOAT), also commonly referred to as themultidrug-resistance-associated protein (MRP2).6,9,14

This process is the major driving force of bilirubintransport and is the rate-limiting step in bilirubin ex-cretion by the liver.15

Table 1. Reports of Jaundice and Sepsis

Author (Year) N M/F Age TB/DB (mg %) Alk Phos ALT/AST Agents of Infection Bacteremia Site of Infection Deaths Notes

Bernstein et al.(1962)

9 8/1 2-8 weeks 12-22/4-7 E. coli (5) 8 UTI (4) 9

Paracolon (2)P. Aeruginosa (1)Streptococcus (grp A)

Hall et al. (1963) 11 10/1 15-65 years 2-17/.4-14 5-21 (KAU/100mL)

Gr. � Diplococci (5) Lungs (11) 2

Hamilton et al. (196) 24 13/11 � 1 day-13weeks

3-31/1-16 E. coli (18) 18 Urine (16) 11

A. Aeruginosa (4) Umbilicus (2)Eye (1)

Kibukamusoke et al.(1964)

21 21/0 17-65 years 3-27 8-19 (KAU/100mL)

8-150/13-150 Lungs (21) 1

Eley et al. (1965) 5 2/3 35-54 years 3-23/8-15 11-26 (KAU/100mL)

16-34/24-88(U/ml)

Str. pyogenes (2) 3 Intraabdominal (4) 1

E. coli (1) UTI (1)Proteus (1)Bacteroids (1)

Vermillion etal.(1969)

7 4/3 18-72 years 5-24/4-16 3-26(mU/mL)

1-3 (IU/ml) E. coli (3) 7 Lung (3) 6

Streptococcus (3) Intraabdominal (2)Pseudomonas (2) Pleural (1)S. aureus (2)

Miller et al. (1969) 9 1.2-2.5 E. coli (8) Appendicitis (9) 0Rooney et al. (1971) 22 19/3 1-3 weeks 7-50/1-37 E. coli (14) 19 UTI (9) 0

Proteus (3) CSF (1)Klebsiella (2) Umbilical (1)

Miller et al. (1976) 30 15/15 15-27 years 2-20 (DB mean6.78)

mean 128 mean 47.6 S. aureus (4) 11 Pneumonia (9) 13

P. aeruginosa (2) UTI (6)Paracolon Peritonitis (6)Klebsiella (6) Soft tissue (4)

Ng et al. (1971) 6 6/0 2-8 weeks 4-33/3-21 20-41 (KAU/100mL)

E. coli (5) 4 UTI (6) 0

Paracolon (1)Borges et al. (1972) 13 8/5 2 months-3

years3-31/2-14 28-300/50-920

(U/mL)E. coli (5) UTI (10) 0

Proteus (5) Lung (4)Streptococcus (2)Staphlyococcus (2)

Franson et al. (1985) 23 10/13 25-77 years 2-24/2-14 56-1694 23-3300 E. coli (8) 23 Lung (8) 14Klebsiella (3) Abdominal cavity

(5)Staphylococcus (6) UTI (4)Streptococcus (2) IV catheter/graft/

skin (3)

HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 231

Disorders of Bilirubin Metabolism DuringSystemic Infection

Various mechanisms can lead to hyperbilirubinemiaalone during systemic infection (Table 2). These are dis-cussed in detail in the following sections.

Increased Bilirubin Load/HemolysisThe development of hemolysis causes an increased bil-

irubin load in septic individuals. In early studies, hemo-lysis was believed to be the principal mechanism ofjaundice in sepsis.16 Using light microscopy, Tugswell etal. found excess iron-containing pigment in the liver of

patients with pneumonia and noted ferritin containinglysosomes in Kupffer cells.17 This was believed to be com-patible with hemolysis and secondary iron overload. Al-though hemolysis contributes to jaundice in sepsis, it isunlikely that it is the principal mechanism because thejaundice results from conjugated hyperbilirubinemia.18-20

Table 3 lists various mechanisms of hemolysis in the set-ting of sepsis.

Hemolysis may occur by multiple mechanisms in thesetting of bacterial infection.21-22 These may be catego-rized as mechanisms of hemolysis (1) associated with nor-mal red cells and (2) related to underlying red cell defects.

The severe forms of many infections from gram-posi-tive and gram-negative bacteria have been associated withhemolysis of normal red cells. Of these bacteria, Clostrid-ium perfringens can give rise to severe, often fatal hemoly-sis in persons with normal red cells.23-24 Cl. perfringensproduces phospholipase C, a lecithinase that reacts withred cell membrane lipoproteins to release lysolecithin,which, in turn, lyses red cell membranes, producing he-molysis.25 In addition, this bacterium also produces pro-teolytic exotoxins that cause enzymatic dissolution ofmembrane proteins.26 Other infections that commonlycause hemolysis in normal red cells are malaria and babe-siosis.27 Escherichia coli infection periodically may lead tohemolysis of normal red blood cells (RBCs).28 Aside frombacterial infection directly causing hemolysis, multipledrugs (e.g., penicillin, antimalarial medications, sulfamedications, or acetaminophen), hypersplenism from in-fection, portal hypertension, or neoplasm can increase thesequestration and phagocytosis of erythrocytes.21,28

Immunologically mediated red cell injury is anothermechanism by which hemolytic anemia occurs in normalRBCs of patients with sepsis. Overall, infections accountfor about 8% of cases of autoimmune hemolytic anemia(AHA) and for approximately 27% of such cases in chil-dren.22 Immunologically mediated hemolysis may de-velop by 3 mechanisms: antibody directed to red cell

Fig. 1. Normal bilirubin metabolism. Bilirubin dissociates from al-bumin at the sinusoidal surface of the hepatocyte and is taken up by thehepatocyte. Inside the hepatocyte, bilirubin is bound by a group ofcytosolic proteins that prevent its efflux from the cell. Bilirubin is thenconjugated to monoglucuronides and diglucuronides by the enzymeuridine diphosphate-glucuronosyltransferase. Bilirubin glucuronides areexcreted into bile against a steep concentration gradient by a canalicularmembrane protein termed canalicular multispecific organic anion trans-porter (cMOAT), also commonly referred to as the multidrug-resistance-associated protein (MRP2). This process is the major driving force ofbilirubin transport and is the rate-limiting step in bilirubin excretion by theliver.

Table 2. Mechanisms of Hyperbilirubinemia in Sepsis

1. Hemolysisa. In normal red cellsb. In RBCs with red cell enzyme defects (G6PD)c. Pathologic changes to RBCs secondary to infectiond. Drug-induced hemolysis

2. Hepatic dysfunctiona. Decreased bilirubin uptakeb. Decreased canalicular transportc. Decreased clearance of conjugated bilirubind. Hepatic ischemia

i. Hypotensionii. Prolonged Hypoxia

e. Hepatocellular injury (mild reactive hepatitis to overt hepatocellularnecrosis)

3. Cholestasis

Table 3. Mechanisms of Hemolysis in Sepsis

1. Normal RBCsa. Infections directly causing hemolysis (e.g. Clostridium perfringens)b. Immunologically mediated red cell injury

1. Cold agglutinin–associated hemolytic anemiaa. Mycoplasma pneumoniaeb. Legionella

2. Paroxysmal cold hemoglobinuriac. Drug-induced hemolysisd. Transfusion reactionse. Hypersplenism

2. Underlying red blood cell defectsa. Inherited enzyme deficiencyb. Sickle cell diseasec. Hemoglobinopathies

232 CHAND AND SANYAL HEPATOLOGY, January 2007

antigens (IgM or IgG mediated), antigen/antibody com-plexes, or polyagglutination.22 IgM antibodies give rise tointravascular hemolysis, and IgG antibodies give rise toextravascular hemolysis.22

Several pathogens, for example, Mycoplasma pneumoniaeand Legionella may cause “cold agglutinin”–associated he-molytic anemia.22,25 The cold agglutinins, which are oftenIgMs, bind to red cells at low temperatures, fix complement,and cause intravascular hemolysis. On the other hand, IgGantibodies, for example, Donath-Landsteiner antibodies inparoxysmal cold hemoglobinuria, often cause extravascularhemolysis. This condition has been associated with upperrespiratory tract infections and a variety of infections thatnormally do not lead to sepsis syndrome, for example, syph-ilis, varicella, Epstein-Barr, measles, and mumps.22,25,29 He-molysis and jaundice from paroxysmal cold hemoglobinuriamay be severe in cold weather.

In individuals with underlying red cell defects, thethreshold for hemolysis is often lower than in normalindividuals. A common defect associated with an in-creased propensity for hemolysis in a variety of circum-stances including sepsis is glucose-6-phosphatedehydrogenase (G-6-PD) deficiency.1 Many types of in-fections as well as antibiotics can cause hemolytic anemiain patients with this deficiency. G-6-PD is required forregeneration of nicotinamide adenine dinucleotide dehy-drogenase (NADPH), which is essential for reducing theamount of oxygen radicals.30 In the absence of G-6-PD,red cell NADPH stores are diminished, thereby loweringthe threshold for oxidant-stress-mediated cell injury. Sep-sis is often associated with oxidant stress, and this mayinduce hemolysis, particularly in those with a loweredthreshold for oxidant-mediated injury.

Microangiopathic hemolytic anemias may be triggered bya variety of infections such as Shigella, Campylobacter, andAspergillus.31 Disseminated intravascular coagulation (DIC)may also cause hemolysis with infections; up to 60% of allcases of DIC have been attributed to infections, with manybacterial, viral, fungal, and parasitic pathogens implicated.25

Drugs are a major cause of hemolysis in patients withsepsis (Table 4).31,32 This occurs through a variety ofmechanisms,34 an apparently major one of which is in-creased oxidant stress. Finally, hemolysis of nonviableerythrocytes may occur during massive blood transfu-sions, resorption of large hematomas, or trauma. Theseadditional factors are commonly encountered in patientswith sepsis in the ICU.

Hepatocyte Dysfunction as a Cause ofHyperbilirubinemia

In addition to increased bilirubin load, decreased bili-rubin uptake, intrahepatic processing, and canalicular ex-

cretion are also important mechanisms of jaundiceassociated with infection. This is supported by the mainlyconjugated hyperbilirubinemia that occurs in sepsis.Many studies have examined the effects of sepsis on thefunction of organic anion transporters in the liver. Tetra-bromosulfophthalein (BSP) is taken up by hepatocytes bythe sodium-independent transport system, the basolateralOATP.12 Bilirubin is a presumed substrate for this trans-porter system.12 Hepatic uptake of BSP is reported to bemarkedly lower in lipopolysaccharide (LPS)-treated ani-mals. BSP, glutathione, and sulfolithocholyltaurine(SLCT) are excreted at the canalicular membrane throughMRP2.12 There is also a decrease in canalicular transportof glutathione and SLCT, suggesting decreased MRP2activity. Roelofsen et al. studied the transport of bilirubinin a rat model of sepsis.9 In this study, LPS was injectedinto rats intravenously to induce endotoxemia. The trans-port of bilirubin and another organic acid, taurocholate,were studied 18 hours after the infusion. Sinusoidal up-take, hepatic content, and canalicular excretion of biliru-bin were all decreased in endotoxemic rats compared to incontrol animals.9 Also, a 50% decrease in steady-stateelimination of bilirubin was observed in livers exposed toendotoxin.6,9

It is unlikely that bilirubin conjugation is substantiallyaffected by sepsis because more than 60% of the bilirubinin blood is conjugated.9 Also, when endotoxin was ad-ministered to rats, the clearance of conjugated bilirubindecreased to the same degree that unconjugated bilirubindid, suggesting that the conjugation of bilirubin was notcontributing to the impairment in bilirubin clearance.9

This is further supported by the finding that the degree ofbilirubin conjugation in livers exposed to endotoxin wasnot substantially different from normal controls.9

Decreased Bile FlowCholestasis is the predominant mechanism by which

jaundice develops in sepsis. Extrahepatic cholestasis is

Table 4. Antibiotics Associated with Hemolysis

Immune Complex Mediated

Quinine

Autoantibody Medicated

SulfonamidesPenicillinCephalosporinsIndinivir

Hemolyis in G6PD

NitrofurantoinPhenazopyridinePrimaquineSulfonamides

HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 233

caused by obstruction of the hepatic or common bile ductand directly impedes the flow of bile. This can result froma primary infection such as cholangitis or can becomesecondarily infected. Partial biliary obstruction and ob-struction as a result of cholelithiasis are more commonlycomplicated by infection of the biliary tree, which couldfurther lead to decreased bile flow.

Sepsis-Associated CholestasisNormal Bile Acid Flow

Before elaborating on the potential mechanisms ofcholestasis in sepsis, it is important to understand thesteps in the formation of bile (Fig. 2). Bile is formed by theinflow of water along osmotic gradients produced by se-cretion of bile salts into hepatic canaliculi. Bile salts arethe principal solute secreted into this space, and bile flowis mainly driven by the osmotic forces generated by thesecretion of bile salts into hepatic canaliculi. This is alsoknown as bile-salt-dependent bile flow, whereas the gen-eration of bile from osmotic forces related to other solutesis known as bile-salt-independent flow.

Bile salts are derived from de novo synthesis in the liverand from reabsorption of bile salts from the intestine. Bileacids are transported to the liver following intestinal ab-sorption. They are taken up by hepatocytes via transportproteins on the basolateral (sinusoidal) membranes. Theprincipal mediator of this basolateral transport of bile ac-ids is the Na-K-ATPase pump, which is ATP dependentand maintains an inwardly directed sodium gradient. It is

an integral component of the basolateral membrane, andNa-K-ATPase pumps are found throughout the hepaticlobule. Sodium-dependent taurocholate cotransporter(NTCP) is the principal transporter in the uptake of con-jugated bile salts from plasma into hepatocytes.35 Thishighly efficient pathway results in a high first-pass clear-ance of bile salts. The unconjugated bile salt cholate, or-ganic ion sulfobromophthalein (BSP), and otherlipophilic compounds are primarily transported fromplasma into hepatocytes by sodium-independent trans-port systems such as organic anion transport proteinsOATP 1, OATP 2, and OATP 3.35

Bile acids are transported from the basolateral mem-brane to the canalicular membrane by cytosolic trans-porter proteins. Transcytosolic transport occurs through2 main methods: (1) binding to cytosolic proteins anddiffusing to apical domains (mainly conjugated primaryand secondary bile acids) and (2) vesicular trancytosis.Vesicular transport is responsible for a very small amountof total bile flow, and the role of this type of transport isunclear.

The passage of bile salts into biliary canaliculi is therate-limiting step in bile formation. This passage is mostlyATP dependent and occurs against a steep concentrationgradient. There are many ATP-dependent transporters onthe canalicular membrane. Among these are the multi-drug resistance family and the bile salt export pump(BSEP). Conjugated bile salts are excreted into bilethrough the BSEP. The multiple drug resistance 1 trans-porter is responsible for transporting hydrophobic or-ganic cations.36 Water and inorganic ions enter bile bydiffusion across tight junctions, which provide a barrierfor bile salts, prohibiting the regurgitation of formed bileinto the space of Disse.

Mechanisms and Mediators of Cholestasis Associatedwith Infections

The liver has a central role in the regulation of hostdefenses. It serves as a source of inflammatory mediatorsand is a major site of the removal of bacteria and endo-toxins from systemic circulation.37-38 Kupffer cells (KCs)of the liver make up 80%-90% of the fixed-tissue macro-phages of the reticuloendothelial system (RES) and rep-resent terminally differentiated macrophages. KCs takeup bacteria, particles, and endotoxins (LPS) and are stim-ulated to release a wide range of products implicated inliver injury, such as tumor necrosis factor, interleukin 1and interleukin 6, superoxides, lysosomal enzymes, pro-coagulants, and platelet-activating factor.9,39-41

Hepatic injury without biliary obstruction may accom-pany systemic infection in adults with pneumococcalpneumonia, streptococcal bacteremia, salmonella infec-

Fig. 2. Normal bile acid flow and bile formation. Bile acids aretransported from the basolateral membrane to the canalicular membraneby cytosolic transporter proteins. Transcytosolic transport occurs by 2main methods: (1) binding to cytosolic proteins and diffusion to apicaldomains (mainly conjugated primary and secondary bile acids) and (2)vesicular trancytosis. The passage of bile salts into the biliary canaliculusis the rate-limiting step in bile formation, which is ATP dependent.Conjugated bile salts are excreted into bile through the BSEP. Themultiple drug resistance 1 (MDR1) transporter is responsible for trans-porting hydrophobic organic cations across the canalicular membrane.The tight junctions between hepatocytes provide a barrier to bile salts,prohibiting the regurgitation of formed bile into the space of Disse.

234 CHAND AND SANYAL HEPATOLOGY, January 2007

tions (especially typhoid fever), and Escherichia coli bac-teremia.42 This can range from mild reactive hepatitis toovert hepatocellular necrosis that, it has been shown, usu-ally resolves when the bacteremia is appropriately treated.Hepatocellular injury is not considered a frequent occur-rence during extrahepatic bacterial infection. Most stud-ies that reviewed liver histology in hyperbilirubinemia orhepatic abnormalities in bacterial infection have notedvery mild to no inflammation (see Table 1).20 The mech-anism of hepatic injury depends on the underlying infec-tion, yet most likely there is an unspecified toxinelaborated by the offending bacteria that ultimately leadsto hepatocellular injury.20,42

Ischemic liver damage may occur as a consequence ofhypotension or prolonged hypoxia in sepsis. Hepaticblood flow is depressed in sepsis and nutrient blood flowto the liver is reduced, which can lead to Kupffer celldysfunction and hepatocellular alteration.43 The lack ofoxygen, mainly to the centrizonal cells and later fromdelivery of oxygen-derived free radicals from reperfusion,leads to hepatocellular damage and thus may result incentrilobular necrosis of the liver.4,44,45 Mediation of hep-atocellular injury via necrosis and/or apoptosis has beenattributed to nitric oxide (NO). This was demonstrated inseptic animal models when inhibition of NO productiongave rise to reductions in both hepatocyte necrosis andapoptosis.46

The underlying state of endotoxemia and the prod-ucts released in response to infection appear to play akey role in the pathophysiology of the cholestasis ofsepsis. Various effects of this state on the liver that leadto cholestasis are listed in Table 5. Decreased hepato-cellular function has been demonstrated to occur earlyafter the onset of sepsis despite increased cardiac out-put and hepatic perfusion.47 This suggests that the hep-atocellular dysfunction in sepsis may be associated withthe release of proinflammatory cytokines such as tumornecrosis factor alpha (TNF-�) or interleukin 6 (IL-6).47-48 Various investigations have confirmed the cen-tral role of endotoxemia in the genesis of cholestasisassociated with sepsis.41 Direct invasion of the liver bybacteria is not a major cause of cholestasis or hepatic

injury in most cases of septicemia.41 Several studieshave shown a quantitative reduction in bile flow withinthe isolated perfused livers of rats following LPS orcytokine administration.

TNF-� is a cytokine released by macrophages, endo-thelial cells, and Kupffer cells and is the primary mediatorof the systemic effects of endotoxins. TNF-� has beenimplicated in endotoxin-induced cholestasis by the find-ing that immunization with anti-TNF-� antibodiesblocked endotoxin-associated reduction in bile flow andbile salt excretion.49 LPS, TNF-�, and interleukins 1�and 6 all have been shown to mediate these effects, givingrise to cholestasis in the liver.6,50 Procoagulants releasedby activated Kupffer cells induce microvascular thrombo-sis and have been postulated to cause circulatory distur-bance, which, in turn, could contribute to endotoxin-induced hepatic injury.41

Abnormalities in Bile Acid Formation and FlowEndotoxemia does not affect bile acid synthesis, cyto-

solic bile acid transport, or the permeability of tight junc-tions.51 LPS and cytokines appear to mainly affecthepatocyte uptake and excretion of bile acids. Table 5 listsvarious steps in bile acid transport that possibly are af-fected in sepsis, thus giving rise to cholestasis. Endotox-emia decreases the basolateral and canalicular transport ofbile acids (cholate, taurocholate, and chenodeoxycholate)and organic anions (BSP and the taurine conjugate ofsulfolithocholate).6,11 It is also postulated that LPS maystimulate degradation of membrane proteins as well.50

Several studies have observed endotoxin-induced inhi-bition of basolateral membrane Na-K-ATPase activ-ity.50,52-53 Endotoxin may cause decreased function ofNa-gradient dependent transporters at the basolateralmembrane such as the NTCP.14,49 It has also been ob-served that endotoxin affects membrane fluidity; this maybe the mechanism involved in reducing Na-K-ATPaseactivity after endotoxin administration.50,54 TNF-� andIL-1� modulate gene expression of transporters NTCPand BSEP at both the transcriptional and the posttran-scriptional levels.12 In a study by Green et al., 16 hoursafter intraperitoneal administration of LPS, both proteinexpression and functional activity of NTCPs were re-duced by more than 90%.50

Impaired hepatocyte transport function has also beendetected at the canalicular level. Cholyltaurine (CT) andchenodeoxycholyltaurine (CDCT) are substrates for can-alicular bile acid transporters.12 ATP-dependent CT andCDCT transport was markedly decreased in a rat sepsismodel.51 This appears to result from down-regulation oftransporters at the canalicular membrane.6,40,51

Table 5. Mechanisms of Cholestasis of Sepsis

Decreased basolateral transport of bile acidsInhibition of basolateral membrane Na-K-ATPase activityDecreased basolateral membrane fluidityDown-regulation of transportersDecreased NTCP function

Decreased canalicular transport of bile acidsDown-regulation of transportersDecreased BSEP functionDecreased MRP2 function

HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 235

Bile-acid-dependent and -independent flows are re-duced in septic models compared to in controls.6,49-50 Themain evidence for this is the inhibition of biliary excretionof GSH and, to a lesser extent, of HCO3

� after LPSadministration.6,49 Maximum reduction in bile acid flowoccurs 12-18 hours after endotoxin and/or cytokine ad-ministration.6

Clinical SyndromesThe jaundice of sepsis is usually cholestatic and can

occur within a few days of the onset of bacteremia andmay even appear before other clinical features of the un-derlying infection become apparent.55 In the absence ofintraabdominal infection, abdominal pain is rare. Simi-larly, pruritus is not a major manifestation of cholestasisassociated with infection. Hepatomegaly occurs abouthalf the time.55 Conjugated hyperbilirubinemia in therange of 2-10 mg/dL is often seen, although rarely higherlevels can be seen.19 This is particularly true in those withpostoperative jaundice who also are septic and on TPN.Serum alkaline phosphatase is usually elevated but rarelymore than 2-3 times above the upper limit of normal.55

Serum aminotransferase is generally only modestly ele-vated (Table 6).55

Specific Clinical Scenarios of Infection and Jaundice

Biliary Tract Disease. Obstruction or infection ofthe hepatobiliary tree should be considered a potentialcause of jaundice, especially when a patient presents withright upper quadrant pain, jaundice, and fever. Cholan-gitis most commonly occurs secondary to obstruction ofthe biliary tract with a gallstone or after biliary interven-tion. Less commonly, cholangitis may occur after obstruc-tion from a tumor of the ampulla, bile duct, or pancreas.Laboratory results will show leukocytosis, conjugated hy-perbilirubinemia, and elevation of alkaline phosphatasedisproportionate to transaminasemia. Acute cholangitishas a more severe course than jaundice associated withextrahepatic infections.

Liver Abscess and Pylephlebitis. Biliary tract diseaseis the most common condition associated with liver ab-scess.56 This includes infection (cholangitis) that may oc-cur secondary to choledocholithiasis, biliary stricture, ormalignancy.57 Another potential cause of pyogenic ab-scess is spread through the portal vein from an intraab-

dominal primary site to the liver.58 Almost a third of liverabscesses are cryptogenic.59 Patients present with fever,chills, and weight loss. Abdominal complaints most oftenare vague or absent. Up to two thirds of patients havehepatomegaly. Alkaline phosphatase levels are invariablyelevated, with less frequent elevation of bilirubin and ami-notransferases. Optimal treatment includes prompt diag-nosis, percutaneous or surgical drainage of the abscess,and broad-spectrum enteric antibiotic coverage. Progno-sis depends on prompt recognition and treatment, with acure rate ranging from 80% to 100%.56

ICU Setting. A patient presenting with jaundice inthe ICU is a frequently encountered problem. Infections,hemodynamic instability, renal insufficiency, hepatotoxicdrugs, multiple blood transfusions, and/or TPN admin-istration are some of the potential causes of jaundice,which usually presents 1-2 weeks after onset of the initi-ating event. Jaundice under these circumstances is usuallyof a cholestatic type, with mainly conjugated hyperbiliru-binemia and only slightly elevated AST and ALT.43 Whenthere is no obvious biliary obstruction; underlying sys-temic infection is highly likely. Sepsis is the most com-mon etiology of jaundice and cholestasis in the ICU. Thisis especially true in patients who are in an ICU due totrauma. In a retrospective study by Boekhorst et al., thedevelopment of jaundice in the ICU was shown to have apoor prognosis.43 This could be a result of a delay indiagnosis of the instigating factor. If the underlying pro-cess is detected and adequately treated in a timely fashion,the prognosis is usually good.

Gram-Negative Bacterial Infections. Cholestasis is aknown complication of gram-negative bacterial infection,especially in infants. This syndrome is more frequent inthe neonatal period and may account for as much as athird of the cases of neonatal jaundice.22 Most cases ofsepsis associated with cholestatic jaundice have evidenceof gram-negative bacteremia, with Escherichia coli themore common pathogen.20,60 Pyelonephritis, peritonitis,appendicitis, diverticulitis, pneumonia, and meningitisare types of infections observed to cause jaundice. Theurinary tract is the most common site of infection associ-ated with this syndrome, especially in the neonatal per-iod.60 Liver histology shows intrahepatic cholestasis withKupffer cell hyperplasia and little or no evidence of cellu-lar necrosis. Aside from cholestasis, liver histology revealsan almost normal hepatic parenchyma.20 The manifesta-tions of the underlying infection usually dominate thepresentation.55 Jaundice and cholestasis are usually revers-ible and subside completely after resolution of the infec-tion.

Pneumonia. The male-to-female ratio of patientswho develop jaundice with pneumococcal pneumonia is

Table 6. Liver Test Abnormalities in Sepsis

● Conjugated hyperbilirubinemia: total bilirubin ranging from 2 to 10 mg/dL● Elevated alkaline phosphatase: rarely more than 2-3 times upper limit of

normal● Mild elevation of aminotransferases

236 CHAND AND SANYAL HEPATOLOGY, January 2007

10 to 1.18 Most investigators think that pneumonia-asso-ciated jaundice is a result of hepatocellular damage.20

Many patients with pneumonia, with or without jaun-dice, have abnormalities suggestive of hepatocellular dam-age.20 Hepatic necrosis has more commonly beenidentified in liver biopsies of patients with pneumo-nia.17,60 Liver histology consistently shows patchy necro-sis and dilated biliary canaliculi with bilirubinostasis.20

The prognosis is good after complete resolution of theinfection.

Clostridium perfringens. Clostridium perfringens is acommonly isolated clostridial species that can cause awide spectrum of clinical manifestations, from transientbacteremia to massive red blood cell hemolysis, shock,and death. Clostridial hemolysis has been described as arare complication of septic abortion, gall bladder disease,and surgical procedures.61 Severe bacteremia may result inmassive hemolysis, hemoglobinuria, shock, and death.Clostridium perfringens produces a large variety of toxinsand virulence factors. The alpha toxin, a lecithinase, iscapable of hydrolyzing sphingomyelin and lecithin tophosphoryl choline and diglyceride.62 Lysolecithins re-leased from cell membranes also act as hemolysins. Lyso-lecithins also produce RBC membrane failure, whichaccounts for the profound or fatal hemolytic anemia inclostridial sepsis.61 Striking hemoglobinemia and hemo-globinuria are seen in this condition, and the high plasmahemoglobin level may produce marked dissociation be-tween blood hemoglobin and hematocrit levels. Acuterenal failure and hepatic failure usually develop. Theprognosis in this clinical setting is very poor, with morethan half the patients dying even with proper and exten-sive treatment.63-64 Therapy consists of high-dose penicil-lin and surgical debridement.63

Leptospirosis. Leptospirosis is a zooanthroponosistransmitted among animals and occasionally from ani-mals to humans. In the incubation period, the leptospiraorganisms disseminate to different organs, especially theliver, kidneys, muscles, and lungs. Experimental data sug-gest that after the leptospira gain access to the blood-stream, they concentrate in the liver, where theyreproduce.65-66 There are two classical forms of presenta-tion of leptospirosis, the icteric and anicteric forms. Theicteric form is the less common. A severe presentation ofthe disease, occurring in only 5% to 10% of all leptospiralinfections, is known as Weil’s disease. This is associatedwith high fever, severe hepatic function impairment, in-tense jaundice, renal insufficiency, hemorrhagic diathesis,and cardiovascular compromise. Although serum biliru-bin may be extremely high, serum aminotransferase andalkaline phosphatase are only slightly to moderately ele-vated. The mortality rate for this presentation is high.

Typhoid Fever. Typhoid fever, also known as entericfever, is an acute systemic illness caused by Salmonellatyphi. Typhoid fever is an infection that not only causesjaundice but also induces liver injury.20,67 Hepatomegalyoccurs in about 30% of patients, and jaundice occurs inabout a third of patients with hepatomegaly. Alkalinephosphatase is usually 2-3 times the normal level, andserum aminotransferases rarely are more than 5 times theupper limits of normal. Rarely, ALT values may be mark-edly elevated.20 The diagnosis is made by (1) isolatingsalmonellae from the blood or stool and (2) observing arise in the titer of the Widal reaction during the course ofthe illness. The etiology of the hepatic damage in typhoidfever is believed to be secondary to the effect of endotox-in.68 Previous studies have demonstrated that injection ofSalmonella typhi endotoxin produces focal hepatic necro-sis. Other studies have suggested that liver injury mayoccur by local release of cytotoxins or local inflammatoryreactions within reticuloendothelial cells.68 Cholangitisand biliary stasis are apparently not important in thepathogenesis of hepatic lesions.67 The histology of thelivers of patients with typhoid fever shows focal cell ne-crosis with mononuclear cell infiltration and markedKupffer cell hyperplasia with mild cholestasis.20 Typhoidnodules, aggregations of Kupffer cells, are characteristic oftyphoid fever and are randomly distributed throughoutthe hepatic lobule.68 Follow-up liver biopsies have showncomplete resolution within 2 weeks after control of infec-tion.20

Natural HistoryThe presence of jaundice and sepsis or the degree of its

severity does not seem to influence survival or predict theoverall prognosis of the patient.20,69 The overall prognosisdepends on the underlying infection. There usually iscomplete resolution of hepatic dysfunction and cholesta-sis if the underlying condition is adequately treated, yetthe outcome may be guarded if detection and treatmentare delayed.4,6,14,69 Certain causes of jaundice in a criti-cally ill patient such as acalculous cholecystitis and as-cending cholangitis have a very poor prognosis.

HistologyThe most prominent finding in sepsis is intrahepatic

cholestasis. Histologically, bile is found in the bile cana-liculi and in hepatocyte cytoplasm (Fig. 3A-C). Bile back-flow into the perisinusoidal spaces may lead to bile uptakeby Kupffer cells. There may also be some cholestasis-re-lated parenchymal changes including feathery degenera-tion of the hepatocyte cytoplasm. Apoptosis when presentappears as rounded bile-tinged apoptotic bodies in the

HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 237

hepatic lobule. An increased amount of smooth endoplas-mic reticulum as a result of cholestasis may lead to hepa-tocytes having a ground-glass appearance.

Evaluation of Jaundice in an Infected Patient. Theguiding principles in the evaluation of a given patient areconsideration of (1) the differential diagnosis, (2) specificdiagnoses likely to have negatively affect the patient ifmissed, and (3) therapeutic options available when a di-agnosis can be made. Table 7 outlines the recommendedsteps for evaluating a patient at risk for sepsis of jaundice.The outcome of sepsis-associated jaundice is linked toeffective treatment of the sepsis. When jaundice developsin a patient with an established diagnosis of infection, thepossibility of sepsis-related jaundice is obvious. On theother hand, a high index of suspicion is often necessary todiagnose this condition when jaundice is the presentingmanifestation of infection. The presence of hyperbiliru-

binemia and abnormal hepatic parameters may draw at-tention from assessing a more serious underlying diseaseprocess and lead to an unnecessary search for hepatic orbiliary disease. However, if a septic source is not known,the possibility of hepatic or biliary infection as the cause ofjaundice should also be considered. There are many spe-cific entities that require special attention.

Given the common causes of jaundice and the differentcircumstances in which it is encountered, a thorough,systematic approach should be carried out to evaluate thecause (Table 7). Table 8 lists various etiologies in thedifferential diagnosis in this setting. The type of jaundice,that is, unconjugated versus conjugated and isolated hy-perbilirubinemia versus jaundice with liver enzyme ab-normalities, provides valuable clues that should guidefurther workups. Unconjugated hyperbilirubinemiashould initiate a search for hemolysis and potential causesof hemolysis. On the other hand, with a predominantlycholestatic jaundice, it is imperative to exclude a poten-tially treatable hepatobiliary cause of sepsis and jaundice.Imaging studies to evaluate the hepatobiliary tract areextremely valuable for this purpose. Sonography is rela-tively inexpensive and can be performed at the bedsides ofcritically sick patients. Also, Doppler sonography can ex-clude vascular occlusion as a cause of jaundice. However,sonography is not sensitive enough to pick up small ab-scesses, and a CT scan should be performed when a he-patic abscess is suspected.

Table 7. Evaluation of Patient at Risk forSepsis with Jaundice

1. Assess the type of jaundiceˆ Conjugated versus Unconjugated■ Unconjugated—initiate a search for hemolysis■ Conjugated

● Search for a hepatobiliary causeE Imaging studies

■ US (with or without Doppler)■ CT

ˆ Isolated jaundice versus jaundice associated with liver enzyme elevation2. Full workup to evaluate for infection

ˆ Complete blood count with differentialˆ Urine analysisˆ Pan culture

■ Blood■ Urine■ Sputum■ Catheter tips■ Drains■ Other potential sources of infection

ˆ Imaging■ CXR■ Further imaging of potential sites of infection (rule out abscess,hepatobiliary disease, etc.)

ˆ Empiric antibiotic coverage: in selected cases, hepatic parameters mayimprove within a couple of weeks if they were secondary to infection alone

Fig. 3. Liver biopsies of subjects with cholestasis showing (A) bileplugs (black arrows), (B) pericholangitis, and (C) intrahepatic inspissatedbile in a subject with TPN-induced cholestasis.

238 CHAND AND SANYAL HEPATOLOGY, January 2007

In patients at risk for sepsis who develop jaundicewithout other features of infection, blood cultures,urine cultures, and a chest X-ray should be obtained asa minimum workup to exclude sepsis. Also, culturesshould be sent from intravascular catheter tips, drains,or any other source of potential infection. If an obviouscause is still not apparent, further aggressive evaluationfor underlying infection or iatrogenic causes should besought. There are no controlled data that either vali-date or refute giving empiric antibiotic coverage to allpatients with jaundice who have not yet shown otherfeatures of infection. Frequently, empiric antibioticcoverage with a broad-spectrum antibiotic is given tothose who are likely to be unable to tolerate sepsis.Hepatic parameters, which usually improve within 1-2weeks of therapy for the underlying infection, shouldbe followed closely.

Hepatocellular jaundice is diagnosed when hyperbil-irubinemia is accompanied by high AST and ALT levelsand only modest or no elevation of alkaline phosphatase.This is usually a result of ischemia, toxins, viral infection,or iatrogenic injury. Hepatitis viral serology tests shouldbe done. A Tylenol level may be obtained if this drug hasbeen used to treat fever associated with infection. Typi-cally, ALT levels are markedly elevated in such patients.The passage of biliary sludge may sometimes be associatedwith a rapid rise in AST that declines just as rapidly afterpassage of the sludge. A hepatobiliary sonogram can beused to confirm the presence of sludge. A liver biopsy doesnot usually aid in management of this situation.

ManagementThe most important part of management is early diag-

nosis and treatment of infection (Table 9). Other addi-tional steps in management follow.

Correction of Fluid and Electrolyte Imbalances.Initial management should always include aggressive in-travascular volume repletion and vasopressive agents ifneeded to maintain adequate mean arterial blood pressurefor organ perfusion.

Treatment of Infection. The only effective treatmentof cholestasis of sepsis is the appropriate management ofthe underlying infection. Appropriate antibiotic therapyshould be initiated as soon as possible. Septic foci shouldbe removed or drained. A delay in the diagnosis of infec-tion and the initiation of antibiotic therapy significantlyworsens the prognosis.

Enteral Feeding, Enteral feeding may help to resolvecholestasis. Healthy individuals show a decreased serumbilirubin with continuous enteral feeding. In infants, cho-lestasis resolves when enteral feeding is introduced.70

Ursodeoxycholic Acid. Ursodeoxycholic acid can po-tentially improve bile flow and bilirubin levels in TPN-AC- and drug-induced cholestasis. Currently, the clinicalevidence is insufficient to support the use of ursodeoxy-cholic acid to treat cholestasis from these causes.71,72

Glycine Administration. Glycine serum concentra-tions are decreased in sepsis. At a cellular level, glycinedecreases the influx of calcium into Kupffer cells, therebyreducing the release of TNF. This reduction in TNF mayplay a beneficial role in treatment of sepsis-associated cho-lestasis and hepatocellular dysfunction. Yang et al. dem-onstrated a beneficial effect of glycine on hepatocytefunction and integrity in sepsis.73 After administration ofthis nonessential amino acid early after onset of polymi-crobial sepsis in an animal model, hepatocellular functionmarkedly improved and the mortality rate decreased from50% to 0% 10 days after the onset of sepsis.73

Nitric Oxide Donor Administration. Nitric oxide(NO) is a paracrine-acting gas enzymatically synthesizedfrom l-arginine. Cholestasis and endotoxemia have been

Table 9. Management

Treatment of Infectionˆ Antibioticsˆ Drainage of abscessˆ Removal of potentially infected drains, IV lines, cathetersˆ Correction of fluid and electrolyte imbalances

Early Introduction of enteral feedingPotential future treatments

ˆ Glycine administrationˆ Ursodeoxycholic acidˆ Nitric oxide donor administrationˆ N-acetyl-L-cyteine (NAC)

Table 8. Differential Diagnosis

Biliary tract diseaseˆ Cholecystitis (cholelithiasis/biliary sludge/acalculous)ˆ Cholangitisˆ Biliary tract obstruction (gallstone, stent obstruction, tumor of the ampulla/bile duct/pancreas, postbiliary intervention)

Liver diseaseˆ Hepatitisˆ Liver abscessˆ Hepatic ischemia—secondary to hemodynamic instability

Systemic Infectionˆ Pneumoniaˆ UTIˆ Bacteremia/septicemiaˆ Other sites of primary infection

Hemolysisˆ Specific infectionsˆ Drugsˆ Multiple blood transfusions

Hepatotoxic drugs/toxinsˆ Antibioticsˆ TPNˆ Tylenol

HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 239

shown to cause hepatocyte apoptosis through caspase-mediated pathways. In vitro studies show that NO donorsattenuate hepatic apoptosis via interruption of mitochon-drial apoptotic signaling through S-nitrosylation ofcaspases.74,75 Brown et al. showed that NO has a hepato-protective effect against this liver injury.76 They showedthat providing NO by administrating molsidomine (aNO donor) resulted in improved survival in septic ratmodels and decreased liver injury and hepatocyte apopto-sis.76

N-Acetyl-l-Cysteine. N-acetyl-l-cysteine (NAC) hasbeen used as a free-radical scavenger, working either as adirect scavenger or by increasing intracellular stores ofglutathione. Prior administration of NAC allowed an im-proved cardiac index and lower maximal TNF levels inendotoxemic dogs compared to controls in a study byZhang et al.77

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