REVIEW Sepsis-Induced

Nisha Chand and Arun J. Sanyal

aundice and hepatic dysfunction frequently accom- studies have reported widely varying numbers, from 0.6% pany a variety of bacterial infections. The relationship to 54%. This variability probably reflects both the report- between sepsis and jaundice, particularly in a pediat- ing bias and the populations of subjects studied (Table J 4,5 ric population, was reported as early as 1837.1 Jaundice 1). Sepsis is more likely to manifest with jaundice in may result either directly from bacterial products or as a infants and children than in adults. In this population, consequence of the host’s response to infection. Fre- males have a higher incidence of jaundice. However, in quently, both factors contribute to the development of adults, no gender predilection has been reported. jaundice. In addition, specific infections that target the Jaundice has been associated with infections caused by liver may cause jaundice because of the liver injury asso- several organisms including aerobic and anaerobic gram- ciated with hepatic infection. Although jaundice may be negative and gram-positive bacteria. Gram-negative bac- an isolated abnormality, it is often associated with features teria cause most of these cases. The primary site of of cholestasis. In critically ill patients, the development of infection is most often intraabdominal, but infection of jaundice and/or cholestasis complicates the clinical pic- various other sites such as urinary tract infection, pneu- ture and poses a clinical challenge both in diagnostic eval- monia, endocarditis, and meningitis have been associated uation and in management. In this article, we review the with this complication.4,6,7 Other specific infections current concepts about the pathogenesis of jaundice and known to cause jaundice are infections of the hepatobili- cholestasis with infection, their clinical presentation and ary tree, clostridial infection, typhoid , and legio- diagnostic assessment, and the optimal management of nella. these clinical problems. Although jaundice can occur in isolation in patients with septicemia, it is frequently associated with other el- Epidemiologic Considerations ements of cholestasis. Because the principal clinical man- ifestation of cholestasis is also jaundice, the published Jaundice is a well-known complication of sepsis or ex- literature has primarily focused on the syndrome of jaun- trabacterial infection. Sepsis and bacterial infection are dice, and the exact incidence of cholestasis with jaundice responsible for up to 20% of cases of jaundice in patients versus isolated jaundice remains unclear. of all ages in a community hospital setting.2 The inci- dence of jaundice in newborns and early infants varies Pathophysiology between 20% and 60%.3 There are no data from large- The pathogenesis of jaundice in systemic infections scale prospective studies on the incidence of hyperbiliru- is multifactorial. The development of jaundice may binemia in adults with sepsis. Several small retrospective occur from an aberration in the processing of bilirubin by hepatocytes or from other effects on the liver that

Abbreviations: AHA, autoimmune hemolytic ; BSEP, bile salt export lead to the accumulation of bilirubin in the body. Such pump; BSP, tetrabromosulfophthalein; cMOAT, multispecific organic anion trans- processes include increased bilirubin load from hemo- porter; DIC, disseminated intravascular coagulation; IL, interleukin; KCs, Kupffer lysis, hepatocellular injury, and cholestasis from the cells; LPS, lipopolysaccharide; MRP2, multidrug-resistance-associated protein; NO, septic state and from various drugs used for the treat- nitric oxide; NTCP, sodium-dependent taurocholate cotransporter; OATP, organic anion transport protein; RBC, red blood cells; RES, reticuloendothelial system; ment of sepsis. The molecular and biochemical mech- SLCT, sulfolithocholyltaurine; TNF, tumor necrosis factor. anisms by which jaundice develops in subjects with From the Division of , and Nutrition, Department sepsis is best considered in the context of normal bili- of Internal Medicine, Virginia Commonwealth University Medical Center, Rich- mond, VA. rubin metabolism. Received May 28, 2006; accepted October 16, 2006. Address reprint requests to: Dr. Arun J. Sanyal, Professor of Medicine, Pharma- Normal Bilirubin Metabolism cology and Pathology, Virginia Commonwealth University Medical Center, MCV Bilirubin is the end product of the breakdown of the Box 980341, Richmond, VA 23298-0341. E-mail: [email protected]; fax: 804-828-4945. heme moiety of hemoproteins. In humans, 4 mg of bili- Copyright © 2006 by the American Association for the Study of Liver Diseases. rubin is formed daily from the degradation of hemopro- Published online in Wiley InterScience (www.interscience.wiley.com). teins, 80% of which is derived from hemoglobin.8 DOI 10.1002/hep.21480 Potential conflict of interest: Dr. Sanyal received grants from Sanofi-Aventis and Unconjugated bilirubin is a highly hydrophobic molecule Debiorision. and circulates tightly but reversibly bound to albumin in

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

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. 9 8/1 2-8 weeks 12-22/4-7 E. coli (5) 8 UTI (4) 9 (1962) Paracolon (2) P. Aeruginosa (1) Streptococcus (grp A) Hall et al. (1963) 11 10/1 15-65 years 2-17/.4-14 5-21 (KA Gr. ϩ Diplococci (5) Lungs (11) 2 U/100 mL) Hamilton et al. (196) 24 13/11 Ͻ 1 day-13 3-31/1-16 E. coli (18) 18 Urine (16) 11 weeks A. Aeruginosa (4) Umbilicus (2) Eye (1) Kibukamusoke et al. 21 21/0 17-65 years 3-27 8-19 (KA 8-150/13-150 Lungs (21) 1 (1964) U/100 mL) Eley et al. (1965) 5 2/3 35-54 years 3-23/8-15 11-26 (KA 16-34/24-88 Str. pyogenes (2) 3 Intraabdominal (4) 1 U/100 (U/ml) mL) E. coli (1) UTI (1) Proteus (1) Bacteroids (1) Vermillion et 7 4/3 18-72 years 5-24/4-16 3-26 1-3 (IU/ml) E. coli (3) 7 Lung (3) 6 al.(1969) (mU/ mL) Streptococcus (3) Intraabdominal (2) Pseudomonas (2) Pleural (1) S. aureus (2) Miller et al. (1969) 9 1.2-2.5 E. coli (8) (9) 0 Rooney 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 mean mean 128 mean 47.6 S. aureus (4) 11 Pneumonia (9) 13 6.78) P. aeruginosa (2) UTI (6) Paracolon (6) Klebsiella (6) Soft tissue (4) Ng et al. (1971) 6 6/0 2-8 weeks 4-33/3-21 20-41 (KA E. coli (5) 4 UTI (6) 0 U/100 mL) Paracolon (1) Borges et al. (1972) 13 8/5 2 months-3 3-31/2-14 28-300/50-920 E. coli (5) UTI (10) 0 years (U/mL) 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) 14 Klebsiella (3) Abdominal cavity (5) Staphylococcus (6) UTI (4) Streptococcus (2) IV catheter/graft/ skin (3) plasma. Figure 1 shows normal bilirubin metabolism at gated to monoglucuronides and diglucuronides by the the hepatocyte. Bilirubin dissociates from albumin at the enzyme uridine diphosphate-glucuronosyltrans- sinusoidal, basolateral membranes of hepatocytes and is ferase.13 Conjugation of bilirubin converts it from a taken up inside in a carrier-mediated process that requires highly hydrophobic molecule to a relatively hydro- inorganic anions such as ClϪ.6,9,10 Organic anion trans- philic molecule that can be excreted into bile.6,9 Bili- port proteins (OATPs) are on the basolateral membranes rubin glucuronides are excreted into bile against a steep of hepatocytes.11 Their role in bilirubin transport has still concentration gradient by a canalicular membrane pro- not been directly established, but bilirubin is a presumed tein, the canalicular multispecific organic anion trans- substrate of OATPs.12 porter (cMOAT), also commonly referred to as the Following uptake into a hepatocyte, bilirubin is multidrug-resistance-associated protein (MRP2).6,9,14 bound by a group of cytosolic proteins (mainly gluta- This process is the major driving force of bilirubin thione S-transferases, GST) that prevent its efflux transport and is the rate-limiting step in bilirubin ex- from the cell. Within a hepatocyte, bilirubin is conju- cretion by the liver.15 232 CHAND AND SANYAL HEPATOLOGY, January 2007

Table 3. Mechanisms of Hemolysis in Sepsis 1. Normal RBCs a. Infections directly causing hemolysis (e.g. Clostridium perfringens) b. Immunologically mediated red cell injury 1. Cold agglutinin–associated hemolytic anemia a. Mycoplasma pneumoniae b. Legionella 2. Paroxysmal cold hemoglobinuria c. Drug-induced hemolysis d. Transfusion reactions e. Hypersplenism 2. Underlying red blood cell defects a. Inherited enzyme deficiency b. Sickle cell disease c. Hemoglobinopathies

Fig. 1. Normal bilirubin metabolism. Bilirubin dissociates from al- bumin at the sinusoidal surface of the hepatocyte and is taken up by the patients with pneumonia and noted ferritin containing hepatocyte. Inside the hepatocyte, bilirubin is bound by a group of lysosomes in Kupffer cells.17 This was believed to be com- cytosolic proteins that prevent its efflux from the cell. Bilirubin is then conjugated to monoglucuronides and diglucuronides by the enzyme patible with hemolysis and secondary . Al- uridine diphosphate-glucuronosyltransferase. Bilirubin glucuronides are though hemolysis contributes to jaundice in sepsis, it is excreted into bile against a steep concentration gradient by a canalicular unlikely that it is the principal mechanism because the membrane protein termed canalicular multispecific organic anion trans- 18-20 porter (cMOAT), also commonly referred to as the multidrug-resistance- jaundice results from conjugated hyperbilirubinemia. associated protein (MRP2). This process is the major driving force of Table 3 lists various mechanisms of hemolysis in the set- bilirubin transport and is the rate-limiting step in bilirubin excretion by the ting of sepsis. liver. Hemolysis may occur by multiple mechanisms in the setting of bacterial infection.21-22 These may be catego- Disorders of Bilirubin Metabolism During rized as mechanisms of hemolysis (1) associated with nor- Systemic Infection mal red cells and (2) related to underlying red cell defects. The severe forms of many infections from gram-posi- Various mechanisms can lead to hyperbilirubinemia tive and gram-negative bacteria have been associated with alone during systemic infection (Table 2). These are dis- hemolysis of normal red cells. Of these bacteria, Clostrid- cussed in detail in the following sections. ium perfringens can give rise to severe, often fatal hemoly- sis in persons with normal red cells.23-24 Cl. perfringens Increased Bilirubin Load/Hemolysis produces phospholipase C, a lecithinase that reacts with The development of hemolysis causes an increased bil- red cell membrane lipoproteins to release lysolecithin, irubin load in septic individuals. In early studies, hemo- which, in turn, lyses red cell membranes, producing he- lysis was believed to be the principal mechanism of molysis.25 In addition, this bacterium also produces pro- jaundice in sepsis.16 Using light microscopy, Tugswell et teolytic exotoxins that cause enzymatic dissolution of al. found excess iron-containing pigment in the liver of membrane proteins.26 Other infections that commonly cause hemolysis in normal red cells are malaria and babe- siosis.27 infection periodically may lead to Table 2. Mechanisms of Hyperbilirubinemia in Sepsis hemolysis of normal red blood cells (RBCs).28 Aside from 1. Hemolysis bacterial infection directly causing hemolysis, multiple a. In normal red cells b. In RBCs with red cell enzyme defects (G6PD) drugs (e.g., , antimalarial medications, sulfa c. Pathologic changes to RBCs secondary to infection medications, or acetaminophen), hypersplenism from in- d. Drug-induced hemolysis fection, , or neoplasm can increase the 2. Hepatic dysfunction 21,28 a. Decreased bilirubin uptake sequestration and phagocytosis of erythrocytes. b. Decreased canalicular transport Immunologically mediated red cell injury is another c. Decreased clearance of conjugated bilirubin mechanism by which hemolytic anemia occurs in normal d. Hepatic ischemia i. Hypotension RBCs of patients with sepsis. Overall, infections account ii. Prolonged Hypoxia for about 8% of cases of autoimmune hemolytic anemia e. Hepatocellular injury (mild reactive to overt hepatocellular (AHA) and for approximately 27% of such cases in chil- necrosis) dren.22 Immunologically mediated hemolysis may de- 3. Cholestasis velop by 3 mechanisms: antibody directed to red cell HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 233 antigens (IgM or IgG mediated), antigen/antibody com- Table 4. Associated with Hemolysis plexes, or polyagglutination.22 IgM antibodies give rise to Immune Complex Mediated intravascular hemolysis, and IgG antibodies give rise to Quinine extravascular hemolysis.22 Autoantibody Medicated Several pathogens, for example, Mycoplasma pneumoniae and Legionella may cause “cold agglutinin”–associated he- Sulfonamides 22,25 Penicillin molytic anemia. The cold agglutinins, which are often IgMs, bind to red cells at low temperatures, fix complement, Indinivir and cause intravascular hemolysis. On the other hand, IgG Hemolyis in G6PD antibodies, for example, Donath-Landsteiner antibodies in Nitrofurantoin paroxysmal cold hemoglobinuria, often cause extravascular Phenazopyridine hemolysis. This condition has been associated with upper Primaquine respiratory tract infections and a variety of infections that Sulfonamides normally do not lead to sepsis syndrome, for example, syph- 22,25,29 ilis, varicella, Epstein-Barr, measles, and mumps. He- cretion are also important mechanisms of jaundice molysis and jaundice from paroxysmal cold hemoglobinuria associated with infection. This is supported by the mainly may be severe in cold weather. conjugated hyperbilirubinemia that occurs in sepsis. In individuals with underlying red cell defects, the Many studies have examined the effects of sepsis on the threshold for hemolysis is often lower than in normal function of organic anion transporters in the liver. Tetra- individuals. A common defect associated with an in- bromosulfophthalein (BSP) is taken up by hepatocytes by creased propensity for hemolysis in a variety of circum- the sodium-independent transport system, the basolateral stances including sepsis is glucose-6-phosphate OATP.12 Bilirubin is a presumed substrate for this trans- 1 dehydrogenase (G-6-PD) deficiency. Many types of in- porter system.12 Hepatic uptake of BSP is reported to be fections as well as antibiotics can cause hemolytic anemia markedly lower in lipopolysaccharide (LPS)-treated ani- in patients with this deficiency. G-6-PD is required for mals. BSP, glutathione, and sulfolithocholyltaurine regeneration of nicotinamide adenine dinucleotide dehy- (SLCT) are excreted at the canalicular membrane through drogenase (NADPH), which is essential for reducing the MRP2.12 There is also a decrease in canalicular transport 30 amount of oxygen radicals. In the absence of G-6-PD, of glutathione and SLCT, suggesting decreased MRP2 red cell NADPH stores are diminished, thereby lowering activity. Roelofsen et al. studied the transport of bilirubin the threshold for oxidant-stress-mediated cell injury. Sep- in a rat model of sepsis.9 In this study, LPS was injected sis is often associated with oxidant stress, and this may into rats intravenously to induce endotoxemia. The trans- induce hemolysis, particularly in those with a lowered port of bilirubin and another organic acid, taurocholate, threshold for oxidant-mediated injury. were studied 18 hours after the infusion. Sinusoidal up- Microangiopathic hemolytic may be triggered by take, hepatic content, and canalicular excretion of biliru- a variety of infections such as Shigella, Campylobacter, and bin were all decreased in endotoxemic rats compared to in 31 Aspergillus. Disseminated intravascular coagulation (DIC) control animals.9 Also, a 50% decrease in steady-state may also cause hemolysis with infections; up to 60% of all elimination of bilirubin was observed in livers exposed to cases of DIC have been attributed to infections, with many endotoxin.6,9 25 bacterial, viral, fungal, and parasitic pathogens implicated. It is unlikely that bilirubin conjugation is substantially Drugs are a major cause of hemolysis in patients with affected by sepsis because more than 60% of the bilirubin 31,32 sepsis (Table 4). This occurs through a variety of in blood is conjugated.9 Also, when endotoxin was ad- 34 mechanisms, an apparently major one of which is in- ministered to rats, the clearance of conjugated bilirubin creased oxidant stress. Finally, hemolysis of nonviable decreased to the same degree that unconjugated bilirubin erythrocytes may occur during massive blood transfu- did, suggesting that the conjugation of bilirubin was not sions, resorption of large hematomas, or trauma. These contributing to the impairment in bilirubin clearance.9 additional factors are commonly encountered in patients This is further supported by the finding that the degree of with sepsis in the ICU. bilirubin conjugation in livers exposed to endotoxin was not substantially different from normal controls.9 Hepatocyte Dysfunction as a Cause of Hyperbilirubinemia Decreased Bile Flow In addition to increased bilirubin load, decreased bili- Cholestasis is the predominant mechanism by which rubin uptake, intrahepatic processing, and canalicular ex- jaundice develops in sepsis. Extrahepatic cholestasis is 234 CHAND AND SANYAL HEPATOLOGY, January 2007

an integral component of the basolateral membrane, and Na-K-ATPase pumps are found throughout the hepatic lobule. Sodium-dependent taurocholate cotransporter (NTCP) is the principal transporter in the uptake of con- jugated bile salts from plasma into hepatocytes.35 This highly efficient pathway results in a high first-pass clear- ance of bile salts. The unconjugated bile salt cholate, or- ganic ion sulfobromophthalein (BSP), and other lipophilic compounds are primarily transported from plasma into hepatocytes by sodium-independent trans- port systems such as organic anion transport proteins OATP 1, OATP 2, and OATP 3.35 Fig. 2. Normal bile acid flow and bile formation. Bile acids are transported from the basolateral membrane to the canalicular membrane Bile acids are transported from the basolateral mem- by cytosolic transporter proteins. Transcytosolic transport occurs by 2 brane to the canalicular membrane by cytosolic trans- main methods: (1) binding to cytosolic proteins and diffusion to apical porter proteins. Transcytosolic transport occurs through domains (mainly conjugated primary and secondary bile acids) and (2) vesicular trancytosis. The passage of bile salts into the biliary canaliculus 2 main methods: (1) binding to cytosolic proteins and is the rate-limiting step in bile formation, which is ATP dependent. diffusing to apical domains (mainly conjugated primary Conjugated bile salts are excreted into bile through the BSEP. The and secondary bile acids) and (2) vesicular trancytosis. multiple drug resistance 1 (MDR1) transporter is responsible for trans- Vesicular transport is responsible for a very small amount porting hydrophobic organic cations across the canalicular membrane. The tight junctions between hepatocytes provide a barrier to bile salts, of total bile flow, and the role of this type of transport is prohibiting the regurgitation of formed bile into the space of Disse. unclear. The passage of bile salts into biliary canaliculi is the rate-limiting step in bile formation. This passage is mostly caused by obstruction of the hepatic or common ATP dependent and occurs against a steep concentration and directly impedes the flow of bile. This can result from gradient. There are many ATP-dependent transporters on a primary infection such as cholangitis or can become the canalicular membrane. Among these are the multi- secondarily infected. Partial biliary obstruction and ob- drug resistance family and the bile salt export pump struction as a result of cholelithiasis are more commonly (BSEP). Conjugated bile salts are excreted into bile complicated by infection of the biliary tree, which could through the BSEP. The multiple drug resistance 1 trans- further lead to decreased bile flow. porter is responsible for transporting hydrophobic or- ganic cations.36 Water and inorganic ions enter bile by Sepsis-Associated Cholestasis diffusion across tight junctions, which provide a barrier Normal Bile Acid Flow for bile salts, prohibiting the regurgitation of formed bile Before elaborating on the potential mechanisms of into the space of Disse. cholestasis in sepsis, it is important to understand the steps in the formation of bile (Fig. 2). Bile is formed by the Mechanisms and Mediators of Cholestasis Associated inflow of water along osmotic gradients produced by se- with Infections cretion of bile salts into hepatic canaliculi. Bile salts are The liver has a central role in the regulation of host the principal solute secreted into this space, and bile flow defenses. It serves as a source of inflammatory mediators is mainly driven by the osmotic forces generated by the and is a major site of the removal of bacteria and endo- secretion of bile salts into hepatic canaliculi. This is also toxins from systemic circulation.37-38 Kupffer cells (KCs) known as bile-salt-dependent bile flow, whereas the gen- of the liver make up 80%-90% of the fixed-tissue macro- eration of bile from osmotic forces related to other solutes phages of the reticuloendothelial system (RES) and rep- is known as bile-salt-independent flow. resent terminally differentiated macrophages. KCs take Bile salts are derived from de novo synthesis in the liver up bacteria, particles, and endotoxins (LPS) and are stim- and from reabsorption of bile salts from the intestine. Bile ulated to release a wide range of products implicated in acids are transported to the liver following intestinal ab- liver injury, such as tumor necrosis factor, interleukin 1 sorption. They are taken up by hepatocytes via transport and interleukin 6, superoxides, lysosomal enzymes, pro- proteins on the basolateral (sinusoidal) membranes. The coagulants, and platelet-activating factor.9,39-41 principal mediator of this basolateral transport of bile ac- Hepatic injury without biliary obstruction may accom- ids is the Na-K-ATPase pump, which is ATP dependent pany systemic infection in adults with pneumococcal and maintains an inwardly directed sodium gradient. It is pneumonia, streptococcal bacteremia, salmonella infec- HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 235

Table 5. Mechanisms of Cholestasis of Sepsis injury in most cases of septicemia.41 Several studies Decreased basolateral transport of bile acids have shown a quantitative reduction in bile flow within Inhibition of basolateral membrane Na-K-ATPase activity the isolated perfused livers of rats following LPS or Decreased basolateral membrane fluidity Down-regulation of transporters cytokine administration. Decreased NTCP function TNF-␣ is a cytokine released by macrophages, endo- Decreased canalicular transport of bile acids thelial cells, and Kupffer cells and is the primary mediator Down-regulation of transporters ␣ Decreased BSEP function of the systemic effects of endotoxins. TNF- has been Decreased MRP2 function implicated in endotoxin-induced cholestasis by the find- ing that immunization with anti-TNF-␣ antibodies blocked endotoxin-associated reduction in bile flow and tions (especially typhoid fever), and Escherichia coli bac- bile salt excretion.49 LPS, TNF-␣, and interleukins 1␤ teremia.42 This can range from mild reactive hepatitis to and 6 all have been shown to mediate these effects, giving overt hepatocellular necrosis that, it has been shown, usu- rise to cholestasis in the liver.6,50 Procoagulants released ally resolves when the bacteremia is appropriately treated. by activated Kupffer cells induce microvascular thrombo- Hepatocellular injury is not considered a frequent occur- sis and have been postulated to cause circulatory distur- rence during extrahepatic bacterial infection. Most stud- bance, which, in turn, could contribute to endotoxin- ies that reviewed liver histology in hyperbilirubinemia or induced hepatic injury.41 hepatic abnormalities in bacterial infection have noted 20 very mild to no inflammation (see Table 1). The mech- Abnormalities in Bile Acid Formation and Flow anism of hepatic injury depends on the underlying infec- Endotoxemia does not affect bile acid synthesis, cyto- tion, yet most likely there is an unspecified toxin solic bile acid transport, or the permeability of tight junc- elaborated by the offending bacteria that ultimately leads tions.51 LPS and cytokines appear to mainly affect to hepatocellular injury.20,42 hepatocyte uptake and excretion of bile acids. Table 5 lists Ischemic liver damage may occur as a consequence of various steps in bile acid transport that possibly are af- hypotension or prolonged hypoxia in sepsis. Hepatic fected in sepsis, thus giving rise to cholestasis. Endotox- blood flow is depressed in sepsis and nutrient blood flow emia decreases the basolateral and canalicular transport of to the liver is reduced, which can lead to Kupffer cell bile acids (cholate, taurocholate, and chenodeoxycholate) dysfunction and hepatocellular alteration.43 The lack of oxygen, mainly to the centrizonal cells and later from and organic anions (BSP and the taurine conjugate of 6,11 delivery of oxygen-derived free radicals from reperfusion, sulfolithocholate). It is also postulated that LPS may 50 leads to hepatocellular damage and thus may result in stimulate degradation of membrane proteins as well. centrilobular necrosis of the liver.4,44,45 Mediation of hep- Several studies have observed endotoxin-induced inhi- atocellular injury via necrosis and/or apoptosis has been bition of basolateral membrane Na-K-ATPase activ- 50,52-53 attributed to nitric oxide (NO). This was demonstrated in ity. Endotoxin may cause decreased function of septic animal models when inhibition of NO production Na-gradient dependent transporters at the basolateral 14,49 gave rise to reductions in both hepatocyte necrosis and membrane such as the NTCP. It has also been ob- apoptosis.46 served that endotoxin affects membrane fluidity; this may The underlying state of endotoxemia and the prod- be the mechanism involved in reducing Na-K-ATPase 50,54 ␣ ucts released in response to infection appear to play a activity after endotoxin administration. TNF- and ␤ key role in the pathophysiology of the cholestasis of IL-1 modulate gene expression of transporters NTCP sepsis. Various effects of this state on the liver that lead and BSEP at both the transcriptional and the posttran- to cholestasis are listed in Table 5. Decreased hepato- scriptional levels.12 In a study by Green et al., 16 hours cellular function has been demonstrated to occur early after intraperitoneal administration of LPS, both protein after the onset of sepsis despite increased cardiac out- expression and functional activity of NTCPs were re- put and hepatic perfusion.47 This suggests that the hep- duced by more than 90%.50 atocellular dysfunction in sepsis may be associated with Impaired hepatocyte transport function has also been the release of proinflammatory cytokines such as tumor detected at the canalicular level. Cholyltaurine (CT) and necrosis factor alpha (TNF-␣) or interleukin 6 (IL- chenodeoxycholyltaurine (CDCT) are substrates for can- 6).47-48 Various investigations have confirmed the cen- alicular bile acid transporters.12 ATP-dependent CT and tral role of endotoxemia in the genesis of cholestasis CDCT transport was markedly decreased in a rat sepsis associated with sepsis.41 Direct invasion of the liver by model.51 This appears to result from down-regulation of bacteria is not a major cause of cholestasis or hepatic transporters at the canalicular membrane.6,40,51 236 CHAND AND SANYAL HEPATOLOGY, January 2007

Table 6. Liver Test Abnormalities in Sepsis dominal primary site to the liver.58 Almost a third of liver ● Conjugated hyperbilirubinemia: total bilirubin ranging from 2 to 10 mg/dL abscesses are cryptogenic.59 Patients present with fever, ● Elevated alkaline phosphatase: rarely more than 2-3 times upper limit of chills, and weight loss. Abdominal complaints most often normal ● Mild elevation of aminotransferases are vague or absent. Up to two thirds of patients have hepatomegaly. Alkaline phosphatase levels are invariably elevated, with less frequent elevation of bilirubin and ami- notransferases. Optimal treatment includes prompt diag- Bile-acid-dependent and -independent flows are re- nosis, percutaneous or surgical drainage of the abscess, 6,49-50 duced in septic models compared to in controls. The and broad-spectrum enteric coverage. Progno- main evidence for this is the inhibition of biliary excretion Ϫ sis depends on prompt recognition and treatment, with a of GSH and, to a lesser extent, of HCO3 after LPS cure rate ranging from 80% to 100%.56 6,49 administration. Maximum reduction in bile acid flow ICU Setting. A patient presenting with jaundice in occurs 12-18 hours after endotoxin and/or cytokine ad- the ICU is a frequently encountered problem. Infections, 6 ministration. hemodynamic instability, renal insufficiency, hepatotoxic Clinical Syndromes drugs, multiple blood transfusions, and/or TPN admin- istration are some of the potential causes of jaundice, The jaundice of sepsis is usually cholestatic and can which usually presents 1-2 weeks after onset of the initi- occur within a few days of the onset of bacteremia and ating event. Jaundice under these circumstances is usually may even appear before other clinical features of the un- of a cholestatic type, with mainly conjugated hyperbiliru- derlying infection become apparent.55 In the absence of binemia and only slightly elevated AST and ALT.43 When intraabdominal infection, abdominal pain is rare. Simi- there is no obvious biliary obstruction; underlying sys- larly, pruritus is not a major manifestation of cholestasis temic infection is highly likely. Sepsis is the most com- associated with infection. Hepatomegaly occurs about mon etiology of jaundice and cholestasis in the ICU. This half the time.55 Conjugated hyperbilirubinemia in the is especially true in patients who are in an ICU due to range of 2-10 mg/dL is often seen, although rarely higher trauma. In a retrospective study by Boekhorst et al., the levels can be seen.19 This is particularly true in those with development of jaundice in the ICU was shown to have a postoperative jaundice who also are septic and on TPN. poor prognosis.43 This could be a result of a delay in Serum alkaline phosphatase is usually elevated but rarely diagnosis of the instigating factor. If the underlying pro- more than 2-3 times above the upper limit of normal.55 cess is detected and adequately treated in a timely fashion, Serum aminotransferase is generally only modestly ele- the prognosis is usually good. vated (Table 6).55 Gram-Negative Bacterial Infections. Cholestasis is a known complication of gram-negative bacterial infection, Specific Clinical Scenarios of Infection and Jaundice especially in infants. This syndrome is more frequent in Disease. Obstruction or infection of the neonatal period and may account for as much as a the hepatobiliary tree should be considered a potential third of the cases of neonatal jaundice.22 Most cases of cause of jaundice, especially when a patient presents with sepsis associated with cholestatic jaundice have evidence right upper quadrant pain, jaundice, and fever. Cholan- of gram-negative bacteremia, with Escherichia coli the gitis most commonly occurs secondary to obstruction of more common pathogen.20,60 Pyelonephritis, peritonitis, the biliary tract with a or after biliary interven- appendicitis, , pneumonia, and meningitis tion. Less commonly, cholangitis may occur after obstruc- are types of infections observed to cause jaundice. The tion from a tumor of the ampulla, bile duct, or pancreas. urinary tract is the most common site of infection associ- Laboratory results will show , conjugated hy- ated with this syndrome, especially in the neonatal per- perbilirubinemia, and elevation of alkaline phosphatase iod.60 Liver histology shows intrahepatic cholestasis with disproportionate to transaminasemia. Acute cholangitis Kupffer cell hyperplasia and little or no evidence of cellu- has a more severe course than jaundice associated with lar necrosis. Aside from cholestasis, liver histology reveals extrahepatic infections. an almost normal hepatic parenchyma.20 The manifesta- and Pylephlebitis. Biliary tract disease tions of the underlying infection usually dominate the is the most common condition associated with liver ab- presentation.55 Jaundice and cholestasis are usually revers- scess.56 This includes infection (cholangitis) that may oc- ible and subside completely after resolution of the infec- cur secondary to choledocholithiasis, biliary stricture, or tion. malignancy.57 Another potential cause of pyogenic ab- Pneumonia. The male-to-female ratio of patients scess is spread through the portal vein from an intraab- who develop jaundice with pneumococcal pneumonia is HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 237

10 to 1.18 Most investigators think that pneumonia-asso- Typhoid Fever. Typhoid fever, also known as enteric ciated jaundice is a result of hepatocellular damage.20 fever, is an acute systemic illness caused by Salmonella Many patients with pneumonia, with or without jaun- typhi. Typhoid fever is an infection that not only causes dice, have abnormalities suggestive of hepatocellular dam- jaundice but also induces liver injury.20,67 Hepatomegaly age.20 Hepatic necrosis has more commonly been occurs in about 30% of patients, and jaundice occurs in identified in liver biopsies of patients with pneumo- about a third of patients with hepatomegaly. Alkaline nia.17,60 Liver histology consistently shows patchy necro- phosphatase is usually 2-3 times the normal level, and sis and dilated biliary canaliculi with bilirubinostasis.20 serum aminotransferases rarely are more than 5 times the The prognosis is good after complete resolution of the upper limits of normal. Rarely, ALT values may be mark- infection. edly elevated.20 The diagnosis is made by (1) isolating Clostridium perfringens. Clostridium perfringens is a salmonellae from the blood or stool and (2) observing a commonly isolated clostridial species that can cause a rise in the titer of the Widal reaction during the course of wide spectrum of clinical manifestations, from transient the illness. The etiology of the hepatic damage in typhoid bacteremia to massive red blood cell hemolysis, shock, fever is believed to be secondary to the effect of endotox- and death. Clostridial hemolysis has been described as a in.68 Previous studies have demonstrated that injection of rare complication of septic abortion, gall bladder disease, Salmonella typhi endotoxin produces focal hepatic necro- and surgical procedures.61 Severe bacteremia may result in sis. Other studies have suggested that liver injury may massive hemolysis, hemoglobinuria, shock, and death. occur by local release of cytotoxins or local inflammatory Clostridium perfringens produces a large variety of toxins reactions within reticuloendothelial cells.68 Cholangitis and virulence factors. The alpha toxin, a lecithinase, is and biliary stasis are apparently not important in the capable of hydrolyzing sphingomyelin and lecithin to pathogenesis of hepatic lesions.67 The histology of the phosphoryl choline and diglyceride.62 Lysolecithins re- livers of patients with typhoid fever shows focal cell ne- leased from cell membranes also act as hemolysins. Lyso- crosis with mononuclear cell infiltration and marked lecithins also produce RBC membrane failure, which Kupffer cell hyperplasia with mild cholestasis.20 Typhoid accounts for the profound or fatal hemolytic anemia in nodules, aggregations of Kupffer cells, are characteristic of clostridial sepsis.61 Striking hemoglobinemia and hemo- typhoid fever and are randomly distributed throughout globinuria are seen in this condition, and the high plasma the hepatic lobule.68 Follow-up liver biopsies have shown hemoglobin level may produce marked dissociation be- complete resolution within 2 weeks after control of infec- tween blood hemoglobin and hematocrit levels. Acute tion.20 renal failure and hepatic failure usually develop. The prognosis in this clinical setting is very poor, with more Natural History than half the patients dying even with proper and exten- The presence of jaundice and sepsis or the degree of its sive treatment.63-64 Therapy consists of high-dose penicil- severity does not seem to influence survival or predict the lin and surgical debridement.63 overall prognosis of the patient.20,69 The overall prognosis Leptospirosis. Leptospirosis is a zooanthroponosis depends on the underlying infection. There usually is transmitted among animals and occasionally from ani- complete resolution of hepatic dysfunction and cholesta- mals to humans. In the incubation period, the leptospira sis if the underlying condition is adequately treated, yet organisms disseminate to different organs, especially the the outcome may be guarded if detection and treatment liver, kidneys, muscles, and lungs. Experimental data sug- are delayed.4,6,14,69 Certain causes of jaundice in a criti- gest that after the leptospira gain access to the blood- cally ill patient such as acalculous and as- stream, they concentrate in the liver, where they cending cholangitis have a very poor prognosis. reproduce.65-66 There are two classical forms of presenta- tion of leptospirosis, the icteric and anicteric forms. The Histology icteric form is the less common. A severe presentation of the disease, occurring in only 5% to 10% of all leptospiral The most prominent finding in sepsis is intrahepatic infections, is known as Weil’s disease. This is associated cholestasis. Histologically, bile is found in the bile cana- with high fever, severe hepatic function impairment, in- liculi and in hepatocyte cytoplasm (Fig. 3A-C). Bile back- tense jaundice, renal insufficiency, hemorrhagic diathesis, flow into the perisinusoidal spaces may lead to bile uptake and cardiovascular compromise. Although serum biliru- by Kupffer cells. There may also be some cholestasis-re- bin may be extremely high, serum aminotransferase and lated parenchymal changes including feathery degenera- alkaline phosphatase are only slightly to moderately ele- tion of the hepatocyte cytoplasm. Apoptosis when present vated. The mortality rate for this presentation is high. appears as rounded bile-tinged apoptotic bodies in the 238 CHAND AND SANYAL HEPATOLOGY, January 2007

binemia and abnormal hepatic parameters may draw at- tention from assessing a more serious underlying disease process and lead to an unnecessary search for hepatic or biliary disease. However, if a septic source is not known, the possibility of hepatic or biliary infection as the cause of jaundice should also be considered. There are many spe- cific entities that require special attention. Given the common causes of jaundice and the different circumstances in which it is encountered, a thorough, systematic approach should be carried out to evaluate the cause (Table 7). Table 8 lists various etiologies in the differential 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 guide further workups. Unconjugated hyperbilirubinemia should initiate a search for hemolysis and potential causes of hemolysis. On the other hand, with a predominantly cholestatic jaundice, it is imperative to exclude a poten- tially treatable hepatobiliary cause of sepsis and jaundice. Imaging studies to evaluate the hepatobiliary tract are extremely valuable for this purpose. Sonography is rela- tively inexpensive and can be performed at the bedsides of critically 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.

Fig. 3. Liver biopsies of subjects with cholestasis showing (A) bile Table 7. Evaluation of Patient at Risk for plugs (black arrows), (B) pericholangitis, and (C) intrahepatic inspissated Sepsis with Jaundice bile in a subject with TPN-induced cholestasis. 1. Assess the type of jaundice ˆ Conjugated versus Unconjugated ■ Unconjugated—initiate a search for hemolysis ■ Conjugated hepatic lobule. An increased amount of smooth endoplas- ● Search for a hepatobiliary cause mic reticulum as a result of cholestasis may lead to hepa- E Imaging studies ■ US (with or without Doppler) tocytes having a ground-glass appearance. ■ CT Evaluation of Jaundice in an Infected Patient. The ˆ Isolated jaundice versus jaundice associated with liver enzyme elevation guiding principles in the evaluation of a given patient are 2. Full workup to evaluate for infection consideration of (1) the differential diagnosis, (2) specific ˆ Complete blood count with differential ˆ Urine analysis diagnoses likely to have negatively affect the patient if ˆ Pan culture missed, and (3) therapeutic options available when a di- ■ Blood agnosis can be made. Table 7 outlines the recommended ■ Urine ■ Sputum steps for evaluating a patient at risk for sepsis of jaundice. ■ Catheter tips The outcome of sepsis-associated jaundice is linked to ■ Drains effective treatment of the sepsis. When jaundice develops ■ Other potential sources of infection ˆ Imaging in a patient with an established diagnosis of infection, the ■ CXR possibility of sepsis-related jaundice is obvious. On the ■ Further imaging of potential sites of infection (rule out abscess, other hand, a high index of suspicion is often necessary to hepatobiliary disease, etc.) diagnose this condition when jaundice is the presenting ˆ Empiric antibiotic coverage: in selected cases, hepatic parameters may improve within a couple of weeks if they were secondary to infection alone manifestation of infection. The presence of hyperbiliru- HEPATOLOGY, Vol. 45, No. 1, 2007 CHAND AND SANYAL 239

Table 8. Differential Diagnosis Management Biliary tract disease ˆ Cholecystitis (cholelithiasis/biliary sludge/acalculous) The most important part of management is early diag- ˆ Cholangitis nosis and treatment of infection (Table 9). Other addi- ˆ Biliary tract obstruction (gallstone, stent obstruction, tumor of the ampulla/ tional steps in management follow. bile duct/pancreas, postbiliary intervention) Correction of Fluid and Electrolyte Imbalances. ˆ Hepatitis Initial management should always include aggressive in- ˆ Liver abscess travascular volume repletion and vasopressive agents if ˆ Hepatic ischemia—secondary to hemodynamic instability Systemic Infection needed to maintain adequate mean arterial blood pressure ˆ Pneumonia for organ perfusion. ˆ UTI Treatment of Infection. The only effective treatment ˆ Bacteremia/septicemia of cholestasis of sepsis is the appropriate management of ˆ Other sites of primary infection Hemolysis the underlying infection. Appropriate antibiotic therapy ˆ Specific infections should be initiated as soon as possible. Septic foci should ˆ Drugs be removed or drained. A delay in the diagnosis of infec- ˆ Multiple blood transfusions Hepatotoxic drugs/toxins tion and the initiation of antibiotic therapy significantly ˆ Antibiotics worsens the prognosis. ˆ TPN Enteral Feeding, Enteral feeding may help to resolve ˆ Tylenol cholestasis. Healthy individuals show a decreased serum bilirubin with continuous enteral feeding. In infants, cho- lestasis resolves when enteral feeding is introduced.70 In patients at risk for sepsis who develop jaundice Ursodeoxycholic Acid. Ursodeoxycholic acid can po- tentially improve bile flow and bilirubin levels in TPN- without other features of infection, blood cultures, AC- and drug-induced cholestasis. Currently, the clinical urine cultures, and a chest X-ray should be obtained as evidence is insufficient to support the use of ursodeoxy- a minimum workup to exclude sepsis. Also, cultures cholic acid to treat cholestasis from these causes.71,72 should be sent from intravascular catheter tips, drains, Glycine Administration. Glycine serum concentra- or any other source of potential infection. If an obvious tions are decreased in sepsis. At a cellular level, glycine cause is still not apparent, further aggressive evaluation decreases the influx of calcium into Kupffer cells, thereby for underlying infection or iatrogenic causes should be reducing the release of TNF. This reduction in TNF may sought. There are no controlled data that either vali- play a beneficial role in treatment of sepsis-associated cho- date or refute giving empiric antibiotic coverage to all lestasis and hepatocellular dysfunction. Yang et al. dem- patients with jaundice who have not yet shown other onstrated a beneficial effect of glycine on hepatocyte features of infection. Frequently, empiric antibiotic function and integrity in sepsis.73 After administration of coverage with a broad-spectrum antibiotic is given to this nonessential amino acid early after onset of polymi- those who are likely to be unable to tolerate sepsis. crobial sepsis in an animal model, hepatocellular function Hepatic parameters, which usually improve within 1-2 markedly improved and the mortality rate decreased from weeks of therapy for the underlying infection, should 50% to 0% 10 days after the onset of sepsis.73 be followed closely. Nitric Oxide Donor Administration. Nitric oxide Hepatocellular jaundice is diagnosed when hyperbil- (NO) is a paracrine-acting gas enzymatically synthesized irubinemia is accompanied by high AST and ALT levels from l-arginine. Cholestasis and endotoxemia have been and only modest or no elevation of alkaline phosphatase. This is usually a result of ischemia, toxins, viral infection, Table 9. Management or iatrogenic injury. Hepatitis viral serology tests should Treatment of Infection be done. A Tylenol level may be obtained if this drug has ˆ Antibiotics been used to treat fever associated with infection. Typi- ˆ Drainage of abscess ˆ Removal of potentially infected drains, IV lines, catheters cally, ALT levels are markedly elevated in such patients. ˆ Correction of fluid and electrolyte imbalances The passage of biliary sludge may sometimes be associated Early Introduction of enteral feeding Potential future treatments with a rapid rise in AST that declines just as rapidly after ˆ Glycine administration passage of the sludge. A hepatobiliary sonogram can be ˆ Ursodeoxycholic acid used to confirm the presence of sludge. A liver biopsy does ˆ Nitric oxide donor administration not usually aid in management of this situation. ˆ N-acetyl-L-cyteine (NAC) 240 CHAND AND SANYAL HEPATOLOGY, January 2007 shown to cause hepatocyte apoptosis through caspase- 20. Zimmerman H. Jaundice due to bacterial infection. 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