Professional Documents
Culture Documents
Sepsis-Induced Cholestasis
Nisha Chand and Arun J. Sanyal
J
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
ric population, was reported as early as 1837.1 Jaundice 1).4,5 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 fever, 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-
ements of cholestasis. Because the principal clinical man-
Epidemiologic Considerations 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 anemia; 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,
nitric oxide; NTCP, sodium-dependent taurocholate cotransporter; OATP, organic
septic state and from various drugs used for the treat-
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 Gastroenterology, Hepatology 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
Box 980341, Richmond, VA 23298-0341. E-mail: ajsanyal@hsc.vcu.edu; fax:
Bilirubin is the end product of the breakdown of the
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
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. ⫹ Diplococci (5) Lungs (11) 2
U/100
mL)
Hamilton et al. (196) 24 13/11 ⬍ 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) Appendicitis (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 Peritonitis (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 Cl⫺.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
antigens (IgM or IgG mediated), antigen/antibody com- Table 4. Antibiotics 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
Penicillin
molytic anemia.22,25 The cold agglutinins, which are often Cephalosporins
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-
ilis, varicella, Epstein-Barr, measles, and mumps.22,25,29 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-
dehydrogenase (G-6-PD) deficiency.1 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
amount of oxygen radicals.30 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 anemias 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
Aspergillus.31 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
bacterial, viral, fungal, and parasitic pathogens implicated.25 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
sepsis (Table 4).31,32 This occurs through a variety of in blood is conjugated.9 Also, when endotoxin was ad-
mechanisms,34 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
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
very mild to no inflammation (see Table 1).20 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
delivery of oxygen-derived free radicals from reperfusion, sulfolithocholate).6,11 It is also postulated that LPS may
leads to hepatocellular damage and thus may result in stimulate degradation of membrane proteins as well.50
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-
attributed to nitric oxide (NO). This was demonstrated in ity.50,52-53 Endotoxin may cause decreased function of
septic animal models when inhibition of NO production Na-gradient dependent transporters at the basolateral
gave rise to reductions in both hepatocyte necrosis and membrane such as the NTCP.14,49 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
ucts released in response to infection appear to play a activity after endotoxin administration.50,54 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,
duced in septic models compared to in controls.6,49-50 The and broad-spectrum enteric antibiotic coverage. Progno-
main evidence for this is the inhibition of biliary excretion 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
administration.6,49 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,
ministration.6 hemodynamic instability, renal insufficiency, hepatotoxic
drugs, multiple blood transfusions, and/or TPN admin-
Clinical Syndromes 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
Biliary Tract 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 gallstone or after biliary interven- appendicitis, diverticulitis, 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 leukocytosis, 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-
Liver Abscess 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 cholecystitis 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
icteric form is the less common. A severe presentation of Histology
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
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
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