Sepsis-induced cholestasis

Jaundice and hepatic dysfunction frequently accompany a variety of bacterial infections. The relationship between sepsis and jaundice, particularly in a pediat- ric population, was reported as early as 1837.1 Jaundice may result either directly from bacterial products or as a consequence of the host's response to infection. Frequently, both factors contribute to the development of jaundice. In addition, specific infections that target the liver may cause jaundice because of the liver injury associated with hepatic infection. Although jaundice may be an isolated abnormality, it is often associated with features of cholestasis. In critically ill patients, the development of jaundice and/or cholestasis complicates the clinical picture and poses a clinical challenge both in diagnostic evaluation and in management. In this article, we review the current concepts about the pathogenesis of jaundice and cholestasis with infection, their clinical presentation and diagnostic assessment, and the optimal management of these clinical problems. AHA, autoimmune hemolytic anemia; BSEP, bile salt export pump; BSP, tetrabromosulfophthalein; cMOAT, multispecific organic anion transporter; DIC, disseminated intravascular coagulation; IL, interleukin; KCs, Kupffer cells; LPS, lipopolysaccharide; MRP2, multidrug-resistance-associated protein; NO, nitric oxide; NTCP, sodium-dependent taurocholate cotransporter; OATP, organic anion transport protein; RBC, red blood cells; RES, reticuloendothelial system; SLCT, sulfolithocholyltaurine; TNF, tumor necrosis factor. Jaundice is a well-known complication of sepsis or extrabacterial infection. Sepsis and bacterial infection are responsible for up to 20% of cases of jaundice in patients of all ages in a community hospital setting.2 The incidence of jaundice in newborns and early infants varies between 20% and 60%.3 There are no data from large-scale prospective studies on the incidence of hyperbilirubinemia in adults with sepsis. Several small retrospective studies have reported widely varying numbers, from 0.6% to 54%. This variability probably reflects both the reporting bias and the populations of subjects studied (Table 1).4, 5 Sepsis is more likely to manifest with jaundice in infants and children than in adults. In this population, males have a higher incidence of jaundice. However, in adults, no gender predilection has been reported. Jaundice has been associated with infections caused by several organisms including aerobic and anaerobic gram-negative and gram-positive bacteria. Gram-negative bacteria cause most of these cases. The primary site of infection is most often intraabdominal, but infection of various other sites such as urinary tract infection, pneumonia, endocarditis, and meningitis have been associated with this complication.4, 6, 7 Other specific infections known to cause jaundice are infections of the hepatobiliary tree, clostridial infection, typhoid fever, and legionella. Although jaundice can occur in isolation in patients with septicemia, it is frequently associated with other elements of cholestasis. Because the principal clinical manifestation of cholestasis is also jaundice, the published literature has primarily focused on the syndrome of jaundice, and the exact incidence of cholestasis with jaundice versus isolated jaundice remains unclear. The pathogenesis of jaundice in systemic infections is multifactorial. The development of jaundice may occur from an aberration in the processing of bilirubin by hepatocytes or from other effects on the liver that lead to the accumulation of bilirubin in the body. Such processes include increased bilirubin load from hemolysis, hepatocellular injury, and cholestasis from the septic state and from various drugs used for the treatment of sepsis. The molecular and biochemical mechanisms by which jaundice develops in subjects with sepsis is best considered in the context of normal bilirubin metabolism. Bilirubin is the end product of the breakdown of the heme moiety of hemoproteins. In humans, 4 mg of bilirubin is formed daily from the degradation of hemoproteins, 80% of which is derived from hemoglobin.8 Unconjugated bilirubin is a highly hydrophobic molecule and circulates tightly but reversibly bound to albumin in plasma. Figure 1 shows normal bilirubin metabolism at the hepatocyte. Bilirubin dissociates from albumin at the sinusoidal, basolateral membranes of hepatocytes and is taken up inside in a carrier-mediated process that requires inorganic anions such as Cl−.6, 9, 10 Organic anion transport proteins (OATPs) are on the basolateral membranes of hepatocytes.11 Their role in bilirubin transport has still not been directly established, but bilirubin is a presumed substrate of OATPs.12 Normal bilirubin metabolism. Bilirubin dissociates from albumin at the sinusoidal surface of the hepatocyte and is taken up by the hepatocyte. Inside the hepatocyte, bilirubin is bound by a group of cytosolic proteins that prevent its efflux from the cell. Bilirubin is then conjugated to monoglucuronides and diglucuronides by the enzyme uridine diphosphate-glucuronosyltransferase. Bilirubin glucuronides are excreted into bile against a steep concentration gradient by a canalicular membrane protein termed canalicular multispecific organic anion transporter (cMOAT), also commonly referred to as the multidrug-resistance-associated protein (MRP2). This process is the major driving force of bilirubin transport and is the rate-limiting step in bilirubin excretion by the liver. Following uptake into a hepatocyte, bilirubin is bound by a group of cytosolic proteins (mainly glutathione S-transferases, GST) that prevent its efflux from the cell. Within a hepatocyte, bilirubin is conjugated to monoglucuronides and diglucuronides by the enzyme uridine diphosphate-glucuronosyltransferase.13 Conjugation of bilirubin converts it from a highly hydrophobic molecule to a relatively hydrophilic molecule that can be excreted into bile.6, 9 Bilirubin glucuronides are excreted into bile against a steep concentration gradient by a canalicular membrane protein, the canalicular multispecific organic anion transporter (cMOAT), also commonly referred to as the multidrug-resistance-associated protein (MRP2).6, 9, 14 This process is the major driving force of bilirubin transport and is the rate-limiting step in bilirubin excretion by the liver.15 Various mechanisms can lead to hyperbilirubinemia alone during systemic infection (Table 2). These are discussed in detail in the following sections. The development of hemolysis causes an increased bilirubin load in septic individuals. In early studies, hemolysis was believed to be the principal mechanism of jaundice in sepsis.16 Using light microscopy, Tugswell et al. found excess iron-containing pigment in the liver of patients with pneumonia and noted ferritin containing lysosomes in Kupffer cells.17 This was believed to be compatible with hemolysis and secondary iron overload. Although hemolysis contributes to jaundice in sepsis, it is unlikely that it is the principal mechanism because the jaundice results from conjugated hyperbilirubinemia.18-20 Table 3 lists various mechanisms of hemolysis in the setting of sepsis. Hemolysis may occur by multiple mechanisms in the setting of bacterial infection.21, 22 These may be categorized as mechanisms of hemolysis (1) associated with normal red cells and (2) related to underlying red cell defects. The severe forms of many infections from gram-positive and gram-negative bacteria have been associated with hemolysis of normal red cells. Of these bacteria, Clostridium perfringens can give rise to severe, often fatal hemolysis in persons with normal red cells.23, 24 Cl. perfringens produces phospholipase C, a lecithinase that reacts with red cell membrane lipoproteins to release lysolecithin, which, in turn, lyses red cell membranes, producing hemolysis.25 In addition, this bacterium also produces proteolytic exotoxins that cause enzymatic dissolution of membrane proteins.26 Other infections that commonly cause hemolysis in normal red cells are malaria and babesiosis.27 Escherichia coli infection periodically may lead to hemolysis of normal red blood cells (RBCs).28 Aside from bacterial infection directly causing hemolysis, multiple drugs (e.g., penicillin, antimalarial medications, sulfa medications, or acetaminophen), hypersplenism from infection, portal hypertension, or neoplasm can increase the sequestration and phagocytosis of erythrocytes.21, 28 Immunologically mediated red cell injury is another mechanism by which hemolytic anemia occurs in normal RBCs of patients with sepsis. Overall, infections account for about 8% of cases of autoimmune hemolytic anemia (AHA) and for approximately 27% of such cases in children.22 Immunologically mediated hemolysis may develop by 3 mechanisms: antibody directed to red cell antigens (IgM or IgG mediated), antigen/antibody complexes, or polyagglutination.22 IgM antibodies give rise to intravascular hemolysis, and IgG antibodies give rise to extravascular hemolysis.22 Several pathogens, for example, Mycoplasma pneumoniae and Legionella may cause “cold agglutinin”–associated hemolytic anemia.22, 25 The cold agglutinins, which are often IgMs, bind to red cells at low temperatures, fix complement, and cause intravascular hemolysis. On the other hand, IgG antibodies, for example, Donath-Landsteiner antibodies in paroxysmal cold hemoglobinuria, often cause extravascular hemolysis. This condition has been associated with upper respiratory tract infections and a variety of infections that normally do not lead to sepsis syndrome, for example, syphilis, varicella, Epstein-Barr, measles, and mumps.22, 25, 29 Hemolysis and jaundice from paroxysmal cold hemoglobinuria may be severe in cold weather. In individuals with underlying red cell defects, the threshold for hemolysis is often lower than in normal individuals. A common defect associated with an increased propensity for hemolysis in a variety of circumstances including sepsis is glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1 Many types of infections as well as antibiotics can cause hemolytic anemia in patients with this deficiency. G-6-PD is required for regeneration of nicotinamide adenine dinucleotide dehydrogenase (NADPH), which is essential for reducing the amount of oxygen radicals.30 In the absence of G-6-PD, red cell NADPH stores are diminished, thereby lowering the threshold for oxidant-stress-mediated cell injury. Sepsis is often associated with oxidant stress, and this may induce hemolysis, particularly in those with a lowered threshold for oxidant-mediated injury. Microangiopathic hemolytic anemias may be triggered by a variety of infections such as Shigella, Campylobacter, and Aspergillus.31 Disseminated intravascular coagulation (DIC) may also cause hemolysis with infections; up to 60% of all cases of DIC have been attributed to infections, with many bacterial, viral, fungal, and parasitic pathogens implicated.25 Drugs are a major cause of hemolysis in patients with sepsis (Table 4).31, 32 This occurs through a variety of mechanisms,34 an apparently major one of which is increased oxidant stress. Finally, hemolysis of nonviable erythrocytes may occur during massive blood transfusions, resorption of large hematomas, or trauma. These additional factors are commonly encountered in patients with sepsis in the In to increased bilirubin bilirubin and canalicular excretion are also mechanisms of jaundice associated with infection. This is by the conjugated hyperbilirubinemia that occurs in sepsis. Many studies have the effects of sepsis on the of organic anion in the liver. is taken up by hepatocytes by the transport the basolateral Bilirubin is a presumed substrate for this transporter uptake of is reported to be lower in BSP, and are excreted at the canalicular membrane through There is also a in canalicular transport of glutathione and SLCT, et al. studied the transport of bilirubin in a of In this was into to induce The transport of bilirubin and another organic studied the hepatic and canalicular excretion of bilirubin all in to in a in of bilirubin was in to 9 is unlikely that bilirubin is by sepsis because more than 60% of the bilirubin in blood is was to the of conjugated bilirubin to the that bilirubin that the of bilirubin was not to the in bilirubin This is by the that the of bilirubin in to was not from normal is the mechanism by which jaundice develops in sepsis. cholestasis is caused by of the hepatic or common bile and directly the of This can result from a primary infection such as or can and as a result of are more commonly by infection of the tree, which lead to bile on the mechanisms of cholestasis in sepsis, it is to the in the of bile 2). is formed by the of by of bile into hepatic are the principal into this and bile is by the by the of bile into hepatic This is also known as bile the of bile from related to other is known as Normal bile and bile are from the basolateral membrane to the canalicular membrane by cytosolic transporter transport occurs by (1) to cytosolic proteins and to (mainly conjugated primary and secondary bile and (2) The of bile into the is the rate-limiting step in bile which is bile are excreted into bile through the The multiple 1 transporter is responsible for hydrophobic organic the canalicular The between hepatocytes a to bile the of formed bile into the of are derived from in the liver and from of bile from the are to the liver following are taken up by hepatocytes transport proteins on the basolateral The principal of this basolateral transport of bile is the which is and an directed is an of the basolateral and are found the hepatic taurocholate is the principal transporter in the uptake of conjugated bile from into This highly results in a of bile The bile salt organic and other are primarily from into hepatocytes by transport such as organic anion transport proteins and are from the basolateral membrane to the canalicular membrane by cytosolic transporter transport occurs through (1) to cytosolic proteins and to (mainly conjugated primary and secondary bile and (2) transport is responsible for a small amount of bile and the role of this of transport is unclear. The of bile into is the rate-limiting step in bile This is and occurs against a steep concentration There are many on the canalicular these are the and the bile salt export bile are excreted into bile through the The multiple 1 transporter is responsible for hydrophobic organic and inorganic bile by which a for bile the of formed bile into the of The liver has a role in the of as a of and is a major site of the of bacteria and from systemic Kupffer cells of the liver up of the of the reticuloendothelial and up bacteria, and and are to release a of products in liver injury, such as tumor necrosis 1 and 6, and injury may accompany systemic infection in adults with pneumonia, infections typhoid and Escherichia coli This can from to hepatocellular necrosis it has been the is injury is not considered a during bacterial infection. studies that liver in hyperbilirubinemia or hepatic in bacterial infection have noted to no Table The mechanism of hepatic injury on the underlying infection, most likely is an by the bacteria that to hepatocellular liver may occur as a consequence of or in sepsis. blood is in sepsis and blood to the liver is which can lead to Kupffer cell dysfunction and hepatocellular The of to the cells and from of from to hepatocellular and may result in necrosis of the of hepatocellular injury necrosis and/or has been attributed to nitric This was in septic of rise to in both hepatocyte necrosis and The underlying state of and the products in response to infection to a role in the of the cholestasis of sepsis. Various effects of this state on the liver that lead to cholestasis are in Table hepatocellular has been to occur early the of sepsis increased and hepatic This that the hepatocellular dysfunction in sepsis may be associated with the release of such as tumor necrosis or Various have the role of in the of cholestasis associated with of the liver by bacteria is not a major cause of cholestasis or hepatic injury in most cases of Several studies have a in bile the isolated of following or is a by and Kupffer cells and is the primary of the systemic effects of has been in cholestasis by the that with antibodies in bile and bile salt LPS, and and all have been to these rise to cholestasis in the by Kupffer cells induce and have been to cause which, in turn, contribute to hepatic not bile cytosolic bile or the of and to hepatocyte uptake and excretion of bile Table 5 lists various in bile transport that are in sepsis, rise to cholestasis. the basolateral and canalicular transport of bile and and organic anions and the of is also that may degradation of membrane proteins as Several studies have of basolateral membrane may cause of at the basolateral membrane such as the has also been that membrane this may be the mechanism in reducing and of and at both the and the In a by et of LPS, both protein and of by more than hepatocyte transport has also been at the canalicular and are for canalicular bile and transport was in a sepsis This to result from of at the canalicular and are in septic to in The for this is the of excretion of to a of in bile occurs and/or The jaundice of sepsis is and can occur a of the of and may other clinical features of the underlying infection In the absence of infection, is is not a major manifestation of cholestasis associated with infection. occurs about the hyperbilirubinemia in the of is often higher can be This is particularly in those with jaundice also are septic and on is but more than the upper of is (Table or infection of the hepatobiliary be considered a cause of jaundice, a with upper jaundice, and most commonly occurs secondary to of the tract with a or may occur from a tumor of the bile or results conjugated and of to has a more severe than jaundice associated with infections. tract is the most common condition associated with liver This infection that may occur secondary to or cause of is through the portal from an primary site to the a of liver are with fever, and most often are or to of patients have are with of bilirubin and treatment or of the and on and with a from 80% to A with jaundice in the is a frequently encountered multiple blood transfusions, and/or are of the causes of jaundice, which of the Jaundice these circumstances is of a with conjugated hyperbilirubinemia and and is no underlying systemic infection is highly Sepsis is the most common of jaundice and cholestasis in the This is in patients are in an to trauma. In a retrospective by et the development of jaundice in the was to have a This be a result of a in of the factor. the underlying process is and in a the is is a known complication of gram-negative bacterial infection, in This syndrome is more in the and may account for as as a of the cases of cases of sepsis associated with jaundice have of gram-negative with Escherichia coli the more common pneumonia, and meningitis are types of infections to cause jaundice. The urinary tract is the most common site of infection associated with this syndrome, in the shows cholestasis with Kupffer cell and or no of Aside from liver an normal hepatic The of the underlying infection the Jaundice and cholestasis are and of the infection. The of patients develop jaundice with pneumonia is 10 to that jaundice is a result of hepatocellular Many patients with pneumonia, with or jaundice, have of hepatocellular necrosis has more commonly been in liver of patients with shows necrosis and with The is of the infection. Clostridium perfringens is a commonly isolated clostridial that can cause a of clinical from to massive red blood cell hemolysis, and hemolysis has been as a complication of septic and may result in massive hemolysis, hemoglobinuria, and Clostridium perfringens produces a large variety of and The a is of and to and from cell membranes also as also membrane which for the or fatal hemolytic anemia in clostridial and hemoglobinuria are in this and the may between blood and and hepatic The in this clinical setting is with more than the patients with and of and is a and from to In the the organisms to the and data that the to the in the There are forms of presentation of the and The is the A severe presentation of the in to of all infections, is known as This is associated with fever, severe hepatic jaundice, and Although bilirubin may be and are to The for this presentation is fever, also known as fever, is an systemic caused by is an infection that not causes jaundice but also liver occurs in about of patients, and jaundice occurs in about a of patients with is the normal and are more than 5 the upper of may be The is by (1) from the blood or and (2) a rise in the of the during the of the The of the hepatic in typhoid is believed to be secondary to the of studies have that of produces hepatic Other studies have that liver injury may occur by release of or reticuloendothelial and are apparently not in the pathogenesis of hepatic The of the of patients with typhoid shows cell necrosis with cell and Kupffer cell with of Kupffer are of typhoid and are the hepatic liver have of The of jaundice and sepsis or the of its not to or the of the The on the underlying infection. There is of hepatic dysfunction and cholestasis the underlying condition is the may be and treatment are 6, causes of jaundice in a critically ill such as and have a The most in sepsis is cholestasis. bile is found in the bile and in hepatocyte into the may lead to bile uptake by Kupffer cells. There may also be including of the hepatocyte as in the hepatic increased amount of as a result of cholestasis may lead to hepatocytes a of subjects with cholestasis bile and bile in a with cholestasis. The in the evaluation of a are of (1) the (2) specific likely to have the and a can be Table 7 the for a at for sepsis of jaundice. The of jaundice is to treatment of the sepsis. jaundice develops in a with an of infection, the of jaundice is On the other hand, a of is often to this condition jaundice is the manifestation of infection. The of hyperbilirubinemia and hepatic may from a more underlying process and lead to an for hepatic or However, a septic is not the of hepatic or infection as the cause of jaundice also be There are many specific that the common causes of jaundice and the circumstances in which it is a be to the cause (Table Table lists various in the in this The of jaundice, that versus conjugated and isolated hyperbilirubinemia versus jaundice with liver enzyme that Unconjugated hyperbilirubinemia a for hemolysis and causes of hemolysis. On the other hand, with a jaundice, it is to a hepatobiliary cause of sepsis and jaundice. studies to the hepatobiliary tract are for this is relatively and can be at the of critically can as a cause of jaundice. However, is not to up small and a be a hepatic is In patients at for sepsis develop jaundice other features of infection, blood and a be as a to sepsis. be from intravascular or other of infection. an cause is still not evaluation for underlying infection or causes be There are no data that either or to all patients with jaundice have not other features of infection. Frequently, with a is to those are likely to be to sepsis. which of for the underlying infection, be jaundice is hyperbilirubinemia is by and and or no of This is a result of infection, or injury. be A may be this has been used to associated with infection. are in such The of may be associated with a rise in that as of the A hepatobiliary can be used to the of A liver not in management of this The most of management is early and treatment of infection (Table Other additional in management management include intravascular and to blood for The treatment of cholestasis of sepsis is the management of the underlying infection. be as as be or A in the of infection and the of the may to cholestasis. individuals a bilirubin with In cholestasis is can bile and bilirubin in and cholestasis. the clinical is to the of to cholestasis from these are in sepsis. a the of into Kupffer thereby reducing the release of This in may a role in treatment of cholestasis and hepatocellular et al. a of on hepatocyte and in of this early of sepsis in an hepatocellular and the from to 10 the of is a from and have been to cause hepatocyte through In studies that hepatic of through of et al. that has a against this liver that by in in septic and liver injury and hepatocyte has been used as a either as a or by stores of of an and lower in to in a by et