Differential Diagnosis

The long list of diagnoses depicted in Box 22-1 divides the causes of hyperbilirubinemia into two large groups according to whether the predominant abnormality is an increase in the circulating concentration of unconjugated (indirect) bilirubin or an increase in the concentration of conjugated (direct) bilirubin. Although this classification scheme is useful under some circumstances, many of the diagnoses listed in Box 22-1 are extremely rare and very unlikely to be encountered by the intensivist caring for critically ill (adult) patients. A more useful classification scheme is depicted in Box 22-2. In this scheme, the causes of jaundice are lumped into three primary categories: extrahepatic obstruction to bile flow, increased bilirubin production, or impaired excretion secondary to hepatocellular necrosis and/or intrahepatic cholestasis and/or hepatitis. Often multiple mechanisms are involved at once.

The incidence of hyperbilirubinemia among critically ill patients is quite variable. Jaundice is present in more than 50% of patients with intraabdominal sepsis, 33% of victims of severe polysystemic trauma, and from 3% to more than 20% of intensive care unit (ICU) patients recovering from cardiac surgery.^3–6 Determining the cause of hyperbilirubinemia of new onset is important when managing ICU patients because some problems can be corrected. Exclusion of a mechanical cause for jaundice (e.g., obstruction of the common bile duct due to choledocholithiasis or stricture) assumes the highest priority because failure to correct this sort of problem in a timely fashion can lead to serious morbidity or even mortality.

Iatrogenic injuries to the common bile duct are fortunately quite rare, although the incidence of this complication is greater after laparoscopic cholecystectomy than after open excision of the gallbladder.⁷ Damage to the biliary tree, stricture of biliary anastomoses, or retained stones after cholecystectomy or common bile duct exploration present as hyperbilirubinemia and elevated circulating levels of alkaline phosphatase or gamma-glutamyl transpeptidase. Most often the diagnosis is made by detecting dilation of intrahepatic and extrahepatic bile ducts using ultrasonography.

By exceeding the capacity of the liver to conjugate and excrete bilirubin into the bile, hemolysis can produce jaundice. However, the liver can excrete about 300 mg/day of bilirubin,⁸ so clinically significant hyperbilirubinemia is only apparent if the rate of hemolysis (i.e., number of red blood cells lysed per unit time) is fairly rapid. Approximately 10% of the erythrocytes in an appropriately crossmatched unit of packed red blood cells undergo rapid hemolysis, yielding about 250 mg of bilirubin.⁹ Accordingly, transfusion of a single unit of packed red blood cells is not likely to increase serum total bilirubin concentration. However, transfusion of multiple units of blood over a short period almost inevitably leads to some degree of hyperbilirubinemia, particularly if hepatic function is already impaired. Other reasonably common causes of acute hemolysis in ICU patients include sickle cell disease, immune-mediated hemolytic anemia, and disseminated intravascular coagulation.

Any condition that leads to extensive hepatocellular damage will increase circulating total bilirubin concentration. Conditions in this category that are commonly encountered in ICU patients include viral hepatitis, “shock liver,” alcoholic hepatitis, and hepatocellular injury induced by drugs, especially acetaminophen.¹⁰ In most forms of jaundice due to hepatic inflammation or hepatocellular damage, circulating levels of transaminases are elevated to a greater extent than total bilirubin concentration. Making a diagnosis of acetaminophen overdose early is very important because specific therapy using N-acetylcysteine can be lifesaving.¹⁰

Two other conditions commonly associated with jaundice in ICU patients are sepsis and total parenteral nutrition (TPN). Both are associated with the development of intrahepatic cholestasis. Hyperbilirubinemia is a common occurrence in patients with extrahepatic infections leading to the development of severe sepsis.^11,12 Persistent hyperbilirubinemia in septic patients is associated with a significantly increased risk of mortality.¹² Efforts to understand the pathophysiologic mechanisms responsible for cholestatic jaundice due to sepsis have largely focused on lipopolysaccharide (LPS)-induced alterations in the function and expression of various bile acid transporters.^13–16 Nevertheless, another factor that probably contributes to the development of intrahepatic cholestasis is back-leakage of bile from the canalicular spaces into the sinusoids.^17–19

The basis for TPN-induced cholestasis is probably multifactorial. Prolonged bowel rest and ileus may promote bacterial overgrowth and increased translocation of LPS into the portal vein on this basis. Phytosterols are present in the lipid emulsions used for TPN and have been associated with cholestasis, especially in premature infants.²⁰ Results from two retrospective studies suggest that administration of more than 1 g/kg/day of lipid emulsion is associated with increased incidence of hepatocellular dysfunction.^21,22 These data, however, were derived by studying patients receiving TPN at home for very prolonged periods and may not be applicable to ICU patients. In any case, TPN is associated with the development of jaundice and hepatocellular damage. Accordingly, except in rare cases, most ICU patients are better served by receiving enteral rather than parenteral nutrition.