Jaundice

Differential diagnosis

The multitude of diagnoses depicted in Box 23.1 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 23.1 are extremely rare and highly unlikely to be encountered by the intensivist caring for critically ill (adult) patients. A more useful classification scheme is depicted in Box 23.2 . In this scheme, the causes of jaundice are grouped into three primary categories: extrahepatic obstruction to bile flow, increased bilirubin production, and impaired excretion secondary to hepatocellular necrosis and/or intrahepatic cholestasis and hepatitis. It is common for multiple mechanisms to be involved simultaneously.

Hyperbilirubinemia occurs frequently in critically ill patients and is an independent risk factor for an unfavorable outcome. ^, In a retrospective study of adult patients admitted to an intensive care unit (ICU) with severe sepsis or septic shock, the mortality rate was 12%, 24%, and 42% for individuals with a peak serum bilirubin concentration during the first 72 hours that was ≤1, 1.1–2, or >2 mg/dL, respectively. In another retrospective study, hyperbilirubinemia was a significant risk factor for the development of acute respiratory distress syndrome (ARDS) among patients admitted to an ICU with sepsis. In one widely cited study, hyperbilirubinemia occurred in 217 of 2857 trauma patients who had an Injury Severity Score greater than 14 and survived for longer than 48 hours after admission to the hospital. In this study, hyperbilirubinemia was significantly associated with an increased length of stay in the ICU and death. Hyperbilirubinemia is also common in ICU patients who are recovering from cardiac surgery. ^, In this category of ICU patients, risk factors for the development of hyperbilirubinemia include prolonged cardiopulmonary bypass time, prolonged aortic cross-clamp time, and use of an intraaortic balloon pump.

Determining the cause of new-onset hyperbilirubinemia 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 because of choledocholithiasis or stricture) assumes the highest priority because failure to correct this type of problem in a timely fashion can lead to serious morbidity or even mortality. Fig. 23.2 shows an approach to handling new-onset hyperbilirubinemia in an adult patient. Hyperbilirubinemia is multifactorial, and although laboratory values evaluating the production and excretion of bilirubin can guide the workup, a liver biopsy or cholangiography is necessary when no other diagnosis can be confirmed.

Iatrogenic injuries to the common bile duct are fortunately quite rare. Damage to the biliary tree, stricture of biliary anastomoses, and retained stones after cholecystectomy or common bile duct exploration present as hyperbilirubinemia and elevated circulating levels of alkaline phosphatase or gamma-glutamyltransferase. Most often the diagnosis is made by detecting the 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 result in jaundice. However, the liver can excrete approximately 300 mg/day of bilirubin, and therefore clinically significant hyperbilirubinemia is only apparent if the rate of hemolysis (i.e., the number of red blood cells lysed per unit time) is fairly rapid. Approximately 10% of the erythrocytes in an appropriately cross-matched unit of packed red blood cells undergo rapid hemolysis, yielding about 250 mg of bilirubin. Accordingly, transfusion of a single unit of packed red blood cells is not likely to increase the total serum bilirubin concentration. However, transfusion of multiple units of blood over a short period almost inevitably leads to some degree of hyperbilirubinemia, particularly if hepatic functionality is already impaired. Other 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 the 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. In most forms of jaundice resulting from hepatic inflammation or hepatocellular damage, circulating levels of transaminases are elevated to a greater extent than the total bilirubin concentration. Making a diagnosis of acetaminophen overdose early is extremely important because specific therapy using N -acetylcysteine can be lifesaving.

Efforts to understand the pathophysiologic mechanisms responsible for cholestatic jaundice resulting from sepsis have largely focused on lipopolysaccharide (LPS)-induced alterations in the function and expression of various bile acid transporters. Nevertheless, another factor that likely contributes to the development of intrahepatic cholestasis is the back-leakage of bile from the canalicular spaces into the sinusoids.