↑direct bilirubin = intra-hepatic or post-hepatic
↔direct bilirubin = pre-hepatic cause
Aspartate transaminase (AST)
↑ALT<↑↑AST = ethanol
↑↑↑ALT>↑↑AST = viral, shock liver
Non-specific, also ↑ in bone disease
Non-specific, also ↑ with severe hepatocellular damage
Diagnostic evaluation: Postoperative jaundice is evaluated by performing a directed physical exam and obtaining laboratory and additional studies, which need to be interpreted with attention to the individual medical history of the patient. Serum bilirubin levels with both direct (conjugated) and indirect (unconjugated) bilirubin levels confirm the diagnosis of hyperbilirubinemia and provide the first diagnostic clue between pre-hepatic and intra-hepatic or post-hepatic causes. Elevations of primarily unconjugated bilirubin suggest a pre-hepatic etiology. Elevations of the hepatic transaminases alanine transaminase (ALT) and aspartate transaminase (AST) may indicate the presence and degree of hepatic injury, while alkaline phosphatase is more specific to biliary dysfunction.
If pre-hepatic causes such as hemolytic anemias are suspected, additional laboratory testing including hemoglobin, hematocrit, direct and indirect Coombs‘ test, haptoglobin level, and reticulocyte count may help confirm the diagnosis. Viral serology testing could also establish the diagnosis of viral hepatitis. If biliary obstruction is suspected, right upper quadrant ultrasonography may confirm the initial suspicion from laboratory data.
Pre-hepatic hyperbilirubinemia: Pre-hepatic causes of jaundice occur as a result of an imbalance of bilirubin metabolism producing a relative overproduction of bilirubin. Hemolysis is the most common source of bilirubin overproduction. Bilirubin is produced primarily by the catabolism of hemoglobin from senescent red blood cells (with a small fraction derived from destruction of immature, defective red blood cells in the bone marrow). Only about 15% of bilirubin is derived from non-erythropoietic sources. Under normal circumstances around 1% of red blood cells are replaced daily. More rapid destruction of red blood cells as occurs with hemolytic anemia will therefore markedly increase bilirubin production in proportion to the quality of red blood cells that are hemolyzed.
Postoperative hemolysis may occur owing to a number of diverse etiologies. Hemolysis may be secondary to sickle cell disease or glucose-6-phosphate dehydrogenase (G6PD) deficiency among patients with pre-existing red blood cell pathology. Autoimmune medication-induced hemolysis may occur as a result of the introduction of new medications perioperatively. Although over 125 medications have been identified as causing autoimmune hemolysis, penicillins and cephalosporins are the most frequently encountered in the surgical patient.[6] If blood transfusion has occurred, acute hemolytic transfusion reaction or delayed hemolytic transfusion reaction may cause hemolysis, but delayed reactions are rarely implicated in causing jaundice. Rarely, massive blood transfusion could also overwhelm the conjugation mechanism by the liver and lead to jaundice without the overt transfusion reaction.[7] Mechanical destruction of red blood cells may occur because of stress upon the red blood cell during cardiopulmonary bypass, intra-aortic balloon pump counterpulsation, or passage through left ventricular assist devices, extracorporeal membrane oxygenators, and mechanical valves. Hemolysis is usually mild and peripheral blood smears typically show red blood cell fragments (schistocytes). Pre-existing hemoglobinopathies which are not typically associated with hemolytic crisis, such as thalassemias, may increase red blood cell fragility and hemolysis risk during major cardiac procedures.[8] Reabsorption of heme from large hematomas or gastrointestinal bleeding may also cause pre-hepatic jaundice. Lastly, unconjugated hyperbilirubinemia may produce kernicterus in infants characterized by icteric discoloration of the basal ganglia and bilirubin-mediated neurotoxicity. Kernicterus is very rarely observed in adults.[9]
Although clinically useful for categorizing and managing jaundice, the division between pre-hepatic, intra-hepatic, or post-hepatic is seldom mutually exclusive. Most cases of postoperative jaundice have components of each. Hemolysis often does not cause jaundice since the liver is able to compensate for increased bilirubin production. Hemolysis will cause jaundice if increased bilirubin production exposes diminished hepatic capacity. The clinical importance of the interrelationship between production, conjugation, and excretion and the difficulty it presents in neatly separating jaundice into pre-hepatic, intra-hepatic, or post-hepatic etiologies is best exemplified by Gilbert’s syndrome.
Gilbert’s syndrome: Familial non-hemolytic jaundice or unconjugated benign bilirubinemia is most commonly referred to by the eponym Gilbert’s syndrome. An inherited defect of the UGT1A1 gene leads to impaired production of the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme responsible for hepatic glucuronidation of unconjugated bilirubin. The syndrome is common and affects about 6% of the population.[10] Affected individuals typically have severely diminished glucuronosyltransferase activity (~30% normal) and develop jaundice with minor stress including fasting, fever, or emotional stress. Surgical patients with Gilbert’s syndrome often have modest levels of unconjugated bilirubin prior to surgery but become symptomatic from perioperative stress. Jaundice without dark urine or elevated urobilinogen should raise suspicion for Gilbert’s syndrome, and the diagnosis is confirmed by a moderately elevated level of unconjugated bilirubin in the absence of other laboratory abnormalities. Treatment is supportive and aimed at reversing the underlying precipitating factor such as fever and infection.[11,12] Although the actual pathophysiological lesion of Gilbert’s syndrome is intra-hepatic, failure of the liver to increase the conjugation of bilirubin produces pre-hepatic pattern laboratory abnormalities with minimal increases in unconjugated bilirubin production, which would be otherwise trivial in unaffected individuals.
Intra-hepatic hyperbilirubinemia
Intra-hepatic causes of jaundice involve direct injury to the hepatocytes. Classic laboratory findings induced marked elevation of hepatic transaminases with modest elevation or normal values of alkaline phosphatase. Hypoperfusion due to prolonged hypotension, congestive heart failure, and sepsis may cause ischemic injury to the hepatocytes. Viral hepatitis is also associated with blood transfusion and IV drug users. Alcohol is a direct toxin to the liver, while a history of alcohol abuse may suggest chronic hepatic insult leading to cirrhosis. Acetaminophen is directly hepatotoxic and presents a unique risk to the surgical patient. Acetaminophen is frequently prescribed postoperatively and since it is also contained in other products in combination with codeine, hydrocodone, oxycodone, or tramadol, clinical caution must be exercised not to inadvertently prescribe acetaminophen from multiple products. Inhaled anesthetics have also been implicated in cases of postoperative jaundice.
Halothane hepatotoxicity and hepatitis: Very rarely, inhalational anesthetics can cause hepatitis leading to jaundice. Shortly after the introduction and widespread use of halothane, reports of hepatotoxicity related to its use appeared and led to the recognition of halothane hepatitis.[13–16] Two distinct types of hepatitis from inhalational agents have been described. The first form, also known as halothane hepatotoxicity, is more common, clinically mild, and thought to be related to the formation and accumulation of hepatotoxic intermediate metabolites (trifluoroacetyl acid). Elevations in AST and ALT are typically mild and the clinical progression self-limited. The other progressive and fulminant form of hepatic injury, commonly known as “halothane hepatitis,” may be immune-mediated and is idiosyncratic. It is characterized by mass hepatic necrosis with marked elevation in AST, ALT, and bilirubin. The mortality rate is extremely high (50–75%) with an incidence of between 1:10,000 and 1:35,000. Risk factors include previous exposure to the inhalational agent, obesity, and female sex (two fold risk vs. male gender). The immunological nature of halothane hepatitis is supported by clinical symptoms of fever, rash, eosinophilia, and antibodies to hepatocytes.[17]
Hepatic injury from halothane has been reported more than 500 times, and halothane remains a source of potential hepatic injury in developing nations.[17] Fortunately, more modern volatile anesthetics have a lesser potential for hepatic injury. Nonetheless, there are sporadic reports of hepatitis from isoflurane,[18–25] desflurane,[26–31] and sevoflurane.[32–37]
It should be noted that “halothane hepatitis” is a diagnosis of exclusion. Other causes of hepatitis must be systematically excluded first. Definitive diagnosis is made by clinical suspicion and laboratory evidence of liver injury. A liver biopsy is usually not necessary for diagnosis, but the presence of centrilobular necrosis supports the diagnosis of halothane hepatitis.
Post-hepatic hyperbilirubinemia
Post-hepatic jaundice, or obstructive jaundice, includes instances of failure to excrete conjugated bilirubin. Cholestasis may be intra-hepatic and associated with elevations of alkaline phosphatase with minimal disturbance of hepatic transaminases. Intra-hepatic cholestasis is observed after major abdominal and cardiac procedures, several weeks of total parenteral nutrition, or with pregnancy-induced cholestasis. Cholestasis may also be extra-hepatic and associated with biliary obstruction. Biliary obstruction secondary to non-calculus cholelithiasis, choledocholithiasis, retained bile duct stone, and biliary stasis is common postoperatively from biliary and abdominal surgery. A mixed pattern of cholestasis and hepatocellular jaundice with elevation of both transaminases and alkaline phosphatase is often observed. Less frequently, common bile duct stricture secondary to recurrent pancreatitis or bile duct tumor may also cause jaundice.
| Pre-hepatic | Intra-hepatic | Post-hepatic (biliary) |
|---|---|---|
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