INTRODUCTION — Postoperative jaundice, the presence of bilirubin elevation with or without clinical icterus appearing in the period following surgery, occurs as a result of numerous causes. This topic review will provide an overview of postoperative jaundice and a suggested approach for evaluation and management.
CLASSIFICATION — There is no widely accepted classification of postoperative jaundice. Nevertheless, postoperative jaundice can be considered a part of a spectrum of abnormal liver biochemical tests, which are common in the postoperative period. A subset of patients who develop abnormal liver biochemical tests have preexisting liver disease, increasing their vulnerability to further hepatic injury from a variety of causes. Others develop liver biochemical abnormalities without preexisting liver disease. The distinction is potentially important since it can help clarify contributing causes, influence prognosis, and may guide long-term management.
We have found it useful conceptually to subdivide postoperative jaundice into three categories: prehepatic, intrahepatic, and posthepatic:
●Prehepatic, which results from overproduction of bilirubin such as from hemolysis or a resolving hematoma.
●Intrahepatic, which results from injury to hepatocytes or biliary epithelial cells and is due to a variety of causes such as hepatic ischemia, infection, and drug toxicity. All of these conditions may be more likely and clinically more severe in patients with preexisting liver disease.
●Posthepatic, which is due to obstruction of the extrahepatic biliary tree. Examples include a retained common bile duct stone or a direct biliary tract injury from upper abdominal surgery.
These categories are not mutually exclusive since several factors are typically involved in causing postoperative jaundice. The clinical challenge is considering the multitude of causes in an effort to determine if intervention is possible.
PREHEPATIC — Overproduction of unconjugated bilirubin can lead to jaundice. In the surgical setting, overproduction is usually due either to pathologic red blood cell breakdown (hemolysis) or erythrocyte breakdown after excessive bleeding. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia", section on 'Disorders associated with unconjugated hyperbilirubinemia' and "Bilirubin metabolism".)
Hemolysis can result from a transfusion reaction, with certain medications, or from mechanical effects due to shearing forces from exposure of red blood cells to intravascular devices. (See "Hemolytic transfusion reactions" and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Pathogenesis'.)
Pain, fever, or chills around the time of red blood cell transfusion, coupled with dark urine, suggest a transfusion reaction as the cause of jaundice. Surgery can exacerbate hemolysis in patients with a preexisting hemolytic disease or a genetic predisposition to hemolysis (eg, sickle cell disease, hereditary spherocytosis, or glucose-6-phosphate dehydrogenase deficiency).
Gilbert's syndrome is an autosomal recessive defect in bilirubin glucuronidation and is the most common inherited disorder of bilirubin conjugation leading to recurrent episodes of unconjugated hyperbilirubinemia (see "Gilbert syndrome"). While the unconjugated hyperbilirubinemia these patients experience is of little clinical consequence, it can be seen postoperatively reinforcing the need to determine if a patient has a preoperative history of hyperbilirubinemia. A series of seven patients undergoing cardiopulmonary bypass showed a mean preoperative total bilirubin of 2.6 mg/dl with a mild mean rise to 3.5 mg/dl six hours post bypass which then declined to levels below the preoperative mean total bilirubin level by 72 hours postoperatively. Direct bilirubin levels remained relatively stable and the changes in total bilirubin levels had mirrored those of the indirect bilirubin levels. These results suggest that patients with Gilbert's syndrome undergoing cardiac surgery under bypass may have a transient and early increase in total bilirubin with rapid resolution which do not routinely lead to sustained bilirubin elevations. For this reason, Gilbert's syndrome should not be automatically assumed to be causing postoperative jaundice .
Patients who have undergone surgery that exposes the blood flow to shearing forces (eg, cardiopulmonary bypass) can develop unconjugated hyperbilirubinemia due to mechanical red blood cell breakdown. Patients at greatest risk include young children, patients who have undergone extensive surgery with a long operative time, patients with preoperative heart failure and congestive hepatopathy, and patients who have received prolonged hemodynamic support from a ventricular assist devices, intra-aortic balloon pump, or extracorporeal membrane oxygenation [2-4].
Erythrocyte breakdown occurs in patients with internal bleeding, with subsequent resorption of the extravasated blood. Surgical trauma patients who have multiple injuries to muscle and soft tissue may be at particular risk. In other patients, a declining hematocrit may be a clue that jaundice is, at least in part, due to resorption of extravasated blood. Trauma patients with hemorrhage are also more likely to require blood transfusions, the breakdown of which can compound the jaundice seen in these patients. A review of case series and reports of jaundice in trauma patients showed that an overproduction of bilirubin due to hemolysis of transfused blood and breakdown of extravasated blood was the most common causative factor .
INTRAHEPATIC — Multiple insults in the perioperative period can lead to hepatocellular or canalicular dysfunction, including total parenteral nutrition, hypoxia, ischemia, drugs, newly acquired viral hepatitis, and sepsis.
As noted above, liver dysfunction associated with perioperative insults may be more likely and clinically more severe in patients with preexisting liver disease. The clinical course depends upon the type of liver disease, its severity, the surgical procedure, and the type of anesthesia. (See "Assessing surgical risk in patients with liver disease".)
Underlying liver disease is not always recognized during preoperative evaluation. Thus, the possibility that underlying liver disease could be contributing to jaundice should be considered. The following will summarize some of the important causes of intrahepatic jaundice.
Ischemia — The liver's complex vascular supply and high metabolic activity make it particularly vulnerable to circulatory disturbances. Ischemic hepatitis (also referred to as shock liver) refers to diffuse hepatic injury resulting from acute hypoperfusion. The hemodynamic insult is usually evident clinically before liver injury is recognized. Liver injury is typically recognized by a rapid rise in serum aminotransferase levels and an early massive rise in lactate dehydrogenase levels. Peak aminotransferase levels are usually reached one to three days after the hemodynamic insult and can be 25 to 250 times the upper limit of normal. Ischemic hepatitis is often accompanied by additional evidence of end-organ hypoperfusion, especially acute tubular necrosis of the kidney. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)
Drug-induced liver injury — Drug-induced liver injury (DILI) occurs with many drugs through a variety of mechanisms. Diagnosis can be difficult since the relationship between drug exposure and hepatic toxicity is not always clear, although supportive features are onset after beginning the drug and improvement after withdrawal. Although contemporary inhaled anesthetic agents uncommonly cause DILI, the degree of hepatic metabolisms correlates with the likelihood of a toxic reaction. Isoflurane, desflurane, and sevoflurane undergo less hepatic metabolism than halothane or enflurane and have the lowest risk of hepatitis. (See "Assessing surgical risk in patients with liver disease" and "Drug-induced liver injury".)
Total parenteral nutrition — Total parenteral nutrition (TPN) in critically ill patients has been associated with postoperative jaundice. In one study, 30 percent of patients receiving TPN had liver dysfunction as defined by biochemical evidence of cholestasis, liver necrosis, or both . The use of excessive caloric amounts of TPN was noted to be a risk factor for liver dysfunction.
Parenteral nutrition causes both cholestasis and the development of biliary sludge . It has been shown that late initiation of parenteral nutrition is associated with enhanced organ function recovery, reduced incidence of infections, and shorter ICU stays . In this study, a patient who had begun parenteral nutrition later had hyperbilirubinemia above 3 mg/dl but fewer clinically relevant increases in GGT or alkaline phosphatase, leading the authors to conclude that increased bilirubin levels during critical illness do not necessarily signify worsening cholestatic liver disease. A later study tested this hypothesis and showed that withholding parenteral nutrition until day eight in critically ill patients increased the plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, alkaline phosphatase, and ALT, and that hyperbilirubinemia in critical illness does not necessarily reflect cholestasis and may instead be reflective of an adaptive response that would not occur if parenteral nutrition were initiated earlier . The implication of these data is that elevations in bilirubin in critically ill patients when TPN is initiated early in their illness may not reflect true cholestasis.
Sepsis — Sepsis can induce cholestasis and jaundice. However, the mechanism is unclear. The Surviving Sepsis Campaign Guidelines define liver dysfunction during sepsis as an increase in bilirubin concentration >2 mg/dl and an INR >1.5. Elevated bilirubin and jaundice in this setting may not reflect sepsis alone and may indicate related acute liver failure instead, making bilirubin a poor measure to distinguish acute liver failure from other liver dysfunction .
Critical illness — Liver dysfunction in critically ill patients is a complex phenomenon and many factors may cause jaundice in the postoperative patient who is critically ill . In fact, abnormal liver function tests, including elevations in bilirubin, have been reported in up to 61 percent of patients admitted to the ICU [11-13]. These results may not always reflect the same degree of hepatic disease as in non-critically ill patients, but sustained elevations almost always reflect a complicated course in critically ill patients.
Cardiac surgery — Ten to 40 percent of patients undergoing cardiac surgery have been reported to develop postoperative jaundice [2,3,14-16]. Postoperative jaundice in cardiac surgery is multifactorial in nature. Causative factors include both cardiac surgery specific factors, such as cardiopulmonary bypass, and factors not specific to cardiac surgery, such as age, heart failure status, and sepsis [2,16-20]. Postoperative jaundice associated with cardiac surgery has been associated with a postoperative mortality rate of 17.4 percent . A systematic review and meta-analysis, which included 3876 participants showed that postoperative hyperbilirubinemia was associated with increase in in-hospital mortality (OR 7.29, 95% CI 3.53-15.09) .
Viral hepatitis — Viral hepatitis is an uncommon cause of postoperative jaundice, but can occur in the rare case of hospital outbreaks or in patients with preoperative exposure. The exacerbation of underlying chronic hepatitis B is also possible in patients with chronic infection, particularly in patients receiving immunosuppression. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
POSTHEPATIC — Biliary obstruction related to choledocholithiasis, biliary stricture, or bile leaks remains one of the most common cause of postoperative jaundice in patients undergoing abdominal surgery. Patients undergoing cholecystectomy, pancreatic surgery, or resections of tumors of the liver, gallbladder, or bile ducts are at particular risk.
Surgery performed near the periphery of the bile ducts or gallbladder is associated with a risk of a bile leak or a stricture from dysfunctional biliary epithelial healing. A bile duct stricture can be due to surgical scarring or a narrow anastomosis. Bile leaks can occasionally present with jaundice and hyperbilirubinemia. In addition, patients undergoing cholecystectomy can retain stones in the bile ducts, causing obstruction. An unintended interruption or obstruction (eg, due to clips) in the bile duct can become clinically evident immediately or days after surgery. (See "Complications of laparoscopic cholecystectomy".)
Bile leaks — Bile leaks after upper abdominal surgery are most commonly due to injury to the bile ducts or the ducts of Luschka. The ducts of Luschka are small ducts occasionally present at the gallbladder fossa, originating from the right hepatic lobe and draining into the extrahepatic bile ducts. Most leaks are symptomatic and detected during the first week following surgery. Endoscopic therapy is successful in resolving approximately 90 percent of bile leaks after cholecystectomy. (See "Complications of laparoscopic cholecystectomy" and "Endoscopic management of postcholecystectomy biliary complications".)
Biliary strictures — The management of bile duct strictures after upper abdominal surgery depends on the location of the stricture, its severity, and the extent of delay until its recognition. Endoscopic and surgical approaches may be required. (See "Endoscopic management of postcholecystectomy biliary complications".)
Acalculous cholecystitis — Acalculous cholecystitis is an acute necroinflammatory disease of the gallbladder with a multifactorial pathogenesis. It can occur in any hospitalized patient, but most frequently it occurs in the critically ill. In the critically ill, who may be intubated and sedated, it may present with unexplained fever, leukocytosis, or vague abdominal discomfort. Abnormal liver biochemical tests may include hyperbilirubinemia, a mild increase in serum alkaline phosphatase and aminotransferase levels. (See "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management".)
MULTIFACTORIAL CAUSES — As noted above, postoperative jaundice is usually attributable to more than one cause. The following conditions are examples of causes that have several contributing mechanisms.
Benign postoperative jaundice — The term "benign postoperative jaundice" was added to the medical lexicon to recognize the common occurrence of postoperative jaundice from a multifactorial etiology [22,23]. Because the term encompasses a multitude of potentially contributing causes, it is not particularly helpful for identifying specific contributing causes that could potentially be amenable to intervention. Nevertheless, it still provides a useful description for patients with multiple possible causes of postoperative jaundice.
The clinical features are overshadowed by those of the underlying condition. One review found that patients can develop severe jaundice with bilirubin levels as high as 40 mg/dL . Aminotransferase levels are usually less than five times the upper limit of normal, while the alkaline phosphatase levels are usually less than four times the upper limits of normal.
The diagnosis remains one that depends upon excluding other causes, especially those that are amenable to intervention. A liver biopsy is rarely required, but when it has been performed, it has shown centrilobular congestion and cholestasis .
Despite the name, the course is not always benign. Prognosis depends mainly upon the underlying condition. In those who recover, jaundice will resolve gradually over weeks to months.
Bacterial infections — Severe bacterial infections are commonly associated with cholestasis. Contributing causes include hypotension, hemolysis, medications, and bacterial endotoxins, which downregulate bilirubin and bile salt transporters. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia", section on 'Sepsis and low perfusion states'.)
In one review of the literature, the total bilirubin was between 5 and 50 mg/dL, the alkaline phosphatase between two to three times the upper limit of normal, and the aminotransferases only mildly elevated . Diagnosis is usually established by the clinical context and exclusion of other causes. A liver biopsy is generally not needed. In one review of biopsies obtained immediately after death in 15 patients with sepsis, the most common findings were centrilobular necrosis (80 percent), portal inflammation (73 percent), steatosis (73 percent), lobular inflammation (67 percent), hepatocellular apoptosis (67 percent), and cholangitis/cholangiolitis (20 percent) .
EVALUATION — Evaluation is based upon a careful history, review of medications, perioperative course, and laboratory and imaging tests. The following checklist can help to guide evaluation:
●Does the patient have known liver disease or risk factors for liver disease such as a history of alcoholism, intravenous drug use, a family history of liver disease?
●Are there any preoperative liver biochemical tests or imaging tests?
●Are there postoperative imaging tests?
●Did the patient receive transfusions?
●What was blood loss around surgery?
●Was this a trauma patient with significant soft-tissue bleeding?
●Did the patient receive a cardiopulmonary bypass or an intra-aortic balloon pump?
●Did the patient have upper abdominal surgery in which the bile duct could have been injured?
●Does the patient have heart failure now, or did the patient have heart failure preoperatively?
●Does the pattern of liver biochemical and other laboratory tests provide clues? For example, does the patient have evidence of hemolysis (eg, indirect hyperbilirubinemia, circulating spherocytic red cells, increased lactic dehydrogenase concentration, reduced serum haptoglobin, increased reticulocyte count or percentage)? Did the aminotransferases rise to high levels that could be supportive of ischemic hepatitis?
●What type of anesthesia did the patient receive?
●Did the patient receive drugs known to be associated with drug-induced liver disease?
●Was the patient septic?
●Is the patient febrile?
●Does the patient have stigmata of chronic liver disease (eg, spider angiomata, hepatosplenomegaly, ascites, and gynecomastia)?
●Does the patient have right upper quadrant pain?
●Does the patient have any biochemical evidence of acute liver failure or chronic liver disease? Is their evidence of synthetic dysfunction? Is the serum albumin level low?
●Does the patient have an elevated INR that cannot be explained by cholestasis or malnutrition? Were these abnormalities present prior to the patient's procedure?
●If a patient has an elevation in the INR, can this be explained by a coagulopathy or clotting disorder? If not, could the elevation be caused by acute liver failure?
Further diagnostic evaluation should be based upon the history obtained above. As a general rule, we obtain a right upper quadrant ultrasound if imaging has not already been performed. A CT scan, MRI, or MRCP may also be needed, depending on the clinical context. We also obtain hepatitis serology (HBsAg, HBsAb, HBeAg, HCV ab or RNA, HAV IgM).
MANAGEMENT AND PROGNOSIS — Management and prognosis depend upon the underlying cause and the identification of causes for which specific intervention is possible . As noted above, patients with biliary tract obstruction from bile duct injury may require endoscopic, radiologic, or surgical intervention. Patients in whom drug-induced liver injury is suspected should receive alternative medications. Patients with acalculous cholecystitis should receive appropriate percutaneous or surgical therapy. In other patients, the clinical course largely depends upon the resolution of the underlying condition (such as sepsis).
Jaundice will resolve in weeks to months after the underlying causes have resolved. If the bilirubin elevation is minor, follow-up testing can be performed less frequently on a weekly basis or less frequently until resolution. If the bilirubin elevation is high, follow-up testing should be performed more frequently at least until it begins to decline for more than one day.
Jaundice that persists beyond the initial postoperative period and that cannot be explained needs to be pursued. Alternative explanations that are not directly related to the patient's procedure need to be explored further and liver biopsy may be considered.
Patients with severe cholestasis may have an elevated prothrombin time, which may respond to vitamin K. Prolonged cholestasis may lead to malabsorption of fats and other fat soluble vitamins, and thus nutritional evaluation may be required. INR should be monitored until normalization unless another explanation such as a coagulopathy or medication is provided.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal liver biochemical tests".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Jaundice in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Postoperative jaundice is defined as the presence of bilirubin elevation with or without clinical icterus appearing in the period following surgery.
●We have found it useful conceptually to subdivide postoperative jaundice into three categories: prehepatic, intrahepatic, and posthepatic. However, the cause of jaundice is usually multifactorial. (See 'Classification' above.)
●Evaluation is based upon a careful history, review of medications, perioperative course, and laboratory and imaging tests. The checklist described above can provide a framework for evaluating the patient. (See 'Evaluation' above.)
●Management and prognosis depend upon the underlying cause and the identification of causes for which specific intervention is possible. (See 'Management and prognosis' above.)
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