Symposium on Diseases of the Liver
Postoperative Jaundice Raymond S. Koff, MD.*
A wide spectrum of postoperative hepatic dysfunction exists, ranging from trivial abnormalities to deep jaundice simulating extrahepatic obstruction or hepatic failure. Transient and minimal elevations of serum transaminases and abnormal bromosulphophthalein metabolism, commonly observed within 72 hours of uneventful anesthesia and surgerY,6.!! are nonspecific and of no clinical importance. Another common phenomenon is the development of postoperative jaundice or striking impairment of hepatic function in patients with pre-existing cirrhosis or other intrinsic liver disease recognized in the preoperative period. Severe jaundice may accompany renal failure in the postoperative period. Regardless of the primary mechanism, impaired renal function depresses renal excretion of conjugated bilirubin, leading to extreme hyperbilirubinemia. Patients with the hereditary hyperbilirubinemias, Gilbert's syndrome (an unconjugated hyperbilirubinemia), and the Dubin-Johnson syndrome (conjugated and unconjugated hyperbilirubinemia, impaired hepatic anion excretion, and melanin pigmentation of hepatocytes) may experience striking increases in hyperbilirubinemia after the stress and fasting associated with surgical procedures in the absence of overtly increased pigment loads, parenchymal disease or extrahepatic bile duct obstruction. The remaining causes of postoperative jaundice and hepatic dysfunction may be classified into three broad groups (Table 1): postoperative jaundice due to overproduction of bilirubin; postoperative hepatocellular disease; and postoperative extrahepatic biliary tract obstruction.
POSTOPERATIVE OVERPRODUCTION OF BILIRUBIN Although the normal liver may be able to conjugate and excrete a bilirubin load 2 to 3 times greater than that usually handled, in some patients, for reasons still unknown, jaundice caused by impaired uptake, conjugation, and hepatic excretion of bilirubin may develop when the bilirubin load resulting from hemolysis is only moderately increased. Although unconjugated hyperbilirubinemia is characteristic of hemolysis, the conjugated bilirubin fraction may also rise owing to an associated, "Chief, Hepatology Section, Veterans Administration Hospital; Associate Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts
Medical Clinics of North America- Vol. 59, No. 4, July 1975
Classification of Postoperative Jaundice
I. Pre-existing hepatocellular diseases II. Hereditary, familial disorders of bilirubin metabolism III. Overproduction of bilirubin A. Hemolysis 1. Transfusion-associated 2. Chronic hemolytic states 3. Glucose-6-phosphate dehydrogenase deficiency 4. Open heart surgery B. Hematoma resorption and pulmonary embolism IV. Hepatocellular disease A. Hepatitis-like 1. Viral hepatitis 2. Post-pump syndrome 3. Drug and anesthetic-induced hepatitis 4. Impaired perfusion a. Congestive heart failure b. Shock c. Hypoxemia B. Intrahepatic cholestasis 1. Sepsis 2. Drug-induced cholestasis 3. Postoperative cholestasis C. Fatty liver and/or cirrhosis following intestinal bypass D. Hepatic resection E. Hepatic dysfunction following liver transplantation V. Extrahepatic biliary tract obstruction following bile duct surgery VI. Acute postoperative cholecystitis VII. Postoperative pancreatitis
unexplained excretory impairment often observed following anesthesia for surgery. Transfusion-associated hemolysis may result from either the premature destruction of transfused exogenous red cells in blood stored for prolonged periods or from hemolytic transfusion reactions. Within the first 24 hours after transfusion, approximately 10 per cent of 2 week old and 20 per cent of 3 week old erythrocytes are destroyed. 14 This premature hemolysis yields approximately 250 and 500 mg of bilirubin per unit respectively. Transfusion of multiple units of stored red cells will result in a bilirubin load exceeding the capacity of the liver to take up, conjugate, and excrete the pigment, resulting in mild clinical jaundice. Hemolytic in vivo transfusion reactions are uncommon and may not become apparent until several days after the transfusion, since seriously ill patients may have defects in the mechanisms responsible for the rapid removal of injured red cells from the circulation. 17 The resulting hyperbilirubinemia resulting from immune hemolysis may be delayed. Excessive hemolysis may result from the stress of surgery in patients with chronic hemolytic states such as sickle cell anemia. A striking hemolysis and hyperbilirubinemia may develop in patients with glucose-6-phosphate dehydrogenase deficiency after exposure to a variety of drugs received before, during, or after surgery. Severe infection may also precipitate hemolysis in these patients in the absence of drug exposure. Drug-induced hemolysis has also been observed in patients with so-called "unstable" hemoglobins. Infrequently, hemolysis occurs following open-heart surgery be-
cause of physical trauma and fragmentation of red cells resulting in enhanced sequestration and destruction of the affected cells. After heart-valve prosthetic surgery a Coombs-positive autoimmune hemolytic anemia has been observed in a few patients. Hematoma resorption may also result in an increased pigment load. The duration of the associated hyperbilirubinemia may be prolonged. Mild jaundice may occur in pulmonary embolus and infarction as a result of destruction of red cells in areas of hemorrhagic infarction as well as resulting from impaired liver function owing to right heart congestion.
POSTOPERATIVE HEPATOCELLULAR DISEASE Liver cell injury and frank necrosis may be related to a number of events occurring before, during, or after surgery. Injury may be manifest by a striking elevation of serum transaminase levels. If damage is extensive, the synthetic function of the liver will be affected, and prothrombin time prolonged. Subsequently, serum albumin level may be depressed. In some instances hepatic encephalopathy ensues. Bilirubin and alkaline phosphatase levels are variably elevated. Although this pattern of hepatic injury may be described as hepatitis-like, and may result from viral or drug hepatitis, other etiologic factors may be responsible. The pattern of injury may be less clear-cut, however, and may resemble more closely that seen in extrahepatic obstruction or intrahepatic cholestasis. In these instances serum transaminases may be modestly increased, serum albumin normal, and prothrombin time normal unless cholestasis.is prolonged. Jaundice may be the salient clinical feature and elevation of serum alkaline phosphatase levels may be the most striking biochemical abnormality. A mixed picture of hepatocellular necrosis and cholestasis is frequently encountered in patients with postoperative hepatic dysfunction.
HEPATOCELLULAR DISEASE Postoperative Virjil Hepatitis Sporadic nonparenterally transmitted hepatitis A or B might be expected to occur ocgasionally in individuals exposed to infectious contacts prior to surgery. There is no evidence to support the concept that the stress of anesthesia and surgery activates latent hepatitis virus infection. In contrast, the presence of clinically apparent viral hepatitis at the time of surgery is associated with a high risk of serious postoperative complications. 7 Elective surgery is therefore contraindicated in patients with known pre-existing viral hepatitis.
Post-Pump (Extracorporeal Circulation) Syndrome A syndrome characterized by focal hepatic necrosis and hepatic inflammation has been observed in a number of patients 3 to 8 weeks after extracorporeal circulation. Fever, splenomegaly, atypicallymphocytosis, and abnormal liver function tests indicate anicteric hepatitis. AI-
though other agents may occasionally be responsible, cytomegalovirus, most likely introduced in blood transfused during extracorporeal circulation, has been isolated from a number of affected patients and cytomegalovirus antibody titer has increased. 4 Drug and Anesthetic-Induced Hepatitis Drug-induced hepatitis may simulate viral hepatitis or extrahepatic obstruction or a combination of both. A thorough history of drug exposure extending well into the preoperative period and recognition of extrahepatic allergic reactions, urticaria, rash, arthralgia, fever, leukocytosis, and eosinophilia accompanying or preceding the hepatic dysfunction will suggest the diagnosis. Impaired Perfusion Syndromes Regardless of the underlying cause, diminished cardiac output, shock, or hypoxemia lead to decreased hepatic blood flow or hepatic oxygen supply, or both. Centrizonal hepatic parenchymal cell degeneration or necrosis may result. Acute right-sided heart failure is associated with clinical jaundice in less than 5 per cent of affected patients. Mild hyperbilirubinemia is considerably more common and the unconjugated fraction may be increased. Although total serum bilirubin levels greater than 10 mg per dl and transaminase levels above 500 u have been recorded in severe congestive heart failure, with extensive centrilobular necrosis, the existence of strikingly elevated bilirubin levels in such patients always raises the suspicion of pulmonary infarction. The severity of the centrizonal hepatic necrosis associated with shock and hypoxemia appears to be related to the duration of the impaired perfusion state, as well as to the severity of the hypoxemia. Jaundice of variable degree, moderate to striking elevations of serum transaminases, and impaired synthetic function, reflected by a prolongation of the prothrombin time, and hepatic encephalopathy are occasionally observed. Recovery is a regular feature, provided the underlying process can be controlled. When it cannot be corrected, fatal massive hepatic necrosis may ensue. Even in the absence of recognized hemolysis, cardiopulmonary bypass surgery has been associated with postoperative jaundice, presumably because of impaired hepatic perfusion. Most affected patients become jaundiced within a few days of surgery and serum bilirubin usually reaches its maximum level between the seventh and tenth postoperative days. In a minor proportion of patients who have undergone cardiopulmonary bypass, jaundice becomes evident during the second postoperative week. In this group of patients serum transaminase levels may be extremely high, reflecting extensive centrilobular necrosis. Postoperative Intrahepatic Cholestasis Jaundice may be the initial manifestation of intra-abdominal and less commonly intrathoracic sepsis. Regardless of whether subphrenic or perinephric abscess, pyelonephritis, appendicitis, or other lesions are responsible, intra-abdominal infection may produce the clinical picture of intrahepatic cholestasis. Although such septic states may be accompanied by hemolysis and increased pigment loads, cholestasis with minimal hepatocyte degeneration is the predominant histologic alter-
ation and occurs without direct invasion of the liver by bacteria. High fever, leukocytosis, and elevated alkaline phosphatase with cholestatic jaundice in the postoperative period should always suggest the possibility of intra-abdominal sepsis or ascending cholangitis. Single or multiple hepatic abscesses are manifest by chills, fever, leukocytosis, right upper quadrant abdominal pain, and hepatic enlargement with minimal abnormalities in liver function tests. Jaundice is infrequent unless cholangitis or multiple abscesses are present. Acute suppurative cholangitis with miliary hepatic abscesses due to extrahepatic biliary tract obstruction may be a difficult diagnostic problem since it is frequently associated with moderately high elevation of serum transaminases. 2 Postoperative intrahepatic cholestasis rarely may be the clinical manifestation of post-transfusion viral hepatitis. In the absence of relevant drug or viral exposure, there remains a group of patients who develop jaundice on the first or second postoperative day!6 Peak hyperbilirubinemia, which may reach levels as high as 40 mg per dl, occurs on the third to tenth days following surgery. Serum transaminase levels are normal or mildly elevated and serum alkaline phosphatase levels are variable. Jaundice recedes and usually disappears during the third postoperative week. Liver biopsy discloses cholestasis without hepatocyte necrosis or inflammatory changes. This entity has been termed benign postoperative intrahepatic cholestasis. 16 The term "benign" seems inappropriate in this setting since half the patients were considered poor operative risks, and, in fact, half of these died of extrahepatic complications. None developed hepatic coma or evidence of hepatic failure. Severe postoperative intrahepatic cholestasis, simulating obstructive jaundice, may also be seen, particularly in elderly patients who have has surgery for cardiovascular disease. lo In these patients, diminished renal glomerular filtration may have contributed in part to the striking bilirubin levels because of impaired renal bilirubin excretion. Serum alkaline phosphatase levels were markedly evevated in approximately 50 per cent of cases and peak levels were reached after the maximal bilirubin rise in about 50 per cent of patients. Serum transaminase levels were usually below 300 u. Postoperative liver dysfunction was probably due to a number of factors: prolonged hypotension, impaired hepatic perfusion, congestive heart failure, pigment overload, and sepsis, each contributing to impaired hepatic excretory function. All affected patients died without evidence of liver failure and postmortem examination revealed only cholestasis with minimal centrizonal hepatocyte degeneration.
Fatty Liver and/or Cirrhosis After Intestinal Bypass Surgery Massive triglyceride accumulation and postoperative hepatic dysfunction varying between mild abnormalities of liver chemistries and deep jaundice associated with hepatic coma has been observed in patients undergoing intestinal bypass for control of morbid obesity.1.8 In some instances, cirrhosis has been demonstrated after bypass surgery. It has been thought that jejunal-ileal bypass surgery is less frequently associated with the development of liver disease than jejunal-colic bypass; however, convincing data to support this notion are not yet available. AI-
though essential amino or fatty acid deficiency may be implicated, the pathophysiologic mechanism of post-bypass hepatic disease remains to be determined.
Hepatic Resection Postoperative jaundice, elevated serum alkaline phosphatase, a progressive decline in serum albumin, and prolongation of prothrombin time are commonly observed after major hepatic resection. The extent of resection and the functional capacity of the nonresected liver mass are the major determinants of both the severity and the duration of the postoperative abnormalities. Liver Transplantation Septic hepatic infarction after liver transplantation is manifest by fever, marked elevation of serum transaminase levels, mild hyperbilirubinemia, filling defects on hepatic scanning and gram-negative bacteremia. 5 This complication has been reported as early as 2 days and as late as 3 months after transplantation and is presumably due to mechanical distortion of the hepatic arterial tree. Hepatic necrosis after hepatic artery ligation is rare if hepatic oxygenation and portal venous inflow are normal, since the hepatic arteries are not end arteries,13 as was formerly believed. In the acute syndrome of hepatic rejection, clinical manifestations may resemble those observed in biliary obstruction. 12 Liver biopsy, immunologic testing, and radiologic visualization of the biliary system may be helpful in making this distinction. In the chronic hepatic rejection syndrome, cirrhosis has been observed as a sequel.
EXTRAHEPATIC BILIARY TRACT OBSTRUCTION AFTER BILE DUCT SURGERY Retained biliary calculi may occur following common duct exploration for gallstone obstruction. 3 Percutaneous or retrograde cholangiography may demonstrate the site of obstruction before reoperation, if extrahepatic obstruction becomes manifest after removal of the T-tube. In the absence of biliary stones, mild jaundice with minimal elevation of serum transaminase levels, and normal or elevated levels of serum alkaline phosphatase, has been described infrequently following cholecystectomy for acute cholecystitis. 15 The setting in which this complication occurs raises the suspicion of retained biliary calculi. However, the jaundice is transient and calculi cannot be demonstrated. Although inflammation and hepatic necrosis may be found at the site of the gall bladder bed, their role in the mechanism of post-cholecystectomy jaundice is uncertain. Bile duct injury with stricture formation occurs most often after cholecystectomy, and the junction of the cystic and common hepatic ducts is the most common site of injury. Approximately 50 per cent of affected patients develop hyperbilirubinemia within 2 to 5 days of surgery and typically present clinical features of obstructive jaundice with cholangitis. In the remainder incomplete obstruction of a narrowed duct may subsequently become complete when complicated by
cholangitis. Clinical features may then appear weeks to years after surgery. In rare instances, the common bile duct is inadvertently ligated. Progressive jaundice is evident in as early as 12 to 48 hours, but almost always within a week of surgery. External or internal biliary fistula formation follows accidental transection of the bile duct. Reoperation with repair is mandatory when the duct has been either totally occluded or transected.
ACUTE POSTOPERATIVE CHOLECYSTITIS Acute cholecystitis is an uncommon postoperative complication which may follow nonbiliary tract and, in fact, extra-abdominal surgery.9 Though approximately 50 per cent of affected patients have noncalculous cholecystitis, the mechanisms responsible are uncertain. Jaundice may develop in about 30 per cent, suggesting surgically remediable extrahepatic bile duct obstruction, but it should be noted that even in these patients, evidence of obstruction may not always be found at reoperation. The clinical presentation, with onset within a few days to as long as 4 weeks after surgery, includes abdominal pain, nausea, vomiting, and fever. Abdominal tenderness, a right upper quadrant mass, and leukocytosis are commonly noted. Liver function tests reveal mild abnormalities. At surgery, gangrenous changes in the gall bladder will be demonstrated in about one third.
POSTOPERATIVE PANCREATITIS Acute postoperative pancreatitis has been described most frequently after gastric and biliary tract surgery. Jaundice may occur in about 30 per cent of patients, presumably because of interference with biliary flow as a result of edema and inflammation in the head of the pancreas. Direct trauma to the gland or interference with its blood supply or drainage have been postulated to be responsible factors, and in some instances concurrent biliary tract disease may be present. Pancreatitis has also been reported after surgical procedures anatomically unrelated to the pancreas, and in the absence of biliary tract disease. Postoperative hemorrhagic pancreatitis with jaundice after renal transplantation has been a primary cause of death in a few patients. 1s Whether pretransplant uremia, drug treatment, or other factors are responsible for pancreatitis in these immunosuppressed patients remains to be determined. Hepatology Section Veterans Administration Hospital Boston, Massachusetts 02130