Jaundice

434 T.J. Kearney

sign). The patient’s urine is dark and his stools gray, sometimes with silver streaks.

Case 3

A 23-year-old man presents to the emergency room with fatigue and jaundice. The patient is an intravenous drug user. Examination reveals an enlarged, tender liver. The urine is dark, but his stools are brown. The bilirubin level is mildly elevated, but alkaline phosphatase is normal. Serum transaminases are very high. A hepatitis panel is obtained.

Introduction

The appearance of jaundice in a patient is a visually dramatic event. It invariably is associated with significant illness, although long-term outcome is dependent on the underlying cause of the jaundice. Jaundice is a physical finding associated with a disturbance of bilirubin metabolism. It often is accompanied by other abnormal physical findings and usually is associated with specific symptoms. The student should be able to classify jaundice broadly as obstructive or nonobstructive based on history and physical examination. The appropriate use of blood tests and imaging allows further refinement of the differential diagnosis.

In general, nonobstructive jaundice does not require surgical intervention, whereas obstructive jaundice usually requires a surgical or other interventional procedure for treatment. Greater emphasis is placed on surgical jaundice than on medical jaundice in this chapter.

Bilirubin Metabolism and the Classification of Jaundice

Bilirubin is a normal body product that results from the breakdown of heme primarily from red blood cells but also from other body constituents. This bilirubin, known as unconjugated or indirect bilirubin, is bound to albumin and is not water-soluble. Indirect bilirubin is transported into hepatocytes. There it is conjugated with glucuronic acid to form conjugated bilirubin. Conjugated bilirubin is soluble in water and also is referred to as direct bilirubin. The conjugated bilirubin then is released into the biliary tree and from there into the intestinal tract. In the colon, the bilirubin undergoes further conversion into several products, including urobilinogen. A portion of the urobilinogen is reabsorbed, while the remainder passes in the stools. The brown color of normal stool is due to these breakdown products of bilirubin metabolism.

An interruption in any portion of the metabolic pathway can result in an excess of bilirubin and the clinical syndrome of jaundice. Patients with jaundice have yellow skin, usually with itching. The sclerae usually are the first site of color abnormality, typically becoming yellow with a bilirubin level of about 2.5 mg/dL. Skin yellowing is evident at levels of 4 to 5 mg/dL, depending on skin pigmentation.

24. Jaundice 435

The urine usually is dark, since the kidneys excrete the excess bilirubin. Stools may be gray if no bilirubin is excreted into the intestinal tract as in obstructive jaundice. Gray stool usually is a sign of complete lack of bilirubin excretion into the intestinal tract. In medical or nonobstructive jaundice, bilirubin does pass into the intestinal tract and the stools remain brown. These signs and symptoms are common to all patients with jaundice. Additional signs and symptoms may be present depending on the cause of the jaundice. These accompanying findings often contain the key to proper classification of the jaundice.

It is clear that multiple mechanisms can produce jaundice. Overproduction of bilirubin from hemolysis can overwhelm the liver’s ability to excrete. Hemolysis may be secondary to a congenital hemolytic syndrome or may be acquired in transfusion reactions, trauma, or sepsis. Deficiencies of unconjugated bilirubin uptake into the hepatocytes can produce jaundice. The most common reason for this is Gilbert’s syndrome, a congenital reduction in the enzyme bilirubin glucuronyl transferase. This condition affects about 5% to 7% of the general population. Sepsis and certain drugs (e.g., rifampin) also can impair uptake. In neonates, immaturity of the conjugating and transport system can cause jaundice. These conditions are considered prehepatic jaundice.

Hepatic jaundice, most commonly from viral hepatitis, results from hepatocyte dysfunction. Other acquired or congenital conditions, including alcoholic hepatitis, Wilson’s disease, hepatic cirrhosis, drug reactions, primary biliary cirrhosis, and exposure to hepatotoxins (carbon tetrachloride, acetaminophen), may cause hepatic jaundice. Patients may progress to complete hepatic failure. Genetic defects, such as Dubin-Johnson and Rotor’s syndrome, may be responsible for impaired excretion of conjugated bilirubin.

Finally, posthepatocyte obstruction to bile flow can produce jaundice. This final cause often is called surgical or obstructive jaundice due to the requirement for an intervention in most cases in order to relieve the obstruction. Obstructive jaundice can be divided further into benign and malignant obstruction.

Algorithm 24.1 lists a schema for a general classification of jaundice: prehepatic, hepatic, and posthepatic. Obstructive jaundice often is referred to as posthepatic since the defect lies in the pathway of bilirubin metabolism past the hepatocytes. The other forms of jaundice are referred to as nonobstructive jaundice. These forms are due to a hepatocyte defect (hepatic jaundice) or a prehepatic condition. Table 24.1 lists some common and uncommon causes of the three major categories of jaundice: prehepatic, hepatic, and posthepatic.

Obstructive Jaundice

Benign Stone Disease

In Case 1 the patient is acutely ill with jaundice. The previous right upper quadrant pain suggests biliary colic from gallstones. Tenderness in the right upper quadrant (Murphy’s sign) suggests cholecystitis. The

24. Jaundice 437

Table 24.1. Classification and causes of jaundice.

biliary sepsis and require urgent intervention to decompress the biliary system.

The patient in Case 1 was placed on intravenous antibiotics to cover the most common biliary pathogens: Klebsiella, Escherichia coli, and Enterococcus. Blood tests for bilirubin revealed elevated direct and indirect bilirubin. The combined bilirubin level was 7.3 mg/dL. The presence of elevated direct bilirubin implies that this is not just prehepatic jaundice. Prehepatic jaundice from hemolysis rarely causes a bilirubin level above 5.0 mg/dL in the absence of other hepatic dysfunction. The alkaline phosphatase level was elevated markedly, but the transaminases were normal. This pattern suggests biliary obstruction without any inherent abnormality of the hepatocytes. Other useful markers of hepatocyte function include prothrombin time and albumin. The proteins required for the coagulation pathway as well as albumin are synthesized in the liver. Abnormalities suggest hepatocyte dysfunction. Elevated prothrombin time usually responds to vitamin K administration in obstructive jaundice but not in hepatic jaundice. These levels were normal in this patient. Amylase and lipase levels also should be evaluated due to the association between choledocholithiasis and pancreatitis (gallstone pancreatitis). This patient had mildly elevated amylase. This pattern of abnormalities suggests biliary obstruction with normal hepatocytes (Table 24.2). The history is suggestive of benign biliary obstruction.

An ultrasound was ordered; it revealed stones in the gallbladder with gallbladder wall thickening and a dilated common bile duct. A stone could be seen in the distal common bile duct. The normal common bile duct should be under 10 mm in diameter. Ultrasound is the procedure of choice for patients with suspected benign obstructive jaundice from gallstone disease (see Algorithm 24.1). The main limitation of ultrasound is its inability in many cases to visualize the most distal portion of the common bile duct due to duodenal or colonic gas.

438 T.J. Kearney

Table 24.2. Evaluation of liver function tests in jaundice.

Source: Reprinted from Mulvihill SJ. Pancreas. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001, with permission.

This patient needs two interventions for two problems. The impacted stone needs to be removed from the common bile duct. The gallbladder needs to be removed to prevent future episodes of common duct stones and to relieve the cholecystitis. In previous decades, the patient would have undergone open cholecystectomy with open cholangiography and common bile duct exploration (CBDE).

With the advent of laparoscopic and endoscopic techniques in the 1990s, the management plan becomes more complex. Individual hospital and physician abilities may influence the choice and timing of procedures.

Patients with cholelithiasis are quite common. In general, asymptomatic cholelithiasis does not require treatment. The condition results from an imbalance among levels of bile acid, lecithin, and cholesterol in the gallbladder. There are several scenarios in which patients with asymptomatic cholelithiasis should consider prophylactic cholecystectomy. These include patients with hematologic disorders, such as sickle cell disease or hereditary spherocytosis. Immunocompromised patients and patients requiring immunosuppression (e.g., renal transplant) with cholelithiasis should undergo cholecystectomy. The signs of acute cholecystitis can be masked by the immunosuppressive state. Cholecystectomy in diabetic patients formerly was thought to require prophylactic surgery due to the high rate of gangrenous cholecystitis. This recommendation is controversial, however. Patients with a porcelain gallbladder have a high rate of harboring gallbladder cancer and should have surgery. The majority of otherwise normal patients with asymptomatic cholelithiasis will not suffer an episode of cholecystitis. Prophylactic surgery is not recommended.

24. Jaundice 439

Patients with mildly symptomatic cholecystitis can be managed safely in most cases with laparoscopic cholecystectomy. Although shock-wave lithotripsy, bile acids, and gallbladder perfusion with solvents all have been tried to dissolve gallstones, surgery remains the main form of therapy. In elective cases, the rate of conversion to open cholecystectomy is under 5%, and the rate of bile duct injury (a rare but extremely serious complication) is about 3 per 1000 cases. Patients undergoing elective laparoscopic cholecystectomy with normal liver function tests rarely have common bile duct (CBD) stones and do not require an intraoperative cholangiogram, provided the anatomy is delineated clearly. Mildly elevated bilirubin or alkaline phosphatase levels or a history of jaundice or pancreatitis make CBD stones more likely. An intraoperative cholangiogram would be prudent in such circumstances. The discovery of CBD stones would require laparoscopic or open CBD exploration or postcholecystectomy endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction. The gallbladder always should be inspected at the time of removal to evaluate for the rare case of unsuspected gallbladder cancer.

Gallbladder cancer is seen in about 1 of 200 cholecystectomy specimens and is the fifth most common gastrointestinal tract cancer in the United States. Stage I gallbladder cancer (confined to the mucosa) is treated with simple cholecystectomy. Advanced gallbladder cancer (stages III and IV) rarely is curable. The treatment of stage II gallbladder cancer (no extension beyond the serosa or into the liver) is controversial, but most experts would recommend radical cholecystectomy, which includes removal of the gallbladder and a wedge of the hepatic gallbladder bed along with a biliary node dissection.

Patients with suspected acute cholecystitis are managed best with intravenous hydration, antibiotics, and cholecystectomy within 24 to 48 hours. The diagnosis is made by history and physical exam and confirmed with ultrasound or occasionally by biliary scintigraphy using technetium 99 m (99mTc)-labeled hepatic 2,6-dimethyl-iminodiacetic acid (HIDA) compounds scan. The practice of “cooling down” the patient and scheduling elective cholecystectomy at a later date is less desirable than early cholecystectomy. This approach has been validated by clinical trials (Table 24.3). Originally, acute cholecystitis was felt to be a contraindication to laparoscopic cholecystectomy. The majority of patients today can undergo laparoscopic cholecystectomy in the setting of acute cholecystitis if an experienced surgeon is available.

Cholecystectomy, whether laparoscopic or open, does not address the management of patients presenting with CBD stones (choledocholithiasis). At many institutions, this patient would undergo ERCP with endoscopic sphincterotomy (ES). A CBD stone would be found in the majority of patients, and the stone could be extracted in greater than 90% of patients. The patient then would undergo laparoscopic cholecystectomy. If the ERCP with ES was unsuccessful, CBD exploration would be needed; CBD exploration could be either open or laparoscopic. Another option would be laparoscopic cholecystectomy with planned laparoscopic common bile duct exploration, skipping the preoperative ERCP. Laparoscopic CBDE can be accomplished with a

442 T.J. Kearney

Table 24.4. Periampullary cancer.

Pancreatic adenocarcinoma

Cholangiocarcinoma of distal common bile duct

Ampullary cancer

Duodenal cancer

transcystic duct approach or via a choledochotomy. This procedure requires advanced laparoscopic skills. The patient also could be managed primarily with an open cholecystectomy with intraoperative cholangiogram. Open common bile duct exploration then could be performed. Finally, ERCP and ES could follow laparoscopic cholecystectomy. However, this last scenario might require further intervention if common duct stones were seen but could not be extracted via ERCP with ES. Ultimately, the experience of the surgical team and gastroenterologist and the availability of specialized equipment influence the exact management algorithm at a particular institution.

Malignancy

Case 2 also presents a patient who is quite ill. The history of insidious onset of jaundice with weight loss strongly suggests a malignancy. The dilated gallbladder locates the patient’s obstruction at a point distal to the junction of the common hepatic duct with the cystic duct. His laboratory profile, with elevated bilirubin and alkaline phosphatase, would be similar to that of the first patient. His albumin might be low due to poor nutrition. Although ultrasound could be used as an initial screening test, computed tomography (CT) of the abdomen would be a better choice (see Algorithm 24.1). This patient almost certainly has cancer. An evaluation of the periampullary area is accomplished better with fine-cut CT. In addition, metastases can be identified and surgical resectability often can be predicted based on local involvement of the superior mesenteric artery and vein.

Periampullary cancer usually occurs from one of the four causes listed in Table 24.4. This patient has an ampullary cancer, one of the rarer causes of periampullary obstruction. The silver streaks in the gray stools represent intermittent bleeding into the lumen of the duodenum. The blood coats the gray stools, causing a silver discoloration. Usually, pancreatic adenocarcinoma is the cause of malignant periampullary obstruction. Patients without signs of distant metastases and without signs of local unresectability are candidates for pancreaticoduodenec- tomya—Whipple procedure. The cure rate (survival at 5 years) is about 20%. Survival from bile duct, ampullary, and duodenal cancers is slightly better then for pancreatic adenocarcinoma.

Most experienced pancreatic surgeons prefer direct referral without any other interventional studies. There is no convincing evidence that preoperative biliary decompression provides any advantage to patients with resectable lesions, and it may be harmful. Patients with distant metastases or local unresectability almost always should undergo ERCP with placement of a biliary stent. This relieves obstruction. Brush

24. Jaundice 443

biopsy often can provide a diagnosis, and the patient can receive palliative systemic therapy without requiring an operation. In some cases, local resectability is not clear after CT imaging. Angiography can be used to assess potential involvement of unresectable vessels. Newer technologies, such as endoscopic ultrasound (EUS), magnetic resonance cholangiopancreatography (MRCP), and magnetic resonance angiography (MRA), can provide additional anatomic information.

Another cause of malignant biliary obstruction is cholangiocarcinoma. This rare tumor occurs much less frequently then pancreatic cancer. When obstruction occurs in the distal common bile duct, the patient is managed as a patient with periampullary cancer. Intrahepatic cholangiocarcinoma usually does not cause jaundice, since a portion of the liver remains unobstructed. Cholangiocarcinoma in the common hepatic duct or at the bifurcation of the right and left hepatic duct (Klatskin’s tumor) represents the most common site of extrahepatic cholangiocarcinoma. Patients present with obstructive jaundice, but they typically do not have a dilated gallbladder. Ultrasound reveals dilated intrahepatic ducts, but it also reveals a collapsed extrahepatic system and gallbladder. Percutaneous transhepatic cholangiography (PTC) is preferred to ERCP for upper bile duct tumors due to better delineation of the proximal extent of the tumor. Stents can be placed percutaneously for palliation in unresectable cases. If the tumor is localized and there are no distant metastases, resection is indicated. The entire extrahepatic biliary system is removed, and biliary drainage is reestablished with a Roux-en-Y hepaticojejunostomy. Occasionally a partial hepatectomy is required to provide a negative margin of resection. Aggressive surgical resection of hilar bile duct cancer can produce cure (5-year survival) in about 20% of patients.

Uncommon Causes

There are other rare causes of biliary obstruction that are not related to cancer but that are not secondary to gallstone disease either (Table 24.5). They are mentioned here for completeness. Benign bile duct strictures can result from operative injury. The rate of bile duct injury from laparoscopic cholecystectomy is estimated at 0.3%, higher than the 0.1% estimate from the open cholecystectomy era. Patients often are managed initially with endoscopic balloon dilation and stent placement. Long-term success usually requires definitive surgical excision, with reconstruction similar to malignant biliary strictures. The other cause of benign biliary stricture that must be mentioned is sclerosing cholangitis: an inflammatory narrowing of the biliary ducts usually

Table 24.5. Uncommon causes of biliary obstruction.

Benign biliary stricture (iatrogenic)

Sclerosing cholangitis

Biliary atresia

Choledochal cyst

444 T.J. Kearney

associated with inflammatory bowel disease. The rise in bilirubin is more gradual. The disease ultimately results in cirrhosis of the liver. Patients with isolated strictures are rare and can be treated with resection. Usually, liver transplantation is required once end-stage liver disease occurs. A congenital cause of biliary obstruction is biliary atresia. These pediatric patients require decompressive hepatic portoenterostomy (Kasai procedure). Many of these patients progress to further biliary obstruction, cirrhosis, and eventual liver transplantation. Finally, choledochal cysts, an entity with unknown etiology that can be congenital or acquired, can require resection and bilioenteric reconstruction.

Hepatic Jaundice

Viral Hepatitis

The patient’s presentation in Case 3 suggests nonobstructive jaundice. This patient is at high risk of viral hepatitis due to his IV drug usage. He also should be tested for HIV infection. Other conditions also can result in hepatocyte injury. These include alcoholic hepatitis, cirrhosis, and drug or toxin induced hepatocellular injury. Patients with such illnesses have a clinical picture consistent with liver malfunction and failure, and the jaundice is merely a representation of this underlying liver failure. Often, liver biopsy is required to confirm a diagnosis in equivocal situations (see Algorithm 24.1). There usually is no requirement for surgical intervention, except for cases of fulminant hepatic failure or end-stage liver disease requiring liver transplantation.

Medical management of viral hepatitis is generally supportive. Treatment for chronic hepatitis B includes the use of interferon or lamivudine. Both hepatitis A and B can be prevented through preexposure vaccination. Hepatitis immune globulin can be used for postexposure prophylaxis. Medical management of alcoholand toxin-induced liver damage also is primarily supportive in nature. Acetaminophin poisoning can be treated with acetylcysteine, but most hepatic toxins do not have a specific antidote.

Summary

Jaundice is a manifestation of an abnormality with bilirubin metabolism. The abnormality may be prehepatic, hepatic, or posthepatic. There are certain signs and symptoms common to all jaundiced patients (yellow skin, itching). Specific items from the history and physical examination along with blood work can help the clinician classify jaundice into obstructive and nonobstructive jaundice. Surgical or other mechanical intervention almost exclusively is restricted to cases of obstructive (posthepatic) jaundice. Imaging evaluation of the gallbladder and biliary system plays an important role in the evaluation of obstructive jaundice by locating the site and disclosing the nature of

24. Jaundice 445

the obstruction. Ultrasound imaging usually is the first step for suspected biliary stone disease. The physician’s level of suspicion about benign versus malignant causes of obstructive jaundice will lead to different radiologic tests and interventions.

Stone disease usually is managed with laparoscopic gallbladder removal. Stones in the biliary system may pass spontaneously if small. More often, an endoscopic procedure is required to clear the bile ducts. Laparoscopic techniques also are available. Patients with malignant causes of obstructive jaundice are seriously ill. Major surgical resections are required for cure, and only a minority of patients are cured of their malignancy. Excellent palliation can be achieved, however, either with surgical bypass or stents. Surgical bypass tends to be more durable, but immediate morbidity is higher. Algorithm 24.1 summarizes the management of the jaundiced patient, with an emphasis on surgical therapy of obstructive jaundice.

Selected Readings

Barkun AN, Barkun JS. Useful predictors of bile duct stones in patients undergoing laparoscopic cholecystectomy. Ann Surg 1994;220(7):32–39.

Bauer TW, Morris JB. The consequences of major bile duct injury during laparoscopic cholecystectomy. J Gastrointest Surg 1998;2(1):61–66.

Harris HW. Biliary system. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001.

Houdart R, Pernicieni T. Predicting common bile duct lithiasis: determination and prospective validation of a model predicting low risk. Am J Surg 1995;170(7):38–43.

Klempnauer J, Ridder GJ, Waisielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 1997;15(3):947–954.

Newman L, Newman C. An institutional review of the management of choledocholithiasis in 1616 patients undergoing laparoscopic cholecystectomy. Am Surg 1994;60(4):273–277.

Yeo CJ, Sohn TA, Cameron J. Periampullary adenocarcinoma: analysis of 5-year survivors. Ann Surg 1998;227(6):821–831.