Primary biliary cirrhosis

Nonsuppurative cholangiopathies are chronic cholestatic diseases that occur as a result of inflammatory fibrosis of the biliary system. The nonsuppurative cholangiopathies are primary biliary cirrhosis and primary sclerosing cholangitis. Primary biliary cirrhosis and primary sclerosing cholangitis may be difficult to differentiate clinically but are distinct from suppurative cholangitis, which is a medical emergency caused by an infection of the biliary tract. Patients with suppurative cholangitis have acute onset of pain and fever with leukocytosis and cholestasis.[1]

Primary biliary cirrhosis and primary sclerosing cholangitis differ in terms of epidemiology and associated conditions but often present with similar symptoms and can have identical biochemical findings. Obstruction within the biliary tree results in symptoms and complications common to both diseases, including fatigue, pruritus, jaundice, steatorrhea, fat-soluble vitamin deficiencies and eventual end-stage biliary cirrhosis with portal hypertension, ascites, portosystemic encephalopathy and bleeding varices. If left untreated, both diseases have a progressive course of destructive cholangitis with resultant biliary cirrhosis, portal hypertension, ascites, variceal bleeding and premature death.[2]

Hepatic Biochemistry

Patients with biliary sclerosis or sclerosing cholangitis present with a cholestatic pattern on biochemical liver testing (Table 1). Most notable is a marked increase in alkaline phosphatase, which is usually six to 10 times the upper limit of normal. This is in contrast to the pattern of hepatocellular injury, which consists of elevated transaminase levels (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) and changes the differential diagnosis.[3]

Although fatigue is a frequent complaint, little is known about the etiology. The severity of fatigue generally follows the progression of liver disease. Unfortunately, no specific therapy for fatigue is available. Pruritus is another frequent complaint and is sometimes severe. A number of treatment possibilities may reduce pruritus. Cholestyramine (Questran), an anion exchange resin, has been widely and successfully used in a dosage of 8 to 12 g per day, given in divided doses before meals. Cholestyramine binds bile salts, preventing their reabsorption in the terminal ileum. It also is effective in reducing the hypercholesterolemia that occurs in these patients. More recently, reports have suggested increased stimulation of central opiate receptors from endogenous opiate ligands as an etiology of pruritus. Opiate receptor antagonists such as naloxone (Narcan, Talwin) have therefore been tried, and treatment has been successful. Mild cases of pruritus can be managed with antihistamines. Other therapies include medications that induce the cytochrome P-450 enzymes that theoretically increase catabolism of an unidentified pruritogen. Rifampin (Rifadin, Rimactane), activated charcoal, apheresis and phototherapy with ultraviolet B light have also been used.

Reduction of dietary fat intake (to less than 40 g per day) and use of medium-chain triglycerides can reduce steatorrhea and improve caloric assimilation. Deficiencies in fat-soluble vitamins (vitamins A, D, E and K) can be assessed by measurement of prothrombin time, serum 25-hydroxyvitamin D and serum carotene levels. Deficiencies can be corrected by oral or injectable vitamin supplements. Vitamin A can be given in a dosage of 15,000 units per day to prevent and reduce symptoms of night blindness. Little information exists concerning vitamin E and vitamin K, but both can be replaced if deficiency is suspected. Metabolic bone disease in primary biliary cirrhosis is common, and no effective treatment has been documented. Some recommendations, however, can be made. Oral calcium should be given in a dosage of 1.0 to 1.5 g per day. Vitamin D can be given in amounts of 50,000 units weekly

Gallstones occur more frequently in patients with both diseases as a result of chronic cholestasis with formation of both cholesterol and pigment stones. However, data regarding an increased incidence of symptomatic gallstones are lacking. With progression to end-stage cirrhosis, the complications of portal hypertension frequently develop, including ascites, portosystemic encephalopathy and bleeding varices. Therapies for portosystemic encephalopathy, ascites and bacterial peritonitis are similar to approaches to other forms of chronic liver disease.

Bleeding varices are best treated by sclerotherapy or variceal banding while awaiting transplantation. If the patient is a candidate for transplantation, portosystemic shunt surgery is not recommended since it may cause anatomic problems with future transplant surgery. One option, if available, is transjugular intrahepatic portocaval shunt when sclerotherapy and banding have failed. This is a relatively new technique that is performed by interventional radiologists who create a tunnel through the liver parenchyma. A graft is inserted through the tunnel and the graft lumen size is adjusted to lower portal pressure, which will decrease bleeding and the incidence of recurrent bleeding.

Complications more specific to primary sclerosing cholangitis include bacterial cholangitis, dominant bile duct strictures and cholangiocarcinoma. Broad-spectrum antibiotics that access the biliary tree are required for bacterial cholangitis. Bacterial cholangitis rarely occurs unless there has been manipulation of the biliary tract (ERCP or surgery) or development of dominant strictures of a large bile duct leading to biliary stasis. Prophylactic antibiotics such as ciprofloxacin (Cipro), 500 mg orally twice daily, may be used in patients with frequent recurrent infections.

Dominant, large duct stricture formation should be considered when jaundice, pruritus or fever related to infectious cholangitis has an acute onset. If the stricture is accessible via ERCP or percutaneous cholangiography, balloon dilation is the current therapy of choice. Cytologic examination should be performed to exclude carcinoma of the biliary tract.

A large number of experimental therapies have been evaluated in the past 10 to 15 years, largely with disappointing results. Drugs that have been found to be ineffective include cyclosporine (Sandimmune), azathioprine (Imuran), D-penicillamine (Cuprimine, Depen), corticosteroids and colchicine. Ursodiol (Actigall) is a bile acid that is less hepatotoxic than those that accumulate in patients with cholestatic liver disease.[2,9] When administered, ursodiol replaces the more toxic bile acids in the biliary tree, resulting in a reduction of hepatocyte toxicity.

Treatment with ursodiol in patients with primary biliary cirrhosis usually results in improvement or correction of biochemical abnormalities, such as alkaline phosphatase and bilirubin. Its effect on the progression of the disease, development of portal hypertension or mortality is not clear. A recent long-term study[10] using ursodiol acid in patients with primary biliary cirrhosis showed improvement in symptoms, a slowing of the progression of disease and a reduction in the mortality rate as well as need for referral for liver transplantation. Although ursodiol is not approved by the U.S. Food and Drug Administration for use in patients with primary biliary cirrhosis, and the long-term benefits of its use in these patients are not yet clear, the lack of significant side effects makes this agent an attractive choice for the treatment of biliary cirrhosis. Ursodiol, however, does not appear to be of great benefit as a single agent in patients with primary sclerosing cholangitis.

Methotrexate, an immunomodulatory drug, has been studied in the treatment of primary sclerosing cholangitis. A recent long-term study did not find methotrexate to be effective in the treatment of primary sclerosing cholangitis, although selected patients may benefit.[2,11] In contrast to ursodiol, methotrexate therapy can lead to serious complications, including bone marrow suppression and interstitial pneumonitis. The use of methotrexate for the treatment of chronic cholestatic liver disease should be restricted to carefully conducted clinical trials.

REFERENCES

[1.] Wiesner RH, LaRusso NF, Ludwig J, Dickson ER. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985;88(1 Pt 1):108-14. [2.] Kaplan MM. Primary biliary cirrhosis - a first step in prolonging survival [Editorial]. N Engl J Med 1994;330:1386-7. [3.] Herrera JL. Abnormal liver enzyme levels. Clinical evaluation in asymptomatic patients. Postgrad Med 1993;93(2):119-20,125,129-32. [4.] Herrera JL. Abnormal liver enzyme levels. The spectrum of causes. Postgrad Med 1993;93(2):113-6 [5.] Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1987;316:521-8. [6.] DiPalma JA, Strobel CT, Farrow JG. Primary sclerosing cholangitis associated with hyperimmunoglobulin M immunodeficiency (dysgammaglobulinemia). Gastroenterology 1986;91:464-8. [7.] Farrant JM, Hayllar KM, Wilkinson ML, Karani J, Portmann BC, Westaby D, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991;100:1710-7. [8.] Klion FM, Fabry TL, Palmer M, Schaffner F. Prediction of survival of patients with primary biliary cirrhosis. Examination of the Mayo Clinic model on a group of patients with known endpoint. Gastroenterology 1992;102:310-3. [9.] Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med 1994;330:1342-7 [10.] Markus BH, Dickson ER, Grambsch PM, Fleming TR, Mazzaferro V, Klintmalm GB, et al. Efficiency of liver transplantation in patients with primary biliary cirrhosis. N Engl J Med 1989;320:1709-13. [11.] Kaplan MM, Knox TA. Treatment of primary. biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology 1991;101:1332-8.

The Authors

STEPHEN E. BUCKLEY, M.D. is serving a fellowship in gastroenterology at the University of South Alabama College of Medicine, Mobile. He completed a residency in medicine and received a medical degree from the University of South Alabama College of Medicine. Dr. Buckley served an internship in medicine at the University of Miami School of Medicine.

JACK A. DIPALMA, M.D. is director of the Division of Gastroenterology at the University of South Alabama College of Medicine. He received a medical degree from New York Medical College, Valhalla. Dr. DiPalma served a residency in internal medicine at U.S. Air Force Medical Center Keesler, Keesler Air Force Base, Miss., and served a fellowship in gastroenterology at Wilford Hall U.S.A.F. Medical Center, San Antonio.

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