Primary Biliary Cirrhosis (PBC) is a cholestatic liver disease which should be considered in any woman over age 20 with an elevated alkaline phosphatase blood test. This review emphasizes the natural history of PBC, diagnostic testing for PBC, and the current treatment approaches.

A "Small Duct" Disease

Primary Biliary Cirrhosis is one of the cholestatic liver diseases, meaning that it affects the bile ducts and biliary epithelial cells within the liver. This is an autoimmune liver disease in that the key pathology involves the attack upon the small, microscopic bile ducts by immune system inflammatory cells. The result is a chronic granulomatous inflammatory infiltrate invading and progressively destroying the small bile ducts within the portal tracts of the liver. The classic pathologic feature is "ductopenia", a paucity of intralobular bile ducts seen on liver biopsy, and replacement of the portal tracts with fibrosis. After decades of injury, the result is cirrhosis and premature death.

It is not known what triggers the onset of this autoimmune process. Many environmental factors have been proposed including bacterial, viral and yeast infections; selenium deficiency; and several medications. Genetic factors must play a role in susceptibility as PBC is associated with certain HLA phenotypes, including HLA-DR8, and abnormalities in cell-mediated immunity can be found in the first-degree relatives of patients with PBC. The attack on the biliary epithelium consists mainly of CD4 helper and CD8 cytotoxic T cells. The autoimmune nature of these T cells is evidenced by their ability to attack autologous liver cells in vitro.

Hypergammaglobulinemia is a characteristic of PBC. Serum IgM levels are often elevated and are a marker for following disease activity. However, B lymphocytes are not abundant within the biliary infiltrates and it is believed that the high antibody levels are not part of the destructive process within the liver.

The characteristic serum antibody of Primary Biliary Cirrhosis is the anti-mitochondrial antibody (AMA). The AMA level is elevated in more than 95% of PBC patients. The presence of both an elevated serum alkaline phosphatase and a positive AMA secures the diagnosis of PBC in most cases (see below). AMA is a family of antibodies directed against the pyruvate dehydrogenase enzyme complex which is located on the inner membrane of mitochondria. The E2 subunit of this enzyme complex (PDC-E2) is the protein against which the AMA is most often reactive. One feature of PBC is the expression of PDC-E2 on the apical surface of biliary epithelial cells, a location where this protein is not found in normal subjects. Though the AMA is are not believed to be pathogenic, circulating antigen-antibody complexes are increased in PBC and complement activation is high. It is speculated that these conditions could underlie the development of autoimmunity.

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A Disease of Glacial Pace

More than 90% of patients with PBC are women, usually between age 30 and 65 at the time of diagnosis. Approximately 30% of patients are diagnosed at an early, asymptomatic stage. Typically a routine blood test ordered by a primary care physician will reveal an elevated alkaline phosphatase level. The rate of disease progression is variable; some patients become symptomatic and progress to end-stage cirrhosis in five years though the asymptomatic patient with early disease (Stage I by liver biopsy) is likely to live for 20 years.

The most common symptom is fatigue, sometimes so severe as to cause sleep disturbances and depression. Fatigue can occur very early in the course of the disease and does not correlate with the severity as judged by laboratory tests or liver biopsy. There may be associated muscle weakness or discomfort suggestive of fibromyalgia. The second most common symptom is pruritus (itching without rash) which often is intermittent. The pruritus can be so severe as to precipitate the need for liver transplantation. Portal hypertension with variceal hemorrhage is another complication which can occur early in the course of the illness before there is cirrhosis (termed "pre-sinusoidal portal hypertension"). These patients respond very well to interventions such as transjugular intrahepatic portacaval shunting (TIPS) or portacaval shunt surgery.

Cholestasis can lead to diminished intestinal bile salt concentrations with resulting malabsorption, deficiency of fat-soluble vitamins, and weight loss. Osteopenia is 4-fold increased in PBC and can lead to debilitating fractures. Bone density testing should be performed in all PBC patients. Xanthomata are common, especially around the eyes (xanthelasma), on the palms, on the soles, or on the buttocks.

Patients with PBC often have other autoimmune disorders. Autoimmune thyroid disease should be considered in any patient with chronically abnormal liver tests and especially those with PBC. Other illnesses include the sicca syndrome (in up to 70% of patients!), CREST syndrome, Raynaud's phenomenon, celiac sprue, and ulcerative colitis. Of note, the serum cholesterol is elevated in most PBC subjects but premature atherosclerosis is uncommon.

The features of advanced PBC are no different from those of other causes of cirrhosis and include muscle wasting, weakness, gastrointestinal bleeding, ascites, encephalopathy, the hepatopulmonary syndrome, and hepatocellular carcinoma.

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An Easy Diagnosis

Compared with some liver diseases, the diagnosis of PBC is simple and straightforward. PBC should be considered in any patient—especially a woman—with an alkaline phosphatase elevated for more than six months. The hallmark of PBC is the positive anti-mitochondrial antibody (AMA). The most common scenario is that a primary care physician detects an elevated alkaline phosphatase level as part of routine screening tests. The hepatic origin of the alkaline phosphatase can be confirmed by checking that the serum gamma glutamyl transpeptidase (GGTP or GT) is also elevated. When these tests are positive, the diagnosis of PBC is near certain.

Generally a liver biopsy is performed to establish the stage of PBC. This is essential for offering prognostic information to the patient and for recommending treatment. Due to the slow pace PBC and the variety of treatments available, it is common to perform a biopsy every 5 years as a guide for treatment changes.

Further testing is always needed in order to exclude other causes of cholestatic liver disease. PBC is a "small duct" disease, meaning that tests such as ultrasound, computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) should be normal. An ultrasound or computed tomography (CT) of the liver is ordered to exclude large bile duct obstruction such as by gallstones, tumors or strictures.

Medications should be scrutinized carefully since over a hundred prescription drugs have been shown to cause biliary cholestasis. Some of the more important ones include antibacterials (erythromycin, quinolones, antifungals, floxacins, semisynthetic penicillins, tetracycline, trimethoprim-sulfa, protease inhibiters), neuroleptics (phenothiazines, tricyclic antidepressants, fluoxitine/Prozac), anti-epileptics, anti-cancer agents, hypoglycemics, estrogens, progestins, anti-inflammatory agents, and cardiovascular drugs (captopril, thiazides, chlorthalidone). Over-the-counter drugs should not be overlooked -- fatal cholestatic liver disease has been caused by NSAID's and herbal drugs!

Primary Sclerosing Cholangitis (PSC) is another autoimmune liver disease with an elevated alkaline phosphatase. In PSC, the AMA should be negative and ultrasound or ERCP will demonstrate large bile duct narrowing and strictures. The p-ANCA blood test (perinuclear antineutrophil cytoplasmic antibody) is positive in 82%. Many patients with PSC will have inflammatory bowel disease and PSC is more common in men. There is a small group of patients with a cholestatic autoimmune disease named "Autoimmune Cholangiopathy" (AIC). These patients have cholestatic blood test abnormalities (bilirubin, alkaline phosphatase) and liver biopsies identical to PBC but with a normal AMA and ERCP. They will have a positive anti-nuclear antibody (ANA) or anti-smooth muscle antibody (ASMA) suggesting the autoimmune nature of their disorder. Unlike PSC for which there is not an established effective treatment, AIC responds to treatments used for PBC (see below).

Other causes of chronic cholestasis to consider include sarcoidosis, histiocytosis X, Hodgkin's disease (without hepatic tumor present), ischemia, congestive heart failure, graft versus host disease following transplantation, hepatic transplant rejection, and a prolonged phase of acute viral hepatitis, especially in Hepatitis A.

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Effective Treatments Available

Primary Biliary Cirrhosis is always treated, even in the early, asymptomatic stages. Fortunately effective treatments are available. As with any chronic disease where there may be minimal symptoms in the early stages and a variable course, the challenge for the physician is to find treatments with minimal toxicity and expense in the early stages, but to monitor the disease course closely so as to be ready to advance in the later stages to therapies which may be more potent and which may carry the greater risks of side effects.

Ursodeoxycholate (UDCA, Urso, ursodiol, Actigall) normally represents less than 5% of the bile acids in human bile. This increases to 40-60% of bile acids when ursodeoxycholate is given therapeutically. The use of this agent as a medicine derives from ancient Asian medical traditions where drinking the bile of bears was found to be useful for jaundice. Indeed, UDCA is found in high concentrations in bear gallbladder and it is from bears that this chemical obtained its name, Urso urso is the species name of the grizzly bear.

UDCA is used in PBC at a dose of 12-15mg/kg/day (generally 1000-1500mg) taken once or twice daily by mouth. This use is approved by the U.S. Food and Drug Administration. UDCA therapy improves bile acid transports and secretion by the biliary epithelium. Several large, randomized, double-blind studies have established that long term treatment results in improved liver blood tests, improvement in some symptoms, improved biliary inflammation, decreased rate of progression to cirrhosis, and improved survival. Therapy is life-long as acceleration of disease has occurred when UDCA is withheld. The drug is probably harmless; mild diarrhea sometimes occurs. One clinical caveat is that different UDCA preparations do not have equal bioavailability (the best is Urso 250) and, therefore, this may be one condition for which generic drug substitution is unwise.

Colchicine often is added to UDCA treatment. Colchicine is prescribed at a dose of 0.6mg twice a day by mouth because of its potential anti-inflammatory and antifibrotic effects. Several studies have demonstrated mild improvements in liver tests using colchicine and at least one found an improvement in pruritus. However, none found a benefit for the liver histology or survival of PBC patients. Side-effects are rare and the cost is low at the doses above so that colchicine is likely to continue to be recommended.

Methotrexate is the most promising of the immune suppressing agents that have been tested in PBC. It is given at the dose of 15mg per week taken by mouth as three divided doses 12 hours apart. In small studies, methotrexate has improved symptoms, liver blood tests, and progression of histology when used for several years. Large, multicenter trials are needed to confirm these findings. Severe side effects may occur with methotrexate use including bone marrow suppression, worsening of liver disease, and potentially fatal pulmonary disease. Methotrexate can be considered for a well-informed, compliant patient who has well-documented disease progression despite the use of ursodeoxycholate and colchicine. A recent European trial claimed that a decrease in mortality was achieved using a combination of azathioprine, prednisone, and UDCA.

Other single agents tested and found not to be helpful include prednisone, penicillamine, cyclosporine, chlorambucil, azathioprine, thalidomide, S-adenosylmethionine. Budesonide, another glucocorticosteriod, may be useful in combination with UDCA but further studies are needed.

Important supportive treatments are available for the complications of PBC. Pruritus can be treated with ursodeoxycholate (see above), cholestyramine (4g po tid), and rifampin (150mg po bid or tid). The sicca syndrome can be palliated with moistening agents. Upper endoscopy is recommended to be performed every three years to screen for esophageal varices. Osteoporosis should be sought using bone density testing and treated with calcium (1500mg/d), vitamin D (1000 IU/d), and a biphosphonate. Fat-soluble vitamins can be offered by mouth if a deficiency is suspected though routine serum testing is not advised since deficiency is rare.

Liver transplantation is the treatment of last resort in primary biliary cirrhosis but these patients generally do quite well. It is exceedingly rare for PBC to recur in the graft. Referral for transplantation evaluation is considered for symptomatic patients with cirrhosis by biopsy and with an elevated bilirubin. Other features suggesting advanced stage include prolonged prothrombin time, decreased serum albumin level, intractable pruritus, severe osteoporosis, and ascites.

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References

Heathcote EJ. Management of Primary Biliary Cirrhosis. Hepatology 2000; 31: 1005-1013.

Goldblatt JR, Taylor PJS, Lipman T. et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002;122;1235-1241.

Angulo P, Batts KP, Therneau TM et al. Long-term ursodeoxycholic acid delays histological progression in Primary Biliary Cirrhosis. Hepatology 1999; 29: 644-647.

Williams CN, Al-Knawy B, Blanchard W. Bioavailability of four ursodeoxycholic acid preparations. Aliment Pharmacol Ther 2000; 14: 1133-1139.

Kaplan MM, Schmid C, Provenzale D. et al. A prospective trial of colchicine and methotrexate the treatment of primary biliary cirrhosis. Gastroenterology 1999 117: 1173-1180.

June/July, 2002 Jacksonville Medicine

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