by: Todd Sack, M.D. - Retired
Primary biliary cirrhosis (PBC) is a cholestatic liver disease in which 90% of patients are women, usually between age 30 and 65 at the time of diagnosis. PBC typically extends over many decades with a recent trend toward recognition at earlier stages of disease (1). In both Europe and North America there is a decreasing incidence of liver transplant secondary to PBC (2,3). PBC should be considered in cases in which there is an elevated alkaline phosphatase, particularly if the patient is female. This review emphasizes the natural history of PBC, diagnostic testing for PBC, and the current treatment approaches.
Making the Diagnosis:
Primary biliary cirrhosis is a cholestatic liver disease, meaning that it affects the bile ducts and biliary epithelial cells within the liver. It is not known what triggers the onset of this autoimmune process. Environmental or genetic factors may play a role in susceptibility to PBC.
PBC is an autoimmune liver disease in which there is an attack by the bodies immune system upon the small, microscopic bile ducts. On liver biopsy, a chronic granulomatous inflammatory infiltrate invading and progressively destroying the small bile ducts within the portal tracts of the liver is seen. 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. Without therapy, the 10 year survival of asymptomatic patients ranges from 50%-70%, while the median survival for symptomatic patients ranges from 5-8 years (4,5).
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 90-95% of PBC patients and only 0.5- 1% of normal controls (6). Still, assuming that 0.5% of the population is positive for AMA fewer than 10% of patient’s with AMA will develop PBC (7). The presence of both an elevated serum alkaline phosphatase and a positive AMA is predictive of PBC in most cases (see diagnosis below).
The Etiology of a “small duct disease”
Fatigue is the most common symptom reported by patients with PBC and affects up to 78% of patients (8-14). Fatigue does not correlate with the severity of disease nor the histologic stage of liver injury on biopsy. It is recommended to check thyroid function in patients with PBC as hypothyroidism occurs in up to 20% of patients with PBC (15,16). The fatigue may cause sleep disturbances and depression. The second most common symptom in PBC occurring in 20-70% of patients is pruritus (itching) which may be intermittent and worse at night, often exacerbated with contact to fabrics, heat and pregnancy (17,18). This pruritus is thought to be secondary to bile acids or increased opioid neurotransmission (19,20). Late in the course of PBC, portal hypertension with variceal hemorrhage/portal gastropathy can occur sometimes before there is cirrhosis.
Cholestasis can lead to diminished intestinal bile acid concentrations with resulting malabsorption, deficiency of fat-soluble vitamins, and weight loss. Still clinically important deficiencies of fat-soluble vitamins A, D, E, K are uncommon (21-23). Osteoporosis is the bone disorder seen most often in PBC occurring in up to one-third of patients with a relative risk increase compared to age and gender matched healthy patients of 4.4 (24,25). Bone density testing should be performed in all PBC patients. Total cholesterol is often elevated in PBC, however, the high-density lipoprotein cholesterol is disproportionately elevated compared to the more atherogenic low-density lipoprotein cholesterol. Patients with PBC are NOT at significantly increased risk of death from premature atherosclerosis (26,27). 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, CREST syndrome, Raynaud’s phenomenon, celiac sprue, and ulcerative colitis may also occur with increased frequency in those with PBC.
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.
An Easy Diagnosis
As mentioned above, 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 hepatic origin of the alkaline phosphatase can be confirmed by checking the serum gamma glutamyl transpeptidase (suggests liver source of alkaline phosphatase) or fractionating the alkaline phosphatase (to r/o bone or placenta as the source).
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 of liver injury in PBC, surveillance for progression may include liver biopsy, serum markers of fibrosis or non-invasive testing such as liver elastography. In liver elastogrpahy an ultrasound (or MRI) sends mechanical waves through the liver to determine the stiffness of the liver and thus estimate the stage of fibrosis.
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 such as amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, erythromycin, rifampin and antifungals. Other agents causing cholestasis include estrogens and cardiovascular agents such as captopril (28,29)
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 usually 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, particularly ulcerative colitis.
There is a small group of patients with a cholestatic autoimmune disease named “Autoimmune Cholangiopathy” (AIC). These patients have cholestatic blood test abnormalities (elevated bilirubin & alkaline phosphatase) and liver biopsies identical to PBC but with a normal AMA. They usually will have a positive anti-nuclear antibody (ANA) or anti-smooth muscle antibody (ASMA) suggesting the autoimmune nature of their disorder (30-35). Unlike PSC for which there is not an established effective treatment, AIC responds to treatments used for PBC (see below).
Effective Treatments Available
Primary Biliary Cirrhosis is always treated, even in the early, asymptomatic stages.
Ursodeoxycholate (UDCA, Urso, ursodiol, Actigall) at a dose of 13-15 mg/kg/day (generally 1000-1500 mg daily) is approved for PBC by the U.S. Food and Drug Administration (1). Studies have demonstrated consistent evidence of biochemical improvement, histologic improvement and in some cases improved survival with the use of UDCA (36,37). UDCA use has resulted in a decreased need for liver transplantation (38). Therapy is life-long as acceleration of disease has occurred when UDCA is withheld. The drug has rare side effects; mild diarrhea, weight gain or thinning of the hair sometimes occurs. One clinical caveat is that different UDCA preparations do not have equal bioavailability and, therefore, this may be one condition for which generic drug substitution is unwise. It is also important that UDCA be taken at least two hours prior to or after bile acid binding agents such as cholestyramine or colestid (1).
Neither colchicine nor methotrexate are approved by the FDA for use as a therapy for PBC. Data supporting any potential benefit has been derived mostly from case series and small controlled trials, not all of which have suggested a benefit. Some hepatologists will use these medications with UDCA, however their role is generally considered unproven. If used, colchicine is prescribed at a dose of 0.6 mg twice a day. It is believed to have anti-inflammatory and antifibrotic effects with mild improvements in liver tests However, no benefit for liver histology or survival of PBC patients. If used, methotrexate is given at the dose of 15 mg per week. It is possible methotrexate may improved symptoms, liver blood tests, and progression of histology when used for several years. Severe side effects may occur with methotrexate use including bone marrow suppression, worsening of liver disease, and potentially fatal pulmonary disease.
Important supportive treatments are available for the complications of PBC. For fatigue, patients should be assessed for anemia, hypothyroidism, depression and sleep disorders. Modafinil at a dose of 100-200 mg/day has been associated with decreased daytime somnolence (39). In addition to UDCA, pruritus may be treated with bile acid binding agents such as cholestyramine at 4-16 grams daily (40,41). Rifampin at a dose of 150 mg daily to twice daily has been shown to relieve pruritus (42,43). Opioid receptor antagonists including naloxone infused IV and naltrexone orally have been shown by meta-analysis to significantly reduce pruritus (42). Naltrexone is often started at a low dose such as 12.5 mg daily with a slow titration over several weeks to 50 mg daily to reduce the chance of producing an opiod withdrawal reaction.
The sicca syndrome can be palliated with artificial tears. If artificial tears are not effective pilocarpine or cyclosporine emulsion can be used. In patients with PBC as in other chronic liver conditions, the American Association for the Study of Liver Disease recommends that an upper endoscopy be performed at the time of diagnosis or suspected diagnosis of cirrhosis to screen for esophageal varices (44). Some providers elect to screen sooner as there are cases of non-cirrhotic portal hypertension in PBC. Osteoporosis should be sought using bone density testing at the time of diagnosis of PBC and every 2-3 years (1). For all perimenopausal and postmenopausal women daily calcium (1500mg/d) and vitamin D (1000 IU/d) is advisable as long as there is no history of renal stones. In patients with osteoporosis, a biphosphonate such as alendronate has been shown to significantly increase bone density (45-47). 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, however, when required, patient’s with PBC do better than most other etiologies of liver failure (1). PBC is currently the sixth leading cause of liver transplant in the U.S. (down from the most common cause in the mid 1980’s). Approximately 20-25% of patients who undergo liver transplant for PBC have recurrent PBC in the graft after 10 years, however, recurrent disease does not affect graft survival (48). Referral for transplantation evaluation is considered for symptomatic patients with cirrhosis by biopsy, who have model for end stage liver disease (MELD) scores of 12-15 or who have hepatic decompensations such as encephalopathy, bleeding from varices, or the development of ascities.
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