Primary biliary cirrhosis is one of the more common forms of chronic liver disease. The estimated prevalence is four to 14 cases per 100,000 people. It is characterized by chronic inflammation and destruction of small interlobular intrahepatic bile ducts, leading to chronic cholestasis, cirrhosis and portal hypertension. Primary biliary cirrhosis is a multisystem, autoimmune disease that primarily affects the liver. It is also called «dry gland syndrome» because ductular epithelium is damaged in the pancreas, salivary and lacrimal glands, and liver.
Primary biliary cirrhosis primarily (> 90%) is a disease of middle-aged women. The disease has not been seen in children. The age of onset ranges from 20 to 80 years with a mean age of 50. It affects all races and socioeconomic classes and seems to be associated with HLA-DR8 haplotype.
Histopathology of Primary biliary cirrhosis includes gradual destruction of interlobular bile ducts with a lymphocytic and plasma cell rich inflammatory reaction, leading to progressive cholestasis, disappearance of bile ducts, portal fibrosis, and ultimately cirrhosis. The disease can be divided histologically into four stages of increasing severity. However, because the inflammation is patchy throughout the liver and the typical changes of all four stages sometimes can be found in a single liver biopsy specimen, it is often difficult to follow the course of the disease or the efficacy of a treatment program.
- In stage I, there is a florid destruction of small bile ducts with mononuclear cell infiltrate. The cells damaging the bile ducts are cytotoxic (OKT8) cells that are surrounded by OKT4 helper/inducer cells. The infiltrate is confined to the portal tracts. Granulomas may be seen.
- In stage II, the lesion is more widespread with inflammation spilling into the periportal parenchyma. There is loss of bile ducts with few remaining irregular-appearing ones.
- In stage III, fibrous septa extend between triads and form fibrous bridges.
Stage intravenous represents the end stage with frank cirrhosis and absence of bile ducts in portal tracts. Hepatic copper accumulation occurs due to chronic cholestasis, and levels of hepatic copper may be higher than those found in patients with Wilson’s disease.
Clinical presentation. In 50% to 60% of patients, the disease presents insidiously with fatigue and pruritus. Usually, jaundice follows months or years later. In 25% of patients, jaundice may be the presenting symptom.
Darkening of the skin, hirsutism, anorexia, diarrhea, and weight loss may also be present. Less commonly, patients may present with a complication of portal hypertension, such as variceal bleeding or ascites, or have the disease identified during the workup of an accompanying connective tissue disease such as Surgren’s syndrome, scleroderma or CREST syndrome, systemic lupus erythematosus, or thyroiditis or during routine blood screening. In fact, up to 50% of the patients are asymptomatic when initially diagnosed. Physical findings are variable and depend on the extent of the disease. Hepatomegaly, splenomegaly, spider angiomata, palmar erythema, hyperpigmentation, hirsutism, and xanthomata may be present.
Renal tubular acidosis with defective urinary acidification after an acid load occurs frequently in Primary biliary cirrhosis, but it is usually subclinical. Deposition of copper in the kidneys may cause the renal dysfunction. An increased susceptibility to urinary tract infection has been observed in women with Primary biliary cirrhosis; the cause of this susceptibility is unknown. Also, there appears to be an increased prevalence of hepatocellular and breast cancer among patients with Primary biliary cirrhosis.
Serum tests. Serum alkaline phosphatase level is usually elevated markedly (2-20 times normal). The values for 5’-nucleotidase and Оі-glutamyltranspeptidase parallel those for alkaline phosphatase. Serum transaminase levels are slightly elevated (1-5 times normal). The serum bilirubin level usually rises with the progression of the disease and is a prognostic indicator of the disease. Serum albumin and the prothrombin time are normal early in the course of the disease. A low serum albumin level and prolonged prothrombin time that are not corrected by vitamin K therapy indicate advanced disease: Both findings are poor prognostic signs.
Serum lipid levels may be strikingly elevated. Patients with early Primary biliary cirrhosis tend to have slight elevations of low-density lipoproteins (low-density lipoprotein) and very-low-density lipoproteins (VLDL) and striking elevations of high-density lipoproteins (HDL). Patients with advanced disease have marked elevations of low-density lipoprotein and decreased HDL; lipoprotein X is present in patients with chronic cholestasis. These changes in serum lipoprotein composition appear to be due to inhibition of hepatic lipase activity in early Primary biliary cirrhosis and decreased cholesterol esterification in advanced disease. Serum ceruloplasmin is normal or elevated in contrast to Wilson’s disease.
Serology and immunologic abnormalities
Serum IgM levels are markedly increased (4-5 times normal), whereas IgA and IgG levels are commonly within normal limits. The hallmark of the disease is the presence of antimitochondrial antibody, which is present in more than 99% of the patients. It is usually present in high titer and is predominantly IgG. Antimitochondrial antibody has no known inhibitory effect on mitochondrial function and it does not affect the course of the disease. The finding of a significant antimitochondrial antibody titer (> 1:40) is strongly suggestive of Primary biliary cirrhosis, even in the absence of symptoms and the presence of normal levels of serum alkaline phosphatase. The liver biopsy in these patients shows the characteristic lesions of Primary biliary cirrhosis. Demonstration of antimitochondrial antibody by indirect immunofluorescence lacks complete diagnostic specificity, however, because antimitochondrial antibody may be found in other disorders using this technique.
Newer techniques now available are more sensitive than immunofluorescence in detecting antimitochondrial antibody. These include radioimmunoassays, enzyme-linked immunosorbent assays, and immunoblotting technique. A Primary biliary cirrhosis-specific mitochondrial antibody termed M2 has been characterized. The M2 autoantibody reacts with four antigens on the inner mitochondrial membrane. These are the E2 components and protein X of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase complex is one of the three related multienzyme complexes (the 2-oxo-acid dehydrogenase complexes) of the Krebs cycle. These complexes are loosely associated with the inner face of the inner mitochondrial membrane. Two other antimitochondrial antibodies that are associated with Primary biliary cirrhosis are anti-M4 and anti-M8, which react with antigens on the outer mitochondrial membrane.
Anti-M8 is found only in patients who have anti-M2, and its presence may be associated with a more rapidly progressive course. The presence of anti-M4 with anti-M2 identifies the chronic active hepatitis-Primary biliary cirrhosis overlap syndrome, and anti-M9 may identify cases with a benign clinical course. Other AMAs are found in syphilis (anti-M1), drug-induced disorders (anti-M3 and -M6), collagen vascular diseases (anti-M5), and some forms of myocarditis (anti-M7). Other autoantibodies such as antinuclear antibody, rheumatoid factor, and antithyroid antibodies may also be present in some patients.
The complement system appears to be in a chronically activated state in patients with Primary biliary cirrhosis due to activation of the classic complement pathway. There are decreased numbers of circulating T lymphocytes (both T4 and T8) and abnormalities of the regulation and function of these cells. Bile duct cells in patients with Primary biliary cirrhosis express increased amounts of the class I histocompatibility-complex antigens HLA-A, HLA-B, and HLA-C and class II HLA-DR antigens on their cell membrane, in contrast to normal bile duct cells. These bile duct cells in patients with Primary biliary cirrhosis are good targets for attack by activated cytotoxic T cells. Indeed, the bile duct lesion in Primary biliary cirrhosis resembles that found in graft-versus-host disease and in instances of rejection of hepatic allografts – disorders that are known to be mediated by cytotoxic lymphocytes.
Diagnosis of Primary biliary cirrhosis is not difficult in a middle-aged woman presenting with pruritus, an elevated alkaline phosphatase level, and the presence of antimitochondrial antibody in the serum. Pathopneumonic findings in the liver biopsy confirm the diagnosis. However, if atypical features are present, such as absence of the mitochondrial antibody, male gender, or young age, other possibilities need to be excluded.
The differential diagnosis of Primary biliary cirrhosis includes extrahepatic bile duct obstruction, primary sclerosing cholangitis, cholangiocarcinoma, sarcoidosis, drug-induced liver disease, chronic active hepatitis, and cholestatic viral hepatitis.
The anatomy of the extra- and intrahepatic ducts may be satisfactorily demonstrated with endoscopic retrograde cholangiography to rule out the first three of these possibilities.
The prognosis for asymptomatic patients with Primary biliary cirrhosis is better than that for symptomatic patients. Patients who are asymptomatic at the time of diagnosis may have a normal life expectancy. Cases of prolonged survival with minimal progression of the disease and symptoms are well described. In symptomatic patients, advanced age, elevated serum bilirubin levels, decreased serum albumin levels, and cirrhosis each correlate with shortened survival.
The treatment of Primary biliary cirrhosis can be divided into three areas: (a) management of symptoms, (b) specific drug treatments to halt the progression of the disease, and (c) hepatic transplantation.
Relief of symptoms
Pruritus is the most distressing symptom of Primary biliary cirrhosis. The cause of pruritus is not known. It may be related to the retention of bile salts in the skin, or it may be immunologically mediated.
Oral cholestyramine is the treatment of choice. By binding and removing bile salts in the intestine, it interrupts the enterohepatic circulation and thus decreases the blood levels of bile salts. The usual dosage is 4 g before and 4 g after breakfast. Many patients require another 8 g with the evening meal. Cholestyramine reduces vitamin A, D, E, and K absorption and may contribute to worsening of osteoporosis, osteomalacia, and hypoprothrombinemia.
Rifampin, a potent inducer of hepatic drug metabolizing enzymes, also relieves itching. Cholestipol, naloxone, naltrexone, cimetidine, UVB light, and metronidazole have also been reported to be of benefit in some patients.
Plasmapheresis, relieves itching in refractory cases.
Skin xanthomas and xanthelasmas are likely to occur when the total serum lipids exceed 1800 mg/dl. Cholestyramine, 12 to 16 g per day, is the treatment of choice. Treatment with corticosteroids, phenobarbital, and plasmapheresis also has been reported to result in regression of the lipid deposits. Repeated plasmapheresis or plasma exchange may relieve symptoms of xanthomatous neuropathy. Clofibrate therapy of hypercholesterolemia is contraindicated in Primary biliary cirrhosis.
The incidence of gallstones is increased in Primary biliary cirrhosis, occurring in about 40% of the patients. Gallstone disease may complicate the course of Primary biliary cirrhosis and should be addressed appropriately by endoscopic sphincterotomy or surgery.
Steatorrhea is common and may reach levels as high as 40 g of fat per day in patients with Primary biliary cirrhosis. In such patients, nocturnal diarrhea, weight loss, and muscle wasting may be prominent. Malabsorption in Primary biliary cirrhosis is multifactorial. The progressive bile duct lesion in these patients reduces bile salt concentrations in the small intestine and markedly decreases micelle formation and fat absorption. Also, the incidence of celiac sprue is increased in this patient population, which adds to the malabsorption.
Pancreatic dysfunction may also be present. Since medium-chain triglycerides do not require micelle formation for absorption, 60% of the dietary fat intake may be given as medium-chain triglycerides to these patients.
Patients should be screened for fat-soluble vitamin deficiency. Oral vitamin A (25,000-50,000 units per day) should be given to patients with advanced Primary biliary cirrhosis to prevent night blindness, with monitoring of serum levels to prevent toxicity. Some patients may require oral zinc supplementation for improved dark adaptation. Vitamin E deficiency is also common in patients with Primary biliary cirrhosis, but routine supplementation is not indicated. Vitamin K deficiency and hypoprothrombinemia may be monitored by following the prothrombin time. Oral vitamin K supplementation usually corrects this deficiency.
Hepatic osteodystrophy is osteoporosis and osteomalacia with secondary hyperparathyroidism. In Primary biliary cirrhosis, fat malabsorption and steatorrhea interfere with calcium absorption both by malabsorption of vitamin D and by loss of calcium with unabsorbed long-chain fatty acids. Vitamin D deficiency in Primary biliary cirrhosis may be corrected with oral doses of vitamin D, between 400 and 4,000 IU daily. Since the hepatic and renal hydroxylation of vitamin D remains intact with Primary biliary cirrhosis, the more expensive hydroxylated vitamin D preparations are not necessary. For the correction of osteoporosis, postmenopausal patients with Primary biliary cirrhosis should be given calcium supplements together with vitamin D prophylaxis.
Specific drug treatment.
Even though the etiology of Primary biliary cirrhosis is unknown, it is well accepted that it is an autoimmune disease. Defects of both cellular and humoral immunity have been demonstrated. Also, with chronic cholestasis, there is intraparenchymal copper deposition and progressive hepatic fibrosis. Thus, drugs chosen to treat the hepatic lesion of Primary biliary cirrhosis are those that stimulate or suppress the immune response, chelate copper, or decrease collagen formation. Corticosteroids, cyclosporin, azathioprine, chlorambucil, D-penicillamine, triethylene tetramine dihydrochloride, and zinc sulfate have been used in controlled trials in the treatment of Primary biliary cirrhosis and have been found to be ineffective.
Ursodeoxycholic acid at doses of 12 to 15 mg/kg of body weight per day is now used as the initial therapy of Primary biliary cirrhosis. It improves the serum alkaline phosphatase, aminotransferase, IgM, and bilirubin levels. Histologic improvement is less impressive, but the rate of worsening is slowed. Also, the need for cholestyramine is decreased in patients with pruritus. It appears that ursodeoxycholic acid is safe, effective, well tolerated and its efficacy is maintained for up to 10 years. It also significantly prolongs the time before liver transplantation is required.
Colchicine, an antiinflammatory and anticollagen agent at doses of 0.6 mg daily or twice daily, has been shown to decrease mortality from liver disease and improve serum levels of bilirubin, albumin, alkaline phosphatase, aminotransferases, and cholesterol. After 2 to 4 years, however, there is no improvement in histology, symptoms, or physical findings. Except for diarrhea in a few patients, there is no toxicity. Colchicine slows the progression of Primary biliary cirrhosis but does not stop it. It seems likely that colchicine is of some benefit to patients with Primary biliary cirrhosis.
Low-dose oral pulse methotrexate 0.25 mg/kg per week induces striking improvement in biochemical tests, fatigue, and pruritus. In some patients, histologic improvement also has been seen. In one study 15% of patients with Primary biliary cirrhosis treated with methotrexate developed interstitial pneumonitis. This high incidence has not been seen in other studies. At this time, methotrexate is best reserved for patients with Primary biliary cirrhosis who do not respond to Ursodeoxycholic acid and/or colchicine and are noted to be clinically worsening.
Most patients with Primary biliary cirrhosis are initially treated with Ursodeoxycholic acid 12 to 15 mg/kg body weight per day. In patients whose liver chemistry tests do not normalize in 6 months and/or whose liver biopsies fail to improve or worsen after one year of treatment with Ursodeoxycholic acid , colchicine is added to the treatment regimen. Methotrexate is added if the liver biopsy does not improve or worsens after one year of treatment with Ursodeoxycholic acid and colchicine. It is reported that using this individualized approach of stepwise combination therapy more than 80% of patients with precirrhotic Primary biliary cirrhosis has responded by improvement of their symptoms, normalization of the liver chemistry tests and improvement of the liver histology.
Liver transplantation is an effective treatment for Primary biliary cirrhosis, with 1- and 5-year survival rates of 75% and 70% in most centers. Transplantation markedly improves chances for survival, and results are better with earlier transplantation. Patients developing cirrhosis should be referred to transplant centers and placed on waiting lists. Clinical variables have been determined at transplant centers to help in assessing the timing of transplantation. Recurrence of Primary biliary cirrhosis in the grafted liver is rare.