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PRIMARY BILIARY CIRRHOSIS

Primary biliary cirrhosis is about 10 times more common in women than men. The explanation is unknown, but autoimmune conditions are known to be more common in women. All races are affected. The changing prevalence reflects increasing physician awareness, better diagnosis (especially with the availability of the serum mitochondrial antibody test), and the recognition of more asymptomatic patients. There is family clustering; usually, mothers and daughters are affected, and the presentation is earlier in the second generation. Prevalence of circulating mitochondrial antibodies is increased in the relatives of patients. Histocompatibility antigen studies give highly variable results, often depending on the geographic location of the patients studied. It is difficult to make a coherent study from these observations. They suggest a strong immunogenetic background for PBC that runs in families.

Presentation

In the 1950s and 1960s, the typical patient was an itching, deeply jaundiced and pigmented middle-aged or elderly woman. Her skin was covered with xanthomas, and she was kyphotic. It was soon realized that this was the presentation of end-stage disease that now is rarely attained. In 1958, presymptomatic disease was described.

Course

Eventually, all patients will develop symptoms. Fatigue is very common, affecting 68% of patients. It is associated with depression and poor sleep quality. (Cholestatic rats show behavior consistent with that seen in depression. With time, pruritus increases, bones become thin, jaundice deepens, and, finally, the picture is that of chronic hepatocellular failure. Hepatocellular carcinoma is rare in cirrhotic patients but is a relatively common cause of death in male PBC patients.

Associated Conditions

Primary biliary cirrhosis is associated with almost every known or postulated autoimmune condition. Collagen diseases, especially Sjogren's syndrome, rheumatoid arthritis, and thyroid disorders are particularly common. Primary biliary cirrhosis may be associated with scleroderma and with calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly.

Pulmonary abnormalities include lymphocytic interstitial pneumonitis. Gas-transfer studies may be abnormal. Chest radiograms may show nodules and interstitial fibrosis. Mediastinal lymphadenopathy is common.

Prognosis

The course of PBC is variable and unpredictable. Some patients never become symptomatic, and others run a progressively downhill course. At present, the patient with end-stage PBC faces not death but possible liver transplantation.

Indications for Transplantation for Primary Biliary Cirrhosis

 

Quality of life

 

Bone thinning

 

Pruritus

 

Child class B or C

 

1-year survival rate, 90%

A rise in serum bilirubin level is a bad prognostic sign. The development of hepatocellular failure (edema, ascites, and encephalopathy) or significant portal hypertension (bleeding varices) is also very serious.

Prognostic models have been developed. The Mayo model depends on age, serum bilirubin, and albumin levels, prothrombin time, and edema. Serum bilirubin level and the Mayo model are very good predictors of survival. The Mayo model can yield a precise estimate of survival in an individual patient. Such models do not take into account time-dependent factors. They cannot predict a life-threatening episode such as bleeding varices.

Treatment

General measures, including maintenance of nutrition and replacement of fat-soluble vitamins, apply to all patients with cholestasis.

The pathogenesis of pruritus in cholestatic patients is unknown, but recent evidence suggests increased neurotransmission and neuromodulation by endogenous opioids in the central nervous system. Pruritus is usually controlled by cholestyramine, but oral nalmefene and opiate antagonists have given promising results.

Osteomalacia is rare and can be corrected by vitamin D and calcium supplements. The major problem is osteoporosis, which is of low-turnover type. The osteoporosis may be related to the accumulation of toxins that impair osteoblast function. Calcitonin is of no value. Biphosphonates may be useful, and cyclical etidronate can be tried. Estrogens stimulate bone formation, and postmenopausal women with PBC.

The recognition that PBC is probably an autoimmune disease led to trials of immunosuppressive drugs. The trials tended to be poorly controlled, with small numbers enrolled and short follow-up of participants. Drugs tested included azathioprine, D-penicillamine, chlorambucil, cyclosporin A.

Results in terms of survival, biochemical tests, and hepatic histology tended to be inconclusive. Methotrexate is the drug most recently tried, but after 6 years, the Mayo score and bilirubin were higher in those receiving the drug than those receiving placebo. Colchicine is of little, if any, benefit. Combination therapy may be more helpful, in particular, ursodeoxycholic acid plus azathioprine or cortisone or methotrexate plus other drugs, but no significant benefit.

Ursodeoxycholic Acid

Ursodeoxycholic acid (URSO) is a nonhepatotoxic, hydrophilic bile acid that protects cell membranes against the detergent effect of hydrophobic bile acids, stimulates the excretion of toxic bile acids, and increases anion exchange in the liver.

Liver Transplantation

Indications for liver transplantation are a poor quality of life, so that the patient is house-bound, has intractable pruritus, hepatocellular failure (deepening jaundice, encephalopathy, ascites), or bleeding varices. Results are better if referral is early. A model using age, renal failure, Child's class, and United Network for Organ Sharing (UNOS) criteria can be used to predict the

The 1-year survival rate after transplantation is about 85% to 90%, and a 5-year survival rate of 60% to 70% is reported. Twenty-five percent of patients will need a retransplant, usually because of the development of the vanishing bile duct syndrome. The disease almost certainly recurs in the transplanted liver. Mitochondrial antibody levels increase.