Primary Biliary Cirrhosis (PBC)

This is a slowly progressive disease of the liver and biliary system, with destruction of the small interlobular bile ducts, cholestasis, fibrosis and eventually cirrhosis. Cirrhosis is a late feature.

There is much to suggest an auto-immune aetiology. The aetiology is probably partly genetic and partly environmental.¹ A popular hypothesis is that the disease is environmentally triggered in genetically predisposed individuals.^2,3 The rate of concordance amongst identical twins is amongst the highest of all auto-immune diseases.⁴ Families with a strong family history have been described.⁵

• The prevalence has been estimated as 12.9 per 100,000 population in the UK with up to 90% being women.
• It is commoner amongst those of northern European descent and less common amongst those of African origin.
• Diagnosis is usually between about 45 and 55 years old.
• The prevalence appears to be rising since 1980. This may be in part due to increased survival but also better awareness of the disease leading to more frequent diagnosis. Nevertheless, there does seem to be evidence of a true increase in incidence.⁶

History

About 25% are diagnosed as a result of blood tests taken for other reasons and are asymptomatic at the time.⁷

• Fatigue is the most common symptom in PBC and occurs in 65% and is often the presenting symptom.^8,9,10,11 It appears to be associated with a higher mortality.¹¹
• Around 55% report pruritis and in 10% this is severe. It is usually assumed to be due to deposition of bile pigments in skin although evidence is lacking and it may be due to central opioid neurotransmission.^12,13,14
• Right upper quadrant pain or discomfort occurs in 10 to 15%
• At a later stage the patient may present with jaundice of cholestatic origin with dark urine and pale stool.
• Sjogren's syndrome may be present with dry eyes and dry mouth

Examination

• Hepatomegaly occurs in 25%
• Hyperpigmentation occurs in 25%
• Splenomegaly occurs in 15%
• Jaundice occurs in 10%
• Xanthelasma may occur in the later stages
• Only in advanced disease will there be cirrhosis with associated features (including ascites, spider naevi and other features of portal hypertension)

There may be other diseases present too, especially those of auto-immune origin.¹⁵ These include:

• Thyroid disease
• Systemic sclerosis including its variant of CREST (calcinosis, Raynaud's phenomenon (o)esopogeal motility disorder, sclerodactyly and telangiectasiae)
• Coeliac disease
• Extrahepatic malignancy
• Hepatocellular carcinoma
• Seropositive arthritis
• Seronegative arthritis
• Cholelithiasis (gallstones)

The link with extrahepatic malignancy has been disputed¹⁶ and the association with hepatocellular carcinoma may be more than for any other form of cirrhosis.¹⁷

• FBC is often normal but ESR is elevated
• Abnormal LFTs are to be expected but are not invariable. Alkaline phosphatase is usually elevated as it is a cholestatic condition and, less consistently, transaminases are raised. Bilirubin is often normal at first but rises as the disease progresses whilst PTT and albumin are normal until a late stage. IgM is raised.
• When bilirubin rises this suggests disease progression and it heralds liver failure.
• Lipid levels and cholesterol levels are raised in 85% but risk of CHD is not raised as HDL cholesterol is elevated.
• Auto-antibodies are characteristic and in this disease the most specific are anti-mitochondrial antibodies that are present in 90 to 95% with a specificity of 98%. About 35% also have anti-nuclear antibodies. There may well be other autoantibodies, especially related to the thyroid.
• Monitor thyroid function
• Imaging of the liver excludes causes of obstruction like stones. Ultrasound is most commonly used but CT and MRI may be employed. As the disease progresses there may be features suggestive of portal hypertension and cirrhosis.
• Finally, liver biopsy is required to stage the disease.

1. Portal stage with portal inflammation and bile duct abnormalities
2. Periportal stage with periportal fibrosis, with or without periportal inflammation
3. Septal stage with septal fibrosis and active inflammation
4. Cirrhotic stage with nodules with various degrees of inflammation

Autoimmune hepatitis, reaction to phenothiazines, sarcoidosis.

Treatment can aim to alleviate symptoms or to slow the disease. Measuring outcomes in clinical trials involving patients with liver disease can be difficult.¹⁸ Only liver transplantation offers a cure but the disease has been reported in the transplanted liver.

• Fatigue is a very common symptom and has an adverse effect on quality of life.¹⁹ It is difficult to treat.²⁰
• Pruritis may be treated with sedating antihistamines in the early stages but later cholestyramine or colestipol are used. They sequester bile salts but it takes between 1 and 4 days before there is any effect. Again it is a very difficult symptom to treat.^21,14
• Rifampicin has helped some patients unresponsive to cholestyramine but its mode of action is unknown. Plasmapheresis is also effective but for severe, intractable pruritis a liver transplant offers the only hope.
• Ursodeoxycholic acid (UDCA) slows progression of the disease. Patients with early disease have clinical, biochemical, and histological improvement²² but its value in late disease is dubious. Any benefit in improving mortality is not supported in a recent Cochrane review.²³ However there are studies which appear to show improved mortality.^24,25,26,27
• Drugs are used to inhibit the auto-immune process:
  • Methotrexate is well established although its basis has been criticised as anecdotal rather than based on RCTs.²⁸ It is not recommended for use outside clinical trials and appears to increase mortality.²⁹
  • Steroids may help but osteoporosis is a concern.
  • Cyclosporin may be beneficial.³⁰ However it is recommended that it should only be used in the context of a clinical trial.³¹ It has a high rate of complications such as renal dysfunction and hypertension.
  • A Cochrane review found inadequate evidence of the effectiveness of colchicine and it may increase mortality.³²
  • Azathioprine was recommended after a large international trial in 1985 showed beneficial effects and few adverse effects.³³ However a recent Cochrane review does not support this demonstrating adverse effects and no demonstrable benefits.³⁴
  • D-Penicillamine does not appear to reduce morbidity or mortality and causes significant adverse effects.³⁵
• As liver failure sets in a transplant offers the only hope for cure. Increasing prothrombin time, elevated bilirubin and decreased albumin all point to the time being due.³⁶ After 2 to 5 years from the transplant between 8 and 16% will have recurrence of the disease as the underlying auto-immune process remains.³⁷ This figure may rise to 50% by 10 years.³⁸ There also tends to be more problems of chronic rejection than with other indications for transplantation.

• Although osteoporosis is often cited as a complication of PBC, the risk of osteoporosis is no more than for other women of that age unless they have cirrhosis that is a risk irrespective of aetiology.³⁹
• Renal tubular acidosis occurs in around half of patients with PBC. Copper deposition in the renal tubules or an autoimmune phenomenon may be the mechanism.
• Around 20% develop hypothyroidism
• Hepatocellular carcinoma develops in about 6% but this represents about 4% of women with the disease and 20% of men.⁴⁰
• There may be malabsorption of fats with steatorrhoea and fat soluble vitamin deficiency
• Complications of cirrhosis are described in the article

The median survival time is about 6 to 12 years if symptomatic at diagnosis but around 16 years if asymptomatic.
The most important indication of serious progression of the disease is rapid development of severe cholestasis independent of the histological stage.⁴¹