Five M2-specific antigens have been further defined using immunoblot techniques, of which the E2 component of the pyruvate dehydrogenase complex (PDC) is the major M2 autoantigen (72 kDa E2 subunit (PDC,E2)). The presence of AMA in high titre is unrelated to the clinical or histological picture and its role in pathogenesis is unclear. Antibodies against nuclear antigens, e.g. anti gp210, are present in 50% of patients and correlate with progression towards liver failure.
It seems likely that an environmental factor acts on a genetically predisposed host via molecular mimicry initiating autoimmunity. E. coli and N. aromaticivorans antibodies are present in high titre. Halogenated hydrocarbons mimic the PDC autoepitopes.
Although damage to bile ducts is a feature, antibodies to bile ductules are not specific to PBC. Biliary epithelium from patients with PBC expresses aberrant class II HLAs, but it is not known whether this expression is the cause or result of the inflammatory response. Cell-mediated immunity is impaired (demonstrated both in vitro and by skin testing); cytotoxic DC4+ and CD8+ T lymphocytes directly produce biliary epithelium damage. They recognize the inner lipoyl domain and lipoic acid also recognized by AMA. There is an increased synthesis of IgM, thought to be due to a failure of the switch from IgM to IgG antibody synthesis. No specific associated Class 2 MHC loci have been found.
Asymptomatic patients are discovered on routine examination or screening and may have hepatomegaly, a raised serum alkaline phosphatase or autoantibodies.
Pruritus is often the earliest symptom, preceding jaundice by a few years. Fatigue, which is often disabling, may accompany pruritus, particularly in progressive cases. When jaundice appears, hepatomegaly is usually found. In the later stages, patients are pigmented and jaundiced with severe pruritus. Pigmented xanthelasma on eyelids or other deposits of cholesterol in the creases of the hands may be seen.
The classical picture presents little difficulty with diagnosis (high serum alkaline phosphatase and the presence of AMA); this can be confirmed by the characteristic histological features although this is not necessary except in doubtful cases. There is a group of patients with the histological changes of PBC but the serology of autoimmune hepatitis. This has been given the name of autoimmune cholangitis and responds to steroids and azathioprine. In the jaundiced patient, extrahepatic biliary obstruction should be excluded by ultrasound and, if there is doubt about the diagnosis, MRCP (or ERCP) should be performed to make sure that the bile ducts are normal.
Ursodeoxycholic acid (10-15 mg/kg) improves bilirubin and aminotransferase levels. It should be given early in the asymptomatic phase. It is not clear if prognosis is altered. Symptoms are not improved. Steroids improve biochemical and histological disease but may lead to increased osteoporosis and other side-effects and should not be used.
Malabsorption of fat-soluble vitamins (A, D and K) occurs and supplementation is required when deficiency is detected and prophylactically in the jaundiced patient. Bisphosphonates are required for osteoporosis. Despite raised serum lipid concentrations there is no increased risk from cardiovascular disease, although this has been recently disputed by one group.
Pruritus is difficult to control, but colestyramine, one 4 g sachet three times daily, can be helpful, although it is unpalatable. Rifampicin, naloxone hydrochloride and naltrexone (opioid antagonists) have been shown to be of benefit. Intractable pruritus can be relieved by plasmapheresis or a molecular absorbent re-circulating system (MARS).
The lack of effective medical therapy has made PBC a major indication for liver transplantation.
The complications are those of cirrhosis. In addition, osteoporosis, and rarely osteomalacia and a polyneuropathy can also occur.
Course and prognosis
This is very variable. Asymptomatic patients and those presenting with pruritus will survive for more than 20 years. Symptomatic patients with jaundice have a more rapidly progressive course and die of liver failure or bleeding varices in approximately 5 years. Liver transplantation should therefore be offered when the serum bilirubin reaches 100 μmol/L. Transplantation has a 5-year survival of at least 80%.
Figure: Macroscopic and microscopic anatomy of the liver. a. The liver has two lobes viewed anteriorly (left) and posteriorly (right). b. Cross section of a hepatic lobule, illustrating microscopic structure.
Autoimmune disorders (e.g. Sjogren’s syndrome, scleroderma, thyroid disease) occur with increased frequency. Keratoconjunctivitis sicca (dry eyes and mouth) is seen in 70% of cases. Renal tubular acidosis, membranous glomerulonephritis, coeliac disease and interstitial pneumonitis are also associated with PBC.
■ Mitochondrial antibodies - measured routinely by ELISA (in titres > 1 : 160) - are present in over 96% of patients; M2 antibody is specific. Other non-specific antibodies (e.g. anti-nuclear factor and smooth muscle) may also be present.
■ High serum alkaline phosphatase is often the only abnormality in the liver biochemistry.
■ Serum cholesterol is raised.
■ Serum IgM may be very high.
■ Ultrasound can show a diffuse alteration in liver architecture.
■ Liver biopsy shows characteristic histological features of a portal tract infiltrate, mainly of lymphocytes and plasma cells; approximately 40% have granulomas. Most of the early changes are in zone 1. Later, there is damage to and loss of small bile ducts with ductular proliferation. Portal tract fibrosis and, eventually, cirrhosis is seen. Hepatic granulomas are not specific and are also seen in sarcoidosis, tuberculosis, schistosomiasis, drug reactions, brucellosis, parasitic infestation (e.g. strongyloidiasis) and other conditions.
• Variable dependent on stage of diagnosis. Fatigue and pruritus are the usual presenting symptoms. However, as many as 48% to 60% may be asymptomatic.
• Pruritus may first occur during pregnancy but is distinguished from pruritus of pregnancy because it persists into the postpartum period.
• Pruritus is worse at night, under constricting, coarse garments; in association with dry skin; and in hot, humid weather.
• Musculoskeletal complaints caused by inflammatory arthropathy in 43% to 70% of patients: 5% to 10% develop chronic ra; 10% develop “arthritis of PBC.”
• Unexplained RUQ pain.
Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is a chronic disorder in which there is a progressive destruction of bile ducts, eventually leading to cirrhosis. Ninety per cent of those affected are women in the age range 40-50 years. PBC is frequently being diagnosed in its milder forms. The prevalence is approximately 7.5 per 100 000, with a 1-6% increase in first-degree relatives. PBC has been called ‘chronic non-suppurative destructive cholangitis’; this term is more descriptive of the early lesion and emphasizes that true cirrhosis occurs only in the later stages of the disease.
EPIDEMIOLOGY & DEMOGRAPHICS
• PBC affects all races and accounts for 0.8% to 2.2% of deaths from cirrhosis worldwide.
• Approximately 97% of patients are female.
• PBC is reported only rarely in Africa and the Indian subcontinent.
• Prevalence estimates range from 19 to 151 cases per million population whereas incidence estimates range from 3.9 to 15 cases per million population per year.
• Genetic factors are important in the development of PBC; however, there is no clear dominant or recessive pattern of inheritance. Prevalence in families with one affected member is estimated to be 100 times higher than the general population. There is a weak association between PBC and HLA-DR8.
• Onset typically occurs between the ages of 30 and 65 years.
• Associated with Sjögren’s syndrome, arthritis, Raynaud’s phenomenon, and scleroderma.
The aetiology is unknown, but immunological mechanisms play a part. Serum anti-mitochondrial antibodies (AMA) are found in almost all patients with PBC, and of the mitochondrial proteins involved, the antigen M2 is specific to PBC.