These target antigens are located in the inner mitochondrial matrix and catalyze the oxidative decarboxylation of keto acid substrates (Fig. 3). The E2 enzymes have a common structure consisting of the N-terminal domain containing the lipoyl group or groups. The peripheral subunit-binding domain is responsible, at least in part, for binding the E1 and E3 components together, whereas the C-terminal, which houses the active site, is responsible for the acyltransferase activity. The entire PDC-E2 is a large multimeric structure containing approximately 60 units bound together. In fact, it is larger than a ribosome and requires the presence of the lipoyl domains for the metabolism of pyruvic acid. Primary biliary cirrhosis appears to be the only disease in which autoreactive T cells and B cells responding to the PDC E2 are detected. A number of studies using oligopeptides or recombinant proteins have demonstrated that the dominant epitope recognized by antimitochondrial antibodies is located within the lipoyl domain.
T-cell mitochondrial response
The T cells infiltrating the liver in primary biliary cirrhosis are specific for the PDC-E2. Moreover, the frequency of the precursors of autoreactive CD4+ T cells is 100 to 150 times as high in the liver and the regional lymph nodes as in the circulation. The frequencies of CD8+ T cells, natural killer T cells, and B cells that are reactive with the PDC-E2 also are higher in the liver than in the blood.
The bile-duct cell and apoptosis
Clearly, a paradox of primary biliary cirrhosis is that mitochondrial proteins are present in all nucleated cells, yet the autoimmune attack is directed with high specificity to the biliary epithelium. It is therefore of considerable interest that there are qualitative differences between the metabolic processing of the PDC-E2 during apoptosis of bile-duct cells and its processing during apoptosis of control cells. Three recent findings suggest that these differences may be of considerable importance for understanding primary biliary cirrhosis (Fig. 4).f bile in the liver). There are two types of biliary cirrhosis:
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Antinuclear Antibodies
Autoantibodies directed at nuclear antigens are found in approximately 50 percent of patients with primary biliary cirrhosis, and often in patients who do have antimitochondrial antibodies. The most common antinuclear patterns are nuclear-rim and multiple nuclear dots produced by autoantibodies directed at GP210 and nucleoporin 62 within the nucleopore complex and nuclear body protein sp100, respectively. Nuclear-rim and nuclear-dot patterns are highly specific for the disease.
PATHOLOGY
Primary biliary cirrhosis is divided into four histologic stages. However, the liver is not affected uniformly and a single biopsy may demonstrate the presence of all four stages at the same time. By convention, the disease is assigned the most advanced histologic stage of those present. The characteristic lesion of primary biliary cirrhosis is asymmetric destruction of the bile ducts within the portal triads (Fig. 5). Stage 1 is defined by the localization of inflammation to the portal triads. In stage 2, the number of normal bile ducts is reduced, and inflammation extends beyond the portal triads into the surrounding parenchyma. In stage 3, fibrous septa link adjacent portal triads. Stage 4 represents end-stage liver disease, characterized by frank cirrhosis with regenerative nodules.
CLINICAL PRESENTATION
History
About 25% are diagnosed as a result of blood tests taken for other reasons and are asymptomatic at the time.
g Fatigue is the most common symptom in PBC and occurs in 65% and is often the presenting symptom. It appears to be associated with a higher mortality.
g 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.
g Right upper quadrant pain or discomfort occurs in 10 to 15%
g At a later stage the patient may present with jaundice of cholestatic origin with dark urine and pale stool.
g Sjogren's syndrome may be present with dry eyes and dry mouth
Examination
g Hepatomegaly occurs in 25%
g Hyperpigmentation occurs in 25%
g Splenomegaly occurs in 15%
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