The role of Helicobacter spp. in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis

Helicobacter species DNA has been detected in liver tissue of patients affected by primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). To investigate a potential causative relation between Helicobacter species and PBC/PSC, we compared the presence of Helicobacter species-specific DNA in liver tissue of patients with PBC/PSC (n=18/n=13) with those of a control group of patients with various liver diseases with known cause (n=29). A PCR with Helicobacter genus-specific 16S rRNA primers was performed on DNA isolated from paraffin embedded liver tissue. Control patients had hepatitis-B (n=9), alcoholic cirrhosis (n=14), or non-cirrhotic metabolic liver disease (n=6). There was no significant difference between the incidence of Helicobacter spp.-specific DNA in PBC/PSC (9/31; 29%) and the control group (10/29; 34%). Sequence analysis confirmed Helicobacter spp. DNA. Because Helicobacter spp. DNA can be found in approximately one-third of all samples tested, it is unlikely that PSC and PBC are caused by Helicobacter infection.     

Opioid peptides and primary biliary cirrhosis.

Patients with liver disease have increased plasma concentrations of the endogenous opioid peptides methionine enkephalin and leucine enkephalin. As an initial investigation to determine whether opioid peptides contribute to any of the clinical manifestations of hepatic disease nalmefene, a specific opioid antagonist devoid of agonist activity, was given to 11 patients with cirrhosis. They all experienced a severe opioid withdrawal reaction on starting the drug. In the nine patients with primary biliary cirrhosis pruritus was greatly alleviated, fatigue seemed to improve, and plasma bilirubin concentration, which had been rising, showed a modest fall in all except one patient. These results indicate that blocking opioid receptors has an effect on some of the metabolic abnormalities of liver disease.     

Treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects middle age women. Most patients are diagnosed when asymptomatic. The disease is characterised by chronic, granulomatous inflammation of the small bile ducts, which leads to progressive ductopenia, cholestasis, fibrosis, cirrhosis and eventual liver failure. All PBC patients with abnormal liver biochemistry should be considered for therapy. Ursodeoxycholic acid (URSO) treatment reduces intracellular hydrophobic bile acid levels and thereby may have a cytoprotective effect on cell membranes. URSO may also act as an immunomodulating agent. Multicenter randomised controlled trials proved that the treatment is associated with a marked improvement in serum biochemical markers of cholestasis, i.e. bilirubin, ALP, GGT, including fall in serum cholesterol levels. Treatment does not seem to benefit the symptoms of fatigue, pruritus, and osteoporosis. UDCA has been shown when given in a dose of 15 mg/kg daily for up to 4 years to prolong the time to liver transplantation or death. Immunosuppressive therapy: based on the immunological abnormalities, several immunosuppressive drugs have been tested. Neither azathioprine nor cyclosporine was found in large enough trials to show beneficial effect on survival. D-penicillamine, cholchicin, methotrexát, prednisolone were found without significant long-term benefit. Combination therapy with URSO and budenoside appears to add some benefit to URSO monotherapy, but further studies are needed. Liver transplantation. The most crucial question is the timing. Serum bilirubin, Mayo risk score and some other factors such as uncontrollable pruritus and severe osteoporosis influence the decision. Recurrence of PBC in allograft is rare, the progress is slow, and is no reason for not recommending transplantation. Symptomatic treatment of pruritus, sicca syndrome and preventive treatment of osteoporosis, neuropathy and fat soluble vitamin deficiency is also important.     

Mitochondria and autoimmunity in primary biliary cirrhosis

Primary biliary cirrhosis is an enigmatic autoimmune liver disease that predominantly affects women and is characterized by antimitochondrial antibodies and specific destruction of small bile ducts. Interestingly, patients with this disease not only have high titer antibodies to mitochondria, but also highly directed, liver-specific CD4 and CD8 cells directed at the same mitochondrial autoantigens. These mitochondrial autoantigens are all members of the 2-oxo dehydrogenase complex family and include the E2 component of pyruvate dehydrogenase as the major autoantigen. Moreover, the epitopes recognized by CD4, CD8 T cells and autoantibody, are all directed within the same region, namely the lipoyl domain of pyruvate dehydrogenase complex-E2. All cells in the body have mitochondria but there appear to be specific destruction of biliary cells. We believe that this specific destruction is secondary to a highly directed mucosal response that focuses on biliary cells because of the involvement of a polymeric immunoglobulin receptor, the presence of immunoglobulin A in mucosal secretions, and the unique apoptotic properties of biliary epithelium.     

Breast cancer in women with primary biliary cirrhosis.

The occurrence of extrahepatic malignancy was studied in 195 unselected patients who satisfied predetermined biochemical, immunological, and histological criteria for the diagnosis of primary biliary cirrhosis. The incidence of breast cancer in women with primary biliary cirrhosis was found to be significantly higher than in an age and sex matched control population from the same well defined geographical area (p less than 0.0015). The association of breast cancer and primary biliary cirrhosis remains unexplained, though diminished immunological surveillance, fat soluble vitamin deficiency, or endocrine dysfunction may play a part.     

Copper accumulation in primary biliary cirrhosis

Summary Ultrastructural and X-Ray microanalytical aspects of primary biliary cirrhosis were analysed and compared to those of normal liver. Electron microscopic studies showed a significant increase of dense lipofuscin-like granules in PBC compared to the hepatocytes of normal liver (665%). These granules (0.3–2.7 m in diameter) were formed by the association of primary lysosomes and lipid droplets. X-Ray microanalysis of these structures showed the presence of Calcium, Phosphorus, Potassium, Chlorine, Sulphur, Aluminium and Copper. The coexistence of Sulphur with other mineral elements suggests the occurence of metalloproteins binding these elements. These findings provide evidence that intralysosomal sequestration of mineral elements, especially copper protects the hepatocytes from cytotoxic effects.     

Anti-DNA antibody idiotypes in primary biliary cirrhosis

A significant increase in 16/6 Id--a major cross-reactive idiotype of anti-DNA antibodies (Ab) derived from a patient with systemic lupus erythematosus (SLE) and hitherto identified in SLE patients and their relatives, was found in 16/17 patients with primary biliary cirrhosis (PBC). The increased serum level of Ab with the 16/6 idiotype (16/6 Id) in PBC patients (median 50 ng/ml) was not found in 6/7 of the patients' spouses nor among 27/28 healthy controls or most patients with other types of cirrhosis. The quantity of 16/6 Id was not correlated to either the stage of disease or the presence of antimitochondrial, antinuclear, or anti-dsDNA antibodies. However, 16/6 Id could be shown to be associated with anti-ssDNA antibodies. The high frequency of the lupus-derived 16/6 Id in PBC may accompany the polyclonal B-cell activation seen in that disease. Of 14 healthy first-degree relatives of the PBC patients, 4 (29%) also had elevated serum 16/6 Id (20-25 ng/ml) and the cluster of 3 of them in a single family may indicate a genetic predisposition to develop PBC.     

Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis.

A study was performed to assess the incidence of previous hysterectomy and dilatation and curettage among women with primary biliary cirrhosis. In 87 patients with primary biliary cirrhosis hysterectomy or dilatation and curettage had been performed significantly more often than among 100 age matched normal controls and 80 age matched patients with chronic active hepatitis or alcoholic liver disease. Among the 47 patients with primary biliary cirrhosis who had undergone hysterectomy or dilatation and curettage operations had been performed at a mean of 10.7 years and 13.2 years, respectively, before the onset of disease. The main indication for hysterectomy among patients with primary biliary cirrhosis and controls was menorrhagia. These menstrual disorders may be a consequence of high concentrations of oestrogens in patients with primary biliary cirrhosis.     

Vitamin A treatment for night blindness in primary biliary cirrhosis.

Three patients with late stage primary biliary cirrhosis were found to have appreciable night blindness. Serum vitamin A concentrations were low in all three patients despite regular intramuscular supplementation in two. All patients responded dramatically to high dose oral supplementation, with full recovery of adaptation to dark and visual fields. Oral rather than intramuscular vitamin A supplementation seems appropriate in the prevention of ocular complications of vitamin A deficiency in biliary cirrhosis.     

Chromosomal aberrations in patients with primary biliary cirrhosis

Summary Chromosomal aberrations in untreated lymphocyte cultures, bleomycin (BLM)-induced aberrations and sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of 11 patients suffering from primary biliary cirrhosis (PBC) and 14 matched control individuals were analysed. The lymphocytes of the PBC patients had on average a lower mitotic index (2.3) compared with controls (3.5) in the untreated cultures. The mean baseline rate of aberrations of the cultured lymphocytes of the patients was 5.3 aberrations per 100 metaphases (%); this was significantly different (P=0.0291) from that of the controls with a mean of 2.3%. In lymphocytes of the patients and controls, most of the aberrations observed took the form of gaps; there was an almost equal breakage rate in both groups (0.5% and 0.4%, respectively). The average number of mitoses with aberrations in the PBC patients studied was double that of the controls (4.9% and 2.3% respectively, P=0.0323). The mean number of the BLM-induced aberrations was 54.0% and 27.7% for the lymphocytes of the patients and controls, respectively. The mean number of the aberrant mitoses in the BLM cultures was 6 times higher than that of the untreated cultures for both groups, 25.7% and 14.6% respectively (P=0.018). The chromosomal distribution of baseline and induced aberrations was not random. The PBC patients had a mean number of 8.7 SCE per mitosis, which was significantly higher than the SCEs in the controls (6.3 SCE per mitosis; P=0.0156). The evidence suggests that the chromosomes of the lymphocytes of PBC patients may be less stable than those of the control individuals in this study.