Pathogenesis And Mechanisms Of Primary Biliary Cirrhosis In Family Members

Background Primary biliary cirrhosis(PBC) is a slowly progressive autoimmune disease of the liver which easily affects women and is characterized by portal inflammation and immune- mediated destruction of the intrahepatic bile ducts, gradually leading to cholestasis, cirrhosis, and eventually liver failure. It is diagnosed more frequently now than a decade ago because of its greater recognition by physicians and the widespread use of the antimitochondrial antibodies(AMA) test, which are positive in 90 to 95 percent of patients and are often detectable years before clinical signs appear. It was reported that most of the PBC patients have no symptoms and are incidentally diagnosed abnormal results in routine liver tests. Some PBC patients detected in the hospital had progressed to the advanced stage. It is currently accepted that timely treatment with ursodeoxycholic acid before the development of late stage disease can halt disease progression and extend survival free of liver transplantation.A handful of previous researches have discovered that there are a lot of descriptive reports of PBC clusters within the same family. It was estimated that 1% to 7.1% of PBC patients would have another family member with the disease. PBC seems to be more frequent in people who have a family history of the disease, especially in first degree relatives (FDRs).Although the study of PBC has carried out several years, the pathogenesis of PBC remains unkown. It was currently accepted that PBC pathogenesis is multifactorial, and the interplay of genetic susceptibility and environmental factors leads to the disease. Numerous studies have investigated that PBC patients always clustered in a representative family and occurred in monozygotic twins strongly with relatively high concordance rate, both of that indicated that genetic factors play a crucial role in modulating PBC. In addition, CD4+ and CD8+ T lymphocytes infiltration of the portal tract and aberrant expression of human leukocyte antigen(HLA)classâ… andâ…¡haplotypes on the biliary epithelial cells may show that HLA molecules play an important role in the pathogenesis of PBC. DRB1*0701 were found with significantly higher frequency in Chinese individuals with PBC and there was no association with DRB1*0801 reported. In contrast,It is reported that DRB1*0801 was found with significantly higher frequency in China. As far as we known the gene susceptibility of HLA in complex diseases of rare occurrence such as PBC remains unclear and the genetic studies is challenging.Objective This study was to investigate: (1) the clinical significance and biochemical indicators of familial PBC, (2) HLA genotyping in the FDRs of PBC, (3) the mechanisms of PBC in order to improve our understanding of this disease.Methods This study described 129 cases of FDRs in thirty-one PBC families in China. All biochemical profiles were measured using clinical biochemical analysis kits, autoantibodies were tested in each sample by immunoblotting and indirect immunofluorescence, and HLAâ…¡genotyping was analyzed using sequence-specific primers polymorphism chain reaction.Results These subjects comprised 10 patients, 65 siblings and 54 offspring of index patients. Five of thirty-one families had immune abnormalities, however, PBC was only detected in a case of one family. The incidence of liver abnormality and familial PBC accounted for 16.1% and 3.2% separatly in our study.All the FDRs were not aware of the presence of chronic liver diseases at all and 7 FDRs were diagnosed abnormal results in autoantibodies tests during the study. Two sisters and five daughters were ANA positive. Two sisters had ANA at titers equal to 1:320, One daughter had 1:160 and four daughters had 1:40. However, only one sister of these abnormal FDRs had AMA detected by IIF at titers equal to 1:160 and ANA specta revealed that it belonged to the AMA-M2 type.Apart from the cilinical history of the PBC patients and their FDRs, laboratory abnormalities were detected in FDRs with abnormal results during the study. Two abnormal FDRs had liver enzyme abnormalities. Elevations of ALT and AST above the upper limit of normal were observed in these two subjects. ALP and GGT were observed in seven FDRs and all of them were normal. Interestingly, three sisiters were diagnosed abnormal results in routine liver tests at the same time in the same family. One sister felt fatigue and had liver metastasis detected by ultrasound, but the other two sisters had no symptoms and were diagnosed abnormal results only in routine liver tests during the study, especially PBC was detected in one sister of this family, which exhibited antimitochondrial antibody M2(AMA-M2) positive. She was advised to accept drug treatment and to repeat liver enzyme tests in 6 months. She was taking 60 mg every day of deoxycholic acid one year ago and didn't extensively get worse.Among the affected members of family No.1, three people had some HLAâ…¡-DRB1 haplotypes(*08,*12) in common. Two members of family No.2 had the same HLAâ…¡-DRB1 haplotypes (*08,*15). Members of family No.4 had one common HLAâ…¡-DRB1 haplotype (*12) and one member had HLAâ…¡-DRB1 haplotypes (*04,*07). One affected member of family No.3 had the HLAâ…¡-DRB1 haplotype (*13), another one had the HLAâ…¡-DRB1 haplotype (*07,*11). Both members in family No.3 and family No.4 had one common HLAâ…¡-DRB1 haplotype (*07). In addition, family No.5 didn't have any common HLAâ…¡-DRB1 haplotypes. Mother in family No.5 had two HLA haplotypes(*03,*12), but daughter in the family had two HLAâ…¡-DRB1 haplotypes (*09,*14).Conclusion In the same family, PBC clusters together and the incidence of immune abnormality and familial PBC accounted for 16.1% and 3.2% separatedly in China.. Moreover, our data indicated that HLAâ…¡-DRB1(*08) allele may play a key role in the pathogenesis of PBC .