Clinical Course and Genetic Susceptibility of Primary Biliary Cirrhosis: Analysis of a Prospective Cohort

Abstract

BackgroundNatural history of primary biliary cirrhosis (PBC) is partially characterized in patients from the Mediterranean area whose genetic background differs from that of Northern Europeans.ObjectivesWe aimed to describe genetic susceptibility and clinical course of PBC in patients from Southern Italy.MethodsSocio-demographic, clinical, biochemical and histological data at diagnosis as well as disease progression of 81 PBC consecutive patients were collected. All subjects were treated with Ursodeoxycholic acid at a dose of 15 mg/kg. HLA class II DRB1 alleles were compared with those of 237 healthy control subjects. IL28B genotyping for IL28B rs12979860 C/T and rs80899917 G/T was performed in a sub-group of patients.ResultsHLA-DRB1*07 (RR 5.3, P = 0.0008) and HLA-DRB1*08 (RR n.c. P = 0.0005) were significantly associated with the risk of PBC development. Patients younger than 45 years had significantly higher alanine aminotransferase (P = 0.038) and alkaline phosphatase levels (P = 0.047) than older cases. In comparison to non-CC rs12979860, patients with CC rs12979860 genotype showed an early histological stage at onset (93.8% vs. 62.5%, P = 0.03). After a mean follow-up of 61 months, three patients died, one underwent liver transplantation and sixteen (21.9%) had progression of the disease. At multivariate analysis, extrahepatic autoimmune disease (P = 0.04), pruritus (P = 0.008) and advanced histological stage (P < 0.0001) were independent risk factors for disease progression.ConclusionsHLA-DRB1*07 and HLA-DRB1*08 alleles increase susceptibility to disease development. At onset, higher biochemical activity was observed in younger patients, whereas rs12979860 CC genotype was associated with milder histological stage. Pruritus and coexistence of extrahepatic autoimmune diseases were significantly associated with poorer prognosis.

Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis

“…We further searched the genotype-tissue expression portal for these two SNPs, which turns out that they are also strong eQTLs for the similar set of the genes within the region among multiple tissues. Notably, this HLA locus has been previously linked with hepatitis B virus/hepatitis C virus-related liver cirrhosis [ 39 , 40 ] as well as primary biliary cirrhosis, [ 41 ] suggesting an essential role of these genes in increasing the susceptibility to liver fibrosis.…”

Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis

“…30 In a cross-sectional study, patients of Hispanic ethnicity with PBC had an increased prevalence of overlap syndrome, reduced response to UDCA treatment, and more frequent complications of portal hypertension than non-Hispanic patients. 10 In addition, genetic susceptibility for early onset PBC has been reported, 31 and coexisting impact of metabolic syndrome. 32 Approximately 30% of patients with PBC may have metabolic syndrome, which is consequently correlated with a higher risk of cardiovascular events.…”

Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis

“…Modifiers of PBC progression have also not been fully elucidated [15][16][17]. Nevertheless, as much as 26% of patients with PBC are expected to develop liver cirrhosis within 5 years from diagnosis despite the ursodeoxycholic acid (UDCA) treatment [18].…”