ABSTRACT
BACKGROUND: Fibrosis progression in autoimmune hepatitis can be attenuated by immunosuppressive treatment; however, some patients progress despite therapy. Single nucleotide polymorphisms (SNPs) such as PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 are associated with non-alcoholic fatty liver disease and fibrosis progression, whereas a splice variant in HSD17B13-rs72613567:TA has been shown to be protective. AIM: To analyse the impact of different SNPs on the long-term outcome of patients with autoimmune hepatitis. METHODS: We included 239 patients into this study who had been treated between 1983 and 2018 for autoimmune hepatitis. Genomic DNA was isolated from whole blood and SNPs were determined by PCR analysis. Liver biopsies were available for 215/239 patients (90%). Clinical and laboratory patient data were assessed by chart review. RESULTS: Mean age at baseline was 42.1 years with 74.1% being female. The median follow-up was 9.4 years (IQR 3.5-15.0), 11.7% of the patients (n = 28) died or required liver transplantation. In the Kaplan-Meier analysis of the combined endpoint time to liver transplantation or death, we observed that patients with the PNPLA3-rs738409 GG variant met more frequently the primary endpoint (P = 0.005). In Cox regression analysis PNPLA3-rs738409 GG as well as liver cirrhosis were identified as strong predictors for time to liver transplantation or death (HR 4.5 [CI 1.48-13.72], P = 0.008 and HR 9.24 [CI 2.11-40.44], P = 0.003, respectively). Neither steatosis, diabetes mellitus nor obesity were associated with outcome. CONCLUSIONS: PNPLA3-rs738409 variant GG is a predictor for time to liver transplantation or death and may help to identify autoimmune hepatitis patients at risk for disease progression.
Subject(s)
Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/genetics , Lipase/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Child , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genotype , Hepatitis, Autoimmune/pathology , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Prognosis , Retrospective Studies , Young AdultABSTRACT
UNLABELLED: Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by a loss of tolerance toward the hepatocellular epithelium. Liver transplantation (LT) represents the ultimate therapeutic option for a fulminant course or end-stage liver disease. The aim of this study was to elucidate the clinical, serological, and genetic features of remission, relapse, and overall and LT-free survival. Between 2000 and 2014, 354 AIH patients from Hannover Medical School were included. Clinical, laboratory, and histological reports were analyzed. DRB1 allele analyses were performed in 264 AIH and 399 non-AIH patients. Cox's regression analysis was performed to identify factors significantly associated with survival. Patients diagnosed in childhood were at higher risk for relapses (P=0.003), requirement for LTs (P=0.014, log rank), and had a reduced life expectancy (P<0.001, log rank). Detection of soluble liver antigen/liver pancreas antigen (SLA/LP) antibodies was significantly associated with reduced overall and LT-free survival (P=0.037; P=0.021). Cirrhosis, which was evident in 25% at first diagnosis, was found to be a predictor of poor survival and requirement for LT (P=0.003; P=0.009). DRB1*04:01-positive phenotype was associated with a higher rate of complete remissions and with a lower frequency of cirrhosis and LTs. There were no significant differences for subsequent relapses or survival in patients achieving either partial or complete remission. CONCLUSION: Diagnosis<18 years, histological cirrhosis at first diagnosis and SLA/LP antibodies are major risk factors for a poor short- and long-term outcome. These patients are in need of high surveillance. Separating patients with positive SLA/LP antibodies into a third group may be reconsidered. DRB1*04:01 positivity has been identified in association with a favorable clinical outcome.
Subject(s)
Hepatitis, Autoimmune/mortality , Adolescent , Adult , Aged , Autoantigens/immunology , Child , Child, Preschool , Female , Hepatitis, Autoimmune/surgery , Humans , Liver Transplantation , Male , Middle Aged , Proportional Hazards Models , RecurrenceABSTRACT
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for persistent infection of hepatocytes. The aim of this study was to determine changes in intrahepatic cccDNA in patients with chronic hepatitis B (CH-B) during 48 weeks of antiviral therapy and its correlation to virological, biochemical, and histological parameters. Twenty-six HBsAg-positive CH-B patients received combination treatment with pegylated interferon alpha-2b (peg-IFN) and adefovir dipivoxil (ADV) for 48 weeks. Paired liver biopsies from before and at the end of treatment were analyzed for intrahepatic HBV-DNA. Median serum HBV-DNA had decreased by -4.9 log10 copies/mL at the end of treatment and was undetectable in 13 individuals (54%). Median intrahepatic total HBV-DNA and cccDNA had decreased by -2.2 and -2.4 log10, respectively. Changes in intracellular HBV-DNA positively correlated with HBsAg serum reduction and were accompanied by a high number of serological responders. Eight of 15 HBeAg-positive patients lost HBeAg, and five developed anti-HBe antibodies during treatment. These eight patients exhibited lower cccDNA levels before and at the end of therapy than did patients without HBeAg loss. Four patients developed anti-HBs antibodies. ALT normalized in 11 patients. The number of HBs-antigen- and HBc-antigen-positive hepatocytes was significantly lower after treatment, suggesting the involvement of cytolytic mechanisms. In conclusion, combination therapy with peg-IFN and ADV led to marked decreases in serum HBV-DNA and intrahepatic cccDNA, which was significantly correlated with reduced HBsAg.
