ABSTRACT
Autoimmune hepatitis (AIH) recurs after liver transplantation and significantly impacts graft function and patient survival. In this case report, we present 2 cases of male patients with refractory recurrent AIH after liver transplantation. Each patient lost their first graft due to refractory continuous AIH. We have not noticed a similar refractory course for our female patients with AIH post-transplantation at our center. Based on our single-center experience there appears to be a gender disparity in the aggressive nature of AIH recurrence after transplantation. Despite the aggressive nature of recurrent AIH in both patients, graft loss occurred beyond 3 years for both patients and did not influence the 1- and 3-year patient survival. If these findings are validated, they may have significant impact on post-transplantation immunosuppression management in male patients.
Subject(s)
Hepatitis, Autoimmune/diagnosis , Liver Failure/complications , Liver Failure/therapy , Liver Transplantation/adverse effects , Female , Graft Survival , Hepatitis, Autoimmune/etiology , Hepatitis, Autoimmune/therapy , Humans , Immunosuppressive Agents/therapeutic use , Inflammation , Liver Cirrhosis/diagnosis , Liver Cirrhosis/etiology , Liver Cirrhosis/therapy , Liver Transplantation/methods , Male , Middle Aged , Recurrence , Treatment OutcomeABSTRACT
OBJECTIVE: Allelic variation (rs738409CâG) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. DESIGN AND METHODS: Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. RESULTS: Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment-insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. CONCLUSIONS: In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.
Subject(s)
Alleles , Fatty Liver/genetics , Genetic Variation , Genotype , Lipase/genetics , Liver/pathology , Membrane Proteins/genetics , Obesity, Morbid/genetics , Adult , Blood Glucose/metabolism , C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Diabetes Mellitus, Type 1/genetics , Fatty Liver/etiology , Fatty Liver/metabolism , Female , Fibrinogen/metabolism , Fibrosis , Humans , Insulin Resistance/genetics , Liver/enzymology , Male , Middle Aged , Multivariate Analysis , Non-alcoholic Fatty Liver Disease , Obesity, Morbid/complications , Obesity, Morbid/metabolism , Prospective Studies , Risk FactorsABSTRACT
In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 x 10(-3) in 1,560 individuals of the original linkage cohort, P = 8 x 10(-4) in 920 unrelated individuals of the replication cohort, combined P = 9.9 x 10(-6)). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans.
