Adipocyte Fatty Acid-Binding Protein as a Predictor of Outcome in Alcohol-induced Acute-On-Chronic Liver Failure.

BACKGROUND: Alcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF). OBJECTIVES: The primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90. METHODS: In this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assay method. The patients were followed up for 90 days. RESULTS: Twenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 [1.08-1.5]; P = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score (HR: 3.3[1.15-9.54]; P = 0.02), L-FABP (HR: 0.69 [0.52-0.91]; P = 0.009), and serum protein levels (HR: 0.03 [0.003-0.36]; P = 0.005) predicted mortality. A-FABP (1.17 [1.07-1.29]; P = 0.001), and serum bilirubin (1.05 [0.99-1.12]; P = 0.06) predicted development of organ failure, and only mDF (HR: 1.04 [1.01-1.07]; P = 0.009) predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders. CONCLUSIONS: In a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.

Polymorphisms in UGT1A1 Gene Predispose South Indians to Pigmentous Gallstones.

BACKGROUND/OBJECTIVES: Pigmentous gallstones occur in South Indians despite significant higher levels of circulating cholesterol. This study was conducted to identify the biochemical and/or genetic causes for the formation of pigmentous gallstones in this ethnic group. METHODS: Plasma lipid profile, bile cholesterol, acids, and phospholipid levels were estimated in patients with gall stone disease and age, sex matched controls using standard protocols. Twenty-seven SNPs related to cholesterol and bilirubin metabolism pathway genes were genotyped in the study population using the Sequenom platform. An equilibrium phase diagram involving bile salt-phospholipid-cholesterol was generated to relate phenotype with the genotype. RESULTS: There were no significant differences in the lipid profiles between the patients (n = 305) and controls (n = 177). Biliary cholesterol, acids, and phospholipids were significantly different between patients and controls. Single locus analysis revealed association of variants in ABCG6, ABCG8, and UGT1A1 genes with the disease; however when correction was applied as multiple testing was done, only one variant (rs6742078) in UGT1A1 gene was found to be associated with gall stone disease. Equilibrium phase diagram suggested that few samples were in the crystal formation zone. The mutant, but not wild type or heterozygous genotype of SNPs (rs6742078 and rs887829) in UGT1A1 gene, was associated with significantly higher levels of bilirubin. CONCLUSIONS: Higher incidence of pigment stones in South Indians could be due to raised serum bilirubin levels that may be ascribed to variant in the UGT1A1 gene involved in glucuronidation of free bilirubin.

Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects: A pilot study.

AIM: To investigate genetic susceptibility in Indian subjects with non-alcoholic fatty liver disease (NAFLD) by performing a pooled genetic study. METHODS: Study subjects (n = 306) were recruited and categorized into NAFLD and control groups based on ultrasound findings of fatty infiltration. Of the 306 individuals, 156 individuals had fatty infiltration and thus comprised the NAFLD group. One hundred and fifty (n = 150) individuals were normal, without fatty infiltration of the liver, comprising the control group. Blood samples, demographic and anthropometric data from the individuals were collected after obtaining informed consent. Anthropometric data, blood glucose, lipids and liver function tests were estimated using standard methods. Genome wide association studies done to date on NAFLD were identified, 19 single nucleotide polymorphisms (SNPs) were selected from these studies that were reported to be significantly associated with NAFLD and genotyping was performed on the Sequenom platform. Student's t test for continuous variables and χ(2) test was applied to variant carriers from both groups. Required corrections were applied as multiple testing was done. RESULTS The mean age of the control group was 39.78 ± 10.83 and the NAFLD group was 36.63 ± 8.20 years. The waist circumference of males and females in the control and NAFLD groups were 80.13 ± 10.35; 81.77 ± 13.65 and 94.09 ± 10.53; 92.53 ± 8.27 cms respectively. The mean triglyceride and alanine transaminase (ALT) levels in the control and NAFLD groups were 135.18 ± 7.77 mg/dL; 25.39 ± 14.73 IU/L and 184.40 ± 84.31 mg/dL; 110.20 ± 67.05 IU/L respectively. When χ(2) test was applied to the number of individuals carrying the variant risk alleles between the control and NAFLD group, a significant association was seen between rs738409 of the patatin-like phospholipase domain containing 3 (PNPLA3) gene (P = 0.001), rs2073080 of the PARVB gene (P = 0.02), rs2143571 of SAMM50 gene (P = 0.05) and rs6487679 of the pregnancy zone protein (PZP) gene (P = 0.01) with the disease. Variant single nucleotide polymorphisms (SNPs) in NCAN and PNPLA3 gene were associated with higher levels of ALT, whereas variant SNPs in APOC3, PNPLA3, EFCAB4B and COL13A1 were associated with high triglyceride levels. Apart from the above associations, rs2073080, rs343062 and rs6591182 were significantly associated with high BMI; rs2854117 and rs738409 with high triglyceride levels; and rs2073080, rs2143571, rs2228603, rs6487679 and rs738409 with high ALT levels. CONCLUSION: Pooled genetic analysis revealed an association of SNPs in PNPLA3, PARVB, SAMM50 and PZP genes with NAFLD. SNPs in NCAN and PNPLA3 gene were associated with higher levels of ALT, whereas variant SNPs in APOC3, PNPLA3, EFCAB4B and COL13A1 were associated with high triglyceride levels.