Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland.

OBJECTIVES: Alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) are steatotic liver diseases and major causes of cirrhosis. Only a minority of patients with risk factors develop cirrhosis and genetic cofactors may be important in pathogenesis. Mutations in the Wilson's and α-1-antitrypsin genes are not uncommon and we speculated that they may act as cofactors. METHODS: We investigated α-1-antitrypsin phenotyes and caeruloplasmin levels in patients undergoing elective liver transplantation. We compared patients with alcohol and NAFLD with nonsteatotic liver disease patients: viral hepatitis B or C, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. RESULTS: Two hundred and thirty-one patients were included in the study. Pretransplant caeruloplasmin levels and α-1-antitrypsin phenotypes were available in 197 and 112 patients, respectively. α-1-Antitrypsin Z phenotypes were significantly more common in the alcohol and NAFLD group: 12/56 versus 3/56 (P<0.05). Serum caeruloplasmin (0.3±0.01 vs. 0.39±0.01 g/l, P<0.01) and serum copper levels (13.5±0.9 vs. 19.3±0.9 µmol/l, P<0.01) were significantly lower in the alcohol and NAFLD patients compared with the viral and autoimmune patients. CONCLUSION: In this study, we found the α-1-antitrypsin Z phenotype was more common, and serum caeruloplasmin and copper levels were lower in patients with fatty liver diseases. We suggest that mutations in the α-1-antitrypsin and Wilson's genes may act as cofactors in the pathogenesis of fatty liver diseases.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.