Adult idiopathic cholestasis: a condition more common in the Canadian Inuit?

Despite extensive investigations, some patients have no identifiable cause for their cholestatic liver enzyme abnormalities. The aim of this study was to document the clinical, laboratory, radiologic and histologic features of adult patients with idiopathic cholestasis (AIC). A computerised database of referred patients to a tertiary care hospital outpatient department for assessment of hepatobiliary disorders between 2005 and 2015 was employed to identify and describe features associated with AIC. Of 6,560 patient referrals, sufficient documentation to warrant a diagnosis of AIC was present in 17 (0.26%) cases. Of the 17, a disproportionate number were Canadian Inuit (7/60, 12% Inuit referrals vs. 10/6,500, 0.16% non-Inuit referrals, p<0.0001). The median age of the 17 subjects was 57 years and nine (53%) were female. Clinical and/or laboratory evidence of autoimmune disorders was present in six (35%) cases. Clinical features of hepatic decompensation, radiologic findings in keeping with cirrhosis and histologic confirmation of cirrhosis were present in 47%, 31% and 42% of individuals, respectively. There were no significant improvements in cholestatic liver enzymes and function tests in those treated with ursodiol and/or immunomodulants (n=7) compared to those left untreated (n=10). In conclusion, AIC is a rare condition diagnosed by exclusion. It appears to be more common in the Canadian Inuit population and those with autoimmune disorders. Advanced liver disease is a frequent finding at presentation. Intervention with ursodiol and/or immunomodulants does not appear to be of therapeutic value.

Racial and ethnic disparities in access to and utilization of living donor liver transplants.

Living donor liver transplantation (LDLT) is a comparable alternative to deceased donor liver transplantation and can mitigate the risk of dying while waiting for transplant. Although evidence exists of decreased utilization of living donor kidney transplants among racial minorities, little is known about access to LDLT among racial/ethnic minorities. We used Organ Procurement and Transplantation Network/United Network for Organ Sharing data from February 27, 2002 to June 4, 2014 from all adult liver transplant recipients at LDLT-capable transplant centers to evaluate differential utilization of LDLTs based on race/ethnicity. We then used data from 2 major urban transplant centers to analyze donor inquiries and donor rule-outs based on racial/ethnic determination. Nationally, of 35,401 total liver transplant recipients performed at a LDLT-performing transplant center, 2171 (6.1%) received a LDLT. In multivariate generalized estimating equation models, racial/ethnic minorities were significantly less likely to receive LDLTs when compared to white patients. For cholestatic liver disease, the odds ratios of receiving LDLT based on racial/ethnic group for African American, Hispanic, and Asian patients compared to white patients were 0.35 (95% CI, 0.20-0.60), 0.58 (95% CI, 0.34-0.99), and 0.11 (95% CI, 0.02-0.55), respectively. For noncholestatic liver disease, the odds ratios by racial/ethnic group were 0.53 (95% CI, 0.40-0.71), 0.78 (95% CI, 0.64-0.94), and 0.45 (95% CI, 0.33-0.60) respectively. Transplant center-specific data demonstrated that African American patients received fewer per-patient donation inquiries than white patients, whereas fewer African American potential donors were ruled out for obesity. In conclusion, racial/ethnic minorities receive a disproportionately low percentage of LDLTs, due in part to fewer initial inquiries by potential donors. This represents a major inequality in access to a vital health care resource and demands outreach to both patients and potential donors.

Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome.

Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a>50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in approximately 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.

Autoimmune hepatitis in a North American Aboriginal/First Nations population.

North American Aboriginal populations are at increased risk for developing immune-mediated disorders, including autoimmune hepatitis. In the present study, the demographic, clinical, biochemical, serological, radiological and histological features of autoimmune hepatitis were compared in 33 First Nations (FN) and 150 predominantly Caucasian, non-FN patients referred to an urban tertiary care centre. FN patients were more often female (91% versus 71%; P=0.04), and more likely to have low serum albumin (69% versus 36%; P=0.0006) and elevated bilirubin (57% versus 35%; P=0.01) levels on presentation compared with non-FN patients. They also had lower hemoglobin, and complement levels, more cholestasis and higher serum immunoglobulin A levels than non-FN patients (P=0.05 respectively). Higher histological grades of inflammation and stages of fibrosis, and more clinical and radiological evidence of advanced liver disease were observed in FN patients, but the differences failed to reach statistical significance. The results of the present study suggest that in addition to being more common, autoimmune hepatitis may be more severe in FN populations, compared with predominantly Caucasian, non-FN populations.

alpha1-Antitrypsin deficiency is not an important cause of childhood liver diseases in a multi-ethnic Southeast Asian population.

AIM: We conducted a prospective study to determine the role of alpha1-antitrypsin (alpha1AT) deficiency in the pathogenesis of neonatal cholestasis and other childhood liver diseases in a multi-ethnic Southeast Asian population. METHODS: Prospective patients with neonatal cholestasis (group 1), other liver diseases (group 2) and children with other medical conditions (group 3) referred to the Paediatric Unit, University of Malaya Medical Centre, Malaysia, from May 2002 to June 2005, were screened for alpha1AT level and phenotype. alpha1AT level below 80 mg/dL was considered as low. RESULTS: Of the 114 patients (group 1, n = 53; group 2, n = 42; group 3, n = 19) screened, seven patients (6% of total; group 1, n = 1; group 2, n = 4; group 3, n = 2) had a alpha1AT level below 80 mg/dL. All had marginally low level (range 57-79 mg/dL), but none had a clinical diagnosis of alpha1AT deficiency. One patient had PiZ- heterozygous phenotype (alpha1AT level 217 mg/dL) while another patient had PiMS heterozygous. CONCLUSIONS: alpha1AT deficiency is not an important cause of neonatal cholestasis and childhood liver diseases in Malaysian children. In Malaysian children with neonatal cholestasis or other liver diseases, routine assay for alpha1AT phenotype is not recommended if there is no family history of neonatal cholestasis of uncertain aetiology, or if alpha1AT level is above 80 mg/dL.

Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).

Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.

Obstructive jaundice in the South African black population.

We report the causes of obstructive jaundice in 56 black South African patients. Chronic pancreatitis and malignant biliary obstruction occurred with equal frequency. These two conditions may be difficult to differentiate clinically and radiologically, and only operative pancreatic biopsy may be diagnostic. Choledocholithiasis caused jaundice in only 7.1% of the patients, reflecting the relatively low prevalence of gallstones in this population.