Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Osteoporosis is a common complication of liver transplantation. Its pathogenesis is multifactorial, but preexisting bone disease in patients with chronic liver disease is likely to play an important role. The aim of this study was to evaluate bone mineral density in adult patients with chronic liver disease prior to liver transplantation. A total of 243 consecutive patients (128 male, 115 female; mean age 51.1years) with chronic liver disease undergoing assessment for transplantation, were recruited over a 4-year period. BMD measurements were made using dual energy X-ray absorptiometry in the lumbar spine (L1-L4) and femoral neck (FN). Osteoporosis and osteopenia were defined by WHO criteria. Osteoporosis at either L1-L4 or FN was present in 36.6%, osteopenia in 48.1%, and normal BMD in only 15.2% of patients. There was no difference in prevalence of osteoporosis between males and females (P = 0.442). Women with osteoporosis were on average 10 years older (56.2 +/- 1.4 years) than those with normal bone density (46.4 +/- 2.3 years) P = 0.002; in men, no statistically significant age effect was found. Patients with osteoporosis had on average lower body weight than those with normal bone density (64.9 +/- 1.8 kg vs 74.2 +/- 2.2 kg) P = 0.003. T-scores in patients with cholestatic liver disease were lower than in non-cholestatic disease and the lowest BMD values were found in patients with cystic fibrosis. Logistic regression revealed that in women, increasing age (P = 0.004; OR = 1.12; CI 1.04-1.21) and lower body weight (P = 0.01; OR = 0.95; CI 0.91-0.99) were significant independent risk factors for osteoporosis but menopausal status (P = 0.1; OR = 0.24; CI 0.05-1.32) and presence or absence of cholestasis (P = 0.326; OR = 1.54; CI 0.65-3.67) were not. There were no independent risk factors in men. This study demonstrates a high prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation, men and women being equally affected. With the exception of increasing age and lower body weight in women, no independent risk factors were found, emphasizing the importance of BMD measurements in these patients and the need for prophylactic measures to optimize bone health.

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