Relationship between non‐alcoholic steatohepatitis, PNPLA3 I148M genotype and bone mineral density in adolescents

Background & Aims It is uncertain whether non‐alcoholic steatohepatitis ( NASH ) is a risk factor for low bone mineral density ( BMD ). Our aim was to investigate: (a) associations between NASH and BMD values and (b) associations between PNPLA 3 I148M genotypes and BMD , in children with histologically proven non‐alcoholic fatty liver disease ( NAFLD ). Methods BMD area (g/cm 2 ) was measured using dual‐energy X‐ray absorptiometry ( DEXA ). NASH was diagnosed by a Steatosis, Activity and Fibrosis ( SAF ) score and FLIP algorithm. Genotyping for patatin‐like phospholipase domain containing‐3 ( PNPLA 3) I148M genotype (rs738409) ( CC , CG and GG ) was undertaken using the TaqMan SNP genotyping allelic discrimination method. Logistic regression was used to test associations [ OR (95% CI s)] between low BMD , and both NASH and PNPLA 3 I148M genotypes. Results Thirty‐four adolescents (mean age 13.8 ± 1.1 years) with histologically confirmed NAFLD were studied. Subjects with NASH (n = 25) had a lower BMD (means ( SD s) 0.87 ± 0.06 vs 0.97 ± 0.12, P  = 0.005), compared to subjects without NASH . Subjects with PNPLA 3 CG + GG genotypes had a lower BMD compared with subjects with PNPLA 3‐ CC genotype (means ( SD s) 0.79 ± 0.20 vs 0.92 ± 0.10, P  = 0.009). PNPLA 3 CG + GG genotypes were independently associated with NASH [ OR (95% CI s 1.78, 1.24, 2.99)], and low BMD was associated with both PNPLA 3 CG + GG ( OR 3.62 (95% CI s 1.21, 5.53), P  = 0.028) and with SAF score ( OR 2.76 (95% CI s 1.12, 5.41), P  = 0.045). Conclusions Taken together the independent associations between: (a) low BMD and PNPLA 3 CG + GG genotype; (b) low BMD and NASH ; and (c) PNPLA 3 CG + GG genotype and NASH , provide support for a causal relationship between NASH and low BMD .