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

Liver Int. 2018 Dec;38(12):2301-2308. doi: 10.1111/liv.13955. Epub 2018 Sep 25.


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 PNPLA3 I148M genotypes and BMD, in children with histologically proven non-alcoholic fatty liver disease (NAFLD).

Methods: BMD area (g/cm2 ) 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 (PNPLA3) 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% CIs)] between low BMD, and both NASH and PNPLA3 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 (SDs) 0.87 ± 0.06 vs 0.97 ± 0.12, P = 0.005), compared to subjects without NASH. Subjects with PNPLA3 CG+GG genotypes had a lower BMD compared with subjects with PNPLA3-CC genotype (means (SDs) 0.79 ± 0.20 vs 0.92 ± 0.10, P = 0.009). PNPLA3 CG+GG genotypes were independently associated with NASH [OR (95% CIs 1.78, 1.24, 2.99)], and low BMD was associated with both PNPLA3 CG+GG (OR 3.62 (95% CIs 1.21, 5.53), P = 0.028) and with SAF score (OR 2.76 (95% CIs 1.12, 5.41), P = 0.045).

Conclusions: Taken together the independent associations between: (a) low BMD and PNPLA3 CG+GG genotype; (b) low BMD and NASH; and (c) PNPLA3 CG+GG genotype and NASH, provide support for a causal relationship between NASH and low BMD.

Keywords: BMD; NASH; PNPLA3; children.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Adolescent
  • Alleles
  • Bone Density*
  • Bone and Bones / diagnostic imaging
  • Case-Control Studies
  • Child
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lipase / genetics*
  • Liver / pathology
  • Logistic Models
  • Male
  • Membrane Proteins / genetics*
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Polymorphism, Single Nucleotide
  • Risk Factors


  • Membrane Proteins
  • Lipase
  • adiponutrin, human