Are Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Inherited?
Are Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Inherited?
Is there a genetic predisposition for the development of nonalcoholic fatty liver disease or the progression to nonalcoholic steatohepatitis?
Yes, according to emerging evidence.
The etiologies of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have, for many years, been postulated to be multifactorial, with substantial genetic components. Clinical case series, which documented familial clustering of NAFLD and NASH and the racial and ethnic differences in the prevalence of these disorders, strongly implied a genetic susceptibility. However, the true heritability and specific genetic basis of NAFLD and NASH were largely undetermined. Clinical and translational science has now shed light on these issues.
Schwimmer and associates conducted a familial aggregation study to test the hypothesis that NAFLD is highly heritable. The investigators used magnetic resonance imaging to quantify liver fat fraction in family members of overweight children with biopsy-proven NAFLD and overweight children without NAFLD. Fatty liver (defined as a liver fat fraction > 5%) was present in 17% of siblings and 37% of parents of overweight children who did not have NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Because genetic factors are a major determinant of whether an individual has NAFLD, family members of children with NAFLD should be considered at high risk for the disease. The bottom line is that obesity is clearly a risk factor for NAFLD, but this is strongly modified by the underlying genetic predisposition.
To complement this clinical observation, we now have some insight into the genetic susceptibility to NAFLD. The first NAFLD and NASH gene -- the adiponutrin/PNPLA3 genotype -- was recently identified. Romeo and colleagues carried out a genome-wide association scan of nonsynonymous sequence variations in a large number of patients to identify genetic variants that contributed to differences in hepatic fat content. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat content (NAFLD) and with hepatic inflammation (NASH). The allele was most common in Hispanic patients, the group most susceptible to NAFLD. Hepatic fat content was more than 2-fold higher in PNPLA3 rs738409(G) homozygotes than in noncarriers. Another allele of PNPLA3 (rs6006460[T], encoding S453I) was associated with lower hepatic fat content in black patients, the group at lowest risk for NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and interindividual differences in hepatic fat content and susceptibility to NAFLD and NASH.
Another susceptibility factor was reported by Petersen and associates, who discovered that carriers of apolipoprotein C3 (APOC3) variant alleles (C-482T, T-455C, or both) had a 30% increase in fasting plasma apolipoprotein C3 concentration, compared with the wild-type homozygotes. These variants were also associated with a 60% increase in fasting plasma triglyceride concentration, a 2-fold increase in plasma triglyceride concentration after an oral fat tolerance test, and a 46% reduction in plasma triglyceride clearance. Overall, 38% of Asian-Indian men with at least 1 of 2 single-nucleotide polymorphisms in the gene encoding apolipoprotein C3 (T-455C and C-482T) had NAFLD and insulin resistance compared with none of those without the variants (P < .001). A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and NAFLD. The good news is that hepatic steatosis and insulin resistance in carriers of these high-risk variants can be reversed by weight loss.
Additional studies to examine the complex relationship between genes and environment in the development of NAFLD and progression to NASH are clearly warranted. Prevention of the adverse outcomes of hepatic steatosis will depend on studies that screen populations with fatty livers for genetic and epigenetic factors that modulate susceptibility. Biomarkers and blood tests with improved sensitivity and specificity for detecting NAFLD and NASH and the genetic predisposition will soon be available. Early detection will hopefully allow an entire family to create a healthy lifestyle with regular exercise and a heart- and liver-healthy diet.
Question
Is there a genetic predisposition for the development of nonalcoholic fatty liver disease or the progression to nonalcoholic steatohepatitis?
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Response from William F. Balistreri, MD
Dorothy M.M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio |
Yes, according to emerging evidence.
The etiologies of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have, for many years, been postulated to be multifactorial, with substantial genetic components. Clinical case series, which documented familial clustering of NAFLD and NASH and the racial and ethnic differences in the prevalence of these disorders, strongly implied a genetic susceptibility. However, the true heritability and specific genetic basis of NAFLD and NASH were largely undetermined. Clinical and translational science has now shed light on these issues.
Schwimmer and associates conducted a familial aggregation study to test the hypothesis that NAFLD is highly heritable. The investigators used magnetic resonance imaging to quantify liver fat fraction in family members of overweight children with biopsy-proven NAFLD and overweight children without NAFLD. Fatty liver (defined as a liver fat fraction > 5%) was present in 17% of siblings and 37% of parents of overweight children who did not have NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Because genetic factors are a major determinant of whether an individual has NAFLD, family members of children with NAFLD should be considered at high risk for the disease. The bottom line is that obesity is clearly a risk factor for NAFLD, but this is strongly modified by the underlying genetic predisposition.
To complement this clinical observation, we now have some insight into the genetic susceptibility to NAFLD. The first NAFLD and NASH gene -- the adiponutrin/PNPLA3 genotype -- was recently identified. Romeo and colleagues carried out a genome-wide association scan of nonsynonymous sequence variations in a large number of patients to identify genetic variants that contributed to differences in hepatic fat content. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat content (NAFLD) and with hepatic inflammation (NASH). The allele was most common in Hispanic patients, the group most susceptible to NAFLD. Hepatic fat content was more than 2-fold higher in PNPLA3 rs738409(G) homozygotes than in noncarriers. Another allele of PNPLA3 (rs6006460[T], encoding S453I) was associated with lower hepatic fat content in black patients, the group at lowest risk for NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and interindividual differences in hepatic fat content and susceptibility to NAFLD and NASH.
Another susceptibility factor was reported by Petersen and associates, who discovered that carriers of apolipoprotein C3 (APOC3) variant alleles (C-482T, T-455C, or both) had a 30% increase in fasting plasma apolipoprotein C3 concentration, compared with the wild-type homozygotes. These variants were also associated with a 60% increase in fasting plasma triglyceride concentration, a 2-fold increase in plasma triglyceride concentration after an oral fat tolerance test, and a 46% reduction in plasma triglyceride clearance. Overall, 38% of Asian-Indian men with at least 1 of 2 single-nucleotide polymorphisms in the gene encoding apolipoprotein C3 (T-455C and C-482T) had NAFLD and insulin resistance compared with none of those without the variants (P < .001). A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and NAFLD. The good news is that hepatic steatosis and insulin resistance in carriers of these high-risk variants can be reversed by weight loss.
Additional studies to examine the complex relationship between genes and environment in the development of NAFLD and progression to NASH are clearly warranted. Prevention of the adverse outcomes of hepatic steatosis will depend on studies that screen populations with fatty livers for genetic and epigenetic factors that modulate susceptibility. Biomarkers and blood tests with improved sensitivity and specificity for detecting NAFLD and NASH and the genetic predisposition will soon be available. Early detection will hopefully allow an entire family to create a healthy lifestyle with regular exercise and a heart- and liver-healthy diet.
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