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Nonalcoholic Steatohepatitis: Epidemiology, Screening, Risk Assessment, Diagnosis, and Management

Quentin M. Anstee, BSc, MB BS, PhD, MRCP(UK), FRCP
Program Director
Philip N. Newsome, PhD, FRCPE
Released: August 21, 2019

Risk Factors for NASH and NAFLD

Obesity and Metabolic Syndrome
Obesity is closely associated with NAFLD and represents the most common risk factor for this condition.[1] Indeed, the worldwide rate of obesity among those with NAFLD is 51.34%, climbing to 81.83% among those with NASH.[11] In comparison, the global rate of obesity was 13% in 2016.[20] Worldwide, approximately 1.9 billion adults are overweight and 650 million are obese, with rates of obesity exceeding 50% in certain parts of the world, including the Pacific islands, Kuwait, Libya, and Qatar.[20,21] Of greater concern is the increasing prevalence of obesity in children and adolescents, with approximately 18% of children worldwide being categorized as overweight or obese in 2016 compared with 4% in 1975.[20] In developed regions, obesity is strongly linked to economic deprivation, with the most socioeconomically deprived children being much more likely to be obese compared with the most affluent.[22] For example, an analysis of obesity rates among US youths aged 2-19 years from the 2011-2014 NHANES study reported that the rate of obesity was highest in those with the lowest income (18.9%) and lowest in those with the highest income (10.9%).[23] Interventions aimed at mitigating weight gain are addressed later in this module, but success requires broader societal changes to the obesogenic environment regarding food pricing and availability, along with greater access to facilities for exercise and youth physical activity programs.[20]

Other features of metabolic syndrome are closely associated with an increased risk for NAFLD, including type 2 diabetes mellitus (T2DM) and dyslipidemia.[1] Compared with the general population worldwide, of whom 8.8% have diabetes—overwhelmingly T2DM—those with NAFLD and NASH exhibit markedly higher T2DM rates of 22.51% and 43.63%, respectively.[11,24] Dyslipidemia is similarly enriched among those with NAFLD (present in 69.16%) and NASH (72.13%). Further reflecting the close relationship between dyslipidemia and these hepatic conditions, a cross-sectional study of 44,767 patients in Taiwan who received a health checkup at a single institution reported that the rate of NAFLD increased as the ratios increased for total cholesterol:high density lipoprotein cholesterol ratio and triglycerides:high density lipoprotein cholesterol.[25] Patients in the quartile with the lowest ratios had an NAFLD rate of 33.41% compared with 78.04% among those in the quartile with the highest ratios.

Many studies have suggested that individuals of Asian origin are at increased risk for NAFLD, insulin resistance, T2DM, and metabolic syndrome and that these events often occur at lower BMI than is observed in other ethnic groups.[12] This may reflect differences in fat distribution between the subcutaneous and visceral compartments for individuals of different ethnic origin and likely accounts for the observation of lean NAFLD frequently reported in Asian individuals. Such findings have led to revisions of BMI thresholds prompting screening for diabetes in Asian populations and support screening for NAFLD in Asian patients at lower BMI values than would be expected in non-Asian cohorts.[26]  

Genetic Predisposition
Genomewide association studies have identified single nucleotide polymorphisms (SNPs) in several genes associated with an increased risk of NAFLD and/or disease severity across a range of populations.[6] The most widely studied genetic risk factor for NAFLD is the PNPLA3 gene encoding adiponutrin, which is involved in lipogenesis and lipolysis in hepatocytes and adipocytes.[16] PNPLA3 SNPs (eg, rs738409 C > G [I148M]) are associated with an increase in not only the prevalence and severity of NASH but also the risk of hepatocellular carcinoma.[27] A meta-analysis of 16 studies reported that compared with those with NAFLD who were CC homozygous at PNPLA3 rs738409, those who were GG homozygous exhibited both significantly higher liver fat content (an increase of 73%; P < 1 x 10-9) and significantly higher odds for progressing to NASH (odds ratio: 3.488; P < 2 x 10-4).[28] SNPs in PNPLA3 have also been suggested to account for the differences in the prevalence of NAFLD among different US ethnic groups.[16] Another important genetic factor is TM6SF2, which encodes for a regulator of liver fat metabolism and is also associated with enhanced development of NASH and associated liver damage.[6,15,29] Other SNPs associated with NAFLD include those in KLF6, PPARα, PPARγ, and HSD17B13; these genes are involved in the regulation of lipid handling and insulin sensitivity.[30,31] Further work will be needed to determine the utility of identifying these SNPs in patient management.

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