Nonalcoholic Fatty Liver Disease

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Nonalcoholic fatty liver disease (NAFLD) describes two histopathologic conditions occurring in the absence of alcohol intake: nonalcoholic fatty liver (NAFL), defined by the presence of macrovesicular steatosis within 5% of hepatocytes, and nonalcoholic steatohepatitis (NASH), defined by steatosis plus the additional histologic features of inflammation and ballooning hepatocytes. Clinically, NAFLD is often a diagnosis of exclusion.
  • NAFLD is a dynamic process that may resolve with treatment or develop into cirrhosis over time. NASH has become the leading cause for liver transplantation in U.S. adult women and second leading cause in U.S. adult men.
  • NAFLD is strongly associated with obesity, although disease may be present among children who have normal weight.

EPIDEMIOLOGY

  • The incidence and prevalence of NAFLD are rising, although disease burden is heterogeneous.
  • The incidence of NAFLD in children has increased over time, from 36 per 100,000 in 2009 to 58.2 per 100,000 in 2018.
  • The prevalence of NAFLD is approximately 10% in the general pediatric population but varies by age; affects 0.7% of all 2- to 4-year-olds, 17.3% of all 15- to 19-year-olds, and up to 30% of adults in the United States.
  • Nearly 40% of obese children have NAFLD.
  • Fatty liver prevalence also differs by race and ethnicity, with Hispanics and Asians significantly more likely to have NAFLD compared to African Americans.

RISK FACTORS

  • Obesity
  • Male gender
  • Older pediatric age
  • Hyperinsulinemia, insulin resistance, and diabetes
  • Poor diet high in fructose and added sugars
  • Physical inactivity
  • High birth weight

Genetics

  • The heritability of NAFLD is estimated from 20% to 70% depending on the study design, ethnicity, and the methodology.
  • Large genome-wide association studies (GWAS) have uncovered multiple single nucleotide polymorphisms (SNPs) that confer risk for NAFLD development and/or progression. Three SNPs that are most strongly associated with disease include the following:
    • Patatin-like phospholipase domain-containing 3 (PNPLA3), rs738409 C>G (I148M)
    • Transmembrane 6 superfamily member 2 (TMS6F2), rs58542926
    • Glucokinase gene regulator (GCKR), rs780094
  • The carrier frequency of some SNPs varies significantly and may explain much of the ethnicity disparities. Hispanic populations have high carrier frequencies of the I148M PNPLA3 risk allele, for example, whereas African-American populations have a high carrier frequency of a protective PNPLA3 allele, S453I.
  • Other mechanisms that are possibly conferring risk include rare variants, gene–gene and gene–environment interaction, epigenetic variations, and mitochondrial DNA variability.

GENERAL PREVENTION

  • Lifestyle modification (i.e., healthy diet and daily moderate- to high-intensity exercise) is the best way to prevent NAFLD.
  • Avoid/limit sweetened foods and beverages. A diet low in fructose and added sugars is associated with decreased visceral and hepatic fat, improved alanine aminotransferase (ALT), and improved insulin resistance.

PATHOPHYSIOLOGY

NAFLD occurs due to a confluence of genetic, lifestyle, metabolic, and biologic factors. Disease heterogenicity, in turn, may be explained by the relative strength of these factors among individuals. Several of the most important factors are as follows:

  • Intestinal dysbiosis is strongly associated with NAFLD and may cause disease or hasten progression through breakdown of the gut barrier, endotoxemia, altered bile acid profiles, and/or decreased short-chain fatty acid concentrations.
  • Hyperinsulinemia paradoxically leads to increased hepatic gluconeogenesis, decreased glycogenosis, and increased fatty acid lipolysis. The changes in glucose metabolism further worsen hyperinsulinism, whereas increased lipolysis is thought to produce excess free radicals that hasten disease progression.
  • Genetics: Multiple SNPs play a large role in NAFLD development and progression.
  • Lifestyle: A high added-sugar diet and sedentary lifestyle contribute to the hepatic steatosis.

COMMONLY ASSOCIATED CONDITIONS

  • Insulin resistance and type 2 diabetes
  • Severe obesity
  • Dyslipidemia
  • Obstructive sleep apnea
  • There is a strong association with heart disease in adults.

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