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This is an updated version of the article that appeared in print.

Am Fam Physician. 2020;102(9):603-612

Related letter: NAFLD in Children and Adolescents

Related letter: Updated Statistics for Liver Biopsy Risk

Patient information: See related handout on nonalcoholic fatty liver disease, written by the authors of this article.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial affiliations.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States, affecting up to 30% of adults. There are two forms of NAFLD: nonalcoholic fatty liver (NAFL), defined as 5% or greater hepatic steatosis without hepatocellular injury or fibrosis, and nonalcoholic steatohepatitis (NASH), defined as 5% or greater hepatic steatosis plus hepatocellular injury and inflammation, with or without fibrosis. Individuals with obesity are at highest risk of NAFLD. Other established risk factors include metabolic syndrome and type 2 diabetes mellitus. Although NAFLD is common and typically asymptomatic, screening is not currently recommended, even in high-risk patients. NAFLD should be suspected in patients with elevated liver enzymes or hepatic steatosis on abdominal imaging that are found incidentally. Once other causes, such as excessive alcohol use and hepatotoxic medications, are excluded in these patients, risk scores or elastography tests can be used to identify those who are likely to have fibrosis that will progress to cirrhosis. Liver biopsy should be considered for patients at increased risk of fibrosis and when other liver disorders cannot be excluded with noninvasive tests. Weight loss through diet and exercise is the primary treatment for NAFLD. Other treatments, such as bariatric surgery, vitamin E supplements, and pharmacologic therapy with thiazolidinediones or glucagon-like peptide-1 analogues, have shown potential benefit; however, data are limited, and these therapies are not considered routine treatments. NAFL typically follows an indolent course, whereas patients with NASH are at higher risk of death from cardiovascular disease, cancer, and end-stage liver disease.

Nonalcoholic fatty liver disease (NAFLD) comprises a continuum of fatty liver disease that occurs in the absence of alcohol use or other secondary causes of hepatic steatosis. There are two manifestations of NAFLD (Figure 1).1 One is nonalcoholic fatty liver (NAFL), which is defined as 5% or greater hepatic steatosis without evidence of hepatocellular injury or fibrosis. The other is nonalcoholic steatohepatitis (NASH), which is defined as 5% or greater hepatic steatosis with hepatocellular injury and inflammation, with or without fibrosis.1

WHAT'S NEW ON THIS TOPIC

It is projected that 100 million people in the United States will have nonalcoholic fatty liver disease by 2030, with direct medical costs of about $103 billion annually.

By 2030, nonalcoholic steatohepatitis is predicted to become the leading indication for liver transplantation in U.S. adults, surpassing hepatitis C.

Clinical recommendationEvidence ratingComments
Routine screening for NAFLD is not recommended, even for high-risk adults.1 CConsensus guidelines; lack of evidence surrounding diagnosis, treatment, and benefit of screening
Patients with hepatic steatosis detected incidentally on imaging who have normal liver enzyme findings and no liver-related symptoms or signs should be assessed for metabolic risk factors (e.g., obesity, diabetes mellitus, dyslipidemia) and alternate causes of hepatic steatosis, such as excessive alcohol consumption or medication use.1,21 CConsensus guidelines
Ultrasonography is the imaging test of choice for patients with suspected NAFLD.24,25 CLimited-quality disease-oriented evidence
Noninvasive tools such as decision aids (NAFLD Fibrosis Score or Fibrosis-4 Score) or liver stiffness measurements using vibration-controlled elastography or magnetic resonance elastography are clinically useful for identifying patients with NAFLD who have a higher likelihood of developing fibrosis or cirrhosis.1,18,2729,35 CModerate-quality disease-oriented evidence
A liver biopsy should be offered to patients with NAFLD who are at increased risk of nonalcoholic steatohepatitis or advanced fibrosis based on noninvasive testing or if noninvasive testing cannot rule out other possible causes of chronic liver disease.1 CConsensus guideline and usual practice
Weight loss through diet and exercise is the primary treatment for NAFLD. A loss of 7% to 10% of total body weight is needed to improve the histopathologic abnormalities in the liver associated with NAFLD.1 CConsensus guidelines
There is insufficient evidence to support bariatric surgery, vitamin supplements,thiazolidinediones (pioglitazone [Actos]), and glucagon-like peptide-1 analogues (liraglutide [Victoza]) as first-line/primary treatments for NAFLD.1,6,21,3944,46,48 CLow- to high-quality disease-oriented evidence from randomized controlled trials and expert opinion
Statins should be used to treat dyslipidemia in patients with NAFLD.1,21 CConsensus guidelines and usual practice

Differentiating NAFL from NASH is important because they have different prognoses. NAFL follows a more indolent course, whereas patients with NASH are at risk of progression from fibrosis to cirrhosis and development of hepatocellular carcinoma.

NAFLD is the most common form of liver disease in the United States and other developed countries, with rates in the adult population estimated to be between 10% and 30%.2 About one-third of people with NAFLD have NASH.3 The prevalence of NAFLD increases with age, and it is more common in males and those of Hispanic descent.4

It is projected that 100 million people in the United States will have NAFLD by 2030, with direct medical costs of about $103 billion annually.5,6 Having tripled since 2004, NASH is predicted to become the leading indication for liver transplantation in U.S. adults by 2030, surpassing hepatitis C.7

Who Is at Risk of NAFLD?

People with obesity are at the highest risk of NAFLD. Metabolic syndrome and type 2 diabetes mellitus are other established risk factors. Emerging evidence shows that other conditions, such as genetic factors, sleep apnea, and hypothyroidism, are contributors (Table 1). 2,813

Established
Obesity (highest risk)
Metabolic syndrome (Table 2)
Type 2 diabetes mellitus
Emerging evidence
Genetic variation of the PNPLA3 gene
HIV
Hypothyroidism
Obstructive sleep apnea
Polycystic ovary syndrome

EVIDENCE SUMMARY

Although not all individuals with NAFLD are overweight,14 the prevalence of NAFLD is directly proportional to body weight, with 37% to 93% of those undergoing bariatric surgery having NAFLD and 26% to 44% having NASH.8 However, any of the components of metabolic syndrome (Table 215 ) increase the risk of NAFLD.2,15

Presence of any three of these five criteria is diagnostic:
Blood pressure
≥ 130 mm Hg systolic or ≥ 85 mm Hg diastolic, or antihypertensive pharmacotherapy needed in a patient with a history of hypertension
Fasting glucose level
≥ 100 mg per dL (5.55 mmol per L) or pharmacotherapy needed for elevated glucose level
HDL cholesterol level
< 50 mg per dL (1.29 mmol per L) in women or < 40 mg per dL (1.04 mmol per L) in men, or pharmacotherapy needed for reduced HDL cholesterol level
Triglyceride level
≥ 150 mg per dL (1.69 mmol per L) or pharmacotherapy needed for elevated triglyceride level
Waist circumference
≥ 35 in (89 cm) in women or ≥ 40 in (102 cm) in men

For example, some studies suggest that 33% to 66% of patients with type 2 diabetes develop NAFLD, often accompanied by advanced fibrosis. Likewise, those with NAFLD are at higher risk of developing type 2 diabetes. This bidirectional relationship makes the data on prevalence difficult to interpret because each can occur concurrently.9,10 In patients with NAFLD, having type 2 diabetes is a risk factor for progression to NASH, cirrhosis, and death, and poor glycemic control is also associated with poorer outcomes.2

Dyslipidemia is another metabolic risk factor for NAFLD. A study of 44,000 patients with dyslipidemia found the prevalence of NAFLD was 54% in this population, and this increased to 78% among those with the highest triglyceride to high-density–lipoprotein cholesterol ratios.11

Genetic factors are also involved in the risk of NAFLD. A study of 339 adults found that those with NAFLD who had the high-risk allele of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene had a twofold greater risk of advanced fibrosis (P = .006).12 The PNPLA3 gene is responsible for making a protein found in adipocytes and hepatocytes.

A 2019 review showed that obstructive sleep apnea is associated with more severe forms of NAFLD, and treating the apnea may improve associated liver injury.13 Higher rates of NAFLD are also observed in patients with polycystic ovary syndrome or hypothyroidism. Low thyroid function may worsen the progression of liver damage, whereas thyroid replacement therapy may improve liver function.13

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