- Nonalcoholic fatty liver disease (NAFLD) is an overarching concept that includes simple steatosis and nonalcoholic steatohepatitis (NASH).
- NAFLD is commonly associated with the metabolic syndrome, obesity, diabetes, and hyperlipidemia; 80% of patients with the metabolic syndrome have NAFLD.
- Patients generally present without clinical symptoms but with mild transaminase elevations; NAFLD is the most common cause of increased serum transaminase levels.
- NAFLD is a clinical diagnosis after exclusion of other causes of liver disease.
- Ultrasound, computed tomography, and magnetic resonance imaging are useful for the detection.
- Liver biopsy is currently required to distinguish NASH from NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, the hepatocellular accumulation of triglycerides in the absence of significant alcohol consumption. Simple steatosis connotes fat accumulation in the absence of inflammation in the liver. By contrast, nonalcoholic steatohepatitis (NASH) indicates the presence of inflammation and fibrosis in association with hepatic steatosis. NAFLD is sometimes used as an overarching term that includes simple steatosis and NASH, but is also commonly employed to connote simple steatosis.
Whereas the histopathology of NAFLD and NASH is similar to that of alcohol-related liver disease, the etiology is quite distinct. An abundance of basic and clinical research has demonstrated that the metabolic underpinnings of NAFLD are rooted in insulin resistance. Indeed, NAFLD is commonly associated with other manifestations of insulin resistance including obesity, diabetes, and hyperlipidemia. Although early studies suggested NAFLD to be a benign condition, it is now apparent that NAFLD is a major cause of liver-related morbidity and mortality.
The absence of signs and symptoms, combined with a lack of sensitive and specific diagnostic tests, makes estimation of the prevalence of NAFLD difficult. Elevated liver enzymes are not sensitive for detecting NAFLD and there is no current consensus that histopathology is a gold standard for diagnosis. Although likely an underestimate for these reasons, the prevalence of NAFLD is considered to be in the range of 20% in the United States and between 11.5% and 46% of the general population. By contrast, the prevalence of NASH is much lower, and in the range of 2% to 3%. As a result, the prevalences of NAFLD and NASH easily exceed chronic hepatitis C (HCV) infection, which afflicts 1.8% of the U.S. population. Recently, a common polymorphism in the gene encoding patatin-like phospholipase-3 (PNPLA3) (synonym adiponutrin) was shown to be strongly associated with NAFLD and its histopathologic severity.
Population-based studies have revealed that NAFLD is more common in men than women. It is more common in Hispanics compared with whites and more common in whites than blacks. It is assumed that the prevalence of NAFLD will increase over time in parallel to the epidemic of obesity and diabetes. Of particular concern is that NAFLD is increasing in the pediatric population, with prevalences estimated at around 3% of children and 20–50% of obese children.
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Association of NAFLD with the Metabolic Syndrome, Obesity, Diabetes, and Hyperlipidemia
Insulin resistance represents the most important risk factor for the development of NAFLD. Because insulin resistance is also the hallmark of the metabolic syndrome, it is not surprising that there is a close connection between NAFLD and the metabolic syndrome. Indeed, steatosis may simply characterize the hepatic manifestation of the metabolic syndrome. The metabolic syndrome is generally defined as the coexistence of three or more of the following findings: (1) increased waist circumference, (2) hypertriglyceridemia, (3) hypertension, (4) elevated fasting plasma glucose, and (5) low high-density lipoprotein (HDL) cholesterol level. Patients with metabolic syndrome have a 4- to 11-fold higher risk of developing NAFLD, and the prevalence of metabolic syndrome in patients with NAFLD ranges from 18% to 67%, depending on body weight. In NAFLD patients with the metabolic syndrome, the risk of NASH is elevated threefold.
There is also a close association of NAFLD with obesity. The prevalence of obesity in patients with NAFLD is reported to vary from 30% to 100%. In obese patients (body mass index [BMI] ≥30) the risk of NAFLD is elevated 4.6-fold. Importantly, the frequency of NASH also varies in proportion to weight. The prevalence of NASH is 3% of the lean population, but rises to 19% in obesity and to nearly 50% in morbidly obese individuals. Consistent with the close relationship of NAFLD with the metabolic syndrome, NAFLD is more common in individuals with an abdominal concentration of fat, even at lower BMI.
The prevalence of NAFLD is high in the type 2 diabetic population (50%), and the prevalence of type 2 diabetes in NAFLD patients ranges from 10% to 75%. The prevalence of NAFLD appears to increase as continuous function of fasting plasma glucose. Importantly, NASH is disproportionately represented in type 2 diabetics, with significant fibrosis and cirrhosis present in approximately 20%. In hyperlipidemic patients, the overall prevalence of fatty liver is 50%, with hypertriglyceridemia and mixed dyslipidemia conferring a fivefold risk of NAFLD. The prevalence of hyperlipidemia associated with NAFLD varies from 20% to 90%. In keeping with a strong link to the metabolic syndrome, low HDL cholesterol levels are also commonly observed in patients with NAFLD. Emerging evidence suggests that hypertension is linked to NAFLD through its relationship to insulin resistance.