Nonalcoholic fatty liver disease: A manifestation of the metabolic syndrome

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ABSTRACTNonalcoholic fatty liver disease (NAFLD) has become the most common form of liver disease, affecting 20% to 30% of the US population. Its clinical manifestations are usually absent or subtle, and it usually comes to medical attention incidentally when aminotransferase levels are found to be elevated or a radiographic study reveals that the liver is fatty. Primary NAFLD is now considered the hepatic manifestation of the metabolic syndrome. The pathogenesis is thought to be a multiple-hit process involving insulin resistance, oxidative stress, apoptosis, and adipokines. In general, the prognosis for simple steatosis is very good; however, nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatocellular carcinoma in 10% to 15% of patients. There is no established treatment for NAFLD except for weight loss and treating each component of the metabolic syndrome.


  • The clinical spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma.
  • NAFLD is closely associated with metabolic syndrome, insulin resistance, and obesity.
  • Weight loss and treating components of the metabolic syndrome are central to the treatment of NAFLD. Insulin sensitizers such as biguanides and glitazones, antioxidants such as vitamin E, and lipid-lowering agents have shown promise in small clinical trials, but the evidence remains preliminary.



As the nation gets heavier, our livers will get fattier. The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rising in tandem with the rise in obesity ever since the term nonalcoholic steatohepatitis (NASH, a subtype of NAFLD) was coined by Ludwig in 1980.1 Yet, despite an explosion of research on NAFLD and gains in understanding its epidemiology and pathogenesis, a number of issues remain unresolved, including how to treat it.


NAFLD is a spectrum. The mildest form is simple fatty liver, or simple steatosis. Next is NASH, or fatty liver with inflammation and evidence of damage to hepatocytes (liver cells). Still more severe is cirrhosis, and in its most extreme form NAFLD can progress to hepatocellular carcinoma or liver failure. The distinction between simple steatosis and NASH is important because their prognoses and management are different.


NAFLD is the most common cause of elevated liver enzymes and also one of the most common forms of liver disease in the world. It is now estimated to affect about 20% to 30% of people in the United States and other Western countries. In contrast, the prevalence of chronic hepatitis C virus infection is estimated at 3% of the world’s population. In comparison to the prevalence of NAFLD, the prevalence of NASH is much lower: 2% to 3% in the United States.2 The incidence of NAFLD is expected to rise further with the increase in obesity in the United States.

NAFLD is even more common in people who are morbidly obese, ie, who have a body mass index greater than 40 kg/m2. In a series of studies of morbidly obese patients undergoing bariatric surgery (N = 1,620), the prevalence of hepatic steatosis was 91% (range 85%–98%), and the prevalence of NASH was 37% (range 24%–98%). NASH was not predicted by age or body mass index, but it was more common in men, people with diabetes, and people with insulin resistance.3

Obesity is also increasing in prevalence in children. Since liver biopsies were not done in most pediatric studies, the pediatric prevalence data are based on elevated aminotransferase levels and on ultrasonographic findings of echogenic livers. The overall prevalence of NAFLD in children is estimated at 3% to 10%, but it may be much higher in obese children.4

Arun et al5 found that the prevalence of NASH in morbidly obese men was almost twice as high as in morbidly obese women (60.3% vs 30.9%). In contrast, earlier studies suggested that NAFLD was more prevalent in women. This higher incidence of NASH may also reflect the higher incidence of metabolic syndrome in morbidly obese men (91.4% vs 76.2%).

Less common in African Americans

In the United States, African Americans have consistently been found to have the lowest prevalence of NAFLD. In a California population study of 159 newly diagnosed NAFLD cases, non-Hispanic whites accounted for 45%, followed by Hispanics (28%), Asians (18%), and African Americans (3%). After controlling for the ethnic composition of the entire cohort, Hispanics had the highest rate of NAFLD and African Americans the lowest.6 In Eastern countries such as Japan, the prevalence of NAFLD is estimated to be about 9.3%. Interestingly, about half of the people with NAFLD in Japan were not overweight.7

The difference in prevalence of NAFLD in different ethnic groups may be explained by their different rates of metabolic syndrome (21.6% in African Americans vs 23.8% in whites vs 31.9% in Mexican Americans8) as well as other genetic and environmental factors.


NAFLD is usually clinically silent, and its impact has most likely been underestimated. Symptoms, if present, are minimal and non-specific, such as fatigue and right upper quadrant discomfort. Most findings on physical examination are also normal. Most patients seek care because of an incidental finding of elevated aminotransferase levels or radiographic studies suggesting the liver is fatty.9

The estimated prevalence of aminotransferase elevations in the general population from the third National Health and Nutrition Examination Survey data is 7.9%,10 with about two-thirds of cases unexplained. Of the unexplained cases, most are strongly associated with metabolic syndrome and probably represent underlying NAFLD.10

Yet aminotransferase levels are typically normal or elevated by less than five times the upper limit of normal (usually < 250 IU/L).9 In contrast to those with alcoholic hepatitis, most patients with NAFLD have a ratio of aspartate aminotransferase to alanine aminotransferase of less than 1. As the disease progresses, the aspartate aminotransferase level increases more than the alanine aminotransferase level, so if the ratio is more than 1, more advanced liver disease may be suspected.11

Levels of other liver enzymes such as alkaline phosphatase and of acute-phase reactants such as ferritin may also be elevated. Ferritin is believed to reflect hepatic injury, inflammation, or insulin resistance.

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