The Emerging Epidemic of Nonalcoholic Fatty Liver Disease

Rowen K. Zetterman, MD


January 21, 2011

In This Article

Clinical Features


Patients with NAFLD may lack symptoms of liver disease, or such symptoms can be found during evaluation of other medical conditions or symptoms. A common presentation is finding abnormal liver tests on routine blood testing. Some patients present with continuous, burning right upper quadrant pain or hepatomegaly. NAFLD might be discovered during an evaluation of fatigue, malaise, or weakness, following the identification of a fatty liver on ultrasound, or when testing a patient for suspected hemochromatosis. A careful history for ethanol ingestion should also be obtained; a diagnosis of NAFLD should be applied only to patients who consume < 20 g of pure ethanol equivalent (approximately 2 American beers) daily.

Physical Findings

Hepatomegaly is typical, although signs of chronic liver disease, such as ascites or jaundice, are rare even in the presence of advanced liver disease. Truncal obesity with increased waist circumference is common. Lipodystrophy with sparing of the face occurs in adults with limb lipodystrophy. Acanthosis nigricans is noted in 50% of children with NASH.[18]

Laboratory Features

Liver tests may be normal[19] or include mild elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), although these values are rarely more than 2 or 3 times normal.[20] Most patients will have an AST/ALT ratio of < 1,[21] whereas an AST/ALT ratio > 1 in patients with NASH may be associated with cirrhosis.[22] Alkaline phosphatase and gamma glutamyltranspeptidase levels are normal or slightly elevated. Circulating cytokeratin 18 fragment levels, a marker of apoptosis, are elevated in patients with NASH.[23,24]

Both serum ferritin levels and transferrin saturation may be high, although levels consistent with hemochromatosis are not observed.[25] The ratio of desialylated transferrin to total transferrin is said to separate patients with NASH from alcoholic fatty liver because the ratio is elevated in alcoholic fatty liver and not in NASH.[26] Its clinical utility remains to be defined. Glucose intolerance and hyperlipidemia are frequent, and low-titer antinuclear antibody levels occur.[27]

Pathologic Features

Liver biopsy remains the gold standard for the diagnosis of NAFLD and NASH.[28] NAFL includes simple fatty change of > 5% of hepatocytes and is typically macrovesicular and perivenular (centrilobular).[29] Nuclear vacuolation of hepatocytes is frequent, and megamitochondria and siderosis are observed.

With NASH, focal hepatocellular necrosis, steatosis, ballooning degeneration of hepatocytes, and lobular inflammation may extend throughout the lobule.[30] Mononuclear and polymorphonuclear leukocyte parenchymal inflammation is usually mild. Bile duct injury may develop but not result in duct loss. Perivenular alcoholic hyalin (Mallory bodies) may be present. Cholestasis is infrequent. Fibrosis may be minimal or severe and initially is pericellular or perisinusoidal. Bridging fibrosis is uncommon. Cirrhosis is initially micronodular, with transition to macronodular cirrhosis over time. Hepatocellular carcinoma can develop in 5%-7% of patients.[31]

A histologic NAFLD activity score can be determined by estimating the sum of the degree of steatosis (score 0-3), lobular inflammation (0-2), and hepatocellular ballooning (0-2).[32] A score of 5 or more indicates NASH.

Radiologic Features

Hepatic ultrasound is the best screening test for fatty liver, but it fails to identify fatty change in one third of affected patients.[33] The ultrasound image appears hyperechoic or bright from the associated fat. Liver fat distribution may be diffuse or focal. Ultrasound transient elastography can estimate the presence of hepatic fibrosis,[34] although its effectiveness is limited if marked fatty change of the liver is present.[35] CT may also be used to screen for fatty liver with hepatic density less than that of the spleen (liver/spleen ratio < 0.9). With MRI, the T1-weighted image will also identify fatty change. None of these modalities can separate patients with simple fatty liver from those with NASH.[33]


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