Paul Angulo and Keith D. Lindor
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized clinicopathological condition that may progress to end-stage liver disease. The pathological picture resembles that of alcohol-induced liver injury, but the disease occurs in patients who deny alcohol abuse. NAFLD involves a wide spectrum of liver damage, ranging from simple, uncomplicated steatosis, to steatohepatitis, to advanced fibrosis and cirrhosis. Nonalcoholic steatohepatitis (NASH) represents a stage within the spectrum of NAFLD, and it is defined histologically by the presence of steatosis along with necroinflammatory activity, mostly of lobular distribution, regardless of the presence of fibrosis or Mallory’s hyaline. NAFLD must be differentiated from the steatosis with or without metabolic/genetic conditions. The diagnosis of NAFLD also requires the exclusion of other liver diseases that may present with steatosis, such as viral, autoimmune, and metabolic/hereditary liver disease, along with a thorough effort to exclude alcohol abuse. The clinical implications of NAFLD are derived mostly from its common occurrence in the general population, as well as its potential to progress to cirrhosis and liver failure.
Epidemiologic features. Obesity, type 2 (non–insulin-dependent) diabetes mellitus, and hyperlipidemia, alone or in combination, are comorbid conditions frequently associated with NAFLD. There is a direct correlation between the degree of obesity and the prevalence and severity of NAFLD. The prevalence of NAFLD increases by 4.6-fold in obese people. With any degree of obesity, type 2 diabetes mellitus significantly increases the prevalence and severity of NAFLD. NAFLD may affect any age group, and has been described in most racial groups.
Prevalence. NAFLD affects 10–24% of the general population in different countries. The prevalence of NAFLD, however, increases significantly to 57.5–74.0% in obese individuals. NAFLD affects 2.6% of children, and this figure increases to 22.5–52.8% in the obese pediatric population. NAFLD is the cause of asymptomatic elevation of aminotransferases in 42–90% of cases once other causes of liver disease are excluded, and represents a common explanation for abnor-mal liver tests in blood donors.
Clinical features. Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis. Mild to moderate elevation of serum aminotransferases (ALT, AST) is the most common and often the only laboratory abnormality found in patients with NAFLD.
Liver histology. NAFLD is histologically indistinguishable from the liver damage resulting from alcohol abuse. The presence of fibrosis is a histological finding that is a matter of concern, as it suggests more advanced and severe liver injury.
Pathogenesis. The primary metabolic abnormality leading to lipid accumulation (steatosis), is not well understood, although it could potentially result from insulin resistance and alterations in the uptake, synthesis, degradation, or secretory pathways involved in the hepatic lipid metabolism.
Diagnosis. Once other liver diseases have been excluded, a clinical suspicion of NAFLD can only be confirmed with a liver biopsy, which remains not only the best diagnostic tool for confirming NAFLD, but also the most sensitive and specific means of providing important prognostic information. The presence of cirrhosis on liver biopsy requires periodic endoscopic surveillance for gastroesophageal varices, and possible screening for liver cancer.
Prognosis. The prognosis in NAFLD is still being defined, but it seems to be substantially determined by the severity of liver damage found on liver biopsy. Patients with pure steatosis on liver biopsy seem to have the best prognosis within the spectrum of nonalcoholic fatty liver disease, whereas features of steatohepatitis or more advanced fibrosis are associated with a worse prognosis.
Management of associated conditions. The treatment of patients with NAFLD has typically focused on the management of associated conditions, as well as on the discontinuation of potentially hepatotoxic drugs known to produce NAFLD. In patients with diabetes mellitus or hyperlipidemia, good metabolic control is always recommended, although it is rarely effective in reversing NAFLD.
Pharmacological therapy directed specifically at the liver disease has only recently been evaluated in patients with NAFLD. Encouraging results have been reported with pilot studies evaluating gemfibrozil, ursodeoxycholic acid, betaine, N-acetylcysteine, vitamin E (alpha-tocopherol) and insulin-sensitizer drugs (thiazolidinedione, metformin). However, these medications still have to be evaluated in carefully controlled clinical trials with sufficient statistical power, an extended follow-up period, and clinically relevant end points.
Conclusions. NAFLD is an increasingly important chronic liver disease. The increased attention that has been given to this condition in recent years has led to a greater understanding and awareness of NAFLD. Future work is required to achieve a better definition of the natural history of the condition, to elucidate its pathogenesis, and to develop effective treatment options for this often progressive disease.
The original article will be published in Gastroenterol Hepatol 2002; 17 (suppl): in press.