Introduction

Nonalcoholic fatty liver disease (NAFLD) is a common cause of elevated liver function tests and is marked histologically by deposition of fat, primarily macrovesicular, in hepatocytes. Although a benign disorder in the majority of instances, up to 20% of patients with NAFLD have nonalcoholic steatohepatitis (NASH), and can progress to cirrhosis, liver failure and hepatocellular carcinoma. Several risk factors for NAFLD have been identified, including elevated body mass index (BMI), type 2 diabetes mellitus, advancing age and hypertriglyceridemia. The pathophysiologic basis of NAFLD is thought to be insulin resistance. Most experts consider NAFLD to be the hepatic manifestation of the metabolic syndrome, which includes persons with some combination of insulin resistance, obesity, hypertension and dyslipidemia.

Patients with NAFLD often have elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with ALT > AST. Patients with an AST > ALT may have cirrhosis or alcoholic hepatitis. The alkaline phosphatase is elevated in about 1/3 of patients with NAFLD, and many patients also have an elevated gamma glutaryl transpeptidase (GGT). The ALT level in NAFLD does not correlate with liver biopsy findings and NASH with progressive fibrosis and cirrhosis can occur with normal ALT. NAFLD patients also may have an echogenic liver on ultrasound examination, consistent with fatty infiltration. Other imaging studies, including CT scan and MRI, also can detect hepatic fat.

The American Gastroenterological Association (AGA) and American Association for the Study of Liver Diseases (AASLD) have published a joint medical position statement on NAFLD (Gastroenterology Nov. 2002; 123: 1702-1725). This statement notes that NASH can be diagnosed only by liver biopsy, and that liver biopsy is useful for diagnosis and prognosis. However, the statement does not make a specific recommendation to perform liver biopsy on patients suspected of NAFLD or NASH. Instead, it recommends that if a biopsy is not performed, then the ramifications of not doing a biopsy should be explained to the patient. These ramifications include inability to tell the patient whether or not NASH is present and, therefore, whether the patient is at significant risk for development of progressive fibrosis.

Treatment recommendations made by the AGA and AASLD include a diet resulting in initial but gradual weight loss of 10% body weight plus aerobic exercise. There are no recommendations made for treatment of NAFLD or NASH with medication. Small trials have been conducted with several medications for the treatment of NASH, however. Some of these medications that may be effective include vitamin E, vitamin E and vitamin C combined, metformin, gemfibrozil and thiazolidinediones (pioglitazone or rosiglitazone). None of these medications have been validated in large randomized controlled trials nor are FDA approved for treatment of NAFLD or NASH.

The following guidelines are proposed for diagnosis and treatment of NAFLD and NASH in ANMC patients.

Diagnosis of NAFLD

1. Definite NAFLD: Liver biopsy documentation of steatosis in the absence of other liver diseases.
2. Probable NAFLD: Ultrasound compatible with NAFLD, i.e., showing fatty infiltration of liver. A CT scan or MRI of the abdomen also can detect hepatic fat. An elevated ALT and presence of one or more of the above risk factors of metabolic syndrome may be helpful in the diagnosis.
3. Diagnosis of NAFLD also requires the following:
4. 1. Consumption of alcohol must be limited to 20 grams (approximately 2 drinks) or less per day.
   2. There must be no evidence of other chronic liver diseases. This specifically includes testing for hepatitis B (HBsAg); hepatitis C (anti-HCV); autoimmune hepatitis (ANA, smooth muscle antibody, serum IgG) and primary biliary cirrhosis (anti-mitochondrial antibody, serum IgM) in women; and hemochromatosis (Fe, TIBC, Fe saturation, ferritin). Consideration also can be given to testing for Wilson disease in persons < 45 years old (ceruloplasmin) and alpha-1-antitrypsin deficiency (a-1-antitrypsin level), but both conditions are quite rare. Any medication or toxin effect also should be considered.

Diagnosis of NASH

Diagnosis of NASH can be made only by liver biopsy, with documentation of steatosis and inflammation. Imaging studies such as ultrasound, CT scan and MRI can detect fat but not inflammation in the liver.

Algorithm for Approach to NAFLD

The above algorithm is a guideline for approach to patients with probable NAFLD, utilizing a conservative approach with a treatment trial prior to liver biopsy. There is no clinical evidence to support or refute this approach. However, it may avoid the potential risks of performing a procedure (liver biopsy), which can give the patient a diagnosis and prognosis but may not change the treatment plan. Because of the possibility of NASH with its risk of progressive fibrosis and cirrhosis, persons who fail to respond to conservative measures should be counseled about the risks and benefits of a liver biopsy.

Treatment of NAFLD and NASH

1. Weight loss diet with initial goal of gradual loss of 10% body weight.
2. Aerobic exercise program where feasible, with minimum goal of 30 minutes 4-5 days per week.
3. Maximize treatment of diabetes and hyperlipidemia when present.
4. Consider the use of the following medications in a patient with NASH:
   1. Metformin in type 2 diabetes. Metformin should be used for treatment of NASH in non-diabetics only in the context of a clinical trial or with full informed consent of the patient.
   2. A thiazolidinedione (rosiglitazone or pioglitazone) in type 2 diabetes. These medicines should be used for treatment of NASH in non-diabetics only in the context of a clinical trial. Weight gain has been associated with the use of thiazolidinediones
   3. Gemfibrozil in hypertriglyceridemia.
   4. A statin preparation in hypercholesterolemia.
   5. Vitamin E 400 IU daily or Vitamin E 400 IU daily + Vitamin C 500 mg daily.
5. Patients should be considered for immunization against hepatitis A and hepatitis B if not already immune.

Revision 1.2006