Nonalcoholic Fatty Liver Disease MAX BAYARD, M.D., JIM HOLT, M.D., and EILEEN BOROUGHS, M.D. East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee Nonalcoholic fatty liver disease is a common condition associated with metabolic syndrome. It is the most common cause of elevated liver enzymes in U.S. adults, and is diagnosed after ruling out other causes of steatosis (fatty infiltration of liver), particularly infectious hepatitis and alcohol abuse. Liver biopsy may be considered if greater diagnostic and prognostic cer- tainty is desired, particularly in patients with diabetes, patients who are morbidly obese, and in patients with an aspartate transaminase to alanine transaminase ratio greater than one, because these patients are at risk of having more advanced disease. Weight loss is the primary treatment for obese patients with nonalcoholic fatty liver disease. Medications used to treat insulin resistance, hyperlipidemia, and obesity have been shown to improve transaminase levels, steatosis, and histologic findings. However, no treatments have been shown to affect patient-oriented outcomes. (Am Fam Physician 2006;73:1961-8, 1969. Copyright © 2006 American Academy of Family Physicians.) S Patient information: ormerly called nonalcoholic steato- Nonalcoholic fatty liver disease has been A handout on nonalcoholic hepatitis (NASH), nonalcoholic fatty associated with metabolic syndrome in fatty liver disease, written by the authors, is provided liver disease now refers to a spectrum observational studies and has been described on page 1969. of diseases of the liver ranging from as the hepatic component of this syndrome. Fsteatosis (i.e., fatty infiltration of the liver) to The most common risk factors for the devel- NASH (i.e., steatosis with inflammation and opment of steatosis are obesity, diabetes, and hepatocyte necrosis; Figure 1) to cirrhosis. hypertriglyceridemia. Other causes include Nonalcoholic fatty liver disease is the most toxins, medications, and inborn errors of common cause of elevated liver enzymes in metabolism (Table 1).5 adults in the United States1 and the most com- mon cause of cryptogenic cirrhosis, which is Diagnosis cirrhosis that cannot be explained by hepatitis, DIFFERENTIAL DIAGNOSIS alcohol abuse, toxin exposure, autoimmune Numerous conditions cause liver enzyme disease, congenital liver disease, vascular out- elevation and steatosis. Table 2 lists the more flow obstruction, or biliary tract disease.2 In common causes of elevated liver enzymes the United States, estimates of the prevalence of and their corresponding historical, physical, nonalcoholic fatty liver disease range from 16 to and laboratory findings. 23 percent.3 However, in a recent population- The diagnosis of nonalcoholic fatty based study, 31 percent of the 2,287 participants liver disease requires exclusion of alco- had steatosis diagnosed by nuclear magnetic holic liver disease and viral hepatitis (Fig- spectroscopy.4 Patients who used alcohol were ure 2). Although many persons likely have included in these numbers, but there was no a combination of alcoholic and nonalco- difference in steatosis between patients using holic fatty liver disease, the diagnosis of alcohol and patients who did not use alcohol. nonalcoholic fatty liver disease requires The prevalence of nonalcoholic fatty liver dis- that daily alcohol intake be less than ease becomes greater with increasing body 20 g per day for women and less than 30 g weight. Two thirds of patients with a body per day for men. This equates to two stan- mass index (BMI) of 30 kg per m2 or greater, dard alcoholic drinks per day for men and and more than 90 percent of patients with a 1.5 standard alcoholic drinks per day for BMI greater than 39 kg per m2, have steatosis.1 women. A standard drink contains 14 g of In the United States, up to 8.6 million persons alcohol (e.g., 12 oz of beer, 5 oz of wine, or who are obese may have steatohepatitis.1 1.5 oz of spirits). Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2006 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Nonalcoholic Fatty Liver Disease SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Although treatment of metabolic syndrome with statins, metformin (Glucophage), glitazone medications, C 13-17, 20, and lifestyle changes may improve histologic and physiologic endpoints in patients with nonalcoholic 21 fatty liver disease, use of these medications is not recommended solely as a treatment for this disease. Weight loss should be approximately 1 to 2 lb (0.45 to 0.90 kg) per week; more rapid weight loss, C5 particularly following bariatric surgery, may worsen nonalcoholic fatty liver disease. Statins have not been shown to be harmful in patients with elevated transaminase levels associated with C29-32 nonalcoholic fatty liver disease. If statins are indicated for treatment of dyslipidemia, transaminase levels should be monitored closely. Biopsy should be considered in individuals at increased risk of more advanced liver disease and in those for C 3, 5 whom lifestyle changes do not result in normalization of transaminase levels if accurate diagnosis and prognosis are desired and the risks of biopsy are deemed acceptable. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1874 or http://www.aafp.org/afpsort.xml. Figure 1. Top left: Liver biopsy from a patent with nonalcoholic steatohepatitis. The arrows at P and C indicate portal (zone 1) and central vein (zone 3) areas, respectively. There is moderate accumulation of globular fat. Top right: A portal tract contains a mild mononuclear inflammatory cell infiltrate and a lipogranuloma (arrow). Bottom left: High magnifica- tion of a hepatocyte containing a dense hyaline Mallory body (H). An adjacent swollen binucleated cell is a balloon cell (B). Bottom middle: Polymorphonuclear leucocytes within a hepatic lobule (arrows). Two hepatocytes at the upper right corner of the photograph contain Mallory bodies. Bottom right: Occasional acidophil bodies (arrow) were present. Sec- tions were stained with hematoxylin and eosin and photographed originally with 10, 40, and 100 X objectives. 1962 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006 Nonalcoholic Fatty Liver Disease CLINICAL FINDINGS Computed tomography is no more sensitive than ultra- Most patients with nonalcoholic fatty liver disease are sonography and is more expensive. However, it can asymptomatic, but some may complain of fatigue and identify other liver pathology (e.g., masses) more effec- right upper quadrant abdominal fullness or pain. Up tively. Imaging modalities (i.e., computed tomography, to 50 percent of patients with this disease have hepato- magnetic resonance imaging, or ultrasonography) cannot megaly.5 Patients with cirrhosis from nonalcoholic fatty distinguish steatosis from steatohepatitis.9 liver disease will have findings similar to patients with cirrhosis from other causes. LIVER BIOPSY The role of liver biopsy in nonalcoholic fatty liver disease LABORATORY EVALUATION is controversial. Arguments against routine liver biopsy Laboratory abnormalities often are the only sign of non- include the generally benign course of the disease in most alcoholic fatty liver disease. The most common abnormal cases, lack of established effective therapies, and risks of laboratory test results are elevated alanine transaminase biopsy.5 Although liver biopsy generally is safe, transient (ALT) and aspartate transaminase (AST), usually one to pain occurs in 30 percent of patients, severe pain in 3 per- four times the upper limits of normal.5 However, patients cent, and significant complications in fewer than 3 percent. with nonalcoholic fatty liver disease may have normal The risk of death is 0.03 percent,10 but biopsy is the only transaminase levels. The ratio of AST/ALT usually is less reliable method of diagnosing NASH and determining the than 1 (in alcoholic liver disease, this ratio typically will prognosis.5 Patients who are likely to have more advanced be greater than 2) but may increase as the severity of the liver disease should be considered for biopsy. Risk factors liver damage increases.6 Alkaline phosphatase may be for more advanced disease include diabetes, morbid obe- elevated up to twice the upper limit of normal5; I-gluta- sity (BMI > 39 kg per m2), advanced age, and an AST/ALT myltransferase (GGT) also may be elevated. ratio greater than 1.11 Biopsy also may be considered in individuals who have persistent elevations in liver enzymes IMAGING STUDIES despite lifestyle changes.3 The American Gastroentero- Imaging studies assist in the diagnosis of nonalcoholic logical Association states that the decision to perform a fatty liver disease through identifying fatty infiltrate in liver biopsy in a patient with suspected nonalcoholic fatty the liver. Ultrasonography of the liver has a sensitivity liver disease and the timing of the biopsy must be indi- of 82 to 89 percent and a specificity of 93 percent for vidualized and should include the patient in the decision- identifying fatty liver infiltrate.7,8