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Harrison's Internal Medicine > Chapter 303. Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver >

Nonalcoholic Fatty Liver Disease

NAFLD was first described in the 1950s when fatty liver was characterized in a group of obese patients. In 1980, Ludwig
and colleagues at the Mayo Clinic described 20 obese, diabetic, nonalcoholic patients who had similar findings on liver
biopsy to patients with alcoholic liver disease, and the term nonalcoholic steatohepatitis was introduced. The prevalence
of NAFLD in the United States and Europe ranges from 1420%. This increased prevalence relates directly to the obesity
epidemic seen in these populations. In the United States, NASH is thought to occur in ~3% of the general population, with
fibrosis due to NASH being seen in >40% of significantly obese patients. The spectrum of NAFLD includes simple
hepatic steatosis, which over time can progress to NASH, with the subsequent development of fibrosis and cirrhosis.
Causes of macrovesicular steatosis are listed in Table 303-3. It is now known that many patients with hitherto identified
"cryptogenic" cirrhosis in fact have liver disease on the basis of NASH, with the resolution of the steatosis once patients
become catabolic due to cirrhosis.

Most patients who come to medical attention with NAFLD are identified as a result of incidentally discovered elevated
liver enzymes (ALT, AST). When patients are symptomatic, symptoms include fatigue or a vague right upper quadrant
discomfort. ALT is generally higher than AST, and aminotransferases are only mildly (1.52 times the upper limit of
normal) elevated. Recent studies have shown that many patients can have advanced NASH and even cirrhosis due to
NASH with normal liver enzymes indicating that the prevalence of the disease may be even greater than was previously
suspected. NASH is frequently seen in conjunction with other components of the metabolic syndrome (hypertension,
diabetes mellitus, elevated lipids, and obesity), with NAFLD being considered the hepatic manifestation of this syndrome
(Chap. 236). Insulin resistance is the underlying link between these various disorders and numerous studies have shown
that virtually all patients with NASH have insulin resistance. Abnormal ferritin values are seen in ~50% of patients with
NASH, and an elevated ferritin level may be a marker of insulin resistance in NASH.

The diagnosis of NAFLD requires a careful history to determine the amount of alcohol used. Most investigators in the
field of fatty liver disease require that <20 g/d of alcohol be consumed to exclude alcoholic liver disease. Laboratory
testing for hepatitis B and C, iron studies, and autoimmune serologies should also be determined. Imaging studies can
show characteristic features of a fatty liver, but the ultimate diagnosis of either hepatic steatosis or NASH requires liver
biopsy. Liver biopsy shows characteristic macrovesicular steatosis with occasional microvesicular fat being identified. A
mixed inflammatory infiltrate is found in a lobular distribution. The histologic features of NASH are very similar to those
seen in alcoholic liver disease; Mallory's hyaline can be seen in both disorders, although the number of hepatocytes
containing Mallory's hyaline is frequently greater in alcoholic liver disease than in NASH. The fibrosis that occurs in
NASH has a characteristic perivenular and perisinusoidal distribution. Most studies show that up to 3040% of NASH
patients can develop advanced fibrosis, with cirrhosis being identified in 1015% of individuals. Increasingly, patients are
being identified with cryptogenic cirrhosis who have most likely had NASH for decades. These patients can develop liver
failure and require liver transplantation, and some patients can progress to the development of hepatocellular cancer.
Nonalcoholic Fatty Liver Disease: Treatment

The mainstay of treatment of fatty liver disease is weight loss and exercise, which is often difficult to achieve in this
population. As an aid to weight loss, orlistat, which is a reversible inhibitor of gastric and pancreatic lipase, has been
shown to result in a small decrease in body weight and is usually fairly well tolerated. Bariatric surgery has been utilized
and shows striking success, but is obviously a fairly drastic maneuver for induction of weight loss. Recent studies have
focused on the presence of insulin resistance at the center of the pathophysiologic mechanisms of NAFLD. The
thiazolidinedione medications are PPAR gamma inhibitors, which improve insulin sensitivity within the adipocyte and
skeletal muscle by upregulating specific protein kinases involved in decreasing fatty acid synthesis. Two drugs
pioglitizone and rosiglitizoneare currently available and are being evaluated as potential therapeutic options in the
treatment of NASH. Antioxidants have also been utilized, and small studies have shown benefit from vitamin E
supplementation. Treatment of hyperlipidemia with statin-type agents has shown improvement in liver enzymes, but they
have not been assessed for effects on histology. Ursodeoxycholic acid has been utilized and improves liver enzymes in
patients with many liver diseases, but it has not been definitely helpful for fatty liver disease. At present, efforts should be
directed to encouraging patients with NAFLD to lose weight.