Definition and causes

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized form of chronic liver disease. It encompasses a spectrum of conditions associated with lipid deposition in hepatocytes. It ranges from steatosis (simple fatty liver), to nonalcoholic steatohepatitis (NASH—fatty changes with inflammation and hepatocellular injury or fibrosis), to advanced fibrosis and cirrhosis (Fig. 1). Studies have suggested that although simple fatty liver is a benign condition, NASH may progress to fibrosis and lead to end-stage liver disease. The disease is mostly silent and often discovered through incidentally elevated liver enzyme levels. It is strongly associated with obesity and insulin resistance and is currently considered by many as the hepatic component of the metabolic syndrome (see later). NASH cirrhosis is now one of the leading indications for liver transplantation in the United States.

Because NAFLD resembles alcoholic liver disease, but occurs in people who drink little or no alcohol, excessive daily alcohol consumption (more than 20 g/day in women and 30 g/day in men within the last 5 years) must be ruled out before making the diagnosis. Numerous other conditions leading to fatty liver must be excluded by history, physical examination, and appropriate testing (Box 1).

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Prevalence and risk factors

Accurate epidemiologic data are not available because of a lack of population-based studies and reliable noninvasive screening tools. There is disagreement about the methods used to diagnose NASH, and there is no clear consensus on the clinical implications of histologic changes nor the influence of the amount of alcohol ingested. The prevalence of NAFLD is affected by many factors, including genetics (predilection to alcohol abuse, gender) and environment, and is therefore difficult to define. In general, however, the risk of liver disease increases with the weight of the patient.

From the available data, NAFLD is estimated to be present in one third of the general population in the United States. The prevalence of NASH is more difficult to determine. It seems to occur in approximately 3% of the population but may be found in more than 25% of obese individuals.

The prevalence of overweight individuals (body mass index [BMI] = 25 kg/m²) in the United States has risen to more than 65%, and obesity (BMI = 30 kg/m²) is now present in more than 30% of the adult U.S. population. It may be estimated that more than 60 million Americans have NAFLD. The increasing prevalence of childhood obesity in the United States is alarming, affecting 15% of children between 6 and 19 years of age, with an additional 30% considered overweight. Similar demographics of fatty liver prevalence can be found in children. Thus, the increases in pediatric NAFLD and NASH will have serious implications for adult hepatology.

Affected individuals generally present between the fourth and sixth decades of life and are more frequently women (50%-80%). However, there are numerous reports of NAFLD in children and nonobese individuals. NAFLD has been described in all ethnic groups, with some variation in clinical characteristics. There may be a familial tendency for fatty liver and NASH, because kindreds with NASH and cryptogenic cirrhosis—possibly a form of burned-out NASH, in which the characteristic histologic picture of steatohepatitis has disappeared with the progression of the disease—have been reported.

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Pathophysiology and natural history

Pathophysiology

The pathogenesis of both NAFLD and NASH remains poorly defined. The development of NASH has been suggested to be the result of a two-hit process. With the initial hit, macrovesicular steatosis occurs. Insulin resistance and subsequent hyperinsulinemia seem to lead to alterations in the hepatic pathways of uptake, synthesis, degradation, and secretion of free fatty acids, and ultimately to accumulation of lipids in the hepatocytes. These changes seem to make the liver susceptible to a second hit, resulting in an inflammatory response and progression of liver damage. Oxidative stress, mainly caused by mitochondrial dysfunction, and proinflammatory cytokines such as tumor necrosis factor a, are believed to play an important role in the progression of liver damage in NAFLD. In addition, adiponectin, an adipocyte-produced protein, is one of the attractive candidates for modulating liver injury. Adiponectin is secreted by adipocytes in inverse proportion to the BMI and metabolically acts to reduce body fat, improve insulin sensitivity, and decrease serum free fatty acid levels. Finally, hepatocyte apoptosis, an organized form of cell death, has been identified as a potential key component of the second hit involved in NAFLD progression.

Natural History

Available data have suggested that the natural history of NAFLD seems to be determined by the severity of the histologic damage. Most patients with NAFLD have pure steatosis without inflammation and have been reported to have a benign clinical course. On the other hand, patients with NASH are believed to be at increased risk for advanced disease; progression to cirrhosis and its complications have been shown to occur in more than 20% of patients. At the time of initial biopsy, as many as one third of NASH patients may have advanced hepatic fibrosis, whereas 10% to 15% have well-established cirrhosis. In addition, it is now recognized that a large proportion of patients with cryptogenic cirrhosis have burned-out NASH. NASH-associated cirrhosis may decompensate with subacute failure and is an increasing indication for liver transplantation. However, it may recur after transplantation. Furthermore, the association between NASH or cryptogenic cirrhosis and hepatocellular carcinoma (HCC) is increasingly being described. Japanese data have suggested that the cumulative rate of HCC at 5 years may be as high as 15% in their population. Overall, the morbidity and the mortality have been shown to be significantly higher in NASH patients compared with the general population.

Although much progress has been made, further studies are needed to define the pathogenesis of NAFLD clearly and explain the apparent interindividual variation in the susceptibility to progress to more advanced liver disease. Genetic factors have been suggested to play an important role in this variation, and several new candidate genes have recently been proposed.

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Signs and symptoms

Most patients with NAFLD are asymptomatic, and the liver disease is often discovered incidentally when laboratory examination shows elevated liver enzyme levels. It is the most common cause of unexplained persistent elevation of liver enzyme levels after hepatitis and other chronic liver diseases have been excluded. The most common symptoms that bring NAFLD to medical attention are malaise, fatigue, and right upper quadrant or diffuse abdominal discomfort. Hepatomegaly may be found on clinical examination in 75% of patients. When cirrhosis appears, stigmata of chronic liver disease, such as spider angiomata, ascites, splenomegaly, hard liver border, palmar erythema, or asterixis, can be present. The patient may complain of jaundice or pruritus, or present with a complication of portal hypertension (e.g., ascites, variceal bleeding, or encephalopathy). Most patients have associated features of the metabolic syndrome ( Table 1 ): obesity (47% to 90%), diabetes mellitus (28% to 55%), and variable incidences of hyperlipidemia (4% to 92%) and hypertension.

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Diagnosis

NAFLD is usually diagnosed during further evaluation for elevated aminotransferase levels found in one of three situations: (1) on routine checkup; (2) when monitoring is performed for possible side effects of drugs (most often cholesterol-lowering medication); or (3) for nonspecific symptoms. NAFLD can also be identified incidentally on imaging or, less frequently, on liver biopsy done for other reasons. Some centers screen for NAFLD in high-risk groups that include patients with elements of the metabolic syndrome.

Clinical evaluation includes a careful history and physical examination. It is particularly relevant to inquire about excess alcohol consumption—defined as more than 30 g/day for men and more than 20 g/day for women within the last 5 years; 350 mL (12 oz) of beer, 120 mL (4 oz) of wine, and 45 mL (1.5 oz) of hard liquor each contain 10 g of alcohol—and to define the nonalcoholic nature of the condition. Moreover, it is necessary to exclude the alternative causes of fatty liver (see Box 1). It is most important to include anti–hepatitis C antibody as well as serum ceruloplasmin levels in young patients.

Primary noninvasive evaluation may be used to confirm the diagnosis of fatty liver disease, given the risks and costs of a liver biopsy. Clinical factors and basic laboratory evaluation, particularly in patients aged 45 years and older, or those with obesity, type 2 diabetes mellitus, or an aspartate aminotransferase–to–alanine aminotransferase (AST/ALT) ratio of more than 1, have been shown to be predictors of more severe histologic disease and may be useful in making a decision regarding when to order a biopsy. Histologic evaluation is the gold standard and should be considered.

Laboratory Evaluation

In a patient with suspected NAFLD or NASH, useful baseline testing should include levels of AST, ALT, total and direct bilirubin, and fasting serum glucose, as well as a lipid panel. Mild to moderate elevation of serum aminotransferase levels is most commonly found (mean range, 100 to 200 IU/L). Generally, the ratio of AST to ALT is less than 1, but this ratio increases as fibrosis advances. Liver enzyme levels may be normal in a large proportion of patients with NAFLD; normal aminotransaminase levels do not exclude the presence of advanced disease. Serum alkaline phosphatase and γ-glutamyl transpeptidase levels may also be mildly abnormal. Given that more than 80% of patients with NAFLD have some components of the metabolic syndrome, serum levels of fasting cholesterol and triglycerides, as well as fasting glucose, should be determined. Albumin, bilirubin, and platelet levels are usually normal unless the disease has evolved to cirrhosis. Some patients with NAFLD may have low titers of autoimmune antibodies (antinuclear and anti–smooth muscle antibody), as well as an elevation of ferritin and transferrin saturation. The role of these markers is still unclear.

Imaging

A liver ultrasound examination is useful for confirming steatosis. Fatty infiltration of the liver produces a diffuse increase in echogenicity and vascular blurring (Fig. 2). Unfortunately, ultrasound cannot rule out steatohepatitis or fibrosis, and its sensitivity drops sharply when the degree of steatosis decreases below 30%. Both computed tomography (CT) and magnetic resonance imaging (MRI) studies, especially the new technique of magnetic resonance spectroscopy, are more sensitive modalities for the quantification of steatosis. However, none of these imaging techniques has sufficient sensitivity and specificity for staging the disease and cannot distinguish between simple bland steatosis and NASH with or without fibrosis.

Liver Biopsy

Liver biopsy is of unquestioned value in determining the presence of steatosis, distinguishing steatosis from steatohepatitis, and assessing the degree of fibrosis. Because the diagnostic accuracy of noninvasive diagnostic tools is low, histology is the only reliable means to grade the severity of the disease and thus estimate prognosis. The biopsy is also helpful in ruling out an alternative diagnosis. In a series of patients with elevated liver enzyme levels without obvious cause, NAFLD was confirmed on biopsy in about 75% of subjects, with the rest having other causes of aminotransferase level elevation. In addition to establishing the cause and severity of disease, histology permits the monitoring of disease progression and the response to therapy, because aminotransaminase levels may decrease during the course of the disease regardless of whether fibrosis progresses or improves.

NAFLD is histologically indistinguishable from liver damage resulting from alcohol abuse. The steatosis seen in NAFLD is macrovesicular. In adults, similar histologic findings can be found in a number of conditions (see Box 1). The spectrum of abnormalities varies from simple bland steatosis to NASH, in which steatosis is associated with mixed inflammatory cell infiltration and liver injury. Cell injury is manifested by hepatocyte ballooning, as well as by Mallory hyaline and acidophil bodies.

Despite the advantages of liver biopsy, its overall role in the evaluation of patients with NAFLD is unsettled, in large measure because of its risks and poor patient acceptance. In patients with risk factors for NAFLD (i.e., the metabolic syndrome), 3 to 6 months are often allowed for a trial of weight loss and for possible improvements in imaging studies and biochemical markers of liver disease. In the subset of patients most likely to have NASH or advanced disease (those with older age, higher BMI, type 2 diabetes, AST/ALT ratio = 1, clinical suspicion) and in those with an unclear diagnosis, a liver biopsy should be considered earlier (Fig. 3).

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Treatment

Although numerous clinical trials have been undertaken since the last American Gastroenterological Association Technical Review on Nonalcoholic Fatty Liver Disease, there is no consensus on the effectiveness of any therapeutic agent in the treatment of NAFLD. Patients should avoid alcohol and other hepatotoxins. The goal of treatment is to improve steatosis and prevent the development of fibrosis, which may lead to cirrhosis and its complications. Because the prognosis of NASH depends on risk factors (e.g., obesity, insulin resistance, type 2 diabetes), these conditions have been the focus of treatment. Treatment proposed for NAFLD has been based on the two-hit hypothesis, the first being fatty liver infiltration (linked to obesity and insulin resistance), and the second being oxidative stress.

Treatment of Obesity

Although no randomized clinical trials exist, weight reduction has been widely studied in adults and has been shown to improve not only the biochemical results but also the histology. Slow, consistent weight loss through diets designed to produce a caloric deficit of 500 to 1000 cal/day is advised. Reduction of dietary carbohydrates, in particular dietary fructose, is the most beneficial and has been found to improve the lipid profile in overweight patients. High- to moderate-intensity exercise (30 minutes, three to five times a week) has also been advocated to reduce the risk of comorbidities associated with obesity. However, more realistically, the subjects should be encouraged to incorporate moderate activity into everyday life (e.g., climbing stairs, walking instead of driving).

Pharmacologic treatment of obesity in NASH is still experimental. Several drugs have been studied, including sibutramine, a serotonin reuptake inhibitor, and orlistat, producing fat malabsorption, both of which have been shown to improve liver enzyme levels and sonographic signs of fatty liver. Finally, bariatric surgery is now suggested for patients with a BMI of more than 40 kg/m², or for those with a BMI of more than 35 kg/m² and obesity-related comorbidities. Studies have suggested an improvement in histology in these patients. However, the safety of bariatric surgery in patients with cirrhosis is still under investigation.

Pharmacologic Therapy

Insulin-Sensitizing Agents

NASH patients with diabetes are at higher risk of developing more aggressive disease. Insulin-sensitizing agents have been tested in adults and are of benefit. Peroxisome proliferator-activated receptor-gamma agonists (thioglitazones), as well as metformin, have been shown to improve insulin resistance, surrogate markers of fatty liver, and possibly histology. However, hepatotoxicity has been described with thioglitazones, and a more common side effect is paradoxical weight gain and fat redistribution. A multicenter trial involving metformin in adults and children with NAFLD is ongoing. The routine use of these agents in nondiabetic subjects with NAFLD should, however, be discouraged outside of clinical trials.

Lipid-Lowering Agents

The literature concerning lipid-lowering medication and NAFLD is sparse. Reports have demonstrated improvement in transaminase levels with different classes of drugs, but there is a lack of histologic follow-up in most of these studies. Although one of the most common side effect of statins is liver enzyme level elevation, evidence has pointed out that patients with elevated baseline transaminase levels (likely having NAFLD) who receive statin treatment do not have a higher incidence of liver enzyme level elevation or hepatotoxicity than liver disease control subjects who do not receive statins. Moreover, the clinical relevance of the current recommendation that liver biochemistry should be checked before and periodically (usually 12 weeks) after treatment initiation has not been substantiated in the NAFLD population.

Hepatoprotective Therapy

Several therapeutic agents believed to offer hepatocyte protection have been evaluated. Antioxidants have been hypothesized to decrease the oxidative stress and slow the progression of the disease. Several trials in humans with NAFLD have supported an effect of vitamin E on the improvement of transaminase levels and fibrosis. A phase 3 clinical trial is underway. Despite small adult studies suggesting a role of ursodeoxycholic acid in the improvement of NASH, a large, randomized, placebo-controlled trial has demonstrated no benefits from ursodeoxycholic acid over placebo on liver biochemistry and histology. Betaine and N-acetylcysteine have shown promising effects, but larger trials are needed.

Thus, emerging data from recent trials have suggested that weight loss through lifestyle modifications, as well as several insulin-sensitizing, antioxidant, and hepatoprotective medications, may be of benefit in patients with NAFLD ( Table 2 ). However, many of these interventions need to be evaluated in carefully controlled long-term studies before a treatment recommendation is adopted.

Liver Transplantation

In patients with decompensated NAFL cirrhosis, liver transplantation should be considered. Coexisting conditions (e.g., morbid obesity, severe complications of diabetes, cardiac disease) and fear of intraoperative and post-transplantation complications, may preclude transplantation candidacy in these patients. A thorough pretransplantation evaluation, as well as better weight and metabolic derangement control, may be necessary. When transplanted, most patients will have persistent metabolic syndrome, with long-term implications. Moreover, NAFLD has been shown to recur in the liver allograft, with a possible rapid progression to steatohepatitis and cirrhosis.

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Prevention and screening

More than 50 million Americans have been estimated to have metabolic syndrome, and 80% of them probably have NAFLD. Furthermore, about one third of the U.S. population suffering from type 2 diabetes mellitus has fatty liver. The prevalence of NAFLD in the United States seems to be substantially greater than the 2% prevalence of hepatitis C virus infection and is believed to be increasing. Given such high prevalence, the American Gastroenterological Association Technical Review on Nonalcoholic Fatty Liver Disease, published in 2002, stated that “physicians should actively check for the presence of NAFLD in those who are overweight and/or diabetic.” On the other hand, however, screening is complicated by the fact that the accuracy of noninvasive diagnostic tools remains poor and there is no clearly established treatment for NAFLD. Basic laboratory evaluation of liver enzyme levels may point to the diagnosis but cannot rule out NAFLD if normal, and imaging techniques have poor sensitivity for low-grade steatosis. Moreover, because these tests do not differentiate simple steatosis from NASH, a liver biopsy must be discussed with the patient if the suspicion of NASH is strong. Therefore, although generalized screening for fatty liver in all at-risk patients may be difficult, it is certainly warranted to look for and actively manage the metabolic syndrome (obesity, diabetes, hyperlipidemia, and hypertension). Prevention of obesity and its complications is now a major public health goal.

Summary

• Nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity and diabetes, is increasingly being recognized in the western population.
• Simple fatty liver is the most common form of NAFLD and seems to be a benign condition. In contrast, nonalcoholic steatohepatitis may progress to advanced fibrosis and cirrhosis.
• The diagnosis is often made after incidentally finding elevated liver enzyme levels or by clinical suspicion in patients with obesity or diabetes. Laboratory results or imaging examinations may confirm the diagnosis. However, at present, only a liver biopsy can differentiate simple steatosis from NASH.
• There is no clear consensus on the effectiveness of the pharmacologic treatment of NAFLD. Several therapies, including insulin-sensitizing, antioxidant agents, and hepatoprotective medications, have been studied. Lifestyle modifications, particularly weight loss, have been shown to be particularly beneficial.

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Conclusions

NAFLD affects a substantial portion of the general population and is associated with the metabolic syndrome, which includes obesity, insulin resistance, hyperlipidemia, and hypertension. Patients with NAFLD not only suffer from the metabolic sequela of insulin resistance but have increased overall mortality. Although simple fatty liver seems to be a benign condition, some patients may progress to NASH and ultimately to cirrhosis. Because of the consequences of the disease, we emphasize the importance of the detection of NAFLD in high-risk groups, including obese patients, as well as those with evidence of insulin resistance or other components of the metabolic syndrome. Screening and surveillance methods should be applied more uniformly from center to center, and reliable noninvasive techniques are needed for the diagnosis of NAFLD and the detection of progressive liver disease. The diagnosis of NAFLD should prompt management of the metabolic risk factors. Weight loss regimens are believed to be helpful, and numerous drugs have been investigated in small studies. Large, randomized, clinical trials are necessary to determine the real benefit of these agents. Finally, studies on the pathogenesis of NAFLD may not only improve our understanding of the mechanisms involved in NAFLD progression, but may lead to potentially novel therapeutic strategies to treat this condition.

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Suggested Readings

• The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology. 129: 2005; 113-121.
• The histological course of non-alcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 42: 2005; 132-138.
• Nonalcoholic fatty liver disease. N Engl J Med. 346: 2002; 1221-1231.
• Current best treatment for non-alcoholic fatty liver disease. Expert Opin Pharmacother. 4: 2003; 611-623.
• Statins and hepatotoxicity: Focus on patients with fatty liver. Hepatology. 41: 2005; 690-695.
• Long-term prognosis of fatty liver: Risk of chronic liver disease and death. Gut. 53: 2004; 750-755.
• Pharmacologic management of nonalcoholic fatty liver disease. Clin Liver Dis. 8: 2004; 715-728.
• The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 8: 2004; 521-533.
• Nonalcoholic steatohepatitis: Recent advances from experimental models to clinical management. Clin Biochem. 38: 2005; 203-217.
• Evaluation and management of non-alcoholic steatohepatitits. J Hepatol. 42: 2005; S2-S12.
• American Gastroenterological Association: AGA technical review on nonalcoholic fatty liver disease (national guidelines). Gastroenterology. 123: 2002; 1705-1725.