Published April 4, 2006

Anna
Wieckowska, MD

Department of
Gastroenterology
and Hepatology


William D.
Carey, MD




Department of
Gastroenterology
and Hepatology

 

Copyright 2005
The Cleveland Clinic Foundation

 
DEFINITION

 

Chapter Outline

Definition

Prevalence

Pathophysiology

Signs and Symptoms

Diagnosis

Therapy

Outcomes

Conclusions

References

National Guidelines

AGA technical review on nonalcoholic fatty liver disease

American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease

 


 

 

 

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 (Figure 1). Studies suggest 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 below). 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 (350 ml [12 oz] of beer, 120 ml [4oz] of wine and 45 ml [1.5 oz] of hard liquor each contain 10 g of alcohol). Numerous other conditions leading to fatty liver must be excluded by history, physical examination, and appropriate testing (Table 1). Imaging can sometimes reveal fatty infiltration, but a scan or ultrasound without features of fatty liver cannot rule out the diagnosis. In addition, imaging studies cannot distinguish between simple steatosis and more severe liver injury. This can be achieved only by obtaining a histologic specimen. Grading and staging of the disease may be important, since only NASH has been shown to progress, in some patients, to more advanced liver disease. Current therapies focus on correction of the underlying risk factors and avoidance of factors that promote the progression of liver disease, and several novel therapies are under investigation.1 However, pharmacotherapy for NAFLD is in its infancy.

PREVALENCE

Accurate epidemiologic data are not available owing to lack of population-based studies and reliable noninvasive screening tools. There is disagreement in the methods used to diagnose NASH, and 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. 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.2

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 US population.3 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 old, with an additional 30% considered overweight. Similar demographics of fatty liver prevalence can be found in children.4 Thus, the increase in pediatric NAFLD/NASH will have serious implications for adult hepatology.

Affected individuals generally present in the fourth and sixth decade of life and are more frequently female (50%-80%). However, there are numerous reports of NALFD in children and nonobese individuals. NAFLD has been described in all ethnic groups, with some variation in clinical characteristics.5 There may be a familial tendency for fatty liver and NASH, as kindreds with NASH and cryptogenic cirrhosis (a possible "burned-out" NASH, in which the characteristic histologic picture of steatohepatitis has disappeared with the progression of the disease) have been reported.6

PATHOPHYSIOLOGY

The pathogenesis of both NAFLD and NASH remains poorly defined. Current concepts suggest that the development of NASH is a "two-hit" process. With the initial hit macrovesicular steatosis results. 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 make the liver susceptible to a "second hit," resulting in inflammatory response and progression of liver damage. Oxidative stress, mainly as a consequence of mitochondrial dysfunction, and proinflammatory cytokines such as tumor necrosis factor-alpha, are thought to play a central role in the progression from simple steatosis to steatohepatitis and cirrhosis. Recently, adiponectin, an adipocyte-produced protein, has gained considerable attention as a possible key regulator of liver injury in NAFLD. Adiponectin is secreted by adipocytes in inverse proportion to BMI and metabolically acts to reduce body fat, improve insulin sensitivity, and decrease serum free fatty-acid levels. Finally, hepatocyte apoptosis, a specific form of cell death that is characterized by organized nuclear and cellular fragmentation, has been identified as a potential key component of the second hit involved in NAFLD progression.7,8

Although much progress has been made, more studies are needed to clearly define the pathogenesis of NAFLD and the progression to more severe liver disease such as NASH or cirrhosis.
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 enzymes after hepatitis and other chronic liver diseases have been excluded. 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.9 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 (ascites, variceal bleeding, or encephalopathy). Most patients have associated features of the metabolic syndrome10 (Table 2): obesity (47% to 90%), diabetes mellitus (28% to 55%), and variable incidence of hyperlipidemia (4% to 92%) and hypertension.11

DIAGNOSIS

The diagnosis of NAFLD is most commonly made during further evaluation for elevated aminotransferases found in one of three situations: on routine checkup, when monitoring is performed for possible side effects of drugs (most often cholesterol-lowering medication), or 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 >30 g/day for males and >20 g/day for females) and to define the nonalcoholic nature of the condition. Moreover, it is necessary to exclude the alternative causes of fatty liver (Table 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 or more, or those with obesity, type 2 diabetes mellitus, or an aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio >1, are predictors of more severe histologic disease1 and may be useful in making a decision regarding when to order a biopsy. Histologic evaluation is the gold standard and should be considered.12

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 aminotransferases is the most common finding (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.1 Liver enzymes may be normal in a large proportion of patients with NAFLD; normal aminotransaminases do not exclude the presence of advanced disease.11 Serum alkaline phosphatase and gamma-glutamyl transpeptidase, 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 performed. 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.9 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 (Figure 2). Unfortunately, ultrasound cannot rule out steatohepatitis or fibrosis, and its sensitivity drops sharply when the degree of steatosis decreases below 30%.13,14 Both computed tomography (CT) and magnetic resonance (MRI) studies (especially the new technique of magnetic resonance spectroscopy) are more sensitive modalities for quantification of steatosis.15 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.13,15

Liver Biopsy

Liver biopsy is of unquestioned value in determining the presence of steatosis, distinguishing steatosis from steatohepatitis, and assessing the degree of fibrosis. Since 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 alternative causes. In a study of patients with elevated liver enzymes without obvious cause, NAFLD was confirmed on biopsy in about 70% of subjects, and 20% to 30% of patients were found to have alternative causes of aminotransferase elevations.16 In addition to establishing the cause and severity of disease, histology permits to monitor disease progression and the response to therapy, as aminotransaminase levels may decrease during the course of the disease regardless of whether fibrosis progresses or improves.17

NAFLD is histologically indistinguishable from liver damage resulting from alcohol abuse. The steatosis in NAFLD is mostly macrovesicular. In adults, similar histological findings may be found in a number of conditions (Table 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 (Figure 1). Cell injury is manifested by hepatocyte ballooning, as well as by Mallory hyaline and acidophil bodies. At the time of initial biopsy, 30% to 40% of patients with NASH may have advanced fibrosis and 10% to 15%, cirrhosis.9

Despite the advantages of liver biopsy, its overall role in the evaluation of patients with NAFLD is unsettled, in large measure due to its risks and to poor patient acceptance. In patients with risk factors for NAFLD (ie, the metabolic syndrome), 3 to 6 months are often allowed for a trial of weight loss and for possible improvement in imaging 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 (Figure 3).

THERAPY

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.18,19 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. Since the prognosis of NASH depends on risk factors (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.20,21 Slow, consistent weight loss through diets designed to produce a caloric deficit of 500 to 1,000 calories per day is advised. Reduction of dietary carbohydrates, in particular dietary fructose, is the most beneficial and has been shown to improve the lipid profile in overweight patients. Rapid weight loss is not indicated because it may increase the progression of the disease. 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 (eg, climbing stairs, walking instead of driving the car).12

Pharmacologic treatment of obesity in NASH is still experimental. Several drugs have been studied including sibutramine, a serotonin reuptake inhibitor, and orlistat, producing fat malabsorbtion. Both drugs improved liver enzymes and sonographic signs of fatty liver in a recent nonrandomized trial, but liver histology has not been evaluated.22 Finally, bariatric surgery is now suggested for patients with a BMI of >40 kg/m2 , or for those with a BMI >35 kg/m2 and obesity-related comorbidities. Studies suggest an improvement in histology in these patients.23,24 However, the safety of bariatric surgery in patients with cirrhosis is still under investigation.

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-γ agonists (thioglitazones) as well as metformin have been shown in small trials to improve insulin resistance, surrogate markers of fatty liver, and possibly histology.25 Only one study was controlled, and it included a combination of pioglitazone and vitamin E versus vitamin E alone. There was a better effect in the combination group.26 However, hepatotoxicity has been described with thioglitazones, and a more common side effect is paradoxical weight gain and fat redistribution.27 A more recent randomized, controlled trial of metformin versus vitamin E or prescriptive diet in nondiabetic NAFLD patients showed that metformin was of most benefit, with an improvement in histology.28 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 demonstrate improvement in transaminases with different classes of drugs, but there is a lack of histologic follow-up in most of the studies.19 Although one of the most common side effect of statins is liver enzyme elevation, recent evidence points out that patients with elevated baseline transaminases (likely having NAFLD) who received statin treatment did not have a higher incidence of liver enzyme elevation or hepatotoxicity than the liver disease controls who did not receive statins.29 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.30

Hepatoprotective Therapy

Several therapeutic agents thought to offer hepatocyte protection have been evaluated. Antioxidants have been hypothesized to decrease the oxidative stress and slow the progression from simple fatty liver to NASH. In humans with NAFLD, vitamin E has been tested in small, open-label pilot studies and in a recent randomized, controlled trial that confirmed the improvement in transaminases and fibrosis.31 A phase 3 clinical trial is under way. Despite small adult studies suggesting a role of ursodeoxycholic acid in improvement of NASH, the only large, randomized, placebo-controlled trial demonstrated no benefits from ursodeoxycholic acid over placebo on liver biochemistry and histology.32 Betaine, a hepatoprotective agent, has shown promising effects in a randomized, placebo-controlled trial.33 Finally, an non-controlled study of 11 adult patients with NASH showed a decrease in transaminase after 3 months of treatment with N-acetylcysteine.34 A larger controlled trial of 35 patients with NASH has shown similar effects. However, because of a short 4-week treatment period, the results are difficult to interpret, as the changes may be a reflection of the natural transaminase variations in the disease.35

Thus, emerging data from recent trials suggest 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 3) . However, many of these interventions need to be evaluated in carefully controlled long-term studies before a treatment recommendation is adopted.

OUTCOMES
The natural history of NAFLD is variable. The available data in adults suggest that the natural history of NAFLD is determined by the severity of the histologic damage. A study of 106 adult patients with pure steatosis without inflammation showed a benign clinical course, as only one patient developed cirrhosis over a median follow-up of 9 years.36 On the other hand, patients with NASH are thought to be at increased risk for the development of cirrhosis and its complications. A recent population-based cohort study in Olmsted County, Minnesota, has examined the natural history and outcome of adult NAFLD/NASH.37 A total of 420 patients with NAFLD were followed for up to 23 years. Overall and liver-related mortality were significantly higher than in the general population, liver disease being the third leading cause of death in this study.37 In children, a single longitudinal study evaluated 57 children, with a mean follow-up time of 5.5 years (up to 16 years).38 In that group, one developed cirrhosis and end-stage liver disease, requiring liver transplantation 6 years after NAFLD diagnosis, and four of five who had a second liver biopsy (after 3.3 years) showed progression of fibrosis. In addition, it is now recognized that a large proportion of patients with cryptogenic cirrhosis have burned-out NASH.39 NASH-associated cirrhosis may decompensate with subacute failure, is an increasing indication for liver transplantation, and may recur after transplantation.40

The association between NASH or cryptogenic cirrhosis and hepatocellular carcinoma ( HCC ) is increasingly being described.41 A recent report suggested that the combination of obesity, NASH, and liver cancer was an emerging new triad.42 In a study of 219 Japanese patients with NASH, 20 developed HCC; the cumulative rate of HCC at 5 years was 15.6%. Older age and more advanced fibrosis were predictors of cancer development.43 A recent case report described two cases of NASH-related HCC occurring in noncirrhotic livers.44 The carcinogenic mechanism is unclear but may be related to oxidative stress.

Although surveillance for HCC should be part of the management of patients with NASH cirrhosis, there is not enough evidence at present to apply this strategy to patients without cirrhosis.

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 metabolic sequelae 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 diagnosis of NAFLD as well as detection of progressive liver disease. The diagnosis of NAFLD should prompt management of the metabolic risk factors. Weight loss regimens are thought 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.25
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