AGA technical review on nonalcoholic fatty liver disease☆☆☆

Article Outline

• Abstract
• Methods
• History of discovery of NAFLD
• Nomenclature
• Histologic criteria for the diagnosis of fatty liver and steatohepatitis
• Grading and staging of steatohepatitis
• Clinical spectrum of NAFLD
  • Epidemiology of NAFLD
    • Incidence and prevalence
    • Demographics
    • Familial clustering of NAFLD
  • Iron overload and NASH
  • Symptoms
  • Physical signs
  • Laboratory abnormalities
• How is NAFLD diagnosed?
  • How good are the diagnostic criteria?
  • Can NAFLD be diagnosed by noninvasive methods?
  • What is the role of a liver biopsy in the diagnosis of NAFLD?
  • Distinguishing between alcoholic fatty liver disease and NAFLD
  • Can alcoholic steatohepatitis and NASH coexist in the same patient?
  • Diagnosis of NAFLD in the setting of cryptogenic cirrhosis
• What is the natural history of NAFLD?
• NAFLD in selected patient populations
  • NAFLD in children
  • NAFLD in the morbidly obese individual
  • NAFLD in syndromes of insulin resistance
  • NAFLD and hepatitis C
  • NAFLD and liver transplantation
• Treatment of NAFLD
  • Treatment of risk factors
    • Weight management
    • Pharmacologic treatment of insulin resistance
  • Lipid-lowering agents
  • Drugs that protect hepatocytes
• Summary
• Acknowledgements
• References
• Copyright

Abstract 

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterized histologically by mainly macrovesicular hepatic steatosis and occurs in those who do not consume alcohol in amounts generally considered to be harmful to the liver. There are 2 histologic patterns of NAFLD: fatty liver alone and steatohepatitis. NAFLD is an increasingly recognized cause of liver-related morbidity and mortality. In this review, the existing literature regarding the nomenclature, clinical and histologic spectrum, natural history, diagnosis, and management of this condition are discussed.

GASTROENTEROLOGY 2002;123:1705-1725

Back to Article Outline

Methods 

This report is based on the following: (1) a formal review and analysis of the literature on NAFLD (Index Medicus, 1950–1966; MEDLINE, 1966–2001), (2) several published guidelines and meta-analyses, including the American Gastroenterological Association's policy statement on guidelines, (3) the Manual for Guideline Development (American Gastroenterological Association: Clinical Practice and Practice Economics Committee)¹ as well as the policy statement on the development and use of practice guidelines of the American Association for the Study of Liver Diseases,² and (4) 12 years of experience on the part of the author in managing patients with liver diseases. There is a paucity of controlled data (types I and II as defined by the NHS center for reviews and dissemination)³ on NAFLD. This report summarizes the published literature and includes reported case series and case reports. Letters and abstracts have been included only when they represent the only literature in a given area or have been cited frequently in existing literature.

Back to Article Outline

History of discovery of NAFLD 

The association of macrovesicular steatosis of the liver with inflammatory changes and fibrosis in obese subjects has been known for several decades.⁴ However, it was largely ignored as a clinical entity until several reports⁵, ⁶, ⁷ documented the development of liver failure in some patients following surgical jejunoileal bypass for morbid obesity. The hepatic histology in such patients was indistinguishable from that seen in alcoholic hepatitis and included macrovesicular steatosis, Mallory bodies, ballooning degeneration, hepatocyte necrosis, and fibrosis.⁸ Similar hepatic lesions subsequently were described in obese patients who had neither abused alcohol nor undergone weight-loss surgery⁹, ¹⁰, ¹¹ and in diabetic individuals.¹², ¹³, ¹⁴ In 1980, Ludwig et al.¹⁵ introduced the term “nonalcoholic steatohepatitis” (NASH) to describe these histologic findings in those who did not consume alcohol. Other synonyms used to describe this entity include nonalcoholic steatonecrosis,¹⁶ fatty liver hepatitis,⁹ and nonalcoholic fatty hepatitis.¹⁷

Back to Article Outline

Nomenclature 

A complete diagnosis of fatty liver disease ideally should define the histology, including the stage and grade of the disease as well as its etiology (Table 1). Traditionally, fatty disorders of the liver have been classified as alcoholic or nonalcoholic. NAFLD includes both nonalcoholic fatty liver and NASH. NAFLD is associated with numerous etiologies (Table 2), and the underlying mechanisms as well as the natural history of the disease may vary with the specific etiology.

Table 2. Conditions associated with steatohepatitis

NOTE. All conditions except alcoholism are usually referred to as nonalcoholic steatohepatitis.

Using the term “nonalcoholic” to describe fatty liver disease associated with all of these etiologies renders the condition heterogeneous in terms of etiology and, possibly, natural history as well as response to therapy. This makes the condition harder to study and is therefore unsatisfactory. There is currently no consensus on the best way to classify fatty disorders of the liver.

Table 1. Nomenclature of fatty disorders of the liver

Back to Article Outline

Histologic criteria for the diagnosis of fatty liver and steatohepatitis 

The principal histologic feature of NAFLD is the presence of macrovesicular fatty change in hepatocytes with displacement of the nucleus to the edge of the cell.¹⁸, ¹⁹, ²⁰, ²¹ The original descriptions of steatohepatitis included the additional presence of Mallory bodies, ballooning degeneration, predominantly lobular neutrophilic inflammation, and Rappaport zone III perisinusoidal fibrosis.⁹, ¹³, ¹⁵, ¹⁸ It is now appreciated that, in a given patient, only some of these features may be present.²² Mallory bodies are less frequently seen in NASH compared with alcoholic steatohepatitis and may even be absent.²³, ²⁴ Also, in many individuals, atypical features (e.g., predominantly lymphocytic inflammation or portal fibrosis) are present. It is not known whether these histologic patterns represent different stages of steatohepatitis or separate clinicopathologic conditions with overlapping histologic expression. Despite an attempt to standardize the histologic diagnostic criteria for steatohepatitis during a workshop at the National Institutes of Health in 1998, no consensus exists on this subject.

An important consideration is the reliability with which the individual histologic parameters of steatohepatitis can be recognized. Nineteen individual parameters grouped under steatosis, hepatocyte injury, inflammation, and fibrosis were evaluated in a blinded manner by 4 pathologists and twice by 2 pathologists in one study.²⁵ Substantial concordance was observed with respect to assessment of extent of steatosis, sinusoidal location of steatosis, perivenular fibrosis, grade of fibrosis, ballooning degeneration, and glycogen nuclei. There was, however, considerable interobserver variation in the assessment of inflammation.

Back to Article Outline

Grading and staging of steatohepatitis 

An universally accepted histologic grading and staging system for steatohepatitis does not exist. The histologic grade indicates the activity of the steatohepatitic lesion, whereas the stage reflects the degree of fibrosis (Table 1). In a retrospective analysis,²⁶ those with florid steatohepatitis characterized by fat, ballooning degeneration, Mallory bodies, or perisinusoidal fibrosis had a poorer long-term outcome than those with fat and only nonspecific lobular inflammation. Based on these findings, the former histologic phenotype has been referred to as “big NASH” and the latter as “little NASH.” This remains to be prospectively validated.

In another study, Brunt et al.²⁷ scored a total of 10 findings to develop a grading and staging system for NASH. These included hepatic macrovesicular steatosis, hepatocellular ballooning, intra-acinar inflammation, portal tract inflammation, Mallory's hyaline, acidophil bodies, glycogen nuclei, lipogranulomas, and hepatocellular iron. Each of these was scored separately. Three parameters of hepatic fibrosis were scored: perisinusoidal fibrosis, portal fibrosis, and bridging fibrosis. Based on these, the necroinflammatory activity was graded as mild, moderate, or severe (Table 3).

Table 3. Grading and staging of NAFLD

Data from Brunt et al.²⁷

It was found that the serum alanine aminotransferase (ALT) levels correlated with the severity of the grade of steatohepatitis. The stage of the disease was further classified from 1 to 4 based on the degree of fibrosis. This grading and staging system has not yet been prospectively validated.

Back to Article Outline

Clinical spectrum of NAFLD 

NAFLD is a heterogeneous disorder. The heterogeneity stems from the variability in the definitions of the term “steatohepatitis” as well as its varied clinical associations. The epidemiology, clinical associations, and clinical features of NAFLD are reviewed below.

Epidemiology of NAFLD 

Incidence and prevalence 

The true incidence and prevalence of NAFLD are unknown. The published studies may be divided into 2 broad categories: (1) studies focused on selected patient subpopulations and (2) population-based studies. Virtually all of the former studies focus on specific subsets within a hospital-based patient population (e.g., diabetic or obese individuals),¹¹, ²⁸, ²⁹ thereby introducing both selection and ascertainment bias. Population-based studies have primarily used imaging modalities to diagnose NAFLD.³⁰, ³¹, ³², ³³, ³⁴ Although such studies can detect a fatty liver, they do not provide data on steatohepatitis, which requires a liver biopsy for confirmation.

Fatty liver disease was found in 20% of 126 otherwise healthy young adults with normal ALT levels being evaluated as donors for adult living-related orthotopic liver transplantation (OLT).³⁵ These data corroborate studies of automobile and air-crash victims who underwent liver biopsies.³⁶ In an autopsy study of 351 apparently nonalcoholic subjects,³⁷ steatohepatitis was found in 2.7% of lean individuals and 18.5% of obese patients. The risk factors for steatosis included diabetes, rapid preterminal weight loss, and the use of intravenous dextrose in the last week of life. These data, however, may be potentially biased due to preterminal events that could have led to a fatty liver.

Despite the limitations of the published data, several facts stand out consistently. Fatty liver and NASH occur in all age groups.³⁸, ³⁹ The prevalence increases with increasing body weight,¹⁹, ³¹, ⁴⁰, ⁴¹, ⁴², ⁴³ and fatty liver has been documented in up to 10%–15% of normal individuals and 70%–80% of obese individuals. Correspondingly, about 3% of nonobese individuals³⁷ and 15%–20% of morbidly obese subjects²⁸, ³⁸ have steatohepatitis. These findings are particularly of concern given the increasing prevalence of obesity in virtually all age groups.⁴⁴, ⁴⁵, ⁴⁶

Demographics 

Both fatty liver and NASH have been reported in all age groups, including children.³³, ⁴⁷ The highest prevalence is in those between 40 and 49 years of age.²², ²⁹, ³⁸, ³⁹, ⁴⁸ Although studies published before 1990¹⁵, ⁴⁹, ⁵⁰ (Table 4) emphasized that NASH occurred mostly in women (53%–85% of all patients), more recent studies²², ²⁹ have shown that NASH occurs with equal frequency in men (~50%). Interestingly, it has been suggested that the fibrotic component is reported to be more prominent than the inflammatory component in Japanese subjects in a manner analogous to alcoholic liver injury in these subjects.⁵¹ Within the United States, little data on the ethnic breakdown of subjects with NAFLD are available.

Table 4. Histologically characterized series of cases with NAFLD

r, retrospective; CT, clinical trial, nonrandomized; NA, not applicable.

Familial clustering of NAFLD 

Obesity⁵² and diabetes⁵³ are often clustered within families. The causes of such familial clustering include both genetic and environmental factors.⁵⁴ One would therefore also expect cases of steatohepatitis to be clustered within families, especially if several members are obese or diabetic. In a recent study,⁵⁵ 8 families with a total of 18 members with NAFLD, including NASH with cirrhosis, were described. A clear-cut pattern of inheritance of risk for NAFLD was not identified. However, the risk factors for NAFLD within these kindreds included female sex, obesity, and type 2 diabetes mellitus. Others have also reported the occurrence of NAFLD in multiple members of a family.⁵⁶ Several instances of fatty liver also have been described in patients with rare familial disorders (e.g., hypobetalipoproteinemia)⁵⁷, ⁵⁸ and a kindred with diabetes and hemolytic anemia due to a deficiency of red cell Mg²⁺–adenosine triphosphatase.⁵⁹ In such cases, despite the presence of an underlying familial disorder, no systematic studies of the prevalence of fatty liver or steatohepatitis in the affected families have been reported.

There is increasing evidence that NAFLD often represents the hepatic component of a “metabolic” syndrome characterized by obesity, hyperinsulinemia, peripheral insulin resistance, diabetes, hypertriglyceridemia, and hypertension (Figure 1).¹⁴, ³⁴, ⁴², ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1. 

  NAFLD as a manifestation of syndrome-X.

Although the molecular basis of these interactions is not fully understood and is currently the subject of intense investigation, their clinical association seems to be well established.

Obesity, defined by a body mass index (BMI) >30 kg/m²,⁶⁵ is clearly associated with NASH. However, most patients are only moderately overweight and are 10%–40% over their ideal body weight.³⁷, ⁵⁰, ⁶⁶ The likelihood of developing NASH increases with the degree of obesity, and about 15%–20% of morbidly obese patients (BMI >35 kg/m²) have NASH.⁴¹, ⁶⁷ Also, numerous reports have documented resolution of a fatty liver following gradual weight loss.⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰ Subjects with truncal obesity are more prone to develop both diabetes and hypertension as well as fatty liver.⁷¹, ⁷² In one study,⁷¹ the waist-to-hip ratio and male sex accounted for all of the variance in liver fat content. However, obesity is not invariably present in patients with NASH (Table 4), and many individuals with NASH have a normal body weight.²²

Type 2 diabetes mellitus is a major component of the metabolic syndrome previously noted and is associated with both obesity and NASH.¹⁵, ⁴⁸, ⁴⁹ Both obesity and diabetes are associated with peripheral insulin resistance, hyperinsulinemia, increased free fatty acid levels, and hypertriglyceridemia.³², ⁶¹, ⁷³, ⁷⁴ Diabetes is not only associated with NAFLD but also may be a risk factor for development of progressive fibrosis.⁷⁵

The metabolic and cellular mechanism(s) linking insulin resistance to NAFLD are not fully understood. Two studies have found decreased insulin extraction by the liver, which contributes to hyperinsulinemia in patients with NAFLD.⁷⁶, ⁷⁷ Recently, the presence of peripheral insulin resistance, increased free fatty acid levels, increased mitochondrial fatty acid β oxidation, and increased hepatic lipid peroxidation were identified in patients with either fatty liver alone or NASH without cirrhosis.⁷⁸ The degree of abnormality was greater in those with NASH. In addition, NASH was also associated with specific mitochondrial abnormalities with intramitochondrial paracrystalline inclusions.⁷⁸, ⁷⁹ These, along with studies in experimental models of steatohepatitis,⁸⁰, ⁸¹ are now beginning to provide a framework of understanding linking obesity, insulin resistance, and steatohepatitis.

In addition to the components of the metabolic syndrome previously noted, NAFLD has been associated with several rare disorders of lipid metabolism (e.g., abetalipoproteinemia⁸²) and some rare syndromes characterized by severe insulin resistance (e.g., lipoatrophic diabetes and Mauriac syndrome).⁷³, ⁸³ The liver disease in abetalipoproteinemia as well as lipodystrophy can progress to advanced fibrosis and cirrhosis.⁸², ⁸⁴, ⁸⁵, ⁸⁶ NAFLD has also been associated with Weber-Christian syndrome.⁸⁷ The biochemical basis for NAFLD in such syndromes and their natural history are unknown and may be variable.

NAFLD has also been described with the use of several drugs (e.g., diltiazem, amiodarone, and tamoxifen).⁸⁸, ⁸⁹, ⁹⁰ There is increasing appreciation of lipoatrophy and severe hyperlipidemia associated with development of fatty liver in patients being treated with highly active antiretroviral drugs (e.g., indinavir).⁹¹, ⁹², ⁹³ This has been associated with the development of severe insulin resistance.⁹⁴, ⁹⁵ The incidence, mechanism, and natural history of iatrogenic NAFLD are unknown. Occupational exposure to several types of chemicals (e.g., organic solvents and dimethylformamide) are also associated with fatty liver disease.⁹⁶ The prevalence of such exposures and their impact on the epidemiology of NAFLD are unknown. Until such time that the mechanisms of steatohepatitis in these patient populations and their natural history are resolved, it is best to consider steatohepatitis in these populations separately from most patients with NAFLD.

Iron overload and NASH 

Bacon et al.²² first reported that many patients (18 of 31) with NASH had biochemical evidence of iron overload. In this series, despite elevation of transferrin saturation and serum ferritin level, the hepatic iron index was <1.9 in all patients. In another study,⁹⁷ a serum ferritin level >300 mmol/L was found in 26 of 42 patients (62%), whereas a transferrin saturation >55% was present in 9 of 41 patients (22%) with NASH. Overall, 31% of patients were either homozygous or heterozygous for the Cys282Tyr mutation, values significantly higher than in the general population. However, once again, the hepatic iron index was <1.9 in all. The prevalence of the His63Asp mutation was similar to that in the general population. In yet another study,⁹⁸ the prevalence of heterozygosity for either mutation was significantly higher in subjects with NASH compared with controls of similar ethnicity. However, biochemical parameters of iron stores and hepatic iron staining were not significantly different. The significance of the HFE mutations in NASH remains to be fully established. Also, the possibility of referral bias in the reported studies cannot be fully excluded. The presence of iron overload has been reported to be associated with increased hepatic fibrosis.⁹⁷ However, these data have been refuted in 2 other series.⁷⁵, ⁹⁹

Symptoms 

As with many other types of chronic liver disease, most patients with NAFLD in cross-sectional studies are asymptomatic (Table 4). The liver disease is either discovered incidentally during routine laboratory examination or workup of conditions such as hypertension, diabetes, or morbid obesity. In many asymptomatic subjects, elevated ALT levels are discovered when a hepatic panel is ordered to monitor subjects treated with antihyperlipidemic drugs. Elevated ALT levels or sonographic evidence of fatty liver is sometimes noted during workup of suspected gallstone disease. NAFLD is the most common cause for unexplained persistent elevation of ALT levels once hepatitis C and other known causes of chronic liver disease have been excluded.¹⁰⁰

Only limited data on symptomatology are available from longitudinal studies, and the likelihood of developing symptoms over time as well as the predictors of future development of symptoms are not known. When symptoms occur, they are usually nonspecific. Fatigue is probably the most commonly reported symptom and does not correlate well with the severity of the histologic lesion.²² Another common symptom is right upper quadrant discomfort, which is typically of a vague, nondescript aching character. A smaller fraction of patients experience symptoms indicative of more serious liver disease and may develop pruritus, anorexia, and nausea. The development of ascites, anasarca, variceal hemorrhage, or symptoms of hepatic encephalopathy indicates decompensated cirrhosis. Similarly, jaundice occurs late in the course of NASH and indicates advanced liver disease.

Physical signs 

There are no pathognomonic signs of NASH. Obesity is the most common abnormality on physical examination and is present in 30%–100% of patients in various cross-sectional studies.¹⁵, ²², ³⁷, ⁴⁹ The most common finding of liver disease is hepatomegaly, which has been reported in up to 50% of subjects in different studies.¹⁵, ²² A smaller percentage of patients have stigmata of chronic liver disease. Of the various stigmata known, the presence of spider nevi and palmar erythema are most common.⁴⁸ Jaundice, edema, asterixis, and signs of portal hypertension occur in those with advanced cirrhosis. Muscle wasting may occur as the liver disease becomes more advanced but is often underestimated due to edema and preexisting obesity.

Laboratory abnormalities 

In hospital-based populations of patients with NASH, most subjects (50%–90%) have abnormal aminotransferase activities.¹⁵, ²², ²⁹, ⁴⁹ The degree of enzyme elevation is not marked and is usually between 1 and 4 times the upper limit of normal values (Table 5).

Table 5. Histologically characterized series of cases with NAFLD: Laboratory values

r, retrospective; CT, clinical trial nonrandomized.

Although the ALT levels are higher than aspartate aminotransferase (AST) levels in most instances,¹⁵, ⁴⁸, ⁴⁹, ¹⁰¹ the AST level may occasionally be higher than the ALT level, especially in the presence of cirrhosis.²² However, the AST/ALT ratio is almost never >2. In those patients with elevated ALT levels, the elevation is usually persistent although the precise value may fluctuate. Less commonly, the serum ALT level remains persistently normal. ALT values do not correlate with the degree of steatosis or fibrosis.³⁹ Although γ-glutamyltransferase levels may be elevated, there are little data on the frequency and degree of elevation. The alkaline phosphatase level may also be variably elevated up to twice the upper limit of normal.¹⁵, ²², ²⁹, ⁴⁹

As expected, measures of hepatic functional capacity do not become abnormal until cirrhosis and liver failure set in. The serum albumin level and prothrombin time become abnormal before the serum bilirubin level does. In a diabetic subject with NASH, isolated hypoalbuminemia may also occur due to proteinuria related to diabetic nephropathy. Hematologic parameters are usually normal unless cirrhosis and portal hypertension lead to hypersplenism. Across several series,¹⁵, ¹⁰², ¹⁰³ about 10%–25% of patients have been noted to have a positive antinuclear antibody, a marker of autoimmunity. The significance of this observation is unclear. About 30%–50% of patients with NASH have either diabetes or glucose intolerance.¹⁵, ³⁷, ⁴⁹, ⁵⁰, ¹⁰³ A fasting lipid profile shows hypertriglyceridemia in 20%–80% of patients.¹⁵, ⁴⁸, ⁴⁹, ⁵⁰, ¹⁰³

Back to Article Outline

How is NAFLD diagnosed? 

How good are the diagnostic criteria? 

Powell et al.⁴⁸ originally proposed 3 criteria for the diagnosis of NASH: (1) a histologic picture of steatohepatitis, (2) convincing evidence of minimal or no alcohol consumption (<40 g/wk), and (3) absence of serologic evidence of viral hepatitis. Although these criteria are used widely in clinical practice, each criterion has specific limitations that bear discussion.

The variability in the histologic expression of NASH has been a source of debate and has prevented the development of a validated and universally accepted set of diagnostic criteria for steatohepatitis. There is also controversy regarding the precise cutoffs in terms of alcohol consumption in the diagnosis of NAFLD. It is generally believed that a fatty liver does not develop with alcohol consumption levels <20 g/day. The original cutoff of <40 g/wk for the diagnosis of NAFLD may therefore be too stringent. However, there are no published and universally accepted threshold levels of alcohol intake that separate alcoholic fatty liver disease from NAFLD.

Determination of the extent of alcohol consumption is easier said than done. Assessment of the amount of alcohol consumed from that reported by patients is notoriously inaccurate. Questioning of family members may be useful in some instances. The shortcomings of this approach have led to the development of direct and surrogate markers of alcohol consumption.

Random blood alcohol levels have been advocated to determine the extent of alcohol consumption,¹⁰⁴ but it is not always possible to obtain random blood samples. Also, the number of negative tests necessary before a person can be considered not to be an alcohol user is unknown. Furthermore, the optimal interval between such tests remains to be established, and it is not possible to determine the average amount of alcohol consumed over extended periods of time by a single or even 2 random blood alcohol levels.

Several surrogate markers of excessive alcohol consumption over a period of time have also been evaluated. These include serum γ-glutamyltransferase levels,¹⁰⁵ mean corpuscular volume,¹⁰⁵ AST levels, AST/ALT ratio,¹⁰⁶ mitochondrial AST levels,¹⁰⁷, ¹⁰⁸ and desialylated transferrin levels.¹⁰⁹ The first 4 tests are both widely available and relatively inexpensive. Unfortunately, they lack both sensitivity and specificity, and neither the negative nor positive predictive values are high enough to be clinically useful.¹⁰⁵, ¹⁰⁶ The clinical utility of the other markers has not been examined outside of a few limited clinical studies. In one such study,¹¹⁰ desialylated transferrin/total transferrin ratio was found to distinguish between those with alcoholic steatohepatitis versus NASH with greater accuracy than the mitochondrial AST/total AST ratio. It has been reported that plasma pseudocholinesterase levels are elevated in those with a fatty liver¹¹¹; their clinical utility in differentiating between alcoholic steatohepatitis and NASH remains to be defined.

The presence of non-A, non-B hepatitis (hepatitis C) was originally believed to constitute an exclusion criteria for the diagnosis of NASH.⁴⁸ Several investigators have now seen patients with hepatitis C who clearly have histologic evidence of a classic steatohepatitis rather than the predominantly portal lymphocytic infiltrate with mild to moderate steatosis seen in hepatitis C.¹¹² In such cases, the presence of 2 diagnoses (i.e., hepatitis C and NASH) may be considered.

Can NAFLD be diagnosed by noninvasive methods? 

There are no accurate noninvasive methods for the diagnosis of NASH. The presence, degree, and pattern of aminotransferase elevation are nonspecific and do not provide an etiologic diagnosis.¹⁰⁵ Even when the index of suspicion for NASH is high (e.g., in an obese, diabetic individual), the aminotransferase levels do not distinguish between fatty liver alone and NASH.¹⁵, ⁶⁷ The presence of fat in the liver can be diagnosed in many cases using various imaging modalities.

Ultrasonography, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) have all been used to diagnose NAFLD. Of these, sonography is the least expensive and MRI is the most expensive modality. There are 4 sonographic findings of diffuse fatty change in the liver¹¹³: (1) a diffuse hyperechoic echotexture (bright liver), (2) increased liver echotexture compared with the kidneys, (3) vascular blurring, and (4) deep attenuation. In a small retrospective study,¹¹⁴ a combination of these parameters allowed diagnosis of fatty liver (defined histologically by fat present in >30% of each lobule) with a sensitivity of 83% and specificity of 100%. Recently, using both 10-MHz as well as 3.5-MHz transducers,¹¹⁵ frequency-dependent attenuation of an ultrasound beam passed through the liver was shown to correlate well with its fat content.

Liver fat content also can be semiquantitatively estimated by MRI¹¹⁶ as well as CT scans.¹¹⁷ Normally, the CT attenuation values for the liver range from 50 to 75 Hounsfield units¹¹³, ¹¹⁸, ¹¹⁹ when a non–contrast-enhanced scan is obtained. With increasing hepatic steatosis, the liver attenuation values decrease by about 1.6 Hounsfield units for every milligram of triglyceride deposited per gram of liver tissue.¹²⁰ Thus, in those with a fatty liver, the hepatic attenuation is less than that of the blood vessels, giving the appearance of a contrast-enhanced scan in a non–contrast-enhanced scan.¹¹⁷, ¹¹⁹

When intravenous contrast is used, both the liver and splenic attenuation values increase. However, the hepatic values increase to a lesser degree than the splenic values, thereby increasing the difference in hepatic to splenic values.¹²¹ When a diagnosis of a fatty liver is based simply on a qualitative assessment of the differential attenuation during a contrast-enhanced CT scan, the sensitivity and specificity are 54% and 95%, respectively.¹²² Using a cutoff of 20.5 Hounsfield units 80–100 seconds after intravenous contrast injection, a fatty liver could be diagnosed with 86% sensitivity and 87% specificity.¹²² At 100–120 seconds, a difference in hepatic and splenic attenuation of 18.8 Hounsfield units had a sensitivity and specificity of 93% each.¹²² Thus, the diagnostic accuracy of differential changes in hepatic-splenic attenuation are time dependent and protocol specific. These data have been corroborated by another study in which the sensitivity was even lower (54%–71%).¹²³ An unenhanced hepatic CT scan remains the optimal CT method for detection of a fatty liver.¹²² If hepatic attenuation is higher than the spleen, fatty liver can be excluded with relative confidence.¹²² Single-energy CT scans are superior to double-energy CT scans for the determination of fat content, especially when iron overload is also present.¹²⁴ By CT imaging,¹²⁵ the distribution of the fat is unequal with lower attenuation values in the right lobe compared with the left.

There is considerable interindividual variability as well as intraindividual variability during multiple examinations in the absolute liver attenuation numbers. This is due to nonidentical calibration of different machines, different types of CT scanners, differing regions of interest during multiple examinations, and changes in hepatic fat content. Accurate assessment of fatty liver and changes in hepatic fat content require careful calibration and obtainment of the region of interest at the same level during each examination. The latter requires use of landmarks that move equally with the liver during the various phases of respiration and include the same blood vessels seen in previous examinations. Another way to avoid these confounding variables is to compare the hepatic attenuation values with those of the spleen.

Differences in the precession frequency (3.7 ppm) between water and fat protons can be used in opposed-phase images in which the fat signal is subtracted from the water signal to diagnose fatty liver using MRI.¹¹⁶, ¹²⁶, ¹²⁷ In such cases, T1-weighted gradient-echo images obtained with echo times keeping the water and fat spins out of phase show a loss of liver hepatic signal intensity relative to in-phase images. The fatty liver also has a lower signal intensity compared with adjacent muscle.¹²⁶ Several newer modifications in MRI techniques have resulted in considerable improvement in the ability to diagnose a fatty liver by MRI.¹²⁸, ¹²⁹, ¹³⁰, ¹³¹, ¹³², ¹³³

In a direct comparison of CT scan with sonography,¹²⁴ sonography was found to be more sensitive in detecting fatty change. However, when fatty change is patchy or focal, CT scan and MRI are superior to sonography.¹¹³ Also, when a semiquantitative assessment is required or when multiple comparative studies are planned over time, CT imaging is superior to sonography.

Despite the utility of these imaging modalities in the diagnosis of diffuse fatty disorders of the liver, none of these modalities can distinguish between fatty liver versus steatohepatitis. Moreover, diffuse fibrosis is also associated with a hyperechogenic ultrasound pattern and cannot be distinguished from fatty liver with accuracy by ultrasonography. Thus, liver biopsy remains the only accurate way to diagnose steatohepatitis.

What is the role of a liver biopsy in the diagnosis of NAFLD? 

The value of a liver biopsy for the diagnosis of NAFLD in routine clinical practice is hotly debated. Arguments against a liver biopsy include the generally good prognosis of most patients with NAFLD, the lack of an established form of effective therapy, and the risks and costs associated with a biopsy. On the other hand, there is little controversy that a liver biopsy is the only accurate method for the diagnosis of NASH,¹⁵, ¹⁸, ²² as shown by the poor positive predictive value (56%) of clinical and laboratory evaluation for the diagnosis of NASH using histology as the gold standard.¹³⁴

Sorbi et al.¹³⁵ recently studied the clinical utility of a liver biopsy in routine clinical practice. A total of 36 subjects with persistently elevated ALT levels for which a diagnosis could not be established by noninvasive methods underwent a liver biopsy. A presumptive diagnosis and plan of management were identified before the biopsies were performed. The liver biopsy changed the diagnosis in 14% of cases as well as altered the frequency of monitoring laboratory studies in 36% of cases and the treatment recommendations in 12 patients. Importantly, 10 of 12 subjects were offered experimental therapy.

Although it is essential to include only biopsy-proven cases of NASH in clinical trials, the decision to perform a liver biopsy in routine clinical practice should take into consideration the specific clinical questions that are relevant in a given case (e.g., exclusion of alternate causes of liver disease, ascertainment of degree of fibrosis, and determination of long-term prognosis). Thus, both the decision to perform a liver biopsy in a patient with suspected NAFLD and the timing of the biopsy must be individualized and should include the patient in the decision-making process.

Distinguishing between alcoholic fatty liver disease and NAFLD 

In most instances, it is fairly easy to distinguish alcoholic fatty liver disease from NAFLD. This is particularly true in hospitalized populations, where those with alcoholic hepatitis are usually sicker, have higher serum bilirubin levels, and have an AST/ALT ratio >2.¹⁰⁵, ¹³⁶ The AST/ALT ratio is usually <1 in patients with NAFLD and may be used to differentiate it from alcoholic liver disease.¹³⁷ However, in an ambulatory care setting, alcoholic liver disease has also been found to be associated with a similar AST/ALT ratio.¹³⁸ The pathologic changes of steatohepatitis are more severe in those with alcoholic hepatitis with greater inflammation, a greater degree of hepatocellular injury, frequent Mallory bodies, and a greater degree of perisinusoidal fibrosis.¹³⁶ Those with nonalcoholic liver disease, however, have a greater prevalence of glycogen nuclei. Whereas about 8%–10% of patients with NASH have cirrhosis, 39% of ambulatory and 80%–90% of hospitalized patients with alcoholic hepatitis also have cirrhosis.¹³⁶, ¹³⁸ These data indicate that distinction between NAFLD and alcoholic liver disease may not always be easy, particularly in those who consume modest amounts of alcohol. In such cases, reassessment after a period of abstinence may be necessary to establish the diagnosis of NAFLD.

Can alcoholic steatohepatitis and NASH coexist in the same patient? 

By definition, NAFLD cannot be diagnosed in a subject who consumes excessive amounts of alcohol. However, both alcoholic fatty liver disease and NAFLD commonly occur in the population. It has been shown that the prevalence of a fatty liver is highest in obese individuals who consume excessive alcohol.⁴², ¹³⁹, ¹⁴⁰ It is therefore conceivable that these conditions may occur together in the same individual. However, no reliable methods exist to diagnose both alcoholic fatty liver disease and NAFLD in the same individual. Also, a safe level of alcohol intake that does not accelerate the progression of NASH has not been established. Conversely, a specific threshold level of alcohol intake above which the progression of NASH is accelerated has not been shown. Clearly, more work needs to be done to clarify the relationship between alcoholic fatty liver disease and NAFLD.

Diagnosis of NAFLD in the setting of cryptogenic cirrhosis 

Cryptogenic cirrhosis is diagnosed when a specific etiology for cirrhosis cannot be established. Many patients with cryptogenic cirrhosis have risk factors for NAFLD and may indeed have had NASH.¹⁴¹, ¹⁴² However, in a given individual, the diagnosis of NASH as a cause of cryptogenic cirrhosis poses several challenges.¹⁴³ These include the decrease in hepatic steatosis after development of cirrhosis.⁴⁸ Indeed, steatosis may completely disappear. The frequency with which this happens and the time course of disappearance of fat remain to be defined. Also, Mallory bodies rarely are seen and ballooning degeneration is a relatively nonspecific finding. Finally, the presence of centrilobular perisinusoidal fibrosis is not possible in the absence of normal lobular architecture. Thus, the possibility of underlying NASH usually is surmised from a “gestalt” of the constellation of clinical and histologic findings present in an individual case.

Back to Article Outline

What is the natural history of NAFLD? 

Only limited data are available on the natural history of the spectrum of histologic lesions seen in macrovesicular fatty disorders of the liver that are not associated with the use of alcohol. It is generally believed that there are several distinct histologic states in the natural history of these disorders that indicate progression of the lesion (Figure 2).

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2. 

  Stages in the progression of NAFLD.

These include a fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and eventually cirrhosis.²² It has also been noted that, following development of cirrhosis, fatty change may disappear.⁴⁸

Cross-sectional studies of nonalcoholic fatty liver¹⁵, ⁴⁹ indicate that most subjects have a fatty liver alone. It is currently believed that it is rare for such patients to progress to steatohepatitis or steatosis with fibrosis over time. In one study,²⁹ no instances of progression to steatohepatitis were noted over a 10-year period. Other studies⁴⁸, ⁵⁰ also corroborate these data. In contrast, at least one instance of progression from fatty liver alone to steatohepatitis has been noted in a patient after liver transplantation.¹⁴³ Also, morbidly obese individuals with a fatty liver alone who undergo rapid weight loss following jejunoileal bypass¹⁴⁴, ¹⁴⁵ or proximal gastric bypass⁶⁷ have been reported to develop steatohepatitis.

At the time of initial presentation, about 30%–40% of patients with NASH have advanced fibrosis,²², ⁵⁰ whereas 10%–15% have established cirrhosis.¹⁵, ²², ⁴⁸, ⁵⁰ Although one study⁴⁸ did not find any relationship between the histologic stage and the presence or degree of obesity or diabetes, another study²² found that those with cirrhosis were more likely to be female (62%) and obese (62%). In a recent large cross-sectional study,⁷⁵ 144 subjects with NASH were studied. No fibrosis was found in 26%, whereas 17% had cirrhosis. By multivariate analysis, increasing age, obesity, and diabetes were noted to be independent predictors of bridging fibrosis or cirrhosis. Another recent study has confirmed the relationship between the degree of obesity and the likelihood of advanced fibrosis.¹⁴⁶

Assessment of the rate of progression of NASH to NASH with fibrosis and eventually cirrhosis is confounded by the limited data available. The published studies are all retrospective, and few patients have undergone multiple biopsies during follow-up. Powell et al.⁴⁸ followed up 42 patients for a median duration of 4.5 years; during this time, 6 of 13 patients showed progression of fibrosis and 1 patient developed cirrhosis. Similarly, 5 of 13 patients developed increasing fibrosis over a mean follow-up of 3.5 years in another study.⁵⁰

In an important report²⁶ (Table 6), 132 subjects with NAFLD were grouped into 4 categories based on their liver histology: (1) fatty liver alone, (2) fat plus lobular inflammation, (3) fat plus ballooning degeneration, and (4) fat plus ballooning plus either Mallory hyaline or fibrosis.

Table 6. Comparison of outcomes for various histologic patterns of NAFLD

NOTE. Based on retrospective analysis of 132 patients with follow-up of up to 18 years.²⁶

Cirrhosis was present in 4 of 19 subjects in group 3 and 14 of 26 subjects in group 4. A retrospective analysis of survival over 18 years of follow-up showed a 33%, 30%, 26%, and 44% mortality in the 4 groups, respectively. Liver-related deaths were highest in groups 3 and 4; however, even in those with fatty liver alone, 1 liver-related death was reported.

The precise risk of mortality in patients with NAFLD is not known. In the retrospective, cross-sectional series published before 1999,¹⁵, ⁴⁸, ⁴⁹, ⁵⁰, ¹³⁶, ¹³⁸, ¹⁴⁷, ¹⁴⁸, ¹⁴⁹ a total of 11 deaths among 299 patients (3.1%) were reported. In a longitudinal study,⁴⁸ only 1 of 42 patients died during a median follow-up of 4.5 years, apparently confirming the low mortality noted in cross-sectional studies. However, more recent reports have challenged the notion that NASH is associated with a low (<5%) mortality. In a study of 30 patients with NASH followed up for more than 10 years published only in abstract form,¹⁵⁰ the 5-year survival was only 67% and the 10-year survival was 59%. Although the overall mortality was not significantly different from that of an age- and sex-matched population, the liver-related mortality was increased. In another series,²⁶ the liver-related mortality was 7 of 54 over an 18-year follow-up in those with fatty liver, ballooning degeneration, and Mallory bodies or perisinusoidal fibrosis. Although most patients with NASH without bridging fibrosis or cirrhosis have a very low risk of death up to 5–10 years from the time of diagnosis, those with more advanced disease are at higher risk of dying as a consequence of their NASH. It is important to note that all of the data available are retrospectively collected and have all of the limitations of such data; there is a critical need for prospective studies in this area.

Many factors may contribute to mortality in patients with NAFLD. These include obesity and diabetes and their complications, other comorbidities associated with obesity and diabetes, and the liver disease itself. There are no published data clearly identifying the relative contributions of these factors to mortality in NAFLD, although one study found that the presence of cirrhosis independently increased the relative risk of mortality.²⁶ Of the liver-related causes of mortality, the development of liver failure, complications of cirrhosis (e.g., variceal hemorrhage and ascites), and hepatocellular carcinoma can all contribute to mortality. However, the precise incidence of these specific complications is not known.

Histologic improvement may also occur, especially in those with only minimal fibrosis. Following weight loss,⁶⁸ the liver histology may improve with a decrease in inflammation, number of Mallory bodies, and even perisinusoidal fibrosis. This is particularly true when the weight loss is achieved slowly and when exercise is part of the weight-loss regimen.¹⁵¹, ¹⁵² On the other hand, rapid weight loss may accelerate progression of the disease. In many instances, liver failure becomes manifest during a period of rapid weight loss regardless of its mechanism.¹⁴⁵, ¹⁵³, ¹⁵⁴

Back to Article Outline

NAFLD in selected patient populations 

NAFLD in children 

NAFLD has been reported in the pediatric population. In a retrospective review of liver biopsy specimens, Baldridge et al.⁴⁷ found that 82 of 650 cases had hepatic steatosis, of which 14 were considered to have NASH with varying degrees of fibrosis. Similar data have been reported by others.³⁰, ³⁹, ¹⁵⁵ Although most reported cases of fatty disorders of the liver in children have been noted around the age of puberty, isolated instances have been reported in those as young as 7–8 years of age.³³ Several studies of obese children³⁰, ³⁸, ³⁹ have shown evidence of fatty liver disease, documented by sonography or increased ALT levels, in up to 50%–60% of affected children. Unfortunately, these data have the same limitations as other studies using sonography. However, given that 25%–30% of children in the 6- to 12-year age group and 7%–10% of children in the 12- to 17-year age group are obese,⁴⁵, ¹⁵⁶, ¹⁵⁷ it is likely that NAFLD is relatively common in the general population.

The clinical picture of NASH in the pediatric population is similar to that in adults. Many children are asymptomatic. The most common symptoms include right upper quadrant aching discomfort and fatigue.⁴⁷, ¹⁵⁸ Obesity and hepatomegaly are the most common physical findings. Most affected children have elevated ALT levels.⁴⁷, ¹⁵⁸ Cirrhosis related to NASH has been described in a 10-year-old child.¹⁵⁵ The duration of obesity may also be a determinant of the likelihood of progression to cirrhosis.⁴³

Although NAFLD is an established cause of chronic liver disease in children, many clinical issues remain to be elucidated, including the mechanisms by which it develops, a detailed description of the histology, and the natural history of the disease.

NAFLD in the morbidly obese individual 

The recognition of NAFLD as a clinical entity has its origin in descriptions of fatty liver and fibrosis along with variable degrees of inflammation in morbidly obese individuals⁵, ⁶, ¹⁵⁹, ¹⁶⁰ and the frequent development of progressive liver failure following jejunoileal bypass in these patients.¹⁵⁹, ¹⁶¹, ¹⁶² As early as 1973, Kern et al.¹⁶⁰ described fatty liver in 151 obese subjects, of whom 92 had fibrosis and 6 had cirrhosis. These were followed by other reports of a high incidence of cirrhosis and diabetes in morbidly obese individuals.⁹, ¹³, ¹⁴⁷, ¹⁶³, ¹⁶⁴ These initial studies led to numerous publications confirming the association of morbid obesity with NASH.¹¹, ¹³⁹ In a comprehensive review of 1515 morbidly obese patients reported in the literature, Anderson and Gluud⁴¹ noted that fatty change was present in 80% of subjects whereas portal inflammation and fibrosis were present in about 30% of subjects and cirrhosis in 3% of individuals. Obesity has been identified as an independent risk factor for the development of hepatic fibrosis.²⁶, ⁷⁵

A characteristic feature of morbid obesity-related steatohepatitis is the development or worsening of steatohepatitis following rapid and massive weight loss usually following jejunoileal bypass.¹⁵, ¹⁴⁵, ¹⁶¹, ¹⁶⁵, ¹⁶⁶, ¹⁶⁷, ¹⁶⁸ When this leads to subacute hepatic failure, it has also been referred to as subacute NASH.¹⁵ The prevalence of hepatic steatosis increased from 66% to 95% in the first year after jejunoileal bypass but returned to baseline values by 5–7 years in one study.¹⁶² During the first 18 months, some patients also show a marked increase in inflammation and hepatocellular injury that may manifest as subacute liver failure.¹⁵³ Preoperative perisinusoidal fibrosis is a risk factor for the postoperative development of liver failure and progressive fibrosis.¹⁶⁷, ¹⁶⁹ It is likely that, in such individuals, surgery precipitates metabolic or other changes that accelerate the hepatocellular injury producing liver failure. Some patients respond to shunt takedown.¹⁵³ Glucose-free, amino acid infusions¹⁷⁰ have been reported to improve hepatic steatosis following jejunoileal bypass. Also, improvement in hepatic histology has been reported following treatment with metronidazole.¹⁴⁴

The dangers of the jejunoileal bypass have led to the use of proximal gastric bypass as the procedure of choice for bariatric surgery.¹⁷¹, ¹⁷² Direct comparisons of gastric bypass with jejunoileal bypass show that the former is as efficacious yet safer than the latter.⁶⁸, ¹⁷¹, ¹⁷² Recent data indicate that the risks of worsening liver histology are linked to the rapidity of weight loss rather than the type of surgery used. In a carefully performed study, Luyckx et al.⁶⁷ studied liver histology before and after gastroplasty in 528 morbidly obese subjects. Following rapid weight loss, the degree of steatosis improved. However, this was associated with an increase in lobular inflammation. Thus, although the risks of subacute liver failure are decreased following gastroplasty, the liver histology may worsen initially. Over time, the hepatic histology improves along with an improvement in parameters of insulin resistance.¹⁷³ Gallstones are more prevalent in obese individuals¹⁷⁴ and therefore more likely to occur in those with NASH. Indeed, sonographically diagnosed fatty liver has been associated with an increased prevalence of gallstone disease.¹⁷⁵, ¹⁷⁶

NAFLD in syndromes of insulin resistance 

There are several distinct clinical syndromes associated with severe insulin resistance that are associated with NAFLD. Diabetes mellitus associated with lipoatrophy is the prototypic example of such a condition.⁸³, ¹⁷⁷, ¹⁷⁸, ¹⁷⁹ In such patients, progressive hepatomegaly due to fatty change (fat alone or steatohepatitis with or without fibrosis) occurs frequently. This often causes right upper quadrant discomfort, early satiety, and nausea. Over time, as fibrosis progresses, portal hypertension and splenomegaly can occur. Although the natural history of NASH in syndromes associated specifically with insulin resistance has not been well characterized, progression to cirrhosis can occur.

NAFLD and hepatitis C 

Hepatitis C and NAFLD are both common causes of liver disease. It is therefore not surprising that they can coexist in the same individual. In the presence of hepatitis C, portal and lobular inflammation cannot be used to assess the presence of fatty liver disease. Also, minor degrees of hepatic steatosis often are seen in those with hepatitis C. A confounding factor in published studies is the failure to clearly identify those instances in which fatty liver disease was related to an alcoholic versus nonalcoholic etiology. The degree of steatosis and body mass index are associated with the likelihood of advanced fibrosis.¹¹², ¹⁸⁰, ¹⁸¹ An association between hepatitis C genotype 3 and hepatitis C core protein with hepatic steatosis also has been described.¹⁸², ¹⁸³, ¹⁸⁴, ¹⁸⁵ An increase in serum triglyceride levels also occurs during interferon therapy.¹⁸⁶, ¹⁸⁷ The long-term implications of this phenomenon, if any, are unknown.

NAFLD and liver transplantation 

Fatty disorders of the liver affect the availability of organs as well as the outcomes of OLT. Recent data³⁵, ¹⁸⁸ indicate that up to 20% of potential donors have hepatic steatosis. Hepatic macrovesicular steatosis is associated with primary nonfunction of the graft following OLT, and a survey¹⁸⁹ of 25 liver transplant centers in the United States found that livers with more than 30% fat were discarded by most centers. There are several potential mechanisms that contribute to the poorer function of the fatty grafts, including decreased ability to generate adenosine triphosphate¹⁹⁰ and the generation of toxic metabolites.¹⁹¹ The high prevalence of fatty change in potential organ donors may reflect both the high prevalence in the population and the use of dextrose solutions before declaration of brain death. In contrast to macrovesicular steatosis, livers with microvesicular steatosis can be safely used for liver transplantation.¹⁹²

There are only a few small published series of patients with documented NASH who have undergone OLT. NASH has been reported to recur,¹⁹³, ¹⁹⁴, ¹⁹⁵, ¹⁹⁶ and some patients develop fibrosis within a relatively short period of time. In those with morbid obesity and liver failure precipitated by a jejunoileal bypass, severe NASH with fibrosis has been reported after OLT,¹⁹⁷ necessitating takedown of the bypass. A time-dependent increase in the risk of developing fatty liver after OLT has been found in subjects with cryptogenic cirrhosis with a clinical-histologic phenotype suggestive of NASH¹⁴³; a 100% recurrence of fatty liver occurs by 4–5 years. However, only 3 of 27 subjects developed steatohepatitis and all of the subjects did well clinically.

NAFLD also can develop in those who receive a liver transplant for indications other than NASH. The risk of developing fatty liver is approximately 20% in those who receive a transplant for alcoholic liver disease, hepatitis B, or primary biliary cirrhosis.¹⁴³ The development of NAFLD following OLT may be related in part to the weight gain that occurs commonly after transplantation.¹⁹⁸ Such weight gain has been reported to occur mainly between 2 and 16 months after transplantation in most patients.¹⁹⁸ The cumulative steroid dose has also been implicated in the pathogenesis of NAFLD after OLT.¹⁴³ The intermediate-term (5–10 years) outcomes of most patients with de novo development of NAFLD after OLT is excellent and, in one study, no instances of graft loss due to NAFLD occurred in this group.¹⁴³

Back to Article Outline

Treatment of NAFLD 

The treatment of any condition requires consideration of the natural history of the condition, the relative efficacy and safety of the therapeutic options, and cost. As previously noted, NASH can progress to cirrhosis.²², ⁷⁵, ¹⁹⁹ This is particularly true in the presence of bridging fibrosis.²⁶ Also, those with fat and ballooning degeneration or fat, ballooning degeneration and Mallory bodies or perisinusoidal fibrosis may be at greater risk for progression.²⁶ Older subjects and those with severe obesity or diabetes are also considered at risk for more advanced disease.⁷⁵ These factors must be kept in perspective when considering the therapeutic options for a given patient.

There are no published controlled trials of treatment modalities for NAFLD. It is therefore not possible to make any statements on relative risk of improvement with any modality. In the absence of treatment modalities of proven efficacy, therapy is directed toward correction of the risk factors for NASH (i.e., insulin resistance, decreasing delivery of fatty acids to the liver, and use of drugs with potentially hepatoprotective effects).

Treatment of risk factors 

Weight management 

There are several small anecdotal reports of improvement in liver histology following weight loss.⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰ However, there are no randomized clinical trials of weight control as a treatment of NAFLD. In overweight individuals with elevated aminotransferase levels, weight reduction by 10% or more has been shown to correct aminotransferase activities and decrease hepatomegaly.²⁰⁰ Despite the absence of randomized studies, obese subjects with NAFLD require weight management because of the benefits of weight loss on their cardiovascular risk profile.

The National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) clinical guidelines for the management of obesity provide specific recommendations for the selection of adult subjects for weight-loss treatment.²⁰¹ In children, an expert committee from the Maternal and Child Health Bureau, Department of Health and Human Services, has recommended that those with a BMI greater than the 95th percentile or greater than the 85th percentile with complications of obesity should be evaluated for treatment.²⁰² In such patients, it is important to exclude genetic and endocrine disorders associated with obesity.

The NHLBI-NIDDK expert clinical guidelines for weight loss recommend that the initial target for weight loss should be 10% of baseline weight.²⁰¹ It is important to note that most weight-loss regimens can achieve a modest 5%–10% weight loss.²⁰³, ²⁰⁴, ²⁰⁵ This results in considerable improvement in insulin sensitivity²⁰⁶, ²⁰⁷ and cardiovascular risk profile.²⁰⁵, ²⁰⁸ Very rapid weight loss may cause worsening of steatohepatitis and may precipitate liver failure.⁶⁷ Also, the risk of gallstone disease increases exponentially when the rate of weight loss exceeds 1.5 kg/wk.²⁰⁹ The NHLBI-NIDDK guidelines further suggest that weight loss should proceed at a rate of 1–2 lb/wk.²⁰¹ Several studies have shown that the risk of development of gallstones during weight loss can be decreased with the use of ursodeoxycholic acid (UDCA).²¹⁰, ²¹¹, ²¹², ²¹³ In morbidly obese individuals undergoing rapid weight loss, the use of UDCA for prevention of gallstones has been shown to be cost-effective.²¹⁴ The fear of potential adverse health consequences of weight cycling during attempts at modest weight loss (up to 10% of baseline) in unselected populations of obese patients is unproven and should not deter attempts to achieve such weight loss.²¹⁵

The NHLBI-NIDDK clinical guidelines for weight loss do not make any specific recommendation about monitoring liver functions while a patient undergoes weight loss. In patients with NAFLD, it would seem prudent to monitor for liver dysfunction, especially when the weight loss is rapid and severe (>2.5 lb/wk). Although there are no data on which to base scientific recommendations about the frequency of such monitoring, many experts check liver function tests once a month.

Diet is an important component of any weight-loss regimen. Saturated fats in the diet worsen insulin resistance,²¹⁶, ²¹⁷, ²¹⁸ whereas dietary fiber can improve insulin resistance.²¹⁹, ²²⁰ There are no controlled studies of the value of diet in the management of NAFLD. Dietary supplementation with polyunsaturated fatty acids may improve insulin sensitivity and cardiovascular risk profile.²²¹, ²²², ²²³ However, the effects of such a dietary modification on NAFLD are unknown. The roles of specific fiber supplements designed to decrease insulin resistance or dietary fat have not been evaluated.

In the absence of clinical trials that specifically address the value of dietary modification in NAFLD, it seems prudent to recommend a heart-healthy diet as recommended by the American Heart Association²²⁴ for those without diabetes or a diabetic diet as recommended by the American Diabetes Association²²⁵ for those with diabetes. Several systematic reviews and guidelines for the management of obesity have been published in the past 5 years.²⁰¹, ²⁰², ²²⁶, ²²⁷, ²²⁸, ²²⁹, ²³⁰ Readers are referred to these for a detailed analysis of the value of dietary modification for weight loss. Dietary changes alone often are associated with a high failure rate in achieving and maintaining weight loss.²⁰⁷, ²²³, ²³¹ The specific psychological, social, cultural, and economic factors responsible for this are yet to be defined. Dietary modification is most likely to be successful when accompanied by behavior-modification therapy,²⁰¹, ²³⁰ including cognitive-behavioral modification and hypnosis-based therapies.²³², ²³³

The value of exercise in achieving and maintenance of weight loss is now well established.²³⁴, ²³⁵, ²³⁶, ²³⁷, ²³⁸, ²³⁹, ²⁴⁰ Exercise has been shown to increase the oxidative capacity of muscle cells and utilization of fatty acids for oxidation.²⁴¹ This decreases fatty acid and triglyceride accumulation in the myocytes and thereby improves insulin sensitivity.²⁴² The degree of improvement in insulin sensitivity is related to the intensity of the exercise.²⁴³ However, a recent meta-analysis of clinical trials of exercise did not find sufficient evidence to prove that physical activity altered the dyslipidemia associated with obesity.²⁴⁴ Also, exercise alone is insufficient to achieve and maintain weight loss in many subjects.²⁰⁵ However, when weight loss can be achieved, this can be associated with improved hepatic histology.⁷⁰, ¹⁵¹, ²⁴⁵ Several studies that have evaluated the success of nonpharmacologic approaches to weight loss have recently been reviewed.²⁴⁶ Physician-oriented strategies are associated with the poorest outcomes, whereas partner-oriented strategies and a structured approach to weight loss are associated with the best outcomes. Patient-oriented strategies have intermediate results. Both aerobic exercise and resistance training have been shown to be beneficial in reducing weight.²⁰⁴, ²⁴⁵ Intermittent exercise also has been found to be as effective as daily exercise in a randomized controlled trial involving obese women.²⁴⁷

The role of weight-reducing pharmacologic regimens in NAFLD also remains to be studied. Currently, 3 drugs are approved for weight reduction: phentermine, sibutramine, and orlistat. Although the value of these drugs in achieving weight loss is established,²⁴⁸, ²⁴⁹, ²⁵⁰, ²⁵¹, ²⁵², ²⁵³, ²⁵⁴, ²⁵⁵ their value in the management of NAFLD remains to be shown. The NHLBI-NIDDK guidelines for management of obesity recommend that pharmacotherapy be considered as an adjunct to lifestyle modification for patients with a BMI ≥30 kg/m² and no concomitant obesity-related risk factors or diseases.²⁰¹ Pharmacotherapy may also be considered in those with a BMI ≥27 kg/m² with concomitant risk factors or diseases such as hypertension, dyslipidemia, coronary artery disease, type 2 diabetes mellitus, and sleep apnea. Sibutramine should not be used in those with a history of hypertension, coronary artery disease, congestive heart failure, arrhythmias, or history of stroke. Morbidly obese subjects (BMI ≥35 kg/m²) may be considered for more aggressive weight-loss programs, including proximal gastric bypass. This operation has been shown to be superior to vertical-banded gastroplasty as well as jejunoileal bypass.¹⁷², ²⁵⁶, ²⁵⁷, ²⁵⁸, ²⁵⁹, ²⁶⁰, ²⁶¹, ²⁶² However, such patients should be evaluated carefully before starting any therapy for both the presence of other obesity-related diseases as well as their risk of developing decompensated liver disease during rapid weight loss. Such risks must be integrated with the clinical profile of the patient to develop an individually tailored treatment plan for each patient.

Pharmacologic treatment of insulin resistance 

Insulin resistance seems to be the common denominator in many cases of NASH. NASH is associated with decreased insulin-mediated suppression of lipolysis.⁷⁸ Consequently, subjects with NASH have high serum-free fatty acid concentrations, allowing greater hepatic fatty acid uptake and oxidation. Increased fatty acid delivery to the liver also may have complex effects within the hepatocytes, including interference with insulin function,²⁶³, ²⁶⁴, ²⁶⁵, ²⁶⁶ preferential utilization of fatty acids for mitochondrial oxidation,⁷⁸, ²⁶⁷ and the proapoptotic mitochondrial uncoupling protein 2 expression.²⁶⁸, ²⁶⁹ These, along with other potential intrahepatic abnormalities, culminate in the development of steatohepatitis. These considerations, along with the well-known association of NASH with obesity and diabetes, have led to attempts to treat NASH by treating insulin resistance.

There are no controlled data on the use of pharmacologic agents for the management of NASH by improving insulin resistance (Table 7).

Table 7. Treatment trials in NAFLD

There are 2 classes of drugs that have been shown to correct insulin resistance: (1) biguanides (e.g., metformin) and (2) thiazolidinediones (e.g., rosiglitazone and pioglitazone). The former work by mechanisms that are undefined. In an animal model of steatohepatitis, treatment with metformin improved hepatic steatosis and inflammation.²⁷⁰ In a recent study, metformin was associated with an improvement in serum aminotransferase activities.²⁷¹ However, no histologic data were provided. The use of this drug remains experimental.

Thiazolidinediones are drugs that act via peroxisome proliferator activated receptor γ and improve insulin sensitivity. A small nonrandomized series of patients with NASH were treated with troglitazone for up to 6 months.²⁷² Of the 10 subjects studied, 1 had diabetes and 3 had cirrhosis. Following treatment, mean ALT values improved in 9 of 10 subjects and the inflammatory scores improved from moderate to mild in 5 subjects. The inflammatory score worsened in 1 patient but remained the same in another. Although these initial data are interesting, caution must be exercised in interpreting the data due to the possibility of error because of the low number of subjects studied. Moreover, the study was not long enough to study any effects on hepatic fibrosis, and troglitazone has now been withdrawn from the market due to its hepatotoxicity. In another study in which troglitazone was used in 13 patients with diabetes with lipodystrophy, there was a decrease in serum free fatty acid levels but no changes in visceral fat were noted.²⁷³ However, liver histology was not examined and 1 patient developed troglitazone hepatotoxicity, which required discontinuation of the drug. It is also worth noting that the effects of different drugs on the insulin sensitivity of various metabolic pathways are variable.²⁷⁴ Thus, data from one agent may not be applicable to another agent. Despite these limitations, these studies set the stage for future trials using other thiazolidinediones.

Lipid-lowering agents 

Hypertriglyceridemia is often associated with NASH. In one controlled trial,¹⁴⁸ clofibrate had no beneficial effects on liver functions or hepatic histology; in another small controlled trial, gemfibrozil improved liver chemistry.²⁷⁵ However, no histologic data are available from the latter study. Thus, in general, such agents are not used for the treatment of patients with NASH. Based on the current understanding of the pathogenesis of NAFLD, there is no rationale for the use of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors for the treatment of patients with NAFLD. There also are no data on the use of such drugs for NAFLD.

Drugs that protect hepatocytes 

Several drugs believed to be hepatoprotective have been used in patients with NASH. These include UDCA, betaine, vitamin E, lecithin, β-carotene, and selenium. Of these, peer-reviewed published data are available on betaine, UDCA, and vitamin E.

To date, there is only one published series of 11 pediatric patients with NASH who received vitamin E (DL-α-tocopherol) 400 IU/day orally.²⁷⁶ The baseline ALT levels were elevated in all subjects. The dosage was increased if the ALT level remained elevated, and ultimately a dosage varying from 400 to 1200 IU/day was used. During a mean follow-up of 5.2 months, the ALT level either improved markedly or normalized in all cases. Although these data are encouraging, the potential weakness of this study is the lack of histologic confirmation of NASH before therapy or of improvement after therapy.

The value of UDCA, a hydrophilic bile acid with hepatoprotective properties, on NASH was examined in a controlled trial.¹⁴⁸ Use of UDCA was associated with improved liver enzyme levels and a decrease in hepatic steatosis. However, the long-term effects and optimal dose of UDCA have not been established. The usual dose of UDCA is 10–15 mg · kg⁻¹ · day⁻¹ orally. In another single uncontrolled series, 10 children treated with taurine supplements orally had radiologic resolution of their fatty liver.²⁷⁷ Radiologic improvement was accompanied by a decrease in glycine/taurine-conjugated bile acids.

In 2 recent studies,²⁷⁸, ²⁷⁹ betaine supplements were given for the treatment of patients with NASH. Betaine is a precursor of S-adenosyl methionine, a hepatoprotective factor. In one study,²⁷⁸ 10 subjects received betaine anhydrous for 12 months in 2 daily divided doses. Seven of 10 subjects completed 1 year of treatment. In this group, an improvement in aminotransferase activity as well as liver histology was noted. Similarly, a 25% improvement in hepatic steatosis was reported in a randomized controlled study in which betaine was administered along with diethanolamine glucuronate and nicotinamide ascorbate for 8 weeks.²⁷⁹ These findings now require confirmation in large, long-term prospective trials.

There are no data to support or refute the use of phlebotomy for those with NASH. If used at all, it should be restricted to those with documented evidence of iron overload.

Back to Article Outline

Summary 

NAFLD is a major cause of liver-related morbidity in North America. It is frequently associated with the presence of insulin resistance. There is increasing evidence that NAFLD can progress to cirrhosis and liver failure. Physicians should actively check for the presence of NAFLD in those who are overweight and/or diabetic. There is no established treatment for NAFLD. Treatment usually is directed toward optimizing body weight. The role of pharmacologic agents remains to be established, and much more work is necessary to define the pathogenesis of this condition and to develop effective treatment.

Back to Article Outline

Acknowledgements 

The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the author: Alfred Baker, M.D., Helen Te, M.D., Karen Eun-Young Kim, M.D., and J. Sumner Bell, M.D. The members of the American Association for the Study of Liver Diseases Practice Guidelines Committee who contributed to the development of these papers include Henry Bodenheimer, M.D., David E. Bernstein, M.D., Gary L. Davis, M.D., James Everhart, M.D., Thomas Faust, M.D., Stuart Gordon, M.D., Donald Jensen, M.D., Maureen Jonas, M.D., Jacob Korula, M.D., Michael Lucey, M.D., Timothy McCashland, M.D., Jan Novak, M.D., Melissa Palmer, M.D., Rajender Reddy, M.D., Margaret Shuhart, M.D., Thomas Shaw-Stiffel, M.D., and Brent Tetri, M.D.

Back to Article Outline

References 

1. American Gastroenterological Association . Position and policy statement: policy statement on the use of medical practice guidelines by managed care organizations and insurance carriers. Gastroenterology. 1995;108:925–926
   • View In Article
   • Full-Text PDF (162 KB)
   • CrossRef
2. Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE, et al. Purpose of quality standards for infectious diseases. Infectious Diseases Society of America. Clin Infect Dis. 1994;18:421
   • View In Article
   • MEDLINE
   • CrossRef
3. NHS center for reviews and dissemination . undertaking systematic reviews of research on effectiveness: CRD guidelines for those carrying out or commissioning reviews. CRD report #4. York: University of York; 1996;
   • View In Article
4. Zelman S. The liver in obesity. Arch Intern Med. 1958;90:141–156
   • View In Article
5. Payne JH, Dewind LT, Commons RR. Metabolic observations in patients with jejunocolic shunts. Am J Surg. 1963;106:273–289
   • View In Article
   • MEDLINE
   • CrossRef
6. Catlin R. Liver dysfunction after intestinal bypass. JAMA. 1963;185:1693–1694
   • View In Article
7. McGill DB, Humpherys SR, Baggenstoss AH, Dickson ER. Cirrhosis and death after jejunoileal shunt. Gastroenterology. 1972;63:872–877
   • View In Article
8. Peters RL, Gay T, Reynolds TB. Post-jejuno-ileal bypass hepatic disease. Its similarity to alcoholic liver disease. Am J Clin Pathol. 1975;63:318–331
   • View In Article
   • MEDLINE
9. Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med. 1979;67:811–816
   • View In Article
   • Abstract
   • Full-Text PDF (2709 KB)
   • CrossRef
10. Thaler H. Relation of steatosis to cirrhosis. Clin Gastroenterol. 1975;4:273–280
    • View In Article
    • MEDLINE
11. Nasrallah SM, Wills CE, Galambos JT. Hepatic morphology in obesity. Dig Dis Sci. 1981;26:325–327
    • View In Article
    • MEDLINE
    • CrossRef
12. Itoh S, Tsukada Y, Motomura Y, Ichinoe A. Five patients with nonalcoholic diabetic cirrhosis. Acta Hepatogastroenterol Stuttg. 1979;26:90–97
    • View In Article
    • MEDLINE
13. Falchuk KR, Fiske SC, Haggitt RC, Federman M, Trey C. Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology. 1980;78:535–541
    • View In Article
    • Abstract
    • Full-Text PDF (1501 KB)
14. Hornboll P, Olsen TS. Fatty changes in the liver: the relation to age, overweight and diabetes mellitus. Acta Pathol Microbiol Immunol Scand A. 1982;90:199–205
    • View In Article
    • MEDLINE
15. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438
    • View In Article
    • MEDLINE
16. Baker AL. Nonalcoholic steatonecrosis: a unique histopathologic lesion of the liver with multiple causes. Surv Dig Dis. 1985;3:154–164
    • View In Article
17. French SW, Eidus LB, Freeman J. Nonalcoholic fatty hepatitis: an important clinical condition. Can J Gastroenterol. 1989;3:189–197
    • View In Article
18. Lee RG. Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler. Hepatology. 1995;21:1742–1743
    • View In Article
    • MEDLINE
    • CrossRef
19. Galambos JT, Wills CE. Relationship between 505 paired liver tests and biopsies in 242 obese patients. Gastroenterology. 1978;74:1191–1195
    • View In Article
    • Abstract
    • Full-Text PDF (760 KB)
20. Nagore N, Scheur PJ. The pathology of diabetic hepatitis. J Pathol. 1988;156:155–160
    • View In Article
    • MEDLINE
    • CrossRef
21. Hall PD. Pathological spectrum of alcoholic liver disease. Alcohol Alcohol Suppl. 1994;2:303–313
    • View In Article
    • MEDLINE
22. Bacon BR, Farahvash MJ, Janney CG, Neuschwander Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994;107:1103–1109
    • View In Article
    • Abstract
    • Full-Text PDF (1691 KB)
23. Christoffersen P, Petersen P. Morphological features in non-cirrhotic livers from patients with chronic alcoholism, diabetes mellitus or adipositas. A comparative study. Acta Pathol Microbiol Scand A. 1978;86A:495–498
    • View In Article
    • MEDLINE
    • CrossRef
24. Gluud C, Christoffersen P, Andersen T, Morton JA, McGee JO. Occurrence and significance of Mallory bodies in morbidly obese patients. An immunohistochemical study. Acta Pathol Microbiol Immunol Scand A. 1984;92:39–43
    • View In Article
    • MEDLINE
25. Younossi ZM, Boparai N. Agreement in pathologic interpretation of liver biopsy specimens in posttransplant hepatitis C infection. Arch Pathol Lab Med. 1999;123:143–145
    • View In Article
    • MEDLINE
26. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (90 KB)
    • CrossRef
27. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474
    • View In Article
    • MEDLINE
    • CrossRef
28. Anderson T, Christoffersen P, Gluud C. The liver in consecutive patients with morbid obesity: a clinical morphological and biochemical study. Int J Obes. 1984;8:107–115
    • View In Article
    • MEDLINE
29. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719
    • View In Article
    • MEDLINE
    • CrossRef
30. Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP, Saviano MC, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997;42:1428–1432
    • View In Article
    • MEDLINE
    • CrossRef
31. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med. 1988;27:142–149
    • View In Article
    • MEDLINE
    • CrossRef
32. Kawasaki T, Hashimoto N, Kikuchi T, Takahashi H, Uchiyama M. The relationship between fatty liver and hyperinsulinemia in obese Japanese children. J Pediatr Gastroenterol Nutr. 1997;24:317–321
    • View In Article
    • MEDLINE
    • CrossRef
33. Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine aminotransferase activity in obese children. Acta Paediatr. 1997;86:238–241
    • View In Article
    • MEDLINE
    • CrossRef
34. Ikai E, Ishizaki M, Suzuki Y, Ishida M, Noborizaka Y, Yamada Y. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens. 1995;9:101–105
    • View In Article
    • MEDLINE
35. Marcos A, Fisher RA, Ham JM, Olzinski AT, Shiffman ML, Sanyal AJ, et al. Selection and outcome of living donors for adult to adult right lobe transplantation. Transplantation. 2000;69:2410–2415
    • View In Article
    • MEDLINE
    • CrossRef
36. Ground KEV. Prevalence of fatty liver in healthy adults accidentally killed. Aviat Space Environ Med. 1984;55:59–61
    • View In Article
    • MEDLINE
37. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;11:74–80
    • View In Article
    • MEDLINE
    • CrossRef
38. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci. 1995;40:2002–2009
    • View In Article
    • MEDLINE
    • CrossRef
39. Noguchi H, Tazawa Y, Nishinomiya F, Takada G. The relationship between serum transaminase activities and fatty liver in children with simple obesity. Acta Paediatr Jpn. 1995;37:621–625
    • View In Article
    • MEDLINE
40. Nomura F, Ohnishi K, Satomura Y. Liver function in moderate obesity: study in 535 moderately obese subjects among 4613 male company employees. Int J Obes. 1986;10:349–354
    • View In Article
    • MEDLINE
41. Anderson T, Gluud C. Liver morphology in morbid obesity: a literature study. Int J Obes. 1984;8:97–106
    • View In Article
    • MEDLINE
42. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–117
    • View In Article
    • MEDLINE
43. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T, Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr. 1984;3:408–414
    • View In Article
    • MEDLINE
    • CrossRef
44. Popkin BM, Udry JR. Adolescent obesity increases significantly in second and third generation U.S. immigrants: the National Longitudinal Study of Adolescent Health. J Nutr. 1998;128:701–706
    • View In Article
    • MEDLINE
45. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord. 1998;22:39–47
    • View In Article
    • MEDLINE
46. Johnson-Down L, O'Loughlin J, Koski KG, Gray-Donald K. High prevalence of obesity in low income and multiethnic schoolchildren: a diet and physical activity assessment. J Nutr. 1997;127:2310–2315
    • View In Article
    • MEDLINE
47. Baldridge AD, Perez-Atayde AR, Graeme-Cook F, Higgins L, Lavine JE. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr. 1995;127:700–704
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1545 KB)
    • CrossRef
48. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80
    • View In Article
    • MEDLINE
    • CrossRef
49. Diehl AM, Goodman Z, Ishak KG. Alcoholic liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology. 1988;95:1056–1062
    • View In Article
    • Abstract
    • Full-Text PDF (1274 KB)
50. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol. 1989;20:594–598
    • View In Article
    • MEDLINE
    • CrossRef
51. Nonomura A, Mizukami Y, Unoura M, Kobayashi K, Takeda Y, Takeda R. Clinicopathologic study of alcohol-like liver disease in non-alcoholics; non-alcoholic steatohepatitis and fibrosis. Gastroenterol Jpn. 1992;27:521–528
    • View In Article
    • MEDLINE
52. Lee JH, Doe J. Familial risk ratios for extreme obesity: implications for mapping human obesity genes. Int J Obes Relat Metab Discord. 1997;21:935–940
    • View In Article
53. Trevisan R. The epidemiology of diabetes mellitus. Nephrol Dial Transplant. 1998;13(Suppl):2–5
    • View In Article
    • CrossRef
54. Chagnon YC. Familial aggregation of obesity, candidate genes and quantitative trait loci. Curr Opin Lipidol. 1997;8:205–211
    • View In Article
    • MEDLINE
    • CrossRef
55. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med. 2000;108:9–13
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (239 KB)
    • CrossRef
56. Altman AR, Gottfried EB, Paronetto F, Lieber CS. Idiopathic familial cirrhosis and steatosis in adults. Gastroenterology. 1979;77:1211–1216
    • View In Article
    • Abstract
    • Full-Text PDF (937 KB)
57. Castellano G, Garfia C, Gomez-Coronado D, Arenas J, Manzanares J, Colina F, et al. Diffuse fatty liver in familial heterozygous hypobetalipoproteinemia. J Clin Gastroenterol. 1997;25:379–382
    • View In Article
    • MEDLINE
    • CrossRef
58. Ogatta H, Akagi K, Nagamatsu A, Suzuki N, Nomiyama K, Fujishima M. Fatty liver in a case with heterozygous familial hypobetalipoproteinemia. Am J Gastroenterol. 1997;92:339–342
    • View In Article
    • MEDLINE
59. Kagimoto T, Higaki T, Nagata K, Morino Y, Takatsuki K. An interesting syndrome of hemolytic anemia, degeneration of the liver and diabetes associated with a high red cell Mg-ATPase, detected by 31P spectroscopy. NMR Biomed. 1989;2:93–97
    • View In Article
    • MEDLINE
    • CrossRef
60. Hsieh SD, Yoshinaga H, Muto T, Sakurai Y. Regular physical activity and coronary risk factors in Japanese men. Circulation. 1998;97:661–665
    • View In Article
    • MEDLINE
61. Ikai E, Honda R, Yamada Y. Serum gamma-glutamyl transpeptidase level and blood pressure in nondrinkers: a possible pathogenetic role of fatty liver in obesity-related hypertension. J Hum Hypertens. 1994;8:95–100
    • View In Article
    • MEDLINE
62. Maruhama Y, Abe R, Okuguchi F, Oikawa S, Ohneda A, Goto Y. Interactions of obesity and glucose-stimulated insulin secretion in familial hypertriglyceridemia. Diabetes. 1978;27:682–693
    • View In Article
    • MEDLINE
63. Lonardo A. Fatty liver and nonalcoholic steatohepatitis. Where do we stand and where are we going?. Dig Dis. 1999;17:80–89
    • View In Article
    • MEDLINE
    • CrossRef
64. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107:450–455
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (168 KB)
    • CrossRef
65. Lyznicki JM, Young DC, Riggs JA, Davis RM, Council on Scientific Affairs, American Medical Association . Obesity: assessment and management in primary care. Am Fam Physician. 2001;63:2185–2196
    • View In Article
    • MEDLINE
66. Ludwig J, McGill DB, Lindor KD. Nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 1997;12:398–403
    • View In Article
    • MEDLINE
    • CrossRef
67. Luyckx FH, Desaive C, Thiry A, Dewe W, Scheen AJ, Gielen JE, et al. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord. 1998;22:222–226
    • View In Article
    • MEDLINE
68. Ranlov I, Hardt F. Regression of liver steatosis following gastroplasty or gastric bypass for morbid obesity. Digestion. 1990;47:208–214
    • View In Article
    • MEDLINE
69. Park HS, Kim MW, Shin ES. Effect of weight control on hepatic abnormalities in obese patients with fatty liver. J Korean Med Sci. 1995;10:414–421
    • View In Article
    • MEDLINE
70. Eriksson S, Eriksson KF, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand. 1986;220:83–88
    • View In Article
    • MEDLINE
    • CrossRef
71. Kral JG, Schaffner F, Pierson RN, Wang J. Body fat topography as an independent predictor of fatty liver. Metabolism. 1993;42:548–551
    • View In Article
    • MEDLINE
    • CrossRef
72. Gillum RF, Mussolino ME, Madans JH. Body fat distribution and hypertension incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Int J Obes Relat Metab Disord. 1998;22:127–134
    • View In Article
    • MEDLINE
73. Van Steenbergen W, Lanckmans S. Liver disturbances in obesity and diabetes mellitus. Int J Obes Relat Metab Disord. 1995;19(Suppl 3):S27–S36
    • View In Article
74. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerothic cardiovascular disease. Diabetes Care. 1991;14:173–194
    • View In Article
    • MEDLINE
75. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–1362
    • View In Article
    • MEDLINE
    • CrossRef
76. Goto T, Onuma T, Takebe K, Kral JG. The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord. 1995;19:841–845
    • View In Article
    • MEDLINE
77. Inokuchi T, Watanabe K, Kameyama H, Orita M. Altered basal C-peptide/insulin molar ratios in obese patients with fatty liver. Jpn J Med. 1988;27:272–276
    • View In Article
    • MEDLINE
    • CrossRef
78. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1248 KB)
    • CrossRef
79. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31:430–434
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (764 KB)
    • CrossRef
80. Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. 1996;111:1645–1653
    • View In Article
    • Abstract
    • Full-Text PDF (623 KB)
    • CrossRef
81. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A. 1997;94:2557–2562
    • View In Article
    • MEDLINE
    • CrossRef
82. Partin JS, Partin JC, Schubert WK, McAdams AJ. Liver ultrastructure in abetalipoproteinemia: evolution of micronodular cirrhosis. Gastroenterology. 1974;67:107–118
    • View In Article
83. Powell EE, Searle J, Mortimer R. Steatohepatitis associated with limb lipodystrophy. Gastroenterology. 1989;97:1022–1024
    • View In Article
    • Abstract
    • Full-Text PDF (475 KB)
84. Shah SS, Desai HG. Apolipoprotein deficiency and chronic liver disease. J Assoc Phys India. 2001;49:274–278
    • View In Article
85. Robertson DA, Wright R. Cirrhosis in partial lipodystrophy. Postgrad Med J. 1989;65:318–320
    • View In Article
    • MEDLINE
    • CrossRef
86. Cauble MS, Gilroy R, Sorrell MF, Mailliard ME, Sudan DL, Anderson JC, et al. Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation. Transplantation. 2001;71:892–895
    • View In Article
    • MEDLINE
    • CrossRef
87. Wasserman JM, Thung SN, Berman R, Bodenheimer HC, Sigal SH. Hepatic Weber-Christian disease. Semin Liv Dis. 2001;21:115–118
    • View In Article
88. Poucell S, Ireton J, Valencia-Mayoral P, Downar E, Larratt L, Patterson J. Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical and electron microscopic studies. Gastroenterology. 1984;86:926–936
    • View In Article
    • Abstract
89. Pessayre D, Bichara M, Degott C, Potet F, Benhamou JP, Feldman G. Perhexiline maleate induced cirrhosis. Gastroenterology. 1979;76:170–177
    • View In Article
    • Abstract
90. Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med. 1995;123:236
    • View In Article
    • MEDLINE
91. Martinez E, Mocroft A, Garcia-Viejo MA, Perez-Cuevas JB, Blanco JL. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet. 2001;357:592–598
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1168 KB)
    • CrossRef
92. Kotler DP, Engleson ES. The lowdown on lipodystrophy. Special report from the 2nd international workshop on adverse drug reactions and lipodystrophy. Posit Living. 2001;10:5–6
    • View In Article
93. Rakotoambinina B, Medioni J, Rabian C, Jubault V, Jais JP, Viard JP. Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1 infected patients receiving triple combination antiretroviral therapy with a protease inhibitor. J Acquir Immune Defic Syndr. 2001;27:443–449
    • View In Article
    • MEDLINE
    • CrossRef
94. Herman JS, Easterbrook PJ. The metabolic toxicities of antiretroviral therapies. Int J STD AIDS. 2001;12:555–562
    • View In Article
    • MEDLINE
    • CrossRef
95. Van der valk M, Bisschop PH, Romjin JA, Ackermans MT, Lange JM. Lipodystrophy in HIV-1 positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS. 2001;15:2093–2100
    • View In Article
    • MEDLINE
    • CrossRef
96. Cotrim HP, Andrade ZA, Parana R, Portugal M, Lyra LG, Freitas LA. Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers [see comments]. Liver. 1999;19:299–304
    • View In Article
    • MEDLINE
    • CrossRef
97. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114:311–318
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (137 KB)
    • CrossRef
98. Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol. 1999;31:421–429
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1100 KB)
    • CrossRef
99. Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O'Neill R, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology. 1999;30:847–850
    • View In Article
    • MEDLINE
    • CrossRef
100. Sonsuz A, Basaranoglu M, Ozbay G. Relationship between aminotransferase levels and histopathological findings in patients with nonalcoholic steatohepatitis (letter). Am J Gastroenterol. 2000;95:1370–1371
     • View In Article
     • MEDLINE
     • CrossRef
101. Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol. 1987;82:650–654
     • View In Article
     • MEDLINE
102. Tajiri K, Takenawa H, Yamaoka K, Yamane M, Marumo F, Sato C. Nonalcoholic steatohepatitis masquerading as autoimmune hepatitis. J Clin Gastroenterol. 1997;25:538–540
     • View In Article
     • MEDLINE
     • CrossRef
103. da Silva PM, Eliseu T, Costa MM, Bastos H, Nobre FL. Nonalcoholic steatohepatitis. Acta Med Port. 1995;8:323–327
     • View In Article
     • MEDLINE
104. Sanson-Fisher R. The measurement of alcohol consumption and alcohol-related problems. Aust Drug Alcohol Rev. 1986;5:309–310
     • View In Article
105. Lewis KO, Paton A. Tools of alcohol detection. Br Med J. 1981;283:1531–1532
     • View In Article
106. Salaspuro M. Use of enzymes for the diagnosis of alcohol-related organ damage. Enzyme. 1987;37:87–107
     • View In Article
     • MEDLINE
107. Nalpas B, Vassault A, Charpin S, Lacour B, Berthelot P. Serum mitochondrial aspartate aminotransferase: a sensitive marker of alcoholism with or without alcoholic hepatitis. Hepatology. 1984;4:893–896
     • View In Article
     • MEDLINE
     • CrossRef
108. Nalpas B, Vassault A, Charpin S, Lacour B, Berthelot P. Serum mitochondrial aspartate aminotransferase as a marker of chronic alcoholism: diagnostic value and interpretation in a liver unit. Hepatology. 1986;6:608–614
     • View In Article
     • MEDLINE
     • CrossRef
109. Storey E, Anderson GJ, Mack U, Powell LJ, Halliday JW. Desialylated transferrin as a serologic marker of chronic excessive alcohol ingestion. Lancet. 1987;1:1292–1294
     • View In Article
     • MEDLINE
110. Fletcher LM, Kwoh Gain I, Powell EE, Powell LW, Halliday JW. Markers of chronic alcohol ingestion in patients with nonalcoholic steatohepatitis: an aid to diagnosis. Hepatology. 1991;13:455–459
     • View In Article
     • MEDLINE
     • CrossRef
111. Nomura F, Ohnishi K, Koen H, Hiyama Y, Nakayama T, Itoh Y, et al. Serum cholinesterase in patients with fatty liver. J Clin Gastroenterol. 1986;8:599–602
     • View In Article
     • MEDLINE
     • CrossRef
112. Ong JP, Younossi ZM, Speer C, Olano A, Gramlich T, Boparai N. Chronic hepatitis C and superimposed nonalcoholic fatty liver disease. Liver. 2001;21:266–271
     • View In Article
     • MEDLINE
     • CrossRef
113. Gore RM. Diffuse liver disease. In:  Gore RM,  Levine MS,  Laufer I editor. Textbook of gastrointestinal radiology. Philadelphia: Saunders; 1994;p. 1968–2017
     • View In Article
114. Yajima Y, Ohta K, Narui T, Abe R, Suzuki H, Ohtsuki M. Ultrasonographical diagnosis of fatty liver: significance of the liver-kidney contrast. Tohoku J Exp Med. 1983;139:43–50
     • View In Article
     • MEDLINE
     • CrossRef
115. Fusamoto H, Suzuki K, Hayashi N, et al.  Obesity and liver disease: evaluation of fatty infiltration of the liver using ultrasonic attenuation. J Nutr Sci Vitaminol Tokyo. 1991;37(suppl):S71–S77
     • View In Article
     • CrossRef
116. Kreft B, Tanimoto A, Baba Y, Zhao L, Chen J, Middleton MA, et al. Diagnosis of fatty liver with MR imaging. J Magn Reson Imaging. 1992;2:463–471
     • View In Article
     • MEDLINE
     • CrossRef
117. Yousefzadeh D, Lupetin AR, Jackson JH. The radiographic signs of fatty liver. Radiology. 1979;131:351–355
     • View In Article
     • MEDLINE
118. Bydder GM, Chapman RWG, Harry D. Computed tomography attenuation values in fatty liver. Comput Tomograph. 1981;5:33–38
     • View In Article
119. Piekarski J, Goldberg HI, Royal SA, Axel L, Moss AA. Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980;137:727–729
     • View In Article
     • MEDLINE
120. Ducommun JC, Goldberg HI, Korobkin M, Moss AA, Kressel HY. The relation of liver fat to computed tomography numbers: a preliminary experimental study in rabbits. Radiology. 1979;130:511–513
     • View In Article
     • MEDLINE
121. Galambos JT. Natural history of alcoholic hepatitis. 3. Histologic changes. Gastroenterology. 1972;63:1026–1035
     • View In Article
122. Jacobs JE, Birnbaum BA, Shapiro MA, Langlotz CP, Slosman F, Rubesin SE, et al. Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. AJR. 1998;171:659–664
     • View In Article
123. Johnston RJ, Stamm ER, Lewin JM, Hendrick RE, Archer PG. Diagnosis of fatty infiltration of the liver on contrast enhanced CT: limitations of liver-minus-spleen attenuation difference measurements. Abdom Imaging. 1998;23:409–415
     • View In Article
     • MEDLINE
     • CrossRef
124. Mendler MH, Bouillet P, Le Sidaner A, Lavoine E, Labrousse F, Sautereau D, et al. Dual-energy CT in the diagnosis and quantification of fatty liver: limited clinical value in comparison to ultrasound scan and single-energy CT, with special reference to iron overload. J Hepatol. 1998;28:785–794
     • View In Article
     • Abstract
     • Full-Text PDF (148 KB)
     • CrossRef
125. Nomura F, Ohnishi K, Ochiai T, Okuda K. Obesity-related nonalcoholic fatty liver: CT features and follow-up studies after low-calorie diet. Radiology. 1987;162:845–847
     • View In Article
     • MEDLINE
126. Outwater EK, Blasbalg R, Siegelman ES, Vala M. Detection of lipid in abdominal tissues with opposed-phase gradient echo images at 1.5 T: techniques and diagnostic importance. Radiographics. 1998;18:1465–1480
     • View In Article
     • MEDLINE
127. Longo R, Pollesello P, Ricci C, Masutti F, Kvam BJ, Bercich L, et al  Proton MR spectroscopy in quantitative in vivo determination of fat content in human steatosis. J Magn Reson Imaging. 1995;5:281–285
     • View In Article
     • MEDLINE
     • CrossRef
128. Fishbein MH, Gardner KG, Potter CJ, Schmalbrock P, Smith MA. Introduction of fast MR imaging in the assessment of hepatic steatosis. Magn Reson Imaging. 1997;15:287–293
     • View In Article
     • Abstract
     • Full-Text PDF (2247 KB)
     • CrossRef
129. Marks DB, Marks AD, Smith CM. Generation of ATP from fatty acids and ketone bodies. In:  Marks DB,  Marks AD,  Smith CM editor. Basic medical biochemistry. Baltimore: Williams and Wilkins; 1996;p. 357–372
     • View In Article
130. Fishbein M, Smith M, Li BU. A rapid MRI technique for the assessment of hepatic steatosis in a subject with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. J Pediatr Gastroenterol Nutr. 1998;27:224–227
     • View In Article
     • MEDLINE
     • CrossRef
131. Chevallier P, Bahadoran P, Buckley MJ, Hebuterne X, Diaine B, Chevallier A, et al. Hepatic multi-nodular focal fatty metamorphosis in acquired porphyria cutanea tarda. Sonographic, CT, and MRI features. Clin Imaging. 1998;22:418–421
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (322 KB)
     • CrossRef
132. Marks SJ, Moore NR, Ryley NG, Clark ML, Pointon JJ, Strauss BJ, et al. Measurement of liver fat by MRI and its reduction by dexfenfluramine in NIDDM. Int J Obes Relat Metab Disord. 1997;21:274–279
     • View In Article
     • MEDLINE
133. Fishbein MH, Stevens WR. Rapid MRI using a modified Dixon technique: a noninvasive and effective method for detection and monitoring of fatty metamorphosis of the liver. Pediatr Radiol. 2001;31:806–809
     • View In Article
     • MEDLINE
     • CrossRef
134. Van Ness MM, Diehl AM. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes?. Ann Intern Med. 1989;111:473–478
     • View In Article
     • MEDLINE
135. Sorbi D, McGill DB, Thistle JL, Therneau TM, Henry J, Lindor KD. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Am J Gastroenterol. 2000;95:3206–3210
     • View In Article
     • MEDLINE
     • CrossRef
136. Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol. 1987;82:650–654
     • View In Article
     • MEDLINE
137. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999;94:1018–1022
     • View In Article
     • MEDLINE
     • CrossRef
138. Pinto HC, Baptista A, Camilo ME, Valente A, Saragoca A, de Moura MC. Nonalcoholic steatohepatitis. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci. 1996;41:172–179
     • View In Article
     • MEDLINE
     • CrossRef
139. Braillon A, Capron JP, Herve MA, Degott C, Quenum C. Liver in obesity. Gut. 1985;26:133–139
     • View In Article
     • MEDLINE
     • CrossRef
140. Iturriaga H, Bunout D, Hirsch S, Ugarte G. Overweight as a risk factor or a predictive sign of histological liver damage in alcoholics. Am J Clin Nutr. 1988;47:235–238
     • View In Article
     • MEDLINE
141. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–669
     • View In Article
     • MEDLINE
     • CrossRef
142. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology. 2000;32:689–692
     • View In Article
     • MEDLINE
     • CrossRef
143. Contos MJ, Cales W, Sterling RK, Luketic VA, Shiffman ML, Mills AS, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2001;7:363–373
     • View In Article
     • MEDLINE
     • CrossRef
144. Drenick EJ, Fisler J, Johnson D. Hepatic steatosis after intestinal bypass—prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology. 1982;82:535–548
     • View In Article
     • MEDLINE
145. Drenick EJ, Simmons F, Murphy J. Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small bowel bypass. N Engl J Med. 1970;282:829–834
     • View In Article
     • MEDLINE
     • CrossRef
146. Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100
     • View In Article
     • Abstract
     • Full-Text PDF (268 KB)
     • CrossRef
147. Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med. 1979;67:811–816
     • View In Article
     • Abstract
     • Full-Text PDF (2709 KB)
     • CrossRef
148. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–1467
     • View In Article
     • MEDLINE
     • CrossRef
149. Hilden M, Juhl E, Thomen AC, Christoffersen P. Fatty liver persisting for up to 33 years. Acta Med Scand. 1973;194:485–489
     • View In Article
     • MEDLINE
     • CrossRef
150. Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis (letter). Gastroenterology. 1995;108:1607
     • View In Article
     • Full-Text PDF (125 KB)
     • CrossRef
151. Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–107
     • View In Article
     • Abstract
     • Full-Text PDF (634 KB)
     • CrossRef
152. Vajro P, Fontanella A, Perna C, Orso G, Tedesco M, De Vincenzo A. Persistent hyperaminotransferasemia resolving after weight reduction in obese children [see comments]. J Pediatr. 1994;125:239–241
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (282 KB)
     • CrossRef
153. Dean RH, Scott HW, Shull HJ, Gluck FW. Morbid obesity: problems associated with operative management. Am J Clin Nutr. 1977;30:90–97
     • View In Article
     • MEDLINE
154. Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12:224–229
     • View In Article
     • MEDLINE
     • CrossRef
155. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48–53
     • View In Article
     • MEDLINE
     • CrossRef
156. Ogden CL, Troiano RP, Briefel RR, Kuczmarski RJ, Flegal KM, Johnson CL. Prevalence of overweight among preschool children in the United States, 1971 through 1994. Pediatrics. 1997;99:E1
     • View In Article
     • CrossRef
157. Rosner B, Prineas R, Loggie J, Daniels SR. Percentiles for body mass index in U.S. children 5 to 17 years of age [see comments]. J Pediatr. 1998;132:211–222
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (196 KB)
     • CrossRef
158. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol. 1983;78:374–377
     • View In Article
     • MEDLINE
159. Snodgrass PJ. Obesity, small-bowel bypass and liver disease. N Engl J Med. 1970;282:870–871
     • View In Article
     • MEDLINE
     • CrossRef
160. Kern WH, Heger AH, Payne JH, Dewind LT. Fatty metamorphosis of the liver in morbid obesity. Arch Pathol. 1973;96:342–346
     • View In Article
     • MEDLINE
161. Kern WH, Payne JH, Dewind LT. Hepatic changes after small-intestinal bypass for morbid obesity. Am J Clin Pathol. 1974;61:763–768
     • View In Article
     • MEDLINE
162. Salmon PA, Reedyk L. Fatty metamorphosis in patients with jejunoileal bypass. Surg Gynecol Obstet. 1975;141:75–84
     • View In Article
     • MEDLINE
163. Petersen P. Fatty liver in patients with moderate alcohol consumption, diabetes mellitus and overweight. Scand J Gastroenterol. 1977;12:781–784
     • View In Article
     • MEDLINE
     • CrossRef
164. Manes JL, Taylor HB, Starkloff GB. Relationship between hepatic morphology and clinical and biochemical findings in morbidly obese patients. J Clin Pathol. 1973;26:776–783
     • View In Article
     • MEDLINE
     • CrossRef
165. White JJ, Moxley RT, Pozefsky T, Lockwood DH. Transient kwaskiorkor: a cause of fatty liver following small bowel bypass. Surgery. 1974;75:829–840
     • View In Article
     • MEDLINE
166. Halloran LG, Hutcher NE, Levinson SA, Schatzki PF, Hume DM. Morphology of the liver before and after intestinal bypass for morbid obesity. Surg Forum. 1974;25:359–361
     • View In Article
     • MEDLINE
167. Marubbio AT. Buchwald H, Schwartz MZ, Varco R. Hepatic lesions of central pericellular fibrosis in morbid obesity, and after jejunoileal bypass. Am J Clin Pathol. 1976;66:684–691
     • View In Article
     • MEDLINE
168. Baddeley RM. Results of jejuno-ileostomy for gross refractory obesity. Br J Surg. 1976;63:801–806
     • View In Article
     • MEDLINE
     • CrossRef
169. Nasrallah SM, Wills CE, Galambos JT. Liver injury following jejunoileal bypass. Are there markers?. Ann Surg. 1980;192:726–729
     • View In Article
     • MEDLINE
     • CrossRef
170. Heimburger SL, Steiger E, Lo Gerfo P, Biehl AG, Williams MJ. Reversal of severe fatty hepatic infiltration after intestinal bypass for morbid obesity by calorie-free amino acid infusion. Am J Surg. 1975;129:229–235
     • View In Article
     • MEDLINE
     • CrossRef
171. Griffen WO, Young VL, Stevenson CC. A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity. Ann Surg. 1977;186:500–509
     • View In Article
     • MEDLINE
     • CrossRef
172. Buckwalter JA. Clinical trial of jejunoileal and gastric bypass for the treatment of morbid obesity: four-year progress report. Am Surg. 1980;46:377–381
     • View In Article
     • MEDLINE
173. Luyckx FH, Scheen AJ, Desaive C, Thiry A, Lefebvre PJ. Parallel reversibility of biological markers of the metabolic syndrome and liver steatosis after gastroplasty-induced weight loss in severe obesity (letter). J Clin Endocrinol Metab. 1999;84:4293
     • View In Article
     • MEDLINE
     • CrossRef
174. Lieverse RJ, Jansen JB, Masclee AA, Lamers CB. Gastrointestinal disturbances with obesity. Scand J Gastroenterol Suppl. 1993;200:53–58
     • View In Article
     • MEDLINE
175. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Ikematsu H, Noguchi A, et al. Prevalence of gallstone disease in a general population of Okinawa, Japan [see comments]. Am J Epidemiol. 1988;128:598–605
     • View In Article
     • MEDLINE
176. Araujo LM, De Oliveira DA, Nunes DS. Liver and biliary ultrasonography in diabetic and non-diabetic obese women. Diabetes Metab. 1998;24:458–462
     • View In Article
     • MEDLINE
177. Moore SJ, Auchterlonie IA, Cole GF, Gray ES, Dean JC. Partial lipodystrophy presenting with myopathy. Dev Med Child Neurol. 1999;41:127–131
     • View In Article
     • MEDLINE
     • CrossRef
178. Hubler A, Abendroth K, Keiner T, Stocker W, Kauf E, Hein G, et al. Dysregulation of insulin-like growth factors in a case of generalized acquired lipoatrophic diabetes mellitus (Lawrence Syndrome) connected with autoantibodies against adipocyte membranes. Exp Clin Endocrinol Diabetes. 1998;106:79–84
     • View In Article
     • MEDLINE
     • CrossRef
179. Ursich MJ, Fukui RT, Galvao MS, Marcondes JA, Santomauro AT, Silva ME, et al. Insulin resistance in limb and trunk partial lipodystrophy (type 2 Kobberling-Dunnigan syndrome). Metabolism. 1997;46:159–163
     • View In Article
     • Abstract
     • Full-Text PDF (1310 KB)
     • CrossRef
180. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29:1215–1219
     • View In Article
     • MEDLINE
     • CrossRef
181. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364
     • View In Article
     • MEDLINE
     • CrossRef
182. Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33:106–115
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (1287 KB)
     • CrossRef
183. Rubbia-Brandt L, Leandro G, Spahr L, Giostra E, Quadri R, Male PJ, et al. Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology. 2001;39:119–124
     • View In Article
     • MEDLINE
     • CrossRef
184. Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol. 1997;78:1527–1531
     • View In Article
185. Fujie H, Yotsuyanagi H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, et al. Steatosis and intrahepatic hepatitis C virus in chronic hepatitis. J Med Virol. 1999;59:141–145
     • View In Article
     • MEDLINE
     • CrossRef
186. Fernandez-Miranda C, Castellano G, Guijarro C, Fernandez I, Schoebel N, Larumbe S, et al. Lipoprotein changes in patients with hepatitis C treated with interferon alpha. Am J Gastroenterol. 1998;93:1901–1904
     • View In Article
     • MEDLINE
     • CrossRef
187. Alexandropoulos EC, Kontochristopoulos GJ, Zakapoulou N. Hypertriglyceridemia during low-dose interferon alpha-2b treatment in a patient with Kaposi's sarcoma. Dermatology. 2001;202:344–345
     • View In Article
     • MEDLINE
     • CrossRef
188. Garcia Urena MA, Colina Ruiz-Delgado F, Moreno Gonzalez E, Jimenez Romero C, Garcia Garcia I, Loinzaz Segurola C, et al. Hepatic steatosis in liver transplant donors: common feature of donor population?. World J Surg. 1998;22:837–844
     • View In Article
     • MEDLINE
     • CrossRef
189. Broughan TA, Douzdjian V. Donor liver selection. The South Eastern Organ Procurement Foundation Liver Committee. Am Surg. 1998;64:785–790
     • View In Article
     • MEDLINE
190. Fukumori T, Ohkohchi N, Tsukamoto S, Satomi S. Why is fatty liver unsuitable for transplantation? Deterioration of mitochondrial ATP synthesis and sinusoidal structure during cold preservation of a liver with steatosis. Transplant Proc. 1997;29:412–415
     • View In Article
     • Full-Text PDF (485 KB)
     • CrossRef
191. Gao W, Connor HD, Lemasters JJ, Mason RP, Thurman RG. Primary nonfunction of fatty livers produced by alcohol is associated with a new antioxidant insensitive free radical species. Transplantation. 1995;59:674–679
     • View In Article
     • MEDLINE
     • CrossRef
192. Fishbein TM, Fiel MI, Emre S, Cubukcu O, Guy SR, Schwartz ME, et al. Use of livers with microvesicular fat safely expands the donor pool. Transplantation. 1997;64:248–251
     • View In Article
     • MEDLINE
     • CrossRef
193. McCaughan GW. Recurrence of nonalcoholic steatohepatitis (NASH) post-liver transplantation (letter). Liver Transpl Surg. 1997;3:683
     • View In Article
     • MEDLINE
     • CrossRef
194. Molloy RM, Komorowski R, Varma RR. Recurrent nonalcoholic steatohepatitis and cirrhosis after liver transplantation. Liver Transpl Surg. 1997;3:177–178
     • View In Article
     • MEDLINE
     • CrossRef
195. Carson K, Washington MK, Treem WR, Clavien PA, Hunt CM. Recurrence of nonalcoholic steatohepatitis in a liver transplant recipient. Liver Transpl Surg. 1997;3:174–176
     • View In Article
     • MEDLINE
     • CrossRef
196. Kim WR, Poterucha JJ, Porayko MK, Dickson ER, Steers JL, Wiesner RH. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation. 1996;62:1802–1805
     • View In Article
     • MEDLINE
     • CrossRef
197. D'Sauza-Gburek SM, Batts KP, Nikias GA, Weisner RH, Krom RAF. Liver transplantation for jejunoileal bypass-associated cirrhosis. Liver Transpl Surg. 1997;3:23–27
     • View In Article
     • MEDLINE
     • CrossRef
198. Palmer M, Schaffner F, Thung SN. Excessive weight gain after liver transplantation. Transplantation. 1991;51:797–800
     • View In Article
     • MEDLINE
     • CrossRef
199. Saadeh S, Younossi ZM. The spectrum of nonalcoholic fatty liver disease: from steatosis to nonalcoholic steatohepatitis. Cleve Clin J Med. 2000;67:96–97 101–104
     • View In Article
     • MEDLINE
200. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–1413
     • View In Article
     • Abstract
     • Full-Text PDF (767 KB)
201. Anonymous . Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med. 1998;158:1855–1867
     • View In Article
     • MEDLINE
     • CrossRef
202. Barlow SE, Dietz WH. Obesity evaluation and treatment: expert committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics. 1998;102:E29
     • View In Article
     • CrossRef
203. Hermansen K. Diet, blood pressure and hypertension. Br J Nutr. 2000;83(Suppl 1):S113–S119
     • View In Article
204. Sothern MS, Loftin JM, Udall JN, Suskind RM, Ewing TL, Tang SC, et al. Safety, feasibility, and efficacy of a resistance training program in preadolescent obese children. Am J Med Sci. 2000;319:370–375
     • View In Article
     • MEDLINE
     • CrossRef
205. Tremblay A, Doucet E, Imbeault P. Physical activity and weight maintenance. Int J Obes Relat Metab Disord. 1999;23(suppl 3):S50–S54
     • View In Article
206. Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Paljarvi L, Laakso M. The effects of weight loss on insulin sensitivity, skeletal muscle composition and capillary density in obese non-diabetic subjects. Int J Obes Relat Metab Disord. 1996;20:154–160
     • View In Article
     • MEDLINE
207. Lean ME. Is long-term weight loss possible?. Br J Nutr. 2000;83(Suppl 1):S103–S111
     • View In Article
208. Balkestein EJ, van Aggel-Leijssen DP, van Baak MA, Struijker-Boudier HA, Van Bortel LM. The effect of weight loss with or without exercise training on large artery compliance in healthy obese men. J Hypertens. 1999;17:1831–1835
     • View In Article
     • MEDLINE
     • CrossRef
209. Weinsier RL, Wilson LJ, Lee J. Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation. Am J Med. 1995;98:115–117
     • View In Article
     • Abstract
     • Full-Text PDF (366 KB)
     • CrossRef
210. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995;122:899–905
     • View In Article
     • MEDLINE
211. Sugerman HJ, Brewer WH, Shiffman ML, Brolin RE, Fobi MA, Linner JH, et al  A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg. 1995;169:91–96 discussion 96–97
     • View In Article
     • Abstract
     • Full-Text PDF (898 KB)
     • CrossRef
212. Worobetz LJ, Inglis FG, Shaffer EA. The effect of ursodeoxycholic acid therapy on gallstone formation in the morbidly obese during rapid weight loss. Am J Gastroenterol. 1993;88:1705–1710
     • View In Article
     • MEDLINE
213. Broomfield PH, Chopra R, Sheinbaum RC, Bonorris GG, Silverman A, Schoenfield LJ, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N Engl J Med. 1988;319:1567–1572
     • View In Article
     • MEDLINE
     • CrossRef
214. Shoheiber O, Biskupiak JE, Nash DB. Estimation of the cost savings resulting from the use of ursodiol for the prevention of gallstones in obese patients undergoing rapid weight reduction. Int J Obes Relat Metab Disord. 1997;21:1038–1045
     • View In Article
     • MEDLINE
215. Anonymous . Weight cycling. National Task Force on the Prevention and Treatment of Obesity. JAMA. 1994;272:1196–1202
     • View In Article
     • MEDLINE
216. Harris RB, Kor H. Insulin insensitivity is rapidly reversed in rats by reducing dietary fat from 40 to 30% of energy. J Nutr. 1992;122:1811–1822
     • View In Article
     • MEDLINE
217. Silberbauer CJ, Jacober B, Langhans W. Dietary fat level and short-term effects of a high-fat meal on food intake and metabolism. Ann Nutr Metab. 1998;42:75–89
     • View In Article
     • MEDLINE
     • CrossRef
218. Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes. 1997;46:1768–1774
     • View In Article
     • MEDLINE
219. Hallfrisch J, Facn , Behall KM. Mechanisms of the effects of grains on insulin and glucose responses. J Am Coll Nutr. 2000;19:320S–325S
     • View In Article
     • MEDLINE
220. Song YJ, Sawamura M, Ikeda K, Igawa S, Yamori Y. Soluble dietary fibre improves insulin sensitivity by increasing muscle GLUT-4 content in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 2000;27:41–45
     • View In Article
     • MEDLINE
     • CrossRef
221. Luo J, Rizkalla SW, Boillot J, Alamowitch C, Chaib H, Bruzzo F, et al. Dietary (n-3) polyunsaturated fatty acids improve adipocyte insulin action and glucose metabolism in insulin-resistant rats: relation to membrane fatty acids. J Nutr. 1996;126:1951–1958
     • View In Article
     • MEDLINE
222. Clarke SD, Baillie R, Jump DB, Nakamura MT. Fatty acid regulation of gene expression. Its role in fuel partitioning and insulin resistance. Ann N Y Acad Sci. 1997;827:178–187
     • View In Article
     • MEDLINE
     • CrossRef
223. Montagne O, Vedel I, Durand-Zaleski I. Assessment of the impact of fibrates and diet on survival and their cost-effectiveness: evidence from randomized, controlled trials in coronary heart disease and health economic evaluations. Clin Ther. 1999;21:2027–2035
     • View In Article
     • Abstract
     • Full-Text PDF (666 KB)
     • CrossRef
224. Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ, et al. AHA dietary guidelines: revision 2000. A statement for healthcare professionals from the nutrition committee of the American Heart Association. Stroke. 2000;31:2751–2766
     • View In Article
     • CrossRef
225. Clark MJ, Sterrett JJ, Carson DS. Diabetes guidelines: a summary and comparison of the recommendations of the American Diabetes Association, Veterans Health Administration, and American Association of Clinical Endocrinologists. Clin Ther. 2000;22:899–910 discussion 898
     • View In Article
     • Abstract
     • Full-Text PDF (772 KB)
     • CrossRef
226. Miller WC, Koceja DM, Hamilton EJ. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int J Obes Relat Metab Disord. 1997;21:941–947
     • View In Article
     • MEDLINE
227. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320–328
     • View In Article
     • MEDLINE
228. Stern JS, Hirsch J, Blair SN, Foreyt JP, Frank A, Kumanyika SK, et al. Weighing the options: criteria for evaluating weight-management programs. The Committee to Develop Criteria for Evaluating the Outcomes of Approaches to Prevent and Treat Obesity. Obes Res. 1995;3:591–604
     • View In Article
     • MEDLINE
229. Howell WH, McNamara DJ, Tosca MA, Smith BT, Gaines JA. Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis. Am J Clin Nutr. 1997;65:1747–1764
     • View In Article
     • MEDLINE
230. Brown SA, Upchurch S, Anding R, Winter M, Ramirez G. Promoting weight loss in type II diabetes. Diabetes Care. 1996;19:613–624
     • View In Article
     • MEDLINE
231. Tang JL, Armitage JM, Lancaster T, Silagy CA, Fowler GH, Neil HA. Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects. BMJ. 1998;316:1213–1220
     • View In Article
     • MEDLINE
     • CrossRef
232. Kirsch I. Hypnotic enhancement of cognitive-behavioral weight loss treatments—another meta-reanalysis. J Consult Clin Psychol. 1996;64:517–519
     • View In Article
     • MEDLINE
     • CrossRef
233. Allison DB, Faith MS. Hypnosis as an adjunct to cognitive-behavioral psychotherapy for obesity: a meta-analytic reappraisal. J Consult Clin Psychol. 1996;64:513–516
     • View In Article
     • MEDLINE
     • CrossRef
234. Petrides AS, Matthews DE, Esser U. Effect of moderate exercise on insulin sensitivity and substrate metabolism during post-exercise recovery in cirrhosis. Hepatology. 1997;26:972–979
     • View In Article
     • MEDLINE
     • CrossRef
235. Fogelholm M, Kukkonen-Harjula K, Nenonen A, Pasanen M. Effects of walking training on weight maintenance after a very-low-energy diet in premenopausal obese women: a randomized controlled trial. Arch Intern Med. 2000;160:2177–2184
     • View In Article
     • MEDLINE
     • CrossRef
236. Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000;133:92–103
     • View In Article
     • MEDLINE
237. Blumenthal JA, Sherwood A, Gullette EC, Babyak M, Waugh R, Georgiades A, et al. Exercise and weight loss reduce blood pressure in men and women with mild hypertension: effects on cardiovascular, metabolic, and hemodynamic functioning. Arch Intern Med. 2000;160:1947–1958
     • View In Article
     • MEDLINE
     • CrossRef
238. Donnelly JE, Jacobsen DJ, Heelan KS, Seip R, Smith S. The effects of 18 months of intermittent vs. continuous exercise on aerobic capacity, body weight and composition, and metabolic fitness in previously sedentary, moderately obese females. Int J Obes Relat Metab Disord. 2000;24:566–572
     • View In Article
     • MEDLINE
     • CrossRef
239. Andersen RE, Wadden TA, Bartlett SJ, Zemel B, Verde TJ, Franckowiak SC. Effects of lifestyle activity vs structured aerobic exercise in obese women: a randomized trial [see comments]. JAMA. 1999;281:335–340
     • View In Article
     • MEDLINE
     • CrossRef
240. Weinstock RS, Dai H, Wadden TA. Diet and exercise in the treatment of obesity: effects of 3 interventions on insulin resistance. Arch Intern Med. 1998;158:2477–2483
     • View In Article
     • MEDLINE
     • CrossRef
241. Bylund AC, Bjuro T, Cederblad G, Holm J, Lundholm K, Sjostroom M, et al. Physical training in man. Skeletal muscle metabolism in relation to muscle morphology and running ability. Eur J Appl Physiol. 1977;36:151–169
     • View In Article
242. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000;49:677–683
     • View In Article
     • MEDLINE
     • CrossRef
243. Kang J, Robertson RJ, Hagberg JM, Kelley DE, Goss FL, DaSilva SG, et al. Effect of exercise intensity on glucose and insulin metabolism in obese individuals and obese NIDDM patients. Diabetes Care. 1996;19:341–349
     • View In Article
     • MEDLINE
244. Stefanick ML. Physical activity for preventing and treating obesity-related dyslipoproteinemias. Med Sci Sports Exerc. 1999;31:S609–S618
     • View In Article
     • MEDLINE
     • CrossRef
245. Eriksson J, Tuominen J, Valle T, Sundberg S, Sovijarvi A, Lindholm H, et al. Aerobic endurance exercise or circuit-type resistance training for individuals with impaired glucose tolerance?. Horm Metab Res. 1998;30:37–41
     • View In Article
     • MEDLINE
     • CrossRef
246. Newell SA, Bowman JA, Cockburn JD. Can compliance with nonpharmacologic treatments for cardiovascular disease be improved?. Am J Prev Med. 2000;18:253–261
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (523 KB)
     • CrossRef
247. Jakicic JM, Winters C, Lang W, Wing RR. Effects of intermittent exercise and use of home exercise equipment on adherence, weight loss, and fitness in overweight women: a randomized trial. JAMA. 1999;282:1554–1560
     • View In Article
     • MEDLINE
     • CrossRef
248. Yanovsky SZ, Yanovsky JA. Obesity. N Engl J Med. 2002;346:591–602
     • View In Article
     • CrossRef
249. Allison TG, Squires RW, Johnson BD, Gau GT. Achieving National Cholesterol Education Program goals for low-density lipoprotein cholesterol in cardiac patients: importance of diet, exercise, weight control, and drug therapy. Mayo Clin Proc. 1999;74:466–473
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (7264 KB)
     • CrossRef
250. Fanghanel G, Cortinas L, Sanchez-Reyes L, Berber A. A clinical trial of the use of sibutramine for the treatment of patients suffering essential obesity. Int J Obes Relat Metab Disord. 2000;24:144–150
     • View In Article
     • MEDLINE
     • CrossRef
251. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med. 1999;106:179–184
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (100 KB)
     • CrossRef
252. Cordero-MacIntyre ZR, Peters W, Libanati CR, Espana RC, Howell WH, Lohman TG. Effect of a weight-reduction program on total and regional body composition in obese postmenopausal women. Ann N Y Acad Sci. 2000;904:526–535
     • View In Article
     • MEDLINE
     • CrossRef
253. Lindgarde F. The effect of orlistat on body weight and coronary heart disease risk profile in obese patients: the Swedish Multimorbidity Study. J Intern Med. 2000;248:245–254
     • View In Article
     • MEDLINE
     • CrossRef
254. Heymsfield SB, Segal KR, Hauptman J, Lucas CP, Boldrin MN, Rissanen A, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med. 2000;160:1321–1326
     • View In Article
     • MEDLINE
     • CrossRef
255. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. 2000;9:160–167
     • View In Article
     • MEDLINE
     • CrossRef
256. Hall JC, Watts JM, O'Brien PE, Dunstan RE, Walsh JF, Slavotinek AH, et al. Gastric surgery for morbid obesity. The Adelaide Study. Ann Surg. 1990;211:419–427
     • View In Article
     • MEDLINE
     • CrossRef
257. Naslund I. Gastric bypass versus gastroplasty. A prospective study of differences in two surgical procedures for morbid obesity. Acta Chir Scand Suppl. 1987;536:1–60
     • View In Article
     • MEDLINE
258. Sugerman HJ, Wolper JL. Failed gastroplasty for morbid obesity. Revised gastroplasty versus Roux-Y gastric bypass. Am J Surg. 1984;148:331–336
     • View In Article
     • MEDLINE
     • CrossRef
259. Pories WJ, Flickinger EG, Meelheim D, Van Rij AM, Thomas FT. The effectiveness of gastric bypass over gastric partition in morbid obesity: consequence of distal gastric and duodenal exclusion. Ann Surg. 1982;196:389–399
     • View In Article
     • MEDLINE
     • CrossRef
260. Laws HL, Piantadosi S. Superior gastric reduction procedure for morbid obesity: a prospective, randomized trial. Ann Surg. 1981;193:334–340
     • View In Article
     • MEDLINE
     • CrossRef
261. Sugerman HJ, Starkey JV, Birkenhauer R. A randomized prospective trial of gastric bypass versus vertical banded gastroplasty for morbid obesity and their effects on sweets versus non-sweets eaters. Ann Surg. 1987;205:613–624
     • View In Article
     • MEDLINE
     • CrossRef
262. Griffen WO, Young VL, Stevenson CC. A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity. Ann Surg. 1977;186:500–509
     • View In Article
     • MEDLINE
     • CrossRef
263. Manco M, Mingrone G, Greco AV, Capristo E, Gniuli D, De Gaetano A, et al. Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides. Metabolism. 2000;49:220–224
     • View In Article
     • Abstract
     • Full-Text PDF (518 KB)
     • CrossRef
264. Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol. 1999;277:E1130–E1141
     • View In Article
     • MEDLINE
265. Arslanian S, Suprasongsin C. Glucose-fatty acid interactions in prepubertal and pubertal children: effects of lipid infusion. Am J Physiol. 1997;272:E523–E529
     • View In Article
     • MEDLINE
266. Mingrone G, DeGaetano A, Greco AV, Capristo E, Benedetti G, Castagneto M, et al. Reversibility of insulin resistance in obese diabetic patients: role of plasma lipids. Diabetologia. 1997;40:599–605
     • View In Article
     • MEDLINE
     • CrossRef
267. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose-fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances in diabetes mellitus. Lancet. 1963;1:785–789
     • View In Article
     • MEDLINE
268. Rashid A, Wu TC, Huang CC, Chen CH, Lin HZ, Yang SQ, et al. Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver. Hepatology. 1999;29:1131–1138
     • View In Article
     • MEDLINE
     • CrossRef
269. Simoneau JA, Kelley DE, Neverova M, Warden CH. Overexpression of muscle uncoupling protein 2 content in human obesity associates with reduced skeletal muscle lipid utilization. FASEB J. 1998;12:1739–1745
     • View In Article
     • MEDLINE
270. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998–1003
     • View In Article
     • MEDLINE
     • CrossRef
271. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in nonalcoholic steatohepatitis. Lancet. 2001;358:893–894
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (60 KB)
     • CrossRef
272. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519–525
     • View In Article
     • MEDLINE
     • CrossRef
273. Arioglu E, Duncan-Morin J, Sebring N, Rother KI, Gottlieb N, Lieberman J, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes [see comments]. Ann Intern Med. 2000;133:263–274
     • View In Article
     • MEDLINE
274. Ide T, Nakazawa T, Mochizuki T, Murakami K. Tissue-specific actions of antidiabetic thiazolidinediones on the reduced fatty acid oxidation in skeletal muscle and liver of Zucker diabetic fatty rats. Metabolism. 2000;49:521–525
     • View In Article
     • MEDLINE
     • CrossRef
275. Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis (letter). J Hepatol. 1999;31:384
     • View In Article
     • Full Text
     • Full-Text PDF (144 KB)
     • CrossRef
276. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study [see comments]. J Pediatr. 2000;136:734–738
     • View In Article
     • Abstract
     • Full-Text PDF (1032 KB)
     • CrossRef
277. Obinata K, Maruyama T, Hayashi M, Watanabe T, Nittono H. Effect of taurine on the fatty liver of children with simple obesity. Adv Exp Med Biol. 1996;403:607–613
     • View In Article
     • MEDLINE
278. Abdelmalek MF, Angulo P, Jorgenson RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2001;96:2711–2717
     • View In Article
     • MEDLINE
     • CrossRef
279. Miglio F, Rovati LC, Santoro A, Setnikar I. Efficacy and safety of oral betaine glucuronate in nonalcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung. 2000;50:722–727
     • View In Article
     • MEDLINE
280. Garcia-Monzon C, Martin-Perez E, Iacono OL, Fernandez-Bermejo M, Majano PL, Apolinario A, et al. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol. 2000;33:716–724
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (1063 KB)
     • CrossRef