Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Metabolic Syndrome: one Disease Entity
Christine Pocha, MD, PhD Staff Physician Hepatitis C Lead Clinician Department of Medicine/ Gastroenterology Stratton VA Medical Center Albany, NY
As Americans become the fattest people in the world, the prevalence of nonalcoholic fatty liver disease and the metabolic syndrome is rising dramatically. Insulin resistance, which is commonly associated with obesity, is the most reproducible factor in nonalcoholic fatty liver disease. Liver disease may also play a pivotal role in the pathophysiology of insulin resistance. Because nonalcoholic fatty liver disease can be the earliest marker of underlying metabolic syndrome, affected individuals should also be evaluated for other features of the syndrome, such as hyperlipidemia, hypertension, and glucose intolerance, to institute appropriate interventions that may prevent the development of serious cardiovascular conditions. The author of this article proposes that nonalcoholic fatty liver disease should be part of a new definition of the metabolic syndrome and that patients in whom insulin resistance is suspected should be screened for liver disease.
Syndrome X was first described in 1988 as a constellation of cardiovascular risk factors consisting of abdominal obesity, hypertension, an atherogenic lipid profile, and glucose intolerance or type 2 diabetes mellitus.1 A decade later, the World Health Organization proposed diagnostic criteria for the metabolic syndrome that included the presence of insulin resistance plus at least 2 of the following conditions: hypertension, abdominal obesity, or mixed dyslipidemia.2
In a landmark 1980 article, a “hitherto unnamed disease that mimics alcoholic hepatitis” was described by Ludwig and colleagues and was named nonalcoholic steatohepatitis (NASH).3 NASH has since been recognized as part of a spectrum of hepatic disease known as nonalcoholic fatty liver disease (NAFLD) that occurs in people who consume little or no alcohol.4 Ludwig recognized a strong association between NAFLD and obesity or obesity-related diseases, including type 2 diabetes mellitus. More recent studies have identified risk factors that may help distinguish between NASH, as a severe manifestation of NAFLD, and simple steatosis. These risk factors include female gender, age 50 years and older, hypertension, aspartate aminotransferase (AST) level of 45 IU/L or greater, body mass index (BMI) of 30 kg/m2 or more, AST/alanine aminotransferase (ALT) ratio of 0.80 or more, and hyaluronic acid concentration of 55 mg/L or more.5,6 NAFLD in a secondary form is associated with total parenteral nutrition, small bowel bypass procedures, choline deficiency, certain drugs, toxins, and hepatitis C.
Although not all NAFLD cases are secondary to insulin resistance, in clinical practice almost all patients will be insulin resistant. In fact, impaired insulin activity, together with the different features of the metabolic syndrome, is a common early finding in NAFLD and may play an important role in inducing liver disease.
It is the belief of this author that NAFLD serves as a marker for the frequent coexistence of metabolic abnormalities, such as obesity, insulin resistance, and dyslipidemia. This raises the question: Should patients with features of the metabolic syndrome be screened for evidence of NAFLD, or should NAFLD be incorporated into the new definition of the metabolic syndrome?
Prevalence of NAFLD In the United States, the true prevalence of the metabolic syndrome and NAFLD are difficult to establish conclusively. An estimated 22% of American adults have the metabolic syndrome; this doubles to nearly 44% in those older than age 60.7 Current estimates suggest that from 17% to 33% of Americans have NAFLD, approximately one third of whom also have NASH.8 Thus, the prevalence of NAFLD in the United States appears to be substantially greater than the 1.8% prevalence of hepatitis C virus infection.9
NAFLD can be considered the most prevalent form of hepatic disease in the United States and is a particular problem among obese individuals. Based on current population data, about 33 million obese adults in this country have steatosis or steatohepatitis.10 In a study of 212 morbidly obese patients, 93% of the participants had NAFLD.11 NASH is already the most common hepatic disease among children in North America.12
Diabetes affects 7% of the US adult population,13 and as many as 63% (or 13.1 million) of patients with diabetes have NAFLD.14 Despite the high incidence of fatty liver disease in patients with type 2 diabetes, primary care providers and diabetologists seldom regard liver disease as a problem in their patients with diabetes. But a population-based study of more than 7000 patients with type 2 diabetes showed that standardized mortality ratios were higher for liver disease than for cardiovascular disease (2.52 versus 1.34).15
NAFLD and Obesity Steatohepatitis is found in more than one third of obese individuals regardless of diabetes status,6,16 and NASH in more than 30% of morbidly obese persons.11 Obesity, particularly central or truncal, is strongly correlated with insulin resistance. Although the precise mechanism behind this association is unclear, release of free fatty acids from abdominal adipocytes into the portal circulation seems to play an important role.
The rising prevalence of obesity in the United States has provoked a new health crisis. The latest data indicate that prevalence increased from 12% of adults in 1991 to 30% in 1999-2002.17 The proportion of children and adolescents (aged 6-19 years) who are overweight more than tripled during the past 25 years, from 5% to 16%.17 The prevalence of the metabolic syndrome is high among obese children and adolescents (up to 50% among those who are severely obese), and biomarkers of increased risk of adverse cardiovascular outcomes (eg, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol [HDL-C] and high C-reactive protein levels) are already present in these youngsters.18 It is estimated that the number of obese Americans (ie, BMI >30 kg/m2) may reach 40% by 2025.19
There is a direct relationship between weight gain and the development of insulin resistance and the hypertransaminasemia of NAFLD. In fact, weight gain seems to precede the ALT elevation associated with NAFLD; however, NAFLD is also common in severely obese people with normal transaminase levels. One study showed that almost half of morbidly obese individuals had NAFLD, and more than 20% had definite histologic evidence of NASH, without hypertransaminasemia.20 In morbidly obese individuals, the risk of liver disease progressively increases as the number of metabolic syndrome features rises; about 2% of these patients have unexpected cirrhosis.21
Thus, it would be prudent to evaluate any person with a BMI of at least 25 kg/m2 (ie, the threshold for “overweight”) for the manifestations of insulin resistance. In a study of 93 overweight patients, significant predictors of liver fibrosis were age above 50 years, BMI of 28 kg/m2 or more, ALT level more than twice the upper limit of normal, and a triglyceride level of 1.7 mmol/L or more.22 Obesity and insulin resistance have also been associated with fibrosis and cirrhosis in other liver diseases. A BMI of 25 kg/m2 or higher has been correlated with steatosis and fibrosis in patients with hepatitis C virus infection23 as well as with alcoholic liver disease.24
Pathophysiology and Natural History of NAFLD Insulin resistance is the most reproducible factor in the development of NAFLD, and (by means of several enzymatic pathways) it leads to fat accumulation in hepatocytes by lipolysis and hyperinsulinemia.25 However, it is still unclear whether insulin resistance causes NAFLD or develops as a consequence of hepatic steatosis. Of interest, in a study of 13 patients who had NASH but not diabetes and 12 healthy controls, insulin resistance manifested as lower glucose utilization and increased lipolysis during hyperinsulinemic-euglycemic insulin clamp testing.26
NAFLD is thought to result from 2 mechanisms (Figure). The first is an accumulation of lipids in the hepatocytes that results in steatosis. The second mechanism is multifactorial and involves oxidative stress, lipid peroxidation, and abnormal cytokine production that result in steatohepatitis and fibrosis. Nevertheless, the pathogenesis of NAFLD remains poorly understood and hypothetical. It is not known why simple steatosis develops in some patients, whereas steatohepatitis and progressive disease develop in others. It is now appreciated that NAFLD is not a benign disease. Certain patients may develop progressive liver disease, ranging from steatohepatitis to cirrhosis to hepatocellular carcinoma or even acute and subacute liver failure.27,28 One case-control study of 23 patients with cryptogenic cirrhosis showed that type 2 diabetes, hypertriglyceridemia, and normal aminotransferase levels were independently associated with the development of hepatocellular carcinoma.28
Diagnosis Most patients with NAFLD are asymptomatic,4 and workup is often precipitated by the finding of abnormal transaminase levels. The AST/ALT ratio is usually less than 1, which is distinct from the classic picture of alcoholic liver disease, in which this ratio is usually more than 2.4 The ratio, however, tends to increase as significant fibrosis or cirrhosis develops, but it rarely rises above 2.4 Ultrasound, computed tomography, and magnetic resonance imaging are insensitive if the degree of steatosis is less than 33%.29 None of these modalities can reliably identify fibrosis or stage the disease.
Liver biopsy is the only method for establishing the diagnosis and determining the presence and extent of specific necroinflammatory changes and fibrosis. The rationale for biopsy in patients with suspected NAFLD is based on the knowledge that the existence or absence of histologic criteria for NASH is the most important marker for disease progression. However, physicians who care for patients with abnormal transaminase levels should base their decision about performing biopsy on an estimation of the individual’s risk for developing NASH and fibrosis.
Treatment With a lack of proven efficacious and safe pharmacotherapy for NAFLD, treatment focuses on associated conditions. Treatment should target insulin resistance, which plays a crucial role in both the metabolic syndrome and NAFLD. Management in patients who also have the metabolic syndrome includes lifestyle modification and treatment of glucose intolerance or frank diabetes, hypertension, and dyslipidemia.
Exercise and diet Physical activity, as simple as walking 30 minutes each day, when combined with a good nutrition program, has been shown to promote weight loss and help prevent diabetes.30 Weight loss improves liver enzymes and metabolic abnormalities.31 In obese children, weight loss has resulted in normalization of biochemical and ultrasonographic liver abnormalities.32 For patients with type 2 diabetes, weight reduction is the mainstay of therapy, and glucose control plays a less important role. Although surgical weight loss may result in significant improvement of liver morphology in severely obese persons, a rapid weight loss (eg, as a result of starvation diets or bariatric surgery) can exacerbate steatohepatitis and should be avoided.
Pharmacotherapy Several empirical and semiempirical trials of promising agents have been conducted. Most have been small, only a few had a placebo control, and many lacked histologic follow-up. The Table summarizes the published experience with the drug treatment of NASH to date.
Table
Published data on the treatment of NASH
Outcome
Treatment*
Patients
Duration of treatment, mo
Chemistry
Histology
Diet (weight reduction)31
50
2-111
Improved vs baseline
NA
Diet + exercise42
31
15
Improved vs baseline
Improved vs baseline
UCDA33
24
12
Improved vs baseline
Improved vs baseline
UCDA34
126
24
Unchanged vs placebo
Unchanged vs placebo
Vitamin E44
11
4-10
Improved vs baseline
NA
Vitamins E and C45
45
6
Unchanged vs placebo
Improved vs placebo
Vitamins E and C46
28
6
Improved vs baseline
NA
Atorvastatin43
27†
6
Improved vs baseline
Improved vs baseline
Betaine47
7
12
Improved vs placebo
Improved vs placebo
Clofibrate33
16
12
Unchanged vs baseline
Unchanged vs baseline
Gemfibrozil48
46
1
Improved vs placebo
NA
Metformin36
20
4
Improved vs baseline
NA
Metformin37
55
12
Improved vs placebo
NA
Nateglinide49
10‡
5
Improved vs no treatment
Improved vs no treatment
Rosiglitazone41
30
12
Improved vs baseline
Improved vs baseline
Pioglitazone39
18
4
Improved vs baseline
Improved vs baseline
Pioglitazone + vitamin E40
20
12
Improved vs vitamin E alone
Improved vs vitamin E alone
Troglitazone50§
10
3-6
Improved vs baseline
Improved vs baseline
*Reference number.
†Patients were also hyperlipidemic.
‡Patients also had type 2 diabetes.
§Troglitazone is no longer available.
NA = not available; NASH = nonalcoholic steatohepatitis; UCDA = ursodeoxycholic acid.
Cytoprotective and antioxidant agents. Among the various hepatoprotective drugs, ursodeoxycholic acid (eg, Actigall, URSO 250, Ursodiol), vitamin E, and betaine (Cystadane) have all been studied, but none has shown conclusive evidence of benefit. Use of ursodeoxycholic acid, 13 to 15 mg/kg daily for 12 months, in patients with NASH does appear to significantly improve liver enzymes, and one small study of 24 patients also showed significant improvement in histologic grade of steatosis.33 However, a larger study of 126 patients with NASH found that 2 years of ursodeoxycholic acid therapy at the same dosages was no better than placebo.34 Whether higher doses, such as those used to treat primary biliary cirrhosis, would be beneficial is unknown.
Antihyperlipidemic agents. Fibrates and niacin effectively lower triglyceride and raise HDL-C levels. Gemfibrozil (Lopid) inhibits free fatty-acid mobilization from adipose tissue and reduces the production and increases the clearance of very-low-density lipoprotein. But neither gemfibrozil nor clofibrate have shown benefits for patients with NASH in clinical trials.33
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the first-line treatment for hypercholesterolemia. Although many patients with NAFLD have hyperlipidemia, their elevated serum aminotransferase levels make physicians wary about prescribing lipid-lowering agents, especially statins. However, many patients with NAFLD have risk factors for coronary artery disease, so the benefits they would derive from cholesterol-lowering therapy would most likely outweigh any theoretical risk of liver injury. In addition, evidence suggests that statin-induced liver injury is uncommon and is no more likely to occur in patients with chronic liver disease than in those without it.35 Thus, lipid-lowering agents should be prescribed for patients with NAFLD unless contraindicated, with careful monitoring of transaminase levels during therapy.
Antidiabetic and insulin-sensitizing agents. The association between NAFLD and hyperinsulinemic insulin resistance provides another possible target for treatment. Researchers have tried to determine whether treatment of insulin resistance will affect patient outcomes. The use of insulin has not been addressed adequately. Metformin HCl (Glucophage) has been shown to have beneficial effects on liver enzyme levels and histology in patients with NASH.36,37 This agent might improve hepatic insulin resistance by decreasing hepatic expression of the tumor necrosis factor that promotes lipid accumulation and adenosine triphosphate depletion in the liver.38
Troglitazone, a thiazolidinedione that improves insulin resistance, had shown promising results in trials conducted before it was removed from the market due to rare but severe hepatotoxicity. Pioglitazone HCl (Actos), a thiazolidinedione with a better safety profile, has been shown in 2 pilot studies involving a total of 28 patients to improve the histologic and biochemical features of NASH.39,40 Another study of 30 patients with NASH showed that the improved insulin sensitivity with rosiglitazone maleate (Avandia) therapy resulted in an improvement in the histologic markers of NASH.41 Unfortunately, both pioglitazone and rosiglitazone are associated with weight gain that might well negate any benefits they can offer.
Conclusion With the rising prevalence of obesity, NAFLD and the metabolic syndrome are becoming increasingly recognized conditions in the US population, and both can have serious health consequences. Insulin resistance almost invariably occurs concomitantly with primary NAFLD associated with the metabolic syndrome. Conversely, liver disease may also play a primary role in the genesis of hyperinsulinemia and insulin resistance. Therefore, NAFLD should be added to the definition of the metabolic syndrome, and patients with features of insulin resistance should be screened for liver disease. Furthermore, this author postulates that NAFLD can be the earliest marker for underlying metabolic syndrome, and patients should be screened for hyperlipidemia, hypertension, and insulin resistance.
Key elements in the treatment of the metabolic syndrome are weight management and the control of diabetes and dyslipidemia. Further investigation is needed to determine the effects on NAFLD of treating comorbid conditions with antidiabetic and antilipid medications.
Self-assessment test 1. Which of the following statements about NAFLD is NOT true? A. Its prevalence is higher than that of hepatitis C virus infection B. It occurs in more than half of patients with diabetes C. It is always associated with elevated transaminase levels D. Weight gain can precede ALT elevations
2. All these statements about fatty liver and obesity are true, except: A. Steatohepatitis is more common in obese patients with diabetes than in those without diabetes B. Steatohepatitis occurs in 9 out of 10 severely obese persons C. Risk of liver disease increases with increasing number of metabolic syndrome features D. Obesity and insulin resistance are associated with NAFLD
3. Which of the following techniques is used for definitive diagnosis of NAFLD? A. Measurement of AST/ALT ratio B. Ultrasound C. Computed tomography D. Liver biopsy
4. Which of these statements about the treatment of patients with NAFLD is NOT true? A. Statins are contraindicated B. The benefits of thiazolidinediones may be outweighed by their side effects C. Exercise and a low-calorie diet may normalize transaminase levels in obese children D. Treatment should target insulin resistance
5. All these treatments have been shown to improve the histologic abnormalities in NASH, except: A. Clofibrate B. Rosiglitazone C. Pioglitazone D. Diet plus exercise
Answers: 1. C; 2. A; 3. D; 4. A; 5. A.
References 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. 1. Diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation. Diabet Med. 1998;15:539-553.
3. Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438.
4. American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705-1725.
5. Palekar NA, Naus R, Larson SP, et al. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 2006;26:151-156.
6. Boza C, Riquelme A, Ibanez L, et al. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg. 2005;15:1148-1153.
7. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359.
8. Farrell GD, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(suppl 1):S99-S112.
9. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341: 556-562.
10. Kunde SS, Lazenby AJ, Clements RH, et al. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005;42: 650-656.
11. Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg. 2005;15:310-315.
12. Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis. 2004;8:549-558, viii-ix.
14. Kelley DE, McKolanis TM, Hegazi RAF, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003;285:E906-E916.
15. de Marco R, Locatelli F, Zoppini G, et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care. 1999; 22:756-761.
16. Rodriguez-Hernandez H, Gonzalez JL, Rodriguez-Moran M, et al. Hypomagnesemia, insulin resistance, and non-alcoholic steatohepatitis in obese subjects. Arch Med Res. 2005;36:362-366.
18. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:2362-2374.
19. Kopelman PG. Obesity as a medical problem. Nature. 2000;404: 635-643.
20. Merriman RB, Weston S, Bagetelos K. Nonalcoholic fatty liver disease is common in morbidly obese individuals with normal aminotransferases. Digestive Disease Week 2003; May 18-21, 2003; Orlando, Fla. Abstract 105897.
21. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999; 84: 1513-1517.
22. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117-1123.
23. Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29: 1215-1219.
24. Naveau S, Giraud V, Borotto E, et al. Excess weight risk factor for alcoholic liver disease. Hepatology. 1997;25:108-111.
25. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346:1221-1231.
26. Comert B, Mas MR, Erdem H, et al. Insulin resistance in non-alcoholic steatohepatitis. Dig Liver Dis. 2001;33:353-358.
27. Caldwell SH, Hespenheide EE. Subacute liver failure in obese women. Am J Gastroenterol. 2002;97:2058-2062.
28. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134-140.
29. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002; 123:745-750.
30. Laaksonen DE, Lindstrom J, Lakka TA, et al. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes. 2005;54:158-165.
31. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408-1413.
32. Vajro P, Fontanella A, Perna C, et al. Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr. 1994;125:239-241.
33. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23: 1464-1467.
34. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39: 770-778.
35. Russo MW, Jacobson IM. How to use statins in patients with chronic liver disease. Cleve Clin J Med. 2004;71:58-62.
36. Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893-894.
37. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082-1090.
38. Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998-1003.
39. Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107-1115.
40. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004; 39:188-196.
41. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008-1017.
42. Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004;53:413-419.
43. Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol. 2003;17:713-718.
44. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734-738.
45. Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485-2490.
46. Ersoz G, Gunsar F, Karasu Z, et al. Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment. Turk J Gastroenterol. 2005;16: 124-128.
47. Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001;96:2711-2717.
48. 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.
49. Morita Y, Ueno T, Sasaki N, et al. Nateglinide is useful for nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes. Hepatogastroenterology. 2005;52: 1338-1343.
50. Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96: 519-525.
Practice points
There is a direct relationship between weight gain and the development of insulin resistance and the hypertransaminasemia of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease can progress to serious liver disease, such as cirrhosis or liver cancer.
Most patients with nonalcoholic fatty liver disease are asymptomatic; hence all patients with the metabolic syndrome should be screened for the disease.
Imaging studies are not diagnostic. Liver biopsy is the only method for establishing the diagnosis.
Treatment should focus on any associated conditions, such as insulin resistance, diabetes, hypertension, or dyslipidemia.
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