Chat with us, powered by LiveChat Janice is a 45yo Caucasian female with symptoms of Non Alcoholic Fatty Liver Disease.Her BMI is 40 and she was diagnosed with DM type 2 3 years ago. Her last HgbA1c was 7.4. She lives a s - Writingforyou

Janice is a 45yo Caucasian female with symptoms of Non Alcoholic Fatty Liver Disease.Her BMI is 40 and she was diagnosed with DM type 2 3 years ago. Her last HgbA1c was 7.4. She lives a s

Janice is a 45yo Caucasian female with symptoms of Non Alcoholic Fatty Liver Disease.Her BMI is 40 and she was diagnosed with DM type 2 3 years ago. Her last HgbA1c was 7.4. She lives a sedentary life style. She state she has significant fatigue and but is otherwise asymptomatic. What diagnostics would you order for Janice? Why? What treatment plan would you recommend for her? What is her prognosis? 2 references APA 7th edition

Treating Non ETOH fatty liver disease.NP.Nov2015.pdf Click for more options

36 The Nurse Practitioner • Vol. 40, No. 1 www.tnpj.com36 The Nurse Practitioner • Vol. 40, No. 11

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. The Nurse Practitioner • November 2015 37

onalcoholic fatty liver disease (NAFLD) covers a wide spectrum of fatty liver issues, ranging from simple fatty infi ltration in liver cells (hepatocytes)

to nonalcoholic steatohepatitis (NASH), to cirrhosis and/ or hepatocellular carcinoma (HCC).1 With the increasing prevalence of obesity, type 2 diabetes mellitus, and metabolic syndrome, the prevalence of NAFLD is also increasing, and NPs will be caring for these patients more frequently.2 This article seeks to improve the understanding of the spectrum of NAFLD and provide up-to-date treatment recommendations.

■ Background and prevalence of NAFLD

NAFLD is defi ned as biopsy- or imaging-proven hepatic steatosis, in which other causes of fatty liver have been excluded, including alcoholic liver disease, genetic diseases, or medication-related causes.3,4 (See Defi nition of signifi cant alcohol consumption.) NAFLD should be considered as a diagnosis in patients who have had other causes of liver disease excluded and who have one or more risk factors for NAFLD (see Risk factors for development of NAFLD).

Ninety percent of patients with NAFLD have one or more of the following risk factors: obesity, insulin resistance, met- abolic syndrome, type 2 diabetes mellitus, cardiovascular

disease, hypertension, dyslipidemia, elevated triglyceride levels, and/or low high-density lipoprotein levels.3-5

The prevalence of NAFLD is approximately 20% world- wide and 25% in Western countries, making it one of the most common causes of liver disease.2-4,6 NAFLD

occurs in one in three individuals in the devel- oped world and is more common in patients with severe obesity and diabetes.3,7,8 Mortality and disease evolution to fi brosis or cirrhosis is increased in older patients with NAFLD.3

Cardiovascular disease-related events are the most common causes of mortality in patients with NAFLD.3 NASH, which is a pro- gression from simple fatty liver disease to

infl ammation and injury, is the third most common cause of liver disease requiring a liver transplant in the

United States.3,4,7 According to Charlton and colleagues, by 2020, NASH will be the leading cause of liver transplant in the United States.9 Patients with NASH can progress to cirrhosis and/or HCC.

■ Pathophysiology of NAFLD

The pathophysiology of NAFLD is complex and not com- pletely understood. Day and James sought to describe the process of fatty liver disease progression as the “two hits

By Amanda Chaney, MSN, ARNP, FNP-BC



Keywords: lifestyle modifi cations, liver disease, nonalcoholic fatty liver disease

Abstract: Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide

health crisis. It is important for NPs to understand the spectrum of

NAFLD. Although lifestyle modifi cations are the fi rst-line treatment,

the NP should be aware of current and future medication

management to help the patient live a healthy life.


fatty liver disease

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

38 The Nurse Practitioner • Vol. 40, No. 11

Treating the patient with nonalcoholic fatty liver disease

theory.12” In the fi rst hit, steatosis, or fatty infi ltration in the liver, occurs from issues with insulin resistance and fatty acid metabolism.2,10-12 Increased free fatty acid to the liver causes hepatic steatosis. Insulin resistance increases lipolysis from adipose tissue. This process leads to release of proin- fl ammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin-6), oxidative stress, and infl ammation.13

These, along with molecular endotoxins and genetic factors, are thought to contribute to the second hit.2,4,14,15 The second hit results in oxidative stress and steatohepatitis.12

Dietary choices can also play a part. With high amounts of cholesterol to the liver (either from diet or genetics), fatty acids are converted to nontriglyceride metabolites. These particles contribute to hepatocyte injury. High con- sumption of sugar—particularly fructose—reduces intracel- lular adenosine triphosphate and is converted to fat, which is deposited in the liver.5 Collagen is deposited in the liver and causes fi brosis as infl ammation and liver injury occur.4

As this process continues, fi brosis can turn into cirrhosis and/or HCC. As the hepatocytes become fatty, patients are at higher risk for developing diabetes mellitus, cardiovas- cular disease, and complications related to these diseases.7

■ Diagnosing NAFLD

It may be diffi cult to know when to suspect NAFLD, since most patients are asymptomatic.4,5,7 Some symptoms that present are vague, including abdominal discomfort, fatigue, and nausea.2 Higher-risk patients include patients who have type 2 diabetes mellitus and who are obese. These patients are not only at higher risk for liver disease progression but also cardiovascular disease and death.7 There is currently no diagnostic screening tool or recommendations for

screening for NAFLD in primary care, even if a patient has several risk factors to suggest this disease.3 In most cases, NAFLD is found incidentally when a patient has elevated liver enzymes or when it is seen on radiologic imaging stud- ies as hepatic steatosis.2,4

History. A complete history should be obtained in the patient who has liver disease when NAFLD is suspected. Occasional symptoms that may occur include right upper quadrant abdominal pain, pruritus, and jaundice. Gener- ally, the patient is without symptoms. Other etiologies of liver disease should be excluded. Current lifestyle and dietary habits, including alcohol consumption history, should be noted. Social history should include current or prior intra- vascular or other illicit drug use, blood transfusions, and sexual activity.4

Physical exam. Physical exam should include vital signs, height, weight, body mass index (BMI), BP, and waist cir- cumference. Hepatosplenomegaly may be present if the patient has evidence of portal hypertension.2,4 Dorsocervi- cal lipohypertrophy, an increased amount of fat distribution along the cervical spine, may be present and has been noted in patients with NASH.16

Lab fi ndings. Labs to exclude other causes of liver disease include: total protein, alanine aminotransferase (ALT), as- partate aminotransferase (AST), alkaline phosphatase, albu- min, total bilirubin, hepatitis B surface antigen, hepatitis C antibody, ferritin, iron, fasting blood glucose, hemoglobin A1C, lipid panel, and low-density lipoprotein cholesterol, prothrombin time, and insulin levels.4

Patients with NAFLD commonly have elevated ferritin levels, and 20% have elevated uric acid levels.2,3 Most patients with NAFLD will have a mild elevation of AST and ALT, although some will be normal.2 There are no imaging or biomarker tests that can differentiate between hepatic ste- atosis and NASH.8 Cytokeratin-18 fragment levels are the most researched tool to predict NASH, which is an indicator of hepatocyte apoptosis.7

Radiologic fi ndings. Imaging studies to evaluate for NAFLD could include ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Ultrasound cannot identify infl ammation or fi brosis, but it is the fi rst imaging study done to evaluate for hepatic steatosis, for which it has a sensitivity of 60% to 94% and specifi city of 66% to 97%.4,7 It is inexpensive and extensively available. CT scan can be done to assess the structure of the liver.4 It is an option for determining hepatic steatosis; however, there is signifi cant radiation associated with this imaging study.7

MRI is accurate for quantifying the extent of hepatic steato- sis, but it is expensive.4 Magnetic resonance spectroscopy is accurate in identifying steatosis and has the potential to become an ideal test for grading and determining the

Defi nition of signifi cant alcohol consumption3

Men Greater than 21 drinks per week over a 2-year period

Women Greater than 14 drinks per week over a 2-year period

1 drink = ~10 g alcohol

Risk factors for development of NAFLD3,4,8

• Age, older than 45

• Diabetes mellitus

• Hispanic ethnicity

• Portal hypertension

• Insulin resistance

• Metabolic syndrome

• Obesity

• Family history signifi cant for metabolic syndrome,

cardiovascular disease, chronic liver disease

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Treating the patient with nonalcoholic fatty liver disease The Nurse Practitioner • November 2015 39

presence of steatosis; however, it is costly and with limited availability.7

Noninvasive measures. Risk scores, such as the NAFLD fi brosis score and the NASH test, have been used to try to determine patients who have NASH but can be inaccu- rate (see Noninvasive fi brosis scoring tools).5,17-19 Transient elastography is a newer imaging study on the hori- zon. Described as a pulse-echo ultra- sound, it has shown usefulness in determining the presence of fi brosis. This may be helpful in determining if liver biopsy is necessary.7

Liver biopsy. Liver biopsy is the gold standard for determining if NAFLD is present and for staging severity of disease.7 Complications, including bleeding and infection, occur in 1% to 3% of patients; death occurs in 0.01% of patients.7 Misdiagnosis can occur in many cases. Staging and diagnosis are subjective and can vary by the pathologist.7 Additionally, there is a higher risk of complica- tion and diffi culty obtaining an adequate sample in patients who are obese.7

A liver biopsy should be considered in patients with highly elevated liver function tests (LFTs) or patients with elevated LFTs and a normal BMI.4 The pathology report may include fi ndings indicative of NAFLD such as: Mallory hya- line, hepatocyte ballooning, and lymphocytic and neutro- philic infl ammatory infi ltrate in perivenular areas. Other fi ndings may state hepatocyte necrosis, apoptosis, and degree of fi brosis—graded and staged.4,8

■ NAFLD treatment options

Patients with NAFLD without liver injury have an excellent prognosis, and their management is primarily aimed at prevention and reversal of hepatic injury and fi brosis.3-5 The aim is to prevent progression to cirrhosis and HCC if NASH is present, thereby avoiding cirrhosis complications.2,20 Man- aging other comorbidities including dyslipidemia, sleep apnea, hypertension, diabetes mellitus, and obesity is es- sential.3-5 Unfortunately, there is no pharmacologic treat- ment for NAFLD.2,20 Primary care considerations include ensuring hepatitis A and B immunizations and recommend- ing elimination of alcohol consumption.4 Some specialists are supportive of more intensive management of patients with diabetes mellitus and NAFLD.7 Targher and colleagues note that NAFLD is an independent risk factor for cardio- vascular disease, so careful and prompt disease management is essential for an optimal patient outcome.21

Lifestyle changes. Initial treatment should include lifestyle changes, such as increased physical activity, a low cholesterol/low-fat diet, decreased caloric consumption, avoidance of trans fats, and weight loss.3-5,8 Lifestyle modi- fi cations not only have the potential to improve liver disease but can also improve common comorbidities (for example, hypertension, diabetes, and hyperlipidemia).20

Diet and exercise. Current recommendations include decreased caloric consumption, increased physical activ- ity, and weight loss. The Mediterranean diet has shown improvement in hepatic steatosis and insulin sensitivity in NAFLD patients.22,23 Encouraging a reduction in calories along with good food choices is recommended. Dietary changes should include complete avoidance of high-fruc- tose corn syrup and trans fats, as these dietary choices are associated with hepatic steatosis development and insulin resistance.8 Patients with NAFLD should not consume alcohol.3 Interestingly, some studies have been performed supporting that coffee consumption is associated with reducing hepatic fi brosis. One or two cups of unsweetened coffee can be seen as a benefi t in patients with NAFLD.24-26

Weight loss of 3% to 10% can improve disease progres- sion and normalization of AST levels, but weight gain can lead to NASH recurrence.3-5,27 Hepatic steatosis can be re- duced with even a 3% weight loss.3,28 Exercise, both with and without weight loss, has shown benefi ts for the patient with NAFLD.29,30 Patients should be made aware that exercise with reduction in caloric intake will likely lead to weight loss, and even a small amount of weight loss will be extremely ben- efi cial to liver improvement.20 There is positive evidence that exercise will decrease liver steatosis.6,31

Behavioral changes. Behavioral changes and psychoso- cial therapy can assist in helping the patient make necessary

Noninvasive fi brosis scoring tools5,17,18

Scoring tool

Components Scoring


fi brosis


Calculation using age, platelet,

ALT, AST, and albumin levels,

BMI, glucose intolerance or

diabetes mellitus

• <-1.455: predictor of absence

of signifi cant fi brosis

• ≤-1.455 to ≤0.675: indeterminate


• >0.675: predictor of presence

of signifi cant fi brosis

NASH test18 Calculation using lab values

including alpha 2 -macroglobulin,

haptoglobin, apolipoprotein A1,

total bilirubin, gamma-glutamyl

transpeptidase, fasting blood glu-

cose, triglyceride level, cholesterol,

ALT and AST, and age, gender,

weight, and height.

Scoring is established into

one of three groups:

N0: No Nash

N1: Borderline

N2: Nash

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

40 The Nurse Practitioner • Vol. 40, No. 11

lifestyle changes.8 Engaging the patient in his or her care is important for patient success. Identifying patient struggles, establishing short- and long-term goals, and supporting patient’s self-esteem can help the patient be successful. Mak- ing the patient aware of the benefi ts of these lifestyle changes can help. Supplying the patient with adequate resources is important for self-monitoring of dietary intake and exercise activity. A support group of other patients who have had

similar experiences and successes is helpful. Patients should have return visits to monitor and encourage progress. Oth- er resources to consider include consultation with a dietitian and psychologist.

As mentioned above, alcohol consumption should be stopped. Some patients may fi nd this challenging and may need additional support to accomplish this goal, including social work support and/or joining a support group.

Prescription medications. Studies have been con- ducted to see if metformin administration is associated with improved liver histology, but it is not recommended for treatment of NASH.3,8,32 Thiazolidinediones have been shown to improve the sensitivity of insulin and have some anti-infl ammatory and antiatherosclerotic properties.20

Research has shown improvements in liver steatosis.32-36

The study (PIVENS), Pioglitazone versus Vitamin E versus Placebo for Treatment of Non-diabetic Patients with Non- alcoholic Steatohepatitis, showed that nondiabetic patients with NASH taking pioglitazone and vitamin E saw de- creased hepatic infl ammation; fi brosis was not affected.36

Pioglitazone has been studied for NASH treatment; how- ever, long-term use and safety have not been established.1,5

Therefore, it is not considered a treatment strategy for management of NAFLD (including NASH) due to its ad- verse reactions, which include weight gain, death from cardiovascular events, and osteoporosis.37 Rosiglitazone has very restricted use in the United States because of its association with increased risk of coronary events.5 The majority of patients with NASH in these studies did not have diabetes.3

Ursodeoxycholic acid has been investigated in the treat- ment of NAFLD. It is a cytoprotective agent that reduces proinfl ammatory cytokines and prevents cellular apoptosis.2

Current research does not recommend its use.3,8,38-40 Other medications researched in the treatment of fatty liver

included: orlistat, gemfi brozil, Vitamin C, betaine, n-acetyl- cysteine, and sibutramine.41-47 However, none have been deemed safe for the treatment of NAFLD.

Over-the-counter medications. Vitamin D defi ciency has been found to be an independent factor associated with NAFLD and the severity of NASH.48 Vitamin D levels should be monitored and maintained. Disease progression and liver injury are caused by oxidative stress in patients with NASH.

Due to this knowledge, antioxidants— particularly vitamin E—are thought to improve liver disease in patients with NAFLD.3 Vitamin E is not recommend- ed for patients with diabetes who have NASH, NAFLD without liver biopsy, NASH cirrhosis, or patients with cryp- togenic cirrhosis.3 Miller and colleagues

performed a meta-analysis that determined a rise in all-cause mortality in patients taking high-dose vitamin E (doses of 400 international units/day). Although vitamin E has few noted adverse reactions, results of this meta- analysis should not be overlooked. It should be prescribed cautiously.13,49,50

Omega-3 fatty acid supplements have also been investi- gated in the treatment of NAFLD. These supplements are not recommended to treat NAFLD; however, they are recom- mended for treatment of hypertriglyceridemia, a common comorbidity of NAFLD, and can be given in those cases.3

Increasing intake of omega-3 fatty acids has been docu- mented to reduce hepatic steatosis and is an option for over- all cardiovascular health.8,51 Benefi ts are seen in supplement doses less than 1 g/day; however, there have not been any controlled trials establishing the degree of improvement in hepatic steatosis or the ideal dosage.51 Research has noted that probiotics decrease aminotransferases and improve liver histology by decreasing gastrointestinal bacterial overgrowth (a contributor of oxidative stress).52,53 A meta-analysis by Ma and colleagues noted that probiotics can improve insulin resistance, liver aminotransferases, total cholesterol, and decrease TNF-alpha in patients with NAFLD.54 More studies are needed to determine proper dosing.13

Other options. Bariatric surgery is not recommended as a treatment for NAFLD or NASH, but it has been not- ed that patients who have undergone bariatric surgery have seen improvement in liver histology.3 Patients with NAFLD and dyslipidemia should be on an HMG-CoA reductase inhibitor (statin) to treat their dyslipidemia, given there are no contraindications. Several research studies have stated that there is no evidence to suggest statins will cause liver injury.3,8,55-57 Patients with cirrhosis from NAFLD should undergo screening for HCC and esophagogastroduodenoscopy for gastroesophageal varices.3

Hepatology consultation should be requested, preferably

Omega-3 fatty acid is recommended

to treat hypertriglyceridemia, a common

comorbidity of NAFLD.

Treating the patient with nonalcoholic fatty liver disease

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Treating the patient with nonalcoholic fatty liver disease The Nurse Practitioner • November 2015 41

to a transplant center. There is no need for routine liver biopsy to evaluate the progression of the disease.3

■ Understanding NAFLD

NAFLD encompasses a range of nonalcohol-related liver disease extending from simple fatty permeation of the liver cells to infl ammation (NASH) to cirrhosis.8 It is essential that NPs understand the complexity of NAFLD. Unfortu- nately, medication management of NAFLD is limited. More research is needed to fi nd new treatment modalities. Behav- ioral therapy, including dietary and physical activity chang- es, has been shown to improve liver disease. NPs are key providers to help and guide this select group of patients to a state of better health.


1. Levene AP, Goldin RD. Physiological hepatic nuclear vacuolation—how long does it persist? Histopathology. 2010;56(4):426-429.

2. Corrado RL, Torres DM, Harrison SA. Review of treatment options for nonalcoholic fatty liver disease. Med Clin North Am. 2014;98(1):55-72.

3. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023.

4. Wilkins T, Tadkod A, Hepburn I, Schade RR. Nonalcoholic fatty liver disease: diagnosis and management. Am Fam Physician. 2013;88(1):35-42.

5. Schuppan D, Schattenberg JM. Nonalcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. J Gastroenterol Hepatol. 2013;28(suppl 1):68-76.

6. Keating SE, Hackett DA, George J, Johnson NA. Exercise and nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;57 (1):157-166.

7. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of nonalcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013;58(5):1007-1019.

8. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Scientifi cWorldJournal. 2013;2013:481893.

9. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249-1253.

10. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion and specifi c association with the insulin resistance syndrome. Hepatology. 2002;35(2):373-379.

11. Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107(5):450-455.

12. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842-845.

13. Schwenger KJ, Allard JP. Clinical approaches to nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(7):1712-1723.

14. Sookoian S, Pirola CJ. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis. 2012;16(3):467-485.

15. Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50(10):2111-2116.

16. Cheung O, Kapoor A, Puri P, et al. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology. 2007;46(4):1091-1100.

17. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fi brosis score: a noninvasive system that identifi es liver fi brosis in patients with NAFLD. Hepatology. 2007;45(4):846-854.

18. Poynard T, Ratziu V, Charlotte F, et al. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with nonalcoholic fatty liver disease. BMC Gastroenterol. 2006;6:34.

19. Francque SM, Verrijken A, Mertens I, et al. Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients. Clin Gastroenterol Hepatol. 2012;10(10):1162-1168; quiz e87.

20. Mahady SE, George J. Management of nonalcoholic steatohepatitis: an evidence-based approach. Clin Liver Dis. 2012;16(3):631-645.

21. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341-1350.

22. Ryan MC, Itsiopoulos C, Ward G, et al. The Mediterranean Diet: Improvement in Hepatic Steatosis and Insulin Sensitivity in Individuals with Nafl d. Hepatology. 2011;54:465a-466a.

23. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(3):229-241.

24. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fi brosis. Hepatology. 2012;55(2):429-436.

25. Anty R, Marjoux S, Iannelli A, et al. Regular coffee but not espresso drinking is protective against fi brosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J Hepatol. 2012;57(5):1090-1096.

26. Torres DM, Harrison SA. Is it time to write a prescription for coffee? Coffee and liver disease. Gastroenterology. 2013;144(4):670-672.

27. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-129.

28. Patel AA, Torres DM, Harrison SA. Effect of weight loss on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2009;43(10):970-974.

29. Johnson NA, Sachinwalla T, Walton DW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50(4):1105-1112.

30. Finucane FM, Sharp SJ, Purslow LR, et al. The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial. Diabetologia. 2010;53(4):624-631.

31. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of nonalcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56(1):255-266.

32. Idilman R, Mizrak D, Corapcioglu D, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28(2):200-208.

33. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-2307.

34. Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenter- ology. 2008;135(1):100-110.

35. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176-1184.

36. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-1685.

37. Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in nonalcoholic steatohepatitis—a systematic review and meta analysis. J Hepatol. 2011;55(6):1383-1390.

38. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39(3):770-778.

39. Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4(12):1537-1543.

40. Santos VN, Lanzoni VP, Szejnfeld J, Shigueoka D, Parise ER. A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Braz J Med Biol Res. 2003;36(6):723-729.

41. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology. 2009;49(1):80-86.

42. Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfi brozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999;31(2):384.

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