https://doi.org/10.5812/jhrt-119454

Non-alcoholic Steatohepatitis Diagnosis and Treatment Medical and Surgery, Based on Guideline Updates: A Mini Review

authors:

avatar Mohsen Arabi 1 , avatar Raheleh Alimoradzadeh ORCID 2 , avatar Alireza Makian 2 , avatar Seyed Javad Shariat Nabavi 3 , avatar Farshad Divsalar 4 , avatar Mitra Kazemi Jahromi ORCID 5 , *

Family Medicine Department, Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
Firoozabadi Clinical Research Development Unit (FACRDU), University of Medical Sciences (IUMS), Tehran, Iran
Isfahan AL-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Infectious Diseases and Tropical Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
Endocrinology and Metablism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
Journal of Health Reports and Technology: Vol.8, issue 3; e119454
published online: June 28, 2022
article type: Review Article
received: September 11, 2021
revised: February 7, 2022
accepted: March 4, 2022

How To Cite Arabi M, Alimoradzadeh R, Makian A, Shariat Nabavi S J, Divsalar F, et al. Non-alcoholic Steatohepatitis Diagnosis and Treatment Medical and Surgery, Based on Guideline Updates: A Mini Review. J Health Rep Technol. 2022;8(3):e119454. https://doi.org/10.5812/jhrt-119454.

Abstract

Nonalcoholic fatty liver disease (NAFLD) refers to fat accumulation in hepatic cells due to alcohol consumption, hepatitis, and drugs. The prevalence of this disease has been reported at 20 - 50% in western and 12 - 13% in Latin countries. Patients who suffer from obesity, diabetes, and insulin resistance may be affected more than others. This disease is symptomless, and its paraclinical diagnosis is achievable by increasing the hepatic enzymes. Ultrasonography and fibroscan are some of the common diagnostic methods for this disease. The first treatment for this disease is weight loss and physical activities. Vitamin E can improve histopathological changes in terms of medications. While pioglitazone is an effective blood sugar-lowering drug, metformin has no role in treating diabetes or prediabetes.

1. Context

Nonalcoholic fatty liver refers to fat accumulation (over 5%) in the liver cells due to alcohol consumption, hepatitis C, and drugs (1-5). NAFLD is classified into two groups, including nonalcoholic fatty liver and nonalcoholic steatohepatitis. The former case is a benign fat accumulation in hepatic cells with no progress. However, the histopathology of NASH led to the hepatic cells damage and inflammation. The progress to hepatic cirrhosis and even HCC in such cases is probable (6-10). This disease is accompanied by obesity, diabetes, dyslipidemia, and other symptoms of metabolic syndrome.

Nonalcoholic fatty liver should be considered in cases of minimal alcohol consumption (6, 11). The NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Furthermore, NAFL is considered one of the most common reasons to develop chronic liver disease, as well as one of the most significant health problems (7, 10-13). Further, NAFLD is related to obesity, diabetes, dysplasia, and hypertension involving liver manifestations in metabolic syndrome. NAFLD histology has been identified as hepatic steatosis and divided into nonalcoholic fatty liver and nonalcoholic steatohepatitis. NAFL is often considered a benign clinical condition without progress, while NASH can lead to cirrhosis and HCC carcinoma. Additionally, NASH is histologically distinguished by liver steatosis, which may lead to liver cell damage and inflammation (10-14).

2. Methods

The evidence reported in the current review was obtained through searching for publications available on MEDLINE, ISI Web of Science, and EMBASE through January 2022 using the following keywords: “Nonalcoholic fatty liver,” “NAFLD,” “NASH,” “Nonalcoholic Steatohepatitis,” “diagnosis,” “treatment,” and “guideline.” Relevant papers with acceptable quality were considered for this study.

In this review, we evaluated the prevalence of fatty liver disease, its clinical features, diagnosis, and treatment. In addition, we focused on evidence related to lifestyle intervention, medical treatment, surgery, and liver transplantation as various choices in the treatment and management of liver disease.

2.1. Prevalence

The prevalence of NAFLD relies on the studies population and its definition (15-18), which is about 20 - 40% in the Western countries and 12 - 30% in Asian countries. Based on the data related to the annual aging survey, 9 - 30% of Japanese adults were diagnosed with ultrasound (US). NASH occurs in 10 - 20% of the cases of NAFLD, with an estimated prevalence of 3 - 5% worldwide. In addition, NAFLD/NASH is mainly identified in middle-aged postmenopausal women and men (19-27).

The severity of risk factors can lead to more prevalence of NAFLD, 10 - 20% of which are related to non-obese subjects, while about 50% have a BMI of more than 25 kg.m-2 (however, less than 30 kg.m-2), 80% of those have BMI more than 30 kg.m-2. Further, NAFLD is common among about 50% of patients with type 2 diabetes (6).

The number of NAFLD is 20 - 30% of the whole population, while 2 - 3% are recognized with NASH. In addition, NAFLD is more prevalent among people with central obesity, type 2 diabetes, insulin resistance, dyslipidemia, and high blood pressure (7, 8, 28, 29).

2.2. Clinical Features

NAFLD is asymptomatic based on the EASL guideline except for cirrhosis in the liver. Hence, NAFLD should be detected during regular checkups or clinical reviews of other diseases. Most patients with NAFLD are obese, and many have type 2 diabetes, dyslipidemia, and/or high blood pressure. Therefore, NAFLD has not considered a liver disease, but a metabolic syndrome (5). The NAFLD is defined according to the three criteria, including nonalcoholic, detection of steatosis either by imaging or histology, and proper exclusion of other liver diseases. Hence, NAFLD patients have a fatty liver with no inflammation or tissue damage. However, NASH is determined based on steatohepatitis on liver biopsy, which is associated with inflammation and tissue damage.

2.3. Diagnosis

Ultrasonography is the first and most common diagnostic method in NAFLD. The major finding in the ultrasonography analysis is the increased hepatic echogenicity (6). This method does not suffice in ruling out the other causes of steatosis, such as viral and medication-related hepatitis (13). Measurement of the hepatic fibrosis biomarkers, such as FIBS.APRI and elastography are among the other non-invasive methods of NAFLD diagnosis. These methods can help diagnose and evaluate of the fibrosis severity in NAFLD patients and decline the need for biopsy (Figure 1) (5).

Diagnostic flow-chart for evaluating and monitoring the disease severity in the presence of suspected NAFLD and cardio-metabolic factors. (1) Steatosis biomarkers: Fatty Liver Index, Steato Test, NAFLD fat score; (2) Liver tests: ALT, AST or GGT; (3) Any increase in ALT, AST, or GGT; (4) Serum fibrosis markers: NAFLD Fibrosis Score, FIB-4, Commercial tests (e.g., FibroTest, FibroMeter, or ELF scores); (5) Low risk: Showing no/mild fibrosis; medium/high risk indicates significant fibrosis or cirrhosis.
Diagnostic flow-chart for evaluating and monitoring the disease severity in the presence of suspected NAFLD and cardio-metabolic factors. (1) Steatosis biomarkers: Fatty Liver Index, Steato Test, NAFLD fat score; (2) Liver tests: ALT, AST or GGT; (3) Any increase in ALT, AST, or GGT; (4) Serum fibrosis markers: NAFLD Fibrosis Score, FIB-4, Commercial tests (e.g., FibroTest, FibroMeter, or ELF scores); (5) Low risk: Showing no/mild fibrosis; medium/high risk indicates significant fibrosis or cirrhosis.
Figure 1.

Diagnostic flow-chart for evaluating and monitoring the disease severity in the presence of suspected NAFLD and cardio-metabolic factors. (1) Steatosis biomarkers: Fatty Liver Index, Steato Test, NAFLD fat score; (2) Liver tests: ALT, AST or GGT; (3) Any increase in ALT, AST, or GGT; (4) Serum fibrosis markers: NAFLD Fibrosis Score, FIB-4, Commercial tests (e.g., FibroTest, FibroMeter, or ELF scores); (5) Low risk: Showing no/mild fibrosis; medium/high risk indicates significant fibrosis or cirrhosis.

2.4. Biopsy Indication

The indications of biopsy conductance in NASH are: (1) in patients with an increased chance of disease progression, and biopsy should be repeated every five years in these patients; (2) high hepatic enzyme levels, which increases AST/ALT for three months (3, 30); (3) metabolic syndrome, in which patients do not respond to the treatment for 6 months; (4) ruling out the other causes of chronic hepatic diseases (31, 32).

2.5. Treatment

2.5.1. Lifestyle Intervention

About 3 - 5% weight loss can effectively improve steatosis, and 25% calorie reduction can also be included. Physical activities should be 3 - 4 times a week in 30 - 60 min fast walking (14, 32).

2.5.2. Medical Treatment

2.5.2.1. Vitamin E

Vitamin consumption (800 IU/day) is accompanied by reduced hepatic enzymes and histological improvements (33-37).

Some studies reported the non-effectiveness of vitamin E among diabetic patients (32).

WJG and EGO guidelines did not mention vitamin E administration (Table 1).

Table 1.

Medical Treatment Based on Guidelines Updates

VariablesWGO GUIDELINEWJGEASLBrazil
ThiazolidineNot recommend (14)NASH patients, particularly with fibrosis (≥ stage F2) (13)It is utilized for the selected NASH patients (5)It is used for treating steatohepatitis diagnosed through biopsy (31)
MetforminNot recommend (14)Not recommend (13)Little evidence is available for a histological effect of metformin in NASH (5)Not recommend (31)
Vitamin ENot recommend (14)Not recommend (13)Vitamin E (800 IU/day) can play a role in improving steatosis, inflammation, ballooning, and induced resolution among 36% NASH patients (5)Vitamin E (800IU/day) is suggested for the patients by diagnosing histologically; No evidence is available for suggesting vitamin E for diabetic patients (31)
Ursodeoxycholic acid (UDCA)--Indicated some biochemical without any histological improvement (5)Not recommend (31)

2.5.2.2. Metformin

AASLD, WJG, EASL, and WGO did not mention histological improvement and reduced hepatic enzymes by metformin consumption (10, 38) (Tables 1 - 2).

Table 2.

Medical Treatment Based on Guideline Updates

VariablesAASLDJapan
ThiazolidineIt is implemented to cure steatohepatitis among biopsy-proven NASH patients (10)Patients with insulin resistance (6)
MetforminNot recommend (10)Not recommend (6)
Vitamin EVit E: Vitamin consumption (800 IU/day) is accompanied by reduced hepatic enzymes and histological improvements (34-36). Vitamin E is not suggested to cure NASH among diabetic patients (10).Some studies reported the non-effectiveness of vitamin E among diabetic patients.
Ursodeoxycholic acid (UDCA)Not recommend (10)Not recommend (6)

2.5.2.3. Pioglitazone

This drug has been recommended in the studied guidelines for diabetic and prediabetic patients suffering from NFLD, but it was not recommended by WGO guidelines (10, 39) (Table 1).

2.5.2.4. HMG-CoA Reductase Inhibitors (Statins)

This drug class has not been recommended in any of the studied guidelines. Japan guidelines only recommended it in NFLD patients with simultaneous dyslipidemia (6, 40-42).

2.5.2.5. UDCA

It is not recommended in any of the guidelines, the European guideline only mentioned partial hepatic enzyme improvement with no effect on the histological improvements (5, 42-46).

2.5.2.6. Pentoxifylline

It is only mentioned in Japanese guidelines and EASL for a slight improvement in histology in stages above or equal to 2. The minor improvement in liver-related complications are perisinusoidal and periportal lesion (stage 2 fibrosis), bridging fibrosis (stage 3 fibrosis), cirrhosis (stage 4 fibrosis) (5, 6, 47-51).

2.5.2.7. Angiotensin II Receptor Antagonist

Angiotensin II receptor antagonists (ARB) are recommended for NASH patients suffering from hypertension (52-54).

2.5.2.8. Iron Depletion

Iron depletion can improve the NAS score without worsening fibrosis (55). The Pathology Committee of the NASH Clinical Research Network designed and proposed a validated histological feature scoring system to determine all spectrum of damages of NAFLD. The scoring system of NAS includes 14 histological characteristics, four of which are assessed semi-quantitatively: (1) steatosis (0 - 3); (2) lobular inflammation (0 - 2); (3) hepatocellular ballooning (0 - 2); and (4) fibrosis (0 - 4). Another nine features are considered to be present or absent (56).

2.5.3. Surgery

2.5.3.1. Bariatric (Metabolic) Surgery

Bariatric surgery is regarded as an alternative for metabolic complications to reduce weight among patients, who cannot adapt to lifestyle changes and pharmacotherapy, along with consistent results during the long term (41-43, 55). Laparoscopic Roux-gastric bypass surgery is valuable and cost-effective in obese patients (BMI ≥ 30 kg/m2) with mild, moderate, and severe NASH in all three stages of fibrosis (F0 - F3), which is only helpful and cost-effective in the F3 stage in overweight NASH patients (BMI: 25 - 29.9 kg/m2).

2.5.3.2. Liver Transplantation

Liver transplantation is considered a suitable procedure for Nonalcoholic steatohepatitis. Patients experiencing liver failure and/or Hepatocellular carcinoma are regarded as the candidates for liver transplantation (49-51).

3. Conclusions

Hepatic cirrhosis can develop from untreated fatty liver disease, which can even progress toward hepatocellular carcinoma as one of the most common hepatic diseases. Laboratory evaluations and ultrasonography in high-risk patients (diabetes, obesity) are crucial in their symptomless nature. Lifestyle change is the primary treatment for this disease, and medications such as vitamin E and pioglitazone are also helpful.

References

  • 1.

    Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372-84. [PubMed ID: 20494470]. https://doi.org/10.1016/j.jhep.2010.04.008.

  • 2.

    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6. [PubMed ID: 18436948]. [PubMed Central ID: PMC2335261]. https://doi.org/10.1136/bmj.39489.470347.AD.

  • 3.

    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(2):112-7. [PubMed ID: 10644271]. https://doi.org/10.7326/0003-4819-132-2-200001180-00004.

  • 4.

    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274-85. [PubMed ID: 21623852]. https://doi.org/10.1111/j.1365-2036.2011.04724.x.

  • 5.

    European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402. [PubMed ID: 27062661]. https://doi.org/10.1016/j.jhep.2015.11.004.

  • 6.

    Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatol Res. 2015;45(4):363-77. [PubMed ID: 25832328]. https://doi.org/10.1111/hepr.12511.

  • 7.

    Sanyal AJ, American Gastroenterological A. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1705-25. [PubMed ID: 12404245]. https://doi.org/10.1053/gast.2002.36572.

  • 8.

    Chan HL, de Silva HJ, Leung NW, Lim SG, Farrell GC, Asia-Pacific Working Party on N. How should we manage patients with non-alcoholic fatty liver disease in 2007? J Gastroenterol Hepatol. 2007;22(6):801-8. [PubMed ID: 17565632]. https://doi.org/10.1111/j.1440-1746.2007.04977.x.

  • 9.

    Okanoue T. JSH Consensus Kobe 2009: diagnosis and treatment of NASH. Kanzo. 2009;50:741-7.

  • 10.

    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107(6):811-26. [PubMed ID: 22641309]. https://doi.org/10.1038/ajg.2012.128.

  • 11.

    Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319-34. [PubMed ID: 28107283]. [PubMed Central ID: PMC5413933]. https://doi.org/10.1097/MPG.0000000000001482.

  • 12.

    Bagheri Lankarani K, Ghaffarpasand F, Mahmoodi M, Lotfi M, Zamiria N, Heydari ST, et al. Non Alcoholic Fatty Liver Disease in Southern Iran: A Population Based Study. Hepat Mon. 2013;13(5). e9248. [PubMed ID: 23922564]. [PubMed Central ID: PMC3734894]. https://doi.org/10.5812/hepatmon.9248.

  • 13.

    Zhu JZ, Hollis-Hansen K, Wan XY, Fei SJ, Pang XL, Meng FD, et al. Clinical guidelines of non-alcoholic fatty liver disease: A systematic review. World J Gastroenterol. 2016;22(36):8226-33. [PubMed ID: 27688665]. [PubMed Central ID: PMC5037092]. https://doi.org/10.3748/wjg.v22.i36.8226.

  • 14.

    Review T, LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, et al. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48(6):467-73. [PubMed ID: 24921212]. https://doi.org/10.1097/MCG.0000000000000116.

  • 15.

    Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2012;47(5):586-95. [PubMed ID: 22328022]. https://doi.org/10.1007/s00535-012-0533-z.

  • 16.

    Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124-31. [PubMed ID: 20858492]. https://doi.org/10.1053/j.gastro.2010.09.038.

  • 17.

    Hou XH, Zhu YX, Lu HJ, Chen HF, Li Q, Jiang S, et al. Non-alcoholic fatty liver disease's prevalence and impact on alanine aminotransferase associated with metabolic syndrome in the Chinese. J Gastroenterol Hepatol. 2011;26(4):722-30. [PubMed ID: 21418302]. https://doi.org/10.1111/j.1440-1746.2010.06509.x.

  • 18.

    Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;25(8):883-9. [PubMed ID: 17402991]. https://doi.org/10.1111/j.1365-2036.2007.03246.x.

  • 19.

    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-95. [PubMed ID: 15565570]. https://doi.org/10.1002/hep.20466.

  • 20.

    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(3):664-9. [PubMed ID: 10051466]. https://doi.org/10.1002/hep.510290347.

  • 21.

    Yoshioka Y, Hashimoto E, Yatsuji S, Kaneda H, Taniai M, Tokushige K, et al. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol. 2004;39(12):1215-8. [PubMed ID: 15622489]. https://doi.org/10.1007/s00535-004-1475-x.

  • 22.

    Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y, Onji M, et al. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2010;45(1):86-94. [PubMed ID: 19789837]. https://doi.org/10.1007/s00535-009-0128-5.

  • 23.

    Tokushige K, Hashimoto E, Horie Y, Taniai M, Higuchi S. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey. J Gastroenterol. 2011;46(10):1230-7. [PubMed ID: 21748549]. https://doi.org/10.1007/s00535-011-0431-9.

  • 24.

    Mencin AA, Lavine JE. Nonalcoholic fatty liver disease in children. Curr Opin Clin Nutr Metab Care. 2011;14(2):151-7. [PubMed ID: 21178608]. https://doi.org/10.1097/MCO.0b013e328342baec.

  • 25.

    Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50(4):1282-93. [PubMed ID: 19637286]. [PubMed Central ID: PMC2757471]. https://doi.org/10.1002/hep.23119.

  • 26.

    Nobili V, Alisi A, Panera N, Agostoni C. Low birth weight and catch-up-growth associated with metabolic syndrome: a ten year systematic review. Pediatr Endocrinol Rev. 2008;6(2):241-7. [PubMed ID: 19202511].

  • 27.

    Nobili V, Marcellini M, Marchesini G, Vanni E, Manco M, Villani A, et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care. 2007;30(10):2638-40. [PubMed ID: 17536073]. https://doi.org/10.2337/dc07-0281.

  • 28.

    Chen CH, Huang MH, Yang JC, Nien CK, Yang CC, Yeh YH, et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol. 2006;40(8):745-52. [PubMed ID: 16940890]. https://doi.org/10.1097/00004836-200609000-00016.

  • 29.

    Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol. 2003;38(10):954-61. [PubMed ID: 14614602]. https://doi.org/10.1007/s00535-003-1178-8.

  • 30.

    Sohrabpour A, Rezvan H, Amini-Kafiabad S, Dayhim M, Merat S, Pourshams A. Prevalence of Nonalcoholic Steatohepatitis in Iran: A Population based Study. Middle East J Dig Dis. 2010;2(1):14-9. [PubMed ID: 25197507]. [PubMed Central ID: PMC4154901].

  • 31.

    Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998;114(4):842-5. [PubMed ID: 9547102]. https://doi.org/10.1016/s0016-5085(98)70599-2.

  • 32.

    Cotrim HP, Parise ER, Figueiredo-Mendes C, Galizzi-Filho J, Porta G, Oliveira CP. Nonalcoholic Fatty Liver Disease Brazilian Society of Hepatology Consensus. Arq Gastroenterol. 2016;53(2):118-22. [PubMed ID: 27305420]. https://doi.org/10.1590/S0004-28032016000200013.

  • 33.

    Tokushige K, Yatsuji S, Hashimoto E, Kabutake A, Tobari M, Taniai M, et al. Familial aggregation in patients with non-alcoholic steatohepatitis. Intern Med. 2008;47(5):405-10. [PubMed ID: 18310971]. https://doi.org/10.2169/internalmedicine.47.0476.

  • 34.

    Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39(4):909-14. [PubMed ID: 15057893]. https://doi.org/10.1002/hep.20140.

  • 35.

    Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66-75. [PubMed ID: 22050199]. [PubMed Central ID: PMC3488596]. https://doi.org/10.1111/j.1365-2036.2011.04912.x.

  • 36.

    Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136(6):734-8. [PubMed ID: 10839868].

  • 37.

    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15(10):1667-72. [PubMed ID: 11564008]. https://doi.org/10.1046/j.1365-2036.2001.01083.x.

  • 38.

    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-85. [PubMed ID: 20427778]. [PubMed Central ID: PMC2928471]. https://doi.org/10.1056/NEJMoa0907929.

  • 39.

    Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology. 2009;49(1):80-6. [PubMed ID: 19053049]. https://doi.org/10.1002/hep.22575.

  • 40.

    Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-9. [PubMed ID: 19827166]. [PubMed Central ID: PMC2799538]. https://doi.org/10.1002/hep.23276.

  • 41.

    Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med. 2014;370(21):2002-13. [PubMed ID: 24679060]. [PubMed Central ID: PMC5451259]. https://doi.org/10.1056/NEJMoa1401329.

  • 42.

    Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H, Raverdy V, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260(5):893-8. discussion 898-9. [PubMed ID: 25379859]. https://doi.org/10.1097/SLA.0000000000000945.

  • 43.

    Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology. 2015;149(2):379-88. quiz e15-6. [PubMed ID: 25917783]. https://doi.org/10.1053/j.gastro.2015.04.014.

  • 44.

    Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135(1):100-10. [PubMed ID: 18503774]. https://doi.org/10.1053/j.gastro.2008.03.078.

  • 45.

    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176-84. [PubMed ID: 18718471]. https://doi.org/10.1053/j.gastro.2008.06.047.

  • 46.

    Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853-60. [PubMed ID: 19811343]. https://doi.org/10.1080/00365520902845268.

  • 47.

    Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial. Therap Adv Gastroenterol. 2009;2(3):157-63. [PubMed ID: 21180541]. [PubMed Central ID: PMC3002518]. https://doi.org/10.1177/1756283X09105462.

  • 48.

    Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51(2):445-53. [PubMed ID: 19877169]. https://doi.org/10.1002/hep.23270.

  • 49.

    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):1249-53. [PubMed ID: 21726509]. https://doi.org/10.1053/j.gastro.2011.06.061.

  • 50.

    Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12(3):394-402 e1. [PubMed ID: 24076414]. https://doi.org/10.1016/j.cgh.2013.09.023.

  • 51.

    Heuer M, Kaiser GM, Kahraman A, Banysch M, Saner FH, Mathe Z, et al. Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience. Digestion. 2012;86(2):107-13. [PubMed ID: 22846254]. https://doi.org/10.1159/000339344.

  • 52.

    Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40(5):1222-5. [PubMed ID: 15382153]. https://doi.org/10.1002/hep.20420.

  • 53.

    Yokohama S, Tokusashi Y, Nakamura K, Tamaki Y, Okamoto S, Okada M, et al. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol. 2006;12(2):322-6. [PubMed ID: 16482638]. [PubMed Central ID: PMC4066047]. https://doi.org/10.3748/wjg.v12.i2.322.

  • 54.

    Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15(8):942-54. [PubMed ID: 19248193]. [PubMed Central ID: PMC2653406]. https://doi.org/10.3748/wjg.15.942.

  • 55.

    Valenti L, Fracanzani AL, Dongiovanni P, Rovida S, Rametta R, Fatta E, et al. A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia. World J Gastroenterol. 2014;20(11):3002-10. [PubMed ID: 24659891]. [PubMed Central ID: PMC3961977]. https://doi.org/10.3748/wjg.v20.i11.3002.

  • 56.

    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-21. [PubMed ID: 15915461]. https://doi.org/10.1002/hep.20701.