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References

References to studies included in this review

Athyros 2006 {published data only}

Athyros VG, Mikhailidis DP, Didangelos TP, Giouleme OI, Liberopoulos EN, Karagiannis A, et al. Effect of multifactorial treatment on non‐alcoholic fatty liver disease in metabolic syndrome: a randomised study. Current Medical Research and Opinion 2006;22(5):873‐83.

Nelson 2009 {published data only}

Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomised placebo controlled trial. Journal of Clinical Gastroenterology 2009;43(10):990‐4.

References to studies excluded from this review

Antonopoulos 2006 {published data only}

Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as a novel treatment of non‐alcoholic fatty liver disease in hyperlipidaemic patients. Atherosclerosis 2006;184:233‐4.

Athyros 2010 {published data only}

Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long‐term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study: a post‐hoc analysis. Lancet 2010;376:1916‐22.

Carnelutti 2012 {published data only}

Carnelutti A, Donnini D, Nadalutti G, De Luca L, Cappello D, Cugini F, et al. Effect of statin therapy vs diet in hypercholesterolaemia patients affected by nonalcoholic steatohepatitis (NASH). Digestive and Liver Disease 2012;44S:S25.

Gomez 2006 {published data only}

Gomez‐Dominguez E, Gisbert JP, Moreno‐ Monteagudo JA, Garcia‐Buey L, Moreno‐Otero R. A pilot study of atorvastatin treatment in dyslipemic, non‐alcoholic fatty liver patients. Alimentary Pharmacology and Therapeutics 2006;23:1643‐7.

Han 2012 {published data only}

Han KH, Rha SW, Kang HJ, Bae JW, Choi BJ, Choi SY, et al. Evaluation of short‐term safety and efficacy of HMG‐CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). Journal of Clinical Lipidology 2012;6(4):340‐51.

Harlander 2001 {published data only}

Harlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120A:544.

Hatzitolios 2004 {published data only}

Hatzitolios A, Savopoulos C, Lazaraki G, Sidiropoulos I, Haritanti P, Lefkopoulos A, et al. Efficacy of omega‐3 fatty acids, atorvastatin and orlistat in non‐alcoholic fatty liver disease with dyslipidaemia. Indian Journal of Gastroenterology 2004;23:131‐4.

Kiyici 2003 {published data only}

Kiyici M, Gulten M, Gurel S, Nak SG, Dolar E, Savci G, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Canadian Journal of Gastroenterology 2003;17(12):713‐8.

Lewis 2007 {published data only}

Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, et al. Efficacy and safety of high‐dose pravastatin in hypercholesteraemic patients with well compensated chronic liver disease: results of a prospective, randomised, double blind, placebo‐controlled, multicenter trial. Hepatology 2007;46(5):1453‐63.

Rallidis 2004 {published data only}

Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193‐6.

Tavakkoli 2009 {published data only}

Tavakkoli H, Adilipour H, Ghaemaghami Z, Minakari M, Adibi P. Simvastatin in treatment of non‐alcoholic steatohepatitis: a clinical trial. Govaresh 2009;14:28.

Additional references

AGA 2012

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 Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592–609.

Ahmed 2006

Ahmed MH. Rosuvastatin: a safe and effective treatment for dyslipidaemia associated with non‐alcoholic steatohepatitis (NASH). Scandinavian Journal of Gastroenterology 2006;41(5):631.

Athyros 2005

Athyros VG,  Mikhailidis DP,  Papageorgiou AA,  Didangelos TP,  Peletidou A,  Kleta D,  et al. Targeting vascular risk in patients with metabolic syndrome but without diabetes. Metabolism 2005;54:1065‐74.

Bacon 1994

Bacon BR, Faravash MJ, Janney CG, Neuschwander‐Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103‐9.

Ballantyne 2003

Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, et al. Risk for myopathy with statin therapy in high‐risk patients. Archives of Internal Medicine 2003;163:553‐64.

Brunt 1999

Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander‐Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. American Journal of Gastroenterology 1999;94:2467‐74.

Brunt 2001

Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Seminars in Liver Disease 2001;21(1):3‐16.

Brunt 2005

Brunt EM. NASH: pathologic features and differential diagnosis. Seminars in Diagnostic Pathology 2005;22:330‐8.

Brunt 2007

Brunt EM. Pathology of fatty liver disease. Modern Pathology 2007;20 Suppl 1:S40.

Cello 1990

Cello JP, Grendell JH. The liver in systemic conditions. In: Zakim D, Boyer TD editor(s). Hepatology. Philadelphia: WB Saunders, 1990:1428.

Cheung 2008

Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Seminars in Liver Disease 2008;28(4):351‐9.

Fujita 2009

Fujita K,  Nozaki Y,  Wada K,  Yoneda M,  Fujimoto Y,  Fujitake M,  et al. Dysfunctional very‐low‐density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 2009;50:772‐80.

Gluud 2001

Gluud C. Alcoholic hepatitis: no glucocorticosteroids?. In: Leuschner U, James OFW, Dancygier H editor(s). Steatohepatitis (NASH and ASH) ‐ Falk Symposium 121. Lancaster: Kluwer Academic Publisher, 2001:322‐42.

Gluud 2007

Gluud C, Brok J, Gong Y, Koretz RL. Hepatology may have problems with putative surrogate outcome measures. Journal of Hepatology 2007;46(4):734‐42.

Gluud 2013

Gluud C, Nikolova D, Klingenberg SL, Alexakis N, Als‐Nielsen B, Colli A, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2013, Issue 11. Art. No.: LIVER.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane‐handbook.org.

Hsiao 2007

Hsiao PJ, Kuo KK, Shin SJ, Yang YH, Lin WY, Yang JF, et al. Significant correlations between severe fatty liver and risk factors for metabolic syndrome. Journal of Gastroenterology and Hepatology 2007;22(12):2118‐23.

ICH‐GCP 1997

International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, PA 19063‐2043, USA: Barnett International/PAREXEL, 1997.

Istvan 2001

Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG‐CoA reductase. Science 2001;292:1160‐4.

Jakobsen 2013

Jakobsen JC, Gluud C. The necessity of randomized clinical trials. British Journal of Medicine and Medical Research 2013;3(4):1453‐68.

Kashani 2006

Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006;114:2788‐97.

Kjaergard 2001

Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9.

Kliener 2005

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;41:1313‐21.

Lee 1988

Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Human Pathology 1989;20:594‐8.

Lomas 1991

Lomas J. Words without action? The production, dissemination, and impact of consensus recommendations. Annual Review of Public Health 1991;12:41‐65.

Ludwig 1980

Ludwig J, Viggiano TR, McGill DB, Ott BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings 1980;55:434‐8.

Lundh 2012

Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.MR000033.pub2]

Moher 1998

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13.

NCEP ATP III report

Executive summary of the third report of the National Cholesterol Education Program (NCEP), Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA2001; Vol. 285:2486‐97.

Ness 1996

Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low density lipoprotein receptor protein degradation. Archives of Biochemistry and Biophysics 1996;325:242‐8.

Poonam 2007

Poonam M, Zobair M. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). American Journal of Gastroenterology 2007;102:2716‐7.

Powell 1990

Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell W. The natural history of nonalcoholic steatohepatitis: a follow up study of forty‐two patients for up to 21 years. Hepatology 1990;11(1):74‐80.

Puri 2007

Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, et al. A lipidemic analysis of nonalcoholic fatty liver disease. Hepatology 2007;46(4):1081‐90.

Rofsky 1995

Rofsky NM, Fleshaker H. CT and MRI of diffuse liver disease. Seminars in Ultrasound, CT, and MR 1995;16:16‐33.

Royle 2003

Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603.

Saadeh 2002

Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745‐50.

Sanyal 2001

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(5):1183‐92.

Savovic 2012

Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Health Technology Assessment 2012;16(35):1‐82.

Savovic 2012a

Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Annals of Internal Medicine 2012;157(6):429‐38.

Schulz 1995

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12.

Schwenzer 2009

Schwenzer NF,  Springer F,  Schraml C,  Stefan N,  Machann J,  Schick F. Non‐invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. Journal of Hepatology 2009;51(3):433‐5.

Taylor 2013

Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD004816.pub5]

Tobert 1988

Tobert JA. Efficacy and long‐term adverse effect pattern of lovastatin. American Journal of Cardiology 1988;62:28J.

Vale 2011

Vale N, Nordmann AJ, Schwartz GG, de Lemos J, Colivicchi F, den Hartog F, et al. Statins for acute coronary syndrome. Cochrane Database of Systematic Reviews 2011, Issue 6. [DOI: 10.1002/14651858.CD006870.pub2]

Villanueva 2009

Villanueva CJ,  Monetti M,  Shih M,  Zhou P,  Watkins SM,  Bhanot S,  et al. Specific role for acyl CoA: Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 2009;50:434‐42.

Wang 2006

Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006;147(2):943‐51.

Wei 2006

Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. American Journal of Physiology, Endocrinology and Metabolism 2006;291(2):E275‐81.

Wood 2008

Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5.

Yeh 2007

Yeh MM, Brunt EM. Pathology of nonalcoholic fatty liver disease. American Journal of Clinical Pathology 2007;128:837‐4.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Athyros 2006

Methods

Randomised clinical trial with three parallel groups

Participants

Participants were free of diabetes mellitus (DM) (ie, fasting glucose levels < 7 mmol/L; 126 mg/dL) and cardiovascular disease (diagnosed on the basis of personal history, clinical examination findings, and non‐invasive methods).

The inclusion criteria were (a) the presence of the metabolic syndrome (MetS) (NCEP ATP III definition) (NCEP ATP III report), (b) low‐density lipoprotein cholesterol (LDL‐C) > 3.4 mmol/L (130 mg/dL), (c) ultrasonographic evidence of fatty liver, and (d) elevated serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) activity.

Other causes of liver disease were excluded.

Interventions

189 participants were randomly allocated to atorvastatin 20 mg/day (n = 63) versus micronised fenofibrate 200 mg/day (n = 62) versus both drugs (n = 61). All participants had both biochemical and ultrasonographic evidence of NAFLD at baseline.

All participants received:

  • lifestyle advice, including exercise (walking for at least 30 min, 5 days a week, or equivalent exercise) and a low‐fat and low‐calorie diet (NCEP ATP III report); and

  • treatment for hypertension (mainly inhibitors of the renin‐angiotensin system), impaired fasting glucose (metformin), obesity (orlistat), and dyslipidaemia (randomly allocated to atorvastatin 20 mg/day (n = 63) or micronised fenofibrate 200 mg/day (n = 62) or both drugs (n = 61)).

Outcomes

At the end of treatment, 67% of participants taking atorvastatin, 42% taking fenofibrate, and 70% taking combination treatment no longer had biochemical plus ultrasonographic evidence of NAFLD (P < 0.05 versus baseline for all comparisons).

The percentage of participants who no longer had evidence of NAFLD was significantly higher (P < 0.009) in the atorvastatin and combination groups compared with the fenofibrate group.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers were used for generation of allocation sequence.

Allocation concealment (selection bias)

Unclear risk

The method of allocation concealment was unclear.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

It was an open‐labelled trial.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It was an open‐labelled trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes, dropouts, and withdrawals were pointed out precisely in the trial.

Selective reporting (reporting bias)

Low risk

All relevant outcomes were available in the trials. No reporting bias was detected.

Other bias

Unclear risk

It is not clear whether sample size calculations were performed.

Nelson 2009

Methods

Double‐blind randomised placebo‐controlled trial with two parallel groups.

Participants

Sixteen adults, 18 years of age or older, with documented NASH based on liver biopsy using criteria established by Brunt et al (Brunt 2005), were included. All participants had compensated liver disease with haemoglobin values of 12 g/dL or greater in females and 13 g/dL or greater in males; a white blood cell count > 3000/mm3, neutrophil count > 1500/mm3, platelets > 70,000/mm3, albumin > 3.0 g/dL, in addition to normal total bilirubin, prothrombin time, and International normalised ratio. Other requirements included serum creatinine < 1.4 mg/dL and elevated serum lipid panel manifested by total cholesterol > 200 mg/dL, LDL > 130 mg/dL, or TGs > 200 mg/dL.

Interventions

Participants were randomly assigned to receive simvastatin 40 mg (n = 10) versus placebo (n = 6) once daily for 12 months.

Outcomes

Fourteen participants completed the trial, and 10 underwent 1 year repeated liver biopsy. Although a 26% reduction in low‐density lipoprotein was seen in the simvastatin group compared with the placebo group, no statistically significant improvement in serum aminotransferases, hepatic steatosis, necro‐inflammatory activity, or stage of fibrosis was noted within or between groups.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method was not reported.

Allocation concealment (selection bias)

Unclear risk

The method was not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The trial was described as double‐blind, but it was not reported who was blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The trial was described as double‐blind, but it was not reported who was blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Reported data about the withdrawals were unclear.

Selective reporting (reporting bias)

High risk

Not all outcomes were reported.

Other bias

Unclear risk

It is not clear whether sample size calculations were performed.

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Antonopoulos 2006

Inappropriate study design (uncontrolled clinical trial).

Athyros 2010

A few participants in the control group received statin.

Carnelutti 2012

Only an abstract of the study was available.

Gomez 2006

Inappropriate study design (uncontrolled clinical trial).

Han 2012

Both intervention and control groups received statin.

Harlander 2001

Inappropriate study design (uncontrolled clinical trial).

Hatzitolios 2004

Inappropriate study design (controlled before and after clinical trial).

Kiyici 2003

Inappropriate study design (uncontrolled clinical trial).

Lewis 2007

Inappropriate participants (patients with chronic liver disease).

Rallidis 2004

Inappropriate study design (uncontrolled clinical trial).

Tavakkoli 2009

Inappropriate study design (uncontrolled clinical trial).

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 1

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Table 1. Search results

Source of the search

Number of records

CHBG Controlled Trial Register

51

Cochrane Central Register of Controlled Trials

78

MEDLINE (Ovid)

116

EMBASE (Ovid)

518

Science Citation Index EXPANDED

91

Total number of references identified

851

Number of duplicates excluded

198

Number of references in final list

653

Figures and Tables -
Table 1. Search results
Table 2. Baseline and after treatment laboratory variables in Nelson et al trial

 

Statin (n = 10)

Placebo  (n = 6)

Before treatment

After treatment

Mean decrease

Before treatment

After treatment

Mean decrease

ALT (U/L)

70.4

49.5

20.9

66.8

75.3

‐8.5

AST (U/L)

43.3

36.5

6.8

42.8

49.3

‐6.5

ALP (U/L)

86.1

89.7

‐3.6

74.3

73

1.3

TG (mg/dL)

388.7

490

‐101.3

335.3

361.7

‐26.4

ALT = alanine aminotransferase
AST = aspartate aminotransferase
ALP = alkaline phosphatase
TG = triglycerides

Figures and Tables -
Table 2. Baseline and after treatment laboratory variables in Nelson et al trial
Table 3. Baseline and after treatment laboratory variables in Athyros et al trial

 

Statin (n = 63)

Fenofibrate  (n = 62)

Before treatment

After treatment

Mean decrease

Before treatment

After treatment

Mean decrease

ALT (U/L)

54

32

22

52

36

16

AST (U/L)

38

25

13

39

27

12

ALP (U/L)

110

75

35

108

78

30

TG (mg/dL)

203.8

142.2

61.6

194.9

115.6

79.3

ALT = alanine aminotransferase
AST = aspartate aminotransferase
ALP = alkaline phosphatases
TG = triglycerides

Figures and Tables -
Table 3. Baseline and after treatment laboratory variables in Athyros et al trial
Table 4. Level of evidence for each outcome

Outcome

Biochemical improvement

 

Radiological improvement

No improvement in histology

Serious adverse effects

Evidence

Low‐quality systematic review

Low‐quality randomised clinical trial

Small sample size in low‐quality randomised clinical trial

Low‐quality systematic review

 

Level of evidence

2

2

2

2

Grade of recommendation

B

B

B

B

Figures and Tables -
Table 4. Level of evidence for each outcome