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Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (nafld) not responding to lifestyle interventions*

Annals of Hepatology 2007; 6(4): October-December: 222-226 Original Article
Metformin is effective in achieving biochemical
response in patients with nonalcoholic fatty liver disease
(NAFLD) not responding to lifestyle interventions*
Ajay Duseja;1 Ashim Das;2 Radha Krishan Dhiman;1 Yogesh Kumar Chawla;1 Kiran K. Thumburu;1 Sanjay Bhadada;3 Anil Abstract
same cohort treated only with lifestyle interventions
(disease controls). Results:
Thirteen (52%) patients
Background: Insulin resistance plays an important
had class III (n = 5) or class IV (n = 8) disease amount-
role in the pathogenesis of NAFLD. Pharmacological
ing to histological NASH. Of these 13 patients none
treatment of patients with NAFLD is still evolving. In-
had severe inflammation and none had stage 4 fibro-
sulin sensitizing drugs like metformin may be effec-
sis (cirrhosis). All 25 patients with NAFLD had insulin
tive in these patients. Twenty five adult patients with
resistance in comparison to healthy controls. In com-
NAFLD who did not achieve normalization of alanine
parison to disease controls (127.5 ± 41.8 vs. 118 ±
transaminases (ALT) after 6 months of lifestyle inter-
21.6 p = NS), all patients treated with metformin had
ventions and UDCA were treated with metformin
partial biochemical response (mean ALT 122.2 ± 26.8
500mg tid for 6 months. Insulin resistance was deter-
vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them achieved
mined by HOMA- IR. Liver function tests were done
complete normalization of ALT. Conclusions: Met-
monthly and patients were defined having no re-
formin is effective to achieve biochemical response in
sponse, partial response or complete biochemical re-
patients with NAFLD who do not respond to lifestyle
sponse depending on the change in ALT. Results were
interventions and UDCA.
compared with 25 patients with NAFLD from the
Key words: Nonalcoholic steatohepatitis, NASH, insu-
* This work was presented at the Asian Pacific Digestive Week at lin resistance, diabetes mellitus, metabolic syndrome,
Cebu City, Philippines in November 2006 (J Gastroenterol UDCA, metformin,
Hepatol 2006; 21 (suppl 6): A457).
Introduction
2 Histopathology.
3 Endocrinology.
Nonalcoholic fatty liver disease (NAFLD) includes Postgraduate Institute of Medical Education & Research, patients with simple steatosis and nonalcoholic steato- hepatitis (NASH), which can even progress to cirrhosis and hepatocellular carcinoma.1,2 Pharmacological treat-ment of patients with NAFLD is still evolving and since Nonalcoholic fatty liver disease - NAFLD, nonalcoholic insulin resistance (IR) plays a key role in the pathogene- steatohepatitis - NASH, , insulin resistance -IR, ursodeoxycholic sis of nonalcoholic fatty liver disease (NAFLD), insulin acid - UDCA, alanine transaminase - ALT, hepatitis B surfaceantigen -HBsAg, anti hepatitis C virus antbodies - anti HCV, sensitizing drugs like metformin may have role in the anti-nuclear antibody - ANA, anti-smooth muscle antibody - ASMA, anti-liver kidney microsomal antibody - LKM, anti- Objective of this study was to determine the role of met- mitochondrial antibody - AMA, body mass index -BMI, world formin in achieving biochemical response in patients with health organization – WHO, fasting plasma glucose - FPG, highdensity lipoprotein –HDL, low density lipoprotein - LDL, nonalcoholic fatty liver disease who did not respond to life- triglycerides - TG, tumor necrosis factor alpha - TNF-α, style interventions and ursodeoxycholic acid (UDCA).
homeostasis model assessment for insulin resistance - HOMA- IR.
Patients and methods
Address for correspondence:Dr. Ajay Duseja MD, DM, MNAMS, FACGDepartment of Hepatology Patients
PGIMER Chandigarh, IndiaPhone-91-172-2756336 Fax-91-172-2744401 In a prospective analysis (April 2001 – March 2007), 25 patients with NAFLD who did not have complete biochemi- Manuscript received and accepted: 10 and 17 October 2007 cal response after 6 months of lifestyle interventions and Ajay Duseja et al. Metformin is effective in achieving biochemical response in patients with (NAFLD) UDCA were included in the study after an informed consent.
Metabolic syndrome
The project had the approval of institute’s ethical committee.
Life style interventions included moderate sustained exercise Metabolic syndrome was defined by the presence of at like brisk walking, jogging, swimming, cycling etc at least for least ≥ 3 out of five modified adult treatment panel III 30-45 minutes per day, low fat and low calorie diet and slow criteria including modified abnormal waist as per the weight reduction (10% of base line in 6 months, not more Asia Pacific criteria, FPG >110 mg/dL, hypertension than 1.6 Kg/week) in those with overweight and obesity.
(blood pressure ≥ 130/85 mmHg or on anti-hypertensive UDCA was given in a dosage of 300 mg twice daily. Inclu- drugs), serum triglycerides > 150 mg/dL, and serum high sion criteria were adult (> 16 yrs.) nonalcoholic individuals density lipoprotein (HDL) < 40 mg/dL (males) & < 50 (total abstinence or intake less than 20 g/day, confirmed by two family members) with raised serum alanine aminotrans-ferase (ALT) (> 1.5 x ULN x at least 6 months), ultrasound Histopathology
showing hyperechoic liver or other features of steatosis, nega-tive viral markers (HBsAg, anti HCV - 3rd generation), nega- Histologically patients were classified into four tive autoimmune markers [anti-nuclear antibody (ANA), anti- classes as per Matteoni et al (Class – 1 = Simple ste- smooth muscle antibody (ASMA), anti-liver kidney microso- atosis, Class – 2 = Steatosis + lobular inflammation, mal antibody (LKM), anti-mitochondrial antibody (AMA)], Class – 3 = + Ballooned hepatocytes, Class – 4 = + normal serum ceruloplasmin & absent Keyser Fleisher rings Mallory hyaline or fibrosis) and those patients with on slit lamp examination, normal iron parameters and a liver bi- class 3 or 4 were defined as having NASH.14 Further opsy consistent with NAFLD. Pregnant females and patients patients with NASH were graded and staged according with diabetes mellitus were excluded from the study.
Controls
Insulin resistance
Twenty five patients with NAFLD from the same cohort Insulin resistance was determined by homeostasis with comparable age, gender, BMI, waist, baseline ALT, model assessment for insulin resistance ( HOMA- IR) cal- insulin resistance and metabolic syndrome were included culated as the product of fasting insulin (µU/L) and fast- as disease controls. These patients were also non respond- ing plasma glucose (mmol/L) divided by 22.5. An abso- er to lifestyle interventions and UDCA and were contin- lute value of HOMA-IR > 1.64 was taken as abnormal.3,16 ued on only lifestyle interventions without metformin Treatment and follow up
Anthropometry
Patients were treated with tablet metformin 500 mg/tid for 6 months in addition to the life style interventions.
All patients underwent a detailed physical examina- Disease controls were continued on only lifestyle inter- tion including anthropometry. Overweight (BMI ≥ 23 ventions without metformin. Liver function tests were but < 25 kg/m2), obesity (BMI ≥ 25 kg/m2) and abnor- done monthly and patients were defined as having no re- mal waist circumference [> 90 cm (males), > 80 cm (fe- sponse, partial response or complete biochemical re- males)] were defined as per the Asia Pacific criteria.10,11 sponse depending on the change in ALT.
Biochemistry
Statistical analysis
Diabetes mellitus was defined as per the WHO criteria with fasting plasma glucose (FPG) ≥ 126 mg/dL or plas- All data is expressed in mean ± SD until otherwise ma glucose ≥ 200 mg/dL in a symptomatic patient or a 2- specified. Students‘t’ test, chi square test and Mann- hour plasma glucose on glucose tolerance test ≥ 200 mg/ Whitney U test were used to determine the differences be- dL12 and patients qualifying these criteria were excluded tween different groups. A p value of < 0.05 was taken as from the study. Lipid profile was taken as abnormal when serum cholesterol was > 200 mg/dL, serum high-densitylipoprotein (HDL) < 40 mg/dL in males & < 50 mg/dL in females, serum low-density lipoprotein (LDL) > 130 mg/dL and serum triglycerides were > 150 mg/dL.13 Patients
In addition to measurement of fasting serum insulin levels (radioimmunoassay), fasting C-peptide (ELISA) There were 25 patients (males 17 mean age 36.4 ± 9.2 and serum TNF- α (ELISA) levels were also determined years). Other clinical and biochemical details including metabolic syndrome are shown in Table I.
Annals of Hepatology 6(4) 2007: 222-226 Histopathology
had partial biochemical response (mean ALT 122.2 ±26.8 vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them Details of the histopathology are shown in Table II.
achieved complete normalization of ALT and continue to Thirteen (52%) patients had class III (n = 5) or class IV do so on follow up for 3 months (Figure 1). No patient (n = 8) disease amounting to histological NASH. Of these experienced any side effect and there were no dropouts.
13 patients none had severe inflammation and none hadstage 4 fibrosis (cirrhosis).
Discussion
Insulin resistance
Insulin resistance, which is responsible for increased lipolysis from adipose tissue and hepatic steatosis, is Patients with NAFLD had significantly higher HOMA- very common in patients with NAFLD.3,17 Increased fatty IR in comparison to the historical healthy controls.
acid oxidation, oxidative stress and cytokines may lead (Mean HOMA – IR = 7.6 ± 2.9 vs 1.4 ± 1.2) (p = < 0.01).
on to steatohepatitis and its consequences in some ofthese patients.18 All our patients with NAFLD had IR as Treatment
demonstrated by significantly higher HOMA-IR in com-parison to healthy controls. High C-peptide to insulin ra- Though BMI did not change significantly in both the tio (Table I) in our patients with NAFLD is indicative of groups, in comparison to disease controls (127.5 ± 41.8 primary insulin resistance in these patients rather than vs 118 ± 21.6 p = NS), all patients treated with metformin the hyperinsulinemia occurring due to decreased hepaticextraction of insulin due to any liver disease.1 First line of treatment in patients with NAFLD is al- Table I. Baseline characteristics of 25 patients with NAFLD.
ways weight reduction by life style interventions andcontrol of other risk factors. Pharmacological treatment for NAFLD is still evolving and there is no single agent, which is effective in achieving the complete response.19 Earlier studies did show UDCA to be an effective mode of treatment in these patients20 but a recent randomized placebo controlled trial showed that UDCA is no better than placebo in the treatment of patients with NASH.21 The options in patients like ours who do not respond to above measures are limited. Since insulin resistance is the major pathogenetic mechanism, insulin-sensitizing drugs have a role in the treatment.22-24 Thiazolidinediones group of drugs including troglitazone, rosiglitazone and BMI – Body mass indexALT – Alanine aminotransferaseTNF – Tumor necrosis factorHDL – High-density lipoproteinLDL – Low-density lipoproteinTG – Triglycerides Table II. Liver histology in 25 patients with NAFLD.
NASH (class III+ IV) on histology (n =13) Figure 1. Shows significant change in ALT in the patients who
got metformin (patients) in comparison to those continued on only lifestyle modifications (disease controls). There was nochange in BMI in both groups.
Ajay Duseja et al. Metformin is effective in achieving biochemical response in patients with (NAFLD) pioglitazone have been used in the treatment of NAFLD.
3. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui Troglitazone has been withdrawn from the market due to JM, Fung C, Karim R, et al. NASH and insulin resistance: Insulin its potential hepatotoxicity, which has been described hypersecretion and specific association with the insulin resistancesyndrome. Hepatology 2002; 35: 373-9.
even with rosiglitazone and pioglitazone.22-24 4. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Metformin through its anti- TNF and insulin sensitiz- Sanchez-Avila F, Montano-Reyes MA, Uribe M. Insulin sensitiz- ing actions is an effective drug for achieving biochemi- ers in treatment of nonalcoholic fatty liver disease: Systematic cal response in patients with NAFLD, and data on its use review. World J Gastroenterol 2006 28; 12: 7826-31.
5. Duseja A, Murlidharan R, Bhansali A, Sharma S, Das A, Das R, both experimental25 and in patients4-9 with NAFLD is Chawla Y. Assessment of insulin resistance and effect of evolving. Most of the studies on metformin are open la- metformin in nonalcoholic steatohepatitis – a preliminary report.
bel studies.4,8 One randomized trial using metformin Indian J Gastroenterol 2004; 23: 12-5.
found it to be better than vitamin E and lifestyle inter- 6. Marchesini G, Brizi M, Bianchi G, Tomasserti S, Zoli M, Melchionda N. Metformin in nonalcoholic steatohepatitis. Lan- ventions in improving the liver biochemistry and histo- logical activity including steatosis, inflammation and fi- 7. Uygun A, Kadayifci A, Isik AT, Ozqurtas T, Deveci S, Tuzun A, brosis and none of the patients had any side effects.9 In Yesilova Z, et al. Metformin in the treatment of patients with non- another study 36 patients with NASH were randomized alcoholic steatohepatitis. Aliment Pharmacol Ther 2004; 19: 537-44.
8. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin to lipid and calorie-restricted dietary treatment alone and in the treatment of non-alcoholic steatohepatitis: a pilot open metformin 850 mg b.d. plus dietary treatment for 6 label trial. Aliment Pharmacol Ther 2004; 20: 23-8.
months. The mean serum alanine/aspartate aminotrans- 9. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova ferase, insulin and C-peptide levels decreased and the in- N, David E, et al. A randomized controlled trial of metforminversus vitamin E or prescriptive diet in nonalcoholic fatty liver dex of insulin resistance improved significantly from disease. Am J Gastroenterol 2005; 100: 1082-90.
baseline in the group given metformin, significantly 10. Steering Committee of the Western Pacific region of the World greater than those in the group given dietary treatment Health Organization. The International Association for the study alone. Though not significant, more patients in the met- of Obesity and the International Study Task Force. The Asia-Pacific perspective; redefining obesity and its treatment, 8-56.
formin group showed improvement in the necro-inflam- Australia: Health Communications; 2000.
matory activity, compared with the group given dietary 11. Dhiman RK, Duseja A, Chawla Y. Asians need different criteria for defining overweight and obesity. Arch Intern Med 2005; Though we did not evaluate them for histological im- 12. World Health Organization. Definition, diagnosis and classifica- provement, our patients had significant biochemical re- tion of diabetes mellitus and its complications – Part 1: Diagnosis sponse in comparison to patients continued only on life- and classification of diabetes mellitus, 31-3. Geneva: World Health style interventions with normalization of ALT in 14 (56%) of them. We also found it to be safe with no patient 13. Expert panel on detection evaluation and treatment of high cho- lesterol in adults. Executive summary of the third report of the experiencing any side effect and there were no dropouts.
national Cholesterol Education Program (NCEP) expert panel on Our study has certain drawbacks. Number of patients detection, evaluation and treatment of high blood cholesterol in is small and results may change with large number of pa- adults (Adult Treatment panel III). JAMA 2001; 285: 2486-97.
tients. We evaluated patients only for biochemical re- 14. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Non-alcoholic fatty liver disease: a spectrum of sponse and since ALT may not have good correlation clinical and pathological severity. Gastroenterology 1999; 16: with histology in patients with NAFLD, improvement in ALT in our patients may not signify histological re- 15. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander – Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grad-ing and staging the histological lesions. Am J Gastroenterol 1999; In conclusion, our study shows that insulin resistance 16. Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A, Metformin is an alternative option to achieve bio- Kalra N. Clinicopathological profile of Indian patients with non- chemical response in patients with NAFLD who do not alcoholic fatty liver disease is different from that in the west. DigDis Sci 2007; 52: 2368-74.
respond to lifestyle interventions and UDCA. Results 17. Duseja A, Das A, Dhiman RK, Chawla YK, Das R, Bhadada S, need to be reproduced in larger number of patients in a Sialy R, et al. Indian patients with nonalcoholic fatty liver disease randomized placebo controlled trial with histological presenting with raised transaminases are different at presentation.
World J Gastroenterol 2007; 13: 649-50.
18. Day C, James O: Steatohepatitis: a tale of two «hits»? (Editorial).
Gastroenterology 1998; 114: 842-5.
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2. Duseja A, Nanda M, Das A, Das R, Bhansali A, Chawla Y. Preva- 21. Lindor KD, Kowdley KV, Heathcote EJ, Harrisson ME, Jorgensen lence of obesity, diabetes mellitus and hyperlipidemia in patients R, Angulo P, Lymp JF, et al. Ursodeoxycholic acid for treatment with cryptogenic liver cirrhosis. Trop Gastroenterol 2004; 25: of nonalcoholic steatohepatitis: results of a randomized trial.
Annals of Hepatology 6(4) 2007: 222-226 22. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, 24. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Ster- Sheppard BL. A pilot study of a thiazolidinedione, Troglitazone in ling RK, Stravitz RT, et al. A pilot study of vitamin E versus nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96: 519-25.
vitamin E and pioglitazone for the treatment of nonalcoholic 23. Neuschwander–Tetri BA, Brunt EM, Wehmeier KR, Oliver D, steatohepatitis. Clin Gastroenterol Hepatol 2004; 2: 1107-15.
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