Metformin superior to low‑fat diet for the treatment of patients with nonalcoholic fatty liver disease and/or steatohepatitis Bashkim Resuli, Vigjilenca Demiraj, Adriana Babameto, Klara Sema, Valdete Malaj University Service of Gastroenterology and Hepatology, Mother Theresa Hospital, Tirana, Albania Introduction Nonalcoholic fatty liver disease
process: 1) the development of steatosis caused (NAFLD) constitutes a worldwide health chal‑ by insulin resistance in the muscle, adipose tissue, lenge. Cases of fatty liver diseases with inflam‑ and liver and 2) cytokine‑mediated inflammation, mation that resemble alcoholic steatohepatitis lipid peroxidation, and apoptosis.17‑19 but occur in nondrinkers were first described 30 Assessing liver injury in insulin resistant states years ago.1,2 In the last decade, the disorder has has become a major concern and no less of a chal‑ aroused a real interest. NAFLD is believed to ac‑ lenge given the current diagnostic tools. Liver bio‑ count for up to 90% of the cases of elevated liv‑ psy is regarded as the gold standard for the as‑ er function tests in patients without an identifi‑ sessment of fatty liver disease; however, its inva‑ able cause of liver disease.3 Recent studies have siveness limits its use, especially in outpatients made it clear that a subset of patients who devel‑ and research. On the other hand, sonography has op nonalcoholic steatohepatitis (NASH), most‑ shown significantly high specificity and relative‑ ly those with alanine transaminase (ALT) levels ly high sensitivity for the diagnostic occurrence higher than twice the upper limit of normal, are at increased risk of progression to liver disease The search for the therapy of NASH is ongoing. and may experience all complications of cirrho‑ Based on the concept of insulin resistance, a num‑ sis, such as end‑stage liver disease and hepatocel‑ ber of pilot studies have shown that reduction of lular carcinoma.4‑8 Indeed, it can be argued that body weight and improvement of insulin sensitiv‑ most cases of cryptogenic cirrhosis, which ranks ity by metformin or thiazolidinediones provide as the third leading indication for liver transplan‑ positive bio chemical and histo logical results.22‑29 tation after alcohol and hepatitis C, are due to Metformin hydrochloride (N,N‑dimethylimidodi‑ carbonimidic diamide hydrochloride) is an anti‑ The rising prevalence of obesity, diabetes, hyperglycemic drug of the biguanide class, which and meta bolic syndrome evidently results in decreases hepatic glucose production, decreases an increasing prevalence of NAFLD. This trend intestinal glucose absorption, and improves in‑ is of particular concern in the pediatric popu‑ sulin sensitivity by increasing peripheral glucose lation, in which the reported increase in obesi‑ uptake and utilization. Despite that, it is known ty will undoubtedly result in a higher evidence that metformin therapy can lead to body weight and prevalence of pediatric and adult NAFLD in the future.10,11 In Albania, excess weight and obe‑ The objective of this study was to evalu‑ sity is becoming the major public health problem, ate the efficacy of metformin compared with primarily in middle‑aged women.12 NAFLD and low‑fat diet (LFD) in patients with NAFLD and/ NASH are frequently observed in conjunction with other components of the meta bolic syn‑ drome, such as arterial hypertension, diabetes, Patients and methods Study population The study
obesity, and elevated lipids, which are considered was a 24‑week prospective controlled trial com‑ Conflict of inter est: none declared.
the hepatic manifestations of the syndrome.13‑16 paring metformin plus LFD with LFD alone in 61 Why insulin resistance leads to fatty liver injury outpatients with NAFLD and/or NASH, 46 men is not completely clear. The most widely accept‑ (75%) and 15 women (25%), who presented at our Copyright by Medycyna Praktyczna, Kraków 2012 ed patophysio logical model of NAFLD is a two‑hit university department of gastroenterology and POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (Suppl 1) hepatology during 2008–2009. All patients ful‑ was more than 3.6 and body mass index more filled the following criteria: 1) insulin resistance than 27.5 kg/m2. Pre‑ and post‑treatment body (Homeostasis Model Assessment Insulin Resi‑ mass, bio chemical data, and insulin resistance stance – HOMA‑IR) value above 3.6; 2) elevation were compared. The efficacy endpoints at 24 we‑ in the levels of ALT and aspartate transaminase eks of the treatment were the normalization of (AST); and 3) ultrasound evidence of fatty liver. ALT and decreased insulin resistance.
The exclusion criteria were as follows: 1) presen‑ ce of hepatitis B and C virus infection markers Statistical analysis Continuous variables are pre‑
(HBsAg and anti‑HCV); 2) evidence of alcoho‑ sented as mean ± standard deviation. Group com‑ lic liver disease (less than 20 g ethanol per day); parisons were conducted using the t test. Diffe‑ 3) evidence of auto immune liver disease; 4) use rences were considered significant at the P level of insulin‑sensitizing and hepatotoxic drugs in the previous 6 months; 5) presence of diabetes or a severe systemic disease; 6) evidence of meta‑ Results Baseline body weight, bio chemical data,
bolic liver disease (α‑1‑antitrypsin deficiency, Wil‑ and insulin resistance (HOMA‑IR) of the patients son disease, or hemo chromatosis); 7) active sub‑ are presented in TABLE 1. Both groups were simi‑
lar in terms of age, sex, body weight, bio chemical The study was approved by the National Eth‑ ics Committee. Informed consent was obtained Significantly more patients treated with met‑ formin plus LFD (group A) achieved normal se‑rum ALT and AST levels and improvement of in‑ Procedures Patients were divided into 2 gro‑
sulin resistance compared with patients treated ups. Group A included 35 patients (26 men and with LFD alone (group B; P <0.05; TABLE 2).
9 women; mean age, 41.8 ±8.1 years) receiving There was no significant difference in body metformin 850 mg/daily plus low‑fat dietary weight loss, fasting and postprandial blood glu‑ regime that aimed to reduce fat to 30% or lower cose, total cholesterol, triglyceride and HDL as generally recommended for 24 weeks. Group cholesterol between the 2 groups (P >0.005) B included 26 patients (20 men and 6 women; (TABLE 2).
mean age, 42.6 ±7.3 years) receiving the same No serious adverse events of metformin were dietary counseling for the same period of time. observed and treatment was not discontinued in No vitamins or other nutritional supplements were prescribed. Blood samples were obtained before and after the treatment (0 and 24 weeks) Discussion There is currently no proven and
to determine serum levels of bilirubin, ALT and approved treatment for patients with NAFLD AST, fasting and postprandial blood glucose, fa‑ and/or NASH. Although body weight loss and sting insulin, total cholesterol, triglycerides, and life‑style modifications have been shown to be high‑density lipoprotein (HDL) cholesterol.
effective,31,32 only a minority of patients are able HOMA‑IR was calculated using the formula: to adhere to sustained and intensive dietary inter‑ HOMA‑IR = fasting plasma insulin (microU/ml) vention.33‑35 In the present study, we observed × FPG (mg/dl)/405. We assumed IR when HOMA that body mass loss (4–6 kg) at the end of treat‑ment with LFD alone was associated with nor‑malization of ALT in 21 of 26 patients (82%) and TABLE 1 Baseline characteristics of body weight, bio chemical data and insulin
attenuation of insulin resistance only in 20% of the patients (TABLE 2).
On the other hand, we found that a 24‑week treatment with metformin at doses of 850 mg/dai‑ ly plus LFD was associated with a significantly higher rate of the normalization of ALT levels and improvement of insulin resistance when com‑ pared with LFD alone. These data clearly indicate the beneficial effect of metformin on insulin ac‑ tion. In fact, the role of hyperinsulinemia and in‑ creased insulin resistance as major pathogenic fac‑tors in the development of NAFLD and/or NASH, and in this manner the therapeutic value of in‑ sulin‑sensitizing agents including thiazolidine‑ diones or biguanides, has been demonstrated in several trials.28,36‑39 Moreover, it has been shown that bio chemical response to treatment with metformin continued during a 6‑ to 12‑month Data are presented as mean ± standard deviation.
follow‑up period, suggesting the sustained ef‑fect of the drug.40 Abbreviations: ALT – alanine transaminase, AST – aspartate transaminase, HDL – high-density lipoprotein, HOMA-IR – Homeostasis Model Assessment Insulin The meta bolic effect of metformin is thought to Resistance, LFD – low-fat diet, MET – metformin be mediated through the activation of adenosine BRIEF COMMUNICATION Metformin superior to low‑fat diet for the treatment.
TABLE 2 Body weight, bio chemical data, and insulin resistance at 24 weeks
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10 de Alvis NM, Day CP. Non-alcoholic fatty liver disease: The mist gradu‑
ally clears. J Hepatol. 2008; 48 (Suppl 1): 104-112.
11 World Health Organisation (WHO). The World Health Report 1998. Life
in the 21th century – a vision for all. Geneva: WHO 1998.
12 Shapo L, Pomerleau J, McKee M, et al. Body weight patterns in a coun‑
try of transition: a population-based survey in Tirana City, Albania. Public 13 Cheung P, Kapoor A, Puri P, et al. The impact of fat distribution on
the severity of nonalcoholic disease and meta bolic syndrome. Hepatology. 14 Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, ste‑
Data are presented as number (percentage).
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15 Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a meta-
Abbreviations: NS – nonsignificant, others – see TABLE 1
bolic pathway to chronic liver disease. Hepatolgy. 2005; 42: 987-1000.
16 Marchesini G, Marzochi R, Natale S. NAFLD - Why not to treat the in‑
sulin resistance? In: Non‑alcoholic steatohepatitis: from cell bio logy to clin‑ ical practice (Monothematic Conference of the European Association for monophosphate (AMP)‑activated protein kinase the Study of the Liver [EASL], Estoril, Portugal, September 2004). Lisbon, in hepatic and peripheral tissue either directly or 17 Marchesini G, Brizi M, Bianchi M, et al. Nonalcoholic fatty liver dis‑
indirectly through another serine‑threonine ki‑ ease: a feature of meta bolic syndrome. Diabetes. 2001; 50: 1844-1850.
nase known as LKB1.41 It has also been demon‑ 18 McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin
strated that the activation of AMP kinase leads Gastroenterol. 2006; 40 (Suppl 1): 17-29.
to transactivation of genes that inhibit gluconeo‑ 19 Larter C, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH:
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genesis and lipogenesis and promote fat acid and 20 Lee s, Park SH, Kim JH. Non invasive assessment of hepatic steato‑
glucose uptake in the liver and muscles.24 sis: Prospective comparison of the occurrence of imaging examinations. It is also known that metformin therapy can lead to weight loss.24,25,30 Body weight loss (4–6 kg) 21 Saadeh S, Yonussi ZM, Remer EM, et al. The utility of radio logical
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B (TABLE 2). These results provide evidence that
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re‑evaluation of the positive results after the end non‑alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol of treatment, as well as short period of treatment 26 Schwimmer JB, Middleton MS, Deutch R, Lavine JE. A phase 2 clini‑
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27 Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone
treatment for nonalcoholic steatohepatitis. Hepatology. 2004; 39: 188-196.
In conclusion, therapy directed at improving 28 Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E ver‑
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30 Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled tri‑
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37 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Interim re‑
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38 Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver dis‑
ease in obese, leptin-deficient mice. Nat Med. 2000; 6: 998-1003.
39 Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic ste‑
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