j3阿托伐他汀治疗非酒精性脂肪肝的试验研究

A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients E. GO´MEZ-DOMI´NGUEZ, J . P . GISBERT, J . A . MORENO-MONTEAGUDO, L . GARCI´A-BUEY & R. MORENO-OTERO Gastroenterology and Hepatology Service, Hospital Universitario la Princesa and Instituto de Salud Carlos III, Madrid, Spain Correspondence to: Dr R. Moreno-Otero, Gastroenterology Service, Hospital Universitario de la Princesa, Diego de Leo´n 62, E-2806 Madrid, Spain. E-mail: rmoreno.hlpr@salud.madrid.org Publication data Submitted 28 January 2006 First decision 27 February 2006 Resubmitted 7 March 2006 Accepted 11 March 2006 SUMMARY Background Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies avail- able. Atorvastatin is a new 3-hydroxy-3-metylglutaryl coenzyme A reductase inhibitor that reduces lipid serum levels. Aim To evaluate the effectiveness and safety of atorvastatin in dyslipemid, non-alcoholic fatty liver patients. Patients and methods We prospectively enrolled 25 patients with NAFLD; 22 of them comple- ted the study. Body mass index, serum lipids, liver function tests and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treatment. Normalization of transam- inases and/or improvement in liver density were treatment end points. Patients received atorvastatin (10–80 mg/daily) according to basal serum choleresterol levels; additionally, they were given standard weight-loss counselling and encouraged to follow a low fat diet. Results All 22 patients (14 men, mean age 47 � 10 years) had high cholesterol levels at baseline and 11 (44%) also presented high trygliceride levels. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months when 20% of patients presented with normal transaminase levels, while the other patients showed a 10% reduction in basal levels. Mean cholesterol levels were 268.5 � 44.2 and 186.8 � 14.4 mg/dL before and after treatment, respectively (P < 0.05). The mean body mass index was 27.4 � 3.1 at baseline and 26.3 � 2.8 kg/cm2 at the end of treatment (P > 0.05). No side effects were reported. Conclusions Serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment. Therapy with atorvastatin in NAFLD patients with hyperlipidemia was found to be both effective and safe. Aliment Pharmacol Ther 23, 1643–1647 Alimentary Pharmacology & Therapeutics ª 2006 The Authors 1643 Journal compilation ª 2006 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2006.02926.x INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) encom- passes a range of progressive conditions.1–3 Its natural history is not yet well understood, but it is currently believed that patients with steatosis alone rarely deteriorate over time, 4–6 and has been demonstrated with the increasing incidence of obesity and diabetes in Western countries, NAFLD has become a growing problem. Although its true prevalence is unknown, some estimates suggest that it might affect one-third of American adults – a figure also suggested for Europe and Japan.7–11 Non-alcoholic fatty liver disease, is the hepatic manifestation of the metabolic syndrome that encom- passes central obesity, hypertension, hypertriglyce- ridaemia, low levels of high-density lipoprotein cholesterol and hyperglycaemia.8–10, 12 The pathogene- sis of NAFLD includes two steps: first, the healthy liver becomes steatotic; then, the second step is elicited by oxidative stress and cytokine synthesis. This leads to exacerbation of insulin resistance, followed by oxida- tive stress and organelle dysfunction within liver cells, resulting in an inflammatory process, hepatocellular degeneration and fibrosis.13 Currently, there are no proven effective therapies available for the treatment of NAFLD and strategies have mainly led to treat or control underlying risk factors.1–4, 7, 11, 14 Promising pharmacological treat- ments have been observed with the use of anti- oxidants, insulin sensitizers, hepatoprotectants or lipid-lowering agents. Therapeutic results have been demonstrated with multiple agents and currently larger randomized trials are underway; these will hopefully clarify the role of specific pharmacological treatments.8, 11, 14 Control of hyperlipaemia with hypolipaemic drugs is controversial in these patients. Approximately 80% have elevated choleresterol and triglyceride serum levels. Controlling elevated levels of cholesterol and triglycerides with diet, exercise and cholesterol-lowering medications may help to stabilize or reverse NAFLD.8, 15–18 Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.19–23 The aim of our pilot study was to evaluate the effectiveness and safety of atorvastatin in the treatment of patients with NAFLD. PATIENTS AND METHODS We prospectively enrolled patients after satisfying the following inclusion criteria: (i) abnormal results on liver test during the 6 months prior to enrolment; (ii) fatty liver disease assesses by ecography; (iii) no clinical or serological evidence of other chronic liver disease; and (iv) no history of alcohol abuse or other identifiable causes of fatty liver disease. Body mass index (BMI), serum lipids, liver function test and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treat- ment. Because of the fact that all our patients were asymptomatic and without clinical or ecographic signs of advanced liver disease, no biopsies were performed. All patients received atorvastatin (10–80 mg/daily) according to basal choleresterol level for 6 or 12 months until obtaining the end point of treatment. Normalization of transaminases and/or improvement in liver density were considered as the end point of treatment. Additionally, all patients were given stand- ard weight-loss counselling and encouraged to follow a low fat diet. Although rare, hepatotoxicity has been reported with atorvastatin. Therefore, subjects made monitoring visits to our centre to ensure safety and adherence. Before participating in the study each sub- ject gave written voluntary assent and consent. All study variables were treated as continuous variables. Summary outcome measures were reported as mean � s.d. For all analyses, a two-tailed P < 0.05 was considered significant. Statistical software used was SPSS 11.05 for windows (Chicago , IL, USA). RESULTS Twenty-five subjects were enrolled, 22 patients, 14 men, with a mean age of 47 � 10 years completed the study. At baseline, all patients had high cholesterol levels and 11 of them (44%) also presented high triglyceride levels. There were five diabetic patients and in two patients hyperglycaemia was diagnosed during treatment. Baseline data are shown in Table 1. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months, and at that moment, 20% of patients presented normal transaminase levels, while the other patients showed a 10% reduction in basal levels (Figures 1–3). Mean 1644 E . GO´MEZ-DOMI´NGUEZ et al. ª 2006 The Authors, Aliment Pharmacol Ther 23, 1643–1647 Journal compilation ª 2006 Blackwell Publishing Ltd choleresterol levels were 268.5 � 44.2 and 186.8 � 14.4 mg/dL before and after treatment, respectively, with a significant difference between them (P < 0.05). The mean BMI was 27.4 � 3.1 at baseline and 26.3 � 2.8 kg/cm2 at the end of treatment (P > 0.05). Liver fat measured by echography and analysed by the same gastroenterologist did not change significantly after treatment. There was no statistical difference between clinical and epidemiological variables in both groups, 6 and 12 months of treatment. No side effects were reported in our study. DISCUSSION Non-alcoholic fatty liver disease, a spectrum of liver disorders characterized by the accumulation of fat in hepatocytes, is the hepatic manifestation of meta- bolic syndrome.1, 4, 7, 12 The relevance of this condi- tion is illustrated by two ominous facts: (i) it may progress to severe liver disease including cirrhosis, hepatocellular carcinoma or even rapidly progressive liver failure,9–11 and (ii) it could become the most common form of liver disease in the near future.4– 7, 12 All subjects enrolled in our study had typical epidemiological features: middle age with metabolic risk factors.11, 15 All were asymptomatic and NAFLD was detected because of abnormal results of liver tests performed for unrelated issues. Diagnosis inclu- ded fatty liver disease assessed by ecography and several exclusion criteria: no clinical or serological evidence of other chronic liver disease and no his- tory of alcohol abuse or other identifiable causes of fatty liver disease.24, 25 Regarding clinical management, changes in life hab- its had demonstrated efficacy in a previous series.11 A diet low in calories and saturated fat and an exercise programme, even when patients are not overweight or obese, may reduce inflammation, lower elevated levels of liver enzymes and decrease insulin resist- ance.7, 16, 17, 24 However, in clinical practice, the impact of these counsellings are often very modest and allow patients not to follow any therapeutic strategies.11, 14 Two of our patients did not know that they were diabetic at the moment of inclusion and they presented complications of this disease. Neverthe- less, all our patients had known for at least 12 months before being enrolled in the study that they had dyslipaemia and were overweight, but they had not changed their way of lifestyle. In the current study, no statistical changes in weight loss were observed. However, aminotransfereses, cho- lesterol and triglyceride serum levels significantly improved. The absence of a control group limited the ability to determine the true impact of pharmaco- therapy, but considering that these parameters did not previously improve treatment it is possible that the beneficial effects seen in this study were caused by atorvastatin. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining continued treatment for 12 months and at that moment, 20% of them presented normal transa- minase levels. There was significant improvement in Table 1. Clinical and laboratory features before treatment Age (years) 47 � 10 Gender (% male) 56 Hypercholesterolaemia (%) 100 Hypertriglyceridae (%) 44 Hyperglycaemia (%) 28 Basal aminotransferases (U/I) AST 46.7 � 20.5 ALT 72.7 � 44.1 GGT 137.5 � 80.1 ALP 101.1 � 37.6 Weight (kg) 77.8 � 12.5 BMI (kg/cm2) 27.4 � 3.1 Cholesterol (mg/dL) 268.3 � 44.2 Triglyceride (mg/dL) 236.2 � 193.4 Data shown as mean � s.d. AST, aspartate amino trans- ferase; ALT, alanine amino transferase; GGT, gammaglutamil transpeptidase; ALP, alkaline phosphatase; BMI, Body mass index. 0 50 100 150 200 250 300 Week 0 Week 12 Week 24 Week 36 Week 48 GGT AST ALT Figure 1. Mean aminotransferase and gammaglutamil transpeptidase serum levels at baseline and during treat- ment with atorvastatin. ATORVASTATIN TREATMENT IN NON-ALCOHOLIC FATTY L IVER PATIENTS 1645 ª 2006 The Authors, Aliment Pharmacol Ther 23, 1643–1647 Journal compilation ª 2006 Blackwell Publishing Ltd aminotransferase levels at baseline and at the end of treatment in both groups (Figures 1–3). Currently, there are no proven effective therapies available for the treatment of NAFLD and strategies have mainly led to treat or control underlying risk fac- tors.7, 11, 14–18, 21 Atorvastatin is an inhibitor of HMG- CoA reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, and early and rate-limi- ting step in cholesterol biosynthesis.18–22 Previous data about treatment with atorvastatin in NAFLD patients are promising11, 14 and although statin drugs can have adverse effects on muscles and the liver, these effects are uncommon.26–29 In our series, all patients who received treatment with atorvastatin showed a reduc- tion in their cholesterol, triglycerides and serum ami- notransferase levels. Moreover, we found no significant elevation of liver enzymes during atorvastatin treat- ment and no adverse effects were observed. In conclusion, serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment, although there were no rele- (a) (b) (c) 0 10 20 30 40 50 60 70 80 90 AST baseline AST end of treatment 0 20 40 60 80 100 120 ALT baseline ALT end of treatment 0 50 100 150 200 250 300 350 GGT baseline GGT end of treatment Figure 3. Patients after 48 weeks of treatment. Paired values for subjects before and after treatment of (a) aspar- tate amino transferase, (b) alanine amino transferase and (c) gammaglutamil transpeptidase. 20 0 40 60 80 100 120 AST baseline AST end of treatment 0 50 100 150 200 250 300 ALT baseline ALT end of treatment 0 20 40 60 80 100 120 140 160 GGT baseline GGT end of treatment (a) (b) (c) Figure 2. Patients after 24 weeks of treatment. Paired values for subjects before and after treatment of (a) aspar- tate amino transferase, (b) alanine amino transferase and (c) gammaglutamil transpeptidase. 1646 E . GO´MEZ-DOMI´NGUEZ et al. ª 2006 The Authors, Aliment Pharmacol Ther 23, 1643–1647 Journal compilation ª 2006 Blackwell Publishing Ltd vant changes in patient’s habits as demonstrated by no reduction in BMI. The use of atorvastatin in NAFLD patients with hyperlipidaemia was found to be both effective and safe. Consequently, multicentre, con- trolled clinical trials using this drug are warranted. ACKNOWLEDGEMENT Supported in part (grant 03/02) by the Instituto de Salud Carlos III, Madrid. REFERENCES 1 Ludwig J, Viggiano TR, McGill DB, Ott BJ. Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434–8. 2 Ludwig J, McGill DB, Lindor KD. Review: non-alcoholic steatohepatitis. J Gast- roenterol Hepatol 1997; 12: 398–403. 3 Sheth SG, Gordon FD, Chopra S. Non- alcoholic steatohepatitis. Ann Intern Med 1997; 126: 137–45. 4 Hui AY, Wong VWS, Chan HLY, et al. Histological progression of non-alco- holic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005; 21: 407–413. 5 Wong VW, Chan HL, Hui AY, et al. Clinical and histological features of non-alcoholic fatty liver disease in Hong-Kong Chinese. Aliment Pharmacol Ther 2004; 20: 45–9. 6 Fassio E, Alvarez E, Domı´nguez N, et al. Natural history of non-alcoholic steato- hepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004; 40: 820–6. 7 American Gastroenterological Associ- ation medical position statement: non- alcoholic fatty liver disease. American Gastroenterological Association. Gastro- enterology 2002; 123: 1702–4. 8 Ramesh S, Sanval AJH. Evaluation and management of non-alcoholic steato- hepatitis. J Hepatol 2005; 42 (Suppl. 1): S2–12. 9 Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Non-alcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103–9. 10 Caldwell S, Oelsner D, Iezzoni J, Hes- penheide E, Battle E, Driscoll C. Crypto- genic cirrhosis. Clinical characterization and risk factors for underlying disease. Hepatology 1999; 29: 664–9. 11 Comar KM, Sterling RK. Review article: drug therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2005; 23: 207–15. 12 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Non- alcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413–9. 13 Medina J, Ferna´ndez-Salazar LI, Garcı´a- Buey L, et al. Approach to the patho- genesis and treatment of non-alcoholic steatohepatitis. Diabetes Care 2004; 27: 2057–66. 14 Marchesini G, Natale R, Manini R, et al. Review article: the treatment of fatty liver disease associated with the meta- bolic syndrome. Aliment Pharmacol Ther 2005; 22 (Suppl. 2): 17–9. 15 Oonawala A, Nair S, Thuluvath P. Pre- valence of obesity and diabetes in patients with cryptogenic cirrhosis. Hep- atology 2000; 32: 689–91. 16 Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997; 27: 103–7. 17 Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of diet- ary weight loss in morbidity obese sub- jects. J Hepatol 1991; 12: 224–9. 18 Angulo P, Lindr KD. Treatment of non- alcoholic fatty liver: present and emer- ging therapies. Semin Liver Dis 2001; 21: 81–8. 19 Berk-Planken II, Hoogerbrugge N, Stolk RP, Bootsma AH, Jansen H: Atorvastatin dose-dependently decreases hepatic lipase activity in type 2 diabetes; effect of sex and the LIPC promoter variant. Diabetes Care 2003; 26: 427–32. 20 Clark LT. Treating dyslipemia with sta- tins: the risk-benefit profile. Am Heart J 2003; 145: 387–9. 21 Funatsu T, Suzuki K, Goto M, et al. Pro- longed inhibition of cholesterol sı´ntesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HEPg2 cells. Atherosclerosis 2001; 157: 107–15. 22 Harlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001; 120A: 544. 23 Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of non-alcoholic steato- hepatitis. Can J Gastroenterol 2003; 17: 713–8. 24 Agrawal S, Bonkovsky HL. Management of non-alcoholic steatohepatitis. An analytic review. J Clin Gastroenterol 2002; 35: 253–61. 25 Powell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of non-alcoholic steato- hepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11: 74–80. 26 Joseph AE, Saverymuttu SH, al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchyma liver dis- ease. Clin Radiol 1991; 43: 26–31. 27 Parra JL, Reddy KR. Hepatotoxicity of hypolipidemic drugs. Clin Liver Dis 2003; 7: 415–33. 28 Gershovich OE, Lyman AE Jr. Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature. Pharmacotherapy 2004; 24: 150–4. 29 Perger L, Kohler M, Fattinger K, Flury R, Meier PJ. Fatal liver failure with atorvastatin. J Hepatol 2003; 39: 1095–97. ATORVASTATIN TREATMENT IN NON-ALCOHOLIC FATTY L IVER PATIENTS 1647 ª 2006 The Authors, Aliment Pharmacol Ther 23, 1643–1647 Journal compilation ª 2006 Blackwell Publishing Ltd