A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients

Authors


Dr R. Moreno-Otero, Gastroenterology Service, Hospital Universitario de la Princesa, Diego de León 62, E-2806 Madrid, Spain.
E-mail: rmoreno.hlpr@salud.madrid.org

Abstract

Summary

Background

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies available. 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 completed 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 transaminases 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.

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses 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 encompasses central obesity, hypertension, hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol and hyperglycaemia.8–10, 12 The pathogenesis 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 oxidative 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 treatments have been observed with the use of antioxidants, 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 treatment. 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 standard 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 subject 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 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.

Table 1.   Clinical and laboratory features before treatment
  1. Data shown as mean ± s.d. AST, aspartate amino transferase; ALT, alanine amino transferase; GGT, gammaglutamil transpeptidase; ALP, alkaline phosphatase; BMI, Body mass index.

Age (years)47 ± 10
Gender (% male)56
Hypercholesterolaemia (%)100
Hypertriglyceridae (%)44
Hyperglycaemia (%)28
Basal aminotransferases (U/I)
 AST46.7 ± 20.5
 ALT72.7 ± 44.1
 GGT137.5 ± 80.1
 ALP101.1 ± 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
Figure 1.

 Mean aminotransferase and gammaglutamil transpeptidase serum levels at baseline and during treatment with atorvastatin.

Figure 2.

 Patients after 24 weeks of treatment. Paired values for subjects before and after treatment of (a) aspartate amino transferase, (b) alanine amino transferase and (c) gammaglutamil transpeptidase.

Figure 3.

 Patients after 48 weeks of treatment. Paired values for subjects before and after treatment of (a) aspartate amino transferase, (b) alanine amino transferase and (c) gammaglutamil transpeptidase.

Discussion

Non-alcoholic fatty liver disease, a spectrum of liver disorders characterized by the accumulation of fat in hepatocytes, is the hepatic manifestation of metabolic syndrome.1, 4, 7, 12 The relevance of this condition 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 included fatty liver disease assessed by ecography and several exclusion criteria: no clinical or serological evidence of other chronic liver disease and no history of alcohol abuse or other identifiable causes of fatty liver disease.24, 25

Regarding clinical management, changes in life habits 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 resistance.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. Nevertheless, 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, cholesterol and triglyceride serum levels significantly improved. The absence of a control group limited the ability to determine the true impact of pharmacotherapy, 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 transaminase levels. There was significant improvement in 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 factors.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-limiting 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 reduction in their cholesterol, triglycerides and serum aminotransferase levels. Moreover, we found no significant elevation of liver enzymes during atorvastatin treatment 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 relevant 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, controlled clinical trials using this drug are warranted.

Acknowledgement

Supported in part (grant 03/02) by the Instituto de Salud Carlos III, Madrid.

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