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Effects of statins on the liver: clinical analysis of patients with ischemic stroke

Li-san, ZHANG; Zheng-xia, LIU; Wen, LÜ; Xing-yue, HU

Section Editor(s): WANG, De

doi: 10.3760/cma.j.issn.0366-6999.2011.06.017
Original article
Free
SDC

Background Statins are one of the most common agents prescribed for ischemic stroke patients, but their side effects on the liver are worrisome to both physicians and patients. This study aimed to analyze the features and related factors of the hepatic side effects of statins in patients with ischemic stroke.

Methods Four hundred and eighty-one patients with ischemic stroke who had been treated with statins at our department from July 1, 2008 to June 30, 2009 were investigated retrospectively. Liver function, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within 6 months after they began to use statins and related factors were analyzed.

Results The incidence of mild ALT and AST elevation, less than three times the upper limit of normal, and the incidence of moderate elevation, ALT and AST levels 3-10 times the upper limit of normal, in ischemic stroke patients who had been treated with statins were 2.3% and 2.1%, respectively. These incidences were higher than in patients with common hyperlipidemia or coronary heart disease. The relatively high incidence was associated with older age (≥65 years) and chronic liver diseases, and was not related to the type of stroke, gender, and reduction of low-density lipoprotein. The levels of ALT and AST normalized after withdrawal of statins or lowering the dosage. None of the patients developed hepatic failure.

Conclusions Asymptomatic elevation of ALT and AST after administration of statins is more likely to occur in ischemic stroke patients than in others, and the elevation is related to age and chronic liver diseases. However, statins are still safe for ischemic stroke patients.

Edited by

Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China (Zhang LS, Liu ZX, Lü W and Hu XY)

Correspondence to: Prof. HU Xing-yue, Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China (Tel: 86-571-86006906. Fax: 86-571-86006902. Email: zls09@zju.edu.cn) This study was supported by the grants from Natural Science Foundation of Zhejiang Province (No. Y2090184) and the Project of Chinese Traditional Medicine of Zhejiang Province (No. 2006Y005).

(Received May 6, 2010)

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-limiting enzyme in cholesterol biosynthesis, and they lower plasma low-density lipoprotein (LDL) cholesterol by causing intracellular cholesterol depletion and upregulating the expression of LDL receptors.1 Therapeutic intervention aimed at lowering cholesterol levels both in primary and secondary prevention shows a clear reduction in the incidence of coronary heart disease and ischemic stroke.2-4 In addition, statins have beneficial effects in the treatment of acute stroke by their neuroprotective activity, which is not related to their regulation of cholesterol metabolism.5,6 As a result, statins are recommended in various stroke management guidelines, and are prescribed for most ischemic stroke patients.7

In general, statins are safe and beneficial, but their well-known adverse effect, hepatotoxicity, is always worrisome for both physicians and patients.7 The safety of statins in patients with common dyslipidemia and coronary heart disease has been well assessed.8-10 However, the safety in ischemic stroke patients has rarely been studied.4 It is very important to evaluate the safety of statins in such patients because they are different from those with common dyslipidemia or coronary heart disease.11 In the present study we retrospectively investigated the liver function of 481 ischemic stroke patients who had been treated with statins in our department from July 1, 2008 to June 30, 2009. We considered such factors as age, gender, chronic liver diseases, other agents, and type of stroke.

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METHODS

The clinical data from 505 patients with ischemic stroke who had been treated at the Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (Hangzhou, China) from July 2008 to June 2009 were analyzed retrospectively. Statins were given to 481 patients, and liver function, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), was monitored several times at different intervals over six months. Atorvastatin, pravastatin fluvastatin, simvastatin and rosuvastatin were used in 455, 12, 7 and 3 patients, respectively. The duration of treatment ranged from three months to six months. The demographics and other characteristics of these patients are shown in Table 1. The highest levels of ALT and AST were analyzed. As previously suggested,8 hepatic impairment was classified into three types. In the mild type, the level of ALT or AST increased by less than three times the upper limit of the normal value. In the moderate type, the level of ALT or AST increased by 3 to 10 times the upper limit of normal values. This increase was asymptomatic, but steps must be taken to prevent further injury to the liver; including statin withdrawal, lowering the dosage, or liver protective therapy. In the severe type, the levels of ALT or AST increased by more than 10 times the upper limit of normal value, or the level of serum bilirubin was greater than 3 mg/dl, or there was acute hepatic failure which required treatment. Statistical software SPSS 13.0 was used to run the chi-square test and linear regressions.

Table 1

Table 1

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RESULTS

Effects of age on the hepatic impairment induced by statins

In 10 patients the levels of ALT or AST were elevated by three times the upper limit of normal values after statin treatment. Two of the 10 patients were younger than 65 years, and eight were older than 65 years (Table 2). There was a significant difference in incidence of moderate hepatic impairment between the ≥65 years and <65 years old populations (χ2=4.018, P=0.045). In addition, the increased levels of ALT or AST after statin treatment were related to age not only in patients with moderate hepatic impairment, but also in those with mild hepatic impairment (Figure 1).

Table 2

Table 2

Figure 1.

Figure 1.

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Effects of chronic liver diseases on hepatic impairment induced by statins

Sixty-eight of our patients had chronic liver diseases. Thirty were HBsAg positive, one was HCV-Ab positive, 49 had fatty liver diagnosed by ultrasound, and four had schistosoma-induced liver disease. The incidence of hepatic impairment was 8.82% (6/68) in those with chronic liver disease, whereas there was a low incidence of 0.97% (4/413) in those without chronic liver disease (χ2=17.696, P <0.001) (Table 3).

Table 3

Table 3

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Correlation between LDL reduction and hepatic impairment induced by statins

Because statins are effective at lowering LDL, hepatic impairment is thought to be associated with the reduction of LDL. In this study, the increased levels of ALT and AST were not related to lower LDL levels, suggesting that different mechanisms are involved in hepatic impairment (Figure 2).

Figure 2.

Figure 2.

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Outcomes of the patients who had moderate hepatic function impairment

Of the 10 patients who developed moderate hepatic function impairment, nine used atorvastatin and one used simvastatin. Atorvastatin and simvastatin were stopped in nine patients, and the high dose of 40 mg/d was reduced to 10 mg/d in the remaining patient who used atorvastatin. Hepatinicas, such as glutathione, Essentiale Forte N and so on, were used in eight patients. After one to two months, the hepatic function of these patients normalized.

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DISCUSSION

Cardiovascular disease (CVD) is one of leading causes of death worldwide,11 and statins have become one of the basic therapies for CVD treatment because of their lipid-lowering effects, direct reduction of inflammation, improving endothelial function, and stabilizing atherosclerotic plaque.5,12,13 However, one of the most clinically important adverse effects is liver toxicity, reflected by increased levels of ALT and AST. In our patients with ischemic stroke, the incidences of mild and moderate elevation of ALT or AST were 2.3% and 2.1%, respectively. The incidence is higher than reported in studies including mostly patients with common dyslipidemia and coronary heart disease.9,14,15

Since statins inhibit cholesterol synthesis in the liver much more than in any other tissue,16 increased levels of ALT and AST among liver enzymes have been found in clinical trials of lovastatin. According to different studies, however, the incidence of elevated serum liver enzymes varies among different patients. For example, Cohen et al17 reported that starting and intermediate dosages of all statins are associated with asymptomatic elevation in ALT or AST levels three times the upper limit of normal value or higher at a rate of <1%. A meta-analysis of the data from three major randomized clinical trials of pravastatin therapy, i.e., the Cholesterol and Recurrent Events (CARE) trial, the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, and the West of Scotland Coronary Prevention Study (WOSCOPS), found the percentage of patients with ALT or AST levels three times the upper limit of normal values or higher was 1.4%.18 Until now, the total incidence of elevated serum liver enzymes among patients on treatment with statins generally is no more than 3,14 which is lower than the total incidence in our ischemic stroke patients (4.4%). We found that the incidence of moderate elevation of hepatic enzymes in patients older than 65 years old was significantly higher than in those younger than 65. It is very interesting that there is a positive correlation between the elevation of hepatic enzymes and age. Although, the factors related to the liver toxicity of statins remain controversial, age is one possible factor and may account for the high elevation of ALT or AST levels in our ischemic stroke patients. We found that patients with ischemic stroke were older than those with dyslipidemia by about 20 years and than those with coronary heart disease by about 10 years at occurrence of disease. Most statins, including the most commonly-used atorvastatin in our patients, are metabolized mainly by cytochrome P450.19 In addition, old patients have more basic diseases such as insufficiency of renal function and hypoalbuminemia, and need more drugs for hypertension, diabetes, and infection, which disturb the metabolism of statins.

According to some reports,17,20,21 there is no influence of chronic liver disease on the statin-elevated ALT and AST levels. However, we found that chronic liver disease did contribute to the elevation of ALT or AST levels induced by statins. Some reports concluded that statins are safe to use for the prevention of coronary disease and ischemic stroke even in the setting of chronic liver disease.21 Other studies even concluded that the percentage of patients with ALT levels three times the upper limit of normal value or higher was equal to that of those using both statins and placebo.17,18,21 However, re-evaluation is necessary since chronic liver disease decreases the capacity of liver function. In this study we found that hepatic enzymes in the patients with chronic liver diseases were more likely to be elevated than in those without such diseases. Therefore, attention should be paid to this issue but it does not mean that statins cannot be used in patients with chronic liver disease.

In addition, the elevation of hepatic enzymes was not linked to lowering the LDL serum level. Other researchers have also speculated that the mechanism of hepatic enzymes elevation was separate from that of LDL reduction.20,21 They suggested that the elevation of hepatic enzymes depends on the pharmacokinetics of statins. The more quickly the statins are metabolized, the less elevation of hepatic enzymes. Thus aggressive lipid-lowering therapy which decreases LDL by at least 30% is safe.

We conclude that although statins are more likely to increase asymptomatic ALT and AST levels in ischemic stroke patients than in other patients, they are safe. However, monitoring liver function is necessary when statins are used.

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Keywords:

statins; liver function; ischemic stroke; alanine aminotransferase; aspartate aminotransferase

© 2011 Chinese Medical Association