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).
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).
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.
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.
1. Grigore L, Norata GD, Catapano AL. Combination therapy in cholesterol reduction: focus on ezetimibe and statins
. Vasc Health Risk Manag 2008; 4: 267-278.
2. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative Group. Effects of cholesterollowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757-767.
3. Nassief A, Marsh JD. Statin therapy for stroke prevention. Stroke 2008; 39: 1042-1048.
4. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-559.
5. Cimino M, Gelosa P, Gianella A, Nobili E, Tremoli E, Sironi L. Statins
: multiple mechanisms of action in the ischemic brain. Neuroscientist 2007; 13: 208-213.
6. Stepień K, Tomaszewski M, Czuczwar SJ. Neuroprotective properties of statins
. Pharmacol Rep 2005; 57: 561-569.
7. Athyros VG, Kakafika AI, Tziomalos K, Papageorgiou AA, Karagiannis A. Statins
for the prevention of first or recurrent stroke. Curr Vasc Pharmacol 2008; 6: 124-133.
8. Vasudevan AR, Hamirani YS, Jones PH. Safety of statins
: effects on muscle and the liver. Cleve Clin J Med 2005; 72: 990-993, 996-1001.
9. Koren MJ, Feldman T, Mendes RA. Impact of high-dose atorvastatin in coronary heart disease patients age 65 to 78 years. Clin Cardiol 2009; 32: 256-263.
10. McKenney JM. An assessment of statin safety. Am J Manag Care 2006; 12: S310-S317.
11. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: e21-e181.
12. Reeves MJ, Gargano JW, Luo Z, Mullard AJ, Jacobs BS, Majid A, et al. Effect of pretreatment with statins
on ischemic stroke
outcomes. Stroke 2008; 39: 1779-1785.
13. Shen CX, Chen HZ, Ge JB. The role of inflammatory stress in acute coronary syndrome. Chin Med J 2004; 117:133-139.
14. de Denus S, Spinler SA, Miller K, Peterson AM. Statins
and liver toxicity: a meta-analysis. Pharmacotherapy 2004; 24: 584-591.
15. Alsheikh-Ali AA, Karas RH. The relationship of statins
to rhabdomyolysis, malignancy, and hepatic toxicity: evidence from clinical trials. Curr Atheroscler Rep 2009; 11: 100-104.
16. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998; 19: 26-37.
17. Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97: 77C-81C.
18. Pfeffer MA, Keech A, Sacks FM, Cobbe SM, Tonkin A, Byington RP, et al. Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project. Circulation 2002; 105: 2341-2346.
19. Willrich MA, Hirata MH, Hirata RD. Statin regulation of CYP3A4 and CYP3A5 expression. Pharmacogenomics 2009; 10: 1017-1024.
20. Chalasani N. Statins
and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005; 41: 690-695.
21. Vuppalanchi R, Chalasani N. Statins
for hyperlipidemia in patients with chronic liver disease: are they safe? Clin Gastroenterol Hepatol 2006; 4: 838-839.
Keywords:© 2011 Chinese Medical Association
statins; liver function; ischemic stroke; alanine aminotransferase; aspartate aminotransferase