The Effect of Atorvastatin on Liver Function among Patients with Coronary Heart Disease in Gaza Strip

Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are considered as one of the most important drugs and the drug of choice for reducing an abnormal cholesterol level. Statins are normally used to decrease the risk of coronary heart disease (CHD), but they tend to be associated with liver adverse effects. The objective of this prospective study was to investigate the effect of atorvastatin therapy on the liver function in patients with CHD. Study comprised of 66 newly diagnosed CHD patients who were selected from UNRWA clinics in the Gaza Strip. The patients were clinically examined and treated with atorvastatin (10 40 mg/day). A questionnaire was used to collect the data concerning patient’s characteristics. Total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), liver enzymes tests such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and total and direct blood bilirubin were measured before starting treatment and after 3 and 6 months of treatment. The results showed a significant increase in the mean values of ALT, AST, total bilirubin and direct bilirubin levels after 3 months then decreased after the next 3 months, but they were higher than the baseline with insignificant association.


Introduction
Coronary heart disease (CHD) is the principle cause of morbidity and mortality worldwide [1].The main cause of CHD is atherosclerosis that develops in the arteries that encircle the heart and supply it with blood [2].
Many studies have proved the link between coronary heart disease and cholesterol.Framingham Study which is one of the first studies showed a direct link between high blood cholesterol levels and development of CHD.It showed a link between other risk factors, such as hypertension, cigarette smoking, male gender, family history, and age, with CHD development [3].
Dietary modification would reduce the levels of blood cholesterol by 10% -20%, but for further reduction, cholesterol lowering drugs are usually required.The most recent drugs developed for this purpose are statins or 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors which used for prevention and treatment of CHD; they lower cholesterol levels by 20% -30%, and even more at higher doses, and this has been clinically proven to produce an equivalent decrease in the risk of myocardial infarction and death [4].Statins have become one of the best-selling medication classes to date since their introduction into the marketplace in 1986, and include the following drugs commercially available in the US: atorvastatin, lovastatin, pravastatin, fluvastatin, simvastatin and rosuvastatin [5].Statins are highly effective in reducing cardiovascular mortality and are widely prescribed with best selling.More than 145 million prescriptions were written for statins in the US in 2005, including atorvastatin, the best selling prescription drug in the world [6] [7].
Statins considered the drugs of first choice for modifying lipid risk factors for CHD, in addition to reversible inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase.They have an ability to produce large reductions in low-density lipoprotein cholesterol (LDL-C) and ability to increase HDL cholesterol (HDL-C) [8] [9].Statins like all medications, have potential adverse effects.The most serious are liver and muscle adverse effects.Cognitive loss, neuropathy, sexual dysfunction and, pancreatic dysfunction are examples of other adverse effects [7].
Hepatic dysfunction includes either liver enzymes elevations as a result of liver injury or liver function disturbances.The last two were studied according to the current guidelines which recommend measuring transaminases (ALT = alanine aminotransferase, AST = aspartate aminotransferase) levels before initiating therapy.12 weeks after starting therapy, signs of potential hepatotoxicity such as jaundice, malaise, fatigue, and lethargy should alert physicians to measure transaminase levels and liver function tests.Fractionated bilirubin levels are recommended to rule out hepatic injury [10].
Abnormal hepatic transaminase levels are recognized as an infrequent occurrence of statin therapy.In particular, the transaminases seem to increase within the first 3 and 6 months of therapy [11].In the majority of clinical trials, elevated ALT levels three times greater than the upper limit of normal on two or more measurements have been considered as a safety endpoint.It was found that 1% of patients receiving low to intermediate statins dose (10 -40 mg daily ) and in 2% -3% of patients on high dose therapy (80 mg/daily) ALT elevation occurs [12].
Because of the absence of data concerning the hepatic toxicity of statins in Palestine, the present study was performed to evaluate the hepatic adverse effects of statins by measuring the serum ALT, AST activities and serum direct and total bilirubin concentration in a number of newly diagnosed patients with CHD.

Study Design and Patient Population
This study was undertaken over a period of 6 months from November 2010 till July 2011 in UNRWA health centers in Gaza Strip-Palestine.Ethical approval was obtained from the UNRWA and Helisinki committee in the Ministry of Health.

Sample and Sampling
Sixty six patients were newly diagnosed with CHD participated in the study, 37 males and 29 females, the mean age of both males and females was between 55 ± 10.3 years.The Patients were treated with atorvastatin at therapeutic dose with a range of (10 -40) mg daily once a day at bedtime according to cardiologist assessment.

Inclusion Criteria
1) Newly diagnosed patients with CHD.
2) Patients with normal liver functions and liver enzymes.
3) Patients with abnormal liver functions and liver enzymes were excluded from the study.4) Patients with hepatitis B & C or any liver diseases or any disease which may cause alteration of liver function tests were excluded from the study.This may be aided by taking history, and physical and clinical examination of the patients 5) Patients on continuous administration of statins treatment or other lipid lowering agents were also excluded from the study.
6) Patients receiving other medications affecting liver functions or liver enzymes.

Tools of the Study
Patient's data were collected from the medical record, an interview questionnaire and clinical examination.Colorimetric methods were used for determination of total cholesterol [13], TG [14], HDL-C, LDL-C [15].Photometric colorimetric methods were used for determination of ALT, AST, and total and direct blood bilirubin.

Statistical Design
Data were analyzed using the statistical package for social science (SPSS) computer program version 16.Descriptive statistics were performed to describe all variables.Chi-square was used to investigate the association between the study variables.Paired T-test was used to study the differences between the variables means.The significant of the association was tested at an alpha level of P < 0.05.

Patient Characteristics
The patient characteristics, family history and lipid parameters are listed in Table 1.Fifty six percent of patients were with heart disease family history.Forty three percent of patients were smokers.Fifty seven percent were obese.All the participants were treated with atorvastatin (10 -40 mg) with the majority (83%) were receiving a daily dose of 20 mg.[16], all the values are mg/dL.

Distribution of Study Population by the Liver Transaminases and Bilirubin
According to the data shown in Table 2, 98.5% of the study population was within the normal ALT range.This percent decreased after 3 months to 81.8% and accordingly, 18.2% of the patients have abnormal values of ALT.On the other hand, all the patients had normal values of AST at the baseline.However, the percent of patients with abnormal high AST levels increased to 9.1% at the first three months of the study and then decreased to 3% after 6 months.Similarly, the percent of abnormal total and direct bilirubin increased in the first three months and then decreased at the last three months of the study period.

The Effect of Statins on Liver Function and Liver Enzymes
1) The effect of statins on liver transaminases Results shown in Table 3 indicated a significant increase in the mean values of ALT and AST levels after 3 months of statins treatment compared to pre-treatment values.The new attainable levels of ALT and AST after 6 months of treatment were higher than the baseline levels; however, they were statistically insignificant. 2

) The effect of statins on bilirubin
The data shown in Table 4 pointed out a significant increase in the mean values of total and direct bilirubin after 3 months of statins treatment compared to pretreatment values.The new attainable levels of bilirubin after 6 months were higher than the baseline levels, however, they were statistically insignificant (p > 0.05).

The Relationship between Statins and Aminotransferases
The results of the current study revealed a mild to moderate asymptomatic but statistically significant elevations  of aminotransferases exceeding 1X upper normal limits (UNL).However, no case was with severe elevation higher than 3X UNL was found.This elevation can be identified as "transaminitis" in which liver enzyme levels are elevated in the absence of proven hepatotoxicity [17].Furthermore, the obtained results showed a significant increase in the mean values of ALT levels after 3 and 6 months of statins treatment compared to pre-treatment values.On the other hand, the mean values of AST increased significantly only at the first 3 months post-statins treatment compared to the pre-treatment values (p < 0.001) and then decreased back to an insignificant level (20.61 ± 9.915 U/L) at the last three months.This difference between the ALT and AST elevation, post-statin treatment, may be related to the higher sensitivity of ALT to hepatic inflammation [18].The results obtained were similar to the results found in a study provided by Chang & Schiano [19] who declared that generally mild aminotransferases elevation associated with statin occurs within the first 12 weeks and is asymptomatic and improves spontaneously.The incidence ranges from 0% to 3%.Similarly, another study conducted by Al-Jubori & Mahmood [20] demonstrated a mild elevation of ALT and AST activities less than 3 X the UNL post-statin treatments.On the other hand, several studies reported higher elevation values of ALT and AST activities more than 3X UNL [21]- [23].Furthermore, several clinical cases of autoimmune hepatitis an acute cholestatic hepatitis were reported after atorvastatin treatment [24].
Castro [25] reported another case of 72 years-old man who developed acute cholestatic hepatitis after atorvastatin treatment at a higher dose than lower doses.After treatment discontinuation, the patient made a full recovery.Elevations of all measured hepatic parameters in the current study were observed.This may indicate that the pattern of hepatotoxicity caused by atorvastatin is a mixed pattern of liver damage and hepatocellular damage [6].
Review of literature revealed varied periods of therapy at which the hepatic effect of statins was detected; 3 and 6 months [11]; 4 months [26]; 2 -4 times during the first year of treatment and 1 -2 times per year subsequently [27].
The mechanisms behind these adverse effects are unclear, but a few possibilities have been suggested.It has been noted that statins can induce a transient acute phase response on initiation, especially at high doses [28] [29] and this may represent a transient chemical hepatitis due to disturbance of the cholesterol-bile acid pathways [30].Moreover, it was speculated that the increased transaminases serum activity reflects alterations to the hepatocellular membrane (e.g., enhanced permeability) that permit leakage of these intracellular proteins [21].The former mechanisms appear to be a pharmacodynamic effects rather than a representation of cellular and particularly liver toxicity [31].

The Relationship between Statins and Bilirubin
The published data on the effect of statins on bilirubin are rare in comparison with articles related to the effect of statins on liver transaminases.Some studies assessed total bilirubin [17].As one of the liver parameters; some assessed fractioned bilirubin [12] and others assessed both [32].Since 2001, a total bilirubin level of more than 2X UNL has been used in combination to transaminases to define clinically-significant abnormal liver function, with confirmation required by additional clinical and laboratory data [33].One case of a 68 years old man was on atorvastatin 20 mg/day, showed abnormal elevation in both total and direct bilirubin which was 7.4 and 4.5 mg/dl respectively in addition to transaminitis [32].
In this study both total and direct bilirubin were measured and the relationship between them and statins treatment were analyzed.According to the results obtained, there was a significant increase in the mean values of total bilirubin in the first 3 months of study period increased from (0.659 ± 0.2179 mg/dL) to (0.796 ± 0.2461 mg/dL), at (p < 0.01).This is similar to the results obtained in a previous study in which patients on simavastatin and lovastatin (10 -20 mg) showed statistically significant elevation in the total bilirubin level [20].On the other hand, there was a mild increase, however, statistically insignificant, in the direct bilirubin mean value after 3 and 6 months of atorvastatin treatment.This insignificant relation may be due to the antioxidant effect of statins which is one of the most important of statins pleiotropic properties; a recent study on mice administered statins showed that statins increase the plasma antioxidant level [34].
Statins have also been reported to up-regulate antioxidant enzymes: catalase, superoxide dismutase and glutathione peroxidase, which eliminate free radicals by the generation of water and oxygen [35]- [37].Thus that might be related to the short term of period of the study and the small sample size.

Some Risk Factors for Statins Liver Adverse Effects
The incidence of statins-induced hepatotoxicity is uncommon events and the reported incidence is very low [38].The incidence of statin-induced liver injury may increase because of the presence other risk factors which could increase patient liver-injury susceptibility.Three risk factors (obesity, dose, drug interaction) were studied.
Several studies showed that obese individuals may have higher levels of serum transaminases than their lean counterparts [39].However; other studies concluded that the administration of statins to obese patients seems to be equally safe with the use of these drugs in lean subjects [40].
The results of the current study show that there was no significant relationship between liver enzyme elevation and the dose of statins.This was in agreement of Shepherd [41].And it was different from other studies that indicate that the enzymes and bilirubin emerge with higher doses.The results of this study may be not real due to that no high dose (80 mg) was administered from any of the patients, such (10, 20, 40 mg) doses which were available in the study were classified as low and moderate doses respectively [42] [43].
Shepherd [44] found that the rate of liver enzyme elevation with atorvastatin 80 mg/dL was four times greater compared with atorvastatin 10 mg/dL.Thus, hepatotoxic effects were related to the drug and dose used.Bhardwaj & Chalasani [6] also found that higher doses leading to greater frequency of transminases elevations and described it a dose-related phenomenon.The results of this study might be different to the new studies due to the range of doses used (10 -40 mg) is considered a low to moderate dose, no patient was on higher doses (80 mg).
In our study, the selected patients were asked about the most common drugs that interact with atorvastatin.The results showed that there was no drug interaction between these drugs and atorvastatin except diltiazem.There was a significant relationship between diltiazem co-administered with statins and transminitis.This result was similar to Law & Rudnicka [45] who reported that diltiazem increases the plasma levels of statins, and may lead to statin-related adverse effects.Gladding [46] found that the toxicity of statins metabolized by cytochrome P450 3A4, such as simvastatin and atorvastatin, is enhanced when the drugs are prescribed in high doses with diltiazem.

Conclusion
In conclusion, the effects of atorvastatin on both blood tranaminases and bilirubin levels support the previous findings of potential statin hepatotoxicity.Therefore, the FDA labeling information for all statins recommends liver function testing before putting a patient on a statins, 12 weeks after initiation, at any dose increase, and "periodically" for long-term maintenance therapy.These recommendations are based on expert opinion only, because most data suggest that significant liver damage from statins is very rare and that routine monitoring of liver enzymes is not necessary.The ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins agrees with the FDA, although it specifies "periodically" to mean annually [47].
*The classification according to NCEP

Table 2 .
Distribution of study population by the liver transaminases and bilirubin variables (n = 66).

Table 3 .
Levels of liver enzymes ALT, AST (U/L) before and at 3 and 6 months during the study period (n = 66).
a Difference of means between before Atorvastatin and 3 months after Atorvastatin; b Difference of means between before Atorvastatin and 6 months after Atorvastatin; c Difference of means between 3 months after Atorvastatin and 6 months after Atorvastatin.

Table 4 .
Levels of total and direct bilirubin for the patients before and at 3 and 6 months during study period (n = 66).Difference of means between before statins and 3 months after atorvastatin; b Difference of means between before statins and 6 months after atorvastatin; c Difference of means between 3 months after statins and 6 months after atorvastatin.