INTRODUCTION:

Atorvastatin are HMGCoA reductase inhibitors which decreases the low-density lipoprotein (LDL) levels and stabilises atherosclerotic plaques. Statins are prescribed for the treatment of dyslipidaemia and for the prevention of cardiovascular diseases^1-3. Statins are one of the major drugs in decreasing the rates of mortality in patients with high cardiovascular risk by decreasing β-natriuretic peptide levels and inflammatory mediators TNF-α⁴. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme of the isoprenoid pathway required for the synthesis of cholesterol and further it inhibits synthesis of cholesterol. Statins plays a critical role in dyslipidaemia by decreasing low density lipoproteins (LDLs) levels by several mechanisms and thus it reduces cardiovascular mortality^5-7.

One of the main complications of statin therapy is statin induced liver injury which is a rare event with a rate of incidence of 1-10 in every 10000 evident individuals. In addition to the benefit of atorvastatin in preventing cardiovascular disease they increase the liver enzyme levels⁸.Even though liver toxicity is an issue associated with statins, they are safe for preventing coronary disease and death and they are preferred due to its benefits. Here we report three patients who presented with significant elevation in aspartate aminotransferase (AST) and alanine transaminase (ALT) immediately after atorvastatin therapy.

Clinical Features:

Case 1:

A 72-year-old male known case of CAD (MI, unstable angina, TVD) type 2 DM, systemic hypertension, on medication was admitted to the hospital because of acute onset of breathlessness for 3 days, vomiting for 2 days, decreased food or water intake, decreased urine output for 2 days. On laboratory test evaluation, cardiac enzymes were found to be elevated (CKMB - 7.94, troponin T - 3.94, CK - 2178, NT PRO BNP was elevated 16792) and his baseline liver biochemistries were normal. Patient was diagnosed ACS NSTEMI with CHF.ECG taken showed sinus rhythm with new onset of LBBB/moderate to severe LV dysfunction (EF 37%) was developed. He was started on IV Lasix infusion, Inj heparin, antiplatelets and other supportive medications. He had hypotension hence he was given injection dobutamine and adrenaline infusion. The patient had a previous medical history of atorvastatin 10mg. During hospitalisation he was prescribed with 40mg of atorvastatin. After 24hrs of atorvastatin therapy his laboratory analysis showed sudden increase in liver function tests. The patient’s bilirubin was 3.79mg/dl, alkaline phosphatase was 252.0U/L, alanine aminotransferase (ALT) level was 177.3U/L and aspartate aminotransferase (AST) level was 106.5U/L. All other causes of abnormal liver biochemistries were normal (Table 1). Then atorvastatin was withhold. Then his ALT, AST, ALP became normal after 6 days. His RUCAM score is 7.

Case 2:

A 41-year-old male with no known comorbidities was admitted with complaints of left side chest pain. ECG taken suggestive of anteroseptal STEMI. He was immediately taken up for primary PTCA. Check angiogram confirmed the diagnosis of coronary artery disease -single vessel disease (mild LAD 99% stenosis). Subsequently he underwent primary PTCA with stent to mild LAD. Post procedure period was uneventful. Echo done showed RWMA+ Mid and apical septum- hypokinetic and thinned apex-Mildly hypokinetic with preserved thickness, fair LV systolic function, normal diastolic function, MVP-mild AML A2 prolapse, good LV function. USG abdomen showed hepatomegaly with grade 2 fatty infiltration. He was started with Beta blockers, antiplatelets and statins. He was given phase 1 cardiac rehabilitation. His baseline LFTs were normal. ALT and AST elevated within 1 day of atorvastatin 80mg then statin dose was decreased to 20mg. The patient’s bilirubin was 1.01mg/dl, alanine aminotransferase (ALT) was 79.4u/l and aspartate aminotransferase (AST) level were 104.4u/l. Other LFTs such as alkaline phosphatase lactate dehydrogenase, gamma-glutamyl transpeptidase were normal (Table 1). Then statins were withhold and ALT and AST was recovered to baseline level after 2 days of discontinuing the therapy. Then he was again discharged with atorvastatin 40mg and it does not cause any notable elevation of ALT and AST levels during the 1 month follow up observation. His RUCAM score is 6

Case 3:

A 77-year-old male with known case of diabetes and dyslipidaemia was admitted with complaints of chest pain associated with 2 episodes of vomiting and headache. His ECG showed ST elevation in V1-V5 diagnosed with anterior wall MI and accelerated hypertension. His baseline LFT values are normal. His check angiogram showed Triple vessel disease and he underwent primary PTCA with stent to Mid LAD. Echo done showed mild concentric LVH, RWMA + mid and apical septum/apical anterolateral wall hypokinetic with mild thinning. Moderate LV systolic dysfunction (EF 40%), good RV function. He was started on antianginal medications with atorvastatin. He was started with atorvastatin 10mg initially and then switched to 40mg. After initiating 40mg his LFT values showed some abnormalities. His alkaline phosphatase was 108.0u/l and aspartate transaminase were 80.2u/l levels. Then statin therapy was discontinued. After stopping statins his LFT values came to baseline after 3 days. He was then discharged with 40mg of atorvastatin and that does not cause any changes in his AST levels during his follow up after one month. His RUCAM score is 8.

Table 1: Atorvastatin induced liver enzyme elevations; clinical features of patients.

Clinical features	Case 1	Case 2	Case 3
Age (years)	72	41	77
Concomitant drugs	no	no	No
Latency to onset:
<12 weeks	-	yes	Yes
>1 year	yes	-	-
HBsAg and HCV-Ab	negative	negative	Negative
Peak ALT (IU/L)	121.1	100.8	40.7
Peak AST (IU/L)	188.4	104.4	132.2
Peak ALP (IU/L)	252.0	69.0
Peak direct Bilirubin (mg/dl)	3.79	0.29	0.29
Peak Total Bilirubin (mg/dl)	5.24	1.09	1.11
Initial R ratio	R<2	R>5	R<2
RUCAM Score	7	6	8

DISCUSSION:

Atorvastatin and liver injury:

Coronary artery disease death rates are found to be 3 times higher than stroke rates as reported from WHO 2002^[9].Statins are the generally prescribed medication over the world because it can reduce mortality and morbidity in cardiovascular diseases in patients with hyperlipidaemia¹⁰. Early clinical trials suggest that aminotransferase elevations were observed in patients prescribed with atorvastatin. Even though, statin induced liver injury is a rarely observed one¹¹. Under certain clinical conditions atorvastatin can cause acute elevation of hepatic enzymes which are rarely associated with symptoms. Permanent liver damage causing chronic liver injury, liver transplantation or death are rare with statins.

Here we discuss 3 cases of elevated serum aminotransferases (ALT and AST) which are asymptomatic and two cases with normal bilirubin level and three of them with normal INR level. There was no history of fever, rashes, itching and jaundice and the patients had no history of previous liver injury. The patients were initiated with statins to prevent the risk of cardiovascular disease and one of the patients was already on treatment with atorvastatin 10mg and during hospitalisation he was increased to atorvastatin 40mg due to his worsen condition. Cases 2 and 3 were observed with serum aminotransferase elevation after 24hrs of statin therapy. In case 1, elevation of liver enzymes was contributed by recent development of LV dysfunction, acute renal shutdown, and concomitant increase in statin dosage.

Atorvastatin induced liver injury is correlated with mixed effect of liver injury often occurring immediately after beginning the treatment or after several months or years of therapy. There are three categories of drug induced liver injury: hepatocellular type injury, cholestatic type injury and mixed type injury which includes features of both the hepatocellular and cholestatic form of injury. These types of injury are defined conforming to serum ALT and ALP levels and the ratio (R) of ALT/ALP. Hepatocellular injury is defined as serum alanine aminotransferase (ALT) elevation which is greater than the upper limit of normal (ULN) by 2 times and R>5 and cholestatic liver injury is elevation in alkaline phosphatase (ALP) which is asymptomatic and R<2 and mixed liver injury defined as ALT elevation 2 times than ULN and R>2 but <5^12,13. Our two cases showed ALP 2 folds higher than ULN and R ratio <2, so considered as cholestatic injury group and 1 case with ALT 2 folds higher than ULN and ALP value remaining normal and R ratio> 5 which is considered as hepatocellular injury group. It is observed that patient with hepatocellular injury tends to be younger when we compare both hepatocellular and cholestatic cases but did not vary by type of statin, gender, distribution of latencies or body mass index (BMI). None of the cases had undergone liver biopsy, no liver transplant, chronic liver injury and death¹⁴.

Drug induced liver injury due to statins can be easily evaluated using a scale called Roussel-Uclaf causality assessment method (RUCAM). RUCAM system gives an overall score of biochemical, clinical, serologic and radiologic characteristics of liver injury that is due to a fixed drug. The score is calculated by 8 separate factors in seven categories. These factors include: (1) onset of time; (2) course of treatment; (3) risk factors; (4) correlated drugs; (5) nondrug +=causes of drug injury; (6) previous history of hepatotoxic drugs and (7) reaction to rechallenge. The result is assessed by adding all the scores and defined as: >1 and <2 unlikely >3 and <5 possible >6 and <8 probable and >8 highly probable¹⁵. Our 3 cases were calculated as probable case.

Prolonged latency is one of the salient features of statin induced liver injury. Case 2 and 3 were observed with serum aminotransferase elevation after 24hrs of statin therapy and case 1 showed their elevation immediately after increasing their current dose to a higher dose due to recent development of LV dysfunction and acute renal shutdown. Cases with prolonged latency are unusual. Drugs such as methyldopa, minocycline, nitrofurantoin shows a prolonged latency and they normally present with a syndrome like chronic hepatitis rather than hepatocellular or cholestatic hepatitis.

Mechanisms of statin induced liver injury have not been entirely understood. One of the major mechanisms of statin induced liver injury is mitochondrial dysfunction. It has been shown in animal models. There is an increase in mitochondrial superoxide after initiating statin treatment and it can cause the mitochondrial impairment. Reactive oxygen species are produced by hepatocytes using statins. These ROS causes lipid peroxidation and cytotoxicity by decrease in mitochondrial membrane potential. All these effects are time and dose dependent. Some studies suggest that liver injury by statins may be caused by idiosyncratic and immunologic mechanisms. Another mechanism is by lactic acidosis however it is not verified that lactic acidosis is an addictive side effect associated with statins. Drug – drug interactions can also lead to hepatotoxicity of statins.

CONCLUSION:

Asymptomatic increase in aminotransferases is a class effect of statins which is rare, usually ranging from mild and then to moderate in severity and they suddenly returns to normal ranges after discontinuation. We have reported 3 cases of statin induced liver injury which became normal after withdrawal of statins. Therefore, our report suggests that whenever starting statins it is important to monitor the Liver function tests to avoid statin induced injury and initiate with lower doses.

ACKNOWLEDGEMENTS:

The authors thank Dr Shantikumar Nair, Dean of Rsearch at Amrita Institute of Medical Science, Kochi for their contributions and assistance with the review of the case.

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

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Received on 18.05.2021 Modified on 08.12.2021

Research J. Pharm. and Tech. 2022; 15(8):3507-3510.

DOI: 10.52711/0974-360X.2022.00588