The Effects of Melatonin on Elevated Liver Enzymes During Statins Treatment
Condition: Hepatopathy
MeSH terms: Liver Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction. Statins are generally well tolerated but not devoid of side effects. Quite
      often it is manifested by asymptomatic increase in the level of aspartate and alanine
      aminotransferase. In such cases patients to administer hepatoprotective drugs, but most of
      them used for this purpose are ineffective. The aim of this study was assess the usefulness
      of melatonin in counteracting the adverse hepatic events from statins. Methods. The research
      program included 60 patients(aged 47-65 years, 41 women and 23 men)with hyperlipidemia taking
      atorvastatin or rosuvastatin in dose 20-40 mg daily. The patients were randomly allocated in
      two groups. Group I (n=30) was recommended to take the same statin at a standardized daily
      dose of 20 mg together with melatonin at a dose 2 x 5 mg, at 7:00 and 21:00. In group II
      (n=30) patients took statins with placebo at the same time of the day. Follow-up laboratory
      tests (AST, ALT, GGT, ALP, cholesterol, triglycerides) were evaluated after 2,4 and 6 mounts
      of treatment.
    

Detailed description: 
      Introduction Statins are widely used in the treatment and prevention of lipid metabolism
      disorders. They are generally well tolerated but not devoid of side effects. These include,
      among others, muscular symptoms, arthritis, headaches, gynecomastia. Myositis and
      rhabdomyolysis associated with increased activity of creatinine kinase and serum creatinine
      levels are rare but serious adverse events of statin therapy. The risk of these complications
      is increased in elderly patients with chronic diseases and in alcohol abusers.

      Furthermore, statins cause hepatotoxic effect which is observed in several percent of treated
      patients, usually in the first weeks of the therapy . Most frequently it is manifested by
      asymptomatic increase in the level of aspartate and alanine aminotransferase. This is usually
      a temporary increase, but in some patients the level of these enzymes exceeds 3 times the
      normal limit, which is a matter of concern. In such cases, patients expect the decision to
      discontinue the treatment or to administer hepatoprotective drugs. Acetylcholine, sylibinin,
      phospholipids and other drugs used for this purpose are not always effective. Therefore,
      there is still search for alternative drugs for the protection of liver.

      In own study melatonin was used for this purpose because previous experimental studies had
      demonstrated that it protected liver against harmful effects of many toxic agents as well as
      the consequences of ischemia-reperfusion model.

      The liver is an organ in which there comes to intensive metabolic and detoxification
      processes. In their course large amounts of reactive oxygen species are generated and they
      exert a toxic effect on hepatocytes. A complex antioxidant system - in which metabolized
      there melatonin (pineal and from other sources) is an important part - prevents that.

      The main melatonin metabolic pathway in the liver is through hydroxylation pathway at the C-6
      position by 6-hydroxylase and P450 cytochromes (CYP1A1, CYP1A2, CYP2P19, CYP1B1 isozymes).
      The 6-hydroxymelatonin, formed in this process, is conjugated with sulphate and glucuronide
      to 6-hydroxymelatonin sulphate or glucuronide. In this process melatonin and its metabolites
      exert high antioxidant activity.

      An alternative metabolic pathway includes melatonin oxidation to N-acetyl-formyl-5-
      methoxykynuramine (AFMK) and N-acetyl-5-methoxykynuramine (AMK). The kynurenine pathway of
      melatonin metabolism leads to formation of a series of free radical scavengers.

      Furthermore, melatonin decreases the production of proinflammatory cytokines and inhibits
      hepatic fibrogenesis. Owing to its multidirectional action in liver, apoptosis and necrosis
      decrease, the integrity is protected and regeneration is improved.

      The aim of this study was to assess the usefulness of melatonin in counteracting the adverse
      hepatic events from statins.

      Material and Methods Patients and Data Collection The research program included 30 subjects,
      aged 47-68 years, 41 women and 23 men. All women were I the postpostmenopausal period.
      Recruitment and diagnostic tests were conducted in the Department of Gastroenterology,
      Medical University of Lodz and Outpatient Consulting Clinic "Gastro" in Lodz.

      The research study was performed in the years 2012-2016. Therapeutic Procedures After
      inclusion into the study, all patients were recommended the same balanced diet with limited
      animal fats and simple carbohydrates of caloric content of 1600 kcal. At the same time, they
      were recommended to continue the treatment with the same statin at a daily dose of 20 mg.

      The patients were randomly allocated into two groups. Group I (n=30) was recommended to take
      statin together with melatonin (LEK-AM, Poland) at a dose of 2x5 mg, at 7:00 a.m. and 9:00
      p.m. In Group II (n=30) patients took statin with placebo (LEK-AM, Poland) at the same dose
      and time of the day.

      Follow-up laboratory tests (AST, ALT, GGT, ALP, cholesterol and triglycerides) were evaluated
      after 2,4 and 6 months of treatment.

      Ethical procedures A written consent was obtained from the patients and the Bioethics
      Committee of the Medical University in Lodz approved the study protocol (RNN/45/12/KB).

      Tests were conducted in accordance with the Declaration of Helsinki and with the principles
      of Good Clinical Practice.

      Statistical analysis All parameters were checked for normality using the Shapiro-Wilk test.
      Wilcoxon's rank sum test was used for the comparison of basal treatment differences between
      each liver enzyme level. Comparison of parameters in four time series was calculated using
      ANOVA Friedman test. Mann-Whitney U test was used for nonparametric data to perform the
      comparison between groups. Calculation were made using Statistical 9.1 Microsoft Co.
      software, and statistical significance was established at p< 0,05.

      Acknowledgments This work was supported by the grant from the Polish Ministry of Science and
      Higher Education No: NN 402 54 37/40.

      Competing Interests The authors declare that they have no competing interests.
    

Intervention name(s): Melatonin 10 mg; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): melatonin 10mg daily p.o.; Placebo 10mg daily p.o.
Other intervention name(s): Melatonin Lek-AM 10mg; Placebo 10mg
Intervention MeSH terms: Melatonin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: statins liver enzymes melatonin