Statins unmasking a mitochondrial myopathy: A case report and proposed mechanism of disease. .

To the Editor: Since their introduction, statins have revolutionized the treatment and prognosis of atherosclerotic vascular disease. Reductions in both cardiovascular and total mortality have been demonstrated in high-risk primary, (1) high-risk secondary, (2) and low-risk secondary (3, 4) prevention trials. The first clinically available statin was lovastatin. When first introduced, the incidence of myopathy with lovastatin was estimated to be 0.5%. (5) As newer statins were introduced and their use increased, the estimated incidence of myopathy decreased. The current estimated incidence of myopathy in connection with statins is less than 0.1% of patients. (6) Statins are safe and efficacious drugs. In this letter, we describe a patient with coronary artery disease who was unable to tolerate any statin. After careful evaluation, we determined that his myalgias were due to an underlying mitochondrial myopathy, not to his medication. Statins merely exacerbated his symptoms.

Statins, in addition to inhibiting production of cholesterol, decrease production of ubiquinone, a precursor of coenzyme Q. Decreased levels of coenzyme Q are one of several known defects underlying mitochondrial myopathies. We postulate that patients who develop myalgias on statins may have an underlying muscle disorder, either primary or secondary. Patients who develop myalgias on HMG CoA reductase inhibitors should be evaluated for underlying medical disease before the symptoms are ascribed to the statin.

The patient was a 56-year-old man with known coronary artery disease who had undergone both coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. He developed severe myalgias, profound weakness, and marked creatine phosphokinase (CPK) elevation on all statins. He was referred to the Lipid Clinic for further evaluation. A chart review revealed several baseline CPKs in the mid-300s. Thyroid evaluation was normal. Shortly after Mevacor was started, the patient complained of severe myalgias. CPKs increased to more than 4,000 U/L. The use of pravastatin and simvastatin resulted in similar symptoms and CPK elevation. After taking a careful history, we determined that the patient had had mild symptoms and CPK elevation before starting statins. His muscle weakness was most pronounced in the shoulder girdle. He had difficulty in using his arms overhead for extended periods. He had only modest weakness in his hip girdle and legs. The patient was able to complete 12 minutes of exercis e testing on a Bruce protocol before stopping because of leg fatigue. He was also noted to have sensorineural hearing loss.

An electromyogram obtained while the patient was off statins demonstrated mild sensory and motor-axonal neuropathy and was suggestive of mild, noninflammatory myopathy. A muscle biopsy demonstrated ragged red fibers and paracrystalline inclusions. Special staining demonstrated enhancement of mitochondria, suggesting mitochondrial proliferation. A diagnosis of mild mitochondrial myopathy was made. We concluded that the use of statins exacerbated a mitochondrial myopathy in this patient. The patient is currently taking niacin extended-release tablets (Niaspan) and cholestyramine for his dyslipidemia.

Statins are generally considered safe medications. The incidence of liver toxicity is low. For all statins, ALT and AST elevations exceeding three times the upper limits of normal are dosedependent and reported in only 0.9 to 1.9% of patients. (9-14) The development of hepatotoxicity usually occurs in the first few weeks to months of treatment. All patients requiring lipid-lowering medication should have baseline ALT and AST levels. Follow-up levels should be obtained at 6 weeks, 3 months, 6 months, and 1 year. Unless the dose is increased, pravastatin and simvastatin do not require further liver enzyme momtoring if no enzyme elevations are detected during the first year of therapy. (9,10) The newer statins--cerivastatin, fluvastatin, and atorvastatin--require periodic liver enzyme monitoring. (11-14)

Myalgias due to statins can occur spontaneously at any time during treatment. Symptoms include muscle aches, malaise, and low-grade fever. Patients may mistake these for a viral syndrome. (9) The symptoms abate shortly after cessation of the statin. Some experts think that patients developing myalgias on one statin can safely tolerate a different statin. (10) When rechallenging with the new statin, patients should be started at low doses and be titrated cautiously. All patients should have a baseline CPK level. Monitoring of serum CPK levels, however, may not predict myalgias. The mechanism of myalgias with statins is not clear. Initially, the varying lipophilicity and protein binding among statins was implicated. Highly lipophilic and protein bound statins, such as lovastatin, were suspected to be more toxic to muscles than hydrophobic statins such as pravastatin.

Improved understanding of hepatic drug metabolism, however, may explain the mechanism and incidence of statin-associated myositis. Most drugs are metabolized in the liver by the cytochrome P450 3A4 system. Simvastatin, atorvastatin, and lovastatin use this pathway. Drugs that inhibit the CYP450 3A4 pathway hinder the metabolism and elevate serum levels of these statins, potentially precipitating myalgias (Table 1). Fluvastatin uses the GYP 450 4C9 pathway, whereas pravastatin does not use the CYP45O system. Varying excretion pathways and drug interactions may explain why patients can tolerate one but not another statin as well as the seemingly sporadic Onset of myalgias. (15) The mechanism of statins precipitating myositis can be explained by the isoprenyl synthetic pathway. The isoprenyl synthetic pathway is most commonly associated with cholesterol metabolism (Fig. 1). HMG-CoA reductase inhibitors inhibit the conversion of HMGCoA to mevalonate, the rate-limiting step in cholesterol synthesis. Mevalonate is also an intermediate in the metabolism of dolichol, isopentenyl, and ubiquinone. Dolichol is a carrier of oligosaccharides in glycoprotein metabolism. Isopentenyl adenine is a precursor of t-RNA. (16) The clinical implications of inhibiting these metabolic pathways are not known. Ubiquinone is converted to coenzyme Q, a component of the oxidative phosphorylation chain. Deficiency of coenzyme Q can lead to mitochondrial myopathy. (8) Our patient had an underlying defect in his oxidative phosphorylation pathway--a mitochondrial myopathy.

We postulate that use of statins decreased production of coenzyme Q and exacerbated his myopathy. Patients may also have an underlying medical illness that manifests as myalgias and elevated serum CPK levels. Statins merely exacerbate their disease (Table 2). Before initiating statin therapy, baseline CPK level and medical history should be obtained, and a physical examination should be performed. Subsequent CPK levels do not predict the development of myalgias, because the onset of symptoms is sporadic.

Statins are safe and effective medications. The incidence of serious complications is rare. When patients develop elevated CPK levels and myalgias while on HMG-CoA reductase inhibitors, a careful search should be made to exclude underlying medical diseases and drug interactions before implicating the statin.

Benjamin J. Diaczok, MD

Department of Internal Medicine Providence Hospital

Southfield, MI

Wayne State University 

Detroit, MI

R. Shali, MD

Department of Internal Medicine Providence Hospital

Southfield, MI

[FIGURE 1 OMITTED]

Table 1

Statin metabolism and potential drug interactions

               Route of   Drugs that inhibit
Statin        Metabolism  metabolism

Lovastatin    CYP450 3A4  Erythromycin
Simvastatin   CYP450 3A4  Itraconazole
Atorvastatin  CYP450 3A4  Diltiazem
Cerivastatin  CYP450 3A4  Cyclosporin
Pravastatin      none
Fluvastatin   CYP450 2C9  Phenytoin, diclofenac, tolbutamide

Table 2

Causes of elevated serum CPK

Common causes

  Alcohol intoxication
  Muscle trauma
  Hypothyroidism
  Hyperthyroidism
  Seizure
  Drug overdose

Uncommon causes

  Hypokalemia
  Dermatomyositis
  Polymyositis
  Hypophosphatemia
  Hypomagnesemia
  Hyponaterimia
  Hyperparathyroidism

Rare causes

  Sepsis
  Spider bites
  Snake bites

References

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