When Statins get Physical: A Curious Cause of Statin Myopathy

Puja P. Patel, DO; Christopher D. Jackson, MD

Disclosures

South Med J. 2022;115(4):266-269. 

In This Article

Case Report

A 61-year-old African American male with hypertension, hyperlipidemia, pes planus, lumbar radiculopathy, and osteoarthritis presented to the emergency department with worsening myalgias and weakness for 3 months. He reported pain bilaterally in his upper and lower extremities, abdomen, and back. His pain worsened with exertion and improved with rest. On a review of systems, he noted fatigue, sporadic subjective fevers, generalized muscle spasms, tea-colored urine, and progressive difficulty in rising from a seated to a standing position and raising his arms above his head. He denied dyspnea, new rashes, focal neurologic symptoms, or prior weakness. His medications included amlodipine 10 mg/day, vardenafil 5 mg as needed, and cetirizine 10 mg as needed. Although prescribed atorvastatin 80 mg for years, the patient began taking it 3 months before presenting to the emergency department. He denied a family history of systemic lupus erythematosus, rheumatoid arthritis, or inflammatory myopathy. He reported no significant alcohol, tobacco, or intravenous drug use.

General Medicine Service Commentary

The classical triad and diagnostic criteria for rhabdomyolysis are as follows:[1]

  • Elevation in creatine kinase values >5 times the upper limit of normal

  • Creatinine elevation, consistent with pigment nephropathy

  • Classic triad of weakness, muscle pain, and reddish/brown urine (urinalysis: +blood, no red blood cells, +myoglobin)

Determining the etiology is vital for appropriate treatment and prognostication. The causes of rhabdomyolysis are broadly divided into three categories: traumatic, nontraumatic exertional, and nontraumatic nonexertional.[2] Asking about dermatologic and musculoskeletal symptoms is an integral part of the evaluation. Once recognized, early and aggressive fluid resuscitation is the standard of care.

His vital signs on admission included a temperature of 98.7 °F, blood pressure of 146/91 mm Hg, heart rate of 75 bpm, and a respiratory rate of 20 bpm. He exhibited 3/5 strength in his right hip flexors and hamstrings and 3/5 strength in his left hip flexors and hamstrings on the musculoskeletal examination. His upper extremity strength testing was 5/5 bilaterally with intact reflexes and sensation to light touch, deep touch, pain, and temperature. Laboratory workup revealed a creatine phosphokinase (CPK) value of >32,000 μg/L, an erythrocyte sedimentation rate of 56 mm/hour, aspartate aminotransferase >750 U/L, alanine aminotransferase 814 U/L, and a creatinine of 0.8 mg/dL. The urinalysis showed 2+ blood without casts, red blood cells, albuminuria, or glucosuria. The urine drug screen was negative.

The patient's clinical examination and laboratory studies seemed consistent with myopathy, given the weakness and elevation of his CPK and aspartate aminotransferase levels. Given no obvious source of trauma or seizures, the patient's medication list was reviewed. Although his myopathy was attributed mainly to atorvastatin, it is interesting to note that he was taking amlodipine in addition to atorvastatin. After discontinuing atorvastatin, he received aggressive fluid resuscitation for the treatment of drug-induced myopathy.

Rheumatology Service Commentary

Drug-induced myopathies range from mild myalgias with or without weakness to fulminant rhabdomyolysis with acute renal failure.[3] The differential diagnosis in this case is exhaustive, with essential representative diagnoses outlined as follows:

  • Polymyositis

  • Dermatomyositis

  • Antisynthetase syndrome

  • Inclusion body myositis

  • Immune-mediated necrotizing myopathy

  • Drug-induced myositis

  • Paraneoplastic syndrome

In this case of suspected drug-induced myopathy, our differential included polymyositis, dermatomyositis, antisynthetase syndrome, inclusion body myositis, drug-induced myositis, and paraneoplastic syndrome. A notable laboratory workup for our patient can be seen in the Table.

There are >150 documented agents that have been associated with myopathy and rhabdomyolysis, with statins being the most commonly implicated.[4] Statins are effective and generally safe; however, muscle toxicity remains a concern. Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare, yet devastating complication of statin use and can occur at any time after the initiation of the therapy.[5] The mechanism of muscle toxicity is not well understood; however, it is hypothesized that statins trigger an overexpression and subsequent autoimmunity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in genetically susceptible patients.[6]

Statins, otherwise known as HMGCR inhibitors, are metabolized by the cytochrome P450 system; therefore, it also is prudent to note that inhibitors of this system may lead to myopathies. This was pointed out in 2018, with the concomitant use of calcium channel blockers and statin medications. Most incidences, however, have been noted with the addition of amlodipine to simvastatin while our patient was taking atorvastatin and amlodipine.[7]

General Internal Medicine Commentary

Patients with myopathy or rhabdomyolysis typically experience an increase in CPK within 12 hours of the onset of muscle injury, followed by a peak in 1 to 3 days and a steady decline 3 to 5 days after cessation of the offending agent.[1] Despite appropriate management and statin discontinuation, our patient's CPK remained unchanged with worsening myalgias. After several days, he experienced significantly diminished strength, with a paradoxical improvement in CPK levels to 25,000 μg/L. We ordered a magnetic resonance image of the right lower extremity, which showed a variable degree of edema within different muscle groups, specifically in the semimembranosus and central muscle bundles of the abductor magnus. Deep muscle involvement also was found to be present in the rectus femoris and quadriceps groups.

The diagnosis of SINAM is rare. Given the degree of edema and weakness with a paradoxical improvement in CPK levels, a muscle biopsy was ordered. The Internal Medicine team consulted Neurology to rule out motor neuron disorders as a cause of this patient's presentation.

Neurology Service Commentary

The measurement of serum muscle enzymes is typically conducted when evaluating for muscle weakness of myalgias.[8] Typically, CPK levels >1000 μg/L will distinguish primary muscle disease from neurogenic causes of weakness; however, there have been some modest increases in CPK levels in motor neuron diseases.[8] An electromyogram can help distinguish weakness from myopathy versus neuropathy. Myopathy is characterized by significant muscle fiber conduction velocity slowing, which correlates with prolonged compound muscle action potentials and altered muscle excitability. In contrast, abnormal sensory nerve action potentials are characteristic of polyneuropathy.[9]

A definite diagnosis of polyneuropathy requires that the following criteria be met: the patient develops limb weakness after non-neuromuscular causes have been excluded, electromyography shows the axonal motor and sensory polyneuropathy, and absent decremental response to repetitive stimulation.[9]

Muscle biopsy remains the gold standard for confirming muscle involvement in the disease process. Critical illness neuropathy presents as morphological signs of axonal degeneration in types 1 and 2 fibers, resulting in extensive denervation and atrophy of muscles.[9]

Rheumatology Service Commentary

Polyneuropathy and myopathy often coexist and subsequently may not easily be differentiated from each other. Although the pathophysiology of the two entities is not entirely understood, some criteria serve as guidance for the correct diagnosis. A definite diagnosis of myopathy requires that the following criteria be met: the patient develops limb weakness after non-neuromuscular causes have been excluded; compound muscle action potential amplitudes are <80% of the expected lower limit in ≥2 nerves without conduction block; sensory nerve action potential amplitudes are >80% of the standard lower limit; needle electromyography shows short duration, low-amplitude motor unit potentials with early or regular full recruitment, with or without fibrillation potentials, in conscious and collaborative patients, or increased compound muscle action potential duration or reduced muscle membrane excitability on direct muscle stimulation in noncollaborative patients; absent decremental response to repetitive nerve stimulation; and muscle histopathology shows primary myopathy.[9]

Although these criteria are helpful, there is considerable overlap with polyneuropathy; therefore, muscle biopsy remains the gold standard for distinguishing between these two disorders. Myopathies have a spectrum of phenotypes; however, they are pathologically classified into five subtypes: thick filament myopathy, acute myopathy with scattered necrosis, acute myopathy with diffuse necrosis, disuse cachectic myopathy, and rhabdomyolysis.[9]

SINAM is differentiated from statin-associated myopathy alone by the presence of HMGCR antibodies, the degree of CPK elevation, the preference for proximal muscle involvement, and the incomplete resolution of symptoms on cessation of statin therapy.[10] Muscle biopsy in these cases uniquely features muscle necrosis with myofiber regeneration and minimal inflammation.[11] Although this patient's CPK levels decreased, they were not substantial, and his symptoms paradoxically worsened. As a result of this presentation, SINAM remained high on the differential.

The patient's muscle biopsy showed rare fibers undergoing regeneration. There were scattered fibers with necrosis and phagocytosis. Mild lymphocyte infiltrates were seen, but no upregulation of the major histocompatibility complex. No angular atrophic fibers were seen. One vacuolated fiber was seen on the border, which was hard to analyze because it had some rimmed vacuoles, but no other evidence of rimmed vacuoles was seen. It was concluded that this biopsy showed abnormal muscle with findings suggestive of regeneration from necrosis confirming the diagnosis of SINAM.

After the muscle biopsy, the patient was empirically started on prednisone 15 mg 4 times per day to treat this autoimmune myopathy. Although this brought about a dramatic improvement in his clinical picture, he could still achieve his baseline activity level. At that time, his CPK level was reported at 22,500 μg/L (Figure). Anti-HMGCR antibodies were obtained, and he did ultimately test weakly positive; however, it is essential to note that this sample was taken and returned after the patient was placed on immunosuppressive treatment.

Figure.

Creatine phosphokinase levels.

Because of his improved condition and stabilization of his CPK at 17,000 μg/L (Figure), he was discharged after 2 weeks with a steroid taper. Given his illness, he was eventually started on azathioprine 50 mg twice daily. He completed 8 weeks of azathioprine therapy and his steroid taper with no change in his physical status. As such, he was started on monthly intravenous immunoglobulin, with a dramatic resolution of his physical frailty and improved CPK levels to < 15,000 μg/L.

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