Peer Reviewed

Case In Point

A Case of Statin-Induced Myopathy

Volume 61 - Issue 5 - May 2021

 

AUTHORS:
Prathayini Paramanathan, HBSc1 • Muhammad Abbas2 • Preslav Valchev, RN, BSN3 • Priscilla Itua1 • Parastoo Taravati, HBSc4

AFFILIATIONS:
1All Saints University College of Medicine, Saint Vincent and the Grenadines
2Avalon University School of Medicine, Curaçao
3Saint James School of Medicine, Anguilla
4Saint James School of Medicine, Saint Vincent and the Grenadines

CITATION:
Paramanathan P, Abbas M, Valchev P, Itua P, Taravati P. A case of statin-induced myopathy. Consultant. 2021;61(5):e3-e5. doi:10.25270/con.2020.06.00022

Received April 2, 2020. Accepted June 9, 2020. Published online June 18, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

ACKNOWLEDGEMENT:
The patient’s primary care physician was Seema Elahi, MD, an emergency medicine and internal medicine attending physician at Northshore University Health System in Chicago, Illinois.

CORRESPONDENCE:
Preslav Valchev, RN, BSN, Saint James School of Medicine, 1480 Renaissance Dr, Ste 300, Park Ridge, IL, 60068 (pvalchev@mail.sjsm.org)

 

A 79-year-old man presented to the emergency department (ED) for increasingly severe bilateral proximal upper- and lower-extremity muscle weakness, balance deficit, and loss of strength and mobility.

History. His medical history included congenital hearing loss, primary hypertension, hyperlipidemia, type 2 diabetes, primary osteoarthritis, gastroesophageal reflux disease, atrial fibrillation, coronary artery disease, cholelithiasis, benign tumor of the colon, benign prostatic hyperplasia, and varicose veins of the lower limbs.

Approximately 4 months prior to presentation at the ED, the patient’s ability to carry out daily activities, such as personal care, walking, climbing stairs, driving, household duties, and exercising, had become limited. Six weeks prior to presentation, he had gone to Mexico on vacation, where his symptoms had worsened. He reported having an unintentional weight loss of 9 kg, excessive fatigue, and repeated falls. On his return from Mexico, he experienced impaired balance, mobility, and endurance, and as a result, had started using a walker. Otherwise, his medical history did not include any previous muscle weakness or neurological abnormalities, and his family history was negative for autoimmune diseases.

Physical examination. Upon arrival to the ED, the patient's vital signs were stable. His blood pressure was slightly elevated to 147/90 mm Hg; he had a pulse rate of 69 beats/min and oxygen saturation of 95%. He was afebrile. On physical examination, the patient had moderate upper-extremity weakness, severe bilateral hip weakness on flexion, and mild left knee weakness on extension. He demonstrated poor balance and an unsteady gait with decreased bilateral step length. Deep tendon reflexes in the upper and lower extremities were intact bilaterally.

Diagnostic tests. Laboratory test results showed a markedly elevated creatine kinase (CK) level of 1254 U/L and a markedly elevated serum myoglobin level of 900 µg/L, as well as an elevated aspartate aminotransferase (AST) level of 108 U/L and an elevated alanine aminotransferase (ALT) level of 223 U/L. The rest of the results, including those of a thyroid panel and kidney function tests, were within normal limits. Urinalysis results were normal except for an elevated urine pH of 8.5. To rule out other causes of myopathy, further laboratory workup, including tests for troponin, antinuclear antibodies, C-reactive protein, and erythrocyte sedimentation rate test, were performed, the results of which were all unremarkable.

To further investigate the lower-extremity weakness, magnetic resonance imaging (MRI) of the right and left femurs was performed. The results showed subcutaneous edema of the bilateral thighs and nonspecific diffuse edema of the bilateral quadriceps; no fluid collection was seen. MRI of the brain without contrast was also performed to exclude any intracranial pathology. The results were unremarkable except for mild nonspecific, cerebral white-matter hyperintensity, which may reflect chronic microvascular changes. At this point, muscle biopsy was performed to rule out any neuromuscular disorders. The results showed rare necrotic fibers with regenerative and degenerative changes; the results were negative for inflammatory infiltrates, vasculitis, and fibrosis and ruled out dystrophic and atrophic changes.

After reviewing the patient’s medication list, it was found that he had been taking atorvastatin, 80 mg once daily, for the past 2 years and 2 months. His other medications were as follows: a multivitamin with folic acid, 400 µg once daily; acetaminophen, 650 mg every 6 hours as needed; diphenhydramine hydrochloride, 25 mg as needed; docusate sodium, 100 mg once daily at bedtime; pantoprazole sodium, 20 mg once every morning; metformin, 500 mg twice daily; subcutaneous insulin lispro, 100 U/mL once after meals and at bedtime; metoprolol tartrate, 12.5 mg once daily; subcutaneous enoxaparin sodium, 40 mg once daily; and tamsulosin hydrochloride, 0.4 mg once every evening.

Differential diagnosis. At this point, the differential diagnoses included inflammatory myopathy, rhabdomyolysis, toxic myopathy, hypothyroid-induced myopathy, Guillain-Barré syndrome (GBS), systemic lupus erythematosus (SLE), Lambert-Eaton myasthenic syndrome (LEMS), and systemic sclerosis.

Treatment. The patient was admitted to the hospital for monitoring due to the elevated CK level. His use of atorvastatin was immediately halted. He was started on intravenous methylprednisolone, 500 mg every 12 hours, and intravenous immunoglobulin (IVIG), 0.4 mg/kg daily; the IVIG was stopped on the third day due to the development of a rash. It was concluded that if his CK level continued to increase, azathioprine and methotrexate would be added to the regimen.

Outcome and follow-up. Upon cessation of atorvastatin, the patient’s bilateral proximal upper- and lower-extremity muscle weakness showed some improvement. Extensive bloodwork and imaging studies were performed to rule out other pathologies. His CK level was repeated 5 days after admission; it showed signs of improvement. The patient was then released from the hospital in a wheelchair, was prescribed oral methylprednisolone, 20 mg once daily, and was encouraged to follow up with his primary care provider (PCP) in 4 weeks and start physical therapy (PT).

After following-up with his PCP, the patient attended intensive PT sessions for 2.5 months with the goal of improving muscle strength and movement. At the initial sessions, he showed unsteadiness with single-limb balance exercises, proximal muscle weakness, and proximal muscle myalgia. He performed various strength exercises such as tandem stance, gluteal press, lateral stepover, and calf raises. Slowly, he demonstrated increased activity tolerance and improved quadriceps strength. He continued to perform strength and balance exercises at home, and he followed up with a PT session during which the therapists concluded that he was physically stable with mild balance deficit.

Discussion. Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors, are a class of lipid-lowering medications that reduce the illness and mortality rates in individuals who are at high risk for cardiovascular disease. More specifically, they are prescribed to patients with hyperlipidemia to lower total cholesterol levels and reduce the risk of a myocardial infarction or stroke.

Statins work by inhibiting the rate-limiting enzyme, HMG-CoA reductase, in the mevalonate pathway. They are effective and generally safe agents.1 However, statin-associated muscle symptoms (SAMS) such as myalgia, myositis, and myopathy are among the possible adverse effects.2 Observational studies have shown that 10% to 15% of individuals on statin therapy experience SAMS.3

The precise pathophysiology of statin-induced myopathy is not fully understood.4 Clinical manifestations associated with statin-induced myopathy range from mild to severe. Commonly, patients report bilateral proximal upper- and lower-extremity muscle weakness and less commonly myalgia; these symptoms begin 2 weeks to 4 years after initiation of statin therapy.5 Electromyography findings often report more myopathic changes in the proximal muscles.6 More-severe adverse effects of statin use, such as myositis and myopathy, manifest later in the course.7 Our patient presented with bilateral proximal upper- and lower-extremity muscle weakness, balance deficit, and strength and mobility loss.

When investigating symptoms, it is important to rule out other conditions that often present in a similar manner; thus, it is imperative to perform a full workup. We began by investigating the patient’s complete medical history, including history of present illness, specifically considering the onset, duration, and pattern of progression of his symptoms; his past medical history; and his family history. We then considered his physical examination findings and the results laboratory tests and imaging studies.

Prior to diagnosing statin-induced myopathy, we explored various differential diagnoses. Amyloidosis and collagen-vascular diseases present with diffuse systemic involvement; thus, they were eliminated, given that the patient presented solely with musculoskeletal system symptoms. Rheumatoid arthritis, polymyositis, dermatomyositis, and SLE were further ruled out, since the patient did not present with any skin problems or joint pain or swelling, and he had negative serology test results for autoimmune antibodies. The location and pattern of muscle weakness aid in the diagnosis. The patient presented with bilateral, proximal upper- and lower-extremity muscle weakness, sparing the bulbar muscles; bulbar muscle weakness manifests as dysphagia and dysarthria and is seen in LEMS and myasthenia gravis. Furthermore, GBS was eliminated, given the fact that it involves ascending muscle paralysis.7 The patient’s thyroid panel results were normal, thus ruling out hypothyroid-induced myopathy.8 The patient’s elevated CK level of 1254 U/L and serum myoglobin of 900 µg/L, along with his use of atorvastatin, 80 mg once daily, for the past 2 years and 2 months, led to the conclusion of statin-induced toxic necrotizing myopathy.9

Interestingly, there is another variant of statin-induced necrotizing myopathy called necrotizing autoimmune myopathy. A differential characteristic between our patient’s case and necrotizing autoimmune myopathy is that when atorvastatin was withdrawn, our patient’s symptoms improved dramatically; in the latter, cessation of statin therapy will not alleviate the patient’s symptoms, and the myopathy will progress for months.9 Furthermore, necrotizing autoimmune myopathy is also associated with elevated antibodies against HMG-CoA reductase, for which our patient was not tested, given that his symptoms improved after cessation of statin therapy.10 Many medications and substances are toxic to the muscles, leading to adverse effects.11 Although our patient was taking numerous medications prior to and during his hospitalization that also may have led to necrotizing myopathy, his response to the cessation of atorvastatin allowed for the diagnosis of statin-induced toxic necrotizing myopathy.

Various explanations are being investigated as to why statin therapy sometimes results in myopathy. One explanation is that statins reduce ubiquinone concentrations in skeletal muscles. Ubiquinone, also known as coenzyme Q10, is a component of the electron transport chain and plays a crucial role in energy production in muscles.12 A 2018 meta-analysis showed that ubiquinone improved SAMS.13 However, this explanation has been controversial, since other evidence suggests that although statins reduce levels of ubiquinone in the blood, it is unclear as to whether they do the same in muscles.14 A 2015 meta-analysis showed that ubiquinone supplementation had no effect on SAMS.15

Certain statins have been associated with different degrees of SAMS. One study showed that the incidence of rhabdomyolysis was 0.44 per 10,000 patients treated with statins other than cerivastatin; this risk was more than 10 times greater if cerivastatin was used.16 Another study showed that lovastatin induces the expression of atrogin-1, a ubiquitin-protein ligase that plays a role in muscle fiber damage; knockdown of atrogin-1 in in vitro animal models prevented myopathy.17 Statin-induced myopathy is more likely to occur with statins that have lipophilic properties, most commonly atorvastatin and simvastatin.5 hydrophilic statins such as pravastatin and rosuvastatin have less tissue absorption and are less likely to have adverse effects.5 In contrast, pravastatin, pitavastatin, and fluvastatin have the lowest risk of myopathy. The metabolism of pravastatin and pitavastatin by modes other than cytochrome enzymes decrease their risk of drug toxicity and myopathy18; the lower risk associated with fluvastatin is due to its extended-release formulation limiting its exposure.19

In addition to drug mechanisms causing SAMS, researchers are investigating causes at the genetic level. Such studies include variations in cytochrome P450 genes and their impact on statin metabolism.20 The solute carrier organic anion transporter family member 1B1 gene (SLCO1B1) codes for a transporting polypeptide that is responsible for the hepatic uptake of statins; a loss of the function variant SLCO1B1 is associated with increased statin plasma levels. This is particularly seen with atorvastatin and simvastatin, ultimately increasing their exposure to skeletal muscles.21

Our patient had been prescribed atorvastatin, 80 mg once daily, to treat hyperlipidemia; as a result, he developed statin-induced myopathy. The specific etiology is unclear; however, it is likely that the combination of atorvastatin’s lipophilic property and the patient’s possible genetic predispositions may have resulted in SAMS.

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