The dark side of cholesterol guidelines: Statin-induced rhabdomyolysis with multiple organ involvement

LEARNING OBJECTIVE #1: Myopathy is a common side effect of statin therapy with a wide spectrum of severity and presentation. Recognize the clinical features of statininduced myonecrosis and rhabdomyolysis. LEARNING OBJECTIVE #2: New cholesterol guidelines trend towards a lower threshold of starting high intensity statin medications but it is important to be cognizant of their potentially lethal side effect profile. CASE: A 66-year-old man with non-small cell lung cancer (post chemotherapy and radiation therapy), chronic ischemic cardiomyopathy, and hypertension was brought in by family members to our emergency room with a complaint of progressive and fully debilitating muscle weakness and fatigue over 2 weeks' duration. His weakness began in the thighs and trunk, but over time began to include his back, shoulders, and neck. He stated his weakness was so profound that he was unable breath without keeping his head in full extension. He denied any pain symptoms. Initial laboratory values on presentation included CPK 4198 U/L (nl: 5-180), CKMB 102 ng/mL (nl: 0-5), Troponin T 0.12 ng/ mL (nl: <0.03), Platelets 63 k/cmm (nl: 130-440), BUN 43 mg/dL (nl: 9-20), Creatinine 7.2 mg/dL (nl: 0.5-1.2), AST 528 U/L (nl: 0-45), ALT 201 U/L (nl: 0-40), and Total Bilirubin 2.0 mg/dL (nl: 0.0-1.3). Urinalysis detected significant globulin, with follow-up confirmation of myoglobin. On gaining more information it was noted that 2 weeks prior he was seen by his primary care physician who adjusted his atorvastatin dosage from 20 mg daily, a dose he had been on for several years, to 40 mg daily in accordance to new cholesterol guidelines for coronary artery disease. After careful exclusion of other causes a diagnosis of statin-induced rhabdomyolysis with both hepatic dysfunction and acute renal failure was made. He was treated with aggressive yet cautious intravenous hydration in the setting of his cardiomyopathy with baseline EF of 20 %, paying close attention to urine output and respiratory efforts. His atorvastatin was discontinued. He had a prolonged hospital course of 13 days due to the tenuous status of balancing fluid resuscitation with his heart failure. His renal function, liver function tests and platelets all gradually returned to normal and he was seen in clinic 3 weeks after discharge with full recovery to his prior level of independence. DISCUSSION: Statins are a widely-used class of medication for lipid-lowering therapy and have been shown to be effective in the primary and secondary prevention of coronary disease. They are felt to be safe in the majority of patients, with common side effects including hepatotoxicity and myopathy. Myopathy is a relatively common side effect of statin use with a wide spectrum of severity, ranging from mild pain and weakness to severe rhabdomyolysis as in our case. Sequelae of rhabdomyolysis include kidney injury, hepatic dysfunction, electrolyte disorders, acid/base disorders, and hematologic disturbances such as disseminated intravascular coagulation. While pain is a common complaint of severe statin-induced myositis and myonecrosis, patients may rarely present with only weakness in the absence of pain such as our case. Therapy is directed at correcting the underlying disorder, fluid support, and preventing or treating the sequelae. Mortality in patients with severe complications including acute renal failure has been observed to be 58 % in the ICU setting. Statin-induced myopathy is a relatively common side effect, with observation between 10 and 25 %, and higher effect seen in observational studies vs. controlled trials however clinical rhabdomyolysis is rare. Occurrence and severity of myopathy due to statin use has been shown to exhibit dose-dependency, and some statins may show increased risk, with cerivastatin having been pulled from the market due to increased reported rate of fatal rhabdomyolysis. There is also increased risk when statins are combined with other lipid-lowering agents, with the greatest risk appearing to be when a statin is combined with fibrate therapy. Other risk factors include elderly patients, low body mass, underlying renal, hepatic, metabolic, or endocrine disorders, alcohol consumption, surgery, strenuous physical exertion, and CYP-450-affecting medications. In cases of frank rhabdomyolysis, statin reintroduction may be considered on a case-by-case basis, but it is recommended to discontinue therapy. Recent cholesterol guidelines such as Adult Treatment Panel IV from the ACC/AHA have trended towards a lower threshold of starting statin medications, particularly the high intensity statins atorvastatin and rosuvastatin. Guidelines aim to do the greatest benefit to the greatest population with their recommendations coming from a variety of resources ranging from double-blinded clinical trials to expert opinion. It is important to remember that even widely-used therapies which are considered to have strong positive benefit may have severe and potentially fatal complications. When complications are rare and nonspecific, clinical suspicion should be higher if there is a strong temporal association or other risk factors are present.