Fenofibrate monotherapy-induced rhabdomyolysis in a patient with hypothyroidism: A rare case report and literature review.

RATIONALE: Fenofibrate is a fibric acid derivative indicated for use in hypertriglyceridemia and mixed dyslipidemia treatment among adults. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation, which is the most serious and fatal side effect of fenofibrate. The objective of this paper is to discuss fatal side effect of fenofibrate and keep safe medication. PATIENT CONCERNS: A patient with hypothyroidism who presented with rhabdomyolysis during fenofibrate monotherapy for hypertriglyceridemia was reported. DIAGNOSES: Fenofibrate Monotherapy Induced Rhabdomyolysis.
INTERVENTIONS: Fenofibrate was stopped. Adequate fluid resuscitation, mannitol diuresis, myocardium protection, hepatoprotection and urine alkalinization with sodium bicarbonate were performed. OUTCOMES: Blood tests were normal and the patient was good and discharged 2 weeks later. LESSONS: 13 cases associated with fenofibrate monotherapy-induced rhabdomyolysis were reviewed, which had been published in the English literature. The severity of fenofibrate muscle toxicity may be the result of the combination of two rhabdomyolysis enhancers, such as hypothyroidism and female gender. To avoid it, strict clinical and laboratory monitoring should be maintained, particularly hypothyroidism. Patients should be informed of possible potentially irreversible effects after taking fibrates.

Introduction

Rhabdomyolysis is a clinical, and biochemical syndrome characterized by skeletal muscle injury, muscle necrosis, and the release of muscle cell constituents into systemic circulation. While fenofibrate monotherapy-induced rhabdomyolysis is rare, it is a serious, even fatal side effect of fenofibrate[ that is often associated with acute renal failure (ARF) and myoglobinuria. Comorbidities, such as renal, or liver disease, hypothyroidism (HTD), diabetes mellitus (DM), female gender, high dose, and advanced age (older than 65 years old) are major risk factors for fenofibrate-induced rhabdomyolysis.[ We report the case of a patient with HTD who experienced rhabdomyolysis while on fenofibrate monotherapy for hypertriglyceridemia.

Case report

A 36-year-old sterile woman was admitted twice to the hospital. Seventeen years prior to her second admission, she had undergone an initial craniotomy, and the pathological diagnosis showed pituitary adenoma. Her post-operative course was benign. Two months prior to her second admission, she complained of chills, hypohidrosis, pachulosis, fatigue, and anorexia. Fifteen days prior to her second admission, she had an endocrine test showing a marked decrease in basal hormone levels (i.e., cortisol, thyroid, and gonadal hormones). Her liver function, and renal function tests were within normal limits, and there was no history of coronary heart disease. Pituitary hypofunction was diagnosed, and she was admitted to our hospital. The patient took prednisone, and levothyroxine, and had started to use 200 mg micronized fenofibrate a day for hypertriglyceridemia (triglyceride [TG] level of 10.72 mmol/L). After taking fenofibrate for 15 days, the patient complained of diffuse myalgia, and muscle weakness, which had not been alleviated for 2 days. She was readmitted to the hospital. Except for muscle weakness, her physical examination was normal. Laboratory testing at admission revealed the following: a marked increase in creatinine kinase (CK) of 9890 U/L (approximately 51 times the upper limit of normal), TG of 0.67mmol/L, serum creatinine (Cr) of 140 μmol/L, blood urea nitrogen (BUN) of 11.70 mmol/L, and blood myoglobin of greater than 500 ng/mL. A diagnosis of fenofibrate monotherapy-induced rhabdomyolysis and rhabdomyolysis-induced ARF was made. Because of the seriousness of her side effects, and the fact that her TG level was within normal range, fenofibrate was discontinued. Adequate fluid resuscitation, mannitol diuresis, myocardium protection, hepatoprotection, and urine alkalinization with sodium bicarbonate were performed. At the end of 5 days, the patient's CK and Cr concentrations had declined to 2350 U/L and 106 μmol/L, respectively. After suspending fenofibrate, the blood test irregularities gradually improved. Two weeks after her second admission, the patient's laboratory values were normal, the patient was well, and she was discharged. After discharge, the patient did not resume hypolipidemic drugs. Rather, her blood lipids were controlled through diet and exercise. Under this regimen, her TGs remained within normal range.

Discussion

Fenofibrate is a fibric acid derivative indicated for use as mono- or combination therapy in adults with hypertriglyceridemia and mixed dyslipidemia (DL).[ Micronized fenofibrate is better absorbed than standard preparations, which allows for lower daily dosage and once daily administration.[ In general, fenofibrate is well tolerated and side effects are fairly uncommon (e.g., gastrointestinal, and musculoskeletal symptoms, cutaneous reactions, fatigue, headache, vertigo, sleep disorders, and loss of libido).[ However, fenofibrate monotherapy-induced rhabdomyolysis can occur.

We report a new case of fenofibrate monotherapy-induced rhabdomyolysis. The patient was diagnosed with rhabdomyolysis based on myalgia, muscle weakness, prominent elevation of CK, lactate dehydrogenase, aspartate aminotransferase, and Cr serum levels.[ Those values represent a broad clinical spectrum, from asymptomatic elevation of muscle enzymes to potentially, life-threatening clinical situations such as electrolyte disturbances, and ARF, the most common complication of rhabdomyolysis (10–40% of patients).[ Because fenofibrate led to such serious side effects, and the patient's TG level was normal, then she discontinued fenofibrate, and other hypolipidemic drugs, after which her TG levels remained satisfactory. Thus, one limitation of this case study lies in that it does not investigate the treatment of hyperlipidemia in patients with fenofibrate-induced rhabdomyolysis.

For a more in-depth analysis, we searched for relevant studies in the English literature in the PubMed, and Embase electronic databases from inception to August 1, 2016. The following terms were used: fenofibrate, fibrates, hypertriglyceridemia, and rhabdomyolysis. In addition, the reference lists of all accepted papers were manually searched to ensure that no studies were ignored. Thirteen cases of fenofibrate monotherapy–associated rhabdomyolysis were found (Tables 1 and 2). Nevertheless, the cause of rhabdomyolysis could not be precisely defined. The majority of cases were associated with additional risk factors for muscle injury,[ while one patient with HTD presented with rhabdomyolysis while on fenofibrate monotherapy for hypertriglyceridemia. Monotherapy-induced, and hypothyroid-associated rhabdomyolysis were rarely described, with only 3 cases having been published in English literature. Consequently, the precise pathophysiology of rhabdomyolysis in HTD remains unclear.[

Table 1

A summary of reported 13 cases of rhabodomyolysis associated with fenofibrate monotherapy.

Table 2

A summary of reported 13 cases of rhabodomyolysis associated with fenofibrate monotherapy.

HTD is associated with impairment of mitochondrial oxidative metabolism and many other metabolic pathways. These metabolic abnormalities may sensitize muscle cells to other factors related to muscle injury and increase the risk of rhabdomyolysis. Thyroid hormones that regulate genes encoding structural, and regulatory proteins are lower in the skeletal muscles of hypothyroid patients compared to that of euthyroid patients.[ Previously reported cases of HTD were due to thyroid diseases. Our patient's case is the first reported for thyroid hypofunction after craniotomy for pituitary adenoma. In her case, the severity of fenofibrate-induced muscle toxicity may have been the result of the combination of 2 confounding risk factors for rhabdomyolysis: HTD and the female gender. To avoid rhabdomyolysis, strict clinical, and laboratory monitoring should be employed, especially, for those with HTD. In addition, patients should be informed of the possible, potentially, irreversible effects of taking fibrates.

Acknowledgements

The authors thank all the other staff of the neurosurgery department of the second affiliated hospital of Bengbu medical college for their support.

Author contributions

Conceptualization: Dawei Wang.

Data curation: Dawei Wang, Yanqiu Wang.

Formal analysis: Dawei Wang, Yanqiu Wang.

Funding acquisition: Yanqiu Wang.

Investigation: Dawei Wang.

Resources: Dawei Wang.

Software: Yanqiu Wang.

Supervision: Dawei Wang.

Visualization: Dawei Wang.

Writing – review & editing: Dawei Wang.