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Canadian Family Physician•Le Médecin de famille canadien Vol 53: march • mars 2007Current Practice
•Pratique courante
Case Report
H
ypothyroidism is a well-known cause of second- ary dyslipidemia, and its link to atherosclerosis has been known for 125 years.1,2 Elevated circulating levels of the apolipoprotein B100 containing lipoproteins, very low-density lipoprotein, and low-density lipoprotein, are the principal lipid abnormalities seen in patients with hypothyroidism.Hypothyroidism is also a risk factor for statin-induced myopathy (SIM)3,4 and even spontaneous myopa- thy.5-8 Muscle aches, cramps, and weakness are the typi- cal clinical features, irrespective of the precipitant.3,4,7 Other factors increasing the risk of SIM include con- comitant use of fibrates, hepatic cytochrome P-450 inhibitors, major trauma, and surgery.4 Rhabdomyolysis, the most feared and potentially fatal complication of SIM,9 is also rarely caused by isolated hypothyroid- ism.6,8 Data from clinical trials4 show the rate of SIM in the general population to be 0.1% to 0.2%; the rate of hypothyroid-induced myopathy is unknown. Because of these associations, patients’ thyroid status should always be considered before initiating lipid-lowering medications and, for patients receiving statin therapy, thyroid function should be assessed whenever myo- pathic symptoms or resistance to therapy is noted. We describe a case of hypothyroidism-induced dyslipidemia in which the patient lacked the classic symptoms of hypothyroidism. This led to an incorrect diagnosis of primary dyslipidemia, inappropriate initiation of statin therapy, and severe SIM.
Case description
A 55-year-old man with a history of hypertension was first found to be dyslipidemic during an investigation
for coronary artery disease in 2003. An angiography demonstrated 2-vessel disease, which was treated medically. His medical history included 2 lumbar dis- cectomies, chronic lower back pain, and associated lower extremity pain. His initial lipid profile showed a total cholesterol level of 10.8 mmol/L and a low-density lipoprotein cholesterol level of 8.5 mmol/L, with normal high-density lipoprotein cholesterol and triglyceride levels (Table 1). At that time, he was taking 81 mg of acetylsalicylic acid daily, 5 mg of ramipril daily, 0.4 mg/h via nitroglycerine patch, 100 mg of atenolol daily, and 25 mg of chlorthalidone daily. Rosuvastatin was then initiated by his cardiologist.
Within 4 weeks of starting the treatment, the patient began experiencing lower-extremity myalgia and cramping, which he attributed to the chronic lumbar disease. When the symptoms persisted for 3 months, however, his family physician measured his serum creatine kinase (CK), which was markedly elevated at 4517 U/L (normal level is 55 to 170 U/L). Severe SIM was diagnosed and thyroid-stimulating hor- mone level was subsequently checked (for the sake of clinical completeness) and was markedly increased at 114 mU/L (0.3 to 4.2 mU/L), with a free thyroxine level of 2.0 pmol/L (8 to 21 pmol/L). Rosuvastatin was discontinued and replaced with 10 mg of ezetimibe daily, and 0.1 mg of levothyroxine daily was prescribed.
Values for both lipids and thyroid-stimulating hormones had markedly improved by the time he visited our lipid clinic in November 2004.
On historical review, the patient denied experienc- ing any of the classic symptoms of hypothyroidism, such as cold intolerance, hair loss, dry skin, or constipation.
After starting levothyroxine therapy, however, he noticed that he required less sleep, was more alert at work, and gained muscle bulk in his legs. As he was not meeting the lipid targets for secondary prevention, we decided to introduce the low-potency statin pravastatin, at a dose of 20 mg daily. The patient was cautioned to discontinue this medication if any muscle symptoms returned, and follow-up CK and aspartate aminotransferase tests were arranged for 3 weeks after the visit. The patient devel- oped muscle aches several days after starting pravastatin and stopped the medication. Thus, there was no signifi- cant change in his lipid profile (Table 1). He tolerated fluvastatin, however, and on this therapy his lipid profile improved considerably (Table 1).
Asymptomatic hypothyroidism and statin-induced myopathy
Simona L. Bar
MDDaniel T. Holmes
MD FRCPCJiri Frohlich,
MD FRCPCDr Bar is a Clinical Associate in the Division of Cardiac Surgery at Vancouver General Hospital in British Columbia.
Dr Holmes is a Medical Biochemist at St Paul’s Hospital and a Clinical Assistant Professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia in Vancouver. Dr Frohlich is Academic Director of the Healthy Heart Program and Lipid Clinic at St Paul’s Hospital and is a Professor of Pathology and Laboratory Medicine at the University of British Columbia.
This article has been peer reviewed.
Cet article a fait l’objet d’une revision par des pairs.
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Table 1. Sequential laboratory and medication information. Reference intervals: thyroid-stimulating hormone 0.3 to 4.2 mU/L; creatine kinase 55 to 117 U/L; high-density lipoprotein cholesterol 0.90 to 2.20 mmol/L; triglycerides 0.45 to 2.20 mmol/L; low-density lipoprotein cholesterol 2.00 to 3.40 mmol/L; and serum creatinine 70 to 133 μmol/L. DATeTOTAL CHOLeSTeROL (MMOL/L) HIGH-DeNSITY LIPOPROTeIN CHOLeSTeROL (MMOL/L) LOW-DeNSITY LIPOPROTeIN CHOLeSTeROL (MMOL/L)TRIGLYCeRIDeS (MMOL/L) TOTAL CHOLeSTeROL/ HIGH-DeNSITY LIPOPROTeIN CHOLeSTeROLCReATINe KINASe (U/L) THYROID- STIMULATING HORMONe (MU/L)
SeRUM CReATININe (µMOL/L)MeDICATIONS November 200310.801.508.501.667.2NMNMNMRosuvastatin 10 mg/d initiated February 20046.011.303.702.154.6NMNMNMRosuvastatin 10 mg/d June 20044.201.402.101.463.04517NM135Rosuvastatin stopped; ezetimibe 10 mg/d initiated July 20046.991.094.692.686.43120NM136Ezetimibe 10 mg/d August 20047.411.09NM4.686.71446114.60140Ezetimibe 10 mg/d; levothyroxine 0.1 mg/d initiated November 20045.211.013.501.535.21534.80NMLevothyroxine 0.1 mg/d; ezetimibe 10 mg/d; pravastatin 20 mg/d initiated* February 20055.701.093.292.755.21435.40NMEzetimibe 10 mg/d; levothyroxine 0.15 mg/d December 20056.101.403.702.224.4327NMNMFluvastatin 20 mg/d started; levothyroxine 0.15 mg/d; niacin ER 500 mg/d initiated; ezetimibe 10 mg/d January 20064.201.301.301.123.21631.99NMFluvastatin 20 mg/d; ezetimibe 10 mg/d; niacin ER 500 mg/d; levothyroxine 0.15 mg/d NM = not measured. *Discontinued by patient shortly after prescription because myalgia recurred.
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Discussion
We describe a case of hypothyroidism-induced dyslip- idemia that illustrates a few important points.
First, hypothyroidism, even when profound, might be nearly asymptomatic. Despite the fact that our patient had a thyroid-stimulating hormone level higher than 100 mU/L, he did not have classic hypo- thyroid symptoms, although he recognized some drowsiness and muscle wasting retrospectively.
Second, use of statins in hypothyroid patients is dangerous. Although the biochemical mechanism of both hypothyroid myopathy and SIM remain unclear, hypothyroidism increases the risk of SIM.3,4 With respect to the mechanism of hypothyroid myopathy, some have hypothesized that defects in glycogenoly- sis or impaired mitochondrial oxidation are responsi- ble.6 Theories for the cause of SIM include reduction in small guanosine 5’-triphosphate–binding proteins and reduced cholesterol synthesis causing skeletal myocyte membrane instability.10 Presumably, these mechanisms are synergistic when statins are pre- scribed to hypothyroid patients. Generally, myopa- thy is more likely to occur at higher statin doses.11 Other lipid-lowering medications, such as fibrates and even ezetimibe, an inhibitor of intestinal choles- terol absorption, can cause myopathy.12
Third, although the patient’s initial response to rosuvastatin monotherapy was good (Table 1), in our experience, hypothyroidism-induced dyslipid- emia sometimes is resistant to lipid-lowering ther- apy. This is true whether a patient has an underlying primary dyslipidemia that is exacerbated by hypo- thyroidism or a purely secondary dyslipidemia.
Although all patients should be assessed for hypo- thyroidism and, if necessary, treated to attain a euthyroid state before beginning statin therapy, the unfortunate reality is that many are not. Thus, for patients in whom biochemical responses to lipid- lowering therapy are suboptimal, the history should be reviewed to see whether thyroid status has in fact been previously evaluated. Further, if a patient’s dyslipidemia gets worse without apparent cause or he or she develops SIM unexpectedly, hypothyroid- ism should be considered.
Next, the case demonstrates that patients must report the development of muscle pains to their physicians. It also shows that biochemical test- ing is imperative in patients with possible myo- pathic symptoms. The Adult Treatment Panel III of the National Cholesterol Education Program13 and the ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins11 recommend that a baseline CK measure be established before initiating statin therapy and that CK be remeasured and compared with the baseline if patients report any muscle symptoms. More frequent measurements of CK and
transaminases might be indicated among patients receiving maximal doses of medications and those receiving combination therapy, typically with fibrates.
Finally, statins are not necessarily contraindicated in patients who have developed SIM while hypothy- roid.10,14 However, caution must be exercised with reinitiating statin therapy in this context, and patients should always be instructed that, if muscle pains or flulike symptoms develop, the statin should be imme- diately discontinued and their physicians contacted.
Conclusion
The dangers of statin use in hypothyroid patients have been illustrated and the necessity for appropriate bio- chemical monitoring has been emphasized. Statin ther- apy is safe and effective when patients are appropriately diagnosed, educated, and followed up. Statins can be cautiously reinitiated once a euthyroid state has been established in patients who developed SIM while hypo- thyroid.
competing interests None declared
Correspondence to: Dr Daniel T. Holmes, 1081 Burrard St, Vancouver, BC V6Z 1Y6;
telephone 604 806-8591; fax 604 806-8590;
e-mail dtholmes@interchange.ubc.ca EDITOR’S KEY POINTS
•
In this case of hypothyroidism-induced dyslipidemia, the patient lacked the classic symptoms of hypothy- roidism.
•
Within 4 weeks of starting statin therapy, the patient began experiencing lower-extremity myalgia and cramping, which he attributed to chronic lumbar disease.
•
This case demonstrates that using statins in hypo- thyroid patients is dangerous; patients should be warned explicitly to report development of muscle pains to their physicians.
POINTS DE REPèRE Du RéDaCTEuR
•
Dans ce cas de dyslipidémie secondaire à une hypo- thyroïdie, les signes classiques de l’hypothyroïdie étaient absents.
•
Moins de 4 semaines après le début d’un traitement par statine, le patient commença à ressentir des douleurs et crampes musculaires, qu’il attribua à une lombalgie chronique.
•
Ce cas illustre le fait que l’utilisation des statines
est dangereuse chez l’hypothyroïdien; les patients
devraient être avisés de signaler toute douleur mus-
culaire nouvelle à leur médecin.
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references
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2. Morris MS, Bostom AG, Jacques PF, Selhub J, Rosenber IH.
Hyperhomocystinemia and hypercholesterolemia associated with hypothy- roidism in the third US National Health and Nutrition Examination Study.
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Neuromuscular findings in thyroid dysfunction: a prospective clinical and elec- trodiagnostic study. J Neurol Neurosurg Psychiatry 2000;68:750-5.
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ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40(3):567-72.
12. Fux R, Morike K, Gundel UF, Hartmann R, Gleiter CH. Ezetimibe and statin- associated myopathy. Ann Intern Med 2004;141(8):671-2.
13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
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