Asymptomatic hypothyroidism and statin-induced myopathy

Hypothyroidism is a well-known cause of secondary 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 myopathy.^5–8 Muscle aches, cramps, and weakness are the typical clinical features, irrespective of the precipitant.^3,4,7 Other factors increasing the risk of SIM include concomitant 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 hypothyroidism.^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 myopathic 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 discectomies, 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.

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.

DATE	TOTAL CHOLESTEROL (MMOL/L)	HIGH-DENSITY LIPOPROTEIN CHOLESTEROL ( MMOL /L)	LOW-DENSITY LIPOPROTE IN CHOLESTEROL ( MMOL /L)	TRIGLYCERIDES (MMOL/L)	TOTAL CHOLESTEROL/ HIGH-DENSITY LIPOPROTEIN CHOLESTEROL	CREATINE KINASE (U/L)	THYROID- STIMULATING HORMONE (MU/L)	SERUM CREATININE (μMOL/L)	MEDICATIONS
November 2003	10.80	1.50	8.50	1.66	7.2	NM	NM	NM	Rosuvastatin 10 mg/d initiated
February 2004	6.01	1.30	3.70	2.15	4.6	NM	NM	NM	Rosuvastatin 10 mg/d
June 2004	4.20	1.40	2.10	1.46	3.0	4517	NM	135	Rosuvastatin stopped; ezetimibe 10 mg/d initiated
July 2004	6.99	1.09	4.69	2.68	6.4	3120	NM	136	Ezetimibe 10 mg/d
August 2004	7.41	1.09	NM	4.68	6.7	1446	114.60	140	Ezetimibe 10 mg/d; levothyroxine 0.1 mg/d initiated
November 2004	5.21	1.01	3.50	1.53	5.2	153	4.80	NM	Levothyroxine 0.1 mg/d; ezetimibe 10 mg/d; pravastatin 20 mg/d initiated*
February 2005	5.70	1.09	3.29	2.75	5.2	143	5.40	NM	Ezetimibe 10 mg/d; levothyroxine 0.15 mg/d
December 2005	6.10	1.40	3.70	2.22	4.4	327	NM	NM	Fluvastatin 20 mg/d started; levothyroxine 0.15 mg/d; niacin ER 500 mg/d initiated; ezetimibe 10 mg/d
January 2006	4.20	1.30	1.30	1.12	3.2	163	1.99	NM	Fluvastatin 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.

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 hormone 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 experiencing 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 developed muscle aches several days after starting pravastatin and stopped the medication. Thus, there was no significant change in his lipid profile (Table 1). He tolerated fluvastatin, however, and on this therapy his lipid profile improved considerably (Table 1).

Discussion

We describe a case of hypothyroidism-induced dyslipidemia 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 hypothyroid 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 glycogenolysis or impaired mitochondrial oxidation are responsible.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 prescribed to hypothyroid patients. Generally, myopathy is more likely to occur at higher statin doses.¹¹ Other lipid-lowering medications, such as fibrates and even ezetimibe, an inhibitor of intestinal cholesterol absorption, can cause myopathy.¹²

Third, although the patient’s initial response to rosuvastatin monotherapy was good (Table 1), in our experience, hypothyroidism-induced dyslipidemia sometimes is resistant to lipid-lowering therapy. This is true whether a patient has an underlying primary dyslipidemia that is exacerbated by hypothyroidism or a purely secondary dyslipidemia. Although all patients should be assessed for hypothyroidism 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, hypothyroidism should be considered.

Next, the case demonstrates that patients must report the development of muscle pains to their physicians. It also shows that biochemical testing is imperative in patients with possible myopathic 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 hypothyroid.^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 immediately discontinued and their physicians contacted.

Conclusion

The dangers of statin use in hypothyroid patients have been illustrated and the necessity for appropriate biochemical monitoring has been emphasized. Statin therapy 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 hypothyroid.

EDITOR’S KEY POINTS

• In this case of hypothyroidism-induced dyslipidemia, the patient lacked the classic symptoms of hypothyroidism.

• 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 hypothyroid patients is dangerous; patients should be warned explicitly to report development of muscle pains to their physicians.

POINTS DE REPÉRE DU RÉDACTEUR

• Dans ce cas de dyslipidémie secondaire à une hypothyroïdie, 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 musculaire nouvelle à leur médecin.