Download Asymptomatic hypothyroidism and statin

Case Report
Current Practice
•
Pratique courante
Asymptomatic hypothyroidism
and statin-induced myopathy
Simona L. Bar
MD Daniel T. Holmes
MD FRCPC Jiri Frohlich,
H
ypothyroidism 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
Dr 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.
Can Fam Physician 2007;53:428-431
428 MD FRCPC
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.
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).
Canadian Family Physician • Le Médecin de famille canadien Vol 53: march • mars 2007
6.01
4.20
6.99
7.41
5.21
5.70
6.10
4.20
February 2004
June 2004
July 2004
August 2004
November 2004
February 2005
December 2005
January 2006
1.30
1.40
1.09
1.01
1.09
1.09
1.40
1.30
1.50
1.30
3.70
3.29
3.50
NM
4.69
2.10
3.70
8.50
LOW-DENSITY
LIPOPROTEIN
CHOLESTEROL
(mmol/L)
NM = not measured.
*Discontinued by patient shortly after prescription because myalgia recurred.
10.80
November 2003
Date
TOTAL CHOLESTEROL
(mmol/L)
HIGH-DENSITY
LIPOPROTEIN
CHOLESTEROL
(mmol/L)
1.12
2.22
2.75
1.53
4.68
2.68
1.46
2.15
1.66
TRIGLYCERIDES
(mmol/L)
3.2
4.4
5.2
5.2
6.7
6.4
3.0
4.6
7.2
TOTAL
CHOLESTEROL/
HIGH-DENSITY
LIPOPROTEIN
CHOLESTEROL
163
327
143
153
1446
3120
4517
NM
NM
CREATINE KINASE
(U/L)
1.99
NM
5.40
4.80
114.60
NM
NM
NM
NM
THYROIDSTIMULATING
HORMONE (mU/L)
NM
NM
NM
NM
140
136
135
NM
NM
SERUM
CREATININE
(µmol/L)
Fluvastatin 20 mg/d;
ezetimibe 10 mg/d; niacin
ER 500 mg/d; levothyroxine
0.15 mg/d
Fluvastatin 20 mg/d started;
levothyroxine 0.15 mg/d;
niacin ER 500 mg/d
initiated; ezetimibe 10 mg/d
Ezetimibe 10 mg/d;
levothyroxine 0.15 mg/d
Levothyroxine 0.1 mg/d;
ezetimibe 10 mg/d;
pravastatin 20 mg/d
initiated*
Ezetimibe 10 mg/d;
levothyroxine 0.1 mg/d
initiated
Ezetimibe 10 mg/d
Rosuvastatin stopped;
ezetimibe 10 mg/d initiated
Rosuvastatin 10 mg/d
Rosuvastatin 10 mg/d
initiated
Medications
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.
Case Report
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Vol 53: march • mars 2007 Canadian Family Physician • Le Médecin de famille canadien 429
Case Report
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 lipidlowering 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 Program 13 and
the ACC/AHA/NHLBI Clinical Advisory on the Use
and Safety of Statins 11 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
430 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 repère 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.
•
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. 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 [email protected]
Canadian Family Physician • Le Médecin de famille canadien Vol 53: march • mars 2007
Case Report
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