Key words
Freidreich’s ataxia - pericardial effusion - hypothyroidism - levothyroxine
Case Report
A 15 year-old white female with a past medical history significant for Friedreich’s
ataxia, hypertrophic cardiomyopathy, atrial flutter/fibrillation, anxiety and depression
was found to have a new pericardial effusion on routine echocardiogram.
She also complained of decreased energy levels, swelling of extremities and face and
dry skin. Her parents reported that she had gained 25 pounds over 3 months. Vitals
were stable and physical exam revealed the following abnormalities: a grade II/VI
systolic ejection murmur at the right upper sternal border and apex that radiated
to the carotids, slurred speech, an unsteady gate and Tanner stage I breasts.
Aripiprazole had been recently added to her medical management but otherwise no changes
to her medications had occurred. Her medications consisted of aspirin, atenolol, baclofen,
clonazepam, sertraline, trazodone, losartan, atomoxetine, co-enzyme Q10 and omega-3
polyunsaturated fatty acid. Adverse reactions such as weight gain and edema have been
reported as side effects of aripiprazole, atenolol and trazodone, but not pericardial
effusions.
Her last echocardiogram, 3 months prior, revealed a severely hypertrophied left ventricle
(mass 52.62 g/m2), trivial aortic valve insufficiency with normal left ventricular
systolic function. Her echocardiogram at time of evaluation revealed similar results
but now showed a small posterior pericardial effusion.
Also concerning was that her electrocardiogram (ECG) which 3 months prior demonstrated
normal sinus rhythm with normal axis, now showed sinus rhythm with right axis deviation,
inverted T waves in inferolateral leads and 1–1.5 mm ST elevation in lead V2. Furthermore,
her laboratory workup revealed worsening of her troponin I levels and elevated levels
pro-brain natriuretic peptide ([Table 1]).
Table 1 Laboratory and Imaging Studies.
Studies
|
Findings At Diagnosis
|
Findings 3 Months Prior to Diagnosis
|
Findings 4 Months After Diagnosis
|
Normal Range
|
Troponin I
|
0.066 ng/mL
|
0.052 ng/mL
|
0.018 ng/mL
|
0.0–0.034 ng/mL
|
Pro-Brain Natriuretic Peptide
|
421 pg/mL
|
----------------
|
169 pg/mL
|
0-125 pg/mL
|
Ferritin
|
38 ng/mL
|
32 ng/mL
|
-------------
|
10–70 ng/mL
|
TSH
|
990 mIU/L
|
-----------------
|
1.44 mIU/L
|
0.35–3.75 mIU/L
|
Free T4
|
<0.5 ng/dl
|
-----------------
|
1.24 ng/dl
|
0.76–1.46 ng/dl
|
ECG
|
- Normal sinus rhythm - Right axis deviation - 1-1.5 ST elevation in lead V2
|
- Normal sinus rhythm - Normal axis
|
---------------
|
|
Echocardiogram
|
- Hypertrophied left ventricle (mass 52.62 g/m2) - Trivial aortic valve insufficiency - Small posterior pericardial effusion (1–3 mm) - Normal left ventricular systolic function
|
- Hypertrophied left ventricle - Trivial aortic valve insufficiency - No pericardial effusion - Normal left ventricular function
|
- Hypertrophied left ventricle (mass 48.57 g/m2) - No pericardial effusion - Normal left ventricular function
|
|
Due to laboratory and imaging studies, there was great concern that her pericardial
effusion was secondary to myocardial cell death. However, there was also suspicion
that she might have thyroid disease to explain her symptoms and physical exam findings.
Thyroid function tests were obtained which revealed a TSH level of 990 mIU/L (0.358–3.75),
Free T4 <0.5 ng/dL (0.76–1.46), Thyroid peroxidase antibody 316 IU/mL (0–5.6), Thyroglobulin
antibody 8.6 IU/mL (<116). Thyroid ultrasound revealed normal thyroid gland size with
no nodules and increased vascularity consistent with thyroiditis. Due to her delayed
puberty a bone age was obtained that demonstrated a bone age of 12 years and 0 months
at a chronological age of 15 years and 0 months.
The patient was started on low dose thyroid hormone replacement with levothyroxine
12.5 mcg daily, and the dose was slowly titrated up with careful monitoring of her
cardiac exam. One month after initiating levothyroxine, her pericardial effusion had
resolved. By 4 months her troponin I level was within normal range. She had also developed
glandular breast tissue palpable on exam. Four months after initiating levothyroxine
therapy, she reached a final treatment dose of 88 mcg daily, which normalized her
free T4 and TSH level (1.24 ng/dL and 1.44 mIU/L respectively). The patient reported
improved energy levels and that edema of her extremities and face had resolved. Physical
examination at that time showed her heart rate and rhythm were regular with no rubs,
murmurs or gallops. Her neurologic exam was unchanged. Neck was supple with no thyromegaly.
Genitourinary exam revealed Tanner stage 2–3 pubic hair and breasts were Tanner stage
3.
Discussion
We report a pediatric patient with Friedreich’s ataxia and known cardiac disease with
new onset pericardial effusion associated with profound hypothyroidism. Friedreich's
ataxia is an autosomal recessive neurodegenerative disorder characterized by spinocerebellar
and sensory ataxia and often associated with cardiomyopathy. It is caused by a mutation
in the FXN gene, located on chromosome 9q21.11, which codes for frataxin. Individuals
with Friedreich's ataxia have a reduced amount of frataxin in their cells. Reduced
frataxin levels decrease the activity of proteins that contain iron sulfur clusters
which leads to impairment of energy production in the mitochondria [1]
[2].
Review of the literature at the time of this report revealed no association between
Freidreich's Ataxia and autoimmune hypothyroidism. Even though there is no association
between these disease processes, the cardiomyopathy could be exacerbated when they
coincide. As individuals have energy production impairment caused by the Friedrech’s
ataxia and reduced cellular energy expenditure caused by the hypothyroidism [3].
Hypothyroidism is a condition that occurs when the thyroid gland makes little or no
thyroid hormone. There are many causes of acquired hypothyroidism but it is most often
caused by autoimmune thyroiditis [4]
[5]. Autoimmune thyroiditis is characterized by lymphocytic infiltration of the thyroid
gland which results in the production of thyroid specific antibodies. The two targets
for thyroid antibodies commonly tested are thyroglobulin, the storage protein of thyroid
hormones, and thyroid peroxidase, the rate-limiting enzyme in thyroid hormone production
[6]. The prevalence of autoimmune thyroid disease peaks in early to mid-puberty and
occurs more frequently in females. It is estimated that 18% of the general population
has positive thyroid antibodies [7]. Hypothyroidism should be considered as a potential etiology for the common and
well-known symptoms of fatigue, weight gain, dry skin, hair loss, cold intolerance,
edema, depression, menstrual irregularities, or constipation ([Fig. 1]). If left untreated hypothyroidism may lead to long-term morbidity including growth
failure, pubertal delay, and impaired cognitive function and development [8].
Fig. 1 Symptoms of hypothryroidism.
A less recognized complication of untreated hypothyroidism is decreased cardiac function
characterized by decreased cardiac output, decreased cardiac contractility, bradycardia
and an increase in peripheral vascular resistance. Decreased thyroid hormone alters
the expression of enzymes, calcium-activated ATPase and phospholamban, which regulate
the calcium concentrations in cardiomyocytes. The alterations of these enzymes hinder
systolic contraction and diastolic relaxation resulting in reduced cardiac contractility.
Peripheral vascular resistance is increased in hypothyroidism due to a decreased release
of endothelial-derived relaxation factor from the endothelium of smooth muscle cells.
The increase in peripheral vascular resistance results in reduced cardiac output.
Common clinical cardiac manifestations resulting from hypothyroidism include bradycardia,
exertional dyspnea, hypertension, edema and pericardial effusions [9]. Pericardial effusions are a common cardiac manifestation of clinical hypothyroidism
in adults, however, this is an uncommonly reported complication in children [10]. Another interesting finding in our patient is that she initially had elevated troponin
I levels. Increased concentrations of creatine kinase and its MB fraction are commonly
seen in hypothyroidic patients, however, the association between hypothyroidism and
elevated troponin levels is less clear as conflicting reports can be found [11]
[12].
Treatment for pericardial effusions secondary to hypothyroidism is best accomplished
by administering levothyroxine at a dose sufficient to normalize thyroid function
tests. Pericardial effusions typically resolve in 2–12 months after treatment is started
[10]. Physicians must be careful to avoid rapid correction of hypothyroidism as it has
been shown to cause cardiac injuries and pseudo tumor cerebri [13]
[14]. There are no guidelines as to what dosage to start and how fast to increase, but
previous recommendations include using low-dose thyroxine, 25 micrograms or less,
and titrating to a final dose over 4.5 to 6 months [15]. Our patient was started on levothyroxine 12.5 micrograms daily and the dose was
slowly increased to a final dose of 88 mcg over 4.5 months. She developed no signs
or symptoms of pseudotumor cerebri or cardiac failure. She did begin spontaneous puberty
after levothyroxine replacement had begun.
Conclusion
In this reported 15 year old female with Friedrich's ataxia, hypothyroidism manifested
in worsening cardiac function, delayed puberty, dry skin, fatigue and weight gain.
This case illustrates thyroid hormone's essential role in cardiac function. Autoimmune
hypothyroidism commonly occurs, and physicians should consider screening thyroid function
in any patient with poor or worsening cardiac function. If profound hypothyroidism
is discovered, treatment should be initiated with low dosages of levothyroxine and
carefully titrated to a dose sufficient to normalize thyroid function tests.