Myxedema Coma in a Patient with Subclinical Hypothyroidism

Introduction

M yxedema coma is a life-threatening manifestation of severe hypothyroidism (1). The classic presentation is with overt and typically severe biochemical hypothyroidism. Subclinical hypothyroidism is considered a mild form of hypothyroidism, defined biochemically as elevated serum thyrotropin (TSH) concentrations with normal thyroid hormone levels (thyroxine [T4] and triiodothyronine [T3]) (2). The occurrence of myxedema coma in association with subclinical hypothyroidism has not previously been reported. We describe a patient with subclinical hypothyroidism who developed clinical manifestations of myxedema coma.

Patient

A 47-year-old woman was referred to our endocrine clinic in May 2008 with complaints of fatigue and laboratory findings of persistent subclinical hypothyroidism: free T4 [FT4] 14.3 pmol/L (reference range 10.3–24.5), TSH 14.0 mU/L (reference range 0.4–4.0; Fig. 1). She had no specific symptoms of hypothyroidism, was not taking any medications, and had regular menstrual cycles. Systemic examination was unremarkable. Her body mass index was 28 kg/m². The thyroid gland was not palpable, but thyroid peroxidase antibodies were positive (250 IU/mL, reference range 0–34.0). We initiated treatment with 50 μg of levothyroxine daily. She complied poorly with treatment, often forgetting to take her medications. She was admitted to hospital a month later, feeling dreadful and complaining of pains in the arms and calves. On arrival she was lethargic, with heart rate of 88/minute and blood pressure of 100/60 mmHg. She had tender nonpitting edema of the limbs. Ankle reflexes were difficult to elicit due to gross limb swelling. The electrocardiogram was normal. Serum glucose, calcium, liver, and kidney profiles were normal. White cell count (12 × 10⁹/L) and C-reactive protein (33 mg/L) were raised. Thyroid function tests showed persisting subclinical hypothyroidism: FT4 10.7 pmol/L, FT3 2.7 pmol/L, and TSH 6.09 mU/L. Creatinine phosphokinase was noted to be high (27,138 U/L). At this stage a tentative diagnosis of a viral illness with myositis was entertained. We increased the dose of T4 to 100 μg daily and commenced intravenous hydrocortisone 100 mg 6-hourly pending laboratory exclusion of adrenal insufficiency.

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FIG. 1.

Serial thyroid function tests (a, FT4, FT3; b, TSH) of patient from initial clinic review (week 0) to hospital admission (week 4–12) and after discharge (week 12–24). Dosage of levothyroxine (T4) in μg/day is shown in the bars at the bottom of the chart. Intravenous T3 was administered for 72 hours in week 4 after diagnosis of myxedema. Symptom severity was rated as follows: asymptomatic (−), mild to moderate lethargy (+), severe lethargy with cramps (++), and severe features of myxedema coma (+++). Reference ranges for thyroid hormones are as follows: FT4 10.3–24.5 pmol/L, FT3 2.67–7.03 pmol/L, and TSH 0.4–4.0 mU/L. Assays were performed by an electrochemiluminescence assay and analyzed on the Roche E170 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). FT4, free thyroxine; FT3, free triiodothyronine; TSH, thyrotropin.

Overnight, she grew increasingly drowsy, and by morning had become unarousable, hypothermic (33.2°C), and hypotensive. Repeat biochemistry showed hyponatremia, metabolic acidosis, and elevated urea and creatinine levels. A random serum cortisol returned as 2062 nmol/L, excluding adrenal insufficiency. Serum gonadotrophins were within the reference limits. A computerized tomography scan of the brain was unremarkable. She was transferred to the intensive treatment unit where she remained hypotensive despite treatment with large volumes of intravenous colloids and broad-spectrum antibiotics. Urine and blood cultures and autoimmune screen returned negative. An echocardiogram showed a moderate-sized pericardial effusion.

We now made a diagnosis of myxedema coma and started intravenous 3,5,3’-T3 20 μg 8-hourly. She responded dramatically, regaining consciousness within 12 hours. T3 was stopped after five doses and oral T4 was re-commenced at 100 μg daily. Biochemical derangements and thyroid functions subsequently normalized. Electrolytes and urea returned to baseline levels within 5 days, whereas serum creatinine phosphokinase (CK) levels dropped to less than half peak levels after 1 week (10,124 U/L) and had normalized by the second week.

On recovery she developed bilateral foot drop, which was confirmed on nerve conduction studies to be secondary to common peroneal nerve damage. This was attributed to compression neuropathy from muscle edema. She improved partially with physiotherapy and was able to mobilize with crutches on discharge from hospital 8 weeks later. After discharge, an adrenocorticotrophic hormone (ACTH) stimulation test confirmed a normal adrenal response, and magnetic resonance imaging of the pituitary gland showed no abnormalities. We subsequently sent off an admission sample to a reference laboratory for FT4 estimation by equilibrium dialysis. This returned as normal (FT4 12.4 pmol/L; reference range 10.3–38) and was consistent with our routine laboratory assay (FT4 11.1 pmol/L). Genetic studies performed after discharge showed no mutation in the thyroid hormone receptor β gene, associated with thyroid hormone resistance. At subsequent clinic reviews she developed further symptoms of lethargy, coinciding with a drop in FT4 levels to lower reference values. This improved with T4 dose adjustment to maintain FT4 levels in the upper range and TSH at low-normal levels (Fig. 1). She remains in good general health on a T4 dose of 175 mcg daily.

Discussion

Myxedema coma represents the extreme expression of severe hypothyroidism (1). It is a relatively rare endocrine emergency, typically seen with longstanding neglected or unrecognized hypothyroidism (1,3). The characteristic clinical picture is that of decompensated hypothyroidism with altered mental state and defective thermoregulation (1,3). A precipitating factor such as infection, cold exposure, use of sedative medications, or noncompliance with thyroid hormone replacement is usually apparent (1,3). In our patient the diagnosis was suggested clinically by the development of hypothermia, circulatory collapse, and coma, and was further supported by a favorable response to parenteral T3. Other features of severe hypothyroidism included hyponatremia, pericardial effusion, myopathy, and neuropathy. Possible triggering factors in this case could have been a viral illness or sepsis, coupled with noncompliance with treatment.

A striking feature of our presentation, however, was that thyroid function tests were only mildly deranged despite florid clinical manifestations (Fig. 1). Discrepancies between thyroid function tests and clinical presentation are a recognized feature of severe hypothyroidism (4). In myxedema coma thyroid hormone levels correlate poorly with disease severity or outcome (3). Such inconsistencies notwithstanding, accounts of myxedema coma in the literature have exclusively been in association with overt hypothyroidism. To the best of our knowledge, ours is the first description of myxedema coma in a patient with subclinical hypothyroidism. Other causes of discordant thyroid hormone biochemistry were unlikely in this case. FT4 estimation by equilibrium dialysis excluded analytical interference, and molecular analysis for the thyroid hormone receptor β gene, which is associated with thyroid hormone resistance, was negative. Further, pituitary hormone levels were within normal limits, leaving subclinical hypothyroidism as the sole abnormality.

The prevalence of subclinical hypothyroidism ranges from about 4%–10% in adults (2). Despite intense research focus the significance of this biochemical diagnosis continues to be debated. Although the majority of individuals are asymptomatic, some patients exhibit abnormalities of cardiovascular function, lipid metabolism, and neurocognitive performance, similar to those seen in overt hypothyroidism (2). The variable clinical expression may to some extent be explained by the wide range of the population-based laboratory reference for normal thyroid hormones (5). Since the intra-individual range is maintained within relatively narrow limits, a patient's thyroid function may be abnormal and yet remain within reference values (5). Further, circulating thyroid hormone levels may not always reflect tissue bioactivity, due to genetic or other unidentified factors (2,4). Thus, it is possible that our patient's thyroid hormone levels at presentation were outside her set point for normal despite falling within our laboratory's reference limits. Interestingly, sustained symptomatic improvement, although subjective, was only achieved when her thyroid hormone levels were maintained in the upper reference range (Fig. 1).

Our presentation highlights the need for careful evaluation in patients with disparate laboratory findings. Myxedema coma carries a guarded prognosis even with the best of modern treatment. The relative merits of different treatment regimens with T3 or T4 remain undecided, and early recognition and management in an intensive care setting continues to offer the best hope of recovery (3). A potentially serious pitfall would thus be to overlook the diagnosis in patients with mild or subclinical hypothyroidism. We conclude that clinicians should be alert to the possibility of myxedema coma even in patients with subclinical hypothyroidism.