Deterioration of symptoms after start of thyroid hormone replacement

Doctors often arrange thyroid function tests for patients presenting with general symptoms of tiredness, and in some cases hypothyroidism is subsequently diagnosed. Lack of clinical response to thyroxine replacement is not uncommon in cases of “subclinical hypothyroidism.” A deterioration of symptoms, however, may signify a potentially life threatening alternative diagnosis.

Case reports

Case 1

A 26 year old woman with type 1 diabetes, presented with a five week history of lethargy, nausea, feeling lightheaded on standing, occasional vomiting, and four unexplained severe hypoglycaemic episodes. The hypoglycaemic episodes occurred unexpectedly (no change in dietary intake, amount of physical exertion, amount of alcohol ingestion, or dose or timing of insulin therapy).

Thyroid function tests showed a serum concentration of thyroid stimulating hormone of 37.30 mU/l (reference range 0.5-5.7 mU/l) and free thyroxine 12.7 pmol/l (9-22 pmol/l). The patient was started on 25 μg thyroxine daily. This resulted in an immediate exacerbation of symptoms, which prompted a referral to an endocrinologist. On examination she was pigmented and had orthostatic hypotension (92/50 mm Hg supine, 86/60 mm Hg standing). She was hyponatraemic (serum sodium 121 mmol/l) and hyperkalaemic (serum potassium 5.5 mmol/l). Basal serum cortisol was undetectable (<20 nmol/l) and failed to respond to stimulation with synthetic adrenocorticotrophin (short Synacthen (tetracosactide) test). Random plasma concentration of adrenocorticotrophin was raised (328 pmol/l (0-l0.3 pmol/l)), ambulant plasma aldosterone concentration was low (55 pmol/l (reference range 100-450 pmol/l)), and plasma renin activity was correspondingly raised (19.7 pmol/ml per hour (1.1-2.7 pmol/ml per hour)). Adrenal and thyroid microsomal antibodies were positive. The patient's condition improved dramatically with glucocorticoid and mineralocorticoid replacement therapy.

Four weeks later the results of her thyroid function tests still showed hypothyroidism (free thyroxine 9 pmol/l, thyroid stimulating hormone 34.5 mU/l) despite receiving adequate glucocorticoid replacement therapy (random cortisol in early afternoon 376 nmol/l). It was concluded that she had permanent hypothyroidism, and thyroxine therapy was continued, with appropriate adjustment in the dose.

Case 2

A 51 year old woman presented with a two month history of cold intolerance, weight gain, and constipation. Hypothyroidism was suspected and was confirmed biochemically by her general practitioner (results unavailable), and the patient was started on thyroxine 50 μg daily. A few weeks later the patient's general practitioner advised her to increase her thyroxine dose to 100 μg daily as the results of her thyroid function tests continued to be abnormal (serum concentration of thyroid stimulating hormone 6.59 mU/l, free thyroxine 16 pmol/l).

A deterioration of symptoms and detection of abnormal concentrations of electrolytes (serum sodium 130 mmol/l, potassium 5.4 mmol/l) led to an endocrine referral. On examination she was pigmented. Blood pressure was 140/80 mm Hg lying and standing. Thyroid function tests showed a serum thyroid stimulating hormone of 0.91 mU/l, and serum free thyroxine 25 pmol/l. A short Synacthen test showed a normal baseline concentration but inadequate response (baseline cortisol 533 nmol/l; 30 and 60 minutes after Synacthen 538 nmol/l and 574 nmol/l respectively). Plasma adrenocorticotrophin was marginally raised (18.5 pmol/l), plasma aldosterone was low to normal (250 pmol/l), and plasma renin activity was high (19.1 pmol/ml per hour). A long Synacthen test confirmed primary adrenal failure (serum cortisol concentrations at baseline, 30 minutes, and 1, 2, 4, 8, 12, and 24 hours were 466, 601, 616, 684, 763, 733, 714, and 451 nmol/l respectively). Adrenal and thyroid microsomal antibodies were positive. The patient was started on hydrocortisone and fludrocortisone, with prompt resolution of her symptoms. Thyroxine therapy was continued.

Six weeks later her serum thyroid stimulating hormone remained raised (serum 8.1 mU/l) despite adequate steroid replacement (random cortisol 711 nmol/l). It was concluded that she had permanent hypothyroidism, and thyroxine replacement therapy was continued, with appropriate adjustment in the dose.

Discussion

Hypothyroidism is a common disease with a lifelong risk in women that approaches 10%.¹,² The treatment of hypothyroidism is usually simple, and referral to secondary care is unnecessary.³,⁴ Patients with hypothyroidism may have other autoimmune diseases such as type 1 diabetes, Addison's disease, or pernicious anaemia.⁵ Addison's disease is rarer than hypothyroidism, with an estimated prevalence of 60 cases per million population,⁵ but as many as 25% of patients with Addison's disease have hypothyroidism.⁶ Combined thyroid and adrenal insufficiency may also result from pituitary failure, though in such cases a low serum thyroxine concentration in association with a normal or low serum concentration of thyroid stimulating hormone should alert the clinician to the underlying diagnosis. The coexistence of thyroid and adrenal insufficiency therefore is greater than may be expected from the individual prevalences of these diseases. Furthermore, raised serum concentrations of thyroid stimulating hormone in the absence of primary thyroid failure can be a feature of adrenal insufficiency⁷ and may resolve after glucocorticoid replacement.⁸ Several factors can lead to misdiagnosis of hypothyroidism in patients with Addison's disease: symptoms of both conditions may be similar and non-specific; skin pigmentation in Addison's disease may not be recognised by the patient or relatives because of its insidious development, and may even be absent⁹; hypothyroidism is common, whereas Addison's disease is rare; thyroid function tests are easily accessible, cheap, and easy to interpret. The biochemical diagnosis of Addison's disease usually requires more sophisticated tests more appropriate in a secondary care setting; the serum concentration of thyroid stimulating hormone is often raised in adrenal failure.

It is both unrealistic and unnecessary to screen every patient with a raised serum concentration of thyroid stimulating hormone for Addison's disease. In our experience, however, most patients presenting in this manner have additional clinical features that should alert the clinician to this possibility. They include skin and mucosal pigmentation, postural hypotension, weight loss, and hyperkalaemia. Failure to reach a correct diagnosis in patients with a raised serum concentration of thyroid stimulating hormone who have Addison's disease (even in patients with only borderline adrenal failure, as in case 2) can lead to an adrenal crisis if thyroxine is introduced before glucocorticoid replacement.¹⁰ It is imperative that Addison's disease be excluded when a patient's clinical state deteriorates shortly after the introduction of thyroxine.

Suspect Addison's disease if a patient's symptoms worsen after thyroxine is given for suspected hypothyroidism