An uncommon cause of hyperthyroidism
Hyperthyroidism is a commonly encountered endocrine problem in primary care settings. Most patients have primary hyperthyroidism and its biochemical presentation is straightforward: an elevated free thyroxine (T4) (or free triiodothyronine [T3]) level plus an unmeasurable thyroid-stimulating hormone (TSH) level due to negative feedback from the thyroid gland. Perplexing thyroid function test results may create a diagnostic challenge to clinicians, as in the patient case presented herein.
A 55-year-old man presented in 2011 with almost one year history of heat intolerance, mild palpitation and significant weight loss. His family members noted he had mild neck swelling and hand tremor. Physical examination revealed a moderately-sized diffuse goitre and clinical signs of hyperthyroidism, including fast resting pulse rate, fine hand tremor and sweaty palms. The patient’s family history of thyroid disease was negative. There was no dysthyroid eye sign. Blood tests for thyroid function showed:
· Sensitive TSH (sTSH) = 0.29 mIU/L (reference range, 0.27–4.20 mIU/L)
· Free T3 = 10.3 pmol/L (reference range, 3.10–6.80 pmol/L)
· Free T4 = 30.6 pmol/L (reference range, 12.0 – 22.0 pmol/L)
Results of other blood tests were normal. Thyroid autoantibodies were negative. Thyroid ultrasound showed diffuse enlargement of the thyroid gland, and the formal report mentioned “Graves’ thyroiditis was one of the possibilities”.
The patient was treated as having Graves’ disease with carbimazole. However, his response was suboptimal. (Table 1)
As the patient’s hyperthyroidism remained poorly controlled with carbimazole therapy, he was treated with radioactive iodine in January 2013. Thyroid function test just before radioactive iodine treatment showed:
· sTSH = 1.02 mIU/L
· Free T4 = 32.7 pmol/L
However, hyperthyroidism persisted even after radioactive iodine treatment. (Table 2)
In 2014, the patient was referred to the endocrine clinic of a university-affiliated hospital for considering a second course of radioactive iodine treatment. Despite good compliance with drug therapy, the patient’s hyperthyroid symptoms showed modest improvements only in 2011–2013. He appeared hyperthyroid with a diffuse goitre. His visual field was intact by confrontation test.
Suppressed serum TSH with elevated free T4/T3 point to primary hyperthyroidism, the most common causes of which are Graves’ disease and toxic thyroid nodules.1 When serum TSH level is inappropriately normal and levels of thyroid hormones are high, alternative diagnoses should be considered:
1. Assay interference: When the one-step analog method is used, the presence of anti-iodothyronine autoantibodies (anti-T4 +/- anti-T3) can lead to spuriously raised total T4 and total T3 levels. Free T4, free T3 and TSH are usually normal, however. Rarely, TSH level can be increased in TSH immunometric assay if there are heterophilic antibodies directed against mouse gamma-globulin. In cases of assay interference, patients are euthyroid clinically.
2. TSH-secreting pituitary tumour: Patients are clinically hyperthyroid. Free T4/T3 and total T4/T3 are raised, while serum TSH is detectable (from low to normal or even high).
3. Thyroid hormone resistance: A rare familial syndrome of tissue resistance to thyroid hormones. Its biochemical picture is quite similar to TSH-secreting pituitary tumour.
4. Familial dysalbuminaemic hyperthyroxinaemia: Another very rare familial condition in which abnormal forms of albumin cause falsely elevated total T4/T3 levels, while free T4 and free T3 levels are normal and patients are euthyroid.
Failure to differentiate primary hyperthyroidism from the above four mentioned conditions will result in inappropriate treatment. The present patient was clinically hyperthyroid, with a normal TSH level and a high free T4/T3 level upon presentation. The differential diagnoses should be TSH-secreting pituitary tumour and thyroid hormone resistance. However, a wrong diagnosis of primary hyperthyroidism was made and he received radioactive iodine to the thyroid gland, which was deemed to be futile.
Further investigations and management
Repeated thyroid function test showed a similar pattern of normal TSH level and elevated free thyroid hormones:
· TSH = 2.40 mIU/L
· Free T4 = 25.3 pmol/L
· Free T3 level of 8.91 pmol/L.
His alpha subunit level was raised to 2.9 IU/L (reference range < 0.8 IU/L).
A tentative diagnosis of TSH-secreting pituitary adenoma was made. Pituitary MRI with contrast revealed a 1.3 x 1.0 x 1.1 cm round hypo-enhancing area in the anterior pituitary, suggestive of macroadenoma. (Figure) Other anterior pituitary function tests showed central (hypogonadotrophic) hypogonadism and a raised prolactin level of 1,500 mIU/L (reference range < 324mIU/L ). Perimetry for visual field found a mild degree of bitemporal hemianopia. Trans-sphenoidal surgery was recommended, but the patient did not accept surgical treatment. He was then started on cabergoline and received radiotherapy in late 2014. Subsequently, his hyperthyroid symptoms were controlled and his thyroid hormones were normalized:
· sTSH = 2.00 mIU/L
· Free T4 = 20.6 pmol/L
TSH-secreting pituitary adenoma is a rare cause of hyperthyroidism, accounting for 0.5–3 percent of all pituitary adenoma. It is usually benign in pathology. Hyperthyroid symptoms are mild due to the slow tumour growth. A small goitre can be present without signs of ophthalmopathy. Many patients present with symptoms related to the mass effect of the tumour, such as field visual defects and hypopituitarism.
Biochemically, TSH-secreting pituitary adenoma is characterized by a nonsuppressed serum TSH with high free T4 and T3 levels. Sometimes the TSH level can be misleading if it is just in the low-normal range, as in this patient. The majority of patients have a high serum alpha subunit of glycoprotein hormones. Of note, 20–25 percent of the adenoma also co-secrete other anterior pituitary hormones, especially growth hormone and prolactin. In patients with large tumours, there may also be various degrees of hypopituitarism (such as the central hypogonadism in this patient). Therefore, a full anterior pituitary hormone workup for hypersecretion and hyposecretion should be performed in all patients suspected of having TSH-secreting pituitary adenoma.2,3 MRI of the pituitary usually shows a macroadenoma.
Transsphenoidal resection of the adenoma remains the mainstay of treatment.2,3 TSH-secreting pituitary adenoma expresses somatostatin receptors, and medical treatment with somatostatin analogs (eg, octreotide) is therefore effective in restoring euthyroidism before surgery. In contrast to primary hyperthyroidism, thionamides (eg, carbimazole and propylthiouracil) are ineffective in TSH-secreting pituitary adenoma. Given that this patient did not accept surgical treatment and his tumour co-secreted prolactin, a dopamine agonist (cabergoline in our patient) can be given as the alternative treatment.
Interpretation of a thyroid function test can be challenging. If TSH is not typically suppressed and thyroid hormone level is raised, clinicians should consider assay interference and uncommon causes of hyperthyroidism as differential diagnoses. In the latter case, referral to endocrinologists can avoid inappropriate thyroid gland ablative therapy.