Case 1

A 24-year old female presented with palpitation, weight loss and oligomenorrhoea in the recent 4 months. Physical examination revealed diffuse non-tender symmetrical goiter and bilateral exophthalmos.

Question: How to interpret the TFT results?

Answer: The clinical picture together with the suppressed TSH and grossly elevated FT4 pointed towards Graves' disease as the most likely diagnosis. Testing on thyroid peroxidase antibody (anti-TPO Ab) and anti-TSH receptor antibody are not routinely required when the clinical signs and the TFT results are already diagnostic,^7,8 but they are helpful in identifying the autoimmune nature of thyroid problems if there is no obvious clinical signs and if the aetiology of the disease would have an impact on patient management, e.g. hyperthyroidism during pregnancy.^7,8 If thyroiditis is suspected, erythrocyte sedimentation rate should be checked and it should be elevated.

Case 2

Patient in Case 1 had been treated with carbimazole for 3 months. She was found to be clinically euthyroid on follow-up.

Question: Should the dosage of carbimazole be increased in view of the suppressed TSH?

Answer: No. Suppression of TSH can remain for several months in patients under good control with anti-thyroid therapy, attributing to the delayed recovery of the pituitary-thyroid axis. Adjustment of anti-thyroid drug regime should be based on FT4 with monitoring once every 4-6 weeks for the first 4-6 months, and less frequently (approximately every 3 months) when the patient is on maintenance dose.^7,9

Case 3

A 30-year old female complained of weight loss, tremor and heat intolerance in the recent 6 months. Physical examination revealed a right-sided 2 cm thyroid nodule.

Question: Did the patient have hyperthyroidism?

Answer: Although FT4 was normal, the clinical findings and the suppressed TSH were suggestive of hyperthyroidism. Testing the FT3 level in this patient would be helpful in making the diagnosis:

The elevated FT3 result confirmed the suspicion of T3 toxicosis, which is seen in a minority of patients with hyperthyroidism. FT3 instead of FT4 is the test of choice for monitoring patients with T3 toxicosis.

Case 4

A 19-year old female complained of hand tremor, insomnia and palpitation in the recent 3 months. Her body mass index was 20.0 kg/m² three months ago, and had reduced to 18.4 kg/m² in this visit. She had no goiter or thyroid eye sign on examination, but had profuse sweating, hand tremor and a pulse rate of 96/min.

Question: Did the patient have T3 toxicosis?

Answer: T3 toxicosis was a possible diagnosis. However, three features in the TFT results suggested the diagnosis of thyrotoxicosis factitia where the patient was taking T3 analogue: 1) suppressed TSH, 2) suppressed endogenous production of thyroid hormones, as reflected by the low FT4, and 3) grossly elevated FT3 level. Tiratricol, which is a T3 analogue, is used for the treatment of non-tumoral pituitary resistance to thyroid hormone, and is also used for weight reduction, though its use for the latter condition is unorthodox. This drug is known to cross-react with many commercial FT3 immunoassays,^10,11 giving rise to falsely high FT3 results. Testing on serum thyroglobulin (Tg) level may help to differentiate between thyrotoxicosis factitia from other causes of hyperthyroidism where in the former condition, the Tg level is suppressed or low-normal. Hyperthyroidism due to inflammation, excessive stimulation or physical destruction of the thyroid gland would have elevated Tg level.¹²

On further history taking, the patient admitted that she had been taking an over-the-counter weight reduction agent which consisted of tiratricol in the recent 3 months

Case 5

A 74-year old lady was found to have low mood, poor memory and constipation by her relatives and was brought to the clinic. Physical examination revealed pallor, loss of eyebrows, cold peripheries and slow-relaxing reflexes. 

Question: How to interpret the TFT results?

Answer: Elevated TSH and low FT4 levels were compatible with primary hypothyroidism. Testing on FT3 level is not necessary for making the diagnosis. The incidence of spontaneous primary hypothyroidism increases with age and the presence of anti-thyroid antibodies further increases the risk.¹³ Levothyroxine (L-T4) is the preferred drug for long-term replacement.^8,12,14 Due to the slow re-equilibration of TSH, its level should only be rechecked 6-8 weeks after the commencement or adjustment of the therapy,^7,8,12 with the L-T4 dosage titrated against the TSH level. Target TSH level between 0.5 to 2.0 mIU/L¹² or within the reference interval^7,8 have been advocated. Once the TSH level is normalized, a follow-up TSH level should be checked once every 6 to 12 months.^8,12 FT4 level fluctuates according to the time of daily dosing and its level is expected to be elevated if blood is taken within the first few hours after taking L-T4 despite the simultaneous TSH level is normal in an optimized regime. Monitoring the FT4 level is not required unless compliance is a concern, in which case discordant TSH and FT4 results (both values high) might be observed if the patient only resumes the thyroxine replacement just before the blood collection.

Case 6

A 50-year old man complained of double vision, malaise and impotence.

Question: How to interpret these TFT results?

Answer: The inappropriately normal TSH in the presence of low FT4 in this clinical setting is compatible with central or secondary hypothyroidism. When there is clinical suspicion of secondary hypothyroidism, both TSH and FT4 should be requested because TSH alone would be misleading. Referral to endocrinologists for additional tests on pituitary function may be required and it is important to clarify the adrenal status before commencing L-T4 replacement therapy to avoid precipitating an Addisonian crisis. In secondary hypothyroidism, FT4 instead of TSH level should be monitored when the patient has been put on L-T4 replacement. FT4 level should be optimized to within the upper third of the reference interval, with blood collected before the daily dose of L-T4.^7,12 Annual FT4 checking should be performed after stabilized on L-T4 replacement.

Case 7

A 65-year old lady who had a 5-year history of hypertension was having an annual checkup. 

Question: How to interpret these TFT results?

Answer: Mildly elevated TSH together with normal FT4 were compatible with subclinical hypothyroidism. The findings should be confirmed by repeating the TFT within 6 months.^7,12 Testing on thyroid autoantibodies is warranted because patients with positive antibodies are prone to develop overt hypothyroidism. L-T4 replacement will benefit those with TSH level greater than 10 mIU/L but routine treatment for those with TSH level between 5 to 10 mIU/L remains debatable.^7,8,15

Case 8

A 40-year old man had a pre-employment checkup.

He did not complain of any thyrotoxic symptoms and he was clinically euthyroid. TFT was repeated a few months later, showing similar results.

Question: Was the patient thyrotoxic?

Answer: Despite the elevated thyroid hormone levels, the patient remained euthyroid and the TSH level was not suppressed. This condition is known as euthyroid hyperthyroxinaemia. The differential diagnoses of euthyroid hyperthyroxinaemia include RTH, familial dysalbuminaemic hyperthyroxinaemia (FDH) and TBG excess. RTH is an autosomal dominant condition. About 90% of the cases were caused by mutation in the THRB gene,^16,17 producing defective thyroid hormone receptor beta and disrupting the negative feedback loop in the pituitary-thyroid axis. Patients with RTH may be hypothyroid, euthyroid or hyperthyroid, depending on the basis of their genetic defect. FDH is another autosomal dominant condition and the defect lies in the ALB gene. The mutant albumin has abnormally high affinity to T4, leading to falsely high FT4 results in homogenous or one-step FT4 immunoassays using T4 analogue.¹⁸ T3 measurement is not affected. TBG excess could be an inherited or iatrogenic condition. Its effect is best appreciated in TT4 measurement. The disturbed binding equilibrium with displacement of thyroid hormones from their binding proteins on initiation of some therapies such as salicylate, phenytoin, and frusemide, and interference in the TSH or thyroid hormone immunoassays might also give rise to TFT pattern seen in this case.¹⁹ If the patient exhibits symptoms and signs of hyperthyroidism, TSH-secreting pituitary tumour should be considered. When faced with these TFT results, anti-thyroid treatment should be withheld and referral to an endocrinologist for further management is recommended.

In this case, further investigations on the patient and his family members showed that the patient and some of his family members had RTH. Several cases on local patients with RTH have been reported.^11,20,21

Case 9

A 23-year old female had a routine checkup. She did not have any history of thyroid problem. She had no symptoms or signs of hypothyroidism.

Question: Did the patient have subclinical hypothyroidism?

Answer: The extent of TSH elevation and the high-normal thyroid hormone levels make the diagnosis of subclinical hypothyroidism highly unlikely. When there are discordances in the clinical findings and the biochemical results, the laboratory should be contacted to discuss about the possibility of errors in any stage of the pre-analytical, analytical or post-analytical results. In this case, there was interference in the TSH assay, causing the spuriously high TSH result stage. The patient's TSH was normal when measured by another TSH assay platform and she did not have any thyroid dysfunction. Interference of the thyroid hormone immunoassays by autoantibodies, heterophile antibodies and rheumatoid factors are well-recognised.^22,23 Grossly different TFT results when performed in different laboratories using different immunoassay platforms in an otherwise euthyroid patient should prompt the clinicians to think about immunoassay interference.

Case 10

A 78-year old man with history of hypertension on anti-hypertensive was having a routine body check. There was no personal or family history of thyroid problem. Physical examination revealed a bilaterally enlarged multinodular goiter. ECG showed atrial fibrillation.

Question: Was the patient thyrotoxic?

Answer: Suppressed TSH and normal FT4 and FT3 were compatible with subclinical hyperthyroidism. The causes of subclinical hyperthyroidism are similar to those of overt hyperthyroidism, but patients remain asymptomatic or only mildly symptomatic, and could be found in less than 2% of the adult or elderly population.^8,15 Repeating the assessment of the thyroid status is necessary to confirm the biochemical abnormality and to exclude the progression to overt hyperthyroidism. The risks of atrial fibrillation and osteoporosis are increased in patients with subclinical hyperthyroidism and periodic monitoring of the thyroid function is warranted. Therapy should be individualized and referral to endocrinologist should be considered.