Generally, thyroid function test (TFT) interpretation is straightforward. However, in certain conditions causes unusual TFT patterns are likely. In such cases, clinical correlation is warranted. 

The thyrotropin-releasing hormone is released from the hypothalamus, which catalyzes the release of thyroid-stimulating hormone (TSH) from the pituitary gland. TSH prompts the thyroid gland to release thyroid hormone, which in turn, provides negative feedback to the pituitary against TSH. Thus, thyroid release is under tight equilibrium. Relatively small changes in free-T4 cause significant TSH alterations – a sensitive parameter for measuring thyroid function.

However, in certain conditions, the feedback mechanism malfunctions, such as – central hypothyroidism, non-thyroidal illness, recently treated thyrotoxicosis, resistance to thyroid hormone, TSH secreting pituitary adenoma.

Diagnosis of thyroid dysfunction must follow:

• High TSH – hypothyroidism; can occur with low Free T3/T4 levels (clinical hypothyroidism) or normal Free T3/T4 levels (sub-clinical hypothyroidism).
• Low TSH – hyperfunctioning of the thyroid gland – high Free T3/T4 levels (clinical hyperthyroidism) or normal Free T3/T4 levels (sub-clinical hyperthyroidism).

Clinical Conditions:

• Clinical hyperthyroidism – Grave’s disease, toxic nodular goiter, toxic adenomas, acute thyroiditis, drugs like amiodarone, excess Iodine intake or thyroxine ingestion, pregnancy-related (hyperemesis or mole), and congenital hyperthyroidism. 
• Clinical hypothyroidism – Autoimmune thyroiditis (Hashimoto’s; atrophic), post-radioiodine therapy/thyroidectomy, hypothyroid phase of thyroiditis, drugs like amiodarone, lithium, TKIs, and ATDs, Iodine deficiency or excess, neck radiation, Riedel’s thyroiditis, thyroid infiltration (tumor, amyloid), and congenital hypothyroidism.
• Sub-clinical hyperthyroidism – recent hyperthyroidism treatment, certain drugs like steroids or dopamine, assay interference, and NTIs.
• Sub-clinical hypothyroidism – poor compliance to thyroxine, thyroxine malabsorption, drugs like amiodarone, assay interference, NTI recovery phase, and TSH resistance.

Euthyroid sick syndrome: Common finding after chronic illness. Pre-illness TFT is detrimental in assessing thyroid hormone replacement therapy.

Heterophilic Antibody Interference: Incidence 0.05%-6%. Heterophilic antibodies like Human Anti-Mouse (HAMA) can cause falsely elevated TSH levels.

Conditions leading to Thyroid Hormone Resistance:

• Goiter, palpitation, Resting tachycardia
• Primary thyroid hormone resistance with normal peripheral tissue response
• Clinical euthyroid/hypothyroid
• Peripheral thyroid hormone resistance
• Thyroid receptor mutation – TR beta-gene
• Generalized and primary resistance to thyroid hormone – different phenotypic manifestation of a single genetic identity

Discordant TFTs – Steps to follow when Thyroid function fails to respond to the clinical scenario:

• Step 1: Re-evaluate clinical history

• Step 2: Re-assess thyroid status

• Step 3: Decide with TFT – is likely to be discordant
• Step 4: Exclude TH and/or TSH assay interference – specialist lab input may be necessary
• Step 5: Investigate for rare generic/acquired disorders of HPT function – consider specialist referral