Table 2.
Causes of anomalous TFTs in patients receiving levothyroxine therapy [30,63].
| TFT patterns/LT4 dosage requirements | Cause | Explanation |
|---|---|---|
| A. Normal TSH, mildly ↑FT4; (± higher than predicted L-T4 requirementsa) | Normal physiological variant | To abolish symptoms and normalise TSH concentrations, some individuals exhibit mildly elevated FT4 (possibly reflecting less efficient deiodination of T4 to T3); FT3 is typically normal |
| B. ↑TSH, low normal or ↓FT4; (Requirement for high L-T4 dosages to normalise TSHa) | (i) Maladministration | Patients should be advised to take L-T4 on an empty stomach; certain foodstuffs (e.g. fibre, espresso coffee) and some medications (e.g. iron, calcium, PPIs, sucralfate, aluminium hydroxide, cholestyramine, colestipol) may impair L-T4 absorption |
| (ii) Malabsorption syndromes | L-T4 malabsorption occurs with coeliac disease, achlorhydria, lactose intolerance (lactose is a constituent of some L-T4 preparations) | |
| (iii) Increased TH metabolism or excretion | Phenytoin, carbamazepine, phenobarbitone, rifampicin and some tyrosine kinase inhibitors (e.g. Imatinib) increase L-T4 requirements by enhancing hepatic metabolism of TH; occasional cases of increased urinary TH loss complicating nephrotic syndrome have also been reported | |
| (iv) Increased TH binding capacity | Oral oestrogen therapy or gonadotrophin-induced rise in oestrogen concentrations (e.g. IVF treatment) results in a marked increase in TBG and hence TH binding capacity, necessitating an increase in L-T4 therapy; similar effects are seen with SERMs and mitotane | |
| C. Unexpected change in L-T4 dosage requirements to maintain clinical and biochemical euthyroidism | Change in LT4 preparation | Not all L-T4 preparations are of comparable potency/bioavailability; changes in preparation are generally best avoided but, if necessary, should prompt more frequent TFT monitoringb |
| D. ↑TSH, normal FT4 | TSH assay interference | Heterophilic antibody interference in the TSH assay may yield falsely elevated results; FT3 is normal |
| E. Persistent ↑TSH, with ↓, ↑ or normal FT4, despite treatment with high L-T4 dosages | Poor compliance | Owing to their differing half-lives, intermittent thyroxine ingestion may result in normal or even elevated TH concentrations, but fails to normalize TSH |
| F. Supraphysiologic L-T4 required to normalise TSH, but with resultant ↑FT4 (and ↑FT3) | Resistance to thyroid hormone | Typically seen following inappropriate thyroid ablation or concomitant primary hypothyroidism in a patient harbouring a mutation in the human thyroid hormone receptor β (THRB) gene |
Key: FT4, free thyroxine; FT3, free triiodothyronine; L-T4, levothyroxine; PPI, proton pump inhibitor; SERMs, selective oestrogen receptor modulators; TFTs, thyroid function tests; TH, thyroid hormone; TSH, thyroid stimulating hormone/thyrotropin.
In athyreotic individuals total daily levothyroxine requirements can be estimated based on body weight and usually fall in the range 1.6–2.0 mcg/kg (NB: the elderly typically require lower dosages, and caution must be exercised when commencing treatment in those with confirmed/suspected ischaemic heart disease or arrhythmias).
The UK Medicines and Healthcare products Regulatory Agency (MHRA) have recently suspended one preparation of levothyroxine following discovery that it yielded variable control [64].