Case study

A 76-year-old lady presented to her GP relaying a long history of fatigue and sweating. Past medical history included type 2 diabetes, hypertension, chronic kidney disease (CKD) and ischaemic heart disease.

Routine bloods revealed an unremarkable full blood count, inflammatory markers, haematinics, glycosylated haemoglobin (HbA1c), bone chemistry and renal function confirming stable CKD3 (eGFR 42ml/min/1.73m2).

Thyroid function assessment revealed a thyrotropin (TSH) level below the reference interval (0.17 (0.4 -4.9 mu/L)), although free thyroxine (fT4 -13.0 (9-19 pmol/L)) and free triiodothyronine (fT3 - 4.5 (2.6-5.7 pmol/L)) were within the normal distribution. Her TSH had been previously measured on numerous occasions and was found to be mildly and persistently suppressed (0.17- 0.44mu/L) for almost a decade (Figure 1), although, at every time point her free thyroid hormones were within the reference range.

Figure 1: Graph highlighting mild (stage 1) subnormal TSH values over an eight-year period


On further enquiry, the patient denied any weight loss, palpitations, anxiety or tremor. Furthermore, no causative medication was noted to account for the subnormal TSH. Clinical assessment did not reveal a palpable goitre, thyroid nodule, ophthalmopathy, or adrenergic signs of thyrotoxicosis. Assessment of her pulse and blood pressure was unremarkable. Subsequent measurement of anti-thyroid peroxidase antibodies (TPO-Ab) and TSH receptor antibodies (TRAb) were negative. In light of her ongoing suppressed TSH, a DEXA scan was arranged revealing a T score of -2.8 SD, thus confirming osteoporosis. The patient was commenced on weekly alendronate (70mg) as well as calcium/vitamin D supplementation.

The patient was also referred to the endocrinology team to further manage her longstanding subclinical hyperthyroidism. In order to prevent further bone mineral density loss, as well as attenuate the risk of atrial fibrillation, she was subsequently commenced on a small dose of the anti-thyroid drug (ATD) carbimazole (5mg) and safety-netted regarding the rare risk of agranulocytosis.

Subnormal TSH: background and diagnostic pitfalls

Although estimates vary, the reported prevalence rate of endogenous subclinical hyperthyroidism is in the region of 2-3%.1 It is defined biochemically, by the suppression of TSH below the normal reference range (<0.4mu/L), with fT4 and fT3 usually in the middle or upper end of the normal distribution. Subclinical hyperthyroidism can be further stratified into mild (stage 1: 0.1-0.39 mu/L) or severe (stage 2: <0.1mu/L) disease.2

Prior to subclinical hyperthyroidism being diagnosed, fT3 and fT4 should be checked to exclude overt biochemical hyperthyroidism, although in practice, most laboratories will automatically add these tests should the TSH fall outside the reference range.

Exogenous causes of a subnormal TSH finding must be excluded and will mirror the biochemical profile of endogenous subclinical hyperthyroidism (low TSH and high-normal fT3/fT4). Careful history taking may elucidate the following:2-4

  • Overtreatment of primary hypothyroidism (the commonest scenario in primary care)
  • Intentional TSH suppressive therapy with thyroid replacement hormones; e.g. adjunctive treatment of differentiated thyroid cancers, or rarely treatment of large goitres
  • Surreptitious use of thyroid replacement hormones (a degree of suspicion is required)
  • Iodinated contrast media (commonly used in radiology; TSH abnormalities usually being transient)
  • Iodine containing herbal remedies such as seaweed supplements.

Other secondary (non-thyroidal) causes that may present with subnormal TSH levels (but usually in the presence of a low-normal fT3/fT4) should also be considered in order to distinguish from biochemically endogenous subclinical hyperthyroidism:2-4

  • Drugs; e.g. high dose glucocorticoids, dopamine, bromocriptine
  • Severe illness (euthyroid sick syndrome)
  • Psychiatric illness
  • Late first trimester pregnancy
  • Hypothalamic/pituitary disease (often isolated low fT4).

Once secondary causes for subclinical hyperthyroidism have been excluded, one can then consider the primary endogenous (thyroidal) causes below.2,4 The aetiologies are shared with those for overt hyperthyroidism, highlighting the propensity for such patients to progress towards further biochemical thyroid dysfunction:

  • Thyroiditis: abnormal thyroid biochemistry is usually transient. Examples include post- partum thyroiditis, subacute painful/silent thyroiditis and drug- induced thyroiditis (such as amiodarone, lithium and interferon therapy)
  • Graves’ disease (the commonest cause of endogenous hyperthyroidism)
  • Toxic multinodular goitre
  • Autonomous nodule.

Subclinical hyperthyroidism: why treat?

The relationship between borderline low/normal TSH values and clinical outcomes is subject to debate. Firstly, traditional reference ranges are derived from statistical rather than clinical principles and may therefore arbitrarily exclude important patient subgroups,5 such as those who are at greater risk of developing complications. Furthermore, deciding on the timing of subclinical hyperthyroidism treatment, especially in mild cases, is often not straightforward, as a proportion will revert back to the normal reference range over time.6 However, given that individuals with severe subclinical hyperthyroidism are more likely to progress to overt hyperthyroidism, they should be considered to be higher risk.3

Meta-analyses and observational studies have shown that untreated severe endogenous subclinical hyperthyroidism is associated with atrial fibrillation, diastolic dysfunction as well as major cardiovascular events and all- cause mortality.2-4,6

In addition, severe subclinical hyperthyroidism is strongly associated with osteoporotic fractures, with some studies also relaying a fracture risk association with mild endogenous subclinical hyperthyroidism.4 More recently, a prospective cohort study in older people also determined that the risk of dementia was significantly higher (HR 2.38, CI = 1.13; 5.04) in those with severe subclinical hyperthyroidism compared to euthyroid individuals.7

Case study discussion

This case above presents an older lady with longstanding mild subclinical hyperthyroidism, albeit with some notable risk factors. In the context of her established ischaemic heart disease, the inclination for intermittent monitoring of her TSH (over an eight-year period) was perhaps, the incorrect strategy to follow.

Treating her subclinical hyperthyroidism would likely attenuate the risk of further complications such as symptomatic angina as well as the development of atrial fibrillation. Furthermore, the deleterious effect of subclinical hyperthyroidism upon her bone health and fracture risk should also have prompted clinicians to consider a DEXA scan at an earlier stage with subsequent referral to secondary care (Figure 2).  

Figure 2: A suggested algorithm for the assessment of subnormal TSH in primary care (adapted from an algorithm produced by The European Thyroid Association 2015 2)


End points

  • TSH receptor antibodies (TRAb) provide high diagnostic sensitivity and specificity for Graves’ disease.
  • USS thyroid is usually only warranted if TRAb are negative or there is a palpable nodule or multinodular goitre. An USS will confirm the presence as well as characterise thyroid nodules, but, will not provide additional information regarding the functional (‘toxic’) nature of a nodule. A thyroid (radionuclide) uptake scan may therefore be considered by secondary care.
  • Management may involve 12 to 24 months of ATD treatment (carbimazole or propylthiouracil (PTU)) for Graves’ disease or alternatively radioactive iodine (RAI) for toxic. adenomas/multinodular disease. Longstanding low dose ATD medication may be considered in elderly/ frail individuals at high risk of relapse who do not wish to pursue RAI/surgery.
  • Patients require counselling about the risk of agranulocytosis with ATDs and must be advised to seek an urgent FBC should they develop a severe sore throat or systemic upset. PTU is also very rarely associated with fulminant liver failure making it a second-line ATD in many cases.

Dr Amro Maarouf, Department of Clinical Biochemistry, Good Hope Hospital, University Hospitals Birmingham

Conflict of interest: none

Acknowledgements: Professor Sudarshan Ramachandran, Consultant in Chemical Pathology/Metabolic Medicine and Dr Adeeba Ahmed, Consultant Endocrinologist at University Hospitals Birmingham NHS Foundation Trust whose collective insight and contribution was invaluable in writing this manuscript.



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