Subnormal TSH

This is an important but complex topic. If you feel it is too technical just read this screen and the Summary for an overview of how a subnormal TSH leads to hypothyroidism with apparently normal blood hormone levels. The follow-on screens and links present further evidence with technical detail.

Subnormal TSH can be considered a milder form of central hypothyroidism (CH) which is usually caused by failure of the pituitary or hypothalamus and often associated with deficiencies of other pituitary hormones. Subnormal TSH and central hypothyroidism are essentially the same thing, but CH is considered rare because it is generally associated with a physical cause such as an adenoma. On the other hand, subnormal TSH can be due to a change in function such as a sustained period of TSH suppression which sometimes occurs during high dose thyroid hormone therapy, autoimmune hypothyroidism or Graves’ disease. This down-regulates the hypothalamic pituitary thyroid axis leading to TSH levels that are lower than expected. Graves’ antibodies can also cause a subnormal TSH by their direct effect on TSH receptors in the pituitary.

TSH is also subnormal in non-thyroidal illness (NTI) or low T3 syndrome. This occurs during severe illness such as heart attack, very low-calorie diets or clinical depression and is thought to be a natural response to help the body cope with such challenges.

Most of this content is evidenced based but some logical deduction is needed to explain why patients with ‘normal’ hormone levels can be so dreadfully hypothyroid. The topic is written in a style that should make it easy to distinguish hard facts from hypothesis or logical deduction. We might consider this content hypothesis because there are few studies of the effects of TSH on cellular T3 levels.

We will see that normal thyroid function test (TFT) results can be associated with quite severe hypothyroidism and life changing impacts such as loss of job, separation from partner or endless investigations into conditions such as fibromyalgia, CFS/ME and IBS.  Subnormal TSH results in insufficient fT3 and fT4 – BOTH hormones are lower than they should be.  Subnormal TSH also reduces type-2 deiodinase (D2) which converts T4 to T3 locally causing local hypothyroidism.  The effects of lower serum hormone levels combined with reduced D2 activity lead to low T3 levels in organs such as the brain causing local hypothyroidism that can be severe.

Consider two patients with hypothyroid signs and symptoms: –

Patient 1

  • TSH 12.0 (0.27 – 4.2)
  • fT4 13.0 (12.0 – 22.0)
  • fT3 5.4 (3.1 – 6.8)

This patient is told they have ‘subclinical hypothyroidism’ (even if they have signs and symptoms of clinical hypothyroidism). Their TSH is above 10.0 so they will be given levothyroxine therapy.

Patient 2

  • TSH 1.20 (0.27 – 4.2)
  • fT4 13.0 (12.0 – 22.0)
  • fT3 3.4 (3.1 – 6.8)

This patient has severe signs and symptoms but are told they are not hypothyroid ‘because their blood tests are normal’. We shall see later that the reason they are hypothyroid is because their TSH is not elevated. Their doctor doesn’t understand why the patient is dreadfully hypothyroid, so the patient is blamed for the doctor’s ignorance: –

Toft AD, Beckett GJ. Thyroid function tests and hypothyroidism. BMJ. 2003 Feb 8;326(7384):295-6. doi: 10.1136/bmj.326.7384.295. PMID: 12574021; PMCID: PMC1125169.

We’ve seen this attitude in Functional Disorders. This is gravely disappointing; we are entitled to good science. Why do these patients exhibit signs and symptoms of hypothyroidism? Why do they respond to thyroid hormone therapy? Rather than denying the existence of such cases and blaming patients the endocrine community should adopt good scientific practice and deliver adequate patient care.

Hypothyroidism with normal serum concentrations of both thyroxine (T4) and thyroid stimulating hormone (TSH) exists. It exists in ARTH and as we shall see, when TSH is subnormal. I know of over 50 cases of hypothyroidism with normal blood test results caused by a subnormal TSH. No doubt there are other forms of hypothyroidism that also present with normal serum hormone levels.

This is nothing new. More than 30 years ago Dr Robert D Utiger pointed out that there will be hypothyroid patients with a normal TSH due to subnormal TSH secretion. At that time there was little understanding of deiodinase mechanisms so Utiger could not anticipate the effects reduced TSH and bioactivity has on deiodinase and local T3 levels.

Utiger, Robert. (1988). Thyrotropin Measurements: Past, Present, and Future. Mayo Clinic proceedings. Mayo Clinic. 63. 1053-6. 10.1016/S0025-6196(12)64925-8.

Note the comment about glycosylation. TSH that is less glycosylated is less potent, often considerably so. In secondary hypothyroidism when the pituitary is damaged the hippocampus responds by secreting more TRH producing bioactive TSH. This might not happen in subnormal TSH caused by a down-regulated axis, certainly the numbers (low fT3) suggest this is the case. Consequently, we can expect subnormal TSH to produce more severe symptoms than secondary hypothyroidism arising from a damaged pituitary. This is counter-intuitive, we can see an adenoma but we can’t see a down-regulated axis.

Why is Patient 2 so hypothyroid?

There are two reasons Patient 2 will be hypothyroid. The first is rather obvious, their fT3 is 3.4 compared to Patient 1 who has an fT3 of 5.4. Some tissues are able to convert T4 to T3 and so the reduction in fT3 could be mitigated IF this conversion were to take place and be upregulated (the lower fT3 strongly suggests the opposite is happening). Tissues unable to convert T4 to T3 will suffer a substantial reduction (37%) in hormone supply.

The second reason is more important. We must ask the question ‘where is the T3 coming from’. When fT4 is below average and TSH not elevated little T3 is coming from the thyroid, most is coming from ‘Type-2 deiodinase’ (D2). D2 activity takes place in crucial organs such as the brain, heart and skeletal muscles. Thus, when fT3 and fT4 are low normal it is reasonable to conclude that there is reduced D2 activity, otherwise serum fT3 would be higher. Hence, these tissues (brain, heart and skeletal muscles) have reduced D2 activity and will suffer from local hypothyroidism. So, in addition to reduced circulating T3 these organs are deprived of much of the T3 that they would usually make from T4. This explains why some patients with apparently ‘normal’ hormone levels suffer from severe hypothyroidism.

Why is there reduced D2 activity?

There is evidence that TSH stimulates T4 to T3 conversion, including Type-2 deiodinase. If the pituitary produces less TSH than normal (for given fT3, fT4 levels) and it has less bioactivity it follows that D2 activity will be substantially reduced.

TSH is not a single molecule but a collection of ‘isoforms’, TSH molecules with varying characteristics and potency. Patients with the same TSH as determined by a blood test may have TSH that varies considerably in bioactivity. The TSH assay measures presence (immuno-response) not activity, as pointed out by the late Dr Gordon Skinner.

it is surely errant to equate biological activity with immunological presence; a graveyard has a high density of people with little activity‘. Dr. Gordon RB Skinner’s response to Dr Graham H Beastall regarding proposed British Thyroid Association Guidelines for the Use of Thyroid Function Tests.

Insufficient TRH stimulation of the pituitary from the hypothalamus leads to lower levels of TSH with isomers of reduced bioactivity. Thus, in the case of Patient 2 their TSH of 1.20 might have the equivalent bioactivity of a TSH of 0.5 from a patient with a healthy axis. Their low TSH in the presence of low normal fT3, fT4 is the critical factor.

Misinterpretation of TFTs

TSH, fT3 and fT4 are interdependent. TSH stimulates thyroidal secretion of hormone and conversion of T4 to T3. In turn thyrotropin releasing hormone (TRH) stimulates the pituitary to secrete TSH whilst both fT3 and fT4 supress TRH and TSH. TSH, fT3, fT4 are interdependent, it is wrong to treat them as if they are independent variables. These hormones cannot be interpreted in isolation. What matters is not just whether each hormone is within its reference interval but crucially whether the normal relationship between them exists, whether the axis is intact.

Next, we see the devastating consequences a subnormal TSH has in real life.