Subclinical hypothyroidism or central hypothyroidism—The danger of thyroid function misinterpretation

2. CASE HISTORY

An 80‐year‐old man was reviewed in the ambulatory care clinic following a referral from an anesthetist. His accompanying documentation reported a background of type 2 diabetes, ischemic heart disease, atrial fibrillation, and chronic kidney disease. His list of regular medications comprised of amitriptyline, bisoprolol, gliclazide, quinine, ramipril, simvastatin, temazepam, warfarin, calcium tablets, and co‐codamol.

He was being considered for surgical excision of a suspicious left ureteric lesion, and during his preoperative assessment, he was noted to be anemic and hypotensive, prompting referral. Upon review, he reported a long history of worsening lethargy, weight loss, and occasional episodes of hypoglycemia but denied any headaches or visual disturbance. He also denied dizziness on standing, but his blood pressures revealed a significant postural drop (91/54 mm Hg lying, 70/51 mm Hg standing). His heart rate was stable at 70 beats per minute, ECG showed sinus rhythm, and he did not display any signs suggestive of dehydration.

Baseline investigations revealed a macrocytic anemia with a hemoglobin of 80 g/L and a mean cell volume of 105 fL—reticulocyte, white cell, and platelet counts were normal. Renal function was also at his baseline, and HbA1c was 37 mmol/mol. To investigate the anemia further, thyroid function and hematinics were checked. Hematinic levels were adequate (vitamin B12 541 ng/L, folate 8.18 ng/L, and ferritin 115.1 μg/L); however, he had a profoundly low T4 of 5.6 pmol/L (normal range 10‐19.8 pmol/L) and borderline elevated TSH of 5.63 mIU/L (normal range 0.35‐5.5 mIU/L).

Review of his previous results revealed that his T4 checked a year prior to this was also low (7.6 pmol/L) with a TSH within the normal range (2.5 mIU/L). Moreover, his thyroid function had been checked several times during the previous 2 years demonstrating a similar pattern and he had been given the label of “subclinical hypothyroidism,” for which he was not on any treatment. The acute medicine team appropriately questioned this diagnosis and following discussion with the endocrine outreach team, the correct interpretation of central hypothyroidism was made. At this point, the decision was made to postpone his surgery to enable further investigation and optimization of his clinical state.

Thyroxine replacement was required; however, prior to this a synacthen stimulation test was arranged which demonstrated an inadequate cortisol response (basal: 144 nmol/L, 30 minutes: 333 nmol/L, 60 minutes: 473 nmol/L) and a baseline ACTH level within the normal range. Further pituitary function testing also revealed a slightly elevated prolactin, low insulin‐like growth factor‐1, low luteinizing hormone, and normal follicle‐stimulating hormone (in the context of a low testosterone level). These results were suggestive of pan‐anterior hypopituitarism, and a subsequent MRI pituitary confirmed an almost empty sella with a small area of residual pituitary tissue visible (see Figure 1).

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He was commenced on oral hydrocortisone before starting levothyroxine 50 μg once daily. He initially developed palpitations on this dose but gradually settled on a dose of 25 μg twice weekly. By the time of his next review 3 months later, his blood pressure and full blood count had normalized, and he felt much better. He was therefore referred for another urology appointment with a view to rebooking for surgery. However, 2 months later, he was admitted to hospital with a severe respiratory tract infection, and after a seven‐day admission, he unfortunately passed away.


— Update: 04-01-2023 — cohaitungchi.com found an additional article Treating subclinical thyroid dysfunction in pregnancy probably has no benefit from the website evidence.nihr.ac.uk for the keyword hypothyroidism nhs cks.


Testing for and then treating pregnant women with mild or “subclinical” underactive thyroid did not improve pregnancy outcomes, newborn baby outcomes, or the child’s IQ at three to five years.

A clearly underactive thyroid (clinical hypothyroidism) in pregnancy has been linked with various adverse outcomes for the mother and baby, including pre-eclampsia, preterm birth, congenital defects and neurodevelopmental delay. This needs treatment. However, there has been debate around the harms and benefits from treating only mildly abnormal blood test results in women who do not show signs of thyroid problems, subclinical hypothyroidism.

These two linked trials randomised 1,203 women with borderline abnormal levels of thyroid-related hormones (but not “clinical” or “overt” hypothyroidism) to receive thyroid replacement treatment, with levothyroxine, or placebo. Treatment had no benefits for mother or baby, including the main outcome of child IQ by three to five years of age.

This supports current UK practice, which does not routinely screen all pregnant women for subclinical thyroid dysfunction.

Why was this study needed?

The thyroid gland produces hormones that help to regulate the body’s metabolism. Around 15 in every 1,000 women in the UK have an underactive thyroid though fewer women in pregnancy have the condition, about four in every 1,000 women. People with definite (clinical) low thyroid hormones can feel tired or depressed, gain weight and experience muscle aches, it can also lead to high cholesterol. In pregnancy there can also be harms to the unborn child including failure to develop normally and reduced intelligence. Therefore, clinical hypothyroidism during pregnancy is usually treated with levothyroxine, a drug that replaces thyroid hormone.

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However, the exact risks associated with borderline blood levels, and the cut-off thyroid levels for treatment are not clear. There could even be harms from unnecessarily treating women with sub-clinical hypothyroidism. About 5% of women screened in pregnancy would be labelled as having sub-clinical hypothyroidism, depending on definitions.

What did this study do?

This study comprised two randomised controlled trials of women identified through antenatal clinic screening prior to 20 weeks of pregnancy. They were found to have only one abnormal of the two indicator hormones; both are abnormal in clinical hypothyroidism. The practicalities of screening meant that women were at 16 weeks gestation when they started treatment.

One trial included 677 women with “subclinical” hypothyroidism defined by normal thyroid hormone (thyroxine, T4) levels, but high thyroid stimulating hormone (TSH) levels of 4.00mU/L or greater. These women were randomised to either 100µg of levothyroxine or a placebo, with dose adjustment.

The other trial included 526 women with hypothyroxinemia, defined by low thyroxine (T4) levels (less than 0.86ng/dL) but normal TSH levels. They were randomised to either 50µg of levothyroxine or placebo, with dose adjustment.

The main outcome examined was the child’s IQ at three to five years, but several others were also measured.

What did it find?

  • Levothyroxine treatment during pregnancy had no significant effect on child IQ at age three to five years. In the high TSH trial the difference in IQ score was zero (95% confidence interval [CI] -3 to 2), and in the low T4 trial, -1 (95% CI -4 to 1).
  • Treatment also did not affect the child’s cognitive, motor, language, information processing ability or their behaviour up to five years of age.
  • Levothyroxine treatment had no effect on the frequency of any other adverse maternal or neonatal outcomes in either trial, such as pre-eclampsia, preterm birth, birth weight, neonatal intensive care admission, miscarriage or stillbirth.

What does current guidance say on this issue?

There is no UK guidance to screen for hypothyroidism from the National Screening Committee or in the NICE antenatal guideline. Nor is there guidance to treat sub-clinical hypothyroidism

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NICE Clinical Knowledge Summaries outline various criteria for testing thyroid function for women who are pregnant or planning a pregnancy. This includes testing for those over 30 years of age, with thyroid swelling or symptoms of thyroid dysfunction, with a personal or family history of a thyroid condition, with diabetes, morbid obesity or an autoimmune condition, after head or neck radiotherapy, or after past miscarriage or preterm delivery.

What are the implications?

This large trial indicates that treating subclinical hypothyroidism or hypothyroxinemia does not affect pregnancy outcomes or newborn outcomes, or affect the child’s neurodevelopment up to five years of age. This agrees with the previous large UK CATS trial of screening that reported while this study was underway.

This suggests that there is no advantage to treating women in this subclinical and asymptomatic group, and therefore no benefit in screening. This aligns with current UK practice, which does not routinely screen all pregnant women for thyroid dysfunction.

The results do not apply to women with overt thyroid disorders or to those discovered in early pregnancy before 16 weeks. There could be a small benefit to the developing foetus if the problem were detected and treatment started very early in pregnancy, but this is unknown.

Citation and Funding

Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.

This trial was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the US National Institute of Neurological Disorders and Stroke.

Bibliography

BTF. Thyroid in Pregnancy – FAQs. Harrogate: British Thyroid Foundation; 2015.

CKS. Hypothyroidism: screening for hypothyroidism. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: assessment. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: levothyroxine. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: preconception or pregnant. London: National Institute for Health and Care Excellence; 2016.

NHS Choices. Underactive thyroid (hypothyroidism). London: Department of Health; 2015.


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