Identification of Resistance to Exogenous Thyroxine in Humans

[helvella]

For those who have certain unusual test results and effects from levothyroxine, this paper does consider causes.

Note that as they did not find DIO2 mutations, this is something which could be dismissed on those grounds. A doctor who has some idea of DIO2, sees a negative result, and assumes all is well. Clearly that would be wrong but it is a real problem with the interpretation and management of those who have had a DIO2 test. If it is positive, it just might unlock sensible treatment. If not, you might get dismissed even more forcefully.

Thyroid . 2020 Jun 5. doi: 10.1089/thy.2019.0825. Online ahead of print.

Identification of Resistance to Exogenous Thyroxine in Humans

Nerea Lacámara 1 , Beatriz Lecumberri 2 , Beatriz Barquiel 3 , Arancha Escribano Muñoz 4 , Isabel González-Casado 5 , Cristina Alvarez-Escolá 6 , Fernando Aleixandre 7 , Francisco Morales 8 , Rocío Alfayate 9 , MariaCarmen Bernal 10 , Raquel Miralles 11 , Ilgin Yildirim 12 , Ahmet Gökhan Özgen 13 , Juan Bernal 14 , Pere Berbel 15 , Jose Carlos Moreno 16

• PMID: 32498666

• DOI: 10.1089/thy.2019.0825

Abstract

Background:

Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2(-/-) mice show central resistance to exogenous T4. Patients with Resistance to Exogenous Thyroxine (RETH) have not been described.

Aim:

To identify hypothyroid patients with TSH unresponsiveness to levothyroxine (L-T4) and to characterize the clinical, hormonal and genetic features of human RETH.

Methods:

We investigated hypothyroid patients with elevated TSH under L-T4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3 and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4 and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-β (THRB) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2) and THRB were fully sequenced.

Results:

Eighteen hypothyroid patients (9 of each sex, 3-59 years) treated with L-T4 showed elevated TSH (15.5±4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8±2.4 pmol/L; RR: 9-20.6) and TSH/fT4 ratio (0.74±0.25; RR: 0.03-0.13). Despite increasing L-T4 doses from 1.7±1.0 to 2.4±1.7 µg/kg/day, TSH remained elevated (6.9±2.7 mU/L). Due to hyperthyroid symptoms, L-T4 doses were reduced, and TSH increased again to 7.9±3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2±2.4 -RR: 11.3-15.3- and 2.5±1.4 -RR: 7.5-8.5-, respectively) whereas rT3/T4 was increased (0.6±0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but allele dose did not correlate with RETH.

Conclusions:

Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant posttranslational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.

pubmed.ncbi.nlm.nih.gov/324...

Full paper behind paywall here:

liebertpub.com/doi/10.1089/...

[jimh111]

Thanks for posting this, another paper to pick up at the British Library when there is a printed copy and the liberary opens.

I fear it may be another example of poor quality research getting published. Peer review seems to consist of just checking that a few rules and procedures are followed.

They coin a new term 'Resistance to Exogenous Thyroxine (RETH)' but don't seem to have checked whether the same TFT pattern occurred before the patients were put on levothyroxine. They also state that when the patients we given increased doses 'Due to hyperthyroid symptoms, L-T4 doses were reduced'. This clearly indicates there is no resistance to thyroid hormone.

They failed to measure fT3. Carried out lots of fancy tests but decided to omit measuring the free component of the active hormone.

They compared various ratios with patients with THRB mutations but not with control subjects. TRB RTH can present as pituitary resistance to thyroid hormone (PRTH) or general resistance to thyroid hormone (GRTH). Hormone ratios will vary greatly between patients with mutations of the TRB gene. Did they choose PRTH or GRTH patients? Indeed some people with these mutations are perfectly well.

A simple reason for an elevated TSH with normal fT4 is selenium deficiency. It's not clear if this was excluded. I think a more likely explanation is that these patients have high levels of blocking TSH receptor antibodies. This would lead to a high TSH with fairly normal fT3 and fT4. i.e. abnormal TFTs but happy subjects. The worst thing you could do is put them on levothyroxine. Treat the patient not the numbers.

The last sentence goes into wild speculation when they haven't even checked the basics.

How many endocrinologists does it take to change a lightbulb? Sixteen going by this paper.

I wonder if the group were given a little project so that they could add a research study to their CVs. Maybe the full paper will be more informative but the abstract suggests it should have been binned during peer review. So many good doctors can't get valid research published, peer review is little more than politics.

Thanks for posting this and giving me an opportunity to moan!

[Nanaedake in reply to jimh111]

Thank you for your thoughts too.