Immunometabolic signatures predict recovery from thyrotoxic myopathy in patients with Graves' disease

[helvella]

Excess thyroid hormone, as occurs in Graves disease, is known to affect muscle. Both muscle and bone effects of thyroid hormone are frequently brought up as reasons not to prescribe T3 (liothyronine), or to reduce doses of T4 and/or T3.

This paper goes somewhat deeper and examines changes in quantities of certain substances found in the blood (metabolites) and T-cells.

I have long seen thyroid hormone testing (as in blood levels of T4 and T3) as just one factor. One that can be measured but the meaning of which is not always obvious. But we need to be aware that these levels are variable over time (within the day as well as over longer periods). And a level which is fine for one individual is not fine for another.

Looking at the impact of thyroid hormones on other substances could be a fruitful avenue. They might help reveal the actual impact of thyroid hormone on metabolism. They might lead to really simple and cheap tests - for example, if a substance accumulates in urine, a simple dip test might be feasible. Or even an electronic detection mechanism.

Further, if we know what happens to the various substances in significant hyperthyroidism, there is a possibility that they could demonstrate lack of these changes in simple low TSH situations which are due to higher does of T4 and/or T3. That is, we might be able to show whether the effects of TSH suppressive doses have the same impact as overt hyperthyroidism - or not.

Immunometabolic signatures predict recovery from thyrotoxic myopathy in patients with Graves' disease

Daiki Setoyama, Ho Yeop Lee, Ji Sun Moon, Jingwen Tian, Yea Eun Kang, Ju Hee Lee, Minho Shong, Dongchon Kang, Hyon-Seung Yi

First published: 30 December 2021

doi.org/10.1002/jcsm.12889

Abstract

Background

Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T-cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease.

Methods

One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time.

Results

In both patient groups, methimazole-induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend <0.01). Senescent CD8+CD28−CD57+ T-cell levels in peripheral blood were positively correlated with acylcarnitine levels (P < 0.05) and decreased during thyrotoxicosis recovery (P < 0.05). High levels of senescent CD8+ T cells at Week 0 were significantly associated with small increases in handgrip strength after 12 weeks of methimazole treatment (P < 0.05), but not statistically associated with Five Times Sit to Stand Test performance.

Conclusions

Restoring euthyroidism in Graves' disease patients was associated with improved skeletal muscle function and performance, while thyroid hormone-associated changes in plasma acylcarnitines levels correlated with muscle dysfunction recovery. T-cell senescence-related systemic inflammation correlated with plasma acylcarnitine levels and was also associated with small increases in handgrip strength.

Full paper freely accessible here:

onlinelibrary.wiley.com/doi...

[diogenes Remembering]

We have directly compared the thyroid patterns of thyrotoxicosis and elevated FT4/3 caused by oral T4. The paper shows that the two situations are entirely different, so that one would expect different outcomes between natural hyperthyroidism and "T4-induced iatrogenic effects"Paper is downloadable:

Heterogenous Biochemical Expression of Hormone Activity in Subclinical/Overt Hyperthyroidism and Exogenous Thyrotoxicosis (ie overtreatment with T4)

February 2020Journal of Clinical and Translational Endocrinology 19:100219

DOI: 10.1016/j.jcte.2020.100219

Project: Complexity in Medicine: Practical Problems, Their Definitions, Models, and Solutions

Lab: Thyroid Lab Rudolf Hoermann

Rudolf Hoermann, John Edward M Midgley ,Rolf Larisch, Johannes W. Dietrich

[diogenes Remembering in reply to diogenes]

I'm adding the abstract here:

Background: Subclinical hyperthyroidism/thyrotoxicosis originates from different causes and clinical conditions, sharing the laboratory constellation of a suppressed TSH in the presence of thyroid hormone concentrations within the reference range.

Aim: Presentation of hyperthyroidism can manifest itself in several ways. We questioned whether there is either a consistent biochemical equivalence of thyroid hormone response to these diagnostic categories, or a high degree of heterogeneity may exist both within and between the different clinical manifestations.

Methods: This secondary analysis of a former prospective cross-sectional trial involved 461 patients with untreated thyroid autonomy, Graves’ disease or on levothyroxine (LT4) after thyroidectomy for thyroid carcinoma. TSH response and biochemical equilibria between TSH and thyroid hormones were contrasted between endogenous hyperthyroidism and thyrotoxicosis (LT4 overdose).

Results: Concentrations of FT4, FT3, TSH, deiodinase activity and BMI differed by diagnostic category. Over various TSH strata, FT4 concentrations were significantly higher in LT4-treated thyroid carcinoma patients, compared to the untreated diseases, though FT3 levels remained comparable. They were concentrated in the upper FT4- but low deiodinase range, distinguishing them from patients with thyroid autonomy and Graves’ disease. In exogenous thyrotoxicosis, TSH and FT3 were less responsive to FT4 concentrations approaching its upper normal/hyperthyroid range.

Conclusions: The presence or lack of TSH feedforward activity determines the system response in the thyroidactive (hyperthyroidism) and no-thyroid response to treatment (thyrotoxicosis). This rules out a consistent thread of thyroid hormone response running through the different diagnostic categories. TSH measurements should therefore be interpreted conditionally and differently in subclinical hyperthyroidism and thyrotoxicosis.

.

[Charlie-Farley in reply to diogenes]

Hello there diogenes and helvella ,

Has there ever been an attempt to ‘map’ symptoms experienced by the subject against doses of medication, be that for hypothyroidism or hyperthyroidism.

I have read much anecdotal information from forum members, but research seems to be dominated by an attempt to hone diagnostics via testing. Is there any research that has dared to go down the rabbit hole of qualitative data with granted all it’s inherent problems (reliability, individual perception etc).

I mapped my symptoms against dose as I worked towards securing a therapeutic level of Levothyroxine (and I do mean I worked 😂). I even noted a hierarchy within my symptoms which I found extremely exciting. Even though I had not gone through this experience before, the symptoms that were manifest at the start reduced as the medication was increased. But the last few niggling symptoms remained until I was on a therapeutic dose.

The utilisation of symptoms as well as diagnostic tests could be the way to tailor treatment to individuals with all our inherent complexities and to calibrate tests against an individual. The current situation is so often patient ‘in range’ / ping-pong in cup - job done. I battled that one 🙄

I’m musing today - sorry of it appears waffle.

Just interested …..

[diogenes Remembering in reply to Charlie-Farley]

For me the trouble is that a particular symptom is not closely related to the hormone levels causing it. Hypothyroidism for example can manifest itself in dry skin, loss of eyebrows, raised cholesterol, tiredness, and feeling cold. But not all of those symptoms will appear in an individual perhaps, and, if they do, at different stages of the ilness. The onset of disease will be as individual as the test regime necessary to treat it successfully, and consistent readiness to alter the regime with age and change of circumstances.

[Charlie-Farley in reply to diogenes]

Hi Diogenes

Totally agree with everything you say but yet just wondering if people were to map their symptoms against dose increases/changes that the process might shed light on that very individual response we all recognise.

In my experience, GPs mainly over rely on tests, don’t seem to have a clear understanding of interpretation and limitations and symptoms have become little more than an irritation that gets in the way of the ‘in range’ therefore ok diagnosis.