Mathematical analysis of T4/T3 dosing

[diogenes]

This upcoming paper is joined with ours in the same edition of Frontiers.

However, do not judge it on a personal level. It simply shows, against different situations, a general trend which either supports or does not the use of combined therapy. It indicates optimum dosing schedules for T3. It is therefore to be looked at as a statistical model, suitable for promoting optimum dosing and what with. Within the limits therefore, individual trials can be made by a person to find their optimum treatment regimen. Note that combined therapy is generally somewhat better than T4 only. Also note that mutations in the DIO2 gene have an effect on this.

The paper will emerge together with ours - based on equivalent modelling techniques.

Optimal hormone replacement therapy in hypothyroidism - a model predictive control approach

Tobias M. Wolff1*, Johannes W. Dietrich2, 3, 4 and Matthias A. Müller1

1Institute of Automatic Control, Leibniz University Hannover, Germany

2Department of Internal Medicine I, Ruhr University Bochum, Germany

3Center for Rare Diseases Ruhr, Ruhr University Bochum, Germany

4Diabetes Centre Bochum-Hattingen, Germany

In this paper, we address the problem of optimal thyroid hormone replacement strategy development for hypothyroid patients. This is challenging for the following reasons. First, it is difficult to determine the correct dosage leading to normalized serum thyroid hormone concentrations of a patient. Second, it remains unclear whether a levothyroxine (L-T4) monotherapy or a liothyronine/levothyroxine (L-T3/L-T4) combined therapy is more suitable to treat hypothyroidism. Third, the optimal intake frequency of L-T3/L-T4 is unclear. We address these issues by extending a mathematical model of the pituitary-thyroid feedback loop to be able to consider an oral intake of L-T3 and L-T4. A model predictive controller (MPC) is employed to determine optimal dosages with respect to the thyroid hormone concentrations for each type of therapy. The results indicate that the L-T3/L-T4 combined therapy is slightly better (in terms of the achieved hormone concentrations) to treat hypothyroidism than the L-T4 monotherapy. In case of a specific genetic variant, namely genotype CC in polymorphism rs2235544 of gene DIO1, the simulation results suggest that the L-T4 monotherapy is better to treat hypothyroidism. In turn, when genotype AA is considered, the L-T3/L-T4 combined therapy is better to treat hypothyroidism. Furthermore, when genotype CC of polymorphism rs225014 (also referred to as c.274A>G or p.Thr92Ala) in the DIO2 gene is considered, the outcome of the L-T3/L-T4 combined therapy is better in terms of the steady-state hormone concentrations (for a T3 setpoint at the upper limit of the reference range of healthy individuals). Finally, the results suggest that two daily intakes of L-T3 could be the best trade-off between stable hormone concentrations and inconveniences for the patient.

[suztango]

Thanks for this. Is the paper saying that for those with DIO1 polymorphism its best to treat with T4 mono therapy? I have DIO1 and I can only take a little T4. The more T4 I take, the worse I feel. (I am now on a majority of T3 medication.)

[diogenes Remembering in reply to suztango]

Yes, it suggests T4 only may be better, but once again, do not take this paper as an individual's anecdote. It is only a statistical trend.

[BB001 in reply to suztango]

You're the same as me. I've too have Dio1 mutations and can take very little T4. I can demonstrate from blood test results spanning years that my fT3/FT4 conversion rate is poor.

My concern is that this statement that T4 is better for patients such as you and I will be applied on a blinkered basis as a blanket policy for all such patients, even when it patently doesn't apply. Same as currently happens for the requirement for TSH to be in range even if taking T3 which has a suppressive effect on TSH.

[Nat107]

Hi Diogenes thank you for that information, I have DIO1 gene rs2235544 mine being A/C s and feel awful on t4 Levothyroxine alone is this because of one faulty gene tia

[diogenes Remembering in reply to Nat107]

This paper talks about the gene in question:

08 Aug; 93(8): 3075–3081.Published online 2008 May 20. doi: 10.1210/jc.2008-0397

PMCID: PMC2515080

PMID: 18492748

A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine

Vijay Panicker, Christie Cluett, Beverley Shields, Anna Murray, Kirstie S. Parnell, John R. B. Perry, Michael N. Weedon, Andrew Singleton, Dena Hernandez, Jonathan Evans, Claire Durant, Luigi Ferrucci, David Melzer, Ponnusamy Saravanan, Theo J. Visser, Graziano Ceresini, Andrew T. Hattersley, Bijay Vaidya, Colin M. Dayan, and Timothy M. Frayling

Abstract

Introduction: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones.

Methods: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T4 replacement. Suggestive findings were taken forward into three additional studies in people not on T4 (total n = 2513) and metaanalyzed for confirmation.

Results: A SNP in the DIO1 gene, rs2235544, was associated with the free T3 to free T4 ratio with genome-wide levels of significance (P = 3.6 × 10−13). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T3/T4 ratio and free T3 and decrease in free T4 and rT3. There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels.

Conclusions: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T3 to free T4. This should prove a valuable tool to assess the relative effects of circulating free T3 vs. free T4 on a wide range of biological parameters.

[Nat107 in reply to diogenes]

Thank you very much Diogenes

[BB001 in reply to Nat107]

You're the same as me and Suztango. There's obviously more to it than 'faulty Dio1 gene mutation means your ok on T4', because we're all not!

[Nat107 in reply to BB001]

Totally agree

[helvella Administrator Thyroid UK]

It will be one significant edition of Frontiers.

I think it interesting that there is a specific case which might be better treated by L-T4 monotherapy.

Do you, or the authors, have percentage of population figures for each of the identified cases?

[diogenes Remembering in reply to helvella]

I haven't but Johannes may.

[jgelliss]

Diogenes this is amazing . For many that can identify which category they fall into it can be very helpful. But for those of us that don't know or unsure it's a bit like shooting in the dark.

[Musicmonkey]

I have DIO1 polymorphism rs2235544 1 54375570 A (defective) C (no defect) Heterozygous

I have DIO2 polymorphism

rs225014 14 80669580 T (defective) C (no defect) Heterozygous

From the information above, I am unsure whether one defective DIO1 means T4 treatment is better or not, but it is certainly contradicted my my DIO2 genetic polymorphism.

I started on combination therapy 6 years ago and it changed my life. However my specialists don't understand enough about treating my condition, so I am under constant threat of having my T3 either removed or reduced. Currently I am on 30 mcg T3 (split into 3 doses) and 25 mcg of T4 daily.

The information above should help me explain things more scientifically hopefully.

Thank you for sharing diogenes