maandag 10 september 2012

Inzicht in schildklierhormoon: slechts het begin, niet het einde

In 2004 en 2005 verschenen twee artikelen van onder meer P. Saravanan en C. M. Dayan op de site Hot Thyroidology van de European Thyroid Association en in The Journal of Clinical Endocrinology & Metabolism. Beschreven werd hoe in die jaren het inzicht van de werking van schildklierhormoon en de effecten van vervangend schildklierhormoon in feite slechts aan het begin stond. Met alle ontwikkelingen in de laatste jaren en nu zelfs met de publicatie van een (experimentele) Europese richtlijn voor de behandeling met L-T4 en L-T3, is er alle reden om aandacht te besteden aan deze artikelen. Zoals Saravanan en Dayan stelden: het was geen einde, maar een begin.

Understanding thyroid hormone action and the effects of thyroid hormone replacement – Just the beginning not the end
P Saravanan en CM Dayan

Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial
P Saravanan, DJ Simmons, R Greenwood, TJ Peters en CM Dayan

Future directions

New developments in thyroid hormone biology have indicated multiple levels at which variations in the pathway of thyroid hormone action could have clinically important effects but at present evidence of clinical relevance is limited. To make progress in this area and determine whether inter-individual variations in the pathway of thyroid hormone action contribute to psychological morbidity, predispose to other conditions and/or determine failure to respond adequately to thyroid hormone replacement in some individuals is a complex task.

Progress is required in 4 areas

  1. There is a need for new markers of thyroid action in different tissues. In particular, it will be important to determine whether individuals who respond poorly to thyroid hormone in terms of psychological well-being fail to improve in any more objective measures that could relate to thyroid hormone action e.g. sleep pattern or serotonergic responses. These could then be used to monitor response to intervention more objectively.
  2. Studies are required to identify any variations or polymorphisms in elements of the pathway of thyroid hormone action - e.g. T3/rT3 ratio, deiodinase or transporter polymorphisms - which predict the psychological response to thyroid hormone or correlate with other potentially thyroid hormone related effects (eg sleep parameters, echocardiographic changes or changes in bone turnover).
  3. Future intervention studies with T4 alone or in combination with T3 should be large in order:
    • to carry sufficient power to see any clinical significant effect,
    • to allow correlations to be drawn between response to therapy and baseline measures of thyroid hormone action or metabolism and
    • to be sufficiently long-term enough to enable assessment of the risk to the heart and skeleton of potential overplacement. Such studies also need to be very carefully blinded to distinguish placebo effects from effects attributable to the intervention.
  4. Future studies involving T3 replacement will require careful attention to dosing, dose titration and dosing ratios with T4. We have shown that despite chronic combined T3/T4 therapy wide fluctuations persist in the free T3 levels. Thus, use of new low-dose and slow-release preparations to allow careful monitoring and physiological replacement will be particularly valuable.

Partial substitution of thyroxine (T4) with tri-iodothyronine showed a modest beneficial effect after 3 months. Interestingly, thyroid function ‘drifted’ between 3 and 12 months of follow-up (with a fall in the T3/T4 ratio) and the effect was lost.

Conclusions

Despite 100 years of thyroid hormone replacement, controversy still exists about the optimum replacement therapy for hypothyroid patients. Several recent studies have given insight in to the complex thyroid hormone metabolism. These support the hypothesis that serum and tissue levels of thyroid hormones may diverge significantly and vary between tissues.
The dissatisfaction experienced by some individuals on thyroxine replacement despite normal TSH levels may in part relate to this. If so, it should be seen as a pointer to greater understanding of the action of thyroid hormone and its predisposing effects on morbidity in many conditions rather than an unwelcome clinical frustration. If so, we are the beginning of a road of discovery rather than at the end of an unsuccessful chapter in thyroid hormone replacement.

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