Many thanks Rita for your helpful and educational reply as ever. Thanks also to David Wright who gave a similar perspective.
Yes these patients are primary hypothyroid patient on long term thyroxine replacement. We use TSH as frontline test and if it is below or above the reference range, then free T4 is automatically added and if TSH < 0.2 mU/L then a FT3 is added also. This rule is used for all patients including those on thyroxine replacement hence I see this phenomenon of relatively low FT3 compared to FT4 very frequently.
Rita raised an interesting point that TSH responds differently to exogenous thyroxine compared to endogenous thyroxine, but I thought that T4 has to change to T3 at tissue level to exert its effect i.e T4 is a pro-hormone, hence any suppression of TSH is due to excessive T3 effect but its normal to low serum level in such patients doesn't reflect this explanation, unless tissue FT3 concentration at hypothalamic-pituitary level is completely different from serum FT3. David also mentioned the fact that the intact thyroid gland secrete up to 30% of the peripheral T3 poole and this is lacking in primary hypothyroid patients.
I would welcome
further debate on this interesting issue.
Mohammad
________________________________
From: Rita Horvath <
[log in to unmask]>
To:
[log in to unmask] Sent: Thursday, March 7, 2013 2:45 AM
Subject: Re: Thyroxine over-replacement
Mohammad, I copy here the relevant extract from a book chapter that I wrote in 2008 in the book Evidence-based Medical Monitoring (Eds: Paul Glasziou, Les Irwig, Jeffrey Aronson). It might help in explaining the below phenomenon. If interested, happy to send to you the whole book chapter with the below quoted ref-s.
Assuming that these are primary
hypothyroid patients on T4 for some time, the real Qs are
- are these patients with these values clinically euthyroid and well?
- Why were all these tests requested (if these are simple primary hypothyr. patients)? Or are these patients who were recently started on T4?
NB: Due to the logarithmic relationship between TSH and fT4 we all think that TSH is the best and most sensitive marker of thyroid status, and thus TSH is the first line recommended test for monitoring patients on levothyroxine. I believe the picture is more complex than we think as TSH reacts somewhat differently to exogenous T4 replacement than to endogenous T4-T3 conversion. We use TSH as the best marker as we simply do not have a better one so far to assess the tissue effects of thyroid hormones.
Hope the below helps rather than confuses
many…J
Suggest also see this link for the most recent guideline on the topic:
http://aace.metapress.com/content/b67v7mk73g3233n2/fulltext.pdfExtract from the book chapter:
In the absence of a true and reliable reference standard for the assessment of thyroid status at the tissue or organ level, it has become challenging to prove whether TSH is an equally good marker of exogenous as well as of endogenous T4 metabolism. When considering this point, it has to be remembered that exogenous thyroxine has a different effect on thyroid status, and patients taking levothyroxine commonly have supranormal free T4 (the key regulator of TSH feedback), while free T3 (the key regulator of tissue effects) is normal [35, 36, 37, 41]. Therefore, logic may dictate that T3 or free T3 would be a better marker of thyroid status at the tissue and end-organ levels.
In practice, many clinicians use a combination of peripheral hormone and TSH assays, particularly when poor patient adherence to therapy is suspected [23, 26, 38, 53, 54].
Several pre-analytical, biological, and analytical problems need to be considered when using free T4 or free T3 measurements during levothyroxine replacement. Free T4 concentrations remain raised by about 13%for up to 6–9 hours after administration of a dose of levothyroxine and thus fluctuate more, owing to variations in sampling times during clinic visits [13, 14]. Therefore, if free T4 values are to be measured, the daily dose should be withheld before phlebotomy. Even though free hormones have lower intra-individual biological variation than TSH, interpretation of values is hampered by the fact that each patient has an individual set-point for maintaining euthyroidism and a normal TSH feedback response. Therefore, the wide population reference ranges cannot be used when
individuals are monitored and free hormone concentrations are not informative without another marker of thyroid status (for example, TSH).
In summary:
Peripheral thyroid hormone measurements in isolation are unhelpful, as the individual set-point of patients for maintaining the euthyroid state is unknown. Furthermore, these tests are prone to pre-analytical variations which could grossly mislead therapeutic decisions.
The TSH assay in isolation is not the most ideal test for monitoring, as it has large biological variation and thus a relatively small signal-to-noise ratio. In addition, it reflects the effect of exogenous T4 on the pituitary secretion of TSH rather than its effects on tissues and end-organ function. In the absence of appropriate evidence, further studies are needed on the diagnostic usefulness of TSH alone or in combination with free T4 or T3/free T3 measurements in monitoring patients taking levothyroxinereplacement
and in predicting treatment outcomes.
Kind regards, Rita
Prof. Andrea Rita Horvath, MD, PhD, EurClinChem, FRCPath, FRCPA
Past President of the European Federation of Clinical Chemistry and Laboratory Medicine
Clinical Director, SEALS North, Department of Clinical Chemistry
Level 4, Campus Centre, Prince of Wales Hospital
Barker Street, Randwick, NSW 2031, Sydney, Australia
Tel: (+612)-9382 9078
Fax: (+612)-9382 9099
Mobile No: (+61)-404 027 843
From:Clinical biochemistry discussion list [mailto:[log in to unmask]] On Behalf Of Mohammad Al-Jubouri
Sent: Thursday, 7 March 2013 4:06 AM
To:
[log in to unmask]Subject: Thyroxine over-replacement
We may have discussed this in the past in more than one occasion, but here we go again: exogenous T4 replacement is associated with relatively lower serum FT3 compared to FT4, these are three set of results for 3 patients on
thyroxine replacement as examples:
1st patient: TSH < 0.05 mU/L, FT4 23.3 pmol/L and FT3 3.0 pmol/L
2nd patient: TSH 0.17 mU/L, FT4 25.1 pmol/L and FT3 4.4 pmol/L
3rd patient: TSH < 0.05 mU/L, FT4 25.1 pmol/L and FT3 5.7 pmol/L
In all 3 patients, Free T4 is higher than the reference range of (10 - 20) and TSH is suppressed, but FT3 is within the reference range of (3.5 - 6.5) in two patients and less in one patient. So is this thyroxine over-replacement even though the active thyroid hormone FT3 is not raised?
thanks
Mohammad
Dr. M A Al-Jubouri, MB ChB, MSc, FRCP Edin, FRCPath
Consultant Chemical Pathologist
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