The Differential Diagnosis of Discrepant Thyroid Function Tests: Insistent Pitfalls & Updated Flow-Chart Based on a Long-Standing Experience

[helvella]

We often see members posting results which, at least initially, are odd and maybe make little sense. This paper recognises and discusses such test results.

Quite long and takes some effort to read - but worth it if you are interested.

The Differential Diagnosis of Discrepant Thyroid Function Tests: Insistent Pitfalls and Updated Flow-Chart Based on a Long-Standing Experience

Irene Campi,1,2,* Danila Covelli,3 Carla Moran,4 Laura Fugazzola,1,2 Chiara Cacciatore,1 Fabio Orlandi,5 Gabriella Gallone,6 Krishna Chatterjee,4 Paolo Beck-Peccoz,7 and Luca Persani1,7,*

Abstract

Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHβ) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis. Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging. Results: 88 patients were correctly diagnosed as RTHβ with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHβ (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHβ (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHβ a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHβ showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 μUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHβ patients had small pituitary lesions, leading to unnecessary surgery in one case. Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.

Full paper freely accessible here:

europepmc.org/article/MED/3...

[Agitator23]

Thanks for this Helvella. This is really interesting to me. It's the situation I find myself in. I have an appointment with an endocrinologist next week and I will use some of this information. They seem to be a lot of members of this forum who have blood test results which suggest central hypothyroidism. I think it's much more prevalent than is accepted.

[helvella Administrator Thyroid UK in reply to Agitator23]

My suspicion is that impaired production of TSH is much more common than is appreciated.

It would be somewhat surprising (to me!) if there weren't a scale from very slightly to almost totally impaired. No idea what distribution there might be but, if we even consider the possibility that this is something that can worsen over time, there are likely to be many in the "very slight" category. Enough for TSH to always be a little lower than would otherwise be expected. Enough to push medics to reduce doses.

In time, many of those will move to "slight", "moderate", "moderately severe" or "severe". (Or however else you define the scale.) And this might take many years, even decades.

I'm not saying anything really novel here. There was a study which found that some degree of autoimmune pituitary disease was really widespread in older people. (Seem to remember it was a Swedish paper but have several times failed to find it again.)

This is also why I am so sceptical of the idea that older people should expect higher TSH levels. If there is a process - whether it happens in all of us or only a significant percentage - where TSH would be expected to drop over time, the fact that we see rising TSH actually implies a worse situation. If your pituitary doesn't keep TSH "normal" due to impairment, what does it mean that your TSH actually rises above "normal"?

Imagine when thyroid levels are OK, that person only produces enough TSH to register 0.5 where a person with fully functioning pituitary would be expected to reach 1.0.

That person then has deterioration of their thyroid such that their TSH rises to 1 - corresponding to 2 for a person with fully functioning pituitary. (Of course, that would be dismissed.) Then up to 5 (corresponding to 10). Yet is is suggested that higher TSH is to be expected in older people...

Obviously, I have just chosen numbers to illustrate - not properly considered and not experimental or researched.

[jgelliss in reply to helvella]

Helvella Thank you for another Great post. It took me many years to come to my realization that symptoms (Cellular) over lab results are much more telling how one feels. One needs to tune in and keep journals of symptoms. This is what mostly helps me even now . Labs always showed that I was in range. Yet Dr's felt that I didn't need further evaluations. I ended up having TT. Lesson learned trust yourself. What you feel is what you feel regardless even if labs are in range.