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Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population: Di@bet.es study

Interesting - patients found to have reduced FT4 and reduced FT3 associated with lower ferritin levels. But without change of TSH.

Surely, if the TSH test is so exquisitely sensitive and is the best test for hypothyroidism, it would reveal the lower FT4 and FT3 levels regardless of ferritin level?

It certainly seems to imply that ferritin measurement (preferably full iron assessment) is required for proper assessment. Indeed, it also seems to suggest that TSH, FT4 and FT3 should be tested in those with low ferritin. Although I am usually highly critical of labs changing what is tested, in this case, automatically doing TSH, FT4 and FT3 might not be a bad idea. (Trouble, of course, if lab has no idea of patient background.)

Odd that it should crop up in what appears to be diabetes research...

Hypothyroxinemia = low T4 blood level

Hypotriiodothyroninemia = low T3 blood level

Sci Rep. 2018 Apr 26;8(1):6571. doi: 10.1038/s41598-018-24352-9.

Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population: Di@bet.es study.

Maldonado-Araque C1, Valdés S2,3, Lago-Sampedro A1,4, Lillo-Muñoz JA5, Garcia-Fuentes E6,7, Perez-Valero V5, Gutierrez-Repiso C1,8, Goday A9, Urrutia I4,10, Peláez L1, Calle-Pascual A4,11, Castaño L4,10, Castell C12, Delgado E13,14,15, Menendez E13,14,15, Franch-Nadal J4,16, Gaztambide S4,17, Girbés J18, Ortega E7,19, Vendrell J4,20, Chacón MR21, Chaves FJ4,22, Soriguer F1,4, Rojo-Martínez G1,4.

Author information

1 Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain.

2 Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain. sergio.valdes@hotmail.es.

3 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. sergio.valdes@hotmail.es.

4 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.

5 UGC de Laboratorio (Bioquímica). Hospital Regional Universitario de Málaga, Málaga, Spain.

6 UGC de Aparato Digestivo. Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain.

7 CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.

8 UGC de Endocrinología y Nutrición. Hospital Universitario Virgen de la Victoria. IBIMA, Málaga, Spain.

9 Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona, Spain.

10 Hospital Universitario Cruces, BioCruces, UPV/EHU, Barakaldo, Spain.

11 Department of Endocrinology and Nutrition, Hospital Universitario S. Carlos de Madrid, Madrid, Spain.

12 Public Health Agency of Catalonia, Department of Health, Barcelona, Spain.

13 Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Oviedo, Spain.

14 Department of Medicine, University of Oviedo, Hospital Central de Asturias, Oviedo, Spain.

15 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.

16 EAP Raval Sud, Institut Català de la Salut, Red GEDAPS, Primary Care, Unitat de Suport a la Recerca (IDIAP - Fundació Jordi Gol), Barcelona, Spain.

17 Department of Endocrinology and Nutrition, Hospital Universitario Cruces - UPV-EHU, Baracaldo, Barcelona, Spain.

18 Diabetes Unit, Hospital Arnau de Vilanova, Valencia, Spain.

19 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.

20 Department of Endocrinology and Nutrition, Hospital Universitario Joan XXIII, Institut d'Investigacions Sanitaries Pere Virgili, Tarragona, Spain.

21 Joan XXIII University Hospital. IISPV., Tarragona, Spain.

22 Genomic Studies and Genetic Diagnosis Unit, Fundación de Investigación del Hospital Clínico de Valencia-INCLIVA, Valencia, Spain.

Abstract

Previous studies have suggested that iron deficiency (ID) may impair thyroid hormone metabolism, however replication in wide samples of the general adult population has not been performed. We studied 3846 individuals free of thyroid disease, participants in a national, cross sectional, population based study representative of the Spanish adult population. Thyroid stimulating hormone (TSH), free thyroxin (FT4) and free triiodothyronine (FT3) were analyzed by electrochemiluminescence (E170, Roche Diagnostics). Serum ferritin was analyzed by immunochemiluminescence (Architect I2000, Abbott Laboratories). As ferritin levels decreased (>100, 30-100, 15-30, <15 µg/L) the adjusted mean concentrations of FT4 (p < 0.001) and FT3 (p < 0.001) descended, whereas TSH levels remained unchanged (p = 0.451). In multivariate logistic regression models adjusted for age, sex, UI, BMI and smoking status, subjects with ferritin levels <30 µg/L were more likely to present hypothyroxinemia (FT4 < 12.0 pmol/L p5): OR 1.5 [1.1-2.2] p = 0.024, and hypotriiodothyroninemia (FT3 < 3.9 pmol/L p5): OR 1.8 [1.3-2.6] p = 0.001 than the reference category with ferritin ≥30 µg/L. There was no significant heterogeneity of the results between men, pre-menopausal and post-menopausal women or according to the iodine nutrition status. Our results confirm an association between ID and hypothyroxinemia and hypotriiodothyroninemia in the general adult population without changes in TSH.

PMID: 29700318

DOI: 10.1038/s41598-018-24352-9

ncbi.nlm.nih.gov/pubmed/297...

29/04/2018 08:14 Edited to add from the full paper:

ID may alter the synthesis of thyroid hormones by multiple mechanisms: ID induces ineffective erythropoiesis, thus reducing the transport of oxygen to the different tissues required for multiple enzymatic reactions. ID has also been shown to increase in-vitro hepatic reverse triiodothyronine deiodination, suggesting that under conditions of ID, thyroid hormones tend to be metabolized by an inactivating route. Also, ID may lower thyroperoxidase activity and therefore interfere with the synthesis of thyroid hormones. Although these mechanisms described could be explanatory, our results suggest the implication of additional hypothalamic-pituitary mechanisms, given the lack of TSH response to the decrease in the levels of peripheral hormones. Accordingly, the experiments carried out by Tang et al. in iron deficient rats subjected to low temperatures, showed decreased levels of TSH, FT4 and FT3, which reverted to normal if stimulated with synthetic thyrotropin releasing hormone (THR), suggesting that ID may impair the hypothalamic secretion of THR. In line with this observation, the study from Eftekhari in Iranian adolescents with ID, showed that despite increases in FT3 and FT4 concentrations, the TSH concentration was unaffected by iron supplementation. Since no separate mechanism on its own fully explains the results found in our study, it is likely that a combination of mechanisms may be involved.

Link to full paper:

nature.com/articles/s41598-...

29/04/2018 10:26 - Added this older abstract which appears relevant:

Effects of cold exposure or TRH on the serum TSH levels in the iron-deficient rat.

Tang F1, Wong TM, Loh TT.

Author information

1 Department of Physiology, Faculty of Medicine, University of Hong Kong.

Abstract

Normal and iron-deficient rats were exposed to cold at 4 degrees C for 1 hr or 5 hrs and the serum TSH, T3 and T4 levels were compared with those in rats kept at room temperature (20 degrees C). There was a rise in serum TSH, T3 and T4 levels in response to 1 hr and 5 hrs of cold exposure in normal, but not in iron-deficient rats. Although pituitary TSH contents were lower in iron-deficient rats, the increases in serum levels of TSH following administration of TRH were similar in both normal and iron-deficient rats. The results suggest that the inability to respond to cold in iron-deficient rats may be due to a reduction in the release of TRH from the hypothalamus.

PMID: 3146537

DOI: 10.1055/s-2007-1010899

ncbi.nlm.nih.gov/pubmed/314...

29 Replies
oldestnewest

It's what we've discovered by experience but here it is confirmed in scientific research.

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True!

Btw, is there a group for iron deficiency?

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If you search communities:

healthunlocked.com/find

... you could enter iron, anemia or anaemia - and not find a dedicated iron deficiency site. The opposite - haemochromatosis, some "other" anaemias - sickle cell and pernicious, but not what you are asking for - so far as I could see.

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Will read it sometime. Here is the full study nature.com/articles/s41598-... .

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Thanks Jim.

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Does seem to hammer another nail into coffin for TSH as 'gold standard' diagnostic tool.

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interesting. So does this suggest that improved iron levels should result in a better thyroid hormones metabolism? what causes the iron deficiency in the first place?

I've had very low levels of iron for a long time (even before thyroid issues were suspected), and despite supplementing, they take a long time to raise, but seem drop really quickly. So I've wondered if low hormones impair fixation or absorption of iron.... Also I seem to be ok antibody wise, so it's not hasimotos, plus I've a strong Spanish heritage, if genetics are in any way involved! 🤔

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Cause is not discussed in the abstract - but is obviously what we want to know.

I am convinced that low hormones can cause low iron - my simplistic approach says:

Low hormones mean that the high-energy process of producing stomach acid is impaired. The reduced acidity makes absorption of iron less effective. Hence lowered iron unless on a diet which is high in readily available iron.

On the other hand, if low iron reduces the ability of the hypothalamus to produce TRH, or the ability of the pituitary to produce TSH, then we might see what has been observed in this study.

If we concluded that low iron causes lowered thyroid hormones, and low thyroid hormones cause low iron, I'd expect to see people with low thyroid hormones, low iron, and TSH not rising as much as would have been predicted. Such people would not be diagnosed as hypothyroid until their pituitary does eventually raise TSH despite the low iron levels.

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helvella just a thought, but recently my son's Levo was raised by 25mcg and his very reasonable 700+ B12 level has shot up to 1,500. His Levo is now a little over range and, as usual his FT3 was not done. Hopefully will see Endo in June. Just thought this might be the kind of thing you are thinking of. All this has happened when he was not even taking B12. Thanks for the post.

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I have now read some of the original paper - including their discussion as to cause. See the original post. Am glad I included TRH in my first response to you! :-)

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My thyroid specialist here in Denmark told me that my ferritin level must be 70/80 in order for my NDT to work. Last year, I presented with RT3 and a ferritin level of 7. In recent months after taking iron supplements religiously, RT3 has improved and ferrtin now at 24. I still can’t raise it above 24 though. Cannot lose weight, terrible headaches and lethargic.

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I often suggest trying sources of iron such as haem and ferritin supplements. Both are absorbed in the gut by different pathways.

I am always concerned about the hard statement of ferritin being 70 or over. Ferritin is not the perfect indicator of iron and it could well be that if full iron investigations were done, we'd come up with a different conclusion.

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Agreed. At one time my ferritin was 150. I was not supplementing and still felt I was anemic. My FT3 and FT4 were near the bottom as well.

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My ferritin has dropped from 60 to 35 in last 6 months. No wonder I feel rough. Heart racing and pounding wakes me up within 30 mins of going to sleep every night. Sometimes throughout the night. Is it worth an adrenal test?

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Perhaps the appropriate approach to increasing iron levels would be the best idea?

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Trying to raise ferritin but I wasn’t sure if that explained the racing heart or whether it could be adrenal related. I don’t have Hashimotos so am unsure whether the same advice applies to me in respect of adrenals

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My understanding of the impact of adrenal issues on the heart is poor to non-existent - I hope someone else can reply here! :-)

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I had that problem when I was on too low of a thyroid hormone. Are you sure you are not hypothyroid? The adrenals could be involved when your cortisol is very high and has an impact on your thyroid hormone causing it to lower.

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Could be high adrenaline. Due to either low thyroid hormones or low blood sugar. Try bed time snack before sleeping or when you wake up have a sip of OJ or something. Small thing but might make a difference. But it could be the low iron as you say. I know when my iron is low I get fast heartbeat even just by going upstairs.

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Interesting article. Would be good to know if results were different in people with Hashis. I have always had high ferritin but T4 and T3 low in range and under range TSH, so I don't seem to fit the bill!

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I am convinced that there are many causes of the pituitary producing apparently insufficient TSH. I'd even add a question - could excess iron also cause this? Guess this could be asked of the Haemochromatosis people!

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In idiopathic haemochromatosis in males - a mixed picture:

Acta Endocrinol (Copenh). 1981 Oct;98(2):178-83.

Pituitary function in idiopathic haemochromatosis: hormonal study in 36 male patients.

Charbonnel B, Chupin M, Le Grand A, Guillon J.

Abstract

Thirty-six male patients with idiopathic haemochromatosis were subjected to measurements of basal plasma values of testosterone, LH and FSH and to an LRH test. Nineteen were also subjected to basal plasma determinations of T3, T4, cortisol, TSH and prolactin and to a TRH test. In 11 cases GH values were measured before, during and after an arginine infusion. Seventeen patients were found to hae low levels of testosterone, LH and FSH, and no gonadotrophin responses to LRH. Seventeen others had normal levels of these three hormones, with normal responses to LRH. The two remaining patients had normal testosterone values but very increased gonadotrophin values: a fact which remains unexplained. Basal levels of prolactin, GH, T3, T4, and TSH were normal: cortisol levels were either normal or increased in cases of poorly controlled diabetes. Prolactin responses to TRH were always normal. TSH responses to TRH were impaired in 2 cases, and GH responses to arginine in 3 cases. Considering that other factors may be involved in the few impairments found in TSH and GH stimulations, it is concluded that the only indisputable pituitary insufficiency in about half of the cases of idiopathic haemochromatosis is gonadotrophic.

PMID: 694282

ncbi.nlm.nih.gov/pubmed/679...

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Very interesting reply Helvella, thank you.

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My brother’s test results last year showed that his TSH was 1.78 while FT4 was 28% in range. Just recently his TSH is around the same, like 1.20 but T4 is near two thirds of range and T3 is half way in range! Since being found to have iron deficiency he’s been supplementing ever since.

I was planning to and still am going to rerun his tests next week to confirm the results, T4/T3 was called in by the doc to be run on 4th day of lab still holding he blood sample (they only ran TSH first). I assumed lab interference or that they accidentally ran someone else’s blood sample lol!

Now I come across this article. Pretty damn interesting alright!

I do wonder if my serum iron is really as good as my ferritin has suggested it to be all these years. Will get a full iron test done soon along with the thyroid tests. But my ferritin has been like 200, then dropping to 150 and just in past few months dropping to 100 and now recently 70. As I’m overweight I wonder if the serum iron is normal despite the decent stores.

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Thought I’d add and I think this is important.

While the chicken or egg question of the thyroid and iron is a good one, there are other causes of slowed metabolism and/or poor digestion.

Intestinal bowel disease can decrease absorption, and with the reduced iron, further reduction of thyroid hormones can present low thyroid symptoms. There are also other endocrine problems other than the thyroid that can have similar effects on metabolism.

One thing I forgot to mention about my younger brother is that the Endo ran a bunch of tests and his LH is above the range, FSH is high-normal and testosterone is low-normal. While we haven’t seen the Endo for the follow up yet from what I’ve read this is indicative of primary hypogonadism, meaning that my brother’s low bio active testosterone probably decreased his metabolism.

I was pretty convinced he had a thyroid problem but still need to investigate further. Need to rerun the frees. Interestingly, his TPOab was 33 (<35). Would need an ultrasound of the thyroid but not sure if doc would give us that.

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This could suggest that ferritin is a useful marker for hypothyroidism, given other supporting symptoms. This is what is wanted, a compilation of markers that are on the face of it nonthyroidal to give a suite of tests automatically done eg cholesterol, SHBG, alkaline phosphatase to confirm hypothyroidism. This list is a valuable assemblage of indirect indicators for thyroid dysfunction.

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I know cholesterol goes up when hypothyroid, but what about SHBG and alkaline phosphatase? Do they go up or down?

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Down

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Thank you. :)

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