Skip to main content

Undertreated hypothyroidism due to calcium or iron supplementation corrected by oral liquid levothyroxine

Abstract

Purpose

The aim of this study was to assess whether oral liquid levothyroxine would correct tablet levothyroxine malabsorption induced by calcium or iron, two sequestrants of levothyroxine.

Methods

Nineteen adult hypothyroid patients with tablet levothyroxine malabsorption caused by calcium and/or iron supplements were switched from tablet to liquid levothyroxine at the same dose. Primary outcomes were: (1) significantly lower mean serum thyroid-stimulating hormone with the liquid compared with the tablet formulation, and (2) significantly greater rate of serum thyroid-stimulating hormone less than or equal to 4.12 or 2.5 mU/L.The mean follow-up was 25.2 ± 16.5 weeks.

Results

TSH was lower with liquid levothyroxine compared with tablet levothyroxine (7.48 ± 5.8 vs. 1.95 ± 1.3 mU/L, P < 0.001), both in the calcium group (8.74 ± 7.2 vs. 2.15 ± 1.4, P < 0.001) and iron group (8.74 ± 7.2 vs. 1.68 ± 0.9, P < 0.001). Thyroid-stimulating hormone levels ≤4.12 mU/L in all patients, calcium group and iron group were more frequent post-switch (95, 87 and 100%) compared to pre-switch (26, 22 and 29%, P < 0.001), and so were thyroid-stimulating hormone levels ≤2.50 mU/L (66, 59 and 76% compared to 5, 9 and 0%, P < 0.001). The pattern held comparing the first liquid levothyroxine thyroid-stimulating hormone levels and the first tablet levothyroxine thyroid-stimulating hormone levels or the corresponding rates of thyroid-stimulating hormone levels below the target.

Conclusions

Liquid levothyroxine is resistant to the sequestration by calcium or iron. The high rate of thyroid-stimulating hormone normalization already at the first check (6–8 weeks) should avoid frequent adjustments in levothyroxine doses and assays of thyroid-stimulating hormone, with consequent financial savings.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. A. Garmendia Madiaraga, S. Santos Palacios, F. Guillén-Grima, J.C. Galofré, The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J. Clin. Endocrinol. Metab. 99, 923–931 (2014)

    Article  Google Scholar 

  2. J.G. Hollowell, N.W. Staehling, W.D. Flanders, W.H. Hannon, E.W. Gunter, C.A. Spencer, L.E. Braverman, T.S.H. Serum, T(4), and thyroid antibodies in the United States population (1988 to 1994): national health and nutrition examination survey (NHANES III). J. Clin. Endocrinol. Metab. 87, 489–499 (2002)

    CAS  Article  PubMed  Google Scholar 

  3. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I. Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber, American association of clinical E, American thyroid association taskforce on hypothyroidism: clinical practice guidelines for hypothyroidism for hypothyroidism in adults: cosponsored by the American association of clinical endocrinologists and the American thyroid association. Thyroid 22, 1200–1235 (2012)

    CAS  Article  PubMed  Google Scholar 

  4. J. Jonklaas, A.C. Bianco, A.J. Bauer, K.D. Burman, A.R. Cappola, F.S. Celi, D.S. Cooper, B.W. Kim, R.P. Peeters, M.S. Rosenthal, A.M. Sawka, Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24, 1670–1751 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  5. H.S. Pearce, G. Brabant, L.H. Duntas, F. Monzani, R.P. Peeters, S. Razvi, J.L. Wemeau, 2013 ETA guideline: management of subclinical hypothyroidism. Eur. Thyroid J. 2, 215–228 (2013)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. H.B. Burch, K.D. Burman, D.S. Cooper, J.V. Hennessey, A 2013 survey of clinical practice patterns in the management of primary hypothyroidism. J. Clin. Endocrinol. Metab. 99, 2077–2085 (2014)

    CAS  Article  PubMed  Google Scholar 

  7. Medicines Use and Spending Shifts. A Review of the Use of Medicines in the U.S. in 2014 https://www.imshealth.com/files/web/IMSH%20Institute/Reports/Medicines_Use_and_Spending_Shifts/Medicine-Spending-and-Growth_1995-2014.pdf Accessed 30 Aug 2016

  8. N.W. De Jong, G.M. Baljet, Use of T4, T4 +T3, and T3 in the Dutch population in the period 2005-2011. Eur. Thyr. J. 1, 135–136 (2012)

    Article  Google Scholar 

  9. R. Vita, P. Fallahi, A. Antonelli, S. Benvenga, The administration of L-thyroxine as a soft gel capsule or liquid solution. Expert Opin. Drug Deliv. 11, 1103–1111 (2014)

    CAS  Article  PubMed  Google Scholar 

  10. C. Virili, P. Trimboli, F. Romanelli, M. Centanni, Liquid and softgel levothyroxine use in clinical practice: state of the art. Endocrine 54, 3–14 (2016)

    CAS  Article  PubMed  Google Scholar 

  11. A.M. Formenti, G. Mazziotti, R. Giubbini, A. Giustina, Treatment of hypothyroidism: all that glitters is gold? Endocrine 52, 411–413 (2016)

    CAS  Article  PubMed  Google Scholar 

  12. S. Benvenga, When thyroid hormone replacement is ineffective? Curr. Opin. Endocrinol. Diabetes Obes. 20, 467–477 (2013)

    CAS  Article  PubMed  Google Scholar 

  13. P.N. Taylor, A. Iqbal, C. Minassian, A. Sayers, M.S. Draman, R. Greenwood, W. Hamilton, O. Okosieme, V. Panicker, S.L. Thomas, C. Dayan, Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern. Med. 174, 32–39 (2014)

    CAS  Article  PubMed  Google Scholar 

  14. N.R. Campbell, B.B. Hasinoff, H. Stalts, B. Rao, N.C. Wong, Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann. Intern. Med. 117, 1010–1013 (1992)

    CAS  Article  PubMed  Google Scholar 

  15. C.R. Schneyer, Calcium carbonate and reduction of levothyroxine efficacy [letter]. JAMA 279, 750 (1998)

    CAS  Article  PubMed  Google Scholar 

  16. N. Singh, P.N. Singh, J.M. Hershman, Effect of calcium carbonate on the absorption of levothyroxine. JAMA 283, 2822–2825 (2000)

    CAS  Article  PubMed  Google Scholar 

  17. P. Colucci, C. Seng Yue, M. Ducharme, S. Benvenga, A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur. Endocrinol. 9, 40–47 (2013)

    Article  Google Scholar 

  18. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J. Clin. Endocrinol. Metab. 99, 4481–4486 (2014)

    CAS  Article  PubMed  Google Scholar 

  19. P. Fallahi, S.M. Ferrari, S. Marchi, N. De Bortoli, I. Ruffilli, A. Antonelli, Patients with lactose intolerance absorb liquid levothyroxine better than tablet levothyroxine. Endocrine, (2016) doi:10.1007/s12020-016-1090-7

  20. P. Fallahi, S.M. Ferrari, A. Antonelli, Oral L-thyroxine liquid versus tablet in patients with hypothyroidism without malabsorption: a prospective study. Endocrine 52, 597–601 (2016)

    CAS  Article  PubMed  Google Scholar 

  21. Z. Baloch, P. Carayon, B. Conte-Devolx, L.M. Demers, U. Feldt-Rasmussen, J.F. Henry, V.A. LiVosli, P. Niccoli-Sire, R. John, J. Ruf, P.P. Smyth, C.A. Spencer, J.R. Stockigt, Guidelines Committee, N.A.o.C.B., Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13, 3–126 (2003)

    Article  PubMed  Google Scholar 

  22. L. Wartofsky, R.A. Dickey, The evidence for a narrower thyrotropin reference range is compelling. J. Clin. Endocrinol. Metab. 90, 5483–5488 (2005)

    CAS  Article  PubMed  Google Scholar 

  23. S. Benvenga, L. Bartolone, M.A. Pappalardo, A. Russo, D. Lapa, G. Giorgianni, G. Saraceno, F. Trimarchi, Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid 18, 293–301 (2008)

    CAS  Article  PubMed  Google Scholar 

  24. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. Endocrine 43, 154–160 (2013)

    CAS  Article  PubMed  Google Scholar 

  25. M. Centanni, L. Gargano, G. Canettieri, N. Viceconti, A. Franchi, G. Delle Fave, B. Annibale, Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N. Engl. J. Med 354, 1787–1795 (2006)

    CAS  Article  PubMed  Google Scholar 

  26. I. Sachmechi, D.M. Reich, M. Aninyei, F. Wibowo, G. Gupta, P.J. Kim, Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. Endocr. Pract 13, 345–349 (2007)

    Article  PubMed  Google Scholar 

  27. R. Vita, S. Benvenga, Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule. Endocr. Pract 20, e38–e41 (2014)

    Article  PubMed  Google Scholar 

  28. H.G. Fein, R.S. Rivlin, Anemia in thyroid diseases. Med. Clin. North Am 59, 1133–1145 (1975)

    CAS  Article  PubMed  Google Scholar 

  29. M.C. Perrin, J.P. Blanchet, G. Mouchiroud, Modulation of human and mouse erythropoiesis by thyroid hormone and retinoic acid: evidence for specific effects at different steps of the erythroid pathway. Hematol. Cell Ther. 39, 19–26 (1997)

    CAS  Article  PubMed  Google Scholar 

  30. E. Marqusee, S.J. Mandel, The blood in hypothyroidism, in Werner & Ingbar’s The Thyroid: a clinical and fundamental text, 9th edn., ed. By L.E. Braverman, R.D. Utiger, (Lippincott Williams & Wilkins, Philadelphia, 2005). pp. 803–805

  31. H. Cinemre, C. Bilir, F. Gokosmanoglu, T. Bahcebasi, Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J. Clin. Endocrinol. Metab. 94, 151–156 (2009)

    CAS  Article  PubMed  Google Scholar 

  32. L.H. Duntas, L. Papanastasiou, E. Mantzou, D.A. Koutras, Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism. Exp. Clin. Endocrinol. Diabetes 107, 356–360 (1999)

    CAS  Article  PubMed  Google Scholar 

  33. M. Erdogan, A. Kösenli, S. Ganidagli, M. Kulaksizoglu, Characteristics of anemia in subclinical and overt hypothyroid patients. Endocr. J 59, 213–220 (2012)

    CAS  Article  PubMed  Google Scholar 

  34. G. Skeie, T. Braaten, A. Hjartåker, M. Lentjes, P. Amiano, P. Jakszyn, V. Pala, A. Palanca, E.M. Niekerk, H. Verhagen, K. Avloniti, T. Psaltopoulou, M. Niravong, M. Touvier, K. Nimptsch, J. Haubrock, L. Walker, E.A. Spencer, N. Roswall, A. Olsen, P. Wallström, S. Nilsson, C. Casagrande, G. Deharveng, V. Hellström, M.C. Boutron-Ruault, A. Tjønneland, A.M. Joensen, F. Clavel-Chapelon, A. Trichopoulou, C. Martinez, L. Rodríguez, G. Frasca, C. Sacerdote, P.H. Peeters, J. Linseisen, A. Schienkiewitz, A.A. Welch, J. Manjer, P. Ferrari, E. Riboli, S. Bingham, D. Engeset, E. Lund, N. Slimani, Use of dietary supplements in the European prospective investigation into cancer and nutrition calibration study. Eur. J. Clin. Nutr. 63, S226–S238 (2009)

    CAS  Article  PubMed  Google Scholar 

  35. I. Zamfirescu, H.E. Carlson, Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid 21, 483–486 (2011)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. C.J. Diskin, T.J. Stokes, L.M. Dansby, L. Radcliff, T.B. Carter, Effect of phosphate binder upon TSH and L-thyroxine dose in patients on thyroid replacement. Int. Urol. Nephrol. 39, 599–602 (2007)

    CAS  Article  PubMed  Google Scholar 

  37. A.S. Ettinger, H. Lamadrid-Figueroa, A. Mercado-García, K. Kordas, R.J. Wood, K.E. Peterson, H. Hu, M. Hernández-Avila, M. Téllez-Rojo, Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican women. Nutr. J. 13, 116 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  38. F. Vaisman, C.M. Coeli, L.S. Ward, H. Graf, G. Carvalho, R. Montenegro Jr, M. Vaisman, How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J. Endocrinol. Invest. 36, 485–488 (2013)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This was an independent study, and, thus, we did not receive any funds to perform it.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roberto Vita.

Ethics declarations

Conflict of interest

S.B. was an invited speaker at symposia organized by IBSA. The other authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Benvenga, S., Di Bari, F. & Vita, R. Undertreated hypothyroidism due to calcium or iron supplementation corrected by oral liquid levothyroxine. Endocrine 56, 138–145 (2017). https://doi.org/10.1007/s12020-017-1244-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-017-1244-2

Keywords

  • Hypothyroidism
  • Undertreated hypothyroidism
  • Levothyroxine replacement therapy
  • Malabsorption of levothyroxine