Iodide Transport Defect and Breast Milk Iodine

in European Thyroid Journal
Authors:
Tetsuya Mizokami Tajiri Thyroid Clinic, Kumamoto

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Shuji Fukata Tajiri Thyroid Clinic, Kumamoto
Department of Medicine, Kuma Hospital, Kobe

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Akira Hishinuma Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, Japan

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Takahiko Kogai Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, Japan

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Katsuhiko Hamada Tajiri Thyroid Clinic, Kumamoto

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Tetsushi Maruta Tajiri Thyroid Clinic, Kumamoto

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Kiichiro Higashi Tajiri Thyroid Clinic, Kumamoto

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Junichi Tajiri Tajiri Thyroid Clinic, Kumamoto

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*Tetsuya Mizokami, MD, Tajiri Thyroid Clinic, 2-6-3 Suizenji, Kumamoto 862-0950 (Japan), E-Mail tetsuyamizokami@hotmail.com
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Background: Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS, and iodine for thyroid hormone synthesis is thereby supplied to the infant in the breast milk. Case Description: A 34-year-old Japanese woman was diagnosed with ITD caused by a homozygous NIS gene mutation T354P. She had begun treatment of primary hypothyroidism with levothyroxine at the age of 5. She delivered a baby at the age of 36. The iodine concentration in her breast milk was 54 µg/l. She took a 50-mg potassium iodide tablet daily to supply iodine in the breast milk, starting on the 5th day postpartum. Her breast milk iodine concentration increased to 90 µg/l (slightly above the minimum requirement level). The patient weaned her baby and stopped taking the daily potassium iodide tablet 6 weeks postpartum, and the baby began to be fed with relatively iodine-rich formula milk. The baby's thyroid function remained normal from birth until 6 months of age. Conclusion: Possible iodine deficiency in the infant breast-fed by an ITD patient should be kept in mind. Prophylactic iodine supplementation is essential for such infants in order to prevent severe iodine deficiency.

Abstract

Background: Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS, and iodine for thyroid hormone synthesis is thereby supplied to the infant in the breast milk. Case Description: A 34-year-old Japanese woman was diagnosed with ITD caused by a homozygous NIS gene mutation T354P. She had begun treatment of primary hypothyroidism with levothyroxine at the age of 5. She delivered a baby at the age of 36. The iodine concentration in her breast milk was 54 µg/l. She took a 50-mg potassium iodide tablet daily to supply iodine in the breast milk, starting on the 5th day postpartum. Her breast milk iodine concentration increased to 90 µg/l (slightly above the minimum requirement level). The patient weaned her baby and stopped taking the daily potassium iodide tablet 6 weeks postpartum, and the baby began to be fed with relatively iodine-rich formula milk. The baby's thyroid function remained normal from birth until 6 months of age. Conclusion: Possible iodine deficiency in the infant breast-fed by an ITD patient should be kept in mind. Prophylactic iodine supplementation is essential for such infants in order to prevent severe iodine deficiency.

What Is Known about This Topic?

• Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS.

What Does This Case Report Add?

• The iodine concentration in an ITD patient's breast milk is low. Possible iodine deficiency in the infant breast-fed by an ITD patient should be kept in mind.

Introduction

Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations [1]. NIS mediates active iodide transportation, and plays an important role in concentrating iodide in the thyroid. NIS is also expressed in several other tissues, including the salivary glands, placenta, and lactating mammary gland [1]. In the lactating mammary gland, NIS concentrates iodide, and the infant is thereby supplied with iodine in the breast milk. We herein report on a pregnant ITD patient homozygous for an NIS mutation. She took potassium iodide tablets after delivery to supply iodine to her baby in the breast milk. This is the first report, to our knowledge, to focus on measurement of the breast milk iodine concentration (BMIC) in a patient with ITD.

Materials and Methods

Breast milk samples of 13 lactating Japanese women served as controls, with their consent. Three women had hypothyroidism treated with levothyroxine (LT4) (2 due to post 131I therapy of Graves' hyperthyroidism, and one due to postsurgical treatment of Graves' hyperthyroidism). One patient had euthyroid Hashimoto's thyroiditis and one had no thyroidal abnormalities. Eight patients with Graves' hyperthyroidism were treated with potassium iodide (5 at 50 mg per day, and 3 at 50 mg every other day).

BMIC was determined by Hitachi Chemical Clinical Laboratory (Tokyo, Japan). Breast milk was ultracentrifuged with a molecular weight cutoff of 50,000 Da. The iodine concentration in the clear fluid of the whey layer was measured employing a commercial iodine measurement kit (Hitachi Chemical Co., Ltd., Tokyo, Japan) [2]. This kit has adopted an ammonium persulfate digestion microplate method using the Sandell-Kolthoff reaction in a sealing cassette [3]. The coefficient of variation was less than 15%, the detection limit 25 μg/l, and the range of measurement 25-500 μg/l [2]. The accuracy of the kit was 80-120% of the value determined by inductively coupled plasma mass spectrometry [2]. Samples showing values over the measurement range were remeasured after dilution to obtain quantitative results.

Case Report

Our patient was the sister of a previously reported Japanese man with ITD with the same homozygous NIS mutation [4]. Their parents were cousins, the mother being heterozygous for the NIS mutation. The patient was diagnosed with primary hypothyroidism at age 5. She was treated with LT4, but her medication adherence was poor. Soon after her brother's hypothyroidism was attributed to ITD due to the NIS mutation, she visited our clinic to undergo a detailed thyroid examination at age 34. She was 154 cm in height and 60 kg in weight. She had no apparent mental deficits. On ultrasonography, the thyroid was small and contained several small hypoechoic nodules. Serum free T4 and thyrotropin (TSH) levels were 13.0 pmol/l (reference interval: 11.6-23.2) and 160.35 mIU/l (reference interval: 0.22-3.30), respectively, with prescription of LT4 150 µg/day. Serum antithyroid peroxidase and antithyroglobulin antibodies were negative. The serum thyroglobulin level was 82.8 ng/ml. Neither the thyroid nor the salivary glands were visualized by 99mTcO4- scintigraphy. We genetically tested for the NIS gene mutation with her consent. ITD due to homozygous NIS mutation T354P was diagnosed. She became pregnant at age 36 and gave birth to a baby girl weighing 2,270 g by caesarean section at 38 gestational weeks. Free T4 and TSH levels were 18.0 pmol/l and 3.49 mIU/l in the umbilical cord serum, and the baby's serum levels were 24.5 pmol/l and 2.93 mIU/l on the 5th day after birth. The patient's BMIC was 54 µg/l. To manage the baby's iodine state, we administered potassium iodide to the patient to supply iodine in the breast milk. She began taking a tablet containing 50 mg of potassium iodide daily on the 5th day postpartum, and BMIC rose to 90 µg/l 3 days thereafter. The patient ceased breast feeding and stopped taking the potassium iodide tablet 6 weeks after delivery, and the baby began to be fed with a relatively iodine-rich commercial formula. The baby's thyroid functions were confirmed to be normal at 2 and 6 months after birth. The patient's serum free T3, free T4, and TSH levels were 3.36 pmol/l (reference interval: 3.38-6.61), 13.0 pmol/l, and 2.660 mIU/l, respectively, with 175 µg/day of oral LT4.

BMIC in the Present Patient and Control Subjects

Figure 1 shows the BMIC of our present patient and the control subjects (n = 13). The BMIC in the lactating Japanese women (n = 5) ranged from 166 to 2,560 µg/l (median 214). The BMIC ranged from 3,150 to 47,000 µg/l (median 28,350) in the patients with Graves' disease treated with 50-mg potassium iodide tablets every 1 or 2 days (n = 8).

Fig. 1
Fig. 1

BMICs of control subjects (n = 13) and the present patient. KI-: group without intake of potassium iodide (n = 5) and the present patient. KI+: group with Graves' disease treated with potassium iodide (n = 8) and the present patient during intake of potassium iodide. Circles: the present patient; dots: controls.

Citation: European Thyroid Journal 5, 2; 10.1159/000446496

Discussion

Our patient had the T354P NIS mutation, which is the most common mutation in Japan. Although this patient did not begin treatment with LT4 during the neonatal period, she had no apparent neurodevelopmental deficits. The clinical features of ITD patients with NIS mutations are heterogeneous, and their broad spectrum of manifestations range from extremely small goiters to huge goiters, and from euthyroidism to overt hypothyroidism [5]. The Japanese people generally consume rather large amounts of iodine in traditional foods. Substantial iodine intake may have compensated for impaired active iodide transport due to the mutated NIS in our present patient. Moreover, there might be partial compensation for the functions of the mutated NIS due to iodide transport through nonspecific channels or carriers, or even via diffusion [6].

The baby is probably heterozygous for the NIS mutation. No patients were reported in her husband's pedigree. Since NIS is located at the apical membrane (maternal side) of placental syncytiotrophoblasts, the efficacy of iodide transport across the placenta is assumed to be decreased in ITD patients with NIS mutations. However, in this case, the baby's thyroid function was normal at birth. Substantial maternal iodine supplementation and the following placental characteristics may have compensated for impaired iodide transport due to the mutated NIS. Although its capacity is much lower than that of the thyroid, the placenta stores iodine to be supplied to the fetus [7]. Additionally, type 3 iodothyronine deiodinase, which is present in the placenta, plays a role in supplying iodine to the fetus [8]. While autoregulation of NIS in the lactating mammary gland seems minimal or absent [9], it is suggested that NIS in the placenta is autoregulated to keep iodide transport unaltered [10]. Finally, several iodide transporters are presumed to be involved in placental transport [10].

The reported median BMIC in lactating women ranges from 35 to 155 μg/l in the United States [11]. BMIC less than 50 μg/l is considered to indicate iodine deficiency [12], and BMIC exceeding 80 μg/l is required for an infant before the commencement of weaning foods [13]. Since the lactating mammary gland with the inactivating NIS mutation is not able to effectively concentrate iodide in breast milk, the BMIC of ITD patients would presumably be low. In fact, our patient's BMIC was 54 µg/l, clearly lower than that of lactating Japanese women in general. Our patient's BMIC increased modestly to 90 μg/l after taking a daily 50-mg potassium iodide tablet, a level just above the minimum iodine requirement. Although NIS is not regulated by TSH in the breast [1], the BMIC in patients with Graves' hyperthyroidism may differ from that in euthyroid or hypothyroid patients. Nevertheless, the BMIC during potassium iodide intake was much lower in this patient than in control subjects with Graves' hyperthyroidism. Infants breast-fed by ITD patients are at risk for developing severe iodine deficiency, especially in iodine-deficient geographic areas. Prophylactic iodine supplementation is essential for such infants in order to prevent severe iodine deficiency. In spite of NIS mutation, the BMIC of ITD patients can be increased above the minimum requirement level by supplying high doses of iodine.

Commercial infant formulas generally contain much lower amounts of iodine than breast milk. The iodine contents of commercial formulas vary considerably among manufacturers as well as among branded product lots. Japanese commercial formulas are not iodized by law. The iodine content in these formulas also warrants attention as some infants are fed only such formulas.

In conclusion, clinicians need to be aware of possible iodine deficiency in the infant breast-fed by an ITD patient.

Disclosure Statement

The authors have no conflicts of interest to disclose.

Footnotes

verified

References

  • 1

    Portulano C, Paroder-Belenitsky M, Carrasco N: The Na+/I- symporter (NIS): mechanism and medical impact. Endocr Rev 2014;35:106-149.

    • Crossref
    • PubMed
    • Export Citation
  • 2

    Package insert of iodine measurement kit (Yodomonit, in Japanese). Hitachi Chemical Co., Ltd. 2012. http://www.info.pmda.go.jp/tgo/pack/21900AMZ00077000_A_01_01 (accessed April 10, 2016).

    • PubMed
    • Export Citation
  • 3

    Ohashi T, Yamaki M, Pandav CS, Karmarkar MG, Irie M: Simple microplate method for determination of urinary iodine. Clin Chem 2000;46:529-536.

    • PubMed
    • Export Citation
  • 4

    Fukata S, Hishinuma A, Nakatake N, Tajiri J: Diagnosis of iodide transport defect: do we need to measure the saliva/serum radioactive iodide ratio to diagnose iodide transport defect? Thyroid 2010;20:1419-1421.

    • Crossref
    • PubMed
    • Export Citation
  • 5

    Kosugi S, Sato Y, Matsuda A, Ohyama Y, Fujieda K, Inomata H, Kameya T, Isozaki O, Jhiang SM: High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. J Clin Endocrinol Metab 1998;83:4123-4129.

    • Crossref
    • PubMed
    • Export Citation
  • 6

    Vulsma T, de Vijlder JJM: Genetic defects causing hypothyroidism; in Braverman LE, Cooper DS (eds): Werner and Ingbar's The Thyroid. A Fundamental and Clinical Text, ed 10. Philadelphia, Lippincott Williams and Wilkins, 2013, pp 535-551.

    • PubMed
    • Export Citation
  • 7

    Burns R, O'Herlihy C, Smyth PP: The placenta as a compensatory iodine storage organ. Thyroid 2011;21:541-546.

    • Crossref
    • PubMed
    • Export Citation
  • 8

    Chan S, Kachilele S, Hobbs E, Bulmer JN, Boelaert K, McCabe CJ, Driver PM, Bradwell AR, Kester M, Visser TJ, Franklyn JA, Kilby MD: Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies. J Clin Endocrinol Metab 2003;88:4488-4495.

    • Crossref
    • PubMed
    • Export Citation
  • 9

    Laurberg P, Nøhr SB, Pedersen KM, Fuglsang E: Iodine nutrition in breast-fed infants is impaired by maternal smoking. J Clin Endocrinol Metab 2004;89:181-187.

    • Crossref
    • PubMed
    • Export Citation
  • 10

    Andersen SL, Nøhr SB, Wu CS, Olsen J, Pedersen KM, Laurberg P: Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition. Eur J Endocrinol 2013;168:723-731.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Leung AM, Pearce EN, Braverman LE: Iodine nutrition in pregnancy and lactation. Endocrinol Metab Clin North Am 2011;40:765-777.

    • Crossref
    • PubMed
    • Export Citation
  • 12

    Bazrafshan HR, Mohammadian S, Ordookhani A, Abedini A, Davoudy R, Pearce EN, Hedayati M, Azizi F, Braverman LE: An assessment of urinary and breast milk iodine concentrations in lactating mothers from Gorgan, Iran, 2003. Thyroid 2005;15:1165-1168.

    • Crossref
    • PubMed
    • Export Citation
  • 13

    Zimmermann MB: Iodine deficiency and endemic cretinism; in Braverman LE, Cooper DS (eds): Werner and Ingbar's The Thyroid. A Fundamental and Clinical Text, ed 10. Philadelphia, Lippincott Williams and Wilkins, 2013, pp 217-241.

    • PubMed
    • Export Citation

 

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  • Fig. 1

    BMICs of control subjects (n = 13) and the present patient. KI-: group without intake of potassium iodide (n = 5) and the present patient. KI+: group with Graves' disease treated with potassium iodide (n = 8) and the present patient during intake of potassium iodide. Circles: the present patient; dots: controls.

  • 1

    Portulano C, Paroder-Belenitsky M, Carrasco N: The Na+/I- symporter (NIS): mechanism and medical impact. Endocr Rev 2014;35:106-149.

    • Crossref
    • PubMed
    • Export Citation
  • 2

    Package insert of iodine measurement kit (Yodomonit, in Japanese). Hitachi Chemical Co., Ltd. 2012. http://www.info.pmda.go.jp/tgo/pack/21900AMZ00077000_A_01_01 (accessed April 10, 2016).

    • PubMed
    • Export Citation
  • 3

    Ohashi T, Yamaki M, Pandav CS, Karmarkar MG, Irie M: Simple microplate method for determination of urinary iodine. Clin Chem 2000;46:529-536.

    • PubMed
    • Export Citation
  • 4

    Fukata S, Hishinuma A, Nakatake N, Tajiri J: Diagnosis of iodide transport defect: do we need to measure the saliva/serum radioactive iodide ratio to diagnose iodide transport defect? Thyroid 2010;20:1419-1421.

    • Crossref
    • PubMed
    • Export Citation
  • 5

    Kosugi S, Sato Y, Matsuda A, Ohyama Y, Fujieda K, Inomata H, Kameya T, Isozaki O, Jhiang SM: High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. J Clin Endocrinol Metab 1998;83:4123-4129.

    • Crossref
    • PubMed
    • Export Citation
  • 6

    Vulsma T, de Vijlder JJM: Genetic defects causing hypothyroidism; in Braverman LE, Cooper DS (eds): Werner and Ingbar's The Thyroid. A Fundamental and Clinical Text, ed 10. Philadelphia, Lippincott Williams and Wilkins, 2013, pp 535-551.

    • PubMed
    • Export Citation
  • 7

    Burns R, O'Herlihy C, Smyth PP: The placenta as a compensatory iodine storage organ. Thyroid 2011;21:541-546.

    • Crossref
    • PubMed
    • Export Citation
  • 8

    Chan S, Kachilele S, Hobbs E, Bulmer JN, Boelaert K, McCabe CJ, Driver PM, Bradwell AR, Kester M, Visser TJ, Franklyn JA, Kilby MD: Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies. J Clin Endocrinol Metab 2003;88:4488-4495.

    • Crossref
    • PubMed
    • Export Citation
  • 9

    Laurberg P, Nøhr SB, Pedersen KM, Fuglsang E: Iodine nutrition in breast-fed infants is impaired by maternal smoking. J Clin Endocrinol Metab 2004;89:181-187.

    • Crossref
    • PubMed
    • Export Citation
  • 10

    Andersen SL, Nøhr SB, Wu CS, Olsen J, Pedersen KM, Laurberg P: Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition. Eur J Endocrinol 2013;168:723-731.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Leung AM, Pearce EN, Braverman LE: Iodine nutrition in pregnancy and lactation. Endocrinol Metab Clin North Am 2011;40:765-777.

    • Crossref
    • PubMed
    • Export Citation
  • 12

    Bazrafshan HR, Mohammadian S, Ordookhani A, Abedini A, Davoudy R, Pearce EN, Hedayati M, Azizi F, Braverman LE: An assessment of urinary and breast milk iodine concentrations in lactating mothers from Gorgan, Iran, 2003. Thyroid 2005;15:1165-1168.

    • Crossref
    • PubMed
    • Export Citation
  • 13

    Zimmermann MB: Iodine deficiency and endemic cretinism; in Braverman LE, Cooper DS (eds): Werner and Ingbar's The Thyroid. A Fundamental and Clinical Text, ed 10. Philadelphia, Lippincott Williams and Wilkins, 2013, pp 217-241.

    • PubMed
    • Export Citation