Preventable hypothyroidism in a total parenteral nutrition-dependent infant with short bowel syndrome

INTRODUCTION

Iodine plays a key role in thyroid hormone synthesis. Dietary iodine is absorbed and transported into the thyroid follicular cells through the sodium-iodide symporter. Thyroid peroxidase (TPO) oxidizes iodide and attaches it to tyrosine residues on thyroglobulin (Tg) proteins, creating monoiodotyrosine (MIT) and diiodotyrosine (DIT). TPO combines pairs of DIT molecules to form thyroxine (T4), and pairs of MIT and DIT molecules to form triiodothyronine (T3). T4 and T3 are stored in the colloid, bound to Tg, and released in circulation when needed.^[1] These thyroid hormones are critical for the growth and maturation of many target tissues, including the brain and skeleton. Untreated severe hypothyroidism in infancy and early childhood results in intellectual disabilities and developmental delays.

Typical total parenteral nutrition (TPN) formulations do not contain iodide; patients with no oral intake can receive iodine through transdermal absorption from external sources, such as iodine-containing skin disinfectants. Absence of these external sources of iodine due to a change in skin disinfectant practice can lead to severe iodine deficiency. Infants, with their limited ability to store intrathyroidal iodine, may be particularly vulnerable.^[2]

In the following case, severe hypothyroidism was diagnosed and managed in an 8-month-old infant with iodine deficiency who had received long-term TPN.

CASE REPORT

An 8-month-old girl infant, born at 34 weeks’ gestation with a birth weight of 1.9 kg, diagnosed with jejunal atresia and status post exploratory laparotomy for intestinal obstruction, was referred to the endocrinology clinic for incidentally detected hypothyroidism. The patient had elevated thyroid-stimulating hormone (TSH) levels of >100 µU/mL (normal range: 0.87–6.43 µU/mL) and low free T4 of 0.24 ng/dL (normal range: 0.82–1.4 ng/dL). Since the age of 1 month, she had been receiving nutrition through TPN and intralipids. Her length was 62.1 cm (−2.9 standard deviation [SD]) and weight was 6.46 kg (−1.78 SD). There were no reported symptoms of hypothyroidism. Physical examination showed short stature, but no evidence of congenital hypothyroidism, such as a widely open anterior fontanelle, macroglossia, puffy facies, hypotonia, or severe developmental delay. This led us to believe that severe hypothyroidism could have been a recent development. There was no prior record of thyroid function testing.

DISCUSSION

Children with long-term parenteral nutrition (PN) and short bowel syndrome (SBS) are at high risk of iodine deficiency.^[2] Infants and neonates are particularly vulnerable due to smaller intrathyroidal iodine stores.^[2] Iodide is not currently included in TPN products in the U.S.^[3] The American Society for Clinical Nutrition and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) both recommend a daily dose of 1 µg/kg/day of parenteral iodine for children receiving TPN for this reason. Yet, children receiving the ESPGHAN-recommended 1 µg/kg/day of parental iodine are still at risk for iodine deficiency, with median urinary iodine concentrations of 89 µg/L, indicating inadequate status.^[4] In a study of 24 children who received PN for a mean of 21.5 months, 83.3% had iodine deficiency at baseline, which reduced to 45.8% after starting enteral or oral nutritional formula.^[5] In another study of 27 children with short gut syndrome with a mean PN of 27 months, 83–85% had iodine deficiency with approximately 33% developing hypothyroidism.^[6] In another study, all SBS patients had urinary iodine concentrations <100 µg/L within 4 weeks of PN initiation, compared to only half of non-SBS patients, especially when enteral intake is minimal.^[7]

In addition, the most common topical disinfectants used for central lines do not contain iodine. Although these non-iodine-based dressings reduce the risk of skin infections, they increase the risk of iodine deficiency in children who receive chronic TPN.^[2] It is important to recognize this limitation as iodine deficiency can lead to hypothyroidism which, if left untreated in young children, can lead to severe neurodevelopmental disability.

The recommended dietary allowance for iodine varies with age: 110 µg/day for term neonates; 110–130 µg/day for infants; 90 µg/day for children aged 1–8 years; 120 µg/day for children aged 9–13 years; and 150 µg/day for adolescents and adults.^[8] We recommend screening for iodine deficiency after 4 weeks of TPN-only nutrition in children, specifically those under 3 years of age with SBS, by obtaining a spot UIC. The World Health Organization (WHO) considers a median UIC of 100–199 µg/L to be adequate, 21–99 µg/L as mild to moderate deficiency, and levels below 20 µg/L as severe iodine deficiency.^[9] If severe iodine deficiency is detected, a TSH level should also be obtained to screen for hypothyroidism. Elevated serum Tg is a sensitive biomarker of iodine deficiency in patients on PN, indicating thyroid stress and adaptation to inadequate iodine intake, attempting to maximize thyroid hormone production before overt hypothyroidism develops.^[10] In iodine-deficient populations, serum Tg correlates with UIC and thyroid size, while TSH and thyroid hormones may remain normal until iodine stores are severely depleted, making Tg a sensitive early indicator of iodine deficiency along with UIC levels.^[3] A median Tg <13 µg/L indicates iodine sufficiency.^[10]

Prophylactic use of skin dressings with iodine should be considered for children with SBS who are receiving exclusively chronic TPN therapy to prevent the development of hypothyroidism from iodine deficiency. While iodine deficiency is curable with supplementation, it is important to monitor UIC periodically; high levels of iodine can paradoxically lead to hypothyroidism through a mechanism called the Wolff-Chaikoff effect. This is a protective mechanism which temporarily inhibits thyroid hormone synthesis when the gland is exposed to excess iodide.^[11] This creates a narrow therapeutic window for optimal iodine supplementation. The Wolff-Chaikoff effect is also clinically relevant when using iodine-containing antiseptics in neonates and infants, as transcutaneous absorption can deliver substantial iodine loads to the thyroid gland, potentially causing transient hypothyroidism.^[11] The WHO considers a UIC of ≥300 µg/L to be excessive.^[9]

Due to the need for rapid normalization of hypothyroidism in this young child who was scheduled for impending surgery and not being entirely sure how much iodine would be absorbed topically, immediate treatment of hypothyroidism with levothyroxine was instituted along with topical iodine dressings. In older children with hypothyroidism due to iodine deficiency, iodine repletion can be instituted first without starting levothyroxine to restore the euthyroid state.^[12]

Other micronutrient deficiencies can occur in children receiving long-term TPN. Other deficiencies to consider in these children include vitamin D, zinc, iron, selenium, copper, vitamins A, E, and B12.^[13]

CONCLUSION

To conclude, iodine deficiency should be considered, screened for, and managed, along with other micronutrient deficiencies, in high-risk situations, as highlighted by our case.