Severe Hypothyroidism and Large Goiter due to Iodine Deficiency in an Adolescent Male in the United States: A Case Report and Review of the Literature

Acquired hypothyroidism due to iodine deficiency is extremely rare in the United States due to the introduction of table salt iodization in the 1920s (Leung et al., 2012). We present the case of an adolescent male with a history of mild autism spectrum disorder and an extremely restrictive diet who was found to have iodine deficiency as the etiology for his rapidly enlarging goiter and antibody-negative hypothyroidism. Thyroid-stimulating hormone (TSH) was 416 μIU/mL (0.350–5.500 μIU/mL), free thyroxine (T4) was <0.1 ng/dL (0.80–1.80 ng/dL), and triiodothyronine (T3) was 41 ng/dL (82–213 mg/dL) at diagnosis. The patient's 24-hour urinary iodine was undetectable. He was started on iodine supplementation with rapid visible improvement of goiter within two weeks and normalization of thyroid function tests within four weeks. Thorough dietary history and nutritional screening are important in cases of acquired hypothyroidism and/or goiter. Alternatively, diets that are low in iodized salt, dairy, bread, and seafood should raise concern for iodine deficiency, and patients with suspected or proven iodine deficiency should be screened for hypothyroidism.


Introduction
Iodine defciency is uncommon in the United States and hence an uncommon cause of hypothyroidism. Trends in median urinary excretion of iodine as tracked by the National Health and Nutrition Examination Survey (NHANES) demonstrated that while the average individual in the United States is iodine sufcient, the median urinary iodine content has been decreasing over time. Fortunately, children's median urinary iodine excretion has been relatively stable (mean value of 190 µg/L from 2011-2014 data) [2].
Because there is no public-health mandate for salt iodization in the United States, personal dietary choices determine iodine sufciency. A transition to less iodized forms of salt and health trends encouraging decreased salt intake may be two factors contributing to a reduction in iodide intake [3]. While primary sources of dietary iodine include fsh, seafood, grains, and iodized salt, children and adolescents receive 53-70% of their daily iodide intake from dairy [4]. Iodine defciency is diagnosed by urine iodine concentrations less than 100 mcg/L [5]. Iodine is necessary for the production of thyroid hormones (T3 and T4) and its defciency leads to hypothyroidism [6].
We report the case of a 13-year-old male presenting with a rapidly enlarging goiter who was found to have markedly elevated TSH, undetectable free T4 and low total T3 levels, and negative autoimmune thyroiditis antibodies. Iodine defciency was identifed as the ultimate etiology of his

Case Presentation
A 13-year-old male with a history of mild autism spectrum disorder, anxiety, and attention-defcit hyperactivity disorder presented to his pediatrician with neck swelling in the setting of two months of fatigue. He had been sleeping over twelve hours per day and did not have sufcient energy to complete his schoolwork. Ultrasound of the thyroid was interpreted by radiology as consistent with autoimmune thyroiditis (see Table 1 for detailed description and thyroid gland dimensions); however, thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies were negative. He was referred to pediatric endocrinology for further evaluation and management. A review of the growth charts revealed growth deceleration starting at 10 years old, with height percentiles decreasing from the 60 th to the 35 th percentile and weight percentiles declining from the 75 th to the 25 th percentile. Te mother reported a very restrictive diet. He ate specifc brands of bread and peanut butter, neither of which contained iodine. His diet included some chicken but no seafood, fsh, dairy, or processed or canned foods. He did not consume iodized table salt. Restriction of diet was largely related to the patient's preference for certain foods in the context of his autism spectrum disorder. In addition, a year prior to the presentation, the family had eliminated dairy from the patient's diet due to presumed lactose intolerance.
On examination, vital signs were within normal limits. Height was at the 36 th percentile and weight was at the 54 th percentile. Physical examination revealed symmetric, frm thyromegaly without distinct nodules. Te right lobe measured 8 cm, and the left lobe measured 8.5 cm (Figure 1(a)).
Given his severe dietary restrictions, the possibility of iodine defciency was considered. Te patient was initially started on a low dose of levothyroxine (25 mcg daily [0.5 mcg/kg/day]) with a plan for slow, stepwise increases while his 24-hour urinary iodine was pending. Urinary iodine concentration from 24-hour collection resulted as <5.0 µg/L (26-705.0 µg/L), confrming severe iodine defciency. He has been prescribed iodine supplementation of 150 mcg daily. Given his very restrictive diet, iron studies and vitamin levels were assessed. He was found to have mild iron defciency (elevated total-iron binding capacity −505 µg/dL-with normal iron, ferritin, and hemoglobin) and vitamin C defciency (serum vitamin C undetectable at <5 µmol/liter) and was started on a multivitamin with iron. Vitamins D and B12 were not defcient because he had already been receiving supplementation prior to the presentation. Two weeks after iodine replacement, the family reported signifcant improvement in the size of his goiter, as well as his energy level (Figure 1(b)). Eggs were reintroduced successfully into his diet. Repeated laboratory evaluation one month after iodine initiation showed normalization of values with TSH of 0.707 μIU/mL (0.350-5.500 uIU/mL) and free T4 of 1.45 ng/dL (0.80-1.80 ng/dL). Te small dose of levothyroxine was discontinued following these test results, and thyroid function remained normal on subsequent follow-ups after 2 months. On follow-up examination 5 months after iodine supplementation was started, the patient had a much decreased albeit persistent goiter, with the left lobe measuring 6.5 centimeters and the right lobe measuring 6.0 centimeters.

Discussion
Iodine is a necessary component for the synthesis of T3 and T4. Initially, with mild iodine defciency, there is upregulation of sodium-iodide symporters to increase iodine uptake into the thyroid gland, and renal iodine excretion is reduced. As the severity of defciency worsens, there is a preferential synthesis of T3 over T4. Severe and prolonged defciency of dietary iodine leads to a decreased production of both T3 and T4 with a subsequent appropriate elevation of TSH [5]. TSH has the secondary efect of inducing hypertrophy and hyperplasia of the thyroid follicular cells that leads to goiter [15]. Initially, goiters are smooth; however, with long-standing defciency, patients can develop thyroid nodules which are associated with an increased risk of thyroid cancer [16].
Te necessary iodine intake to maintain sufciency varies by age. Te World Health Organization recommends 90 µg per day for children under 5 years, 120 µg per day for children aged 6-12,150 µg per day for adolescents over the age of 12 and adults, and 250 µg per day for pregnant and lactating women. For our adolescent patient, a target supplementation of 100-299 µg would avoid both insufciency and excess [5].
When unacknowledged, iodine defciency not only leads to hypothyroidism but can impair growth and cognitive development [17]. Tere are few modern case reports of iodine defciency in developed nations secondary to diets restricted for autism spectrum disorder, food aversion, and food allergies (Table 1) [7][8][9][10][11][12]. All except two patients were treated with iodine supplementation. One patient was treated with kelp capsules containing 400 ug of iodine/ capsule per parental request [9] and another with oral aversion was given nasogastric feeds rich in iodine content resulting in the normalization of thyroid function tests [11]. Ikomi et al. reported iodine defciency in 85% (17/20) and acquired hypothyroidism in 33% (8/27) of patients younger than 17 years on parenteral nutrition for more than 6 months. No signifcant association was observed between the duration of parenteral nutrition and iodine defciency or hypothyroidism [18].
Because the body relies exclusively on iodide ingestion through diet or supplementation to achieve iodine sufciency, changes in personal or family dietary patterns would Case Reports in Endocrinology explain why some children are iodine defcient. In addition to health concerns about excessive salt consumption, there have been trends toward more specialized diets recently. Patients with vegan diets rely primarily on iodized table salt or foods such as seaweed for their iodine content [19] and are thus at high risk for iodine defciency. A study on women in Boston found that a majority of vegetarians and vegans studied had not consumed iodized table salt in the last 24 hours and were not on an iodine-containing multivitamin [20].
Management of iodine defciency involves reintroducing iodine into the diet. Tyroid function tests rapidly normalize after repletion, and levothyroxine, if started, can be discontinued. Te patients' large goiters also improve quickly with near resolution noted at three-monthfollow-up visits [8,21]. Ongoing monitoring of thyroid function tests should be performed as thyrotoxicosis can develop secondary to iodine supplementation [21].
Te present case highlights the importance of thorough dietary history and nutritional screenings in cases of hypothyroidism and/or goiter. Diets that are low in iodized salt, dairy, bread, and seafood should raise concern for iodine defciency and prompt urinary testing by 24-hour urine collection, which produces more reliable values than testing from spot urine collections [22]. Patients with suspected or proven iodine defciency due to restrictive diets or parenteral nutrition should be screened for hypothyroidism. Repletion and maintenance of dietary iodine are expected to lead to prompt resolution of symptoms of hypothyroidism.

Data Availability
Te [clinical and laboratory parameters] data used to support the fndings of this study are included within the article.

Conflicts of Interest
Te authors declare that they have no conficts of interest.