Thyroid function tests of iodine deficiency goiter can mimic thyroid hormone resistance alpha

Introduction

There have been isolated case reports describing acquired hypothyroidism due to iodine deficiency in American children, typically caused by a restrictive diet with inadequate iodine intake [1], [2], [3], [4]. Iodine deficiency related hypothyroidism was also observed in significant proportion of children on chronic parenteral nutrition that failed to include iodine [5].

Populations with mild iodine deficiency are clinically and biochemically euthyroid and some may develop goiter. Moderate to severe iodine deficiency causes slight elevation of thyrotropin/thyroid stimulating hormone (TSH) level with normal or low T4 levels. Severe iodine deficiency results in elevated TSH, low thyroxine (T4) and normal or slightly increased triiodothyronine (T3) due to preferential synthesis and secretion of T3 over T4. Those with chronic iodine deficiency usually develop goiter and overt hypothyroidism [6].

We present an otherwise healthy 6-year-old girl who presented with goiter. Her thyroid function studies showed normal TSH, low free T4 and elevated free T3 and T3 levels that mimics biochemical picture of thyroid hormone (TH) resistance alpha.

Case presentation

A 6-year-old girl was referred to pediatric endocrinology for abnormal thyroid laboratory reports that were done as part of evaluation of acquired goiter of 1½ years. She was without hypothyroid or hyperthyroid symptoms. Past medical history showed normal newborn thyroid screening. She was evaluated for macrocephaly at one year of age with cranial ultrasound which was normal. She had normal growth and development. She was a strict vegan and was not on any nutritional supplements. Family used non-iodized salt. Most of the vegetables consumed by the family came from their own farm which included cruciferous vegetables and soya. Family history revealed benign thyroid nodule in maternal grandmother. On examination she had stable vitals, height of 124.6 cm (z score=1.60), weight 25.5 kg (z score =1.23) and body mass index 16.45 kg/m² (z score=0.71). She had diffuse, non-tender, smooth enlargement of thyroid gland, soft in consistency with both lobes measuring 6–7 cm vertically (Figures 1 and 2). Initial laboratory tests done outside showed TSH 5.04 uIU/mL (0.35–5.5 uIU/mL), free T4 (FT 4) 0.3 ng/dL (0.8–1.8 ng/dL), total T4 2.4 mcg/dL (4.5–12 mcg/dL), reverse T3<5 ng/dL (8.3–22.9), total T3 258 ng/dL (94–241 ng/dL) and negative thyroid peroxidase antibody (<28 IU/mL) and thyroglobulin antibody (17.9 U/mL). Ultrasound of thyroid showed grossly enlarged thyroid gland with heterogenous echotexture, microcystic changes and fibrous septations. Her serum thyroglobulin level was 1,098 ug/L (normal <13 ug/L), and urine spot iodine was 15.8 ug/L (median urine iodine concentration <20 ug/L – severe iodine deficiency [6]) confirming a diagnosis of IDG. The patient was started on 150 ug of iodine per day and family started using iodized salt. Thyroid function studies done after 3 months of iodine supplementation showed TSH 2.72 uIU/mL, total T3 182 ng/dL, Total T4 9.3 ug/dL, reverse T3 17.2 ng/dL. She remained clinically and biochemically euthyroid one year after her initial presentation with no change in the goiter size.

Figure 1:

Patient with goiter.

Figure 2:

Symmetric goiter.

Discussion

We describe a 6-year-old healthy child, raised on a vegan diet presenting with IDG with normal TSH, low T4 and free T4, elevated T3 and FT3 and low reverse T3.

Hypothyroxinemia, a biochemical abnormality characterized by low T4 and normal TSH along with elevated T3 (low serum T4/T3 level) as seen in our patient is characteristic of TH resistance alpha [7]. Similar biochemical picture can also occur in those with disorders of decreased TH synthesis – congenital hypothyroidism due to dyshormonogenesis and acquired hypothyroidism due to iodine deficiency and in those with Allan–Herndon–Dudley syndrome due to mutation in TH transmembrane transporter MCT8 [7]. Patients with Allan–Herndon–Dudley syndrome have severe psychomotor delay, congenital hypotonia and progressive spastic paralysis and X linked mode of inheritance, making it easily distinguishable from other conditions mentioned above [7]. Thyroid dyshormonogenesis is characterized by elevated TSH with low T4 usually, but those with partial iodide organification defects and Pendrin gene or apical iodide transporter defects may show normal TSH with low/low normal T4 levels [8]. Patients with resistance to TH alpha can exhibit wide variation in the severity of phenotypes ranging from mild phenotypes with minimal symptoms to severe phenotypes with growth and psychomotor retardation, skeletal dysplasia, macrocephaly, facial dysmorphism and symptoms of hypothyroidism [7, 9]. They can also have normocytic or macrocytic anemia or mild elevation in creatine kinase levels [9]. Our patient was evaluated at one year of age for the concern of macrocephaly and had normal cranial US. She had normal hemoglobin (13.6 g/dL) at presentation. We had thought of referring her to genetic clinic while waiting for urine iodine and thyroglobulin results. Low urine iodine and elevated thyroglobulin level confirmed a diagnosis of IDG in our patient.

TH levels are maintained by a feedback control mechanism involving hypothalamus, pituitary, and thyroid gland [7]. Local TH signaling is mediated by intrathyroidal and extrathyroidal mechanisms [10] and systemic TH signaling by the hypothalamus–pituitary–thyroid (HPT) axis [7]. On reaching the target tissues, THs enter cells using transmembrane TH transporters like MCT 8 and MCT 10. Once inside the cells, iodothyronine deiodinase enzymes (Dio) metabolize thyroid hormones to active (T4 to T3 by Dio 1 and 2) or inactive (T4 to rT3 and T3 to T2 by Dio 3) forms [7]. Combined action of Dio enzymes along with differences in the expression of transmembrane thyroid hormone transporters permit different tissues to control intracellular thyroid hormone levels preserving clinical euthyroidism in most tissues, independently from the levels present in the general circulation [10]. Active thyroid hormone, T3 mediates its action through TH receptors – alpha and beta [7].

Iodine deficiency incites intra and extra thyroidal autoregulatory mechanisms. Initially there will be increase in vascularity and iodine uptake. With persistence of reduced iodide availability, intrathyroidal autoregulatory changes results in preferential synthesis of T3 over T4, resulting in low serum T4, normal or slightly elevated T3 and normal TSH as a result of normal T3. Proportion of thyroglobulin that are fully iodinated decrease and that of poorly iodinated thyroglobulin increase, resulting in its leakage into the blood stream. Increase in serum T3/T4 ratios and thyroglobulin level are markers of these TSH independent autoregulatory mechanisms. There will be increase in thyroid weight and volume as a result of these autoregulatory changes and do not mean TSH level is or has been increased. At target tissues level, integral action of transmembrane thyroid hormone transporters and deiodinase enzymes play a key role in maintaining normal intracellular T3 level and clinical euthyroidism as long as possible. In all except infants, both the intrathyroidal and the extrathyroidal mechanisms reacting to iodine deficiency are fully operative even with mild iodine deficiency. So, patients remain clinically and biochemically euthyroid until intrathyroidal and extrathyroidal mechanisms fail to maintain a normal T3 at tissue level with severe and chronic iodine deficiency [10]. This TSH independent autoregulation explains for the characteristic biochemical abnormality seen in our patient with IDG.

The most common cause of acquired goiter among children and adolescents in developed nations is chronic autoimmune thyroiditis while iodine deficiency remains the most common cause of goiter worldwide [1]. Best sources of iodine include seafood, dairy products, and eggs. Vegans or those with multiple food allergies, lactose intolerance or restrictive eating are at risk of developing iodine deficiency. Consumption of goitrogens also contributes to iodine deficiency in vulnerable population with marginal iodine status [2]. Coexisting deficiencies of iron, Vitamin A and selenium further worsen iodine status in those with limited iodine stores [4]. There have been case reports of reemergence of IDG among individuals on a restrictive diet in US [1], [2], [3], [4].

Our patient was a strict vegan making her vulnerable to iodine deficiency. Her diet included cabbage, broccoli, and cauliflower. She also liked soy very much and consumed it daily. Cruciferous vegetables and soy contain goitrogens [2] which interfere with iodine uptake which might have further contributed to iodine deficiency in our patient.

Patient’s thyroid function studies mimicked thyroid hormone resistance alpha with high T3/T4 levels, low reverse T3 and normal TSH. This diagnosis was also considered initially in our patient as patients with TH resistance can have milder presentation with minimal symptoms. Even after a meticulous search we could not find a case report on children with IDG having a biochemical picture mimicking TH resistance alpha. A study investigating TH profile in fifty goitrous children of 6–11 years living in an iodine deficiency endemic area reported normal T4 and TSH levels in all subjects except three. Two patients had low T4 with elevated TSH and one had elevated T4 with normal TSH. Twenty-four % of the subjects exhibited elevated T3 [11].

The patient responded well to iodine supplementation with normalization of thyroid function tests at 3 months and continued to remain clinically and biochemically euthyroid on follow up. A diagnosis of IDG should be considered in those with restricted diet when presents with acquired goiter and though not common, those with IDG may have thyroid function tests mimicking thyroid hormone resistance alpha.

Learning points

1. Iodine deficiency goiter may present with low FT 4, elevated T3 and normal TSH mimicking the biochemical picture of thyroid hormone resistance alpha.

2. Genetic testing for thyroid hormone resistance alpha can be deferred in a patient with iodine deficiency goiter with biochemical picture mimicking thyroid hormone resistance alpha until after treatment with iodine supplements fails to normalize the thyroid function abnormality.

3. Low urine iodine and elevated serum thyroglobulin confirm a diagnosis of iodine deficiency.

What is new?

1. This is a rare patient with iodine deficiency goiter with laboratory findings mimicking that of thyroid hormone resistance alpha.

2. We document treatment, follow up care and normalization of thyroid function tests mimicking thyroid hormone resistance alpha in a patient with iodine deficiency goiter with iodine supplements precluding the need for genetic testing for thyroid hormone resistance alpha.

3. The mechanism underlying the biochemical picture mimicking thyroid hormone resistance alpha in iodine deficiency is discussed.