Mild Hypothyroidism in Childhood

Who, When, and How Should Be Treated?

Maria Cristina Vigone; Donatella Capalbo; Giovanna Weber; Mariacarolina Salerno

Disclosures

J Endo Soc. 2018;2(9):1024-1039. 

In This Article

Mild Hypothyroidism in Children

Mild hypothyroidism after the neonatal period can be defined as TSH 4.5 to 10 mIU/L in the presence of normal FT4.

Data on the epidemiology of SH in childhood are scarce; the prevalence of mild subclinical thyroid dysfunction in children and adolescents according to two large population studies ranges between 1.7% and 2.9%.[51,52]

Most studies indicate that SH in children frequently resolves spontaneously or may persist without progressing to overt hypothyroidism. In a large Israeli study, 73.6% of children with mild SH normalized their TSH over 5 years, whereas in ~25% of them, TSH remained stable.[52] Moreover, a 2-year prospective study on 92 children demonstrated that mild SH resolved spontaneously in 41.3% of participants, remained stable in 46.7%, and progressed to hypothyroidism (TSH >10 mIU/L) only in 12.0%.[53]

However, the natural history of SH substantially depends on its etiology, as discussed in the next paragraphs.

Hashimoto Thyroiditis

Hashimoto thyroiditis (HT) is one of the most frequent causes of persistent SH in children and adolescents.[54] The underlying cause of HT is still unknown, even though several genetic and environmental factors have been associated with this disorder.[55] HT is particularly common in children with genetic conditions, such as Down syndrome (DS) or Turner syndrome,[56] and in patients with other autoimmune diseases (i.e., celiac disease or type 1 diabetes mellitus).[56,57]

The clinical course of HT is highly variable depending on the severity of the immunological damage.[56] Thyroid function at presentation may vary from euthyroidism to overt hypothyroidism or, occasionally, hyperthyroidism. In a retrospective multicenter study on 608 children and adolescents (age range 2.5 to 18.0 years), euthyroidism was observed in 52.1% of patients at presentation, whereas SH and overt hypothyroidism were detected in 19.2% and 22.2% of patients, respectively.[58]

The risk of progression to overt hypothyroidism in children affected by autoimmune SH is higher with respect to those affected by nonautoimmune forms. A worsening of thyroid function was indeed observed after 3 years of follow-up among 21.4% of children with HT compared with 13.6% of patients with isolated hyperthyrotropinemia in a retrospective multicenter study.[57] These data were further confirmed in a 2-year prospective study that documented an increased risk of progression to overt hypothyroidism among children with mild SH associated with HT (53.1%) with respect to children with a mild nonautoimmune form (11.1%).[59]

The long-term thyroid function was also evaluated in a recent 5-year prospective study on 127 girls with mild autoimmune and nonautoimmune SH. At the end of the study, 61.9% of girls with mild nonautoimmune SH normalized thyroid function, 26.2% maintained unchanged their TSH, and only 11.9% progressed to overt hypothyroidism. Conversely, in the group with autoimmune mild SH, a progressive deterioration of thyroid function was observed in 30.6% of girls, and only 10.6% normalized their TSH.[60]

Levels of TSH and thyroid peroxidase antibodies at presentation and concomitant celiac disease were associated with an increased risk of developing overt hypothyroidism in children with HT.[57] Moreover, in girls with HT, the association with either Turner syndrome or DS further increased the risk of thyroid function deterioration.[60]

Obesity

An isolated mild increase in TSH levels, associated with FT4 values and free T3 values that are within or slightly above the upper normal range, is a common finding in children who are overweight and obese, with a prevalence ranging between 7% and 23%.[61,62]

Nearly one-third of children with obesity and elevated TSH levels have a hypoechogenic thyroid gland pattern at ultrasound,[63,64] which could represent a feature of thyroid derangement due to obesity itself or an early marker of a seronegative autoimmune thyroiditis. However, autoimmune thyroiditis has seldom been reported as a cause of a mild TSH increase in childhood obesity, and a recent study on a large cohort of 938 children and adolescents with obesity reported that only 7% had autoimmune thyroiditis.[65]

Further mechanisms that may lead to increased TSH levels in children with obesity are mutations in the TSHR gene, functional derangements in the hypothalamic-pituitary-thyroid axis, and thyroid hormone resistance. However, the most promising link between obesity and elevated TSH levels seems to be the increased leptin-mediated production of pro-TRH, because leptin is able to stimulate and thus regulate the hypothalamic-pituitary-thyroid axis function.[62]

Despite the uncertainty regarding the underlying mechanism, the findings that abnormalities in thyroid function and TSH mostly normalize after weight loss support the hypothesis that the TSH increase in patients who are obese is reversible and seems to be a consequence rather than a cause of obesity.[62,65,66]

Moreover, the mild increase in TSH levels in obesity might represent an adaptive response designed to reduce the availability of energy for conversion into fat;[62] therefore, treatment with thyroxine seems unnecessary in children who are obese.

Genetic Syndromes

It is well established that patients with DS are at increased risk for the development of thyroid hormone abnormalities, including either congenital or acquired hypothyroidism.[67] A high prevalence of SH has been reported among these children, ranging from 25.3% to 60.0%.[68]

The underlying cause of the isolated elevations in TSH levels among children with DS has not been elucidated. In addition to thyroid autoimmunity, possible mechanisms include a central disorder causing inappropriate release of TSH, production of TSH with lowered activity, and some degree of TSH insensitivity in the thyroid gland.[69]

The natural history has yet to be defined[70] even though mild hypothyroidism in DS seems to be frequently self-limiting;[3] therefore, regular monitoring of thyroid function is recommended.

The effectiveness of L-T4 administration among children with DS and subtle thyroid abnormalities is still controversial. A recent study[71] suggests that the treatment with L-T4 in the first 2 years of life may lead to an improvement in the hypothalamic-pituitary-thyroid axis set-point and to a reduction in the risk of developing thyroid autoimmunity. However, randomized, double-blind, controlled studies are needed to establish the effectiveness of L-T4 therapy in children with DS.

Another genetic syndrome frequently associated with mild hypothyroidism is pseudohypoparathyroidism type 1a, a rare genetic disorder caused by deficiency of Gsα, leading to multiple hormone resistance.[72]

Iodine Deficiency and Excess

The relation between iodine intake and thyroid disorders is U-shaped because both deficient and excess iodine intake can impair thyroid function.

Although iodine deficiency is often thought to be a problem of developing countries, industrialized countries are not immune. In moderate to severe iodine deficiency, mean serum TSH concentration often slightly increases, whereas T4/FT4 remains normal. As iodine deficiency becomes more severe, TSH further rises, and goiter and overt hypothyroidism can develop.[73]

On the other hand, increasing iodine intake also leads to a small increase in the incidence of mild SH, more often in individuals positive for thyroid antibodies.[73]

Drugs that contain iodine, such as amiodarone and its main metabolite, desethylamiodarone, are known to cause an elevation in TSH levels, blocking the ability of the type 2 iodothyronine deiodinase to mediate conversion of T4 to T3.[74] Moreover, recent attention has been paid to the role of iatrogenic iodine excess from radiographic contrast. In a recent study, children receiving iodinated radiographic contrast had an increased risk (2.6-fold) of developing hypothyroidism, although the duration and impact of such thyroid dysfunction remain unclear.[75]

Alterations in thyroid function have been reported after treatment with[131]I-metaiodobenzylguanidine in children with neuroblastoma despite protection with potassium iodide. The occurrence of thyroid dysfunction increases over time; therefore, continuous screening for thyroid alterations in these survivors is recommended.[76]

Finally, cough suppressants and nutritional supplements containing iodine may also cause thyroid dysfunction.[77]

Medications and Exposure to Ionizing Radiation

Treatment with interferon (IFN)–α has been associated with alterations of thyroid function.[78] An autoimmune mechanism has been hypothesized, but also nonautoimmune thyroid dysfunction can be related to IFN-α.[78,79] In a recent study on 61 children with chronic hepatitis C receiving therapy with IFN-α and ribavirin, 27.94% developed SH and 6.6% developed autoimmune thyroiditis during treatment; SH was transient in most cases (93.4%), whereas autoimmune thyroiditis persisted in 75% of cases 24 weeks after the end of treatment.[79]

Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, and valproic acid) can also impair thyroid function.[80] Even though the underlying mechanisms are not completely understood, accelerated clearance of TH or interference with the regulation of pituitary TSH secretion has been suggested.[80,81]

Lithium treatment has been associated with the development of thyroid dysfunction. The common clinical side effects of the drug are hypothyroidism and goiter. The prevalence of lithium-induced hypothyroidism varies between 6% and 52% according to several series, and it is usually subclinical, although severe hypothyroidism has been reported. Hypothyroidism may occur without thyroid enlargement as well as with goiter. Furthermore, lithium exacerbates preexisting autoimmune thyroid disease by accelerating the increase in thyroid antibody titer. Therefore, thyroid function should be tested and carefully monitored in patients receiving lithium therapy.[82]

Therapeutic as well as environmental exposure to ionizing radiation during childhood can cause mild thyroid dysfunction. Although primary hypothyroidism in childhood cancer survivors is a well-known effect[83] the prevalence of SH compared with overt hypothyroidism is not yet well defined.

The incidence of SH has been reported ~26.5% in children who had received irradiation before bone marrow transplantation, with a tendency to resolve spontaneously over years in most cases.[84]

Finally, a clear association has also been reported between iodine-131 exposure in Ukraine and Belarusian children and thyroid dysfunction, including SH.[85,86]

Endocrine Disruptors

Several endocrine disruptors, such as chemicals, food, and consumer products, can interfere with thyroid function by acting on different points of regulation of thyroid hormone.[87] Human studies investigating the relationship between chemical exposures and alterations in circulating levels of thyroid hormones led to variable results, possibly because an association between chemical exposures and circulating hormones is difficult to test directly in humans; however, there is evidence that perfluorinated chemicals, polychlorinated biphenyls and dioxins, bisphenol A, perchlorate, and phthalates may have thyroid-disrupting properties in humans.[88]

In particular, dioxins and polychlorinated biphenyls may cross the placenta and be excreted in breast milk. In utero or perinatal exposure to these chemicals has been associated with increased TSH levels in infants in some but not all studies, with unclear long-lasting effects in older ages.[88] Further studies are needed to clarify the relationship between mild thyroid dysfunction and the exposure to endocrine disruptors in children.

Idiopathic SH

The term idiopathic SH refers to those patients with a persistent mild increase in TSH levels in whom no clear etiology has been identified.

processing....