Endocrinology Metabolism

Acquired Hypothyroidism

Are you sure the patient has hypothyroidism?

Symptoms

The most common symptom is goiter, which is present in 70-80% of children who are evaluated for hypothyroidism. Children can present with fatigue (22%), weight gain (10%), linear growth retardation (8%), cold intolerance (7%), constipation (6%), menstrual irregularities (5%) and headache (2%). Hair loss and dry skin is also seen in hypothyroidism. In addition, children may have pubertal delay or rarely, in cases of long-standing severe hypothyroidism, precocious puberty.

Signs

Goiter is the most common physical exam finding. In the case of autoimmune hypothyroidism, the goiter is typically non-tender, firm, and symmetrically enlarged. Nodules or pseudo-nodules can be present. Hypothyroidism produces poor linear growth with height being more severely affected than weight, so these children may be relatively overweight for their height. However, the incidence of overweight/obesity in children with hypothyroidism is the same as in the general population. See Figure 1 and Figure 2.

Figure 1.

Growth chart of hypothyroid child demonstrating growth failure

Figure 2.

BMI chart of hypothyroid child demonstrating relative increase in BMI

Other signs include bradycardia, proximal muscle weakness, delayed relaxation of deep tendon reflexes and myxedema, which presents in the face and dorsum of hands and feet. Myxedema is responsible for the coarsening of facial features which can be seen with long-standing untreated hypothyroidism. Patients may have delayed bone age. Children with long-standing severe hypothyroidism may have enlargement of the sella turica and pituitary due to thyrotrope hyperplasia. See Figure 3.

Figure 3.

Enlargement of the pituitary and sella turica due to severe hypothyroidism

Key laboratory findings

Elevated serum thyroid-stimulating hormone (TSH) and low serum thyroxine (T4) are consistent with a diagnosis of hypothyroidism.

Causes of acquired hypothyroidism

Hashimoto thyroiditis (also called autoimmune hypothyroidism or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in children and adolescents. As with other autoimmune conditions, there is a female predominance (approximately 2:1). A family history of autoimmune hypothyroidism is reported in 40-50% of cases.

Autoimmune hypothyroidism may occur in the setting of other autoimmune conditions, most commonly Type 1 diabetes mellitus. It is also associated with Addison's disease, celiac disease, vitligo and systemic lupus erythematosus.

Chromosomal abnormalities predispose to autoimmune hypothyroidism. Children with Down's and Turner syndromes have increased rates of hypothyroidism, and routine screening in these individuals is recommended. Children with Down's syndrome should have a TSH checked at birth, 12 months, then annually after the first year of life. Girls with Turner syndrome should have a TSH obtained annually after age 4 years.

Other conditions should be considered in the differential diagnosis of acquired hypothyroidism. Although uncommon in the United States, iodine deficiency is the most common cause of hypothyroidism worldwide. Following treatment of Graves' disease or thyroid cancer, hypothyroidism results from radioiodine therapy and surgical resection of the thyroid gland. Radiation to the neck for other diseases (most commonly Hodgkin's lymphoma or prior to a bone marrow transplant also places children at risk of hypothyroidism.

Medications that disrupt thyroid function include anti-thyroid drugs (propylthiouracil or methimazole), lithium, amiodarone and anti-epileptic drugs. Other goitrogens include cassava, broccoli, sweet potato, soybeans and certain industrial chemicals, such as perchlorate and polychlorinated biphenyls.

Tumor, surgery or trauma can cause secondary or central hypothyroidism. Acute or chronic illness can lead to low TSH and T4 concentrations, which may be mistaken for central hypothyroidism. However, this non-thyroidal illness (most commonly known as "euthyroid sick" syndrome) does not require treatment, and thyroid function normalizes with recovery from the disease process.

Thyroid hormone circulates bound to thyroid hormone binding globulin (TBG). Familial TBG deficiency, which is inherited in an X-linked pattern, leads to a low T4 with a normal serum TSH and free T4 levels (depending on the assay).

What else could the patient have?

Hypothyroidism can produce multiple non-specific symptoms. Depression or other mood disorders should be considered in children and adolescents with fatigue. Despite a widespread belief in the connection between hypothyroidism and obesity, hypothyroidism is not a cause of significant weight gain. Obese children often have mildly elevated TSH, which have been shown to normalize with weight loss. This finding has led to the suggestion that obesity causes a relative TSH resistance. Treatment of a mildly elevated TSH in obese children is not warranted.

Key laboratory and imaging tests

Patients with primary hypothyroidism have an elevated serum TSH and a low serum total or free T4. An elevated TSH and normal T4 are consistent with subclinical hypothyroidism (also referred to as compensated hypothyroidism). This process may be transient or permanent, with decreasing T4 and increasing TSH in the latter case.

Interpretation of thyroid function tests can be difficult. Serum total T4 concentrations are affected by levels of TBG and may be falsely elevated in cases of binding protein excess (oral contraceptive use or pregnancy) or falsely low in cases of low binding protein (TBG deficiency). Free T4 is a better measure of thyroid hormone because it is not affected by binding protein levels. However, discrepancies in 1-step analog laboratory methods may result in imprecise free T4 levels. T3 levels are not useful for the diagnosis or monitoring of hypothyroidism and should not be ordered.

As the most common cause of hypothyroidism is autoimmune, anti-thyroid antibodies (anti-thyroid peroxidase, anti-thyroglobulin) should be obtained. Anti-thyroid peroxidase antibody is preferred and is more predictive of developing clinical disease.

A normal TSH with a low total T4 suggests TBG deficiency and a TBG level, a free T4 by equilibrium dialysis, or a free T4 index can be obtained. Central hypothyroidism may also present with a normal (or low) TSH with a low T4. After TBG deficiency has been ruled out, additional studies will be necessary to determine the cause of the central hypothyroidism, including an MRI of the pituitary.

Other tests that may prove helpful diagnostically

In the case of autoimmune hypothyroidism, additional testing is typically unnecessary. On ultrasound, a Hashimoto's thyroid gland will always appear heterogeneous. The indication for ultrasound in autoimmune hypothyroidism is the finding of a nodule or marked asymmetry of the thyroid on physical exam. Routine surveillance ultrasound is not recommended. There is no role for scintigraphy in the evaluation of acquired hypothyroidism.

Management and treatment of the disease

Once the diagnosis of hypothyroidism has been established, treatment should be initiated with levothyroxine. Levothyroxine tablets should be taken once a day according to weight-based dosing. If possible, brand name levothyroxine should be prescribed, since there are small variations in the absorption of various generic brands. See Figure 4.

Figure 4.

Weight-based dosing of Levothyroxine

Suspensions and liquid preparations of levothyroxine should not be used, because they are unstable and do not provide reliable dosing. For younger children, the tablet may be crushed and mixed with a small amount of liquid or food.

Due to the long half-life of levothyroxine, repeat TSH and total or free T4 should be obtained 6-8 weeks after initiating treatment. Once a dose has been established, thyroid function should be monitored 1-2 times a year. Tests should be repeated 6-8 weeks after a dose change.

The treatment of subclinical hypothyroidism is controversial. The majority of practitioners will start treatment when the TSH is greater than 10 uIU/mL, but there is no consensus on the need for treatment with TSH between 5 and 10 uIU/mL. Treatment with levothyroxine of patients with autoimmune hypothyroidism reduces goiter size, even in children with subclinical hypothyroidism.

Although absorption of levothyroxine is greatest on an empty stomach, dosing is frequently easiest at a mealtime. A higher dose of levothyroxine can be used to compensate for decreased absorption, because it is more important to remember to take the medication than trying to take it on an empty stomach. Levothyroxine can also be administered at bedtime.

Many medications decrease the absorption of levothyroxine, including antacids, such as H2 blockers and proton pump inhibitors, ferrous sulfate, calcium carbonate and bile acid sequestrants. Levothyroxine should be administered at a different time than these medications. Soy products also decrease the absorption of levothyroxine and children may require higher dosing if they are ingesting soy. Patients with achlorydria and gastrointestinal disorders, such as celiac disease, may require larger doses of levothyroxine.

There is no data to support the use of Cytomel in children and adolescents. Nontraditional over the counter thyroid hormone products should not be used.

What’s the Evidence?/References

De Vries, L, Bulvik, S, Philip, M. " 2009 Chronic autoimmune thyroiditis in children and adolescents: at presentation and during long-term follow-up". Arch Dis Child. vol. 94. pp. 33-37.

(Describes the clinical characteristics of 114 children and adolescents with autoimmune hypothyroidism. Percentages of presenting symptoms were taken from this study.)

Counts, D, Varma, SK. "2009 Hypothyroidism in children". Pediatrics in Review. vol. 30. pp. 251-257.

(Excellent review of pediatric hypothyroidism aimed at general practitioners.)

Bull, MJ. "the Committee on Genetics 2011 Health supervision for children with Down's syndrome". Pediatrics. vol. 128. pp. 393-406.

(Comprehensive guidelines for the care of a child with Down syndrome including recommendations for thyroid screening.)

Bondy, CA. "Turner Syndrome Study Group 2007 Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group". J Clin Endocrinol Metab. vol. 92. pp. 10-25.

(Comprehensive guidelines for the care of a girl with Turner syndrome including recommendations for thyroid screening.)

O'Grady, MJ. "Cody D 2011 Subclinical hypothyroidism in children". Arch Dis Child. vol. 96. pp. 280-284.

(A thorough review of subclinical hypothyroidism including discussion of treatment controversies and subclinical hypothyroidism in Down's syndrome.)

Reinehr, T, de Sousa, G, Andler, W. "2006 Hyperthyrotropinemia in obese children is reversible after weight loss and is not related to lipids". J Clin Endocrinol Metab. vol. 91. pp. 3088-3091.

(A study that demonstrates an elevated TSH is a consequence and not a cause of obesity.)
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