Hypothyroidism in Infancy and Childhood

Richard Levy, M.D.
Assistant Professor of Medicine and Pediatrics Rush-Presbyterian/St. Luke’s Medical Center, Chicago, Illinois

Case Summary

Peter R, a 15-year-old male, was referred to a pediatric endocrinologist by his pediatrician because of a decreased growth rate since the age of 10.

Peter’s medical history was unremarkable, but his parents were concerned about his short stature and observed that his interest in participating in sports had diminished and that he was sluggish and hard to motivate.

On physical examination Peter was found to be a short, somewhat stocky while male with a sallow complexion, normal speech and a normal – not noticeably lethargic – demeanor. His thyroid was palpable but not enlarged. His blood pressure was 90/50 mmHg, and his heart rate was 62.

Peter was assessed to be at Stage 3 of puberty on the Tanner scale – normal for his age. His deep tendon reflexes appeared to be normal, and he seemed to have good muscular development – although later examination revealed that to be pseudomuscular hypertrophy associated with hypothyroidism (Kocher-Debré-Sémélaigne syndrome). Peter’s bone age was that of a 12 1/2 year old.

Peter’s T4 was less than 1 ug/dl, his T3 resin uptake was 36% and his TSH>64 S.I. units. Elevated antithyroid antibody titers established a diagnosis of chronic lymphocytic thyroiditis (CLT) – Hashimoto’s disease.

On a replacement regimen of 0.1 mg qd of levothyroxine tablets, Peter quickly began to catch up on the growth curve. His complexion returned to normal, and according to his parents he is now a “real ball of fire”. Peter’s repeat T4 was 8.0 ug/dl and his highly sensitive TSH (immunoradiometric assay) was 0.76 S.I. units, falling within the normal range (0.7-5.0).

Peter R: A “Typical” Adolescent Presentation

Peter, an adolescent, was found to have acquired hypothyroidism due to lymphocytic thyroiditis -Hashimoto’s disease – which is by far the most common cause of hypothyroidism in mid-late childhood and adolescence, occurring in up to 1.2% of the school age population. While no histocompatibility-linked antigens (HLA) that would suggest a predisposition for Hashimoto’s disease have been identified, there is a familial tendency for its occurrence, and a predominance of females to males and whites to blacks of about 4:1. The elevation of antithyroid antibodies reflects this immune-mediated destruction of thyroid tissue. Hashimoto’s disease has been associated with other autoimmune disorders, including Addison’s disease, hypoparathyroidism (as well as a form of pseudohypoparathyroidism), pernicious anemia and insulin-dependent diabetes mellitus. It also has been associated with Turner’s and Klinefelter’s syndromes.

Additional causes of acquired hypothyroidism include goitrogen ingestion, therapy for hyperthyroidism (including iodine 131 and surgery) and pituitary or hypothalamic dysfunction.

Congenital Hypothyroidism

Congenital hypothyroidism, found in newborns and in early childhood, is less common – occurring in about one of every four to five thousand patients tested, with a predominance of females to males of 2:1 and whites to blacks of over 5:1. Congenital hypothyroidism may be due to several etiologies:

• Thyroid dysgenesis, including aplasia or hypoplasia of the thyroid gland; and ectopy of the thyroid, often with hypoplasia, in which there is insufficient tissue to match the demands of the infant or growing child. Together these abnormalities account for over 80% of the cases. A definitive diagnosis may be obtained with an iodine 123 or a technetium 99m scan.
• Dyshormonogenesis, a serious error in thyroid hormone synthesis. There may also be end organ unresponsiveness, defects in the receptors on the thyroid or at the peripheral tissue level.
• Hypopituitarism (secondary hypothyroidism) due to pituitary aplasia or midline brain developmental defects. There may also be hypothalamic dysfunction (tertiary hypothyroidism).

Growth Failure

Peter’s clinical appearance, medical history and biochemical profile constitute a classic picture of hypothyroidism secondary to adolescent-onset Hashimoto’s disease. His growth retardation in mid-late childhood served as a red flag to his pediatrician. Hypothyroidism is easily the most common endocrinologic cause of growth failure in this age group.

Observations by Peter’s parents of their son’s diminished interest in physical exercise and lack of motivation could have been viewed as typical signs of adolescence or – when viewed as part of the total picture – as fatigue and lethargy caused by hypothyroidism.

Peter’s sallow complexion (from high carotene concentrations), low blood pressure, slow heart rate, pseudomuscular hypertrophy and retarded bone age, while not dramatically diagnostic, complement a panel of blood chemistries that clearly indicate hypothyroidism caused by autoimmune thyroid disease: T4<1ug/dl, T3 resin uptake = 36%, TSH>64 S.I. units elevated antimicrosomal titer (1:1600) and also an elevated cholesterol (304 mg/dl).

Cholesterol. Elevated cholesterol such as Peter’s can be a nice tip-off to hypothyroidism for the astute pediatrician, even before signs of disease are apparent. And because cholesterol is part of routine SMA, it’s an economical and accessible indicator. With the movement toward early detection and prevention of heart disease, pediatricians are beginning to take new interest in their patients’ cholesterol and triglyceride levels. It’s worth mentioning that the cholesterol level, unlike triglycerides, is reasonably accurate in a nonfasting state.

Goiter. The fact that Peter did not have a goiter should not prevent making a diagnosis of Hashimoto’s disease. If thyroid tissue is being stimulated by TSH from the pituitary there may be a goiter; there will not be a goiter if the patient has inadequate thyroid tissue or if his thyroid has essentially “burned out” by the time the disease is detected.

Titration and replacement in the adolescent. I treat with levothyroxine tablets because it’s good physiologic medication, opposed to a combination T3/T4 preparation. While there are weight and surface area dos guidelines for titrating infants and smaller children, titrating replacement therapy for the adolescent is really more of a subjective, trial-and-error process.

Knowing that levothyroxine tablets have a long – 7-9 day – half-life, and that Peter would clear the drug more slowly because of his longstanding hypothyroidism, I picked a reasonably low – 0.1 mg – starting dose for his general size (about 2 ug/kg). As I did with Peter, I see the newly diagnosed hypothyroid patient 4 to 5 weeks after initiation of therapy. At that point, I test the response to treatment with levothyroxine tablets by measuring T4 and T3 resin uptake and using a highly sensitive TSH assay; I repeat this in 3 to 4 months or so to assure myself that his growth has picked up. I then see the patient every 6 months to verify that his response to levothyroxine tablets replacement therapy has not changed until linear growth is essentially complete. When you following TSH, rather than only the T4 and T3 resin uptake, it’s quite apparent whether the patient has been taking his medication on a regular basis or whether he’s “loaded up” right before coming to the office, since TSH levels take 3 to 4 weeks to fully reflect the thyroid hormone replacement.

Neonatal Hypothyroidism

Hypothyroidism in the young child, particularly the neonate, is truly an urgent situation. Because proper development of normal brain and neural tissue in early life required adequate levels of thyroid hormone, deficiency can cause severe, irreversible mental and physical handicaps, a condition known as cretinism. As we know, the major part of brain development – 90% – occurs during the first 2 years of life.

Because of the serious implications of undetected thyroid deficiency in the age group, there’s good clinical and financial justification for a national screening program.

Screening. Today, in the United States, neonates are required to be screened for low T4 levels on the third to fifth day of life, at the same time that blood is obtained on a piece of filter paper for PKU testing. Usually, a TSH assay is performed on the same blood spot from infants whose T4 results are in the lowest 3% to 10%. One program routinely rescreens at 4 to 6 weeks and has increased its detection of congenital hypothyroidism by over 10%. Results are sent directly to the pediatrician. In the case of a low T4 and elevated TSH, the patient must be retested with standard T4 and TSH determinations.

Effect on IQ. The longer the child with hypothyroidism remains untreated, the greater is his loss of intellectual capacity, as gauged by standard intelligence testing (“IQ”). Ultimate IQ has been shown to be significantly higher among children whose hypothyroidism was detected and properly treated prior to 6 weeks of age versus those whose hypothyroidism went untreated for 6 to 12 weeks.

Borderline T4 readings. Because neonatal hypothyroidism is usually caused by an ectopic or hypoplastic hypothyroid gland, there may be some thyroid hormone released that will be picked up on a T4 assay. Small amounts of additional hormone may be absorbed from breast milk. Therefore, pediatricians should have a high index of suspicion regarding a low-normal T4 reading and should retest the patient as soon as possible.

Clinical presentation. For all practical purposes, over 90% of all cases of neonatal hypothyroidism are detected by laboratory screening, reducing the opportunity for clinical diagnosis. Occasionally, however, I see a report in the literature about a patient with hypothyroidism masked by Down’s syndrome. This points out the need to keep one’s diagnostic skills honed in order to pick up the occasional hypothyroid infant or young child who may have escaped detection. It also points out the association of other congenital abnormalities (up to 20%) with hypothyroidism, which may confuse its diagnosis.

The hypothyroid newborn can present with a wide range of symptoms that might be attributed to various other disorders. When assess as a part of the total picture, however, these are the classic signs and symptoms of hypothyroidism in the infant: jaundice, feeding problems, hoarse cry, lethargy, hypothermia, hypotonia, distended abdomen, and mottled skin. As time passes one may also notice macroglossia, umbilical hernia and patent fontanelles.

Urgency for Replacement in the Neonate

Most contemporary medical opinion indicates that newborns with low-normal T4 and elevated TSH (>10 S.I. units) after the first few weeks of life should be regarded as hypothyroid and treated prophylactically for their first 2 to 3 years. After this time, if there is a question whether the results represented a transient condition (such as placental transfer of maternal goitrogens or anti-TSH receptor antibodies), the thyroid hormone may be safely withdrawn and the T4 and TSH levels measured in 3 to 4 weeks.

In any case, therapy must be initiated quickly and then monitored, as over- and under-replacement pose serious, lifelong consequences for the infant:

• Chronic overtreatment or over-replacement of thyroid hormone can cause craniosynostosis – premature closure of the cranial sutures – and abnormal brain maturation. Other skeletal effects of overdosing are closure of epiphyses and possible osteoporosis. Overtreated infants are irritable, nervous and have problems gaining weight.
• Chronic under-replacement retards physical and intellectual growth and poses all of the eventual problems consistent with hypothyroidism.

Neonatal titration. I have found 12 to 15 ug/kg of levothyroxine tablets to be a reasonable starting dose in the infant. After 2 weeks, I lower the dosage, attempting to maintain T4 between 10 and 15 ug/dl. I see the patient and monitor T4 and T3 resin uptake, and run a highly sensitive TSH assay every 1 to 2 months in the first year and every 3 to 4 months during the second year, the period of exceptionally rapid growth and hormone demand. There is recent evidence that small and transient variations in highly sensitive TSH concentrations are not particularly significant.

The hypothyroid child may be protected against overtreatment by increased deiodination of thyroxine to the relatively inactive reverse triiodothyronine instead of to triiodothyronine, which appears to be the most important in regulating TSH levels. The best index of optimal thyroxine therapy may be a normal response to administration of TRH (TSH-releasing hormone). Generally, a stable replacement dose is achieved by 3 years of age.

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Copyright © 1993 Thyroid Foundation of Canada/La Fondation canadienne de la Thyroïde.
Reprinted from Thyrobulletin, Vol. 14, No. 1, 1993.