Pediatrics

Hyperthyroidism

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal hyperthyroidism? What are the typical findings for this disease?

Key signs on physical examination are the following

  • Tachycardia

  • Hyperactivity

  • Thyromegaly

Other signs and symptoms include the following

  • Prematurity

  • Small for gestational age

  • Poor weight gain despite a voracious appetite

  • Irritability

  • Poor sleep

  • Hypertension

  • Proptosis with lid retraction and stare

  • Warm, flushed skin

  • Microcephaly with craniosynostosis

  • Frontal bossing

  • Hyperreflexia

  • Hepatosplenomegaly

  • High-output congestive heart failure in severe cases

  • Rarely fetal hydrops

What other disease/condition shares some of these symptoms?

Neonatal drug withdrawal syndromes share signs and symptoms with neonatal thyrotoxicosis.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

What is the diagnostic evaluation of neonatal Graves disease? How often should laboratory tests be obtained?

Maternal evaluation: Suspect neonatal Graves disease in a mother with active Graves disease or a history of treated Graves disease (medicallyor even with thyroid removal by surgery or radiation), as TRS-Abspersist despite treatment of the disease. Maternal TRS-Abs greater than 350%-500%(normal <125%) during pregnancy have been demonstrated to correlatewith a greater risk for neonatal Graves disease.

Fetal ultrasonography should be performed to evaluate thyroid size. The recommendation for antithyroid drug treatment of maternal Graves disease is to titratetherapy to obtain maternal fT4 and T4 levels in the mildly hyperthyroidrange to minimize fetal exposure to antithyroid medication.

Neonatal evaluation: The diagnosis of hyperthyroidism depends on a high T4, fT4, and/or high triiodothyronine (T3) levels with a low or undetectable TSH level. Infants should be monitored closely in the first few days of life as hyperthyroidism may not manifest until maternal antithyroid drugs, if present, are cleared from the neonate's system. Serial thyroid function tests should be followed weekly until the picture is clear. Neonatal thyrotoxicosis resulting from transplacental antibodies typically persists for 1-3 months, sometimes up to 6 months, until maternal antibodies are cleared.

What factors affecting fetal thyroid development can cross from the maternal circulation to the fetus?

See Table I. Maternal-Placental-Fetal Physiology: What Components Affecting Fetal Thyroid Development Cross the Placenta?

Table I.

Maternal-Placental-Fetal Physiology: What Components Affecting Fetal Thyroid Development Cross the Placenta?
Cross the Placenta Do Not Cross the Placenta
fT4, T4, T3 TRH
IgG antibodies TSH
Iodine
Antithyroid medications
Lithium
Propranolol

Would imaging studies be helpful? If so, which ones?

Postnatal imaging studies are not helpful in assessing for neonatal hyperthyroidism.

Confirming the diagnosis

Figure 1 presents an algorithm for neonatal thyrotoxicosis.

Figure 1.

Algorithm for neonatal thyrotoxicosis.

If you are able to confirm that the patient has neonatal hyperthyroidism, what treatment should be initiated?

Once recognized, neonatal hyperthyroidism should be treated aggressively for relief of thyrotoxic symptoms and prevention of longer term adverse effects on the cardiovascular system, skeleton, and central nervous system. Hospital admission may be required if tachycardia is severe enough to warrant electrocardiographic monitoring.

Beta-blockers: Propranolol 2 mg/kg/d divided in three to four doses/day or atenolol 1-2 mg/kg once daily is the quickest method to control cardiovascular and neuromuscular hyperactivity.

Iodine: This may be administered as Lugol solution (5% iodine and 10% potassium Iodide, 126 mg iodine/mL) 1 drop (8 mg) every 8 hours or SSKI (saturated solution of potassium iodide) 1-2 drops daily. Iodine rapidly inhibits the release of stored thyroid hormone and can be given for several days.

Antithyroid drugs:Methimazole (MMI) versus propylthiouracil (PTU)

MMI 0.5-1.0 mg/kg/d divided three times daily is the antithyroid drug of choice in infants and children because of reports of increased hepatotoxicity rates and vasculitis observed in children receiving PTU but not MMI therapy.

PTU 5-10 mg/kg/d divided three times daily is equally effective and has historically been the preferred antithyroid drug because of the added benefit of decreasing T4 to T3 conversion and ease of administration. Because of its safety profile, PTU is not recommended as first-line therapy in children.

Glucocorticoids: In very ill infants, pharmacologic doses of corticosteroids may be used as adjunctive treatment. In addition to antiinflammatory effects, they also inhibit thyroid hormone secretion and decrease peripheral T4 to T3 conversion.

Endocrine consultation is indicated when biochemical thyrotoxicosis is confirmed in an infant or child.

After treatment is initiated, what follow-up monitoring should occur?

If a therapeutic response is not observed within 24-36 hours, iodide therapy and antithyroid drugs may be increased. Infants should be followed with frequent clinical and biochemical monitoring to ensure that hyperthyroidism is controlled and hypothyroidism is avoided. The time to resolution is variable, and treatment should be tapered as T4 and T3 levels fall into the low-normal range.

Neonatal thyrotoxicosis due to maternal antibodies typically resolves within 1-3 months, after antibodies are cleared. Monitoring of TSH is generally not helpful, as serum TSH levels may demonstrate a delay in recovery for some time after the infant has become euthyroid.

What are the adverse effects associated with each treatment option?

The primary adverse effects seen are those associated with antithyroid drug treatment (MMI or PTU). Milder reactions are urticarial or papular skin rashes, transient leukopenia, arthralgias, and myalgias. Severe reactions include lupus-like vasculitis, agranulocytosis, and hepatitis. Side effects are dose-related and more commonly manifest in the treatment of Graves disease. When used in the scenario of neonatal hyperthyroidism, they are most commonly transient. In general, drug toxicity in neonatal hyperthyroidism is uncommon.

What are the possible outcomes of neonatal hyperthyroidism?

What is the prognosis of neonatal hyperthyroidism?

With prompt initiation of proper therapy, most infants show rapid improvement. Some studies, however, have raised concerns regarding the long-term cognitive performance despite rapid treatment, suggesting that fetal hyperthyroidism has adverse effects on the developing nervous system.

An 11-year follow-up of 26 pregnancies in 20 women with Graves disease showed that in the 92% of children who survived, 7/24 (29% of survivors) had central nervous system problems related to synostosis, motor difficulties, or severe hyperactivity. Eleven children (46% of survivors) had poor growth (height and weight <10th percentile). Eight children (33% of survivors) were of school age but below the normal grade level for age. There have also been reports of infants with prolonged central hypothyroidism that was thought to result from fetal hyperthyroidism and consequent disruption of hypothalamic-pituitary-thyroid axis development.

What causes this disease and how frequent is it?

Transient Graves disease due to transplacental transfer ofthyroid-stimulating hormone (TSH) receptor-stimulating antibodies(TRS-Ab) from a mother with autoimmune hyperthyroidism, is the most common cause of neonatal hyperthyroidism. Estimates report that approximately 2% of infants born to mothers with Graves disease manifest neonatal hyperthyroidism, or 1/25,000 births. The male-female ratio is 1:1. Other causes are the following:

Permanent, antibody-negative, congenital hyperthyroidism

TSH receptor activating germline mutations that are inherited as autosomal dominant traits or sporadic mutations. Thyrotoxicosis is non-remitting unless definitive treatment is carried out.

McCune-Albrightsyndrome, a somatic GNAS alpha activating mutation of the TSH receptor,has also been reported as a cause of neonatal hyperthyroidism.

Pituitary thyroid hormone resistance consisting of high thyroxine (T4) levels, high free thyroxine (fT4) levels with normal or high TSH levels. Because of variable resistance in different target organs and tissues, this condition maybe asymptomatic or present with variable symptoms of thyrotoxicosis.

False causes of misdiagnosed "congenital hyperthyroidism"

Thyroxine-binding globulin excess consisting of high T4 levels, normal fT4 levels, and normal TSH levels. This is a normal variant in which an individual is clinically euthyroid and does not require treatment.

Physiologic transient peak of serum T4 levels on second day of life.

How can neonatal hyperthyroidism be prevented?

In the setting of pregnancy and known maternal Graves disease, it is important to monitor the fetus for signs of hyperthyroidism. During the third trimester, if fetal goiter is detected on prenatal ultrasonography and the fetal heart rate exceeds 160 beats/min, maternal antithyroid medication should be increased until the fetal heart rate is normal. If maternal hypothyroidism develops, replacement levothyroxine should be given to restore euthyroidism in the mother.

What is the evidence?

Huang, S, Kappy, MS, Allen, DB, Geffner, ME. "Thyroid". Pediatric practice: endocrinology. McGraw-Hill Professional. 2010. pp. 107-29..

(This chapter provides an overview of thyroid disease with review of the differential diagnosis of thyrotoxicosis and management of the thyrotoxic pediatric patient.)

LaFranchi, SH, Hanna, CE, Kappy, MS, Allen, DB, Geffner, ME. "The thyroid gland and its disorders". Principles and practice of pediatric endocrinology. Charles C Thomas. 2005. pp. 312-14.

(A detailed comprehensive chapter on thyroid gland development, physiology, thyroid hormone metabolism, and thyroid gland disorders.)

Rivkees, SA, Szarfman, A. "Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children". J Clin Endocrinol Metab. vol. 95. 2010. pp. 3260-7.

(An analysis of the safety profile of MMI and PTL based on 40 years of data collected by the US FDA's Adverse Event Reporting System. This study detected higher than expected reports of severe hepatotoxicity and vasculitis with PTL but not with MMI use. It is now recommended that MMI be the antithyroid drug of choice in children with thyrotoxicosis. PTL is recommended as first-line therapy only in pregnancy because of the potential teratogenicity of MMI.)
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