Endocrinology and Metabolism

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Chapter 8

Endocrinology and Metabolism

Hypocalcemia

In newborn infants there is a physiologic decline in serum total and ionized calcium during the first 48 hours of life. This decline is exaggerated in preterm infants compared with term infants, with a direct correlation between serum calcium and gestational age ( Fig. 8-1). Because no symptoms are specific for early hypocalcemia in preterm infants, the diagnosis is made by demonstrating a serum calcium level below 7 mg/dL (1.75 mmol/L).

Calcium therapy may block the normal physiologic adaptation to hypocalcemia, which includes increasing serum levels of parathyroid hormone (PTH) and 1,25(OH)2 vitamin D in the first few days of life.

Further arguments against the need for the treatment of incidentally noted hypocalcemia in the preterm infant are the following:

In the absence of additional data, it is conventional to treat all serum calcium levels below 6 mg/dL, even in asymptomatic neonates. The addition of 200 mg/kg/day of 10% calcium gluconate to standard IV solutions provides 20 mg/kg/day of elemental calcium. If symptoms are present (especially cardiac arrhythmia or seizures), a bolus of 100 mg/kg of 10% calcium gluconate (10 mg/kg elemental calcium) may be given intravenously over 10 minutes with careful cardiac monitoring. One should be cautious using a peripheral IV means to administer calcium because calcium can be very irritating to tissues.

Recent studies in premature infants using stable isotopes of calcium showed a true calcium absorption rate of 50% to 90%. Thus to meet an accretion rate of 100 mg/kg/day with an absorption rate of 75% and an assumed retention rate of 75% (which may be on the high side), oral intake of calcium for growing premature infants should be about 200 mg/kg/day. This large intake in infants with very low birth weight can be achieved only with special formulas for low-birth-weight infants or mineral fortifiers for breast milk–fed preterm infants.

This problem is much more difficult to address, although intestinal absorption is not a factor. In the early weeks of life with fluid intakes of 150 mg/kg/day, it is difficult to exceed an IV calcium intake of 60 mg/kg/day in the smallest premature infants (weight <1000 g) with standard total parenteral nutrition (TPN) solutions. When the concentration of calcium exceeds 60 mg/dL (3 mEq/dL) in TPN solutions, precipitation with phosphate may occur, depending on variables such as temperature, pH, amino acid content, and even the method by which the nutrients are added to the solution.

Clinical rickets develops in preterm infants with very low birth weight who are fed human milk not fortified with minerals and vitamins. Typically, the disease presents after 8 weeks of life with severe hypophosphatemia, “relative hypercalcemia,” and hypercalciuria. The x-ray findings mimic those of rickets resulting from vitamin D deficiency. The biochemical findings are the result of low mineral intake. Because human milk is low in both calcium and phosphorus, the very low phosphorus intake (about 50% of calcium intake) severely limits deposition of calcium in bone.

Caution: Because treatment with phosphorus alone can result in severe hypocalcemia, supplements of both minerals are imperative.

Seizures secondary to hypocalcemia are very unlikely in a previously healthy term infant at 2 weeks of age. The differential diagnosis includes late infantile tetany associated with high phosphate load (e.g., feedings with cow milk), acid–base disturbances caused by diarrhea treated with alkali therapy, and congenital hypomagnesemia (rare).

Treatment of hypocalcemic seizures is the same for both premature and term infants. In general, 10% calcium gluconate containing 9.4 mg/mL of elemental calcium is the drug of choice. The usual dose of 2 mL/kg body weight (18 mg/kg of elemental calcium). Infusion should occur slowly over the course of 10 minutes with heart rate monitoring. Make sure the line is patent before infusing calcium.

Hypercalcemia

There are three fractions of calcium in serum: ionized calcium (50%), calcium bound to serum proteins (40%), and calcium complexed to serum anions (10%). Ionized calcium and total calcium can be measured in most hospital laboratories.

Normal values (in milligrams per deciliter, expressed as mean± standard deviation and range) depend on chronologic age and laboratory variation (to a lesser degree):

Normal values (in milligrams per deciliter, expressed as mean ± standard deviation and range) depend on gestational age:

Total serum calcium above 10.8 mg/dL or ionized serum calcium above 5.4 mg/dL.

15. What are some of the causes of hypercalcemia in neonates?

16. How is acute hypercalcemia managed in newborn infants?

Williams syndrome is the likely diagnosis in an infant with hypercalcemia and supravalvular stenosis who was born small for gestational age. It results from a deletion of the elastin gene on 7q11.23. Affected infants are often described as having “elfin” faces.

The most likely diagnosis is an autosomal dominant mutation of the calcium-sensing receptor, or “hypocalciuric hypercalcemia.” The infant’s urinary calcium level will be inappropriately low for the serum calcium. In the heterozygous state this is generally thought to be a benign condition, and treatment is not indicated. Rare cases of homozygous mutations result in severe neonatal hyperparathyroidism, which is a life-threatening disorder.

A defect in the intestinal transport of tryptophan causes excretion of blue, water-insoluble tryptophan metabolites. The reason that these children have high calcium levels is not well understood.

Hypomagnesemia and Hypermagnesemia

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Intracellular and extracellular types of magnesium reactions are important.

Magnesium is the second most abundant intracellular cation after potassium and helps to regulate cellular metabolism. As part of the magnesium-adenosine triphosphate complex, it is essential for all biosynthetic processes, including glycolysis, formation of cyclic adenosine monophosphate, and transmission of the genetic code. In addition, any reaction that uses or produces energy requires magnesium.

Only 1% of magnesium is contained in extracellular fluid. However, extracellular concentrations are critical for maintenance of electric potentials of nerve and muscle membranes and for the transmission of impulses across the neuromuscular junction. Magnesium and calcium may act synergistically or antagonistically in many of these processes.

Most infants are asymptomatic. On rare occasions the following signs and symptoms may be seen:

Hypomagnesemia usually increases the secretion of PTH, thereby increasing calcium levels. In chronic magnesium-deficient states, however, secretion of PTH is reduced. In such circumstances hypomagnesemia may induce hypocalcemia.

In extreme cases cardiorespiratory function ceases, and death ensues.

Thyroid Disorders

Congenital hypothyroidism occurs in 1 in 4000 liveborn infants.

32. What are the embryonic stages of development of the fetal hypothalamic–pituitary–thyroid axis?

The hypothalamic–pituitary–thyroid axis is in place by the end of the first trimester. The thyroid and pituitary glands reach mature secretory capacity by 30 to 35 weeks of gestation. The feedback interrelationship among the units is fully established when hypothalamic TRH maturation is completed by 1 to 2 months after birth.

The amount of T4 secreted by the fetal thyroid gland increases slowly until midgestation (20 to 24 weeks) when, stimulated by increasing amounts of TSH from the fetal pituitary, T4 levels begin to increase more rapidly, reaching a normal adult level by approximately 30 weeks’ gestation. Thereafter T4 increases slowly to high normal levels at term gestation.

The amount of circulating TSH begins to increase in midgestation (20 weeks) and reaches a peak level of approximately 15 μU/mL by 30 weeks’ gestation. The TSH level then declines gradually to about 10 μU/mL at term.

Maternal TSH does not cross the placenta, but maternal iodine crosses the placenta freely and is essential for the synthesis of thyroid hormones by the fetus.

The placenta is a barrier to the passages of thyroid hormones and contains enzymes that break down maternal T4 and T3 into inactive metabolites. Only a small percentage of circulating maternal T4 and very little (if any) T3 reaches the fetus. However, the amount of maternal T4 that does cross the placenta is significant. During the first 10 to 12 weeks of gestation, all of the circulating T4 in the fetus is from maternal sources; thus early brain development depends on maternal hormone. Even after the fetus synthesizes its own T4 in the second and third trimesters, maternal T4 is essential for normal neurologic development, including neuronal proliferation and maturation, dendritic arborization, and synapse formation. It accounts for approximately 30% of fetal T4 levels at term.

Within 15 to 20 minutes after birth, the fetal pituitary releases a surge of TSH, probably in response to cooling. TSH reaches a peak of about 80 μU/mL in approximately 30 minutes, decreases rapidly over the first 24 hours of life, and then drops more gradually to levels comparable to normal adult levels by the end of the first 1 to 2 weeks of life.

Serum T4 levels increase rapidly, reaching a peak level of about 17 μg/dL at 24 hours. T4 then gradually decreases to levels at the upper limit of normal adult values over the first 4 to 5 weeks of life. Free T4 levels follow the same pattern, reaching a peak of 3.5 ng/dL at 24 to 36 hours.

The levels of TRH, TSH, T4, free T4, and T3 are lower in premature infants than in term infants, and the postnatal surges of TSH and T4, although qualitatively similar, are blunted. These differences are related directly to gestational age: the lower the gestational age, the lower the levels and responses of thyroid-related hormones ( Table 8-1).

TABLE 8-1

SERUM THYROXINE (µg/dL) AT DIFFERENT GESTATIONAL AGES

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Mean (standard deviation).

Adapted from Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978;92:963–7.

The term refers to infants with low birth weight (30 to 35 weeks’ gestation) or very low birth weight (<30 weeks’ gestation), who have an even more attenuated rise in T4, after which T4 levels drop below cord levels in the first week of life. Then they rise gradually over 3 to 6 weeks to approach levels of term infants ( Table 8-2).

The premature infant with low T4 and persistently elevated TSH has either transient or permanent hypothyroidism and should be treated with T4 until the nature of the condition becomes clear. However, whether premature infants with low T4 and normal TSH levels should be treated remains controversial.

This question has not yet been answered. There are some case reports in the literature suggesting that breastfeeding delays the onset of hypothyroidism, but others argue against that finding.

Signs and symptoms of hypothyroidism are subtle at birth, and the characteristic appearance of cretinism may not be apparent for 3 to 4 months. The brain requires thyroid hormone for normal development until approximately 2 to 3 years of age, and deficiency of thyroid hormone during this period causes irreversible brain damage to an extent related directly to the length of time of the hypothyroidism. Thus it is of vital importance to identify a hypothyroid infant as quickly as possible, even before clinical signs appear.

A heel-stick blood sample is taken at discharge or 3 days of life, whichever is earlier. In most parts of the United States, T4 is measured first, then TSH is measured in samples with the lowest 10% to 29% of T4 results.

See Table 8-3.

TABLE 8-3

CAUSES OF CONGENITAL HYPOTHYROIDISM AND INCIDENCE OF EACH

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From Fisher FA. Disorders of the thyroid in the newborn and infant. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: Saunders; 1996. p. 57.

The thyroid-stimulating immunoglobulins (TSIs) cross the placenta and may cause fetal thyrotoxicosis, resulting in goiter, tachycardia, rapid skeletal maturation, premature birth, and congestive heart failure. Long-term neurologic deficits may result because excessive T4 reduces neuronal proliferation.

Only approximately 1 in 70 neonates born to thyrotoxic mothers exhibit clinical thyrotoxicosis. Such infants may show a phase of transient hypothyroidism caused by antithyroid drugs (half-life, 2 to 3 days), then thyrotoxicosis resulting from maternal TSIs. Transient congenital hypothyroidism can result from transplacental transfer of maternal thyrotopin-blocking antibodies.

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