Alan H. Klein

Thyroid Development and Disorders of Thyroid Function in the Newborn

THE recent implementation of screening programs for the detection of congenital hypothyroidism has focused attention on the unique thyroid physiology and pathophysiology of the newborn. A high prev...

Screening for congenital hypothyroidism: Results of screening one million North American infants

Pilot programs for screening of newborn infants for congenital hypothyroidism began in North America in 1972. To date, the five oldest programs (Quebec, Pittsburgh, Toronto, Oregon Regional, and New England Regional) have screened 1,046,362 infants. A total of 277 infants with congenital hypothyroidism have been detected and seven have been missed, resulting in a total of 284 affected infants in the screened population and an overall incidence of one in 3,684 live births. Of the affected infants, 246 were determined to have primary hypothyroidism, an incidence of one in 4,254 births. Ten infants with secondary-tertiary hypothyroidism were detected in Quebec, Oregon, and Toronto, an incidence of one in 68,200 births. Of all the infants with primary hypothyroidism who were adequately studied, 63% were determined to have aplastic or hypoplastic glands, 14% normal or enlarged glands, and 23% ectopic thyroid tissue. The estimated minimum incidence of infants with TBG deficiency is one in 8,913 births. Only 8 of the 277 detected infants were suspected clinically to have congenital hypothyroidism prior to the time of confirmation of the diagnosis at 4 to 8 weeks of age. The cost of screening varied from

Neonatal thyroid function in congenital hypothyroidism

0.70 to

Effect of Fetal Thyroidectomy on Newborn Thermogenesis in Lambs

1.60 per infant, depending on which costs were included in the estimate. Preliminary evidence from Quebec suggests that infants treated in the program have normal developmental testing scores at 18 months of age.

Effect of thyroid status on lung and heart beta-adrenergic receptors in fetal and newborn sheep

In the cord blood of seven infants with congenital hypothyroidism detected in our newborn screening programs, thyroxine values ranged from 2.5 to 6.7 mug/dl and thyrotropin, from 105 to 975 muU/ml; triiodothyronine values were normal. On follow-up, T3 levels increased to normal in five infants, there was a significant negative correlation between the T3 value and the severity of thyroprevia as reflected in the TSH levels and the number of clinical features present. This increase in T3 may explain in part why the diagnosis of this disease is difficult during the first few months of life and why early treatment is effective. This observation provides further rationale for the widespread institution of newborn screening programs for congenital hypothyroidism.

Effects of changes in cell size and ouabain sensitive respiration on development of brown adipose tissue thermogenesis in the rabbit.

ABSTRACT.: We investigated the effect of the transient neonatal hyperthyroid state on thermogenesis at birth by measuring rectal temperature, plasma free fatty acids, plasma catecholamines, and in vitro brown adipose tissue respiration in thyroidectomized (n = 6) and sham operated (n = 5) fetal sheep. Surgery was performed at an average of 133 days of gestation followed by cesarean delivery at 146 days. Fetuses were delivered into a constant room temperature of 25° C. Serial measurements were made in utero before delivery and at timed intervals after birth. Serum 3,3′,5 triiodothyronine and thyroxine concentrations in the neonatal period were normal in sham operated and nondetectable in thyroidectomized fetuses. Rectal temperatures and serum free fatty acid levels were reduced in thyroidectomized newborns. Plasma epinephrine concentrations were increased and the hypothyroid neonates were acidotic when compared to control animals. In vitro basal and norepinephrine stimulated brown adipose tissue respiration were reduced in thyroidectomized compared to control animals. These results indicate that thyroid hormone deficiency impairs non shivering thermogenesis in brown adipose tissue and leads to hypothermia despite augmented plasma epinephrine values.

UNEXPLAINED HYPOGLYCEMIA IN BECKWITH-WEIDSMANN SYNDROME WITH BLUNTED GROWTH HORMONE RESPONSE

The effect of altered thyroid status on the development of beta-adrenergic receptor (BAR) density and affinity was investigated in ovine fetal and newborn heart and lung. Fetal (119-121 days gestation) and newborn (2-3 days of age) sheep underwent either thyroidectomy alone, thyroidectomy plus infusion of a large dose of T3 or sham operation. Eight days later BAR were measured in heart and lung using the tritiated radioligand dihydroalprenolol. There was no apparent effect of altered thyroid status on fetal heart or lung BAR density or affinity. In contrast, the newborns thyroidectomized and infused with T3 had a 96% increase in heart BAR density and an 83% increase in lung BAR compared to the thyroidectomized only or sham-operated newborns which were similar. These results suggest that in the near term ovine fetus heart and lung tissue BAR are neither dependent on nor responsive to thyroid hormones, whereas in the newborn period heart and lung BAR are highly responsive to thyroid hormones.

210 PRESENCE OF A PULMONARY VASCULAR “CRITICAL PRESSURE” IN INTACT CANINES: POSSIBLE EFFECT ON CAPILLARY WEDGE PRESSURE MEASUREMENTS

Summary: Basal brown adipose tissue (BAT) cell respiration increased significantly from 24 days gestation to 10 days postnatal age and demonstrated a significant positive correlation with cell size (r = 0.93, P < 0.01). After adjustment for variation due to cell size, basal respiration at 24 and 31 days fetal age were not significantly different (P> 0.05), whereas basal respiration at 10 days postnatal age was greater than that in either of the two fetal groups (P < 0.025). Ouabain did not have a consistent suppressive effect on basal respiration. Catecholamine-stimulated respiration increased significantly from 24 to 31 days gestation with no further increase at 10 days of postnatal age. Although there was a significant correlation between stimulated respiration and cell size (r = 0.92, P < 0.01), adjustment for cell size did not change this pattern of development.Mean (±S.E.) ouabain suppression of catecholamine-stimulated respiration increased from 42.8 ± 4.4% at 24 days gestation to 61.9 ± 2.9% at 31 days (p < 0.001) and 69.9 ± 1.6% at 10 days postnatal age. Stimulated respiration independent of sodium-potassium transport (respiration in the presence of ouabain) varied from a mean of 24.0 ± 4.3 μl O2/106 cells ± h at 24 days of age to 312 ± 41 μl O2/106 cells ± h at 31 days (P < 0.001) and 250 ± 24 μl O2/106 cells ± h at 10 days postnatal age. Sodium-potassium transport dependent respiration (e.g., the difference between total stimulated respiration and respiration in the presence of ouabain) increased from 17.8 ± 3.6 μl O2/106 cells ± h at 24 days to 533 ± 104 μl O2/106 cells ± h at 31 days and 561 ± 51 μl O2/106 cells ± h at 10 days postnatal age. For both sodium-potassium dependent and independent respiration measurements, mean results in the 31 day fetal and 10 day postnatal animals were similar and significantly greater than the measurements for 24 day fetal animals (P < 0.01).These results suggest that the increase in basal BAT respiration in the rabbit during fetal life is dependent on increasing BAT cell volume and not on changes in ouabain sensitive respiration. In contrast, the maturation of stimulated respiration is largely independent of changes in cell volume but is dependent on changes in both ouabain sensitive and insensitive respiration.

ABSENCE OF TRANSSYNAPTIC BETA ADRENERGIC RECEPTOR REGULATION IN OVINE FETAL LUNG AND HEART

We report a 34 week female infant, birth weight=3.7 Kg, length=49.5 cm with macroglossia, microcephaly, diastasis recti, pulmonic stenosis, visceromegaly, abnormal ear crease and multiple other problems including increased direct bilirubin and liver function tests. Severe hypoglycemia developed when weaned from parenteral nutrition at 6 weeks of age. Initial studies revealed growth hormone (GH)=7.7 ng/ml, cortisol (C)=9.7 mcg/ml, insulin (I)=2.1 mcU/ml when blood glucose (BG) = 21 ms/dl. Euglyccmia was maintained by continuous gastric feeding. Subsequent fasting showed GH=1.1, I <2.5, C=19.4, IGF I <0.6 U/ml, IGF II=532 ng/ml, C-peptide=1.1 ng/ml when BG=35. IV glucagon increased BG to 52. Therapy with GH (1 U IM QD) did not ameliorate hypoglycemia. Repeat glucagon stimulation on GH therapy demonstrated maximum I= 10 mcU/ml 1 minute after infusion and maximum GH= 3.7. Liver biopsy was negative for glycogen storage disease. Brain HRI and chromosomes were normal. Hyporbilirubinenia resolved during GH therapy. One week post GH therapy an argininc infusion test revealed:The reason for the hypoglycemia is unclear. Hyperinsulinemia or abnormal IGF I and II were not demonstrated. GH therapy was unsuccessful. Factors other than insulin, growth hormone and the known IGFs appear to play an important part in the macrosomia and hypoglycemia seen in this infant.

EFFECT OF FETAL THYROIDECTOMY ON THE METABOLIC RESPONSE TO BIRTH IN LAMBS

In intact, open-chested canine preparations, cardiac output (Q), pulmonary artery pressure (Ppa), pulmonary capillary wedge pressure (PCW), left atrial pressure (Pla), and airway pressure (PA) were measured. In a Zone II condition, pulmonary vascular pressure-flow [(Ppa - PA) - Q] relationships were determined. The mean pressure axis intercept, the average critical pressure (PC), was 15.9mmHg (range 9.4 - 18.1mmHg). These data confirm the presence of a Pc in the intact canine pulmonary vascular bed as has been previously described in isolated canine lung lobes. The presence of a PC>PA should influence Pcw measurements. During small (2–3mmHg) step-wise changes in PA over a range of PA (3–26nmHg) we observed that Pcw accurately reflected Pla at low PA and then diverged sharply. After diverging from Pla, PCW increased as PA increased with an average slope of 0.74 (range 0.61 – 0.86); PCW always exceeded PA. The breakpoint of PCW from Pla did not occur at the boundary between Zone II and Zone III of west but rather, when PA was still substantially less than Pla (mean 7mmHg less). These findings suggest that driving pressure in Zone II is the difference between Ppa and Pc, not Ppa – PA. Since PCW is either Pla or Pc, the Pcw can be taken as the pertinent back pressure to flow under all conditions.