Michael Kaplan

Hypothyroidism after Treatment with Interleukin-2 and Lymphokine-Activated Killer Cells

The development of a goiter and hypothyroidism in a 28-year-old man in whom metastatic melanoma had been treated with interleukin-2 and lymphokine-activated killer cells (LAK cells) prompted us to assess thyroid function in patients undergoing this therapy. Thirty-four patients with advanced neoplasms who had received interleukin-2 and LAK cells were followed for at least four weeks after treatment. Seven patients (21 percent) had laboratory evidence of hypothyroidism, with a decline in the serum thyroxine concentration to below normal (less than or equal to 35 nmol per liter; normal, 65 to 148), a decline in the serum free thyroxine index, and a rise in the serum thyrotropin concentration (peak values, 7.2 to 166 mU per liter; normal, 0.5 to 5.5) 6 to 11 weeks after treatment. Two patients had elevated serum thyrotropin levels before treatment, which increased further after treatment. In two patients, these abnormal values returned to normal within 10 months. All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. Five of the seven patients with hypothyroidism (71 percent) but only 5 of the 27 euthyroid patients (19 percent) had evidence of tumor regression (P less than 0.02). None of 11 patients treated with interleukin-2 but not LAK cells had hypothyroidism. We conclude that treatment with interleukin-2 and LAK cells can cause hypothyroidism, possibly by exacerbating preexisting autoimmune thyroiditis, and that it may be associated with a favorable tumor response.

Iodothyronine Metabolism in Rat Liver Homogenates

To investigate mechanisms of extrathyroidal thyroid hormone metabolism, conversion of thyroxine (T(4)) to 3,5,3-triiodothyronine (T(3)) and degradation of 3,3,5-triiodothyronine (rT(3)) were studied in rat liver homogenates. Both reactions were enzymatic. For conversion of T(4) to T(3), the K(m) of T(4) was 7.7 muM, and the V(max) was 0.13 pmol T(3)/min per mg protein. For rT(3) degradation, the K(m) of rT(3) was 7.5 nM, and the V(max) was 0.36 pmol rT(3)/min per mg protein. Production of rT(3) or degradation of T(4) or T(3) was not detected under the conditions employed. rT(3) was a potent competitive inhibitor of T(4) to T(3) conversion with a K(i) of 4.5 nM; 3,3-diiodothyronine was a less potent inhibitor of this reaction. T(4) was a competitive inhibitor of rT(3) degradation with a K(i) of 10.2 muM. Agents which inhibited both reactions included propylthiouracil, which appeared to be an allosteric inhibitor, 2,4-dinitrophenol, and iopanoic acid. Sodium diatrizoate had a weak inhibitory effect. No inhibition was found with alpha-methylparatyrosine, Fe(+2), Fe(+3), reduced glutathione, beta-hydroxybutyrate, or oleic acid. Fasting resulted in inhibition of T(4) to T(3) conversion and of rT(3) degradation by rat liver homogenates which was reversible after refeeding. Serum T(4), T(3), and thyrotropin concentrations fell during fasting, with no decrease in serum protein binding as assessed by a T(3)-charcoal uptake. There was no consistent change in serum rT(3) concentrations. Dexamethasone had no effect in vitro. In vivo dexamethasone administration resulted in elevated serum rT(3) concentrations after 1 day, and after 5 days, in inhibition of T(4) to T(3) conversion and rT(3) degradation without altering serum T(4), T(3), or thyrotropin concentrations. Endotoxin treatment had no effect of iodothyronine metabolism in liver homogenates. In kidney homogenates the reaction rates and response to propylthiouracil in vitro were similar to those in liver. No significant T(4) to T(3) conversion or rT(3) production or degradation could be detected in other tissues. These data suggest that one iodothyronine 5-deiodinase is responsible for both T(4) to T(3) conversion and rT(3) degradation in liver and, perhaps, in kidney. Alterations in serum T(3) and rT(3) concentrations induced by drugs and disease states may result from decreases in both T(3) production and rT(3) degradation consequent to inhibition of a single reaction in the pathways of iodothyronine metabolism.

Effect of Tri-Iodothyronine Replacement on the Metabolic and Pituitary Responses to Starvation

To determine the implication of decreased T3 production during fasting, seven normal men were fasted for 80 hours on two occasions; they received 5 microgram of T3 every three hours durnig the second fast. The mean serum T3 concentration declined during the control fast from 120 to 73 ng per deciliter (P less than 0.01), but remained slightly above base-line values during the T3 fast. Mean serum T4 concentrations did not change, and mean serum rT3 concentrations increased, during both fasts. The peak serum TSH increment after TRH was 11.1 micromicron per milliliter before fasting, 8.9 (not significant) after the control fast and 2.2 (P less than 0.01) after the T3 fast. Urea excretion was 9.1 per cent higher during the T3 fast; there were no differences in the changes in blood glucose, plasma fatty acids or other substrates during the two fasts. Pretreatment with potassium iodide lowered serum T4 concentrations and increased the serum TSH response to TRH after fasting. We conclude that the decrease in serum T3 concentrations during fasting spares muscle protein. Fasting is accompanied by a lower set point of TSH secretion, which remains sensitive to changes in serum thyroid hormone concentrations.

Phenolic and Tyrosyl Ring Deiodination of Iodothyronines in Rat Brain Homogenates

Conversion of thyroxine (T(4)) to 3,5,3-triiodothyronine (T(3)) in rat brain has recently been shown in in vivo studies. This process contributes a substantial fraction of endogenous nuclear T(3) in the rat cerebral cortex and cerebellum. Production of T(4) metabolites besides T(3) in the brain has also been suggested. To determine the nature of these reactions, we studied metabolism of 0.2-1.0 nM [(125)I]T(4) and 0.1-0.3 nM [(131)I]T(3) in whole homogenates and subcellular fractions of rat cerebral cortex and cerebellum. Dithiothreitol (DTT) was required for detectable metabolic reactions: 100 mM DTT was routinely used. Ethanol extracts of incubation mixtures were analyzed by paper chromatography in t-amyl alcohol:hexane:ammonia and in 1-butanol:acetic acid. Rates of production of iodothyronines from T(4) and T(3) were greater at pH 7.5 than at 6.4 or 8.6 and greater at 37 degrees C than at 22 degrees or 4 degrees C. Lowering the pH, reducing the protein or DTT concentrations, and preheating homogenates to 100 degrees C all increased excess I(-) production but reduced iodothyronine production. In cerebral cortical homogenates from normal rats, products of T(4) degradation were as follows (percent added T(4)+/-SEM in nine experiments): T(3), 1.9+/-0.5%; 3,3,5-triiodothyronine (rT(3)), 34.0+/-2.4%; 3,3-diiodothyronine (3,3-T(2)), 5.8+/-1.6%; 3-iodothyronine (3-T(1)), </=2.5%; and excess I(-), 4.7+/-1.2%. In the same experiments, products of T(3) degradation were 3,3-T(2), 63.3+/-5.5%, and 3-T(1), 12.6+/-1.4%. Cerebral cortical homogenates from hyperthyroid rats and normals were similar in regard to T(4) to T(3) deiodination. In contrast, in cerebral cortical homogenates from hypothyroid rats, phenolic ring deiodination rates were increased and tyrosyl ring deiodination rates were decreased compared with normals.T(4) to T(3) conversion rates in cerebellar homogenates were greater than rates in cerebral cortical homogenates from the same normal rats and less than rates in cerebellar homogenates from hypothyroid rats. T(4) and T(3) tyrosyl ring deiodination rates were greatly diminished in cerebellar homogenates compared with cerebral cortical homogenates in normal and hypothyroid rats. High-speed (1,000-160,000 g) pellets from cerebral cortical homogenates were enriched in phenolic and tyrosyl ring deiodinating activities relative to cytosol. Fractional conversion of T(4) to T(3) was inhibited by T(4), iopanoic acid, and rT(3), but not by T(3). Tyrosyl ring deiodination reactions were inhibited by T(3), T(4), and iopanoic acid, but not by rT(3). These studies demonstrate separate phenolic and tyrosyl ring iodothyronine deiodinase enzymes in rat brain. The brain phenolic ring deiodinase serves in vivo as a T(4) 5-deiodinase and closely resembles anterior pituitary T(4) 5-deiodinase in physiological and biochemical characteristics. The physiological significance of the tyrosyl ring iodothyronine deiodinase enzyme is unclear; it shares several properties with rat hepatic T(4) 5-deiodinase.

Maturational Patterns of Iodothyronine Phenolic and Tyrosyl Ring Deiodinase Activities in Rat Cerebrum, Cerebellum, and Hypothalamus

To explore the control of thyroid hormone metabolism in brain during maturation, we have measured iodothyronine deiodination in homogenates of rat cerebrum, cerebellum, and hypothalamus from 1 d postnatally through adulthood. Homogenates were incubated with (125)I-l-thyroxine (T(4)) + [(131)I]3,5,3-l-triiodothyronine (T(3)) + 100 mM dithiothreitol. Nonradioactive T(4), T(3), and 3,3,5-triiodothyronine (rT(3)) were included, as appropriate. The net production rate of [(125)I]T(3) from T(4) in 1-d cerebral homogenates was similar to the rate in adult cerebral homogenates (9.9+/-2.5[SEM]% vs. 8.9+/-1.2% T(4) to T(3) conversion in 2 h). Production of T(3) was not detectable in 1-d cerebellar and hypothalamic homogenates. The net T(3) production rate in adult cerebellar homogenates was twice as great as, and that in adult hypothalamic homogenates similar to, the rate in cerebral homogenates. Tyrosyl ring deiodination rates of T(4) and T(3) were more than three times as great in cerebral homogenates from 1-d-old rats as in adult cerebral homogenates. In cerebellar homogenates from 1-d-old rats, tyrosyl ring deiodination rates were much greater than the rates in adult cerebellar homogenates, but less than those in 1-d cerebral homogenates. In 1-d hypothalamic homogenates, tyrosyl ring deiodination rates were the highest of all the tissues tested, whereas rates in adult hypothalamic homogenates were similar to those in adult cerebral homogenates. During maturation, T(4) 5-deiodination rates increased after 7 d and exceeded adult rates between 14 and 35 d in cerebral and cerebellar homogenates, and at 28 and 35 d in hypothalamic homogenates. In cerebral homogenates, the peak in reaction rate at 28 d reflected an increase in the maximum enzyme activity (V(max)) of the reaction. T(4) and T(3) tyrosyl ring deiodination rates decreased progressively with age down to adult rates, which were attained at 14 d for cerebrum and cerebellum and at 28 d for hypothalamus. These studies demonstrate quantitative differences in T(4) 5-deiodinase activities in cerebrum, cerebellum, and hypothalamus at all ages, with the overall maturational pattern differing from the developmental patterns of both the pituitary and hepatic T(4) 5-deiodinases. Iodothyronine tyrosyl ring deiodinase activities also vary quantitatively among these same brain regions and exhibit a pattern and a time-course of maturation different from that of the T(4) 5-deiodinase. These enzymes could have important roles in the regulation of intracellular T(3) concentrations and, hence, on the expression of thyroid hormone effects.

Thyroid function in the preterm infant: a longitudinal assessment.

Serum T 4 , T 3 , rT 3 , TSH, and charcoal index-T 3 (a measure of TBG) tests were performed on samples collected from cord blood and at 24, 48, and 72 hours, and at 1, 2, and 3 weeks of age in 35 preterm infants. Appropriate-for-gestational age preterm infants (N=13) served as control subjects and had an increase during the first few days of life in mean TSH, T 4 , and T 3 values, although the magnitude of the changes was less than that reported for full-term infants. T 3 and T 4 values between 1 and 3 weeks of age remained lower than the relatively hyperthyroid levels existent in term infants. Results from infants with hyaline membrane disease (N=15) demonstrated depressions of TSH, T 4 , and T 3 values immediately after birth with T 3 values remaining significantly lower than those of AGA control subjects at 1, 2, and 7 days of age. Seven small-for-gestational age infants had increases in mean TSH, T 4 , and T 3 values which were similar to those of control infants during the first few days of life. However, T 3 values were significantly lower at 1 week, and T 3 and T 4 values were diminished ( P 3 , elevated in the cord blood of all infants, fell gradually toward normal term infant levels by 3 weeks. Indirect analysis of TBG failed to demonstrate any differences within or between the patient groups studied. We conclude that normal preterm infants have a pattern of thyroid function qualitatively similar but quantitatively different from that of term infants. The pattern itself is altered by the presence of hyaline membrane disease or intrauterine growth retardation.

Spinal stenosis caused by epidural lipomatosis in cushing's syndrome.

CENTRIPETAL fat deposition is a well known clinical feature of excessive endogenous or exogenous adrenal glucocorticoids. We describe an unusual case of central spinal stenosis caused by excessive epidural fat in a patient with Cushings syndrome secondary to prolonged therapy with high doses of glucocorticoids. Only one other case report of this phenomenon could be located in the medical literature.1 Case Report A 53-year-old woman with Graves disease, euthyroid after radioiodine therapy, had infiltrative ophthalmopathy with optic-nerve involvement. When she was treated with prednisone, 150 mg per day, cushingoid features developed rapidly. Two months after the initiation of therapy, with .xa0.xa0.

Severe Neonatal Hyperbilirubinemia and Kernicterus: Are These Still Problems in the Third Millennium?

Despite efforts to eliminate permanent and irreversible brain damage due to bilirubin encephalopathy and kernicterus, these conditions continue to accompany us into the third millennium. This phenomenon occurs not only in developing countries with emerging medical systems, but in Westernized countries as well. Comprehensive guidelines to detect newborns with jaundice and treat those in whom hyperbilirubinemia has already developed have been formulated in several countries, but have not been successful in completely eliminating the problem. In this appraisal of the situation we review selected aspects of bilirubin encephalopathy and/or kernicterus. We highlight recent reports of severe hyperbilirubinemia and kernicterus, discuss some of the factors responsible for the continuing appearance of these conditions, and briefly review what can be done to decrease bilirubin-related morbidity and mortality to the minimum.

Glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: a complexity of interactions between genes and environment.

Glucose-6-phosphate dehydrogenase deficiency is a commonly occurring genetic condition, likely to be encountered today in virtually any corner of the globe. Sudden episodes of hemolysis associated with the condition may result in exponential increases in serum total bilirubin concentrations to levels at which bilirubin-induced neurologic damage may occur. The hyperbilirubinemia is the result of complex interactions between genes and environment. Neonatal screening programs coupled with parental and medical caretaker education may be successful in limiting the severity of disease.

Neonatal bilirubin production-conjugation imbalance: Effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity

Objective: To evaluate relations between production and conjugation of bilirubin in the pathophysiology of jaundice in glucose-6-phosophate dehydrogenase (G6PD) deficient neonates. Methods: Term and borderline premature (35–37 weeks gestational age), healthy, male, G6PD deficient neonates were studied close to the beginning of the 3rd day. Blood carboxyhaemogobin corrected for inspired CO (COHbc; an index of bilirubin production) and serum total conjugated bilirubin (TCB; a reflection of bilirubin conjugation) were measured in simultaneously drawn blood samples by gas chromatography and reverse phase high performance liquid chromatography respectively. A bilirubin production-conjugation index comprising COHbc/TCB was determined; a high index reflects imbalance between the bilirubin production and conjugation processes. COHbc and TCB individually and the production-conjugation index were studied in relation to serum total bilirubin (STB) concentration. Results: Fifty one G6PD deficient neonates were sampled at 51 (8) hours. COHbc values did not correlate with STB (r u200a=u200a 0.22, p u200a=u200a 0.15). TCB did correlate inversely with STB (r u200a=u200a −0.42, p u200a=u200a 0.004), and there was a positive correlation between the production-conjugation index and STB (r u200a=u200a 0.45, p u200a=u200a 0.002). The production-conjugation index (median (interquartile range)) was higher in the premature (n u200a=u200a 8) than term neonates (2.31 (2.12–3.08) v 1.05 (0.53–1.81), p u200a=u200a 0.003). This difference was the result of changes in TCB. Conclusions: The data show that jaundice in G6PD deficient neonates is the result of an imbalance between production and conjugation of bilirubin with a tendency for inefficient bilirubin conjugation over increased haemolysis in its pathogenesis. Borderline premature infants are at especial risk of bilirubin production-conjugation imbalance.