Richard S. Rivlin

Defects of taste and smell in patients with hypothyroidism

Taste and smell functions were measured in 18 unselected patients with untreated primary hypothyroidism, and in 15 of the 18 patients after treatment with thyroid hormones. Before treatment, 9 of the 18 patients (50 per cent) were aware of some alteration in their sense of taste, and 7 of the 18 patients (39 per cent) were aware of some alteration in their sense of smell. Distoritions of tase (dysgeusia) and smell (dysosmia) were frequent complaints among the untreated patients; dysgeusia was observed by 7 patients (39 per cent) and dysosmia by 3 patients (17 per cent). Median detection and recognition thresholds for four taste stimuli salt (sodium chloride), sweet (sucrose), sour (hydrochloric acid) and bitter (urea), and for two smell stimuli (pyridine and nitrobenzene), were determined in each patient before and after treatment with thyroid hormones. Before treatment, decreased taste acuity (hypogeusia) for at least one stimulus was observed in 14 of the patients (83 per cent); the most common abnormalities were in the detection and recognition of bitter stimuli. Median detection thresholds for both smell stimuli were also markedly elevated (hyposmia) before therapy. Treatment with throid hormones largely reversed both the taste and smell defects. In one patient, taste and smell abnormalities were completely corrected after 16 days of treatment with thyroxine. This study indicates that taste and smell defects are common clinical abnormalities in primary hypothyroidism, and suggests that these defects may contribute to the anorexia and lack of interest in eating which are frequently observed.

Regulation of flavoprotein enzymes in hypothyroidism and in riboflavin deficiency.

Abstract Evidence is reviewed that hypothyroidism and riboflavin deficiency have in common (1) reduced hepatic levels of flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and riboflavin, (2) reduced activities of flavoprotein enzymes and (3) similar alterations in the activities of enzymes metabolizing FMN and FAD. Changes in riboflavin deficiency are generally in the same direction as the changes in hypothyroidism, but are of much greater severity. Riboflavin deficiency differs from hypothyroidism in that in the former condition the activity of FAD pyrophosphorylase, which converts FMN to FAD, is increased, whereas in the latter condition it is unchanged. This finding is consistent with the observations that hepatic FMN levels decline to a greater extent than do FAD levels in riboflavin deficiency, and that both FMN and FAD are reduced similarly but less impressively in hypothyroidism. Adaptation of FAD pyrophosphorylase activity in riboflavin deficiency may represent a physiological mechanism for conserving FAD at the expense of FMN. A study of the induction of mitochondrial α-glycerophosphate dehydrogenase, an FAD-linked enzyme, by thyroid hormone reveals that in riboflavin-deficient rats, increases in activity are markedly less than in either normal or hypothyroid animals similarly treated. This finding is compatible with the hypothesis that the diminished supply of FAD available in riboflavin deficiency imposes a restriction upon the accumulation of the flavoprotein enzymes. With progressive riboflavin deficiency, the decreases in levels of FAD and decreases in induction of α-glycerophosphate dehydrogenase occur together. Hepatic FAD cannot be increased in deficient rats by treatment with thyroid hormone. The results of these experiments provide additional evidence that the rate of synthesis of the coenzymes FMN and FAD may regulate the activities of flavoprotein enzymes. It is suggested that diminished synthesis of FMN and FAD may account in large part for the similarity between hypothyroidism and riboflavin deficiency in the hepatic profile of flavoprotein enzyme activities.

A competitive protein binding assay for urinary riboflavin

Abstract A competitive protein binding assay is described for the determination of riboflavin in human urine. The method uses chicken egg white as the source of specific riboflavin-binding protein and 2-14C-riboflavin as tracer. The average 24-hr urinary output of RF was 1.23 mg in men and 0.79 in women. The method is simple, specific, sensitive, and reproducible.

Chlorpromazine antagonism of thyroxine-induced flavin formation.

Abstract Chlorpromazine inhibits the incorporation of riboflavin into flavin adenine dinucleotide and flavins bound covalently to proteins in vivo in rat liver. In addition, this drug markedly blunts thyroxine enhancement of riboflavin incorporation into flavins, both observations being made at concentrations of chlorpromazine commonly used clinically. These findings indicate that chlorpromazine is a riboflavin antagonist and inhibits effects of thyroxine upon riboflavin metabolism.

Hormonal Regulation of Riboflavin Metabolism

The endocrine glands play an important role in the control of various aspects of riboflavin metabolism. The conversion of the vitamin into its active coenzyme derivatives, FMN and FAD, is subject to hormonal regulation. Hormones influence the metabolic utilization of the vitamin, the magnitude of tissue concentrations, the rate of excretion in urine, and, in certain species, the transport of the vitamin in plasma. Disturbances in the metabolism of riboflavin accompany endocrine disorders both in experimental animals and in man.

Pathogenesis of Brain Dysfunction in Deficiency of Thiamine, Riboflavin, Pantothenic Acid, or Vitamin B6

We have attempted to review the literature available to date concerning the effects of a deficiency of one of four water-soluble vitamins—thiamine, riboflavin, pantothenic acid, and vitamin B6—on the mammalian system and how such deficiency affects the central nervous system and its functioning. These vitamins are all involved in enzyme systems of the body as coenzymes, and a deficiency therefore results in multiple biochemical disturbances. We have tried to relate these biochemical disturbances, where possible, to the accompanying physical and neurological changes.

Regulation of formation of covalently bound flavins in liver and cerebrum by thyroid hormones.

Abstract The effects of thyroxine (T 4 ) and triiodothyronine (T 3 ) treatment upon the formation of [2- 14 C]flavins bound covalently to tissue proteins in liver and cerebrum were measured 1 h after a subcutaneous injection of [2- 14 C]riboflavin in male rats of different ages. In livers of rats of ages 2, 3, and 12 months, T 4 (100 μg/100 g body wt) and T 3 (25 μg/100 g body wt) in daily intraperitoneal doses for 7 days each increased incorporation into covalently bound flavins 50% above that in saline-treated controls. In newborn rats, T 4 in doses of 10 μg/rat for 7 days increased incorporation similarly to that in adults. In adult rats doses of T 3 from 2.5 to 25 μg/100 g body wt were nearly as effective as larger doses of T 3 and T 4 in increasing the formation of covalently bound flavins in liver. In cerebra of newborn rats, T 4 was ineffective in increasing the formation of covalently bound flavins. However, in cerebra of rats of ages 2, 3, and 12 months, both T 3 and T 4 consistently increased the formation of covalently bound flavins. Doses of T 3 from 2.5 to 25 μg/100 g body wt produced significant increases. These findings are of interest in view of our previous demonstration that the formation of flavin adenine dinucleotide, the major tissue flavin, is not increased in rat brain even by massive doses of thyroid hormones. The present results indicate that the formation of the fraction of flavins bound covalently to tissue proteins differs from the usual pattern of brain metabolism of adult rats in being subject to control by thyroid hormones.

Tyrosine and glutamic acid in plasma and urine of patients with altered thyroid function

Abstract The plasma concentrations of glutamic acid and tyrosine were measured in euthyroid, hyperthyroid, and hypothyroid patients. In the group of normal individuals, plasma concentrations of glutamic acid were more variable than were those of tyrosine. Levels of glutamic acid in plasma were elevated proportionately more than were those of tyrosine in hyperthyroidism, but were normal in hypothyroidism. Oral sodium glutamate tolerance in hyperthyroid patients did not differ from that of normal subjects in the mean increments attained from fasting to peak levels. This contrasts with altered tyrosine tolerance previously reported in hyperthyroidism. In hypothyroid patients, after ingestion of a load of sodium glutamate the mean increments from fasting to peak levels were slightly greater than normal. Daily variations in the plasma concentrations of glutamic acid were undemonstrable in normal individuals and were not modified by either hyperthyroidism or hypothyroidism. An unexplained elevation in the plasma concentration of glutamic acid at 2 a.m. was observed in several hyperthyroid patients. The urinary excretion of glutamic acid in a 24-hr period was increased nearly tnefold in hyperthyroid patients compared to results obtained in normal subjects. A similar percentage of the total glutamic acid (31–37%) was excreted during the period from 8 a.m. to 4 p.m. in both normal and hyperthyroid patients. The urinary excretion of tyrosine was also increased in hyperthyroidism; the magnitude of the increase (nearly twofold) was less than that of glutamic acid. These data provide further evidence that in hyperthyroid patients increases in the concentrations of tyrosine and glutamic acid in plasma are consistent findings and demonstrate that the urinary excretion of both of these amino acids is also markedly increased.

Daily variations in plasma concentration of tyrosine in thyrotoxicosis and myxedema

Abstract The plasma concentration of tyrosine has been measured at intervals during two successive 24-hr periods in eight hyperthyroid, six hypothyroid and eight normal individuals hospitalized on a metabolic ward. The time of food intake and the concentration of protein in the diet have been controlled in each subject. The fasting level of tyrosine in hyperthyroid subjects, as previously reported, was elevated above normal. Hyperthyroid subjects did not differ from normal individuals in the mean increment between fasting and peak levels of tyrosine in plasma, the time at which peak levels occurred, or in the difference between values obtained during successive days. In hypothyroidism, by contrast, the mean increment between fasting and peak levels of tyrosine was reduced below normal. The time at which peak levels occurred was delayed and the differences between values obtained during two successive cycles were reduced. These data suggest that thyroid hormone deficiency tends to diminish the daily variations of tyrosine levels in plasma, but that in excessive amounts thyroid hormone does not significantly modify these variations.