monoiodotyrosine and Hypothyroidism

DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review.

Topics: Biomarkers; Congenital Hypothyroidism; Diiodotyrosine; Genotype; Humans; Hydrolases; Hypothyroidism; Infant, Newborn; Iodide Peroxidase; Iodides; Membrane Proteins; Monoiodotyrosine; Neonatal Screening; Phenotype; Prevalence

Topics: Biopsy; Chemical Phenomena; Chemistry; Chromosomes; Congenital Hypothyroidism; Culture Techniques; Decarboxylation; Female; Genes, Dominant; Genes, Recessive; Goiter; Humans; Hypothyroidism; Iodine; Iodine Isotopes; Male; Metabolism, Inborn Errors; Monoiodotyrosine; Oxidoreductases; Thyroid Gland; Thyroxine; Triiodothyronine

Topics: Animals; Biomarkers; Hypothyroidism; Iodide Peroxidase; Iodine; Mice; Mice, Knockout; Monoiodotyrosine; Thyroxine

Topics: Diiodothyronines; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Monoiodotyrosine

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.

Topics: Adult; Amino Acid Sequence; Child; DNA Mutational Analysis; Female; Frameshift Mutation; Goiter; Homozygote; Humans; Hypothyroidism; Iodide Peroxidase; Male; Middle Aged; Molecular Sequence Data; Monoiodotyrosine; Mutation, Missense; Open Reading Frames; Phenotype; Polymerase Chain Reaction; Sequence Deletion

We studied the antithyroid action of cigarette smoking products (nicotine, cotinine, and thiocyanate) in the physiological culture system of porcine thyroid follicles. Iodide uptake, iodine organification, de novo thyroid hormone formation, and iodide efflux were measured in the presence of 0-200 mumol/l nicotine, cotinine, or potassium thiocyanate. Nicotine and cotinine did not inhibit iodide transport or thyroid hormone formation. Thiocyanate concentrations equivalent to serum levels of smokers showed three independent antithyroid actions: (i) inhibition of iodide transport, (ii) inhibition of iodine organification, and (iii) increased iodide efflux. Inhibition of iodide transport by thiocyanate was competitive with iodide and independent of TSH concentration. Thiocyanate did not inhibit TSH mediated cAMP production or Na+K+ ATPase activity, a sodium pump for iodide transport. When 50 mumol/l thiocyanate was added 2 h after incubation with iodide or when 1 mumol/l thiocyanate was added from the beginning of incubation, iodine organification was inhibited without changing iodide transport. De novo thyroid hormone formation was clearly inhibited by 50 mumol/l thiocyanate. Thiocyanate increased iodide efflux although the degrees of iodide efflux by 10 mumol/l and 100 mumol/l thiocyanate did not differ significantly. In summary, thiocyanate, a product of smoking, has three independent antithyroid activities. The data of iodide transport kinetics suggest that thiocyanate can be an antithyroid agent particularly in iodine deficiency.

Topics: Animals; Antithyroid Agents; Cells, Cultured; Cotinine; Cyclic AMP; Hypothyroidism; Iodine; Iodine Radioisotopes; Monoiodotyrosine; Nicotine; Smoking; Sodium-Potassium-Exchanging ATPase; Swine; Thiocyanates; Thyroid Gland; Thyroid Hormones; Thyrotropin

Recently, thyroid microsomal antigen was identified as thyroid peroxidase, and thyroid microsomal antibody was found to inhibit thyroid peroxidase activity in vitro. We investigated the possibility that anti-microsomal antibody inhibits the iodination of tyrosine, in vivo. Immunoglobulin G with or without anti-microsomal antibody from hypothyroid patients with goitrous Hashimoto's thyroiditis inhibited thyroid hormone synthesis in cultured slices of normal human thyroid tissue. IgGs with anti-microsomal antibody inhibited 125I thyroidal uptake and thyroid hormone synthesis stimulated by TSH more than normal IgG did. However, the same results were obtained with IgGs without anti-microsomal antibody. This effect did not involve anti-microsomal antibody, anti-thyroglobulin antibody, TSH-binding inhibitor immunoglobulin, thyroid stimulation-blocking immunoglobulin, or the cAMP level of the thyroid tissue. The ratio of organic I to inorganic I with stimulation by TSH in slices incubated with IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis or normal IgG was not significantly different, but was significantly higher in slices incubated with methylmercaptoimidazole. Therefore, IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis mainly suppressed 125I thyroidal uptake, rather than inhibiting thyroid peroxidase activity. In addition, this IgG was present in the serum of 11 of the 12 hypothyroid patients with Hashimoto's thyroiditis studied. This IgG may be involved in the mechanism that causes hypothyroidism in some patients with goitrous Hashimoto's disease.

Topics: Adult; Amino Acids; Autoantibodies; Culture Techniques; Cyclic AMP; Diiodotyrosine; Female; Humans; Hypothyroidism; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Iodine; Isoantibodies; Male; Middle Aged; Monoiodotyrosine; Thyroid Gland; Thyroiditis, Autoimmune; Thyrotropin; Thyroxine; Triiodothyronine

A 21-year-old goitrous hypothyroid Chinese woman had elevated serum iodotyrosines with a monoiodotyrosine level of 85.9 nmol/l (normal 0.49-0.89 nmol/l) and a diiodotyrosine level of 25.3 nmol/l (normal 0.023-0.53 nmol/l). She was amenorrheic with low luteinizing hormone and follicle-stimulating hormone levels at 5.8 and 2.8 U/l, respectively. The hypogonadotropic hypogonadism was due to an elevated prolactin level of 8.8 nmol/l. She also had a low potassium level of 3.2 mmol/l, and a high urinary aldosterone level of 158 nmol/day. The hyperprolactinemia, hypogonadotropic hypogonadism, hyperaldosteronism and hypokalemia subsided with the administration of bromocriptine 5 mg/day. However, bromocriptine accentuated the hyperiodotyrosinemia, and the patient remained hypothyroid. Levothyroxine therapy lowered the monoiodotyrosine and diiodotyrosine levels, ameliorated all her endocrinopathies, started her periods, and shrank the goiter. She probably had a deiodinase defect which permitted the discharge of accumulated iodotyrosines from the thyroid gland. Since iodotyrosines are tyrosine hydroxylase inhibitors, the hyperiodotyrosinemia causes dopamine synthesis inhibition, and induces the hyperprolactinemia and hyperaldosteronism.

Topics: Adult; Aldosterone; Bromocriptine; Dopamine; Dose-Response Relationship, Drug; Epinephrine; Female; Follicle Stimulating Hormone; Humans; Hyperaldosteronism; Hyperprolactinemia; Hypothyroidism; Luteinizing Hormone; Monoiodotyrosine; Norepinephrine; Prolactin; Thyrotropin; Thyroxine

Normal serum monoiodotyrosine (MIT) levels (n = 152) were 0.69 +/- 0.20 nmol/l. There was wide variation of MIT levels in a 24-hour period without diurnal pattern, and there was no change throughout the menstrual cycle. MIT levels declined upon aging, but levels in hypo- and hyperthyroidism were not significantly different. MIT levels were detected in athyrotic patients (0.32 +/- 0.08 nmol/l). Desiccated thyroid raised the athyrotic MIT levels to the normal range, while levothyroxine did not. Diiodotyrosine (DIT) infusion caused an MIT rise which paralleled but lagged 1 h behind the DIT rise. These data suggest thyroidal as well as nonthyroidal sources of MIT, one of which is deiodination of DIT. Ingestion of 1 g MIT increased serum MIT to 10.6 +/- 1.7 mumol/l in women, and 7.1 +/- 2.3 mumol/l in men 30 min after ingestion; the serum half-life was 45 min.

Topics: Adult; Aging; Circadian Rhythm; Diiodotyrosine; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Menstrual Cycle; Middle Aged; Monoiodotyrosine; Reference Values; Thyroxine

Topics: Animals; Body Weight; Female; Hypothyroidism; Iodine; Male; Monoiodotyrosine; Oxalates; Rats; Sex Factors; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

A sensitivie, reliable gas-chromatographic assay for monoiodotyrosine and diiodotyrosine in human serum is reported. The oxazolidinone-heptafluorobutyric anhydride derivatives allow the quantitation of both compounds in the linear range of 0.2 to 7.6 mg/L of serum. Analytical recovery averaged 88%, and mean accuracy and within-run precision were 98 and 2%, respectively. Concentrations of monoiodotyrosine in serum as low as 20 microgram/L and of diiodotyrosine as low as 100 microgram/L can be detected. Normal serum contains no detectable concentration of either compound, but the method is applicable as a diagnostic tool in the early prediction of thyroid disease. Both compounds were detected in the serum of a hypothyroid subject whose normal thyroid hormone concentrations were being maintained by therapy with desiccated thyroid extract.

Topics: Butyrates; Chromatography, Gas; Diiodotyrosine; Fluorocarbons; Humans; Hypothyroidism; Indicators and Reagents; Monoiodotyrosine; Oxazoles

Topics: Congenital Hypothyroidism; Diiodotyrosine; Female; Goiter; Humans; Hypothyroidism; Infant; Infant, Newborn; Iodine Radioisotopes; Iodoproteins; Male; Metabolic Clearance Rate; Monoiodotyrosine; Radioimmunoassay; Thyroglobulin; Thyroid Function Tests; Thyrotropin; Triiodothyronine

In homogenate supernatants of kidneys of male rats the extent of deiodination of L-diiodotyrosine (L-DJT) and L-thyroxine (L-T4) was investigated in dependence on the thyroid function (hypo- and hyperthyroidized) and also in dependence on age. In rats hypothyroidized by loading with Methylthiouracil (MTU) or Methimazol (MMI) the deiodination for L-DJT and L-T4 was significantly reduced, in rats loaded with 40 mug T4 sc. for 10 days, the deiodination was significantly enhanced compared with untreated control animals. With advancing age (6 weeks, 3 or 12 month) the deiodination activity is highly significantly reduced. The results underline relations between thyroid gland function and deiodination activity in kidney.

Topics: Age Factors; Animals; Diiodotyrosine; Hyperthyroidism; Hypothyroidism; Iodine; Kidney; Male; Methimazole; Methylthiouracil; Monoiodotyrosine; Rats; Thyroid Diseases; Thyroid Hormones; Thyroxine; Triiodothyronine

Topics: Adsorption; Animals; Binding, Competitive; Cattle; Charcoal; Diiodotyrosine; Humans; Hyperthyroidism; Hypothyroidism; Iodine Isotopes; Methods; Monoiodotyrosine; Rabbits; Radioimmunoassay; Sodium Salicylate; Swine; Thyroglobulin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Butanol-insoluble iodinated compounds in the urine of patients with congenital goiters have been generally regarded as iodopeptides. Monoiodohistidine (MIH) and diiodohistidine (DIH) were identified from the urine of four patients with congenital goitrous hypothyroidism. From radioiodine studies, 40-70% of the urinary radioactivity was in the iodide-free fraction from which about 40% was identified as MIH and DIH by crystallizations to a constant specific activity. Iodotyrosines were simultaneously identified in the urine. However the presence of an iodotyrosine-deiodinase activity was demonstrated in the two removed goiters with a normal K(m) for MIT. In vivo iodotyrosine deiodination was normal for hypothyroid subjects. No thyroglobulin was identified in the thyroids from these patients. The major iodoprotein was iodoalbumin which, after in vivo labeling, contained 84-89% of the total soluble protein radioactivity. The thyroxine content of the goiter iodoalbumins and other iodoproteins was extremely low. Iodohistidines were identified in comparable proportions in the iodoalbumin and in the other iodoproteins isolated from each goiter. The average iodohistidine content of these proteins as crystallizable MIH and DIH was in the individual cases 15 and 4% of the in vivo incorporated radioiodine. DIH was identified in all iodoprotein fractions. The mean DIH/MIH ratios from the individual cases were 1.16 and 0.35. The corresponding DIT/MIT ratios were 3.19 and 1.45, respectively. The major consequence of this thyroglobulin defect is the iodination of inappropriate proteins (mainly albumin) resulting in low yields of thyroxine and high yields of iodohistidines. Iodohistidines from the goiter iodoproteins were not deiodinated and, at least for MIH, were quantitatively excreted in the urine of these patients. From the MIH iodoalbumin content and the MIH urinary excretion, goiter iodoalbumin turnover estimates were made and, although elevated, could not maintain a normal thyroxine secretion. The urinary excretion of iodohistidines easily demonstrated by column chromatography is offered as a test for detecting this variety of congenital goiter.

Topics: Adult; Albumins; Albuminuria; Child; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Female; Goiter; Histidine; Humans; Hypothyroidism; Immunodiffusion; Iodides; Iodoproteins; Male; Monoiodotyrosine; Peroxidases; Thyroglobulin; Thyroid Gland

Topics: Adult; Female; Humans; Hypothyroidism; Insulin; Iodides; Monoiodotyrosine; Peroxidases; Thyroid Hormones

Topics: Adult; Chronic Disease; Female; Humans; Hypothyroidism; Iodine; Iodine Isotopes; Middle Aged; Monoiodotyrosine; Thyroid Gland; Thyroiditis; Thyroxine; Triiodothyronine

Topics: Adolescent; Adult; Autoimmune Diseases; Biopsy; Child; Chromatography; Chromatography, Paper; Diiodotyrosine; Humans; Hypothyroidism; Iodine; Iodine Radioisotopes; Middle Aged; Monoiodotyrosine; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroiditis; Thyrotropin; Thyroxine; Triiodothyronine

The effects on thyroid function of an inhibitor of tyrosine dehalogenase, 3-nitro-L-tyrosine (MNT) have been investigated in rats. In preliminary studies, marked inhibition of iodotyrosine deiodination was demonstrated in rats drinking 8 mM MNT. A series of experiments was then performed in which rats received Remington low iodine diet and 8 mM MNT as drinking fluid. This regimen had the following effects, compared to the effects of a low iodine diet alone: (a) a decrease in serum protein-bound iodine, elevation of serum thyrotropin level, goiter, and growth inhibition all prevented or reversed by iodine supplements: (b) on initiation of MNT, a 2- to 3-fold increase in the rate of release of radioiodine from the thyroid and concomitant urinary excretion of large amounts of organic iodine: and (c) after 2 wk of MNT, a greatly increased rate of thyroidal uptake and release of (131)I, an increase in the ratio of monoiodotyrosine-(131)I to diiodotyrosine-(131)I in thyroid proteolysates and the appearance of labeled iodotyrosines in serum. Acute administration of MNT intraperitoneally to rats on either an iodine-deficient or iodine-sufficient diet did not inhibit thyroidal uptake of (131)I or alter the distribution of (131)I among thyroidal iodoamino acids. It is concluded that MNT is an effective inhibitor of iodotyrosine deiodination in vivo, without other important actions on thyroid function. Thus, MNT treatment affords a model for the human dehalogenase defect. By provoking iodotyrosine secretion and consequent urinary loss of iodine, MNT can exaggerate the effects of a low iodine intake, producing goitrous hypothyroidism despite a rapid rate of iodine turnover in the thyroid.

Topics: Administration, Oral; Animals; Blood Proteins; Chromatography, Paper; Diet; Diiodotyrosine; Disease Models, Animal; Hydrolases; Hypothyroidism; Injections, Intraperitoneal; Iodides; Iodine; Iodine Isotopes; Male; Monoiodotyrosine; Nitro Compounds; Organ Size; Protein Binding; Radioimmunoassay; Rats; Rats, Inbred Strains; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Tyrosine

Topics: Female; Humans; Hypothyroidism; Male; Metabolism, Inborn Errors; Molecular Biology; Monoiodotyrosine; Thyroid Hormones; Tyrosine

Topics: Adenocarcinoma; Colloids; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Iodine Isotopes; Iodine Radioisotopes; Iodoproteins; Liver; Monoiodotyrosine; Neoplasm Metastasis; Proteins; Serum Albumin, Radio-Iodinated; Thyroglobulin; Thyroid Neoplasms; Thyroidectomy; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Child; Child, Preschool; Congenital Hypothyroidism; Humans; Hypothyroidism; Infant; Iodine; Male; Monoiodotyrosine; Thyroid Hormones; Time Factors; Tyrosine

Topics: Autoradiography; Centrifugation, Density Gradient; Diiodotyrosine; Goiter; Humans; Hyperplasia; Hypothyroidism; In Vitro Techniques; Iodine; Iodine Isotopes; Iodoproteins; Metabolism, Inborn Errors; Monoiodotyrosine; Proteins; Thyroid Gland

Topics: Adolescent; Diiodotyrosine; Goiter; Humans; Hypothyroidism; Iodides; Iodine; Iodine Isotopes; Metabolic Diseases; Monoiodotyrosine; Thyroid Function Tests; Tyrosine; Urine

Topics: Congenital Hypothyroidism; Humans; Hypothyroidism; Monoiodotyrosine; Syndrome; Tyrosine

Five to 10 per cent of cretinism in the United States is due to some congenital enzymatic defect in thyroid hormone synthesis. The clinical signs of hypothyroidism appear in early infancy. Differentiation from athyreotic cretinism is important because the metabolic defect tends to be familial and its presence in the patient's infant relatives should be diagnosed as early as possible. The differentiation is easily made if a goiter is discernible, but if it is not, radioiodine uptake should be measured, for in this condition the uptake is normal or greater. Thyroid replacement is the treatment in either the athyreotic state or the metabolic deficiency. The three known defects in thyroid hormone synthesis are (1) failure to oxidize iodine to elemental iodine resulting in failure of all subsequent processes; (2) failure to deiodinate free iodotyrosine, and (3) failure to form iodothyronine although the previous steps are accomplished.

Topics: Congenital Hypothyroidism; Goiter; Humans; Hypothyroidism; Infant; Iodides; Iodine; Iodine Radioisotopes; Monoiodotyrosine; Syndrome; Thyroid Hormones

Topics: Body Fluids; Diiodotyrosine; Humans; Hypothyroidism; Monoiodotyrosine; Thyroxine