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2 The Thyroid and Disruption of Thyroid Function in Humans
Pages 35-74

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From page 35...
... A steady supply of thyroid hormones is provided by large reservoirs in the circulation and the thyroid gland. Thyroid hormone biosynthesis and secretion are normally maintained within narrow limits by regulatory mechanisms that are sensitive to small changes in the circulating hormone concentrations.
From page 36...
... The colloid consists mostly of thyroglobulin, a thyroid protein that serves as the framework for production of T4 and T3 and as the storage form of the two hormones. THYROID HORMONE PRODUCTION, TRANSPORT, AND ACTION T4 and T3 aretheonly biologically activesubstancesthatcontainiodine.
From page 37...
... . The symporter is also present in substantialquantitiesinthesalivary glands,stomach,andmammary glands; the iodide that is transported into these tissues is not further metabolized, as it is in the thyroid gland, but instead is secreted unchanged into saliva, gastric juice, or milk.
From page 38...
... T3 is most potent thyroid hormone. T4 is active only after conversion to T3, and reverse T3 has no biologic activity.
From page 39...
... Synthesis and Secretion of Thyroxine and Triiodothyronine in the Thyroid Gland After passage through the symporter into thyroid follicular cells, iodide rapidly diffuses to the apical surface of the cells (Figure 2-1)
From page 40...
... The conversion process in extrathyroidal tissues is regulated, so production of T3 may change independently of changes in the function of the thyroid gland itself. Transport of Thyroid Hormones in Serum The thyroid hormones circulate in the bloodstream in two forms: some as the free (unbound)
From page 41...
... The proteins thus have both storage and buffering functions. Cellular Uptake and Actions of Thyroid Hormones in Tissues Free T4 and free T3 in serum are available for uptake into cells at any time.
From page 42...
... . The interaction of the genes with the receptor-hormone complexes alters the rate at which the genes synthesize molecules of messenger RNA, and thus leads to changes in the rate of synthesis of thyroid hormone-dependent proteins (Mariash et
From page 43...
... In contrast, in the pituitary gland, T3 inhibits the production of TSH, a process termed negative feedback, which ultimately leads to a decrease in hormone synthesis by the thyroid gland. REGULATION OF THYROID HORMONE PRODUCTION Thyroid hormone production is regulated in two ways: · Regulation of thyroid gland synthesis and secretion of T4 and T3 by TSH.
From page 44...
... , which stimulates TSH secretion. The interplay between T3 and TSH maintains thyroid hormone production within a narrow range.
From page 45...
... This tight control of TSH secretion results in maintenance of T4 and T3 production and secretion by the thyroid gland within very narrow limits. Thyroid gland function decreases in people with TSH deficiency, as a result of a pituitary gland disorder, just as it does in people with thyroid disease.
From page 46...
... Lower intakes are associated with increasing frequency of thyroid enlargement (goiter) , biochemical evidence of thyroid hormone deficiency, and ultimately, in people with severe iodide deficiency, hypothyroidism.
From page 47...
... If the problem is iodide deficiency or if thyroid damage or drug blockade of T4 and T3 synthesis and secretion is incomplete, the initial increase in serum TSH concentrations stimulates synthesis and secretion of the two thyroid hormones enough to raise their serum concentrations to normal or near normal. The rise in turn lowers TSH secretion to,
From page 48...
... And people with severe iodide deficiency may have slightly low serum T4 concentrations and high serum TSH concentrations, and over 30% have thyroid enlargement; overt hypothyroidism occurs only if iodide intake is below about 5-10 :g per day (Delange 2000)
From page 49...
... Clinical Consequences of Perturbations of Thyroid Hormone Production Compensation for iodide deficiency or other perturbations in thyroid hormone production, as described above, is the rule. In those cases, adults have no clinical consequences; they have normal serum T4 and TSH concentrations and no clinical abnormalities.
From page 50...
... It is known that thyroid hormone production can fall enough to increase TSH secretion yet remain within the normal range (subclinical hypothyroidism, as defined above)
From page 51...
... Thyroid Overactivity The converse sequence of changes occurs when serum T4 and T3 concentrations rise, whether because of thyroid inflammation and release of thyroid hormones stored in the thyroid gland; because of a thyroid disorder, such as a nodular goiter, that results in secretion of thyroid hormones independently of TSH; because of Graves disease, in which the thyroid gland is stimulated by antibodies that act like TSH; or because of ingestion of T4 or T3 tablets. When serum T4 and T3 concentrations rise, TSH secretion decreases.
From page 52...
... The thyroid gland, pituitary, and hypothalamus form during the first trimester of gestation (Fisher and Brown 2000)
From page 53...
... Thus, as in adults, TSH secretion in fetuses increases if fetal thyroid secretion is inhibited as a result of a thyroid disorder or iodide deficiency or the transfer of a substance that has antithyroid activity. Conversely, fetal TSH secretion is inhibited ifserumT4 concentration increases.
From page 54...
... Thyroid Function in Infants Term Infants At birth, there is a dramatic increase in TSH secretion in healthy term infants, a consequence of the relative hypothermia of the extrauterine environment. Serum TSH concentrations rise abruptly, from 3 to 8 mU/L at delivery to 50 to 70 mU/L in 30-60 minutes (min)
From page 55...
... In those infants, TSH secretion does not increase as much in response to low serum T4 concentrations as it does in more mature infants. Furthermore, preterm infants are more likely to suffer from systemic illness, such as the respiratory distress syndrome, and to be treated with medications, such as glucocorticoids, that reduce TSH or thyroid hormones.
From page 56...
... Effects of Perturbations of Maternal, Fetal, and Child Thyroid Function on Fetal and Child Development The clinical manifestations of hypothyroidism in infants vary widely, according to whether the mother, the fetus, or both have hypothyroidism and how long it persists after birth. The abnormalities are greatest when both mother and fetus are affected; this is most likely to occur in regions of severe iodide deficiency.
From page 57...
... The infants of mothers who have mild iodide deficiency have larger thyroid glands and higher serum TSH or thyroglobulin concentrations at birth than do infants of mothers whose iodide intake is higher (Glinoer et al.
From page 58...
... Their serum TSH concentrations are high and rise further soon after birth as the maternally derived T4 is metabolized and its concentration in the infants' serum falls. Those infants can be identified as having hypothyroidism if screened by measurements of TSH or T4 in blood collected 24-96 hr after birth; such screening has been in place in the United States for about 25 years.
From page 59...
... . Iodide Nutrition in Childhood Adequate iodide intake during infancy and childhood is also important; children with moderate iodide deficiency have learning disabilities and do less well on tests of mental and psychomotor performance than do children with adequate iodide intake (Tiwari et al.
From page 60...
... Therapeutic Uses of Perchlorate The medical literature of the 1960s contains reports of successful treatment with potassium perchlorate of more than 1,000 patients who had hyperthyroidism caused by Graves disease or nodular goiter. The potassium perchlorate was given in doses of 400-2,000 mg per day for many weeks or months (Crooks and Wayne 1960; Morgans and Trotter 1960; summarized in Wolff 1998 and Soldin et al.
From page 61...
... . As serum thyroid hormone concentrations declined, the dose of potassium perchlorate was reduced to an average of 93 mg per day at 12 months.
From page 62...
... There are no reports of the appearance of a new thyroid disorder, thyroid nodules, or thyroid carcinoma in any patient treated with potassium perchlorate for hyperthyroidism. Iodide deficiency in the thyroid gland, a possible consequence of perchlorate administration or exposure, is not associated with an increase in thyroid cancer (Schlumberger 1998)
From page 63...
... The results of thyroid radioiodide uptake measurements on day 2 of perchlorate administration were very similar to those on day 14 in the three higher dose groups (uptake was not measured on day 2 in the lowest dose group) (Table 2-1)
From page 64...
... The serumperchlorate half-life after cessation of this dose averaged 8.1 hr (range, 6.0-9.3) ; the half-life in the other groups could not be measured, because the values were or became undetectable very soon after perchlorate administration was stopped.
From page 65...
... Theywerefreeliving, eating aself-selecteddiet.In the studies in which thyroid radioiodide uptake was measured, the baseline values varied somewhat among the subjects, but no more than expected in healthy people eating their usual diet. The normal range for 24-hr thyroid uptake of radioiodide in many places in the United States is 10-30%, also reflecting variation in dietary iodide intake.
From page 66...
... Summary of Potential Perchlorate-Induced Perturbations of Thyroid Function in Healthy Humans The duration of the studies of potassium perchlorate administration in healthy subjects varied from 2 weeks to 6 months. In all those studies, there were no changes in serum T4, T3, and TSH concentrations to suggest that there had been any decrease in thyroid hormone secretion.
From page 67...
... However, a dose that does not inhibit thyroid iodide uptake will not affect thyroid function, even in subjects with an abnormal thyroid gland or a very low iodide intake. NONTHYROID EFFECTS OF PERCHLORATE The NIS is present in the salivary glands; mammary glands, especially during lactation; stomach; choroid plexus of the brain; and ciliary body of the eye (Dohan et al.
From page 68...
... . However, the decline in serum concentrations ofthoseantibodiesfollows,ratherthanprecedes,thedrug-induceddecrease in thyroid hormone secretion, and declines also occur in patients treated with other drugs, radioiodide, or thyroidectomy.
From page 69...
... 1988. Fine adjustment of thyroxine replacement dosage: Comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment.
From page 70...
... 2001. Plasma membrane transport of thyroid hormones and its role in thyroidhormonemetabolismandbioavailability.
From page 71...
... 2000. Molecular actions of thyroid hormone.
From page 72...
... 1997. Molecular basis of thyroid hormone-dependent brain development.
From page 73...
... 1952. Effect of perchlorate on the human thyroid gland.
From page 74...
... 1998. Perchlorate and the thyroid gland.


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