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135-139 (1996)
Thyroid hormone production is regulated via pituitary Thyroid gland function is regulated by thyrotropin (TSH)
thyrotropin (TSH) modulation of thyroxine (T4) prohor- secretion from the pituitary gland [1].’TSH secretion in turn is
mone secretion by the thyroid gland and regulation of largely regulated by hypothalamic thyroliberin (TRH) secreted
active triiodothyronine (T) production in peripheral tis- into the pituitary portal vascular system to stimulate pituitary
sues via metabolic events influencing activities of the iodo- gland TSH release, and by a feedback-inhibiting loop whereby
thyronine monodeiodinase enzyme systems. Control at free thyroxine (VT’4) acts at both the pituitary and hypothalamic
both levels is developmentally regulated and modified in levels [where it is converted to the active hormone triiodothy-
serious nonthyroidal illness (trauma, infection, cancer, met- ronine (T3)] to inhibit TSH and TRH production, respectively.
TSH stimulates the synthesis and secretion of the prohormone
abolic diseases). Racial and gender differences are of little
T4, which circulates bound to binding proteins in serum. The
significance except for the effects of placental estrogens and
most important of these binding proteins is thyroxine-binding
chorionic gonadotropin during pregnancy. There is a cir-
globulin (TBG), but transthyretin (prealbumin) and albumin
cadian rhythm of TSH secretion, with peak values at the
play secondary roles. T4 is distributed to peripheral tissues,
onset of sleep and nadir concentrations during the after-
where it is metabolized by deiodination to T3 by the iodothy-
noon hours. Peak and nadir concentrations differ by
ronine monodeiodinases (MDIs) type I and type II [2]. Most of
±50%. The effect on circulating T4 and T3 concentra-
the circulating T appears to be derived via hepatic monodeio-
tions is not significant because of the large size of the
dination of T4 by type I MDI. Type II MDI produces T3 for
extrathyroidal T4 pool. In healthy subjects there is no local action in brain, pituitary, and brown adipose tissue. T4 also
significant impact of body weight, physical training, body is deiodinated to inactive “reverse” T3 (ri’3) by a type III MDI
habitus, posture, immobilization, exercise, or ambulatory in most nonhepatic tissues, and T4 can be sulfoconjugated,
Status on thyroid function, and no significant geographic glucuronide conjugated, and (or) deaminated to the thyroacetic
environmental variation. Nutrition also has a minimal im- and thyropropionic acid derivatives. Of all the metabolites, only
pact except for variation in iodine intake. Subthreshold T3 and triiodothyroacetic acid manifest bioactivity.
concentrations of iodine intake are associated with in- All of the hormones can be measured in peripheral blood.
creased TSH secretion, goiter, increased thyroid iodine However, measurements of TRH, the sulfate and glucuronide
uptake, decreased T4 production, an increased T3f1’4 se- conjugates, and triiodothyroacetic acid have little or no clinical
cretion ratio, and an increased ratio of circulating T3/T4 application at the present time. The most important in vitro
concentrations. Excessive iodine intake can block thyroid measurements for routine clinical use include TSH and a direct
hormone biosynthesis by inhibiting the enzymes involved in or indirect measurement of FT4. The latter include the T3 resin
the biosynthetic process, resulting in reduced T4 secretion, uptake and variations. Other measurements include T3, free T3
increased TSH concentrations, goiter, and hypothyroidism (VT3), rT3, TBG, and thyroglobulin.
135
136 NACB Symposium
Fetus
12-20 weeks 5-50 0-50 1-8 2-23 0.5 - - 1
21-30 weeks 35-100 5-12 1.9-8.8 8-33 0.10-0.75 - 6-230 2
31-40 weeks 70-180 12-22 3-12 15-50 0.2-1.5 1.5-7.7 2-54 5
Infant
1-4 days 142-277 28-68 1-39 22-42 1.5-11.4 - 2-110 10
1-4 weeks 106-221 12-30 1.7-9.1 1.6-5.3 0.4-4.5 - 7
1-12 months 76-210 10-23 0.8-8.2 16-36 1.6-3.8 0.17-2.0 - 6
Child
1-5 years 94-193 10-27 0.7-5.7 12-28 1.6-4.1 0.23-1.1 2-65 5
6-10 years 82-171 13-27 0.7-5.7 12-28 1.4-3.7 0.26-1.2 2-65 4
4Data from refs. 3-6 and Corning Nichols Institute Clinical Correlations Division.
Values are 2 SD range.
function in the fetus matures progressively to maximum levels of metabolic clearance; androgens reduce circulating TBG
thyroid hormone production and utilization (per kilogram of concentrations [2]. However, these are predominantly pharma-
body weight) in early infancy [3, 4]. T4, T3, VT4, FT5, and TSH cologic effects manifest during drug administration (contra-
concentrations all are highest during this period, as are T4 ceptive or other therapeutic uses) or during pregnancy in
utilization and presumably production rate. women.
T4 utilization rates decrease progressively with age after birth
/6,1; other indicators decrease more modestly. In adults ages 20 DIETARY INFLUENCES, NUTRITION
to 50 years there are no changes with age in serum T4, FT4, or Caloric restriction tends to reduce thyroid function, with effects
TSH concentrations, but modest decreases in T3 and T4 at both the hypothalamic-pituitary and peripheral tissue levels.
utilization are observed [7]. In subjects >50 years, there are a Basal and TRH-stimulated serum TSH concentrations are
variety of progressive changes in hypothalamic-pituitary thyroid reduced somewhat and the type I MDI activities in peripheral
axis function, as summarized in Table 2 [7]. The net effect of tissues are reduced, with a concomitant reduction in T4-to-T3
these changes on circulating thyroid T4 and TSH concentra-
conversion and a reduction in serum T3 concentrations [8].
tions is minimal. There is a modest, progressive decrease in These effects are related to the extent and duration of the caloric
serum T3 concentrations.
deprivation. In severe and prolonged restriction, as in anorexia
Recent studies show little variation in serum TSH or FT4
nervosa, increased cortisol secretion may contribute to the
concentrations during the hormonal changes of puberty [5].
suppression of TSH release. The mechanism(s) mediating the
In general, thyroid-function indicators in healthy subjects
decreased TSH secretion in response to caloric deprivation is
show little or no clinically significant gender or racial varia-
not clear. Somatostatin antibody abolishes the decline in rats,
tion. Estrogen increases serum TBG concentrations by en-
suggesting increased somatostatin tone, and TRH does not
hancing hepatic sialylation of the molecule, which reduces
reverse the acute decline in TSH during fasting [8/. T4 and FT4
concentrations are not usually altered significantly in association
Table 2. Changes in thyroid function with aging.a with caloric deprivation.
Decreased TRH secretion
Decreased TSH response to TRH CIRCADIAN AND SEASONAL RHYTHMS
Decreased pituitary (negative) feedback sensitivity There is a clear circadian variation in circulating TSH concen-
Decreased T4 secretion trations in animals and in humans. TSH concentrations are low
Decreased T4 disposal during the daytime, increase in the evening, and peak shortly
Decreased (slight) T4 monodeiodination
before sleep f9-1l/. Amounts decline slowly during sleep. Table
Decreased T3 disposal
3 summarizes studies of mean, nadir, and peak serum TSH
No change in serum TSH, T4
concentrations in 98 healthy children, ages 5-18 years, and in
Decreased (slight) serum T3
two cohorts of healthy adults, one younger group (20-27 years,
aFrom ref. 7.
n = 8) and one older (67-84 years, n = 8) [9-11]. TSH is
Clinical Chemistry 42, No. 1, 1996 137
GEOGRAPHIC AND ENVIRONMENTAL INFLUENCES metabolism [19, 20]. These include: (a) reduced serum total and
The geographic and environment factors influencing thyroid FT4; (b) increased serum rT; (c) low, normal, or increased
function include iodine intake and temperature. As mentioned serum T4; and ( normal or low serum TSH.
earlier, the winter/summer effects on thyroid function are The changes in thyroid hormone metabolism are related to
detectable in large studies hut are modest in degree. It is not an inhibition of type I MDI activity, reduced conversion of T4
necessary to develop winter/summer calibrators for thyroid to T3 in peripheral tissues, reduced clearance of rT3, and a
testing. There also may be minor variations in normative serum decreased affinity of TBG for T4, which is associated with
TSH/FT4 concentrations in tropical vs colder geographic areas, reduced serum total T4 but normal FT4 in most subjects [20].
but, again, these are minor in extent. The normal FT4 and TSH concentrations in most subjects and
Subthreshold concentrations of iodine intake in geographic the transient nature of the disorder (as patients recover from
areas of endemic goiter are associated with a variety of alter- their acute illness) have led to designation of the disorder as the
ations in thyroid-function indicators. These include reduced “euthyroid sick syndrome.” The extent of the disorder is related
circulating inorganic iodine concentrations, increased thyroid to the severity and duration of the illness. In severe disease there
iodine uptake, an increased T3/T4 secretion ratio, an increased can be associated reductions in TSH and TBG concentrations,
serum T/F4 concentration ratio, decreased total and FT4 and total and free serum T4 concentrations. Of patients in
concentrations, increased serum TSH concentrations, and a intensive care units, -30-50% manifest low amounts of T3 and
tendency to goiter [18/. These changes are inversely related in T4, and low serum T4 is more frequently seen in severely ill,
degree to the prevailing iodine intake. Recommended amounts moribund patients [20]. In patients with certain liver diseases
of iodine intake are shown in Table 4 /6]. and in patients receiving certain drugs (amiodarone, radiocon-
In severe iodine-deficient areas (<50 .tg of iodine intake/day trast agents), high serum T4 concentrations can be seen-
in adults), there is an increased prevalence of goiter, congenital related to increased serum TBG concentrations or decreased T4
hypothyroidism, neurological and hypothyroid cretinism, and a metabolism, or both [20].
reduction in mean population IQ [18/. Excessive iodine intake Recent information has suggested that these thyroid system
can block thyroid hormone biosynthesis by inhibiting the en- alterations in nonthyroidal illness are related, at least in part, to
zymes involved in the biosynthetic process (the WoIff-Chaikoff increased production of cytokines (including tumor necrosis
effect) [19]. The result is reduced efficiency of T4 synthesis, factor and interleukins [20J), which have been shown to reduce
reduced T4 secretion, increased TSH concentrations, goiter, TSH secretion, inhibit T4 secretion, and inhibit hepatic gene
and hypothyroidism if the iodine excess is chronic. The chronic expression of TBG [20]. Caloric deprivation and glucocorticoid
concentrations likely to produce these effects are variable with hypersecretion may contribute significantly as pathogenetic
age (premature infants are most susceptible) and are summarized factors [20-22]. The thyroid dysfunctions associated with non-
in Table 4. Most instances of iodine-excess hypothyroidism are thyroidal illness are generally considered secondary, adaptive
due to individual dietary and drug effects, but there is some effects, and the patients remain euthyroid. Treatment is focused
variation related to geographic availability of high-iodine food- on the underlying disease.
stuffs such as seafood and kelp.
Excess iodine intake may produce a hyperthyroid state in SURGERY, TRAUMA
individuals with subclinical autoimmune Graves disease in areas Acute trauma, including surgery, also is associated with alter-
of borderline iodine deficiency [20]. In such instances the ations in thyroid-function indicators. The changes are similar to
prevailing amount of iodine intake is such that the excessive those seen in nonthyroidal medical illness and the pathogenesis
thyroid gland stimulation is not sufficient to produce overt is similar, although the process is more acute and recovery may
hyperthyroidism until the increased iodine substrate is provided. be more rapid [20-24]. Experimental studies are ongoing to
This phenomenon, referred to as “Jod-Basedow,” is uncommon. determine whether T replacement therapy in the low-T3
syndrome associated with trauma or surgery may be beneficial.
NONTHYROIDAL ILLNESSES
Systemic disease states, referred to as nonthyroidal illnesses, are
associated with a variety of alterations in thyroid hormone References
1. Dumont JE. Vassart G. Thyroid regulation. In: DeGroot U, Besser
M, Burger HG, Jameson JL. Loriaux DL, Marshall iC, et al., eds.
Table 4. Recommended dietary intakes of iodine and
Endocrinology, 3rd ed. Philadelphia: WB Saunders, 1995:543-59.
probabie safe upper iimits.a
2. Refetoff S. Nicoloff iT. Thyroid hormone transport and metabo-
Dietary IodIne intake, pg/kg per day
__________ lism. In: DeGroot U, Besser M, Burger HG, Jameson JL, Loriaux
Age Recommended Upper limit DL. Marshall JC, et al., eds. Endocrinology, 3rd ed. Philadelphia:
Premature infants 30 100 WB Saunders, 1995:560-82.
Infants 0-6 months 15 150 Thorpe-Beeston JG, Nicolaides KH, McGregor AM. Fetal thyroid
Infants 0-12 months 7 140 function. Thyroid 1992;2:207-17.
Children 1-10 years 3 50 4. Delange F, Fisher DA. The thyroid gland. In: Brook CGD, ed. Clinical
Adolescents/adults 2 30 pediatric endocrinology, 3rd ed. Oxford: Blackwell Scientific,
1995:397-433.
“From ref. 6.
_________ 5. Nelson JC, Clark Si, Borut DL, Tomei RT, Canton El. Age related
Clinical Chemistry 42, No. 1, 1996 139
changes in serum free thyroxine during childhood and adoles- 16. Galbo H. Autonomic neuroendocrine responses to exercise.
cence. I Pediatr 1993:123:899-905. Scand I Sports Sci 1986:8:3-17.
6. Fisher DA, Delange F. Thyroid hormone and iodine requirements in
17. Galbo H. Integrated endocrine responses and exercise. In: De-
man during brain development. In press.
Groot U, Besser M, Burger HG, lameson IL, Loriaux DL, Marshall
7. Solomon DH. Effect of aging on thyroid hormone metabolism. In:
IC, et al., eds. Endocrinology, 3rd ed. Philadelphia: WB Saunders,
Wu SY, ed. Thyroid hormone metabolism. Oxford: Blackwell Sci-
1995:2692-701.
entific, 1991:267-92.
8. Scanlon MF. Neuroendocnine control of thyrotropin secretion. In:
18. Medeiros-Neto G. Iodine deficiency disorders. In: DeGroot U,
Braverman LE, Utiger RD. eds. The thyroid, 6th ed. Philadelphia: Besser M, Burger HG, lameson IL, Loniaux DL, Marshall IC, et al.,
JB Lippincott, 1991:230-56. eds. Endocrinology, 3rd ed. Philadelphia: WB Saunders, 1995:
9. Rose SR. Nisula BC. Circadian variation of thyrotropin in child- 821-33.
hood. I Clin Endocrinol Metab 1989;68:1086-9. 19. Roti E, Vagenakis AG. Effect of excess iodide: clinical aspects. In:
10. Van Coevorden A, Laurent E, Decoster C, erkhofs M, Neve P. Braverman LE, Utiger RD, eds. The thyroid. 6th ed. Philadelphia:
VanCauter E, Mockel I. Decreased basal and stimulated thyro- JB Lippincott, 1991:390-402.
tropin secretion in healthy elderly men. J Clin Endocrinol Metab
20. Chopra II. Nonthyroidal illness syndrome or euthyroid sick syn-
1989:69:177-85.
drome. Endocr Care: in press.
11. Van Cauter E, Turek FW. Endocrine and other biological rhythms.
In: DeGroot U, Besser M, Burger HG, Jameson IL, Loriaux DL, 21. Nicoloff IT, LoPresti IS. Nonthyroidal illnesses. In: DeGroot U,
Marshall JC, et al., eds. Endocrinology, 3rd ed. Philadelphia: WB Besser M, Burger HG, lameson IL, Loniaux DL, Marshall IC, et al.,
Saunders, 1995:2487-548. eds. Endocrinology, 3rd ed. Philadelphia: WB Saunders, 1995:
12. Konno N, Monikawa K. Seasonal variation of serum thyrotropin 665-75.
concentration and thyrotropin response to thyrotropin-releasing 22. Van der Heyden ITM, Doctor R, van Toor H, Wilson IHP, Henne-
hormone in patients with primary hypothyroidism on constant mann G, Krenning EP. Effects of caloric deprivation on thyroid
replacement dosage of thyroxine. I Clin Endocninol Metab 1982; hormone tissue uptake and generation of low T3 syndrome. Am I
54:1118-24. Physiol 1986;251:E156-63.
13. Beck RP, Fawcett DM, Morcos F. Thyroid function studies in
23. Novitzky 0, Human PA, Cooper PKC. Effect of tniiodothyronine (T3)
different phases of the menstrual cycle and in women receiving
on myocardial high energy phosphates and lactate after ischemia
norethindrone with or without estrogen. Am I Obstet Gynecol
and cardiopulmonary bypass: an experimental study in baboons. I
1972:112:369-73.
Thorac Cardiovasc Sung 1988:96:600-7.
14. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction:
a review. Obstet Gynecol 1987;70:789-98. 24. Novitzky D, Cooper DK, Reichart B. Hemodynamic and metabolic
15. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid responses to hormonal therapy in brain-dead potential organ
function. N EngI I Med 1994;331:1072-8. donors. Transplantation 1987:43:852-5.