Non-thyrotropin-dependent thyroid secretion.
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Humans↗
Biomedical subjects
J T Nicoloff
Publications and source records attributed to J T Nicoloff.
Integration of thyroid hormones with hypothalamic factors on pituitary TSH secretion.
A study employing a newly developed fourth generation immunometric serum TSH assay (assay limit 0.001 mu/l was performed to determine the temporal pattern of inhibition of serum TSH in response to a maximal suppressive dose of thyroid hormone (T3, T4 and TRIAC) as compared to the pattern produced by dopamine (DA) and dexamethasone (DEX). Mean onset of inhibition was 24, 48 and 68 minutes for thyroid hormone, DA and DEX, respectively. The inhibitory pattern was uniform and reproducible for the same or different individuals if data were normalized respective to basal TSH values. Inhibitory pattern with thyroid hormone formed two distinct log linear functions: A rapid phase (phase 1) spanning 48 minutes to 24 hours and a slower phase (phase 2) bridging 24 to 1,000 hours. A diurnal variation in phase 1, but not in phase 2 suppression, was observed. A phase 1 response was also produced by DA and DEX but not phase 2. Low dose TRH infusion studies indicated that thyroid hormone and DEX inhibited thyrotroph response at or beyond the TRH receptor, while DEX appeared to inhibit endogenous TRH secretion. No additive effects of DA or DEX on T3 inhibition were seen in phase 1. These studies provide new insight into the mechanism by which these endocrine factors complementarily regulate TSH secretion in man.
Dexamethasone↗
Influence of fasting and refeeding on 3,3',5'-triiodothyronine metabolism in man.
To determine the influence of prolonged fasting and refeeding on rT3 metabolism in man, five euthyroid obese subjects underwent a 13-day fast, followed by a refeeding period. Each patient received an iv dose of 25 muCi [125I]rT3 during the fed control period, on days 7 and 13 of the fast, and on the fourth day after refeeding with a regular diet. Serial blood and urine samples were obtained to determine serum rT3 clearance and production rates and the urinary tracer rT3 deiodination fraction. Significant increases in serum rT3 values were noted by day 7 and remained elevated for the duration of the fast (P less than 0.01). Normalization of rT3 levels occurred after 4 days of refeeding. Both 7 and 13 days of fasting decreased rT3 clearance [132.6 +/- 8.3 L/day (P less than 0.001) and 132.2 +/- 9.5 L/day (P less than 0.001), respectively] without changing rT3 production (36.8 +/- 5.3 and 33.0 +/- 3.7 nmol/D, respectively) compared to control values (207.0 +/- 10.9 L/day and 31.8 +/- 3.8 nmol/day, respectively). Refeeding did not restore rT3 clearance (151.2 +/- 6.9 L/day; P less than 0.002), but significantly reduced blood rT3 production (18.4 +/- 3.8 nmol/day; P less than 0.003). The fractional deiodination of rT3 was significantly reduced on day 7 (42.5 +/- 4.6%; P less than 0.01) and day 13 (41.9 +/- 3.7%; P less than 0.01) of fasting compared to the control value (69.2 +/- 2.8%), while refeeding only partially restored deiodination to baseline (48.4 +/- 5.1%; P less than 0.04). The clearance of rT3 was highly dependent on the fractional deiodination rate (r = 0.83; P less than 0.001). Although rT3 production remained constant during fasting, reduced rT3 production was seen on the fourth day of refeeding. This unique observation explained the fall in serum rT3 to prefasting levels after 4 days of refeeding when rT3 clearance was still inhibited. This study, in context with previous investigations, indicates that T4 conversion to circulating T3 and rT3 in fasting is a highly complex and multifaceted process requiring further investigation to elucidate the mechanism responsible for these alterations.
Adult↗
Characteristics of 3,5,3'-triiodothyronine sulfate metabolism in euthyroid man.
The sulfated conjugate of T3 (T3S) has long been recognized as a normal product of peripheral thyroid hormone metabolism. In order to better understand the role that T3S may play in this process, the metabolic handling of T3S was studied in euthyroid man. After the iv administration of [125I]T3S in man, T3S was found to be rapidly metabolized with estimated mean MCR of 135 +/- 15 liters/day (L/D) after a bolus injection and 127 +/- 8 L/D employing a constant infusion. The primary route of T3S disposal was by deiodination with an efficiency of 92%. The administration of propylthiouracil (PTU, 300 mg every 6 h x 5 days) and iopanoic acid (IA, 500 mg every day x 5 days), both inhibitors of deiodination, decreased clearance compared to control (87 +/- 9 L/D, P less than 0.01 and 46 +/- 10 L/D, P less than 0.002, respectively). A 3-day fast also reduced the clearance of T3S (56 +/- 10 L/D, P less than 0.002). All three maneuvers decreased the total urinary deiodination fraction of tracer T3S (control 91 +/- 2%, PTU 70 +/- 9%, P less than 0.04, IA 26 +/- 3%, P less than 0.0001, and fasting 58 +/- 6%, P less than 0.01). A strong correlation between T3S clearance and deiodination was noted for fasting and IA only (r = 0.78, P less than 0.003). However, no relationship between clearance and deiodination was noted with PTU administration presumably as a result of a compensatory increase in biliary losses of T3S. The urinary thyronine excretion pattern demonstrated the presence of small amounts of labeled T3,3,3'-T2, and 3,3'-T2S with the major metabolite being T3S itself. TSH levels were not influenced by the infusion of stable T3S designed to achieve a serum value greater than 50 ng/dL. No absorption of intact T3S was detected after its oral ingestion. In conclusion, T3S is rapidly cleared from the serum, primarily by deiodination, may undergo nondeiodinative disposal when hepatic deiodination is inhibited by PTU but not with IA or fasting, and has no intrinsic biological activity. Thus, T3S may serve as a metabolite of T3 for its rapid deiodinative disposal. Although the precise role T3S plays in human thyroid hormone metabolism has not been defined, the metabolic characteristics of T3S appear similar to that of an unidentified alternate T4 metabolite formed in low T3 states of fasting and nonthyroidal illness.
Administration, Oral↗
American Thyroid Association guidelines for use of laboratory tests in thyroid disorders.
Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and a raised level of serum thyrotropin confirm the diagnosis of hypothyroidism caused by thyroid gland failure. An increase in free thyroxine estimate combined with a serum sensitive thyrotropin level suppressed to less than 0.1 mU/L establishes the diagnosis of thyrotoxicosis. In sick patients, a normal or raised serum free thyroxine estimate together with a normal level of serum thyrotropin suggests that the patient has neither hypothyroidism nor thyrotoxicosis. Patients with severe illnesses, generally in the intensive care unit, and those treated with certain drugs, as well as individuals with unusual thyroid disorders, may present with confusing laboratory findings. An understanding of the regulation of the thyroid hormone system and/or judicious consultation with an endocrinologist should enable the clinician to diagnose thyroid disease, if present, in such patients.
Female↗
Serum triiodothyronine values. Prognostic indicators of acute mortality due to Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome.
A feasibility study was undertaken prospectively to identify early clinical and laboratory factors predictive of acute hospital mortality in patients with the acquired immunodeficiency syndrome and concurrent Pneumocystis carinii pneumonia. Twenty-six patients hospitalized with bronchoscopy-proved P carinii pneumonia were studied. Nineteen patients survived their episode of P carinii pneumonia, while 7 subjects did not. The only clinical factor associated with mortality was a history of a shorter duration of pulmonary symptoms. Univariate analysis showed decreased total CD8 cell count, total lymphocyte count, serum hemoglobin, serum albumin, total thyroxine, and total triiodothyronine values consistent with a poor outcome. Multivariate logistic regression analysis showed that the single best prognostic indicator of acute mortality appeared to be a total serum triiodothyronine value less than 0.70 nmol/L obtained early in the hospital course, and that the combination of serum triiodothyronine and hemoglobin values provided a better indication for survival. These preliminary observations would appear to justify the further exploration of serial serum triiodothyronine measurements as a potentially valuable prognostic indicator for the treatment of patients with acquired immunodeficiency syndrome infected with P carinii and possibly other intercurrent infectious illnesses.
Acquired Immunodeficiency Syndrome↗
Applications of a new chemiluminometric thyrotropin assay to subnormal measurement.
A new immunochemiluminometric TSH assay (ICMA) was shown to offer improved analytical (+2 SD of zero) and functional (20% interassay coefficient of variation) sensitivity [0.003 vs 0.045 +/- 0.005 (+/- SE; range, 0.01-0.07); 0.018 vs. 0.23 +/- 0.02 (range, 0.10-0.35, mU/L); analytical vs. functional sensitivity limit for the ICMA vs. 10 other TSH immunometric assays, respectively]. The ICMA was used to study the physiological relationship between serum TSH and free T4 [as reflected by free T4 index (FT4I)] values at both steady state and 14 days after acute pharmacological T4 administration (3 mg oral T4 load plus 0.3 mg daily). At steady state, an inverse log/linear relationship was found between serum TSH and FT4I values (log TSH = 2.56 - 0.022 FT4I; r = 0.84; P less than 0.001). Ten to 14 days after acute T4 suppression in 5 euthyroid subjects, serum TSH/FT4I levels had plateaued after decreasing in parallel to the slope of the steady state relationship, suggesting that the degree of T4 suppression of TSH can be predicted from an individual's pituitary TSH/free T4 set-point and the magnitude of the serum T4 elevation achieved. Ambulatory and hospitalized patient sera, previously identified as having low (less than 0.1 mU/L) TSH levels by a less sensitive assay, were restudied by the TSH ICMA. Normal TSH values ranged from 0.39-4.6 mU/L, whereas the majority of hyperthyroid patients [52 of 54 (96% ambulatory) and 22 of 23 (96%, hospitalized)] had undetectable (less than 0.005 mU/L), basal TSH levels and absent TRH stimulated TSH responses. In contrast, most (32 of 37; 86%) of hospitalized nonhyperthyroid patients with low (less than 0.1 mU/L) TSH values due to nonthyroidal illness or glucocorticoid treatment had detectable (greater than 0.01 mU/L) basal and TRH stimulated TSH levels. The positive relationship between basal and TRH-stimulated TSH levels was shown to extend down to the detectability limit of the assay (0.005 mU/L), which further supported the authenticity of the subnormal TSH ICMA measurements. The new TSH ICMA is considered to represent the first of a third generation of clinical TSH assays, since it has a functional (interassay) sensitivity that is 2 orders of magnitude greater than that of typical first generation TSH RIAs and 1 order of magnitude greater than current second generation TSH immunometric methods. Such third generation TSH assays will facilitate both the optimization of T4 therapy as well as the diagnosis of hyperthyroidism in hospitalized patients with nonthyroidal illness.
Adult↗
Does a hidden pool of reverse triiodothyronine (rT3) production contribute to total thyroxine (T4) disposal in high T4 states in man.
A hidden pool of rT3 production represents a source of rT3 that is minimally reflected in circulating rT3 levels. To test for the existence of such a source of rT3 production in man, varying doses of the generalized deiodinase inhibitor iopanoic acid (IA) were administered to four hyperthyroxinemic subjects. The doses employed included low-IA (0.5-g load, then 0.5 g/day for 5 days), mid-IA (1.0-g load, then 1.0 g/day for 5 days), and high-IA (3.0-g load, then 3.0 g/day for 5 days). Each patient received 25 microCi [125I]rT3, iv, in the high T4 state and on day 3 of each IA dosing regimen. Serial blood and urine samples were obtained to determine serum rT3 clearance rates and the urinary thyronine metabolite patterns. Although total serum rT3 values were increased by all IA dosages (P less than 0.001), rT3 was lower with high-IA administration (P less than 0.02) than with low- or mid-IA regimens. Low-IA decreased rT3 clearance to 33 +/- 2 L/day (P less than 0.005), while increasing the daily rT3 production to 76 +/- 8 nmol/day (P less than 0.04) compared to the control values (150 +/- 10 L/day and 53 +/- 8 nmol/day, respectively). Mid-IA also reduced rT3 clearance (23 +/- 4 L/day; P less than 0.005) without changing rT3 production (50 +/- 10 nmol/day), while high-IA reduced both rT3 clearance (21 +/- 2 L/day; P less than 0.005) and production (39 +/- 9 nmol/day; P less than 0.04). Intravenously administered tracer rT3 could not be detected in the urine in the high T4 state, but rT3 could not be detected in the urine in the high T4 state, but was prominent after IA administration. It is concluded that a hidden pool of rT3 production exists in vivo in man. Further, low dose IA serves as a selective inhibitor of liver and kidney deiodinase systems, allowing reflection of this hidden rT3 pool in the blood and urine. It would appear that hypertrophy of this hidden pool of rT3 production occurs in high T4 states and may account for the majority of the unrecognized deiodinative metabolites of T4 generated in hyperthyroxinemia.
Adult↗
Clinical review 12: The use and misuse of the sensitive thyrotropin assays.
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Fluoroimmunoassay↗
Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS)
STUDY OBJECTIVE: To determine alterations in serum thyroid hormone indices in patients with human immunodeficiency virus (HIV) infection. DESIGN: Prospective, single-blind study. SETTING: Large metropolitan hospital where 20% of all patients with the acquired immunodeficiency syndrome (AIDS) in Los Angeles are treated. PATIENTS: Twenty-six inpatients with bronchoscopy-proven Pneumocystis carinii pneumonia and AIDS. Outpatients included 10 persons seropositive for HIV, 10 with AIDS-related complex, and 10 with AIDS. MAIN RESULTS: There were 19 survivors and 7 nonsurvivors of P. carinii infection. Serum triiodothyronine (T3) values generally remained normal until hospitalization, with nonsurvivors having lower values than survivors (0.56 +/- 0.1 nmol/L compared with 1.3 +/- 0.1 nmol/L, P less than 0.002, respectively). Reverse triiodothyronine (rT3) levels were low in persons with AIDS-related complex (0.21 +/- 0.02 nmol/L, P less than 0.001) and in AIDS outpatients (0.17 +/- 0.02 nmol/L, P less than 0.001). Normalization of rT3 occurred after patients were hospitalized (0.28 +/- 0.01 nmol/L). Serum thyroxine-binding globulin values rose with progression of HIV infection (seropositive, 369.7 +/- 18.1 nmol/L, P less than 0.005; AIDS-related complex, 419.1 +/- 37.0 nmol/L, P less than 0.005; AIDS, 423.3 +/- 31.9 nmol/L, P less than 0.005; survivors, 476.3 +/- 24.6 nmol/L, P less than 0.001), whereas nonsurvivors had normal values. All values are compared with normal values (T3, 2.3 +/- 0.04 nmol/L; rT3, 0.28 +/- 0.01 nmol/L; thyroxine-binding globulin, 288.2 +/- 6.9 nmol/L). CONCLUSIONS: Infection with HIV produces unique alterations in thyroid function. A progressive decline in rT3 and elevation in thyroxine-binding globulin accompany advancing HIV infection. The persistence of a normal T3 despite progression of HIV infection may contribute to weight loss. A low serum T3 on admission correlates with mortality.
AIDS-Related Complex↗
Effect of carbohydrate refeeding on free fatty acids after a fast in obese diabetic and obese non-diabetic females.
The metabolic effects of refeeding with oral or intravenous carbohydrate were studied in obese women after ten or 14 days of fasting. Seven patients were refed with protein-free fruit juice for a total of 250 g of carbohydrate (1,000 kcal) over ten hours. The juice was sipped continuously throughout this time, causing a drop in free fatty acids (FFA) from 1.07 +/- 0.08 to 0.61 +/- 0.05 mmol/L (P less than .01) over the first four hours. Over the next four hours, despite continuous ingestion of the carbohydrate and elevated plasma glucose (132 +/- 9 mg/dL) and insulin (2.81 +/- 0.86 ng/mL) (1 ng/mL = 25 microU/mL), FFA rose to 0.99 mmol/L (P less than .01). Similar results were obtained in five patients refed with similar amounts of oral glucose and four patients who received an equivalent amount of glucose intravenously (IV). Refeeding with carbohydrate of obese diabetic and non-diabetic women after a two-week fast caused an abrupt decrease in FFA that was followed after four hours by an increase in FFA and glycerol, despite continued ingestion of carbohydrate glucose and insulin.
3-Hydroxybutyric Acid↗
Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.
To elucidate the mechanisms involved in altering serum 3,3',5'-triiodothyronine (rT3) levels with absolute or relative low 3,5,3'-triiodothyronine (T3) states in man, agents capable of lowering circulating T3 levels were sequentially administered to six euthyroid subjects. These agents included propylthiouracil (PTU) (300 mg/6 h X 5 d), dexamethasone (DEX) (2 mg/6 h X 5 d), and thyroxine (T4) (3.0 mg load and 0.3 mg/d X 5 d). [125I] rT3 clearance rates and rT3 production rates were then determined. Increased serum rT3 levels and rT3/T4 values occurred with both PTU and DEX as compared with control, while T4 increased serum rT3 but did so without changing rT3/T4 values. The rT3 clearance rate was significantly decreased by PTU without altering production rate, while DEX increased the rT3 production rate without altering the rT3 clearance rate. T4 administration did not change rT3 clearance but proportionately increased rT3 production. These responses indicate that circulating rT3 predominantly originates from a non-PTU inhibitable deiodinase enzyme system located in extrahepatic tissues. This enzyme system appears to have a high capacity and low affinity for T4 and can be stimulated by DEX administration.
Adult↗
Revised nomenclature for tests of thyroid hormones and thyroid-related proteins in serum.
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Autoantibodies↗
Thyroxine transfer and distribution in critical nonthyroidal illnesses, chronic renal failure, and chronic ethanol abuse.
Serum T4 kinetic studies were performed in euthyroid patients with acute critical illnesses, chronic renal failure, or ethanol abuse without overt hepatocellular damage and in healthy euthyroid subjects with normal or altered serum T4 binding to determine the relative effects of altered serum T4 binding and extravascular disturbances on T4 transfer and distribution in nonthyroidal illnesses. A three-pool model with rapidly and slowly equilibrating pools exchanging with serum was used to evaluate the potential sites of alterations. Healthy euthyroid subjects with low serum T4-binding globulin levels had increased serum percent free fraction of T4 (%FFT4) and fractional T4 transfer rates (FTR) from serum to both extravascular pools, while those with high serum T4-binding capacity had decreased %FFT4 and FTR from serum to the rapid pool and increased T4 binding in the slow pool. Critically ill patients had significantly reduced serum total T4 (TT4) with increased %FFT4 but decreased FTR from serum to both extravascular pools and reduced T4 binding in the slow pool. Patients with ethanol abuse had normal serum TT4 and %FFT4 but significantly increased FTR from serum to the rapid pool and increased binding in both extravascular pools. Chronic renal failure patients had no alterations in any of these values. The T4 FTR from serum to both extravascular pools were directly related to the serum %FFT4 in healthy subjects and inversely related in the patients. Further, the FTR from the rapid pool to serum were inversely related to rapid pool binding in healthy subjects but not in the patients, while the FTR from the slow pool to serum were unrelated to slow pool binding in both groups. These findings indicate that in patients with nonthyroidal illnesses the transfer of T4 between serum and the extravascular pools is not primarily a reflection of T4 binding to serum binding proteins or extravascular sites. Further, alterations in slow pool binding may be affected by changes in T4 binding to serum binding proteins, which are known to be present in the interstitial fluid of these tissues. Finally, the type and magnitude of the alterations in T4 transfer and distribution in patients with nonthyroidal illnesses appear to differ for rapidly and slowly equilibrating tissues and may be related to the etiology and/or severity of the nonthyroidal disorder.
Acute Disease↗
Alterations in serum thyroid hormonal indices with colestipol-niacin therapy.
A serial blood-lipid-lowering study at the University of Southern California yielded unexpected findings on routine thyroid function monitoring. After 1 year of combined colestipol and niacin therapy, patients had reduced total serum thyroxine (T4) levels and increased triiodothyronine uptake ratios, an indicator of apparent decreases in thyroxine-binding globulin levels. Calculation of the free T4 index partially but not completely corrected for the apparent decrease in thyroxine-binding globulin, as determined by a relatively small decrease in the free T4 index compared with a large decrease in T4. Sequential sampling, using three separate methods, showed reduced thyroxine-binding globulin levels. The mechanism for these changes is unknown, but the fact that these patients were essentially euthyroid needs emphasis because the use of combined colestipol and niacin therapy is becoming more widespread.
Adult↗
Revised nomenclature for tests of thyroid hormones and thyroid-related proteins in serum.
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Autoantibodies↗
Thyroid indices in arterial and venous cord blood: significantly greater levels of reverse triidothyronine in venous blood than in arterial blood.
Paired arterial and venous cord blood samples were obtained from 42 normal newborns (24 males and 18 females). T4 was determined in all paired samples. In addition, other indices were determined: T3 in 40, RT3 in 29, TBG in 29, thyroglobulin (Tg) in 14, and TSH in 11. Gender difference in any of the thyroid indices was not found. Arterial and venous cord serum thyroid indices correlated positively (T4, r = 0.743; T3, r = .907, rT3, r = .920; TBG, r = .752; Tg, r = .934, and TSH, r = .989; P less than 0.005). The difference between the means +/- SD of arterial and venous levels was significant (P less than 0.01) only for rT3 (191 +/- 43.2 v 224 +/- 55.8 ng/dL). Arterial (T4 v T3, r = .453, P less than .005; T4 v RT3, r = .660, P less than 0.005) and venous (T4 v T3, r = .620, P less than 0.005; T4 v rT3, r = .612, P less than 0.005); T3 and rT3 levels correlated positively with T4 levels. In contrast, T3 and rT3 levels for arterial (r = .216, P greater than 0.1) and venous (r = .216, P greater than 0.1) samples did not show a significant correlation. These data are in keeping with earlier reports for animal placental models studied in vitro, suggesting that placental inner ring deiodination of maternal thyroxine is a source of fetal RT3.
Biotransformation↗
Studies on the diurnal pattern of serum 3,5,3'-triiodothyronine.
Seventeen subjects, including 12 mildly obese women, were investigated to determine the presence of a diurnal variation in serum T3 levels. A subset of 8 subjects was studied after fasting for 6 days, while another subset of 5 subjects was studied 2 days after receiving 3 mg T4, orally, to suppress TSH secretion. To negate the influence of hemoconcentration produced by ambulation, serum T3 to T4 ratios (nanograms per microgram) rather than total T3 values were used for analysis. A synchronous diurnal rhythm for mean serum T3 to T4 ratios and TSH values was found, with mean nighttime increases of 7.8% and 49.5%, respectively. The timing of the T3 to T4 and TSH nocturnal peaks for individual subjects, however, were not correlated, suggesting that T3 to T4 ratios changes were not caused by TSH stimulation of thyroid T3 release. During fasting, the diurnal rhythm of serum T3 to T4 was obliterated within 24 h of beginning the fast, although TSH rhythmicity persisted. After the 3-mg oral T4 dose, serum TSH became undetectable, while the diurnal serum T3 to T4 ratio changes persisted. In contrast, there was no detectable diurnal rhythmicity of serum T3 to T4 ratios during either the control or fasting period. We conclude that the diurnal rhythm of serum T3 is not TSH dependent, but, rather, is influenced by some as yet unidentified dietary signal, which alters the efficiency of the peripheral tissue T4 to T3 conversion.
Adult↗