RESUMEN
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.
Asunto(s)
Dexametasona/farmacología , Propiltiouracilo/farmacología , Tiroxina/farmacología , Triyodotironina Inversa/sangre , Adulto , Cromatografía Líquida de Alta Presión , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina Inversa/farmacocinética , Triyodotironina Inversa/orinaRESUMEN
CONTEXT: Changes in thyroglobulin (Tg) and/or Tg antibody (TgAb) methods can disrupt the serial monitoring of differentiated thyroid carcinoma (DTC) patients. OBJECTIVE: This study compared Tg measurements made in TgAb-negative and TgAb-positive sera using four RIA and 10 immunometric assay (IMA) methods. DESIGN: TgAb detection using a panel of 12 direct methods was contrasted with four Tg recovery tests. Sera from 110 normal euthyroid subjects (68 TgAb negative/42 TgAb positive) and 131 TgAb-negative DTC patients had Tg and/or TgAb analyses made by 10 laboratories in four countries. Euthyroid controls were used to compare Tg and TgAb ranges, sensitivities, and TgAb interference, whereas DTC patients were used to study Tg assay specificities, hook effects, and the influence of high Tg levels on TgAb measurements. RESULTS: Tg methods had high between-method variability [47 +/- 3% (+/-sem)] that was only marginally reduced by CRM-457 standardization (37 +/- 3%). All methods had suboptimal sensitivity, and some failed to detect Tg in some normal euthyroid controls. Although direct TgAb measurements were more reliable than exogenous recovery tests, TgAb status was only concordant in 65% of sera. Only four of 42 (9.5%) sera containing TgAb had antibody detected by all direct methods. All IMA methods reported paradoxically undetectable Tg for many TgAb-positive euthyroid controls, suggesting TgAb interference, whereas RIA methods reported appropriate normal range values for these same subjects. Some sera displaying interference had TgAb detected by only a minority of methods. CONCLUSIONS: Specificity differences, suboptimal sensitivity, hook effects, and an inability to reliably detect interfering TgAb compromise the clinical utility of current Tg and TgAb methods. All of the IMA methods were prone to underestimate serum Tg in the presence of TgAb, whereas the RIA methods appeared resistant to TgAb interference.
Asunto(s)
Autoanticuerpos/análisis , Carcinoma/terapia , Tiroglobulina/análisis , Neoplasias de la Tiroides/terapia , Adulto , Carcinoma/sangre , Carcinoma/diagnóstico , Técnicas de Laboratorio Clínico , Estudios de Cohortes , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Estándares de Referencia , Reproducibilidad de los Resultados , Tiroglobulina/sangre , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/diagnósticoRESUMEN
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.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Neumonía por Pneumocystis/sangre , Triyodotironina/sangre , Adulto , Estudios de Factibilidad , Femenino , Hemoglobinas/análisis , Humanos , L-Lactato Deshidrogenasa/sangre , Linfopenia/sangre , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Neumonía por Pneumocystis/diagnóstico por imagen , Neumonía por Pneumocystis/mortalidad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Radiografía , Albúmina Sérica/metabolismo , Hormonas Tiroideas/sangreRESUMEN
Previous studies have suggested that T3 metabolism relies more on nondeiodinative conjugation than on direct deiodinative degradation for its disposal in man. To better define this process, tracer T3 kinetic studies were performed in five euthyroid subjects before and after iopanoic acid (IA) administration to selectively impair T3 deiodinative disposal. Both a low IA (0.5-g load, followed by 0.5 g/day for 7 days) and a high IA (3.0-g load, followed by 3.0 g/day for 7 days) dosing schedule were employed to achieve varying levels of deiodinase inhibition. Additionally, the high IA dose was repeated with simultaneous oral T3 administration (100 micrograms daily) to normalize serum T3 levels that were reduced by IA-induced inhibition of T4 to T3 conversion. The results demonstrated that baseline serum T3 (2.3 +/- 0.1 nmol/L) and T3/T4 (1.9 +/- 0.1 x 10(-2)) values were significantly reduced by both the low IA (1.5 +/- 0.1 nmol/L and 1.2 +/- 0.1 x 10(-2), respectively) and the high IA (1.5 +/- 0.1 nmol/L and 0.9 +/- 0.2 x 10(-2), respectively) dosing schedule and that the addition of oral T3 to the high IA regimen restored both the T3 and T3/T4 levels to near-normal values (2.9 +/- 0.3 nmol/L and 1.7 +/- 0.2 x 10(-2), respectively). Low IA also significantly decreased T3 clearance (30 +/- 4 to 18 +/- 2 L/day; P < 0.005) and fractional urinary tracer recovery (70 +/- 3% to 37 +/- 4%; P < 0.005), whereas high IA produced only a minimal further reduction in clearance (16 +/- 2 L/day; P < 0.01) and urinary tracer recovery (32 +/- 3%; P < 0.05). Surprisingly, oral administration of T3 to the high IA regimen significantly increased T3 clearance (23 +/- 4 L/day; P < 0.01) without changing urinary tracer recovery (34 +/- 5%) compared to the effects of high IA alone. Evaluation of the urinary T3 metabolite pattern demonstrated that the major products of T3 metabolism were T3 sulfate and 3,3-diiodothyronine sulfate. These observations confirm previous results suggesting that the majority of nondeiodinative T3 disposal occurs via T3 sulfate formation. The additional finding that such nondeiodinative disposal may also be influenced by the circulating T3 level leads us to propose that sulfotransferase enzyme systems may play an important role in regulating the prereceptor availability of this ligand.
Asunto(s)
Triyodotironina/análogos & derivados , Triyodotironina/metabolismo , Adulto , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Ácido Yopanoico/farmacología , Masculino , Persona de Mediana Edad , Tironinas/orina , Triyodotironina/sangre , Triyodotironina/farmacologíaRESUMEN
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.
Asunto(s)
Ayuno , Alimentos , Triyodotironina Inversa/sangre , Adulto , Femenino , Humanos , Radioisótopos de Yodo , Cinética , Tasa de Depuración Metabólica , Persona de Mediana Edad , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Triyodotironina Inversa/farmacocinéticaRESUMEN
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.
Asunto(s)
Hipertiroidismo/metabolismo , Yoduro Peroxidasa/metabolismo , Tiroxina/metabolismo , Triyodotironina/biosíntesis , Adulto , Relación Dosis-Respuesta a Droga , Humanos , Hipertiroidismo/enzimología , Inyecciones Intravenosas , Yoduro Peroxidasa/antagonistas & inhibidores , Ácido Yopanoico/administración & dosificación , Riñón/enzimología , Hígado/enzimología , Masculino , Persona de Mediana Edad , Pruebas de Función de la Tiroides , Tiroxina/administración & dosificación , Triyodotironina/fisiologíaRESUMEN
A new method for the measurement of the conversion ratio (CR) of T4 to T3 in euthyroid man is described. In contrast to previously described studies, this investigation relied on sampling of urine rather than plasma after isotopic labeling of the study subject. The CR value determined in six euthyroid men was 0.482 +/- 0.014. Thus, approximately half of the daily T4 production is converted to T3 as determined by this method. A major advantage of this technique is its reproducibility, as demonstrated by the low coefficient of variation of 6.8% in the study group, which is not significantly different from the 6.7% coefficient of variation for replicate determinations on the same sample. Thus, this method may be useful tool in comparing the CR of T4 to T3 in man under varying conditions even if only small differences in conversion efficiencies exist between groups. One apparent discrepancy observed in the present study is that the calculated T3 produced from the conversion of T4 exceeded the simultaneously calculated daily T3 production rate measured in blood. The cause of this discrepancy is presently unknown, but may represent T3 produced from T4 by renal or extrarenal sources which is excreted without contributing to the T3 blood production rate. However, the reproducibility of the method and the smaller amounts of labeled isotope required show promise that this technique may be useful in assessing T4 to T3 conversion in a variety of altered metabolic states.
Asunto(s)
Tiroxina/orina , Triyodotironina/orina , Adulto , Semivida , Humanos , Radioisótopos de Yodo , Cinética , Masculino , Persona de Mediana Edad , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
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.
Asunto(s)
Triyodotironina/análogos & derivados , Administración Oral , Adulto , Ayuno/metabolismo , Humanos , Inyecciones Intravenosas , Radioisótopos de Yodo/metabolismo , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Glándula Tiroides/metabolismo , Triyodotironina/administración & dosificación , Triyodotironina/metabolismo , Triyodotironina/farmacocinéticaRESUMEN
The magnitude and temporal pattern of serum TSH suppression after single or multiple doses of thyroid hormone (T3, T4, or triiodothyroacetic acid) were studied using third and fourth generation TSH assays (sensitivities, 0.01 and 0.001 mU/L, respectively). A constant T3 dose (263 micrograms i.v.) administered at a uniform clock time (1200 h) produced identical serum TSH suppression patterns, (percent of control TSH vs. hours) in euthyroid and hypothyroid subjects. The percent log TSH vs. log time plot revealed three temporally distinct linear suppression phases: phase 1, a rapid TSH suppression, onset 1 h and lasting for 10-20 h; phase 2, slower suppression, onset between 10 and 20 h and lasting for 6-8 weeks; and phase 3, an invariable low TSH level (< 0.01 mU/L) with chronic T3 suppression (100 micrograms four times a day). TSH escaped maximal suppression at a similar serum T3 level in both euthyroid and hypothyroid subjects (2.9 +/- 0.2 vs. 3.5 +/- 0.5 nmol/L, respectively; P > 0.9), despite different basal serum T3 values (2.0 +/- 0.1 vs. 0.6 +/- 0.1 nmol/L, respectively; P < 0.01). Two milligrams of triiodothyroacetic acid or 2 mg T4 given iv at 1200 h produced TSH suppression patterns similar to T3. The phase 1 suppression varied with the clock time of T3 administration, (steeper responses were seen at 2400 vs. 1200 h), whereas phase 2 responses were unaltered. This study shows that thyroid hormone suppression of TSH is a complex, biphasic, nonlinear process, which is reproducible and independent of thyroid status or the thyroid hormone analog used. It is hypothesized that phase 1 reflects inhibition of release of preformed hormone, whereas phase 2 likely reflects inhibition of de novo synthesis and/or thyrotroph storage of TSH. In contrast, phase 3 secretion seems to represent basal constitutive TSH release, which may have relevance to the role of thyroid hormone-suppressive therapy in the treatment of patients with benign or neoplastic thyroid disease.
Asunto(s)
Hormonas Tiroideas/farmacología , Tirotropina/sangre , Adulto , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Tiroxina/farmacología , Triyodotironina/farmacologíaRESUMEN
A new method is described for the estimation of T4 to T3 conversion in man and is applied to the study of hyperthyroid and hypothyroid clinical states. The method employs simultaneous iv injection of [125I]T4 and [131I]T3 with isolation of the labeled T3 tracers in 4- to 8-day pooled urine samples by a combination of solvent extraction, desalting, and immunoprecipitation procedures. Using [131I]T3 as a recovery standard, the T4 to T3 conversion ratio was found to be 0.470 +/- 0.011 in euthyroid subjects. This confirmed our earlier findings of 0.482 +/- 0.014 using a paper chromatographic method and nonsimultaneous isotope administration. The conversion ratio was increased in hypothyroidism to 0.535 +/- 0.011 (P less than 0.02) and decreased in hyperthyroidism to 0.415 +/- 0.009 (P less than 0.01). These changes parallel the fraction of the radioiodine collected in the urine for both T4 and T3; normal values are 77 +/- 4% for T4 and 76 +/- 4% for T3, values in hypothyroidism are 79 +/- 1% for T4 and 79 +/- 3% for T3, and values in hyperthyroidism are 58 +/- 3% for T4 and 58 +/- 5% for T3 (P less than 0.01). These findings indicate that 1) urinary T4 to T3 conversion values are highly reproducible in euthyroid as well as hyperthyroid and hypothyroid states; 2) the reduction in T4 to T3 conversion in hyperthyroidism probably reflects increased T4 disposal by nondeiodinative pathways and possibly the reverse in hypothyroid states; and 3) since urinary T4 to T3 conversion values in euthyroid subjects exceeded all reported conversion values in blood, there may be an alternate pathway of T3 production and disposal which is not reflected in the blood T3 production rate.
Asunto(s)
Hipertiroidismo/orina , Hipotiroidismo/orina , Técnicas de Inmunoadsorción , Tiroxina/orina , Triyodotironina/orina , Adulto , Humanos , Radioisótopos de Yodo , Persona de Mediana EdadRESUMEN
TRH stimulation tests (n = 1109) were performed on 1061 ambulatory and 43 hospitalized patients with varying thyroid status, using a TSH immunochemiluminometric assay with third and fourth generation sensitivity characteristics (functional sensitivity, 0.01 and 0.001 mU/L, respectively). TRH test results were analyzed as both absolute (stimulated minus basal TSH) and fold (stimulated/basal TSH) responses. The absolute TRH response varied 8-fold across the physiological TSH range, whereas the mean fold response remained almost constant (mean +/- SEM, 8.5 +/- 0.2). The fold response became progressively attenuated as basal TSH values declined below physiological levels, becoming essentially absent in clinically thyrotoxic patients with markedly depressed basal serum TSH levels (0.007 +/- 0.002 mU/L). Progressive attenuation also occurred at hypothyroid TSH levels; a markedly impaired fold response (2.5 +/- 0.4) was characteristic of primary hypothyroid patients with basal TSH values greater than 50 mU/L. In untreated central hypothyroid patients with near-normal basal TSH levels, the TRH fold response was impaired (1.7 +/- 0.2), whereas in T4-replaced central hypothyroid patients, fold responses were near normal (5.6 +/- 1.2). Neither nonthyroidal illness, age, or sex appeared to influence the pattern of fold TRH response in the populations evaluated. When using third and fourth generation TSH methodology, the TRH-stimulated TSH fold response is more diagnostically useful than the absolute TRH response. However, if patients have an intact hypothalamic-pituitary axis, there appears to be no diagnostic advantage gained by TRH testing over an accurately measured basal TSH value.
Asunto(s)
Enfermedades de la Tiroides/sangre , Pruebas de Función de la Tiroides , Hormona Liberadora de Tirotropina , Tirotropina/sangre , Adulto , Femenino , Enfermedad de Graves/sangre , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Inmunoensayo , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Valores de Referencia , Tiroxina/uso terapéuticoRESUMEN
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.
Asunto(s)
Hipertiroidismo/diagnóstico , Tirotropina/sangre , Adulto , Autoanálisis , Esquema de Medicación , Femenino , Humanos , Inmunoensayo , Mediciones Luminiscentes , Masculino , Hormona Liberadora de Tirotropina/farmacología , TiroxinaRESUMEN
The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid peroxidase) was increased nearly 3-fold in patients with differentiated thyroid cancers (DTC) compared with the general population (40% vs. 14%, respectively). Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC patients and 10% of the general population. Serial postsurgical serum TgAb and serum Tg patterns correlated with the presence or absence of disease. Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two immunometric assay (IMA) methods to study TgAb interference. TgAb interference, defined as a significant intermethod discordance (>41.7% coefficient of variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera, was found in 69% of the TgAb-positive sera. TgAb interference was characterized by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in sera containing high TgAb concentrations. However, some sera displayed marked interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL) causing interference. Exogenous Tg recovery tests were an unreliable means for detecting TgAb interference. Specifically, the exogenous Tg recovered varied with the type and amount of Tg added and the duration of incubation employed. Further, recoveries of more than 80% were found for some sera displaying gross serum RIA/IMA discordances. The measurement of serum Tg in DTC patients with circulating TgAb is currently problematic. It is important to use a Tg method that provides measurements that are concordant with tumor status. IMA methods are prone to underestimate serum when TgAb is present, increasing the risk that persistent or metastatic DTC will be missed. The RIA method used in this study provided more clinically appropriate serum Tg values in the group of TgAb-positive patients with metastatic DTC. Furthermore, as serial serum TgAb measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may be an additional clinically useful tumor marker parameter for following TgAb-positive patients. Disparities between serial serum Tg and TgAb measurements might alert the physician to the possibility of TgAb interference with the serum Tg measurement and prompt a more cautious use of such data for clinical decision-making.
Asunto(s)
Autoanticuerpos/sangre , Tiroglobulina/inmunología , Neoplasias de la Tiroides/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Diferenciación Celular/fisiología , Niño , Femenino , Pruebas de Hemaglutinación , Humanos , Ensayo Inmunorradiométrico , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Radioinmunoensayo , Valores de Referencia , Caracteres Sexuales , Neoplasias de la Tiroides/patologíaRESUMEN
This article describes the major pathophysiologic alterations that occur in patients with long-standing hypothyroidism and how these alterations may predispose them to the development of a decompensated state, commonly referred to as myxedema coma. Early recognition and the employment of appropriate interventions serve as the cornerstone for successful management of this condition. The use and limitations of thyroid hormone therapy for treatment of this condition are emphasized.
Asunto(s)
Coma/etiología , Mixedema/diagnóstico , Anciano , Coma/terapia , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Mixedema/complicacionesRESUMEN
Thyroglobulin (Tg) measurement is primarily used to monitor patients with differentiated thyroid carcinoma (DTC) for tumor recurrence. Serum Tg levels principally integrate 3 variables: the mass of thyroid tissue present (benign or neoplastic); the degree of thyrotropin (TSH) receptor stimulation and tumor's intrinsic ability to synthesize and secrete Tg--a factor that needs to be assessed by a preoperative serum Tg determination. Serum Tg measurements should be interpreted relative to the TSH status of the patient. When TSH is low (on levothyroxine [LT4] therapy) basal serum Tg may be undetectable and recombinant human thyrotropin (rhTSH) administration may be needed to increase serum Tg into the measureable range. The Tg fold response to rhTSH (rhTSH-stimulated Tg/basal Tg) is an index of the tumor's sensitivity to TSH. Normal thyroid remnant and well-differentiated thyroid tumors display a greater (>10-fold) serum Tg response to TSH stimulation compared with less well-differentiated tumors (<3-fold). The factors influencing the response include the magnitude and chronicity of the serum TSH elevation, the mass of thyroid tissue and the TSH receptor status of the tumor. Technical problems still compromise the clinical utility of serum Tg measurement. Thyroglobulin autoantibodies are present in approximately 20% of all DTC patients and cause either underestimation or overestimation of serum Tg measurements made by immunometric assay (IMA) and radioimmunoassay (RIA) methods, respectively. Other technical problems include poor interassay precision, "hook" effects (IMA methods), intermethod standardization differences, and suboptimal sensitivity for detecting small amounts of tumor during TSH suppression. When TSH is suppressed, the basal serum Tg provides an integrated index of thyroid tissue mass and its capability to secrete Tg. Serial measurements of basal Tg concentrations can be used to monitor tumor progression or regression. The development of a low (<1 ng/mL) serum Tg (on LT4 therapy) by the second postoperative year signifies a low 5-year recurrence risk whereas a rising serum Tg in the face of TSH suppression is an abnormal response consistent with recurrence. The optimal degree of TSH suppression for a patient should be based on clinical judgment, relative to tumor staging and the risks from iatrogenic hyperthyroidism. Despite current technical limitations, serum Tg measurement is the cornerstone of long-term monitoring for most DTC patients. For optimal use of serum Tg, it is necessary to understand the pathophysiology of Tg secretion, the limitations of Tg methods and the use of rhTSH to overcome the insensitivity of current Tg methods.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasia Residual/diagnóstico , Tiroglobulina/sangre , Neoplasias de la Tiroides/diagnóstico , Tirotropina , Humanos , Neoplasia Residual/sangre , Proteínas Recombinantes , Recurrencia , Neoplasias de la Tiroides/sangreRESUMEN
The evolution in thyroid function tests since the 1960s has improved the physician's proficiency in accurately identifying thyroid dysfunction in a patient with suspected thyroid disease. The mainstays of modern thyroid testing strategies are the serum TSH concentration and AMA (anti-TPO) titer. The TSH level serves as an endogenous indicator of the biologically active free T4 fraction and, as a result, is currently the best gauge of the thyroid status of an individual. In addition, the TSH level has other advantages over free T4 estimates in confirming the presence of thyroid disease. First, each individual has his or her own free T4-TSH setpoint, whereby any deviation from this genetically determined relationship changes the serum TSH level. Second, owing to the local nature of the T4 feedback at the pituitary, these alterations in serum TSH values amplify small changes in circulating free T4 values. The net result of these unique attributes of measuring TSH is the ability to detect thyroid dysfunction early in the course of thyroid disease. There are limitations to the use of a TSH determination as a single thyroid function test, however. They include the presence of hypothalamic or pituitary disease or concurrent nonthyroidal illness and the immediate treatment of either hyperthyroidism or hypothyroidism. Because the majority of thyroid diseases involves autoimmune processes of the thyroid gland, the inclusion of an AMA titer in any approach to thyroid testing enhances both the diagnostic and prognostic expertise of the physician. In conclusion, currently available thyroid function tests have enhanced the diagnostic skills of the physician, but their effectiveness relies on clinical judgment rather than guidance from protocol or random application.
Asunto(s)
Enfermedades de la Tiroides/diagnóstico , Autoanticuerpos/sangre , Técnicas de Laboratorio Clínico , Femenino , Humanos , Enfermedades Hipotalámicas/complicaciones , Yoduro Peroxidasa/inmunología , Masculino , Enfermedades de la Hipófisis/complicaciones , Pruebas de Función de la Tiroides , Tiroiditis Autoinmune/diagnóstico , Tirotropina/sangre , Tiroxina/sangreRESUMEN
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.