Use of oral cholecystography agents in the treatment of hyperthyroidism of subacute thyroiditis.

AIM: In this study, we describe our experience in treating subacute thyroiditis patients with 2 OCAs (sodium ipodate and sodium iopanoate). METHODS: We studied 10 consecutive patients with subacute thyroiditis treated with 1 of the 2 oral cholecystography agents (OCAs). RESULTS: Hyperthyroidism was controlled and symptoms improved markedly in each case without any evidence of subsequent relapse of thyroiditis after withdrawal of OCAs. Three of the 10 patients had been treated previously with corticosteroids and had demonstrated relapse of thyroiditis and hyperthyroidism after tapering or withdrawal of steroids. We observed no side effects of treatment with OCAs. CONCLUSION: Our data suggest that OCAs are effective and safe agents for management of hyperthyroidism in patients with subacute thyroiditis, even when they have relapsed after treatment with corticosteroids.

Use of oral cholecystographic agents in the treatment of amiodarone-induced hyperthyroidism.

We describe here five cardiac patients with type II amiodarone-induced hyperthyroidism who were treated prospectively with a combination of an oral cholecystographic agent (sodium ipodate, Oragrafin, or sodium iopanoate, Telepaque) and a thionamide (propylthiouracil or methimazole); amiodarone was discontinued in all patients. All patients improved substantially clinically within a few days of treatment and became euthyroid or hypothyroid in 15-31 wk when treatment was discontinued. Four of the five became hypothyroid and required long-term treatment with L-T(4); the remaining patient was euthyroid, but died from cardiomyopathy and congestive heart failure at 29 wk, when he had been off oral cholecystographic agent and thionamide for 6 wk. We did not find any clinical or biochemical adverse effects of the treatment. Our study suggests that a combination of oral cholecystographic agent and thionamide is a safe and effective treatment of type II amiodarone-induced hyperthyroidism. Data also suggest that hypothyroidism is a common end result of type II amiodarone-induced hyperthyroidism.

A radioimmunoassay for type I iodothyronine 5'-monodeiodinase in human tissues.

We have developed a sensitive, specific and reproducible radioimmunoassay (RIA) for measurement of human type I monodeiodinase (5'-DI) protein. Anti-5'-DI antibody was produced by immunization of rabbits with a conjugate of bovine serum albumin and a 16 amino acid synthetic peptide, corresponding to a portion of the carboxy-terminal region of the human 5'-DI (PI-99). In a final dilution of 1:500, our anti-5'-DI antibody bound about 30%-35% of a tracer amount of 125I-PI-99. The detection threshold of the RIA approximated 0.4 pmol PI-99 or an equivalent amount of 0.4 pmol 5'-DI. The coefficient of variation averaged 5% within an assay and 14% between assays. Dose-response curves of tissue proteins were essentially parallel to that of PI-99. In a total number of 35 normal human tissue samples, the mean (+/- standard deviation [SD], picomole per milligram of protein [pmol]) 5'-DI content was 25 +/- 6.7 in kidney, it was significantly lower (p < 0.05) in liver at 3.9 +/- 1.1, 2.8 +/- 0.8 in intestine, 2.3 +/- 0.98 in adrenal, 4.2 +/- 2.5 in skeletal muscle, 3.8 +/- 1.4 in heart and 2.6 +/- 2.4 in thyroid; it was 1.4 +/- 0.3 in Graves' thyroid. Our data suggest that (1) 5'-DI is distributed widely among human tissues; (2) kidney is the tissue most enriched with 5'-DI; (3) 5'-DI content in the thyroid is not increased in Graves' disease.

Evidence for a role of the type III-iodothyronine deiodinase in the regulation of 3,5,3'-triiodothyronine content in the human central nervous system.

OBJECTIVE: Thyroid hormone is essential for maintaining normal neurological functions both during development and in adult life. Type III-iodothyronine deiodinase (D3) degrades thyroid hormones by converting thyroxine and 3,5,3'-triiodothyroinine (T3) to inactive metabolites. A regional expression of D3 activity has been observed in the human central nervous system (CNS), and a critical role for D3 has been suggested in the regulation of local T3 content in concert with other enzymes. DESIGN: This study was undertaken to further characterize D3 activity in human CNS and to understand its role in the local regulation of T3 content. METHODS: Autoptic specimens from various areas of human CNS were obtained 6--27 h postmortem from 14 donors who died from cardiovascular accident, neoplastic disease or infectious disease. D3 was determined by measuring the conversion of T3 to 3,3'-diiodothyronine. The T3 content was measured by radioimmunoassay in ethanol extracts, using a specific antiserum. RESULTS: High levels of D3 activity were observed in hippocampus and temporal cortex, lower levels being found in the thalamus, hypothalamus, midbrain cerebellum, parietal and frontal cortex, and brain stem. An inverse relationship between D3 activity and T3 content in these areas was demonstrated. CONCLUSIONS: We have concluded that D3 contributes to the local regulation of T3 content in the human CNS.

A study of iodothyronine 5'-monodeiodinase activities in normal and pathological tissues in man and their comparison with activities in rat tissues.

The present study was undertaken to investigate the peripheral iodothyronine 5'-monodeiodination in different human and rat tissues. We studied iodothyronine 5'-monodeiodinase type I (5'-DI) activity in liver, kidney, intestine, right cardiac atrium and skeletal muscle and we compared the results with those in rat tissues. Lodothyronine 5'- monodeiodinase type II (5'-DII) activity was studied in normal and ischemic human heart and in rat normal myocardium and brain. The 5'-DI activity (fmol/min x mg protein) in liver and kidney was significantly higher (p < 0.001, ANOVA) in normal rat tissue than in human. However, no significant differences were observed in 5'-DI activity between normal and tumoral human intestine or between intestinal tissue of man and rat. 5'-DI activity in normal human skeletal muscle was significantly higher than that in rat skeletal muscle (p < 0.05). The 5'-DI activity was lower in human ischemic myocardium when compared to normal myocardium either in humans (p < 0.05) or rat (p < 0.001). The Km of 5'-DI was significantly lower in rat than in human kidney and liver (p < 0.05). We conclude that 1) 5'-DI is distributed widely among extrathyroidal human and rat tissues and 5'-DII activity is detectable both in human and rat heart; 2) 5'-DI activity in liver and kidney is lower in man than in rat; 3) 5'-DI activity in the skeletal muscle is higher in man than in the rat; 4) 5'-DI activity is decreased in tumoral tissues of human liver and kidney and in ischemic myocardium, while no significant difference was found between human and rat cardiac 5'-DII activity.

Serum iodothyronines in the human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis.

UNLABELLED: The pattern of circulating iodothyronines in the fetus differs from that in the adult, being characterized by low levels of serum T3. In this study, concentrations of various iodothyronines were measured in sera from neonates of various postconceptional age (PA). Results obtained in cord sera at birth (PA, 24-40 weeks), reflecting the fetal pattern, were compared with those found during extrauterine life in newborns of 5 days or more of postnatal life (PA, 27-46 weeks). The main findings are: Starting at 30 weeks of PA, serum levels increase linearly during extrauterine life; and at 40 weeks, they are more than 200% of those measured in cord sera from newborns of equivalent PA. Serum reverse T3 (rT3) levels during fetal life are higher than those measured during extrauterine life; but they significantly decrease, starting at 30 weeks of PA. Serum T3 sulfate (T3S) does not significantly differ between the two groups, showing the highest values at 28-30 weeks of PA, and significantly decreasing at 30-40 weeks. T3S levels are directly correlated with rT3, both in fetal and extrauterine life, whereas a significant negative correlation between T3S and T3 is found only during extrauterine life. IN CONCLUSION: 1) changes in serum concentrations of iodothyronines in umbilical cord and during postnatal life indicate that maturation of extrathyroidal type I-iodothyronine monodeiodinase (MD) accelerates, starting at 30 weeks of PA; 2) high levels of type III-MD activity in fetal tissues prevent the rise of serum T3, whereas they maintain high levels of rT3 during intrauterine life; 3) an important mechanism leading to the transition from the fetal to the postnatal thyroid hormone balance is a sudden decrease in type III-MD activity; iv) because placenta contains a high amount of type III-MD, it is conceivable that placenta contributes to maintain low T3 and high rT3 serum concentrations during fetal life and that its removal at birth is responsible for most changes in iodothyronine metabolism occurring afterwards.

Simultaneous measurement of free thyroxine and free 3,5,3'-triiodothyronine in undiluted serum by direct equilibrium dialysis/radioimmunoassay: evidence that free triiodothyronine and free thyroxine are normal in many patients with the low triiodothyronine syndrome.

UNLABELLED: We have devised a practical, sensitive and specific method for simultaneous measurement of free thyroxine (FT4) and free triiodothyronine (FT3) in undiluted serum by direct equilibrium dialysis radioimmunoassay (RIA). Two hundred microliters serum sample was dialyzed against buffer (pH 7.4) for 20 hours at 37 degrees C and approximately 800 microL of the dialysate was used for measuring FT4 and FT3 simultaneously. The assay was set up in polystyrene tubes coated with anti-T4 antibody and available commercially for FT4 measurement (Quest-Nichols Institute, San Juan Capistrano, CA). The mean +/- SE (range) FT4 concentration (ng/dL) was 1.2 +/- 0.04 (0.7.0 to 2.30) in 54 normal subjects. It was significantly increased (3.6 +/- 0.4 [1.8 to 9.6], n = 20) in hyperthyroidism and clearly decreased (0.40 +/- 0.04 [1.10 to 0.70], n = 26] in hypothyroidism. All nonthyroid illness (NTI) patients had normal FT4 except 3, 2 of whom were on amiodarone and 1 had received heparin. Serum FT4 concentration was minimally elevated in 18 newborn cord blood serum (1.40 +/- 0.08 [0.90 to 2.2], cf. normal p < .05). The mean serum FT3 concentration (pg/dL) was 285 +/- 10 (134 to 454) in 54 normal sera. It was clearly increased in hyperthyroidism (1033 +/- 98 [593 to 2134], n = 20, p < .001). However, serum FT3 varied widely in hypothyroidism (27 to 597, mean 235 +/- 24, NS) as did serum total T3 (19 to 175). Interestingly, however, the mean serum FT3 concentration was normal (273 +/- 28 [62 to 575, NS]) in 25 NTI patients. All of these patients had low serum total T3 (46 +/- 5.0 [10 to 84], ng/dL; normal 84 to 160, p < 0.001), while FT3 was clearly normal in 21 of 25 patients and low in the remaining 4 patients. Similarly, among 18 newborn cord blood sera serum FT3 concentration was normal in 15 and subnormal only in the remaining 3 while all had clearly subnormal total T3 (28 to 74 ng/dL). CONCLUSIONS: (1) A practical, sensitive, and specific assay for simultaneous measurement of FT4 and FT3 is described; (2) FT3 is consistently elevated in hyperthyroidism while FT4 is elevated in most (approximately 85%) cases; (3) FT4 is consistently decreased in hypothyroidism but FT3 varies widely; (4). Serum FT3 concentration is normal in approximately 83% of patients with the low T3 syndrome in NTI and newborn cord blood serum. These data suggest that normal FT3 may explain clinical euthyroidism in many patients with the low T3 syndrome.

Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure.

Most patients with advanced congestive heart failure have altered thyroid hormone metabolism. A low triiodothyronine level is associated with impaired hemodynamics and is an independent predictor of poor survival. This study sought to evaluate safety and hemodynamic effects of short-term intravenous administration of triiodothyronine in patients with advanced heart failure. An intravenous bolus dose of triiodothyronine, with or without a 6- to 12-hour infusion (cumulative dose 0. 1 5 to 2.7 microg/kg), was administered to 23 patients with advanced heart failure (mean left ventricular ejection fraction 0.22 +/- 0.01). Cardiac rhythm and hemodynamic status were monitored for 12 hours, and basal metabolic rate by indirect calorimetry, echocardiographic parameters of systolic function and valvular regurgitation, thyroid hormone, and catecholamine levels were measured at baseline and at 4 to 6 hours. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.

Sphingomyelinase and phospholipase A2 regulate type I deiodinase expression in FRTL-5 cells.

We have previously reported (Mol. Cell. Endocrinol. (1994) 101, R31-R35) that the proinflammatory cytokines, tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma), have a marked inhibitory effect on the expression and activity of type I iodothyronine deiodinase (D1) in FRTL-5 rat thyroid cells, while the anti-inflammatory cytokine, transforming growth factor-beta 1 (TGF-beta 1) had no effect. These three proinflammatory cytokines utilize a number of intracellular second messenger systems including the pathways beginning with activation of sphingomyelinase and phospholipase A2. We have studied the time-dependent and dose-dependent effects of sphingomyelinase, ceramide, phospholipase A2 (PLA2), and arachidonic acid on the expression and activity of D1 in FRTL-5 cells. Sphingomyelinase (0.3 U/mL) inhibited D1 activity 55% and reduced D1 mRNA levels 70% to 90% by 8 hours. Similar treatment with 10 U/mL PLA2 inhibited D1 activity 54%. Treatment with 15 microM 5, 8, 11-eicosatriynoic acid (ETI), a nonmetabolizable analog of arachidonic acid, or 15 microM ceramide for 3 hours reduced D1 activity with a half-time of disappearance (t1/2) of 4.2 hours and 3.7 hours, respectively, but ETI and ceramide did not alter the D1 immunoreactivity or mRNA levels. Treatment for 8 hours with cycloheximide (5 or 10 micrograms/mL) had no effect on the D1 mRNA level, but blocked the TNF-induced reduction of this mRNA. We conclude that proinflammatory cytokines inhibit D1 expression and activity in FRTL-5 cells, in part, by activation of sphingomyelinase and PLA2 that results in (1) competitive inhibition of D1 activity by the enzymatic products ceramide and arachidonic acid and (2) reduction of D1 mRNA stability by protein synthesis-dependent mechanisms.

Clinical review 86: Euthyroid sick syndrome: is it a misnomer?

Alterations in thyroid function tests are very common in patients with NTI. Multiple, complex, and incompletely understood mechanisms are involved in these abnormalities. Knowledge of these abnormalities is necessary to avoid errors in the diagnosis of thyroid disease. Measurement of serum TSH, free T4, and free T3 levels by direct equilibrium dialysis/RIA methods probably yield most useful (accurate) information in the setting of NTI. Patients with low free T4 by these methods and normal or low TSH have secondary hypothyroidism. This may be due to NTI per se, drugs administered for treatment of NTI, or associated pituitary or hypothalamic disease; the latter consideration may require evaluation of cortisol reserve, PRL, and/or gonadotropins. A serum TSH level above 20-25 microU/mL probably reflects primary hypothyroidism; accompanying findings of goiter, low free T4, and positive antithyroid antibodies help establish the diagnosis. An elevated serum concentration of rT3 argues against hypothyroidism. Studies have demonstrated no discernible benefit of treatment of NTI patients with T4. Some studies have shown a few benefits of treatment with T3 in selected cases, but much more needs to be learned. There is no evidence of harm by treatment of NTI patients with up to replacement doses of T3. As some NTI patients may indeed be hypothyroid, the term ESS should be replaced with NTIS.

Acute effects of amiodarone administration on thyroid function in patients with cardiac arrhythmia.

Because little has been published on early effects of treatment with amiodarone on thyroid function, we studied serum total and free thyroid hormone, reverse T3, and TSH levels in patients with cardiac arrhythmias during the first 10 days of treatment with a loading dose of amiodarone by iv infusion. Twenty-four patients were enrolled in the study. A standardized loading regimen for the i.v. infusion of amiodarone was used. The protocol provided the i.v. infusion of 20 mg/kg per day on day 1, the i.v. infusion of 10 mg/kg per day on day 2, then 600 mg/day per os for 7-10 days, and finally, in patients chronically treated with the drug, the dose was gradually reduced to 400-200 mg/day per os. Total and free concentrations of T4 tended to progressively and significantly increase (P < 0.0001 repeated measures ANOVA) starting from the fourth day of therapy, whereas total T3 decreased from the second day progressively (P < 0.0001) throughout the study; free T3 did not significantly change. TSH levels early and significantly (P < 0.001, by ANOVA) increased throughout the study, starting from the first day of therapy and reaching at 10 days a value 2.7 times higher than the basal value. Reverse T3 levels progressively and significantly (after 2 days of treatment) increased and paralleled the TSH values, reaching at the 10th day a value about 2 times higher than basal value. In conclusion, our data suggest that after i.v. treatment with amiodarone: 1) TSH is the first hormone to change significantly followed by reverse T3, T4, and T3; 2) the progressive fall of T3 levels reflects an inhibition of the peripheral conversion of T4 to T3; 3) the observed later increase of total and free T4 levels may be explained by a contribution of direct thyroidal stimulation by TSH and/or by a reduction in T4 clearance.

Acute effects of intravenous amiodarone on sulphate metabolites of thyroid hormones in arrhythmic patients.

OBJECTIVES: Factors that contribute to the remarkably rapid decrease in serum T3 and increase in reverse T3 (rT3) levels during illness, fasting, or treatment with some drugs (e.g. amiodarone) are not clear. In order to understand better the effect of acute amiodarone administration on T3 metabolism, especially the sulphation pathway, we performed a prospective study in 8 arrhythmic in-patients treated with a loading dose of amiodarone. DESIGN: Amiodarone was administered by i.v. infusion of 20 mg/kg/day on day 1 and 10 mg/kg/day on day 2, followed by 600 mg/day orally throughout the study. Two serum samples for amiodarone and hormone assays (thyroid hormones, TSH, and the sulphate metabolites of 3'-T1, 3,3'-T2, and T3) were collected before the start of therapy, every 12 h during the first 3 days of amiodarone administration, and then once a day for 2-10 days. SUBJECTS: Eight patients (4 men and 4 women, aged 44-82 years), who were treated with amiodarone because of cardiac dysrhythmia, were enrolled in the study. RESULTS: Serum concentrations of total T4 significantly increased in the last 3 days of the study (ANOVA, P = 0.0002). However, serum total T3 progressively and significantly decreased throughout the study (ANOVA, P < 0.0001). Serum free thyroid hormone concentrations (free T3 and free T4) did not significantly change during the study. Serum rT3 (ANOVA, P < 0.0001) and TSH (ANOVA, P = 0.0009) rapidly and progressively increased throughout the study. Starting from the first 24 h, serum concentrations of T3 sulphate (T3-S) significantly and progressively increased from (mean +/- SD) 0.057 +/- 0.029 nmol/l under basal conditions to 0.089 +/- 0.036 nmol/l after 5 days of amiodarone therapy (ANOVA, P = 0.0011). Since total T3 levels progressively decreased throughout the study, the ratio of the T3-S and total T3 values progressively increased from 4.8 +/- 2.7% under basal conditions to 10.6 +/- 7.3% after 5 days of amiodarone therapy (ANOVA, repeated measures, P < 0.0001). Basal serum concentrations of sulphate metabolites of T2 (T2-S, 2.22 +/- 1.7 nmol/l) and T1 (T1-S, 1.29 +/- 0.74 nmol/l) did not significantly change throughout the study. CONCLUSIONS: Our data indicate that a loading dose of intravenous amiodarone in patients with cardiac dysrhythmias is followed by a very rapid and progressive increase in circulating T3-S levels, possibly due to an inhibition of type 1-iodothyronine de-iodinase. Since T2-S and T1-S, common final metabolites of the thyroid hormone sulphation pathways remained unchanged, our data suggest that the total amount of thyroid hormone degraded by sulphation pathways remains unaltered during amiodarone treatment. Finally our findings are compatible with the view that sulphation represents an important pathway for T3 metabolism in vivo in man.

Direct determination of free triiodothyronine (T3) in undiluted serum by equilibrium dialysis/radioimmunoassay (RIA).

UNLABELLED: We have devised a practical, sensitive, and reliable assay for measurement of free T3 concentration in serum. The assay employs a convenient and disposable plastic equilibrium dialysis cell and a buffer that resembles the in vivo biochemical environment (Nelson JC, Tomei RT 1988 Clin Chem 34:1737). A 200-microliters aliquot of serum was dialyzed against 2.4 mL buffer at 37 degrees C for 18 +/- 2 h and T3 was quantified by RIA of about 1.0-mL aliquot of the dialysate buffer. The detection threshold of the RIA approximated 2 pg/ml permitting accurate measurement of > 200 pg/dL of free T3 directly. Serum specimens that contained less free T3 were spiked with 200 ng/dL of non-radioactive T3 prior to dialysis. Free T3 in the dialysate of these samples was divided by total T3 in serum (after spiking) to determine percent free T3. Free T3 was calculated by multiplying percent free T3 and serum total T3 (before spiking). Free T3 concentration (pg/dL) did not differ appreciably in a serum pool when tested both with and without spiking with exogenous T3. The between assay coefficient of variation of three specimens tested over an 8-month period averaged 20%. Serum free T3 concentration (pg/dL) was [mean +/- SD (n), range, p] [293 +/- 12 (39), 154-440] in normal subjects. It was significantly increased [742 +/- 87 (13), 525-1700, p < 0.001] in hyperthyroidism and significantly decreased in nonthyroidal illness [NTI, 138 +/- 26 (9), 53-320, p < 0.001], cord blood serum [124 +/- 7.5 (11), 93-353, p < 0.001], and third trimester of pregnancy [214 +/- 26 (8), 93-253, p < 0.02]. Serum free T3 concentration varied widely in hypothyroidism 274 +/- 92 (10), 10-923, NS]. CONCLUSIONS: We have described a practical method and initial results of direct measurements of free T3 concentration in health and disease.

Demonstration of thyromimetic effects of 3,5,3'-triiodothyronine sulfate (T3S) in euthyroid rats.

We have previously demonstrated that T3 sulfate (T3S) exhibits thyromimetic effects in hypothyroid rats and that, on a molar basis, its activity approximates 20% that of T3. Since T3S is avidly deiodinated by 5'-deiodinase, type I (5'-DI) and 5'-DI activity is markedly reduced in hypothyroidism, it seemed possible that T3S is active only in hypothyroidism and not in the euthyroid state wherein normal tissue 5'-DI activity will rapidly degrade T3S and little T3S will be left for metabolism (desulfation) to biologically active T3. This study was undertaken to test this possibility. We studied the effect of T3S (4.6, 14, or 42 nmol/day for 7 days, ip) and T3 (1.0, 3.0 or 9.0 nmol/day for 7 days, ip) in groups of male Sprague-Dawley rats (5-6/group); the control group was treated with saline ip. Treatment with both T3 and T3S caused a significant (p < 0.05) increase in hepatic and renal 5'-DI. Similarly, both treatments caused a significant reduction in serum total T4 and TSH levels. In these effects, T3S was approximately one-fifth as potent as T3 on a molar basis. Interestingly, changes in body weight during treatment with T3 and T3S suggested that at doses that caused a comparable tissue or pituitary effect, T3S treatment permitted a significantly greater weight gain than treatment with T3. We conclude that T3S exhibits thyromimetic effects in euthyroid rats in a manner comparable to that in hypothyroid rats. The biological effects of T3S may be due to T3 generated in tissues by desulfation of T3S.

Nonthyroidal illness syndrome or euthyroid sick syndrome?

OBJECTIVE: To characterize the nonthyroidal illness syndrome (NTIS) and to discuss various underlying potential biochemical mechanisms for this condition. METHODS: The pertinent medical literature was reviewed, and studies of thyroid function in systemic non-thyroidal illnesses were summarized. RESULTS: Abnormalities of thyroid function in the NTIS have been classified into four major categories: (1) low triiodothyronine (T3) syndrome, (2) a combination of low T3 and low thyroxine (T4), (3) high T4 syndrome, and (4) other abnormalities. The NTIS has been noted in essentially all severe systemic illnesses and after caloric deprivation, major operations, and administration of some drugs. Some mechanisms that may contribute to low serum T3 in the NTIS are decreased type I 5 -monodeiodinase in tissues, decreased uptake of T4 by tissues, decreased serum binding, increased reverse T3, alterations in selenium status, cytokines, and a decrease in thyrotropin. Decreased thyrotropin may also contribute to low T4 levels in NTIS, as may decreased serum T4-binding proteins, abnormalities in T4-binding globulin, and circulating inhibitors of binding of T4 to serum proteins. Although T4 treatment of patients with NTIS has yielded little improvement, administration of T3 has produced some beneficial effects. CONCLUSION: Further studies should be conducted to determine appropriate patient populations, dose-response ratios, and possible adverse effects of treatment of the NTIS with T3.

Study of serum 3,5,3'-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness.

Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.

Coexistence of struma ovarii and Graves' disease.

A 30-year-old woman with hyperthyroidism due to coexisting Graves' disease and struma ovarii is described. Physical examination revealed a diffusely enlarged thyroid and an abdominal mass. CT scan of the abdomen showed a 25-cm predominantly cystic right ovarian mass. 123I uptake and scan showed 75% thyroid uptake at 4 h and a focus of intense uptake in the left upper quadrant of the abdomen. Preoperative treatment for the hyperthyroidism included propylthiouracil, propranolol, and ipodate. Surgery was performed and pathologic examination of the ovarian mass revealed struma ovarii.

Use of sodium ipodate in management of hyperthyroidism in subacute thyroiditis.

Five hyperthyroid patients (two men and three women) with typical features of subacute thyroiditis were treated with sodium ipodate (Oragrafin; 0.5 g, orally daily or every other day) for 15-60 days; the treatment was stopped when both serum T4 and T3 levels were normal. All patients studied demonstrated a prompt normalization of serum T3, improvement in clinical symptoms of hyperthyroidism, and/or weight gain. We observed no side-effects of treatment with sodium ipodate. Our data suggest that sodium ipodate is a safe and effective agent for management of hyperthyroidism in subacute thyroiditis.

Sulfation pathway of thyroid hormone metabolism in selenium-deficient male rats.

Male Sprague-Dawley rats were fed a selenium-deficient yeast-based laboratory diet or a control diet for 6 wk. The tissue type I 5'-monodeiodinase (5'-MDI) activity and the immunoassayable 5'-MDI were significantly (P < 0.05) reduced in the liver and the kidney but not in the thyroid of selenium-deficient rats. The mean serum concentrations of thyroxine sulfate (T4S), 3,3',5'-triiodothyronine sulfate (T3S), and reverse T3 sulfate (rT3S) (ng/dl) were significantly increased in selenium-deficient rats (15.7, 59.4, and 22.8, respectively, n = 12) compared with control rats (< 1.0, 18.5, and 9.1, respectively, n = 12, P < 0.01). Kinetic studies were carried out during a constant infusion of unlabeled sulfated iodothyronines (T4S, T3S, or rT3S, n = 5-6/group) at a rate of 1 microgram/h by Alzet minipump for 48 h. The data showed that elevated serum concentrations of T4S or T3S in the selenium-deficient rat are due both to reduced metabolic clearance rate (MCR, mean, l.kg-1.day-1, 7.4 for T4S and 4.5 for T3S in selenium deficiency vs. 12 and 9.2, respectively in controls, P < 0.05) and increased production rate (mean, microgram.kg-1.day-1, 1.2 for T4S, and 2.7 for T3S in selenium deficiency vs. 0.12 and 1.7, respectively, in the controls, P < 0.05). However, the increased serum rT3S concentration in selenium-deficient rats is due mainly to reduced MCR (mean, l.kg-1.day-1, 34 vs. 67 in controls, P < 0.05) and its daily production rate remained unchanged in selenium deficiency (mean, microgram.kg-1.day-1, 7.6 vs. 6.1 in the control group, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of humic acids on thyroidal function.

Humic substances (HS) have been implicated as environmental goitrogens. Increased prevalence of goiter has been recently noticed in the blackfoot disease endemic area on the southwest coast of Taiwan, where well water is rich in HS. This study investigated the in vivo effects of humic acids (HA) on the thyroid gland of rats and mice. Groups of mice and rats were fed regular or moderately iodine deficient (approximately 167 vs 700 micrograms l- per kg) chow and distilled water or HA water (1mg/ml) for 3 or 4 months. Serum T4, T3, reverse T3, and/or TSH were measured by radioimmunoassay. Thyroidal 125I uptake was measured in mice at 2 h after injection of 1 microCi125I ip. Treatment of the rat with HA was associated with a significantly (p < 0.05) reduced serum T4 without a change in other parameters of study. Treatment with low iodine diet was associated with a clear increase in serum T3 and a decrease in serum rT3. Rats treated with both HA and low iodine diet showed a significantly reduced serum T4, increased serum T3 and decreased serum rT3. In mice, treatment with low iodine diet significantly increased thyroidal 125I uptake and additional treatment with HA significantly enhanced the effect of low iodine diet. Treatment with HA did not influence thyroid weight of rats or mice given normal or iodine deficient diets. We conclude that HA per se do not induce goiter, but they may enhance the goitrogenic effect of low iodine.