Elevated serum thyroglobulin. A marker of metastases in differentiated thyroid carcinomas.

The presence of human thyroglobulin (HTg) in serum of patients was identical by immunological criteria to the serum standard used in the radioimmunoassay. The serum thyroglobulin levels in untreated patients with differentiated thyroid carcinoma ranged from 22.0 to 445.0 ng/ml with a mean of 144.3 +/- 46.5 ng/ml (SEM) (n = 10). The mean serum thyroglobulin measured postoperatively in seven of these patients was 6.4 +/- 1.5 ng/ml, not statistacally different from the mean level of 5.1 +/- 0.49 ng/ml (range 0-20.7 ng/ml) observed in 71 out of 95 control subjects with detectable HTg levels. By contrast serum HTg levels were normal or undetectable in subjects with medullary carcinoma of the thyroid. HTg levels were within normal limits in sera of patients who had previously undergone successful therapy for a differentiated thyroid carcinoma and in whom no metastases could be documented. The mean level for this group was 4.9 +/- 0.51 ng/ml (n = 43). In contrast, patients with documented metastases had a mean serum thyroglobulin level of 464.9 +/- 155.6 ng/ml (n = 6). The data support the thesis that in differentiated thyroid carcinoma serum thyroglobulin levels are elevated when metastases develop after initial treatment. It is proposed that the measurement of thyroglobulin in the serum represents a simple and valuable adjunct in the posttreatment follow-up of patients with differentiated thyroid cancer.

A radioimmunoassay for serum rat thyroglobulin. Physiologic and pharmacological studies.

A double antibody radioimmunoassay has been developed to measure thyroglobulin in rat (RTg) serum. The lowest detectable quantity measurable was 5.0 ng/ml. Specificity was documented by: (a) fall in serum RTg to undetectable levels after thyroid ablation; (b) the fact that L-thyroxine, D-thyroxine, L-triiodothyronine, D-triiodothyronine, triiodothyroacetic acid, tetraiodothyroacetic acid, triiodothyropropionic acid, moniodotyrosine, diiodotyrosine, and human thyroglobulin (HTg) in concentrations up to 40,000 ng per tube did not cross-react in the assay; (c) the demonstration that constant levels of serum RTg were observed while varying amounts of serum (criterion of parallelism) were introduced in the assay. The mean RTg concentration in tail vein blood of adult Sprague-Dawley rats were 101.5 +/- 13.0 ng/ml (SEM) (n=21); values ranged from 12.0 to 258.0 ng/ml. Chronic administration of a high-iodine diet (HID) did not affect serum thyroglobulin levels. Chronic administration of a low-iodine diet (LID) and propylthiouracil (PTU) led to a statistically significant increase in serum RTg that was accompanied by a significant rise in serum thyrotropin (rTSH). Serum thyroxine (T4) administered to normal rats for 14 days (20 mug/day subcutaneously) depressed serum RTg concentration from a mean level of 119.4 +/- 17.5 ng/ml (n=19) to a mean of 35.0 +/- 0.27 ng/ml (n=19) (P less than 0.001). While rats were on continuous T4 suppression, bovine thyroid-stimulating hormone (bTSH) given intravenously (2 IU) resulted in a mean maximal increment of RTg of 332.0 +/- 81.5 ng/ml (n=6) at 24 h. IgC-(LATS) long-acting thyroid stimulatory injected intravenously resulted in a mean maximal increment of RTg concentration at 96 h of 87.2 +/- 14.3 ng/ml (n=5). Normal IgG had no statistical significant effect of RTg levels at any time after the injection.

Radioimmunoassay for measurement of thyroglobulin in human serum.

A specific and reproducible double antibody radioimmunoassay for the measurement of thyroglobulin (HTg) in human serum has been developed. Since antithyroglobulin autoantibodies combine with the [(131)I] HTg tracer, antibody-positive sera were rejected for measurement. Specificity is demonstrated in that thyroid analogous such as thyroxine (T(4)), triiodothyronine (T(2)) monoiodotyrosine (MIT) and diiodotyrosine (DIT) did not crossreact. Sera previously reacted with anti-HTg-Sepharose contained no immunoassayable HTg. Finally, sera obtained from patients after total thyroid ablation for thyroid carcinoma did not contain demonstrable HTg. The sensitivity of the assay is 1.6 ng/ml, and HTg was detectable in 74% of 95 normal subjects. The mean concentration was 5.1 ng/ml +/-0.49 SEM (range <1.6-20.7 ng/ml). Day to day variation in HTg levels is large in some euthyroid subjects and nearly absent in others. HTg was detectable in 90% of the sera obtained in 23 pregnant women at delivery in whom a mean concentration of 10.1 ng/ml +/-1.3 SEM was observed. The mean level for the corresponding newborn infants at birth was 29.3 ng/ml +/-4.7 SEM a value significantly higher than the mean maternal HTg concentration (P <0.01). A group of 17 thyrotoxic individuals all had elevated HTg levels; the mean for this group was 344.8 ng/ml +/-90.7 SEM. In the acute phase of subacute thyroiditis HTg was also elevated in all of 12 patients, and the mean for this group was 136.8 ng/ml +/-74.6 SEM.

Enterohepatic regulation and metabolism of 3,5,3'-triiodothyronine in hypothyroid rats.

Several steady state indices of thyroid hormone distribution, metabolism, excretion, and absorption were measured in intact hypothyroid and euthyroid rats, to explore the role of intestines and enterohepatic pathways in the dynamic regulation of whole-body thyroid hormone in these two states. Ten rats were studied, 5 normal control (N) and 5 rendered hypothyroid (3.48 vs. 19.8 ng/ml TSH) by surgical thyroidectomy 3.5 weeks earlier (HYPO). High specific activity 125I-labeled T3 (T3*) was infused at the same constant rate for 7 days from osmotic minipumps implanted sc. Daily urine and feces, and seventh-day cardiac and portal venous blood, bile, and whole intestinal contents were assessed. Bowel and feces were homogenized, extracted, and chromatographed, along with serum, bile, and urine samples. Bile, bowel, and fecal extract samples were also hydrolyzed with aryl-sulfatase and/or beta-glucuronidase and chromatographed to identify conjugates and determine total T3* in all fluid and tissue samples. In the N group, the bowel contained 21.2 +/- 1.22 (SD) times more T3* (mass) than plasma (199 ng vs. 9.39 ng), this ratio falling to 9.03 +/- 1.78 in the HYPO group (30.4 ng vs. 3.37 ng), a shift to relatively more T3* in blood. Urinary T3* was zero in both groups. But fecal excretion was 34 +/- 4.43% of total T3* infused (production) in N and only 20.3 +/- 3.05% in HYPO rats, closely paralleling reduced fecal bulk flow, and thus providing more time for T3* absorption. Endogenous T3 and T4 concentrations measured in portal plasma were 15-31% greater in normals and 69-95% greater in HYPO rats than in corresponding systemic plasma samples, a direct indication of absorption of endogenous T3 and T4 in both groups, with greater absorption in the HYPO group. About 66% total T3* was metabolically degraded in N rats, rising to approximately 80% in HYPO rats. Plasma clearance rates of T3 fell more than 50% in HYPO rats, and total T3 production fell to about 20% of normal. It appears that HYPO rats compensate for low T3 by fecally excreting a much smaller fraction of total T3 production, absorbing more T3 and T4, and leaving a larger fraction for T3 action and degradative metabolism.

Critical analysis of [131I]- and [125I]human thyroglobulin labels for radioimmunoassay use.

[125I]- and [131I]thyroglobulin (Tg) tracers obtained by two different oxidation methods, chloramine-T (Chl-T) and lactoperoxidase (LP-ase), were analyzed to assess their suitability in the development of a RIA. Pairs of tracers which were prepared on a single day using these methods with a single source of 131I and 125I were compared. The following conclusions were reached. 1) Both 131I and 125I isotopes, using CHl-T or LP-ase oxidants, produce suitable tracers. 2) [131I]Tg can be used repeatedly for 2 weeks without repurification. 3) [125I]Tg, in contrast, has to be rechromatographed weekly on Sephadex G-200 to maintain assay sensitivity and adequate maximal binding. 4) Under these conditions, 2- or 9-day tracers with either isotope using Chl-T or LP-ase give similar Tg determinations in the serum. 5) The LP-ase-chromatographed 125I tracer seems to lead to higher maximal binding in the assay than the Chl-T-repurified tracer.

Partial adrenalectomy for pheochromocytoma with maintenance of adrenocortical function.

A 30-yr-old woman with malignant hypertension was found to have biochemical evidence of pheochromocytoma. Bilateral adrenal tumors were demonstrated on computerized tomographic scanning and confirmed at the time of surgery. Complete removal of one adrenal gland with partial removal of the other adrenal gland resulted in normalization of her blood pressure and biochemical parameters (norepinephrine and epinephrine) with preservation of adrenocortical function.

Improved diagnosis and management of hyper- and hypothyroidism by timing the arterial sounds.

"Sphygmo-Recording," a non-invasive method for timing the arterial pulse wave contour provides an objective measure of responses to medication in patients with hyper- and hypothyroidism. The QKd interval, i.e., the interval from the onset of the QRS complex (Q) to the onset of the Korotkoff sounds (K) at the brachial artery when the sphygmomanometer cuff is at diastolic pressure (d) is the QKd interval. QKd is normally 205 +/- 12 msec. In the hyperthyroidism the QKd interval may be shortened to 110 msec. In hypothyroidism the QKd interval may be prolonged to 320 msec. Changes in QKd parallel changes in clinical status and serum total T4 and T3, measured by radioimmunoassay. QKd can be used as an objective guide to antithyroid therapy in hyperthyroidism and replacement therapy with thyroid hormone in hypothyroid individuals.

An international cooperative study evaluating serum thyroglobulin standards.

A number of research laboratories have reported great variability in the levels of serum thyroglobulin (Tg) in normal subjects, the reason for which is not immediately apparent. The present study was designed to determine how important these variations were by submitting three identical standards to all participating laboratories. Three lyophilized human sera (standards A, B, and C) with increasing concentrations of Tg (5.3, 30.6, and 80.6 ng/ml, respectively) were submitted to 37 laboratories (40 assays) in 18 different countries. Standard A gave detectable values in 19 assays. The mean serum Tg concentration was 6.3 +/- 1.4 (+/- SEM) ng/ml (n = 18). Standard B was detected in all but 3 assays. The mean serum Tg concentration in standard B was 15.7 +/- 1.4 ng/ml (n = 37). All laboratories were able to detect Tg in standard C, and reported a mean serum Tg concentration of 36.5 +/- 3.2 ng/ml (n = 40). Lyophilization affected the recovery of Tg in our assay. This was confirmed by a study in which lyophilized standards A, B, and C and frozen standards were analyzed in the same assays. The remarkable finding was that the variability in serum Tg values reported by the various assays was great despite the submission of an identical set of standards of each of the laboratories. Wide interassay variation raises problems with respect to the applicability of threshold levels proposed by certain studies. The latter is particularly germane to the follow-up of patients with differentiated thyroid cancer. It is concluded that the development of a world standard for Tg may be a first and important step toward standardization of Tg assays, and that other components of the assays may need standardization as well.

Presence of a specific antiestrogen binding site on human follicular thyroid carcinoma cell line (UCLA RO 82 W-1): inhibition by an endogenous ligand present in human serum.

A receptor for antiestrogens, distinct from the estrogen receptor, has been identified in several tissues including the MCF-7 breast cancer cell line. Estrogen receptors have also been found in normal and pathological thyroid tissue homogenates. We demonstrate the presence of an antiestrogen binding site (AEBS) on a pure human follicular thyroid carcinoma cell line (UCLA RO 82 W-1) using a 3H-tamoxifen (3H-TAM) binding assay. The binding of 3H-TAM to the AEBS was determined after preincubation (30 min) of the cells with excess 17 beta-estradiol (2 mumol/L). Specific and saturable binding of 3H-TAM to the cells was observed. Displacement of the tracer from its binding site was dose dependent. Scatchard analysis revealed a dissociation constant (Kd) of 73 nmol/L, indicating a binding site with moderate affinity and capacity (72 pmol/10(6) cells). Using this assay we were also able to demonstrate the presence of an endogenous ligand for the AEBS in ethanol extracts of human serum. Cell growth and 3H-thymidine incorporation by the follicular thyroid carcinoma cells were inhibited when the cells were exposed to TAM (1.5 mumol/L). In conclusion, TAM is able to bind to a specific receptor on this follicular thyroid carcinoma cell line, and a natural circulating ligand present in ethanol extracts of human serum interferes with its binding.

Thyroid iodine content and serum thyroglobulin: cues to the natural history of destruction-induced thyroiditis.

Twenty-eight patients with destructive thyroiditis were followed to study the natural history of healing of thyroid gland injury. All had sequential measurements of thyroidal iodine [127I] content by fluorescent scanning (normal mean, 10.1 mg), 17 had serial serum thyroglobulin (Tg) measurements (normal, less than 21 ng/ml), and 13 had perchlorate discharge studies during the recovery phase. Seventeen patients had painful subacute thyroiditis (SAT), 9 had painless thyroiditis with thyrotoxicosis (PTT), and 2 had postpartum thyroiditis with thyrotoxicosis (PPT). Thyroidal iodine content decreased from a mean of 9.8 to a nadir of 3.8 mg in patients with SAT and from 8.5 to a nadir of 3.5 mg in patients with PTT. Mean serum Tg concentrations were highest (approximately 165 ng/ml) in both groups 1-3 months after the onset of symptoms. Abnormalities in both 127I content and Tg levels persisted for 2 or more yr in some individuals. No patient had detectable Tg antibodies by hemagglutination, but low titers were detected intermittently by sensitive RIA in 5 PTT patients. Microsomal antibodies were positive in only 1 of 16 SAT patients, but in 4 of 7 PTT patients and in both PPT patients. Three patients had positive perchlorate discharge tests (2 of 8 with SAT, 0 of 4 with PTT, and 1 of 1 with PPT). Permanent hypothyroidism occurred in 3 patients (2 with PTT; 1 with SAT and positive antibodies), but did not correlate with perchlorate results. HLA typing and serum immunoglobulin measurements were not useful for predicting the clinical course. These data indicate that several years may be necessary for complete resolution of destructive thyroiditis; many patients have evidence of thyroid injury persisting long after serum thyroid hormone and TSH levels become normal.

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.

A unique growth factor in patients with acromegaloidism.

Acromegaloidism is a syndrome characterized by features of acromegaly without biochemical evidence of excessive GH or somatomedin production. We searched for a growth factor in the serum of patients with this syndrome. Growth-promoting activity was measured by determining the stimulatory effect of whole and fractionated serum on colony formation by human erythroid progenitors in vitro. Sera from five subjects with acromegaloidism gave a mean (+/- SEM) stimulated colony growth of 211 +/- 4.0 colonies, in contrast to normal sera which yielded a mean colony growth of 100 +/- 11.0 (n = 9; P less than 0.001). When serum was chromatographed on a Sephadex G-200 column, the maximal stimulation of colony growth was found in the fractions coinciding with the descending slope of the second protein peak. Based on gel filtration chromatography, the estimated molecular weight was 70,000 daltons. Epidermal growth factor, nerve growth factor, fibroblast growth factor, and platelet-derived growth factor resulted in no substantial stimulation of colony growth under the conditions used. Although the erythroid progenitor cells of a Laron dwarf were unresponsive to 200 ng/ml human GH, they were clearly stimulated by serum from a patient with acromegaloidism. The present study describes the presence of a heretofore unidentified growth factor in the serum of subjects with acromegaloidism. This factor also stimulated the erythroid precursor cells of a Laron dwarf whose cells were unresponsive to GH. The physiological role of this growth factor in normal man as well as its pathogenic role in subjects with acromegaloidism remain to be established.

Inherited abnormal thyroid hormone-binding protein causing selective increase of total serum thyroxine.

A 9-yr-old boy is described in whom increased serum T4 concentration, increased T3 uptake, and increased free T4 index were associated with a euthyroid clinical state with normal total serum T3. T4-binding globulin (TBG), measured by RIA, was decreased. Reverse flow paper electrophoresis of serum proteins after reaction with radioactively labeled T4 demonstrated increased binding of T4 to a protein with electrophoretic mobility corresponding to albumin. Displacement of serum protein-bo-nd [125I]T4 activity by increasing concentrations of T4 revealed the presence of a low affinity, high binding capacity system with an association constant similar to that of T4-binding prealbumin. This low affinity binding protein cochromatographed with TBG on a DEAE-Sephadex column which normally separates TBG from T4-binding prealbumin. At free T4 concentrations equivalent to those present in the plasma of normal individuals, the T4 bound to free ratio is higher in the patient than in normals and the total serum T4 level is increased in the presence of normal free T4 concentrations. The relative affinity of this abnormal T4-binding protein for T3 is low compared to that of TBG. The patient's father had the same abnormal binding protein, which was not found in his mother or fraternal twin brother. These data suggest an autosomal dominant mode of inheritance of an aberration leading to synthesis of a new protein instead of normal TBG. The new protein is different from TBG in electrophoretic mobility, T4 and T3 binding, and antigenic properties.

Intra-uterine treatment of a hypothyroid fetus.

A woman in her 24th week of gestation was referred for treatment of hypothyroidism, after she underwent radioablation of the thyroid during the 13th week of gestation. Because of the high risk of hypothyroidism in the fetus, prenatal administration of intramuscular T-4 to the fetus was begun at 32 weeks. The last dose of T-4 was given 2 weeks before delivery; cord blood levels of T-4 and T-3 were undetectable and the TSH concentration was markedly elevated. The case illustrates several important physiological concepts regarding thyroid hormone and TSH metabolism in the fetal-placental unit, including the minimal placental permeability to iodothyronines and TSH, independent function (including feedback control) of the fetal hypothalamic-pituitary-thyroid axis, and the TSH response at parturition. In addition we suggest that administration of T-4 to the hypothyroid fetus in utero is an acceptable modality of treatment and may help to minimize irreversible mental retardation in known high risk infants. However, further studies are necessary to assess the effectiveness and safety of this approach.

Serum thyroglobulin in inhabitants of an endemic goiter region of New Guinea.

Serum thyroglobulin Tg(RIA) was studied in 161 residents of the Nomane region of New Guinea. The incidence of antithyroglobulin antibodies (ATA) and antimicrosomal antibodies (anti-M) was also studied to assess the role of autoimmunity in goitrogenesis. ATA were detected in only 4 sera; these sera were excluded from the study since ATA interfere in the Tg radioimmunoassay. Anti-M antibodies were undetectable in all of 105 subjects whose sera were analyzed. Mean (+/-se) serum Tg(RIA) in the 84 nongoitrous (NG) subjects was 163.1 +/- 17.2 ng/ml, whereas that in 77 goitrous (G) subjects was 208.1 +/- 19.8 ng/ml; both values were much higher (P is less than 0.001) than that (5.1 +/- 0.49 ng/ml) in normal Californian subjects. The mean serum thyroid stimulating hormone (TSH) in the NG group (12.1 +/- 2.1 muU/ml) was not statistically different from that in the G group (10.1 +/- 1.5 muU/ml). Serum Tg(RIA) correlated positively with log TSH (r equals 0.38 P is less than 0.001). Intrigued by the finding of goiters in some residents of an endemic goiter region and its absence in other residents exposed to the same environmental factors, we evaluated the possibility that the thyroid glands of subjects who develop goiters may be inherently more responsive to any given level of TSH than those of the inhabitants without goiters. However, the slope of the correlation between serum Tg(RIA) and log TSH was only slightly (0.1 is less than P is greater than .05) higher in G than in the NG group. These studies suggested that factors other than thyroidal responsiveness to TSH must also be important in goiterogenesis of endemic goiter regions. We conclude that 1) serum thyroglobulin is a sensitive parameter of chronic as well as acute thyroidal stimulation; 2) Thyroid autoimmunity and increased thyroidal response to TSH do not explain goiterogenesis in New Guinea and attention should be focused on other possibilities.

Serum albumin and antibodies in the diagnosis of thyroid cancer.

Anti-thyroglobulin antibodies, anti-thyroid microsomal antibodies, serum thyroglobulin, and carcinoembryonic antigen were assayed in sera of patients with a history of thyroid irradiation and in patients with thyroid cancer. In irradiated patients, the frequency of positive results for each test was increased above the frequency found in a control population, with a significant increase at P less than .05 for TGHA and TG levels. However, the tests (with the exception of serum thyroglobulin) did not clearly segregate irradiated patients with benign or malignant lesions from those with no clinically detectable abnormalities. Elevations of serum thyroglobulin above 300 ng/ml were found only in patients with thyroid cancer, but in these patients the diagnosis was usually clinically obvious.

Reversible hypothyroidism in growth hormone-deficient children treated with human growth hormone.

Six children with human growth hormone (hGH) deficiency became hypothyroid during the course of their therapy with hGH. This was accompanied by a decreasing growth rate, clinical symptoms of hypothyroidism and decreased serum T4 concentrations. Three of the 6 patients returned to the euthyroid state, both clinically and biochemically, with cessation of hGH therapy, and reinstitution of hGH precipitated hypothyroidism again in 2 of the three. The patients who remained hypothyroid have evidence of multiple pituitary trophic hormone deficiencies while those who reverted to euthyroidism appear to have isolated hGH deficiency. Evaluation of thyroid function while on hGH showed low T4, free T4 and T3 concentrations. The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was absent or markedly blunted in 4 of 6 patients while receiving long-term hGH therapy but was normal or exaggerated in all patients when tested before or after only 5 days of hGH therapy. These data indicate that exogenous hGH results in an inhibition of the TSH response to TRH. The mechanism of this inhibition is unclear, but we postulate that it may be mediated by somatostatin secretion in response to pulse doses of hGH.

Calcium-sensing by parathyroid glands in secondary hyperparathyroidism.

Calcium-sensing by the parathyroids is abnormal in familial benign hypocalciuric hypercalcemia and in primary hyperparathyroidism (primary HPT), but the role of a calcium-sensing defect in uremic secondary hyperparathyroidism (secondary HPT) remains controversial. To study the regulation of PTH release by calcium, set point estimates were obtained using the four parameter model during in vivo dynamic tests of parathyroid gland function in 31 patients with secondary HPT, 8 patients with advanced secondary HPT studied shortly before undergoing parathyroidectomy (Pre-PTX), 3 patients with primary HPT, and 20 subjects with normal renal function (NL); the response to 2-h i.v. calcium infusions was also evaluated. Neither blood ionized calcium (iCa+2) levels nor the set point for calcium-regulated PTH release differed between secondary HPT and NL; iCa+2 levels and set point values were moderately elevated in Pre-PTX and markedly elevated in primary HPT. Compared with values obtained in NL, the lowest serum PTH levels achieved during calcium infusions, expressed as a percentage of pre-infusion values, were incrementally greater in secondary HPT, Pre-PTX, and primary HPT, whereas the slope of the relationship between iCa+2 and PTH, expressed as the natural logarithm (ln) of percent preinfusion values, decreased incrementally in secondary HPT, Pre-PTX, and primary HPT. The inhibitory effect of calcium on PTH release is blunted both in secondary HPT and primary HPT because of increases in parathyroid gland mass, but a calcium-sensing defect is a late, rather than early, consequence of renal secondary HPT.

Effects of 13 cis-retinoic acid on growth and differentiation of human follicular carcinoma cells (UCLA R0 82 W-1) in vitro.

Dedifferentiation of human thyroid tumors is frequently found in humans. The effect of retinoids (13 cis-RA) was studied on the proliferation and differentiation of a human follicular cell line in vitro (UCLA R0 82 W-1). A significant and dose-dependent reduction (P less than 0.001) in cell number and [3H] thymidine uptake was found in cells exposed to 13 cis-RA up to 10 microM. Higher concentrations of 13 cis-RA, however, led to a dose-dependent restoration of cell proliferation. Various parameters of differentiation increased under the influence of 13 cis-RA (10 microM) over nonexposed cells. The 125I uptake increased 4-fold over that in control nonexposed cells (P less than 0.05). [125I] Epidermal growth factor binding increased 5-fold, and [125I] human TSH binding increased significantly after exposure to 13 cis-RA (P less than 0.02). Deiodinase activity, however, was significantly lower in 13 cis-RA exposed cells than in control cells. The present study shows that 13 cis-RA (10 microM) drives the tumor cells toward a more normal state of proliferation and differentiation.

Endemic goiter in Vietnam.

Endemic goiter involves about 15% of the population of Vietnam. To define the role of various factors which contribute to endemic goiter in Vietnam, we surveyed 935 people in Vancon, a lowland commune with goiter appearing only in the past decade, and 619 people in Dich Giao, a highland commune with endemic goiter treated erratically with iodized salt. In Dich Giao, cassava, a goitrogenic food, constitutes half of the dietary caloric intake. The prevalence of goiter was 45% in Vancon and 28% in Dich Giao. Laboratory studies were carried out in a subgroup of 63 subjects in Vancon, 52 subjects in Dich Giao, and a control group of 46 women in Hanoi. The mean serum TSH levels were 1.4 +/- 0.1 (+/- SE) microU/ml in Hanoi, 3.6 +/- 0.5 microU/ml in Vancon (P less than 0.001), and 2.4 +/- 0.2 microU/ml in Dich Giao (P less than 0.05). The mean serum T4 concentrations were similar in the three groups, but the mean free T4 concentration was low in Vancon. Serum T3 levels and the T3 to T4 ratios were significantly elevated in the goitrous regions. The mean serum thyroglobulin (Tg) concentrations were 27 +/- 3 ng/ml in Hanoi, 101 +/- 20 ng/ml in Vancon (P less than 0.01), and 44 +/- 5 ng/ml in Dich Giao (P less than 0.01). The 4-h thyroid uptake was higher in Vancon than in Hanoi. The urinary iodine concentration was low in both goitrous regions, and urinary thiocyanate was increased in Dich Giao, reflecting the ingestion of cassava. For all regions combined, there was a direct correlation between serum TSH and T3 and between serum TSH and Tg. In Vancon, where iodine deficiency was more severe, there was an inverse correlation between thyroid uptake and the urinary iodine concentration; thyroid uptake correlated directly with serum T3, the T3 to T4 ratio, and serum Tg. In Dich Giao, there was no correlation between urinary thiocyanate and thyroid uptake or urinary iodine levels. The data show that low iodine intake is a major factor in the causation of goiter in Vancon, where iodine deficiency had not been suspected. The ingestion of cassava in Dich Giao did not cause a major change in thyroid hormone economy even though iodine intake was marginally low; the data suggest that the goitrogenic effect of cassava is easily overcome by supplementary iodine, even when it is ingested irregularly.