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The problem of the nodular goiter.

Nodular goiter is a worldwide problem involving millions of persons. Endemic goiter, and associated cretinism, is totally preventable by ensuring an adequate dietary iodine intake and eliminating malnutrition and dietary goitrogens. Therapy, on the other hand, is difficult in that the goiters often do not regress and the cretinoid changes are irreversible. Nonendemic goiter due to autoimmune thyroid disease, genetic defects in thyroid hormone biosynthesis, and environmental goitrogens or neoplasia is not usually preventable. The usual therapy, involving TSH suppression by administration of L-thyroxine orally, will frequently bring about regression of early, diffuse goiters but is often ineffective in bringing about regression of large, multinodular goiters. In these patients, surgical removal of the goiter may be necessary for alleviation of obstructive symptoms. Further research is needed to elucidate the factors involved in the development of these multinodular goiters and to control the autocrine and paracrine factors involved in nodule growth.

Goiter, Endemic

Effect of therapy on the serum thyroglobulin concentration in patients with toxic diffuse goiter, toxic nodular goiter and toxic adenoma.

Serum thyroglobulin (S-Tg) was measured in 104 patients with thyrotoxicosis, 59 of whom had toxic diffuse goiter (Graves' disease), in 30 with toxic nodular goiter and in 15 with toxic adenoma. Before treatment, most patients had increased S-Tg concentrations, regardless of what type of thyrotoxicosis they had. After therapy the course of the S-Tg varied, two major patterns being observed: the S-Tg concentration increased in some patients but decreased in others, although no relationship could be found between these patterns and the outcome of therapy, the presence or absence of thyroglobulin antibodies (Tg-ab) or changes in the Tg-ab titer. However, the median pretreatment concentrations of S-Tg were significantly higher in patients with toxic nodular goiter and toxic adenoma than in those with toxic diffuse goiter (p less than 0.001 and p less than 0.05, respectively), but did not differ significantly between patients with toxic nodular goiter and toxic adenoma. The lowest posttreatment S-Tg concentrations were found after surgery, irrespective of type of thyrotoxicosis. The median pretreatment and posttreatment S-Tg concentrations in patients with toxic diffuse goiter who relapsed, did not differ from those patients in remission. This was also true of patients with toxic nodular goiter. In both groups, however, there was a tendency towards higher pretreatment S-Tg values in patients who subsequently relapsed. Serial determinations of S-Tg, on the other hand, are of limited value in predicting the risk of recurrence, independent of which type of thyrotoxicosis is involved.

Adolescent

The clonal origin of thyroid nodules in euthyroid nodular goiter.

Prevalence of euthyroid nodular goiter varies widely according to the endemia of the region studied. The goiter hyperplasia under goitrogenic stimuli progresses in the formation of nodules. Presently the pathophysiology of the thyroid nodules' formation in euthyroid nodular goiter is unknown. The A. reviews the two current hypothesis on the clonal origin of thyroid nodules. According to one hypothesis the nodule issues as the result of a coordinated replication of a cluster of follicles with an increased growth potential. According to the second hypothesis the formation of new follicles during goitrogenesis is due to a sprouting of one or a few cells from the follicles shell; nodules formation is the result of post-necrotic fibrosis and uneven growth.

Animals

Incidence of carcinoma of the thyroid in nodular goiter.

Since the incidence of cancer in nontoxic nodular goiter as reported by us in 1944 appeared high (17.1%), we made another study during the next four years and discovered an incidence almost identical (17.2%). Our figures on incidence of cancer in nontoxic nodular goiter appeared so high because we were the first authors to break down the goiters into the three different types and to discover that the incidence was high in only one type of goiter and not in the others. The incidence of cancer was only 4.6% in toxic nodular and toxic diffuse goiter added together. For decades, we have known that goiter is a geographic disease. It is possible that carcinoma of the thyroid is slightly geographical. At least it appears that there is a slightly geographical relationship in regard to the 16 patients we have observed in our clinic with cancer during 1944-1949; of these 16 patients, 11 had advanced malignant disease. We cannot have accurate figures on results regarding treatment of our cases until long-term follow-up is concluded.

Carcinoma

Morphologic and functional substrate of thyrotoxicosis caused by nodular goiters.

The pathogenesis of nonimmunogenic thyrotoxicosis caused by nodular goiters--with the exception of true toxic adenoma--was investigated in 11 patients by means of scintigraphic, morphologic and autoradiographic technics. The basic event is the appearance, for unknown reasons, of autonomously functioning follicles which are morphologically indistinguishable from normal follicles. Four basic patterns of intrathyroidal distribution of autonomously functioning follicles are individualized: Type I = multiple individual autonomously functioning follicles scattered throughout the goiter. Type II = clustered autonomous follicles without demarcation from less active parenchyma. Type III = multiple microadenomas. Type IV = autonomous function of the majority of all follicles. In all four types, the autonomous follicles occur without recognizable relation to nodule boundaries. Scintiscans cannot predict the microstructure of these types of goiters. More than one pattern of distribution of autonomously functioning follicles may occur within a single goiter. The growth of thyroid nodules is independent of, and certainly not a prerequisite to, thyrotoxicosis. Rather, the appearance of thyrotoxicosis in this type of multinodular goiter depends on (1) the number of autonomous follicles throughout the gland and (2) their mean hormone-producing capacity per unit of time.

Autoradiography

Simple nodular goiter. Treatment of 58 cases.

The treatment of 58 cases of simple nodular goiter, over a three-year period, is reported. This study was done in the Asella Regional Hospital, situated in the Arssi Region, in the central highland of Ethiopia. This is a frequent disease in this Region, and two provinces at high risk have been identified. Simple nodular goiter masked a carcinoma in 15.4% of cases. The treatment and results are discussed in details.

Adolescent

Thyroid peroxidase activity in human nodular goiters.

1. Thyroid peroxidase (TPO, iodide-oxidation) activity was evaluated in nodular and paranodular tissue samples from 27 patients with nodular goiter (19 "cold" and 8 "hot" nodules), and compared to 11 diffuse toxic goiter and 9 normal thyroid tissue samples. 2. In terms of U/g digitonin solubilized protein, TPO activity was increased in hot nodules (P less than 0.05), although not as much as in diffuse toxic goiters (P less than 0.01). 3. The mean TPO activity of tissues paranodular to a cold nodule was not different from that of normal thyroids. 4. Both the highest and the lowest TPO activities were found in cold nodules, but their mean value did not differ from those of their paranodular tissues or normal thyroids. 5. Inter-tissue variability was significantly increased (P less than 0.01) in cold nodules and in tissues paranodular to a hot nodule. 6. These data show that heterogeneity both within and among tissues contributes to the wide range of TPO activity detected in nodular goiters.

Adult

Serum thyroglobulin level in patients with diffuse and nodular goiter, after therapeutic application of stable iodine.

This study analysed the changes in serum thyroglobulin levels in euthyroid female patients, suffering from diffuse and scintigraphically functional nodular goiter, after therapeutic administration of two preparations of stable iodine: dried bovine thyroid, containing 100 mcg of iodine in one dragee (Thyral, Yugoslav Pharmacopea) and synthetic Na-salt L-thyroxine (Vobenol, with 100 mcg of iodine, too), for relatively short time of following-up, 8 weeks only. Having in mind the key role of TSH in regulation, all aspects of thyroid gland function, the interrelationship between TSH and thyroglobulin concentrations in those patients were also investigated. Prior to the therapy females had elevated thyroglobulin serum concentrations, caused by existence of diffuse and nodular goiter, which reflected an increase in intraglandular turnover of thyroglobulin (192 +/- 140 mcg/L in GROUP A further treated with Thyral and 121 +/- 14.80 +/- mcg/L in GROUP B, whose patients received Vobenol, mean +/- SD). Positive linear correlation between TSH and Tg levels was not established before therapy. Our data indicate that administration of two different preparations containing stable iodine in doses of 100 mcg every second day, during a two months period, resulted in significant decrease in the size of diffuse and nodular goiter, with diminished complains in a great number of patients. In thyroid humoral status, significant decrease of thyroglobulin concentrations was evident in both analysed groups (62 +/- 48 mcg/L, and 60 +/- 66, respectively). Presented results confirmed positive linear correlation between TSH and thyroglobulin in serum samples, after therapy, especially strong in the group treated with dried bovine thyroid.

Adult

[Nodular goiter recurrent after surgery. A study of its pathogenesis and incidence].

We analyzed 33 patients with recurring nodular goiter (from a population of 2,500 operated patients). Recurrence occurred 0.7 to 12 years after surgery. T4, T3, TSH, perchlorate and TRH tests were performed in 18. Results were similar to those in 13 operated patients without recurrence. Administration of thyroid hormone did not influence recurrence. Seven patients with recurring goiter were re-operated on; an encapsulated follicular cancer was found in one. Our results suggest that recurrence of nodular goiter after surgery is not prevented by routine use of thyroid hormone.

Adenoma

[Characteristics and surgical treatment of nodular goiter in middle-aged and aged patients].

Four hundred and two elderly and senile patients with nodular goiter were operated on. In most of them, hypothyrosis (decreased triiodothyronine level and increased thyrotropic hormone content in the blood) was revealed; in all--concomitant diseases (2.9 per a patient) and immunologic disorders; in 47%--cervico-retrosternal location of a goiter. In 65.2% of goiter preparations, the degenerative-sclerotic changes were found, in 33%--lymphoid infiltration of stroma, in 18.7%--malignant growth. Operation is the most effective method of treating elderly and senile patients with nodular goiter. It should be of little trauma relative to normal parenchyma.

Age Factors

New perspectives for diagnosis of nodular goiter by technetium-thallium subtraction scanning.

To improve the scintigraphic differential diagnosis of thyroid nodules, Tc-99m pertechnetate-Tl-201 Cl subtraction scintigraphy (Tc-Tl subtraction scanning) was performed in 106 patients with various histologically proven thyroid nodules. Results were evaluated by comparison with surgical findings and preoperative ultrasonographic results. Thyroid nodules were more successfully detected by Tc-Tl subtraction scanning than by either Tc-99m pertechnetate or Tl-201 Cl scintigraphy alone. Detection of nodules was further improved when images recorded by the three methods were integrally observed (sensitivity 83%, accuracy 89%), with detectability approaching that of ultrasonography. False-positive or -negative Tc-Tl subtraction scans were obtained principally when multiple nodules were present (7 cases) or when no discrepancy existed between the accumulations of Tc-99m pertechnetate and Tl-201 Cl (18 cases). Most colloid nodules exhibited irregular margins, heterogeneous internal accumulations of Tl-201 Cl, and distorted shapes on Tc-Tl subtraction scans, while the majority of adenoma were oval-shaped with smooth margins. Carcinoma were characterized by homogeneous internal accumulation of Tl-201 Cl and distorted shapes.

Diagnosis, Differential

Nontoxic nodular goiter and papillary thyroid carcinoma are not associated with peripheral blood lymphocyte sensitization to thyroid cells.

We tested the claim that uni- and multinodular goiter (UNG and MNG) and papillary carcinoma (PC) of the thyroid are autoimmune thyroid diseases (AITD) similar to Graves' disease (GD) and Hashimoto's thyroiditis (HT). The expression of HLA-DR on cultured thyroid epithelial cells (thyrocytes) from UNG, MNG, and PC after coculture with autologous peripheral blood mononuclear cells (PBMC) was compared with that on GD and HT cells. The thyrocytes also were cultured with interferon-gamma (IFN gamma) alone. A cytotoxicity assay involving 51Cr-labeled thyrocytes, anti-HLA-DR, and complement was used to determine HLA-DR expression. Stimulation of thyrocytes with 200 U/mL IFN gamma induced HLA-DR (expressed as a cytotoxicity index) equally well on all thyrocytes [AITD (n = 6): IFN gamma, 23.8 +/- 7.7 (+/- SD); unstimulated, 3.6 +/- 2.0; UNG (n = 6), MNG (n = 9), and PC (n = 5): IFN gamma, 22.5 +/- 4.7; unstimulated, 4.0 +/- 3.0]. When cocultured with autologous PBMC, the values were: AITD, 24.9 +/- 10.1; UNG, MNG, and PC, 3.8 +/- 3.7 (P less than 0.001). The supernatants from the AITD cocultures had higher IFN gamma concentrations (by RIA) than those from the other cocultures. We conclude that in UNG, MNG, and PC, the peripheral blood helper T-lymphocytes are not sensitized to thyrocyte membrane antigen(s); consequently, little if any IFN gamma is produced in cocultures, and hence, there is no increase in thyrocyte HLA-DR expression, unlike the situation in AITD (GD and HT). Thus, UNG, MNG, and PC are not primarily autoimmune in nature, as defined by a lack of sensitization of the PBMC of such patients to thyroid antigen(s).

Antigens, Surface

Histomorphological and immunohistochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells.

This study was aimed at dissecting the cellular mechanisms that underly the growth of actively expanding human goiter nodules. Thirty-two nodules from different patients, all removed because of steady recent growth, were serially sectioned and screened for 1) histomorphological signs of cell proliferation and 2) in situ expression of the immunohistochemically stained p21ras protooncogene product. Bovine, porcine, and rat thyroid glands (the latter from both T4- and perchlorate-treated animals) were used as controls. In normal glands, only a few follicular cells contain substantial amounts of stainable p21ras. Some of these cells are unusually large, but do not proliferate. In contrast, all goiter nodules contain areas where the epithelial cells are morphologically grossly altered and heavily loaded with p21ras. Cells of this type are mostly clustered in large cohorts coating whole follicles or entire groups of follicles. Only a small fraction of these activated cells actually proliferates at any one point in time. Actively replicating cells are scattered in tiny foci all over the nodules. The earliest proliferating buds are solid, but soon begin to generate microfollicles that enlarge by adding new cells to the follicular epithelium. Regionally heterogeneous p21ras content in morphologically identical cells suggests that growth occurs in bursts and waves. We conclude that goiter nodules grow by episodic proliferation of heterogeneous cohorts of epithelial cells from which new follicles are generated. Only a tiny fraction of all goiter cells proliferate at any one point in time. The molecular mechanisms governing these growth processes are unknown.

Adolescent