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Serum-T4, -T3, FTI, basal TSH and TRH-induced TSH response were measured in 80 patients with simple nontoxic goiter and in 24 patients with nontoxic recurrent goiter in a surgical unit. 55 of the 80 patients with simple goiter and 11 patients with recurrent goiter had normal individual TSH values. Mean FTI and serum T3 were not statistically different from age and sex related normal values, except serum-T3, which was above normal in elderly goiter patients. The incidence of elevated TSH reserve (preclinical hypothyroidism) was significantly higher (p less than 0.0005) in recurrent than in simple goiter (10 of 24 vs. 8 of 80 patients). Simple goiter aptients with preclinical hypothyroidism had a lower-than-normal mean serum T4 level, whereas mean serum T4 and T3 concentrations were higher than normal in preclinically hypothyroid recurrent goiter patients. In these subjects raised TSH values and goitrogenesis possibly may be related to lower sensitivity of the pituitary to thyroid hormones. 17 simple goiter patients and 3 recurrent goiter patients with normal circulating serum T4 and T3 levels showed no response to TSH to TRH. This suprising finding is related to preclinical hyperthyroidism on the basis of autonomously functioning thyroid compartments. In 12 tested patients TRH responsiveness recovered following goiter resection. The mean T3 response to TRH in goiter patients with normal or elevated TSH reserve was subnormal. This indicates that thyroid reserve is potentially decreased even in goiter patients whose thyroid function was, on the evidence of normal TSH values, actually appropriate.
Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.
We analyzed the thyroglobulin (Tg) gene of 2 unrelated patients with congenital goiter and the Tg gene of 2 siblings with the variant type of adenomatous goiter. The clinical characteristics of the patients with congenital goiter and the variant type of adenomatous goiter were very similar, except for serum Tg levels, which were less than 15 pmol/L in the patients with congenital goiter, but 117-181 pmol/L in the patients with the variant type of adenomatous goiter (normal, 15-50 pmol/L). The tissue content of Tg in the thyroid glands of all 4 patients was reduced at 0.9-3.8% of total protein (normal, 19-40%). The missense mutation C1263R was detected in the 2 unrelated patients with congenital goiter; the pedigree study showed an autosomal recessive pattern of inheritance. In the 2 siblings with the variant type of adenomatous goiter, the missense mutation C1995S was homozygously detected. In the Tg complementary DNA of 110 normal subjects, the allelic frequencies of the C1263R and C1995S mutations were each less than 0.5%. Also in the normal subjects were detected 35 nucleotide polymorphisms, the insertion of 3 nucleotides, and 1 alternative splicing, each of which was not associated with any specific thyroid disease. From these data, the molecular mechanism of the C1263R and C1995S mutations was elucidated. We first analyzed the carbohydrate residues of C1263R Tg and C1995S Tg. Sensitivity to treatment by endoglycosidase H suggests that C1263R Tg and C1995S Tg were retained in the endoplasmic reticulum (ER). Also, the presence of endoglycosidase H-resistant Tg as well as endoglycosidase H-sensitive Tg in the patients with the variant type of adenomatous goiter suggests that a fraction of C1995S Tg was transported to the Golgi and associated with the mildly increased serum Tg levels. Native PAGE and Western blot analysis with anti-Tg antibody showed that C1263R Tg and C1995S Tg form high mol wt aggregates in the ER. Our results suggest that missense mutations that replace cysteine with either arginine or serine cause an abnormal three-dimensional structure of Tg. Such misfolded Tg polypeptides are retained in the ER as high mol wt aggregates.
Thyroid function was studied in a large number of subjects residing in Varsi, a town in the province of Parma, Italy. In this area, endemic goiter associated with moderate iodine deficiency [59 +/- 3 (+/- SE) microgram iodine/g creatinine], as defined by WHO criteria, affects 65% of the population. Serum T4, T3, thyroglobulin (Tg), and TSH concentrations were measured by RIA in 1218 subjects. The TSH response to TRH was determined in 108 subjects selected randomly from the groups with different grades of goiter. No significant change in serum T4 concentrations was found in subjects with different grades of goiter. Serum T3 concentrations were higher in subjects with the larger goiters. Serum Tg concentration progressively increased, and serum TSH progressively decreased with increasing goiter size. The TSH response to TRH was diminished in subjects with larger goiters. The findings of decreasing serum TSH concentrations and blunted TSH responses to TRH as goiter size increased suggest the possibility of autonomous thyroid function in the larger goiters in subjects residing in this area of moderate iodine deficiency.
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.
While the concept of iodine deficiency (ID) still dominates most discussions about the pathogenesis of multinodular goiter (MNG), the present review focuses on those mechanisms that may cause MNG in the absence of ID. Among the many facets of MNG that cannot simply be explained by ID, are the frequent occurrence of the disease in patients not exposed to ID, the autonomous growth of goiters - often accompanied by subclinical or even overt thyrotoxicosis -, the inverse relationship between goiter size and serum TSH, the multifocal, heterogeneous and nodular growth pattern, the heterogeneity of function with the familiar patchy iodine metabolism on scintiscans, the growth of clonal and polyclonal nodules, the prominent genetic predisposition. Even the notoriously low intrathyroidal iodine concentration - common to endemic as well as to sporadic goiter - is a secondary, rather than a primary event. Thus, the fundamental process of goitrogenesis, is independent from ID but operates through mechanisms innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. In this view, goiter nodules and nodular goiters are true benign neoplasias arising by mechanisms common to all benign endocrine and nonendocrine neoplasms. However, superimposed iodine shortage greatly enhances the incidence of MNG and shifts its clinical appearance toward younger ages by adding one more growth factor - presumably enhanced TSH secretion - to an intrinsically activated growth regulating network.
BACKGROUND: Goiter rates and iodine deficiency usually show marked improvement in efficacy studies of mandatory iodization of salt, but little is known about the short-term effectiveness of mandatory iodization. OBJECTIVE: The aim of the study was to evaluate, after 1 y, the effectiveness of mandatory iodization of salt at an iodine concentration higher than that occurring under optional iodization on the goiter rates and iodine status of schoolchildren living in an endemically goitrous area. DESIGN: Goiters, measured by palpation, and urinary iodine concentrations of children in grades 4-7 in 4 schools in a known goitrous area in South Africa were assessed before and 1 y after the introduction of mandatory iodization at a higher iodine concentration than occurred with optional iodization. Estimates of the iodine concentration of iodized salt and the proportion of households using iodized salt were also made. RESULTS: Iodine concentration in table salt and household use of iodized salt improved within 1 y. Goiter rates, which varied at baseline from 14. 3% to 30.2% in the 4 schools, remained unchanged, with an overall mean (+/-SE) prevalence of 25.6 +/- 2.5% at baseline and of 27.5 +/- 2.7% 1 y later. The distribution of urinary iodine concentrations in the 4 schools improved substantially from the baseline deficient range. The overall median urinary iodine concentration increased from 0.17 to 1.47 micromol/L. CONCLUSIONS: Mandatory iodization of salt virtually eradicated iodine deficiency within 1 y in South African schoolchildren, but the goiter rate in these children did not decline. Measurement of goiters by palpation may not be appropriate in short-term evaluations of mandatory iodization programs.
Serum thyroglobulin (Tg), T4, T3, FT4, FT3, TSH concentrations and TSH response to iv TRH (delta TSH) were measured in 56 consecutive patients with (multi) nodular goiter from a severely iodine-deficient endemic goiter area in Northeastern Sicily and in 11 non goitrous euthyroid individuals living in the same area. Serum Tg concentrations were sharply increased in goitrous subjects (453 +/- 476 ng/ml) and related to thyroid size and the presence of nodules (chi 2 = 43.5, p less than 0.0005). Serum TSH levels measured in goitrous patients (2.1 +/- 0.9 microU/ml) were significantly lower than those measured in nongoitrous iodine deficient subjects (3.1 +/- 0.9 microU/ml, p less than 0.001) and decreased with increasing goiter size and nodularity (chi 2 = 27.3, p less than 0.05). A similar pattern was shown by the analysis of the delta TSH (chi 2 = 43.1, p less than 0.0005). These results suggest that at least a part of the largest and multinodular goiters become autonomously functioning with duration and growing in size. In 13 goitrous patients with absent or impaired response to TRH, a significant direct relation was apparent between log-Tg and goiter size and nodularity (r = 0.64) with an inverse relationship between serum FT3 and delta TSH (r = 0.73). A computed program analysis based on the combination of different independent variables (x) including age, thyroid size and nodularity, serum TSH, log-Tg and FT3, indicated the existence of a significant negative relationship between these variables and the TSH response to TRH (r = 0.75, p = 0).(ABSTRACT TRUNCATED AT 250 WORDS)
A survey study was performed to assess the prevalence of goiter and thyroid dysfunction in a population of 534 Ethiopian children, one year after arrival in Israel. The overall prevalence of goiter was 43.6%. Children in the age group 1-2 years had the lowest prevalence of goiter (6.7%). A progressive increase in goiter prevalence and size with age was observed, with peak occurrence around puberty for both boys (56.7%) and girls (72.2%). Serum FT4 levels were elevated in 4 children; elevated serum TSH levels (above 4.5 mIU/l) were found in 11 children, all of them had normal FT4 levels. Thus the prevalence of hypothyroidism and hyperthyroidism was 2% and 0.8%, respectively, with an even distribution across the various age groups. All the children were clinically normal. The high prevalence of goiter in this group of Ethiopian children with the low frequency of hypothyroidism may be attributed to the combined effects of food goitrogens and iodine deficiency prevailing in Ethiopia. The standard Israeli diet seems to be adequate in respect to iodine requirements, and no iodine enrichment is needed for children immigrating from Ethiopia.
Serum thyroglobulin (Tg) levels were determined in 98 biologically euthyroid patients with a diffuse or nodular goiter, and compared to values observed in 33 control subjects. Based on the results of clinical examination and thyroid scanning with radioiodine, patients were divided into 3 groups: group 1 with homogeneous diffuse goiters, group 2 with heterogeneous diffuse goiters without palpable nodules, and group 3 with solitary hypofunctioning nodules. The control group had a mean Tg of 37 +/- 15 micrograms/l. Group 1 (n = 32) had a mean Tg of 46 +/- 28 micrograms/l; six (19%) had an elevated Tg level (level greater than 74 micrograms/l). Group 2 (n = 30) had a mean Tg of 133 +/- 134 micrograms/l; fourteen (47%) had an elevated Tg level. Group 3 (n = 36) had a mean Tg of 188 +/- 191 micrograms/l; twenty (56%) had an elevated Tg level. The comparison of Tg between patient groups, and between patients groups and the control group, showed a significantly higher value in the groups of hypofunctioning nodules and heterogeneous diffuse goiters. It is concluded that the elevated serum Tg level in patients with a diffuse or nodular simple goiter is commonly associated with heterogeneity of the thyroid scan.
The operative morbidity rates in patients operated for substernal goiter (SG) vary from one series to another. The aim of this study was to reevaluate the morbidity using a matched technique. Each SG was matched to a cervical goiter for surgical technique, histology and thyroid function. There were 97 SG (75% of women), 43% with normal thyroid function, 28% with mild hyperthyroidism, 29% with hyperthyroidism. 87% of thyroidectomies were bilateral. Mean age was 66.5 +/- 11.5 years versus 55.8 +/- 11.9 years for cervical goiters (p < 0.001). The percentage of men was higher for SG than for cervical goiter (25% versus 10%, p < 0.01). Specimen weighed 166 +/- 109g versus 76 +/- 95g (p < 0.0001). Total volume of drainage was 164.0 +/- 68 ml versus 123.2 +/- 68 ml (p = 0.003). No operative death occurred. Early hypoparathyroidism rate was 3% versus 2% (p = 0.5), and late hypoparathyroidism was 1% versus 0% (p = 0.5). There was a 10 mg/l in serum calcium post-operative drop in both groups but no change in serum phosphate was noted (bilateral thyroidectomies). The early recurrent laryngeal nerve palsy rate was 4% versus 0% (p = 0.06) and 3% versus 0% one year later (p = 0.12). Early postoperative reoperation rate for hemostasis was 2% versus 1% respectively (p = 0.25). We conclude that there is no significant difference in surgical morbidity between thyroidectomies for SG and cervical goiters when patients are operated in specialized centers. Operative fears are not justified.
A retrospective follow-up study of 131I treatment was performed in 10 females (median age 48 years, range 40-74 years) with non-toxic multinodular goiter. The median dose of 131I given was 20 mCi (range 14-65 mCi). Thyroid volume was measured by ultrasonography. The median follow-up period was 26 months (range 12-68 months). Nine patients had a reduction of goiter size: thyroid volume decreased from 88 +/- 14.9 ml (mean +/- SEM) to 49 +/- 10.9 ml 1 year after 131I treatment. The relative decrease of goiter size was 48% after 1 year (N = 9) and 59% after 2 years (N = 5). One patient did not respond and was referred for operation. Side effects were mild spontaneously resolving radiation thyroiditis in one patient and subclinical hypothroidism in four patients. In conclusion, 131I treatment of non-toxic goiter is an effective treatment at the expense of post-radiation (subclinical) hypothyroidism.
1. The effect of the standard 15 mCi dose of 131I on the thyroid function of 25 patients from an endemic goiter region with toxic multinodular goiter of different sizes was determined. 2. The patients were followed for 1 to 5 years and 7 months (mean: 2 years and 10 months). Eighteen patients were treated with the antithyroid drugs propylthiouracil or methimazole before 131I and seven only received 131I. 3. All but three patients achieved euthyroidism after a single dose of 131I. Two patients in the antithyroid treatment group became hypothyroid 2 months and 2 years after the isotope therapy, respectively. Pretreatment with antithyroid drugs did not significantly modify the effectiveness of 131I treatment. 4. This simplified dose regimen of 131I was effective in the treatment of hyperthyroidism caused by multinodular goiter in an endemic region, and the efficacy was independent of the size of the goiter.
This article discusses the diagnostic and therapeutic measures we have used during the past five years to treat 861 patients from an edemic goiter area with various thyroid disorders. The similarities and differences between these patients, with nontoxic goiter, toxic goiter, and thyroid cancer, were compared with those seen in patients with thyroid problems who live in iodine-rich areas.
BACKGROUND: Deficiencies of iodine, iron, and vitamin A are the 3 most common micronutrient deficiencies in developing countries, although control programs, when properly implemented, can be effective. OBJECTIVE: We investigated these deficiencies and their possible interaction in preschool children in the southern Blue Nile area of Sudan. DESIGN: Goiter, signs of vitamin A deficiency, and biochemical markers of thyroid, vitamin A, and iron status were assessed in 984 children aged 1-6 y. RESULTS: The goiter rate was 22. 3%. The median urinary iodine concentration was 0.79 micromol/L and 19.3% of the children had a concentration >1.57 micromol/L. Although serum thyroxine and triiodothyronine concentrations were within reference ranges, the median thyrotropin concentration was 3.78 mIU/L and 44% of the children had thyrotropin concentrations above normal. The mean urinary thiocyanate concentration was high (259 +/- 121 micromol/L). The prevalences of Bitot spots and night blindness were 2.94% and 2.64%, respectively, and 32% of the subjects had serum retinol binding protein concentrations <15 mg/L. A significant positive correlation was observed between thyrotropin and retinol binding protein. Whereas 88% of the children had hemoglobin concentrations <1.86 mmol/L, only 13.5% had serum ferritin concentrations below the cutoff of 12 microg/L and 95% had serum transferrin concentrations above the cutoff of 2.50 g/L. CONCLUSIONS: Our results indicate that goiter is endemic in this region of Sudan despite iodine sufficiency and that both anemia and vitamin A deficiency are health problems in the area. Moreover, consumption of millet, vitamin A deficiency, and protein-energy malnutrition are possible etiologic factors in this endemic area.
In recent years, the widespread use of iodized salt in households and industrially produced foods has considerably improved the shortage of iodine in the German diet. Recent epidemiologic studies have shown that we are now at the threshold of adequacy. Over the last decade, views on the pathogenesis of iodine deficiency goiter have changed: while TSH was previously assumed to be the major factor underlying this form of goiter, experimental data now finger the activation of local growth factors, in particular IGF1. Iodinated organic compounds, in particular iodolacton produced by iodination of unsaturated fatty acids in the thyrocyte, are the key regulators of IGF1 activity by inhibitory action, and iodine is now the therapeutic agent of first choice for iodine deficiency goiter; long-term thyroxine treatment in TSH suppressive doses has been abandoned. The recommended daily dose of iodine is 200 micrograms; higher doses may induce or aggravate autoimmune thyroiditis, and should not be used for a length of time. In pregnant women, an adequate supply of iodine is of critical importance for optimal neurophysiological development, and the general use of iodine supplementation in pregnancy therefore remains mandatory in Germany.
Endemic goiter disease develops as a result of iodine insufficiency in the environment, that induces advancing reproduction of thyrocytes realized by endomitosis. Eventually goiter-transformed gland ceases responding to the lack of iodine in the environment, that is due to the destruction of thyrocyte ++thyroreceptors. It should be taken into account that goiter disease depends upon the female sexual hormones.