Miscellaneous:
Pratt et al., Sutton, UK, studied factors that influenced the response to 50 Gy 131I for active Graves' disease in 50 patients. At 12 months 26/50 patients still required antithyroid drugs, 20/50 patients were euthyroid, and 4/50 patients used T4 supplements. There were no differences between these groups with regard to pretreatment thyroid 131I uptake and effective thyroidal half-life of 131I. The mean functional thyroid volume was slightly higher in the patients still on antithyroid drugs than in the euthyroid patients (19 vs 15 ml). By 18 months only 2/50 patients were still requiring antithyroid drug treatment and 44/50 patients were euthyroid (3 requiring a second dose 131I).
The authors conclude that in the majority of cases euthyroidism can be achieved after a single dose of radioactive iodine, but euthyroidism may appear later in those patients with a higher thyroid volume. (Comment: This study is one of the so many that have been reported on the outcome of thyroid function after treatment with radioactive iodine in patients with Graves' disease. The results have so far limited value in that follow-up time is really very short.)
Daumerie et al., Brussels, Belgium, studied the etiology of pretibial myxedema in 2 patients with this entity in combination with Graves' disease and thyroid associated ophthalmopathy (TAO). The TSH receptor (TSH-R) is considered to be responsible for thyroidal hyperfunction in Graves' disease and maybe also for TAO as reports have suggested expression of this peptide in orbital tissue. In the present report, positive staining, using two monoclonal antibodies against TSH-R, was found in the dermis of 2 patients with pretibial myxedema and not in the dermis of 2 controls. (Comment: Although only 2 patients were studied, the importance of this report lies in the fact that the end product of gene expression i.e. the TSH-R protein was identified. One should realize that in studies where the presence of the mRNA is found, this does not mean that the protein is always expressed.)
Evans et al., Cardiff and Cambridge, UK, report the development of a bioluminescent assay potentially suitable for routine measurement of TSH-R antibodies. As a target cell responsive to measure TSH-R stimulation by TSH, a Chinese Hamster Ovary cell line expressing TSH-R was used and that was stably cotransfected with the cAMP responsive luciferase reporter construct. Preliminary results show 11-24 fold stimulation using a range of 1-10 mU/mL bovine TSH. (Comment: This bioassay has a nice sensitivity. Preliminary results for detection of TSH-R antibodies are promising.)
Morgenthaler et al., Berlin, Germany, and Brussels, Belgium, also developed an assay to measure TSH-R antibodies. They use a system in which circulating TSH-R antibodies compete with labeled TSH for binding to affinity immobilized human recombinant TSH-R. In 94/100 patients with Graves' disease serum was positive for inhibition of TSH binding. The authors state that the human origin of the antigen (TSH-R) and reduced non-specific binding in the solid fase assay, increase clinical sensitivity. (Comment: This assay seems promising for routine use with a high sensitivity. Further clinical studies should show this.)
De Micco et al., Marseille, France, reported thyroperoxidase (TPO) immunocytostaining, using a monoclonal antibody against TPO, of fine needle aspirates (FNA) of thyroid nodules from 4419 patients of whom 1620 underwent surgical resection for suspicion of malignancy or other reasons (large size, physical or psychological discomfort). Results of TPO staining were considered suspect for malignancy if less than 80% of cells were positive. The results of immunostaining were compared with histological diagnosis. The sensitivity of TPO detection towards malignancy was 97.4% and the specificity of the method was 82%. The predictive value was reported to be 56.4% for a positive result and 99.2% for a negative result. The authors conclude that these values are even better than those of conventional cytology. (Comment: It is not known to what extent selection bias for surgery influenced the results. These results are however very interesting and should be confirmed by other laboratories.)
Vlassopoulou et al., Athens, Greece, report outcome and prognostic factors in 245 patients with differentiated thyroid carcinoma (202 papillary and 34 folliculary), followed from 1965 till 1995 with a median follow-up period of 9.3 years. Seventy-four patients were female. During follow-up 9 cancer-related deaths occurred. No significant difference was present between the two histological types at 10 and 15 years. Disease-free survival was negatively affected by extent of disease at diagnosis, male sex, tumor size >4 cm, and age over 60 years. Fugazolla et al., Milan, Italy, describe a large family with familial medullary thyroid carcinoma (FMTC) consisting of three generations and a total of 46 members. In the first generation 2/7 (29%) members appeared to be affected. In the second generation these figures were 6/14 (43%) respectively. The third generation (25 members) is presently under clinical investigation, but 3/8 patients studied so far have an early presentation and aggressive behaviour of the tumor. Taken together, these findings are suggestive of the anticipation phenomenon (earlier presentation of disease at greater severity in successive generations). In all affected patients a mutation in exon 15 (codon 891) was present.
Bauters et al., Lille and Toulouse, France, report a study of FMTC in a family with 5 affected members without pheochromocytoma or hyperparathyroidism. They found a new mutation i.e. in RET exon 8. (Comment: So far mutations have been reported in RET exon 10, 11, and 15. This information is important for screening purposes in families suspected for having FMTC.)
Heshmati et al., Rochester MN, USA, report phenotypic presentation in 86 patients from 24 families with FMTC. Phenotypic representation was related to mutation subtypes in codon 634. Fourteen/twenty- four families had a cysteine to arginine mutation and 10 families other subtypes of mutations. C-cell disease, pheochromocytoma and hyperthyroidism were present in 100%, 65% and 31% of patients with cys. to arg. mutation and in 97, 37, 21% of patients with other mutations respectively. C-cell disease or hyperthyroidism was significantly higher in patients with the mentioned mutation as compared to those with other mutations. Mean age at diagnosis of C-cell disease, pheochromocytoma, and hyperthyroidism were similar in both groups.
Ciampolillo et al., Bari and Milan, Italy, studied the expression of insulin-like growth factor 1 (IGF-1), both at the level of messenger RNA and of the protein in 50 adenomas and 53 differentiated carcinomas of the thyroid. An increased protein immunoreactivity was found in 62% adenomas and 72% of carcinomas as compared to normal thyroid tissue. IGF-1 mRNA was upregulated only in carcinomas. IGF-1 immunoreactivity positively correlated with tumor diameter and extensive capsular invasion but not with tumor type and stage.
Klein et al., Nancy, France, studied expression of vascular endothelial growth factor (VEGF) at the level of the mRNA and of the protein in 17 cases of papillary cancer and 7 cases of follicular carcinoma. At both levels expression of VEGF was more intense in carcinomas than in normal thyroid tissue. Of interest is the fact that expression was also more intense in normal thyroid tissue in close contact with the tumor. (Comment: The previous and this study suggest that growth factors that normally stimulate thyroid growth may also play a role in malignant thyroid growth, although the results so far reported are too preliminar for definite conclusions.)
Belfiore et al., Catania, Italy, studied the long term outcome of thyroid carcinoma in 21 patients with Graves' disease during a 12 year follow-up period. The results were compared to tumors of similar size occurring in 70 euthyroid controls, matched for sex and age. The frequency of clinically important (non-occult) thyroid carcinoma in the Graves' group was 4.7%. Distant metastases occurred in 5/21 (= 23.8%) versus 6/70 (= 8.6%) (p = 0.053). Graves' patients had less favourable cancer outcome, with more frequent recurrent and/or persistent disease or death (p = 0.0162) as compared to controls. Two patients died in the Graves' group and none in the control group. Circulating TSAbs were present in all but one patients of the Graves' group. The authors conclude that carcinomas occur at high frequency in Graves' patients and are more aggressive than those occurring in matched euthyroid controls. (Comment: in an editorial by Mazzaferri [J Clin Endocrinol Metab 70:826,1990] the association between Graves' disease and thyroid carcinoma is tentatively explained by the presence of long term stimulation by TSAbs. However, that the tumors are more aggressive than in euthyroid controls, has been contested [Hales at al. J Clin Endocrinol Metab 75:886,1992].)
Derrien et al., Rennes, France, analyzed exon 10 for mutations of the TSH-R gene and exon 8 and 9 for mutations in the GS-a gene in 37 nodules (22 hot and 15 warm or cold) from patients with multinodular goiter. In none of these nodules mutations were found. The authors suggest that mutations in the gene of the TSH-R and the GS-a protein do not play a major role in the etiology of multinodular goiter.
Tonacchera et al., Pisa, Italy, looked for mutations in the TSH-R gene in exon 10 in nodules from 4 patients with functionally autonomous multinodular goiter. In each goiter 2 hyperfunctioning nodules coexisted. In two goiters the 2 hyperfunctioning nodules contained different activating mutations in the TSH-R gene and in the 2 other goiters only 1 out of the 2 hyperfunctioning nodules contained a mutation in this gene. In the same goiters no mutations were found in this gene in the cold nodules. (Comment: The previous and this report are contradictory. One of the reasons for this may be the definition of multinodular goiter. Although in the classical definition of multinodular goiter the whole thyroid gland is affected in some way either by nodules, hyperplasia, involution, thyroiditis, or degeneration, some authors define multinodular goiter also for those patients that have several nodules in an otherwise normal thyroid. It is about time that people who find different results come together to sort things out.)
Wohlgemuth et al., Leipzig, Germany, investigated small autoradiographically hot areas for TSH-R gene mutations in 8 patients with euthyroid goiter and found in 2 patients mutations that are known to be somatic.
Agretti et al., Pisa, Italy, looked for mutations in the gene of the TSH-R in exon 9 en 10 and of the gene of GS-a protein at codons 201 and 227 in 30 consecutive patients with solitary thyroid nodules. Fifteen patients had a toxic adenoma and 15 a cold nodule. All patients were operated and the surgical specimen was further investigated. In 12/15 of patients with toxic adenoma an activating mutation was found in the TSH-R gene and in one (other) patient with a toxic nodule an activating mutation was found in the GS-a gene. No mutations were found in the cold nodules and the authors conclude that the functionally different nodules appear to have a different origin. (Comment: It would be interesting to know if any mutations are present in the gene of the iodide symporter in these cold nodules.)
Nygaard et al., Herlev and Odense, Denmark, investigated the long term effects of RAI on thyroid function and size in 62 consecutive patients with a solitary toxic thyroid nodule. Median follow-up was 60 months with a minimum of 12 months. A cure-rate of 75% was seen within 3 months and thyroid volume was reduced by 45% within 2 years. Hypothyroidism developed in 8% of patients with a median follow-up of 36 months. (Comment: Although follow-up with regard to development of hypothyroidism is still short, this low figure reported here, is very satisfying. Although the authors do not stress this point, it is important to deliver RAI when surrounding normal thyroid tissue is still suppressed.)
Allory et al., Boulogne-Billancourt, France, tested 68 surgical specimens immunohistologically for proliferation (using MIB-1 antibody) and the presence of thyroglobulin. Twenty-eight specimens were from autonomously functioning thyroid nodules (AFTN), 30 from cold nodules paired for size, and 10 from normal thyroid tissue for control purposes. Expression of proliferation was significantly higher in AFTN than in cold adenomas or normal tissue. No relation was found between proliferation and immunoreactivity for thyroglobulin. (Comment: As AFTN were matched for size with cold nodules, the finding of an increased proliferation in the former is not easily explained.) Leenhardt et al., Paris, France, performed fine needle aspiration biopsy (FNAB), guided by ultrasound, in a series of 516 non-palpable nodules. Diagnostic accuracy of this method was studied on 72/516 cases, in whom 18 thyroid carcinomas were diagnosed at final histology. Diagnosis prior to operation was established in 15/18 carcinomas by FNAB. Thirteen/eighteen presented with a size of 1 cm or greater. The authors conclude that ultrasound guided FAB is indicated when size of the nodule is minimally 1 cm. (Comment: The fact that in 25% (18/72) of "control" cases carcinoma was present, suggests that selection bias torwards malignancy may have been introduced. Furthermore, the important question is, to what extent these tumors are really of biological significance i.e. behave as carcinoma or remain biologically silent. The answer at this moment is not known. At the moment I would discourage physicians to routinely perform ultrasound of the thyroid for the detection of non-palpable thyroid nodules.)
It is still being debated if subclinical hypothyroidism, as defined by an elevated serum TSH but normal T4 and T3 serum parameters is an adequate compensatory mechanism ensuring euthyroidism to all tissues, or a state of less than normal thyroid hormone activity at the tissue level and should therefore be treated with thyroid hormone. Several reports were devoted to this entity, thus Caraccio et al., Pisa, Italy, reported further on their studies about muscle energy metabolism in 12 subclinically hypothyroid subjects with neuromuscular symptoms. In these subjects impaired muscle energy metabolism during dynamic arm exercise was detected in the sense that blood lactate was significantly higher during exercise, suggesting that muscle glycosis exceeds mitochondrial oxidation of pyruvate resulting in enhanced shunting of pyruvate to lactate via lactic dehydrogenase activity. After a six-months course of L-T4 treatment, lactate production completely normalized. (Comment: It should be asked if in patients with subclinical hypothyroidism but without neuromuscular symptoms, similar abnormalities are present.)
Monzani et al., Pisa, Italy, evaluated the prevalence of neuromuscular symptoms in 33 consecutive patients with subclinical hypothyroidism and compared results with age and sex matched controls. Patients filled out a short questionnaire and those with 3 or more neuromuscular symptoms were then studied by electromyography (EMG). Significantly more neuromuscular symptoms were reported by patients versus controls. In 11/33 patients 3 or more symptoms were present and in 8/11 patients abnormal EMG findings (repetitive discharges) were detected. Upon T4 treatment a significant improvement of neuromuscular symptoms was observed, and EMG abnormalities disappeared. Furthermore, plasma total and ionized calcium was, be it in the normal range, significantly lower than in controls. PTH, phosphate and magnesium levels were normal. Calcium parameters normalized upon T4 replacement therapy. Tzotzas et al., Tessaloniki, Greece, compared results of thyroid hormone treatment on lipids and apolipoproteins profile in 24 patients with overt hypothyroidism and 23 patients with subclinical hypothyroidism. They found elevated levels of triglycerides, LDL, apoB, apolipoprotein B/A1 ratio and LP(a) levels before treatment in patients with overt hypothyroidism that decreased significantly after treatment. However, no abnormalities in these parameters were found before and during T4 treatment in patients with subclinical hypothyroidism. (Comment: Other published reports, however, show differences in lipid profile in subclinical hypothyroidism that normalize after thyroid hormone treatment ... the controversy continues.)
Rodien et al., Brussels, Belgium, and Paris, France, report an interesting case of a woman suffering from recurrent gestational thyrotoxicosis lasting beyond the second trimester and sufficiently severe to require antithyroid drug treatment throughout pregnancy. After delivery, thyroid function returned to normal. It appeared that a mutation was present in the TSH receptor of the mother that, upon in vitro testing, was more sensitive to stimulation by hCG than the normal TSH receptor. Thus, a new entity is described in this report in that another cause of non-autoimmune hyperthyroidism is due to a mutation in the TSH receptor that renders it more than normal sensitive to human chorion gonadotrophin. (Comment: Thus, germline mutations in the TSH receptor may lead to hypothyroidism, hyperthyroidism due to constitutive stimulation of the cyclic AMP pathway, or [in this case] rendering it more sensitive to hCG. Furthermore, somatic mutations may lead to formation of autonomously functioning nodules.)
Brix et al., Odense, Denmark, analyzed the genetic influence on the development of non-autoimmune non-toxic goiter in a well defined population of Danish twins. They studied 91 subjects (83 females) representing 81 twin pairs with past or present non-autoimmune non-toxic goiter. They measured concordance rates in monozygotic and dizygotic twins. The pairwise concordance rate for non-toxic diffuse or multinodular goiter was significantly higher in monozygotic twins compared to dizygotic twins (0.56 vs 0.18, p = 0.03). No such influence was present in the case of a solitary non-toxic nodule.
Laurberg et al., Aalborg, Denmark, evaluated the incidence of newly diagnosed frank hypo- and hyperthyroidism in Jutland, Denmark, where the mean iodine intake level is around 60 µg/day in a study of 565,128 persons x years. The overall incidence of hypothyroidism was 13.6/100,000/year and of hyperthyroidism 38.7/100,000/year. Hyperthyroidism was more prevalent at all ages above 10 years. The authors conclude that the finding, that in an area of moderately low iodine intake, hypothyroidism is considerably less common than hyperthyroidism, contrasts with the findings in high iodine intake areas where hypothyroidism is more prevalent. Apparently the iodine intake level in an area is a major determinant of the type of thyroid function disorders.