Iodine intake in Portuguese pregnant women: results of a countrywide study.

BACKGROUND: Iodine is the key element for thyroid hormone synthesis, and its deficiency, even moderate, is harmful in pregnancy, when needs are increased, because of its potential deleterious effects on fetal brain development. In Portugal, no recent data on iodine intake exists. The objective of this countrywide study was to analyze iodine status in pregnant Portuguese women in order to propose adequate measures to the health authorities. SUBJECTS AND METHODS: Using a fast colorimetric method, urine iodine concentration (UIC) was evaluated in 3631 pregnant women followed in 17 maternity hospitals from hinterland and coastal areas in Continental Portugal and the Portuguese islands of Açores and Madeira. RESULTS: Median UIC value was 84.9 µg/l (range 67.6-124.1) in Continental Portugal, 69.5 µg/l in Madeira, and 50.0 µg/l in Açores. The percentage of satisfactory values (>150 µg/l) was 16.8, ranging from 8.8 to 34.1 in the Continent, and being 8.2 in Madeira and 2.3 in Açores. The percentage of values below 50 µg/l was 23.7, ranging from 14.0 to 37.4 in the Continent, 33.7 in Madeira, and 50.0 in Açores. CONCLUSIONS: Our results point to an inadequate iodine intake in pregnant women assisted in most Portuguese maternity hospitals. Considering the potential deleterious effects of inadequate iodine supply in pregnancy, iodine supplementation is strongly recommended in this period of life.

Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred's syndrome.

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendred's syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendred's syndrome.

Detection of thyroglobulin mRNA transcripts in peripheral blood of individuals with and without thyroid glands: evidence for thyroglobulin expression by blood cells.

OBJECTIVE: Recent studies have assigned clinical significance and prognostic value to the detection of thyroglobulin (Tg) mRNA in the blood of patients subjected to total thyroidectomy for a papillary or follicular thyroid carcinoma. In this study, we investigated the diagnostic specificity of Tg mRNA detection, analysing blood samples from healthy volunteers and from patients previously subjected to total thyroidectomy for reasons other than a carcinoma of the follicular epithelium. DESIGN AND METHODS: Total RNA was extracted from whole blood, reverse-transcribed and the cDNA amplified for Tg and glyceraldehyde-3-phosphate dehydrogenase with specific primers. Expression levels were analysed by using a semi-quantitative PCR. In a few cases, Lymphoprep gradients were used to separate the mononuclear and polymorphonuclear cells prior to further analysis by reverse transcription/PCR. RESULTS: Our data suggested that all individuals expressed Tg mRNA. Moreover, no differences in the expression levels between subjects with and without thyroid glands were documented. Documentation of Tg expression by the mononuclear and polymorphonuclear layers in patients without thyroid glands support the hypothesis that both lymphocytes and granulocytes express Tg and may justify a background expression in blood, independently of the presence of follicular cells in circulation. CONCLUSIONS: Tg mRNA expression is not limited to follicular cells of the thyroid gland, and its expression by normal blood cells should be considered in tests performed for diagnostic purposes.

No evidence of increased chromosomal aberrations and micronuclei in lymphocytes from nonfamilial thyroid cancer patients prior to radiotherapy.

The relationship between the presence of high frequencies of chromosomal aberrations in peripheral lymphocytes and predisposition to cancer has been suggested for some cancer diseases. In nonfamilial thyroid cancer, the few reports available are equivocal. The aim of this study was to assess the possible chromosomal instability in peripheral blood lymphocytes from 22 patients suffering from nonfamilial thyroid cancer. For this purpose, 2 classic cytogenetic assays, the chromosomal aberrations assay and cytokinesis-blocked micronucleus assay, were chosen. The frequency of chromosomal aberrations excluding gaps (%) was 1.68 +/- 1.39 (mean value +/- SD) for the patients group versus 2.20 +/- 1.87 for the control group. The frequency of binucleated lymphocytes with micronuclei ( per thousand) was 5.41 +/- 3.51 (mean value +/- SD) for the patients group versus 5.37 +/- 3.21 for the control group. The results obtained revealed no significant differences between both groups. The present study reinforces the idea that constitutional chromosomal instability in peripheral blood lymphocytes is not visible in nonfamilial thyroid carcinomas.

Cytogenetic alterations and oxidative stress in thyroid cancer patients after iodine-131 therapy.

This study aimed to assess two end-points of DNA damage, namely chromosomal aberrations and micronuclei in peripheral lymphocytes, and their possible relationship with oxidative stress (which may be related to DNA damage and repair) in thyroid cancer patients receiving therapeutic doses of (131)I. Nineteen patients receiving 2590 MBq (70 mCi) were studied. Chromosomal aberrations were scored using standard cytogenetic methods and micronuclei scored in cytokinesis-blocked lymphocytes. Oxidative stress was assessed by determining thiobarbituric acid-reactive substances in blood, total plasma antioxidant status and serum uric acid levels. All parameters were assessed before treatment and 1 and 6 months after (131)I administration. The frequency of micronucleated cells per 1000 binucleated cells scored (mean +/- SEM) increased significantly from 5.21 +/- 0.80 to 9.68 +/- 1.22 1 month after treatment (P < 0.01) and to 8.42 +/- 1.28 6 months after treatment (P < 0.05). The frequency of cells with chromosomal aberrations, excluding gaps, per 100 cells, increased significantly from 1.68 +/- 0.41 to 3.47 +/- 0. 55 1 month after treatment (P < 0.01) and to 4.05 +/- 0.46 6 months after treatment (P < 0.01). Oxidative stress parameters showed slight modifications over the time period studied, but the differences were not significant except for a decrease in thiobarbituric acid-reactive products 6 months after therapy (P < 0. 05) and in serum uric acid concentration 1 and 6 months after therapy (P < 0.01). This report demonstrates slight but significant and persistent DNA damage in (131)I-treated patients as assessed by cytogenetic assays. There was no clear correlation between the cytogenetic findings and oxidative stress parameters studied.

An unusual case of papillary carcinoma of the thyroid with cutaneous and breast metastases only.

Cutaneous metastases of thyroid carcinoma are infrequent and, when present, are usually located in the vicinity of a widespread primary tumor. Breast metastases from these tumors are even less common. We report the case of a 64-year-old female with a toxic multinodular goiter in whom a fine-needle biopsy, performed in 1985 at the age of 52, was suggestive of papillary carcinoma of the thyroid. Total thyroidectomy for a papillary carcinoma, follicular variant, was performed in 1988. Four months after surgery, a cutaneous metastasis was discovered in the right thigh. Surgical excision of the lesion followed by treatment with radioactive iodine decreased serum Tg levels from 7495 to 3.3 micrograms/l. Under suppressive therapy with L-thyroxine, serum Tg remained undetectable for the next 4 years. Then, serum Tg levels rose to 3.9-5.6 micrograms/l and a second cutaneous metastasis was removed from the abdominal wall. The patient was again treated with radioactive iodine and the post-treatment whole-body scan did not show any area of increased uptake of the radionuclide. However, serum Tg levels under suppression with L-thyroxine remained elevated at 4-20 micrograms/l for the next 2 years. In August 1995, a 1.5 cm nodule was found in the right breast. Cytological examination was suggestive of a breast metastasis from thyroid carcinoma and the lesion was removed by enucleation. This proved to be a metastasis from a papillary carcinoma of the thyroid. Elevated (19-44 micrograms/l) serum Tg levels persisted postoperatively. A third cutaneous metastasis was revealed by 131I scintigraphy in the right buttock and surgically removed in December 1996. Serum Tg levels have remained undetectable since then. To the best of our knowledge, this is a unique case of a papillary carcinoma of the thyroid with a propensity to metastasize only to the skin and breast during a follow-up of 11 years.

ACTH-producing carcinoma of the pituitary with haematogenic metastases.

The case report is presented of a 47-year-old white woman with Cushing's disease treated by bilateral adrenalectomy in June 1981. A first computed tomography (CT) scan in September 1984 showed a voluminous pituitary adenoma with invasion of the sphenoid sinus and left parasellar extension. The tumour increased progressively in size, a suprasellar extension developed and the optic chiasm was eventually affected. In March 1988 and June 1989 the patient underwent two surgeries for the pituitary tumour, the second followed by radiotherapy. During this period, the ACTH values varied between 100 pmol/l and 403 pmol/l (normal: < 13 pmol/l). After radiotherapy, a progressive shrinking of the tumour was observed and the ACTH concentrations decreased to a lowest value of 27.5 pmol/l. The patient was clinically well until September 1993 when, suddenly, the plasma ACTH concentration increased to very high levels (greater than 965 pmol/l). There was no evidence of tumour growth on the sellar CT scan. In January 1995, an ACTH-producing pituitary carcinoma was diagnosed, based on the presence of bone metastases. The patient died in May 1995.

Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain.

Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG-->ACG) causing a Met-->Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T-->C transversion was identified causing a Cys-->Arg substitution. In conclusion, absence of a germline mutation in RET exons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630.

Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group.

OBJECTIVES: Pheochromocytoma (pheo) is the second component of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. Clinical expression is sometimes poor, and chronology between medullary thyroid carcinoma (MTC) and pheo is not well evaluated. Therefore, a retrospective study was done in eight European countries in order to precise the main characteristics of pheo in MEN 2. SUBJECTS: Data from 300 MEN 2 patients with pheo (274 MEN 2 A and 26 MEN 2 B) were obtained from cases registered by the EuroMen study group, and collected by a medical standardized questionnaire. These cases occurred between 1969 and 1992. RESULTS: Mean age at diagnosis of pheo was 39.5 years (range 14-68 years) in MEN 2A and 32.4 years (range 15-41 years) in MEN 2B patients. Pheo occurred first in 25.1% of the cases (2-15 years before diagnosis of MTC) and after MTC in 40.2% (2-11 years). In other cases (34.7%), MTC and pheo were diagnosed at the same time. Involvement was bilateral in 67.8% of cases. Malignancy was only 4%. Thirty-nine deaths occurred in these 300 patients, 64.1% were linked in pheo, 23.1% to MTC and 12.8% to other causes. Surgery was unilateral in 39.7% of the cases and bilateral adrenalectomy was the first procedure in 48.4%. A bilateral adrenalectomy in two steps had to be done in 11.9% of cases. In conclusion, these results justify systematic and prolonged biochemical screening of pheo during follow-up of MTC and address some questions about the best mode of surgery.

Primary hyperparathyroidism in multiple endocrine neoplasia type 2A.

The rarity of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) led us to study clinical findings, surgical therapy and outcome in 67 patients in order to evaluate our therapeutic strategy. The retrospective study was based on cases registered by the EUROMEN study group (nine participating centres) from 1972 to 1993. Characteristics of PHPT in 67 patients (41 females, 26 males) with MEN 2A were reviewed. All patients underwent exploratory neck surgery; PHPT was confirmed histologically and/or biochemically. The median age at diagnosis of PHPT was 38 years. In 75% of the patients, PHPT and medullary thyroid carcinoma were diagnosed synchronously, while in 4%. PHT was diagnosed earlier. In 18% of the patients, PHPT was diagnosed after thyroidectomy, and in 3%, after discovery of pheochromocytoma. Primary hyperparathyroidism was asymptomatic in 84% of the patients; 15% suffered from renal stones. Serum calcium was slightly elevated in 69% (2.9 +/- 0.2 mmol-1) and normal in 16% of subjects. A single adenomectomy was performed in 42% of the patients, subtotal parathyroidectomy in 31% and total parathyroidectomy with autotransplantation in 16%. Independent from the extent of resection, cure was achieved in 94% of the patients, including 13% with hypoparathyroidism; hypercalcaemia persisted in 3% and no information was available in 3%. In an 8-year follow-up, hypercalcaemia recurred in 12% of the patients, although half had undergone parathyroidectomy totally or subtotally. CONCLUSION. MEN 2A-related PHPT is characterized by a mild hypercalcemia which is mostly asymptomatic and can be cured by simple resection of an enlarged parathyroid gland in most cases.

Biodegradation of trace levels of a complex organic pollutant mixture.

Three bacterial isolates with the ability to grow on a model mixture of ground water contaminants were obtained from a sewage works for treatment of industrial effluents, and from heavily and intermediately contaminated ground. The mixture consisted of benzene, toluene, o-xylene, nitrobenzene, 1,4-dichlorobenzene, o-cresol, naphthalene, tetrachloromethane and trichloroethylene, at concentrations ranging from 150 to 600 micrograms/l (2.1 mg/l in total). A supplement of 50 mg/l phenol was added to support growth and batch cultures were adapted for 6 weeks. Preliminary assays to check for degradative ability and toxicological assessments of the compounds using oxygen uptake rates were undertaken. Each isolate exhibited a different extent of degradation for the compounds. In 18 h incubation, from an initial figure of 1,966 micrograms/l (not including the primary substrate) the highest remaining total organic carbon of 800 micrograms/l was for the isolate from activated sludge. The effect of the organic compounds upon oxygen uptake rate was less marked for the micro-organisms from heavily polluted ground. As far as bioremediation of groundwater is concerned, the combination of both chemical structure variety and extremely low concentrations of individual chemicals in the mixture under investigation, make the present report relevant to many environmental problems.

A kindred with multiple endocrine neoplasia type 2A associated with pruritic skin lesions.

BACKGROUND: A kindred affected by multiple endocrine neoplasia type 2A (MEN 2A), associated with symmetric, bilateral, scapular pruritic skin lesions (PSL), is reported. METHODS: There were 21 members, including the propositus, in four generations. Screening of 10 family members showed a palpable thyroid tumor in 1 and positive results for a pentagastrin test in 7 others. Two of these patients had surgically confirmed pheochromocytoma. Two others had a biochemical diagnosis of pheochromocytoma but did not have surgery. RESULTS: Medullary thyroid carcinoma was confirmed in five patients and nodular C-cell hyperplasia in another. In five affected adults, PSL were observed in the interscapular region, crossing the midline in some. These lesions were characterized by hyperkeratosis and hyperpigmentation. In all the patients, the pruritus had been present long before the clinical or biochemical diagnosis. Skin biopsies were performed in two of these patients. No amyloid deposits were found (Congo red stain and electron microscopic examination were used). Two children (14 and 6 years old) in the fourth generation complained of scapular pruritus, although skin lesions were not apparent. CONCLUSIONS: Localized PSL must be sought when screening for MEN 2A.

Prognostic implications of image cytometric assessments of nuclear DNA distribution pattern of neoplastic cells in thyroid medullary carcinoma. A retrospective study using disaggregated, formalin-fixed, paraffin-embedded specimens.

A modified technique for cytometric analysis of the nuclear DNA distribution pattern of neoplastic cells has been applied on archival histopathological specimens originating from 42 patients who had undergone thyroidectomy for medullary carcinoma of the thyroid gland. Five of the cases were of familial type. The DNA cytometric assessments were made by means of computerized image analysis techniques on Feulgen-stained, intact, cytodiagnostically identified neoplastic nuclei obtained from histopathologically selected areas of paraffin blocks. The nuclei were enriched by means of a cytospin technique after deparaffinization of pronase-induced disaggregation of 50 microns thick sections. Only seven of the tumours were found to consist of neoplastic cells where the nuclei showed a DNA distribution pattern of "aneuploid" type; six of these patients had a rapidly progressive neoplastic disease, but the seventh patient did not. Among all the patients whose tumour cell nuclei showed a cytometric DNA ploidy pattern of "euploid" type, not less than about half had a rapidly progressive neoplastic disease. Thus, even when a refined cytometric technique is used, the value of the nuclear DNA ploidy pattern of the neoplastic cells as a prognostic variable in MTC is limited.

Diffuse sclerosing variant of papillary thyroid carcinoma. A clinicopathologic study of 10 cases.

The clinico-pathologic features of ten cases of the diffuse sclerosing variant (DSV) of papillary carcinoma of the thyroid (PCT) are presented and compared with those of 259 common PCT diagnosed during the same period at the Instituto Português de Oncologia (Centro de Lisboa). The primary therapeutic approach was basically the same in every case and follow-up information was obtained in every patient. DSV comprises 3.4% of our series of PCT. Patients with DSV are suggestively younger (34.7 +/- 19.9), than those with common PCT (42.3 +/- 16.1) regional lymph node metastases and distant metastases are significantly greater in DSV (100.0% and 50.0%, respectively) than in common PCT (38.6% and 14.3%, respectively). No significant differences were found between the two groups with regard to sex-ratio, extrathyroid invasion and mortality rate. No differences were either found regarding the immunohistochemical results: neoplastic cells of both groups showed immunoreactivity with antisera for thyroglobulin, epidermal keratins, S-100 protein and NSE. Some foci of three DSV cases displayed histological and histochemical features resembling those of the so-called mucoepidermoid carcinoma. It is concluded that a) DSV is an exceptional example of PCT in which most of the usual morphologic features of this type of carcinoma are overexpressed; b) DSV is not exclusively found in young patients and, in older patients, merges with other variants of PCT; c) DSV is indeed a more aggressive tumor than common PCT and should therefore be treated accordingly regardless of the age of the patients.

Thyroxine toxicosis in patients with iodine induced thyrotoxicosis.

Serum concentrations of thyroxine (T4) and triiodothyronine (T3) were measured in 74 untreated hyperthyroid patients. Of these, 47 had Graves' disease, 12 had toxic nodular goiter and 15 had iodine induced thyrotoxicosis (IIT). The average serum T4 concentrations were, respectively, 13.5 microgram/100 ml and 13.3 microgram/100 ml (normal 4.5-10.3 microgram/100 ml). The average serum T3 concentrations were in the same order 732 ng/100 ml, 505 ng/100 ml and 378 ng/100 ml )normal 116-288 ng/100 ml). Of the 15 patients with IIT 5 had a pattern of T4-toxicosis (T4 larger than or equal to 10.5 microgram/100 ml; T3 less than 290 ng/100 ml). This pattern was not found in any of the patients from the other two groups. In IIT the ratio between the serum concentrations of serum T4 and T3 is similar to the one observed in normal individuals from non endemic areas. In patients with Graves' disease and toxic nodular goiter the increase in serum T3 is twice as high as the increase in serum T4. It is concluded that in IIT the serum concentrations of T3 and T4 increase in parallel while in the other two groups there is a preferential secretion of T3. As a consequence, a pattern of T4 toxicosis is a likely event in IIT and, when present, may constitute a biochemical characteristic of the condition.