bluuebunny/crossref_metadata_2025 huggingface dataset:
In old age the majority of thyroid peroxidase autoantibodies are directed to a single TPO domain irrespective of thyroid function and iodine intake
Authors: Czarnocka Barbara , Szabolcs István , Pastuszko Danuta , Feldkamp Joachim , Dohán Orsolya , Podoba Jan , Wenzel Bjorn
Published: March 2003

OBJECTIVE

We have examined (1) which epitopes on thyroid peroxidase (TPO) are recognized by TPO autoantibodies (TPO‐Aab) in old age and to what extent? (2) Does the TPO‐Aab pattern differ in euthyroid and hypothyroid elderly subjects or does it depend on their iodine intake?

DESIGN

TPO‐Aab positive sera obtained from a screening study of nursing‐home residents living in areas of varying iodine intake were tested by competition studies with monoclonal antibodies (mAbs) recognizing different epitopes on TPO.

SUBJECTS

The nursing‐home residents with TPO‐Aab positivity were from (A) an iodine abundant area (Eastern Hungary, median iodine excretion ‐MIE‐: 0.462 μmol/mmol creatinine, N = 13); (B) an area of obligatory iodinated salt prophylaxis since the 1950s (Slovakia, MIE: 0.090 μmol/mmol creatinine, N = 11); (C) a moderately iodine‐deficient area (Northern Hungary, MIE: 0.065 μmol/mmol creatinine, N = 13).

MEASUREMENTS

Thirteen murine TPO antibodies generated against several epitopes of the four (A, B, C, D) antigenic domains on the TPO were co‐incubated with the TPO‐Aab positive sera on TPO coated microtitre plates. The amount of mAb bound was estimated after further incubation with goat anti‐mouse antibodies, conjugated with horseradish peroxidase and tetramethylbenzidine as chromogen. The TPO‐Aab positive sera were characterized by the pattern of percen_tage of inhibition of mAb binding caused by the TPO‐Aabs.

RESULTS

TPO‐Aabs inhibited only the binding of mAbs raised against the antigenic domains A (mAb9, mAb2, mAb60) and B (mAb64, mAb59, mAb18, mAb15). The extent of inhibition depended upon the TPO‐Aab titre but in all cases the binding of mAb9 was inhibited to the highest degree. The percen_tage inhibition of mAb9 was (a) 34 ± 17% (M ± SD) caused by sera (N = 8) with TPO‐Aab titre 1/100–1/200 (higher than that of all mAbs recognizing domain B, P < 0.01–P < 0.001), (b) 76 ± 18% caused by sera (N = 14) with TPO‐Aab titre 1/1000 (higher than that of all other mAbs −P < 0.01–P < 0.001, except mAb64), (c) 99 ± 4% caused by sera (N = 15) with TPO‐Aab titre 1/4000–1/16 000 (higher than that of all other mAbs, P < 0.01–P < 0.001). Thus, only mAb9 was inhibited completely by high titres of TPO‐Aabs. The qualitative and quantitative distribution pattern of mAb inhibition was similar in the subgroups of elderly hypothyroid and euthyroid subjects with comparable TPO‐Aab levels, as well as in the subgroups with varying iodine intake.

CONCLUSIONS

(1) In old age, there is a polyclonal TPO autoantibody response but the majority of the autoantibodies are directed to the TPO region mapped by or close to mAb9 (domain A); (2) the autoantibody response does not differ in elderly subjects with or without the clinical manifestations of autoimmune thyroid disease and does not depend on the iodine supply of the elderly subjects.
An audit of the management of thyroid cancer in a district general hospital
Authors: Vanderpump  , Alexander  , Scarpello  , Clayton
Published: March 2003

OBJECTIVE

Thyroid cancer is the commonest endocrine malignancy yet it appeared to present infrequently to the endocrinologists at this large District General Hospital. The management of well‐differentiated thyroid cancer remains controversial with a wide variation in clinical practice. The aim of this survey was to determine the characteristics of the patients diagnosed with thyroid cancer and whether any deficiencies existed in the management of subjects diagnosed with thyroid cancer over a five‐year period using standards of care based upon long‐term outcome data and recently published USA guidelines.

DESIGN AND PATIENTS

Retrospective case‐note survey of all patients newly registered with thyroid cancer from 1990 to 1994 in North Staffordshire (estimated total population 450 000).

RESULTS

The annual incidence of all thyroid cancer was two per 100 000 of which well‐differentiated tumours comprised 70%. Medical records were obtained in 48 new cases (91% of total) identified. Fifteen subjects who presented as surgical emergencies received only palliative treatment and had a poor outcome. Two patients presented with metastatic medullary thyroid carcinoma (3% of total). Thirty‐one patients (97% of whom presented with a thyroid nodule) were referred electively to either surgical (n = 22), ENT (n = 2) or endocrinology (n = 7) outpatients with well‐differentiated papillary (n = 17) and follicular (n = 14) tumours. Thirteen patients (42%) had fine‐needle aspiration cytology performed preoperatively. Of the 22 tumours (71%) greater than 1.5 cm, five (27%) had a total thyroidectomy and two (9%) also had radioiodine ablation. There was inadequate serum thyrotrophin suppression postoperatively in 12 patients (39%) and only five (16%) were being monitored for recurrence with serum thyroglobulin measurements.

CONCLUSIONS

Deficiencies in the optimum management of small, well‐differentiated thyroid cancers were identified. Improved communication between specialties has led to the development of an agreed management protocol to increase the quality of care offered to patients with thyroid cancer and for auditing the coordinated service in the future.
Current management of thyroid‐associated ophthalmopathy in Europe. Results of an international survey
Authors: Weetman A. P. , Wiersinga W. M.
Published: March 2003

OBJECTIVE

To determine how expert thyroidologists assess and treat thyroid‐associated ophthalmopathy (TAO), and if TAO affects treatment of coexistent Graves' hyperthyroidism.

DESIGN

Members of the European Thyroid Association (ETA) were invited to answer a questionnaire which gave details of an index patient and nine variants differing in age, severity of TAO, thyroid state and the presence of diabetes. Eighty‐four responses were received from 19 European countries, representing approximately 60% of the clinically active ETA members.

RESULTS

Disease‐modifying treatment was not considered necessary by 18% for the index case with diplopia and proptosis but 77% used steroids alone or with another treatment; 5% used radiotherapy alone and 18% used it in combination with steroids. Worsening of eye signs after 8 weeks induced a significant shift away from steroids to radiotherapy, surgery, or other immunosuppression. For treatment of associated hyperthyroidism, antithyroid drugs were chosen by 84%, thyroidectomy by 10% and radioiodine by 6%. In recurrent hyperthyroidism, thyroidectomy was preferred by 43%, antithyroid drugs by 32%, and radioiodine by 25%. Major alterations in management of TAO were noted for only 2 of the 9 variants. Optic nerve involvement produced a more thorough evaluation of TAO as an in‐patient, and a preference for surgical decompression (42%). The presence of diabetes induced a greater use of surgery at the expense of steroids, but there was disagreement over the role of radiotherapy in diabetes.

CONCLUSION

Marked geographical variation was noted, particularly in the treatment of thyroid‐associated ophthalmopathy. Observed consensus was nation‐wide rather than Europe‐wide. The appropriate treatment of the patient with thyroid‐associated ophthalmopathy, especially with diabetes or deteriorating eye signs, is controversial even amongst thyroid specialists.
Gestational transient hyperthyroxinaemia (GTH): screening for thyroid function in 23 163 pregnant women using dried blood spots
Authors: Tanaka Shinichi , Yamada Hideto , Kato Emi H. , Furuta Itsuko , Fukushi Masaru , Takasugi Nobuo , Fujimoto Seiichiro
Published: March 2003

OBJECTIVE

Transient elevation of serum free T4 (gestational transient hyperthyroxinaemia; GTH) occurs occasionally during normal pregnancy, especially in early gestation. However, the frequency of GTH and its clinical features remain unclear to date. The aim of this study was to determine the occurrence rate of GTH and the relation between serum levels of hCG, free T4 (fT4), and TSH in a large number of pregnant women.

DESIGN

The four criteria of GTH were as follows: (1) no past history of thyroid disease, (2) negative tests for MCHA and TGHA, (3) no multiple pregnancies or trophoblastic disease and (4) transient hyperthyroxinaemia at less than 16 weeks of gestation. Thyroid function and hCG levels in 23 163 pregnant women were evaluated by mass sreening. If individual fT4 levels were more than the upper limit, blood re‐sampling and the clinical and laboratory analysis of thyroid function were performed to exclude women with thyroid disease. The concentrations of hCG, fT4, and TSH in women with GTH and normal pregnant controls (n = 218) were compared. Regression analysis was performed for the comparison between hCG, fT4, and TSH levels in women with GTH.

MEASUREMENTS

Blood samples were obtained using dried blood spots. Blood levels of fT4 was measured by radioimmunoassay, TSH and hCG were measured by fluoroimmunoassay. Anti‐microsome antibody (MCHA) and anti‐thyroglobulin antibody (TGHA) were measured by indirect agglutination reaction.

RESULTS

GTH was observed in 66 of 23 163 women. The overall occurrence rate of GTH was 0.285%. In 22 of the 66 GTH women, serum TSH was undetectable. Using regression analyses, the concentration of fT4 was correlated with hCG levels in women with GTH (P < 0.05, r = 0.269), whereas the concentration of TSH was not correlated with hCG or fT4 level. The concentrations (M ± SD) of fT4, TSH, and hCG in women with GTH were 42.5 ± 12.3 pmol/l, 0.20 ± 0.31 mU/l and 190.2 ± 98.8 × 103 IU/l, whereas those of controls were 14.6 ± 3.8 pmol/l, 1.43 ± 1.25 mU/l and 60.1 ± 45.1 × 103 IU/l. The concentrations of fT4 and hCG were significantly (P < 0.0001) higher than those of normal controls, and TSH was significantly (P < 0.0001) lower than those of normal controls.

CONCLUSION

The occurrence rate of gestational transient hyperthyroxinaemia was 0.285%, and could possibly be attributed to increased levels of circulating hCG. Based on the data obtained from a large number of pregnant women, we propose gestational transient hyperthyroxinaemia as a definite clinical entity.
No evidence for allelic association of a human CTLA‐4 promoter polymorphism with autoimmune thyroid disease in either population‐based case–control or family‐based studies
Authors: Heward  , Allahabadia  , Carr‐Smith  , Daykin  , Cockram  , Gordon  , Barnett  , Franklyn  , Gough
Published: March 2003

OBJECTIVE

The cytotoxic T lymphocyte associated‐4 (CTLA‐4) gene is a candidate for T‐cell mediated autoimmune disease and polymorphism has been reported to be associated with both type 1 diabetes and autoimmune thyroid disease. A previously unreported polymorphism of the promoter region of the human CTLA‐4 gene has recently been described in a sample of a normal control population. We investigated the distribution of this polymorphism, situated at position ‐318 to the ATG start codon and resulting in a C–T change leading to an Mse I restriction site, in both population based case control studies and family studies in patients with Graves' disease (Caucasian and Hong Kong Chinese), autoimmune hypothyroidism and systemic lupus erythematosus (SLE).

DESIGN

Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the Mse I restriction enzyme.

PATIENTS

One hundred and ninety‐one white UK Caucasian and 98 Hong Kong Chinese patients with Graves' disease, 78 white UK Caucasian patients with Graves' disease plus family members, 92 white UK Caucasian patients with autoimmune hypothyroidism, 13 white UK Caucasian patients with autoimmune hypothyroidism plus family members, 132 white UK Caucasian patients with systemic lupus erythematosus, 355 white UK Caucasian control subjects and 82 Hong Kong Chinese control subjects.

MEASUREMENTS

Frequencies of the C and T alleles were compared between patients and control subjects using the χ2‐test and Fisher's exact test for small numbers.

RESULTS

No association with the T allele was observed in any of the patient groups studied.

CONCLUSION

These data suggest that the C–T change in exon 1 of the promoter region of the CTLA‐4 gene does not play a role, nor is in linkage disequilibrium with a disease causing mutation, in the development of autoimmune disease.
Cytoplasmic staining of erbB‐2 but not mRNA levels correlates with differentiation in human thyroid neoplasia
Authors: Sugg Sonia L. , Ezzat Shereen , Zheng Lei , Rosen Irving B. , Freeman Jeremy L. , Asa Sylvia L.
Published: March 2003

OBJECTIVE

Amplification and overexpression of the erbB‐2 proto‐oncogene in human carcinomas may have prognostic significance. Its role in thyroid carcinoma is controversial. We investigated human thyroid tumours for erbB‐2 gene amplification, activating mutations in the transmembrane domain, quantitative mRNA expression and protein expression.

MATERIALS AND METHODS

DNA and mRNA were extracted from 47 morphologically characterized, frozen thyroid tumours including 10 nodular hyperplasias, 3 follicular carcinomas and 34 papillary carcinomas (4 with tall‐cell features, 2 with insular and 2 with anaplastic de‐differentiation). DNA amplification was analysed by differential PCR. The transmembrane domain of erbB‐2 was sequenced in all tumours for activating mutations in position 659. Levels of mRNA expression were determined by competitive mRNA RT–PCR. Immunohistochemistry (IHC) for erbB‐2 protein expression in corresponding paraffin‐embedded samples was evaluated.

RESULTS

Our results showed no DNA amplification of erbB‐2. Sequencing of the transmembrane domain of erbB‐2 revealed no activating mutations. The level of mRNA expression was variable, 11 papillary carcinomas showing statistically significant elevated mRNA levels compared with corresponding normal thyroid tissue; however, this did not correlate with other indicators of poor prognosis. In contrast to elevated mRNA levels in tumours, the level of protein staining correlated with degree of differentiation, normal and hyperplastic tissue being strongly positive and poorly differentiated tumours negative.

CONCLUSION

There are no mutations or amplifications of the erbB‐2 gene in human thyroid tumours. Elevated erbB‐2 mRNA expression in some thyroid tumours is not associated with clinical features of poor prognosis; however, the significance of the elevated mRNA levels is unclear, as it did not result in protein overexpression. Instead, cytoplasmic erbB‐2 protein detection by IHC correlates with differentiation of human thyroid tumours and may be a feature of good prognosis.
A new chemiluminescent assay for the rapid detection of thyroid stimulating antibodies in Graves' disease
Authors: Watson  , Ajjan  , Phipps  , Metcalfe  , Weetman
Published: March 2003

OBJECTIVE

Thyroid stimulating antibodies (TSAb) are the cause of Graves' disease (GD). At present, these antibodies can only be measured using bioassays, which are generally time consuming and difficult to apply to whole serum. Here we describe a new chemiluminescent assay for the detection of TSAb in serum samples.

METHODS

A Chinese hamster ovary (CHO) cell line, stably transformed with a reporter plasmid containing the firefly luciferase gene under the transcriptional control of multiple cAMP responsive elements (CRE), was transfected with the human thyroid stimulating hormone (TSH) receptor. A clonal cell line, (NA‐4), was obtained which showed a dose‐dependent increase in luciferase activity in response to bovine and human TSH stimulation. NA‐4 was subsequently used to study TSAb activity in 42 GD sera.

RESULTS

Of the GD sera 25 (60%) produced an increase in luciferase activity of 1.4–9 fold that obtained with control sera. Results were compared with an established bioassay for TSAb, based on the direct measurement of intracellular cAMP, and there was a significant correlation between the two assays (r = 0.8; P < 0.0001). IgG from GD patients, but not controls, also increased luciferase activity in NA‐4 cells using concentrations as low as 3mg/l in selected samples.

CONCLUSION

The present report describes a simple, sensitive and rapid assay for the detection of TSAb, with application both in the clinical analysis of GD patient sera and as a potential research tool for use in the isolation of TSAb monoclonal antibodies.
One‐year follow‐up of quality of life in adults with untreated growth hormone deficiency
Authors: Badia X. , Lucas A. , Sanmartí A. , Roset M. , Ulied A.
Published: March 2003

OBJECTIVE

The aim of the study was to evaluate the impact on health‐related quality of life (HRQoL) in untreated GHD patients using the disease‐specific Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire.

DESIGN AND PATIENTS

A cohort of 356 consecutive adult GHD patients, diagnosed after the age of 18 years, from the endocrinology units of 37 Spanish hospitals were included over a 6‐month period in a longitudinal observational quality‐of‐life study. In addition, patients' HRQoL scores were compared to those obtained from a random sample of 963 subjects from the general population recruited by trained interviewers in a 6‐month period and matched by age and sex to figures of the 1991 Spanish census.

MEASUREMENTS

Patients were evaluated at baseline and after 12‐months. Socio‐demographic and health variables such as age,sex, level of education, income level, number of chronic diseases and self‐reported health status were recorded at baseline and follow‐up visits. Patients underwent physical and analytical examination and completed the AGHDA questionnaire. A survey including socio‐demographic, self‐reported health status and the AGHDA questionnaire was administered at the individuals' homes.

RESULTS

Mean score for patients at baseline was 9.4 (CI = 8.4–10.4) and at 12 months 10 (CI = 8.8–11). HRQoL was worse in the case of older patients with a low level of education, lower income levels, reporting having an associated chronic disease and poor self‐reported health status (P < 0.01). Untreated GHD patients maintain or slightly worsen their HRQoL after 12 months of follow‐up, with high individual variability. Although AGHDA scores worsened during the observation period, differences were not statistically significant. AGHDA mean score in controls was 5.49 (CI = 5.27–5.71). Comparison of the mean AGHDA scores between patients and controls previously standardized by level of education and age were statistically different (P < 0.01), indicating that patients declared a worse HRQoL than the general population except for those aged 60–69 years. GHD patients presented a deterioration in HRQoL almost double that of the general population.

CONCLUSIONS

These results permit comparison of patients' scores against reference scores with regard to the desirable effect of treatment. Future use of the AGHDA questionnaire in clinical trials should try to establish a relationship between biological and HRQoL changes.
Recent primary transnasal surgical outcomes associated with intraoperative growth hormone measurement in acromegaly
Authors: Abe Takumi , Lüdecke Dieter K.
Published: March 2003

OBJECTIVE

Since 1983, we have measured GH intraoperatively to improve the surgical outcome for acromegalic patients with GH secreting pituitary adenomas. Here, we present the recent results of primary surgery in patients with acromegaly to examine the effect of improved surgical techniques and experience.

PATIENTS AND MEASUREMENT

Intraoperative GH concentrations were measured in 78 consecutive acromegalic patients who had not previously undergone surgery between May 1992 and April 1994 (45 females and 33 males, age range, 21–70 years, mean, 47.1 ± 1.3). All patients were followed for at least 3 years. Direct transnasal tumour extirpation was performed. Intraoperative GH measurements were assayed 0, 20 and 60 min after tumour removal. A plasma GH level ≤ 4.5 μg/l at 60 min after initial tumour removal was used as a criterion of radical tumour removal. In cases with intraoperative plasma GH concentrations ≥ 40 μg/l prior to tumour resection, the half‐life of the GH concentration at 20 min was used to assess completeness of tumour removal. In these cases, it was defined as having acheived a 50% reduction in plasma GH at 20 min compared to 0 min after tumour resection. To obtain intraoperative GH measurements, mild anaesthesia was continued for an average of 82± 23 min.

RESULTS

Radical tumour removal was determined intraoperatively in 51 patients and subsequently confirmed in 50 patients (98.0%). In 18 of 27 patients with incomplete tumour removal, immediate reoperation was performed under continuous anaesthesia. In 11 of these 18 patients, endocrinological remission was achieved (14.1%; 11/78). None of the remaining nine patients who did not undergo secondary surgery achieved remission. Secondary surgery improved the remission rate from 85.7% (12/14) to 92.9% (13/14) in microadenomas and from 70.1% (38/54) to 88.9% (48/54) in non‐invasive macroadenomas. Remission was not observed in patients with image‐proven extrasellar extension.

CONCLUSIONS

Secondary surgery based on intraoperative GH measurement improves the outcome of tumour resection in patients with non‐invasive GH secreting macroadenomas.
A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF‐I without significant deterioration in glucose tolerance
Authors: Bülow Birgitta , Marie Erfurth Eva
Published: March 2003

OBJECTIVE

Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF‐I response.

DESIGN

The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF‐I, and in patients with sub‐normal serum IGF‐I levels (all but two) we aimed for a serum IGF‐I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week.

PATIENTS

Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21–28).

MEASUREMENTS

Overnight and 24‐h fasting levels of glucose, insulin and IGFBP‐1 were measured. Directly after the 24‐h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP‐1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bioimpedance analysis (BIA) and quality of life was assessed using a self‐rating questionnaire, Qol‐AGHDA.

RESULTS

After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24‐h fasting levels of glucose, insulin and IGFBP‐1, an oral glucose tolerance test (after 24‐h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP‐1 levels and the IGFBP‐1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median −2.9%; range −1.0–(−6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = −0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy.

CONCLUSIONS

In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP‐1 suggest that serum IGFBP‐1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF‐I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.
Laparoscopic adrenalectomy for phaeochromocytoma: endocrinological and surgical aspects of a new therapeutic approach
Authors: Col V. , De Cannière L. , Collard E. , Michel L. , Donckier J.
Published: March 2003

OBJECTIVES

To evaluate the results of laparoscopic resection of phaeochromocytoma with a focus on pre‐and intra‐operative endocrinological and pharmacological aspects.

DESIGN

Retrospective study based on review of case notes and intraoperative anaesthetic records.

PATIENTS

Eight patients (four men, four women) aged 13 to 70 (median: 45) years with symptomatic phaeochromocytoma (two patients with MEN IIa syndrome) diagnosed 6–36 months before adrenalectomy in four patients and just before operation in the four remaining patients. All patients presented with hypertension.

MEASUREMENTS

Pre‐ and postoperative blood pressure (BP) was assessed using a sphygmomanometer, intraoperative measurements being obtained by intra‐arterial line. Adrenaline (A), noradrenaline (NA), metadrenaline (metA), normetadrenaline (normetA) and vanillylmandelic acid (VMA) were measured in 24‐h urine samples. Adrenal imagery consisted in all patients of abdominal computed tomography and [131I] metaiodobenzylguanidine (MIBG) scintigraphy, and in 2 patients, adrenal magnetic resonance imaging and octreotide scintigraphy. Determination of plasma volume was performed by isotopic method.

RESULTS

Median (range) preoperative systolic and diastolic BP was 140 (130–240) and 90 (80–150) mm Hg, respectively. Predominant catecholamine secretion consisted of A in four patients (A pattern) and of NA (NA pattern) in the other four. Tumours smaller than 30 mm usually secreted A while larger ones secreted NA. Pre‐ and intra‐operative BP control was straightforward in all but two patients with preferential NA secretion. The median number of systolic and diastolic BP peaks were higher in patients with NA pattern (n = 6, range: 3–9) than in those with A pattern (n = 1.5, range: 1–6). Total duration of pneumoperitoneum ranged from 120 to 240 (median: 195) min. Intra‐ and post‐operative complications included intra‐abdominal bleeding, laparoscopically controlled (in one case), and upper pole kidney ischaemia in another. Postoperative hospital stay ranged from 4 to 11 days. All patients were asymptomatic postoperatively and pharmacologically controlled hypertension persisted in two of them

CONCLUSIONS

Laparoscopic adrenalectomy is a safe and efficient technique to remove phaeochromocytoma in terms of intra‐ and postoperative morbidity, with a low complication rate. Pre‐ and intra‐operative pharmacological blood pressure control is as effective as in conventional adrenalectomy, with greater instability in noradrenaline secreting tumours.
Differentiated thyroid cancer: a retrospective analysis of 832 cases from Greece
Authors: Tzavara  , Vlassopoulou  , Alevizaki  , Koukoulis  , Tzanela  , Koumoussi  , Sotsiou  , Thalassinos
Published: March 2003

OBJECTIVE

To analyse the initial manifestations, pathological findings, therapy, outcome and prognostic factors in patients with papillary and follicular carcinoma.

PATIENTS

832 patients with well differentiated thyroid carcinoma managed in our department during a period of 30 years (1965–1995). Follow‐up data were available for 609 patients for a mean of 5.5 years (range 1–38 years), the remainder having been lost to follow‐up.

RESULTS

The patients were 677 (81%) with papillary and 155 with follicular carcinoma. They were predominantly female (75%), presenting mainly with a single nodule (53%), while at the time of diagnosis 72% had intrathyroidal carcinomas (class I), 17% had nodal metastases (class II), 7% soft tissue invasion (class III) and 4% distant metastases (class IV). Fifty‐five percent of the patients had a complete thyroidectomy (36% had a near total or total thyroidectomy and 19% near total or total thyroidectomy plus block dissection), 2.6% received external radiotherapy and 94% had radioactive iodine as part of the treatment of the original disease. Kaplan‐Meier survival analysis was used to calculate both cancer related mortality and disease free survival in the patients followed‐up. Although mortality (21 cancer‐related deaths) was slightly higher for follicular than papillary carcinoma (10% vs. 5% and 16% vs. 10% in 10‐and 15‐year survival, respectively) the difference was not statistically significant. Extent of disease at diagnosis, male sex, tumour size and age > 60 years affected probability of cancer death. Cox's proportional hazard regression analysis for disease free survival showed that adverse independent prognostic factors were, for papillary carcinoma, male sex, class II or higher, tumour size > 1 cm and age > 60 years, while for follicular, class III or higher, size > 4 cm and age > 40 years.

CONCLUSIONS

We conclude that there is a higher prevalence of follicular carcinoma in our country probably due to a moderate degree of iodine deficiency still existing in Greece. Age and extent of disease at diagnosis were important prognostic factors affecting morbidity and mortality, whereas sex, tumour features and histological type were of minor importance. All these prognostic factors and their relative importance should be taken in consideration in the management of this disease.
Serum leptin levels in healthy ageing men: are decreased serum testosterone and increased adiposity in elderly men the consequence of leptin deficiency?
Authors: Van den Saffele Jan K. , Goemaere Stefan , De Bacquer Dirk , Kaufman Jean Marc
Published: March 2003

OBJECTIVE

The limited information on serum leptin levels in elderly men suggests the occurrence of an age‐related decrease, with disruption of the relationship between fat mass and leptin levels. A relative leptin deficiency might thus be implicated in the increase of fat mass and decrease of serum testosterone levels in elderly men. Therefore, we have reevaluated the age‐related changes in serum leptin levels and their relationship with adiposity and androgen levels in a large group of community dwelling men.

SUBJECTS AND MEASUREMENTS

Serum leptin and androgen levels were measured in 271 healthy, ambulatory elderly men (median age 74 years), as well as in 61 middle‐aged (median 43 years) and 40 young (median 25.5 years) controls. Adiposity was assessed by anthropometrical measurements (body mass index; BMI) and by estimation of fat mass by the bio‐impedance method.

RESULTS

Serum leptin levels, whether or not adjusted for BMI, were found to increase with age, the values tending to level off after the age of 45 years, and were strongly correlated to BMI (r = 0.77) and fat mass assessed by the bio‐impedance method (r = 0.81). Linear regression analysis showed a similar slope for the relationship between BMI and serum leptin in the three age groups. Multiple linear regression analysis indicated BMI, age and serum insulin, but not serum testosterone, as significant independent correlates of serum leptin. Serum (free) testosterone levels were negatively correlated with age and serum leptin, also after partialization for BMI: rank correlation coefficients vs. age and serum leptin, respectively, were − 0.20 (P < 0.001) and − 0.16 (P < 0.01) for total testosterone and − 0.60 (P < 0.001) and − 0.23 (P < 0.001) for free testosterone. Dehydroepiandrosterone sulphate (DHEAS) and leptin levels emerged as significant independent correlates in a multiple linear regression model for total serum testosterone; BMI and serum insulin became highly significant correlates in the same model when leptin was omitted from the independent variables.

CONCLUSION

Ageing in men is accompanied by a rise of serum leptin levels with a maintained strong association between serum leptin and adiposity in elderly men. Testosterone does not appear to be a major determinant of serum leptin in healthy men, while leptin does emerge as a negative correlate of serum testosterone. Increased fat mass and decreased testosterone production in elderly men cannot be attributed to a relative leptin deficiency.
Effects of short‐term hormone replacement on serum leptin levels in postmenopausal women
Authors: Lavoie Helene B. , Taylor Ann E. , Sharpless Julie L. , Anderson Ellen J. , Strauss Carrie C. , Hall Janet E.
Published: March 2003

OBJECTIVE

Leptin is a hormone which is secreted by adipocytes and appears to influence the reproductive axis. Previous studies have demonstrated higher leptin levels in relation to body fat mass in women compared to men, higher levels in normally cycling compared to postmenopausal women, and a decrease in leptin levels with increased age. The purpose of this study was to determine whether oestrogen replacement with or without progesterone increases serum leptin levels in postmenopausal women, independently of changes in body fat, and to determine if ageing affects leptin levels at baseline or in response to hormone replacement.

PATIENTS

Twenty‐one healthy postmenopausal women on no hormone replacement were studied at baseline, after 1 month of oestrogen (E2: estraderm 50 μg/day) and after a further month of oestrogen and 7 days of progesterone (P: progesterone 100 mg per vagina bid) designed to achieve physiological hormone levels. Subjects included 11 younger (45–55 years) and 10 older (70–80 years) postmenopausal women.

RESULTS

The relationship between leptin and the absolute fat mass (% body fat × weight [kg]) at baseline was not different between the younger and older postmenopausal women. The adequacy of physiological hormone replacement was confirmed in all subjects. Despite the absence of an effect of hormone replacement on weight, body mass index (BMI), % and absolute fat mass (bioimpedance) or waist‐hip ratio, there was an increase in serum leptin levels with hormone replacement (15.4 ± 1.7, 17.6 ± 1.7, and 18.1 ± 1.6 μg/l; mean ± SEM at baseline, with E2, and with E2 + P, respectively; P < 0.001 vs. baseline) for the group as a whole. An increase in leptin with hormonal treatment was seen in both the younger (15.1 ± 2.1, 18.1 ± 2.4, and 18.5 ± 1.9 μg/l; P < 0.01) and the older (15.7 ± 2.8, 17.0 ± 2.5, 17.7 ± 2.8 μg/l; P = 0.06) postmenopausal women.

CONCLUSIONS

(1) Short‐term physiological oestrogen replacement increases serum leptin levels in postmenopausal women independently of changes in fat mass; and (2) physiological progesterone replacement does not influence leptin levels in postmenopausal women.
Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin‐releasing hormone
Authors: Quinton Richard , Barnett Philip , Coskeran Patsy , Bouloux Pierre‐Marc G.
Published: March 2003

The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH action. Because of the anatomical inaccessibility of the hypophyseal portal circulation, direct measurement of GnRH levels in human subjects is not possible. Previous investigators have attempted to unravel this problem through the use of GnRH stimulation tests and the limitations of this approach may explain the differing results obtained. We used the more physiological approach of treating a male GHS patient for four weeks with GnRH, 7–10 μg/pulse, delivered subcutaneously at 90 minute frequency via a portable minipump. This therapy failed to induce any rise in plasma gonadotrophin and testosterone concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins maintained physiological plasma testosterone concentrations and induced testicular enlargement with induction of spermatogenesis. The data indicate that the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two clinical observations are consistent with progressive involution of gonadotrophic function, rather than a congenital gonadotrophin deficiency. First, the patient's development was arrested at early mid‐puberty at the time of original presentation and, second, effective spermatogenesis was induced extremely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary dysfunction might thus have been in evolution since late childhood.
Association of CTLA4 gene A–G polymorphism with type 1 diabetes in Chinese children
Authors: Lee Yann‐Jinn , Huang Fu‐Yuan , Lo Fu‐Sung , Wang Wei‐Chu , Hsu Chyong‐Hsin , Kao Hsin‐An , Yang Tzu‐Yao , Chang Jan‐Gowth
Published: March 2003

OBJECTIVE

The CTLA4 (cytotoxic T lymphocyte associated antigen‐4) gene encodes the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. Thus it is a strong candidate gene for T cell‐mediated autoimmune disease. There is polymorphism at position 49 in exon 1 of the CTLA4 gene, providing a A–G exchange. This polymorphism is reportedly associated with type 1 diabetes in Caucasians but not in a small data set of Chinese. We wished to test this polymorphism in a larger and more homogeneous data set of Chinese children with type 1 diabetes and normal adult controls.

DESIGN

A population‐based case‐control study of a CTLA4 gene 49 A–G polymorphism was performed to look for an association with type 1 diabetes in Chinese children.

PATIENTS

We analysed this polymorphism in 253 unrelated children (128 boys) with type 1 diabetes (age at diagnosis 7.1 ± 3.7 years) and 91 randomly selected normal adults. All individuals were Han Chinese.

RESULTS

The genotype and gene frequencies of children with type 1 diabetes differed significantly from those of adult controls (P = 0.0091 and P = 0.0051, respectively). Genotype CTLA4 49 G/G and G allele conferred a risk of type 1 diabetes (RR = 2.13, 95% CI = 1.31–3.46, P = 0.0022; RR = 1.68, 95% CI = 1.17–2.43, P = 0.0051, respectively).

CONCLUSIONS

This study demonstrates that CTLA4 49 A–G polymorphism is associated with type 1 diabetes in Han Chinese children. The CTLA4 49 G allele confers an increased risk of type 1 diabetes.
Identification of missense mutations in the SRD5A2 gene from patients with steroid 5α‐reductase 2 deficiency
Authors: Vilchis  , Méndez  , Canto  , Lieberman  , Chávez
Published: March 2003

BACKGROUND AND OBJECTIVE

Mutations of the steroid 5α‐reductase type 2 (SRD5A2) gene in karyotypic males result in a spectrum of external genitalia phenotypes ranging from complete female to nearly complete male. Here we performed genomic DNA analyses from individuals bearing the enzyme deficiency in order to detect the molecular abnormalities.

PATIENTS

Four unrelated 46,XY patients of Mexican origin with ambiguous external genitalia were studied. A fertile, phenotypically normal male was also included.

MEASUREMENTS

Coding sequence abnormalities of the SRD5A2 gene were assessed by exon‐specific polymerase chain reaction, single‐stranded conformational polymorphism and sequencing analysis.

RESULTS

Five different missense mutations (two of them novel mutations) were identified. Three subjects presented homozygous single base mutations. These were located at exon 2 (G115D), exon 4 (P212R) and exon 5 (R246Q), and such changes have been described previously. The fourth patient was a compound heterozygote who presented two mutations located in exons 1 and 2. We found a hitherto unreported G → A transition at the second nucleotide of codon 85 in exon 1 (GGC → GAC), substituting glycine for aspartic acid (G85D). This patient also presented an identical alteration at codon 115 of exon 2, which was carried by his father (G115D). Finally, in another subject who was included originally as a control, we found a C → A transversion (yet undescribed) at codon 245 in exon 5 (S245Y).

CONCLUSIONS

Four different single base mutations that cause amino acid substitutions were detected in the steroid 5α‐reductase type 2 gene of affected individuals. One patient and a normal control had two previously undescribed mutations. Although in the latter individual we cannot exclude the possibility that the base change is a genetic polymorphism, the molecular screening of 100 chromosomes suggests strongly that the change at codon 245 does represent a heterozygous mutation. Further studies, including the recreation of the mutations, will help to reveal the biochemical consequences resulting from these changes.
Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload
Authors: Chatterjee R. , Katz M.
Published: March 2003

OBJECTIVE

To determine the severity and reversibility of the lesion in the hypothalamic–pituitary (H‐P) axis of male transfusion‐dependant thalassaemic patients with failed puberty (FP).

DESIGN AND SUBJECTS

The hypothalamic–pituitary axes of 20 male thalassaemic patients (study group) were compared with two male subjects with idiopathic hypogonadotrophic hypogonadism (IHH) and five prepubertal healthy siblings (control group). GnRH‐gonadotrophin insufficiency was characterized by nocturnal 12 h ultradian gonadotrophin profiles followed by a 100 μg GnRH bolus test (GBT) 4–6 times at 6 monthly intervals. Thalassaemic and IHH patients were then subjected to pulsatile subcutaneous GnRH infusions every 120 minutes for 3 months. Ultradian gonadotrophin profiles and GBT were repeated after 6 weeks of GnRH infusion and again at 3 months following infusion.

MEASUREMENTS

FSH and LH were measured by radio‐immunoassay. Ferritin was assayed by an immunoradiometric method.

RESULTS

Patients with IHH who were apulsatile prior to infusion, developed normal gonadotrophin pulses with marked increment in their gonadotrophin responses to the GBT after 3 months of GnRH infusion. In contrast, the thalassaemic patients with apulsatile failed puberty (AFP) remained apulsatile (nonresponders) and had no increment in their gonadotrophin responses to the GBT after GnRH infusion. All patients with pulsatile failed puberty (PFP) had abnormal gonadotrophin pulses prior to GnRH infusion. Their pulse defects were either totally or partially corrected (responders) following infusion. The serum ferritin levels (9500 ± 500 μg/l vs. 5966.67 ± 1139 μg/l; P < 0.01) and percentage of organ dysfunction (87% vs. 17%; P < 0.01) were higher in the nonresponders than the responders.

CONCLUSIONS

This study shows that thalassaemic patients with severe organ damage and iron overload are likely to be apulsatile with irreversible damage to their hypothalamo–pituitary axis, while those with less severe iron overload are likely to have potentially reversible hypogonadotrophic hypogonadism (HH). Our results also suggest that gonadotrophin pulse parameters, rather than the gonadotrophin response to a GnRH bolus following prolonged pulsatile GnRH infusion, may be more useful in discriminating reversible from irreversible hypogonadotrophic hypogonadism.
Impaired β‐cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients
Authors: Kasayama Soji , Otsuki Michio , Takagi Miki , Saito Hiroshi , Sumitani Satoru , Kouhara Haruhiko , Koga Masafumi , Saitoh Youichi , Ohnishi Takanori , Arita Norio
Published: March 2003

OBJECTIVE

Abnormal glucose tolerance is often demonstrated in acromegalic patients. Although insulin resistance is a common feature of acromegaly, it remains unclear whether the extent of insulin resistance per se determines the abnormal glucose tolerance. In order to elucidate this issue, we investigated insulin sensitivity and β‐cell function in acromegalic patients.

DESIGN

Twenty‐four acromegalic patients were studied in comparison with 24 healthy control subjects. To estimate insulin sensitivity and β‐cell function, we used correct homeostasis model assessment (HOMA) model, a computer‐solved model. We also investigated the effects of surgical success on both parameters.

RESULTS

HOMA insulin sensitivity (HOMA‐%S) in the acromegalic patients was 74 ± 51 (SD)%, significantly lower than that in 24 healthy controls (144 ± 49%). HOMA‐%S in 12 normal glucose tolerance (NGT) patients was 54 ± 31%, not significantly different from that in impaired glucose tolerance (IGT; n = 11) or diabetes mellitus (DM; n = 1) patients (93 ± 60%). By contrast, HOMA β‐cell function (HOMA‐%β) in the NGT acromegalic patients was 163 ± 67%, significantly higher than the IGT/DM acromegalic patients (89 ± 34%) and the healthy controls (72 ± 19%). In 11 patients who achieved complete normalization of GH excess after surgery, HOMA‐%S significantly increased to control ranges (from 76 ± 26 to 159 ± 61%) within 2 weeks after the surgical success.

CONCLUSIONS

We conclude that insulin sensitivity is reduced to a similar extent in acromegalic patients with normal glucose tolerance and those with impaired glucose tolerance or diabetes. Compensatory hyperfunction of β‐cells appears to counterbalance the reduced insulin sensitivity in the acromegalic patients with normal glucose tolerance but not in those with impaired glucose tolerance or diabetes.
A case of adrenocortical carcinoma associated with recurrence after laparoscopic surgery
Authors: Iino Kazumi , Oki Yutaka , Sasano Hironobu
Published: March 2003

Laparoscopic adrenalectomy has become increasingly popular because of its minimally invasive nature, but guidelines for selection of cases suitable for this surgical procedure have not been established. We report a 52‐year‐old woman with adrenocortical carcinoma, manifesting as Cushing's syndrome, treated with laparoscopic adrenalectomy. The tumour was removed in toto and had been histologically diagnosed as adrenocortical adenoma. However, the patient developed intra‐abdominal peritoneal dissemination of carcinoma 15 months after surgery. Review of the histopathological findings of the resected adrenocortical tumour revealed that the neoplasm met five out of nine histological criteria for adrenocortical malignancy, and was diagnosed as adrenocortical carcinoma. Histopathological examination of the tumour was also consistent with adrenocortical carcinoma. The patient responded extremely well to chemotherapy, including carboplatin, etoposide and o,p′‐DDD (1,1‐dichlorodiphenyldichloroethane), and a subsequent CT (computed tomography) scan 12 months after the start of chemotherapy demonstrated no evidence of disease. However, the patient developed neurological impairment, including dysarthria, as a side‐effect of o,p′‐DDD. The patient died of aspiration pneumonia due to a decreased pharyngeal reflex. Postmortem examination revealed no foci of residual carcinoma. This case report emphasizes the importance of excluing possible adrenocortical malignancy in patients considered for laparoscopic adrenalectomy, histopathological diagnosis of adrenocortical malignancy and careful monitoring for neurotoxicity during o,p′‐DDD treatment.