Overexpression of metallothionein I/II: a new feature of thyroid follicular cells in Graves' disease.

CONTEXT: One salient feature of autoimmune thyroid disease is the inappropriate expression of human leukocyte antigen (HLA) class II molecules by thyroid follicular cells. Metallothioneins (MT) are small proteins induced by tissue stress that can contribute to restoring homeostasis of tissue inflammation and have been found to be increased in a transcriptomic analysis of Graves' disease (GD) glands. METHODOLOGY: To assess the role of MT in the pathogenesis of GD, we analyzed MT-I and -II expression and distribution in GD-affected thyroid glands (n = 14) compared with other thyroid diseases (n = 20) and normal thyroid glands (n = 5). Two-color indirect immunofluorescence and semiquantitative morphometry were applied. The relationship between MT and HLA class II expression was analyzed by their degree of colocalization in GD sections, and in vitro induction kinetics and expression of these molecules on the HT93 thyroid cell line were compared by quantitative RT-PCR and flow cytometry using interferon-γ and zinc as stimuli. RESULTS: MT were clearly overexpressed in nine of 14 GD glands. MT expression distribution in GD was almost reciprocal to that of HLA class II. In vitro analysis of MT and HLA class II demonstrated that MT is induced more slowly and at a lower level than HLA. Moreover, the main MT inducer, zinc, reduces interferon-γ-induced class II expression. CONCLUSIONS: These findings show that MT and HLA class II play very different roles in the autoimmune process by affecting the thyroid gland, thereby pointing to the possible role of MT as a marker of cell stress and homeostasis restoration in GD.

Serum autoimmune gastritis markers, pepsinogen I and parietal cell antibodies, in patients with type 1 diabetes mellitus: a 5-year prospective study.

BACKGROUND AND AIM: To determine the temporal evolution of serum markers of autoimmune gastritis, mainly pepsinogen I (PI) and parietal cell antibodies (PCA), in patients with Type 1 diabetes mellitus (DM1). MATERIALS AND METHODS: A 5-yr prospective follow-up study of 168 DM1 patients (87 men, aged 31 ± 9.3 yr) attending the endocrinology outpatient clinic of a university hospital evaluated in 2001 and 2006. Serum PI, gastrin, hemoglobin, cobalamin concentrations, PCA and antibodies to intrinsic factor were measured. RESULTS: In 2001, 11 patients had low PI concentrations and positive PCA (group I), 11 had only low PI concentrations (group II), and 33 had only positive PCA (group III). After 5 yr, PI remained low and PCA positive in all patients from group I. In group II, PI remained low in 4 and normalized in 7. In group III, 4 patients presented low PI concentrations after 5 yr, which remained normal in the other 29 subjects. PCA became negative in 17 patients from group III. In 2001, 3 of the 11 patients of group I had low cobalamin concentrations. In 2006, 2 additional patients from this group presented low cobalamin concentrations. CONCLUSIONS: These results show the importance of determining PI together with PCA, since the presence of abnormal results in both tests, that is low PI and positive PCA, is the association that best identifies patients with a higher risk to decrease cobalamin concentrations during follow-up.

A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4(+) CD25(+) CD127(low/-) FoxP3(+) T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment.

Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon-alpha2a (pegIFN-α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4(+) CD25(+) CD127(low/-) FoxP3(+) regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty-five patients with chronic HCV infection who started pegIFN-α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid-treatment (MT), the end of treatment (ET) and 24weeks post-treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3(+) , CD8(+) , CD3(+) gamma/delta (γδ)(+) , CD19(+) lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4(+) lymphocyte subpopulation and in CD81 expression levels on CD19(+) B cells when BT was compared with ET (all P<0.05). Seventeen patients were nonresponders (NR) and 18 had a sustained virological response (SVR). At baseline, NR patients had higher CD81 expression levels on CD19(+) B cells (P=0.017) and a higher Tregs percentage (P=0.025) than SVR patients. Our results suggest that immunomodulation fluctuates during antiviral treatment and that percentage CD81 expression levels on B cells and Tregs might be useful as an immunological prognostic factor for pegIFN-α2a and ribavirin treatment response in chronic HCV infection.

Effects of GH treatment in GH-deficient adults on adiponectin, leptin and pregnancy-associated plasma protein-A.

OBJECTIVE: GH deficiency (GHD) in adults is associated with adverse effects on metabolism and increased cardiovascular risk. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that promotes IGF-I availability in vascular tissues. PAPP-A levels appear to correlate with carotid intima-media thickness and have been proposed as an early predictor of cardiac events. The aim of our study was to evaluate PAPP-A levels in GHD adults at baseline and after GH replacement and correlate them with changes in body composition, lipid profile, glucose homeostasis, inflammatory markers and in leptin and adiponectin. PATIENTS AND METHODS: Fourteen GHD adults were evaluated at baseline and after 1 year of GH therapy. All patients were compared at baseline with 28 age-, sex- and body mass index (BMI)-matched control subjects. RESULTS: At baseline, GHD adults showed higher PAPP-A levels (P=0.03) and higher leptin (P=0.04), fibrinogen (P=0.002) and highly sensitive C-reactive protein (P=0.01) values than controls. Therapy with GH reduced PAPP-A (P=0.03) and fibrinogen levels (P=0.002) while increased BMI (P=0.01) and reduced waist-hip ratio (WHR; P=0.05) were observed. Insulin and homeostasis model assessment of insulin resistance index increased after treatment (P<0.004/P=0.007), without changes in leptin or adiponectin levels. PAPP-A values correlated positively with BMI and WHR and negatively with adiponectin before and after treatment, with no correlation with glucose homeostasis parameters, lipid profile or leptin. CONCLUSIONS: Our study suggests that PAPP-A expression is increased in GHD adults, and that 1 year of GH replacement therapy is able to reduce PAPP-A levels in this population. However, further studies are required to determine whether this decrease correlates with an improvement in atherosclerosis.

Obesity, adiponectin and inflammation as predictors of new-onset diabetes mellitus after kidney transplantation.

The high incidence of new-onset diabetes mellitus after transplantation (NODAT) suggests the need to find new factors to explain the pathogenesis. Our objectives were (1) to confirm that low levels of pre-transplant adiponectin are an independent risk factor for the development of NODAT in a larger transplanted population; (2) to analyze whether adiponectin is a better predictor of NODAT than other inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and pregnancy-associated plasma protein A (PAPP-A)) and (3) to assess the relationship between obesity, inflammatory markers and NODAT. One hundred ninety-nine non-diabetic patients (128 men; age: 53 +/- 11 years; body mass index (BMI) 24.98 +/- 3.76 kg/m2) were included. Pre-transplant plasma glucose, insulin, adiponectin, CRP, TNF-alpha, IL-6 and PAPP-A were measured. Forty-five patients developed NODAT. Patients with NODAT had a greater BMI (p = 0.005). Adiponectin was lower (p < 0.001) and CRP higher (p = 0.032) in patients with NODAT. Multivariate logistic regression and Cox analysis showed that the calcineurin inhibitor used, pre-transplant BMI and adiponectin were predictors of NODAT. ROC analysis showed that an adiponectin concentration of 11.4 microg/mL had a significant negative prediction for NODAT risk (sensitivity: 81% and specificity: 70%). Of the inflammatory markers studied, adiponectin proved to be an independent predictor of NODAT.

Lack of deleterious effect on bone mineral density of long-term thyroxine suppressive therapy for differentiated thyroid carcinoma.

The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean +/- SD age: 51 +/- 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 +/- 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 +/- 0.148 gr/cm(2) vs 0.956 +/- 0.130 gr/cm(2) in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 +/- 0.329 gr/cm(2) vs 1.155 +/- 0.224 gr/cm(2) respectively, P < 0.05). When premenopausal (n = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma.

Uso de técnicas “específicas” en endocrinología y nutrición / Use of “specific” techniques in endocrinology and nutrition

Los endocrinólogos pueden y deben manejar técnicas específicas para el diagnóstico y tratamiento de las enfermedades endocrinológicas. Nuestra especialidad se ha basado siempre en el diagnóstico clínico y en el estudio e interpretación de las pruebas hormonales, realizadas o no por endocrinólogos. Sin embargo, la mayoría de técnicas específicas para el estudio de las enfermedades endocrinológicas está en manos de otros especialistas. Esta revisión pretende profundizar en las técnicas que se podrían desarrollar desde los propios servicios de Endocrinología y Nutrición por parte de los endocrinólogos. Se analizará en primer lugar la conveniencia de disponer en nuestros servicios de un ecógrafo para la práctica, fundamentalmente, de la ecografía tiroidea y también de realizar nosotros mismos la punción-aspiración con aguja fina. Se valorará la utilidad de disponer de un densitómetro, tanto para el estudio de la osteoporosis como de la composición corporal. En el campo de la diabetes mellitus, se hará énfasis en los sistemas de monitorización continua de glucosa, en los de monitorización ambulatoria de la presión arterial, en los estudios vasculares no invasivos, en los sistemas computarizados para valorar la neuropatía autonómica y en la cámara de retina no midriática para el cribado de la retinopatía diabética. Por último, y en relación con la nutrición, se aborda el uso de la impedanciometría y la calorimetría (AU)

Endocrinologists can and should use specific techniques for the diagnosis and treatment of endocrinological diseases. Our specialty has always been based on clinical diagnosis and on the interpretation of hormone tests, whether performed by endocrinologists or not. However, most of the specific techniques used to investigate endocrinological diseases are performed by other specialists. The present review aims to describe in detail the techniques that could be developed by endocrinologists within departments of endocrinology and nutrition. Firstly, the advantages of having an ultrasonographer to perform mainly thyroid ultrasound examinations in endocrinology departments and the advisability of performing fine needle aspiration within these departments are analyzed. We also evaluate the utility of having a densitometer to study osteoporosis and body composition. Regarding diabetes mellitus, we emphasize systems for continuous glucose monitoring, ambulatory blood pressure monitoring, noninvasive vascular investigations, computerized systems to evaluate autonomic neuropathy and the nonmidriatic fundus camera for the screening of diabetic retinopathy. Lastly, the role of bioelectrical impedance analysis and calorimetry in nutrition will be discussed (AU)

Evaluation of two replacement regimens in primary adrenal insufficiency patients. effect on clinical symptoms, health-related quality of life and biochemical parameters.

OBJECTIVE: To evaluate clinical symptoms, health-related quality of life (HRQL) and biochemical parameters in patients with primary adrenal insufficiency under treatment with two different hydrocortisone regimens (20 mg-0 mg-10 mg/day and 10 mg-5 mg-5 mg/day), each maintained for 3 months and compare results obtained with those in healthy controls. DESIGN, PATIENTS AND METHODS: Twelve patients with primary adrenal insufficiency were studied. Clinical symptoms and HRQL with the Nottingham Health Profile (NHP) were evaluated and Na, K and serum cortisol determined at 09:00 h, 12:30 h and 17:30 h and urinary free cortisol (UFC) throughout the day. Control group comprised 19 healthy subjects. RESULTS: No differences in specific adrenal insufficiency symptoms were detected between the two regimens. HRQL was worse in energy dimension assessed by the NHP compared to the general population, regardless of 20 mg-0 mg-10 mg/day or 10 mg-5 mg-5 mg/day treatment (p=0.03 and p=0.013). The total NHP score was only adversely affected when patients were on the 10 mg-5 mg-5 mg/day hydrocortisone replacement regimen (p=0.008). Serum cortisol concentrations were higher than controls at 09:00 h, and lower at 17:30 h with both regimens, whereas serum cortisol at 12:30 h and UFC were within the 5th-95th percentile normal range only with the 10 mg-5 mg-5 mg/day regimen. CONCLUSIONS: Patients with primary adrenal insufficiency had worse HRQL in the NHP energy dimension compared with the general population, regardless of the hydrocortisone regimen although total score for HRQL was worse only with the 10 mg-5 mg-5 mg/day regimen. Patients on the thrice-daily hydrocortisone regimen showed a more physiological cortisol profile, leading us to recommend initially treating patients with this dose and increasing it in the case of impaired HRQL.

Enfermedad de Addison. Tratamiento sustitutivo con glucocorticoides y su monitorización / Addison´s disease. Hydrocortisone replacement therapy and its monitoring

En esta revisión se repasan algunos aspectos del tratamiento sustitutivo con glucocorticoides en pacientes con enfermedad de Addison. Según opinión de algunos autores, la dosis tradicional de 30 mg/día de hidrocortisona, repartida en dos tomas, podría ser excesiva para la mayoría de los enfermos, por lo que debería administrarse en tres tomas. Así, se ha señalado que la sobreexposición prolongada a los glucocorticoides podría aumentar el riesgo de padecer osteoporosis. Por otra parte, aunque los pacientes con enfermedad de Addison tratados pueden llevar una vida normal, muchos de ellos aquejan fatiga, cansancio y disminución de la tolerancia al estrés, y en varios estudios se demuestra que presentan una alteración significativa de la calidad de vida relacionada con la salud (CVRS). Una explicación para este hallazgo podría ser el déficit de deshidroepiandrosterona (DHEA) que presentan y que también justificaría, al menos en parte, la peor CVRS observada en las mujeres. El tratamiento de este déficit de DHEA mejora algunos aspectos psicológicos. Tampoco resulta fácil establecer una pauta de tratamiento que imite el perfil fisiológico de secreción de cortisol, en los pacientes con enfermedad de Addison, si se consideran criterios bioquímicos. Por todo ello, como recomendación general proponemos iniciar el tratamiento sustitutivo de estos enfermos con 10-5-5 mg/día de hidrocortisona y aumentar esta dosis en los casos en que se detecte alteración de la CVRS (AU)

Protocolo unificado de utilización de la hormona del crecimiento en pacientes adultos deficitarios / Unified protocol for the use of growth hormone (GH) in GH deficient adults

En este artículo se especifica el protocolo unificado de utilización de hormona de crecimiento en pacientes adultos deficitarios: indicaciones para el inicio de tratamiento, diagnóstico bioquímico de la deficiencia de GH, contraindicaciones al tratamiento, dosis recomendadas y seguimiento (AU)

T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity.

Antibodies to glutamic acid decarboxilase (GAD-Abs) are present in the serum of 60-80% of newly diagnosed type 1 diabetes (DM1) patients and patients with autoimmune polyendocrine syndrome (APS) associated with DM1. Higher titre of GAD-Abs are also present in the serum of 60% of patients with stiff-man syndrome (SMS) and all reported patients with cerebellar ataxia associated with polyendocrine autoimmunity (CAPA). Several studies suggest that GAD-Abs may play a critical role in the pathogenesis of SMS and CAPA but little is known about T-cell responsiveness to GAD-65 in these neurological diseases. To analyse cell-mediated responses to GAD, we studied the peripheral blood lymphocyte proliferation and cytokine responses to recombinant human GAD-65 in 5 patients with SMS, 6 with CAPA, 9 with DM1, 8 with APS and 15 control subjects. GAD-65-specific cellular proliferation was significantly higher in SMS than in CAPA, DM1, APS or controls. In contrast, only T cells from CAPA patients showed a significantly high production of interferon-gamma after GAD stimulation, compared to all other patients and controls. No differences were found for IL-4 production. These results suggest that, despite similar humoral autoreactivity, cellular responses to GAD are different between SMS and CAPA, with a greater inflammatory response in CAPA, and this difference may be relevant to the pathogenesis of these diseases.

Características clínicas y tratamiento con hormona del crecimiento en la persona mayor con déficit adquirido en la edad adulta / Clinical characteristics and GH therapy in the aged with GH deficiency acquired in adult age

El déficit de hormona del crecimiento (GH) en el adulto es en la actualidad un síndrome clínico bien reconocido y los efectos beneficiosos del tratamiento sustitutivo con GH en los pacientes deficitarios de esta hormona son cada vez más evidentes. Los sujetos de edad avanzada experimentan cambios en su composición corporal (disminución de la masa magra y aumento de la masa grasa), reducción de la masa ósea y disminución de la función cardíaca y renal que son semejantes a los que presentan los pacientes adultos con déficit de GH. Debido a la similitud en las alteraciones descritas entre los sujetos normales de edad avanzada y los pacientes deficitarios de GH, algunos autores han analizado si la secreción de GH y las características clínicas de los pacientes mayores con enfermedad hipotálamo-hipofisaria eran distintas o iguales a las de los sujetos sanos de la misma edad. En esta revisión se describen diversos estudios que demuestran que los pacientes mayores deficitarios de GH debido a enfermedad hipotálamo-hipofisaria presentan características clínicas y analíticas que son distintas de las de los sujetos control de su misma edad. Asimismo, en estos trabajos se confirma que la terapia con GH ejerce efectos beneficiosos similares en pacientes deficitarios de GH, ya sean de edad avanzada o adultos jóvenes, por lo que la edad no sería un factor excluyente ni limitante para iniciar o continuar el tratamiento con esta hormona (AU)

Postpartum thyroid dysfunction and postpartum depression: are they two linked disorders?

OBJECTIVE: Postpartum has been considered as a period of risk for developing postpartum depression (PD) by some but not all authors, and this PD has been linked with postpartum thyroid dysfunction (PPTD). The major aim of this study was to evaluate the relation between the presence of PPTD and PD. DESIGN AND PATIENTS: Six hundred and forty-one healthy Caucasian women recruited between their 36th week of pregnancy and fourth day postpartum underwent clinical and laboratory evaluation and were checked again at 1 (n = 605), 3 (n = 552), 6 (n = 574), 9 (n = 431), and 12 (n = 444) months postpartum. MEASUREMENTS: At baseline and at each clinical evaluation, Beck Depression Inventory (BDI) was administered to screen PD. The definitive diagnoses of PD was performed by a psychiatrist according to the DSM-III-R criteria. At each visit, we determined serum free T4 and TSH concentrations. Thyroperoxidase and thyroglobulin antibodies were determined only in patients with abnormal hormone concentrations. Postpartum thyroiditis (PPT) was considered to be present in women with overt or subclinical transient hyperthyroidism between 1 and 3 months postpartum and/or overt or subclinical hypothyroidism between 3 and 6 months postpartum. RESULTS: Fifty-six women developed postpartum thyroid dysfunction (PPTD), corresponding to an incidence rate of 11%: 45 with PPT [incidence rate 7.8%; confidence interval (CI) 5.6-10%], eight with Graves' disease (incidence rate 1.5%; CI 0.5-2.5%) and three with nonpalpable toxic thyroid adenoma (incidence rate 0.5%; CI 0-1.5%). Five hundred and eighty of the evaluated women (incidence rate 90.5%; CI 95% 88.2-92.8) presented BDI scores below 21 and therefore the PD diagnoses was excluded. In 50 cases (incidence rate 7.8%; Cl 95% 5.7-9.8), we detected a BDI score over 21 in some evaluations, but the PD diagnosis was not confirmed. Another 11 (incidence rate 1.7%; CI 95% 0.7-2.7) were diagnosed as having PD and required psychiatric treatment. None of the PPTD was diagnosed as having PD. The BDI scores frequency over 21 was similar between healthy women and those with PPTD. Patients with a previous history of depression developed PD more often (P < 0.0001). One hundred and ninety women breast fed their babies for more than 2 months, without observing a higher PD rate or BDI scores over 21 (P = 0.5). CONCLUSIONS: We found a general PD incidence rate of 1.7% in our group of patients. This figure is not higher in women with hormone abnormalities caused by PPTD. Women with a past history of depression present a higher risk of PD while those who breast fed did not have an increased risk.

Inducible myocardial ischaemia in asymptomatic Type 2 diabetic patients.

BACKGROUND: to define the prevalence of inducible myocardial ischaemia in asymptomatic Type 2 diabetic patients and its relation to urinary albumin excretion rate (AER). METHODS: 98 Type 2 diabetic patients aged 56+/-7 years, and 20 non-diabetic volunteers were recruited. Dypiridamole plus exercise thallium-201 myocardial single photon emission computed tomography (SPECT) was performed in all participants. Exclusion criteria were: age <30 or >70 years, evidence of cardiovascular disease, anomalous ECG, autonomic neuropathy or serum creatinine level >177 micromol/l. RESULTS: 36 out of 98 diabetic patients (37%) showed abnormal thallium SPECT (considered as inducible myocardial ischaemia), versus one out of 20 (5%) in control group (odds ratio 7.3 (95% CI 1.1-50.5), P<0.005). Among diabetic patients, prevalence of inducible ischaemia was greater in those with higher urinary AER (AER <30:30-300:> 300 mg/24 h: 26: 53: 88%, and greater in the normoalbuminuric group compared to the control group (26 vs. 5%; P<0.05). An AER >30 mg/24 h was the only independent factor associated with inducible myocardial ischaemia in the multivariate analysis (P=0.009). CONCLUSIONS: raised urinary AER in asymptomatic diabetic patients is a risk factor for present myocardial ischaemia demonstrated by thallium dypiridamole tomography. The prevalence of inducible myocardial ischaemia in asymptomatic diabetic patients without known coronary disease is much higher than in non-diabetic population.

Diagnostic efficiency of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population.

OBJECTIVE: To analyse the diagnostic role of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH (uGH) excretion in adult GH deficiency (GHD). DESIGN: Twenty-seven adults (age range: 18-71 years) with severe GHD, defined by a peak GH response to an insulin tolerance test below 3microg/l in patients with at least one additional pituitary hypofunction. Reference values were established from a selected age- and body mass index-matched population (154 healthy adults grouped in four age groups). METHODS: IGF-I and IGFBP-3 were measured by RIA (Nichols) and results expressed as standard deviation (s.d.) scores from our reference population and assay normative data (s.d. score Nichols). uGH was measured by IRMA. RESULTS: Within the control group, IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio standardisation regarding our control population and IGF-I with respect to the assay normative data resulted in disappearance of age-related differences. However, IGFBP-3 s.d. score Nichols resulted in mean values between +1.4 and +2.5 s.d. score. Greatest diagnostic efficiency was for IGF-I standardised with respect to our controls (97.2%), followed by s.d. score IGFBP-3 (92.9%). s.d. score IGF/IGFBP-3 ratio and uGH showed poor diagnostic efficiency. Any combination of at least two abnormal parameters raised specificity to 100%. IGF-I standardised with respect to assay reference (s.d. score Nichols) showed similar diagnostic value (95.0%) whereas IGFBP-3 showed low sensitivity (33. 3%). Within the GHD patients, those with three or more additional deficiencies had lower s.d. score IGF-I than those with only two or one. CONCLUSION: We underline the importance of an appropriate reference population for correct interpretation of GH secretion markers. Considering our results, specificity obtained with two simultaneous abnormal parameters when referred to an adequate reference population may add valuable information to alternative GH stimulation tests to confirm adult GHD.

Postpartum thyroiditis: epidemiology and clinical evolution in a nonselected population.

Postpartum thyroiditis (PPT) presents in approximately 5% of women. Its incidence, clinical characteristics, and evolution were studied in a nonselected population of Mediterranean women. Six hundred five healthy women, recruited between the 36th week of pregnancy and the 4th postpartum day, underwent initial clinical and biological evaluation and postpartum at 1 (n = 605), 3 (n = 552), 6 (n = 574), 9 (n = 431), and 12 (n = 444) months. PPT was diagnosed in women with transient hyperthyroidism between 1 and 3 months postpartum and/or hypothyroidism between 3 and 6 months postpartum. Permanent hypothyroidism was considered if it was overt and persisted one year after diagnosis. The incidence rate of PPT was 7.8%. Eighty-two percent of PPT patients had hormone abnormalities at the 6th month postpartum, 8.8% showed depression and 51% goiter. PPT was manifest as hyperthyroidism plus hypothyroidism in 35.5% of patients, because only transient hyperthyroidism in 22.2% and as hypothyroidism alone in 42.3%. Five patients with hypothyroidism during PPT (0.82% of the initial population, 11.1% of PPT patients, and 15.6% of hypothyroidism PPT patients) presented permanent hypothyroidism after a follow-up of 39.8 (4.2) months. PPT was found in 7.8% of general Mediterranean population. We recommend evaluation at the 6th postpartum month to diagnose the majority of PPT women and indefinite follow-up of hypothyroid PPT patients to detect permanent hypothyroidism.

Observational study in adult hypopituitary patients with untreated growth hormone deficiency (ODA study). Socio-economic impact and health status. Collaborative ODA (Observational GH Deficiency in Adults) Group.

OBJECTIVE: The aim of the present study was to assess the socio-economic impact at baseline and after one year of follow-up of clinical and health status characteristics and laboratory tests of adult-onset GH deficiency (AGHD), a well-known clinical entity, in a large group of Spanish hypopituitary patients with untreated AGHD. DESIGN AND METHODS: A total of 926 eligible patients with GHD (GH

Growth hormone-binding protein directly depends on serum leptin levels in adults with different nutritional status.

The aim of this work was to assess the relationship between GH-binding protein (GHBP) and leptin. Both peptides are nutritionally regulated, but the recent implication of a role for leptin in the GH axis requires further study. To avoid the sexual dimorphism in leptin values, we performed leptin standardization according to gender (SD score-leptin). The relationship between SD score-leptin and GHBP was studied in 128 adults with different nutritional status [8 groups according to body mass index (BMI)], ranging from severely underweight anorexia nervosa to highly morbid obesity. Both GHBP and SD score-leptin significantly increased according to BMI within the range from 18-27 kg/m2, whereas no significant differences were found among underweight groups (BMI, < 18 kg/m2) or among obesity grades (BMI, > 27 kg/m2). We found a strong correlation between GHBP and SD score-leptin (r = 0.8; P < 0.0001). Multiple regression analysis revealed SD score-leptin to be a significant determinant of GHBP, accounting for 64% of the variation, whereas BMI did not contribute further to explaining changes in GHBP. This suggests a physiological pathway involving both GHBP (the soluble fraction of GH receptor) and leptin. Thus, we might speculate that leptin could be the signal that induces the related nutritional changes observed in GHBP/GH receptor expression.

Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet transplantation.

Clinical transplantation of human islets has a disappointingly low rate of success. We report here the identification of a possible causative factor: endotoxin present in the collagenase preparations used to disperse the pancreatic tissue before islet purification and transplantation. Supporting evidence includes (1) detection of unexpectedly high levels of endotoxin in most collagenase solutions currently used to digest human pancreases; (2) demonstration that supernatants generated during islet separation are able to induce the inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in macrophages; and (3) induction of IL-1, IL-6, and TNF-alpha in the islets during the separation procedure. Cytokine expression was assessed by reverse transcription-polymerase chain reaction and, for TNF-alpha, confirmed by enzyme-linked immunoabsorbent assay. It is proposed that endotoxin and locally induced cytokines carried over with the graft activate the endothelium and promote lymphomonocytic infiltration of grafted islets and surrounding liver tissue favoring primary nonfunction and early rejection. These results also have implications for the numerous experimental procedures that use collagenase, and they point to possible ways to improve islet preparation and transplantation protocols.

One-year follow-up of quality of life in adults with untreated growth hormone deficiency.

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.