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Biomedical subjects

L Chiovato

Publications and source records attributed to L Chiovato.

At least 37 records · Page 2Linked to original sources
PubMed2000

Thyroid and lipid metabolism.

Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With specific regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is influenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esterified fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia.

Adipose Tissue↗
PubMed2000

Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach.

Screening programs for congenital hypothyroidism (CH) dramatically improved the neuropsychological prognosis in affected children. However, mild impairments in cognitive performances, poorer motor skills, defective language abilities, and learning problems have been reported in some studies of early-treated CH children. The occurrence of these defects makes neuropsychological follow-up mandatory. The aim of the present study was to identify those neuropsychological functions that are more frequently affected in early-treated CH children and that might require prompt rehabilitation treatment to prevent permanent defects. The study group involved 24 CH children. Levothyroxine (LT4) treatment (initial dose 8-10 microg/kg per day) was started at mean age of 28 days (range 15-45) and was then adjusted with the goal to keep thyrotropin (TSH) and free thyroid hormone levels in the normal range. Cognitive evaluation was performed at 3, 5, and 7 years of age and did not significantly differ from that of controls. Mean neurological scores were lower in children 5 years of age than in controls. Children with severe neonatal hypothyroidism (serum thyroxine [T4] < 2 microg/dL) had significantly lower neurological scores compared to less affected CH children and normal controls. The most affected functions were balance, extremity coordination, fine motricity, quality of movements, associated movements, and head movements. Language disorders were observed in half of CH children at 3 and 5 years of age, but moderately severe defects were restricted to those with severe neonatal hypothyroidism. In conclusion, a problem-oriented, simplified neuropsychological follow-up of early-treated children with CH should not systematically include the frequent repetition of time-consuming and expensive psychometric tests because individual IQ scores are in the normal range of tests in almost all CH children and can be differentiated from those of normal controls only on a population-statistic basis. Selected tests of motor proficiency are indicated at 3 and 5 years of age to detect those defects in motor skills that appear to be more specifically affected in CH children. Language performances are at particular risk in CH children, and should be always checked at 3 and 5 years of age. Children with even mild language disorders or delayed language achievements should be regularly reevaluated at 6-month intervals and, if no spontaneous improvement is observed, they should receive specific rehabilitation treatment. No further motor and language evaluation is warranted in CH children with normal tests at age 5 years.

Child↗
PubMed2000

Increased frequency of euthyroid ophthalmopathy in patients with Graves' disease associated with myasthenia gravis.

We previously showed that myasthenia gravis (MG) has a mild clinical expression when associated with autoimmune thyroid diseases (AITD). In the present study we have investigated the frequency of thyroid-associated ophthalmopathy (TAO) in patients with Graves' disease (GD) associated with MG as compared with GD patients without MG. A total of 418 patients with GD were studied, 31 with MG and 387 without MG. TAO was evaluated by physical examination, exophthalmometry, computerized tomography, and computerized visual fields assessment. The overall prevalence of TAO was similar in GD patients with MG (61.2%) and in those without MG (56.4%). When the analysis was restricted to GD patients with ocular MG, a greater frequency of TAO was found (84.6%), compared with GD patients without MG or with GD patients with generalized MG, although the differences did not reach the statistical significance. GD patients with MG had a significantly greater prevalence (12.9%) of euthyroid ophthalmopathy (clinically overt ophthalmopathy without previous and/or current hyperthyroidism) than those without MG (3.1%; p = 0.003). The results suggest a preferential association between the ocular manifestations of GD and MG, which may be due to immunological cross-reactivity against common autoimmune targets in the eye muscle as well as to a common genetic background.

Adult↗
PubMed2000

Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene.

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. DNA was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (1568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.

Adenoma↗
PubMed2000

Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.

Congenital hypothyroidism due to impaired thyroid response to TSH was originally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital hypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is increased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases serum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T4 and T3 concentrations were below the sensitivity of the methods, with elevated serum TSH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplastic gland located in the appropriate anatomical position in the neck was found at scintiscan. The gland did not respond after administration of bovine TSH in terms of 131I uptake, serum thyroid hormones, and thyroglobulin secretion. A diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated. Genetic analysis in the propositus showed a homozygous inactivating mutation of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserved threonine at position 477 in the first extracellular loop of the receptor (T477I). The brother, one sister of the father (whose DNA was not available), the mother of the propositus, one sister, and the brother were heterozygous for T477I. All the heterozygous persons were unaffected. After transfection in COS-7 cells, the mutant receptor displayed an extremely low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic reduction in the amount of cAMP accumulation after bovine TSH challenge was observed in cells transfected with the mutant T477I receptor. A structural defect in the mutant TSH receptor protein was probably responsible for the poor routing of the receptor to the cell membrane. This is the first time that a loss of function mutation of the TSH receptor is described in a patient with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness and the first time that an inactivating mutation of the TSH receptor is described in the first extracellular loop.

Adult↗
PubMed2000

Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter.

Toxic multinodular goiter, a heterogeneous disease producing hyperthyroidism, is frequently found in iodine-deficient areas. The pathogenesis of this common clinical entity is still unclear. The aim of the present study was to search for activating TSH receptor (TSHr) or Gs alpha mutations in areas of toxic or functionally autonomous multinodular goiters that appeared hyperfunctioning at thyroid scintiscan but did not clearly correspond to definite nodules at physical or ultrasonographic examination. Surgical tissue specimens from nine patients were carefully dissected, matching thyroid scintiscan and thyroid ultrasonography, to isolate hyperfunctioning and nonfunctioning areas even if they did not correspond to well-defined nodules. TSHr and Gs alpha mutations were searched for by direct sequencing after PCR amplification of genomic DNA. Only 2 adenomas were identified at microscopic examination, whereas the remaining 18 hyperfunctioning areas corresponded to hyperplastic nodules containing multiple aggregates of micromacrofollicules not surrounded by a capsule. Activating TSHr mutations were detected in 14 of these 20 hyperfunctioning areas, whereas no mutation was identified in nonfunctioning nodules or areas contained in the same gland. No Gs alpha mutation was found. In conclusion, activating TSHr mutations are present in the majority of nonadenomatous hyperfunctioning nodules scattered throughout the gland in patients with toxic or functionally autonomous multinodular goiter.

Adenoma↗
PubMed2000

Circulating thyroglobulin transcytosed by thyroid cells in complexed with secretory components of its endocytic receptor megalin.

After its endocytosis from the colloid, some thyroglobulin (Tg) is transcytosed intact across thyrocytes, accounting in part for its presence in the circulation. We previously showed that megalin (gp330), an endocytic Tg receptor, mediates apical to basolateral Tg transcytosis. Here we investigated whether a portion of megalin remains combined with Tg after its transcytosis, using studies with cultured thyroid cells and in vivo observations. FRTL-5 cells, a rat thyroid cell line, cultured on filters in dual chambers form tight junctions and exhibit features of polarity, with expression of megalin exclusively on the upper (apical) surface. After the addition of unlabeled Tg to the upper chamber and incubation at 37 C, some Tg was transcytosed intact across FRTL-5 cells into the lower chamber. Two antimegalin ectodomain antibodies precipitated transcytosed Tg in fluids collected from the lower chamber. After the addition of Tg to surface-biotinylated FRTL-5 cells, an anti-Tg antibody and the two antimegalin ectodomain antibodies precipitated high molecular mass biotinylated material in fluids collected from the lower chamber, corresponding to much of the megalin ectodomain, as well as smaller amounts of lower molecular mass material. The results indicate that Tg transcytosed across FRTL-5 cells remains complexed with megalin ectodomain components, which we refer to as megalin secretory components. In aminotriazole-treated rats, which develop increased megalin-mediated Tg transcytosis, antimegalin antibodies precipitated some of the Tg in the serum. Tg was also precipitated by antimegalin antibodies in sera from patients with Graves' disease, in which we found increased megalin expression on the apical surface of thyrocytes. In contrast, in thyroidectomized patients with metastatic papillary thyroid carcinoma, in whom Tg is directly secreted by neoplastic thyroid cells into the circulation rather than transcytosed, serum Tg was not precipitated by antimegalin antibodies. The detection of Tg-megalin complexes may help identify the source of serum Tg in patients with thyroid diseases.

Adult↗
PubMed1999

The effect of staphylococcal enterotoxin B on thyrocyte HLA molecule expression.

Microbial superantigens have been implicated in the pathogenesis of human autoimmune diseases. In autoimmune glands, thyrocytes inappropriately express HLA-DR molecules and these cells may function as antigen presenting cells (APC) We studied the effect in vitro of staphylococcal enterotoxin B (SEB) on HLA molecule expression on thyrocytes obtained from autoimmune and non-autoimmune glands by immunofluorescence. HLA class I and class II upregulation could be detected by FACS analysis on thyrocytes. Anti-IFN-gamma neutralizing antibodies markedly affect both class I and class II upregulation on thyrocytes. FRTL5 cells were not responsive to SEB. Similarly, a human thyroid cell strain maintained in culture in a conditioned medium was not induced to express HLA products by SEB stimulation. The addition of autologous intrathyroidal lymphocytes caused reestablishment of the SEB effect.

Cells, Cultured↗
PubMed1999

Circulating thyroid autoantibodies in a sample of Italian octo-nonagenarians: relationship to age, sex, disability, and lipid profile.

Circulating thyroid autoantibodies were assessed in a sample of Italian octo-nonagenarians living in a restricted area (Val Vibrata, Abruzzo), and selected according to the absence or presence of chronic illness and disability. The study groups included: Group A ("Successful aging"), 98 free-living healthy, fully independent, octo-nonagenarians (57 males and 41 females, average age +/-SD 83.9+/-3 years); Group B ("Unsuccessful aging"), 62 highly disabled octo-nonagenarians (24 males and 38 females; average age 86.5+/-3.4 years), and Group C (Controls), 91 randomly selected healthy adult controls (42 males and 49 females; age 53.7+/-16.6 SD years, range 20-70). Serum autoantibodies to thyroglobulin (anti-Tg) and to thyroid peroxidase (anti-TPO) were measured by passive hemagglutination and radioimmunoassays (RIA); serum free thyroxine and thyrotropin by RIA. The prevalence of positive thyroid autoantibody tests was not significantly increased in the elderly groups compared to the controls, with the remarkable exception of anti-Tg detected by RIA which were increased in disabled elderly, compared to free-living elderly and controls. Two/62 disabled elderly had subclinical (1) or mild (1) primary hypothyroidism, and one free-living woman aged 90 years was hyperthyroid (toxic nodular goiter). No correlation was found between serum thyroid autoantibodies, thyroid hormones and TSH and serum lipoprotein fractions. The higher prevalence of thyroid autoantibodies found only in disabled, but not in free-living Italian octo-nonagenarians suggests that thyroid autoimmune phenomena in the elderly may be an expression of age-associated disease rather than related to the aging process in itself.

Aged↗
PubMed1999

Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms.

The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gs alpha genes may confer TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and nonfunctioning follicular thyroid adenomas specifically selected for their homogeneous gross anatomy (single nodule in an otherwise normal thyroid gland). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codons 201 and 227 of the Gs alpha gene were also analyzed. At histology, all hyperfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed as follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features indicating malignant transformation (a minimally invasive follicular carcinoma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyperfunctioning follicular thyroid adenomas. In one hyperfunctioning adenoma, which was negative for TShR mutations, a mutation in codon 227 of the Gs alpha gene was identified. At variance with hyperfunctioning thyroid adenomas, no mutation of the TShR or Gs alpha genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings clearly define a different molecular pathogenetic mechanism in hyperfunctioning and nonfunctioning follicular thyroid adenomas. Activation of the cAMP cascade, which leads to proliferation but maintains differentiation of follicular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gs alpha genes are probably involved in nonfunctioning follicular adenomas.

Adenoma↗
PubMed1999

Serum iodothyronines in the human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis.

UNLABELLED: The pattern of circulating iodothyronines in the fetus differs from that in the adult, being characterized by low levels of serum T3. In this study, concentrations of various iodothyronines were measured in sera from neonates of various postconceptional age (PA). Results obtained in cord sera at birth (PA, 24-40 weeks), reflecting the fetal pattern, were compared with those found during extrauterine life in newborns of 5 days or more of postnatal life (PA, 27-46 weeks). The main findings are: Starting at 30 weeks of PA, serum levels increase linearly during extrauterine life; and at 40 weeks, they are more than 200% of those measured in cord sera from newborns of equivalent PA. Serum reverse T3 (rT3) levels during fetal life are higher than those measured during extrauterine life; but they significantly decrease, starting at 30 weeks of PA. Serum T3 sulfate (T3S) does not significantly differ between the two groups, showing the highest values at 28-30 weeks of PA, and significantly decreasing at 30-40 weeks. T3S levels are directly correlated with rT3, both in fetal and extrauterine life, whereas a significant negative correlation between T3S and T3 is found only during extrauterine life. IN CONCLUSION: 1) changes in serum concentrations of iodothyronines in umbilical cord and during postnatal life indicate that maturation of extrathyroidal type I-iodothyronine monodeiodinase (MD) accelerates, starting at 30 weeks of PA; 2) high levels of type III-MD activity in fetal tissues prevent the rise of serum T3, whereas they maintain high levels of rT3 during intrauterine life; 3) an important mechanism leading to the transition from the fetal to the postnatal thyroid hormone balance is a sudden decrease in type III-MD activity; iv) because placenta contains a high amount of type III-MD, it is conceivable that placenta contributes to maintain low T3 and high rT3 serum concentrations during fetal life and that its removal at birth is responsible for most changes in iodothyronine metabolism occurring afterwards.

Female↗
PubMed1999

Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis.

Megalin (gp330) is a multiligand receptor found on the apical surface of selected epithelial cells, including thyroid cells. We recently showed that megalin is a high-affinity receptor for thyroglobulin. Megalin is capable of inducing autoantibodies, as shown in the rat model, Heymann nephritis. Based on this consideration and on the knowledge that autoantibodies against several thyroid antigens develop in patients with autoimmune thyroid diseases, we searched for antimegalin antibodies in 78 patients with autoimmune and nonautoimmune thyroid diseases. We developed an assay, based on flow cytometry, to measure binding of serum IgGs to L2 cells, a rat carcinoma cell line that expresses abundant megalin. After incubation of L2 cells with serum samples and then with fluorescein isothiocynate-conjugated antihuman IgG Fc-specific antibody, the mean fluorescence intensity (MFI) was determined. Using results obtained in sera from 32 normal subjects, we established a cutoff value for MFI (50.62), above which, tests were considered positive. Significantly elevated values were found in 18 patients, including 13 of 26 patients with autoimmune thyroiditis (50.0%) and in 2 of 19 patients with Graves' disease (10.5%). Furthermore, 2 of 19 patients with nontoxic goiter (10.5%) and 1 of 14 patients with differentiated thyroid cancer (7.14%) had MFI values greater than 50.62, associated with the presence of circulating antithyroid autoantibodies. As a control cell line, we used Chinese hamster ovary cells, which do not express megalin. We found that, among the 18 patients with positive tests for binding to L2 cells, only 1 patient with nontoxic goiter had significant binding of serum IgGs to Chinese hamster ovary cells. Binding of serum IgGs to L2 cells was significantly reduced by coincubation with purified megalin in 15 of 18 positive patients (83.33%) and by a rabbit antimegalin antibody in 11 patients (61.11%). Further and more conclusive evidence that positive tests (MFI >50.62) for binding to L2 cells were attributable to serum antimegalin antibodies was demonstrated by immunoprecipitation experiments. After incubation of serum samples with L2 cell extracts, incubation with antihuman IgG Fc-specific agarose beads resulted in immunoprecipitation of megalin in all the 18 positive patients, but not in normal subjects, as assessed by Western blotting using a monoclonal antibody against megalin. Furthermore, the intensity of the band corresponding to megalin precipitated by serum IgGs in the above 18 patients was significantly correlated with the L2 binding MFI. This is the first clear-cut demonstration of antibodies against megalin in humans. Further studies are needed to determine whether antimegalin antibodies have pathogenic significance or diagnostic value in autoimmune thyroid diseases.

Adult↗
PubMed1999

School attainments in children with congenital hypothyroidism detected by neonatal screening and treated early in life.

OBJECTIVE: Evaluation of school attainments in children with congenital hypothyroidism (CH) detected by neonatal screening and treated early in life. PATIENTS AND METHODS: Text comprehension, mathematics, reading, writing and verbal and spatial memory, as indices of school learning, were evaluated in nineteen 5- to 10-year-old children with CH attending nursery or elementary school. l-Thyroxine substitution (starting dose 8-10 microg/kg body weight per day) was initiated at a mean age of 30+/-10 days of life. The control group included 298 unaffected children matched with the CH children for age and school grade. Thirty per cent of controls were classmates of CH children. Intelligence quotients (IQ), language performances and motor development were evaluated in CH children at age 5 years, and were related to their school attainments. School performances of CH children were also compared with their neonatal serum thyroxine (T4) concentration, and with the social-cultural level of the family. RESULTS: Four out of 19 (21%) children with CH, 3 in the nursery and 1 in the elementary school, displayed a generalized learning disorder. Symbol copy, geometric copy, phrase repetition, dictation writing and spontaneous writing were particularly defective in nursery school CH children, while orthographic error recognition was defective in elementary school CH children. School learning disorders in CH children were significantly correlated with a borderline-low IQ, poor language performances and a low social-cultural level of the family, but not with motor skills or neonatal T4 concentration. CONCLUSION: School attainments of early treated CH children were within the normal range in most affected cases. However, about 20% of CH children, most of them attending nursery school, showed a generalized learning disorder. Low IQ scores and poor language performances at age 5 years were associated with defective learning, mainly in CH children living in a poor social-cultural environment. In this subset of CH children, prompt initiation of speech and psychomotor rehabilitation therapy is recommended in order to prevent subsequent school learning disorders.

Child↗
PubMed1998

Prevalence of thyroid autoantibodies in children and adolescents from Belarus exposed to the Chernobyl radioactive fallout.

BACKGROUND: The long-term effects of ionising radiation, including radioiodine, on thyroid function are not well known. We compared thyroid immunity and function in two groups of children from Belarus, one of whom was exposed to the radioactive fallout of Chernobyl. METHODS: We measured serum free thyroxine 4 (free T4), free T3, and thyrotropin hormone (TSH) and the prevalence of thyroid autoantibodies (antithyroglobulin and antithyroperoxidase), in 287 children or adolescents living in Hoiniki (average caesium contamination of 5.4 Ci/km2). We also studied 208 children and adolescents living in Braslav (average contamination <0.1 Ci/km2), who were age 12 years or less at the time of the Chernobyl accident. FINDINGS: The prevalence of antithyroglobulin or antithyroperoxidase, or both, was significantly higher (p=0.0001) in individuals living in Hoiniki (56 [19.5%] of 287) than in those living in Braslav (eight [3.8%] of 208). In both villages, no sex differences were found in the antibody prevalence before age 13 years. Thereafter, a significantly higher prevalence of thyroid autoantibodies was found in girls from Hoiniki. The increase in the prevalence of circulating antibodies in the contaminated group was already apparent in individuals who, at the time of the accident, were in utero or newborn (15.7%), and was even more pronounced in children of 9 years or more (35.1%). No major alterations of serum FT-4, FT-3, or TSH were found. INTERPRETATION: 6-8 years after the Chernobyl accident, a significant increase in thyroid autoimmunity was found in children exposed to radioactive fallout. Pubertal age in girls is a risk factor for increased prevalence of thyroid autoimmunity. The autoimmune phenomena are limited to an increased prevalence of circulating thyroid autoantibodies without evidence of significant thyroid dysfunction. The future development of clinically relevant thyroid autoimmune diseases, especially hypothyroidism, is a possibility.

Adolescent↗