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George J Kahaly

Publications and source records attributed to George J Kahaly.

14 recordsLinked to original sources
PubMed2007

[Polymorphisms of MICA microsatellites in thyroidal autoimmunity].

BACKGROUND: The autoimmune thyropathies Graves' disease (GD) and Hashimoto's thyroiditis (HT) have multiple genetic and environmental backgrounds. Allele alterations of immune genes might contribute to the development of autoimmunity. PATIENTS AND METHODS: This study determined a triplet short tandem repeat (STR) polymorphism in the transmembrane region of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) of 391 subjects (129 patients with GD, 56 patients with HT, and 206 healthy controls). Five common alleles have been reported for MICA. Genotypes were determined by fragment-length analysis in an ABI PRISM automatic sequencer. RESULTS: The prevalence of the MICA allele A9 was raised in patients with HT compared to controls (22.4% vs. 13.1%; p = 0.016; Fisher's exact test). For MICA, the genotype A5.1/A5.1 occurred more frequently in patients with GD than in controls (24.0% vs. 13.6%, odds ratio [OR] = 2.0, 95% confidence interval [95% CI] = 1.1-3.6; p = 0.018). The genotype MICA A6/A9 was decreased in patients with GD in contrast to controls (1.6% vs. 5.8%, OR = 0.2, 95% CI = 0.6-1.2; p = 0.089). Also, in patients with HT, the genotype A5.1/A9 was increased compared to controls (23.2% vs. 10.7%, OR = 2.5, 95% CI = 1.2-5.4; p = 0.025). CONCLUSION: The genotype MICA A5.1/A5.1 may be regarded as a risk factor for the development of GD. Also, the MICA genotype A5.1/A9 could raise the risk for acquiring HT. Finally, the genotype MICA A6/A9 could be seen as a protective factor against GD.

Adult↗
PubMed2005

Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy.

CONTEXT: Glucocorticoids are effective for severe Graves' orbitopathy (GO), which causes substantial morbidity. The question at issue is how best to use them. OBJECTIVE: The objective of this study was to optimize glucocorticoid application in GO. DESIGN: The study design was a randomized trial over 12 wk with 6-month follow-up. SETTING: The study was performed at university joint thyroid and ophthalmic clinics. PATIENTS: Seventy euthyroid out-patients with untreated, active, and severe GO were studied. INTERVENTION: Patients received either once weekly iv methylprednisolone (0.5 g, then 0.25 g, 6 wk each) or oral prednisolone starting with 0.1 g/d, then tapering the dose by 0.01 g/wk. MAIN OUTCOME MEASURES: At 3 months, the primary end point was a composite of improvements in proptosis, lid fissure width, and rate of diplopia in primary gaze, visual acuity, eye muscle thickness, and patient's quality of life. RESULTS: Intravenous glucocorticoid therapy resulted in rapid, significant, and sustained improvement. At 3 months, 27 of 35 patients (77%) in the iv group had a treatment response compared with 18 of 35 (51%) in the oral group (P < 0.01). Improvements over baseline values for disease severity (e.g. visual acuity; P = 0.01) and activity (e.g. chemosis; P < 0.01) and for quality of life (P < 0.001) were greater in the iv group. TSH receptor antibody titers decreased during iv steroid administration (P < 0.001), and smoking had a strong impact on the therapy response (P < 0.001). Additional treatment was required less frequently in the iv group. Intravenous steroids were safe, with different rates of adverse events between the two groups (P < 0.001). CONCLUSIONS: In patients with active and severe GO, iv glucocorticoids were more effective and better tolerated than oral steroids.

Administration, Oral↗
PubMed2005

Thyroid hormone action in the heart.

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypo- or hyperthyroidism. T(3)-induced changes in cardiac function can result from direct or indirect T(3) effects. Direct effects result from T(3) action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T(3) effects, which occur independent of nuclear T(3) receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T(3) effects are mediated by the binding of T(3) to specific nuclear receptor proteins, which results in increased transcription of T(3)-responsive cardiac genes. The T(3) receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T(3) also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum. This T(3) effect results from T(3)-induced increases in the level of the mRNA coding for the sarcoplasmic reticulum calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the sarcoplasmic reticulum.

Animals↗
PubMed2005

Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity.

The etiology of autoimmune thyroid diseases (AITD) is based on genetic and nongenetic factors. Genome-wide screening and linkage analyses have identified several chromosomal regions that are linked to AITD. These are HT-1 (on chromosome 13q33) and HT-2 (chromosome 12q22) for Hashimoto's thyroiditis (HT), and GD-1 (chromosome 14q31), GD-2 (chromosome 20q11.2), and GD-3 (chromosome Xq21) for Graves' disease (GD). Several genes have been proposed as susceptibility or immunoregulatory genes. Most promising genes are those of the major histocompatibility complex (MHC) complex (chromosome 6), the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene (chromosome 2), the CD40 (chromosome 20), the thyroglobulin gene (chromosome 8), and the autoimmune regulator gene (chromosome 21). This review summarizes evidence for pathogenetic involvement of several of these genes in various forms of autoimmune thyropathies. Most genetic data refer to GD, whereas less data are available for HT and thyroid-associated ophthalmopathy. Scarce data refer to AITD within the autoimmune polyglandular syndromes I and II. The realization of family studies in large samples from different populations might provide further insight in the genetic contribution to AITD. Data are also needed on the interaction among susceptibility genes. Finally, additional functional studies are warranted to clarify the possible role of allelic variants in the underlying pathogenic mechanisms of AITD.

Autoimmune Diseases↗
PubMed2004

[Managing Graves' orbitopathy].

Inflammatory orbitopathy is the most common extrathyroidal manifestation of Graves' disease and is characterised by a lymphocyte infiltration into the peribulbar space. Interdisciplinary management is recommended for rapid diagnosis and effective therapy of patients with thyroid orbitopathy. Immunosuppressive treatment is often used initially, and by suppressing inflammatory changes, it may result in both subjective and objective improvement. On the long run, though, decompression surgery is actually regarded as the most effective treatment of thyroid eye disease.

Graves Disease↗
PubMed2003

Treatment of scleromyxoedema with hydroxychloroquine.

BACKGROUND: Scleromyxoedema is a rare disease of unknown aetiology that is characterized by deposition of mucin and sclerotic induration of the skin; it is associated with paraproteinaemia. Patients suffer from progressive disability due to immobilization and cosmetic disfigurement. Treatment of scleromyxoedema is a therapeutic challenge. The antimalarial hydroxychloroquine has a rapid and reliable effect in reticular erythematous mucinosis. PATIENTS AND METHODS: Four consecutive patients (two women, two men; median age: 50 years) with scleromyxoedema, three of them with IgG lambda paraprotein, were treated with hydroxychloroquine. Treatment was initiated with 600 mg p.o. for 10 days, followed by 400 mg for at least 4 weeks, and 200 mg thereafter. RESULTS: Complete remission of skin manifestations was achieved in one patient, whereas three patients achieved a partial remission of 61+, 5 and 25 months' duration. Notably, three patients felt increased mobility and reduced firmness of skin during the first week of treatment, which was reflected in a rapid reduction in dermal thickness. In one patient, dysphagia was reverted as evidenced by normalization of oesophageal clearance. Paraproteinaemia was not influenced at all. Side effects included one case of electroretinogram abnormalities after 19 months of therapy and one case of leucopenia after 3 months. CONCLUSION: Hydroxychloroquine is an effective form of therapy for scleromyxoedema, leading to rapid and prolonged alleviation of symptoms.

Adult↗
PubMed2003

Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up.

Polyglandular autoimmune syndromes (PAS) are rare polyendocrinopathies characterized by the failure of several endocrine glands as well as nonendocrine organs, caused by an immune-mediated destruction of endocrine tissues. This article summarizes extensive clinical, epidemiological, serological, and genetic data of a large collective of patients with PAS (n = 360). Since 1988, more than 15,000 adult patients with endocrine diseases have been screened at the endocrine center of the Mainz University, and 151 of 360 patients with PAS have regularly been followed. Type 1 diabetes, Graves' disease, Hashimoto thyroiditis, Addison's disease, vitiligo, alopecia, hypogonadism, and pernicious anemia were observed in 61%, 33%, 33%, 19%, 20%, 6%, 5%, and 5%, respectively. The most common disease combination was type 1 diabetes and autoimmune thyroid disease. In most patients, type 1 diabetes was the first manifestation of PAS (48%). The longest time intervals between manifestations of the first and second immune endocrinopathies occurred between type 1 diabetes and thyroid disease (13.3 +/- 11.8 yr) and between vitiligo and thyroid disease (16.3 +/- 13.3 yr), but a shorter time interval was observed between Addison's and thyroid diseases. Of the 471 patients with type 1 diabetes screened, 83 (17.6%) were positive for PAS. Subsequently, sera of 126 patients with PAS, 287 with type 1 diabetes, and 303 matched controls were compared for human leukocyte antigens. Patients with PAS had significantly higher frequencies of the human leukocyte antigens A24, A31, B8, B51, B62, DR3, and DR4 (relative risk, 2.35, 2.74, 2.47, 7.17, 2.22, 1.94, and 2.46) vs. controls, and for A31, B15, B52, B55, DR2, DR11, and DR13 (relative risk, 2.51, 7.96, 3.99, 5.36, 4.46, 2.89, and 3.26) vs. type 1 diabetes patients without PAS. In conclusion, patients with autoimmune endocrine disease should be followed on a regular basis. In subjects at risk for PAS, functional screening every 3 yr is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow.

Adult↗
PubMed2003

Multi-center study on the characteristics and treatment strategies of patients with Graves' orbitopathy: the first European Group on Graves' Orbitopathy experience.

UNLABELLED: To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. AIM: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. METHODS: Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. RESULTS: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. CONCLUSIONS: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.

Adult↗
PubMed2002

[Randomized, double-blind crossover study of bioavailability of levothyroxine].

OBJECTIVE: The synthetic thyroid hormone levothyroxine-sodium (LT4) is still the treatment of choice to replace thyroid hormone deficiency in hypothyroidism, and for adjuvant treatment of euthyroid goiter. A change of LT4 preparations during treatment may lead to major changes of thyroid hormone levels. In this study, we compared the bioavailability of two LT4 preparations, L-Thyroxin Henning 100 and Eferox 100. PATIENTS AND METHODS: In a double-blind trial, 60 euthyroid volunteers were randomly assigned to two treatment groups. Over a period of 2 weeks, each group received 0.1 mg/d of the different preparations according to a "crossover design". To monitor the efficacy of the different drugs, baseline serum thyrotropin (TSH) and free thyroxine (fT4) levels were measured with the help of immunoenzyme tests. RESULTS: Compared to Eferox, L-Thyroxin Henning led to continuously higher fT4 levels (p = 0.0004). The area under the concentration-time curve (AUC) of fT4 also confirmed this highly significant difference. With respect to the influencing factors, a higher bioavailability in men compared to women (p = 0.004) was noted. Also, the increase of body weight was related to a lower bioavailability (p = 0.002). Regarding the baseline TSH serum levels, a reduction of 70% in the L-Thyroxin Henning group versus only 56% in the Eferox group was noted after a period of 14 days. Clinical symptoms of hyperthyroidism were not observed in the volunteers under both substances. CONCLUSION: In this study, L-Thyroxin Henning 100 showed a significantly higher bioavailability than Eferox 100 (p = 0.001). According to these findings, we do recommend regular measurements of serum TSH and fT4 levels when changing LT4 preparations of different brands, to cope with metabolic decompensation by using a new LT4 dosage.

Adult↗
PubMed2002

Psychosocial factors in subjects with thyroid-associated ophthalmopathy.

General agreement has emerged that the perceptions of patients of how they are feeling and how they are able to function in daily life should be included in the evaluation and monitoring of the effects of disease and treatment. Thyroid-associated orbitopathy (TAO), an inflammatory autoimmune eye disease, affects 50%-60% of patients with Graves' hyperthyroidism. Having blurred vision and/or diplopia has a detectable and significant impact on functional status and well-being, especially in role limitations caused by physical health problems. Therefore, to assess the impact of TAO on quality of life, we performed a descriptive study on consecutive ophthalmopathy patients with varying degrees of severity of TAO. General quality of life was assessed using a brief, internationally accepted, and standardized general questionnaire: the Medical Outcomes Study (MOS-36). In comparison to a large German reference group, low scores on the MOS-36 were found. Marked and significant differences from the control group were especially observed for the following items: vitality, social functioning, mental health, health perceptions, and body pain. MOS-36 did not correlate with the duration or severity of the ophthalmopathy. These results demonstrate the impact of a common visual symptom on health status and well-being, as measured by the MOS-36. In addition, comparison of the impact of various symptoms and conditions provides important and potentially clinically relevant information. In conclusion, we have shown that TAO has a large influence on the quality of life of these patients. The negative impact on well-being seems not to be related to the usual clinical assessment. These findings underscore the need for quality of-life measurements in prospective and controlled clinical trials.

Adolescent↗
PubMed2002

Cardiovascular hemodynamics and exercise tolerance in thyroid disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiovascular performance are detected with small variations in thyroid hormone serum concentrations. Most patients with thyroid disease experience cardiovascular manifestations, and the most serious complications of thyroid dysfunction occur as a result of cardiac involvement. The increased metabolic state and oxygen consumption that occur in hyperthyroid patients require an increased supply of oxygen and removal of metabolic products from the periphery. This is accomplished by increasing the cardiac output to meet the needs of the periphery. Circulation time is decreased in hyperthyroid patients, and a lowered arterial resistance and increased venous resistance promote the return of blood to the heart. Thyroid hormones may significantly decrease the strength of respiratory and skeletal muscles and affect regulatory mechanisms of adaptation to incremental effort. In hyperthyroidism, cardiovascular exercise testing and analysis of respiratory gas exchange demonstrate low efficiency of cardiopulmonary function as well as impaired chronotropic, contractile, and vasodilatatory reserves, which are reversible when euthyroidism is restored. During exercise, the increment (delta) of minute ventilation (respiratory rate x tidal volume), and oxygen pulse (oxygen uptake per heart beat) are significantly lower in dysthyroidism versus euthyroidism. Especially in older patients with thyroid dysfunction, markedly reduced workload, delta ejection fraction, and delta heart rate, both at the anaerobic threshold as well as at maximal exercise, are observed. In thyrotoxicosis, mitochondria oxidative dysfunction during exercise mostly causes intracellular acidosis, whereas in hypothyroidism, inadequate cardiovascular support appears to be one of the principal factors involved. These abnormalities partly explain why subjects with dysthyroidism are intolerant to exertion. Thus, in thyroid disease, both cardiac structures and function may remain normal at rest, however impaired cardiovascular and respiratory adaptation to effort becomes unmasked during exercise.

Age Factors↗
PubMed2002

Cost estimation of thyroid disorders in Germany.

To assess the economic effects of thyroid disorder-related morbidity in Germany, a systematic review of national and international literature from 1981-2001 was performed. Data from insurance companies, the government department of public health, and the federal office of statistics helped characterize the situation in Germany. Being the most important thyroid disease, endemic iodine-deficiency goiter causes economic costs of approximately 2.1 billion DM per year or 1 billion Euros or 1 billion U.S. dollars. In recent years iodine supplementation of food became better accepted by the German population. This should significantly reduce the prevalence of goiter from 30%-40% to less than 10%. Functional thyroid disorders are observed in 5%-10% of the German population. A more differentiated view of these conditions should lead to specific guidelines for an economic screening and therapy of subpopulations. Lacking valuable data, an actual economic assessment of autoimmune or malignant thyroid diseases cannot be performed. On the other hand, with respect to the costs of specific thyroid therapy, e.g., radioiodine treatment of thyrotoxicosis (mainly toxic nodular goiter), the economic consequences of a new regulation for radiation protection in Germany have been demonstrated recently. Using the actual maximum permissible level of residual activity on discharge from the hospital after radioiodine therapy, length of hospitalization was shortened to 5.1 days in university hospitals and to 5.8 days in nonuniversity institutions. Payment per patient for radioiodine therapy was 1,856 and 1,530 Euros (median value) in university and nonuniversity hospitals, respectively. In conclusion, better prevention of iodine deficiency and its long-term consequences should effectively reduce direct as well as indirect costs and overall economic impact of endemic goiter as the most important thyroid disease in Germany. Sustainable elimination of iodine deficiency is technically possible, but it needs further commitment and support at all levels.

Costs and Cost Analysis↗
PubMed2002

Cardiac involvement in thyroid hormone resistance.

To analyze the cardiovascular alterations thought to occur in resistance to thyroid hormone (RTH), cardiac involvement in 54 patients with RTH was investigated with the help of two-dimensional and Doppler echocardiography. Data from 41 of 54 adult subjects with RTH were also compared with those of 24 and 20 cases with hyperthyroidism (H) and hypothyroidism (h), respectively, as well as 22 healthy euthyroid controls (C). With respect to the type of mutations, no correlation was found between cardiovascular features and genotype. Compared with affected adults, children with RTH showed markedly higher serum free T3 (FT3), free T4 (FT4), and baseline TSH concentrations. Compared with healthy children of comparable age, RTH children had significantly higher heart rate and lower left ventricular (LV) ejection fraction (P = 0.006). Also, higher heart rate and FT4 as well as shorter diastolic relaxation of the myocardium (all P = 0.001) between RTH subjects with and without thyrotoxic cardiovascular features were found. Cardiac symptoms (palpitations, 32% vs. 71%) and signs (sinus tachycardia, 26% vs. 79%; atrial fibrillation, 6% vs. 17%) were significantly less frequent in RTH vs. H (all P = 0.001). Compared with C and h, heart rate, cardiac output, stroke volume, and systolic aortic flow velocity were strongly increased in RTH (all P = 0.0001) and H, although ejection (P = 0.0012) and shortening (P = 0.0001) fractions of the LV were markedly lower in RTH vs. H. Diastolic parameters, such as isovolumic relaxation (P = 0.0001) and deceleration time (P = 0.013), were shorter in RTH vs. h and C. In RTH, positive correlations between FT3 and heart rate, and between FT4 and LV ejection fraction were observed, whereas negative correlations between both FT3 and FT4 and isovolumic relaxation were noted. In conclusion, these findings indicate a modulated hyperthyroid effect on cardiac systolic and diastolic function of the myocardium in RTH, whereas other parameters, such as ejection and shortening fractions of the LV, systolic diameter, and LV wall thickness, were comparable to C. Differences in term of cardiovascular changes were smaller between the RTH and C groups than the RTH and the H or h groups. Thus, an incomplete cardiac response to thyroid hormone is present in RTH.

Adult↗