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Thyroid hormone in health and disease.

Thyroid disease is common, affecting around 2% of women and 0.2% of men in the UK. Our understanding of the effects of thyroid hormones under physiological circumstances, as well as in pathological conditions, has increased dramatically during the last two centuries and it has become clear that overt thyroid dysfunction is associated with significant morbidity and mortality. Both hypo-and hyperthyroidism and their treatments have been linked with increased risk from cardiovascular disease and the adverse effects of thyrotoxicosis in terms of osteoporosis risk are well established. Although the evidence suggests that successful treatment of overt thyroid dysfunction significantly improves overall survival, the issue of treating mild or subclinical hyper- and hypothyroidism remains controversial. Furthermore, the now well-established effects of thyroid hormones on neurodevelopment have sparked a whole new debate regarding the need to screen pregnant women for thyroid function abnormalities. This review describes the current evidence of the effects of thyroid hormone on the cardiovascular, skeletal and neurological systems, as well as the influence of thyroid diseases and their treatments on the development of malignancy. Furthermore we will describe some recent developments in our understanding of the relationship between thyroid status and health.

Atherosclerosis↗

Thyroid function in mothers of hypothyroid newborns.

OBJECTIVE: To assess etiologic significance of maternal autoimmune thyroid disease on incidence of transient congenital hypothyroidism in newborns. METHODS: Thyroid function was assessed in 259 mothers of hypothyroid newborns from the Quebec newborn screening program between 1984 and 1996. Maternal blood samples were taken routinely at the time of follow-up serum sampling of the infants, for measurements of free thyroxine, TSH, and antimicrosomal autoantibodies. Thyroid scans were conducted to characterize the type of thyroid dysfunction in affected infants. Results were compared with similar data from a control population of 1773 pregnant women recruited from Quebec City between 1991 and 1992. These samples were collected at routine second-trimester prenatal screenings. RESULTS: The mothers of congenitally hypothyroid infants had higher prevalence of suppressed serum TSH concentrations compared with the control population (6.1% versus 2.9%, P = .01), higher prevalence of increased serum TSH levels (7.0% versus 0.9%, P < .001), and similar prevalence of positive antimicrosomal antibodies (11.6% versus 12.1%, P = .90). The prevalence of transient congenital hypothyroidism in the study population of hypothyroid infants was 27%, which is significantly greater than the 15% observed in our overall population of 523 congenitally hypothyroid infants studied between 1974 and 1996 (P = .04). Antimicrosomal antibodies were demonstrable in ten (77%) of 13 mothers of infants with transient congenital hypothyroidism, and antimicrosomal antibodies or abnormal serum TSH levels in 13 of 13 (100%). CONCLUSION: These results indicate that most, if not all, cases of transient congenital hypothyroidism were attributable to maternal autoimmune thyroid disease, and presumably to maternal TSH receptor-blocking antibody. They suggest that maternal autoimmune thyroid disease is associated with much higher prevalence of transient congenital hypothyroidism than suspected. Because of the 20% prevalence of autoimmune thyroid disease and thyroid dysfunction in the mothers of congenitally hypothyroid infants, we recommend thyroid assessment of such women, if this information is not available.

Autoantibodies↗

Thyroid function screening in psychiatric in-patients.

During a two-year biochemical screening for thyroid disease amongst 191 psychiatric admissions, 38 (20 per cent) had an abnormal result, 5 were hyperthyroid and 7 hypothyroid. Thyroid dysfunction was associated with female sex and affective psychosis, but not with age. During the three weeks before admission the patients with an abnormal result had been prescribed significantly more phenothiazines, antiparkinsonian drugs and lithium than the patients with normal thyroid function. Almost half of those with abnormal function were physically ill on admission. Despite these findings we concluded that in most patients thyroid dysfunction was not a major determinant of the psychiatric disturbance.

Adult↗

Clinical controversies in screening women for thyroid disorders during pregnancy.

Subclinical hypothyroidism and/or the presence of thyroid peroxidase antibodies (TPOAb) may be associated with subfertility, infertility, spontaneous abortion, placental abruption, preterm delivery, gestational hypertension, preeclampsia, postpartum thyroid dysfunction, depression (including postpartum depression), and impaired cognitive and psychomotor child development. In November 2002, the American Association of Clinical Endocrinologists (AACE) released new guidelines for clinical practice for the diagnosis and treatment of hyperthyroidism and hypothyroidism, which includes a new thyroid-stimulating hormone (TSH) reference range of 0.3 to 3.0 mIU/L. Recently, the AACE recommended screening all women considering conception and/or all gravid women in the first trimester for thyroid dysfunction. However, the American College of Obstetricians and Gynecologists (ACOG) and the United States Preventive Services Task Force (USPSTF) have not endorsed these recommendations. This article reviews the evidence regarding screening women during pregnancy for subclinical hypothyroidism and/or the presence of thyroid peroxidase antibodies.

Female↗

Diagnostic criteria for Graves' ophthalmopathy.

PURPOSE: To propose criteria for the diagnosis of Graves' ophthalmopathy. METHODS: We reviewed the evolution of nomenclature describing Graves' ophthalmopathy. and the diagnostic schema used in key published reports. RESULTS: A laboratory test or clinical finding pathognomonic for Graves' ophthalmopathy currently is not available or recognized. Extant diagnostic criteria may exclude appropriate cases. CONCLUSIONS: Graves' ophthalmopathy is considered to be present if eyelid retraction occurs in association with objective evidence of thyroid dysfunction or abnormal regulation, exophthalmos, optic nerve dysfunction, or extraocular muscle involvement. The ophthalmic signs may be unilateral or bilateral, and confounding causes must be excluded. If eyelid retraction is absent, then Graves' ophthalmopathy may be diagnosed only if exophthalmos, optic nerve involvement, or restrictive extraocular myopathy is associated with thyroid dysfunction or abnormal regulation and if no other cause for the ophthalmic feature is apparent.

Eye Diseases↗

Long-Term Complications of Treatment and Causes of Mortality After Hodgkin's Disease.

The majority of newly diagnosed patients are expected to survive Hodgkin's disease because of effective therapies established during past 30 years. Long-term observations from large populations of treated patients have disclosed a variety of late effects of the disease and its therapy have contributed morbidity and excess mortality to Hodgkin's disease survivors. Secondary cancers have continued to accrue, and the risk relative to the general population has increased to 6.4 (95% confidence intervals: 5.5 to 7.3) in updated experience at Stanford University. Risks are significantly elevated for leukemia (primarily after chemotherapy regimens containing alkylating agents); non-Hodgkin's lymphoma; and tumors of the lung, breast, soft tissues, bone, stomach, pancreas, salivary gland, thyroid, and cutaneous melanoma. Early cardiovascular disease has also been observed and numerically exceeds second cancers as a cause of death in patients with early stage Hodgkin's disease (49 v 47 cases). Pulmonary dysfunction, thyroid dysfunction, infertility, psychosocial changes, gastrointestinal problems, soft-tissue changes, alterations in immunity, and risks for infection have also affected some treated patients. As these problems have been recognized, treatment approaches have been modified over the last 10 to 15 years, and early data suggest a decrease in some treatment sequellae.

Journal Article↗

Catecholamine sensitivity in hyperthyroidism and hypothyroidism.

1. Catecholamine sensitivity in hyper- and hypothyroidism has been studied using a standardised isoprenaline sensitivity test. 2. Seven patients with hyperthyroidism and seven with hypothyroidism were tested both when showing evidence of thyroid dysfunction and again when euthyroid. 3. No significant differences were seen in heart rate responses to isoprenaline when patients became euthyroid compared to their response when either hyperthyroid or hypothyroid. 4. These results indicate that sensitivity to catecholamines is not altered in thyroid dysfunction and, in particular, that hypersensitivity does not occur in spontaneous hyperthyroidism.

Adult↗

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Adult↗

Impact of long-term administration of amiodarone on the thyroid function of patients with Chagas' disease.

The effect of long-term treatment with amiodarone on patients with Chagas' disease has seldom been reported. This nonrandomized observational study attempted to analyze the follow-up of patients with Chagas' disease regarding their clinical evolution, thyroid dysfunction, and goiter. We compared 72 patients with long-term use (11 +/- 5 years) of amiodarone, including 22 patients who developed goiter, to 33 patients who did not use amiodarone, followed-up for 2 to 20 years (7 +/- 11 years). Follow-up of 72 patients for 9 +/- 5.4 years with periodic cardiac and thyroid function evaluations showed that only 26 maintained normal serum thyrotropin (TSH) levels; 24 presented with elevated levels; 4 had low levels, and 18 patients presented with fluctuations of TSH level. Among the 22 patients with goiter, only 3 (14%) patients maintained normal TSH, 8 (36%) had elevated TSH, 2 (9%) had low TSH, and 9 (41%) patients presented with fluctuating serum TSH levels. Most individuals remained clinically euthyroid with no evidence of cardiac impairment that could be attributed to thyroid dysfunction and the arrhythmias were adequately controlled by amiodarone. We suggest that amiodarone treatment may be continued for patients with Chagas' disease with arrhythmias, even in those who develop thyroid function abnormalities or goiter.

Amiodarone↗

A case of total thyroxine-binding globulin deficiency with Graves' disease: fluctuations of plasma triiodothyronine/thyroxine ratio.

A 37-year-old male with total thyroxine-binding globulin (TBG) deficiency associated with Graves' disease is described. Both TBG immunoreactivity and TBG capacity were not detectable in his serum. Serum concentrations of thyroxine-binding prealbumin and albumin were normal. He was initially hyperthyroid. During methimazole-treatment he was maintained in an euthyroid state except for two short hypothyroid periods. His plasma triiodothyronine/thyroxine (T3/T4) ratios during both the untreated hyperthyroid and the methimazole-induced hypothyroid states were higher than those during his methimazole-induced euthyroid state. These findings on changes in his T3/T4 ratio accompanying thyroidal dysfunction were qualitatively comparable with those in patients with Graves' disease with normal TBG levels: that both untreated hyperthyroid and methimazole-induced hypothyroid patients showed higher T3/T4 ratios than methimazole-induced euthyroid patients. These results may provide indirect evidence that changes in hormonal secretion and conversion that raise T3/T4 ratio can occur in thyroidal dysfunctions even in the complete absence of TBG.

Adult↗

Clinical usefulness and limitations of serum thyrotropin measurement by 'ultrasensitive' methods. Comparisons of five kits.

Five different ultrasensitive thyrotropin (TSH) assay kits (Boots-Celltech, Immunotech, ORIS-CIS, Travenol and Boehringer) have been used for TSH measurements in various conditions. All the kits were based on an immunometric method but differed with regard to components and procedure. The sensitivity appeared essentially the same for the five kits (0.10 microU/ml) as well as the intraassay precision (coefficient of variation less than 12%). In contrast, the interassay coefficients of variation in the low TSH range varied from 12.8 to 21.3%. Discrepancies from kit to kit were observed and accounted for by differences in the components and procedure of the kits. Basal serum TSH was determined in normal subjects (n = 261) and in patients with thyroid dysfunction (n = 392). No overlap was shown between normals and patients with overt hypothyroidism. In contrast, an overlap existed between normals and hyperthyroids for all the kits but one. Measurements in patients with nontoxic goiter showed that TSH may be undetectable in clinically euthyroid patients, whatever the kit used. After TRH stimulation, 95% of the 375 patients tested associated either an absence of response to TRH with undetectable basal TSH values, or a blunted response with low basal TSH levels or normal response with normal basal TSH concentrations. However, 9 patients with suppressed TSH showed a response to TRH and 7 patients with normal basal TSH levels presented an exaggerated response to TRH. Taken together, these results demonstrate that even though ultrasensitive measurements of TSH do not meet the expectation of completely discriminating euthyroid from hyperthyroid patients, ultrasensitive TSH assay kits represent a powerful tool in the diagnosis of thyroid dysfunction, which would eliminate, in most instances, the need for TRH test and diminish thyroid hormone assay requests.

Adolescent↗

Prospective study on thyroid autoimmunity and dysfunction related to chronic hepatitis C and interferon therapy.

This study was designed to assess patients with chronic hepatitis C (CHC) for the presence of thyroid autoimmunity and dysfunction, to evaluate the risk of thyroid disorders associated with interferon (IFN) therapy, and to survey the outcome of possible treatment-related thyroid injury. Out of 104 consecutive untreated patients (30 women and 74 men; mean age, 52.7 years), 8 (7.7%) were found seropositive for thyroid autoantibodies (ThyAb), whereas seropositivity in healthy controls was 1/98 (1.3%). The relative increase in risk of developing thyroid autoimmunity associated with CHC was 760% (95% CI, 220-1300%). No patients had abnormalities of thyroid function tests, but on IFN treatment, 3/3 patients showed a rapid over-range rise in circulating thyrotropin, which returned to normal after therapy discontinuation. In the other 5 seropositive patients who refused treatment, thyroid function remained normal. Out of the 58 initially seronegative patients who consented to IFN treatment, 9 (15.5%) developed thyroid autoimmunity. Seven of them (77.7%) had thyroid dysfunction: hypothyroidism in 4 cases, transient thyrotoxicosis in 2 cases. The last patient developed TSH-receptor antibodies and Graves' disease, requiring methimazole therapy. Thyroid function recovered in the former 6 cases following IFN discontinuation. In the 28 initially seronegative patients who refused IFN and participated in a preliminary tauroursodeoxycholic acid trial, antithyroglobulin antibodies alone appeared in one case, but no thyroid dysfunction was observed. The relative risk of thyroid autoimmune disorder associated with IFN therapy was 342% (28-636%). The patients with CHC were unlikely to develop thyroid dysfunction in the absence of IFN therapy, in spite of being ThyAb seropositive. Moreover, a considerable proportion of seronegative patients, when IFN-treated, developed thyroid autoimmunity and then thyroid dysfunction. Both in seropositive and seronegative patients immediate IFN discontinuation normalized thyroid function and hormone replacement therapy was not necessary.

Adult↗

Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study.

We investigated the natural course of subclinical thyroid dysfunctions in geriatric patients, especially regarding their association with mortality rate. Ninety-three randomly selected chronically ill geriatric patients 64- 87 (median: 77) yr of age participated in the screening study with a 2-yr follow-up. Serum thyrotropin (thyroid- stimulating hormone [TSH]), free thyroxine, triiodothyronine, and antibodies against thyroid peroxidase were measured. During the follow-up, patients with suppressed TSH levels who were otherwise euthyroid (untreated) had a higher mortality rate than patients with normal TSH (5/8 vs 18/64; p < 0.05). The initial clinical state of these two subgroups did not differ significantly. Two-thirds of patients with treated hyperthyroidism died. The mortality rate of patients with initially subnormal but not suppressed TSH level was average and did not differ statistically from either the euthyroid or the hyperthyroid groups. Only 1 of 13 euthyroid patients with positive thyroid antibody titers developed a subsequent subclinical hypothyroidism. Subclinical hyperthyroidism was found to be associated with a higher mortality rate in chronically ill geriatric patients, which justifies screening for thyroid dysfunction and treatment of subclinical hyperthyroidism. In addition, a subnormal but measurable TSH was not indicative regarding the future development of hyperthyroidism. Finally, during the 2-yr follow-up, antibody positivity in the euthyroid cases did not prove to be predictive for the subsequent development of hypothyroidism.

Aged↗

Frequency of thyroid disease among Southeast Asian primary care patients.

We prospectively assessed 99 Southeast Asians for the presence of thyroid disease who were attending a primary care clinic devoted to the care of refugees. Subjects were undergoing evaluation as new patients and had no previously diagnosed thyroid abnormality. Each patient had a physical examination performed by his or her primary-care provider, was given a standardized questionnaire that focused on symptoms of thyroid disease and underwent a venipuncture for total thyroxine, triiodothyronine resin uptake and thyrotropin (TSH) concentration. Those who had an abnormal examination, calculated free thyroxine index (FT4I) or TSH level were re-examined by an endocrinologist and had repeat thyroid studies performed. Although 81% of patients reported > or = 1 symptom compatible with thyroid dysfunction, only 17% were found to have laboratory abnormalities. An abnormal FT4I and TSH level was found in 5% and 13% of subjects, respectively, but only one case of clinically significant hyperthyroidism and no cases of hypothyroidism were confirmed. TSH suppression, noted in 12% of subjects, persisted over a median follow-up of 6 months. Among seven patients with an anatomic abnormality of the thyroid, four had an abnormal FT4I or TSH. We conclude that the clinical prevalence of symptomatic thyroid dysfunction among Southeast Asians is comparable to that reported for non-Asian populations, but that the frequency of subclinical hyperthyroidism may be higher. Although symptoms suggestive of thyroid disease are common, routine screening for thyroid disease is not indicated in this study.

Adult↗

Nongenomic Stimulatory Effect of T3 on Calcium Dynamics in GnRH Neurons via Integrin &#x3b1;V&#x3b2;3.

Many clinical studies have identified correlations between thyroid dysfunction and reproductive issues, yet the underlying mechanisms behind this interaction remain poorly understood. In this study, we investigated the effect of triiodothyronine (T3) on the activity of gonadotropin-releasing hormone (GnRH) neurons, a key regulator of the central reproductive axis. Dual labeling confirmed that GnRH neurons express thyroid receptor (TR)&#x3b1; and integrin &#x3b1;V&#x3b2;3 receptors mediating genomic and nongenomic effects of thyroid hormones, respectively. Using calcium imaging in an ex vivo model, we show that T3 induces a rapid and sustained increase of calcium oscillation frequency in GnRH neurons. No change in response was detected after application of T4. The T3 stimulatory effect was not inhibited by a TR-specific antagonist (1-850) but was mimicked by membrane-impermeable T3-BSA, indicating a mechanism independent of nuclear TR signaling. In contrast, the blockade of membrane &#x3b1;V&#x3b2;3 integrins (with cilengitide) prevented the T3-induced increase in GnRH neurons calcium peak oscillation frequency. Further investigation using modulators of intracellular calcium and calcium entry revealed that binding to &#x3b1;V&#x3b2;3 integrin can induce distinct calcium responses depending on the ligand, with T3 triggering a complex response involving multiple channels and calcium sources, possibly with compensatory mechanisms. In sum, these results demonstrate for the first time a direct effect of thyroid hormones on GnRH neuronal activity, with T3 stimulating calcium oscillations through the nongenomic &#x3b1;V&#x3b2;3 integrin pathway. Understanding this thyroid-reproductive axis interaction will help clarify the mechanisms linking thyroid dysfunction to reproductive disorders and pave the way for targeted therapeutic interventions.

Animals↗

Development of hyperthyroidism during long term interferon therapy in a patient with chronic myelogenous leukemia: case report.

In this case report a patient with thyroid dysfunction who received chronic treatment with interferon-alpha (INF-alpha) following a diagnosis of chronic myelogenous leukemia (CML) is described. Generally INF-alpha induced dysthyroidism develops in the earlier phase of INF-alpha treatment. This is a case report of thyroid dysfunction which occurred 4 years after the patient began to receive INF-alpha administration. In addition, INF-alpha was administered to this patient for a longer period than those reported in the literature.

Antineoplastic Agents↗

Increased theophylline clearance in a patient with hyperthyroidism.

The association between thyroid disease and asthma is complex. Treatment of asthma in patients with thyroid disease is further complicated by the effects of thyroid dysfunction on drug metabolism. We report a patient with asthma whose calculated theophylline clearance was 0.156 L/kg/h during active Graves' disease which decreased to 0.042 L/kg/h after a euthyroid state was achieved. The potential mechanisms of this interaction are discussed and the effects of thyroid dysfunction on asthma and drug metabolism are reviewed.

Asthma↗