L-thyroxine Replacement Therapy Research Articles

Effect of long-term l-thyroxine treatment on bone mineral density in young adults with congenital hypothyroidism

To evaluate whether long-term L-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or L-thyroxine dosages at the time of the study or during the pubertal period. The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged L-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.

The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism

The aim of our study was to assess the changes in serum lipid profiles after replacement therapy with L-T4 in patients with subclinical hypothyroidism (SCH), and to see whether there is an improvement in dyslipidemia based cardiovascular risk. Thirty non-smoker pre-menopausal women with newly diagnosed SCH (TSH between 4 and 10 microIU/ml) were involved in our study; twenty-six euthyroid healthy subjects were used as control group. TSH, free T3 (FT3), free T4 (FT4), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured before and after 6 months of L-T4 (50-100 microg/ day) therapy. TSH levels were targeted as < 2.0 microIU/ml. LDL-C was calculated using the Friedewald formula, while the cardiovascular risk was assessed with the TC/HDL-C ratio. Pre-treatment serum TC and LDL-C concentrations in SCH patients were significantly higher than those of euthyroid subjects (199.8 +/- 22.2 vs 181.5 +/- 24.6 mg/dl, p < 0.01; 146.3 +/- 26.1 vs 124.8 +/- 12 mg/dl, p < 0.001, respectively). TC, LDL-C levels and the TC/HDL-C ratio were reduced significantly after 6-month replacement therapy (-21.1 +/- 34.4 mg/dl or -10.5%, p < 0.01; -21.5 +/- 30.3 mg/dl or -14.7%, p < 0.001, respectively; and TC/HDL-C from 4.8 +/- 0.6 to 4.1 +/- 0.5 mg/dl, p < 0.01), while body mass index (BMI) values did not change. In conclusion, even mild elevations of TSH are associated with changes in lipid profile significant enough to raise the cardiovascular risk ratio, and these changes are corrected once the patients have been rendered euthyroid.

Misleading high thyrotropin results obtained with a two-site immunometric assay involving a chimeric antibody.

Serum thyrotropin (TSH) measurements are widely used in the diagnosis of thyroid dysfunction and to monitor l-thyroxine (T4) replacement therapy in primary hypothyroidism. The accepted TSH reference interval in serum is 0.4–4.0 mIU/L, and a TSH concentration between 0.5 and 2.0 mIU/L is generally considered as the optimum therapeutic target during replacement therapy (1). Because of technical problems such as interference from heterophilic antibodies reacting with assay anti-mouse antibodies, immunometric assays may give falsely increased TSH values (1). Chimeric antibodies have been introduced in some assays with a view to eliminate interference from anti-mouse antibodies (2). We report here for the first time two cases of misleading high TSH results obtained with an immunometric assay involving a chimeric anti-TSH antibody. The first case (patient 1), a 56-year-old woman on long-term l-T4 replacement therapy, was referred to the laboratory for biological thyroid follow-up. Her serum TSH concentration had been slightly above the reference interval for 2 years. The TSH value (5.4 mIU/L) measured with the Elecsys immunometric assay performed on the Elecsys 2010 analyzer (Roche Diagnostics) confirmed this finding. This slightly increased TSH value was in agreement with the previous TSH results but disagreed with the free thyroxine (FT4) concentration (20.5 pmol/L) measured on the Elecsys platform, which was within the reference interval (12.2–23.2 pmol/L). As expected, in the serum from this adequately treated patient who was clinically euthyroid, FT4 was in the upper third of the reference interval (1), but surprisingly, TSH remained slightly increased. This unexpected TSH value prompted further TSH measurements with two other methods. The results were 0.51 mIU/L with the ADVIA Centaur TSH-3 assay (Bayer Diagnostics) and 0.27 mIU/L with the Architect TSH assay (Abbott Diagnostics Division). In the one-step Elecsys assay, the first antibody, a mouse biotinylated monoclonal anti-TSH …

Effect of l-Thyroxine Replacement Therapy on Surrogate Markers of Skeletal and Cardiac Function in Subclinical Hypothyroidism

Effect of l-Thyroxine Replacement Therapy on Surrogate Markers of Skeletal and Cardiac Function in Subclinical Hypothyroidism

Sodium handling in congenitally hypothyroid neonates

Early observations emphasized the possible development of hyponatraemia in hypothyroid children and adults, but recently this has been questioned. Aim: To investigate whether hyponatraemia develops in hypothyroid status by examining sodium handling in screening‐detected neonates and infants with congenital hypothyroidism (CH). Methods: Serum thyroid‐stimulating hormone (TSH), free thyroxine (FT4), sodium (Na), creatinine (Cr), urinary Na, Cr, fractional sodium excretion rate (FENa) and other chemicals were measured before and after L‐thyroxine (LT4) replacement therapy in 32 screening‐detected CH neonates (11M, 21F) and 16 age‐matched control neonates. Results: No cases of hyponatraemia were found in the 32 CH neonates. Their serum Na concentrations (139.1 ± 1.5mmol/L, ranging from 136 to 142mmol/L, median 139mmol/L) were not statistically different from those of 16 control neonates (139.3 ± 1.3 mmol/L, ranging from 137 to 142 mmol/L, median 139 mmol/L,). No correlation was found between serum levels of TSH and FT4 and serum Na or FENa. No significant changes were found in serum Na concentrations in hypothyroid neonates two months after LT4 replacement therapy. The serum Na concentration (139.1 ±0.3 mmol/L, n= 25) before treatment did not change statistically (138.9 ± 0.2 mmol/L, n= 25) two months after LT4 replacement therapy. Conclusion: As seen in various earlier reports, hyponatraemia can occur in hypothyroid patients, but no causal relationship exists between them. When hyponatraemia is detected in hypothyroid children, it does not seem to be directly related to lack of thyroid hormones and therefore other possible causes should be sought.

Sodium handling in congenitally hypothyroid neonates.

Early observations emphasized the possible development of hyponatraemia in hypothyroid children and adults, but recently this has been questioned. To investigate whether hyponatraemia develops in hypothyroid status by examining sodium handling in screening-detected neonates and infants with congenital hypothyroidism (CH). Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), sodium (Na), creatinine (Cr), urinary Na, Cr, fractional sodium excretion rate (FENa) and other chemicals were measured before and after L-thyroxine (LT4) replacement therapy in 32 screening-detected CH neonates (11M, 21F) and 16 age-matched control neonates. No cases of hyponatraemia were found in the 32 CH neonates. Their serum Na concentrations (139.1 +/- 1.5 mmol/L, ranging from 136 to 142 mmol/L, median 139 mmol/L) were not statistically different from those of 16 control neonates (139.3 +/- 1.3 mmol/L, ranging from 137 to 142 mmol/L, median 139 mmol/L). No correlation was found between serum levels of TSH and FT4 and serum Na or FENa. No significant changes were found in serum Na concentrations in hypothyroid neonates two months after LT4 replacement therapy. The serum Na concentration (139.1 +/- 0.3 mmol/L, n = 25) before treatment did not change statistically (138.9 +/- 0.2 mmol/L, n = 25) two months after LT4 replacement therapy. As seen in various earlier reports, hyponatraemia can occur in hypothyroid patients, but no causal relationship exists between them. When hyponatraemia is detected in hypothyroid children, it does not seem to be directly related to lack of thyroid hormones and therefore other possible causes should be sought.

Thyroid function and postmenopause

There is an increasing prevalence of high levels of thyroid stimulating hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men. The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease ,about 2.4%; subclinical thyroid disease ,about 23.2%. Among the group with subclinical thyroid disease ,73.8% are hypothyroid and 26.2% are hyperthyroid. The rate of thyroid cancer increases with age. The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate. There can also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression ,memory loss ,cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk ,caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy. Such treatment has been found to be cost-effective. With time ,overt hypothyroidism can develop. Therefore ,routine screening of thyroid function in the climacteric period to determine subclinical thyroid disease is recommended. Hormone replacement therapy (HRT) in women with hypothyroidism treated with thyroxine causes changes in free thyroxine and TSH. Increased binding of thyroxine to elevated thyroxine-binding globulin causes an elevation of TSH by feedback. Since adaptation is insufficient ,there is an increased need for thyroxine in these women taking HRT. TSH levels should be controlled at 12 weeks after the beginning of therapy. At higher age the need for iodine and thyroxine is decreased. Therefore ,therapy has to be controlled. For bone metabolism thyroid hormones play a dominant role. While there are only marginal differences between hypothyroid patients and euthyroid controls ,there are large differences for hyperthyroid patients. Previous thyrotoxicosis and subsequent long-lasting L-thyroxine treatment are together associated with reduction in femoral and vertebral bone density in postmenopausal women. In these cases HRT is important for the control of bone loss.

Thyroid function and postmenopause

There is an increasing prevalence of high levels of thyroid stimulating hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men. The incidence of thyroid disease ina population of postmenopausal women is as follows: clinical thyroid disease ,about 2.4%; subclinical thyroid disease ,about 23.2%. Among the group with subclinical thyroid disease ,73.8% are hypothyroidand 26.2% are hyperthyroid. The rate of thyroid cancer increases with age. The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate. Therecan also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression ,memory loss ,cognitive impairment and a varietyof neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk ,caused by increased serum total cholesterol and low-density lipoproteincholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy. Such treatment has been found to be cost-effective.With time ,overt hypothyroidism can develop. Therefore ,routine screening of thyroid function in the climacteric period to determine subclinical thyroid disease is recommended. Hormone replacement therapy(HRT) in women with hypothyroidism treated with thyroxine causes changes in free thyroxine and TSH. Increased binding of thyroxine to elevated thyroxine-binding globulin causes an elevation of TSH by feedback.Since adaptation is insufficient ,there is an increased need for thyroxine in these women taking HRT. TSH levels should be controlled at 12 weeks after the beginning of therapy. At higher age the need foriodine and thyroxine is decreased. Therefore ,therapy has to be controlled. For bone metabolism thyroid hormones play a dominant role. While there are only marginal differences between hypothyroid patientsand euthyroid controls ,there are large differences for hyperthyroid patients. Previous thyrotoxicosis and subsequent long-lasting L-thyroxine treatment are together associated with reduction in femoraland vertebral bone density in postmenopausal women. In these cases HRT is important for the control of bone loss.

Scintigraphic evaluation of primary congenital hypothyroidism: results of the Greek screening program.

The Greek screening program for primary congenital hypothyroidism was initiated in 1979. By early 2000, thyrotropin measurements had been performed in 1,976,719 newborns, using dried blood spots obtained by heel prick. Among these children, 584 were diagnosed with congenital hypothyroidism (incidence: 1/3,384 births) and were given L-thyroxine (L-T4) replacement therapy. In order to further evaluate and classify the children as having either an aplastic (AT) or an ectopic thyroid gland (ET) or as showing thyroidal dyshormonogenesis (DN, with a nomotopic gland), scintigraphic studies were performed at the age of 2-3 years. In 413 children of this age group (including 24 subsequently diagnosed as having had transient hypothyroidism, in whom L-T4 therapy was not resumed), thyroid hormones were measured and scintigraphic studies were done after withdrawal of L-T4 replacement treatment for 3 weeks. Given the long duration of the study, we used various scintigraphic modalities. In 96 children (group A), scintigraphy was performed using technetium-99m pertechnetate (99mTcO4-; 18.5 MBq given i.v.) and a rectilinear scanner. Seventy-three children (group B) were studied with 99mTcO4- (18.5 MBq given i.v.) and a gamma camera equipped with a pinhole collimator. In these groups, atropine was administered 30 min prior to the study (0.02 mg/kg i.v. or i.m.) in order to reduce the secretion of saliva from the salivary glands. Finally, in the remaining 220 children (group C) iodine-123 sodium iodide (123I-Na) (0.74-1.85 MBq i.v.) and the same gamma camera were used. Between-group comparisons of scintigraphic findings were done with the chi square test. In 191 children from group C, thyroglobulin (Tg) was measured and in 49 children ultrasound (US) was performed (categorising the gland as AT or ET/DN). Comparison of these modalities was done with the kappa statistic. In group A, 61.5% of children had AT, 26.0% had ET and 12.5% had DN; in group B, 28.8% of children had AT, 52.0% had ET and 19.2% had DN; in group C, 23.2% of children had AT, 63.2% had ET and 13.6% had DN. Statistically significant differences in group A versus groups B and C were noted for AT and ET. The implementation of newer scintigraphic modalities, and especially the use of 123I-Na, indicates that the commonest finding in congenital hypothyroidism is ET. Scintigraphy was more concordant with Tg measurements (though at a moderate level) than with US. The latter was even less concordant with Tg values. These results show that the most appropriate approach for the evaluation and classification of congenital hypothyroidism is 123I-Na scanning.

Plasma cholesteryl ester transfer protein activity is high in infants and is not affected by thyroid hormones

We investigated the effects of thyroid dysfunction on cholesteryl ester transfer protein (CETP) by studying plasma CETP activity in hypothyroid infants before and after they were rendered euthyroid by L-thyroxine (LT4) replacement therapy. To exclude environmental factors possibly affecting plasma CETP activity, we selected hypothyroid infants to study plasma CETP activity. Plasma CETP activity was measured as the rate of radiolabeled cholesteryl ester transfer from high-density lipoprotein (HDL) to serum apolipoprotein B (apo B)—containing lipoproteins in plasma from 14 hypothyroid infants before and 2 months after LT4 replacement, 23 normal infants, and 61 normal adults. Relationships between CETP and thyroid hormones were examined separately in the 14 hypothyroid infants and 32 euthyroid infants, including the 14 above-described hypothyroid infants and an additional 18 treated hypothyroid infants. Serum levels of thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were also determined on an autoanalyzer system in our hospital. In contrast to previous reports, we found no differences in plasma CETP activity between hypothyroid infants and age-matched normal infants. LT4 substitution did not cause any changes in plasma CETP activity after therapy. Plasma CETP activity showed no correlation with serum TSH, FT4, and FT3 levels. Both hypothyroid and normal infants were found to have significantly higher plasma CETP activity than normal adults. From these results, we conclude that in infants thyroid hormones do not affect plasma CETP activity, and normal infants have high plasma CETP activity, compared with normal adults.

Treatment with retinoid X receptorgamma-selective ligand (bexarotene) may cause iatrogenic central hypothyroidism.

Thyrotropin (TSH) and, consequently, thyroid hormone secretion (thyroxine (T4) and tri-iodothyronine (T3)) is regulated by a negative feed-back mechanism which is exerted by T3 binding to its own receptor, located in the nucleus of the thyrotrope cells of the anterior pituitary gland. Thyroid hormone receptors (TRs) are known to mediate T3 suppression of TSH b-subunit gene (TSHb) expression, acting at specific thyroid-hormone response elements (TREs) near the transcription start site in the promoter region, and involving interaction with nuclear cofactors, such as the retinoid X receptors (RXRs), coactivators and corepressors (1). RXRs belong to the family of ligand-dependent transcription factors, encompassing 3 distinct isoforms – RXR-alpha, -beta, and -gamma – which are closely related to each other in their DNAand ligand-binding domains. RXRs function as both 9-cis-retinoic acid (9-cis-RA) ligand-dependent receptors and heterodimeric partners for the vitamin D receptor, retinoic acid receptor (RAR), and TRs (2). Mangelsdorf et al. (3) have demonstrated that RXRa and RXRb mRNAs are widely expressed in developing embryo and adult murine tissues, while RXRg mRNA is more restricted in its distribution, being abundant in the thyrotropes within the pituitary gland. RXRs are recognized as the major TR-associated proteins in many positively regulated target genes (4–6). However, their role on negatively regulated promoters remains to be clarified. Recently, it has been reported that RXRg represents the receptor isoform involved in negative regulation of TSHb gene promoter (7). In vitro studies using thyrotrope-derived tumor cells (TtT-97) demonstrated that the binding of T3 and 9-cis-RA to TRs and RXRgs respectively, is able to suppress the promoter activity of the TSHb gene acting at distinct response elements. Moreover, they seem to function cooperatively as demonstrated by the fact that the combination of the two ligands suppresses TSHb gene expression more efficiently than either alone (7). These data suggest that in mice retinoids binding to RXRg can mediate the reduction of TSH secretion independently of T3. According to these in vitro results, several papers reported that the administration in vivo to euthyroid or hypothyroid rats of pharmacological amounts of retinoic acid, an active metabolite of vitamin A, reduces both basal and thyrotropin-releasing hormone (TRH)stimulated TSH secretion, independently of the thyroid status of the animals. This effect seems to be mediated by the binding of the retinoid acid to RXRg and does not result in the appearance of clinical hypothyroidism (7–9). In the last few years, several RXR-selective retinoids have been designed and synthesized for the treatment of human cancers (10). Their efficacy and safety have been investigated by experimental studies in animals with different types of tumors and by in vitro investigations. These studies demonstrated that RXR-selective retinoids possess a relevant antiproliferative effect on tumor cells and may induce apoptosis (11–14). Very recently, Sherman and coworkers (15) assessed thyroid function in a cohort of patients with cutaneous T-cell lymphoma who were receiving high doses of a specific RXRg-selective ligand, bexarotene (Targretin). About 70% of the patients (19/27) treated with bexarotene (daily dose >300 mg/m of body surface area) had symptoms and signs of hypothyroidism, particularly fatigue and cold intolerance. The biochemical picture was characterized by the reduction of the mean serum TSH from 2.2 mU/l at base line to 0.05 mU/l during treatment with bexarotene. Similarly, the mean serum free thyroxine concentration declined from 12.9 pmol/l to 5.8 pmol/l during bexarotene administration. The degree of suppression of TSH secretion tended to be greater in patients treated with higher doses of bexarotene. In all the patients symptoms improved after the initiation of L-thyroxine (L-T4) replacement therapy and euthyroidism was achieved when bexarotene was discontinued, strongly suggesting that the clinical and biochemical hypothyroidism was due to a direct central effect of bexarotene. To correlate these observations with a potential molecular mechanism, TtT-97 thyrotrope tumor cells were transiently transfected with a murine TSHb-promoter-luciferase reporter plasmid and incubated with T3, 9-cis-RA and different concentrations (1 mmol/l and 5 mmol/l) of bexarotene. The authors found that the activity of the TSHb-subunit gene promoter was suppressed by as much as 50% by all three agents. Thus, they concluded that bexarotene can suppress TSH secretion, resulting in central hypothyroidism. These relevant findings are in contrast to those observed in the animals (7–9) and in a clinical trial by European Journal of Endocrinology (2000) 142 324–325 ISSN 0804-4643

Changes in serum apolipoprotein concentrations after L-thyroxine therapy in infants with congenital hypothyroidism.

To further characterize the impact of thyroid hormones on the serum lipid profile, we studied serum apolipoproteins in infants with congenital hypothyroidism before and after L-thyroxine (L-T4) replacement therapy. Serum high-density lipoprotein cholesterol (HDLC) decreased after L-T4 therapy. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels did not change significantly after therapy. Two months after L-T4 replacement therapy, serum apolipoprotein A-I (apo A-I), C-III, and E declined and apo B increased significantly. No significant changes were observed for serum concentrations of apo A-II and C-II after L-T4 substitution. We conclude that in infants, thyroid hormone reduces serum levels of apo A-I, the principal protein component of HDLC, and this may contribute to the decline of serum HDLC concentrations after L-T4 replacement therapy.

Infection par le virus de l'hépatite C et pathologies thyroïdiennes

The combination of hepatitis C virus (HCV) infection and thyroid diseases raises several issues that are the prevalence of thyroid autoimmunity in patients with chronic hepatitis C, the prevalence of HCV infection in patients with autoimmune thyroid diseases, and the effects of interferon alpha treatment on thyroid function in chronic HCV hepatitis. The prevalence of anti-thyroid auto-antibodies ranges from 4.6 to 15% in HCV infection, which is considered as significant by various authors. Results have to be interpreted according to the following: the type of auto-antibodies detected, the age, sex, ethnic origin of the population studied, and characteristics of the control population. Recent data are suggestive of a high prevalence of anti-thyroid auto-antibodies in females with HCV infection. An increased prevalence of HCV infection in patients with Hashimoto's thyroiditis is not confirmed. During treatment of chronic hepatitis C, interferon alpha induces thyroid dysfunctions (3 to 15% of the cases) with various clinical presentations. Hypothyroidism is more common (two out of three cases) than hyperthyroidism (one out of three cases). Hyperthyroidism followed by hypothyroidism has also been described. Clinical symptoms vary, ranging from subclinical to severe manifestations. Thyroid dysfunction may be delayed after discontinuation of the interferon treatment. Hypothyroidism is easily cured by L-thyroxine replacement therapy when necessary, and regression may be observed following discontinuation of interferon treatment. Each case of hyperthyroidism has to be precisely evaluated. Development of anti-thyroid antibodies or an increase in anti-thyroid antibodies titers is often observed during interferon alpha treatment, thus suggesting the existence of immunological mechanisms at the origin of thyroid dysfunction. Furthermore, interferon would directly act on iodine. Clinical studies are still necessary to better clarify the links between HCV infection and thyroid autoimmunity, and to determine risk factors for the development of thyroid dysfunction during interferon alpha therapy. The effects of HCV and interferon alpha on thyroid autoimmunity and function have to be investigated in basic research.

Prevalence of autoantibodies to thyroglobulin in dogs with nonthyroidal illness

Abstract Objective To evaluate a thyroglobulin autoantibody (TgAA) assay and determine a diagnostic threshold. Sample Population Serum samples from dogs with various endocrine abnormalities and from 30 obese adult female Beagles. Procedure TgAA were determined by use of the ELISA. Six experiments were done: 1, definition of positive results for TgAA using samples from normal and T3 autoantibody (T3AA) positive dogs; 2, establishment of prevalence of positive results in 91 clinically normal dogs; 3, evaluation of positive results for sera from dogs with nonthyroidal illnesses; 4, testing of samples from dogs with primary hypothyroidism but absence of T4AA or T3AA, or both; 5, determination of prevalence of false-negative results in dogs that are T4AA and/or T3AA positive, which were (18 dogs) or were not (22 dogs) receiving L-thyroxine replacement therapy; and 6, examination of thyroid biopsy specimens from 18 dogs (8 TgAA positive and 10 TgAA negative). Results Positive results were defined as at least twice (200%) the optical density of the negative-control sample. False-positive results were obtained for only 3.4% of 146 dogs with nonthyroidal illness. Thirty-seven percent of dogs with primary hypothyroidism, but no evidence of T4AA or T3AA, or both, were TgAA positive. False-negative results were found in 1 of 22 and 2 of 18 T3AA-positive dogs with and without thyroid replacement therapy, respectively. Thyroid biopsy specimens from 8 TgAA-positive dogs had evidence of lymphocytic thyroiditis, whereas those from 10 TgAA-negative dogs did not. Conclusion and Clinical Relevance The assay is sensitive and specific for identification of lymphocytic autoimmune thyroiditis in dogs, and has potential for aiding early diagnosis of thyroiditis in dogs and identifying dogs likely to perpetuate hypothyroidism in breeding programs. (Am J Vet Res 1998;59:951–955)

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.

Reversible increase of intraocular pressure in subclinical hypothyroid patients

The aim of the study was to analyse the relationship between the ocular parameters, namely intraocular pressure (IOP), and the early forms of subclinical hypothyroidism. Fifty-three subjects (9 male and 44 female) aged from 18 to 45 years (mean 32 +/- 7 years) were selected for this study. Twenty-nine met the criteria of subclinical hypothyroidism and 24 euthyroid subjects, age- and sex-matched, were used as controls. All individuals underwent a complete ocular examination, including visual field examination and serial measurement of IOP by means of a Goldmann tonometer. A tonographic examination was also performed. The hypothyroid patients showed a substantially higher pressure in both eyes compared with control subjects (right eye = 17.52 +/- 4.74 vs 13.42 +/- 1.95 mmHg, P < 0.0001; left eye = 17.55 +/- 3.99 vs 13.71 +/- 1.55 mmHg, P < 0.0001). Indeed, the tonometric pressure exceeded 18 mmHg in 11 out of the 29 (38%) patients in the right eye and in 8 out of 29 (27%) patients in the left eye. The outflow index was normal in all subjects except in two hypothyroid patients. After two months of L-thyroxine (L-T4) replacement therapy, only one patient continued to show tonometric values above 18 mmHg and the hypothyroid patients showed a significant reduction in mean IOP in both eyes compared with pre-treatment values (right eye = 14.96 +/- 1.32 mmHg, P < 0.0097; left eye = 15.03 +/- 1.38 mmHg, P < 0.0018). Treatment did not lead to any change in the outflow indices; however, the C value (outflow coefficient at the sclerocorneal corner) returned to normal in the two patients with increased pre-treatment tonographic values. These findings indicate that the intraocular pressure is increased even in subclinical hypothyroid patients and that, at this early stage, the impairment is fully reversible with L-T4 therapy.

Bone mineral metabolism and thyroid replacement therapy in congenital hypothyroid infants and young children

Impairment of calcium metabolism and low bone density have been found in hypothyroid adults. We investigated the effect of thyroid replacement therapy on calcium metabolism and bone mineralization in congenital hypothyroid (CH) infants and children. One hundred and 16 Caucasian CH consecutive patients were studied and were grouped according to their age: 23 patients at diagnosis, 20 at 3 mo, 24 at 6 mo, 25 at 12 mo and 24 at 36 mo. Thyroid replacement therapy was started at an initial dose of 6-8 micrograms/kg/day of L-thyroxine, and then decreased progressively. Calcium, phosphorus, magnesium, alkaline phosphatase (AP), parathyroid hormone (PTH) and osteocalcin (BGP) were measured as calcium metabolism indices. Bone mineral content (BMC) was measured at the mid-portion of the right radius AP, PTH and BGP concentrations were significantly higher in subjects at 3 mo of age (p < 0.05). This rise coincided with the end of the period of maximum dosage of L-thyroxine. Mild asymptomatic hypercalcemia was observed in 20 patients. All the other indices did not differ between age groups. BMC values and BMC annual increment were not different from those calculated for age-matched controls. We found that L-thyroxine replacement therapy does not alter bone mineralization of CH infants and children. Only a transitory increase of osteoblastic function was observed after the first few months of therapy.

TSH as an index of L-thyroxine replacement and suppression therapy.

When hypothalamic-pituitary function is normal, serum TSH levels measured by ultrasensitive assay yield bioassays of endogenous thyroid action and thus provide an ideal index of thyroid secretion and its relationship to fluctuating endogenous thyroid levels. It is theoretically possible that patients receiving exogenous L-thyroxine for primary hypothyroidism should have suppressed TSH levels if physiological needs are constantly met. To examine this possibility free thyroxine, FT4 and TSH were measured in 90 clinically euthyroid patients receiving treatment with L-thyroxine for primary hypothyroidism. TSH levels were normal in 44, suppressed in 16 and elevated in 30 patients. FT4 levels were normal in 68, elevated in 13 and suppressed in 9 patients. Normal TSH levels were associated with normal FT4 levels in 79.5% of patients, elevated FT4 levels in 13.6% and low FT4 in 6.8%. Suppressed TSH levels were associated with elevated FT4 levels in 37.5% of patients and normal FT4 levels in 62.5%. When FT4 levels were normal, however, TSH levels were normal in only 51.5% and abnormal in 48.5%. We also examined the possibility that FT4 levels may remain within normal range when TSH is suppressed during L-thyroxine treatment for goitre or cancer. FT4 and TSH were measured in 45 patients on L-thyroxine as TSH suppression treatment. TSH was suppressed in 23 patients (51.1%), normal in 20 (44.4%) and elevated in 2 (4.5%). When TSH was suppressed, FT4 was elevated in 30.4% but normal in 69.6% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of L-thyroxine replacement therapy in children with congenital hypothyroidism

The outcome of L-thyroxine (L-T4) replacement therapy in children with congenital hypothyroidism (CH) remains to be completely evaluated. In this paper the overall pattern of response to L-T4 replacement therapy was studied in a group of 19 children with CH diagnosed by neonatal screening (10 with hypoplastic/aplastic thyroid disease, group H/A; 9 with gland ectopy, group E) who were followed-up for 60 +/- 27 months (mean +/- SD). With 1 exception serum T4 at diagnosis was greater than 2 micrograms/dl in children of group E and less than 2 micrograms/dl in those of group H/A. The initial dose of L-T4 (8-10 micrograms/kg BW/day) was modified in relation to age and weight in order to maintain serum TSH less than or equal to 5 microU/ml and FT3 in the normal range. A general inverse correlation between serum TSH and FT4 or FT3 concentrations was found, and the mean levels of serum FT4 and FT3 were significantly higher according to the following order of TSH results: low TSH (0-0.5 microU/ml) greater than normal (greater than 0.5-5 microU/ml) greater than elevated TSH (greater than 5 microU/ml). TSH levels less than or equal to 5 microU/ml were associated with FT4 values in the upper half of the normal range (54% of observations) or even higher (46%). Elevation of serum FT4 alone with FT3 values in the normal range did not result in clinical thyrotoxicosis, alteration of growth or premature craniosynostosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal integrity in premenopausal and postmenopausal women receiving long-term L-thyroxine therapy

purpose: The impact of long-term L-thyroxine replacement therapy on skeletal integrity is a growing concern because of the large number of women receiving thyroid hormone therapy. The purpose of this study was to examine the hypothesis that long-term L-thyroxine therapy in which the free thyroxine index (FT 4I) is maintained within a physiologic range has minimal impact on vertebral or femoral bone mineral density in both premenopausal and postmenopausel women. patients and methods: We measured hip integral and spinal trabecular and integral bone densities in 28 premenopausal and 28 postmenopausal women who had been receiving L-thyroxine therapy for a median of 12 and 15 years, respectively, and in whom therapy was titrated to keep the FT 4I within the normal range. The relationship between bone density parameters and thyroid hormone status was examined using univariate and multivariate statistical methods. results: Seventy-nine percent of the premenopausal women and 86% of the postmenopausal women had FT 4I values in the normal range at the time of bone density determination. Moreover, throughout the study's duration, the majority of annually measured values were in the normal range for more than 80% of subjects. Premenopausal women had slightly lower bone density than would be expected for age: −6.7% (z = −0.39 ± 0.74 [mean ±SD], p <0.01), −3.1% (z = −0.22 ± 0.78, p = 0.15), and −5.1% (z = −0.36± 0.74, p <0.02) for spinal trabecular, spinal integral, and hip integral bone density, respectively. Postmenopausal women likewise had slightly lower bone density values that were significant only at the hip: −0.2% (z = −0.01 ± 1.01, p = 0.95), −1.0% (z = −0.05 ±1.11, p = 0.80), and −6.2% (z = −0.39 ± 0.80, p <0.02) for spinal trabecular, spinal integral, and hip integral bone density, respectively. When patients with previously treated Graves' disease (n = 4 in each group) were eliminated, the differences in bone density at the hip were no longer seen. Correlation analysis revealed only weak and generally nonsignificant relationships between parameters of thyroid hormone status and bone density at any site in either subgroup. Results of multiple regression analysis among the pooled data of all subjects showed that age provided a consistently significant contribution (R 2 = 0.18 to 0.66) to the variability in bone density at the spine and the hip, but parameters of thyroid hormone status did not. conclusion: These data provide the first supportive evidence that long-term L-thyroxine therapy that maintains the FT 4I in the physiologic range is associated with a statistically significant, but clinically minimal, decrement in spinal and hip bone density in both premenopausal and postmenopausal women. The decrement at the hip was entirely due to the inclusion of patients with treated Graves' disease. Thus, the changes in bone density in women receiving long-term L-thyroxine therapy are minimal at most and should not be a contraindication to therapy.