Primary Thyroid Failure Research Articles

Treatment of hypothyroidism in the Middle East

Hypothyroidism, a deficiency of thyroid hormone usually caused by primary thyroid failure, is a common clinical problem. Levothyroxine therapy (LT4) is demonstrated to improve signs, symptoms, and biochemical abnormalities and improve life.[[1]] However, a recent online survey published by the American Thyroid Association (ATA) illustrates that 10%–15% of hypothyroid patients are not satisfied with their therapy, and the challenge facing practicing physicians is to investigate alternative methods of replacing thyroid hormone deficiency.[[2]]

Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients.

Hypothyroidism is characterized by hypometabolism, and may be seen as a part of secondary failure due to pituitary insufficiency or tertiary due to hypothalamic disease. Secondary and tertiary failures are also referred to as central hypothyroidism. Whereas overt primary hypothyroidism has a well-known affection on the heart and cardiovascular system, and may result in cardiac failure, cardiovascular affection is less well recognized in central hypothyroidism. Studies on central hypothyroidism and cardiovascular outcome are few and given the rarity of the diseases often small. Further, there are several limitations given vast difficulties in diagnosing the condition correctly biochemically, and difficulties monitoring the treatment because normal thyroid-pituitary feedback interrelationships are disrupted. The present review summarizes available studies of central adult hypothyroidism and its possible influence on the cardiovascular system, describe differences from primary thyroid failure and seek evidence for performing guidelines for clinical management of this particular thyroid and hypothalamo-pituitary disorder.

Thyroid dysfunction associated with follicular cell steatosis in obese male mice and humans.

Adult thyroid dysfunction is a common endocrine disorder associated with an increased risk of cardiovascular disease and mortality. A recent epidemiologic study revealed a link between obesity and increased prevalence of hypothyroidism. It is conceivable that excessive adiposity in obesity might lead to expansion of the interfollicular adipose (IFA) depot or steatosis in thyroid follicular cells (thyroid steatosis, TS). In this study, we investigated the morphological and functional changes in thyroid glands of obese humans and animal models, diet-induced obese (DIO), ob/ob, and db/db mice. Expanded IFA depot and TS were observed in obese patients. Furthermore, DIO mice showed increased expression of lipogenesis-regulation genes, such as sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor γ (PPARγ), acetyl coenzyme A carboxylase (ACC), and fatty acid synthetase (FASN) in the thyroid gland. Steatosis and ultrastructural changes, including distension of the endoplasmic reticulum (ER) and mitochondrial distortion in thyroid follicular cells, were uniformly observed in DIO mice and genetically obese mouse models, ob/ob and db/db mice. Obese mice displayed a variable degree of primary thyroid hypofunction, which was not corrected by PPARγ agonist administration. We propose that systemically increased adiposity is associated with characteristic IFA depots and TS and may cause or influence the development of primary thyroid failure.

Risk of Coronary Heart Disease and Mortality for Adults With Subclinical Hypothyroidism

To the Editor: In their study, Dr Rodondi and colleagues 1 addressed the issue of the relationship between subclinical hypothyroidism and coronary heart disease (CHD) or mortality. Previous large prospective cohort studies have provided conflicting results about this extensively studied association. In the study by Rodondi et al, an attempt to reduce the effects of several confounders (including age, sex, degree of thyroid stimulating hormone [TSH] elevation, and pre-existing cardiovascular disease) was performed. 1 However, the finding of no association of risk with subclinical hypothyroidism for TSH concentration up to 10.0 mIU/L may be flawed because it did not provide information about the body mass index (BMI) of the patients diagnosed with subclinical hypothyroidism. This might be a problem because subclinical hypothyroidism, especially when characterized by minor increases in serum TSH levels, is frequently observed among obese patients. 2-4 TheelevatedserumTSHfoundinobese(andparticularly in morbidly obese) patients may be a mere consequence of the excess body weight rather than a condition of primary thyroid failure. 2-4 This concept would imply that obesepatientswithamoderateelevationinserumTSHwould not experience increased systemic vascular resistance, altered endothelial function, increased atherosclerosis, altered coagulability, and lipid abnormalities, which account for the increased risk of CHD associated with subclinical hypothyroidism. 5

Hypothyroidism

<h2>Abstract</h2> Hypothyroidism is common, affecting 1–2% of women. The onset is often insidious and symptoms and signs are vague. It is essential to confirm the diagnosis biochemically before initiating treatment. Measurement of serum thyroid-stimulating hormone (TSH) is a highly sensitive and specific test for primary thyroid failure. Elevation of TSH with normal serum T4 is termed ‘subclinical' hypothyroidism. If free T4 is low, with raised serum TSH, the biochemical diagnosis is overt hypothyroidism. In the UK, hypothyroidism is usually autoimmune (characterized by positive antithyroid antibodies) or iatrogenic (secondary to treatment for hyperthyroidism). Worldwide, iodine deficiency remains a major cause. Overt hypothyroidism is treated with T4 replacement; the aim is to restore serum TSH and free T4 to the normal range and hence abolish relevant symptoms and signs. The starting T4 dose is 100 <i>µ</i>g/day, though lower doses should be used in those with a history of ischaemic heart disease. Serum TSH should be checked no sooner than 6–8 weeks after initiating T4, to prompt dose adjustment. The T4 dose required to restore biochemical euthryoidism is usually 100–125 <i>µ</i>g per day. Over-treatment with T4 (indicated by suppression of serum TSH) should be avoided, because of potential long-term risks. After euthyroidism has been restored, TSH should be checked annually to ensure ongoing compliance. There is little evidence that mild, subclinical hypothyroidism is associated with symptoms or adverse events, so if TSH is less than 10 mU/litre conservative management is reasonable, with annual monitoring of TSH to identify biochemical progression.

Water metabolism disturbances at different stages of primary thyroid failure.

The aim of the present study was to study salt and water metabolism in thyroid deficiency. We performed an oral water loading test (OWL) and a hypertonic 5% saline infusion test (HSI) in 16 patients with overt primary hypothyroidism before replacement treatment (PRE group) and after, in eight patients with subclinical hypothyroidism (SUB group) and in 16 normal individuals (CG group). In the PRE group, a lower free water clearance was detected in the OWL (P < 0.022), with lower plasma osmolality (OWL: P < 0.005; HSI: P < 0.001) and arginine vasopressin (AVP) (OWL: P < 0.001; HSI: P < 0.001) than the CG group, across both tests; they normalized with the replacement treatment. The same plasma abnormalities were detected in the SUB group with the HSI. Although the AVP and thirst thresholds did not differ between the groups, the lag between them was lower in the PRE (4.1+/-3.2 mOsm/kg) and SUB group (2.6+/-2.1 mOsm/kg) than in the CG group (13.3+/-9.2 mOsm/kg) (P < 0.05). There were no differences in atrial natriuretic hormone (ANH), plasma renin activity (PRA) and plasma aldosterone among the groups. These results indicate that plasma hypo-osmolality and low levels of AVP are present in primary hypothyroidism, and indeed are already present in the subclinical phase of the disease. An overlap between the thresholds of thirst and AVP seem to play a role in these abnormalities, but ANH, PRA and plasma aldosterone do not appear to contribute.

Primary thyroid failure and diarrhoea.

Primary thyroid failure and diarrhoea.

Maternal Diabetes Mellitus, a Rat Model for Nonthyroidal Illness: Correction of Hypothyroxinemia with Thyroxine Treatment Does Not Improve Fetal Thyroid Hormone Status

Maintenance of normal maternal thyroxinemia prevents severe triiodothyronine (T3) deficiency of the fetus with primary thyroid failure (1). We have studied whether thyroxine (T4) would also protect the fetal brain when maternal hypothyroxinemia is caused by nonthyroidal illnesses. We have used the streptozotocin-induced diabetes mellitus pregnant rat as a model of maternal nonthyroidal illness. We measured the effects of diabetes mellitus, and of correction of the ensuing maternal hypothyroxinemia with T4 as compared to insulin, on maternal body weight, the outcome of pregnancy, glucose, insulin, T4, T3, reverse T3, and thyrotropin levels in the maternal and fetal circulation, as well as T4 and T3 concentrations in tissues, and iodothyronine deiodinases in liver, lung, and brain. The diabetic mothers showed changes in thyroid hormone status typical of nonthyroidal illnesses. Thyroid hormone status of the fetuses was severely affected: the total T4 and T3 pools decreased to one-third of normal values. T4 and T3 concentrations in the fetal brain were lower than normal and the expected increase in 5'-deiodinase activity was not observed. Although insulin treatment avoided or mitigated these changes, the low cerebral T3 did not improve with T4 treatment of the maternal hypothyroxinemia. Several findings indicated that treatment of the severely ill dams with T4 was actually harmful for the outcome of pregnancy. These negative effects were observed without the expected increase in the maternal or fetal T3 pools.

Thyrotropin-releasing hormone (TRH) binding sites and thyrotropin response to TRH are regulated by thyroid hormones in human thyrotropic adenomas.

In order to see whether, in thyrotropic adenomas with thyrotoxicosis, plasma thyroid hormones regulate the thyrotropin-releasing hormone (TRH) binding sites and the thyrotropin (TSH) response to TRH, we investigated: the presence of TRH binding sites in two cases of thyrotropic adenomas associated with hyperthyroidism and in one case of thyrotropic adenoma secondary to thyroid failure: and the in vitro effect, in a perifusion system, of triiodothyronine (T3) on the response of TSH to TRH in three cases of TSH-secreting adenomas associated with hyperthyroidism. The TRH binding sites were absent in the adenomas associated with high levels of circulating thyroid hormones, whereas they were present in the adenoma secondary to primary thyroid failure (Kd = 47 nmol/l, Bmax = 40 nmol/kg membrane proteins). In vitro, the three adenomas spontaneously released TSH in the perifusion medium (1.49 +/- 0.06 (mean +/- SEM), 7.25 +/- 0.12 and 16.73 +/- 0.36 mIU.l-1 x 10(6) cells-1 x 2 min-1) and exhibited an ample TSH response to 10(-7) mol/l TRH pulses. In two cases, tumoral secretion of fragments was compared with those of fragments maintained since the time of surgical removal in the presence of 10(-8) mol/lT3. The TSH responses to TRH were abolished in the presence of T3 in these two cases. We conclude that thyrotropic adenomas associated with hyperthyroidism are still controlled in vivo by T3. In particular, T3 regulates the TSH response to TRH, probably via a down-regulation of the TRH binding sites.

Central hypothyroidism presenting with pericardial and pleural effusions

Abstract. Serous cavity effusions occur in primary thyroid failure; we describe a patient in whom pleural and pericardial effusions were presenting features of central thyroid failure.

Admission screening by thyroid function tests in an acute general care teaching hospital

To determine the incidence of unrecognized thyroid disease among admissions to a large acute care university teaching hospital, 364 samples taken on consecutive admissions were assayed for thyroid-stimulating hormone (TSH) and free thyroxine index (FTI). Patients with abnormal test results were further evaluated by determination of antimicrosomal and antithyroglobulin antibodies, and charts were reviewed for evidence of prior diagnosis of thyroid disease, especially severe illness, drug treatment that might affect thyroid function tests, and prior diagnosis of thyroid disease. Results of subsequent thyroid function tests performed during the patient's hospitalization were correlated with the admission serum assays, and data on subsequent testing during the following 6 months were also obtained.A total of 3.9% of patients had significantly depressed TSH, and 11.1% of values were significantly elevated. A total of 11.3% of patients had significantly low FTI values, and 1% had significantly elevated values. A total of 7.4% appeared to have the euthyroid sick syndrome, 5.8% appeared to have unrecognized or undertreated primary thyroid failure, 6% had apparent subclinical hypothyroidism, 2% were thyrotoxic, and 2.8% (all women) had suppressed TSH levels for inapparent reasons. Limiting testing to patients over 49 years of age, or to women, would have missed many individuals with abnormal test results. Considering widespread availability of tests, relative costs, and value of the information obtained, it is suggested that the FTI determination would provide an appropriate screening test for patients in a population such as this entering a large, acute care general hospital.

Pituitary enlargement and hyperprolactinaemia due to primary hypothyroidism: Errors and delays in diagnosis

Two young women with pituitary gland enlargement and hyperprolactinaemia were referred for pituitary surgery. Both had received bromocriptine (one patient for 13 years) for presumed prolactinoma. Mild clinical signs of hypothyroidism were present and endocrine tests revealed primary autoimmune thyroid failure. Following thyroxine replacement treatment, the pituitary enlargement and hyperprolactinaemia completely resolved. In both patients the hyperprolactinaemia was relatively mild and menorrhagia had been present for many years. A third patient, a 61-year-old man presenting with bitemporal hemianopia due to pituitary enlargement underwent transphenoidal pituitary surgery. The results of thyroid function tests on admission were not available until after surgery. Although the patient was clinically euthyroid, these revealed primary hypothyroidism and his considerable pituitary enlargement may also have been secondary to thyroid failure. Urgent thyroid function tests should be performed in all patients with pituitary enlargement prior to surgery to exclude hypothyroid induced pituitary swelling.

Abnormal thyroid hormone and thyrotropin levels in homozygous sickle cell disease

Male patients with SS disease had significantly lower T3 and higher TSH levels than a comparison group. Stimulation with TRH in 10 male sibling pairs showed highly significant increases in T3 and TSH in both patients and sibling controls although the increase in TSH was significantly greater in SS disease. The interpretation of these findings is unclear although the thyroid indices indicate an abnormal pituitary-thyroid axis most consistent with a modest primary thyroid failure.

The causes of autoimmune thyroid disease.

RESEARCH on the cause of autoimmune thyroid disease (AITD) has in the past focused on potentially unique and specific abnormalities that could provide a unitary explanation for these illnesses [Graves' disease (GD), Hashimoto's thyroiditis (HT), and primary thyroid failure]. Evolving knowledge of the human immune system and results of studies on thyroid autoimmunity have suggested to us for many years (1) that the cause of autoimmunity is instead multifactorial. We believe that some level of self-reactivity is a normal—indeed, necessary—aspect of immune function. The development of autoimmune disease involves genetic and environmental influences that amplify normal self-reactivity and which evolve over a lifetime. The course is not always unidirectional, since activation of autoregulatory responses can apparently reverse it. In this article we first provide an abbreviated summary of immune function and then review contemporary research on autoimmunity as related to the thyroid gland, including studies tha...

Endocrine involvement in minor (non-H-2) graft-versus-host reaction in mice. Early and primary thyroid failure.

A minor (non-H-2) graft-vs.-host reaction (GVHR) was induced in adult irradiated (DBA/2 X B10.D2)F1 mice by hematopoietic parental B10.D2 cell grafts. Syngeneic (F1) cell transplantation was performed as control. In one set of experiments T4 plasma level (enzyme linked immunosorbent assay) was systematically followed up in individual GVHR and control mice. Compared to the control, GVHR triggered off a significant and sustained decrease of T4 plasma level. In another set of experiments, TSH plasma levels (RIA) were measured in killed animals. GVHR induced an early elevation of plasma TSH. In a third set of experiments, mice undergoing GVHR received daily injections of L-T4 (0.03, 0.15, or 0.3 microgram/mouse). Compared to the control (saline injected) GVHR mice, T4 supply did not improve GVHR state. No positive effect of the high dose and rather a negative effect of both lower doses especially on glucose plasma concentration, were observed. All these data suggest that thyroid gland is primarily and very early involved in the onset of the GVH disease.

ISOLATED ADRENOCORTICOTROPHIN DEFICIENCY AND EMPTY SELLA ASSOCIATED WITH HYPOTHYROIDISM

A case of isolated ACTH deficiency is described. The patient had an empty sella and longstanding radio-iodine induced hypothyroidism. The association between isolated ACTH deficiency, empty sella and hypothyroidism is reviewed. It has not previously been recognized that the commonest endocrine association of isolated ACTH deficiency is primary thyroid failure. ACTH secretion does not recover following thyroxine replacement treatment.

TRH: pathophysiologic and clinical implications.

Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases. The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown. The TSH response to TRH is nowadays widely used as a diagnostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course. But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive.

Effects of i.v. TRH on LH, FSH and GH serum levels in primary hypothyroid children

The occurrence of precocious puberty in children with primary hypothyroidism is a well recognized but poorly understood phenomenon. Several mechanisms have been proposed, but exceptions can be raised for each hypothesis (Lindsay et al, Am J Dis Child 134, 588, 1980). In 9/12 off-therapy primary hypothyroid children and adolescents (aged 1-16 yrs, 9 prepubertal and 3 pubertal) i.v. TRH (5μg/kg) injection elicited an evident increase of serum LH between 15 and 30 min, which exhausted within 90 min. Mean (± SEM) LH serum levels at 15 (2.22±0.45 ng/ml) and 30 min (2.22±0.43) were significantly (p 7 ng/ml)was also recorded in 3/12 hypothyroids. On the contrary FSH serum levels were not substantially modified by TRH bolus, either in the patient or in the control group. An overlap in the pituitary hormonal feed-back mechanism had been hypothesized to explain the occurrence of precocious puberty in primary thyroid failure (Van Wyk and Grumbach, J Pediatr 57, 416, 1960). The nonspecific LH-releasing effect of TRH in our patients especially evident in the pubertal ones supports such hypothesis.

Excess of beta-subunit of thyrotropin (TSH) in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity.

alpha-Subunit and beta-subunit of TSH were measured in the sera of five patients with idiopathic central hypothyroidism due to the secretion of biologically inactive TSH, in seven normal controls matched for bone age and sex, and in five subjects with mild primary thyroid failure before and after TRH (200 micrograms, iv) stimulation. Basal serum alpha-subunit concentration in patients did not differ from that in normal controls (mean +/- SD, 0.40 +/- 0.20 vs. 0.38 +/- 0.28 ng/ml; P, NS), whereas TSH and TSH-beta were significantly higher in patients (TSH, 1.51 +/- 0.74 vs. 0.59 +/- 0.53 ng/ml, P less than 0.025; TSH-beta, 0.56 +/- 0.18 vs. 0.10 +/- 0.02 ng/ml, P less than 0.001). The concentration of TSH-beta was also significantly higher in patients with central hypothyroidism than in subjects with mild primary thyroid failure (0.56 +/- 0.18 vs. 0.24 +/- 0.08 ng/ml; P less than 0.01), although serum TSH levels did not differ in the two groups (1.51 +/- 0.74 vs. 2.16 +/- 0.52 ng/ml; P, NS). alpha-Subunit was significantly higher in primary hypothyroid subjects (1.50 +/- 0.87, P less than 0.05 compared with patients with central hypothyroidism). After TRH, alpha-subunit, TSH, and TSH-beta net increases (peak) were significantly higher in patients with central hypothyroidism than in normal controls (alpha-subunit: 0.95 +/- 0.5 vs. 0.47 +/- 0.19 ng/ml, P less than 0.05; TSH: 7.1 +/- 3.1 vs. 2.9 +/- 1.8 ng/ml, P less than 0.005; TSH-beta: 0.89 +/- 0.35 vs. 0.22 +/- 0.18 ng/ml, P less than 0.005), whereas they did not significantly differ from those recorded in hypothyroid controls. The beta/alpha ratio, which was 1.67 +/- 0.86 in patients and 0.35 +/- 0.18 in normal controls (P less than 0.005), slightly decreased after TRH to 1.24 +/- 0.78 in patients, but remained unchanged in normal controls (0.39 +/- 0.1). After TRH the alpha-subunit peak occurred at 20 min both in patients and in controls, whereas TSH and TSH-beta peaked at 60 min in patients and at 20 min in controls. One patient was given oral TRH (40 mg/day for 4 weeks). The beta/alpha ratio fell from 1.85 to 0.13. Interestingly, serum thyroid hormones, which did not increase after iv TRH and after the first doses of oral TRH, showed a definite increase. Sera from two patients were filtered on Sephadex G-100: in one of them TSH-beta eluted in the same position as labeled reference standard, whereas in the other one radioimmunoassayable TSH-beta eluted near the void volume. The above data indicate that in patients with idiopathic central hypothyroidism due to biologically inactive TSH there is an excess of circulating TSH-beta and suggest that TRH is implicated in the secretion of TSH of full biological potency.

Glucose turnover and indices of recycling in thyrotoxicosis and primary thyroid failure.

1. Glucose turnover was examined by using simultaneous bolus intravenous tracer administration of both [3-3H]glucose and [1-14C]glucose in hyperthyroid and hypothyroid subjects before and during appropriate therapy and in matched controls. 2. In hyperthyroid subjects, total glucose turnover (as indicated by analysis of decay of [3-3H]glucose specific radioactivity) was increased (18.1 ± 1.0 vs 12.4 ± 0.9 μnol kg−1 min−1, P &amp;lt; 0.01), as was the metabolic clearance rate for glucose (3.5 ± 0.3 vs 2.4 ± 0.2 ml kg−1 min−1, P &amp;lt; 0.01). 3. Glucose turnover rates determined with [1-14C]glucose as tracer were lower than total glucose turnover rates in all subjects. This difference represents an index of recycling of the 14C label between glucose and glucose-derived C3 intermediates. 4. The recycling index was increased in hyperthyroidism both in amount (4.7 ± 0.6 vs 1.3 ± 0.3 μmol kg−1 min−1, P &amp;lt; 0.001) and when expressed as a percentage of total glucose turnover (27 ± 3 vs 10 ± 2%, P &amp;lt; 0.001). 5. Turnover rates determined by [1-14C]glucose represent irreversible glucose disposal and were similar in hyperthyroid and control subjects (hyperthyroid 13.4 ± 1.1 vs control 11.2 ± 0.9 μmol kg−1 min−1). The major fraction of the increase in total glucose turnover could thus be accounted for by increased cycling of glucose. 6. Total glucose turnover, metabolic clearance and indices of recycling returned to normal with treatment of hyperthyroidism. 7. In hypothyroidism, total glucose turnover (hypothyroid 8.2 ± 0.3 vs control 11.7 ± 1.2 μmol kg−1 min−1, P &amp;lt; 0.01) and metabolic clearance (hypothyroid 1.6 ± 0.1 vs control 2.3 ± 0.2 ml kg−1 min−1, P &amp;lt; 0.001) were decreased and returned to normal with thyroxine therapy. Indices of glucose recycling were normal.