Low Serum T4 Research Articles

Thyroid function in patients with chronic renal failure

Chronic renal failure affects thyroid function in multiple ways, including low circulating thyroid hormone concentration, altered peripheral hormone metabolism, disturbed binding to carrier proteins, possible reduction in tissue thyroid hormone content, and increased iodine store in thyroid glands. Both plasma triiodothyronine (T3) and thyroxine (T4) are reduced. The low serum T3 is not due to increased T3 degradation or to decreased thyroidal T3 secretion but is a result of impaired extrathyroidal T4 to T3 conversion. The reduction in T4 is attributed to the presence of circulating inhibitors, which impair binding of T4 to thyroxine-binding globulin. Despite decreased circulating T4 and T3, thyroid-stimulating hormone (TSH) is not elevated. This absence of TSH elevation is not due to dysfunction of the hypothalamo-pituitary axis, because truly hypothyroid renal failure patients can mount a high TSH response. Thyroid hormone losses during hemodialysis and peritoneal dialysis are trivial and do not require replacement. Serum inorganic iodide and thyroidal iodine content are increased in renal failure patients, and thyroid gland enlargement is frequently encountered. Experiments performed to correct the low serum T3 level by administration of small doses of LT3 to renal failure patients resulted in lesser nitrogen balance, greater leucine flux, and protein degradation. We speculate that the low thyroid state in uremia serves to defend against protein wasting and that misguided attempts to replete thyroid hormone stores may worsen protein malnutrition. © 2001 by the National Kidney Foundation, Inc.

Three Novel Mutations Causing Complete T4-Binding Globulin Deficiency

Inherited T4-binding globulin deficiency is caused by mutations in the T4-binding globulin gene located on the X chromosome. We describe herein three novel mutations in three different families producing complete T4-binding globulin deficiency. The proposita of a family from Harwichport is a female with XO Turner’s syndrome who expressed only the mutant T4-binding globulin allele. Her T4-binding globulin sequence has a 19-nucleotide deletion in the distal portion of exon 4. This causes a frameshift and a premature stop at codon 384 of the mature protein. Structure analysis with the Swiss PDB-Viewer revealed that this mutation removes β-strand s5B from the core of the T4-binding globulin molecule, leading to a severe folding defect that is likely to prevent synthesis and secretion. The propositi of complete T4-binding globulin deficiency 7 and 8 were 7-month-old and 3-wk-old male infants who were identified because of low serum T4 levels detected during neonatal screening. Sequencing of complete T4-binding globulin deficiency 7 revealed a single nucleotide deletion, a G at position 2690 in exon 3. This leads to an alteration of the amino acid sequence starting at codon 283 and a premature stop at codon 301. Complete T4-binding globulin deficiency 8 also has a deletion of the first nucleotide of exon 4, a G at position 3358. This leads to a frameshift and a premature stop at codon 374. As in the case of complete T4-binding globulin deficiency J, which has also a nucleotide deletion but downstream (position 3421) and a stop at codon 374, these two T4-binding globulin mutants undoubtedly have a defect in intracellular transport and therefore fail to be secreted. This explains the lack of T4-binding globulin in the hemizygous affected subjects.

DOES LOW TRI‐IODOTHYRONINE INDEPENDENTLY PREDICT MORTALITY IN ELDERLY HOSPITALISED PATIENTS?

SUMMARYA fall in serum tri‐iodothyronine (T3) is the earliest abnormality in thyroid hormonal function tests in non‐thyroidal illnesses. Our study shows an association of low serum T3 with patient mortality in elderly hospitalised patients.

Histological changes of thyroid tissues in patients with liver cirrhosis.

Alterations in thyroid hormone regulation and metabolism, such as low serum T3 and T4 with normal TSH, are frequently noted in liver cirrhosis, but few morphological studies have ever been done on thyroid tissue in liver cirrhosis. In this study we analyzed the histological changes of thyroid tissue in the patients with liver cirrhosis. Specimens of thyroid gland obtained from autopsies in 16 cirrhotic patients were examined, and compared with those of two control groups. Control group I consisted of 7 patients with diabetes mellitus and control group II, 12 patients who died from sudden onset of cardiovascular problems. We measured follicular diameter and epithelial width on light micrographs of the central portion of thyroid specimens. We graded the degree of colloid vacuole, lipofuscin deposition in follicular epithelia, regenerative reaction and perivascular fibrosis in 10 consecutive light microscopic fields of the specimen. In the cirrhotic group, mean follicular diameter and epithelial width were significantly shorter and thinner, respectively, than those in the two control groups. Perivascular fibrosis was more prominent in the cirrhosis group than in the controls. These findings suggest that thyroid glands in patients with liver cirrhosis have the characteristic features of hypoactivity.

Changes in serum thyroid hormones levels and their mechanisms during long‐term growth hormone (GH) replacement therapy in GH deficient children

The effects of GH therapy on thyroid function among previous reports have shown remarkable discrepancies, probably due to differences in hormone assay methods, degree of purification of former pituitary-derived GH preparations, dosage schedules, diagnostic criteria, patient selection, duration of treatment and study design. These considerations motivated us to investigate whether and how GH replacement therapy changes serum thyroid hormone levels, including the much less studied rT3 levels, in a group of unequivocally GH-deficient children receiving long-term recombinant human GH therapy. Twenty clinically and biochemically euthyroid children were studied in two therapeutic conditions: on GH replacement therapy for at least 6 months and without GH replacement, either before GH was started or after GH was withdrawn for 30-60 days. Eight patients were on thyroxine replacement treatment and thyroxine doses were kept constant during the study. Blood was collected before and after 15, 20 and 60 minutes of TRH administration in both therapeutic conditions (with GH and without GH). Concentrations of thyroid hormone levels were determined only in sera obtained before TRH administration. FT4, T3 and TSH were measured by immunoflourimetric assays and rT2 was measured by immunoradioassay. Patients were classified into two groups, according to basal TSH levels: group I (TSH > 0.4 mU/l, n = 12) and group II (on thyroxine and TSH < 0.05 mU/l, n = 8). In both groups, serum FT4 levels decreased (17. 0 +/- 1.1 vs. 14.3 +/- 0.9 mU/l, P < 0.001, and 18.0 +/- 1.7 vs. 14. 2 +/- 1.7 mU/l, P < 0.01, respectively), serum T3 levels increased (1.8 +/- 0.1 vs. 2.4 +/- 0.2 nmol/l, P < 0.001, and 1.9 +/- 0.3 vs. 2.4 +/- 0.2 nmol/l, P < 0.05, respectively), and serum rT3 levels decreased (0.35 +/- 0.03 vs. 0.25 +/- 0.03 nmol/l, P < 0.01, and 0. 48 +/- 0.06 vs. 0.34 +/- 0.06 nmol/l, P < 0.01, respectively). Basal (3.2 +/- 0.50 vs. 2.6 +/- 0.72 mU/l, P = 0.28, paired t-test), TRH-stimulated peak TSH levels (13.9 +/- 5.3 vs. 15.9 +/- 8.0 mU/l, P = 0.35, paired t-test) and TRH-stimulated TSH secretion, expressed as area under the curve (609 +/- 97 vs. 499 +/- 53 mU/l.minutes-1, P = 0.15, paired t-test), remained unchanged during GH replacement in group I patients. Low serum FT4 and high serum T3 levels were observed in only one patient each, but low serum rT3 levels were found in six patients (four in group I and two in group II) during GH replacement. These results show that long-term GH replacement therapy in children with unequivocal GHD significantly decreases serum FT4 and rT3 levels and increases serum T3 levels; that these changes are independent of TSH and result from increased peripheral conversion of T4 to T3 and that GH replacement therapy in GH deficient children does not induce hypothyroidism, but simply reveals previously unrecognized cases whose serum FT4 values fall in the low range during GH replacement.

Thyroid function, morphology and prevalence of thyroid disease in a population-based study of Danish centenarians.

To investigate thyroid function, morphology, and autoimmunity in relation to physical function in an unselected population of centenarians. A population-based survey. Denmark. All persons living in Denmark who celebrated their 100th anniversary during the period April 1, 1995 to May 31, 1996, a total of 276 persons. Thyroid hormones (TSH, T4, FT4I, T3, FT3I, and T3RU), thyroid autoantibodies (TPOab and Tgab), thyroid volume, activities of daily living according to the Katz Index of ADL. In all, 207 (75%) of the 276 eligible subjects participated, and 148 agreed to blood tests. Among the participants, 2.9% had previously known hyperthyroidism, and the same proportion had previously known hypothyroidism. The blood tests did not reveal any undiagnosed cases of overt thyroid dysfunction. However 7.2% had a subnormal serum TSH, and 2.9% had an elevated serum TSH; all had normal serum T3 and serum T4 levels. Thyroid autoantibodies were detected in 26 (17.6%) centenarians (11.5% had Tgab and 9.5% had TPOab). Among relatively independent centenarians, low serum T3 was significantly associated with high comorbidity (P = .029), whereas both low serum T3 and thyroid autoantibodies were significantly associated with ADL-dependency (P < .001 and P = .030, respectively). Ultrasonography (n = 50) revealed a small gland with a median volume of 8.3 mL (range 3.2-27.9) compared with an expected volume of 20 mL (14-26) (P < .001). There was no significant relationship to body weight. When examined by ultrasound, only 26% had significant morphological alterations. Thyroid dysfunction does not seem to be more prevalent among centenarians than among younger old people. Low serum T3 is related to poor physical function and co-morbidity, whereas thyroid autoimmunity is related only to poor physical functioning. Despite atrophy of the thyroid gland, these findings suggest that thyroid function is well preserved in centenarians.

Effects of phenobarbital treatment on serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs

Objective To determine whether phenobarbital treatment of epileptic dogs alters serum thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations. Design Cross-sectional study. Animals 78 epileptic dogs receiving phenobarbital (group 1) and 48 untreated epileptic dogs (group 2). Procedure Serum biochemical analyses, including T4 and TSH concentrations, were performed for all dogs. Additional in vitro analyses were performed on serum from healthy dogs to determine whether phenobarbital in serum interferes with T4 assays or alters free T, (fT4) concentrations. Results Mean serum T4 concentration was significantly lower, and mean serum TSH concentration significantly higher, in dogs in group 1, compared with those in group 2. Thirty-one (40%) dogs in group 1 had serum T4 concentrations less than the reference range, compared with 4 (8%) dogs in group 2. All dogs in group 2 with low serum T4 concentrations had recently had seizure activity. Five (7%) dogs in group 1, but none of the dogs in group 2, had serum TSH concentrations greater than the reference range. Associations were not detected between serum T4 concentration and TSH concentration, age, phenobarbital dosage, duration of treatment, serum phenobarbital concentration, or degree of seizure control. Signs of overt hypothyroidism were not evident in dogs with low T4 concentrations. Addition of phenobarbital in vitro to serum did not affect determination of T4 concentration and only minimally affected fT4 concentration. Conclusions and Clinical Relevance Clinicians should be aware of the potential for phenobarbital treatment to decrease serum T4 and increase TSH concentrations and should use caution when interpreting results of thyroid tests in dogs receiving phenobarbital. (J Am Vet Med Assoc 1999:215:489–496)

Regulation and transfer of a murine model of thyrotropin receptor antibody mediated Graves' disease.

In order to replicate a recently described murine model of Graves' disease, we immunized AKR/N (H-2k) mice i.p., every 2 weeks, with either a clone of fibroblasts expressing both the human TSH receptor (hTSHR) and murine major histocompatibility complex (MHC) class II molecules or with fibroblasts expressing the MHC class II molecules alone. Mice were bled, and their thyroid hormone levels measured, at 6, 12, and up to 18 weeks after the first immunization. Between 11-12 weeks after immunization, a significant number of mice began to die spontaneously and were found to have developed large goiters. Thirty to 40% of mice immunized with hTSHR transfected fibroblasts showed markedly increased serum T3 and T4 hormone levels by 12 weeks compared with controls, with the highest thyroid hormone levels being T3: 420 ng/dl (normal < 70) and T4: 16.5 microg/dl (normal < 5). The murine serum demonstrated the presence of antibodies to the TSHR, as evidenced by inhibition of labeled TSH binding to the hTSHR, and these sera had in vitro thyroid stimulating activity. Many of the hyperthyroid mouse exhibited weight loss and hyperactivity and, on examination, their thyroids had the histological features of thyroid hyperactivity including thyroid enlargement, thyroid cell hypertrophy, and colloid droplet formation--all consistent with Graves' disease. In contrast, a small number of mice (< 5%) developed hypothyroidism with low serum T4 levels and markedly increased TSH concentrations and evidence of thyroid hypoplasia. Both hyperthyroidism and hypothyroidism were successfully transferred to naive mice using ip cells of immunized mice. Surprisingly, hypothyroidism occurred in many recipient mice even after transfer from hyperthyroid donors. These results confirmed that immunization with naturally expressed hTSHR in mammalian cells was able to induce functional TSHR autoantibodies that either stimulated or blocked the mouse thyroid gland and induced hyperthyroidism or thyroid failure. Furthermore, both blocking and stimulating antibodies coexisted in the same mice as evidenced so clearly by the transfer of hypothyroidism from hyperthyroid mice. The addition of a Th2 adjuvant (pertussis toxin) caused approximately 50% of the animals to become hyperthyroid beginning early at 9 weeks, whereas a Th1 adjuvant (CFA) delayed the disease onset such that only 10% were hyperthyroid by 12 weeks. As with human autoimmune thyroid disease, the T cell control of this murine model may be critical and requires more extensive investigation.

Thyroid function in the preterm infant.

Thyroid gland function develops and matures during fetal life, with production of serum thyroxine (T4) concentrations beginning around 12 weeks gestation and increasing to term. Infants born prior to term have lower cord serum T4 concentrations that correlate with gestational age or birth weight. This is partially the result of lower thyroxine-binding globulin (TBG) concentrations. The cord serum free thyroxine (FT4) concentrations also correlate with gestational age, but they are not proportionately as low as the cord T4 concentration. Preterm infants have a postnatal thyrotropin (TSH) surge and rise in serum T4 and triiodothyronine (T3), which is qualitatively similar to, but quantitatively smaller than, term infants. In contrast to term infants, preterm infants often experience a fall in serum T4 and T3 in the first week of life to below birth levels. This drop appears to be the result of many factors, including nutritional problems and decreased hepatic TBG production, immaturity of hypothalamic-pituitary control of the thyroid gland, immaturity of the thyroid gland itself, and increased tissue utilization of T4. These changes are impacted by complications of prematurity, such as respiratory distress syndrome (RDS), which result in nonthyroidal illness-like changes. Again, serum FT4 seems less affected, and when measured by equilibrium dialysis may be in the normal range for age. Several studies have correlated different measures of morbidity and mortality in the preterm infant with lower serum T4 concentrations. However, as with adults, it may be that low serum T4 concentrations are a marker of the sickest preemies. Also, as with adults, this has led to speculation that T4 treatment might be beneficial in improving these complications of prematurity, in particular the neurological outcome. While some studies appear to show improvement in some facet of medical complications with T4 treatment, most show no effect. Regarding neurological outcome, the 2 best controlled trials do not show improvement in neuropsychiatric testing outcome assessed up to 2 years of age. One study, however, showed an IQ that was 18 points higher in the T4-treated subgroup less than 27 weeks gestational age. It may be that the most preterm infants, eg, those less than 27 weeks of age, are at a disadvantage compared with their intrauterine counterparts, in that they lack the maternal thyroid hormone contribution and are forced to adapt to extrauterine life before their hypothalamic-pituitary-thyroid axis is mature enough to deal with tissue thyroxine demands. Further controlled studies are needed to determine if this subgroup of infants indeed may benefit from transient thyroid hormone supplementation.

Zinc supplementation on serum levels and hepatic conversion of thyroid hormones in obese (ob/ob) mice.

The supplemental effects of zinc on thyroid status in obese (ob/ob) mice were studied. Four-week-old obese mice and their lean controls were fed either a basal diet or a zinc-supplemented diet (200 mg/kg diet) for 8 wk. Following the 8-wk basal diet, obese mice had lower serum T4 values, as well as hepatic T4 and T3 values, than lean mice (p < 0.05). A significant decrease in hepatic 5'-deiodinase activity was also observed in obese mice. Dietary zinc supplementation significantly reduced serum T4 levels in both the obese and lean mice. However, the zinc-supplemented effects on diminishing hepatic T4 and T3 values, as well as on 5'-deiodinase activities, were found only in obese mice (p < 0.05). Furthermore, the 5'-deiodinase activities in hepatic microsomal pellets after incubation with various zinc concentrations (0.5, 1.0, and 2.5 mM) were also examined. The 5'-deiodinase activities, in hepatic samples from all mice, were significantly attenuated by zinc treatments. However, this effect was more predominant in obese mice following the addition of 0.5 mM zinc. This study suggests that a lower hepatic 5'-deiodinase activity, resulting from a higher zinc level, might be related to abnormal energy metabolism in the ob/ob mice.

Ontogeny of iodothyronine deiodinases in human liver.

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently healthy adult tissue transplant donors, and in liver homogenates from 2 fetuses (20 weeks gestation), 5 preterm infants (27-32 weeks gestation), and 13 term infants who survived up to 39 weeks postnatally. D1 activity was determined using 1 microM [3',5'-125I]rT3 as substrate and 10 mM dithiothreitol (DTT) as cofactor, D2 activity using 1 nM [3',5'-125I]T4 and 25 mM DTT in the presence of 1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 microM T3 (to block D3 activity), and D3 activity using 10 nM [3,5-125I]T3 and 50 mM DTT, by quantitation of the release of 125I. The assays were validated by high performance liquid chromatography of the products, and kinetic analysis [Michaelis-Menten constant (Km) of rT3 for D1: 0.5 microM; Km of T3 for D3: 2 nM]. In liver homogenates, D1 activity was not correlated with age, whereas D3 activity showed a strong negative correlation with age (r -0.84), with high D3 activities in preterm infants and (except in 1 infant of 35 weeks) absent D3 activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/mg protein in fetal livers and to 170-313 pmol/min/mg protein in adult livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in fetuses and <0.1 pmol/min/mg protein in all but one adult. In the latter sample, D3 activity amounted to 0.36 pmol/min/mg protein. D2 activity was negligible in both fetal and adult livers. These findings indicate high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. Therefore, the low serum T3 levels in the human fetus appear to be caused by high hepatic (and placental) D3 activity rather than caused by low hepatic D1 activity. The occasional expression of D3 in adult human liver is intriguing and deserves further investigation.

Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus.

Prolonged fasting is associated with a number of changes in the thyroid axis manifested by low serum T3 and T4 levels and, paradoxically, low or normal TSH. This response is, at least partly, caused by suppression of proTRH gene expression in neurons of the hypothalamic paraventricular nucleus (PVN) and reduced hypothalamic TRH release. Because the fall in thyroid hormone levels can be blunted in mice by the systemic administration of leptin, we raised the possibility that leptin may have an important role in the neuroendocrine regulation of the thyroid axis, through effects on hypophysiotropic neurons producing proTRH. Adult male, Sprague-Dawley rats were either fed normally, fasted for 3 days, or fasted and administered leptin at a dose of 0.5 microg/gm BW i.p. every 6 h. Fasted animals showed significant reduction in plasma total and free T4 and T3 levels compared with controls, that were restored toward normal by the administration of leptin. Percent free T4, but not percent free T3, increased during fasting, further suggesting a reduction in plasma transthyretin levels that did not return to fed levels after leptin administration. By semiquantitative analysis of in situ hybridization autoradiograms, proTRH messenger RNA in medial parvocellular PVN neurons was markedly suppressed in the fasting animals but was restored to normal by leptin administration [fed vs. fast vs. fast/leptin (density units x 10(8)): 8.5 +/- 0.4, 3.2 +/- 0.2, 8.1 +/- 0.8]. In contrast, proTRH messenger RNA in adjacent neurons in the lateral hypothalamus that do not have a hypophysiotropic function remained unchanged by any of the experimental manipulations. These findings indicate that leptin has a selective, central action to modulate the hypothalamic-pituitary-thyroid axis by regulating proTRH gene expression in the PVN but does not have peripheral effects on thyroid-binding proteins. We propose that the fall in circulating leptin levels during fasting resets the set point for feedback inhibition by thyroid hormones on the biosynthesis of hypophysiotropic proTRH, thereby allowing adaptation to starvation.

Different regulation of thyroid hormone transport in liver and pituitary: its possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man.

Nonthyroidal illness (NTI) and fasting in man are characterized by a low serum concentration of T3 and an increased serum concentration of rT3. Since the serum level of T3 is one of the most important factors that determine the metabolic rate, the low serum T3 during NTI or fasting results in reduction of the energy consumption of the body. This can be regarded as an adaptive mechanism to save energy, and thus to conserve protein and to protect organ function. The low serum T3 concentration should preferentially be maintained until recovery from illness or adequate calorie supply. This implies that the low serum T3 should not result in a rise in serum TSH. We postulate that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting. This hypothesis is further elaborated in this paper by comparing (i) the properties of the thyroid hormone uptake mechanism in rat and human hepatocytes, perfused rat liver, and rat anterior pituitary cells, and (ii) the effects of fasting and conditions that mimic NTI on thyroid hormone transport in the same preparations. In addition, the consequences of changes in thyroid hormone transport and peripheral thyroid hormone metabolism during fasting and NTI for the serum level of rT3 and for TSH secretion are discussed. The data are compatible with the existence of different transport systems for thyroid hormone in liver and pituitary. We suggest that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.

The relation between thyroid function and nutritional status in HIV-infected patients.

The effects of human immunodeficiency virus (HIV) infection on thyroid function have been reported in only a few studies with discrepant results. The aim of this study was to assess the relation between nutritional status and thyroid function in HIV infected patients. Prospective, cross-sectional study. A 500-bed teaching and referral hospital serving a population of 450,000. Seventy-five consecutive HIV infected patients between 21 and 40 years of age (mean 31.8 +/- 0.9 years). Nutritional status was evaluated using the body mass index (BMI), triceps skinfold thickness (TSF), mid-arm muscle circumference (MAMC), and serum albumin concentration (SA). Hormone assays for serum T4, free thyroxine index (FTI), T3, reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG), TSH and simultaneous CD4 lymphocyte counts were determined in all patients. Clinical stage was significantly related to nutritional status (P = 0.0001 for BMI, P = 0.0002 MAMC). The more poorly nourished groups had low mean serum T3 and rT3 levels, particularly for muscular (P = 0.0001 for T3 and P = 0.0076 for rT3) and visceral (P = 0.00001 for T3 and P = 0.0021 for rT3) protein compartments. Multivariate analysis showed that two factors, SA and MAMC, correlated significantly and independently with serum T3 and rT3. A close relation exists between serum thyroid hormone levels and nutritional status in HIV infected patients. These patients are probably euthyroid and the abnormal findings in the thyroid function tests are thus a reflection of the severity of illness.

Nonthyroidal Illness Syndrome or Euthyroid Sick Syndrome?

To characterize the nonthyroidal illness syndrome (NTIS) and to discuss various underlying potential biochemical mechanisms for this condition. The pertinent medical literature was reviewed, and studies of thyroid function in systemic non-thyroidal illnesses were summarized. Abnormalities of thyroid function in the NTIS have been classified into four major categories: (1) low triiodothyronine (T3) syndrome, (2) a combination of low T3 and low thyroxine (T4), (3) high T4 syndrome, and (4) other abnormalities. The NTIS has been noted in essentially all severe systemic illnesses and after caloric deprivation, major operations, and administration of some drugs. Some mechanisms that may contribute to low serum T3 in the NTIS are decreased type I 5 -monodeiodinase in tissues, decreased uptake of T4 by tissues, decreased serum binding, increased reverse T3, alterations in selenium status, cytokines, and a decrease in thyrotropin. Decreased thyrotropin may also contribute to low T4 levels in NTIS, as may decreased serum T4-binding proteins, abnormalities in T4-binding globulin, and circulating inhibitors of binding of T4 to serum proteins. Although T4 treatment of patients with NTIS has yielded little improvement, administration of T3 has produced some beneficial effects. Further studies should be conducted to determine appropriate patient populations, dose-response ratios, and possible adverse effects of treatment of the NTIS with T3.

Thyroid hormone therapy in cardiovascular disease

The relationship between thyroid disease states and cardiovascular hemodynamics is well recognized. Although the long-term effects of thyroid hormone are thought to result from changes in myocardial gene expression, attention has recently focused on acute, non-nuclear-mediated actions of L-triidothyronine (T3), the biologically active form of the hormone. Various lines of evidence have documented that T3 can act as a vasodilator and inotrope. With this recognition have come novel treatment strategies targeted at specific clinical conditions including heart failure and cardiac surgery that are associated with impaired cardiovascular performance and low serum T3 levels. An understanding of the mechanisms of action of thyroid hormone on the heart and peripheral vasculature is essential for the rational implementation of thyroid hormone as a therapeutic agent. As outlined in this review, initial clinical experience suggests that the ability of thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment option for physicians caring for patients with cardiovascular illness.

Radioiodine treatment of 524 cats with hyperthyroidism

Objective— To evaluate a protocol for subcutaneous radioiodine treatment of cats with hyperthyroidism in which the dose was determined on the basis of severity of the cat's clinical signs, thyroid tumor size, and magnitude of the serum thyroxine (T4) concentration. Design— Prospective case series. Animals— 524 cats with hyperthyroidism. Procedure— A scoring system based on 3 factors (severity of clinical signs, size of the thyroid gland, and magnitude of the serum T4 concentration) was used to select the dose of radioiodine to be administered subcutaneously. Results— On the basis of the scoring system, 310 (59%) cats were treated with a low dose of radioiodine (&lt; 3.5 mCi; median, 3.0 mCi), 158 (30%) were treated with a moderate dose (3.5 to 4.4 mCi; median, 4.0 mCi), and 56 (11 %) were treated with a high dose (≥ 4.5 mCi; median, 5.0 mCi). At time of discharge from the hospital, serum T4 concentration was still high in 80 (15.3%) cats, but by 6 months after administration of radioiodine, the serum T4 concentration had decreased to within or below reference range in all but 8 (1.5%) cats with persistent hyperthyroidism. Many cats had low serum T4 concentrations at some time after radioiodine treatment, but only 11 (2.1 %) cats developed clinical and clinicopathologic features of hypothyroidism and required supplementation with L-thyroxine. Thirteen (2.5%) cats had a relapse of hyperthyroidism 1.1 to 6.5 years after initial radioiodine treatment. Overall, the response to treatment was considered good in 94.2% of the cats. Median survival time in the cats was 2.0 years; the percentage of cats alive after 1, 2, and 3 years of treatment was 89, 72, and 52%, respectively. Clinical Implications— Results of the study suggest that this method of dose estimation works well and that subcutaneous administration of radioiodine provides a safe and effective means of treating hyperthyroidism in cats.

A 138-nucleotide deletion in the thyroglobulin ribonucleic acid messenger in a congenital goiter with defective thyroglobulin synthesis.

Two siblings (HSN and AcSN) with congenital goitrous hypothyroidism were investigated in terms of clinical, biochemical, and molecular biology. Diagnosis of defective thyroglobulin (Tg) was based on findings of low serum T4, low normal or normal serum T3, a negative percholate discharge test, and the virtual absence of the serum Tg response to challenge by bovine TSH. Only minute amounts of Tg-related antigens were detected by RIA in the goitrous tissue (HSN, 0.82 mg/g, compared to 70-90 mg/g in normal thyroid tissue), as confirmed by sodium dodecyl sulfate-agarose gel electrophoresis that indicated the virtual absence of Tg. The Tg messenger ribonucleic acids (mRNAs) from controls and HSN thyroid tissue were first reverse transcribed and then divided into several portions from positions 57-8448; the resulting complementary DNAs were, in turn, amplified by reverse polymerase chain reaction. The amplification of nucleotides 5165-6048 from control thyroid tissue Tg mRNA showed a fragment of 884 base pairs (bp). In contrast, the fragment present in the HSN was +/- 750 bp and lacked the normal fragment. The sequencing of the smaller fragment revealed that 138 bp were missing between positions 5590-5727 of the HSN Tg mRNA. This deletion does not affect the reading frame of the resulting mRNA and is potentially fully translatable into a Tg polypeptide chain that is shorter by 46 residues. A cysteine residue is maintained by the junction between the proximal T from leucine 1831 and the distal GT from cysteine 1877. DNA genomic polymerase chain reaction amplification excludes a deletion in the Tg gene and indicates that the deleted 138-nucleotide sequences lie in the same exon. The functional consequences of the deletion are not entirely clear, but it is conceivable that the excision of this segment of the Tg molecule could affect the protein structure, resulting in its premature degradation, very low colloid storage, and diminished thyroid hormone production rate.

Environmental polychlorinated biphenyls: acute toxicity of landfill soil extract to female prepubertal rats.

Subsurface soil from a National Priorities List landfill containing about 2.5% polychlorinated biphenyls (PCBs) was extracted and the extract cleaned by Florisil slurry and alumina column chromatography. The refined extract contained 48 mg/mL PCB, mainly trichlorobiphenyls and tetrachlorobiphenyls, traces of polychlorinated naphthalenes, 125 micrograms/mL 2,2-bis-p-chlorophenyl-1,1-dichloroethylene (DDE), and low levels of chlorinated dibenzofurans. The refined extract was dissolved in corn oil and administered intraperitoneally to weanling (day 20) female rats on days 20 and 21; rats were terminated on day 22. Limited data indicated possible hematopoietic effects, including neutrophilia. There were no changes in relative uterus, kidney, or adrenal gland weights between total doses of 3 to 96 mg/kg total PCB. Relative liver weights increased significantly at 36 mg/kg and activities of P450s 1A1 (as ethoxyresorufin O-dealkylase) and 2B (as pentoxyresorufin O-dealkylase) increased at 12 mg/kg and plateaued at 36 (P450 1A1) or 48 (P450 2b) mg/kg. Serum total thyroxine (T4) declined significantly at doses of 36 mg/kg and greater; thyroid follicular epithelial cells were significantly larger within the same dose range, but the follicular colloid area decreased to less than 60% control values at 12 mg/kg and remained at this size through 72 mg/kg. Maximum mobilization of T4 apparently occurred at 12 mg/kg and attenuated measured declines in circulating levels. Even though a large proportion of proven and probable estrogenic chlorobiphenyls (CBs) were present, the lower amounts of more potent antiestrogenic aryl hydrocarbon (Ah) receptor agonists and/or decreased responsiveness because of low serum T4 levels may have antagonized the uterotropic response.

Thyroid Hormone Concentrations In Critically III Canine Intensive Care Patients

SummaryAlterations in thyroid indices in critically ill dogs were studied retrospectively to determine the incidence of the euthyroid sick syndrome and to assess its prognostic relevance to survival. Sixty‐seven dogs were classified as euthyroid bases on a TSH stimulation test. Forty‐one of 67 (61%) of the euthyroid dogs had low baseline serum T4concentrations (&lt;1.5 ug/dl) and 38 of 67 (56%) of the euthyroid dogs had low baseline serum T3concentrations (&lt;75 ng/dl). There was no significant difference between either the baseline or the post‐stimulation serum T4concentrations when values of dogs that survived were compared with those that died. There was, however, a significant difference (P&lt;0.05) between both the baseline and the post‐stimulation values for T3 when survivors (100.3± 81 ng/dl, 143± 66 ng/dl) and non‐survivors (64.2 ± 17.1 ng/dl, 96.6 ± 38.3 ng/dl) were compared. The euthyroid sick syndrome occurs commonly in critically ill dogs. Further, the extent of depression of serum concentrations of T3may be correlated to mortality.