Thyroid dysfunction is a prominent finding in alcoholism. Subclinical and clinical hypothyroidism have been associated with clinical depression and cognitive impairment and may increase the relapse risk among alcoholics. In spite of these important clinical associations, there is no consensus on thyroid dysfunction in alcoholism in the literature. In this paper, we present a review of the literature and develop a hypothesis that may explain dysfunction of the hypothalamic-pituitary-thyroid axis in alcoholism. Based on a Medline research of the years 1980-2001 we found 33 empirical studies that assessed thyroid function in alcoholism. The most consistent findings were a reduction in total thyroxine and total and free triiodothyronine concentrations during early abstinence. About one-third of all alcoholics also displayed a blunted thyroid stimulation hormone (TSH) response in the thyrotrophin-releasing hormone test (TRH-test). Blunting was observed frequently during detoxification, but was also present in some alcoholics after several weeks of abstinence. We suggest that a reduction in peripheral thyroid hormones may be caused by a direct toxic effect of alcohol on the thyroid gland, which induces a central compensatory activation of the hypothalamic-pituitary axis with an increased TRH release. The TRH release induces a downregulation of pituitary TRH receptors, which manifest as a blunted TSH response to the TRH test. We discuss further additional effects of alcohol on thyroid-hormone metabolizing deiodinases and on monoaminergic systems, which may interact directly with mood states among abstinent alcoholics.

2 people from different families had high levels of serum-thyroxine (T4) and a high free T4 (FT4) index but a normal serum triiodothyronine (T3) and serum-reverse-T3 (rT3). The abnormal serum thyroid hormone profile appeared to be inherited in an autosomal dominant manner. Serum-FT4 in affected relatives was normal. The increases in serum-T4 and FT4 index are explained on the basis of an observed increase in affinity of T4 for thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin. The FT4 index did not reflect the true concentration of circulating free T4 in these cases. Thyroid function in the propositi was normal and the results of T4, T3, and rT3 kinetic studies accorded with increased binding of T4 by serum proteins and normal binding of the other iodo-thyronines. This "euthyroid high total T4, normal T3 syndrome" should be kept in mind during diagnostic evaluation of thyroid function.

Little is known about the reaction of normal thyroid glands to the iodine load given by x-ray dyes. We have therefore investigated the short-term effects of high doses of iodine on thyroid parameters in euthyroid patients. We measured free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) serum concentrations before and daily for 1 week after parenteral application of x-ray dyes (coronary angiography: n = 16; computed tomography [CT] of either thorax or abdomen: n = 6; iodine dose range from 300-1221 mg of iodine per kilogram). Inclusion criteria were as follows: normal FT4, normal TSH, negative thyroid antibodies, urinary iodine excretion below 30 microg/dL, no palpable goiter and no euthyroid sick syndrome. All but one patient reacted with a TSH increase. Mean TSH values increased significantly 3-5 days after the iodine load within the normal range. Four patients (18%) had a TSH increase above normal, the maximal observed value being 6.4 microU/mL. Basal TSH values of these four patients were above 2 microU/mL. The day peak TSH concentrations were reached varied from day 1 to day 7, the majority (32%) having the peak on day 3. Peak TSH was significantly correlated with basal TSH values (r = 0.794, p < 0.0001). FT4 and FT3 remained unchanged and there was no significant correlation between the dose of iodine and the TSH reaction. In conclusion, iodine-containing contrast media can induce transiently subclinical hypothyroidism even in euthyroid patients. The TSH reaction seems to depend on the preexisting state of thyroid function.

BACKGROUND

Levothyroxine (LT4) is the recommended treatment for millions of hypothyroid patients. Current guidelines recommend that LT4 tablets be taken in a fasting state, but inability to adhere to this often leads to poor therapy compliance.

METHODS

A randomized, double-blind, placebo-controlled, crossover trial was conducted in previously untreated hypothyroid patients randomly assigned to receive an oral solution of LT4 either at least 30 minutes before breakfast or directly at breakfast time. Each patient completed two six-week treatment periods, with different timing of active LT4 administration: placebo before breakfast and active LT4 at breakfast, or vice versa. At the end of each period, thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) were measured. The primary endpoint was to verify any difference in serum TSH levels whether consuming liquid LT4 at breakfast or 30 minutes prior to breakfast.

RESULTS

A total of 77 patients (64 females; median age 45.4 ± 3.7 years) completed the study. No statistically significant differences in serum TSH, fT4, or fT3 levels were observed whether LT4 was taken at breakfast or 30 minutes before, in a fasting state. No significant effect from the sequence of regimens, breakfast composition, and/or concomitantly administered drugs was observed on the dose of LT4 administered, or on the post-treatment serum TSH values.

CONCLUSIONS

The TICO study suggests that a liquid LT4 formulation can be ingested directly at breakfast, thus potentially improving therapeutic compliance. This observation is of considerable clinical relevance, since non-adherence to LT4 therapy requirements is more likely to cause variability in serum TSH concentrations.

BACKGROUND

Early and accurate prediction of outcome in acute stroke is important and influences risk-optimized therapeutic strategies. Endocrine alterations of the hypothalamic-pituitary axis are amongst the first measurable alterations after cerebral ischaemia. We therefore evaluated the prognostic value of cortisol, triiodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and growth hormone (GH) in patients with an acute ischaemic stroke.

METHODS

In an observational study including 281 patients with ischaemic stroke, anterior pituitary axis hormones (i.e. cortisol, T3, fT4, TSH and GH) were simultaneously assessed to determine their value to predict functional outcome and mortality within 90 days and 1 year.

RESULTS

In receiver operating characteristic curve analysis, the prognostic accuracy of cortisol was higher compared to all measured hormones and was in the range of the National Institutes of Health Stroke Scale (NIHSS). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio (OR) 1.0 (1.0-1.01) and 1.62 (1.37-1.92), respectively, P<0.0002 for both, adjusted for age and the NIHSS] in patients with ischaemic stroke, but added no significant additional predictive value to the clinical NIHSS score.

CONCLUSIONS

Cortisol is an independent prognostic marker for death and functional outcome within 90 days and 1 year in patients with ischaemic stroke. By contrast, other anterior pituitary axis hormones such as peripheral thyroid hormones and GH are only of minor value to predict outcome in stroke.

BACKGROUND

Lithium is an integral drug used in the management of acute mania, unipolar and bipolar depression and prophylaxis of bipolar disorders. Thyroid abnormalities associated with treatment with lithium have been widely reported in medical literature to date. These include goitre, hypothyroidism, hyperthyroidism and autoimmune thyroiditis. This current review explores the varied thyroid abnormalities frequently encountered among patients on lithium therapy and their management, since lithium is still a fundamental and widely drug used in psychiatry and Internal Medicine.

METHODS

PubMed database and Google scholar were used to search for relevant English language articles relating to lithium therapy and thyroid abnormalities up to December 2012. The search terms used were lithium treatment, thyroid abnormalities, thyroid dysfunction, goitre, hypothyroidism, hyperthyroidism, thyrotoxicosis, autoimmune thyroiditis, lithium toxicity, treatment of affective disorders and depression and side effects of antipsychotic drugs. Reference lists of the identified articles were further used to identify other studies.

RESULTS

Lithium affects normal thyroid functioning through multiple mechanisms. At the cellular level, it decreases thyroid hormone synthesis and release. It also decreases peripheral deiodination of tetraiodothyronine (T4) or thyroxine by decreasing the activity of type I 5' de-iodinase enzyme. Hypothyroidism and goitre (clinically and/ultrasonographically detected) are the most prevalent thyroid abnormalities among patients on long term lithium therapy. Lithium induced hyperthyroidism is very infrequent. Lithium increases the propensity to thyroid autoimmunity in susceptible individuals due to its effect of augmenting the activity of B lymphocytes and reducing the ratio of circulating suppressor to cytotoxic T cells.

CONCLUSIONS

Thyroid function tests (serum thyroid stimulating hormone, free thyroid hormones-T4 and triiodothyronine [T3] concentrations and thyroid auto-antibodies) and assessment of thyroid size clinically and by thyroid ultrasonography ought to be performed among patients initiating lithium therapy at baseline and later annually. More frequent assessment of thyroid function status and size during the course of therapy is recommended among middle aged females (≥50 years), patients with a family history of thyroid disease and those positive for thyroid auto-antibodies (anti-thyroid peroxidase and TSH receptor antibodies).

Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of (131)I-labeled triiodothyronine (T(3)) and (125)I-labeled thyroxine (T(4)) and on the concentration and binding of T(4) and T(3) in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T(3) concentration (137 vs. 197 ng/100 ml), T(3) distribution space (39.3 vs. 51.7 liters), T(3) clearance rate (22.9 vs. 30.6 liters/day) and absolute T(3) disposal rate (30 vs. 58 mug/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T(3) also increased during L-thyroxine administration. Increases in serum total T(4) concentration (7.3 vs. 12.8 mug/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T(4) turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 mug/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T(4) and T(3), the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T(4)-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state. The studies have also provided additional evidence of the peripheral conversion of T(4) to T(3) in man and have permitted the calculation that approximately one-third of exogenously administered T(4) underwent deiodination to form T(3). To the extent that a similar fractional conversion occurs in the normal state, it can be calculated that a major fraction of the T(3) in serum derives from the peripheral deiodination of T(4) and that only a lesser fraction derives from direct secretion by the thyroid gland.

Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T3), the biologically active hormone, derives mainly from tissue T4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretin-null mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se. This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.

This study investigated blood lead (Pb-B) levels and Pb-B effects on thyroid functions in long-term low-level-lead-exposed male adolescents who work as auto repairers. Pb-B and ALAD index (logarithm of activated delta-aminolaevulinic acid dehydratase/nonactivated delta-aminolaevulinic acid dehydratase) were measured as indicators of exposure to lead. Thyroid function tests including free thyroxine (FT4), free triiodothyronine (FT3), and thyrotrophin (TSH) were conducted and thyroid ultrasounds were performed in 42 lead-exposed adolescents and 55 healthy control subjects. Mean Pb-B levels and ALAD index were found significantly higher in the study group than in the normal control group (7.3+/-2.92 microg/dl vs. 2.08+/-1.24 microg/dl, P < 0.001 and 0.44+/-0.26 vs. 0.29+/-0.23, P < 0.05, respectively). FT4 levels were found significantly lower in the study group (1.02+/-0.18 mI/mL and 1.12+/-0.14 mIU/mL, P < 0.05). No subject in the control group had an abnormal FT4 level, but FT4 levels were found under normal limits in 11 subjects (26%) in the study group. FT3 and TSH levels in the study and control groups did not differ (P>> 0.05). Thyroid volumes in the study and control groups did not exhibit any significant differences (P>> 0.05). Pb-B was found to be negatively correlated to FT4 levels (r = -0.20, P = 0.044). This study revealed that long-term low-level lead exposure may lead to reduced FT4 level without significant changes in TSH and T3 levels in adolescents even at low Pb-B levels.

OBJECTIVE

Because treatment of the depressed phase of bipolar disorder is a clinical challenge and hypothyroidism is known to be associated with depression, the authors examined the relationship between pretreatment thyroid values and response to antidepressant treatment. It was hypothesized that subjects with lower thyroid function, even within the normal range, would have a poorer response to initial treatment.

METHODS

The subjects were 65 patients in the depressed phase of bipolar I disorder who were enrolled in a larger ongoing study. A panel of thyroid measures, including thyroid-stimulating hormone (TSH), thyroxine, triiodothyronine resin uptake, and free thyroxine index (FTI), were determined before initiation of algorithm-guided treatment. The effect of each thyroid measurement on time to remission was estimated by using the Cox proportional hazards model.

RESULTS

Both lower values of FTI and higher values of TSH were significantly associated with longer times to remission, i.e., slower response to treatment. Outcomes were relatively poor unless patients had FTI values above the median and TSH values below the median. Patients with this optimal profile experienced remission 4 months faster than the remainder of the study group.

CONCLUSIONS

This study provides further evidence that patients with bipolar disorder are particularly sensitive to variations in thyroid function within the normal range. Our results suggest that nearly three-quarters of patients with bipolar disorder have a thyroid profile that may be suboptimal for antidepressant response. It remains to be seen whether pharmacological enhancement of thyroid function will facilitate recovery from bipolar depression.

OBJECTIVE

The importance of diagnosis and treatment of thyroid dysfunction during pregnancy has been widely recognized. We therefore established trimester- and method-specific reference intervals for thyroid testing in pregnant women according to the NACB recommended criteria. Several factors can affect the setting of reference intervals, in particular manufacturer's methodology, euthyroid definition and iodine status.

METHODS

Cross-sectional dataset analysis.

METHODS

Five hundred and five normal pregnant women at different stages of gestation were rigorously selected for setting reference intervals. All were healthy, iodine sufficient, euthyroid and negative for both serum thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb).

METHODS

Thyrotrophin (TSH), total and free thyroxine (TT4 and FT4), total and free triiodothyronine (TT3 and FT3) and anti-TPOAb and anti-TgAb were measured using the Bayer ADVIA Centaur system. Iodine content in drinking water, salt and urine was determined by national standard methods. The 2·5th and 97·5th percentiles were calculated as the reference intervals for thyroid hormone levels during each trimester.

RESULTS

All participants had long-term consumption of iodized salt and median urinary iodine of 150-200 μg/l during each three trimester. The reference intervals for the first, second and third trimesters were, respectively, TSH 0·03-4·51, 0·05-4·50 and 0·47-4·54 mIU/l and FT4 11·8-21·0, 10·6-17·6 and 9·2-16·7 pmol/l. The manufacturer's method, euthyroid definition and iodine status may influence TSH and FT4 reference intervals. Alterations in thyroid hormone concentrations during pregnancy differed at different stage of gestation and to those of a nonpregnant state.

CONCLUSIONS

The trimester- and method-based reference intervals for thyroid tests during pregnancy are clinically appropriate. Some variables should be controlled when establishing reference intervals.

OBJECTIVE

We examined the interrelationships of pituitary thyrotropin (TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxine (L-T4) treatment.

METHODS

This prospective study employing 1912 consecutive patients analyses the interacting equilibria of TSH and free triiodothyronine (FT3) and free thyroxine (FT4) in the circulation.

RESULTS

The complex interrelations between FT3, FT4 and TSH were modulated by age, body mass, thyroid volume, antibody status and L-T4 treatment. By group comparison and confirmation by more individual TSH-related regression, FT3 levels were significantly lower in L-T4-treated vs untreated nonhypothyroid autoimmune thyroiditis (median 4·6 vs 4·9 pm, P < 0·001), despite lower TSH (1·49 vs 2·93 mU/l, P < 0·001) and higher FT4 levels (16·8 vs 13·8 pm, P < 0·001) in the treated group. Compared with disease-free controls, the FT3-TSH relationship was significantly displaced in treated patients with carcinoma, with median TSH of 0·21 vs 1·63 (P < 0·001) at a comparable FT3 of 5·0 pm in the groups. Disparities were reflected by calculated deiodinase activity and remained significant even after accounting for confounding influences in a multivariable model.

CONCLUSIONS

TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization.

Two experiments were conducted to determine the effects of endophyte fungus (Acremonium coenophialum) ingestion in tall fescue diets and environmental temperature on heat dissipation and diet utilization by cattle. In Exp. 1, 12 Angus heifers (average weight 244 kg) were allotted by weight to either an endophyte-free (E-) or endophyte-infected (E+; 381 ppb of ergovaline) diet. Environmental temperature varied between 22 and 32 degrees C. Voluntary DM and water intakes were similar (P>> .10) among treatments. Rectal temperatures and concentrations of prolactin in plasma were lower (P < .05) after ingestion of the E+ diet. Plasma triiodothyronine, thyroxine, and cortisol concentrations were not affected by diet. In Exp. 2, 24 Holstein steers (average weight 114 kg) were allotted by weight to either E- or E+ (285 ppb of ergovaline) and one of two environmental temperatures (22 or 32 degrees C). At 32 degrees C, feed intake was reduced by 22%, and water consumption was increased by 62% compared with steers housed at 22 degrees C. Consumption of E+ reduced feed intake by 10% but did not influence water consumption. Plasma concentration of prolactin was decreased (P < .05) within 48 h after consumption of E+. Rectal temperatures increased in response to both environmental temperature (P < .05) and E+ consumption (P = .06). Digestibilities of DM and OM for E+ were 9% lower (P < .05) than for E-.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper reviews knowledge on the structure and function and evolution of the thyroid hormone binding protein transthyretin (TTR), with particular reference to factors affecting thyroid hormone distribution and delivery to the brain. The pool of thyroid hormones critical for the biological actions of the hormones is the pool of free thyroid hormone. The size of this pool is determined for short time periods by uptake/release of thyroid hormones into/from cell and binding/release of thyroid hormones by thyroid hormone-binding proteins. Both proportions and absolute concentrations of these proteins differ in blood plasma and cerebrospinal fluid (CSF). The most pronounced difference is found for TTR which is the only thyroid hormone-binding plasma protein synthesized in the brain. TTR is also distinct from the other two thyroid hormone-binding plasma proteins in humans by the absence of genetic deficiencies. TTR gene expression was initiated during evolution much earlier in the brain than in the liver. The structure of the domains of TTR involved in thyroxine (TR) T4 binding has been completely conserved for 350 million years. These observations point to a special functional significance of TTR in the brain. It is proposed that this is the determination of the level of free T4 in the extracellular compartment of the brain. T4 can then be converted in the brain to triiodothyronine T3 by specific deiodinases. This T3 can interact with receptors in the cell nuclei, regulating gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-thyroxine (T4) and anti-triiodothyronine (T3) antibodies have been demonstrated in man. It was assumed that antibodies were at least partially saturated in vivo by the hormones. The initial step of the method therefore consisted in a dissociation of the postulated antigen-antibody complex by a 45% ammonium sulfate precipitation. The second part of the method consisted in incubating the euglobulins with trace amounts of 125I-T3 and 131I-T4. The hormones bound to the gammaglobulins were then separated from the free hormones by a column of DEAE Sephadex A-50 in ammonium acetate 0.05 M pH 7.6. The amounts of 125I and 131I bound to the gammaglobulin fraction were then measured. The results in any unknown sample were compared to those obtained when an equal amount of standard serum was identically treated, and the results were expressed as unknown/standard ratios of bound 125I and bound 131I, respectively. The mean binding ratios for T3 and T4 found in sera obtained from 42 normal subjects were 0.7 +/- 0.4 SD and 0.8 +/- 0.5, respectively. Elevated binding ratios for both T3 and T4 were found in sera obtained from 5 out of 43 cases of primary hypothyroidism and in 2 out of 34 cases of hyperthyroidism. The binding ratios were elevated for only T3 in 10 cases of primary hypothyroidism and in 5 cases of hyperthyroidism. Antibodies against T4 were detected in one case of primary hypothyroidism. High binding ratios for T3 were also observed in one patient with secondary hypothyroidism who had received treatment with dessicated thyroid for several years. In most of the positive sera, anti-thyroglobulin antibodies, as measured by passive hemagglutination, could also be detected. For one serum containing anti-T3 antibody and another containing anti-T4 antibody, the binding affinity and capacity were estimated by Scatchard plot analysis; affinity constants were 5.4 x 10(8) L/mol and 1.3 x 10(9) L-mol, respectively; capacities 1.4 ng/ml and 1.2 ng/ml, respectively. The presence of anti-T3 and anti-T4 antibodies in serum may result in an apparent lowering of the serum T3 and T4 concentrations, respectively.

OBJECTIVE

To determine whether thyroid dysfunction is found with increased frequency in patients with rheumatoid arthritis (RA).

METHODS

A controlled prospective survey was conducted on a cohort of patients with RA derived from a hospital clinic and a private surburban rheumatology practice. A control group with similar demographic features was generated from the same sources and included subjects with either osteoarthritis or fibromyalgia. Consecutive patients were evaluated over a six month period. The evaluation included a complete history and physical examination, and determination of serum thyroxine, free thyroxine, triiodothyronine, thyroid stimulating hormone (IRMA), antinuclear antibodies, and rheumatoid factor.

RESULTS

Of the 91 women with RA evaluated, 29 (30%) had evidence of thyroid dysfunction compared with 10 (11%) of 93 controls. The excess thyroid dysfunction is due to either hypothyroidism or Hashimoto's thyroiditis and was independent of age, increasing duration of disease, rheumatoid factor, and antinuclear antibodies.

CONCLUSIONS

Thyroid dysfunction is seen at least three times more often in women with RA than in women with similar demographic features with non-inflammatory rheumatic diseases such as osteoarthritis and fibromyalgia.

Calorie restriction to produce stable long-term adult body weight for approximately 10 years prevents obesity and diabetes in middle-aged rhesus monkeys. To determine whether this dietary regimen also alters energy metabolism, the doubly labeled water method was used to measure total daily energy expenditure. Six adult male rhesus monkeys, which had been calorie-restricted for more than 10 years, were compared to 8 control adult monkeys, which had been fed ad libitum for their entire lives. The calorie-restricted monkeys weighed less than the ad-libitum fed monkeys and had a lower lean body mass and lower fat mass. Total daily energy expenditure was lower in the calorie-restricted than in the ad-libitum fed monkeys, even when corrected for differences in body size using body weight (563 +/- 64 vs 780 +/- 53 kcal/d; p < .04), surface area (547 +/- 67 vs 793 +/- 56 kcal/d; p < .05), or lean body mass (535 +/- 66 vs 801 +/- 54 kcal/d; p < .02) as covariates. Thyroxine (T4) was reduced and the free thyroxine index was suggestively lower in the calorie-restricted monkeys whereas triiodothyronine (T3) was not significantly different. Activity in calorie-restricted monkeys was similar to that of a weight-matched younger adult comparison group. We conclude that the process of preventing obesity by long-term caloric restriction causes a significant and sustained long-term reduction in energy expenditure, even when corrected for lean body mass.

BACKGROUND

This Case Conference reviews the normal changes in thyroid activity that occur during pregnancy and the proper use of laboratory tests for the diagnosis of thyroid dysfunction in the pregnant patient.

METHODS

A woman in the 18th week of pregnancy presented with tachycardia, increased blood pressure, severe vomiting, increased total and free thyroid hormone concentrations, a thyroid-stimulating hormone (TSH) concentration within the reference interval, and an increased human chorionic gonadotropin (hCG) beta-subunit concentration.

OBJECTIVE

During pregnancy, normal thyroid activity undergoes significant changes, including a two- to threefold increase in thyroxine-binding globulin concentrations, a 30-100% increase in total triiodothyronine and thyroxine concentrations, increased serum thyroglobulin, and increased renal iodide clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy produces an overall increase in thyroid activity, which allows the healthy individual to remain in a net euthyroid state. However, both hyper- and hypothyroidism can occur in pregnant patients. In addition, two pregnancy-specific conditions, hyperemesis gravidarum and gestational trophoblastic disease, can lead to clinical hyperthyroidism. The normal changes in thyroid activity and the association of pregnancy with conditions that can cause hyperthyroidism necessitates careful interpretation of thyroid function tests during pregnancy.

CONCLUSIONS

Assessment of thyroid function during pregnancy should be done with a careful clinical evaluation of the patient's symptoms as well as measurement of TSH and free, not total, thyroid hormones. Measurement of thyroid autoantibodies may also be useful in selected cases to detect maternal Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal consequences of maternal thyroid dysfunction.

Turnover rates of glucose and free fatty acids were measured, using 3H-glucose and 14C-l-palmitic acid as tracers, in insulin-requiring diabetic patients at presentation and after insulin treatment. Correlations were sought with rates of substrate oxidation, determined independently from respiratory exchange, and with plasma hormone concentrations. The rates of appearance of glucose and of free fatty acids were increased in the diabetics to 17.6 and 10.2 micronmol min-1 kg-1 respectively. Both rates fell to normal (13.3 and 7.1 micronmol min-1 kg-1) after insulin. In the untreated state there was an inverse relationship between the rates of utilisation of glucose and free fatty acids (r = 0.61; p less than 0.05). It is suggested that this relationship represents the impairment of peripheral glucose utilisation by free fatty acids and by ketone bodies in vivo, so far only demonstrated in vitro. The tracer calculated rates of glucose utilisation correlated well over a wide range with the respiratory quotient in untreated diabetics, while respiratory quotient was inversely related to free fatty acid turnover rates. In untreated diabetics plasma cortisol and 3,3', 5'-triiodothyronine (rT3) were increased whereas thyroxine and 3,5,3'-triiodothyronine (T3) were decreased. 3,5,3'-Triiodothyronine concentration was closely related to the metabolic clearance rate of glucose (p less than 0.05), while cortisol concentrations correlated with glucose production (p less than 0.02) and blood ketone body concentration (p less than 0.02). It is concluded that glucose overproduction is the major contributor to the hyperglycaemia of untreated diabetes.

The thyroid status of 82 institutionalized adults with Down's syndrome has been assessed. Compared to age and sex matched control subjects, these patients had significantly lower mean total serum thyroxine (T4) and triiodothyronine (T3) concentrations (T4; 69.1+/-22.2 nmol/1; (mean+/-SD) vs. 100.1+/-19.1, P less than 0.001; T13; 1.61+/-0.47 nmol/1 vs. 1.76+/-0.34, P less than 0.025), lower free thyroxine index (FTI), (FTI; 66.1+/-22.4 vs. 95.1+/-20.2, P less than 0.001), and higher basal serum thyrotrophin (TSH) concentrations (TSH; 7.6+/-10.7 mU/1 vs. 3.8+/-1.5, P less than 0.001). These changes were not related to age or sex. Abnormalities in one or more test of thyroid function were demonstrated in at least 38 (46%) of the 82 patients. Two main patterns of abnormality were defined: 1) subnormal T4, FTI and elevated basal TSH levels (primary hypothyroidism) in 13 (16%). All seven of the 13 patients in whom TRH tests were performed showed the expected exaggerated TSH response, and seven out of the 13 patients (54%) had positive thyroid antibodies, 2) Subnormal T4, subnormal or low normal FTI, and basal TSH levels within the normal range in 18 (22%). The mean basal TSH concentration was, however, significantly higher than in patients with normal T4 and FTI levels, suggesting a minor degree of thyroid failure. Only two of the 18 patients (11%) had positive thyroid antibodies. Of the 17 patients in the group tested, 13 showed a normal TSH response to TRH, three an exagerrated response (all females), and one had an impaired response. Other patterns of abnormal thyroid function were observed occasionally: one female patient had biochemical T3 toxicosis; another had the biochemical pattern of subclinical hypothyroidism, four patients with normal basal T4, FTI and TSH levels showed an exaggerated TSH response to TRH and one patient had an impaired response. These data indicate that htyroid dysfunction, in particular hypothyroidism, is common in adults with Down's syndrome, though specific tests are usually required to make the diagnosis. The general reduction in thyroid function in Down's syndrome may be due to impaired development of the thyroid gland. However, frank chemical hypothyroidism may occur only when thyroiditis is superimposed on preexisting diminished thyroid reserve.

Inappropriate secretion of thyrotropin (IST) is characterized by elevated serum free thyroid hormone and unsuppressed thyrotropin (TSH) levels, and results from either a TSH-secreting pituitary tumor (nIST) or a selective resistance to thyroid hormone action (nnIST). Although in most patients TSH levels are definitely high, in a quarter of the cases they are within the 'normal range'. In some of these cases, TSH had an elevated biologic activity and an apparent molecular weight smaller than in normals. The current availability of ultrasensitive TSH immunoradiometric assay, able to distinguish suppressed from unsuppressed TSH levels enables the recognition of the disease. The distinction between nnIST and nIST rests on clinical, neuroradiological, and biochemical criteria, the most useful of which are the alpha-subunit:TSH molar ratio (increased in nIST), and the evaluation of the TSH responses to thyrotropin-releasing hormone and high doses of 3,5,3'-triiodothyronine, both qualitatively normal in nnIST, while absent in nIST. The therapy of choice for patients with nIST is pituitary surgery, followed by irradiation in case of surgical failure. Chronic administration of bromocriptine is effective in a minority of cases. The long-acting somatostatin analogue SMS 201-995 has given promising results in 2 patients. In nnIST, bromocriptine is frequently uneffective, while small doses of 3,5,3'-triiodothyronine or 3,5,3'-triiodothyroacetic acid, a thyroid hormone derivative with a strong inhibitory effect on TSH secretion but poor thyromimetic activity on peripheral tissues, are effective in controlling TSH hypersecretion.

Serum levels of thyroid stimulating hormone, thyroxine, triiodothyronine, free T4, thyroxine-binding globulin, reverse T3, and the TSH secretory areas and peak T3 after intravenous injection of 40 micrograms thyrotropin-releasing hormone were determined weekly from day 5 to 6 to 11 weeks of age in 42 unselected full-term and 61 preterm Belgian infants. The results on day 5 indicated a progressive deficit of thyroid function related to the degree of prematurity. In 92 infants this deficit progressively decreased with age and disappeared at 5 to 7 weeks. However, 11 infants developed biochemical evidence of overt but transient hypothyroidism. Belgian neonates are relatively iodine deficient, and this factor affects the constitution of iodine stores within the thyroid gland: (1) the urinary concentrations of iodine in the 103 infants studied in Belgium were markedly lower than in 30 infants from California; and (2) The iodine concentration of the thyroid gland in preterm infants who died during the 10 first days of life was almost three times lower in Brussels than in Toronto. The results indicate that, in Belgium, the effects of relative iodine deficiency on thyroid function are superimposed on and mask the physiologic state of tertiary hypothyroidism in prematurity.

BACKGROUND

In proficiency testing surveys, there are differences in the values reported by users of various analytic methods. Two contributors to this variation are calibrator bias and matrix effects of proficiency testing materials.

OBJECTIVE

(1) To quantify the biases of the analytic methods used to measure thyroid-stimulating hormone, thyroxine, triiodothyronine, free thyroxine, and free triiodothyronine levels; (2) to determine if these biases are within allowable limits; and (3) to ascertain if proficiency testing materials correctly identify these biases.

METHODS

A fresh frozen serum specimen was mailed as part of the 2003 College of American Pathologists Ligand and Chemistry surveys. The means and SDs for each analytic method were determined for this sample as well as for a proficiency testing sample from both surveys. In the fresh frozen serum sample, target values for thyroxine and triiodothyronine were determined by isotope dilution/liquid chromatography/tandem mass spectrometry. All other target values in the study were the median of the means obtained for the various analytic methods.

METHODS

Calibration biases were calculated by comparing the mean of each analytic method with the appropriate target values. These biases were evaluated against limits based on intra- and interindividual biological variation. Matrix effects of proficiency testing materials were assessed by comparing the rank of highest to lowest analytic method means (Spearman rank test) for each analyte.

METHODS

Approximately 3900 clinical laboratories were enrolled in the College of American Pathologists Chemistry and Ligand surveys.

RESULTS

The number of methods in the Ligand Survey that failed to meet the goals for bias was 7 of 17 for thyroid-stimulating hormone and 11 of 13 for free thyroxine. The failure rates were 12 of 16 methods for thyroxine, 8 of 11 for triiodothyronine, and 9 of 11 for free triiodothyronine. The means of the analytic method for the proficiency testing material correlated significantly (P < .05) only with the fresh frozen serum means for thyroxine and thyroid-stimulating hormone in the Chemistry Survey and free triiodothyronine in the Ligand Survey.

CONCLUSIONS

A majority of the methods used in thyroid function testing have biases that limit their clinical utility. Traditional proficiency testing materials do not adequately reflect these biases.

Primary mixed cultures of trypsin-dissociated fetal and newborn rat brain and spinal cord have been grown in a serum-free medium. This medium, containing insulin, selenium, transferrin and triiodothyronine, was optimized for oligodendrocyte survival by determining the number of cells which expressed surface galactocerebroside. Comparison of cultures in serum-containing and serum-free media revealed that galactocerebroside positive (GalC+) oligodendrocytes could be detected earlier in the absence of serum. This early differentiation occurred in the absence of the added hormones and nutrients, whose main function appeared to be to prolong survival of the cells. The effect of serum on the differentiation of oligodendrocytes was studied by comparing the expression of surface GalC in media containing 2.5% or 10% fetal calf serum. At a given time a much greater number of GalC+ oligodendrocytes could be detected at the lower serum concentration. However, when cultures were transferred from 10% serum to serum-free medium (or 1% serum) large numbers of GalC+ oligodendrocytes subsequently appeared, showing that precursors were present in the high-serum medium, but that they were unable to differentiate. Possible explanations of the effect of serum on oligodendrocyte differentiation are discussed.