Subclinical hypothyroidism: deciding when to treat

While screening patients for thyroid disease, physicians often find increased thyrotropin-stimulating hormone (TSH) levels in patients whose free thyroxine (T4) levels are not below normal. This state, termed "subclinical hypothyroidism," is most commonly an early stage of hypothyroidism. Although the condition may resolve or remain unchanged, within a few years in some patients, overt hypothyroidism develops, with low free T4 levels as well as a raised TSH level. The likelihood that this will happen increases with greater TSH elevations and detectable antithyroid antibodies. Because patients with subclinical hypothyroidism sometimes have subtle hypothyroid symptoms and may have mild abnormalities of serum lipoproteins and cardiac function, patients with definite and persistent TSH elevation should be considered for thyroid treatment. Levothyroxine, in a dosage that maintains serum TSH levels within the normal range, is the preferred therapy in these patients.     

Exogenous sphingosine 1-phosphate induces neurite retraction possibly through a cell surface receptor in PC12 cells

Alterations in thyroid function tests are very common in patients with NTI. Multiple, complex, and incompletely understood mechanisms are involved in these abnormalities. Knowledge of these abnormalities is necessary to avoid errors in the diagnosis of thyroid disease. Measurement of serum TSH, free T4, and free T3 levels by direct equilibrium dialysis/RIA methods probably yield most useful (accurate) information in the setting of NTI. Patients with low free T4 by these methods and normal or low TSH have secondary hypothyroidism. This may be due to NTI per se, drugs administered for treatment of NTI, or associated pituitary or hypothalamic disease; the latter consideration may require evaluation of cortisol reserve, PRL, and/or gonadotropins. A serum TSH level above 20-25 microU/mL probably reflects primary hypothyroidism; accompanying findings of goiter, low free T4, and positive antithyroid antibodies help establish the diagnosis. An elevated serum concentration of rT3 argues against hypothyroidism. Studies have demonstrated no discernible benefit of treatment of NTI patients with T4. Some studies have shown a few benefits of treatment with T3 in selected cases, but much more needs to be learned. There is no evidence of harm by treatment of NTI patients with up to replacement doses of T3. As some NTI patients may indeed be hypothyroid, the term ESS should be replaced with NTIS.     

Primary end points in phase III clinical trials of severe head trauma: DRS versus GOS. The American Brain Injury Consortium Study Group

Analysis of patients with persistent hypothyroidism due to Hashimoto's thyroiditis suggested that metabolism of thyroxine (T4), including deiodination to triiodothyronine (T3), was reduced in the elderly. The increase in the serum levels of T4 after oral administration of T4 was augmented in the elderly, whereas increase in the serum T3 level was not. Possibly due to the reduction in the pituitary deiodinase, suppression by T4 administration of serum thyrotropin (TSH) level was the same in elderly as in younger subjects despite a larger increase in the serum levels of T4 in the elderly. Consequently, the amount of T4 required to maintain a normal serum TSH level did not differ between elderly and younger subjects. Other characteristics of elderly patients with Hashimoto's thyroiditis were that goiter size was smaller, that hypothyroidism was more frequent, and that Graves' disease was less frequent.     

Triiodothyronine and thyroxine interrelationships in health and disease

With the recent development of radioimmunoassay techniques for the measurement of serum triiodothyronine (T3) concentration, new concepts have arisen regarding the biologic role of T3 in health and disease and its interrelationships with thyroxine (T4). An awareness of the influence of clinical conditions that affect binding of thyroid hormone to plasma proteins is required in the interpretation of moderately increased or decreased serum T3 values. Hormone preparations containing T3 may produce transient increases in T3 concentration into the hyperthyroid range. Measurements of serum T3 concentration appear to be particularly indicated in clinical situations in which hyperthyroidism is suspected but serum T3 resin uptake and serum T4 values are normal, to exclude the T3-toxicosis syndrome. Also, when serum T4 values are in the hypothyroid range, measurement of serum T3 as well as serum thyrotropin (TSH) concentrations can lead to recognition of abnormalities in thyroid gland biosynthesis. Before a diagnosis of hypothyroidism is made on the basis of a low serum T3 value, one must exclude a variety of clinical nonthyroidal conditions that can result in changes in plasma T3 protein binding or impaired peripheral conversion of T4 to metabolically active T3 without producing a hypometabolic state.     

Improved and effective assays of the glutamic oxaloacetic transaminase by the coenzyme-apoenzyme system (CAS) principle

257 patients have been reviewed 1-5 years (mean 3 years 2 months) after receiving one of five dose regimes of 125I for thyrotoxicosis. The cumulative incidence of hypothyroidism was 34% and of persistent thyrotoxicosis 17%. The group receiving doses between 351 and 500 muCi/g had the highest proportion of euthyroid patients (65%) with the lowest requirement for repeat therapy (46%). In the euthyroid patients, increasing dose of 125I was associated with progressive decline in mean thyroxine (T4) level and free thyroxine index (FTI) within the respective normal ranges, and increase in mean thyroid stimulating hormone (TSH) level to above the normal range. Euthyroid patients with elevated TSH levels had significantly lower T4 and FTI values compared with those with normal TSH, and showed a 3-4-fold increased rate of development of hypothyroidism over 1 year. Euthyroid patients with elevated T3 levels remained euthyroid during the subsequent year and mean T3 levels declined significantly, suggesting that abnormally elevated T3 levels after 125I do not generally indicate impending relapse of thyrotoxicosis. It is concluded that the potential admantages of 125I therapy for thyrotoxicosis in reducing the incidence of hypothyroidism have not been realized in practice.     

Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states

Variation in asparagine-linked carbohydrate chains have a major impact on TSH biological properties. In particular, highly sialylated TSH is characterized by impaired intrinsic bioactivity and prolonged half-life. The aim of the present study was to investigate the changes in the degree of sialylation of circulating TSH isoforms that may occur in several physiological and clinical situations. Bioactivity and terminal sugar residues of immunopurified TSH were studied in 26 normal adults (day- and nighttime serum pools), 2 cord serum pools from normal fetuses during the third trimester, 1 fetus with primary hypothyroidism (PH; 27th week), 1 fetus with resistance to thyroid hormone (RTH; 28th and 33rd weeks), 24 patients with PH (before and during L-T4 treatment), and 5 patients with RTH before and during triiodothyrocetic acid (TRIAC) treatment. Nighttime TSH isoforms have an increased degree of sialylation compared to daytime TSH (35.8 +/- 9.7% vs. 23.8 +/- 5.8%; P < 0.03), thus accounting for the lower bioactivity [biological/immunological TSH ratio (TSH B/I), 1.3 +/- 0.4 vs. 2.0 +/- 0.2; P < 0.0007]. In adult PH, TSH isoforms are highly sialylated (45.4 +/- 7.6%; P < 0.007), showing an impaired bioactivity (0.7 +/- 0.3; P < 0.001). L-T4 therapy was accompanied by a trend toward normalization of TSH biological properties; TSH B/I was higher (1.0 +/- 0.3; P < 0.01), and the degree of sialylation was lower (36.8 +/- 7.0%; P < 0.02). A significant inverse correlation between TSH B/I values and the degree of sialylation was observed (P < 0.001). In normal fetuses, extremely bioactive asialo-TSH isoforms are circulating during the 3rd trimester. The impaired thyroid hormone action, such as that occurring in hypothyroid or RTH fetuses, induces an early expression of alpha-2,6-sialyltransferase activity within thyrotropes and results in the secretion of high amounts of sialylated TSH isoforms (34.6% and 26.3%). A hybrid TSH with peculiar terminal sugar residues and enhanced bioactivity is circulating in patients with RTH (TSH B/I, > or = 2.2). Treatment with low doses of TRIAC can initially reduce thyroid hormone secretion in RTH, mainly through the secretion of TSH isoforms with changed terminal sugar residues and reduced bioactivity (TSH B/I, 0.9-1.7). In conclusion, changes in the terminal sialic acid residues modulate the biological properties of circulating TSH, play a relevant physiopathological role in various situations, and contribute to adjust thyroid-stimulating activity to temporary needs.     

Transient hypothyroidism after iodine-131 therapy for Grave's disease

We studied 355 patients with Grave's disease to characterize transient hypothyroidism and its prognostic value following 131I therapy. METHODS: The patients received therapeutic 131I treatment as follows: 333 received a dose < 10 mCi (6.6 +/- 1.9 mCi) and 22 received a dose > 10 mCi (12.8 +/- 2.9 mCi). Diagnosis of transient hypothyroidism was based on low T4, regardless of TSH within the first year after 131I followed by recovery of T4 and normal TSH. RESULTS: After administration of < 10 mCi 131I, 40 patients developed transient hypothyroidism during the first year; transient hypothyroidism was symptomatic in 15. There was no transient hypothyroidism after high doses (> 10 mCi) of 131I. Iodine-131 uptake > 70% at 2 hr before treatment was a risk factor for developing transient hypothyroidism (Odds ratio 2.8, 95% confidence interval 0.9-9.4). At diagnosis of transient hypothyroidism, basal TSH levels were high (51%), normal (35%) or low (14%); therefore, the transient hypothyroidism was not centralized. If hypothyroidism developed during the first 6 mo after basal TSH > 45 mU/liter ruled out transient hypothyroidism. CONCLUSION: The development of transient hypothyroidism and its hormonal pattern did not influence long-term thyroid function. Since no prognostic factors reliably predicted transient hypothyroidism before 131I or at the time of diagnosis, if hypothyroidism appears within the first months after 131I, the reevaluation of thyroid function later is warranted to avoid unnecessary chronic replacement therapy.     

Comparison between TRH-stimulated TSH and basal TSH measurement by a commercial immunoradiometric assay in the management of thyroid disease

In order to assess the current diagnostic role of the TRH test following the introduction of more sensitive "second generation" TSH assays, we studied a series of 259 outpatients, 237 women and 22 men, mean age 44.7 years (range 12-82), 91 of whom (35%) with untreated simple goiter, 133 (51%) with simple nodular goiter on steady state I-thyroxine treatment, 18 (7%) with overt or subclinical hyperthyroidism and 17 (7%) with overt or subclinical hypothyroidism, compared to a control group of 26 euthyroid healthy subjects. Serum TSH was measured by a commercial immunoradiometric assay (clinical sensitivity 0.1 microU/ml). TSH response to TRH was evaluated 30 minutes after giving 200 micrograms TRH i.v. bolus, the results being analyzed both as absolute increase (delta-TSH=stimulated TSH minus basal TSH) and as relative increase (R-TSH stimulated TSH/basal TSH). Using cut-off values of 0.3-3.2 microU/ml, basal TSH measurement was able to detect hypothyroidism (specificity = 100%) and to exclude hyperthyroidism (sensivity = 96.9%), but failed to accurately prove hyperthyroidism (specificity = 93.4%) and, above all, to exclude hypothyroidism (sensitivity = 35.3%) in our ambulatory patients. The delta-TSH values showed a basal TSH dependent linear increase (r = + 0.87, p < 0.001) both including only patients (n = 139) with basal TSH level in the euthyroidism range and including all patients (n = 223) having TSH responsive to TRH. All the patients with detectable basal TSH level displayed detectable TSH response to TRH, as did 19 (= 23.5%) of 81 patients with undetectable (< 0.1 microU/ml) basal value. In particular: a) for subnormal but detectable basal TSH ranging between 0.1 and 0.2 microU/ml, TSH was always hyporesponsive (delta-TSH < or = 2.5 microU/ml), while between 0.2 and 0.3 microU/ml TSH was hyporesponsive in 72.2% and normoresponsive (delta-TSH > 2.5 and < or = 11.9 microU/ml) in the remaining 27.8%; b) for basal TSH values within the normal range (0.3-3.2 microU/ml). TSH was hyporesponsive in 13.7%, normoresponsive in 74.8% and hyperresponsive in 11.5%; c) for high basal TSH values TSH was always hyperresponsive. The analysis of R TSH showed relatively constant values in the range of euthyroidism and hypothyroidism (m +/- SD: 7.4 +/- 2.3 and 7.7 +/- 3.1, respectively), and a marked differentiation of hyperthyroid patients whose R-TSH values were significantly lower (4.2 +/- 3.4) but had a wide individual variability. Linear regression analysis of basal or stimulated TSH and circulating thyroid hormones showed a close negative relationship, being highly significant between delta-TSH and T4 (r = 0.57, p < 0.001) and delta-TSH and FT4 (r = 0.46, p < 0.001). In conclusion, after the introduction of current second generation TSH immunoradiometric assay, the diagnostic role of the TRH test is greatly limited but not to be excluded: it can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidism and in the precise evaluation of the degree of TSH suppression in patients with a subnormal basal TSH, either for endogenous thyrotoxicosis or I.-thyroxine treatment.     

Clinical significance of thyrotropin measurement by immunoradiometric assay and thyrotropin-releasing hormone test

The levels of serum TSH were measured by a sensitive immunoradiometric assay (IRMA) method and the responses of TSH to TRH stimulation were observed in three groups of hyperthyroidism, primary hypothyroidism and secondary hypothyroidism. The levels of serum TSH were found to be undetected in 98% (1/51) of the patients with hyperthyroidism, very high in 100% (35/35) of the patients with primary hypothyroidism and normal in 91% (30/33) of the patients with secondary hypothyroidism. TRH test showed no responses of TSH in all patients with hyperthyroidism, high responses in all patients with primary hypothyroidism and blunt responses in 69% (11/16) of patients with secondary hypothyroidism. The results indicate that the measurement of serum TSH by IRMA is a sensitive index in the diagnosis of hyperthyroidism and primary hypothyroidism, but can not be differentiated the secondary hypothyroidism from normal conditions. TRH test may be helpful in the differential diagnosis between secondary hypothyroidism and normal conditions.     

Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation

The occurrence of central hypothyroidism in previously euthyroid children during GH therapy has been reported with widely varying incidence. We monitored the acute effects on the hypothalamic-pituitary-thyroid axis in 15 euthyroid children with classic GH deficiency during the first year of GH therapy. All were initially euthyroid, as assessed by normal baseline TSH, T4, free T4, and T3 levels and negative antithyroid antibodies. A thyroid profile (T4, free T4 index, T3, rT3, and TSH) was performed at baseline and 1, 3, 6, 9, and 12-15 months after GH therapy began; a TRH stimulation test was performed at baseline and after 1, 3, and 9 months of therapy. By 1 month, there were significant decreases in T4, free T4 index, and rT3, and significant increases in T3 and the T3/T4 ratio. The changes from baseline values were greatest at 1 month, were almost universal for all thyroid values, and showed a gradual return to baseline from 3-12 months. There were no clinical signs of hypothyroidism and no change in baseline or TRH-stimulated TSH levels or in cholesterol levels, and all patients grew at velocities expected for the treatment schedule. There is little evidence for the development of clinically significant hypothyroidism in the great majority of initially euthyroid patients after GH therapy is begun. T4 supplementation is seldom needed in such patients.     

Hypothyroidism and hyperthyroidism in major depression revisited

BACKGROUND: The aim of our study was to evaluate the prevalence of thyroid abnormalities among depressed outpatients and to examine the response to treatment of those subjects with relatively low or high thyroid hormone levels. METHOD: Outpatients (N = 200) 18 to 65 years of age who met DSM-III-R criteria for major depression were screened for the presence of thyroid abnormalities using a number of thyroid indices. Of these patients, 166 were then treated openly with the antidepressant fluoxetine for 12 weeks. We assessed whether patients with relatively low or high thyroid hormone levels had a different response to treatment compared with other patients. The 17-item Hamilton Rating Scale for Depression (HAM-D-17) was administered during the study to assess changes in depressive symptoms. Thyroid function was assessed by measuring T3, T4, free T4 index (FT4I), T3 uptake (T3U), and serum thyroid-stimulating hormone (TSH) levels. RESULTS: No clinical cases of hyperthyroidism or hypothyroidism were detected. Of the patients examined, 5 (2.6%) had slightly elevated TSH levels (range, 4.7-8.2); none of these had T4 or FT4I levels below the normal range. Subnormal levels of T4 or FT4I were found in 1 subject (0.5%). T3 and T3U levels were below the normal range in a larger number of patients (7.6% and 15.0% respectively), but only 1 of these patients had elevated TSH levels. None of the patients had levels of TSH below the normal range, and only 3 subjects (1.5%) had T4 levels above the normal range. No relationship was found between response rate (assessed as either change in HAM-D-17 score or as remission of depressive symptoms with a HAM-D-17 score < or = 7 for 3 consecutive weeks) and each of the thyroid tests, even after adjusting for baseline severity of depression. CONCLUSION: In depressed outpatients, it appears that hypothyroidism and hyperthyroidism are extremely uncommon and that the presence of subtle thyroid function abnormalities does not have an impact on treatment outcome.     

Bacillus thermoamyloliquefaciens KP1071 alpha-glucosidase II is a thermostable M(r) 540,000 homohexameric alpha-glucosidase with both exo-alpha-1,4-glucosidase and oligo-1,6-glucosidase activities

The lethality of acute renal failure exceeds 50% due to multiorgan dysfunction. In such critically ill patients a reduction of thyroid hormone concentrations without clinical symptoms or laboratory evidence of hypothyroidism frequently occurs. Selenium has recently been shown to play a major role in thyroid hormone metabolism. The aim of this study was to investigate the possible influence of selenium on thyroid hormone metabolism in acute renal failure. Changes in thyroid metabolism were related to the severity of multiorgan failure and to the clinical course. Thyroxine (T4), tri-iodothyronine (T3), free-T4, free-T3, thyrotropin (TSH), serum creatinine, and plasma selenium concentrations in 28 patients (mean age 60 +/- 13) with acute renal failure and multiple-organ dysfunction syndrome were determined initially, and every 3 days after hospital admission. The plasma selenium concentration was found to be reduced compared to normal controls (32 +/- 14 vs. 70-120 micrograms/L). T4 (56 +/- 15 nmol/L, normal range 64-148), T3 (1.31 +/- 0.38 nmol/L, normal range 1.42-2.46), free-T3 (3.1 +/- 1.0 pmol/L, normal range 4.7-9.0), and free-T4 (10.8 +/- 4.0 pmol/L, normal range 10.3-25.8) values were low in 50-70% of the patients at the time of presentation. Plasma TSH concentrations were within the normal range (0.59 +/- 0.79 mU/L, normal range 0.25-3.1), and no clinical symptoms of hypothyroidism were observed. T4 concentration was higher in patients who survived acute renal failure compared to nonsurvivors (62 +/- 22 vs. 51 +/- 16 nmol/L, p < 0.05). Plasma selenium concentration was lower in patients with a severe organ dysfunction syndrome (36 +/- 10 vs. 29 +/- 19 micrograms/L) and correlated with the number of organ failures in these patients (r = -0.247, p < 0.05). T4 and free-T4 values paralleled decreasing selenium concentrations (r = 0.35, p < 0.05). Thyroid hormone levels were reduced in patients with acute renal failure without an increase in TSH. An increase in T4 concentrations became apparent during treatment and may be related to a favorable outcome in acute renal failure. Thyroid hormone concentrations paralleled plasma selenium levels, indicating a possible influence of selenium on thyroid function in acute renal failure.     

Plasma renin and aldosterone in thyroid diseases

The effect of thyroid hormones on the renin-angiotensin-aldosterone system has not been fully resolved. Highly specific immunoassays for measurement of renin, aldosterone, free T4 (fT4), free T3 (fT3) and ultrasensitive TSH enables a direct and more accurate measurement of these hormones. We investigated the relationship between plasma renin, aldosterone and thyroid hormones in the basal state and after intravenous frusemide. This is a cross-sectional study involving 37 patients with thyrotoxicosis, 42 rendered euthyroid with normal fT4, fT3 and TSH levels, 17 with euthyroid levels of fT4 and fT3 but suppressed TSH, and 11 with hypothyroidism. Basal plasma renin was significantly higher in thyrotoxicosis (63.4 +/- 9.8 microU/ml, mean +/- SEM) compared to euthyroid (32.7 +/- 4.4 microU/ml) and hypothyroid (26.7 +/- 9.8 microU/ml). Basal plasma renin for euthyroid with suppressed TSH (41.0 +/- 7.4 microU/ml) was significantly higher than hypothyroid (p = 0.02). Basal plasma aldosterones were not significantly different except for suppressed TSH (157.7 +/- 13 pg/ml), which was higher than normal (109.9 +/- 10.4 pg/ml; p = 0.04). Following frusemide, plasma renin and aldosterone were significantly increased in all groups. Plasma renin was highly correlated to fT3 (r = 0.405, p < 0.001), total T3 (r = 0.359, p < 0.001), fT4 (r = 0.331, p < 0.001) and TSH (r = 0.300, p < 0.001) in the basal state, but less to total T4 (r = 0.248, p < 0.01). Plasma renin correlated poorly to serum aldosterone (r = 0.212, p < 0.03). This study clearly showed that regulation of renin was mainly influenced by fT3, and that aldosterone response to frusemide was blunted in thyrotoxicosis despite normal electrolytes.     

Role of protein degradation in the growth of livers after a nutritional shift

Four patients with idiopathic pituitary dwarfism were shown to have growth hormone (GH), adrenocorticotropin (ACTH), and luteinizing hormone (LH) deficiencies. Basal levels of thyrotropin (TSH) were within normal range in three patients and slightly elevated in one. Exaggerated and delayed responses were obtained after TSH-releasing hormone (TRH) stimulation. Serum thyroxine (T4) values were low (2.3 +/- 0.4 mug/100 ml), while triiodothyronine (T3) levels were in the normal range (1.22 +/- 0.25 ng/ml), both rising substantially after exogenous TSH and consecutive TRH administration. Their hypothyroid state was, therefore, probably due to TRH deficiency. To examine the dose of L-T4 necessary to produce inhibition of the TSH response to TRH, 50 mug/m2/day of L-T4 was administered to these patients. At the end of 4 weeks of replacement, serum T4 rose to 5.2 +/- 0.5 mug/100 ml, whereas T3 was unchanged from the previous levels, after which TSH responses to TRH were completely suppressed in all patients. As a control group, six patients with primary hypothyroidism received gradually increasing doses of L-T4 for 4-week periods, and TSH response to TRH was tested at the end of each dosage of L-T4, until complete inhibition of TSH release was obtained. The primary hypothyroid patients required approximately 150 mug/m2/day of L-T4 for suppression of TSH response to TRH. At this dosage, serum T4 and T3 levels were 8.5 +/- 0.9 mug/100 ml and 2.34 +/- 0.5 ng/ml respectively, which were significantly higher than those levels in the pituitary dwarfs (P less than 0.001 for T4 and P less than 0.01 for T3). These observations indicate that the set point of TSH release in feedback inhibition by throxine is low in idiopathic hypopituitarism with TRH deficiency, and TRH seems to control the pituitary sensitivity to feedback regulation of thyroid hormones.     

MRI-demonstrable regression of a pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy

Although magnetic resonance imaging (MRI) characteristics of pituitary gland hyperplasia in primary hypothyroidism have been previously described, the time span necessary for the regression of the hyperplasia in response to acute thyroid hormone (TH) therapy has not been defined. A 26-yr-old woman underwent 131I ablation 11 yr before admission. Intermittent poor compliance to levothyroxine (LT4) therapy led to inappropriately high serum thyroid-stimulating hormone (TSH) for her triiodothyronine (T3) and thyroxine (T4) levels. The patient was investigated to rule out TSH-secreting pituitary adenoma or resistance to TH. On admission, the patient's clinical features and thyroid function tests, as well as thyrotropin-releasing hormone (TRH) and acute T3 suppression tests, were in favor of profound primary hypothyroidism. MRI revealed symmetrical enlargement of the pituitary gland with distinct morphological characteristics of a macroadenoma. The patient began high-dose TH therapy and was rescanned six days later. The follow-up scan revealed a dramatic shrinkage of the pituitary gland. Four weeks later, serum T4 and TSH were within the normal range, and repeat MRI scan of the pituitary at that time showed a normal gland. This case is the first to document dramatic shrinkage of pituitary hyperplasia in long-standing primary hypothyroidism within one week of acute TH therapy. MRI alone is unable to reliably differentiate between a TSH-secreting pituitary adenoma and hypothyroidism-induced pituitary hyperplasia. Dynamic endocrine testing as well as repeat pituitary MRI after a brief TH trial may provide a firm diagnosis in similar cases.     

Low T3 syndrome

Many nonthyroidal illnesses are associated with reduced serum T3 and, in more severe conditions, T4 concentrations, without increased serum TSH secretion. The term euthyroid sick syndrome (ESS) identifies these low T3 and low T3-T4 states. It may be difficult to exclude central hypothyroidism in patients admitted to medical intensive care units. The mortality rate has been found to be inversely correlated with the serum T4 concentration. These abnormalities are a consequence of altered hepatic T3 production from T4 (through type 1 5'-desiodase inhibition), T4 serum protein binding and hepatic transport, and TSH secretion. Many mediators and drugs are involved in the pathogenesis of ESS. The role of cytokines has recently been emphasized. It remains unclear whether ESS represents a physiological protective mechanism, or a damaging maladaptative response and whether early thyroid hormones administration might improve survival in severe non thyroidal conditions.     

Combined deficiency of thyroid stimulating hormone and growth hormone in a diabetic patient with Hashimoto thyroiditis

We report the case of a 36-year-old female patient with insulin dependent diabetes who developed hypothyroidism of pituitary origin after giving birth. She had low levels of free T4 and TSH with no response to i.v. TRH. Antimicrosome antibodies were increased (1/25000), suggesting Hashimoto's thyroiditis. The other hormones were normal except for a low level of growth hormone and insulin growth factor 1. There were no antibodies against the pituitary. MRI of the pituitary was normal. We suspect a vascular origin for this partial pituitary deficiency.     

Hormonal changes and pituitary histological and immunocytochemical studies of patients with multiple organ failure

OBJECTIVE: We investigated the correlation between the endogenous hormonal changes of pituitary-adrenal and pituitary-thyroid hormones and the prognosis of patients in multiple organ failure, and elucidated the mechanism of blunted thyrotropin (TSH) secretion by histological and immunocytochemical studies of anterior pituitary glands. PATIENTS: Forty-three patients were studied who had been admitted to the intensive care unit of Sapporo Medical University Hospital and had been diagnosed as having multiple organ failure. MEASUREMENTS: Pituitary adrenal hormones [corticotropin (ACTH), cortisol] and pituitary thyroid hormones [TSH, triiodothyronin (T3), free-T3, thyroxine (T4), free-T4, thyroxine-binding globulin (TBG)] were measured, and TSH and prolactin (PRL) responses thyrotropin-releasing hormone (TRH) were examined within 24 hours of admission to the ICU. Individual variables were compared between survivors (n = 19) and nonsurvivors (n = 24). Thirteen patients (five survivors, eight nonsurvivors) were investigated again before discharge from the ICU or death. Morphology was examined by hematoxilin-eosin staining, and avidin-biotin-peroxidase complex immunostaining was used to demonstrate the spectrum of TSH in 14 nonsurvivors. RESULTS: (1) ACTH levels remained within the normal range, while cortisol levels increased to above normal levels. Neither hormone showed significant differences between survivors and nonsurvivors. In nonsurvivors, cortisol levels decreased before death despite the increased ACTH levels. (2) T3 and free-T3 levels decreased markedly to below normal values, and reverse-T3 levels increased markedly to above normal values. Nonsurvivors showed significant differences in TSH, T4 and reverse-T3 levels compared with survivors. (3) TSH response to TRH was blunted in both groups but PRL response to TRH was normal. Nonsurvivors showed severely depressed TSH response. Nonsurvivors continued to show blunted TSH response to TRH, while this improved in survivors. (4) The histological study did not show very serious damages to anterior pituitary glands as TSH secretion was depressed. Many TSH immunoreactive cells were also observed by immunocytochemical study. CONCLUSION: Decreased cortisol, low T4 levels and blunted TSH response to TRH correlated with mortality in MOF patients. Histological and immunocytological studies suggest that blunted TSH secretion is not caused by pituitary damages or TSH exhaustion but by disturbances in TSH secretion. This blunted TSH secretion is reversible and its improvement is an indicator of survival.     

Accelerated evolution of cytochrome b in simian primates: adaptive evolution in concert with other mitochondrial proteins?

We have devised a practical, sensitive and specific method for simultaneous measurement of free thyroxine (FT4) and free triiodothyronine (FT3) in undiluted serum by direct equilibrium dialysis radioimmunoassay (RIA). Two hundred microliters serum sample was dialyzed against buffer (pH 7.4) for 20 hours at 37 degrees C and approximately 800 microL of the dialysate was used for measuring FT4 and FT3 simultaneously. The assay was set up in polystyrene tubes coated with anti-T4 antibody and available commercially for FT4 measurement (Quest-Nichols Institute, San Juan Capistrano, CA). The mean +/- SE (range) FT4 concentration (ng/dL) was 1.2 +/- 0.04 (0.7.0 to 2.30) in 54 normal subjects. It was significantly increased (3.6 +/- 0.4 [1.8 to 9.6], n = 20) in hyperthyroidism and clearly decreased (0.40 +/- 0.04 [1.10 to 0.70], n = 26] in hypothyroidism. All nonthyroid illness (NTI) patients had normal FT4 except 3, 2 of whom were on amiodarone and 1 had received heparin. Serum FT4 concentration was minimally elevated in 18 newborn cord blood serum (1.40 +/- 0.08 [0.90 to 2.2], cf. normal p < .05). The mean serum FT3 concentration (pg/dL) was 285 +/- 10 (134 to 454) in 54 normal sera. It was clearly increased in hyperthyroidism (1033 +/- 98 [593 to 2134], n = 20, p < .001). However, serum FT3 varied widely in hypothyroidism (27 to 597, mean 235 +/- 24, NS) as did serum total T3 (19 to 175). Interestingly, however, the mean serum FT3 concentration was normal (273 +/- 28 [62 to 575, NS]) in 25 NTI patients. All of these patients had low serum total T3 (46 +/- 5.0 [10 to 84], ng/dL; normal 84 to 160, p < 0.001), while FT3 was clearly normal in 21 of 25 patients and low in the remaining 4 patients. Similarly, among 18 newborn cord blood sera serum FT3 concentration was normal in 15 and subnormal only in the remaining 3 while all had clearly subnormal total T3 (28 to 74 ng/dL). CONCLUSIONS: (1) A practical, sensitive, and specific assay for simultaneous measurement of FT4 and FT3 is described; (2) FT3 is consistently elevated in hyperthyroidism while FT4 is elevated in most (approximately 85%) cases; (3) FT4 is consistently decreased in hypothyroidism but FT3 varies widely; (4). Serum FT3 concentration is normal in approximately 83% of patients with the low T3 syndrome in NTI and newborn cord blood serum. These data suggest that normal FT3 may explain clinical euthyroidism in many patients with the low T3 syndrome.     

Treatment of hypothyroidism with once weekly thyroxine

We compared daily T4 therapy with 7 times the normal daily dose administered once weekly in 12 hypothyroid subjects in a randomized cross-over trial. At the end of each treatment we measured serum free T4 (FT4), free T3 (FT3), rT3, and TSH levels and multiple markers of thyroid hormone effects at the tissue level repeatedly for 24 h. Compared with daily administration, the mean serum TSH before the administration of weekly T4 was higher (weekly, 6.61; daily, 3.92 microIU/mL; P < 0.0001), and the mean FT4 (weekly, 0.98; daily, 1.35 ng/dL; P < 0.01) and FT3 (weekly, 208, daily, 242 pg/dL; P < 0.01) were lower. A minimally elevated serum total cholesterol during weekly administration (weekly, 246.8; daily, 232.6 mg/dL; P < 0.03) was the only evidence of hypothyroidism at the tissue level. Compared with daily administration, the mean peak FT4 following weekly administration of T4 was significantly higher (weekly, 2.71; daily, 1.59 ng/dL; P < 0.0001), as was the mean peak FT3 level (weekly, 285; daily, 246 pg/dL; P < 0.01). None of the tissue markers of thyroid hormone effect changed compared to daily T4, and there was no evidence of treatment toxicity, including cardiac toxicity. During weekly T4 administration, autoregulatory mechanisms maintain near-euthyroidism. For complete biochemical euthyroidism a slightly larger dose than 7 times the normal daily dose may be required.