Pitfalls in the interpretation of thyroid function tests in old age and non-thyroidal illness

In hyperthyroidism, measurement of the serum thyroxine (T4) index or free concentration often suffices to establish the diagnosis. In hyperthyroidism, including 3,3',5-triiodothyronine (T3) toxicosis, thyrotrophin (TSH) response to thyrotrophin-releasing hormone (TRH) is blunted. Sensitive measurement of serum TSH may in the future be the first-line screening test not only for primary hypothyroidism but also for hyperthyroidism. In non-thyroidal illness serum T4, reverse T3 and T3 levels change in relation to severity of disease. In mild disease, T4 is initially increases as the severity of the non-thyroidal illness increases. Reverse T3 increases and serum T3 decreases when the patients become more ill. Serum TSH response to TRH is often blunted. In old age similar changes in serum iodothyronine concentrations may take place, probably related to existing non-thyroidal illness. Also many drugs may have different effects on serum parameters of thyroid function. In acute psychiatric diseases increased serum total and free T4 levels and a blunted TRH test may be encountered.     

Thyrotoxicosis with low serum total T3 level in patients with destructive thyroiditis and non-thyroidal illness.

The serum total T3 level, evaluated in 687 patients with thyrotoxicosis diagnosed by an elevated serum free T4 level and suppressed serum TSH level, was found to be high in 98.1% and normal in 1.9% of 592 patients with Graves' hyperthyroidism, and high in 75.8%, normal in 21.1% and low in 3.2% of 95 patients with destructive thyroiditis. Non-thyroidal illness was found in about a third of the patients with thyrotoxicosis and a normal serum total T3 level. The serum total T3 level was low with elevated serum thyroglobulin and reverse T3 levels in three patients with severe non-thyroidal illness, in whom the thyroidal radioactive iodine uptake was suppressed and the thyrotoxicosis resolved spontaneously with a normalization of the serum total T3 level after recovery from the destructive thyroiditis and non-thyroidal illness. It is therefore concluded that thyrotoxicosis with a low serum total T3 level, partially due to associated non-thyroidal illness, is more frequently found in patients with destructive thyroiditis than in those with Graves' hyperthyroidism.     

Relationship among thyrotropin (TSH), thyroid stimulating immunoglobulins, and results of triiodothyronine (T3) suppression test in patients with Graves' disease

To investigate the relationship between TSH and abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease in whom normal thyroid hormone levels in the serum were maintained by antithyroid drug therapy and in patients with euthyroid Graves' disease, determinations were made of the TSH concentration, action of thyroid stimulating immunoglobulins (TSAb and TBII), and T3 suppression. Out of thirty-three patients with hyperthyroid Graves' disease, twelve patients with subnormal TSH levels were all non-suppressible according to the T3 suppression test results and the detectability of TSAb and/or TBII was as high as 75%. In three out of five patients with euthyroid Graves' disease, the serum TSH level was subnormal. All three showed non-suppressibility in the T3 suppression test and positive action of either TSAb or TBII. One of them became clinically thyrotoxic when the TSAb activity was further increased and TBII became positive, and was therefore diagnosed as having hyperthyroid Graves' disease. The present findings suggest that there are still abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease who have low TSH, even if their thyroid hormone concentrations remain normal. Moreover, it is likely that some of the patients with euthyroid Graves' disease are actually in a state of subclinical hyperthyroidism because of the presence of abnormal thyroid stimulator(s).     

Effect of various beta-adrenolytic drugs and calcium channel blocker (nifedipine) on selected indicators of calcium-phosphorus metabolism in patients with hyperthyroidism and simple goiter

The study was aimed at evaluation of the effect of short-term treatment with one of the six beta adrenolytic drugs (propranolol, metoprolol, atenolol, pindolol, nadolol, acebutolol) and calcium antagonist nifedipine on the values of several parameters of calcium-phosphorus metabolism in 81 patients with hyperthyroidism (14 patients with Graves' disease, and 67 patients with toxic nodular goiter), and 82 patients with simple goiter. The patients studied have been divided into seven groups, each receiving one of the investigated drugs during four days. A significant decrease in the urinary excretion of hydroxyproline was found only in the patients with hyperthyroidism receiving propranolol. This effect of propranolol on hydroxyprolinuria was not related to the degree of lowering of serum T3 concentration observed in these patients.     

P-glycoprotein polymorphism in hypo- and hyper-thyroidism patients

P-glycoprotein (Pgp) is encoded by the multidrug resistance gene (MDR1) in humans and is the product of MDR1. It is expressed in various tissues and is related to drug distribution in intestinal erythrocytes, capillary endotel of brain, proximal tubules cells of kidneys and liver canalicular cells. Expression of Pgp is affected by Pgp polymorphism, and exon 26 C3435T polymorphism is the most common one. It has been thought that expression of Pgp is high in C-allele subjects and this situation is responsible for the resistance against some drugs and substances. Pgp may have a role in the distribution of thyroid hormones, drugs used for hypo- and hyperthyroidism and the resistance occurred. For this purpose possible relationship between T and C alleles and frequency of Pgp polymorphism as well as thyroid hormone distribution in patients with hypo- and hyperthyroidism was investigated. Thirty five hyperthyroidism patients diagnosed as Graves’ disease, 78 hypothyroidism patients diagnosed as Hashimoto’s thyroiditis and 100 healthy volunteers were included in the study. According to the results obtained no statistically significant difference was found in Pgp C3435T polymorphism between hypo- and hyperthyroidism patients. In addition, the serum free T3 levels of hyperthyroidism patients with C alleles was higher than those of subjects with T alleles. No statistically significant difference was seen in the CC, CT and TT genotype frequencies between the patients and control groups. In conclusion, it seems that Pgp polymorphism is not a predictor factor for the occurrence of hypo- and hyperthyroidism. There is a significant relationship between Pgp and the elevated serum free T3 levels of hyperthyroidism patients, and further research will help understand this situation.     

Serum T3 level in the patients with hyperthyroidism after therapy.

Serum T3 level in various thyroid diseases was determined in unextracted serum with the Dainabot kit for T3 RIA. The serum T3 level in 33 normal subjects was 0.8-1.6 ng/ml. It was 5.7 +/- 3.5 ng/ml (mean +/- S.D.) in 36 hyperthyroid patients, and undetectable to 0.8 ng/ml in 21 hypothyroid patients. Generally the serum T4 and serum T3 decreased in parallel after radioiodine therapy for hyperthyroidism. However, in some cases the serum T3 level remained high in spite of normalized serum T4 after radioiodine therapy. This state indicated "T3-toxicosis", and hyperthyroidism was apt to recur. When thyroid function was observed for 2 years following radioiodine treatment, the ratio of serum T3 (T3 level before treatment/T3 level after treatment) decreased more significantly as compared with the ratio of serum T4 in euthyroid cases. Serum T3 provides a more sensitive index of thyroid function than serum T4 in euthyroid states after radioiodine or anti-thyroid drug therapy. The present data indicate that the serum T3 level and the T4/T3 ratio are valuable aids in the estimation of prognosis of hyperthyroid patients after various treatments.     

Thyroid function in patients during long-term treatment with amiodarone]

Thyroid function was evaluated in 31 patients with disturbances of heart rhythm both before and after 13 months of treatment with amiodarone. An increase in blood serum T4 concentration and transient increase (only during the first three months of treatment) in TSH concentration have been observed in almost all the patients studied. Clinically evident form of hyperthyroidism was found only in one female patient. In two patients the changes in hormone concentrations suggesting hyperthyroidism were not accompanied by clinical manifestations, and in four patients there was no clinical hypothyroidism despite hormone levels suggesting such a state. In addition to the determinations of T3, T4 and TSH also the results of TRH-TSH test played an important role in diagnosing both hypo- and hyperthyroidism.     

Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH)

Thyroid hormone serum concentrations, the thyrotropin (TSH) and prolactin (PRL) response to thyrotropin-releasing hormone (TRH) were evaluated in patients undergoing cardiopulmonary bypass (CPB) conducted in hypothermia. During CPB a marked decrease of thyroxine (T4) and triiodothyronine (T3) concentration with a concomitant increase of reverse T3 (rT3) were observed similarly to other clinical states associated with the 'low T3 syndrome'. Furthermore, in the present study elevated FT4 and FT3 concentrations were observed. In a group of patients, TRH administered during CPB at 26 degrees C elicited a markedly blunted TSH response. In these patients, PRL concentration was elevated but did not significantly increase after TRH. The increased concentrations of FT4 and FT3 were probably due to the large doses of heparin administered to these patients. Thus, the blunted response of TSH to TRH might be the consequence of the elevation of FT4 and FT3 in serum, however, other factors might play a role since also the PRL response to TRH was blocked.     

Variation of the thyrotropin-releasing-hormone (TRH) stimulated thyrotropin (TSH) response in comparison with the tyhroid-gland-suppression test and the triiodothyronine (T3) and thyroxine (T4) blood levels in the so-called euthyroid endocrine ophthalmopathy]

21 patients with active signs of euthyroid Graves' disease were given 400 mug thyrotropin-releasing hormone (TRH) i.v. All subjects with unresponsiveness to TRH had a nonsuppressible thyroidal 131I-uptake. On the basis of serum total T3 14 patients were hyperthyroid, 2 more had an elevated value of free T3. 4 patients with normal total T3 and nonsuppressible 131I-uptake were unresponsive to TRH, in 2 of them the free T3 fraction was elevated, however. 4 subjects with nonsuppressible 131I-uptake had a TRH stimulated TSH response. 2 of these subjects had hyperthyroid values of free and total T3 in serum and responded to TRH with an exaggerate TSH increment. The variations of TRH responsiveness may demonstrate a different threshold of the pituitary and the peripheral T3 receptors.     

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.     

Acetylation phenotype and serum levels of T3 and T4 in patients with hypertension treated with propranolol

The acetylation phenotype has been investigated in 76 patients with untreated hyperthyroidism. In 65 of these patients including 23 with fast and 42 with slow acetylation phenotype, the blood serum concentrations of thyroxine and triiodothyronine were determined before and after propranolol therapy involving propranolol administration of a dose of 160 mg per day for 6 days. The occurrence of the fast acetylation phenotype among the patients with hyperthyroidism was similar to that found in the healthy population. Propranolol therapy caused a significant decrease in the blood serum concentration of triiodothyronine only in the patients with the slow acetylation phenotype.     

Serum T(4) and serum T(3) concentrations in immature captive whitetip reef sharks, Triaenodon obesus.

Serum T(3) (3,5,3' triiodothyronine) and serum T(4) (thyroxine) concentrations were repetitively assayed by radioimmunoassay over a three-year period in two male and two female immature captive whitetip reef sharks, Triaenodon obesus. These sharks were maintained at the Waikiki Aquarium, Honolulu, Hawaii, in an open system holding pool receiving 568 liters per minute of water from a saltwater well with an iodide concentration of 0.076 mg/liter. No significant male-female difference was observed for either serum T(3) or serum T(4). No seasonal pattern of serum T(3) was detected (P = 0.07). Serum T(3) concentrations ranged (mean +/- SEM) from 0. 52 to 0.83 ng/mL (0.67 +/- 0.01; n = 64). A significant seasonal difference was observed for serum T(4) (P < 0.001). Serum T(4) concentration was higher in winter (October-January) with a mean (range +/- SEM) of 6.58 ng/mL (1.48-8.77 +/- 0.35; n = 24) and lower in summer (May-August) with a mean of 3.62 ng/mL (1.34-5.71 +/- 0. 22; n = 24). The thyroid hormone T(4) has a seasonal rhythm even in immature sharks and may have an important role in physiology. J. Exp. Zool. 284:500-504, 1999.     

甲功五项化学发光免疫分析的基质效应对临床测值的影响

目的:探索评价基质效应在化学发光免疫分析中对甲状腺功能五项指标的影响。方法:选取甲状腺功能五项高值血清,用10种基质牛血清、马血清、山羊血清、水解明胶、BSA、PBS、生理盐水、正常人血清、甲减人血清、甲亢人血清分别对T3、T4、FT3、FT4、TSH的高值血清进行倍比稀释,观察基质效应,另将10种基质用考马斯亮兰法检测蛋白含量,分析蛋白含量与基质效应的关系。结果:T3项目牛血清、水解明胶、BSA有明显基质效应;T4和FT3项目牛血清、水解明胶、BSA、PBS、生理盐水有明显基质效应;FT4项目牛血清、马血清、水解明胶、BSA、PBS、生理盐水有明显基质效应;TSH项目没有发现基质效应,正常人血清、甲减人血清和甲亢人血清对甲状腺功能五项无基质效应。检测结果显示蛋白含量多少与基质效应无关。结论:人血清基质是用于稀释样本,基质效应最小的液体,针对个体差异性进行的选择,稀释T3、T4、FT3、FT4高值血清选择甲减人血清,稀释TSH高值血清选择甲亢人血清,可以得到较为满意的结果。     

Decreased ratio of serum T3:rT3 in patients with hyperthyroidism

In 14 hyperthyroid patient serum T4:rT3 ratio was significantly lower (399 +/- 20) than in the control subjects (572 +/- 20; p less than 0.001). A similar pattern was found for serum T3:rT3 ratio. In the hyperthyroid group the ratio was significantly lower (10.5 +/- 0.5) than in the control group (12.5 +/- 0.6; p less than 0.05). The data suggest that in hyperthyroidism the organism might shift conversion of T4 from biologically active T3 to poorly calorigenic rT3. It seems possible that the proportionately increased generation of rT3 than that of T3 may be a defence mechanism of the body, as it was found in systemic illnesses and starvation.     

Thyrotropin receptor antibody activities significantly correlate with the outcome of radioiodine (131I) therapy for hyperthyroid Graves' disease.

The outcome of 131I therapy for 109 patients with Graves' disease was analysed according to pretreatment laboratory data including thyrotropin receptor antibody (TRAb) activities. Forty-five percent of patients became euthyroid, and 13% of patients became hypothyroid within one year after 131I therapy. Forty-two percent of patients remained hyperthyroid one year after 131I therapy. Pretreatment values for serum T4, T3, and the estimated weight of the thyroid were significantly higher in the hyperthyroid group. The mean for the TRAb index of the hyperthyroid group was significantly higher than that of the euthyroid group. Life table analysis revealed a significant effect of the TRAb index on the rate of hyperthyroidism after 3 months or later. These results appear to suggest that the TRAb index is one of the factors which influence the outcome of 131I therapy for Graves' disease.     

Effects of Long-acting Thyroid Stimulator (LATS) and LATS Protector on Human Thyroid Adenyl Cyclase Activity

The long-acting thyroid stimulator (LATS) has been thought to be responsible for the hyperthyroidism of Graves''s disease. It is detected by its effect on the mouse thyroid gland but cannot be found in all patients with hyperthyroidism. In an attempt to clarify the problem of LATS-negative hyperthyroidism, serum was obtained from untreated patients and its effect in vitro on human thyroid tissue examined, using the activation of adenyl cyclase as a measure of stimulation. Human thyroid adenyl cyclase was activated by both thyroid-stimulating hormone (TSH) and LATS. Thyroid tissue obtained from patients with Graves''s disease was relatively less responsive to LATS than was non-toxic thyroid tissue. Of the 24 samples studied five contained LATS and all of these activated adenyl cyclase. The presence of LATS protector in LATS-negative hyperthyroid patients was confirmed but LATS-negative sera had no effect on human thyroid adenyl cyclase activity.     

Abnormal Fas/FasL and caspase-3-mediated apoptotic signaling pathways of T lymphocyte subset in patients with systemic lupus erythematosus

OBJECTIVES: To explore the relationships between Fas-FasL-mediated signaling pathway and apoptosis disturbance of T lymphocyte subset in patients with SLE. METHODS: Flow cytometry was used to determine the percentage of apoptotic lymphocytes and necrotic lymphocytes by AnnexinV-FITC/PI double staining. Cell surface expression rates of Fas, FasL, and intracellular expression rates of activated caspase-3 were evaluated by two-color flow cytometry analysis in peripheral T lymphocyte subsets of SLE patients with inactive disease (n=22) and with active disease (n=17). The serum concentration of anti-nucleosome antibodies in SLE patients were assayed by ELISA immunoassay methods. Health volunteers (n=13) served as controls. RESULTS: The percentage of early apoptotic cells was enhanced in patients with active disease (P=0.001, vs. control) and in patients with inactive disease (P=0.004, vs. control). Compared with health control, the percentage of necrotic cells was significant higher in patients with active disease (P=0.001). The percentages of CD4(+)T cells expressing Fas (P=0.023, vs. control) and FasL (P=0.001, vs. control) were increased in patients with active disease. But there were no obvious differences of expression rates of Fas and FasL on T cell subset between two disease groups (P>0.05). In patients with active disease the percentage of CD4(+)T cells or CD8(+)T cells expressing intracellular activated caspase-3 significantly increased compared to inactive disease patients (P=0.018, P=0.027, respectively) and health controls (P=0.001, P=0.001, respectively). The serum concentration of anti-nucleosome antibodies was strikingly higher in patients with active disease (P=0.002, vs. patients with inactive disease; P=0.001, vs. control, respectively), however, the serum concentration of anti-nucleosome antibodies was not obviously different between patients with inactive disease and health control group (P=0.473). The percentage of apoptotic cells correlated with the serum concentration of anti-nucleosome antibodies in SLE patients (r(s)=0.350, P=0.031). CONCLUSIONS: Apoptosis of T lymphocyte subset in SLE patients increases. CD4(+)T cells are a state of active apoptosis. Fas/FasL-mediated apoptotic pathways are especially important for CD4(+)T cells undergoing apoptosis in SLE patients with active disease. Increased Fas expression results in a higher susceptibility to Fas-mediated apoptosis, which contributes to the increased levels of intracellular activated caspase-3 and accelerates apoptosis of T lymphocytes. The degree of lymphocytic apoptosis disturbance correlates with the level of anti-nucleosome antibodies in the circulation. Acceleration of lymphocytic apoptosis plays important roles in immune pathologic injury and immune regulation dysfunction.     

Oxidative stress markers during a course of hyperthyroidism

INTRODUCTION: Previous studies have shown the presence of oxidative stress in hyperthyroid patients. The aim of this study was to evaluate the influence of hyperthyroidism on lipid peroxidation, plasma lipoprotein oxidation and antioxidant status. We have estimated the clinical utility of the biochemical parameters analysed as markers of oxidative stress in hyperthyroidism. MATERIAL AND METHODS: Twenty five patients with overt hyperthyroidism because of Graves' disease or toxic multinodular goitre and 20 healthy subjects were included in the study. Lipid peroxidation was evaluated by measurement of peroxides and malondialdehyde with 4-hydroxynonenal (MDA + 4-HNE) concentrations. Autoantibodies against oxidised LDL (anti-oxLDL) were assayed as a marker of lipoprotein oxidation. Changes in the antioxidant defence system were estimated by measurement of total antioxidant status in serum (TAS) and erythrocyte superoxide dismutase activity (SOD). RESULTS: A significant increase in serum concentration of peroxides and MDA + 4-HNE was observed in patients with hyperthyroidism. However, no difference was found in anti-oxLDL concentration and antioxidant status parameters (TAS, SOD) between the control group and the patient group. CONCLUSIONS: Our results indicate an intensification of the oxidative processes caused by an excess of thyroid hormones, which is not accompanied by a response from the antioxidant system. Elevated concentrations of lipid peroxidation products in serum, both peroxides and malondialdehyde with 4-hydroxynonenal, may be useful as markers of oxidative stress during the course of hyperthyroidism.     

Short and long term effects of radioiodine and antithyroid drugs on T4 binding proteins, free T4 and T3, during Graves' disease therapy.

Ninety five patients with Graves' disease were studied before and at three months intervals after antithyroid drugs (ATD) (31 cases) or radioiodine (64 cases) therapy until recovery. Before treatment, the T4 maxima binding capacity of TBPA was significantly decreased 253.5 +/- 11.4 mug/100 ml)(mean + se) (control values: 287 +/- 10.4 mug/100 ml) (alpha = 0.04), especially in 53.7% of patients (m = 177 +/- 8 mug/100 ml). The mean of TBG (m = 20.7 +/- 0.9 mug/100 ml) was not different from euthyroid subjects (m = 19.7 +/- 1.7 mug/100 ml) except in 51.2% of patients who had a low TBG (m = 14.3 +/- 1.1 mug/100 ml). An inverse linear correlation was found between TBG-DFT4 (alpha = 0.05) and DF T 3 (alpha = 0.002), TBPA-log DF T4 (alpha = 0.05) but not between TBG and TBPA. The physiological relationship between DFT3, DFT4, TT3, TBG and TBPA was studied in vitro; after adding increased quantities of T4 to a pool of sera collected from eu, hypo or hyperthyroid patients, DFT4, DFT3, FT3 index increased in linear positive relationship with TT4 concentrations, the kinetic of this phenomena was inversely correlated with T4 maximal binding capacity of TBG or TBPA for T4. Addition of T3 to the same sera did not show any effect on the previous parameters. DFT3 depended on the level of T4 in serum more than T3 concentration and was in inverse relationship with the maximal binding capacity of TBG. This data might explain the paradoxal normal or slightly increased values of DFT3 found in T3 thyrotoxicosis. In patients treated with ATD or radioiodine, TBPA but not TBG increased significantly on year after. However, in subjects with an initial very low TGB or TBPA, this phenomenon occurred on the third month after radioiodine or ATD. During the same period, DF T4 and DF T3 were inversely correlated to TBG and TBPA. In conclusion, important changes in T4 binding proteins and free fractions of thyroid hormones were observed in Graves' disease but were corrected by antithyroid therapy. All these data were in good agreement with the normalisation of thyroid function.     

Effect of intravenous methimazole on serum levels of thyroid hormones in patients with hyperthyroidism resistant to oral thyrostatic drugs

The effectiveness of therapy involving intravenous administration of methimazole applied in patients with hyperthyroidism resistant to oral thyrostatic drugs has been investigated. Methimazole (Favistan, Asta) was administered intravenously to 3 patients (two women and one man, of ages 21, 24 and 67 years, respectively) in whom there was no remission of the disease after oral methimazole therapy lasting at least two months. Blood serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse++ triiodothyronine (rT3) and triiodothyronine binding index (T3I) have been measured and free thyroxine index (FT4I) calculated before the treatment and on the 4-th, 7-th, 11-th, 14-th and 17-th day of the treatment. The mean value of T4 concentration decreased from 17.0 micrograms/dl before the treatment to 9.7 micrograms/dl after the treatment. T3 from 352 to 177 ng/dl, rT3 from 114 to 103ng/dl the value of T3I from 183 to 161%, and that of FT4I from 30 to 17, respectively. A significant fall of T3 level was observed on the 11-th day of the therapy, that of rT3 on the 14-th day, and that of FT4I on the seventh day. It was concluded that the resistance of some patients with hyperthyroidism to the oral thyreostatic therapy may be caused by the defective absorption of these drugs from the intestinal tract.