Concomitant association of thyroid sarcoidosis and Graves' disease

OBJECTIVE: Graves' disease (GD) with sarcoid involvement of the thyroid gland has rarely been reported. METHOD: We report a case of GD with thyroid sarcoidosis in a 28-year-old woman. Thyroid function was assessed by triiodothyronine (T(3)), thyroxine (T(4)), thyroid-stimulating hormone (TSH) and TSH receptor antibodies (TSH-R Ab). Thyroid scintigraphy, ultrasound and fine-needle aspiration biopsy were performed. The patient underwent surgery. RESULT: The patient had a nodular goiter. Serum T(3), T(4) and TSH-R Ab levels were elevated with suppressed TSH level. Scintigraphy showed diffuse activity as seen in GD, and ultrasound revealed that parenchyma was heterogenous. Sarcoidosis was discovered on routine chest X-ray. Although no sarcoid involvement was found on specimen, the thyroid gland showed non-caseating granulomas on histology. CONCLUSION: Since sarcoid involvement of the thyroid gland can cause hypofunction, we report the uncommon infiltration of sarcoidosis with hyperthyroidism.     

Pituitary resistance to thyroid hormone--a case report

Pituitary resistance to thyroid hormone is a very rare cause of hyperthyroidism. It is characterized by normal, or elevated TSH concentration with high concentration of T3 and T4. Here, we present a case of a 24-year-old woman who suffered from mild thyrotoxicosis and diffuse goiter for several years. She had elevated fT3 and fT4 with slightly elevated TSH concentration. Pituitary adenoma was excluded as magnetic resonance imaging showed normal pituitary gland, alpha subunit was within normal range and TSH concentration increased after TRH administration. Sonography revealed normoechogenic, slightly enlarged thyroid gland. Previously, she was given thiamazole, but without any significant amelioration. Thus, the diagnosis of the syndrome of pituitary resistance to thyroid hormone was established. The patient was given bromocriptine at a dose of 10 mg per day. After 2 months of treatment she achieved a state of constant euthyrosis and following next few months thyroid volume diminished.     

Thyroid hormone profiles in goitrous and non-goitrous subjects seen in an endemic goiter area of the Central African Republic]

In the present study T3, T4, TSH serum concentrations were measured in 166 subjects whose goiter grading was ascertained according to WHO classification; 39 of them had no goiter (grading 0), 127 were goitrous with a grading comprised between 1a and 4. The two samples were composed by Males and Females of various ages whose choice was strictly predetermined by random numbers. The median ages of 127 goitrous and 39 non goitrous subjects were respectively 23.5 years and 33.5 years; 30 Males and 5 Females were in the first group; 58 Males and 69 Females in the second. They lived in the Ouham region of Centro African Republic where some of the Authors ascertained a severe goiter endemia due to iodine deficiency and manioc consumption as staple food. All the values of T4 and TSH of the two group of subjects, were significantly different from the control values (p less than 0.01) excepting T3. Goitrous subjects had T4 value lower than non goitrous subjects (p less than 0.05). The subjects of each group were distributed in the four subsequent subgroups: A) with T3, T4, TSH in the normal range; B) with elevated TSH and T3 and T4 in normal range; C) with elevated TSH, subnormal T4, and T3 in normal range; D) with elevated TSH and subnormal T3 and T4. From fig. 1 it can be seen that the 79.5% of goitrous subjects had a supranormal TSH (subgroups B + C + D) and 40.7% of them had a subnormal T4 (subgroups C + D).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in serum T4, T3 and TSH concentrations in newborns and infants with congenital goiter from the Mazovia region.

Thyroid function was investigated in a group of 61 newborns with congenital goiter before starting the therapy with thyroid hormones. The group included 19 girls and 42 boys, of which 27 were of age not exceeding one week (group I), 19 were between the first and the second week (group II), and 15 were between the second week and the third month of life (group III). The concentrations of the thyroid hormones were determined by radioimmunoassay. The values obtained have been compared with the local reference range obtained for the newborns of the Mazovia region. The values remaining outside the reference range were found in 47.5% of the newborns studied. The elevated values of TSH were observed mainly in group I newborns (12 from 27); among group II newborns there was only one with the elevated values, and none among the newborns of group III. thyroxine (T4) values were lowered in 14 among 27 newborns of group I, and in 2 among 19 newborns of group II; all T4 values were normal in group III. The percentage of the elevated values of triiodothyronine (T3) was higher in older newborns (group III). The elevated level of T3 accompanied by the lowered level of T4 with the normal or moderately elevated level of TSH is characteristic for the adaptation to the deficiency of iodine. There is preferential secretion of T3 aimed at maintaining euthyreosis. The elevated levels of T3 found in 30% of newborns with untreated goiter suggest an intrauterine deficit of iodine as a cause of the goiter appearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Similarity and dissimilarity between clinical and laboratory findings, especially anti-thyrotropin receptor antibody in ophthalmic Graves' disease without persistent hyperthyroidism and hyperthyroid Graves' disease

The aim of this study was to investigate thyroid states, significance of anti-TSH receptor antibodies and the clinical courses of patients with euthyroid Graves' ophthalmopathy. The clinical and laboratory finding of 30 patients with euthyroid Graves' ophthalmopathy were briefly as follows: 1) normal sized thyroid or small goiter; 2) negative or weakly positive thyrotropin binding inhibitor immunoglobulin (TBII); 3) normal thyroid [99 m-Tc] pertechnetate uptake; and 4) frequent observations of low serum TSH values. Besides TBII, thyroid stimulating antibody (TSAb) was measured under low salt and isotonic conditions using FRTL-5 rat thyroid cells. Both TBII and TSAb titers were lower in euthyroid Graves' ophthalmopathy than in hyperthyroid Graves' disease. Serum TSH levels frequently became low in patients considered as euthyroid upon the first examination as well as in Graves' patients in remission, reflecting preceding or mild hyperthyroidism. In follow-up studies, these patients with mildly elevated thyroid hormone levels and low TSH levels seldom reached a state of persistent hyperthyroidism, when TBII was negative or only weakly positive.     

A case of the syndrome of inappropriate secretion of TSH.

A girl aged 4 years with goiter and accelerated physical and skeletal growth was found to be hyperthyroid on the basis of elevated serum thyroid hormone level, nevertheless both the basal TSH and TSH responsiveness to TRH were maintained within the normal range. Serum TSH was suppressed by exogenous T3 and dexamethasone administration, but not significantly changed after propylthiouracil (PTU) treatment. The diurnal rhythmicity of anterior pituitary hormones was preserved with the high nocturnal peak of TSH and prolactin. Clinically, neither thyrotoxic signs nor evidences of pituitary tumor were observed. Her accelerated growth and elevated thyroid hormone level appeared to be induced by inappropriate secretion of TSH. In view of the literature, this is the first case of the syndrome of inappropriate secretion of TSH excluding the neoplastic origin in Japan.     

Effects on bone mineral density by treatment of benign nodular goiter with mildly suppressive doses of L-thyroxine in a cohort women study

OBJECTIVES: Thyroid diseases and their treatment may influence the osseous system. The influence that prolonged suppressive L-thyroxine (LT4) therapy may have on inducing subclinical hyperthyroidism on bone metabolism is still a matter of debate. The aim of the present study was to assess the effects of chronic LT4 treatment at mildly inhibiting serum thyroid-stimulating hormone (TSH) doses on bone mineral density (BMD) and biochemical bone remodeling markers in a cohort of women with benign nodular goiter, and to verify the efficacy of the treatment on nodule size. SUBJECTS AND STUDY DESIGN: A total of 200 euthyroid Caucasian women with nodular goiter (age 52.1 +/- 9; 80 pre- and 120 postmenopausal) were enrolled: 96 had been treated with LT4 for at least 3 years and a matched group of 104 had untreated goiter. LT4 therapy was given at a dose sufficient to reduce TSH under the lower limit of the normal range (0.27-4.20 microIU/ml) without suppressing it below the limit of assay sensitivity (0.005 microIU/ml) and maintaining normal serum values of free triiodothyronine (FT3) and free thyroxine (FT4). The adequacy of the dose was evaluated on the basis of serum TSH levels. The osteopenic effect of LT4 treatment was evaluated directly by total body and lumbar spine dual-energy X-ray absorptiometry (DEXA) and indirectly by biochemical parameters (alkaline phosphatase, osteocalcin, calcium, parathyroid hormone) at the baseline and throughout the follow-up. The efficacy of LT4 schedule on thyroid nodule size was assessed on the basis of the ultrasonographic evaluation. RESULTS: Mineralometric data showed no significant difference between BMD values for treated and untreated patients in both pre- and postmenopausal status. In all patients, serum markers of bone turnover were in the normal range, with no differences in the treated and control groups. The TSH concentrations were significantly lower in treated than in untreated patients (p < 0.0001); FT3 and FT4 were in the normal range for all patients. Evaluation of nodule size during follow-up showed a reduction of > or = 30% in 32 of 96 treated patients (33.3%) versus none in those untreated, whilst nodule size remained unmodified in 60 treated patients (62.5%) versus 35 (33.6%) in those untreated, and an increase in nodule size and/or development of new nodules was found in 4 treated patients (4.2%) versus 69 of the 104 untreated patients (66.3%). CONCLUSIONS: This study suggests that at slightly suppressing TSH doses, LT4 therapy has no adverse effects on BMD in both pre- and postmenopausal women, while having an efficacy on nodule size comparable with that reported using an LT4 schedule able to maintain TSH near or below the assay sensitivity limit.     

Acromegaly and hyperthyroidism associated with McCune-Albright syndrome

A 36-year-old man is described having McCune-Albright syndrome, acromegaly likely due to somatotroph hyperplasia and hyperthyroidism due to adenomatous goiter. Sexual precocity was not noted. The sella was narrow in size and no mass was seen. The decline of elevated GH by hyperglycemia and increase by GHRH-44(NH2) may support somatotroph hyperplasia, but plasma GHRH-44(NH2) levels were not elevated. A mass in the right lobe and enlargement of the left lobe of the thyroid were noted. Thyroid hormone levels in serum and thyroidal radioiodine uptake values were elevated, while TSH measurements in serum were low. The radioiodine scan showed a cold nodule in the right lobe and a hot area in the left of the thyroid. Thyroidal radioiodine was not suppressed following T3 given orally. These findings are compatible with functioning glands autonomously as the mechanism for the endocrinopathies associated with the McCune-Albright syndrome.     

Screening of geriatric patients for thyroid dysfunction with thyrotropin-releasing-hormone test, sensitive thyrotropin and free thyroxine estimation

Hospitalized geriatric patients (N = 354) from an iodine-deficient area were screened with sensitive thyrotropin (TSH), free and total thyroxine (FT4, T4) and total triiodothyronine (T3) to determine the occurrence rate of clinical and subclinical thyroid dysfunction. The diagnostic value of the tests was compared to each other and to that of the thyrotropin-releasing-hormone test (TRH-test) in order to find the optimal first line screening test in geriatric patients. Clinical hyperthyroidism was found in 13, subclinical hyperthyroidism in 10, overt hypothyroidism in 6 and subclinical hypothyroidism in 8 cases. 20.6% of the patients were euthyroid but had subnormal TSH response to TRH, as a sign of possible thyroid autonomy. The low occurrence rate of clinical thyroid disorders (4.8%) does not justify the screening of geriatric patients in general, but the high probability of thyroid autonomy makes reasonable the investigation of every geriatric patient before iodine administration. Suppressed basal TSH and high FT4 were found to be both sensitive and specific in diagnosing clinical hyperthyroidism, but the predictive value was insufficient; elevated T4 and T3 are specific, but not sensitive. Basal TSH is sensitive, specific and has a good predictive value in diagnosing euthyroidism, whereas normal T4, FT4 or T3 are not specific enough for euthyroidism. Basal TSH is better as a first line test of thyroid function than FT4. A normal basal TSH confirms euthyroidism by itself. Other tests (TRH test, T4, FT4, T3) are necessary to elucidate the clinical importance of a subnormal or suppressed basal TSH.     

Pituitary-thyroid axis reactivity to hyper- and hypothyroidism in the perinatal period: ontogeny of regulation of regulation and long-term programming of responses.

To evaluate the role of perinatal thyroid status in the development of pituitary-thyroid axis regulation, we administered triiodothyronine to newborn rats for the first five days postpartum to achieve hyperthyroidism, or propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5 to achieve hypothyroidism. Plasma T4, T3, and TSH levels were determined from birth through 50 days postpartum. Administration of exogenous T3 produced the expected immediate suppression of plasma T4 and TSH, with recovery toward normal values beginning within days of discontinuing the T3 regimen. Plasma T3 values were markedly elevated during the period in which T3 was being given, but subsequently became subnormal, with deficits persisting into young adulthood. With the PTU regimen, plasma T4 and T3 levels were markedly suppressed through postnatal day 10, rose over the ensuing two weeks, but nevertheless showed significant deficits into adulthood. TSH levels in the immediate neonatal period were subnormal in the PTU group, despite the marked lowering of circulating thyroid hormones; TSH then rose dramatically to levels four times normal, subsiding to control values by the end of the first month. These results suggest that a critical period exists in which regulation of pituitary-thyroid axis function is programmed. During this phase, TSH secretion can be suppressed by excess thyroid hormones, but cannot be increased by hormone deficiencies. Perhaps more importantly, perinatal thyroid status "programs" its own future reactivity, so that early hypothyroidism results in reduced T4 and T3 levels in adulthood, despite normal levels of TSH.     

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.     

A novel thyroid hormone receptor-beta mutation,not anticipated to occur in resistance to thyroid hormone,causes variable phenotypes

Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.     

Evaluation of the timing to reduce the initial dose of antithyroid drugs in patients with Graves' disease.

The present study was undertaken to evaluate whether the normalization of the serum TSH level in a supersensitive assay during the initial treatment with antithyroid drugs (ATD) is a useful indicator for the reduction of the initial dose of ATD in 50 patients with hyperthyroidism due to Graves' disease. The initial dose of ATD was continued until the achievement of the euthyroid state, and was then reduced either before the serum TSH level was in the normal range in 9 of 29 patients treated with methimazole (MMI) (group MMI-1) and 8 of 21 treated with propylthiouracil (PTU) (PTU-1), or after the serum TSH level was in/above the normal range in 20 of 29 treated with MMI (MMI-2) and 13 of 21 treated with PTU (PTU-2). Although there were no significant differences in age, sex, thyroid function, prevalence of autoantibodies, goiter size, duration of the disease or the initial and modified doses of ATD, the mean durations of the administration of the initial dose of ATD in MMI-2 and PTU-2 were significantly longer than those in MMI-1 and PTU-1, respectively. As a result, 4 (44%) in group MMI-1, 20 (100%) in MMI-2, 2 (25%) in PTU-1 and 7 (54%) in PTU-2 developed low free T4 levels, and 1 (11%) in MMI-1, 15 (75%) in MMI-2 and 3 (23%) in PTU-2 developed low free T3 levels. Serum TSH levels increased over the normal range in 3 (33%) in MMI-1, 18 (90%) in MMI-2 and 5 (39%) in PTU-2.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Goiter and impairment of thyroid function in acromegalic patients: basal evaluation and follow-up.

AIMS: We evaluated morphological, biochemical and cytological thyroid parameters in acromegalic patients, investigated before and after treatment for acromegaly. PATIENTS: 28 acromegalics were investigated before and, in 18 cases, after 2-7 years of therapy. Fourteen patients were from areas of moderate iodine deficiency in Southern Italy. One patient underwent thyroidectomy before entering this study. RESULTS: 19 patients were euthyroid (FT4: 17.7 +/- 0.8 pmol/l and FT3 4.6 +/- 0.2 pmol/l), but TSH was undetectable in 5/19. Among them, TRH-stimulated TSH increase was absent/impaired or exaggerated/delayed in 9 and one cases, respectively. Decreased FT3 and/or FT4 values with low/normal TSH values were detected in 7 cases; TRH-stimulated TSH response was absent/impaired in 2 patients and exaggerated/delayed in another two. Increased free T4 and free T3 concentrations with undetectable TSH levels were found in one. Two euthyroid patients had high TPOAb levels. Goiter was diagnosed in 21 cases and nodules were found in 14/21. 99Tc scintiscan showed "cold" areas in 13/14 cases and a "hot" nodule in the hyperthyroid patient. Acromegalics from iodine deficient areas showed a not significant increase of prevalence of goiter (86 vs. 71 %) and of mean thyroid volume (35 +/- 7 vs. 28 +/- 4 ml, NS), compared to others. Thyroid volume (TV) did not correlate with GH, IGF-1 and TSH levels, the area under the curve of insulin-increase during OGTT, the age of patients or the duration of acromegaly. Fine needle aspiration biopsy (FNAB), performed in 11/14 patients with nodular goiter, showed colloid nodules in 8 cases, hyperplastic nodules in 2 and an adenomatous nodule in one. Neurosurgery, radiotherapy or medical treatment for acromegaly induced a significant decrease of mean GH and IGF-1 levels (21.5 +/- 8.5 vs. 12.9 +/- 9.6 ng/ml, p< 0.005 and 747 +/- 94 vs. 503 +/- 88 ng/ml, p < 0.02, respectively), but both GH and IGF-1 values normalized only in 3 cases. No significant variation of mean TSH levels was found. Although TV normalized in 3 patients, ultrasound evaluation showed a not significant decrease of mean TV and no changes in the diameter and number of nodules. FNAB was unchanged. CONCLUSIONS: Our results suggest that, despite no correlation between serum GH and IGF-1 levels and thyroid volume being found, a decrease in serum GH and IGF-1 levels has favourable effects on thyroid status.     

131I对男性甲状腺功能亢进症血清性激素及甲状腺球蛋白水平影响研究

目的:探讨~(131)I对男性甲状腺功能亢进症患者血清性激素及甲状腺球蛋白水平的影响。方法:收集我院收治的男性甲状腺功能亢进症患者74例,随机分为对照组和实验组,每组各37例,对照组患者给予他巴唑口服,20-30 mg/次,每日口服1次。实验组患者在对照组基础上给予~(131)I治疗。治疗结束后,检测并比较两组患者血清游离三碘甲状腺素(FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)、睾酮(T)、雌二醇(E2)、甲状腺球蛋白(TG)水平的变化以及临床疗效。结果:与治疗前相比,两组患者血清FT3、FT4、T、E2、TG水平均显著下降,TSH水平明显升高(P0.05);与对照组相比,实验组患者血清FT3、FT4、T、E2、TG水平较低,TSH水平以及临床治疗有效率较高(P0.05)。结论:~(131)I能够显著降低男性甲状腺功能亢进症血清FT3、FT4、T、E2、TG水平,升高TSH水平,临床效果较好。     

Hormone profile of hypothyroidism in an area of the Central African Republic with endemic goiter]

In the Ouham region of Centro African Republic, one of the present Authors (B.P.) described a severe goiter endemia due to marked iodine deficiency and high daily intake of manioc as staple food. In the present study serum TSH, T3 and T4 of 233 subjects were determined; 150 of them lived in rural villages (Group 1) and 83 lived in Bocaranga, chief town of the province (Group 2). The blood samples done contemporaneously to the epidemiological survey, were strictly randomized in the population examined. The subjects of each group were divided in 4 sub-groups: A) with TSH, T3 and T4 in normal range; B) with elevated TSH; C) with elevated TSH and sub-normal T4; D) with elevated TSH and sub-normal T3 and T4. An apparently euthyroid pattern of TSH, T3 and T4 was evident in only 60 subjects (19.3% from group 1; 37.35% from group 2); the remaining 173 (80.67% from group 1; 62.65% from group 2) were hypothyroid (subclinical in the sub-group B; mild in the sub-group C; overt in the sub-group D). The mean hormonal values of the apparently euthyroid subjects (sub-group A) in the villages and in the chief town, were significantly different (p less than 0.05) from the control values of our laboratory. More significant differences were clearly evident between the control values and the mean values of sub-groups B, C and D in each of the two groups (1 villages; 2 chief town).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of endocrine dysfunction in HIV-infected men

OBJECTIVE: Endocrine dysfunction is a common problem in patients with human immunodeficiency virus infection (HIV). We therefore evaluated the endocrine function in 31 male homosexual HIV-1-infected men: mean age 37 +/- 7.2 years (range 24-52). METHODS AND MATERIALS: Blood was obtained for baseline T3, T4, TSH, LH, FSH, prolactin, testosterone, ACTH and cortisol values. Endocrine function tests were performed as TRH, CRH, ACTH, LH-RH and HCG tests. RESULTS: Thyroid function: There was a temporarily increased TSH in 3 of 17 patients but normal levels for T3, T4 and fT4 (without thyroid antibodies). One patient showed signs of latent hyperthyroidism (no response in TRH test). Adrenocortical function: Two patients had adrenal insufficiency. They showed a normal baseline cortisol level, an elevated ACTH level and no increase in cortisol levels after stimulation with CRH. All other patients revealed normal responses on the CRH/ACTH tests. Gonadal function: 9 patients had elevated FSH levels (tubular insufficiency), 4 patients additionally had increased LH levels (hypergonadotropic hypogonadism). 5 patients showed signs of tertiary hypogonadism (low LH and testosterone, increase of LH after stimulation with LH-RH). CONCLUSION: In disorders of thyroid and adrenocortical function of primary or tertiary origin, a substitution of hormones should be taken into consideration.     

Pituitary resistance to thyroid hormones.

Pituitary thyroid hormone resistance (PRTH) refers to a particular form of thyroid hormone refractoriness that is accompanied by peripheral hyperthyroidism, as only the TSH-secreting pituitary cells appear to be resistant to the effects of thyroid hormones. The presence of PRTH is suspected and diagnosed on the basis of the finding of high free thyroid hormone levels along with unsuppressed TSH, clinical signs and symptoms of hyperthyroidism and values of at least one of the parameters evaluating peripheral thyroid hormone action in the hyperthyroid range. However, most patients with PRTH present with clinical signs and symptoms of thyroid dysfunction, particularly goiter and tachycardia, overlapping those recorded in patients with generalized thyroid hormone resistance (GRTH), i.e. refractoriness to thyroid hormones at both pituitary and peripheral tissue level. Moreover, most of them display normal values of other parameters evaluating the peripheral effects of thyroid hormones and bear mutations in the gene encoding for T3 nuclear receptors similar to those found in patients with GRTH. These findings are questioning the existence of PRTH as a separate clinical entity and support the view that the various forms of thyroid hormone resistance may be part of a spectrum of disease with variable expression in different issues.     

A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor

In this work we report a novel method to efficiently induce a murine model of Graves' hyperthyroidism. Inbred mice of different strains were immunized by i.m. injection with adenovirus expressing thyrotropin receptor (TSHR) or beta-galactosidase (1 x 10(11) particles/mouse, three times at 3-wk intervals) and followed up to 8 wk after the third immunization. Fifty-five percent of female and 33% of male BALB/c (H-2(d)) and 25% of female C57BL/6 (H-2(b)) mice developed Graves'-like hyperthyroidism with elevated serum thyroxine (T(4)) levels and positive anti-TSHR autoantibodies with thyroid-stimulating Ig (TSI) and TSH-binding inhibiting Ig (TBII) activities. In contrast, none of female CBA/J (H-2(k)), DBA/1J (H-2(q)), or SJL/J (H-2(s)) mice developed Graves' hyperthyroidism or anti-TSHR autoantibodies except SJL/J, which showed strong TBII activities. There was a significant positive correlation between TSI values and T(4) levels, but the correlations between T(4) and TBII and between TSI and TBII were very weak. TSI activities in sera from hyperthyroid mice measured with some chimeric TSH/lutropin receptors suggested that their epitope(s) on TSHR appeared similar to those in patients with Graves' disease. The thyroid glands from hyperthyroid mice displayed diffuse enlargement with hypertrophy and hypercellularity of follicular epithelia with occasional protrusion into the follicular lumen, characteristics of Graves' hyperthyroidism. Decreased amounts of colloid were also observed. However, there was no inflammatory cell infiltration. Furthermore, extraocular muscles from hyperthyroid mice were normal. Thus, the highly efficient means that we now report to induce Graves' hyperthyroidism in mice will be very useful for studying the pathogenesis of autoimmunity in Graves' disease.