Genetic Factors in Hashimoto's Struma

It has previously been established that there is a significant history of thyroid disorders in families of patients with Hashimoto''s struma or chronic thyroiditis. In the present study, 99 relatives of 20 patients with Hashimoto''s struma or chronic thyroiditis were studied with regard to the incidence of circulating thyroid autoantibodies; 42 of these 99 relatives were found to have such antibodies. Twenty of the 99 relatives were shown to have thyroid abnormalities (chiefly goitre); of this group of 20, antibodies were found in 12. In the remaining 79 persons (who had no clinical evidence of thyroid disease), 30 were found to have circulating antithyroid antibodies. The incidence of such antibodies among these relatives is very significantly greater than in the general population.From these and other similar studies, there is strong evidence favouring a genetic predisposition for Hashimoto''s struma and chronic thyroiditis. The mode of inheritance is not yet established, and the pathogenesis of the disease has not yet been elucidated.     

RET/PTC Rearrangements Are Associated with Elevated Postoperative TSH Levels and Multifocal Lesions in Papillary Thyroid Cancer without Concomitant Thyroid Benign Disease

RET/PTC rearrangements, resulting in aberrant activity of the RET protein tyrosine kinase receptor, occur exclusively in papillary thyroid cancer (PTC). In this study, we examined the association between RET/PTC rearrangements and thyroid hormone homeostasis, and explored whether concomitant diseases such as nodular goiter and Hashimoto''s thyroiditis influenced this association. A total of 114 patients diagnosed with PTC were enrolled in this study. Thyroid hormone levels, clinicopathological parameters and lifestyle were obtained through medical records and surgical pathology reports. RET/PTC rearrangements were detected using TaqMan RT-PCR and validated by direct sequencing. No RET/PTC rearrangements were detected in benign thyroid tissues. RET/PTC rearrangements were detected in 23.68% (27/114) of PTC tissues. No association between thyroid function, clinicopathological parameters and lifestyle was observed either in total thyroid cancer patients or the subgroup of patients with concomitant disease. In the subgroup of PTC patients without concomitant disease, RET/PTC rearrangement was associated with multifocal cancer (P = 0.018). RET/PTC rearrangement was also correlated with higher TSH levels at one month post-surgery (P = 0.037). Based on likelihood-ratio regression analysis, the RET/PTC-positive PTC cases showed an increased risk of multifocal cancers in the thyroid gland (OR = 5.57, 95% CI, 1.39–22.33). Our findings suggest that concomitant diseases such as nodular goiter and Hashimoto''s thyroiditis in PTC may be a confounding factor when examining the effects of RET/PTC rearrangements. Excluding the potential effect of this confounding factor showed that RET/PTC may confer an increased risk for the development of multifocal cancers in the thyroid gland. Aberrantly increased post-operative levels of TSH were also associated with RET/PTC rearrangement. Together, our data provides useful information for the treatment of papillary thyroid cancer.     

Hashimoto's thyroiditis with immunoblastic lymphadenopathy and unusual "macaroni cells".

Light and electron microscopic study of the thyroid gland and an enlarged cervical lymph node in a 75-year-old woman with Hashimoto''s thyroiditis disclosed immunoblastic proliferation in the lymph node, marked by collections of striking round cells positive to periodic acid-Schiff (PAS) staining, immunoblasts and plasmacytoid elements in a vascular, fibrous framework. The PAS-positive cells ("macaroni cells") were distended with whorls of angulated tubular material resembling endoplasmic reticulum. Parafollicular-cell hyperplasia and an atypical plasmacytoid focus were noted in the thyroid. Hashimoto''s disease is known to be associated with malignant lymphoma, as are autoimmune and malignant diseases with immunoblastic lymphadenopathy. This is the first report of the association of Hashimoto''s disease and immunoblastic lymphadenopathy. The atypical plasma cells have not previously been described.     

甲状腺乳头状癌合并桥本氏甲状腺炎的BRAF基因表达及侵袭性

目的:比较甲状腺乳头状癌合并桥本氏甲状腺炎与不合并桥本氏甲状腺炎的BRAFV600E基因表达以及侵袭性的区别。方法:2011年9月到2013年9月四川大学华西医院手术治疗并有BRAFV600E基因测定的甲状腺乳头状癌患者226名,均有病理证实。其中合并桥本氏甲状腺炎者50例为研究组,同期随机抽取50例不合并桥本氏甲状腺炎者作为对照组。比较两组性别、年龄、肿瘤大小、数量、BRAFV600E基因表达以及甲状腺外侵犯和淋巴结转移与侵袭性相关的因素的区别。结果:甲状腺乳头状癌合并桥本氏甲状腺炎在男女性别,发病年龄、肿瘤大小上和对照组相比无差异(P0.05);BRAFV600E突变率、甲状腺外侵犯和淋巴结转移都较对照组更低(P0.05)。BRAF基因突变阳性组甲状腺外侵犯和淋巴结转移率较BRAFV600E基因突变阴性组更高(P0.05)。结论:BRAFV600E基因突变的甲状腺乳头状癌患者有更高的甲状腺腺外侵犯和淋巴结转移。甲状腺乳头状癌合并桥本氏甲状腺炎较不合并桥本氏甲状腺炎有着更低的BRAFV600E突变率,更低的甲状腺外侵犯和淋巴结转移。     

Thyroxine,methimazole, and thyroid microsomal autoantibody titres in hypothyroid Hashimoto's thyroiditis.

Ten hypothyroid patients with Hashimoto''s thyroiditis were treated with methimazole 30 mg in addition to thyroxine 0.15 mg daily. Another 10 hypothyroid patients with Hashimoto''s thyroiditis were given thyroxine 0.15 mg alone. After 22 weeks of treatment significant decreases in thyroid microsomal autoantibody titres were observed in both groups (p less than 0.01). There was no difference in the mean change in titre between the two groups. When the patients treated with methimazole were subsequently given thyroxine 0.15 mg alone for a further 22 weeks no additional change in titre was observed. The data suggest that thyroxine, by normalising serum thyroid stimulating hormone concentrations, may reduce the autoantigenic properties of the thyrocytes with a subsequent decrease in autoantibody titres.     

Cowden's Disease: Familial Goiter and Skin Hamartomas—A Report of Three Cases

Multiple hamartoma syndrome (Cowden''s disease) consists of characteristic skin lesions of the face, mucous membranes and distal extremities in association with a variety of benign and malignant internal tumors, especially of the thyroid and breast. We describe a family in which the father, daughter and son were found to have goiter associated with the skin lesions of Cowden''s disease. Review of the 40 reported cases of this syndrome indicates that thyroid disease occurs in two thirds of patients with Cowden''s disease and most often presents as goiter at an early age. Thyroid cancer has occurred in only three (7.5%) of the patients.Surgical removal of the large goiter of the son showed that it was composed of multiple encapsulated follicular adenomas and a few areas of lymphocytic thyroiditis. Studies of the thyroid tissue showed that peroxidase activity was decreased, the thyroglobulin had a reduced content of thyroxine and triiodothyronine (perhaps due to the therapeutic suppression of thyroid-stimulating hormone) and thyroxine 5''-monodeiodinase was greatly increased; increased outer ring monodeiodinase activity may be a characteristic of human follicular adenomas.     

Clinical course of IgG4-related hypophysitis presenting with focal seizure and relapsing lymphocytic hypophysitis

Coexisting of Graves’ disease and functioning struma ovarii is a rare condition. Although the histology of struma ovarii predominantly composed of thyrocytes, the majority of the patients did not have thyrotoxicosis. The mechanism underlying the functioning status of the tumor is still unclear but the presence of thyroid stimulating hormone receptor (TSHR) is thought to play a role. Here we describe the patient presentation and report the TSHR expression of the tumor. A 56-year old Asian woman presented with long standing thyrotoxicosis for 23 years. She was diagnosed with Graves’ disease and thyroid nodules. She had bilateral exophthalmos and had high titer of plasma TSHR antibody. Total thyroidectomy was performed and the histologic findings confirmed the clinical diagnosis. The patient had persistent thyrotoxicosis postoperatively. Thyroid uptake demonstrated the adequacy of the thyroid surgery and the whole body scan confirmed the presence of functioning thyroid tissue at pelvic area. The surgery was scheduled and the patient had hypothyroidism after the surgery. The pathological diagnosis was struma ovarii at right ovary. We performed TSHR staining in both the patient’s struma ovarii and in 3 cases of non-functioning struma ovarii. The staining results were all positive and the intensity of the TSHR staining of functioning struma ovarii was the same as that in other cases of non-functioning tumors, suggesting that the determinant of functioning struma ovarii might be the presence of TSHR stimuli rather than the intensity of the TSHR in the ovarian tissue. In patients with Graves’ disease with persistent or recurrent thyrotoxicosis after adequate ablative treatment, the possibility of ectopic thyroid hormone production should be considered. TSHR expression is found in patients with functioning and non-functioning struma ovarii and cannot solely be used to determine the functioning status of the tumor.     

Primary malignant lymphoma of the thyroid in a patient with long-standing Graves' disease

We have recently encountered a patient with rapidly enlarging thyroid masses histologically diagnosed as diffuse histiocytic lymphoma which developed in the active course of Graves' disease. The primary thyroid lymphoma has been in complete remission after local radiation therapy. The association of Hashimoto's thyroiditis and thyroid lymphoma has well been recognized. Meanwhile, data have accumulated to demonstrate that Hashimoto's thyroiditis and Graves' disease share possible similar causal immunological abnormalities and are closely related entities. However, the association of Graves' disease and primary thyroid lymphoma has never been reported, as far as we know. Therefore, this case may be the first one that supports the natural concept that thyroid lymphoma develops from pre-existing Graves' disease secondary to the similar immunological abnormalities in Hashimoto's thyroiditis.     

Graves' ophthalmopathy.

Graves'' ophthalmopathy usually occurs in association with hyperthyroidism. Its occasional occurrence in the absence of thyroid disease suggests, however, that it may be a separate autoimmune disorder. While the evidence supporting an autoimmune pathogenesis is considerable for the ophthalmopathy, it is not so impressive as that for Graves'' hyperthyroidism: orbital antibodies have not been convincingly demonstrated and autoantigens have not been identified. On the other hand, in patients with Graves'' ophthalmopathy the orbital tissues and eye muscle membranes are infiltrated with lymphoid cells and show evidence of cell-mediated immune reactions. Although there is some evidence that binding of thyroid stimulating hormone fragments and thyroglobulin-antithyroglobulin immune complexes to eye muscle membranes may be important in the pathogenesis of the ophthalmopathy, this needs to be confirmed. The mechanism for the association of hyperthyroidism and ophthalmopathy is unknown, but the association likely reflects an influence of thyroid hormones on the immune system. In view of the autoimmune pathogenesis the logical treatment of Graves'' ophthalmopathy appears to be immunosuppression.     

Transient subclinical hypothyroidism in early pregnancy

In the present study, a new clinical state of transient subclinical hypothyroidism in 12 early pregnant women is documented. The incidence of transient subclinical hypothyroidism was 18 (0.19%) among 9,453 pregnant women examined in this series in Sapporo. The characteristics of transient subclinical early gestational hypothyroidism in our study may be summarized as follows: temporarily increased TSH in the blood (11.7 +/- 6.3 microU/ml; mean +/- S.D.) in early pregnant women at 8.5 +/- 2.4 weeks of gestation, accompanied with or without reduced FT4 which spontaneously return to normal at 17.9 +/- 7.1 weeks; no subjective complaints and no previous history of thyroid disease; small struma; positive titers of antimicrosome antibody and antithyroglobulin antibody; normal serum hCG; negative results for TSH receptor antibody. None of the infants show any physical abnormality such as struma and none of the patients had neck pain or fever suggesting subacute thyroiditis. The presence of autoantibody to the thyroid gland and echographical findings strongly suggest the existence of Hashimoto's thyroiditis in early pregnant women with transient subclinical hypothyroidism, although the cause of transient subclinical early gestational hypothyroidism remains obscure.     

Association of endodermal sinus tumour,testicular teratoma and alpha1-fetoprotein.

An endodermal sinus tumour in the retroperitoneal region was associated with the presence of alpha1-fetoprotein (AFP) in the patient''s serum. At autopsy a simple cystic teratoma of the right testicle was also found. The association of these two tumours has been reported before. The classification of these malignant germ-cell tumours and an understanding of their evolution may be aided by the discovery that AFP is often found in the patient''s serum.     

Selenium and its relationship with selenoprotein P and glutathione peroxidase in children and adolescents with Hashimoto’s thyroiditis and hypothyroidism

The essential trace element selenium (Se) is required for thyroid hormone synthesis and metabolism. Selenoproteins contain selenocysteine and are responsible for biological functions of selenium. Glutathione peroxidase (GPx) is one of the major selenoproteins which protects the thyroid cells from oxidative damage. Selenoprotein P (SePP) is considered as the plasma selenium transporter to tissues. The aim of this study was to evaluate serum Se and SePP levels, and GPx activity in erythrocytes of children and adolescents with treated Hashimoto’s thyroiditis, hypothyroidism, and normal subjects.Blood samples were collected from 32 patients with Hashimoto’s thyroiditis, 20 with hypothyroidism, and 25 matched normal subjects. All the patients were under treatment with levothyroxine and at the time of analysis all of the thyroid function tests were normal. GPx enzyme activity was measured by spectrophotometry at 340 nm. Serum selenium levels were measured by high-resolution continuum source graphite furnace atomic absorption. SePP, TPOAb (anti-thyroid peroxidase antibody), and TgAb (anti-thyroglobulin antibody) were determined by ELISA kits. T₄, T₃, T₃ uptake and TSH were also measured.Neither GPx activity nor SePP levels were significantly different in patients with Hashimoto’s thyroiditis or hypothyroidism compared to normal subjects. Although GPx and SePP were both lower in patients with hypothyroidism compared to those with Hashimoto’s thyroiditis and normal subjects but the difference was not significant. Serum Se levels also did not differ significantly in patients and normal subjects. We did not find any correlation between GPx or SePP with TPOAb or TgAb but SePP was significantly correlated with Se.Results show that in patients with Hashimoto’s thyroiditis or hypothyroidism who have been under treatment with levothyroxine and have normal thyroid function tests, the GPx, SePP and Se levels are not significantly different.     

Hipertiroidismo y captaciones de yodo bajas en una paciente con enfermedad de Graves

Thyrotoxicosis factitia is defined as thyrotoxicosis resulting from exogenous ingestion of thyroid hormone, usually in patients with a psychiatric disorder. Diagnosis can be difficult and this entity should be suspected in patients with high free tiroxine (T4) concentrations, low or suppressed thyroglobulin concentrations, normal urinary iodide excretion and low or suppressed ¹³¹I uptake. To establish the differential diagnosis, thyrotoxicosis factitia must be distinguished from several diseases with low ¹³¹I uptake, such as Graves’ disease, subacute thyroiditis, hyperthyroidism due to excessive iodine intake, struma ovarii and metastasis from thyroid cancer. Treatment is based on b-blockers to reduce symptoms and avoid iatrogeny. We present a case of thyrotoxicosis factitia treated in our outpatient clinic.     

Autoimmunity and hypothyroidism

Primary myxedema and hypothyroid Hashimoto's disease provide a well-documented example of organ-specific autoimmunity in man. Very slight modifications or increased release of thyroglobulin or thyroid antigens in the circulation may cause the rupture of autotolerance for the normal thyroid components, at least when individuals have a genetic predisposition to autoimmune thyroiditis (possibly associated with a predisposition to other autoimmune diseases). The demonstration of an association between HLA and thyroiditis, however, requires additional studies. The basic immunological abnormality responsible for autoimmunization against thyroid components is a defect in suppressor T cells, shown in experimental animals but not firmly established in man. The result of autoimmunization will be the appearance of cytotoxic mechanisms that lead to destruction of the thyroid follicle with progressive fibrosis, antibody-dependent cell-mediated cytotoxicity apparently being of major importance. A recent report shows, in addition, that thyroid atrophy in primary hypothyroidism is associated with the production of antibodies that block the thyroid-growth-promoting activity of TSH. The recent progress made in our understanding of autoimmune thyroiditis will certainly contribute to improving our knowledge of how and when autoimmunization might develop in man.     

Neonatal Hyperthyroidism and Long-acting Thyroid Stimulator Protector

Neonatal hyperthyroidism has been thought to result from transplacental passage of long-acting thyroid stimulator (L.A.T.S.) from a mother with Graves''s disease. A case is presented here in which no L.A.T.S. was detected in the mother or neonate but another immunoglobulin, L.A.T.S. protector, a specific human thyroid stimulator, was shown to be present in the mother''s serum. This stimulator may have been the cause of the neonatal hyperthyroidism.     

Delayed treatment of papillary thyroid carcinoma arising from struma ovarii in a patient with history of bilateral salpingo-oophorectomy: a case report

ObjectiveWe present a case of papillary thyroid carcinoma arising from struma ovarii treated erroneously as ovarian adenocarcinoma for more than 3 years.MethodsWe report clinical, surgical, laboratory, and imaging findings of the study patient and review the relevant literature.ResultsA 64-year-old woman was treated for ovarian adenocarcinoma for more than 3 years before it was determined that she likely had papillary thyroid carcinoma arising from struma ovarii. This is the first reported case of thyroid carcinoma arising from struma ovarii in a patient with a history of bilateral salpingo-oophorectomy. Possible etiologies include residual ovarian tissue after oophorectomy, ectopic thyroid, or metastatic thyroid cancer.ConclusionsIt is important to include struma ovarii and thyroid carcinoma arising from struma ovarii in the differential diagnosis, even with a history of bilateral salpingo-oophorectomy. This case emphasizes the importance of effective communication among the pathologist, oncologist, and surgeon to ensure timely initiation of appropriate therapy and reduced patient morbidity. (Endocr Pract. 2012;18:e1-e4)     

The tyrosine kinase receptor c-met,its cognate ligand HGF and the tyrosine kinase receptor trasducers STAT3, PI3K and RHO in thyroid nodules associated with Hashimoto's thyroiditis: an immunohisto-chemical characterization

Hepatocyte growth factor (HGF) exerts proliferative activities in thyrocytes upon binding to its tyrosine kinase receptor c-met and is also expressed in benign thyroid nodules as well as in Hashimoto''s thyroiditis (HT).The simultaneous expression of HGF/c-met and three trasducers of tyrosine kinase receptors (STAT3, PI3K, RHO) in both the nodular and extranodular tissues were studied by immunohistochemistry in 50 benign thyroid nodules (NGs), 25 of which associated with HT. The ligand/tyrosine kinase receptor pair HGF/c-met and the two trasducers PI3K and RHO were expressed in NGs, regardless of association with HT, with a higher positive cases percentage in HT-associated NGs compared to not HT-associated NGs (25/25 or 100% vs 7/25 or 28%; P<0.001). HGF, PI3K and RHO expression was only stromal (fibroblasts and endothelial cells), in all 32 reactive NGs, while c-met localization was consistently epithelial (thyrocyes). Immunoreactions for HGF, c-met, PI3K and RHO were also apparent in the extra-nodular tissue of HT specimens, where HGF and PI3K were expressed not only in stromal cells but also in thyrocyes along with the c-met. Finally, a positive correlation was observed between the proportion of HGF, c-met, PI3K follicular cells and the grade of lymphoid aggregates in HT. In conclusion, HGF, c-met, PI3K are much more frequently and highly expressed in HT compared to NGs, and among all NGs in those present in the context of HT. A paracrine effect of HFG/c-met on nodule development, based on the prevalent stromal expression, may be suggested along with a major role of HGF/c-met and PI3K in HT. Finally, the expression of such molecules in HT may be regulated by lymphoid infiltrate.Key words: HGF/c-met signaling, PI3K, RHO, Hashimoto''s thyroiditis, thyroid nodules.     

Maladie de Basedow et maladie de Crohn : étiopathogénie croisée ou association fortuite ? (À propos de deux cas)

An increased prevalence of the association between autoimmune thyroid diseases and ulcerative colitis has been suggested, while the association with Crohn's disease has only been reported in about ten cases. We describe two patients, one with Crohn's disease complicated with Graves’ disease and the other one with the reverse sequence. The treatment of hyperthyroidism in such cases must be early and efficient in order to avoid an intensification of the systemic manifestations of Crohn's disease. Genetic, environmental and immunologic aetiologies have been suggested for the pathogenesis of this association, although the exact mechanism remains unclear.     

A case study on Hashimoto's thyroiditis induced electrolyte imbalance

Lymphocytic thyroiditis is an autoimmune condition where auto-antibodies are produced against the thyroid gland. Initially, there might be a hyperthyroidism condition where T3 and T4 levels are high and external inflammation of thyroid gland might be seen, but over the course of time the destruction of thyroid gland can result in hypothyroidism where the complete destruction of thyroid gland. Electrolyte imbalances notably hypokalemia and hypomagnesemia with Hashimoto thyroiditis is a rare condition, in this article we will discuss about the course of treatment a 40-year-old female patient who presented with atypical symptoms of Hashimoto thyroiditis during her stay in the hospital.     

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.