Immunological disturbances in toxic multinodular goitre and active Graves' disease

Cell-mediated and humoral immunity were studied in seventeen patients with toxic multinodular goitre, ten with active Graves' disease and fourteen healthy controls. The study included determination of sheep erythrocyte and complement rosette-forming cells in peripheral blood, immunoglobulin levels, titres of microsomal antibodies and migration inhibition test using thyroid extract and phytohaemagglutinin. When compared with controls the patients showed a positive response to thyroid antigen in the leucocyte migration inhibition test. Microsomal antibodies were detected in seven out of ten active Graves' disease patients against two out of seventeen of those with toxic multinodular goitre. Significantly increased IgG and IgA and decreased IgM levels were found only in the toxic multinodular group. These data provide further evidence for immunological disturbances in toxic multinodular goitre.

Plasma levels of transthyretin and retinol-binding protein in child-a cirrhotic patients in relation to protein-calorie status and plasma amino acids, zinc, vitamin a and plasma thyroid hormones

Transthyretin and retinal-binding protein are sensitive markers of acute protein-calorie malnutrition both for early diagnosis and dietary evaluation. A preliminary study showed that retinal-binding protein is the most sensitive marker of protein-calorie malnutrition in cirrhotic patients, even those with the mild form of the disease (Child A). However, in addition to being affected by protein-calorie malnutrition, the levels of these short half-life-liver-produced proteins are also influenced by other factors of a nutritional (zinc, tryptophan, vitamin A, etc) and non-nutritional (sex, aging, hormones, renal and liver functions and inflammatory activity) nature. These interactions were investigated in 11 adult male patients (49.9 ± 9.2 years of age) with alcoholic cirrhosis (Child-Pugh grade A) and with normal renal function. Both transthyretin and retinol binding protein were reduced below normal levels in 55% of the patients, in close agreement with their plasma levels of retinal. In 67% of the patients (4/6), the reduced levels of transthyretin and retinal-binding protein were caused by altered liver function and in 50% (3/6) they were caused by protein-calorie malnutrition. Thus, the present data, taken as a whole, indicate that reduced transthyretin and retinal-binding protein levels in mild cirrhosis of the liver are mainly due to liver failure and/or vitamin A status rather than representing an isolated protein-calorie malnutrition indicator.

Metabolic disturbances in male broilers of different strains. 2. Relationship between the thyroid and somatotropic axes with growth rate and mortality

Seven male broiler strains (Arbor Acres, Avian Farms, Cobb-500, Hubbard-Peterson, ISA, Naked Neck, and Ross) were compared for their growth rate, feed efficiency, and mortality due to sudden death and ascites. In addition, weekly plasma levels of thyroid hormones [3,3′,5-triiodothyronine (T3) thyroxine (T4), T3: T4 ratio, growth hormone (GH), and insulin-like growth factor-I (IGF-I)] were determined. The highly productive, commercial strains were very similar in their endocrine profiles but differed markedly from the Naked Neck chickens. Naked Neck chickens were characterized by higher plasma T3 and lower T4 levels at similar ages as well as when compared on the same body weight basis. The present findings support the hypothesis that the slightly hypothyroid state of high productive broilers renders them more sensitive to metabolic disorders. Naked Neck chickens also had higher plasma GH levels than those of their age-matched commercial broilers. The coefficient of variation for GH was highest for Naked Neck chickens, which is indicative for an amplified GH burst amplitude. It may be stated that changes in plasma thyroid hormone concentration in indirect response to selection for low feed conversion and fast growth may be causatively linked to susceptibility for metabolic disturbances such as sudden death syndrome and ascites.

Do Thyroid Ultrasonographic Features Change According to Age in Euthyroid Dogs?

The thyroid gland was assessed by ultrasound in healthy euthyroid mixed-breed medium size dogs in different age groups. The objective was to verify ultrasonographic imaging patterns in these groups, as well as to identify possible changes in imaging features resulting from ageing. Thirty dogs - 10 young (<1 year), 10 adult and 10 elderly - without clinical signs or history of thyroid gland disease with complete blood count and thyroid function tests within the reference values were evaluated. Each thyroid lobe was examined by ultrasound for shape, size, echogenicity and echotexture. The analysis of echogenicity and echotexture was made by histogram. Thyroid volume was estimated by the equation for ellipsoid (length x width x height) pi/6. The thyroid volume of the young dogs in this study had a tendency to be higher than in adult dogs (P = 0.068) and older dogs (P = 0.120). The height of the thyroid lobe in the longitudinal plane was significantly higher (P = 0.026) in young dogs compared with the other dogs. The echotexture and echogenicity had no significant differences between groups, but the echogenicity was greater in older dogs. The results point out that ultrasound imaging of the thyroid volume is influenced by age in euthyroid dogs.

Thyroid hormone profile in breast cancer patients in postmenopause

Objective: The aim of this study was to determine thyroid hormone (TH) profile in postmenopausal patients with breast cancer (BC). Subjects and methods: 12 CaM patients stages I or II, without interventions that could interfere with tumor progression were selected, as well as and a control group with 18 postmenopausal women without CaM. We measured serum anti-thyroperoxidase antibody (TPOAB), thyroid-stimulating hormone (TSH), free thyroxine (T4L), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), before and after surgery, besides immunohistochemistry for estrogen (ER) and progesterone (PR) receptors. Results: Four patients with CaM showed changes in thyroid hormone profile: two had hyperthyroidism, one hypothyroidism, and one was positive for TPO-AB. All of them positive for ER and PR.TSH levels in breast cancer patients were not different from levels found in the control group (1.89 +/- 1.56 vs. 2.86 +/- 3.12 mIU/mL), but the levels of T4L in patients with CaM were statistically higher than those of the control group (1.83 +/- 0.57 vs. 1.10 +/- 0.20 ng/dL). Conclusion: These results reinforce the need for assessment of thyroid status in CaM patients, since in the absence of E2, changes in clinical HTs can act in E2-controlled processes. Arq Bras Endocrinol Metab. 2012;56(4):238-43

Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies

The association of RASopathies [Noonan syndrome (NS) and Noonan-related syndromes] and autoimmune disorders has been reported sporadically. However, a concomitant evaluation of autoimmune diseases and an assessment of multiple autoantibodies in a large population of patients with molecularly confirmed RASopathy have not been performed. The clinical and laboratory features were analyzed in 42 RASopathy patients, the majority of whom had NS and five individuals had Noonan-related disorders. The following autoantibodies were measured: Anti-nuclear antibodies, anti-double stranded DNA, anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1, anti-ribosomal P, IgG and IgM anticardiolipin (aCL), thyroid, anti-smooth muscle, anti-endomysial (AE), anti-liver cytosolic protein type 1 (LC1), anti-parietal cell (APC), anti-mitochondrial (AM) antibodies, anti-liver-kidney microsome type 1 antibodies (LKM-1), and lupus anticoagulant. Six patients (14%) fulfilled the clinical criteria for autoimmune diseases [systemic lupus erythematous, polyendocrinopathy (autoimmune thyroiditis and celiac disease), primary antiphospholipid syndrome (PAPS), autoimmune hepatitis, vitiligo, and autoimmune thyroiditis]. Autoimmune antibodies were observed in 52% of the patients. Remarkably, three (7%) of the patients had specific gastrointestinal and liver autoantibodies without clinical findings. Autoimmune diseases and autoantibodies were frequently present in patients with RASopathies. Until a final conclusion of the real incidence of autoimmunity in Rasopathy is drawn, the physicians should be alerted to the possibility of this association and the need for a fast diagnosis, proper referral to a specialist and ultimately, adequate treatment. (c) 2012 Wiley Periodicals, Inc.

Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma

Objective Immune responses against differentiated thyroid carcinomas (DTC) have long been recognized. We aimed to investigate the role of immune cell infiltration in the progression of DTC. Design We studied 398 patients 253 with papillary and 13 with follicular thyroid cancers, as well as 132 with nonmalignant tissues. Patients and measurements Immune cell infiltration was identified using CD3, CD4, CD8, CD20, CD68 and FoxP3 immunohistochemical markers. In addition, we assessed colocalization of CD4 and IL-17 to identify Th17 lymphocytic infiltration and colocalization of CD33 and CD11b to identify infiltration of myeloid-derived suppressor cells (MDSC). Results Immune cells infiltrated malignant tissues more often than benign lesions. The presence of chronic lymphocytic thyroiditis (CLT) concurrent to DTC, CD68+, CD4+, CD8+, CD20+, FoxP3+ and Th17 lymphocytes but not MDSCs was associated with clinical and pathological features of lower tumour aggressiveness and a more favourable patient outcome. A log-rank test confirmed an association between concurrent CLT, tumour-associated macrophage infiltration, and CD8+ lymphocytes and an increased in disease-free survival, suggesting that evidence of these immune reactions is associated with a favourable prognosis. Conclusion Our data suggest that the tumour or peri-tumoural microenvironment may act to modify the observed pattern of immune response. Immune cell infiltration and the presence of concurrent CLT helped characterize specific tumour histotypes associated with favourable prognostic features.

RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family

Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

Surgical approach to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2

We briefly review the surgical approaches to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2 (medullary thyroid carcinoma/multiple endocrine neoplasia type 2). The recommended surgical approaches are usually based on the age of the affected carrier/patient, tumor staging and the specific rearranged during transfection codon mutation. We have focused mainly on young children with no apparent disease who are carrying a germline rearranged during transfection mutation. Successful management of medullary thyroid carcinoma in these cases depends on early diagnosis and treatment. Total thyroidectomy should be performed before 6 months of age in infants carrying the rearranged during transfection 918 codon mutation, by the age of 3 years in rearranged during transfection 634 mutation carriers, at 5 years of age in carriers with level 3 risk rearranged during transfection mutations, and by the age of 10 years in level 4 risk rearranged during transfection mutations. Patients with thyroid tumor >5 mm detected by ultrasound, and basal calcitonin levels >40 pg/ml, frequently have cervical and upper mediastinal lymph node metastasis. In the latter patients, total thyroidectomy should be complemented by extensive lymph node dissection. Also, we briefly review our data from a large familial medullary thyroid carcinoma genealogy harboring a germline rearranged during transfection Cys620Arg mutation. All 14 screened carriers of the rearranged during transfection Cys620Arg mutation who underwent total thyroidectomy before the age of 12 years presented persistently undetectable serum levels of calcitonin (<2 pg/ml) during the follow-up period of 2-6 years. Although it is recommended that preventive total thyroidectomy in rearranged during transfection codon 620 mutation carriers is performed before the age of 5 years, in this particular family the surgical intervention performed before the age of 12 years led to an apparent biochemical cure.

Thyroid function and prevalent and incident metabolic syndrome in older adults: the health, ageing and body composition study

Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults.

Morbidity rate of reoperation in thyroid surgery: a different point of view

Goitre recurrence is a common problem following subtotal thyroid gland resection for multinodular goitre disease. The aim of the present study was to evaluate morbidity rate in relation to the side of initial and redo-surgery for recurrent disease.

Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism

Nitric oxide mediates a wide array of cellular functions in many tissues. It is generated by three known isoforms of nitric oxide synthases (NOS). Recently, the endothelial isoform, NOSIII, was shown to be abundantly expressed in the rat thyroid gland and its expression increased in goitrous glands. In this study, we analyzed whether NOSIII is expressed in human thyroid tissue and whether levels of expression vary in different states of thyroid gland function. Semiquantitative RT-PCR was used to assess variations in NOSIII gene expression in seven patients with Graves' disease, one with a TSH-receptor germline mutation and six hypothyroid patients (Hashimoto's thyroiditis). Protein expression and subcellular localization were determined by immunohistochemistry (two normal thyroids, five multinodular goiters, ten hyperthyroid patients and two hypothyroid patients). NOSIII mRNA was detected in all samples: the levels were significantly higher in tissues from hyperthyroid patients compared with euthyroid and hypothyroid patients. NOSIII immunoreactivity was detected in vascular endothelial cells, but was also found in thyroid follicular cells. In patients with Graves' disease, the immunostaining was diffusely enhanced in all follicular cells. A more intense signal was observed in toxic adenomas and in samples obtained from a patient with severe hyperthyroidism due to an activating mutation in the TSH receptor. In multinodular goiters, large follicles displayed a weak signal whereas small proliferative follicles showed intense immunoreactivity near the apical plasma membrane. In hypothyroid patients, NOSIII immunoreactivity was barely detectable. In summary, NOSIII is expressed both in endothelial cells and thyroid follicular cells. The endothelial localization of NOSIII is consistent with a role for nitric oxide in the vascular control of the thyroid. NOSIII expression in thyroid follicular cells and the variations in its immunoreactivity suggest a possible role for nitric oxide in thyrocyte function and/or growth.

Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues

Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

[ABC of thyroid diseases and their treatment]

Thyroid diseases are caused by a disturbance of thyroid hormone secretion, inflammations or tumors of the thyroid or combinations thereof. Most important causes for hyperthyroidism are Graves' disease and toxic nodular goiters (including toxic adenomas). Hypothyroidism is often caused by Hashimoto's chronic thyroiditis and can occur in patients after thyroidectomy. Chronic hashimoto's thyroiditis and subacute de Quervain's thyroiditis are the thyroid inflammations most frequently seen. Graves' disease and Hashimoto's thyroiditis are autoimmune thyroid diseases. Thyroid tumors encompass benign solitary nodules, diffuse and nodular goiters, papillary, follicular, medullary and anaplastic carcinomas.

Randomized controlled trial on single dose steroid before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function

OBJECTIVE: To evaluate the effects of a single preoperative dose of steroid on thyroidectomy outcomes. BACKGROUND: Nausea, pain, and voice alteration frequently occur after thyroidectomy. Because steroids effectively reduce nausea and inflammation, a preoperative administration of steroids could improve these thyroidectomy outcomes. METHODS: Seventy-two patients (men = 20, women = 52) undergoing thyroidectomy for benign disease were included in this randomized, controlled, 2 armed (group D: 8 mg dexamethasone, n = 37; group C: 0.9% NaCl, n = 35), double-blinded study (clinical trial number NCT00619086). Anesthesia, surgical procedures, antiemetics, and analgesic treatments were standardized. Nausea (0-3), pain (visual analog scale), antiemetic and analgesic requirements, and digital voice recording were documented before and 4, 8, 16, 24, 36, and 48 hours after surgery. Patients were followed-up 30 days after hospital discharge. RESULTS: Baseline characteristics were similar among the 2 treatment groups. Nausea was pronounced in the first 16 hours postoperatively (scores were <0.3 and 0.8-1.0 for group D and C, respectively (P = 0.005)), and was significantly lower in group D compared with group C during the observation period (P = 0.001). Pain diminished within 48 hours after surgery (visual analog scale 20 and 35 in group D and C, respectively (P = 0.009)). Antiemetic and analgesic requirements were also significantly diminished. Changes in voice mean frequency were less prominent in the dexamethasone group compared with the placebo group (P = 0.015). No steroid-related complications occurred. CONCLUSION: A preoperative single dose of steroid significantly reduced nausea, vomiting, and pain, and improved postoperative voice function within the first 48 hours (most pronounced within 16 hours) after thyroid resection; this strategy should be routinely applied in thyroidectomies.