Titers Of Antithyroglobulin Antibodies Research Articles

THU0454 Thyroid Involvement in Patients with Spondyloarthritis

BackgroundThe association between chronic inflammatory diseases and thyroid dysfunction is well recognized. This fact can be attributed to hormonal factors and the presence of a facilitator genetic terrain. Increased prevalence...

Poor prognosis of recurrent and persistent papillary thyroid carcinoma with high anti-thyroglobulin antibody titers

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Hashimoto’s encephalopathy associated with an elevated intrathecal IgG4 level

Hashimoto’s encephalopathy is a steroid-responsive encephalopathy associated with the existence of anti-thyroid antibodies, which is characterized by various neuropsychiatric symptoms [2, 4, 6]. Autoimmune mechanisms are thought to play a pathogenic role in the disorder due to its association with other autoimmune disorders and response to steroid therapy; however the pathological mechanism underlying the disease has not been completely elucidated. We herein report a patient who manifested with steroid-responsive progressive memory disturbance, cerebellar ataxia and dystonia associated with an elevated immunoglobulin G4 (IgG4) level in both the serum and cerebrospinal fluid (CSF). The patient was a 60-year-old Japanese male who presented with a 6-month history of progressive gait disturbance. He developed memory disturbance and involuntary movements of his face and neck 2 months after presentation. There were no vascular risk factors, such as hypertension, diabetes mellitus or dyslipidemia. A neurological examination revealed cerebellar ataxia and grimacing face with cervical dystonia. Neuropsychological assessments revealed that the Mini-Mental State Examination score was 26 and the Frontal Assessment Battery score was 14, which was normal compared to age-matched normal subjects. Laboratory tests showed a high titer of anti-thyroglobulin antibodies (213 IU/ml; normal, \100) while the titer of anti-thyroid peroxidase antibodies in the serum was negative. The results of routine blood tests, the levels of antinuclear and anti-DNA antibodies, anti-SS-A/Ro, antiSS-B/La antibodies, anti-gliadin antibodies, anti-glutamic acid decarboxylase antibodies, myeloperoxidase-antineutrophil cytoplasmic antibodies (ANCA), proteinase-3ANCA, anti-voltage-gated potassium channel antibodies, angiotensin-converting enzyme, T3, T4, TSH and serum B12 and B1were all normal. The serum IgG concentration was 1,310 mg/dl (normal 870–1,600), while the serum IgG4 concentration was elevated (298 mg/dl; normal, 4.8–105) (Table 1). A CSF analysis revealed pleocytosis (21/ll: mononuclear cells 20/ll, polymorphonuclear cells 1/ll) and an elevated protein level of 143 mg/dl. Additional testing of the CSF found elevated levels of IgG (24.6 mg/dl; normal: 0.9–5.5) and IgG4 (3.5 mg/dl; normal: not detected) (Table 1). The IgG index in the patient was 0.79 (normal: 0.33–0.60), while the IgG4 index was 0.65. No oligoclonal bands were detected in the CSF. A cytological examination of the CSF showed no plasma cells, and a CSF culture revealed no infectious pathogens. The results of electroencephalography were normal. A brain magnetic resonance imaging (MRI) study revealed symmetrical periventricular high signal intensity on T2-weighted images and fluid attenuated inversion recovery (FLAIR) images (Fig. 1a). Gadolinium-enhanced T1-weighted images showed no contrast enhancement in the dura mater. There were no findings suggesting cerebral vasculitis or atherosclerosis on MR angiography. Wholebody CT imaging showed no malignancy or complications of IgG4-related disease, such as pancreatitis, retroperitoneal fibrosis or interstitial pneumonia. Esophago-gastroduodenoscopy and colonoscopy showed no malignancy. Y. Hosoi S. Kono (&) T. Konishi H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

Case report: When measured free T4 and free T3 may be misleading. Interference with free thyroid hormones measurements on Roche® and Siemens® platforms

A 59-year old female patient presented with apathy and 6 kg weight gain. Investigations revealed severe primary hypothyroidism (TSH>100 μIU/ml). L-thyroxine (L-T4) was started and titrated up to 75 μg, once daily, with clinical improvement. Other investigations revealed very high titres of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies. After three months, there was a fall in TSH to 12.74 μIU/ml, however, with unexpectedly high free T4 (FT4) - 6.8 ng/ml and free T3 (FT3) - 6.7 pg/ml concentrations [reference range (rr): 0.8-1.9 ng/ml and 1.5-4.1 pg/ml (Siemens®), respectively]. At this stage L-T4 was stopped, and this was followed by a rapid increase in TSH (to 77.76 μIU/ml) and some decrease in FT4 and FT3, however FT4 concentration remained elevated (2.1 ng/ml). Following this, L-T4 was restarted. On admission to our Department, she was clinically euthyroid on L-T4, 88 μg, once daily. Investigations on Roche® platform confirmed mildly elevated TSH - 5.14 (rr: 0.27-4.2 μIU/ml) with high FT4 [4.59 (rr: 0.93-1.7 ng/ml)] and FT3 [4.98 (rr: 2.6-4.4 pg/ml)] concentrations. Other tests revealed hypoechogenic ultrasound pattern typical for Hashimoto thyroiditis. There was no discrepancy in calculated TSH value following TSH dilution (101% recovery). Concentrations of FT4 and FT3 were assessed on the day of discontinuation of L-T4 and after four days by the means of Abbott® Architect I 1000SR platform. These revealed FT4 and FT3 concentrations within the reference range [e.g., FT4 - 1.08 ng/ml (rr: 0.7-1.48)] vs 4.59 ng/ml (rr: 0.93-1.7, Roche®), FT3 - 3.70 pg/ml (rr: 1.71-3.71) vs 4.98 (rr: 2.6-4.4, Roche®)], confirming assay interference. Concentrations of ferritin and SHBG were normal.ConclusionsClinicians must be aware of possible assay interference, including the measurements of FT4 and FT3 in the differential diagnosis of abnormal results of thyroid function tests that do not fit the patient clinical presentation.

Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: a case report and one year follow-up

BackgroundAnti-N-methyl-D-aspartate receptor encephalitis is an increasingly common autoimmune disorder mediated by antibodies to certain subunit of the N-methyl-D-aspartate receptor. Recent literatures have described anti-thyroid and infectious serology in this encephalitis but without follow-up.Case presentationA 17-year-old Chinese female patient presented with psychiatric symptoms, memory deficits, behavioral problems and seizures. She then progressed through unresponsiveness, dyskinesias, autonomic instability and central hypoventilation during treatment. Her conventional blood work on admission showed high titers of IgG antibodies to thyroglobulin, thyroid peroxidase and IgM antibodies to Epstein-Barr virus viral capsid antigen. An immature ovarian teratoma was found and removal of the tumor resulted in a full recovery. The final diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was made by the identification of anti-N-methyl-D-aspartate receptor antibodies in her cerebral spinal fluid. Pathology studies of the teratoma revealed N-methyl-D-aspartate receptor subunit 1 positive ectopic immature nervous tissue and Epstein-Barr virus latent infection. She was discharged with symptoms free, but titers of anti-thyroid peroxidase and anti-thyroglobulin antibodies remained elevated. One year after discharge, her serum remained positive for anti-thyroid peroxidase and anti-N-methyl-D-aspartate receptor antibodies, but negative for anti-thyroglobulin antibodies and IgM against Epstein-Barr virus viral capsid antigen.ConclusionsPersistent high titers of anti-thyroid peroxidase antibodies from admission to discharge and until one year later in this patient may suggest a propensity to autoimmunity in anti- N-methyl-D-aspartate receptor encephalitis and support the idea that neuronal and thyroid autoimmunities represent a pathogenic spectrum. Enduring anti-N-methyl-D-aspartate receptor antibodies from admission to one year follow-up but seroreversion of Epstein-Barr virus viral capsid antigen IgM may raise the important issue of elucidating the triggers and boosters of anti- N-methyl-D-aspartate receptor encephalitis.

A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice

Previous studies by our group, using an experimental autoimmune thyroiditis (EAT) model in Strain 13 inbred guinea pigs, resulted in T cell-mediated delayed hypersensitivity; however, autoantibodies proved not to be cytotoxic to thyroid epithelial cells in the presence or absence of complement proteins. Albeit, T cell-mediated lymphocyte cytotoxicity began to diminish sharply concomitantly with increasing titers of circulating autoantibodies, indicating a skewing of the self-reactive response and amelioration of the EAT. Furthermore, immunization of guinea pigs with thyroglobulin in incomplete Freund's adjuvant (IFA) generated a high titer of antithyroglobulin antibodies and proved to inhibit thyroiditis. These observations indicated that the shift in the immune response from Th1 to Th2 and the production of antibodies were likely responsible for ameliorating EAT. Based upon these results, we extrapolated our studies to design a multivalent vaccine, which shows promise in preventing/reversing T1D in NOD mice. A small pilot study was conducted in which a total of 34 mice, 20 non-immunized controls and 14 immunized with syngeneic islet lysate, were monitored for mean day to diabetes for a total of 28 weeks. Immunization of NOD animals with syngeneic islet lysates resulted in a significant delay in diabetes onset (P < 0.001) as compared to non-immunized controls. To further assess the vaccine's efficacy, robustness, and delay of disease, a large-scale experiment was conducted and monitored for 32 weeks using 106 mice, 64 non-immunized controls and 42 immunized with syngeneic islet lysate. At the end of the study, 90% of the non-immunized group developed diabetes, while less than 25% of the immunized group became diabetic (P < 0.0001). The protective effect, as a result of vaccination, correlated with an increase in the levels of IL-10 and IL-4 cytokines as well as a skewing to Th2-dependent isotype antibodies in serum. Strikingly, adoptive transfer of spleen cells from immunized animals into NOD.scid recipients provided protection against transfer of diabetes by diabetogenic spleen cells. The results of this study provide evidence that vaccination with islet lysate leads to a Th2-dependent skewing of the immune response to islet beta cells as a possible mechanism of protection. This strategy may be implemented as a possible vaccination protocol for arresting and/or preventing T1D in patients.

A rare case of resistance to thyroid hormone coexisting with Graves’ disease

To the Editor, Resistance to thyroid hormone (RTH) is characterized by reduced sensitivity to thyroid hormone, mostly caused by mutation in the thyroid hormone receptor b (TRb) gene. Patients with RTH have increased free triiodothyroxine (FT3) and free thyroxine (FT4) and unsuppressed thyrotropin (TSH) levels [1]. Here, we describe a rare case of RTH coexisting with Graves’ disease (GD). A 17-year-old man presented to the hospital because of fatigue, palpitation, hand tremors, weight loss (6 kg), and a large goiter. His blood pressure and heart rate were 127/76 mmHg and 102 beats/min, respectively. He had no growth or mental retardation. Serum TSH, FT3, and FT4 levels were \0.05 lU/ml (reference 0.541–4.261), 24.5 pg/ml (reference 2.39–4.06), and 6.46 ng/dl (reference 0.71–1.52), respectively. Serum anti-TSH receptor antibody (TRAb) level was[30.0 IU/l (reference\1.0). Titers of anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg) antibodies were 402.0 U/ml (reference \0.2) and 8.4 U/ml (reference \0.3), respectively. Ultrasound revealed a diffusely enlarged thyroid gland with no tumor lesion. These findings were consistent with GD. Methimazole (30 mg) therapy was started, with the dose reduced as thyroid function improved. After 3 months, his TSH level became inappropriately high (8.308 lU/ml), and his FT3 and FT4 levels (6.40 pg/ml and 1.91 ng/dl, respectively) and TRAb titer (13.8 IU/l) were also above the reference ranges. These conditions persisted under treatment with 5–10 mg methimazole (TSH and FT3 levels were 2.930–16.16 lU/ml and 5.10–6.05 pg/ml, respectively). Fluctuations in metabolic parameters such as total cholesterol and alkaline phosphatase were relatively small and unrelated to those of thyroid function (163–211 mg/dl and 280–402 U/l (reference 115–359), respectively). Thyrotoxic symptoms were not observed. After 1 year, TSH, FT3, and FT4 levels were 6.46 lU/ml, 6.01 pg/ml, and 2.13 ng/dl, respectively, whereas TRAb titer decreased to 1.9 IU/l. Since the first visit, the patient’s body weight had increased by 5 kg. Magnetic resonance imaging was negative for TSH-secreting tumor. RTH was verified by sequence analysis; a heterozygous missense mutation, A234T, was found in the TRb gene [2]. His parents had normal thyroid function. Because the patient had typical hyperthyroidism due to GD, increased secretion of TSH due to RTH was not clarified until GD improved. The occurrence of GD in a patient with undiagnosed RTH is rare. Sivakumar et al. [3] could identify RTH in a GD patient because a high dose of levothyroxine was required after radioiodine ablation therapy, unlike the case. In this case, determining the therapeutic target range of the thyroid hormone and methimazole dose was difficult, partly because his thyroid function before the onset of GD was unknown. In addition, hyposensitivity to thyroid hormone varies across tissues within the same patient and across individuals having the same mutation [1]. However, during low-dose methimazole treatment, the absence of apparent thyrotoxic symptoms, weight recovery, and K. Ogawa M. Yoshida (&) M. Miyata Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawa-ku, Nagoya 454-8502, Japan e-mail: myavp@zm.commufa.jp

Prevalence of Thyroid Autoimmunity in Patients with Spondyloarthropathies

To evaluate the prevalence of chronic autoimmune thyroiditis or Hashimoto's thyroiditis (HT) in a group of patients with spondyloarthritis (SpA). We evaluated serum levels of thyroid-stimulating hormone, free triiodothyronine, and free thyroxine, and titers of antithyroglobulin and antithyroid peroxidase (anti-TPO) antibodies in 357 consecutive patients with SpA. We also recruited 318 healthy age-matched controls. Ultrasonography of the thyroid gland was performed in all subjects and rheumatic activity was evaluated. Indices of thyroid autoimmunity were significantly more frequent in patients with SpA than in controls (24.09% vs 10.69%, respectively; p < 0.05). In the SpA group, a higher prevalence of HT was found in patients with an active disease than in those with low-moderate disease levels. Also in the SpA group, patients with a disease duration > 2 years had a higher prevalence of HT and anti-TPO antibodies positivity than patients with a disease duration ≤ 2 years. Ultrasonography detected a significantly higher frequency of thyroid nodules and hypoechoic pattern in patients with SpA than in controls. Among patients with SpA, HT and anti-TPO antibodies positivity were significantly more frequent in patients with peripheral involvement (68.6%) than in patients with axial involvement (31.4%; p < 0.05). Our study shows a significantly higher prevalence of thyroid autoimmunity in patients with SpA as compared to controls. Thyroiditis occurs more frequently in patients with longer disease duration and active rheumatic disease. We suggest that thyroid function tests be part of the clinical evaluation in patients with SpA.

Interferon-Alpha-Induced Destructive Thyroiditis Followed by Graves' Disease in a Patient with Chronic Hepatitis C: A Case Report

Interferon-induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon-alpha (IFN-α) therapy. But, destructive thyroiditis followed by Graves' disease associated with IFN-α therapy is very rarely reported. Herein, we report a rare case of pegylated IFN-α (pegIFN-α) induced destructive thyroiditis followed by Graves' disease in a patient with HCV infection. A 31-yr-old woman suffered from chronic active hepatitis C and was treated with pegIFN-α and ribavirin for 12 months. Results of a thyroid function test and autoantibody levels were normal before IFN-α therapy was initiated. Destructive thyrotoxicosis appeared seven months after the initiation of IFN-α therapy, followed by Graves' thyrotoxicosis two months after the cessation of therapy. The diagnoses of destructive thyroiditis and Graves' disease were confirmed by the presence of TSH receptor antibodies in addition to Tc-99m scintigraphy findings. The patient's antithyroglobulin antibody titer increased gradually during IFN-α therapy and remained weakly positive after IFN-α therapy was discontinued.

Frequency of autoimmune thyroid disease in chronic urticaria.

To determine the frequency of autoimmune thyroid disease in diagnosed cases of chronic urticaria (CU) and the association between hypothyroidism and chronic urticaria if any. Non-interventional, descriptive study. Department of Physiology, Dow University of Health Sciences, Karachi, from December 2004 to January 2006. The patients were selected from Department of Dermatology and Medical Units of Civil Hospital, Jinnah Postgraduate Medical Centre, the Aga Khan Hospital and community clinics. A total number of 60 patients were enrolled in this study. In all patients, serum antithyroid autoantibodies (antithyroglobulin and antimicrosomal/thyroperoxidase), thyroid profile (serum TSH, T3 and FT4), complete blood count, erythrocyte sedimentation rate and IgE levels were carried out. The proportions were compared using chi-square test with significance at p < 0.05. Forty seven (78%) patients were found to have chronic urticaria (history and laboratory reports). Out of 47 patients with diagnosis of CU, elevated titres of antithyroglobulin (TGA) and antimicrosomal antibodies (TMA) were found to be present in 20 (42.6%) and 27 (57.4%) patients respectively. Serum TSH level (thyroid stimulating hormone) was increased and T3, FT4 were decreased in 20 (42.6%) patients (p < 0.001). A total number of 20 (42.5%) patients were found to be hypothyroid with chronic urticaria of greater than 6 weeks duration. This study shows a statistically significant association between hypothyroidism and chronic urticaria. Full thyroid profile (serum thyroid autoantibodies, serum TSH, T3 and FT4) is highly recommended in patients with diagnosis of chronic urticaria.

Autoimmune thyroid disease in patients with anti-GAD positive type 1 diabetes mellitus

Abstract The aim of the study was to determine the frequency and titers of anti-thyroid peroxidase (Anti-TPO), anti-thyroglobulin (Anti-TG), and anti-glutamic acid decarboxylase (Anti-GAD) antibodies in Turkish patients with type 1 diabetes mellitus (DM), and to compare the frequency of anti-TPO and anti-TG titers in the presence or absence of anti-GAD. A total of 104 patients including 56 males and 48 females with type 1 DM and their age-, gender-, and body mass index-matched control group, including 31 males and 27 females, 58 cases in total with an age range of 15-50 years, were recruited into this study. In patients with type 1 DM, positive anti-GAD was detected in 30.8% (n=32). In patients with positive anti-GAD, rate of positive anti-TPO was 37.5%; however, in patients with negative anti-GAD, the rate of positive anti-TPO was 9.7% and the difference was statistically significant (p=0.001). In patients with positive anti-GAD, the rate of positive anti-TG was 18.8%. In patients with negative anti-GAD, the rate of positive anti-TG was 2.8%, and the difference between them was statistically significant (p=0.005). In patients with positive and negative anti-GAD, rates of both positive anti-TPO and anti-TG were 15.6% and 1.4%, respectively, with the difference showing statistical significance (p=0.004). Thyroid autoimmunity in type 1 DM patients with positive anti-GAD was apparently higher; therefore, these patients should be followed more frequently and carefully.

Expression of Immunoregulatory Molecules by Thyrocytes Protects Nonobese Diabetic-H2h4 Mice from Developing Autoimmune Thyroiditis

One approach to prevent tissue destruction by autoimmune attack in organ-specific autoimmune diseases is to protect the target tissue from autoimmune reaction, regardless of its persistent activity. To provide proof-of-principle for the feasibility of this approach, the immunoregulatory molecules, TNF-related apoptosis-inducing ligand (TRAIL) and indoleamine 2, 3-dioxygenase, were expressed in the thyroid glands using adenovirus vector in nonobese diabetic-H2(h4) mice that spontaneously develop thyroiditis. Mice were anesthetized, and the thyroid glands were exposed by neck dissection, followed by in situ infection with adenovirus vector (5 x 10(10) particles per mouse) twice or thrice, starting 1 d or 4 wk before mice were supplied with sodium iodine (NaI) water. After 8 wk NaI provision, the extent of thyroiditis, serum titers of antithyroglobulin antibodies, and cytokine expression in the spleen were examined. In situ infection of adenovirus expressing TRAIL or indoleamine 2, 3-dioxygenase, but not green fluorescent protein, significantly suppressed thyroiditis scores. However, antithyroglobulin antibody titers and expression levels of cytokines (interferon-gamma and IL-4) in the spleen remained unaltered. Importantly, adenovirus infection 4 wk after NaI provision was also effective at suppressing thyroiditis. The suppressive effect of TRAIL appears to be mediated at least partly by accumulation of CD4(+)Foxp3(+) regulatory T cells into the thyroid glands. Thus, localized expression of immunoregulatory molecules efficiently protected the thyroid glands from autoimmune attack without changing the systemic autoimmunity in nonobese diabetic-H2(h4) mice. This kind of immunological intervention, although it does not suppress autoimmune reactivity, may have a potential for treating organ-specific autoimmune diseases.

E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement

To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH. A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 microg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH. This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than beta receptor of thyroid hormone (TRbeta) might modulate the phenotype of RTH.

Recurrence of papillary thyroid cancer suspected by high anti-thyroglobulin antibody levels and detection of peripheral blood thyroglobulin mRNA

The amplification of thyroglobulin (TG) mRNA in peripheral blood of patients with thyroid cancer has been studied for almost one decade, but its real contribution for diagnosis of cancer relapse has not yet been established. In the present paper we report the case of a patient with papillary thyroid cancer with undetectable stimulated serum thyrogobulin levels after thyroid ablation. Follow-up showed the presence of high titers of anti-thyroglobulin antibodies and the presence of TG mRNA in a peripheral blood sample, while cervical ultrasound and thorax and cervical computerized tomography were negative. Reinvestigation confirmed lymph node metastases. Anti-TG antibodies progressively decreased after surgery for metastatic lymph nodes resection followed by radioiodine therapy. Although our recent findings show that patients with positive TG mRNA do not have increased risk of cancer recurrence after 24 months of follow-up, the presence of TG mRNA along with high anti-TG antibodies were important indicators that determined further extensive investigation of tumour relapse in this patient, since positron emission tomography scan was not available at our Institution. A methodological standardization that can distinguish specific from non-specific TG mRNA amplification might be of great interest for the follow-up of differentiated thyroid cancer, especially in patients with high levels of anti-TG antibodies.

Hashimoto's Encephalopathy

Hashimoto's encephalopathy (HE) is a controversial neurological disorder that comprises a heterogenous group of neurological symptoms that manifest in patients with high titers of antithyroid antibodies. Clinical manifestations of HE may include encephalopathic features such as seizures, behavioral and psychiatric manifestations, movement disorders, and coma. Although it has been linked to cases of Hashimoto's thyroiditis or thyroid dysfunction, the most common immunological feature of HE is the presence of high titers of antithyroglobulin or anti-TPO (antimicrosomal) antibodies. At present, it is unclear whether antithyroid antibodies represent an immune epiphenomenon in a subset of patients with encephalopathic processes or they are really associated with pathogenic mechanisms of the disorder. The significance of classifying encephalopathies under the term HE will be determined in the future once the relevance of the role of antithyroid antibodies is demonstrated or dismissed by more detailed experimental and immunopathological studies. The responsiveness of HE to steroids or other therapies such as plasmapheresis supports the hypothesis that this is a disorder that involves immune pathogenic mechanisms. Further controlled studies of the use of steroids, plasmapheresis, or immunosuppressant medications are needed in the future to prove the concept of the pathogenic role of antithyroid antibodies in HE.

Serum antithyroid antibodies in female patients with chronic urticaria.

To determine the frequencies of serum antithyroglobulin and antimicrosomal autoantibodies in female patients with chronic urticaria, and the association between thyroid autoantibodies and chronic urticaria, if any. Non-interventional, case-control analytic study. This study was carried out by the Department of Physiology, Dow University of Health Sciences, Karachi, from December 2004 to January 2006 on patients selected from Department of Dermatology and Medical Units of Civil Hospital, Jinnah Postgraduate Medical Centre and The Aga Khan University Hospital, Karachi and from the Community Clinics in Karachi. A total number of 90 subjects were enrolled and divided in three groups consisting of 30 patients each. Group 1 comprised of patients with diagnosis of chronic urticaria, Group 2 of diagnosed cases of hypothyroidism with/without urticaria, and Group 3 of normal age and gender-matched healthy volunteers. In all patients, serum antithyroid autoantibodies (antithyroglobulin and antimicrosomal) and thyroid profile (serum T3, T4 and TSH levels) was carried out. Chi-square test was used to determine significance of proportion of variables at p < 0.05. Elevated titres of antithyroglobulin antibodies were found to be present in 9 (30%) patients in Group 1 (chronic urticaria), 24 (80%) patients in Group 2 (known cases of hypothyroidism) compared to control. Elevated titres of antimicrosomal antibodies were found to be present in 13 (43.3%) patients in Group 1, 27 (90%) patients in Group 2 (known cases of hypothyroidism) compared to control. The association between hypothyroidism and chronic urticaria with regard to autoantibodies titres was highly significance (p <0.001). A highly statistically significant association was found between chronic urticaria and hypothyroidism with special regard to antithyroglobulin and antimicrosomal autoantibodies. Therefore, assays of these two autoantibodies are justified for the early diagnosis of autoimmune thyroiditis in combination with chronic urticaria for better treatment options.

New immunomodulators in the treatment of Graves’ ophthalmopathy

Steroids have been used in the therapy of the moderate to severe forms of Graves’ ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves’ disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000 mg i.v. twice at two-week interval) and those treated with IVGC (500 mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3–5% CD19+ cells in the periphery, mostly CD19 + 5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly ( P = NS) and did not correlate to CD20+ depletion ( P = NS). CAS values decreased significantly ( P < 0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P < 0.0001) and in those with Graves’ hyperthyroidism and lid signs (ANOVA; P < 0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX ( P < 0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells.

CD4 +CD25 + naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2 h4 mice

NOD-H2 h4 mice, which express I-A k on the NOD background, spontaneously develop autoimmune thyroiditis, a model of Hashimoto thyroiditis in humans, by adding iodide in the drinking water. Parental NOD mice have previously been shown to have intrinsic numerical abnormalities in peripheral lymphocytes and lymphocyte subpopulations such as CD4 +CD25 + naturally occurring regulatory T cells (Treg). Therefore we first investigated whether the similar abnormalities exist in NOD-H2 h4 mice. We observed that, compared with other non-autoimmune disease prone BALB/c and C57BL/6 mice, NOD-H2 h4 mice have lower numbers of splenocytes, CD3 +T, CD4 +T and CD8 +T cells but the ratios of Treg to CD4 +T cells were comparable. Increasing the numbers of peripheral lymphocytes by Complete Freund's Adjuvant immunization or splenocyte transfer did not affect development of thyroiditis, indicating that lymphopenia does not play a critical role in the pathogenesis of thyroiditis. We next examined the significance of Treg by depleting this lymphocyte subset with anti-CD25 antibody. Treg depletion, performed 4 days before the administration of NaI water for 8 weeks, significantly exacerbated thyroiditis ( p < 0.01). Anti-thyroglobulin antibody titers also increased by Treg depletion ( p < 0.01) without changing the IgG2b to IgG1 ratios. In addition, expression levels of mRNA for IFN-γ and IL-4 were enhanced in parallel. However, T 4 levels were similar between antibody-treated and untreated groups. Additional anti-CD25 administration at 3 weekly intervals did not influence these results. These data, together with previous studies on other mouse models of inducible thyroiditis and Graves’ disease, indicate the role played by Treg in keeping anti-thyroid autoimmune reaction in check in experimental autoimmune thyroid diseases.

Psychiatric Presentation of Hashimotoʼs Encephalopathy

Hashimoto's encephalopathy is an unusual condition that is associated with Hashimoto's thyroiditis. Myoclonus, epileptic seizures, dementia, and disturbances of consciousness are the most common features. We present an atypical case of Hashimoto's encephalopathy in a 33-year-old woman who presented with several brief and acute psychotic episodes. After treatment with steroids, there was an improvement in the patient's psychiatric symptoms and electroencephalogram, and antithyroglobulin antibody titers returned to normal levels. It is our opinion that Hashimoto's encephalopathy should be considered in the differential diagnosis of atypical psychosis, especially because this is a treatable syndrome. This is particularly important in patients with a previous history of thyroid disease, despite current normal thyroid function.

Spontaneous Hypothyroidism in the Follow up of Graves Hyperthyroid Patients Treated with Antithyroid Drugs

Spontaneous hypothyroidism may follow the natural course of Graves disease (GD) after treatment with antithyroid drugs (ATD). We studied retrospectively 139 remitted Graves hyperthyroid patients treated with ATD, with a follow-up period of 17.5 years (range 6 to 25 years). Elevated serum concentration of thyroid-stimulating hormone and low serum thyroxine concentrations confirmed the diagnosis. Thirteen patients (median age, 41 years; 26 to 48 years) developed spontaneous hypothyroidism, 4 to 144 months (median, 48 months ) following withdrawal of ATD. The prevalence of hypothyroidism was 9.3% and the incidence was 2.3% per year (13/ 563.6 patients/year of observation). There was no association with types of drugs used or the regimens. Spontaneous hypothyroid patients showed elevated titers (P = 0.02) of serum antithyroid peroxidase antibody (TPOAb) at the end of treatment with ATD, compared with the titers found at the beginning. These patients also had higher titers of TPOAb (P = 0.01) in relation to euthyroid patients. In contrast, the changes in serum antithyroglobulin antibody titers were not significant. Because of the shift from euthyroidism to spontaneous hypothyroidism, GD patients demanded a strict follow up after ATD therapy. It seems that there is an effect of TPOAb on thyroid destruction.