Manifestation Of Graves Research Articles

Novel treatment opportunities in Graves' orbitopathy

Graves' orbitopathy is the most common extrathyroidal manifestation of Graves' disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves' orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves' orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted.

Extrathyroidal manifestations of Graves' disease: a 2014 update.

Graves' orbitopathy (GO), thyroid dermopathy (also called pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves' disease. They occur in 25, 1.5, and 0.3 % of Graves' patients, respectively. Thus, GO is the main and most common extrathyroidal manifestation. Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy. GO and dermopathy have an autoimmune origin and are probably triggered by autoimmunity to the TSH receptor and, likely, the IGF-1 receptor. Both GO and dermopathy may be mild to severe. Mild GO usually does not require any treatment except for local measures and preventive actions (especially refraining from smoking). Currently, moderate-to-severe and active GO is best treated by systemic glucocorticoids, but response to treatment is not optimal in many instances, and retreatments and use of other modalities (glucocorticoids, orbital radiotherapy, cyclosporine) and, in the end, rehabilitative surgery are often needed. Dermopathy is usually managed by local glucocorticoid treatment. No specific treatment is available for acropachy. Novel treatments are presently being investigated for GO, and particular attention is paid to the use of rituximab. It is unknown whether novel treatments for GO might be useful for the other extrathyroidal manifestations. Future novel therapies shown to be beneficial for GO in randomized studies may be empirically used for dermopathy and acropachy.

Pretibial Myxedema: Case Presentation and Review of Treatment Options.

Pretibial myxedema (PM) is a rare autoimmune manifestation of Graves' disease, which commonly presents as diffuse, nonpitting edema of shins and less often as plaques, nodules, or elephantiasis lesions mimicking lymphedema. We present a 57-year-old woman with 12-month history of PM, which occurred a year after treatment of Graves' disease and improved with topical corticosteroids, support stockings, and intralesional steroid injections until recurrence with local erythema and woody edema. A literature review was undertaken of the evidence-based treatment modalities for symptomatic PM: although commonly asymptomatic and self-limited, severe cases of PM may be treated with topical corticosteroid, compressive therapy, and intralesional corticosteroid injections.

Relationship between autoantibody to the angiotensin II-1 receptor and cardiovascular manifestations of Graves' disease.

To investigate the role of autoantibody against angiotensin II-1 receptor (AT1-AA) in patients with cardiovascular manifestations of Graves' disease (GD). The epitope of the second extracellular loop of AT1 receptor (165-191) was synthesized and used as antigens to screen the autoantibody by enzyme linked immunosorbent assay (ELISA). The patients with GD were divided into the patients with cardiovascular manifestations associated to GD (Group A, n=58) and the patients with GD not complicated by heart disease (Group B, n=60). 40 healthy subjects were included in the study (Group C, n=40). Echocardiography was performed and the differences of echocardiography parameters were compared between AT1-AA positive and negative groups in group A. Factors related to left heart enlargement were analyzed by multiple logistic regression. (1) The frequency of AT1-AA in Group A (52.2%, 32/58) were significantly higher than those in Group B (16.7%, 10/60) and Group C (12.5%, 5/40) (all p<0.001). (2) There were no differences in the level of TGAb, TPOAb and TRAb between AT1-AA positive and negative groups in patients with GD (all p>0.05). (3) In patients with cardiovascular manifestations of GD, the ratios between left atrial and ventricular enlargement (LAE and LVE) were significantly higher in the AT1-AA positive group than in the AT1-AA negative group (68.8% vs. 26.9%, 62.5% vs. 23.1%, all p<0.01); the frequency of atrial fibrillation differed significantly between these 2 groups (53.1% vs. 19.2%, p<0.01). (4) Regression analysis demonstrated that the positive AT1-AA and course of GD were significantly correlated to the presence of LAE and LVE. AT1-AA plays an important role in the pathogenesis of cardiovascular manifestations associated to GD. Especially, AT1-AA is involved in left cardiac dilatation of GD complicated by heart disease, which represents a cardio-vascular risk factor for GD patients.

A typical clinical manifestations of Graves' disease

A typical clinical manifestations of Graves' disease

Expression of Thyrotropin Receptor, Thyroglobulin, Sodium-Iodide Symporter, and Thyroperoxidase by Fibrocytes Depends on AIRE

CD34(+) fibrocytes, bone marrow-derived progenitor cells, infiltrate orbital connective tissue in thyroid-associated ophthalmopathy, a manifestation of Graves' disease. In the orbit, they become CD34(+) fibroblasts and coexist with native CD34(-) fibroblasts. Fibrocytes have been shown to express TSH receptor and thyroglobulin. The objective of the study was to determine whether a broader repertoire of thyroid protein expression can be detected in fibrocytes and whether a common factor is responsible. Fibrocytes and fibroblasts were collected and analyzed from healthy individuals and those with Graves' disease in an academic clinical practice. Real-time PCR, Western blot analysis, gene promoter analysis, cell transfections, and flow cytometric cell sorting were performed. We detect two additional thyroid proteins expressed by fibrocytes, namely sodium-iodide symporter and thyroperoxidase. The autoimmune regulator (AIRE) protein appears necessary for this expression. AIRE expression in fibrocytes results from an active AIRE gene promoter and stable AIRE mRNA. Knocking down AIRE with a targeting small interfering RNA reduces the expression of these thyroid proteins in fibrocytes as well as the transcription factors paired box-8 and thyroid transcription factor-1. When compared with an unaffected first-degree relative, levels of these proteins are substantially reduced in fibrocytes from an individual with an inactivating AIRE mutation. Levels of AIRE and the thyroid proteins are lower in orbital fibroblasts from patients with thyroid-associated ophthalmopathy than in fibrocytes. However, when mixed fibroblast populations are sorted into pure CD34(+) and CD34(-) subsets, the levels of these proteins are dramatically increased selectively in CD34(+) fibroblasts. Fibrocytes express four proteins, the aggregate expression of which was previously thought to be restricted to thyroid epithelium. These proteins represent the necessary molecular biosynthetic machinery necessary for thyroid hormone production. Our findings implicate AIRE in the promiscuous expression of thyroid proteins in fibrocytes.

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study.

Background. Graves' disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves' disease (hyperthyroidism, goiter, and presence of orbitopathy) at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves' hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves' hyperthyroidism, entitled “Remission Induction and Sustenance in Graves' Disease (RISG).” Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves' disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25–30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves' disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.

A case of thyrotoxic periodic paralysis as initial manifestation of Graves' disease in a 16-year-old Korean adolescent

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism, with recurrent muscle paralysis and hypokalemia that are caused by an intracellular shift of potassium. TPP is relatively common in Asian males, but is extremely rare in children and adolescents, even for those of Asian descent. We describe a 16-year-old Korean adolescent presenting with a two-week history of episodic leg weakness in the morning. He showed sinus tachycardia, lower leg weakness, and hypokalemia. Thyroid function test showed hyperthyroidism, and thyroid ultrasonography revealed a diffuse enlarged thyroid with increased vascularity, consistent with Graves' disease. He was treated with β-adrenergic blocker and antithyroid drugs. He has been symptom free for one year, as his hyperthyroidism has been controlled well with antithyroid drugs. TPP should be considered in children and adolescents with acute paralysis of the lower extremities and hypokalemia.

Surgical treatment of diffuse toxic goiter in children. A review of the literature

Diffuse toxic goiter (DTG) is an autoimmune disease, to which there is a genetic predisposition. In children DTG is less common than in adults. Manifestation of graves‘ disease in childhood has a number of peculiarities. During the DTG in children is usually manifested thyrotoxicosis, requiring long-term treatment to achieve euthyroid, tendency to relapse and more frequently than adults, accompanied by ophthalmopathy and the large size of goiter. Diagnosis of graves‘ disease is based on the clinical picture of thyrotoxicosis, the existence of which is confirmed by the level of thyroid hormones and TSH in the blood. There are three types of treatment of patients DTG: medical, radioactive iodine therapy and surgery. There is no а single glance at the choice of the volume of operations in children.

The role of adipose tissue in the pathogenesis and clinical manifestation of Graves’ orbitopathy

Graves' orbitopathy (GO) is a inflammatory disease of connective tissue with autoimmune background considered as extrathyroidal component of the Graves' disease. Despite a progress in understanding of some elements of the pathogenesis it still remains one of the most complex topics of clinical endocrinology. Clinical symptoms of the orbitopathy derive from the discrepancy between limited space of the orbit and expansion of pathologically affected orbital tissues. In present paper the current state of knowledge concerning the role of orbital adipose tissue in a multifaceted manifestation of the disease as well as its importance in the immune and inflammatory reaction have been reviewed. The role of the major orbital auto antigens (TSHR and IGF1R) as well as hypotheses concerning the putative link connecting pathology of thyroid gland and orbital tissues were discussed.

Rituximab for thyroid-associated ophthalmopathy

Thyroid associated ophthalmopathy (TAO) is the most frequent extrathyroidal manifestation of Graves' disease, affecting up to 50% of patients, and has a great impact on quality of life. Rituximab is a human/murine chimeric monoclonal antibody that targets CD20, a transmembrane protein expressed on the surface of pre-B and mature B lymphocytes, but not on stem cells, pro-B lymphocytes or plasma cells. Preliminary work has shown that blocking the CD20 receptor on B-lymphocytes with rituximab affects the clinical course of TAO, by reducing inflammation and the degree of proptosis. The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013. We manually searched references of review articles and used the Science Citation Index to identify additional studies citing trials. We contacted the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials. We contacted experts in the field for information about any ongoing trials. We contacted the manufacturers of rituximab for details of any sponsored trials. We sought to include randomised controlled trials (RCTs) of rituximab treatment by intravenous infusion for the treatment of patients with TAO, compared with placebo or intravenous glucocorticoid treatment. Two review authors independently scanned titles and abstracts, as well as independently screened the full reports of the potentially relevant studies. At each stage, the results were compared and disagreements were solved by discussion. No studies were identified that met the inclusion criteria. There are three ongoing studies which are likely to meet inclusion criteria once published, and thus be included in future updates of this review. There is currently insufficient evidence to support the use of rituximab in patients with TAO. There is a need for large RCTs, investigating rituximab versus placebo or corticosteroids in patients with active TAO to make adequate judgement on the efficacy and safety of this novel therapy for this condition.

Treatment of Pretibial Myxedema with Dexamethazone Injected Subcutaneously by Mesotherapy Needles

Pretibial myxedema (PTM) is a rare extrathyroidal manifestation of Graves' disease that requires treatment when the clinical picture is markedly evident. In addition to topical treatment with steroid ointments, there have been previous reports of subcutaneous injections of steroids. This procedure may cause nodular degeneration of the skin due to fat atrophy when standard needles are used. In the present study, we have tried a novel modality of treatment of PTM by injecting a solution of dexamethasone in the subcutaneous tissue using needles employed for mesotherapy. These needles are ≤4 mm long and deliver the medication within the dermis or the first layer of the subcutaneous fat. We have treated five patients, four with diffuse and one with elephanthiasic PTM. We utilized multiple injections of a solution of dexamethasone, lidocaine, and saline in the PTM plaque and in the pretibial area, both in the PTM plaque and in the area surrounding the lesions, once a week for three consecutive weeks. Two patients with a more severe form of PTM underwent another two cycles four to six weeks after initial treatment. Patients were studied before and after treatment by clinical assessment and ultrasound of the pretibial skin. The treatment was well-tolerated, with only moderate pain upon injection of the solution. One month after treatment, all patients showed improvement of PTM at clinical assessment and a reduction of the thickness of the lesions at ultrasound of ∼15%, involving mostly the dermis. Moreover, all patients reported amelioration of the leg appearance. The present study, although preliminary, shows that intralesion steroid injection with mesotherapy needles in PTM is effective and well tolerated, and does not cause undesired long-term modifications of the skin. More studies are warranted to standardize such treatment in larger groups of patients.

Perspectives in the management of thyroid orbitopathy

Despite the huge progress in the understanding of the pathomechanism of thyroid orbitopathy (OT) done during recent years this extrathyroidal manifestation of Graves’ disease still remains one of the most complex problems of clinical endocrinology. The outcome of the management is not satisfying neither for patient nor for physicians. Some likelihood of the improvement of the results may be expected from innovative treatment options basing on the progress in understanding of mechanisms of autoimmunity and inflammation. On the other hand an effort must be done for the progress in the existing treatment regimes. Glucocorticoids have been used in the treatment of severe OT for over 50 years but irrespectively of therapeutic regime any improvement in eye changes may be achieved only in ca. 70% of patients. Numerous schemes of glucocorticoid use should be validated, optimized and meet an individual approach as well as adhere to the local capabilities. The common adjuvant treatment with selenium in Graves’ disease patients may prevent from a development of eye symptoms and possibly will improve the quality of life. The mode of management of hyperthyroidism has an influence on OT. Medical and surgical therapy seem not to deteriorate the course of OT while radioiodine therapy may worsen eye symptoms. OT patients at high risk should get the preventive glucocorticoid treatment. The access to a surgical treatment procedures as orbital decompression and rehabilitative surgery must be assured for OT patients and techniques of surgical procedures should be developed. The results of anticytokine therapy are promising and the progress in this field may be expected while the value of newly developed TSH receptor blocking molecules needs further observations. The frequency of circulating CD40(+) fibrocytes is markedly increased in patients with OT, suggesting that this receptor might represent a therapeutic target for OT. An increase in a local steroidogenesis documented within orbital tissues in an active phase of OT rises the idea of the use of 11β hydroxysteroid dehydrogenase-1 inhibitors in OT patients. These drugs are under intensive clinical investigation for the treatment of type 2 diabetics. Since recommendations basing on EBM according to the pivotal problems of the management OT are still lacking, the system of care for OT patients should be based on centres of excellence with proper experience and multidisciplinary approach.

Pulmonary hypertension, heart failure and hyperthyroidism: A case report

We present a case of acute heart failure as the first manifestation of Graves’ disease. It illustrates some of its cardiovascular complications, particularly atrial fibrillation, pulmonary hypertension and heart failure. This case report highlights the importance of considering hyperthyroidism as a cause of idiopathic pulmonary hypertension, and demonstrates the potential reversibility of its complications.

Hipertensão pulmonar, insuficiência cardíaca e hipertiroidismo: caso clínico

We present a case of acute heart failure as the first manifestation of Graves’ disease. It illustrates some of its cardiovascular complications, particularly atrial fibrillation, pulmonary hypertension and heart failure. This case report highlights the importance of considering hyperthyroidism as a cause of idiopathic pulmonary hypertension, and demonstrates the potential reversibility of its complications.

Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient

Context: Highly active antiretroviral therapy (HAART) inhibits the HIV replication and consequently increases CD4 levels and decreases viral load. This immune system improvement can trigger various immunological phenomena, entity called Immune Reconstitution Syndrome (IRS). Graves’ disease is a late Immune Reconstitution consequence. Patient: We report the case of a 48 years old man with HIV infection who developed Graves’ disease three years after he was on effective HAART because of the Immune Reconstitution Syndrome. At presentation he had a very low CD4 T-cell count (17 cells/μL). When he started HAART he presented a lipodystrophy syndrome. HAART was changed because of the persistent low CD4-T cells count (less than 100 cell/μL). Afterwards serum lipid levels began to decrease and that was the first manifestation of Graves’ disease, which was diagnosed when CD4 T-cells increased up to 343 cell/μL. Our patient developed Graves’ disease 36 months after initiating effective HAART with protease inhibitors which was coincident with viral suppression and a rise of CD4 T cells. Conclusion: The most immunosuppressed patients with a CD4 T cell count less than 100 cells/μL are at greatest risk for the development of Immune Reconstitution Syndrome after HAART initiation. We conclude that clinicians will have to consider the importance of the early diagnosis of thyroid disease to bring an adequate treatment.

A Case of Pancytopenia with Hyperthyroidism

There has been an increase in the number of reports of atypical manifestations of Graves’ disease (GD), such as jaundice, anemia, thrombocytopenia and leukopenia. Pancytopenia also rarely occurs in GD. In this paper, a case of pancytopenia with GD that was successfully treated with an anti-thyroid drug is reported. In this case, a 69-year-old woman showed pancytopenia with a normal peripheral blood smear, bone marrow aspiration smear and bone marrow biopsy. Her thyroid function test and thyroid scintigraphy confirmed her hyperthyroid status. Her laboratory abnormality and clinical condition improved after she was treated with an anti-thyroid drug. This is a rare case of pancytopenia associated with GD.

Correlation between TSH Receptor Antibody Assays and Clinical Manifestations of Graves' Orbitopathy

PurposeTo investigate an association between the levels of serum thyroid-stimulating hormone (TSH)-receptor autoantibodies (TRAbs) and Graves' orbitopathy (GO) activity/severity scores, and compare the performance of three different TRAb assays in assessing the clinical manifestations of GO.Materials and MethodsCross-sectional study. Medical records of 155 patients diagnosed with GO between January 2008 and December 2010 were reviewed. GO activity was assessed by clinical activity score (CAS) and severity graded with the modified NOSPECS score by a single observer. Serum TRAb was measured by three different methods: 1st generation thyrotropin-binding inhibitor immunoglobulin (TBII) assay (TRAb1st); 3rd generation TBII assay (TRAb3rd); and biological quantitative assay of thyroid-stimulating immunoglobulin (TSI) using Mc4-CHO cells (Mc4-CHO TSI assay). Results were correlated with scores of activity/severity of thyroid eye disease.ResultsAll three assays (TRAb1st, TRAb3rd, and Mc4-CHO TSI) yielded results that were significantly positively correlated with CAS (β=0.21, 0.21, and 0.46, respectively; p<0.05) and proptosis (β=0.38, 0.34, and 0.33, respectively; p<0.05). Mc4-CHO TSI bioassay results were significantly positively correlated with all GO severity indices (soft tissue involvement, proptosis, extraocular muscle involvement, and total eye score; β=0.31, 0.33, 0.25, and 0.39, respectively; p<0.05).ConclusionMc4-CHO TSI bioassay was superior over the two TBIIs in assessing active inflammation and muscle restriction due to GO, whereas TBII assay would be sufficient for evaluation of patients with proptosis.

Erratum to "Correlation between TSH Receptor Antibody Assays and Clinical Manifestations of Graves' Orbitopathy" by Jang SY, et al. (Yonsei Med J 2013;54:1033-9.)

Erratum to "Correlation between TSH Receptor Antibody Assays and Clinical Manifestations of Graves' Orbitopathy" by Jang SY, et al. (Yonsei Med J 2013;54:1033-9.)

Unilateral pitting edema of the leg as a manifestation of Graves’ disease: a case report

IntroductionGraves’ hyperthyroidism has a number of well-recognized but relatively rare extrathyroid manifestations such as thyroid acropachy, pretibial myxedema, and congestive heart failure.Case presentationA 38-year-old Caucasian woman presented to the out-patient clinic with symptoms of hyperthyroidism lasting for approximately five months. Remarkably, she had developed pitting edema of her left leg four months before. She had gone through a conventional assessment, but the reason for the edema was not revealed. At presentation to the endocrinology clinic, the skin of both legs was of normal color and pitting edema on her left leg was of a diffuse nature and spread from her toes to two thirds of her leg. The skin surface of her left leg was smooth and had no elevations or discoloration, whereas her right leg appeared normal. Based on signs and symptoms of thyrotoxicosis and suppressed thyroid-stimulating hormone level (less than 0.001mIU/L, local reference of 0.4 to 4), treatment of 10mg of thiamazole three times a day was started. Additional blood tests revealed marked Graves’ hyperthyroidism with elevated free T4 and anti-thyroid receptor antibodies. Within a month, the free T4 level was normalized and the edema was completely cleared and never reappeared during the treatment course of 12 months.ConclusionsTo the best of our knowledge, this is the first description of unilateral treatment-responsive leg edema as a manifestation of Graves’ hyperthyroidism. However, the pathophysiological mechanism underlying this case of edema remains unclear.