Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against

its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Prominent examples include Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjgren's syndrome, Churg-Strauss Syndrome, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis (RA). See List of autoimmune diseases. The misconception that an individual's immune system is totally incapable of recognizing self antigens is not new. Paul Ehrlich, at the beginning of the twentieth century, proposed the concept of horror autotoxicus, wherein a 'normal' body does not mount an immune response against its own tissues. Thus, any autoimmune response was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed 'natural autoimmunity'), normally prevented from causing disease by the phenomenon of immunological tolerance to self-antigens. Autoimmunity should not be confused with alloimmunity. Contents 1 Low-level autoimmunity 2 Immunological tolerance 3 Genetic Factors 4 Sex 5 Environmental Factors 6 Pathogenesis of autoimmunity 7 Classification 8 Diagnosis 9 Treatments 10 See also 11 References 12 External links Low-level autoimmunity While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. First, low-level autoimmunity might aid in the recognition of neoplastic cells by CD8+ T cells, and thus reduce the incidence of cancer. Second, autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response (i.e., when there are few pathogens present). In their study, Stefanova et al. (2002) injected an anti-MHC Class II antibody into mice expressing a single type of MHC Class II molecule (H-2b) to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells (those that have not encountered any antigens before) recovered from these mice 36 hours post-anti-MHC administration showed decreased responsiveness to the antigen pigeon cytochrome C peptide, as determined by Zap-70 phosphorylation, proliferation, and Interleukin-2 production. Thus Stefanova et al. (2002) demonstrated that self-MHC recognition (which, if too strong may contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when foreign antigens are absent. [1] This idea of autoimmunity is conceptually similar to playfighting. The play-fighting of young cubs (TCR and self-MHC) may result in a few scratches or scars (low-level-autoimmunity), but is beneficial in the long-term as it primes the young cub for proper fights in the future. Immunological tolerance Pioneering work by Noel Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that, at least in terms of antibody-producing B lymphocytes, diseases such as rheumatoid arthritis and thyrotoxicosis are associated with of loss of immunological tolerance, which is the ability of an individual to ignore 'self', while reacting to 'non-self'. This breakage leads to the immune system's mounting an effective and specific immune response against self determinants. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin. Three hypotheses have gained widespread attention among immunologists: Clonal Deletion theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of acquired immunological tolerance". Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.[2] Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.[3] In addition, two other theories are under intense investigation: The so-called "Clonal Ignorance" theory, according to which host immune responses are directed to ignore selfantigens[4]

The "Suppressor population" or "Regulatory T cell" theories, wherein regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses. Tolerance can also be differentiated into 'Central' and 'Peripheral' tolerance, on whether or not the above-stated checking mechanisms operate in the central lymphoid organs (Thymus and Bone Marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where self-reactive B-cells may be destroyed). It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance. A puzzling feature of the documented loss of tolerance seen in spontaneous human autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and where there is evidence for an abnormal T cell response it is usually not to the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to DNA, which cannot evoke a T cell response, and limited evidence for T cell responses implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has led to the idea that human autoimmune disease is in most cases (with probable exceptions including type I diabetes) based on a loss of B cell tolerance which makes use of normal T cell responses to foreign antigens in a variety of aberrant ways [5]. Genetic Factors Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically-predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to: Immunoglobulins T-cell receptors The major histocompatibility complexes (MHC). The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity. Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence to suggest that certain MHC class II allotypes are strongly correlated with specific autoimmune diseases: HLA DR2 is strongly positively correlated with Systemic Lupus Erythematosus, narcolepsy[6] and multiple sclerosis, and negatively correlated with DM Type 1. HLA DR3 is correlated strongly with Sjgren's syndrome, myasthenia gravis, SLE, and DM Type 1. HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1 diabetes mellitus, and pemphigus vulgaris. Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and ankylosing spondylitis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease. The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin's linkage analysis of susceptibility to SLE). [edit] Sex A person's sex also seems to have some role in the development of autoimmunity. Nearly 75% of the more than 23.5 million Americans who suffer from autoimmune disease are women, although it is less-frequently acknowledged that millions of men also suffer from these diseases. According to the American Autoimmune Related Diseases Association (AARDA), autoimmune diseases that develop in men tend to be more severe. A few autoimmune diseases that men are just as or more likely to develop as women, include: ankylosing spondylitis, type 1 diabetes mellitus, Wegener's granulomatosis, Crohn's disease and psoriasis. The reasons for the sex role in autoimmunity are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids. It has also been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity.[7] This would tip the gender balance in the direction of the female. Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced X chromosome inactivation.[8] The X-inactivation skew theory, proposed by Princeton University's Jeff Stewart, has recently been confirmed experimentally in scleroderma and autoimmune thyroiditis.[9] [edit] Environmental Factors An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. The hygiene hypothesis attributes these correlations to the immune manipulating strategies of pathogens. Whilst such an observation

has been variously termed as spurious and ineffective, according to some studies, parasite infection is associated with reduced activity of autoimmune disease.[10][11][12] The putative mechanism is that the parasite attenuates the host immune response in order to protect itself. This may provide a serendipitous benefit to a host that also suffers from autoimmune disease. The details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with the host immune signaling. A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases. For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and diabetes mellitus type 1, respectively. This has been explained by the tendency of the infecting organism to produce super-antigens that are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below). Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient. Cigarette smoking is now established as a major risk factor for both incidence and severity of rheumatoid arthritis. [citation needed] This may relate to abnormal citrullination of proteins, since the effects of smoking correlate with the presence of antibodies to citrullinated peptides.[citation needed] [edit] Pathogenesis of autoimmunity Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described: T-Cell Bypass - A normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be bypassed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the -subunit of T-cell receptors in a non-specific fashion. T-Cell-B-Cell discordance - A normal immune response is assumed to involve B and T cell responses to the same antigen, even if we know that B cells and T cells recognise very different things: conformations on the surface of a molecule for B cells and pre-processed peptide fragments of proteins for T cells. However, there is nothing as far as we know that requires this. All that is required is that a B cell recognising antigen X endocytoses and processes a protein Y (normally =X) and presents it to a T cell. Roosnek and Lanzavecchia showed that B cells recognising IgGFc could get help from any T cell responding to an antigen co-endocytosed with IgG by the B cell as part of an immune complex. In coeliac disease it seems likely that B cells recognising tissue transglutamine are helped by T cells recognising gliadin. Aberrant B cell receptor-mediated feedback - A feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response (DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin receptor(PNAR)). This fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent B cells through membrane bound ligands. These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR. More indirect aberrant activation of B cells can also be envisaged with autoantibodies to acetyl choline receptor (on thymic myoid cells) and hormone and hormone binding proteins. Together with the concept of T-cell-B-cell discordance this idea forms the basis of the hypothesis of self-perpetuating autoreactive B cells[13]. Autoreactive B cells in spontaneous autoimmunity are seen as surviving because of subversion both of the T cell help pathway and of the feedback signal through B cell receptor, thereby overcoming the negative signals responsible for B cell self-tolerance without necessarily requiring loss of T cell self-tolerance. Molecular Mimicry - An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens, and amplify the immune response. The idea of molecular mimicry arose in the context of Rheumatic Fever, which follows infection with Group A beta-haemolytic streptococci. Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium. Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a crossreaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the

host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells. Cytokine Dysregulation - Cytokines have been recently divided into two groups according to the population of cells whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF- (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses. Dendritic cell apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.[14] Epitope spreading or epitope drift - when the immune reaction changes from targeting the primary epitope to also targeting other epitopes.[15] In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one. The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells, T-cells in the pathogenesis of autoimmune disease are under investigation. [edit] Classification Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease. Systemic autoimmune diseases include SLE, Sjgren's syndrome, scleroderma, rheumatoid arthritis, and dermatomyositis. These conditions tend to be associated with autoantibodies to antigens which are not tissue specific. Thus although polymyositis is more or less tissue specific in presentation, it may be included in this group because the autoantigens are often ubiquitous t-RNA synthetases. Local syndromes may be endocrinologic (diabetes mellitus type 1, Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), or haematologic (autoimmune haemolytic anaemia), and involve a specific tissue. Using the traditional organ specific and non-organ specific classification scheme, many diseases have been lumped together under the autoimmune disease umbrella. However, many chronic inflammatory human disorders lack the telltale associations of B and T cell driven immunopathology. In the last decade it has been firmly established that tissue "inflammation against self" does not necessarily rely on abnormal T and B cell responses. This has led to the recent proposal that the spectrum of autoimmunity should be viewed along an immunological disease continuum, with classical autoimmune diseases at one extreme and diseases driven by the innate immune system at the other extreme. Within this scheme, the full spectrum of autoimmunity can be included. Many common human autoimmune diseases can be seen to have a substantial innate immune mediated immunopathology using this new scheme. This new classification scheme has implications for understanding disease mechanisms and for therapy development (see PLoS Medicine article. http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030297). [edit] Diagnosis Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. [edit] Treatments Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory, or palliative.[4] Nonimmunological therapies, such as hormone replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat outcomes of the autoaggressive response, thus these are palliative treatments. Dietary manipulation limits the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. Specific immunomodulatory therapies, such as the TNF antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept have been shown to be useful in treating RA. Some of these immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease. Helminthic therapy is an experimental approach that involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely-related treatments available, inoculation with either Necator americanus, commonly known as hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs. [16][16][17][18][19][20] T cell vaccination is also being explored as a possible future therapy for auto-immune disorders. Insulin-dependent diabetes mellitus From Wikipedia, the free encyclopedia Jump to: navigation, search

Insulin-dependent diabetes mellitus (IDDM) is a medical term that describes diabetes mellitus that requires insulin therapy to avoid ketoacidosis. IDDM is often considered a synonym for juvenile diabetes mellitus and type 1 diabetes mellitus, though the three terms are not entirely congruent: Juvenile diabetes is considered an unsatisfactory and somewhat obsolete term because type 1 diabetes can develop in adults, and type 2 can occur in children. IDDM includes type 1 diabetes, but as type 2 diabetes progresses, in some people it may reach a degree of insulin deficiency that requires insulin treatment. Lupus erythematosus is a connective tissue disease.[1] Lupus is a chronic inflammatory disease that occurs when the body's immune system attacks its own tissues and organs. Inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs. Lupus occurs more frequently in women than men, [2] although the reasons for this are unknown. Four types of lupus exist systemic lupus erythematosus, discoid lupus erythematosus, druginduced lupus erythematosus and neonatal lupus. Of these, systemic lupus erythematosus is the most common and serious form of lupus. With treatment, most people with lupus can lead active lives.[citation needed] Types Lupus erythematosus may manifest as a systemic disease or in purely cutaneous forms, categorized into the following types:[3] Chronic cutaneous lupus erythematosus o Discoid lupus erythematosus Childhood discoid lupus erythematosus Generalized discoid lupus erythematosus Localized discoid lupus erythematosus o Chilblain lupus erythematosus (Hutchinson) o Lupus erythematosus-lichen planus overlap syndrome o Lupus erythematosus panniculitis (Lupus erythematosus profundus) o Subacute cutaneous lupus erythematosus o Tumid lupus erythematosus o Verrucous lupus erythematosus (Hypertrophic lupus erythematosus) Complement deficiency syndromes Drug-induced lupus erythematosus Neonatal lupus erythematosus Systemic lupus erythematosus Lupus band test From Wikipedia, the free encyclopedia Jump to: navigation, search

Microphotograph of a histological section of human skin prepared for direct direct immunofluorescence using an anti-IgG antibody. The skin is from a person with systemic lupus erythematosus and shows IgG deposits at two different places: The first is a bandlike deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (antinuclear antibodies are present). Lupus band test is done upon skin biopsy, with direct immunofluorescence staining, in which, if positive, IgG and complement depositions are found at the dermal-epidermal junction.[1]:212 This test can be helpful in distinguishing systemic lupus erythematosus (SLE) from cutaneous lupus, because in SLE the lupus band test will be positive in both involved and uninvolved skin, whereas with cutaneous lupus only the involved skin will be positive.[1]:212 ChurgStrauss syndrome (Redirected from Churg-Strauss Syndrome) Churg-Strauss syndrome

Classification and external resources ICD-10 ICD-9 DiseasesDB eMedicine M30.1 446.4 2685 med/2926 derm/78 neuro/501

MeSH D015267 ChurgStrauss syndrome (also known as allergic granulomatosis) is a medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs (it begins as a severe type of asthma), gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable, nontransmissible. Churg-Strauss syndrome was once considered a type of Polyarteritis nodosa (PAN) due to their similar morphologies. The syndrome was first described by Drs. Jacob Churg and Lotte Strauss at Mount Sinai Hospital in New York City in 1951.[1][2] Contents [hide] 1 Diagnosis 2 Disease stages 3 Risk stratification 4 Treatment 5 Research 6 Famous patients 7 References 8 External links Diagnosis Diagnostic markers include eosinophil granulocytes and granulomas in affected tissue and Anti-neutrophil cytoplasmic antibodies (ANCA) against neutrophil granulocytes. Differentiation from Wegener's granulomatosis can be difficult, though the increasing use of ANCA assays has made the distinction more routine. Wegener's is closely associated with c-ANCA, unlike Churg-Strauss, which shows elevations of p-ANCA. Disease stages This disease has three distinct stages. The first stage often involves the sinuses and the onset of allergies not previously had or the worsening of pre-existing allergies. The second stage involves the onset of acute asthma. Normally, the person would not have had asthma previously. The third and final stage involves the various organ systems. Stage three is by far the most life threatening and painful. Often the person will develop severe nerve pain in their legs, arms and hands. Purple marks will appear on the skin and often sores will appear in the mouth or nose. The disease can affect the heart, lungs, kidneys and liver. People can live for many years in the first two stages before progressing to stage three. Risk stratification The French Vasculitis Study Group has developed a five-point score ("five-factor score" or FFS) that predicts the risk of death in Churg-Strauss syndrome. These are (1) reduced renal function (creatinine >1.58 mg/dL or 140 mol/l), (2) proteinuria (>1 g/24h), (3) gastrointestinal hemorrhage, infarction or pancreatitis, (4) involvement of the central nervous system or (5) cardiomyopathy. Presence of 1 of these indicates severe disease (5-year mortality 26%) and 2 or more very severe disease (mortality 46%), while absence of any of these 5 indicates a milder case (mortality 11.9%).[3] Treatment Treatment for Churg-Strauss syndrome includes glucocorticoids such as prednisolone and other immunosuppressive drugs such as azathioprine and cyclophosphamide. In many cases the disease can be put into a type of chemical remission through drug therapy, but the disease is chronic and life long. A systematic review conducted in 2007 indicated that all patients should be treated with high-dose steroids, but that in patients with an FFS of 1 or higher cyclophosphamide pulse therapy should be commenced, with 12 pulses leading to less relapses than 6. Remission can be maintained with a less toxic drug, such as azathioprine or methotrexate.[4] Research

A case study in 2000 noticed a "marked and severe inflammatory reaction characterized by eosinophilia and glomerulonephritis" and wondered whether this "might have been triggered by the leukotriene receptor antagonist, montelukast."[5] Researchers have searched for links between drugs such as montelukast (brand name of Singulair)[6] and Churg-Strauss syndrome; in another study in 2000, researchers did not find a cause-and-effect relationship and wrote: "The occurrence of Churg-Strauss syndrome in asthmatic patients receiving leukotriene modifiers appears to be related to unmasking of an underlying vasculitic syndrome that is initially clinically recognized as moderate to severe asthma and treated with corticosteroids. Montelukast does not appear to directly cause the syndrome in these patients."[7] A case study in 2006 was inconclusive but suggested the need for further research.[8] Hashimoto's thyroiditis or chronic lymphocytic thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed by a variety of cell and antibody mediated immune processes. It was the first disease to be recognised as an autoimmune disease.[citation needed][1]. This disorder is believed to be the most common cause of primary hypothyroidism in North America. An average of 1 to 1.5 in a 1000 people have this disease. It occurs far more often in women than in men (between 10:1 and 20:1), and is most prevalent between 45 and 65 years of age. In European countries, an atrophic form of autoimmune thyroiditis (Ord's thyroiditis) is more common than Hashimoto's thyroiditis. Contents 1 Causes 2 Presentation 3 Treatment 4 Eponym 5 Possible complications 6 References 7 External links Causes The family history of thyroid disorders is common, with the HLA-DR5 gene most strongly implicated conferring a relative risk of 3 in the UK. In addition Hashimoto's thyroiditis may be associated with CTLA-4 gene since the CTLA-4 antigen acts as an inhibitor to T-Cell activation. The genes implicated vary in different ethnic groups and the incidence is increased in patients with chromosomal disorders, including Turner, Down's, and Klinefelter's syndromes. The underlying specifics of the immune system destruction of thyroid cells is not clearly understood. Various autoantibodies may be present against thyroid peroxidase, thyroglobulin and TSH receptors, although a small percentage of patients may have none of these antibodies present. A percentage of the population may also have these antibodies without developing Hashimoto's thyroiditis. [edit] Presentation Hashimoto's thyroiditis very often results in hypothyroidism with bouts of hyperthyroidism. Physiologically, antibodies against thyroid peroxidase and/or thyroglobulin cause gradual destruction of follicles in the thyroid gland. Accordingly, the disease can be detected clinically by looking for these antibodies in the blood. It is also characterized by invasion of the thyroid tissue by leukocytes, mainly T-lymphocytes. It is associated with non-Hodgkin lymphoma. Symptoms of Hashimoto's thyroiditis include weight gain, depression, mania, sensitivity to cold, fatigue, panic attacks, bradycardia, tachycardia, high cholesterol, reactive hypoglycemia, constipation, migraines, muscle weakness, cramps, memory loss, infertility and hair loss. Hashimoto's thyroiditis is often misdiagnosed as depression, cyclothymia, PMS, and, less frequently as bipolar disorder or as anxiety disorder. Testing for thyroid-stimulating hormone (TSH) and anti-thyroid antibodies can resolve any diagnostic difficulty. [2] Hashimoto's when presenting as mania is known as Prasad's syndrome after Ashok Prasad, the psychiatrist who first described it.[3] Treatment Hypothyroidism caused by Hashimoto's Thyroiditis is treated with thyroid hormone replacement agents such as levothyroxine or Armour. A tablet taken once a day generally keeps the thyroid hormone levels normal. In most cases, the treatment needs to be taken for the rest of the patient's life. In the event that hypothyroidism is caused by Hashimoto's Thyroiditis, it is recommended that the TSH levels be kept as low as possible. As long as the patient's thyroid is active, the body will continue to attack it, and this can wreak havoc on the patient's TSH levels and symptoms. Eponym

The explanation board of Hashimoto Dori in Kyushu University Also known as Hashimoto's disease, Hashimoto's thyroiditis is named after the Japanese physician Hakaru Hashimoto (18811934) of the medical school at Kyushu University,[4] who first described the symptoms in 1912 in a German publication[5]. Possible complications If untreated for an extended period, Hashimoto's thyroiditis may lead to muscle failure, including possible heart failure. An extremely rare condition associated with the thyroiditis is Hashimoto's encephalopathy. A rare association is with lymphoma of the thyroid gland. Hashimoto's thyroiditis can disrupt growth in children and adolescents, therefore it begets close growth monitoring, which may give cause for growth hormone therapy, if the patient's stature is extreme enough. Graves' disease is an autoimmune disease. It most commonly affects the thyroid, frequently causing it to enlarge to twice its size or more (goiter), become overactive, with related hyperthyroid symptoms such as increased heartbeat, muscle weakness, disturbed sleep, and irritability. It can also affect the eyes, causing bulging eyes (exophthalmos). It affects other systems of the body, including the skin, heart, circulation and nervous system. It affects up to 2% of the female population, sometimes appears after childbirth, and has a female:male incidence of 5:1 to 10:1. It has a strong hereditary component; when one identical twin has Graves' disease, the other twin will have it 25% of the time. Smoking and exposure to second-hand smoke is associated with the eye manifestations but not the thyroid manifestations. Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful, particularly to monitor treatment.[1] Contents [hide] 1 History 2 Diagnosis o 2.1 Eye disease 2.1.1 Classification of Graves Eye Disease 2.1.2 Treatment specific to eye problems o 2.2 Other Graves' disease symptoms 3 Incidence and epidemiology 4 Pathophysiology 5 Etiology 6 Treatment o 6.1 Antithyroid drugs o 6.2 Radioiodine o 6.3 Surgery o 6.4 No treatment o 6.5 Symptomatic treatment o 6.6 Treatment of eye disease 7 Notable sufferers 8 Notes 9 See also 10 External links History Graves' disease owes its name to the Irish doctor Robert James Graves ,[2] who described a case of goiter with exophthalmos in 1835.[3] However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. [4] [5] As a result, on the European Continent, the terms Basedow's syndrome[6], or Basedow's disease[7] are more common than Graves' disease.[6][8] Graves' disease[6][7] has also been called exophthalmic goiter[7]

Less commonly, it has been known as Parry's disease[6][7], Begbie's disease, Flajani's disease, Flajani-Basedow syndrome, and Marsh's disease.[6] The names Grave's disease and Parry's disease were based also on other pioneer investigators of the disorder, namely: Robert James Graves and Caleb Hillier Parry, respectively. The rest of the other names for the disease were derived from James Begbie, Giuseppe Flajani, and Henry Marsh.[6] The other names are from several earlier reports that exist but were not widely circulated. For example, cases of goiter with exophthalmos were published by the Italians Giuseppe Flajina[9] and Antonio Giuseppe Testa,[10] in 1802 and 1810, respectively.[11] Prior to these, Caleb Hillier Parry,[12] a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus),[13] described a case in 1786. This case was not published until 1825, but still 10 years ahead of Graves.[14] However, fair credit for the first description of Graves' disease goes to the 12th century Persian physician Sayyid Ismail alJurjani,[15] who noted the association of goiter and exophthalmos in his "Thesaurus of the Shah of Khwarazm", the major medical dictionary of its time.[6][16][17] [edit] Diagnosis

Graves' disease Symptoms Graves' disease may present clinically with one of the following characteristic signs: exophthalmos (protuberance of one or both eyes) fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism/thyrotoxicosis rapid heart beats muscular weakness The two signs that are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid conditions) are exophthalmos and non-pitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a smaller goiter (very mild enlargement of the gland) may be detectable only by physical exam. Occasionally, goiter is not clinically detectable but may be seen only with CT or ultrasound examination of the thyroid. Another sign of Graves' disease is hyperthyroidism, i.e., overproduction of the thyroid hormones T3 and T4. Normothyroidism is also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4. Other useful laboratory measurements in Graves' disease include thyroid-stimulating hormone (TSH, usually low in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be detected serologically. Biopsy to obtain histiological testing is not normally required but may be obtained if thyroidectomy is performed. Differentiating two common forms of hyperthyroidism such as Graves' disease and Toxic multinodular goiter is important to determine proper treatment. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.[18] [edit] Eye disease Further information: Graves' ophthalmopathy Thyroid-associated ophthalmopathy is one of the most typical symptoms of Graves' disease. It is known by a variety of terms, the most common being Graves' ophthalmopathy. Thyroid eye disease is an inflammatory condition, which affects the orbital contents including the extraocular muscles and orbital fat. It is almost always associated with Graves' disease but may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer.

The ocular manifestations that are relatively specific to Grave's disease include soft tissue inflammation, proptosis (protrusion of one or both globes of the eyes), corneal exposure, and optic nerve compression. Also seen, if the patient is hyperthyroid, (i.e., has too much thryoid hormone) are more general manifestations, which are due to hyperthyroidism itself and which may be seen in any conditions that cause hyperthyroidism (such as toxic multinodular goiter or even thyroid poisoning). These more general symptoms include lid retraction, lid lag, and a delay in the downward excursion of the upper eyelid, during downward gaze. It is believed that fibroblasts in the orbital tissues may express the Thyroid Stimulating Hormone receptor (TSHr). This may explain why one autoantibody to the TSHr can cause disease in both the thyroid and the eyes. [19] [edit] Classification of Graves Eye Disease Mnemonic: "NO SPECS":[20] Class 0: No signs or symptoms Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag) Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc) Class 3: Proptosis Class 4: Extraocular muscle involvement (usually with diplopia) Class 5: Corneal involvement (primarily due to lagophthalmos) Class 6: Sight loss (due to optic nerve involvement) [edit] Treatment specific to eye problems For mild disease - artificial tears, steroids (to reduce chemosis) For moderate disease - lateral tarsorrhaphy For severe disease - orbital decompression or retro-orbital radiation [edit] Other Graves' disease symptoms Some of the most typical symptoms of Graves' Disease are included in the following list. All but the eye-related problems and goitre are due to the effects of too much thyroid hormone, and are seen in other hyperthyroid states, including simple thyroid hormone poisoning: Palpitations Increased energy Eye pain, irritation, tingling sensation Tachycardia (rapid heart rate: 100 Fatigue behind the eyes or the feeling of grit or 120 beats per minute, or higher) Mental impairment, sand in the eyes Arrhythmia (irregular heart beat) memory lapses, Swelling or redness of eyes or Hypertension (Raised blood diminished attention span eyelids/eyelid retraction pressure) Decreased concentration Sensitivity to light Tremor (usually fine shaking, e.g., Nervousness, agitation Decrease in menstrual periods hands) Irritability (oligomenorrhea), irregular and scant Hyperhidrosis (excessive sweating) Restlessness menstrual flow (amenorrhea) Heat intolerance Erratic behavior Difficulty Polyphagia (increased appetite) Emotional lability conceiving/infertility/recurrent Unexplained weight loss despite Brittle nails miscarriage increased appetite Abnormal breast Chronic sinus infections Dyspnea (shortness of breath) enlargement Lumpy, reddish skin of the lower legs Muscle weakness (especially in the Goiter (enlarged thyroid (pretibial myxedema) large muscles of the arms and legs) gland) Increased bowel movements or diarrhea and degeneration Protruding eyeballs Panic attacks Diminished/changed sex drive Diplopia (double vision) Insomnia (inability to get enough sleep) [edit] Incidence and epidemiology

Scan of affected thyroid before and after radioiodine therapy. The disease occurs most frequently in women (7:1 compared to men). It occurs most often in middle age (most commonly in the third to fifth decades of life), but is not uncommon in adolescents, during pregnancy, during menopause, or in people over age 50. There is a marked family preponderance, which has led to speculation that there may be a genetic component. To date, no clear genetic defect has been found that would point at a monogenic cause. [edit] Pathophysiology Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter. The infiltrative exophthalmos that is frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball. The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques. There are 3 types of autoantibodies to the TSH receptor currently recognized: TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone. TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles. TBII, Thyrotrophin Binding-Inhibiting Immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor. Another effect of hyperthyroidism is bone loss from osteoporisis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.[21] Etiology

The trigger for auto-antibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.[22] Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes). One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.[22] Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. [23] It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.[24] More recently the role for Y. enterocolitica has been disputed.[25] Treatment Treatment of Graves' disease includes antithyroid drugs which reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131), and thyroidectomy (surgical excision of the gland). As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy preoperative treatment with antithyroid drugs is given to render the patient "euthyroid" (i.e. normothyroid). Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, whilst antithyroid drugs and/or thyroidectomy is used more often in Europe, Japan, and most of the rest of the world. Antithyroid drugs The main antithyroid drugs are carbimazole (UK), methimazole (US), and propylthiouracil (PTU). These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which does not stop on cessation of drug. Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lygole is used to block hormone synthesis before surgery., A randomized control trial testing single dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).[26] A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However two markers were found that can help predict the risk of recurrence. These two markers are a positive Thyroid Stimulating Hormone receptor antibody (TSHR-Ab) and smoking. A positive TSHRAb at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.[27] Radioiodine Further information: Iodine-131 Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are: failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure that they are treated with thyroid hormone before they become symptomatically hypothyroid. For some patients, finding the correct thyroid replacement hormone and the correct dosage may take many years and may be in itself a much more difficult task than is commonly understood.[citation needed] Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radio-iodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. Surgery Further information: Thyroidectomy

This modality is suitable for young patients and pregnant patients. Indications are: a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid) and patients with ophthalmopathy. Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on 1 side and partial lobectomy on other side) are possible. Advantages are: immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea) and scarring. Removal of the gland enables complete biopsy to performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine treatment may be done after surgery, to ensure that all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal chords) are destroyed. Besides this, the only remaining treatment will be Synthroid, or thyroid replacement pills to be taken for the rest of patient's life. Disadvantages are as follows. A scar is created across the neck just above the collar bone line. However, the scar is very thin, and can eventually recede and appear as nothing more than a crease in the neck.Patient may spend a night in hospital after the surgery, and endure the effects of total anesthesia (i.e., vomiting), as well as sore throat, raspy voice, cough from having a breathing tube stuck down the windpipe during surgery.[citation needed] No treatment If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves-Basedow disease is often accompanied by an increase in heart rate, which may lead to further heart complications including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) severely enough that the lids do not close completely at night, severe dryness will occur with a very high risk of a secondary corneal infection which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss as well. [edit] Symptomatic treatment -blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until such time as antithyroid treatments start to take effect. Treatment of eye disease Mild cases are treated with lubricant eye drops or non steroidal antiinflammatory drops. Severe cases threatening vision (Corneal exposure or Optic Nerve compression) are treated with steroids or orbital decompression. In all cases cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while). Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep. Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull. Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves on the eyelids. Eyelid muscles can become tight with Graves, making it impossible to close eyes all the way. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms. Idiopathic thrombocytopenic purpura (ITP) is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic).[1] As most causes appear to be related to antibodies against platelets, ITP is also known as immune thrombocytopenic purpura or immune-mediated thrombocytopenic purpura. Often ITP is asymptomatic, however a very low platelet count can lead to visible symptoms, such as purpura (bruises), or more seriously, bleeding diathesis. Contents 1 Epidemiology 2 Signs and symptoms 3 Pathogenesis 4 Diagnosis 5 Treatment o 5.1 Steroids/IVIG o 5.2 Surgery o 5.3 Anti-D o 5.4 Steroid-sparing agents o 5.5 Thrombopoietin Receptor Agonists o 5.6 Experimental and novel agents o 5.7 Platelet transfusion o 5.8 H. pylori eradication

6 Synonyms 7 Notable individuals diagnosed with ITP 8 References 9 External links Epidemiology A normal platelet count is considered to be in the range of 150,000450,000 per cubic millimeter (mm 3) of blood for most healthy individuals. Hence one may be considered thrombocytopenic below that range, although the threshold for a diagnosis of ITP is not tied to any specific number. The incidence of ITP is estimated at 50100 new cases per million per year, with children accounting for half of that amount. At least 70 percent of childhood cases will end up in remission within six months, even without treatment.[2][3][4] Moreover, a third of the remaining chronic cases will usually remit during follow-up observation, and another third will end up with only mild thrombocytopenia (defined as a platelet count above 50,000).[2] ITP is usually chronic in adults[5] and the probability of durable remission is 2040 percent.[6] The male to female ratio in the adult group varies from 1:1.2 to 1.7 in most age ranges (childhood cases are roughly equal for both genders) and the median age of adults at the diagnosis is 5660.[7] The ratio between male and female adult cases tends to widen with age. In the USA, the adult chronic population is thought to be approximately 60,000with women outnumbering men approximately 2 to 1which has resulted in ITP being designated an orphan disease.[8] The mortality rate of chronic ITP patients varies but increases as a function of age. In a study conducted in the UK, it was noted that ITP patients experience an approximately 60 percent higher rate of mortality than gender- and age-matched comparison subjects without ITP. This increased risk of death with ITP is largely concentrated in middle-aged and elderly patients. Ninetysix percent of reported ITP-related deaths were patients 45 years or older. No significant difference was noted in the rate of survival between males and females.[9] ITP was first described by Paul Gottlieb Werlhof in 1735,[10] and was originally referred to as Werlhofs disease. [11] The first report of a successful therapy for ITP was in 1916, when Paul Kaznelson described a response to splenectomy.[12] Splenectomy remained a first-line remedy until the introduction of steroid therapy in the 1950s. Refractory ITP is a term used in cases where thrombocytopenia persists despite the use of all clinically indicated therapies. [edit] Signs and symptoms Symptoms of ITP include the development of bruises (purpura) and petechiae, especially on the extremities, bleeding from the nostrils and bleeding at the gums, any of which may occur if the platelet count is below 20,000 per mm3.[13] A very low count (<10,000 per mm3) may result in the formation of hematomas in the mouth or on other mucous membranes. Serious and possibly fatal complications due to an extremely low count (<5,000 per mm3) may include subarachnoid or intracerebral hemorrhage, lower gastrointestinal bleeding or other internal bleeding. An ITP patient with an extremely low count is also vulnerable to major internal bleeding caused by abdominal trauma, as might be experienced in a motor vehicle crash. Fortunately, these complications are not likely in a patient whose platelet count is above 20,000. [edit] Pathogenesis In many cases, ITP's cause is not idiopathic but autoimmune,[14] with antibodies against platelets being detected in approximately 60 percent of patients. Most often these antibodies are against platelet membrane glycoproteins IIb-IIIa or Ib-IX, and are of the IgG type. The famous HarringtonHollingsworth experiment established the immune pathogenesis of ITP.[15] The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic macrophages. The IgG autoantibodies are also thought to damage megakaryocytes, the precursor cells to platelets, but this is thought to contribute only slightly to the decrease in platelet numbers. The stimulus for auto-antibody production in ITP is probably abnormal T cell activity.[16][17][18] Preliminary findings suggest that these T cells can be influenced by drugs that target B cells, such as rituximab.[19] Diagnosis The diagnosis of ITP is a process of exclusion. First, the clinician has to determine that there are no blood abnormalities other than low platelet count, and no physical signs except for signs of bleeding. Then, the secondary causes (usually 510 percent of suspected ITP cases) should be excluded. Secondary causes could be leukemia, medications (e.g. quinine, heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency and others.[7][13] In approximately one percent of cases, autoimmune hemolytic anemia and immune thrombocytopenic purpura coexist, which is a condition called Evans syndrome.[7] Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate other possible causes for the thrombocytopenia. Bleeding time is prolonged in ITP patients. However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines.[20] A normal bleeding time does not exclude a platelet disorder.[21]

A bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt.[7] On examination of the bone marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP. An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80 percent specificity of this test is sufficient. [7] Treatment A platelet count below 20,000 is generally an indication for treatment. Patients with a count between 20,000 and 50,000 are usually evaluated on a case-by-case basis, and, with rare exceptions, there is usually no need to treat patients with a count above 50,000.[7] Hospitalization may be recommended in cases of very low counts, and is highly advisable if the patient presents with significant internal or mucocutaneous bleeding. A count below 10,000 is potentially a medical emergency, as the patient may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma. Steroids/IVIG Treatment usually is initiated with intravenous steroids (methylprednisolone or prednisone), intravenous immunoglobulin (IVIg) or a combination of these drugs. A platelet infusion may be administered in an emergency bleeding situation in order to attempt to quickly raise the count. After the platelet count has increased to a safe level, an orally administered steroid, such as prednisone (12 mg/kg per day), is usually prescribed. Most cases respond during the first week of treatment. After several weeks of oral steroid therapy, the dose is gradually reduced. However, 60 to 90 percent of patients relapse after the dose is decreased below 0.25 mg/kg per day and subsequently stopped.[6][7] Surgery Splenectomy is sometimes undertaken, as platelets targeted for destruction will often meet their fate in the spleen. The procedure is potentially risky in ITP cases due to the increased possibility of significant bleeding during surgery. Durable remission following splenectomy is achieved in 60 to 65 percent of ITP cases, less so in older patients.[22] Anti-D A relatively new strategy is treatment with anti-D, but the patient must be Rh-positive. This treatment (with products such as WinRho, Rhophylac or RhoGAM) is normally administered to Rh-negative women during pregnancy and after the birth of an Rh-positive infant to prevent sensitization to the Rh factor, but has been demonstrated effective on some Rh-positive ITP patients. Treatment with anti-D is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.[23] Steroid-sparing agents Immunosuppresants such as mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness. Intravenous immunoglobulin, while sometimes effective, is expensive and the improvement is temporary (generally lasting less than a month). However, in the case of a pre-splenectomy ITP patient with dangerously low platelet counts, and a poor response to other treatments, IVIg treatment can increase the count, making splenectomy less dangerous. IVIg is also commonly used as a long-term (though monthly) treatment. Extreme cases (very rare, especially in children) may require the infusion of vincristine, a chemotherapy agent, to stop the immune system from destroying platelets. However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution. Thrombopoietin Receptor Agonists Romiplostim (trade name Nplate) is a new treatment for stimulating platelet production. Designated an orphan drug in 2003 under USA law, it is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injection. Clinical trials showed it to be effective in treating chronic ITP, especially in post-splenectomy patients.[24] Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.[25] Eltrombopag (trade name Promacta) is an orally-administered agent with an effect similar to that of romiplostim. It has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. [26] Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008. [27] Experimental and novel agents Dapsone (also called Diphenylsulfone, DDS, or Avlosulfon) is an anti-infective sulfone drug. In recent years Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts in 4050 percent of patients administered the drug.[28][29] The off-label use of rituximab, a chimeric monoclonal antibody against the B cell surface antigen CD20, has been shown in preliminary studies to be an effective alternative to splenectomy in some patients.[19][30][31] However, many patients experience significant side-effects, there is a small risk of fatality due to progressive multifocal leukoencephalopathy caused by a reactivated JC virus, and randomized controlled trials are lacking.[32]

Promising results have been reported in a small phase II study of the experimental kinase inhibitor tamatinib fosdium (R788). In a population of 14 patients refractory to other treatments (ten of them having relapsed following splenectomy), nine responded to tamatinib and six achieved >100,000 platelets/uL counts.[33] Platelet transfusion Platelet transfusion alone is normally not recommended except in an emergency, and is usually unsuccessful in producing a long-term platelet count increase. This is because the underlying autoimmune mechanism that is destroying the patient's platelets will also destroy donor platelets. H. pylori eradication Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between H. pylori (Helicobacter pylori) infection and ITP. Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.[34] Synonyms ITP is known by a number of synonyms, but idiopathic or immune thrombocytopenic purpura are the most common names. Others include: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura and thrombocytolytic purpura.