Shock: A possible presenting manifestation of autoimmune polyendocrine syndrome type II

Autoimmune polyendocrine syndrome Type II (APS II), also known as polyglandular autoimmune syndrome Type II or Schmidt syndrome, is constellations of multiple endocrine gland insufficiencies. It is a rare, but most common of the immunoendocrinopathy syndrome. It is characterized by the obligatory occurrence of autoimmune Addison''s disease in combination with thyroid autoimmune diseases and/or Type I diabetes, hypogonadism, hypophysitis, myasthenia gravis, vitiligo, alopecia, pernicious anemia, and celiac disease. Here, we report a case of 38-year-old female patient presented with shock, further diagnosed to have APS II.     

Thymoma-associated autoimmune enteropathy. A report of two cases

Autoimmune enteropathy is an increasingly recognized cause of severe protracted diarrhea, usually affecting infants and children predisposed to autoimmune phenomena. Although this may be a common cause of diarrheal illness, it is scarcely recognized in the American literature. In association with thymoma, a case of so-called graft-vs-host-like colitis and 2 cases of chronic diarrhea associated with thymoma were reported, but, to our knowledge, no cases of autoimmune enteropathy have been reported as such. We describe 2 adults with autoimmune enteropathy found in association with a thymoma.     

Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies

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

Pathogenesis and Clinical Significance of Liver Injury in Celiac Disease

Abnormalities of liver function are one of the manifold extraintestinal manifestations of celiac disease. Although the spectrum of liver manifestations associated with celiac disease is particularly wide, two main forms of liver damage namely, cryptogenic and autoimmune, appear to be strictly related to gluten-sensitive enteropathy. The most frequent finding is represented by a cryptogenic hypertransaminasemia, observed in about a half of untreated celiac patients, as an expression of a mild liver dysfunction with a histological picture of nonspecific reactive hepatitis (celiac hepatitis) reverting to normal after 6–12 months of a strict gluten-free diet. In a few cases, when celiac disease is diagnosed, a more severe liver injury, characterized by a cryptogenic chronic hepatitis or liver cirrhosis, is present. In these patients, liver damage can still improve after a gluten-free diet institution. Moreover, a close association between celiac disease and autoimmune liver disorders has been widely demonstrated. Indeed, celiac disease has been found in 3–7% of patients with primary biliary cirrhosis, in 3–6% with autoimmune hepatitis, and in 2–3% with primary sclerosing cholangitis. Differently from cryptogenic liver injury, autoimmune liver dysfunction, found in celiac disease, does not usually improve after a gluten-free diet. Presently, it is difficult to establish if the two main kinds of liver injury found in celiac disease (cryptogenic and autoimmune) are discrete entities with a different pathogenesis or if they are an expression of the same disorder where genetic factors and the duration of gluten exposure may determine the severity and the pattern of liver injury.     

A practical approach to small bowel biopsy interpretation: Celiac disease and its mimics

While celiac disease is the most common cause of villous remodeling and intraepithelial lymphocytosis in the proximal small bowel, there are many entities that can mimic its histologic appearance. The purpose of this review is to discuss normal small bowel histology and the differential diagnosis of celiac disease. Approaches to evaluate increased intraepithelial lymphocytes are presented, followed by a detailed discussion of the pathology of celiac disease. Particular emphasis is given to those conditions that cause intraepithelial lymphocytosis in the setting of preserved villous architecture, although other important entities, such as peptic injury, idiopathic inflammatory bowel disease, medication injury, eosinophilic (allergic) gastroenteritis, autoimmune enteropathy, common variable immunodeficiency, and infections are also reviewed.     

Natural killer cell lymphoma of small intestine with features of enteropathy but lack of association with celiac disease

A primary small intestinal natural killer (NK) cell lymphoma with pathologic features of enteropathy but lack of association with celiac disease is reported. A 37-year-old man presented with tarry stool, coffee-ground vomitus, and mild fever. He did not have chronic diarrhea or malabsorption. Segmental resection of the duodenum and jejunum showed multicentric transmural infiltration by medium-sized lymphoma cells expressing CD3, CD8, cytotoxic granules, and Epstein-Barr virus by in situ hybridization. The nontumorous mucosa away from the main tumor revealed enteropathy with villous blunting and increased intraepithelial lymphocytes sharing the same immunophenotype as the lymphoma cells. Both lymphoma and nontumorous areas were germline for T-cell receptor-gamma and immunoglobulin heavy chain gene rearrangement. Serologic test by ELISA was negative for anti-transglutaminase. The patient died of repeated gastrointestinal bleeding and sepsis at 2 months. Differential diagnosis of this unique nasal-type NK-cell lymphoma with enteropathy-associated T-cell lymphoma is discussed.     

Lymphocytes bearing the gamma delta T-cell receptor in normal human intestine and celiac disease

Monoclonal antibodies to T-cell receptors were used to investigate the prevalence of the two distinct T-cell subpopulations (TCR alpha beta+ and TCR gamma delta+ cells) in the intestinal mucosa of children with celiac disease (gluten-sensitive enteropathy) as compared with normal intestinal mucosa. TCR gamma delta+ cells were rarely identified in the epithelium of human fetal or normal postnatal intestine and few were present in the lamina propria, whereas the number of distribution of TCR alpha beta+ cells closely resembled that of CD3+ cells. Compared with normal intestine, a significant increase in the number of CD3+, CD8+, TCR alpha beta+, and TCR gamma delta+ intraepithelial lymphocytes was present in celiac disease. Although the mucosal TCR gamma delta+ cells were less numerous than TCR alpha beta+ cells in celiac disease, there was a marked increase in the number of TCR gamma delta+ cells as compared with controls. The ligand recognized by the gamma delta T-cell receptor and the function of these cells have not been determined; however, these findings suggest a possible role for TCR gamma delta+ lymphocytes in mucosal immune responses and tissue injury as seen in celiac disease.     

Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus

Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Felty's syndrome and systemic lupus erythematosus. Felty's syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patient's clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Felty's syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony-stimulating factor dose and frequency should be adjusted at the lowest effective dose.     

Celiac disease: from gluten to autoimmunity

Celiac disease, also known as gluten-sensitive enteropathy and nontropical sprue, is a prevalent autoimmune disorder that is triggered by the ingestion of wheat gluten and related proteins of rye and barley in genetically susceptible individuals. The immune response in celiac disease involves the adaptive, as well as the innate, and is characterized by the presence of anti-gluten and anti-transglutaminase 2 antibodies, lymphocytic infiltration in the epithelial membrane and the lamina propria, and expression of multiple cytokines and other signaling proteins. The disease leads to inflammation, villous atrophy, and crypt hyperplasia in the small intestine. In addition to the intestinal symptoms, celiac disease is associated with various extra-intestinal complications, including bone and skin disease, anemia, endocrine disorders, and neurologic deficits. Gluten-free diet is currently the only effective mode of treatment for celiac disease, but better understanding of the mechanism of the disease is likely to add other choices for therapy in the future.     

Sex differences in autoimmune disease from a pathological perspective

Autoimmune diseases affect ~8% of the population, 78% of whom are women. The reason for the high prevalence in women is unclear. Women are known to respond to infection, vaccination, and trauma with increased antibody production and a more T helper (Th)2-predominant immune response, whereas a Th1 response and inflammation are usually more severe in men. This review discusses the distribution of autoimmune diseases based on sex and age, showing that autoimmune diseases progress from an acute pathology associated with an inflammatory immune response to a chronic pathology associated with fibrosis in both sexes. Autoimmune diseases that are more prevalent in males usually manifest clinically before age 50 and are characterized by acute inflammation, the appearance of autoantibodies, and a proinflammatory Th1 immune response. In contrast, female-predominant autoimmune diseases that manifest during the acute phase, such as Graves’ disease and systemic lupus erythematosus, are diseases with a known antibody-mediated pathology. Autoimmune diseases with an increased incidence in females that appear clinically past age 50 are associated with a chronic, fibrotic Th2-mediated pathology. Th17 responses increase neutrophil inflammation and chronic fibrosis. This distinction between acute and chronic pathology has primarily been overlooked, but greatly impacts our understanding of sex differences in autoimmune disease.     

Autoantibodies and overlap syndromes in autoimmune rheumatic disease

Many patients diagnosed with autoimmune rheumatic disease cannot be categorised easily into one of the established clinical entities such as systemic lupus erythematosus, dermatomyositis, or systemic sclerosis. The term "overlap syndrome" has been increasingly used to identify such patients and is useful in terms of clarifying prognosis and facilitating disease management. This article reviews overlap syndrome in autoimmune rheumatic disease, with particular emphasis on the associated serological markers.     

The pathology of malabsorption: current concepts

Intestinal malabsorption results from a wide variety of causes, which can most easily be organized into three groups. Maldigestion arises from problems with mixing or with digestive mediators, and includes post-gastrectomy patients and those with deficiencies of pancreatic or intestinal enzymes, or of bile salts. Mucosal and mural causes of malabsorption are abundant, and include gluten-sensitive enteropathy, tropical sprue, autoimmune enteropathy, and HIV/AIDS-related enteropathy, as well as mural conditions such as systemic sclerosis. Finally, microbial causes of malabsorption include bacterial overgrowth, Whipple's disease, and numerous infections or infestations that are most frequently seen in immunocompromised patients. An overview of the most common and interesting entities in each of these categories follows, along with a discussion of current concepts. Mucosal conditions and microbial causes of malabsorption are given special attention.     

Autoimmune enteropathy in Infants

In two brothers with autoimmune enteropathy there was total villous atrophy in the small intestine and marked lymphoid cell infiltration in the lamina propria of the entire digestive tract, discovered at autopsy in one of these patients. In addition, the pancreas showed diffuse interstitial infiltration by lymphocytes. The liver was enlarged, with extensive haematopoiesis and cholestasis. Similar lesions in the digestive tract were noticed in the second boy, but on immunosuppressive therapy his diarrhoea gradually disappeared. When he was 16 months of age, percutaneous biopsies showed moderately aggressive chronic hepatitis and a focal interstitial lymphoid infiltrate in the kidney. After 3 years of immunosuppressive therapy (prednisone, cyclosporin), the child ate well and total parenteral nutrition was discontinued. The intestinal lesions had regressed but fibrotic lesions of the liver persisted.     

Antiphospholipid syndrome and vascular ischemic (occlusive) diseases: an overview

Antiphospholipid syndrome (APS) is primarily considered to be an autoimmune pathological condition that is also referred to as "Hughes syndrome". It is characterized by arterial and/or venous thrombosis and pregnancy pathologies in the presence of anticardiolipin antibodies and/or lupus anticoagulant. APS can occur either as a primary disease or secondary to a connective tissue disorder, most frequently systemic lupus erythematosus (SLE). Damage to the nervous system is one of the most prominent clinical constellations of sequelae in APS and includes (i) arterial/ venous thrombotic events, (ii) psychiatric features and (iii) other non- thrombotic neurological syndromes. In this overview we compare the most important vascular ischemic (occlusive) disturbances (VIOD) with neuro-psychiatric symptomatics, together with complete, updated classifications and hypotheses for the etio-pathogenesis of APS with underlying clinical and laboratory criteria for optimal diagnosis and disease management.     

Enteropathy with loss of enteroendocrine and paneth cells in a patient with immune dysregulation: a case of adult autoimmune enteropathy

Autoimmune enteropathy (AIE) is a relatively rare condition found most frequently in children. It presents with persistent watery diarrhea and malabsorption and may require total parenteral nutrition for nutritional support. Rare cases have been reported in adults. On histology, the small intestinal villi are flattened but lack the intraepithelial lymphocytosis of celiac disease. In children and rarely in adults, some cases are linked to the IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked inheritance). We report a 21-year-old man who presented with chronic persistent diarrhea for 4 years. The duodenal biopsies showed villous blunting, chronic inflammation, and decreased to absent goblet cells, Paneth cells, and endocrine cells by histology and electron microscopy. These changes are consistent with an AIE with involvement of non-enterocyte populations. Pathologists must be aware of the possibility of AIE in adults and consider it in the differential diagnosis of duodenitis, intraepithelial lymphocytosis, and small bowel villous flattening.     

Hypercoagulability in celiac disease — An update

Celiac disease is a life-long autoimmune disease affecting multiple organs of genetically susceptible individuals. One of the extra intestinal manifestations of the disease is thromboembolic events like strokes, veins' thrombosis, and pregnancy losses. Hypercoagulable autoimmune diseases like lupus erythematosus and antiphospholipid syndrome, associated with celiac disease just add risk to the patients. Pathogenic predisposing avenues increasing the hypercoagulability in celiac disease are multiple: nutritional deficiencies (B12, folate, and vitamin K), genetic predisposition (MTHFR mutations), thrombophilic autoantibodies, hyperhomocysinemia, endothelial dysfunction and platelet abnormalities. Primary pharmacologic thromboprophylaxis or treating the predisposing factors should be considered on a personal basis.     

Les complications de la maladie cœliaque

Numerous complications can occur in celiac disease, nutritional (growth failure in children, malnutrition, vitamin deficiencies), hematologic (anaemia), bone disease (osteoporosis, fracture), gynaecologic (hypo fertility), cardiovascular (coronaropathy, venous thrombosis), neurological (peripheral neuropathy), hepatic (cytolysis, cirrhosis). Celiac disease is associated with an increased risk of autoimmune diseases (type 1 diabetes, thyroiditis), and cancer (upper digestive tract, hepatocellular carcinoma, lymphoma). The main digestive complications are microscopic colitis and refractory sprue, which are resistant to gluten-free diet. It can be associated with a monoclonal proliferation of intraepithelial lymphocytes (type 2 refractory sprue), which may be considered as a cryptic lymphoma and can lead to invasive T lymphoma, which occurs in one celiac patient in 1000. Gluten-free diet protects from the occurrence of most complications and correct the over-mortality related to these complications.     

Autoantibodies in celiac disease

Autoantibody production is an important feature of many autoimmune disorders, signifying a breakdown of immune tolerance to self-antigens. In celiac disease, an autoimmune enteropathy with multiple extra-intestinal manifestations, autoantibody reactivity to transglutaminase 2 (TG2) has been shown to closely correlate with the acute phase of the disease. It serves as a specific and sensitive marker of celiac disease, and is highly useful in aiding diagnosis and follow-up. Immune reactivity to other autoantigens, including transglutaminase 3, actin, ganglioside, collagen, calreticulin and zonulin, among others, has also been reported in celiac disease. The clinical significance of these antibodies is not known, although some may be associated with specific clinical presentations or extra-intestinal manifestations of celiac disease. This review examines the presence of anti-TG2 and other autoantibodies in celiac disease, discussing their diagnostic value, their potential role in disease pathogenesis and current hypotheses that explain how their release may be triggered.     

Antiphospholipid antibody syndrome and fetal outcome

The presence of antiphospholipid antibodies, lupus anticoagulant and anticardiolipin antibody in patients with systemic lupus erythematosus has been associated with the clinical features of thrombosis, fetal loss and thrombocytopenia, and the syndrome is designated as antiphospholipid antibody syndrome (APS). APS has been increasingly diagnosed in patients without underlying autoimmune disease and is most frequently seen in obstetric patients suffering spontaneous abortion, preeclampsia and intrauterine growth restriction. The hypothesis underlying most research into the pathophysiology of APS is that autoantibodies are not only the markers of the disease, but also directly contribute to the development of clinical features. This review summarizes recent information on the pathophysiology and potential roles of autoantibodies in the obstetric patients suffering, particularly in the subgroup of repeated spontaneous abortions.     

The biopsy pathology of non‐coeliac enteropathy

Tropical sprue (TS) is a malabsorption syndrome of presumed infectious aetiology that affects residents of (or visitors to) the tropics. The histological changes of TS are similar to those of coeliac disease, with increased intraepithelial lymphocytes being central to both. Unlike in coeliac disease, however, a completely flat small bowel biopsy is uncommon in TS. TS typically involves the terminal ileum, whereas coeliac disease does not. Small intestinal bacterial overgrowth (SIBO) has been defined as an increase in number and/or a change in the type of bacteria in the upper gut. Conditions that predispose to SIBO are largely those that decrease or interfere with small bowel motility. The mucosal histology is variable, and may include modest villous blunting accompanied by increased lamina propria and epithelial inflammation. Autoimmune enteropathy (AE) is a family of rare diseases that share common themes such as immunodeficiency states and autoantibodies. AE cases typically have marked villous atrophy similar to that in fully developed coeliac disease, but they lack the intense surface epithelial lymphocytosis. Apoptosis and lymphocyte infiltration at the base of the crypts, crypt abscesses and cryptitis are also seen. Patients with anti‐goblet cell antibodies can have a lack of goblet cells, endocrine cells, and Paneth cells.