Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
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The coeliac disease (CD) or gluten-sensitive enteropathy (GSE) is a permanent intolerance to wheat gliadin and to correlated proteins inducing malabsorption and typical damages of the jejunal mucosa (total or subtotal villous atrophy = SVA) in genetically-predisposed individuals ("DQW2"). A large amount of research has been devoted to CD pathogenesis: the most recent studies, thanks to sophisticated and experimental methods, support the pathogenetic immunological theory and the one of direct cytotoxicity. The correct diagnostic procedure for CD, established in 1970 by the European Society for Pediatric Gastroenterology and Nutrition (ESPGAN), suggested three small bowel mucosal biopsies. In the last years, because of the difficulties of such a practice, the necessity of non-invasive diagnostic approaches has developed; such approaches have been verified in absorption tests (one-hour blood xylose, intestinal permeability methods) and in immunogenetic tests (antibodies antigliadin, anti-reticulin, anti-endomysium, anti 90 KD glycoprotein, anti-human jejunum, HLA I/II antigens). The specific MHC antigens establish CD's incidence in several population and in particular situations, as in first-degree relatives and in diseases associated with CD (dermatitis herpetiformis (DH), insulin dependent diabetes mellitus (IDDM) and other auto-immune syndromes). The specific serum antibodies singly used as first level screening if estimated in combination with absorption tests, reach the highest levels of specificity and sensibility in CD diagnosis. It's anyway fundamental the comparison with at least a typical CD histological feature, caused by a challenge with a sufficient gluten to be carried in dubious cases and in non high auxological risk age (ESPGAN 1989). Adolescence is a period of frequent non compliance with a gluten-free diet and of particular psychological and physical problems: the apparent "gluten insensitivity", typical of teen-agers and adults, recalls the definitions of silent CD and latent CD (iceberg like). In the first case the jejunal mucosa is abnormal and the symptomatology isn't evident. In latent CD, genetically restricted, the mucosa is normal but there are minimal markers of inappropriate immunity to gliadin (at intestinal humoral immunity level) and a possible worsening of histological lesions to the third stage under environmental stimuli. This represents a two-stage model CD. That's why CD is still under-evaluated despite recent statistics reporting an increasing incidence (late and atypical forms). Prevalence rates between 1:300 and 1:4,000 and more are quoted in literature. The necessity of a strict gluten-free diet is confirmed by the evident frequency of lymphoma and by the increased risk of malignancy in untreated CD.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Celiac disease and its diagnostic evolution. Comparisons and experiences in a hospital pediatric department (1975-1992). I]. 152 93

From our studies in Caucasian families of HLA, complement, and glyoxalase alleles have developed the concepts of the complotype and the extended haplotype. complotypes are clusters of the four genes for complement proteins encoded within the MHC designated (in arbitrary order) by their BF, C2, C4A, and C4B alleles. They are inherited in families and occur in populations as functionally single genetic units and exhibit linkage disequilibrium with HLA-B and HLA-DR alleles which are complotype, rather than complement gene allele, specific. In Caucasians, there are 10-12 common sets of HLA-B, DR, complotype sets that show significant linkage disequilibrium. These haplotypes constitute 25-30% of all MHC haplotypes in Caucasians. Because there is evidence for relative fixity of alleles on these chromosomes to an unknown extent beyond the HLA-B-DR interval, they have been called extended MHC haplotypes. It appears likely that it is these extended haplotypes that provide most of the known linkage disequilibrium pairs previously reported for MHC alleles as well as many of the known MHC allele-disease associations. The most common extended haplotype [HLA-B8, DR3, SC01], when it carries GLO2, is increased in type I diabetes mellitus and probably a number of other diseases, including gluten-sensitive enteropathy and membranoproliferative glomerulonephritis. In the families with these disorders studied by us, this haplotype exhibits male segregation distortion, a feature displayed by t-mutants found in wild mouse populations. This feature constitutes an important selective advantage for the chromosome and may contribute to the accumulation of susceptibility mutations for a variety of diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complotypes, extended haplotypes, male segregation distortion, and disease markers. 351 38

Two male infants with severe protracted diarrhoea presenting at 4 months (patient 1) and 10 weeks (patient 2) of age are reported. In both patients jejunal biopsy showed subtotal villous atrophy. Both had specific complement-fixing autoantibodies reacting by immunofluorescence with human duodenal, jejunal, and colonic epithelium. Patient 1 also had hypothyroidism and type 1 diabetes mellitus with thyroid and islet cell autoantibodies. His gut antibodies were of IgG class, reached a titre of 1:512, and remained positive throughout his illness. He died at 16 months of age. Patient 2 had gut antibodies of IgM class, which reached a titre of 1:128 and disappeared at the time of spontaneous recovery of the diarrhoea. The findings suggest that an autoimmune process was the basis for the enteropathy in these patients. We recommend that autoantibody tests should be performed in infants with unexplained protracted diarrhoea.
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PMID:Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. 388 68

An increasing number of diseases are being demonstrated to be due to determinants at more than one genetic locus. It thus becomes of interest to determine the genetic contribution of a specific single locus. A method of estimating a "coefficient of genetic contribution" is described herein, based on a comparison of monozygotic twin concordance data for a specific disease, the empirical sibling recurrence risks, and the sharing of identical by descent genes at the specific locus of interest by pairs of siblings who are both affected. The value of the method is that it requires relatively few assumptions, and does not require knowledge of the mode of inheritance of disease susceptibility at the gene locus of interest. If there are major environmental determinants, this method will give a lower bound for the single locus of interest. To illustrate the method, it is applied to two specific diseases, insulin dependent diabetes mellitus (IDDM) and gluten-sensitive enteropathy (GSE), and a specific locus, the HLA gene complex. The best estimates would appear to be that the HLA "genes" provide a coefficient of 60% for IDDM susceptibilty, but only 30% for GSE. A possible reason for these differences is the markedly increased disease susceptibility of the DR3/DR4 heterozygote for IDDM.
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PMID:Measuring the genetic contribution of a single locus to a multilocus disease. 654 83

Diamine oxidase (DAO) is an enzyme found almost exclusively in the enterocyte of the villous tips. In the basal state plasma DAO activity is low but increases significantly after i.v. injection of heparin. It is well recognised that postheparin plasma activity of DAO reflects clearly the integrity of the small bowel mucosa. The aim of this study was to investigate postheparin plasma DAO activity in diabetics with enteropathy. The study was carried out in a group of 72 individuals subdivided into five groups. Group I consisting of 16 patients with type 1 diabetes, group II--20 patients with type 2 diabetes, group III--8 patients with newly diagnosed type 1 diabetes, group IV--8 diabetics with enteropathy and group V--the control group. Blood samples were taken at the time 0' and at 60' and 120' intervals following i.v. injection of heparin. DAO activity was assessed by RIA methods. Basal values of DAO were nearly the same in all of the subjects (< 50 pmol/min/ml). After injection of heparin a very high DAO activity was observed in all groups (> 400 pmol/min/ml) except group IV (< 270 pmol/min/ml) (p < 0.001). There were no significant differences between the groups according to the type of diabetes, its duration and the methods of treatment. In conclusion, the postheparin plasma DAO activity in diabetics with enteropathy was very low, but of itself, diabetes and its treatments had no effect on the results under investigation.
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PMID:[Plasma activity of diamine oxidase after heparin in patients with diabetic enteropathy]. 747 28

A 21-year-old patient, since the age of 16, presented a familial type of chronic autoimmune thrombocytopenia that responded only partially to various types of immunosuppressive treatment. His prolonged survival, compared to his decreased siblings, was complicated by the appearance of a severe enteropathy. High doses of corticosteroids induced a type 1 diabetes as a major side effect. The introduction of cyclosporine resulted in both a continuous complete clinical remission and a partial hematological remission and allowed the discontinuation of all other medication for 18 months. In uncommon complex autoimmune disease, cyclosporine may represent a safe and effective alternate therapy when other immunosuppressive agents have failed.
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PMID:Prolonged remission induced by cyclosporine in a patient with familial thrombocytopenia and enteropathy. 764 Jan 83

Protracted diarrhea with insulin dependent diabetes mellitus (DM) and hypothyroidism in a 9 month old Japanese girl who was firmly suspected to have autoimmune enteropathy (AIE) is reported. Her severe secretory diarrhea failed to respond to intensive antidiarrheic treatment and was gradually improved with steroid therapy. The circulating autoantibodies to enterocytes in her serum were detected by indirect immunofluorescence technique and the impaired suppressor T (Ts) cell function was proved by plaque forming assay using bead-separated CD4 or CD8 T cells together with CD19 B cells. The anti-enterocyte antibodies were exclusively of immunoglobulin M (IgM) class and were detected with the progress of the protracted diarrhea. Maximum antibody titer was obtained at the onset of DM and the disappearance of autoantibodies was associated with the resolution of the clinical symptoms and signs. The helper functions of adult CD4 T cells to induce Ig-secreting cells from adult and the patient were strikingly suppressed by adult CD8 T cells. However, the CD8 T cells from the patient lost the ability to inhibit the induction of these Ig-secreting cells when stimulated with adult CD4 T cells. Moreover, the patient's CD8 T cells stimulated rather than suppressed the induction of Ig-secreting cells from the patient when stimulated with the patient's CD4 T cells. These results suggest that the impaired Ts cell function in this patient might play some immunological role in the pathogenesis of AIE.
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PMID:A case of intractable diarrhea firmly suspected to have autoimmune enteropathy. 790 1

Celiac disease (CD) is a small intestinal disorder with overt malabsorption in the minority and with subclinical or atypical symptoms in the majority of patients. It is triggered by gluten and related cereal proteins in a unique genetic background (HLA-DQ2 or DQ8 and other unmapped genes). CD is characterized by a highly specific mucosal autoantibody response to tissue transglutaminase. In the intestine this enzyme creates antigenic neoepitopes in gluten peptides which are more efficiently presented to the immune system in the context of HLA-DQ2 or DQ8. Between 3% and 6% of patients with type 1 diabetes mellitus (DM) have (atypical) CD, and the prevalence of a variety of autoimmune diseases in patients with CD correlates with the time of gluten exposure, reaching 35% after 20 years. It is still unknown whether oligosymptomatic CD favors the development of type 1 DM and whether a gluten-free diet modifies the progression of DM in general. Apart from shared or adjacent HLA loci in both diseases, post-translational modification of potential autoantigens by enzymes such as tissue transglutaminase could play a role in the autoimmunity of type 1 DM.
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PMID:Celiac disease and its link to type 1 diabetes mellitus. 1139 50

The development of autoimmune type 1 diabetes involves complex interactions among several genes and environmental agents. Human patients with type 1 diabetes show an unusually high frequency of wheat gluten-sensitive enteropathy; T-cell response to wheat proteins is increased in some patients, and high concentrations of wheat antibodies in blood have been reported. In both major models of spontaneous type 1 diabetes, the BioBreeding (BB) rat and non-obese diabetic mouse, at least half of the cases are diet-related. In studies of BB rats fed defined semipurified diets, wheat gluten was the most potent diabetes-inducing protein source. A major limitation in understanding how wheat or other dietary antigens affect type 1 diabetes has been the difficulty in identifying specific diabetes-related dietary proteins. To address this issue, we probed a wheat cDNA expression library with polyclonal IgG antibodies from diabetic BB rats. Three clones were identified, and the intensity of antibody binding to one of them, WP5212, was strongly associated with pancreatic islet inflammation and damage. The WP5212 putative protein has high amino acid sequence homology with a wheat storage globulin, Glb1. Serum IgG antibodies from diabetic rats and humans recognized low molecular mass (33-46 kDa) wheat proteins. Furthermore, antibodies to Glb1 protein were found in serum from diabetic patients but not in age-, sex-, and HLA-DQ-matched controls. This study raises the possibility that in some individuals, type 1 diabetes may be induced by wheat proteins. Also, it provides a first candidate wheat protein that is not only antigenic in diabetic rats and human patients but is also closely linked with the autoimmune attack in the pancreas.
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PMID:A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. 1240 86

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.
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PMID:Diabetic autonomic neuropathy. 1271 21


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