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Calliopejen1 (talk | contribs) →Conditions Secondary to GSE: remove content moved to subarticle. adding a better summary would be good but i don't know what of the subarticle is most important.... |
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==Conditions Secondary to GSE== |
==Conditions Secondary to GSE== |
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{{main|Conditions secondary to gluten-sensitive enteropathy}} |
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GSE has a wide variety of associated symptoms, however the key symptoms are typically |
GSE has a wide variety of associated symptoms, however the key symptoms are typically |
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restricted to the bowel and associated tissues. These include irritable bowel disease, |
restricted to the bowel and associated tissues. These include irritable bowel disease, |
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with GSE. |
with GSE. |
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===GSEA Dermatitis=== |
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'''Dermatitis herpetiformis'''. ''Triticeae'' glutens are the primary cause of ''[[dermatitis herpetiformis]]''(DH). Epidermal transglutaminase (eTG) is related to tTG and is the autoantigen of DH. It appears that all DH patients have or are susceptible on wheat ingestion to CD. Within CD DH is relatively rare or underdiagnosed with about 5% of patients having DH. Aphthous stomatitis is a common mouth lesion found with celiac disease |
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'''Urticaria'''. Chronic urticaria has been seen in a few cases of CD.<ref name="pmid16609761">{{cite journal | author = Haussmann J, Sekar A | title = Chronic urticaria: a cutaneous manifestation of celiac disease | journal = Can. J. Gastroenterol. | volume = 20 | issue = 4 | pages = 291-3 | year = 2006 | pmid = 16609761 | doi = }}</ref> and are likely the result of fortuitous allergies to wheat, or allergies secondary to GSE. |
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'''Prurigo nodularis'''. [[Prurigo nodularis]] has been identified with celiac diease. <ref name="pmid952746">{{cite journal | author = McKenzie AW, Stubbing DG, Elvy BL | title = Prurigo nodularis and gluten enteropathy | journal = Br. J. Dermatol. | volume = 95 | issue = 1 | pages = 89-92 | year = 1976 | pmid = 952746 | doi = }}</ref><ref name="pmid10521982">{{cite journal | author = Francesco Stefanini G, Resta F, Marsigli L, ''et al'' | title = Prurigo nodularis (Hyde's prurigo) disclosing celiac disease | journal = Hepatogastroenterology | volume = 46 | issue = 28 | pages = 2281-4 | year = 1999 | pmid = 10521982 | doi = }}</ref> |
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===GSEA Gastrointestinal Diseases=== |
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[[Image:Peptic stricture.png|right|thumb|200px|[[Gastroscopy|Endoscopic]] image of peptic stricture, or narrowing of the [[esophagus]] near the junction with the [[stomach]] due to chronic [[gastroesophageal reflux]]. This is the most common cause of [[dysphagia]], or difficulty swallowing, in [[scleroderma]].]] While GI disease is one of the major symptoms of GSE which is characterized by increased levels of IgA/IgG to food proteins<ref name="pmid270982">{{cite journal | author = Ratnaike RN, Wangel AG | title = Immunological abnormalities in coeliac disease and their response to dietary restriction. I. Serum immunoglobulins, antibodies and complement | journal = Australian and New Zealand journal of medicine | volume = 7 | issue = 4 | pages = 349-52 | year = 1977 | pmid = 270982 | doi = }}</ref>, many conditions like chronic constipation and irritable bowel disease persist after GF diet. Some of this may be due to persistent undetected food allergies, increased sensitivity of the damaged gut, or problems masked by GSE itself. |
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'''Irritable Bowel Syndrome'''. In Diarrhea dominant IBS is a common symptom of GSE, increased celiac disease-associated serum IgG was found in treated and untreated CD patients. The IgG was most common in untreated patients with more active DQ2 expression which dropped on GF diet.<ref name="pmid17553753">{{cite journal | author = Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich R | title = Predictors of Clinical Response to Gluten-Free Diet in Patients Diagnosed With Diarrhea-Predominant Irritable Bowel Syndrome | journal = | volume = | issue = | pages = | year = 2007 | pmid = 17553753 | doi = 10.1016/j.cgh.2007.03.021}}</ref>. Some irritable bowel can be the result of other food intolerances, such as casien intolerance, lactose intolerance, or intolerances to non-dextrose sugars in other foods. It can also be result of overgrowth of yeast or bacteria as a result of excesses of unadsorbed nutrients. |
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'''Gastroesophageal Reflux Disease'''. Gastroesophageal reflux disease (GERD) is the indirect result of many factors and some autoimmune diseases like [[schleroderma]]. GSE can cause inflammation and delayed gastric emptying, which can persist through most of the sleeping hours causing GERD. GSE is associated with an increase of food allergies, in some patients this can cause diarrhea, but in others constipation. In some patients the food allergies are the only apparent symptom, and allergies often persist on a GF diet,and can slow down digetstion resulting in delayed gastric emptying and inflammation in the region of the stomach. This can aggrevated GERD. |
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'''Diseases of the Pancreas, Gall bladder, Bile Duct'''. CD is prevelant in [[primary biliary cirrhosis]]<ref name="pmid74661">{{cite journal | author = Logan RF, Ferguson A, Finlayson ND, Weir DG | title = Primary biliary cirrhosis and coeliac disease: an association? | journal = Lancet | volume = 1 | issue = 8058 | pages = 230-3 | year = 1978 | pmid = 74661 | doi = }}</ref><ref name="pmid12385447">{{cite journal | author = Volta U, Rodrigo L, Granito A, ''et al'' | title = Celiac disease in autoimmune cholestatic liver disorders | journal = Am. J. Gastroenterol. | volume = 97 | issue = 10 | pages = 2609-13 | year = 2002 | pmid = 12385447 | doi = }}</ref> and was also found at higher than expected frequencies in autoimmune [[cholangitis]] and primary sclerosing cholangitis.<ref name="pmid12385447"/>. CD is frequently linked to [[pancreatitis]] but also to [[papillary stenosis]]<ref name="pmid10570344">{{cite journal | author = Patel RS, Johlin FC, Murray JA | title = Celiac disease and recurrent pancreatitis | journal = Gastrointest. Endosc. | volume = 50 | issue = 6 | pages = 823-7 | year = 1999 | pmid = 10570344 | doi = }}</ref> and, in India, tropical calcific pancreatitis appears also to be associated with CD.<ref name="pmid8213729">{{cite journal | author = Nanda R, Anand BS | title = Celiac disease and tropical calcific pancreatitis | journal = Am. J. Gastroenterol. | volume = 88 | issue = 10 | pages = 1790-2 | year = 1993 | pmid = 8213729 | doi = }}</ref> |
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===GSEA Endocrine Disorders=== |
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'''Avitaminosis'''. Maladsorption in GSE results in decline of fat soluble vitamins and vitamin B, as well as maladsorption of essential fatty acids. This can cause a wide variety of secondary problems. |
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'''Grave's Disease, Hashimoto's thyroiditis'''. Grave's disease and Hashimoto's thryroiditis |
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are greatly increased in patients with CD. <ref name="pmid8198149">{{cite journal | author = Wortsman J, Kumar V | title = Case report: idiopathic hypoparathyroidism co-existing with [[coeliac disease]]: immunologic studies | journal = Am. J. Med. Sci. | volume = 307 | issue = 6 | pages = 420-7 | year = 1994 | pmid = 8198149 | doi = }}</ref> |
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'''hypocalcinemia'''. <ref name="pmid8186825">{{cite journal | author = Rakover Y, Hager H, Nussinson E, Luboshitzky R | title = Celiac disease as a cause of transient hypocalcemia and hypovitaminosis D in a 13 year-old girl | journal = The Journal of pediatric endocrinology | volume = 7 | issue = 1 | pages = 53-5 | year = 1994 | pmid = 8186825 | doi = }}</ref> |
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'''Diabetes''', Type 1 (Juvenile onset). The incidence of juvenile [[diabetes mellitus type 1|Type 1 Diabetes]] (T1D) is about 1:500 in the U.S. population, and is the result of autoimmune damage to the [[Islets of Langerhans]] cells in the pancreas. The level of adult onset T1D plus ambiguous T1D/T2D is unknown. It is unclear how large a role ''Triticeae'' has in T1D which also shows stong linkage to DQ2.5 and DQ8. Childhood (male) Type 1 diabetes increases the risk for GSE and vice versa<ref name=DiabetesI_GSE>{{cite journal | author = Lampasona V, Bonfanti R, Bazzigaluppi E, Venerando A, Chiumello G, Bosi E, Bonifacio E. | title = Antibodies to tissue transglutaminase C in type I diabetes. | journal = Diabetologia. | volume = 42 | issue = 10 | pages = 1195-1198 | year = 1999 | id = PMID 10525659}}</ref> and it now appears that GSE precedes T1D in many cases<ref>{{cite journal | author = Ludvigsson J, Ludvigsson J, Ekbom A, Montgomery S | title = Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2483-8 | year = 2006 | id = PMID 17065689}}</ref> and an active search for coeliac disease in early juvenile diabetes patients revealed that GF diet resulted in some improvements.<ref>{{cite journal | author = Hansen D, Brock-Jacobsen B, Lund E, Bjørn C, Hansen L, Nielsen C, Fenger C, Lillevang S, Husby S | title = Clinical benefit of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: a population-based screening study with 2 years' follow-up. | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2452-6 | year = 2006 | id = PMID 17065683}}</ref> A high frequency of diabetes patients have antibodies to the GSE autoantigen, tTG<ref name=DiabetesI_tTG>{{cite journal | author = Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, and Eisenbarth GS. | title = One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. | journal = J Autoimmun. | volume = 13 | issue = 1 | pages = 143-148 | year = 1999 | id = PMID 10441179}}</ref> along with increased levels of gluten specific T-cells in T1D patients. From an evolutionary point of view it is difficult to explain the high association of T1D and DQ2.5 given negatively selective nature of the disease in NW European population given the number of studies suggesting that the "Super B8" haplotypes has been under positive selection, and appears to be the most characteristic HLA type in NW Europeans indicating an advanced natural history of the haplotype. A ''T. aesitivum'' storage globulin, Glb-1 (locus), was identified that is similar to the hypersensitizing peanut protein Ara h 1 and other known plant hypersensitizing proteins. Antibodies to this protein correlated with levels of lymphocyte infiltration into Islet regions of the pancreas.<ref name="pmid12409286">{{cite journal | author = MacFarlane AJ, Burghardt KM, Kelly J, ''et al'' | title = A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 54-63 | year = 2003 | pmid = 12409286 | doi = 10.1074/jbc.M210636200}}</ref> Gastrointestinal viruses may play a role.<ref>{{cite journal |author= |title=Viral infections as potential triggers of type 1 diabetes |journal=Diabetes Metab Res Rev |volume= |issue= |pages= |year= |id=PMID 17103489}}</ref><ref>{{cite journal |author=Mäkelä M, Oling V, Marttila J, Waris M, Knip M, Simell O, Ilonen J |title=Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes |journal=Clin Exp Immunol |volume=145 |issue=2 |pages=261-70 |year=2006 |id=PMID 16879245}}</ref><ref>{{cite journal |author=Mäkelä M, Vaarala O, Hermann R, Salminen K, Vahlberg T, Veijola R, Hyöty H, Knip M, Simell O, Ilonen J |title=Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin |journal=J Autoimmun |volume=27 |issue=1 |pages=54-61 |year=2006 |id=PMID 16757149}}</ref> <ref name="pmid7959226">{{cite journal | author = Collin P, Reunala T, Pukkala E, Laippala P, Keyriläinen O, Pasternack A | title = Coeliac disease--associated disorders and survival | journal = Gut | volume = 35 | issue = 9 | pages = 1215-8 | year = 1994 | pmid = 7959226 | doi = }}</ref> |
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'''Infertility'''. GSE can result in high risk pregnancies<ref name="pmid1125150">{{cite journal | author = Ogborn AD | title = Pregnancy in patients with coeliac disease | journal = British journal of obstetrics and gynaecology | volume = 82 | issue = 4 | pages = 293-6 | year = 1975 | pmid = 1125150 | doi = }}</ref> and infertility. Some infertile women have GSE and iron deficiency anemia <ref name="pmid8949641">{{cite journal | author = Collin P, Vilska S, Heinonen PK, Hällström O, Pikkarainen P | title = Infertility and coeliac disease | journal = Gut | volume = 39 | issue = 3 | pages = 382-4 | year = 1996 | pmid = 8949641 | doi = }}</ref> others have zinc deficiency <ref name="pmid1067747">{{cite journal | author = Jameson S | title = Zinc deficiency in malabsorption states: a cause of infertility? | journal = Acta Med. Scand. Suppl. | volume = 593 | issue = | pages = 38-49 | year = 1976 | pmid = 1067747 | doi = }}</ref> and birth defects may be attributed to folic acid deficiencies. |
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===GSEA Neuropathies=== |
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[[Neuropathies]] tend to be associated with late onset celiac disease. Dementia and ataxia appear to be more common. A recent study of children with neuropathies revealed no increase of CD in early onset neuropathies.<ref name="pmid10913732">{{cite journal | author = Lahat E, Broide E, Leshem M, Evans S, Scapa E | title = Prevalence of celiac antibodies in children with neurologic disorders | journal = Pediatr. Neurol. | volume = 22 | issue = 5 | pages = 393-6 | year = 2000 | pmid = 10913732 | doi = }}</ref>. While there are many studies linking CD to various neuropathies such as migraine, encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barre-like syndrome, antiganglioside-positive neuropathy with antibodies. Strong associations remain largely unconfirmed in epidemiologic studies.<ref name="pmid15825133">{{cite journal | author = Bushara KO | title = Neurologic presentation of celiac disease | journal = Gastroenterology | volume = 128 | issue = 4 Suppl 1 | pages = S92-7 | year = 2005 | pmid = 15825133 | doi = }}</ref> A recent study looking for changes in the physiology of the brain found regional cerebral hypoperfusion in 73% of untreated CD<ref name="pmid14984816">{{cite journal | author = Addolorato G, Di Giuda D, De Rossi G, ''et al'' | title = Regional cerebral hypoperfusion in patients with celiac disease | journal = Am. J. Med. | volume = 116 | issue = 5 | pages = 312-7 | year = 2004 | pmid = 14984816 | doi = 10.1016/j.amjmed.2003.09.037}}</ref> The calcification of channels at the surface of the brain appear to be a leading |
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phenomena associated with Migrane, Visual, Auditory, Schizophrenia, Epilepsy, Dementia. The problem is that while these are found increased in GSE the cause of these calcifications |
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is unclear and this may extend beyong GSE to other immunological or allergic phenomena. |
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'''Peripheral neuropathies'''. [[Peripheral neuropathy | Peripheral neuropathies]] are greatly increased in people who have GSE. In clinical CD there is on obvious reason, Avitaminosis and the inability to adsorb essential fatty acids and vitamins can lead to nervous system problems, including sensitivity of the peripheral nervous system. In addition to these problems there are a number or rare autoimmune conditions, secondary autoimmunities, such as fibromyalgia that are more frequent in GSE than in the normal population. <br/> |
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'''Ataxia'''. A sizable fraction of individuals who have gluten sensitive ataxia have signs of GSE (either CD or elevated intraepitheal lymphocytes) and ataxia is a common symptom in GSE.<ref name="pmid9843103">{{cite journal | author = Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, ''et al'' | title = Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia | journal = Lancet | volume = 352 | issue = 9140 | pages = 1582-5 | year = 1998 | pmid = 9843103 | doi = }}</ref> Studies of clinically undefinable ataxia generally had higher proportion of late onset gait ataxia, mild upper limb symptoms, and evidence of peripheral neuropathy, questions were raised about the specificity of testing and false positives. Patients with ataxia and CD have antibodies that react with Purkinje fibers but is restricted to the anti-gliadin IgA/IgG.<ref name="pmid11971090">{{cite journal | author = Hadjivassiliou M, Boscolo S, Davies-Jones GA, ''et al'' | title = The humoral response in the pathogenesis of gluten ataxia | journal = Neurology | volume = 58 | issue = 8 | pages = 1221-6 | year = 2002 | pmid = 11971090 | doi = }}</ref><br/> |
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'''Autism'''. Some cases of autism may be linked to crossreactive allergic response to wheat but these primarily appear to be as a result of milk. A subset of Wheat Sensitive autism and autistic spectrum disorders (ASD) appear to be linked to GSE. Some of the influences may be indirect. Pyridoxine (vitamin B6), Long-chain omega-3 fatty acids, magnesium, benefit large number of ASD cases. Vitamins A, B3, C, folic acid, calcium, zinc, cod liver oil, and digestive enzymes, also offer some benefit.<ref name="pmid12495373">{{cite journal | author = Kidd PM | title = Autism, an extreme challenge to integrative medicine. Part 2: medical management | journal = Alternative medicine review : a journal of clinical therapeutic | volume = 7 | issue = 6 | pages = 472-99 | year = 2002 | pmid = 12495373 | doi = }}</ref>. One of the core features CD, to a lessor degree GSE, is maladsorption and the benefit of nutrient replacement (Essential fatty acids, vitamins, minerals) parallels the above findings, suggesting a large link between autism and CD may be indirect result of maladsorption. However the methodological approach may show a benefit less than implied in these studies.<ref name="pmid16685183">{{cite journal | author = Christison GW, Ivany K | title = Elimination diets in autism spectrum disorders: any wheat amidst the chaff? | journal = Journal of developmental and behavioral pediatrics : JDBP | volume = 27 | issue = 2 Suppl | pages = S162-71 | year = 2006 | pmid = 16685183 | doi = }}</ref><ref name="pmid15825133"/><br/> |
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'''Dementia, epilepsy'''. Epilepsy has been noticed in a sampling of Coeliac Disease patients.<ref name="pmid678891">{{cite journal | author = Chapman RW, Laidlow JM, Colin-Jones D, Eade OE, Smith CL | title = Increased prevalence of epilepsy in coeliac disease | journal = British medical journal | volume = 2 | issue = 6132 | pages = 250-1 | year = 1978 | pmid = 678891 | doi = }}</ref> One prime example is calcium channel obstruction in the brain and [[dementia]].<ref name="pmid3414652">{{cite journal | author = Molteni N, Bardella MT, Baldassarri AR, Bianchi PA | title = Celiac disease associated with epilepsy and intracranial calcifications: report of two patients | journal = Am. J. Gastroenterol. | volume = 83 | issue = 9 | pages = 992-4 | year = 1988 | pmid = 3414652 | doi = }}</ref><ref name="pmid1590524">{{cite journal | author = Gobbi G, Ambrosetto P, Zaniboni MG, Lambertini A, Ambrosioni G, Tassinari CA | title = Celiac disease, posterior cerebral calcifications and epilepsy | journal = Brain Dev. | volume = 14 | issue = 1 | pages = 23-9 | year = 1992 | pmid = 1590524 | doi = }}</ref> There is a growing body of evidence suggesting that subclinical cases in older adults will typically progress toward dementia or epilepsy, a large number of studies in Italy and Spain have documented earlier onset cases, though the autoimmune condition is not known, folic acid maladsorption may be the cause.<br/> |
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'''Visual and Auditory disturbances'''. According to recent studies calcifications of |
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channels seen in dementia can also occur in specific brain areas such as the visual complex in the occipital lobe. Such calcium channel blockages can cause visual problems or partial feild hallucinations (Paroxysmal visual manifestations). <ref name="pmid15489401">{{cite journal | author = Pfaender M, D'Souza WJ, Trost N, Litewka L, Paine M, Cook M | title = Visual disturbances representing occipital lobe epilepsy in patients with cerebral calcifications and coeliac disease: a case series | journal = J. Neurol. Neurosurg. Psychiatr. | volume = 75 | issue = 11 | pages = 1623-5 | year = 2004 | pmid = 15489401 | doi = 10.1136/jnnp.2003.031229}}</ref>. Other papers show a link between migrane, visual aura and cerebral calcifications.<ref name="pmid16178961">{{cite journal | author = D'Amico D, Rigamonti A, Spina L, Bianchi-Marzoli S, Vecchi M, Bussone G | title = Migraine, celiac disease, and cerebral calcifications: a new case | journal = Headache | volume = 45 | issue = 9 | pages = 1263-7 | year = 2005 | pmid = 16178961 | doi = 10.1111/j.1526-4610.2005.00253_2.x}}</ref> Disturbances may be followed by |
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convulsions and associated with gastrointestinal phenomena. |
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'''Depression''', Anger. [[Depression]] in GSE has several causes, in the more severe CD depression can be the result of lower vitamin adsorption and essential fatty acid adsorption (see section on autism). Depression and Anger may also be the result of lower quality of life issues as a result of gluten-free diet.<ref name="pmid12353859">{{cite journal | author = Ciacci C, Iavarone A, Siniscalchi M, Romano R, De Rosa A | title = Psychological dimensions of celiac disease: toward an integrated approach | journal = Dig. Dis. Sci. | volume = 47 | issue = 9 | pages = 2082-7 | year = 2002 | pmid = 12353859 | doi = }}</ref> Depression appears to persist on gluten free diet in a sizable fraction of GSE. <ref name="pmid11346203">{{cite journal | author = Addolorato G, Capristo E, Ghittoni G, ''et al'' | title = Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study | journal = Scand. J. Gastroenterol. | volume = 36 | issue = 5 | pages = 502-6 | year = 2001 | pmid = 11346203 | doi = }}</ref><br/> |
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'''Anxiety'''. [[Anxiety]] is a common feature of GSE, treatment on a gluten-free diet is effective at reducing anxiety, some aspect of which may be do to maladsorption phenomena |
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and cytokine activity (i.e. constant stress). More resolution of anxiety is expected on gluten free diet.<ref name="pmid11346203"/> |
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<br/> |
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===GSEA Arthritis=== |
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Some instance of arthritis with small bowel villous atrophy have been found to resolve |
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on gluten free diet<ref name="pmid3701733">{{cite journal | author = Pinals RS | title = Arthritis associated with gluten-sensitive enteropathy | journal = J. Rheumatol. | volume = 13 | issue = 1 | pages = 201-4 | year = 1986 | pmid = 3701733 | doi = }}</ref>, and anti-connective tissue antibodies have been found in increased levels in celiac disease. <ref name="pmid939804">{{cite journal | author = Williamson N, Asquith P, Stokes L, Jowett W, Cooke WT | title = Anticonnective tissue and other antitissue 'antibodies' in the sera of patients with coeliac disease compared with the findings in a mixed hospital population | journal = J. Clin. Pathol. | volume = 29 | issue = 6 | pages = 484-94 | year = 1976 | pmid = 939804 | doi = }}</ref> In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some ''[[rheumatoid arthritis]]'' (RA) incidences.<ref name=GSE_collagen>{{cite journal | author = Dieterich W, Esslinger B, Trapp D, Hahn E, Huff T, Seilmeier W, Wieser H, and Schuppan D. | title = Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. | journal = Gut. | volume = 55 | issue = 4 | pages = 478-84 | year = 2006 | id = PMID 16188922}}</ref> Although the presence of anti-beef collagen antibodies does not necessarily lead to RA, the RA association with ''Triticeae'' consumption is secondary to GSE and involves DRB1*0401/4 linkages to DQ8<ref name=”GSE_RA”>{{cite journal | author = Molberg O, and Sollid LM. | title = A gut feeling for joint inflammation - using coeliac disease to understand rheumatoid arthritis. | journal = Trends Immunol. | volume = 27 | issue = 4 | pages = 188-194 | year = 2006 | id = PMID 16530013}}</ref> and is debatable. |
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===GSEA Myositis=== |
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'''Dermatomyositis'''. Dermatomyositis is associated with CD in children and more recently established in adults<ref name="pmid11326486">{{cite journal | author = Marie I, Lecomte F, Hachulla E, ''et al'' | title = An uncommon association: celiac disease and dermatomyositis in adults | journal = Clin. Exp. Rheumatol. | volume = 19 | issue = 2 | pages = 201-3 | year = 2001 | pmid = 11326486 | doi = }}</ref><ref name="pmid16779462">{{cite journal | author = Song MS, Farber D, Bitton A, Jass J, Singer M, Karpati G | title = Dermatomyositis associated with celiac disease: response to a gluten-free diet | journal = Can. J. Gastroenterol. | volume = 20 | issue = 6 | pages = 433-5 | year = 2006 | pmid = 16779462 | doi = }}</ref> |
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===GSEA Nephritis=== |
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Celiac disease is associated with immune complex glomerulonephritis. <ref name="pmid428155">{{cite journal | author = Katz A, Dyck RF, Bear RA | title = Celiac disease associated with immune complex glomerulonephritis | journal = Clin. Nephrol. | volume = 11 | issue = 1 | pages = 39-44 | year = 1979 | pmid = 428155 | doi = }}</ref> |
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===GSEA Lymphoma=== |
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GSE increases the risk of cancers of specific types <ref name="pmid789184">{{cite journal | author = Holmes GK, Stokes PL, Sorahan TM, Prior P, Waterhouse JA, Cooke WT | title = Coeliac disease, gluten-free diet, and malignancy | journal = Gut | volume = 17 | issue = 8 | pages = 612-9 | year = 1976 | pmid = 789184 | doi = }}</ref> Among these certain lymphomas (Enteropathy-Associated T-cell Lymphoma) and cancers of the intestinal tract are of greatest risk, approximately 5 fold higher than normal. The majority of EATL cases are reported within 2 years of diagnosis and GF treatment. |
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Activity is focused on alpha, beta and gamma glaidins, cellular immunity and eosinophilic |
Activity is focused on alpha, beta and gamma glaidins, cellular immunity and eosinophilic |
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damage, tTG autoimmunity. Primary remediation limited to Triticeae glutens exclusion with few exceptions. |
damage, tTG autoimmunity. Primary remediation limited to Triticeae glutens exclusion with few exceptions. |
Revision as of 16:28, 12 July 2007
Gluten sensitivity (GS) describes the collection of medical conditions in which the patient responds favorably, either directly or indirectly, to the removal of gluten from the diet. Direct improvement can be seen for patients with gluten-sensitive eosinophilic gastroenteritis or irritable bowel disease, and can be observed clinically by the restoration of villous architecture. Indirect improvements may be seen in the neurological state, treatability of certain autoimmune conditions, or an untreated improvement in autoimmune conditions.
In the literature, "gluten sensitivity" may refer either to gluten-senstive enteropathy GSE (old and current usage) or idiopathic gluten sensitivity (IGS)(current usage), as a sensitivity without an established cause. When GSE is separted from other GS, it is in general reference to IGS and appears, diagnostically, secondarily to other conditions, such as neuropathies, myopathies. In addition, allergies to gluten or other food proteins may exacerbate other diseases such as autoimmune arthritis, the allergies may not be apparent as the exascerbations it results in, creating another class of sensitivities. Gluten-sensitivity is not a recognized disease.
Gluten sensitivity can be divided into three catagories.
- Gluten-sensitive enteropathy - (GSE) For disease diagnosis and treatment see Coeliac disease, for secondary associations see Gluten-sensitive enteropathy
- Gluten-allergy related conditions - Gluten-allergy related sensitivities
- Idiopathic gluten sensitivity - (IGS) refers to gluten reactive phenomena that do not fall into GSE or Gluten allergy. Phenomena are described under Idiopathic gluten sensitivity
This page is divided up along these lines, so that similar conditions associated with each cause (or lack thereof) can be compared.
Prevelance of Gluten sensitivity. In the US approximately 1 in 133 individuals has CD, most are not aware and in many of these they disease is superficially assymptomatic. It has been estimated that between 1 in 80 to 1 in 100 fit the broader criteria of GSE. Less than 10% of these will know of GSE within their lifetime. Gluten allergies and related conditions have been surveyed sporadically, the method of testing is not thorough because recent studies suggest that only fractionated wheat proteins provide an accurate assessment of gluten reactivity, but these studies indicate that greater than 3% of people have some level of reaction to wheat. The idiopathic gluten sensitivity is a new phenomena, by testing randomly for AGA anywhere between 3 and 15% of people tested for CD have no abnormal intestinal pathology but are AGA positive. The idiopathic condition is mainly derived from the study of other diseases, such as neuropathies, myopathies, connective tissue disorders and therefore is much less than 1% in prevelance. In total gluten sensitivity of all kinds is probably in the range of 5%, but apparent symptom associated sensitivity is well below 1% in prevelance.
Fads. Gluten-free dieting needs to be separated from gluten-sensitivity. The gluten free diet has become increasingly popular, and wheat-free aspects have become popular parts of other diets, such as the A-B-O diet. Excepting gluten allergies, most people who require a gluten-free diet are genetically predisposed by the HLA-DQ genetics, and this has nothing to do with the A-B-O genetics. Since wheat is a major source of fast carbs in western societies many improvements may be seen, but with regard to gluten sensitivity it is generally two types of proteins, prolamins and glutelins of the Triticeae glutens that are pathogenic, with a particular deferance to wheat, which has high levels of glutens derived from three ancestral species of wheat or goat grasses.
Triticeae and the potential role of selective evolution in gluten sensitivities. Some of the recently discovered biochemical and immunochemical properties of these proteins suggest they evolved for protection against dedicated or continuous consumption by mammalian seed eaters. One recent publication even begs the question 'is wheat safe for anyone to eat?'. Of key importance to gluten sensitivity is whether overconsumption of wheat results in the increased ability for 'toxic' elements within wheat to penetrate the upper GI tract resulting in disease. Additional factors, such as exercise, medications or food additives, may exacerbate this process.
Silent Disease. Using Anti-gluten antibodies (AGA), analysis of fate of GS reveals that it is positively associated with an increase and decrease of certain diseases. The association persists more than one year after diagnosis for GSE patients, however breast cancer is significantly reduced with gluten sensitivity.[1]
Gluten-sensitive enteropathy
Gluten sensitive enteropathy (GSE) is a condition in which gluten elicits T lymphocyte recognition of gluten, gluten bound to mammalian tissue transglutaminase (tTG), resulting in the production of antibodies to tTG. Since tTG is a 'self' protein GSE is an autoimmune disease. The disease begins with the increase in lymphocyte number within the epithelia of the small intestine and with an increase of (anti-tTG)-tTG complexes seen as deposits. This usually progresses to Coeliac disease (CD). While CD does not cover all GSE related phenomena the Wikipedia page on Coeliac disease is a thorough source of information on the topic.
Marsh grades for Coeliac disease
- Normal Intestinal Morphology
- grade 0
- Subclinical CD
- grades 1 and 2
- CD (by standard duodenal biopsy)
- grades 3 and 4
Involvement of Triticeae proteins
Triticeae glutens are the principle cause of GSE. Cultivars of Triticeae can induced GSE in susceptible individuals. The incidence rate is about 1:100 lifelong risk in most western populations and is one of the most common autoimmune diseases. While considered by some to be an allergic disease, the effects of wheat gliadin (α/β and γ), barley hordein and rye secalin (In some individuals glutenin or glutenin like proteins can play a role) act more as a poison which cause a destructive innate immunity[2] and cellular immunity that flattens the epithelium of affected individuals and causes acute malabsorption. Gluten peptides, particularly when deamidated or transamidated, change protein behavior, the primary target for GSE is tissue transglutaminase (tTG), a protein involved in deamidation and transamidation of the glutamine amide motif.
Genetics of GSE
GSE is mediated by proteins known as MHC antigens or cell surface receptors. In humans, they are called HLA. GSE is mediated by a receptor known as HLA-DQ. HLA-DQ is a variable protein composed of 2 different subunits, DQα and DQβ and these combine to form a heterodimer, DQ. DQα is encoded by the HLA-DQA1 locus. DQβ is encoded by HLA-DQB1 locus. Each person inherits a haplotype, contaning one DQA1 gene and one DQB1 gene, from each parent. Therefore each person can have 2 DQA1 and 2 DQB1 genes (2 alleles for each locus). As a result a person can have 1, 2 or 4 DQαβ isoform(s) depending on if they are a two-locus homozygote, single locus homozygote, or two-locus heterozygote. On the face of DQ furthest from the cell surface DQα and β form a binding cleft as they 'fit' together. This binding cleft binds peptides from gluten if the gluten peptides fits into the isoform.
HLA DQ2.5(HLA DQA1*0501:B1*0201) or HLA DQ8(HLA DQA1*0301:B1*0302) are found in 99% of all GSE. DQ2.5 is found in GSE at high frequency in Western and Central Eurasia, Equitorial & Western Africa, Australia and North America and accounts for the overwhelming majority of GSE incidences detected. An illustration of DQ2.5 haplotype's isoform DQα5β2 is shown. DQ8 is globally distributed but is at very high frequency in indigenous northern South, Central Americans as well as the most native tribes within the US and SE Canada. In the old world it concentrates in Sweden, Finland, Northern Russia, Japan, Korea and Bedoin and is less often associated with GSE.
GSE is very uncommon in countries where Triticeae is not a primary cultivar, even in susceptible populations, but is on the rise in countries with susceptible populations and growing wheat consumption, such as Japan and Latin America. Aside from Triticeae and DQ2.5 (and/or DQ8), other genetic risk factors are not clear, one CTLA4 gene product shows linkage to celiac disease but 33% more frequent in GSE than in non-GSE. In a genome wide survey a new locus on chromosome 4 has been discovered, although, like CTLA4 linkage to disease is weak. Other risk factors such as chronic infection of GI tract by enterovirus, rotavirus may play a role, but GSE is known to have much higher risk in families than in the general DQ2.5 or DQ8 bearing population indicating complex genetic factors are involved.
Conditions Secondary to GSE
GSE has a wide variety of associated symptoms, however the key symptoms are typically restricted to the bowel and associated tissues. These include irritable bowel disease, eosinophilic gastroenteritis, villous atrophy(CD), crypt hyperplasia(CD), all of the common symptoms are discussed on the Coeliac Disease. The focus of this section is on specific autoimmunities[4] or allergic-like responses (IgE or IgA, IgG) markedly increased in GSE. Similar ambiguities with other conditions has resulted because the clinical manifestations of celiac incidences that fall below clinical detection can still promote secondary allergic responses and secondary autoimmune diseases. The frequency in western societies is typically around 1/2 to 1%, but the detection rate are typically 10-fold lower, however the association with other, secondary, diseases remains largely idiopathic, sporadic and with such low counts unable to provide credible statistics. Below is an overview of gluten-sensitive enteropathy associated (GSEA) disorders. Almost every autoimmune disease can be secondary to GSE, few will show significant statistical association, only when considered together do autoimmune diseases show a strong association with GSE.
Key features of GSE
Activity is focused on alpha, beta and gamma glaidins, cellular immunity and eosinophilic damage, tTG autoimmunity. Primary remediation limited to Triticeae glutens exclusion with few exceptions. Secondary conditions associated with GSE can be classified
- Systemic malnutrition phenomena - avitaminosis, inadequate EFA's can result neuropathies, anemias, cancer risk increases, ataxia, migraine, etc.
- Allergic reactions - The phenomena of cytokine involvment, tTG and gliadin as a promotor can cause increased numbers of food allergies. Damage to the gut may facilitate gliadin entry into the GI tract causing gluten-allergies secondary to the disease, like Urticaria and exercise induced anaphylaxis.
- Extended Allergies - Allergic reactions may extend beyond IgE into IgA and IgG, as is seen] with alpha gliadin, but may occur for major antigens.
- Autoimmune disease - Identifying triggers is very difficult, but tTG and gliadin provide a mechanism for presentation to the immune system self and food antigens, which gliadin can make autoimmunogenic.
- Gliadin migration - Damage to the gut identified with exercise induced anaphylaxis and aspirin, along with the innate peptide capabilities suggests that gliadin can enter the blood, but its exact effects are not clear once it is in the blood.
- unknown causes - GSE mediated calcification of central nervous system. Visual Aura, Hallucination, Schizophrenia, Epilepsy, Dementia, and many others. Some speculate these are due to folic acid deficiency resulting from avitaminosis.
Idiopathic gluten sensitivity (IGS)
Idiopathic gluten sensitivities are not as well defined as GSEA and gluten-allergy associated sensitivities. The debate over this subset stems from the fact that identification of all grades of GSE and allergies is not uniformly approached. Most cases of early GSE go undetected, particularly before 2005. There appears to be a small fraction of non-GSE gluten-sensitive indivdiuals that show neither gluten-allergies but do have elevated anti-gliadin IgA or IgG. Common symptoms are peripheral neuropathies and cerebral ataxia. Within the GSEA set these may be explained by calcification of brain channels and avitaminosis. Within the 'true' IGS close examination has not been done. It is unclear how much of the phenomena can be explained by allergies, by contribution of innate immunity, or some altered T-cell mediated immunity.
At present about the only thing that can be defined is an improvement in patient condition on GFD. Some of the categories listed below may be moved to GSE or Gluten allergy with more research or in the case of Crohn's Disease, should be removed as being gluten sensitive.
IGS Neuropathies
Also called gluten-sensitive idiopathic-neuropathies. Diagnosis of IGS neuropathies is on the rise. These diseases were first identified by anti-gliadin IgG (AGA) screening of patients with neuropathies[5]. The method was critiqued because of the large misdiagnosis rate of Coeliac Disease, and becaue AGA exist in the normal population at >12%, far more abundant than cases of neuropathy.[6] Approximately <65% of AGA positive did not have celiac disease and assuming 15% were the result of 'chance' sampling in the normal population it would appear that <50% were idiopathic with regard to anti-gluten antibodies.[7] Some of these cases are the result of underdiagnosis of coeliac disease or inability to diagnose Marsh grade 1 and 2 Coeliac disease (GSE). An additional critique pointed out that several cases of latent GSE, where associated with neuropathies that appeared as a result of avitaminosis, and were unlikely due to AGA.[8], but are secondary consequences of GSE. Therefore ~15% of GSE who were neuropathic could be missed due to AGA-/GSE+ exceptions. The same team that introduced these AGA phenomena has also found patients with Neuropathy that are AGA negative but still had Celiac Disease. Therefore AGA+ may not be directly involved.
Is DQ1 associated with IGS Neuropathy?
Several independent testing groups report a significance of finding DQ1 with patients attempting to diagnose gluten_sensitivity. In the US caucasian population DQ1 (DQ5 and DQ6) is quite common. A survey of 1899 European americans revealed 30 DR-DQ1 genetic haplotypes, with a combined allele frequency of 40.07%. Hardy-Weinberg equilibrium suggest the random phenotype frequency is 64.1%; however since a heterozygous selection coefficient acts on HLA-DQ the phenotype frequency is between 64.1 and 80%. The level of observation of DQ1 would need to be quite high to obtain a significance for frequency greater than 64%. No such report for DQ1 has been made with IGS.
In 2002, a team of British neurologists sorted the IGS Neuropathy (131 individuals) with 41% (58 inds) that were AGA reactive.[9] Although N was not given on DQ studies one assumes that the DQ serotyping was on the set or subset of this 58 individuals or less. Of these 70% (41) were DQ2, of the remaining, 9%(5 of 58) were DQ8+, and the remaining (12) were DQ1. Although the authors made no remarkable claim about DQ1 the claim has propogated among off-clinical testing groups. This study has been the primary support for the DQ1 association. DQ1 typing is notoriously inaccurate, and undertyping and mistyping are common.e.g. DQA1*0502 The presentation was not statistically analyzed for significance and was reported in an editorial. A number of DQ2 or DQ8 patients are either CD, undetected CD, or GSE (testing for the full scale of GSE in 2002 was not technically possible); however the observed normal frequency of DQ2 in Kent was 35%. Therefore we can assume many, but not all DQ2 where GSE. The number of DQ8 was unremarkable relative to the normal DQ8 frequency, the number of DQ2 homozygotes was not disclosed nor the second serotype (every person person has two serotypes although some have one apparent as they are homozygotes) for DQ2, DQ8 or DQ1. The normal frequency for DQ1 in Britian is 36.9%. Assuming that All DQ2 and DQ8 were GSE associated the random probability of a DQ1 is 0.008 (Fisher exact Test 61,40,12,0) indicating a significance of positive association. However, the authors made no attempt to remove GSEA patients from the group. Given an observed frequency of 70% DQ2, based on the random frequency of DQ2 of 35% the expected numbers of GSEA-DQ2 and -DQ8 are at maximum likelihood of 60%(~35), and the remainder are IGS(23). The Fisher exact probability of 0.5 is obtained with DQ1 lower than expected however this analysis is burdened by not knowing the second serotypes of patients. Tentatively, therefore when one eliminates only DQ2 and DQ8 that are likely part of GSE, and then considers DQ1 the association of DQ1 completely disappears. However, a likely 35% of these non-GSE, AGA+ neuropathies and probably result from other immunological conditions, possibly allergies to gluten or extension of an allergic response to include IgA and IgG.[10] But, the typical markers for ataxia such as anti-Purkinje cell or anti-neuronal nuclear antibodies appear not to be the targets of these gluten sensitive responses.[7]
Recently, Synapsin I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia.[11] Fifteen percent of people with elevated antigliadin antibodies do not have CD, and also may not have enteropathy. In cases where enteropathy is subclinical or underdiagnosed, avitaminosis may play a role. Paralleling the neuropathological gliadin issue, it has been recently shown that removing wheat as well as other allergens identified by RAST testing in autoimmune arthritis patients results in the reduction of certain indicators or disease. With wheat, unidentified allergenic motifs can potentially elicit crossreactive autoantibodies. Another possibility that has precedence in EIA is the possible action of glutens directly on nerves or a combination of IgE or IgA and gluten on these neuronal tissues. There are instances of large scale neurological sensitivies to wheat products, such as in North Dakota, and suggest some neuropathies may be due to contamination of wheat with other chemicals or antigens, such as mites.[12]
IGS Cerebral Ataxia. First suggested as a rare but possible cause in small children[13], gluten has been implicated as being a cause in a large percent of idiopathic ataxia.[14]. Recently, Synapsin I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia.[11] Some cerebral ataxia that are gluten sensitive are due to GSE, in one study of the 12 individuals the demostrated gluten sensitivity 7 had some indication of GSE.[15]. There appear to be some differences since idiopathic gluten sensitivity appears to have anti-purkinje antibodies that are not adsorbed by gliadin, as with GSE. [16].
The British team that looked at DQ and IGS neuropathies also looked at DQ and idiopathic Ataxia with somewhat more clarity in their data.[17] Like the previous study allele and phenotype frequencies were not fully disclosed, but an effort was made to identify GSE+ individuals by duodenal biopsy and IEL determinations (although immunohistochemistry with anti-tTG was not done) most GSE (17 of N = 68) should have been identified. Within the same 68 DQ2 had a phenotype was present in 49, DQ8 in 4 and DQ1 in the remainder. Approximately 15 DQ2 and 2 DQ8 could be likely eliminated as GSEA Ataxia, leaving 34 DQ2, 2 DQ8 and 15 DQ1 (Homozygotes and 2nd serotypes not reported). By fisher exact test there appears to be a significant association of DQ2 with IGS Ataxia (p ~ 10E-5). However, there is population data for Britian[18] with a given allele frequency for DQ2 of 26.2% (N=101) and using Hardy-weinberg assement arrived at 46:55 phenotype frequency for DQ2:DQX in Britian suggesting a probability of random DQ2 (N = 34 or more) at 0.012. This indicates by both the authors controls and the general controls that if GSE was carefully assessed in gluten-sensitive ataxia then DQ2 is positively associated with IGS Ataxia.
Cerebral Palsy. A recent study of children with severe cerebral palsy suggest a high percentage have anti-gliadin antibodies[19]
IGS Myopathies (neurological). A recent study of patients with neurological myopathies demostrated large percent were 'gluten sensitive' and many responded favorably with no other treatment. [20]
Schizophrenia, Psychosis. Reductions and remissions of schizophrenic symptoms on gluten free diet have been noted in a subset of schizophrenic patients.[21][22][23]. Many of these definitions were done when the ability to define Marsh 1 and 2 grades CD was poor, and given the "brain calcification" association with GSE, it is likely that some cases of schizophrenia can be explained by GSE. The associations that remain, in terms of treatment results, appear to be weak.
IGS Peripheral Neuropathies. Some of the peripheral neuropathies that are gluten sensitive are due to GSE, in one study of the 12 individuals the demostrated gluten sensitivity 7 had some indication of GSE.[15]. Peripheral neuropathy is reported as a common element in idiopathic neuropathy with AGA, and critics of that claims suggest peripheral neuropathies are common to many neuropathies not specifically gluten-sensitive neuropathies. Peripheral neuropathies are associated with GSE, but no attempt to separate GSEA Peripheral neuropathies from IGS peripheral neuropathies has been done.
IGS Dermatological conditions
Oral Ulcerations. Antiboides to α-gliadin have been significantly increased non-CD individuals with oral ulceration.[24] Anit-α-gliadin antibodies have been found in patients with celiac disease, but are also found in a subset who do not have the disease. The reference comes from a period when testing for subclinical CD was undeveloped.
Ocular exfoliations. Of people with psuedo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA.[25]
Crohn's Disease
Treatment to produce remission of symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy.[26]. A later paper showed little IgE mediated response to the except to dairy [27], and still another paper showed no significant anti-food IgE association[28].
IGS's Key features
Partially excluded from GSE and Gluten-allergy but lacks definition. Conditions associated with IGS are not well defined. Wheat exclusion appears to be primary treatment, and broad taxonomical responses in Patients may vary.
- Some conditions are the result of GSE and must be separated from IGS.
- Allergic reactions - See Gluten-Allergy related disorders.
- Gliadin migration - Damage to the gut identified with exercise induced anaphylaxis and aspirin, along with the innate peptide capabilities suggests that gliadin can enter the blood, but its exact effects are not clear once it is in the blood.
- Sensitizing chemicals - Chemicals, contaminants (such as dust mite particles, lectins, or other elements may cause problem in wheat sensitive people)
- Placebo effects - patient behavior.
- Confused conclusions - both in clinical testing and in interpretation. DQ1 appears to have no association with IGS Neuropathies, but DQ2 appears to be. Is DQ2 active in completely latent forms of GSE?
Why treat gluten allergies as sensitivities?. Over the last 10 years is has become apparent that allergies to certain substances do not behave in predictable ways. Once clear example of this is exercise induced anaphylaxis and asthma, WDEIA is now believed to be induced by injested gluten that finds a way into the blood stream. This pathway is now believed responsible for some forms of eczema. Allergy tests may not reveal allergies to gluten because the unfractionated allergens are 'hidden' from these tests, and most currently available tests cannot detect these new allergens. Finally, allergies typically involve IgE, but some studies indicate there are several classes of responses, for example IgG1,IgG2, IgG4 that are associated with these.[29] Gluten allergy may be a cause of some idiopathic gluten sensitivity.
At present many of the allergens of wheat have not been characterized, the most common fall into the albumin and gliadin class[30].
Allergies typically result from antigen contact with the dermis and associated mucousal tissue. A probable cause of this extension of the allergic response is the infiltration of gluten proteins beyond the lumen of the small intestines. Drugs such as aspirin and NSAIDs may play a role. Also exercise and granular foods such as peanuts may play a role in forcing these proteins into the system. Wheat is a common cause of asthma and eczema particularly in food production, these allergies may extend across wide taxa and are not limited to Triticeae glutens. While other antigens appear to produce similar responses away from the site of initial contact with the dermis, certain qualities of wheat stand out a potential cryptic sensitizing agents, such as the innate peptide in the C-terminal region of alpha gliadin.
Glaidin shows some unusual ability to regulate Natural killer cell/immature dendritic cell cross talk and prevents the killing of dendritic cells that recognize gliadin enabling increases in IgE to gliadin and potentially other antigens.[31]. This activity of gliadin may help to explain the increased number of food allergies in celiac disease, but fails to explain the persistent of food reactions on a gluten-free diet.
Malt allergies. There are exceptions, for example there are cases of barley-malt allergies.[32]
Mite allergy. A second potential source of wheat sensitive allergies responses may not be caused by gluten or any wheat protein, but the mites and mite bits that contaminate Triticeae seeds derivatives.[33]
Cryptic allergies. Recents studies show that detection of wheat allergens using whole wheat sources may not be adequat relative to using purified wheat proteins which are not commonly tested for.[34][35] The studies recommends that people with suspected Triticeae allergies be tested with isolated/purified extracts instead of whole extracts. This may, also need to be extended to hydrolysates of those extracts.
Grass allergies. 3 decades ago the major allergenic components of wheat allergies were examined in bakers. 40 allergens were detected, some cross-reacted with rye proteins and a few cross-reacted with grass pollens.[36] A later study showed that baker's allergy extend over a broad range of cereal grasses (wheat, durum wheat, triticale, cereal rye, barley, rye grass, oats, canary grass, rice, maize, sorghum and Johnson grass) though the greatest similarities were seen between wheat and rye [37] and that these allergies show cross reactivity between seed proteins and pollen proteins[38] including a prominent crossreactivity between the common environment rye pollen and wheat gluten[39][40]
Wheat contains many types of protein, the primary consideration of gluten sensitivity are two protein classes, prolamins and the closely related glutelins. With allergy related disease, reactivities are not restricted to these two classes, but extend to the albumins and globulins, enzymatic proteins that serve the plant as it sprouts and grows, but may also be found in the leaves and pollen. One study has shown that there is a strong IgE reactivity toward the albumin fraction of wheat [41] and less reaction to the glubulin fraction. Another study showed reaction to (α-amylase/trypsin)-inhibitor family of proteins[42] proteins and these inhibitors are also antigenic across broad grass taxa.[43]. Uncharacterized proteins of 26, 35 and 40 kDa size have also been found, some show crossreactivity between species. Thioredoxins and some other proteins found in wheat show a broad range of crossreactivity, a recent study even found crossreactivity between proteins in wheat and corn.[44][45]
Hydrolyzed Wheat Protein (Cosmetics) Allergy. Hydrolyzed Wheat protein is used as an additive in foods and cosmetics. The proteins are often 1 kD in size and may have improved allergenicity relative to wheat. [46] These wheat polypeptides can cause immediate contact urticaria in susceptible people.[47]
Asthma, Anaphylaxis, Nasal Allergies
Exercise-induced anaphylaxis. Wheat gliadins and potentially oat avenins are associated with another disease, known as Wheat Dependent Exercise Induced Anaphylaxis (WDEIA) which is similar to Baker's Allergy as both are mediated by IgE responses.[48] In WDEIA however the ω-gliadins[49] or a high molecular weight glutenin subunit, and similar proteins in other Triticeae genera enter the blood stream during exercise where they cause acute asthmatic or allergic reaction).[50] One recent study of ω-gliadins demonstrated these gliadins are more similar to the bulk of oat avenins than α/β or γ gliadins but, so far, oat avenins have not been linked to WDEIA. The occurrence of both WDEIA and Baker's allergy are increased in GSE. Another recent study shows the WDEIA may be specifically wheat induced. The IgE patients WDEIA and chronic urticaria detected ω5-gliadins expressed by most of the Gli-B1 alleles but almost no responses prolamins extracted from rye or wheat/rye translocates indicating that nascent mutations on the B genome of wheat is the source of WDEIA.[51]. This genome is believed to be derived from an ancient species of Aegilopoides speltoides (see Triticeae) which fused with wild Emmer wheat(AA) to form Poulard wheat (AABB) which is the natural parent species of almost all modern wheats.
A recent study of WDEIA shows that aspirin and exercise both increase the presense of gliadin in the blood stream[52] and may phenomena may extend to NSAIDs, MSG, Benzoate and other synthetic chemical food additives.
Baker's Allergy. Baker's allergy which has a omega-gliadin component also has a thioredoxin hB component.[45]
Food induced Asthma. Wheat is a common cause.[53]
Urticaria, Atopy, Eczema
Contact Sensitivity[54], Atopic Dermatitis[55], Eczema, and Urticaria appear to be related phenomena the cause is generally the believed to be the hydrophobic prolamin components of certain Triticeae, Aveneae cultivars, in wheat one of these proteins is ω-gliadin (Gli-B1 gene product). A study of mothers and infants on an allergen-free diet demonstrated that these conditions can be avoided if wheat sensitive cohort in the population avoid wheat in the first year of life[56]. As with exercise induced anaphylaxis aspirin (also: tartrazine, sodium benzoate, sodium glutamate (MSG), sodium metabisulfite, tyramine) may be sensitizing factors for reactivity.[57] From the Wheat Dependent Exercise Anaphylaxis studies it appears that aspirin and probably NSAIDs allow the entry of wheat proteins into the blood, where IgE reacts within allergens in the dermal tissues.
Autoimmune (Rheumatoid) arthritis
There appears to be an association of rheumatoid arthritis(ARA) both with GSE and gluten allergies[58]. ARA in GSE/CD may be secondary to tTG autoimmunity. In a recent study in Turkey, 8 of 20 ARA patients had wheat reactivities on the RAST tests. When this allergic food and all other patient specific RAST+ foods were removed half of the patients had improved ARA by serological markers. In patients with wheat allergies, rye was effectively substituted.[59] This may indicate that some proportion of RA in GSE/CD is due to downstream effects of allergic responses. In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.[60]
Neuropathies
Migraines. In the late 70s it was reported that people with migraines had reactions to food allergens, like ARA, the most common reaction was to wheat (78%), Orange, eggs, tea, coffee, chocolate, milk, beef, corn, cane sugar, and yeast. When 10 foods causing the most reactions were removed migranes fell precipitously, hypertension declined.[61] Some specific instances are attributed to wheat.[62]
Infantile Autism. Worsening of neurological symptoms in autistic patients with milk and wheat consumption has been reported.[63] However, a swedish study reported a negative impact of a gluten free diet. [64]
Acute psychosis. Wheat and rye allergy (IgE) antibodies have also been found in acute psychosis patients.[65]
Key features
- IgE responses will prevail in the pathology.
- Omega-gliadin and glutenin appear to be primarily involved prolamins/glutelins
- Evidence for gliadin entry into blood and peripheral reaction
- Other allergens in wheat, globulins and albumins can be involved.
- Allergens may cross react over broad taxa. (Wheat, Oats, Corn, etc)
- Cytokine activity may effect other autoimmune disorders.
Immunochemistry of glutens
The immunochemistry of Triticeae glutens is important in several autoimmune diseases. It can be subdivided into innate responses (direct stimulation of immune system), Class II mediated presentation (HLA DQ), Class I meditiated stimulation of killer cells, and Antibody recognition. The DQ restricted class II mediated presentation of gliadin to T-helper lymphocytes appears to be the primary process involved in Coeliac Disease. Numbers in parenthese (###-###) refer to amino acid sequences in the proteins that are immunogenic by the stated categories (Innate, Antibody epitopes, HLA Class II epitopes, HLA Class I epitopes.
Innate immunity
HLA class I restrictions
Restrictions of CD8+ T-lymphocytes (Apoptosis mediators)
- A2 (A*0201 in DQ8+)[67]
- α-/β-gliadins (carboxyl end)
- A-gliadin (123-131), (144-152), (172-180)
- α-/β-gliadins (carboxyl end)
HLA class II restrictions
Restrictions of CD4+ T-lymphocytes (anti-gluten response mediators)
DQ2
DQ2 (α5) - DQα5β2 isoforms
- DQ2.5 - DQ(A1*0501:B1*0201)
- DQα5β201 isoform
- DQ2.2/DQ7.55 - DQ(A1*0201:B1*0202 / A1*0505:B1*0301)
- DQα5β202 isoform
Gliadins
- α-/β-gliadins (amino, central and carboxyl ends)
- -α-2 secalin (8-19), (13-23)[68]
- γ-gliadins
- γ-5 gliadin (60-79), (66-78), (102-113), (115-123), (228-236)[71]
- γ-M369999 gliadin (16-24), (65-76), (70-79), (79-90), (94-102), (115-126), (128-136), (233-241)[71]
- γ-_ gliadin ' 'γ-30' ' motif[70] see details
- -γ- secalin (80-93), (117-125)[68]
- --- hordein (56-69)[68]
- ω-gliadins
- ω-ABI20696 gliadin (T. timopheevii) (96-106)
- ω-5-gliadin
- LMW glutenin
- K1-like (46-60)
- pGH3-like (41-59), GF1(33-51)
- HMW glutenin -[72] (not yet characterized to the epitope level)
DQ8
DQ8 (DQA1*0301:DQB1*0302)
- α-/β-gliadins (carboxyl end)
- α-AJ133612 gliadin (~230-240), (>241-<255)
- γ-gliadins
- γ-M369999 gliadin (~16-24), (>41-<60), (~79-90), (~94-102), (>101-<120)
- HMW glutenin[72](higher then DQ2.5) - (not yet characterized to the epitope level),
Other DQ
Gluten sensitive enteropathy and idiopathic gluten sensitivity has been associated with other DQ isoforms by certain diagnostic laboratories and research groups. DQ2.5 and DQ8 cover the 99+% of all GSE instances within the western eurasian derived population (Europe, Central Asia, North America). There is the small potential that other haplotypes can mediate
this disease in Africa or Asia.
Gluten sensitive neuropathy has been loosely associated with DQ1, others have associated
gluten sensitivities with DQ3. DQ1, DQ2, DQ3 cover all DQ types in the modern population except the rather rare DQ4 haplotypes. Such broad associations lack statistical significance.
Antibody recognition
- IgA/IgG
- A-2 gliadin Â(57-73)-[73]
- glb-1 (a globulin)- implicated in crossreactive autoantigenic antibodies that destroy islet cells in the pancrease of Type 1 diabetes.[74]
- Synapsin I (mammalian, autoantigenic, gliadin crossreactive) [11]
- Tissue Transglutaminase (tTG) - Covelant linkage of tTG to glaidin facilitates the gliadin restricted T-cell activation of tTG reactive B-cells, causing primary autoimmunity in celiac disease.
- IgE (true allergic responses)
- ω-gliadin - antigen responsible for gluten sensitive exercise induced anaphylaxis and Baker's allergy
- HMW Glutenin subunit - antigen responsible for gluten sensitive exercise induced anaphylaxis
- alpha-amylase/trypsin inhibitor subunits - [75][76]
- LTP (albumin/globulin) - [75]
- thioredoxin-hB (wheat allergen #25)[45]- antigen involved in Baker's Allergy, cross reactive with homologous corn thioredoxin.
- Wheat flour peroxidase[77]
- "Q-Q-Q-P-P" motif in undefined gliain[78]
Taming Triticeae Immunochemistry
New immunogenic motifs appear in the literature almost monthly and new gliadin and Triticeae protein sequences appear that contain these motifs. The HLA DQ2.5 restricted peptide "I I Q P Q Q P A Q" produced approximately 50 hits of identical sequences in NCBI-Blast search is one of a several dozen known motifs[68] whereas only a small fraction of Triticeae gluten variants have been examined. For this reason the immunochemisty is best discussed at the level of Triticeae, because it is clear that the special immunological properties of the proteins appear to have basal affinities to this taxa, appearing concentrated in wheat as a result of its three various genomes. Some current studies claim that removing the toxicity of gliadins from wheat as plausbile,[79] but, as the above illustrates, the problem is monumental. There are many gluten proteins, 3 genomes with many genes each for alpha, gamma, and omega gliadins. For each motif many genome-loci are present, and there are many motifs, some still not known. Different strains of triticeae exist for different industrial applications; durum for pasta and food pastes, 2 types of barley for beer, bread wheats used in different areas with different growing conditions. Replacing these motifs is not a plausible task since a contamination of 0.02% wheat in a GF diet is considered to be pathogenic and would require replacing motifs in all known regional varieties, potentially 1000s of genetic modifications.[79] Class I and Antibody responses are downstream of Class II recognition and are of little remedial value in change. The innate response peptide could be a silver bullet, assuming there is only one of these per protein and only a few genome loci with the protein. The bigger question is why late onset gluten sensitivity rapidly rising, is this truly a wheat problem or is it something that being done to wheat, or to those who are eating wheat (for example communicable diseases as trigger)? Some individuals are susceptible by genetics (early onset), but many late onset cases could have variable triggers because there is nothing genetically that separates the 30 to 40% of caucasians that could have Triticeae senstivity from the ~1% that, in their lifetime, will have some level of this disease. Another strategy in making wheat less immunogenic is to insert proteolytic sites in the longer motifs (25-mer and 33-mer) facilitating more complete digestion.
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