Conditions secondary to gluten-sensitive enteropathy

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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[1] 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.

GSEA dermatitis

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

Urticaria. Chronic urticaria has been seen in a few cases of CD.[2] and are likely the result of fortuitous allergies to wheat, or allergies secondary to GSE.

Prurigo nodularis. Prurigo nodularis has been identified with celiac diease. [3][4]

GSEA Gastrointestinal Diseases

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[5], 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.

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.[6]. 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.

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.

Diseases of the Pancreas, Gall bladder, Bile Duct. CD is prevelant in primary biliary cirrhosis[7][8] and was also found at higher than expected frequencies in autoimmune cholangitis and primary sclerosing cholangitis.[8]. CD is frequently linked to pancreatitis but also to papillary stenosis[9] and, in India, tropical calcific pancreatitis appears also to be associated with CD.[10]

GSEA Endocrine Disorders

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.

Grave's Disease, Hashimoto's thyroiditis. Grave's disease and Hashimoto's thryroiditis are greatly increased in patients with CD. [11]

hypocalcinemia. [12]

Diabetes, Type 1 (Juvenile onset). The incidence of Juvenile 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 pancrease. The level of adult onset T1D plus ambiguous T1D/T2D is unknown. It is unclear the 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[13] and it now appears that GSE precedes T1D in many cases[14] and an active search for celiac disease in early juvenile diabetes patients revealed that GF diet resulted in some improvements.[15] A high frequency of diabetes patients have antibodies to the GSE autoantigen, tTG[16] 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 pancrease.[17] Gastrointestinal viruses may play a role.[18][19][20] [21]

Infertility. GSE can result in high risk pregnancies[22] and infertility. Some infertile women have GSE and iron deficiency anemia [23] others have zinc defiency [24] aqnd biurth defects may be attributed to folic acid deficiencies.

GSEA Neuropathies

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.[25]. 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.[26] A recent study looking for changes in the physiology of the brain found regional cerebral hypoperfusion in 73% of untreated CD[27] The calcification of channels at the surface of the brain appear to be a leading 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 is unclear and this may extend beyong GSE to other immunological or allergic phenomena.

Peripheral neuropathies. 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.

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.[28] 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.[29]

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.[30]. 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.[31][26]

Dementia, epilepsy. Epilepsy has been noticed in a sampling of Coeliac Disease patients.[32] One prime example is calcium channel obstruction in the brain and dementia.[33][34] 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.

Visual and Auditory disturbances. According to recent studies calcifications of 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). [35]. Other papers show a link between migrane, visual aura and cerebral calcifications.[36] Disturbances may be followed by convulsions and associated with gastrointestinal phenomena.

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.[37] Depression appears to persist on gluten free diet in a sizable fraction of GSE. [38]

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 and cytokine activity (i.e. constant stress). More resolution of anxiety is expected on gluten free diet.[38]

GSEA arthritis

Some instance of arthritis with small bowel villous atrophy have been found to resolve on gluten free diet[39], and anti-connective tissue antibodies have been found in increased levels in celiac disease. [40] In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.[41] 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[42] and is debatable.

GSEA myositis

Dermatomyositis. Dermatomyositis is associated with CD in children and more recently established in adults[43][44]

GSEA nephritis

Celiac disease is associated with immune complex glomerulonephritis. [45]

GSEA lymphoma

GSE increases the risk of cancers of specific types [46] 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.

References

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