Gluten-sensitive enteropathy–associated conditions
Gluten-sensitive enteropathy–associated conditions are
However, GSEs' association with disease is not limited to common autoimmune diseases. Coeliac disease has been found at increased frequency on followup to many autoimmune diseases, some rare. Complex causes of autoimmune diseases often demonstrates only weak association with coeliac disease. The frequency of GSE is typically around 0.3 to 1% and lifelong risk of this form of
Genetic studies indicate that coeliac disease genetically links to loci shared by linkage with other autoimmune diseases.[3] These linkages may be coincidental with how symptomatic disease is selected from a largely asymptomatic population.
Associated blood disorders
Deficiencies
Avitaminosis.
- Vitamin A – Poor absorption of vitamin A has been seen in coeliac disease.[6] and it has been suggested that GSE-associated cancers of the esophagus may be related to vitamin A deficiency[7][8]
- Folate – Folate deficiency is believed to be primary to the following secondary conditions:
- Megaloblastic anemia
- Calcification of brain channels – epilepsy, dementia, visual manifestations.
- B6 deficiency. Vitamin B6 deficiency can result in neuropathies and increases in pain sensitivity.[9] may explain some of the peripheral neuropathies, pain and depression associated with GSE.[10]
- B12 deficiency
- Vitamin D – Vitamin D deficiency can result in osteopenia and osteoporosis
- Vitamin K – Coeliac disease has been identified in patients with a pattern of bleeding that treatment of prothrombin.[12]
- Vitamin E – deficiency of vitamin E can lead to CNS problems[13] and possibly associated with myopathy[14]
Mineral deficiencies. GSE is associated with the following mineral deficiencies:
- Calcium – Hypocalcemia[11] causing Oesteopenia
- Magnesium – Hypomagnesemia,[15] may lead to parathyroid abnormalities.
- Iron – Iron deficiency anemia
- Phosphorus – Hypophosphatemia,[16] causing Oesteopenia
- Zinc – Zinc deficiencies[17] are believed to be associated with increased risk of Esophagus Carcinoma[8]
- Copper – Deficiency[17]
- Selenium – Deficiency[18] – Selenium and zinc deficiencies may play a role increasing risk of cancer.[19] Selenium deficiency may also be an aggravating factor for autoimmune hyperthyroidism (Graves disease).[20]
Blood factors
Anemia
Megaloblastic anemia (MA) is associated with GSE and is believed to be the result of B12 and folate deficiency.[23] In GSE, it appears to be associated with the IgA-less phenotype.[24] Unlike other forms of megaloblastic anemia, GSEA MA is not a form of autoimmune gastritis.[25]
Pernicious anemia (PA). Pernicious anemia is associated with GSE and is believed to result primarily from malabsorption phenomena.[23]
Iron-deficiency anemia.
Clotting abnormalities
Thromboembolism is a well-described complication of IBD, with a clinical incidence of up to 6% and a three-fold higher risk of disease,[31][32] and the Factor V Leiden mutation further increases the risk of venous thrombosis.[33] Recent studies describe the co-occurrence between coeliac disease, in which IBD is common in venous thrombosis.[34][35]
Dermatitis
A study of patients with dermatitis herpetiformis or coeliac disease revealed significantly more gluten in the blood than controls.[36] This increases the risk of asthma, anaphylaxis and dermatological conditions.
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 to CD after wheat ingestion. Within the pathology of CD, DH is relatively rare or underdiagnosed, with about 5% of patients presenting with DH. Aphthous stomatitis is a common mouth lesion found in those with coeliac disease.
Atopy, urticaria, eczema
Chronic
Rare dermatitis
Prurigo nodularis. Prurigo nodularis has been identified with coeliac disease.[41][42]
Rothmund–Thomson syndrome.
Alopecia areata
GSE has been found to be associated with alopecia areata (patchy baldness),[44] however hair regrowth did not necessarily occur after taking up a gluten free diet.[45][46]
Endocrine disorders
Autoimmune thyroidosis
[Section under construction] Grave's Disease, Hashimoto's thyroiditis. Grave's disease and Hashimoto's thyroiditis are greatly increased in patients with CD.[47] Grave's disease is an autoimmune hyperthyroidism, as GSE is a potentiator for autoimmune disease, but GD is more commonly found and avitaminosis of selenium and other minerals may be a factor in this increase.
Diabetes
Type 1 (Juvenile onset). The incidence of juvenile
Addison's disease
Studies from Sweden suggest that persons with coeliac disease are 11 times more likely to have Addison's disease (primary adrenal insufficiency) relative to the normal population.[57]
Infertility
GSE can result in high risk pregnancies[58] and infertility. Some infertile women have GSE and iron deficiency anemia[59] others have zinc deficiency[60] and birth defects may be attributed to folic acid deficiencies. It has also been found to be a rare cause of amenorrhea.[61]
Gastrointestinal diseases
While GI disease is one of the major symptoms of GSE that are characterized by increased levels of IgA/IgG to food proteins,[62]
Irritable bowel (IBS)
In diarrhea dominant IB - a common symptom of GSE - increased coeliac disease-associated serum IgG was found in treated and untreated CD patients. IgG was most common in untreated patients with more active DQ2 expression, which dropped on GF diet.[63] Some cases of irritable bowel can be the result of other food intolerances, such as casein 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 unabsorbed nutrients. IB may not resolve on GF diet, even becoming more severe in rare cases, as it may not have initially been directly linked to gluten consumption.
Inflammatory bowel disease (IBD)
A recent study of inflammatory bowel disease and coeliac disease found that anti-tTG was increased in inflammatory bowel disease, although most cases were not clinical CD. IBD was increased 10 fold in coeliac disease.[64] Inflammatory bowel disease consists of Crohn's disease, ulcerative colitis and microscopic colitis.
Gastroesophageal reflux disease
Gastroesophageal reflux disease (GERD) is the indirect result of many factors and some autoimmune diseases like
Eosinophilic oesophagitis
One study of 17 children in Italy who were diagnosed with
Diseases of the pancreas, gall bladder, bile duct
Primary biliary cholangitis. CD is prevalent in
Cholangitis. CD also found at higher than expected frequencies in autoimmune
Neurological disorders
Peripheral neuropathies
Ataxia
A sizable fraction of individuals who have gluten ataxia have signs of GSE (either CD or elevated intraepitheal lymphocytes) and ataxia is a common symptom in GSE.[78] 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.[79] A recent Swedish study of 14,000 registered coeliacs showed no association of GSE with Ataxia.[75]
Dementia and epilepsy
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 field hallucinations (
White matter lesions
Ten (of 75) young patients had neurologic findings such as febrile seizures, single generalized seizures, mild ataxia, and muscular hypotonia with retarded motor development, but magnetic resonance imaging detected unilateral and bilateral
Depression
Depression in GSE has several causes; in the more severe CD, depression can be the result of lower vitamin adsorption[10] 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.[87] Depression appears to persist on gluten free diet in a sizable fraction of GSE.[88] Elevated anger has been noted also with GSE.
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 due to malabsorption phenomena and cytokine activity (i.e. constant stress).[88]
Fibromyalgia
Fibromyalgia was found in 9% of adult patients relative to 0.03% in the general population with a link common to IBD.[89] Concurrent IBS is found in 30% to 70%. Small intestinal bacterial overgrowth is associated is common with a transient response to antimicrobial therapy.[90]
Chronic fatigue
Chronic fatigue associated with GSE is a systemic disorder, however there are neurological components that are especially manifest in blood deficiencies like avitaminosis, amineralosis and anemia. Reduced iron and the lack of vitamins folate, B6, B12 and malabsorption of essential fatty acids can cause depression and chronic fatigue.[91] Anti-gliadin antibodies correlate with higher risk for chronic-fatique when no clinical finding of CD is present.[92] While fatigue is reduced on gluten-free diet, bouts of depression can become worse. [91]
Connective tissue disorders
Arthritis
Some instance of arthritis with small bowel villous atrophy have been found to resolve on gluten free diet,[93] and anti-connective tissue antibodies have been found in increased levels in coeliac disease.[94] Anti-rheumatoid factor antibodies are also increased.[95] In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.[96] 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[97] and is debatable. In one instance rheumatoid arthritis was tied directly to refractory disease.[98]
Still's disease
Still's disease (AOSD) is a rheumatic disorder of unknown etiology characterized by a triad of fever, polyarthritis and evanescent rash. An idiopathic case has been reported with coeliac disease.[99]
Myositis
Some myopathies may be the indirect result of malabsorption of fat soluble vitamins such as vitamin E.[14]
Dermatomyositis
Dermatomyositis is associated with CD in children and more recently established in adults.[100][101]
GSEA nephritis
Coeliac disease is associated with immune complex glomerulonephritis.[102] Anti-gliadin IgA antibodies are found also more commonly in patients with IgA Nephropathy. The paper finds a link between GSE and IgA Nephropathy, but not between CD and nephropathy.[103] Calcium oxalate correlates with severity of fat malabsorption in coeliac disease.[104][105]
Precancerous states
CD is associated with two grades of disease linked precancerous states. This condition is known as refractory coeliac disease (RCD), defined as malabsorption due to gluten-related enteropathy (villous atrophy or elevated intraepitheal lymphocytes) after initial or subsequent failure of a strict gluten-free diet (usually 1 year) and after exclusion of any disorder mimicking coeliac disease.[106][107]
- RCD 1 involves precancerous tissues in which transformed T-cells continue to produce a response even though gluten is no longer present.[108] Some RCD1 patients have been treated successfully with immunosuppressants (azathioprine, prednisone) when caught early.[107] Elemental diet (proteins digested to amino acids) seems to be an effective alternative diet,[109] indicating other proteins are stimulating the IEL. 5 year viability is high when treated. DQ representation is similar to non-RCD coeliacs.
- RCD 2 involves neoplastic tissues that the lack of surface expression of usual T-cell markers.[110]
- Increased expression of: Intracytoplasmic CD3e, Surface CD103
- Decreased expression of: CD8, CD4, TCR-alpha/beta
- Increased expression of: Intracytoplasmic CD3e, Surface
- Clonal T-cell expansion in RCD2 is not manageable with steroids (see: RCD 1) and sometimes manageable with chemotherapeutic drugs,[111] however, more aggressive therapies seem more affective.[108] A high percentage of RCD 2 patients spontaneously develop lymphoma (EATL),[111] the 5 year survival rate is markedly lower than RCD1 but higher than lymphoma. DQ2.5/DQ2 individuals are more frequently found.[112]
Causes of RCD.
- Coeliac disease
- Age at CD/GSE diagnosis – most people are over the age of 50 when first diagnosed at RCD
- Dietary noncompliance – Some EATL appears years after diagnosis with non-GF diets.
- Length of latency – The length of time, often unknown in which the person is GSE+.
- Severity – The severity of the microscopic destruction appears to be a factor, and genetics appears now to play a role.[113]
- Genetics – For RCD 2 and EATL, genetics plays large role DQ2.5/DQ2+ individuals are over-represented in the patient set[111][112]
Cancers
GSE, particularly coeliac disease, increases the risk of cancers of specific types.[114] There are two predominant cancers associated with coeliac disease, cancer of the esophagus and lymphoproliferative diseases such as gluten-sensitive enteropathy-associated T-cell lymphoma (EATL).[115] For non-EATL cancers it is thought the mineralemias such as zinc and selenium may play a role in increasing risk.[19] GSE associated cancers are invariably associated with advanced coeliac disease, however, in de-novo EATL, the cancer is frequently detected in advance of the coeliac diagnosis, also EATL is the most common neoplasm.[7]
Esophageal cancer
Adenocarcinoma
Adenocarcinoma of the bowel has been associated with coeliac disease.[7][116][117]
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