Gluten is a recent topic of significant interest and research. It has become a media darling over the past few years for a variety of medical and non-medical reasons, and interest has led to a vast body of literature and information that is occasionally confusing and misleading. This review categorizes the diseases associated with gluten based on confirmed medical facts.
Gluten (from Latin gluten meaning glue) is a composite of storage proteins termed prolamins and glutelins that are stored together with starch in various cereal (grass) grains. It is found in wheat, barley, rye, oat, related species and hybrids (such as spelled, Khorasan, emmer, among others) and the products of these, for example, such as malt. Gluten gives elasticity to dough, allowing for the puffy and chewy texture. About 80% of the protein in bread wheat is gluten. Pasta has a lesser degree of gluten. Imitation meats, beer, soy sauce, and occasionally, ice cream and ketchup have gluten from the included stabilizing agents. Contamination of other food products with gluten is also a common problem. Hair products and cosmetics sometimes contain gluten as well.
Gluten is significant for physicians since it has a spectrum of illnesses associated with it, for example, gluten-sensitive enteropathy or celiac disease (CD), non-celiac gluten sensitivity (NCGS), wheat or grain allergy, gluten ataxia, and dermatitis herpetiformis (DH).
Aretaeus Cappadocia described a non-specific entity termed koiliakos in 250 AD. Koelia is Greek for the abdomen. Francis Adams translated this to English in 1856, using the term Coeliacs or celiacs. Samuel Gee famously said in 1888 that "to regulate the food is the main part of the treatment," and that "if the patient can be cured at all, it must be by means of diet."
Carnegie Brown in 1908 published a book and described peripheral neuritis in patients with CD. There was a discussion about "sprue" and ataxia, but it was hard to prove since the actual diagnosis could not be confirmed with certainty.
Second World War II led to devastation and famine across the world. Most people suffered malnutrition and illnesses, but the subgroup with celiac improved and felt better. Dutch Pediatrician Willem-Karel Dicke noted that mortality of the disease decreased from 30% pre-war numbers to a lesser figure and that this was reversed after the war. His papers were some of the first that mentioned the effect of a wheat-free diet on children.
Eventually, small bowel biopsy methods were developed in the 1950s and 1960s, and diagnosis could be confirmed. In 1961, Taylor published an immunological study and linked the disease to circulating antibodies. Although it was thought to be a food allergy at first, the autoimmune theory was accepted, and HLA-DQ2 was linked to it. In 1966, enteropathy was noted in 9 of 12 patients with dermatitis herpetiformis. In the same year, it was noted that CD was associated with many neurological disorders.
In the 1980s the journal Gastroenterology coined the term “non-celiac gluten sensitivity.” This disease was very prevalent in Europe but not so much in the states. Alessio Fasano, who treated celiac patients in Europe, moved to Boston to work in Massachusetts General Hospital and found that it was a prevalent disease in the United States as well. His 2003 article in the Journal of American Medical Association started a process of recognizing the disease and paved the way for many more studies on the subject.
Studies in the 2000s and 2010s linked the disease to almost everything. Gluten was quickly vilified. The Food and Drug Administration (FDA) started to require the labeling of gluten-free products in 2013. Gluten-free mania ballooned the related global industry to a $3.5 billion per year figure with a forecast of $4.7 billion in 2020. Gluten-free pizza, cookbooks, apps, and restaurants have mushroomed rapidly since.
Gluten-sensitivity is the major cause of CD. Gluten-sensitive enteropathy causes changes in intestinal anatomy and these changes will disappear after gluten avoidance.
Non-celiac gluten sensitivity is the terminology used to describe a diagnosis for "individuals who do not have celiac disease or wheat allergy, but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal." The etiology of non-celiac gluten sensitivity remains unknown.
Also known as “non-celiac wheat sensitivity,” it is probably the most common gluten-related ailment with a prevalence of 0.5% to 13% in the general population. There are no biomarkers for the disease and diagnosis by exclusion requires celiac and wheat allergy to be ruled out. Therefore, many patients suffer symptoms that might be interpreted as irritable bowel syndrome (IBS) for years. Health issues might encourage them to go for a gluten-free diet, and the improvement might make them think they have the CD.
FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) present in gluten-containing grains have been identified as a possible cause of gastrointestinal (GI) symptoms in people with NCGS, in place of, or in addition to, gluten. FODMAPs cause mild wheat intolerance usually limited to GI symptoms.
There is no specific knowledge of how gluten ataxia happens, but antibodies have been postulated to affect the cerebellum to cause the damage. In some hereditary ataxia syndromes, CD antibodies are more commonly found than the normal population. A gluten-free diet might help some patients and reduce the neurologic deficits, but it’s not universally helpful, and occasionally the cerebellum damage will be irreversible and cause atrophy and degeneration.
Dermatitis herpetiformis (DH) is an uncommon cutaneous eruption associated with gluten sensitivity and CD, characterized by intensely pruritic, inflammatory papules and vesicles on the forearm, knees, scalp, or buttocks.
Celiac disease Occurs primarily in Northern European ancestry between 10 and 40 years of age. The reported prevalence has been increasing gradually with improved methods of diagnosis and is now estimated to be 1:70 to 1:300. Screening could result in the recognition and treatment of unrecognized nutritional deficiency states, resolution of mild symptoms, and a potential reduction in the risk for malignancy. However, these benefits require compliance of asymptomatic patients with a difficult dietary regimen which can reduce the quality of life.
Gluten ataxia happens slowly in the fifth or sixth decade of life.
The incidence of DH, in general, is decreasing, and this is presumably because of a higher rate of detection and treatment of CD cases. It is uncommon in children and peaks at fourth and fifth decades of life. Men are more affected than women.
Wheat or Grain Allergy
Grain allergies are common. The most commonly studied of them is wheat allergy which can be IgE mediated or non-IgE mediated. It causes a wide range of clinical syndromes such as atopic dermatitis exacerbations, exercise-induced anaphylaxis, eosinophilic esophagitis (EoE) or CD.
IgE-mediated reactions are typical allergic and anaphylactic issues that range from hives and cutaneous discomfort and itch to oropharyngeal edema and cardiovascular collapse. These are commonly encountered in children.
Non-IgE mixed with IgE reactions can present as atopic dermatitis or EoE. Wheat (after egg and milk) is the third cause of atopia in children and also a frequent cause of eosinophils in the esophagus that causes inflammation and reflux-like symptoms that are not responsive to reflux treatments.
Pathogenesis is the same as CD with autoantibodies causing the rash and manifestations. This is confirmed with the observation that treatment of CD also cures DH and also by sub-epidermal deposition of IgA and neutrophilic dermal infiltrate. Like CD, most DH cases have HLA DQ2 and DQ8 haplotype. Also, there is a strong familial association of the disease. More than 90% of DH cases have small bowel biopsies compatible with gluten sensitivity.
Patients with classic celiac disease or gluten-sensitive enteropathy have symptoms of malabsorption, villous atrophy in pathology, and resolution of symptoms or pathology after avoidance of gluten for a few weeks to months. Usual symptoms are diarrhea, weight loss, malabsorption, steatorrhea, nutrient or vitamin deficiency, and positive antibodies. The degree of pathology varies in the intestine and can range from local infiltration with lymphocytes to advanced flat mucosa but is nevertheless not correlated with severity of symptoms.
Patients with atypical celiac have minimal GI symptoms and mostly present with anemia, dental enamel defects, osteoporosis (vitamin D and calcium deficiency), arthritis, infertility, elevated liver function tests, and neurologic problems (vitamin B deficiencies). Asymptomatic celiac patients have the antibodies and intestinal pathology features but no symptoms.
There is a worldwide shift from children with the classic disease to atypical adult patients, possibly because of breastfeeding and avoidance of gluten in childhood diets. Mortality does increase with this diagnosis; therefore, screening might be beneficial, although even with a gluten-free diet the risk of lymphoma has been reported to be higher. Other than malignancy, many autoimmune diseases like diabetes mellitus 1, IgA deficiency, eosinophilic esophagitis, glossitis, and pancreatitis are present.
Classical NCGS acts like IBS and/or wheat allergy. Also, there is a great resemblance with CD with almost identical intestinal and extra-intestinal manifestations. Wheat allergy can be differentiated from NCGS through fast onset (minutes to hours) and occasional anaphylactic reactions. Serology markers and duodenal biopsies are always negative in NCGS.
NCGS patients also have allergies to food (through IgE) and food preservatives/additives (Sulfites, glutamates, nitrates, benzoates). Lactose and other food intolerances are common in 35%. These sensitivities will make the picture more complicated and diagnosis less straightforward. Some authors believe that the whole disease is a fabrication/imagination and the product of the gluten-free food industry.
Non-IgE reactions include food protein-induced enterocolitis (vomiting and diarrhea 2 to 4 hours after ingestion of allergen in a child that can be severe and cause failure to thrive), proctitis (blood streaked mucousy stool in breastfed or formula-fed infants), and enteropathy (malabsorption, failure to thrive and low proteins).
Ataxia and peripheral neuropathy are the most common neurological manifestations of gluten sensitivity followed by inflammatory myopathy. Dementia is rare but epilepsy associated with gluten has been described in Italy.
Gluten ataxia happens slowly in the fifth or sixth decades of life and is defined as an otherwise idiopathic sporadic ataxia with positive IgA TTG or other serologic markers of gluten sensitivity. It can occur with or without enteropathy. Most frequent clinical features are gait and limb ataxia, ocular signs of cerebellar dysfunction, and dysarthria. Neuroimaging reveals cerebellar atrophy in 60% or more. This is a difficult diagnosis to establish since many other causes of ataxia should be ruled out first.
The intensely pruritic papules and vesicles are grouped and in different stages of maturation (Herpetiform). Elbows and forearms are the most common sites. Face and groin are rarely affected. Erosion and excoriation (often due to excess itching) are commonly observed. The lesions resolve after a while with no scarring although pigmentation might change. Oral lesions can happen as well, but differential diagnosis is vast and definitive confirmation difficult. Enamel defects can happen as well with horizontal grooves or pits.
Although biopsies of gut always show significant pathology compatible with CD, only a minority of patients develop GI symptoms. This may be related to deposition of IgA mostly in the epidermis as opposed to gut and therefore, result in more skin manifestations than GI manifestations.
Testing for celiac is recommended in certain groups of people. GI symptoms such as chronic diarrhea, malabsorption, weight loss, flatulence, and bloating are clear reasons. Some irritable bowel syndrome and lactose intolerance patients will need testing to find an alternative or concomitant diagnosis. Some problems that are not gastrointestinal such as anemia, vitamin deficiencies, liver function abnormalities, growth retardation, recurrent fetal loss, aphthous stomatitis, peripheral neuropathy or ataxia need to be evaluated as well. First degree relatives of celiac patients are also in need of testing.
All tests need to be done while the patient os on a gluten-rich diet. IgA anti-tissue transglutaminase (TTG) is the serologic test of choice after the age of 2, although IgA endomysial assay is an alternative. Endomysial antibodies bind to connective tissue surrounding smooth muscle cells and work against antigens in that tissue called tissue transglutaminase 2 (TTG). Antigliadin test has low predictive value and should not be performed. If IgA deficiency exists (and it is more common in celiac compared to normal population), IgG-deaminated gliadin peptides (DPGs) should be tested. Antibodies might be negative on a gluten-free diet and necessitate intestinal biopsy or genetic testing.
Positive serology and high probability of celiac (regardless of serology) will necessitate small bowel biopsy. Pathology is varied and staining methods can identify areas of villous atrophy. Video capsules sometimes reveal classic features of the disease and alleviate the need for biopsy, this is especially true in more distal disease. The disease is confirmed when serology and pathology are compatible and there is the resolution of symptoms and pathology with a gluten-free diet. In case there is still a diagnostic dilemma after all these steps, genetic testing for susceptibility with HLA DQ2/DQ8 check is required. A negative test will rule out celiac. Occasionally a gluten challenge is needed and serology/pathology response to gluten challenge will yield the diagnosis.
Diagnosis of non-celiac gluten sensitivity is really a clinical one of exclusion by means of negative laboratory and endoscopic findings in the setting of symptoms that are relieved with cessation of ingestion of gluten-containing products. While laboratory findings may show positive or negative results for HLA-DQ2 and HLA-DQ8 testing, anti-tissue transglutaminase, anti-endomysial antibodies, and endoscopic visualization and biopsies are negative in this subset of patients. However, by having patients use a symptom severity scale and food diary, clinicians will see improvement of symptoms when gluten is eliminated from the diet.
The gold standard for diagnosis is a clinician-supervised double-blind, placebo-controlled oral food challenge, although an open challenge will often suffice. Measurement of grain-specific IgE can aid in the diagnosis of IgE-mediated allergy and may eliminate the need for oral food challenges. Skin prick tests and/or in vitro tests for IgE are usually performed in the beginning, followed by food challenges that should be done by an allergy specialist with enough training and experience in dealing with such reactions.
Clinicians can diagnose DH via symptoms and signs, serology and labs, tissue pathology, and direct immunofluorescence microscopy (DIF). DIF is the gold standard with a 92% positivity in DH and with granular IgA deposition in dermal papillae. Serology has a role in diagnosis but more importantly can be checked to assess the success of treatments. The biopsy should be taken from perilesional skin (normal-appearing skin adjacent to a lesion) because biopsies taken from the lesional skin are more likely to yield falsely negative findings.
Treatment consists of a gluten-free diet. Patients should avoid wheat, rye, barley, beers, ales, lagers, and malt vinegar because they are made of gluten-containing grains. Distilled alcoholic beverages and kinds of vinegar like wine are gluten-free. Potato, corn, rice, and soybeans are also gluten-free. Dairy can cause a problem if concomitant lactose intolerance is present. Attention to food labels is of prime importance.
Strict diet is difficult, and compliance can be a challenge. Still, such an approach might prevent micronutrient deficiencies that happen because of celiac and decrease the cancer rate associated with it. Tolerance of gluten and body response to it is highly variable in the general population; so one result is not typical. Response to a gluten-free diet should be monitored clinically, serologically and occasionally with biopsies. Non-responders are those with symptoms or positive serology despite 2 years of a gluten-free diet. A majority of those are people who have a hard time complying with the diet or are accidentally exposed to gluten. The rest might have other pathologies or combined pathologies. In very severe refractory cases prednisone, azathioprine, 6-mercaptopurine, or mycophenolate have been used. One consideration in cases of treatment failure is the development of GI cancers or lymphomas. Nutritional deficiencies should be supplemented.
Treatment follows the same CD treatment guidelines.
Treatment is avoidance of allergen and substitution of wheat with other sources that can supplement the nutrients (cereal and non-cereal grains). Epinephrine pens for IgE mediated reactions are a must.
Although a gluten-free diet will cure the problem and is the mainstay of treatment in the long run; the short-term solution is the use of dapsone. Pruritus improves 72 hours after dapsone is started and skin lesions will resolve in a matter of days. Fifty to 150 mg of dapsone usually control most of the lesions (which is the goal of treatment.) Some side effects exist such as hypersensitivity, hemolysis (especially in G6PD deficient person) and agranulocytosis. Follow-up blood work is usually recommended and includes blood count as well as liver/kidney monitoring. After 3 months of treatment (and if a gluten-free diet has been observed in those 3 months) slow tapering may be attempted.
If dapsone treatment is not feasible, other sulfa agents such as sulfasalazine can be used. Topical steroids might also be beneficial and reduce the itching but cannot cure DH. Systemic steroids are of no value.
IBS, lactose intolerance, NCGS, wheat allergy, Crohn's disease, ulcerative colitis, intestinal infections, bacterial overgrowth
Atopic dermatitis, scabies, itchy bites, bullous pemphigoid, and IgA bullous dermatosis are all in the differential diagnosis either because of severe itch, immune deposition pathology, or a combination
The disease is a chronic life-long issue but today, there are more diagnostic possibilities and treatment options available and living with the disease is much easier than a few decades ago. The majority of cases do respond favorably to gluten-free diets. Some long-term GI malignancies have been reported.
DH is frequently a chronic, life-long issue and requires continuous a gluten-free diet and dapsone. Infrequently, patients can discontinue these permanently. DH is not associated with increased mortality like CD, again presumably since the site of injury is skin and not the gut. Some studies have mentioned reduced mortality in DH.
Complications are not frequent, and the disease is the main issue.
In the case of gluten ataxia, occasionally, a gluten-free diet will not suffice, and cerebellum damage will be irreversible and cause atrophy and degeneration.
A patient should not start a gluten-free diet until tests are done and diagnosis is confirmed. Diet affects test results.
The first step in achieving a gluten-free diet is to eliminate all food, beverages, medication, and cosmetics that have gluten in them. When symptoms are gone, then new questionable items can be added one by one, and the response to them should be evaluated. In case of any symptoms or problems, the new item should be eliminated. 
In general, flour, bread, crackers, baking mixes, pasta, cereal, sauce, condiments, processed meat, beer, ale, lager, and malt vinegar should be avoided. Rice, corn, potato, soybean, fruit, vegetable, meats, eggs, wine, and distilled alcoholic beverages are gluten-free and acceptable to eat or drink. Occasionally, gluten is used in preparing corn and potatoes, specifically, gluing them and packaging them, and can cause symptoms.
Many other items might not have gluten in them, but gluten could have been used in their preparation or packaging. Consult the manufacturer's website and labeling for ingredients.
Patients and primary care physicians should consult and follow-up with a dietician.
The five major illnesses associated with gluten are celiac disease, non-celiac gluten sensitivity, wheat allergy, gluten ataxia, and dermatitis herpetiformis. Each is distinct, but all are related and manageable.
Interdisciplinary work between primary care providers, gastroenterologists, dietician, and nutritionists are needed for optimal management.
The prognosis for patients with gluten sensitivity is lifelong, marked by relapses and remissions. Some patients need life-long monitoring because of the small risk of intestinal malignancies; the quality of life of these patients is poor.
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