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Gluten-Associated Medical Problems
Introduction
Gluten has become a topic of significant scientific and clinical interest in recent years. Although media attention has contributed to increased public awareness of gluten, it has also contributed to the proliferation of inconsistent or misleading information. From a medical perspective, gluten is relevant due to its association with a range of well-characterized disorders. This activity aims to categorize gluten-related conditions based on established scientific evidence, with a focus on their clinical relevance.
Gluten (derived from Latin gluten, meaning "glue") is a composite of storage proteins termed as "prolamins" and "glutelins," which are stored along with starch in various grains. Gluten is found in wheat, barley, rye, certain hybrid and ancient grains (such as spelt, Khorasan, and emmer), as well as in their derivatives (such as malt). Gluten imparts elasticity to dough, helping it maintain structure and producing a light, chewy texture when baked.
Gluten accounts for approximately 80% of the total protein content in traditional bread, whereas pasta contains a lower percentage of protein. Gluten is also commonly found in imitation meats, beer, soy sauce, ice cream, and ketchup, often due to the addition of gluten-based stabilizing agents. Cross-contamination of food products with gluten is a common occurrence. Additionally, some nonfood items, such as hair products and cosmetics, may contain gluten.[1][2]
Gluten is associated with various medical conditions, including celiac disease, non-celiac gluten sensitivity (NCGS), gluten ataxia, and dermatitis herpetiformis.[3]
Historical Perspective
Aretaeus of Cappadocia described a nonspecific entity in 250 CE, termed koiliakos, derived from the Greek term koelia, which refers to the abdomen. In 1856, Francis Adams translated this into English, using the term "coeliacs" or "celiacs." The first comprehensive modern description of celiac disease was provided by British physician Samuel Gee in 1888. He emphasized the importance of dietary management, stating that "To regulate the food is the main part of the treatment" and "If the patient can be cured at all, it must be by means of diet."[4] In 1908, another British physician, Carnegie Brown, published a book that described peripheral neuritis in patients with celiac disease. He also mentioned “sprue” and ataxia, although confirmation of these diagnoses was challenging due to the limited diagnostic tools and clinical evidence available at the time.
World War II brought widespread devastation and famine, leading to malnutrition and illness across much of the world. However, during this time, a unique clinical observation emerged—some individuals with celiac disease experienced significant improvement in their symptoms. In the Netherlands, wartime shortages of wheat and other grains resulted in a significant reduction in gluten consumption, which was accompanied by notable clinical improvements in affected patients.
In 1950, Dutch pediatrician Willem-Karel Dicke formally demonstrated that eliminating wheat, rye, and oats from the diet resulted in dramatic symptom relief in children with celiac disease. Mortality rates from the condition declined during the war but rose again after gluten-containing foods were reintroduced. This trend reversed once gluten was identified as the offending dietary component, and the adoption of a gluten-free diet (GFD) led to a renewed decline in mortality.[5][6]
The development of small bowel biopsy techniques in the 1950s and 1960s enabled the definitive diagnosis of celiac disease. AK Taylor published an immunological study linking celiac disease to circulating antibodies in 1961. Although initially considered a food allergy, celiac disease was later recognized as an autoimmune disorder, with a strong association to the human leukocyte antigen DQ2 (HLA-DQ2). In 1966, researchers observed enteropathy in 9 of 12 patients with dermatitis herpetiformis, and in the same year, they identified an association between celiac disease and neurological disorders.[7][6]
In the 1980s, the journal Gastroenterology coined the term "non-celiac gluten sensitivity." Although this condition was prevalent in Europe, it was less frequently identified in North America. Alessio Fasano, a physician experienced in treating celiac patients in Europe, later moved to Boston to work at Massachusetts General Hospital. There, he demonstrated that the condition was also present in the United States. His 2003 article in the Journal of the American Medical Association helped raise awareness and laid the foundation for further research into gluten-related disorders.[8]
During the 2000s and 2010s, a combination of medical studies and popular media coverage linked celiac disease to a wide range of conditions, contributing to a growing public perception of gluten as harmful. This perception led to the widespread vilification of gluten, even among individuals without a diagnosed gluten-related disorder. In response to increasing consumer demand, the U.S. Food and Drug Administration established regulations in 2013 requiring standardized labeling for gluten-free products. The resulting surge in interest fueled the growth of the gluten-free market, which reached an estimated value of $4.7 billion by 2020. The popularity of GFDs also spurred the rapid expansion in related consumer products, including gluten-free foods, cookbooks, mobile applications, and dedicated restaurant offerings.[9]
This activity reviews the 4 main gluten-associated medical conditions—celiac disease, dermatitis herpetiformis, NCGS, and gluten ataxia. This activity also provides information on the etiology, prevalence, diagnosis, and management of this condition. Please refer to StatPearls' companion resources, "Protein Intolerance," "Celiac Disease," "Ataxia," and "Wheat Allergy," for more information.
Etiology
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Etiology
Celiac Disease
Celiac disease is an autoimmune disorder triggered by the ingestion of gluten in genetically predisposed individuals, resulting in inflammation and damage (enteropathy) of the small intestinal mucosa.[10]
Dermatitis Herpetiformis
Dermatitis herpetiformis is an autoimmune condition triggered by gluten ingestion in genetically predisposed individuals. This condition is regarded as the specific cutaneous manifestation of celiac disease and presents as intensely pruritic vesicles and papules.[11]
Non-Celiac Gluten Sensitivity
NCGS, also known as non-celiac wheat sensitivity, is characterized by the onset of gastrointestinal and/or extraintestinal symptoms that occur after the ingestion of gluten-containing grains, with symptom resolution upon their withdrawal in individuals without celiac disease or wheat allergy. This condition occurs in individuals who do not have celiac disease or wheat allergy. The etiology of NCGS remains incompletely understood; however, current evidence suggests that it involves a combination of immune-mediated mechanisms and other unidentified factors.[12]
Currently, no specific biomarkers for NCGS exist, and diagnosis is made by excluding both celiac disease and wheat allergy. Additionally, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), present in gluten-containing grains, have been identified as potential contributors to gastrointestinal symptoms in NCGS, either independently or in combination with gluten.[13][14]
Gluten Ataxia
Gluten ataxia is a neurological manifestation of gluten sensitivity. This condition is characterized by sporadic, progressive cerebellar ataxia and is often associated with antigliadin antibodies. The etiology of the condition involves an autoimmune response triggered by gluten ingestion in genetically predisposed individuals. Most cases occur without evidence of enteropathy, and the clinical features of gluten ataxia more closely resemble those of NCGS than classical celiac disease.[15][16]
Epidemiology
Celiac Disease
Celiac disease is prevalent worldwide, affecting populations in North America, Europe, Oceania, South America, Asia, and Africa. This condition is commonly diagnosed between the ages of 10 and 40. Although it was once believed to primarily affect individuals of Northern European descent, more recent studies have revealed a broader worldwide prevalence. The reported prevalence has increased in recent decades, likely due to greater awareness and improved diagnostic techniques. Current estimates suggest a prevalence of 1 in 70 to 1 in 300 individuals, with approximately 1% of individuals in Western countries affected, and biopsy-confirmed cases accounting for about 0.7%.[17][18]
Dermatitis Herpetiformis
The incidence of dermatitis herpetiformis has generally declined, likely due to higher detection rates and earlier treatment of individuals with celiac disease. The condition is uncommon in children and most often presents in the fourth and fifth decades of life. Dermatitis herpetiformis is more prevalent in men than in women.[19]
Non-Celiac Gluten Sensitivity
NCGS is likely the most common gluten-related condition, with an estimated prevalence of 0.5% to 13% in the general population.[20] The wide variation in estimates is due to the absence of specific biomarkers and the reliance on clinical response, specifically symptom improvement on a GFD and recurrence upon reintroduction of gluten-containing foods, for diagnosis. Although pediatric cases have been reported, NCGS is more commonly reported in adults, particularly women between the ages of 30 and 50.[21]
Gluten Ataxia
Gluten ataxia accounts for approximately 15% of all ataxia cases and 40% of idiopathic sporadic ataxias. The mean age of onset is approximately 53, with a slight male predominance.[22] Onset may be insidious, and the condition is associated with gluten sensitivity, often occurring independently of celiac disease and more closely linked to NCGS.[16]
Pathophysiology
Celiac Disease
Celiac disease is a chronic autoimmune disorder triggered by dietary gluten in genetically predisposed individuals, primarily those carrying the HLA-DQ2 or HLA-DQ8 alleles. The condition arises from an inappropriate immune response to gliadin, which is a gluten component that resists complete digestion and is deamidated by tissue transglutaminase (tTG) in the lamina propria. This modification enhances gliadin’s affinity for HLA-DQ2 or HLA-DQ8 on antigen-presenting cells, thereby leading to the activation of CD4+ T cells. The ensuing immune cascade involves the release of pro-inflammatory cytokines, the production of tTG autoantibodies by B cells, and CD8+ T cell–mediated epithelial damage, resulting in villous atrophy, crypt hyperplasia, and impaired nutrient absorption.[23][24]
Increased intestinal permeability further amplifies antigen exposure and promotes inflammation. Although HLA-DQ2 or HLA-DQ8 is necessary for the development of celiac disease, it is insufficient, as many individuals carrying these alleles remain asymptomatic. Environmental factors, such as gastrointestinal infections, antibiotic-induced disruption of the gut microbiome, and immune modulation during pregnancy, may contribute to disease onset in genetically predisposed individuals.[25]
Dermatitis Herpetiformis
The pathogenesis of dermatitis herpetiformis mirrors that of celiac disease, involving autoantibodies that cause the characteristic rash. Gluten ingestion triggers the production of immunoglobulin A (IgA) autoantibodies against transglutaminase-3 (TG3), which deposit in the papillary dermis and are pathognomonic for the condition. Similar to celiac disease, most individuals with dermatitis herpetiformis carry the HLA-DQ2 or HLA-DQ8 haplotypes.[26][27]
Non-Celiac Gluten Sensitivity
The pathophysiology of NCGS remains incompletely understood, but it is believed to involve a combination of innate immune responses, increased intestinal permeability, gut dysbiosis, and sensitivity to components of wheat and other grains, including those beyond gluten itself.[28][29]
Gluten Ataxia
Gluten ataxia occurs independently of celiac disease and is more closely associated with NCGS. The hallmark feature of this condition is autoimmunity to TG6—an enzyme primarily expressed in the central nervous system, particularly in the cerebellum, which coordinates balance and movement. Affected individuals frequently exhibit anti-TG6 antibodies in their serum and cerebrospinal fluid (CSF), implicating direct autoimmune involvement of the cerebellum. Many patients also exhibit antigliadin antibodies, which may cross-react with neuronal antigens, further contributing to cerebellar injury and progressive ataxia.[16][30][31]
Histopathology
Celiac Disease
The hallmark histological feature of celiac disease is intestinal villous atrophy accompanied by compensatory crypt hyperplasia. Intraepithelial lymphocytosis, predominantly involving CD8+ T cells, reflects the inflammatory response to gliadin peptides as these lymphocytes infiltrate the epithelial layer. The lamina propria beneath the epithelium also exhibits increased infiltration of immune cells, including T cells, B cells, and plasma cells. The severity of histopathological changes varies and does not always correlate with the severity of clinical symptoms.[32][33][34][24][35]
Dermatitis Herpetiformis
Biopsy of lesions reveals subepidermal vesicle formation with collections of neutrophils concentrated at the tips of the dermal papillae. Direct immunofluorescence reveals granular deposits of IgA in the papillary dermis, which is a diagnostic feature of the condition. More than 90% of patients with dermatitis herpetiformis exhibit small bowel mucosal changes characteristic of celiac disease, ranging from villous atrophy to increased intraepithelial lymphocytes, even in the absence of overt gastrointestinal symptoms.[36][26][37]
Non-Celiac Gluten Sensitivity
Histological findings in NCGS are generally less pronounced and less subtle than those observed in celiac disease. Key features may include preserved intestinal villous architecture, increased intraepithelial lymphocytes, and mild inflammation of the lamina propria.[38]
Gluten Ataxia
Neuropathological findings include loss of Purkinje cells, cerebellar atrophy, gliosis, and lymphocytic infiltration, which is consistent with chronic inflammation. The presence of intrathecal antibody production, including CSF–localized plasma cells and anti-TG6 IgA, further supports a localized autoimmune response. Cerebellar damage may be irreversible, leading to progressive atrophy and degeneration.[16][30][31]
History and Physical
Celiac Disease
Patients with classic celiac disease typically exhibit symptoms of malabsorption, including diarrhea, weight loss, bloating, abdominal pain, nausea, vomiting, steatorrhea, and constipation. Extraintestinal manifestations are also common and may include fatigue, pallor, muscle weakness, balance difficulties, generalized body aches, and infertility. Symptoms often improve or resolve within weeks to months after initiating a GFD.[32][33]
On physical examination, both children and adults may exhibit low body weight with reduced muscle mass, abdominal distension or tenderness, muscle weakness, ataxia, joint or bone tenderness, pallor due to anemia, and signs of vitamin deficiencies such as cheilosis, glossitis, or skin rashes.
Patients with atypical celiac disease exhibit minimal gastrointestinal symptoms and may present with anemia, dental enamel defects, osteoporosis, arthritis, infertility, elevated liver function tests, and neurological complaints. Asymptomatic individuals have positive serum antibodies and exhibit diagnostic intestinal pathology, despite the absence of symptoms.[39]
Dermatitis Herpetiformis
Patients with dermatitis herpetiformis typically present with an intensely pruritic, blistering rash. On physical examination, clusters of erythematous papules and vesicles in various stages of development are most commonly observed on the extensor surfaces of the elbows, forearms, knees, and buttocks. Due to frequent scratching, lesions are often excoriated and eroded.[40][37] Oral involvement is rare but may include erythematous or vesiculobullous lesions, which are usually asymptomatic.[41] Dermatitis herpetiformis typically resolves without scarring, although residual pigmentation changes may persist.
Non-Celiac Gluten Sensitivity
Patients with NCGS typically present with gastrointestinal symptoms such as abdominal pain, bloating, diarrhea, and constipation, often occurring within hours of consuming gluten-containing foods. Extraintestinal symptoms may include headache, fatigue, mood disturbances, and joint pain. Symptoms generally improve or resolve on a GFD and recur upon reintroduction of gluten. The physical examination is usually unremarkable, although mild abdominal tenderness may occasionally be noted.[42]
Gluten Ataxia
Patients with gluten ataxia typically present in their fifth or sixth decade with an insidious onset of gait instability, dysarthria, involuntary eye movements, and progressive loss of coordination in the arms and legs. Most individuals do not exhibit gastrointestinal symptoms. Physical examination findings may include gait ataxia, limb ataxia (in both upper and lower extremities), dysarthria, peripheral neuropathy, and nystagmus.[43][44]
Evaluation
Celiac Disease
When history and physical examination raise suspicion for celiac disease, the 2023 American College of Gastroenterology guidelines recommend initial serological testing with tTG-IgA in patients who are not IgA-deficient. Testing should be conducted while the patient maintains a gluten-containing diet for at least 6 to 8 weeks. The IgA endomysial assay (EMA) is an alternative serological test that confirms celiac disease when tTG-IgA results are borderline or equivocal. However, it is not routinely used as an initial test due to its higher cost and labor-intensive nature than tTG-IgA.[45]
If tTG-IgA levels are elevated, the next step is to perform an esophagogastroduodenoscopy with multiple duodenal biopsies in both children and adults to confirm the diagnosis of celiac disease. Current guidelines recommend obtaining 1 or 2 biopsies from the duodenal bulb and 4 from the distal duodenum to minimize the risk of false-negative results. Characteristic histological findings confirm the diagnosis of celiac disease, particularly in seronegative or borderline cases. Additionally, small bowel biopsies can identify non-celiac enteropathies or malabsorptive disorders, thereby excluding celiac disease. Occasionally, video capsule endoscopy may reveal classic mucosal changes, thereby reducing the need for biopsy. To ensure diagnostic accuracy, patients must be consuming a gluten-containing diet so that histopathological features of celiac disease are present and detectable.[46][47]
Antigliadin antibody testing is no longer recommended due to its low sensitivity and specificity. Instead, tTG-IgA is the preferred first-line serological screening test for celiac disease. In patients with IgA deficiency, which is more common in individuals with celiac disease, IgG-based tests, particularly those targeting IgG deamidated gliadin peptides (DGPs), are suitable alternatives. HLA genetic testing for HLA-DQ2 or HLA-DQ8 can provide supportive diagnostic information; a negative result effectively rules out celiac disease. In rare cases, a gluten challenge may be necessary to confirm the diagnosis when initial findings are inconclusive.[39]
Routine screening for asymptomatic individuals is generally not recommended. However, testing should be considered for certain high-risk groups, including first-degree relatives of individuals with celiac disease, as they have a 10% to 15% increased risk of developing the condition. Celiac disease is also strongly associated with autoimmune disorders such as type 1 diabetes, autoimmune thyroid disease, and autoimmune liver disease. Additionally, individuals with genetic conditions such as Down syndrome and Turner syndrome are at higher risk and may benefit from targeted screening.[45][47]
Dermatitis Herpetiformis
Diagnosis of dermatitis herpetiformis is based on clinical signs and symptoms, serological testing, and skin biopsy with tissue pathology and direct immunofluorescence microscopy. Direct immunofluorescence is considered the gold standard, with approximately 92% of cases demonstrating characteristic granular IgA deposits at the dermal papillae. To optimize diagnostic accuracy, biopsies should be obtained from perilesional skin—normal-appearing skin adjacent to a lesion—as sampling directly from the lesion may lead to false-negative results due to tissue damage or degradation of immune complexes. Although serological testing has a limited role in diagnosis, it is useful for monitoring the response to treatment.[36]
Non-Celiac Gluten Sensitivity
NCGS is a clinical diagnosis made by exclusion. NCGS is characterized by the onset of symptoms triggered by gluten ingestion that improve upon its elimination, provided there is no celiac disease or wheat allergy present. Serological tests for tTG-IgA and EMA are negative, and the duodenal biopsies also show negative results. Endoscopy is typically normal, and histology shows no villous atrophy or increased intraepithelial lymphocytes, distinguishing NCGS from celiac disease. Although HLA-DQ2 and HLA-DQ8 may be present, their presence is not diagnostic of celiac disease.
To support the clinical impression of NCGS, patients may use symptom severity scales and maintain a food diary to document changes in their response to a GFD. In the absence of validated biomarkers, careful clinical observation and systematic symptom tracking remain essential for both diagnosis and ongoing management.[48]
Gluten Ataxia
Neuroimaging reveals cerebellar atrophy, particularly of the vermis, in more than 60% of individuals with gluten ataxia.[44] Neurophysiological studies may show sensorimotor axonal neuropathy. Only a few patients with gluten ataxia demonstrate enteropathy on duodenal biopsy.[16]
Treatment / Management
The cornerstone of managing celiac disease is strict, lifelong adherence to a GFD, which alleviates symptoms, promotes intestinal healing, and reduces the risk of long-term complications. Most patients respond well, with symptom improvement typically occurring within a few days to a few weeks. A study reported that 80% of patients experienced fewer episodes of diarrhea within 60 days. A GFD requires the elimination of wheat, barley, rye, and their derivatives, including commonly consumed products such as beer. Gluten-free alternatives include rice, corn, quinoa, millet, oats, sorghum, amaranth, and buckwheat.
Clinicians must educate patients and caregivers on identifying hidden sources of gluten and avoiding cross-contamination, which may occur in processed foods, medications, or supplements. Label reading is essential, and gluten-free certification offers additional reassurance.[2] Although oats are naturally gluten-free, they must be certified as free of cross-contamination to be safely consumed and can provide nutritional benefits, including fiber and protein.
Adhering to a GFD can be challenging, and unintentional gluten exposure is common. When symptoms persist or serological markers remain positive after 2 years on a GFD, a thorough evaluation of dietary adherence is essential. Noncompliance—whether intentional or accidental—is the primary cause of treatment failure. In rare cases, patients with severe celiac disease unresponsive to dietary measures may benefit from treatment with prednisone, azathioprine, 6-mercaptopurine, or mycophenolate; however, these therapies do not replace a GFD.[49] Clinical follow-up should involve regular symptom assessment, serological testing, and, when indicated, repeat biopsy. Close monitoring helps prevent micronutrient deficiencies and reduces the risk of complications, including intestinal lymphoma.
Nutritional support involves evaluating patients for deficiencies in iron, calcium, folate, zinc, vitamin D, and vitamin B12. A gluten-free multivitamin can help support overall health. Lifelong follow-up should include periodic blood work as clinically indicated, such as a complete blood count and assessments of iron stores, ferritin, folate, vitamin D, and B12 levels.
Following a GFD can place a significant burden on individuals and their families. Gluten-free alternatives for staples such as bread, pasta, and flour are often more expensive and may be perceived as less palatable than their gluten-containing foods.[50] Families must decide whether to adopt a GFD for everyone or only for the affected individual. While the former can be financially burdensome, the latter may complicate meal preparation and contribute to feelings of isolation for the person with gluten sensitivity. Dining out presents additional challenges, often requiring careful review of menus and inquiries about hidden sources of gluten. Beer made from gluten-free grains such as sorghum, millet, rice, or buckwheat provides a safe alternative to traditional brews.[51]
Both celiac disease and NCGS are managed with a GFD, but the rationale, required strictness, and duration of adherence differ. In celiac disease, strict lifelong adherence to a GFD is crucial to prevent autoimmune-mediated intestinal damage and reduce the risk of serious long-term complications. In contrast, individuals with NCGS typically follow a GFD for symptom relief, as gluten exposure does not cause the mucosal injury or long-term health risks seen in celiac disease. For patients with gluten ataxia, a GFD may help reduce neurological deficits, although its effectiveness is not consistent across all cases.[31]
Although a GFD is also the mainstay of dermatitis herpetiformis treatment, dapsone is often used as an adjunctive therapy. Pruritus typically improves within 72 hours of initiating dapsone at doses ranging from 50 to 150 mg, with skin lesions resolving shortly thereafter. However, potential adverse effects include hypersensitivity reactions, hemolysis, particularly in individuals with G6PD deficiency, and agranulocytosis. Regular monitoring, including complete blood counts and liver and kidney function tests, is recommended. Clinicians may consider gradually tapering dapsone after 3 months of treatment and strict adherence to a GFD. If dapsone is not tolerated, alternative sulfonamide agents, such as sulfasalazine, may be used. Topical corticosteroids can help relieve itching, but systemic steroids are generally ineffective.[52](B3)
The primary treatment for gluten ataxia is a GFD, which has been shown to improve or stabilize neurological symptoms and cerebellar imaging findings. Strict adherence—often confirmed by the disappearance of antigliadin antibodies—is associated with the most favorable neurological outcomes. Although a GFD remains the cornerstone of treatment for all gluten-associated conditions, the required level of strictness and treatment goals vary depending on the diagnosis. Ongoing education, regular monitoring, and sustained support are crucial for promoting adherence, managing symptoms, and reducing the risk of complications.
Differential Diagnosis
The differential diagnoses for gluten-associated conditions include gastrointestinal and systemic disorders that can mimic the symptoms of celiac disease or NCGS. A comprehensive history, physical examination, and diagnostic evaluation, including celiac-specific serological testing and small bowel biopsy, are essential to distinguish celiac disease and NCGS from other conditions, as mentioned below.
- Irritable bowel syndrome: This condition is characterized by recurrent abdominal pain, cramping, diarrhea, constipation, and bloating.
- Inflammatory bowel disease: Conditions such as Crohn disease and ulcerative colitis may resemble celiac disease, with overlapping symptoms like abdominal discomfort, chronic diarrhea, and weight loss.
- Lactose intolerance: This condition is characterized by abdominal cramping, bloating, gas, and diarrhea, which may develop independently or as a secondary condition in celiac disease due to villous atrophy.
- Small intestinal bacterial overgrowth: This condition presents with multiple symptoms, including bloating, diarrhea, gas, nausea, fatigue, malabsorption, and unintended weight loss.
- Food allergies or sensitivities: This includes fructose intolerance, which can cause symptoms such as bloating and diarrhea.
- Autoimmune enteropathy: This is a rare and severe condition characterized by diarrhea and histopathological findings similar to celiac disease.[53]
- Tropical sprue: This is endemic to certain tropical regions and causes malabsorption. This condition is characterized by villous atrophy on biopsy and responds to antibiotic treatment.
- Giardiasis: This condition may present with diarrhea and malabsorption, and biopsy findings can include villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. The identification of Giardia trophozoites on the villous surface distinguishes it from celiac disease.[54]
- Pancreatic insufficiency: This leads to malabsorption and steatorrhea, and presents with symptoms that can mimic those of celiac disease.
- Medications: Nonsteroidal anti-inflammatory drugs (NSAIDS), olmesartan, chemotherapeutic agents, immunosuppressants, and some antibiotics can induce enteropathy with villous atrophy. Symptoms may include diarrhea, weight loss, and abdominal pain. An intestinal biopsy reveals histological findings consistent with enteropathy but not specifically celiac disease.[55]
- Wheat allergy may cause abdominal pain, bloating, diarrhea, nausea, fatigue, and headache following wheat ingestion. Symptoms can also include urticaria or exacerbation of preexisting atopic dermatitis. Initial testing typically involves skin prick tests or in vitro IgE assays, followed by a clinician-supervised double-blind, placebo-controlled oral food challenge—the gold standard for diagnosing food allergies. The rapid onset of symptoms (minutes to hours) after wheat ingestion and occasional anaphylactic reactions help distinguish wheat allergy from NCGS.[56][57]
- Up to 35% of patients with NCGS also have coexisting conditions, including IgE-mediated food allergies, lactose intolerance, or sensitivities to food additives and preservatives such as sulfites, glutamates, nitrates, and benzoates. These overlapping conditions can further complicate both diagnosis and management.[1]
- Differential diagnoses in pediatric patients include cow milk protein allergy, gastroesophageal reflux disease, cystic fibrosis, and wheat allergy. These conditions are associated with abdominal discomfort, signs of malabsorption, and poor growth. Non-IgE–mediated food allergy disorders include food protein–induced enterocolitis syndrome (FPIES), which presents with vomiting and diarrhea 2 to 4 hours after allergen ingestion and may lead to poor weight gain; proctocolitis, which causes blood-streaked, mucousy stools in infants; and food protein-induced enteropathy, which manifests as malabsorption, poor growth, and hypoproteinemia.[31]
Skin conditions that may be mistaken for dermatitis herpetiformis include atopic dermatitis, scabies, insect bites, bullous pemphigoid, and IgA bullous dermatosis.
Differential diagnoses of gluten ataxia include a range of neurological conditions that cause progressive ataxia and can be categorized by etiology, as listed below.
- Immune-mediated: Paraneoplatic cerebellar degeneration and multiple sclerosis.[58]
- Genetic: Hereditary spinocerebellar ataxia and Friedreich ataxia.[59]
- Degenerative: Multiple system atrophy, cerebellar type (MSA-C), and idiopathic late-onset cerebellar ataxia.[60]
- Toxic or nutritional: Alcohol-associated cerebellar degeneration and vitamin E deficiency ataxia.[61][62]
- Neoplastic: Posterior fossa tumors
- Vascular: Cerebellar stroke.[63]
Prognosis
With early diagnosis and strict adherence to a GFD, the prognosis for celiac disease is generally excellent. Most patients experience significant symptom relief within weeks to months, and mucosal healing typically occurs within 6 to 24 months, depending on the severity of intestinal damage at the time of diagnosis. Long-term adherence to a GFD reduces the risk of complications, including malnutrition, osteoporosis, anemia, autoimmune disorders, and malignancies, such as enteropathy-associated T-cell lymphoma.[64] However, a subset of patients may not respond to a strict GFD and develop refractory celiac disease, which has a poorer prognosis and requires further evaluation and specialized management.
Dermatitis herpetiformis is often a chronic, lifelong condition that requires adherence to a GFD and treatment with dapsone to manage symptoms. In rare cases, patients may be able to discontinue both the GFD and medication, although this requires careful monitoring for symptom recurrence. Unlike celiac disease, isolated dermatitis herpetiformis is not associated with increased mortality, likely because the primary site of injury is the skin rather than the gastrointestinal tract.[65][66]
The prognosis for NCGS is generally more favorable than that of celiac disease, as symptoms typically resolve with a GFD, and there is no known association with long-term complications. However, the natural history of NCGS remains poorly understood due to the absence of reliable biomarkers and standardized diagnostic criteria, and some individuals may experience fluctuating symptoms that require ongoing dietary management.[10]
The prognosis for gluten ataxia depends on the duration of symptoms before diagnosis and strict adherence to a GFD. Early diagnosis and treatment can slow disease progression and, in some cases, improve neurological function. However, delayed diagnosis and poor compliance with the GFD may lead to irreversible neurological damage due to permanent cerebellar atrophy.[67]
Complications
Complications of celiac disease primarily result from chronic intestinal inflammation and nutrient malabsorption. Common sequelae include vitamin and mineral deficiencies, which may lead to anemia, glossitis, peripheral neuropathy, delayed wound healing, impaired immune function, and osteoporosis with an increased risk of fractures. If left untreated, celiac disease is associated with increased mortality. In children, it may cause delayed puberty, rickets, and dental enamel hypoplasia. Even with adherence to a GFD, individuals remain at elevated risk for infertility, adverse pregnancy outcomes, and enteropathy-associated malignancies, such as T-cell lymphomas and small intestinal adenocarcinomas.[68][69][70]
Additionally, celiac disease is associated with several other autoimmune conditions, including type 1 diabetes, autoimmune thyroiditis, IgA deficiency, eosinophilic esophagitis, and autoimmune pancreatitis. Celiac disease also increases susceptibility to pneumococcal infections, such as sepsis and pneumonia, even in patients who adhere to a GFD. Clinical practice guidelines recommend pneumococcal vaccination for all individuals with celiac disease, especially those who did not complete the full pneumococcal immunization series during childhood.[45]
Complications of dermatitis herpetiformis include an increased risk of lymphoma, although this is less than the risk associated with celiac disease.[27] Long-term treatment with dapsone for symptom control may cause hemolysis or methemoglobinemia.
NCGS is not associated with established long-term complications such as malignancy, malabsorption, or increased mortality. While some evidence suggests a link between NCGS and certain autoimmune or functional disorders, a causal relationship has not been established. Additionally, long-term adherence to a GFD without medical supervision may lead to unintended nutritional imbalances.[71]
Complications of gluten ataxia include progressive and potentially irreversible cerebellar atrophy, leading to persistent limb and gait ataxia, dysarthria, and oculomotor abnormalities. Neurological impairment may continue to progress in some patients despite adherence to a GFD, particularly when diagnosis and treatment are delayed.
Deterrence and Patient Education
Deterrence focuses on minimizing symptom recurrence and reducing the risk of long-term complications through early identification and management of gluten-associated medical conditions. This includes genetic counseling for individuals at risk for celiac disease, screening of first-degree relatives, and educating patients on the importance of strict adherence to a GFD to prevent mucosal damage and related complications. In cases of NCGS and gluten ataxia, deterrence may involve raising awareness of subtle or extraintestinal symptoms to facilitate earlier evaluation and dietary intervention.
The US Preventive Services Task Force advises that current evidence is insufficient to assess the benefits and harms of routine screening for celiac disease in asymptomatic individuals, and therefore does not formally recommend it.[32] However, screening may identify asymptomatic or mildly symptomatic individuals, potentially reducing their risk of long-term complications associated with celiac disease. Clinicians should carefully weigh the benefits of early diagnosis against the challenges of adhering to a restrictive GFD, which can negatively impact quality of life.[17]
Clinicians should educate patients and caregivers on how to identify gluten-containing foods, read food labels carefully, and prevent cross-contamination during food preparation to ensure effective management of celiac disease. Notably, it is also important to raise awareness about hidden sources of gluten in medications, supplements, and processed foods. Common gluten-containing items include wheat flour, rye, barley, bread, most bakery products, crackers, baking mixes, pasta, cereal, certain sauces and condiments, processed meats, beer, ale, lager, and malt vinegar. In contrast, foods such as rice, corn, quinoa, oats (if certified gluten-free), potatoes, soybeans, fruits, vegetables, meats, eggs, wine, and distilled alcoholic beverages are generally gluten-free and considered safe.
Misinformation about gluten is widespread in the media and popular culture. Helpful and accurate information can be found through medical organizations and celiac disease advocacy organizations. Many individuals without a diagnosis of celiac disease or gluten sensitivity choose to avoid gluten-containing foods. This trend is fueled in part by widespread media coverage, celebrity endorsements, and popular diet culture that portray gluten as inherently harmful, despite a lack of scientific evidence. Gluten-free products are often marketed as healthier or more weight-loss friendly than their gluten-containing counterparts, but this is frequently misleading. In reality, many gluten-free processed foods are lower in fiber and protein and higher in sugar, fat, and refined starches, which may lead to poor satiety and potential weight gain when consumed in excess. Unnecessary adherence to a GFD can also make social eating more difficult and is often more expensive due to the higher cost of gluten-free alternatives.
Clinicians play a crucial role in educating patients about gluten-associated medical conditions by clearly differentiating between celiac disease, NCGS, and media-driven health beliefs that do not justify a GFD. Patient education should emphasize evidence-based guidance on diagnosis, management, and the nutritional implications of a GFD, while also addressing common misconceptions and the psychosocial challenges associated with long-term dietary restrictions.
Enhancing Healthcare Team Outcomes
Effective management of gluten-associated medical conditions relies on a collaborative interprofessional healthcare team, including physicians, advanced practice providers, nurses, pharmacists, and registered dietitians. Physicians and advanced practitioners diagnose and manage these disorders, interpret test results, and monitor patient symptoms. Nurses play a vital role in educating and supporting patients by reinforcing dietary recommendations and monitoring for complications during follow-up visits. Pharmacists play a crucial role in reviewing medications and supplements for hidden gluten sources and advising patients on safe alternatives. Registered dietitians provide specialized guidance on implementing and maintaining a nutritionally balanced GFD, addressing the risks of cross-contamination, and accurately interpreting food labels. This coordinated team approach enhances patient safety, promotes adherence, reduces complications, and ultimately improves clinical outcomes and quality of life for individuals with gluten-associated conditions.
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