History and exam

Key diagnostic factors

Multiple studies have shown an association between IgA deficiency and celiac disease. Although the pathogenesis is unclear, it has been proposed that a lack of secretory IgA and Peyer patch malfunction allow for increased free gluten peptides in the submucosa.[24]

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[41] Patients may present with chronic or intermittent diarrhea.

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[41]

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[41] Patients may present with recurrent abdominal pain, cramping, or distension.[52]

Iron deficiency anemia is the most common clinical presentation in adults. One systematic review and meta-analysis showed that 1 in 31 patients with iron deficiency anemia had histologic evidence of celiac disease.[53]

Folate (and rarely vitamin B12) deficiency may lead to a macrocytic anemia.[54]

Characterized by intensely pruritic papulovesicular lesions that occur symmetrically over the extensor surfaces of the arms and legs, as well as on the buttocks, trunk, neck, and scalp.[54] Biopsy-proven dermatitis herpetiformis almost universally occurs in association with celiac disease.com.bmj.content.model.Caption@3f162748[Figure caption and citation for the preceding image starts]: Dermatitis herpetiformis: typical lesions on extensor surface of forearmFrom the collection of Adam Reich MD, PhD [Citation ends].

Other diagnostic factors

Family history of celiac disease or other autoimmune disorders. Members of families who have more than one individual with celiac disease are at higher risk of developing the disease.[23]

History of bone pain or previous fracture, due to vitamin D deficiency and hypocalcemia.

Frequent at diagnosis, with a prevalence of 37%.[59] May be multifactorial; screening for depression, sleep disorders, and thyroid disease is advisable, especially in the absence of iron deficiency anemia.[60][61] 

Likely multifactorial, primarily due to malabsorption but also to changes in motility, metabolism, and appetite.[54] One study reported that 25% of newly diagnosed patients had weight loss at the time of presentation.[62]

In children, faltering growth and delayed puberty are indications for testing for celiac disease.[63]

The association between type 1 diabetes mellitus and celiac disease is well known.[25] Clinicians caring for patients with type 1 diabetes mellitus should consider testing these patients if there are any digestive symptoms or laboratory changes to suggest celiac disease.[55] 

Clinicians caring for patients with autoimmune thyroid disease should be aware of the association with celiac disease and consider testing if symptoms occur.[31][55] Unexplained increasing need for levothyroxine or treatment-refractory hypothyroidism should also lead to celiac disease testing.[56][57] Correspondingly, patients with celiac disease should be screened for thyroid disease.[58]

Association mostly reported in children.[64] Caused by various nutritional deficiencies; may be triggered by gluten exposure and responds to a gluten-free diet.[65] However, differential diagnosis is broad and the process may not be related to celiac disease.[66] 

The exact etiology is unclear but may be due to nutritionally derived abnormalities in mineralization. It is mostly found in children, at the time of the formation of secondary teeth.[64][67]

Vitamin K deficiency may lead to a coagulopathy.

The etiology of neurologic dysfunction may be the result of either vitamin deficiencies (B12, E, or D; folate or pyridoxine) or autoimmune activity against neural antigens. Peripheral neuropathy may persist despite a gluten-free diet.[68][69] 

Cerebellar ataxia is one of the most studied neurologic symptoms. Although it is triggered by gluten ingestion, most people with gluten ataxia do not have celiac disease.[70] Rapid introduction of a gluten-free diet helps prevent irreversible cerebellar damage.[69][71]

Celiac disease may be the cause of 2% to 12% of cases of cryptogenic elevation of serum aminotransferases.[72] Elevated serum aminotransferases typically normalize on a gluten-free diet.[73]

Risk factors

Multiple studies have shown an increased risk in family members, likely secondary to genetic factors.[21][22] Members of families who have more than one individual with celiac disease are at higher risk of developing the disease.[23]

Multiple studies have shown an association between immunoglobulin A (IgA) deficiency and celiac disease. Although the pathogenesis is unclear, it has been proposed that a lack of secretory IgA and Peyer patch malfunction allow for increased free gluten peptides in the submucosa.[24]

The association between type 1 diabetes mellitus and celiac disease is well known.[25] One meta-analysis found a weighted prevalence of celiac disease of 4.5% among patients with type 1 diabetes.[26] This association is probably based on genetic factors favoring autoimmunity, including the presence of human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 and single nucleotide polymorphisms shared by both diseases.[27][28] Leaky gut, with tight junction defects leading to increased passage of luminal peptides into the submucosa, resulting in immune activation, is also hypothesized, as well as enhanced basal expression of inflammatory markers.[29]

Multiple studies have shown an association between thyroid disease and celiac disease. Pathogenesis is similar to that of type 1 diabetes mellitus.[30] Celiac disease may be more prevalent in individuals with hyperthyroidism than those with hypothyroidism.[31]

Patients with Down syndrome have a six-fold increased risk of celiac disease.[32] The mechanism is unclear because celiac disease does not appear to be linked to genes found on chromosome 21.[33]

Some studies have shown an increased prevalence of celiac disease in patients with Sjogren syndrome.[34]

A few studies have shown an increased prevalence of celiac disease in patients with Crohn disease and, to a lesser extent, ulcerative colitis.[35]

Studies have shown an increased prevalence of celiac auto-antibodies in patients with primary biliary cholangitis and other liver diseases, but false positives appear higher in these populations.[36]

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