History and exam

Key diagnostic factors

common

diarrhea

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[68] Patients may present with chronic or intermittent diarrhea.

bloating

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[68]

abdominal pain/discomfort

Patients with longstanding or refractory abdominal symptoms should be screened for celiac disease.[68] Patients may present with recurrent abdominal pain, cramping, or distension.[86]

anemia

Iron deficiency anemia is a frequent 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.[87]

Folate (and rarely vitamin B12) deficiency may lead to a macrocytic anemia.[88]

immunoglobulin (IgA) deficiency

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.[38]

uncommon

dermatitis herpetiformis

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.[88] Biopsy-proven dermatitis herpetiformis almost universally occurs in association with celiac disease.[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].com.bmj.content.model.Caption@792e978d

Other diagnostic factors

common

family history

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.[34]

osteopenia/osteoporosis

History of bone pain or previous fracture, due to vitamin D deficiency and hypocalcemia. Low bone mineral density can be present early in childhood or teenage years.[90]

fatigue

Frequent at diagnosis, with a prevalence of 37%.[91] May be multifactorial; screening for depression, sleep disorders, and thyroid disease is advisable, especially in the absence of iron deficiency anemia.[92][93] 

weight loss

Likely multifactorial, primarily due to malabsorption and due to changes in motility, metabolism, and appetite.[88] One study reported that 25% of newly diagnosed patients had weight loss at the time of presentation.[94]

failure to thrive

In children, faltering growth and delayed puberty are indications for testing for celiac disease.[95] Children and adolescents with celiac disease have shorter stature.[90] There could be a benefit to screen for celiac disease among individuals with short stature.[96]

uncommon

type 1 diabetes

The association between type 1 diabetes mellitus and celiac disease is well known.[39][89]​ 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.[70] 

autoimmune thyroid disease

Clinicians caring for patients with autoimmune thyroid disease should be aware of the association with celiac disease and consider testing if symptoms occur.[46][70]

aphthous stomatitis

Association mostly reported in children.[97] Caused by various nutritional deficiencies; may be triggered by gluten exposure and responds to a gluten-free diet.[98] However, differential diagnosis is broad and the process may not be related to celiac disease.[99] 

dental enamel hypoplasia

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.[97][100]

easy bruising

Vitamin K deficiency may lead to coagulopathy.

peripheral neuropathy

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.[101][102] 

ataxia

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.[103] Rapid introduction of a gluten-free diet helps prevent irreversible cerebellar damage.[102][104]

unexplained elevation of serum aminotransferase levels

Celiac disease may be the cause of 2% to 12% of cases of cryptogenic elevation of serum aminotransferases.[105] Elevated serum aminotransferases typically normalize on a gluten-free diet, unless there is another co-existing liver disorder.[106]

comorbid psychiatric diagnosis

A systematic review and meta-analysis showed an association between celiac disease and an increased risk of depression, anxiety, eating disorders as well as autism spectrum disorder and attention deficit hyperactivity disorder (ADHD).[107]​ However, the associations with ADHD and autism spectrum disorders are still controversial.[108][109] Moreover, distinguishing between specific manifestations of celiac disease and the consequences of suffering from a chronic gastrointestinal disorder and following a strict diet can be challenging. Psychiatric disorders are found among 24% of adults at diagnosis of celiac disease and improvement in psychiatric symptoms occurred in 55% of patients following a gluten-free diet.[91]

Risk factors

strong

family history of celiac disease

Multiple studies have shown an increased risk in family members, likely secondary to genetic factors.[32][33]​ Members of families who have more than one individual with celiac disease are at a higher risk of developing the disease.[34] Concordance among identical twins has ranged from 49% to 86%.[35][36]​ European guidelines have suggested screening asymptomatic first-degree relative with HLA typing.[34] In contrast, guidelines from the United States Preventive Services Task Force state that the evidence is insufficient to recommend for or against screening if relatives are asymptomatic.[37]

immunoglobulin A deficiency

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.[38]

type 1 diabetes

The association between type 1 diabetes mellitus and celiac disease is well known.[39] One meta-analysis found a weighted prevalence of celiac disease of 4.5% among patients with type 1 diabetes.[40] 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.[41][42][43]​​​ 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.[44] One systematic review found that killer immunoglobulin-like receptor genes, enterovirus infection in gut cells, and gut microbiota dysbiosis with the predominance of Bacteroides species were involved in the pathogenesis and development of celiac disease in patients with type 1 diabetes.[43]​ European guidelines recommend routine screening for celiac disease among patients with type 1 diabetes, but optimal screening intervals have not been established.[34]

autoimmune thyroid disease

Multiple studies have shown an association between thyroid disease and celiac disease. Pathogenesis is similar to that of type 1 diabetes mellitus.[45] Celiac disease may be more prevalent in individuals with hyperthyroidism than those with hypothyroidism.[46] Unexplained increasing need for levothyroxine or treatment-refractory hypothyroidism should also lead to celiac disease testing.[47][48] Correspondingly, patients with celiac disease should be screened for thyroid disease.[49]

Down syndrome

Patients with Down syndrome have a six-fold increased risk of celiac disease.[50] The mechanism is unclear because celiac disease does not appear to be linked to genes found on chromosome 21.[51]

Turner syndrome

Celiac disease affects 1 in 22 patients with Turner syndrome.[52]​ The exact underlying mechanism is unclear. One possible explanation may be the susceptibility of patients with Turner syndrome to develop autoimmune diseases.[53][54]

weak

Sjogren syndrome

Some studies have shown an increased prevalence of celiac disease in patients with Sjogren syndrome.[55]

inflammatory bowel disease

A systematic review and meta-analysis found an increased prevalence of celiac disease in patients with Crohn disease and, to a lesser extent, in patients with ulcerative colitis.[56]​ This was subsequently confirmed in a large population-based study.[57]

primary biliary cholangitis

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.[58]​ One cohort study found an increased prevalence of celiac disease in people with primary biliary cholangitis, compared with other liver diseases.[59]

psoriasis

Meta-analysis has shown an association between psoriasis and celiac disease. Patients with psoriasis have twofold increased risk of celiac disease, compared with those without psoriasis.[60]

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