History and exam

Key diagnostic factors

common

diarrhoea

Patients with long-standing or refractory abdominal symptoms should be screened for coeliac disease.[68] Patients may present with chronic or intermittent diarrhoea.

bloating

Patients with long-standing or refractory abdominal symptoms should be screened for coeliac disease.[68]

abdominal pain/discomfort

Patients with long-standing or refractory abdominal symptoms should be screened for coeliac disease.[68] Patients may present with recurrent abdominal pain, cramping, or distension.[84]

anaemia

Iron deficiency anaemia is a frequent clinical presentation in adults. One systematic review and meta-analysis showed that 1 in 31 patients with iron deficiency anaemia had histological evidence of coeliac disease.[86] 

Folate (and rarely vitamin B12) deficiency may lead to a macrocytic anaemia.[87]

immunoglobulin (IgA) deficiency

Multiple studies have shown an association between IgA deficiency and coeliac disease. Although the pathogenesis is unclear, it has been proposed that a lack of secretory IgA and Peyer's patch malfunction allow for increased free gluten peptides in the submucosa.[38]

uncommon

dermatitis herpetiformis

Characterised 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.[87] Biopsy-proven dermatitis herpetiformis almost universally occurs in association with coeliac 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@4895caba

Other diagnostic factors

common

family history

Family history of coeliac disease or other autoimmune disorders. Members of families who have more than one individual with coeliac disease are at higher risk of developing the disease.[34] HLA testing may be appropriate in siblings of probands, to determine risk of developing coeliac disease and need for monitoring.[34]

osteopenia/osteoporosis

History of bone pain or previous fracture, due to vitamin D deficiency and hypocalcaemia. 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 multi-factorial; screening for depression, sleep disorders, and thyroid disease is advisable, especially in the absence of iron deficiency anaemia.[92][93]

weight loss

Likely to be multi-factorial, primarily due to malabsorption and due to changes in motility, metabolism, and appetite.[87] 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 coeliac disease.[95] Children and adolescents with coeliac disease have shorter stature.[90] There could be a benefit to screen for coeliac disease among individuals with short stature.[96]

uncommon

type 1 diabetes

The association between type 1 diabetes mellitus and coeliac disease is well known.[39][88]​ 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 coeliac disease.[73] European guidelines recommend routine screening for coeliac disease among patients with type 1 diabetes, but optimal screening intervals have not been established.[34][89]

autoimmune thyroid disease

Clinicians caring for patients with autoimmune thyroid disease should be aware of the association with coeliac disease and consider testing if symptoms occur.[46][73]

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 coeliac disease.[99] 

dental enamel hypoplasia

The exact aetiology is unclear but may be due to nutritionally derived abnormalities in mineralisation. 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 aetiology of neurological 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 neurological symptoms. Although it is triggered by gluten ingestion, most people with gluten ataxia do not have coeliac disease.[103] Rapid introduction of a gluten-free diet helps prevent irreversible cerebellar damage.[102][104]

unexplained elevation of serum aminotransferase levels

Coeliac disease may be the cause of 2% to 12% of cases of cryptogenic elevation of serum aminotransferases.[105] Elevated serum aminotransferases typically normalise 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 coeliac 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 coeliac 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 coeliac disease and improvement in psychiatric symptoms occurred in 55% of patients following a gluten-free diet.[91]

Risk factors

strong

family history of coeliac disease

Multiple studies have shown an increased risk in family members, probably secondary to genetic factors.[32][33]​ Members of families who have more than one individual with coeliac 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 coeliac 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 coeliac disease is well known.[39] One meta-analysis found a weighted prevalence of coeliac disease of 4.5% among patients with type 1 diabetes.[40] This association is probably based on genetic factors favouring 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 hypothesised, 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 coeliac disease in patients with type 1 diabetes.[43]​ European guidelines recommend routine screening for coeliac 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 coeliac disease. Pathogenesis is similar to that of type 1 diabetes mellitus.[45] Coeliac disease may be more prevalent in individuals with hyperthyroidism than in those with hypothyroidism.[46] Unexplained increasing need for levothyroxine or treatment-refractory hypothyroidism should also lead to coeliac disease testing.[47][48] Correspondingly, patients with coeliac disease should be screened for thyroid disease.[49]

Down's syndrome

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

Turner's syndrome

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

weak

Sjogren's syndrome

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

inflammatory bowel disease

A systematic review and meta-analysis found an increased prevalence of coeliac disease in patients with Crohn's 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 coeliac 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 coeliac disease in people with primary biliary cholangitis, compared with other liver diseases.[59]

psoriasis

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

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