What are the extraintestinal manifestations of celiac disease?

Extraintestinal Manifestations of Celiac Disease

Celiac disease frequently presents with extraintestinal manifestations that may occur without any gastrointestinal symptoms, affecting multiple organ systems including bone, neurological, hematological, dermatological, hepatic, and reproductive systems. 1, 2

Musculoskeletal Manifestations

Bone disease represents one of the most common and well-documented extraintestinal manifestations:

• Osteopenia and osteoporosis occur frequently in untreated celiac disease, with worldwide prevalence ranging from 1.7% to 42% depending on biological sex, geography, age at diagnosis, and clinical phenotype 1
• Increased fracture risk shows a 60-100% excess compared to the general population before diagnosis, though this normalizes after the first year on a gluten-free diet despite persistent low bone mineral density 1
• Arthralgia and arthritis are documented extraintestinal symptoms in both pediatric and adult populations 3, 4

The pathophysiology extends beyond simple malabsorption—genetics, local and systemic immunological factors, lack of physical activity, and potential microbiota abnormalities all contribute to bone deterioration 1

Neurological and Psychiatric Manifestations

Neurological involvement represents a significant category of extraintestinal disease:

• Cerebellar ataxia is a well-established neurological complication 1, 5, 6
• Peripheral neuropathy occurs as both a complication and presenting manifestation 1, 5, 6
• Epilepsy and seizures are documented in both children and adults 1, 5, 3, 4
• Headache is common, affecting 20% of children and 24% of adults at presentation 4
• Depression and psychiatric disorders affect approximately 24% of adults with celiac disease 1, 4
• Cognitive impairment, dementia, and encephalopathy have been reported 5, 6
• Other neurological syndromes include migraine, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, and Guillain-Barré-like syndrome 5

Recent evidence suggests these manifestations relate to gluten-mediated pathogenesis through antibody cross-reaction, immune-complex deposition, direct neurotoxicity, and the gut-liver-brain axis 6

Hematological Manifestations

• Iron deficiency anemia is the most common hematological manifestation, affecting 48% of adults at presentation and often resistant to oral iron supplementation 7, 4
• Anemia may occur even in the absence of gastrointestinal symptoms 2, 7

Dermatological Manifestations

• Dermatitis herpetiformis is a specific skin manifestation of celiac disease 3, 4
• Alopecia occurs in both pediatric and adult populations 3, 4
• Non-specific rashes are documented extraintestinal symptoms 3, 4
• Stomatitis (oral mucosal inflammation) affects both age groups 3, 4

Hepatic Manifestations

• Abnormal liver enzymes occur as an extraintestinal manifestation in both children and adults 3, 4
• Patients with autoimmune liver disease should be screened for celiac disease 2

Reproductive and Endocrine Manifestations

• Infertility and recurrent miscarriages are associated with untreated celiac disease 1, 7, 3, 4
• Adverse pregnancy outcomes occur in undiagnosed disease 1
• Short stature is the most common extraintestinal manifestation in children (33%), though 28% of those unresponsive to gluten-free diet have other comorbidities 1, 4
• Delayed puberty affects pediatric patients 3, 4

Constitutional Symptoms

• Fatigue is extremely common, affecting 28% of children and 37% of adults at presentation 3, 4
• Myalgia (muscle pain) occurs in both populations 3, 4

Associated Autoimmune Conditions

Celiac disease clusters with other autoimmune disorders, which themselves may be considered extraintestinal manifestations:

• Type 1 diabetes (prevalence 5-10% in celiac patients) 2
• Autoimmune thyroid disease (3% prevalence of celiac disease in thyroid patients) 2
• Down syndrome (5.5% confirmed celiac prevalence) 2
• Turner syndrome (6.3% celiac prevalence) 2

Critical Clinical Pitfalls

Many patients present exclusively with extraintestinal symptoms without gastrointestinal complaints, leading to significant diagnostic delay 1, 2, 7. The British Society of Gastroenterology notes that the proportion of newly diagnosed patients with classic malabsorptive symptoms has decreased over time, while non-classical and asymptomatic presentations have gained prominence 2. Only 24% of those with celiac disease are diagnosed, creating a "celiac iceberg" of undiagnosed cases 2, 7.

Response to Gluten-Free Diet

Children demonstrate significantly higher rates of extraintestinal symptom resolution compared to adults, with greater improvement in gastrointestinal versus extraintestinal symptoms at more than 24 months 3. Long duration of symptoms, female sex, and non-adherence to gluten-free diet are the most important predictors of failure to clinically improve 3. Most serological and neurophysiological findings can revert to normal with rigorous gluten-free diet 6.

Left undiagnosed and untreated, even asymptomatic celiac disease leads to higher risk of complications including osteoporosis, infertility, and small bowel lymphoma 2.