The Latest Research: Extraintestinal Manifestations of Celiac Disease

Background

Celiac Disease (CeD) is an autoimmune disorder triggered by an abnormal immune

response to the protein gluten. Diagnosis of CeD is a multi-step process that includes clinical history, serology, histology, symptom improvement and antibody response following implementation of a gluten-free diet (GFD). Currently, the only treatment for CeD is a lifelong GFD. Poor management of CeD can result in severe damage to the small intestine and malabsorption of key nutrients (Lebwohl, 2019). 

Though more research is warranted to fully understand the factors that lead to CeD onset, the type of gluten ingested, maternal diet during breastfeeding, duration of breastfeeding and timing of introduction of gluten do not appear to increase risk for CeD development. However, emerging research does suggest the amount of gluten consumed in the first two years of life has been associated with increased risk for CeD onset in those with a genetic predisposition for CeD (Lebwohl, 2021).

Delayed diagnosis of CeD is a common challenge patients face in the medical system, with an average time to diagnosis of 11 years following symptom onset (Lebwohl, 2021). While prevalence is roughly 1% globally, incidence rates do vary based on differences in diagnostic criteria and diagnosis rates (Lebwohl, 2021). The many symptoms and varied presentation of CeD significantly contribute to these diagnosis challenges.

Clinical Manifestations of CeD

There are over 200 signs and symptoms of CeD. These include both gastrointestinal and systemic presentations and vary highly from patient to patient. Nutrient deficiencies are common with CeD and can be related to inadequate intake or malabsorption in the small intestine. Nutrients of concern include calcium, vitamin D, vitamin B12, folate and iron (El-Matary). 

Following transition to a GFD, malabsorption should improve and nutrient deficiencies are often expected to resolve, though full reversal of nutrient deficiencies can take time. Education on good, gluten-free nutrient sources is important to ensure dietary adequacy long-term and temporary use of a multivitamin or other supplementation may be warranted following initial diagnosis and transition to a GFD.

Clinical Manifestations: Skin

The most common dermatological manifestation of CeD is dermatitis herpetiformis, a chronic, intensely itchy, blistering skin rash that affects roughly 10% of those with CeD (Therrien, 2023). With dermatitis herpetiformis, the elbows, knees and buttocks are some of the most severely affected areas. Dermatitis herpetiformis is more commonly seen in men and in adults and this delayed onset may be a result of the long-term stimulation of the immune system, which contributes to pronounced symptoms (Therrien, 2023). Diagnosis by a trained dermatologist is vital for accurate assessment and medical management. 

Other skin-related symptoms of CeD include psoriasis, an inflammatory autoimmune disease that disproportionately affects those with CeD. In the presence of CeD, psoriasis generally resolves with transition to a GFD. However, note that for those without CeD who have psoriasis a GFD is not indicated treatment. Other rare skin-related conditions include chronic urticaria, leucocytoclastic vasculitis and alopecia areata, all of which generally resolve with a GFD (Therrien, 2023).

Clinical Manifestations: Neurological

The prevalence of neurological symptoms among those with CeD is high, ranging from 6-10% in treated CeD patients and up to 42% in untreated CeD patients (Therrien, 2020). The reasons for these symptoms are not fully understood, but some proposed mechanisms include a connection between cross-reactive antibodies, immune complex deposition, neurotoxicity from gluten ingestion and vitamin and mineral deficiencies. Various neurological presentations of untreated CeD may include chronic headaches and migraines, peripheral neuropathy, brain fog, epilepsy and cognitive defects (Therrien, 2020). Some research suggests gluten affects the brain and causes inflammation or damage, which may also contribute to these symptoms.

Gluten ataxia is another significant neurological manifestation of CeD. It is an immune-mediated condition where the body attacks the nervous system in response to gluten ingestion and leads to symptoms such as poor coordination, tingling in the extremities, and difficulty speaking, among others. Gluten ataxia is often observed in patients at an older age and without traditional gastrointestinal symptoms of CeD, making diagnosis particularly challenging (Croall). Other reasons why neurological symptoms with CeD are often overlooked are related to a lack of clinical consensus on diagnosis and the varied presentation of these conditions. 

Clinical Manifestations: Bones & Oral

Osteoporosis is also highly common with CeD and risk is increased among those with CeD, affecting 26-72% of patients with CeD (Therrien, 2020). This increased risk and prevalence is likely tied to nutrient deficiencies commonly seen with CeD, which affect bone development, mineralization and bone mineral density loss. In addition to a GFD, supplementation is often necessary to restore nutrient balance and reduce the risk CeD poses for bone health complications.

Further, the oral cavity is also highly affected by CeD. Presentation of oral complications related to CeD may include enamel defects, delayed dental eruption, and recurrent canker sores or inflammation (aphthous stomatitis) related to nutrient deficiencies, all of which generally improve with a GFD (Durazzo).

Clinical Manifestations: Hormonal

Hypothyroidism (an underactive thyroid) and hyperthyroidism (an overactive thyroid) can also be signs and symptoms of CeD. Hypothyroidism is more common among patients with CeD and can include weight gain, constipation, slowed heart rate and fatigue, while hyperthyroidism generally presents with weight loss, frequent bowel movements, increased heart rate and fatigue.

Hashimoto’s Disease is an autoimmune thyroid disease where the immune system attacks the thyroid gland, causing a decrease in thyroid hormone production. While 5-10% of adults in the general population are affected by autoimmune thyroid disease and treatment is not always necessary, prevalence among CeD patients is 20-40% (Therrien, 2020). For pediatrics, clinical manifestations may also include decreases in growth, delayed puberty or impacted school performance (Weisbrod). Treatment for both adults and pediatrics includes thyroid hormone replacement.

Note that autoimmune thyroid diseases like Hashimoto’s Disease are not a manifestation of CeD, but rather a result of common genetic predispositions and shared immunity pathways. This is also the case with type 1 diabetes (T1D), where there is a high prevalence of concurrent T1D and CeD due to a common genetic predisposition and shared immunity pathways (Therrien, 2020).

Lastly, among girls, CeD has also been associated with delayed menarche of at least 2 years among untreated females. Amenorrhea may be a frequent complication of poorly managed CeD as well. Menopause may also start earlier among women with untreated CeD women and sex hormones may also be affected by malnutrition and nutritional deficiencies (Therrien, 2020). 

Clinical Manifestations: Liver

Autoimmune liver diseases have also been associated with CeD related to intestinal inflammation and immune reactions to gluten. Manifestations include celiac hepatitis, also referred to as gluten-induced hepatitis, which involves elevated liver enzymes. Abnormal liver enzymes are common at the time of initial CeD diagnosis and generally resolve following implementation of a GFD, though chronic elevation warrants further testing and medical management (Therrien, 2020). 

Liver steatosis may also occur with CeD, potentially due to altered intestinal permeability, alteration of the liver tissue transglutaminase (TTG) by CeD antibodies or changes in macronutrient intake related to a GFD, which may be higher in saturated fat and calories (Aggarwal). Emerging research seeks to understand the high prevalence of fatty liver and metabolic syndrome in patients with CeD and the role of gluten-free foods in the risk for non-alcoholic fatty liver disease (NAFLD) (Alberto).

Clinical Manifestations: Cardiovascular

Patients with CeD also have a higher risk of developing cardiovascular disease, such as myocardial infarction and atrial fibrillation. However, the link between CeD and other cardiovascular events, such as stroke, heart failure and cardiac arrhythmias is unclear. While patients with CeD generally have a lower prevalence of cardiac risk factors, including smoking, hypertension, hyperlipidemia and obesity, the GFD diet may put them at higher risk for cardiovascular disease due to the increased consumption of saturated fat and sugar and decreased intake of complex whole grains associated with a poorly implemented GFD (Wang, 2023). These findings further underline the need for appropriate dietary counseling on the GFD to ensure nutritional balance by building a diet rich in gluten-free whole grains and other fiber-rich, plant-based foods.

Conclusion

CeD presents in many ways and varies highly between patients. Continued findings on the diverse manifestations of CeD underline the importance of asking patients for the full picture of issues they may be experiencing beyond the gastrointestinal. Remain cognizant of the extraintestinal symptoms of CeD that may warrant additional medical intervention to reduce downstream complications and improve quality of life. 

Work closely with a multidisciplinary medical team to treat all symptoms of CeD, both gastrointestinal and otherwise. Successful management of CeD requires regular follow up to ensure dietary adherence and symptom management