Celiac Disease

❓What❓

• Genetic predisposition (HLA-DQ2/DQ8 positivity) ⊕ Gluten consumption → progressive immune-mediated enteropathy of the small bowel → local intestinal syndrome (occult vs. classic) & numerous extra-intestinal symptoms, which can present with minimal-to-no GI symptoms & be *profound*!

❓Epidemiology❓

• Classically seen in people of European descent, but increasingly recognized in other continents; while global serologic prevalence is ~1%, for each seropositive patient diagnosed, ~5-10 seropositive individuals remain undiagnosed due to atypical symptoms

• Risk factors include 1st/2nd degree relatives (~2-20%), autoimmune predilection (e.g. type 1 diabetes, ~3-12%; autoimmune thyroiditis ~4-7%, Sjögren ~4-12%), female sex, & HLA-DQ2/DQ8 positivity*

• While HLA-DQ2/DQ8 positivity is essentially required for the diagnosis, only a fraction of these individuals who consume gluten develop the disease, thus suggesting a strong environmental factor

• Over time, the most common clinical presentation of Celiac disease has shifted from symptoms of malabsorption in childhood to milder multi-organ manifestations that present in both childhood & adulthood, reflecting the systemic nature of the disease remaining unrecognized

* = prevalence of Celiac disease in each group

❓Presentation❓

Intestinal 🌾

• Malabsorption → Nutrient deficiencies, Bloating, Diarrhea
• Small bowel dilatation, jejunoileal fold pattern reversal

Extra-intestinal 🌾

• Minimal-to-no GI symptoms but…
• Mesenteric & RP lymphadenopathy (fluid-fat level, central necrosis)
• Enteropathy-associated T-cell lymphoma vs. Nodular lymphoid hyperplasia

• Diffuse arthralgia (vague) > synovitis (non-erosive)
• Osteoporosis (secondary hyperPTH)
• Osteomalacia (severe vitamin D deficiency)

• Dermatitis herpetiformis (pruritic clustered vesicles, extensor surfaces + scalp)
• Chronic urticaria, eczema, psoriasis, rosacea, alopecia, leukocytoclastic vasculitis
• Recurrent aphthous stomatitis (direct gluten sensitivity vs. deficiency of vitamins A/B12/folate)
• Dental enamel defects (discoloration → structural compromise)

Neurologic 🧠

• Neuropsychiatric (e.g. anxiety, depression, ADHD, psychosis)
• Episodic headaches (potentially vasculitis; MRI brain usually ⊖)
• Ataxia (common, ranging from mild → severe)
• Sensory polyneuropathy/ganglionopathy (mild, subclinical → significant)
• Epilepsy (posterior cerebral calcifications)
• Leukoencephalopathy

• Malnutrition ⊕ (dry eye → keratomalacia 2/2 vitamin A deficiency; night blindness 2/2 vitami nA deficiency; cataracts 2/2 vitamin D deficiency-mediated hypocalcemia; blurry vision 2/2 pseudotumor cerebri 2/2 vitamin A deficiency)
• Malnutrition ⊖ (blurry vision vs. vision loss 2/2 uveitis, occipital cortex calcification; diplopia 2/2 orbital myositis)

• Hypercoagulability (↓ B12 → ↑ homocysteine, ↓ vitamin K → ↓ protein C/S)
• Focal > Multifocal thrombosis* (~80% vs. 20% – hepatic vein ~31%, DVT ~12%; cerebral ~18%; pulmonary ~16%; portal ~15%)

• Lymphocytic gastritis
• MASH (mild transaminosis) → cryptogenic cirrhosis, autoimmune hepatitis
• Hyposplenism

• Hemoptysis (”idiopathic pulmonary hemosiderosis”)

❓Diagnosis❓

Bayesian Decisionmaking ✋

• ↓ low ↓ pre-test probability: serology → confirmatory endoscopy if serology ⊕

• ↑ high ↑ pre-test probability: serologic and endoscopy, regardless of serology results

• Interpretation: notably, abstinence from gluten affects the sensitivity of serologic testing, so this should be accounted for in your decisionmaking

Serologies 🩸

• IgA tissue transglutaminase (tTG) antibody has best test characteristics, with sensitivity of ~90%

• Other options include IgG deamidated gliadin peptide (DGP) & IgA endomysial (EMA), & IgG tTG

⚪ What about IgA levels? If you want the best serologic test, must send IgA level as the tTG sensitivity is dependent on IgA! (If patient has IgA deficiency, serologies then become reliant on IgG testing e.g. deamidated gliadin peptide, DPG)

⚪ What if IgA is low? Should also check remaining immunoglobulin levels to assess for CVID

• Historically, diagnosed upon discovery of small bowel mucosal villous atrophy, intraepithelial lymphocytosis, & crypt hyperplasia

• However, villous atrophy is non-specific (see below), a late manifestation (i.e. will miss early disease), & disease is often patchy (i.e. risk of false ⊖ sampling)

• For this reason, at least 6 random biopsy sites are recommended, even in the absence of gross endoscopic changes

• For this reason, patients with the combination of ⊕ serologies & ⊖ EGD biopsy are considered to have “potential” Celiac disease – there is no consensus whether these cases should undergo diet modification or monitored during continued gluten consumption

• Vitamin B12, folate, & zinc deficiencies (”chicken or egg”)
• Medications (NSAIDs, ARBs)
• Infections (H. pylori, HIV, viral gastroenteritis, giardiasis, Whipple’s)
• Autoimmune (IBD, autoimmune enteropathy)
• Immunodeficiency (CVID)
• Malignancy (enteropathy-associated T cell lymphoma)
• Other (SIBO, eosinophilic gastroenteritis, PUD)

📚 References 📚

• @KirtanPatolia

• Diagnosis of celiac disease in adults

• Marked coagulopathy without liver disease or anticoagulation therapy

• Celiac Disease and Thrombotic Events: Systematic Review of Published Cases

• Nature Celiac Primer

• Celiac Disease and Nonceliac Gluten Sensitivity

• Nonneoplastic Diseases of the Small Intestine: Clinical, Pathophysiologic, and Imaging Characteristics

• Extraintestinal Manifestations of Celiac Disease: Early Detection for Better Long-Term Outcomes

• Extra-Intestinal Manifestations of Coeliac Disease in Children: Clinical Features and Mechanisms

• Ophthalmologic manifestations of celiac disease

• Mesenteric lymph node cavitation syndrome revealing celiac disease: Diagnostic and follow-up imaging findings

• Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease

• Oral and dental manifestations of celiac disease in children: a case–control study

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