Celiac Disease

• Genetic susceptibility and HLA involvement: CD is almost exclusively associated with **HLA-DQ2 (encoded by HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles) or HLA-DQ8 (encoded by HLA-DQA1*03:01 and HLA-DQB1*03:02 alleles)**, present in 30-40% of the general population but required in nearly 98% of CD patients. The HLA-DQ2 and HLA-DQ8 molecules have specific binding pockets with high affinity for deamidated gluten peptides. However, HLA positivity alone is insufficient for disease development, indicating that additional genetic (non-HLA) and environmental factors are critical. Over 40 non-HLA loci have been identified through genome-wide association studies (GWAS), including genes involved in immune regulation (IL2RA, IL21, CTLA4, AIRE) and intestinal barrier function (claudins, MYO9B), suggesting that multiple genetic hits may be required for disease manifestation. The "missing heritability" and observation that only 3-5% of HLA-DQ2/DQ8-positive individuals develop CD underscores the polygenic and multifactorial nature of disease susceptibility.

• Gluten deamidation and adaptive immune activation: Gluten proteins are resistant to complete enzymatic digestion due to their high proline and glutamine content, resulting in generation of immunogenic peptide fragments (notably 31-amino acid α-gliadin fragment 31-43 and 33-amino acid α-gliadin fragment 33-55). The enzyme tissue transglutaminase (tTG) selectively deamidates glutamine residues within these peptides to glutamic acid, a process that dramatically increases peptide binding affinity to HLA-DQ2 and HLA-DQ8 molecules. This deamidated gluten–HLA complex is presented to CD4+ T cells in the lamina propria, activating gluten-specific T helper cells (Th1 and Th17) that secrete pro-inflammatory cytokines including interferon-γ (IFN-γ) and interleukin-17 (IL-17). These T cell responses are coupled with generation of autoantibodies against tissue transglutaminase (anti-tTG IgA) through B cell help, with anti-tTG antibodies crosslinking tTG and activating complement through the alternative pathway, perpetuating local inflammation. The anti-tTG response is highly specific for CD and the basis of serologic testing; these antibodies are believed to contribute to disease pathology through formation of immune complexes and direct complement activation rather than merely being epiphenomenal.

• Intestinal barrier dysfunction and innate immune activation: In addition to adaptive immune mechanisms, CD involves significant perturbations in intestinal barrier integrity characterized by increased zonula occludens-1 (ZO-1) degradation, enhanced claudin endocytosis, and increased expression of the claudin-2 pore-forming protein, all leading to increased paracellular permeability and the "leaky gut" phenotype. This enhanced permeability may be initiated by innate immune stimulation from α-gliadin peptide 31-43, which activates CXCL10 production through MyD88-dependent TLR-like signaling in intestinal epithelial cells and lamina propria innate lymphoid cells (ILCs), recruiting CXCR3+ intraepithelial lymphocytes (IELs) enriched in CD8+ cytotoxic T cells. Increased intraepithelial lymphocyte populations (normally <5-7 per 100 epithelial cells; elevated to >25 in CD) directly damage epithelial cells through perforin and granzyme release. The innate immune component explains why some CD patients develop villous atrophy through type I interferon responses independent of complete gluten-specific T cell activation, and why complete removal of HLA-DQ2/DQ8 disease alleles does not entirely prevent CD manifestations in some patients. Additionally, dysbiosis (characterized by reduced Faecalibacterium prausnitzii and increased pathogenic Gram-negative bacteria) promotes intestinal barrier dysfunction through reduced short-chain fatty acid production and altered lipopolysaccharide exposure.

• Mucosal injury and villous atrophy: The cumulative effects of adaptive T cell responses, B cell-derived antibodies, complement activation, and innate lymphoid cell infiltration result in progressive mucosal inflammation with increased lamina propria cellularity (predominantly CD4+ T cells, plasma cells producing anti-tTG IgA, and B cells), crypt hyperplasia, and ultimately villous atrophy (ranging from partial to total villous blunting). The Marsh classification grades histologic severity: Marsh 0 (normal), Marsh 1 (increased IELs), Marsh 2 (crypt hyperplasia without villous atrophy), Marsh 3a (partial villous atrophy), Marsh 3b (subtotal villous atrophy), and Marsh 3c (total villous atrophy). Villous atrophy dramatically reduces the absorptive surface area (normally 250-400 m²; reduced by 50-90% in severe CD), explaining the malabsorptive consequences. The inflammation and villous injury are reversible upon gluten withdrawal, with mucosal healing occurring over months to years depending on initial severity, though residual increased IELs and subtle lamina propria abnormalities may persist even with strict adherence to a gluten-free diet.

• Epithelial cell death and restitution imbalance: Studies demonstrate that intestinal epithelial cell apoptosis is significantly increased in active CD, mediated by both death receptor (Fas/FasL) and mitochondrial pathways triggered by infiltrating cytotoxic T cells and pro-apoptotic cytokines (IFN-γ, TNF-α, IL-15). This enhanced apoptosis overwhelms the capacity for epithelial restitution and wound repair, perpetuating the mucosal defect. Impaired secretion of gut-protective factors including transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) contributes to inadequate epithelial healing even when gluten is initially withdrawn. The dynamic imbalance between epithelial injury and repair underlies the progressive villous atrophy observed with continued gluten exposure.

• Cross-reactivity and molecular mimicry: Emerging evidence suggests that infections with adenovirus, rotavirus, and enterovirus (particularly reovirus) may trigger disease through molecular mimicry between pathogen epitopes and gluten peptides, or through bystander activation mechanisms that lower the threshold for gluten-specific T cell responses. Additionally, pathogenic bacteria such as Enterobacteriaceae possess epitopes that cross-react with gluten sequences, potentially amplifying gluten-specific responses in genetically predisposed individuals. This explains the observed seasonal variation in CD diagnosis and the clustering of disease onset following infectious episodes in some patients.

• Genetic predisposition (essential but insufficient): HLA-DQ2 positivity (approximately 90% of CD patients) or HLA-DQ8 positivity (approximately 10% of CD patients) is a prerequisite for disease development, present in 30-40% of the general population. HLA testing has high negative predictive value (98-99%) such that HLA-negative individuals have <1% risk of CD and testing negative essentially excludes CD diagnosis. Non-HLA genetic factors including PTPN2, SH2B3, Bach2, TNFAIP3, IL2RA, IL21, REL, and others contribute to disease susceptibility through effects on regulatory T cell differentiation, interferon signaling, and immune tolerance mechanisms. First-degree relatives of CD patients have a 10-15% prevalence of CD compared to 1% in the general population, emphasizing the strong familial aggregation.

• Gluten exposure and timing: Gluten ingestion is the essential environmental trigger, with timing of gluten introduction in infancy potentially influencing disease development (though recent prospective studies have not supported the "window of opportunity" hypothesis that delayed gluten introduction reduces CD risk). The amount and duration of gluten exposure correlate with symptom severity and histologic damage; even small amounts of gluten (as little as 20-100 mg daily, equivalent to a few crumbs of bread) can perpetuate inflammation in susceptible individuals and prevent mucosal healing in established CD. Interestingly, gluten consumption patterns have changed dramatically over the past 50-100 years due to modifications in wheat breeding (selecting for higher gluten content for improved baking properties), though the evidence that modern wheat is inherently more immunogenic than historical varieties remains debated.

• Associated autoimmune and endocrine conditions: CD shows strong association with other autoimmune disorders through shared genetic and immunologic mechanisms, including type 1 diabetes mellitus (prevalence 5-8% in CD vs 0.5% in general population), autoimmune thyroiditis (particularly Hashimoto thyroiditis; prevalence 10-15% in CD), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Screening for CD should be considered in any patient with newly diagnosed autoimmune thyroiditis or type 1 diabetes, and conversely, CD patients should undergo screening for these conditions. These associations reflect both the shared HLA associations (particularly HLA-DQ2) and overlapping autoantigens between CD and these conditions.

• Infections and dysbiosis: Viral infections preceding CD diagnosis (particularly gastrointestinal infections with rotavirus, reovirus, or norovirus) have been epidemiologically associated with disease development, potentially through molecular mimicry or bystander activation mechanisms. Dysbiosis characterized by reduced abundance of beneficial commensals (especially Faecalibacterium prausnitzii) and increased pathobionts has been consistently documented in CD and may both contribute to disease pathogenesis and result from it. Use of broad-spectrum antibiotics in infancy has been associated with increased CD risk in some studies, supporting the role of intestinal microbiota in immune homeostasis.

• Reproductive and life stage factors: Pregnancy and the postpartum period represent high-risk intervals for disease onset due to immune dysregulation, with some studies showing diagnosis clustering in the first postpartum year. Introduction of cow's milk formula (rather than exclusive breastfeeding) has been associated with earlier CD onset in some studies, though recent meta-analyses show inconsistent associations. Age at gluten introduction is not strongly associated with disease risk based on prospective birth cohort data, contrary to older theoretical predictions.

• Celiac disease-associated conditions: CD occurs with increased frequency in patients with Down syndrome (5-15%), Turner syndrome (4-8%), Williams syndrome, IgA nephropathy, and dermatitis herpetiformis (DH; present in 15-25% of DH patients). Patients with dermatitis herpetiformis essentially universally have intestinal changes consistent with CD (even if clinically asymptomatic), though only a minority develop gastrointestinal symptoms.

• Classic malabsorptive syndrome: Presents predominantly in children (ages 6 months to 2 years) following introduction of gluten-containing foods, characterized by chronic diarrhea (loose, fatty, pale, foul-smelling stools reflecting steatorrhea from fat malabsorption), failure to thrive or growth faltering (deceleration of growth velocity and weight gain), abdominal distention (from gas and fluid accumulation due to osmotic diarrhea and dysbiosis), muscle wasting (from protein malnutrition and sarcopenia), and irritability (from malnutrition and chronic illness). Nutritional deficiencies become manifest, including iron deficiency anemia (microcytic, hypochromic from reduced heme iron absorption in the duodenum and proximal jejunum where most iron is absorbed), fat-soluble vitamin deficiencies (vitamins A, D, E, K from impaired intraluminal fat solubilization and reduced absorptive surface area), calcium deficiency (from reduced vitamin D-mediated absorption and increased oxalate malabsorption reducing calcium bioavailability), folate deficiency, and vitamin B12 deficiency (from terminal ileal involvement in some patients or associated pernicious anemia from atrophic gastritis). These nutritional deficiencies cause secondary manifestations including rickets (from severe vitamin D deficiency), osteomalacia (bone pain and myopathy in older children and adults), bleeding tendency (from vitamin K deficiency), dermatitis (from essential fatty acid and micronutrient deficiencies), and neuropsychiatric symptoms (from B vitamin deficiencies).

• Atypical presentation (most common in modern diagnosis): In contemporary developed countries, the majority of CD diagnoses occur in older children, adolescents, and adults presenting with isolated iron deficiency anemia (most frequent single presenting symptom in adults, present in 50-60% of adults with CD), often detected incidentally on laboratory testing without gastrointestinal symptoms. These patients frequently have subtle or entirely absent diarrhea and may paradoxically be constipated, with iron malabsorption disproportionately prominent due to preferential mucosal damage in iron-absorptive regions. Other atypical presentations include short stature or growth retardation (in children without diarrhea; represents primary growth failure from malnutrition and inflammatory cytokine effects), delayed or absent puberty (from malnutrition and increased prolactin from impaired dopamine absorption), amenorrhea or oligomenorrhea (from weight loss and nutritional deficiency), and infertility (from nutritional deficiency and associated autoimmune conditions). Bone disease (osteopenia or osteoporosis) may be the presenting manifestation in adults, resulting from vitamin D malabsorption, calcium malabsorption, and chronic inflammation with increased osteoclast activation from pro-inflammatory cytokines. Neurologic manifestations including ataxia (from vitamin E deficiency and potentially other mechanisms), peripheral neuropathy (mixed sensorimotor from multiple micronutrient deficiencies), epilepsy (particularly temporal lobe epilepsy; present in 2-5% of CD patients), and headache/migraine (increased frequency reported) represent increasingly recognized presentations, with some neurologic syndromes (particularly ataxia and epilepsy) potentially improving partially or completely upon gluten withdrawal.

• Asymptomatic seropositive disease: Increasingly recognized through serologic screening of at-risk populations (relatives of CD patients, patients with associated autoimmune conditions), approximately 15-20% of identified CD patients are completely asymptomatic at the time of diagnosis. These individuals have positive serologies (anti-tTG IgA, anti-endomysial antibodies) and villous atrophy on biopsy but report no gastrointestinal or systemic symptoms upon careful questioning. The natural history of asymptomatic CD is incompletely understood, though prospective data suggest that 20-40% eventually develop symptoms over 5-10 years, while others remain asymptomatic for decades. Current guidelines recommend treatment with a gluten-free diet even for asymptomatic cases due to the risk of complications and potential benefits of mucosal healing, though this recommendation remains somewhat controversial.

• Silent CD (seronegative histologic disease): A subset of patients present with classic mucosal changes and clinical improvement on gluten-free diet but negative or weak

Prerequisite before any testing

• Patient must be eating gluten: serology and histology normalize on a gluten-free diet (GFD). The ACG 2023 celiac guideline stresses that testing be performed on a gluten-containing diet; if already gluten-free, a supervised gluten challenge over several weeks is required before biopsy.

Step 1 — serology (best initial test)

• IgA anti-tissue transglutaminase (anti-tTG IgA) plus total serum IgA: the ACG-endorsed first-line test. Sensitivity and specificity both exceed 90% in untreated disease. Total IgA is drawn simultaneously because selective IgA deficiency is several-fold more common in celiac disease than in the general population and produces a falsely negative anti-tTG IgA.
• If IgA-deficient: switch to IgG-based testing — IgG deamidated gliadin peptide (DGP) or IgG anti-tTG.
• Anti-endomysial antibody (EMA) IgA: near-100% specific; used as a confirmatory second test, not a screen.
• Children under ~2 years: DGP antibodies supplement anti-tTG, whose performance is less reliable in this group.

Step 2 — confirmatory duodenal biopsy (gold standard in adults)

• Upper endoscopy with multiple biopsies: at least four from the distal duodenum plus one to two from the bulb, because injury is patchy. Endoscopic clues — scalloped folds, mosaic pattern, loss of duodenal folds — are suggestive but neither sensitive nor specific.
• **Histology graded by the *Marsh (Marsh–Oberhuber) classification***: intraepithelial lymphocytosis (>25 IELs per 100 enterocytes), crypt hyperplasia, and villous atrophy, with Marsh 3a–3c denoting partial to total atrophy.

Selected exceptions and adjuncts

• ESPGHAN 2020 no-biopsy pathway (children): anti-tTG IgA at or above 10× the upper limit of normal confirmed by a positive EMA on a separate sample permits diagnosis without endoscopy.
• HLA-DQ2/DQ8 typing: useful only to exclude disease given its very high negative predictive value — for equivocal histology, patients already gluten-free, or screening Down syndrome and first-degree relatives.

Immediate stabilization (uncommon but critical)

• Celiac crisis: profuse diarrhea with hypovolemia, metabolic acidosis, hypokalemia, hypocalcemia, and hypoproteinemia. Requires hospitalization, IV fluid and electrolyte repletion, and — per ACG — systemic corticosteroids alongside gluten withdrawal.

First-line and definitive therapy

• Lifelong strict gluten-free diet (GFD): the only disease-modifying treatment (ACG 2023). Eliminate wheat, barley, and rye; pure uncontaminated oats are tolerated by most patients but are introduced with monitoring.
• Referral to a registered dietitian with celiac expertise: guideline-recommended, since trace contamination (crumb-level quantities) sustains inflammation.
• Repletion of deficiencies: iron, folate, vitamin B12, vitamin D, calcium, zinc, and fat-soluble vitamins A/E/K as indicated by baseline labs.
• DXA bone densitometry: recommended given the high prevalence of metabolic bone disease.
• Pneumococcal vaccination: advised because of functional hyposplenism.

Monitoring and escalation

• Serial anti-tTG IgA at roughly 6 and 12 months, then annually: falling titers track adherence, though normalization lags mucosal healing. Persistent symptoms warrant re-evaluation for inadvertent gluten exposure (the most common cause), then for lactose intolerance, microscopic colitis, small intestinal bacterial overgrowth, pancreatic insufficiency, or IBS overlap.
• Nonresponsive disease with confirmed dietary adherence → repeat biopsy for refractory celiac disease (RCD):
• RCD type I (polyclonal IELs with normal immunophenotype): corticosteroids, typically open-capsule budesonide, sometimes with azathioprine.
• RCD type II (clonal TCR rearrangement, aberrant IELs): pre-lymphomatous; managed at referral centers, may involve cladribine or autologous stem cell transplantation.
• Dermatitis herpetiformis: GFD is definitive; sulfone — dapsone gives rapid rash control while the diet takes effect.

What to avoid

• Do not start a GFD before serology and biopsy — it invalidates both.
• No pharmacologic agent substitutes for gluten avoidance; enzyme supplements and "gluten detox" products are not endorsed.
• Screen for occult gluten in medications and supplements, and check for gluten-independent causes before escalating to immunosuppression.

Emergencies

• Celiac crisis: fulminant diarrhea with hypovolemic shock, severe hypokalemia, hypocalcemia, and acidosis from massive malabsorption; rare, more common in young children and undiagnosed adults. Signals itself by hemodynamic instability plus profound electrolyte derangement — treat as an emergency.
• Vitamin K–dependent coagulopathy with bleeding: fat-soluble vitamin malabsorption prolongs the PT/INR; a spontaneously elevated INR that corrects with parenteral vitamin K is the clue.
• Overwhelming encapsulated-organism sepsis: chronic mucosal immune activation produces functional hyposplenism (Howell–Jolly bodies on smear), raising risk from pneumococcus and meningococcus.

Malignant and pre-malignant

• Enteropathy-associated T-cell lymphoma (EATL): arises from clonally expanded aberrant intraepithelial lymphocytes, essentially always via refractory celiac disease type II. Suspect with recurrence of diarrhea, weight loss, fever, abdominal pain, or obstruction/perforation after a period of good control on a GFD.
• Small bowel adenocarcinoma: chronic inflammation-driven dysplasia; presents with obstruction or occult bleeding.
• Ulcerative jejunoileitis: multifocal small bowel ulcers causing stricture, bleeding, or perforation; often overlaps with RCD type II.

Chronic sequelae

• Metabolic bone disease: calcium and vitamin D malabsorption plus inflammatory cytokine–driven osteoclast activation → osteopenia/osteoporosis and fragility fracture; detected by DXA.
• Refractory iron deficiency anemia: duodenal villous loss removes the primary iron-absorptive surface; the classic signal is anemia failing to correct with oral iron.
• Secondary lactose intolerance: brush-border lactase is lost first and returns last, explaining persistent bloating early on a GFD.
• Reproductive and neurologic sequelae: infertility, recurrent miscarriage, low birth weight; gluten ataxia and peripheral neuropathy.

Complications of treatment

• Gluten-free diet itself: often low in fiber, folate, iron, and B vitamins and high in refined starch and fat, producing constipation, weight gain, and dyslipidemia; also imposes real cost and social burden affecting adherence.
• Dapsone for dermatitis herpetiformis: dose-dependent hemolysis (severe in G6PD deficiency) and methemoglobinemia — check G6PD before starting.

• **Best initial test is anti-tTG IgA with a total IgA level**: the total IgA exists solely to catch selective IgA deficiency, which is over-represented in celiac disease and causes a false-negative anti-tTG IgA. If IgA-deficient, order IgG-based serology (IgG DGP or IgG anti-tTG) — this is a favorite two-step stem.
• Single best next step after positive serology in an adult is EGD with duodenal biopsy, not empiric gluten withdrawal. Biopsies must include the distal duodenum (≥4) plus bulb because disease is patchy.
• The commonest distractor: starting a gluten-free diet before testing. Serology and histology normalize, and the patient then needs a formal gluten challenge. If the stem says "already gluten-free," HLA-DQ2/DQ8 typing is the useful move — a negative result essentially excludes celiac disease.
• Classic adult presentation is isolated iron deficiency anemia refractory to oral iron, not diarrhea. Duodenal villous atrophy destroys the main site of iron absorption.
• Dermatitis herpetiformis: intensely pruritic grouped vesicles on extensor surfaces, elbows, knees, buttocks; direct immunofluorescence shows granular IgA deposits in the dermal papillae. Treat with a gluten-free diet plus dapsone; check G6PD first.
• The association examiners love: type 1 diabetes mellitus, autoimmune (Hashimoto) thyroiditis, Down and Turner syndromes, and IgA deficiency. Screen these patients even without GI symptoms.
• Persistent symptoms on a gluten-free diet: inadvertent gluten exposure is by far the most common cause — look for it before invoking refractory disease. True refractory disease type II is the precursor lesion of enteropathy-associated T-cell lymphoma; new weight loss, fever, or obstruction after prior control is the red flag.
• Histology mimics to separate: tropical sprue affects the entire small bowel and responds to tetracycline plus folate; Whipple disease shows PAS-positive foamy macrophages; giardiasis shows trophozoites — none respond to gluten withdrawal.