Gastrointestinal

Celiac disease: diagnosis and gluten-free management

Clinical Overview and When to Suspect Celiac Disease

— Prevalence ~1% in the US, but the majority remain undiagnosed

— Bimodal presentation: early childhood and adults in 3rd–4th decade; female predominance ~2:1

— Strong familial clustering: ~10% risk in first-degree relatives

— Classic GI: chronic diarrhea, steatorrhea, bloating, weight loss, abdominal pain

— Non-classic / "atypical": iron-deficiency anemia refractory to oral iron, unexplained transaminitis, osteoporosis in a young adult, infertility/recurrent miscarriage, peripheral neuropathy, ataxia

— Silent: positive serologies + villous atrophy without symptoms (often found on family screening)

— Dermatologic: dermatitis herpetiformis (pathognomonic skin equivalent)

— Type 1 diabetes mellitus (3–10% comorbidity)

— Autoimmune thyroid disease, autoimmune hepatitis

— Down syndrome, Turner syndrome, Williams syndrome

— IgA deficiency

— First-degree relatives of biopsy-proven celiac patients

Board pearl: Any adult with iron-deficiency anemia that fails to respond to oral iron, or unexplained chronic transaminase elevation without viral/metabolic cause, deserves celiac serologies before invasive workup. On Step 3 vignettes, the "young woman with IDA, osteopenia, and bloating" almost always lands on celiac — and the next best step is IgA tTG plus total IgA, not endoscopy first.

Definition: Immune-mediated enteropathy triggered by dietary gluten (wheat, barley, rye) in genetically susceptible hosts (HLA-DQ2/DQ8), causing villous atrophy of the small intestine and systemic manifestations

Epidemiology:

When to suspect on Step 3:

High-risk groups warranting active screening (even if asymptomatic):

Pathophysiology pearl: Tissue transglutaminase (tTG) deamidates gliadin peptides → bind HLA-DQ2/DQ8 on APCs → CD4 T-cell activation → intraepithelial lymphocyte expansion and villous atrophy

Presentation Patterns and Key History

— Chronic diarrhea (often loose, foul-smelling, floating from fat malabsorption)

— Postprandial bloating, flatulence, cramping

— Weight loss despite normal/increased intake

— Aphthous stomatitis, glossitis

— Hematologic: iron deficiency anemia (impaired duodenal Fe absorption), folate deficiency, less commonly B12

— Skeletal: early osteopenia/osteoporosis from vitamin D and calcium malabsorption; pathologic fractures in a young adult

— Hepatic: isolated AST/ALT elevation (1.5–3× ULN), normalizes on gluten-free diet

— Neurologic: gluten ataxia, peripheral neuropathy, "brain fog," migraines

— Reproductive: delayed menarche, early menopause, infertility, recurrent pregnancy loss, low-birthweight infants

— Dental: symmetric enamel hypoplasia

— Dermatologic: dermatitis herpetiformis — intensely pruritic vesicles on elbows, knees, buttocks, scalp; granular IgA at dermal papillae on DIF

— Symptom relation to bread/pasta/beer (though many patients don't notice)

— Family history of celiac, T1DM, thyroid disease

— Prior unexplained IDA, fractures, or pregnancy loss

— Critical: Is the patient already on a gluten-free diet? Self-initiated GFD invalidates serologies and biopsy

— Failure to thrive, short stature, delayed puberty

— Irritability, abdominal distension, classic diarrhea more common than in adults

— Often detected on T1DM or Down syndrome screening protocols

Key distinction: Wheat allergy (IgE-mediated, urticaria/anaphylaxis minutes after ingestion) vs non-celiac gluten sensitivity (symptoms without serologies or villous atrophy) vs celiac disease (autoimmune, positive serologies + villous atrophy). Only celiac causes the autoimmune comorbidities, malabsorption, and long-term lymphoma risk that drive Step 3 management decisions.

Classic GI syndrome (minority of adult cases):

Non-classic / extraintestinal (majority in adults):

Key history questions:

Pediatric presentation differs:

Physical Exam Findings

— Cachexia, sarcopenia, or paradoxically normal/overweight body habitus (modern presentation)

— Short stature in pediatric patients; delayed Tanner staging

— Pallor from anemia

— Angular cheilitis, atrophic glossitis (iron, B12, folate deficiency)

— Aphthous ulcers

— Dental enamel defects (symmetric, chronologic — Aine classification)

— Distension, tympany; often nonspecific

— Usually nontender; significant tenderness suggests complication or alternate diagnosis

— Dermatitis herpetiformis: grouped vesicles/papules on extensor surfaces (elbows, knees), buttocks, scalp; excoriations may dominate from intense pruritus

— Easy bruising from vitamin K malabsorption

— Hyperpigmentation rarely

— Proximal muscle weakness from vitamin D deficiency–related osteomalacia

— Bone tenderness, kyphosis from vertebral compression fractures

— Distal sensory loss (small-fiber neuropathy), gait ataxia, positive Romberg

— Chvostek/Trousseau signs if severe hypocalcemia

— Severe untreated cases (celiac crisis, rare in adults, more in children): hypotension, dehydration, hypokalemia, metabolic acidosis from profuse diarrhea

— Orthostatics, mucous membrane assessment, capillary refill

— Edema from hypoalbuminemia (protein-losing component)

— Goiter (autoimmune thyroid disease)

— Acanthosis or insulin pump (T1DM comorbidity)

Board pearl: A young adult presenting with dermatitis herpetiformis has celiac disease until proven otherwise — even if completely asymptomatic in the gut. The skin and gut share the same gluten-driven IgA tTG immunology, and >85% of DH patients have enteropathy on biopsy. Step 3 management: skin biopsy of perilesional skin for direct immunofluorescence + serologic confirmation, then lifelong gluten-free diet ± dapsone for skin symptoms.

General appearance:

HEENT:

Abdominal exam:

Dermatologic:

Musculoskeletal/neurologic:

Hemodynamic/volume assessment:

Endocrine clues:

Diagnostic Workup — Initial Labs and Serologies

— IgA tissue transglutaminase (tTG-IgA) — sensitivity ~95%, specificity ~95% — the single best initial test

— Total serum IgA — drawn simultaneously to detect selective IgA deficiency (10× more common in celiac patients; would falsely lower tTG-IgA)

— CBC (microcytic anemia, sometimes macrocytic from folate/B12)

— Iron studies, ferritin (low), TIBC (high)

— Vitamin D 25-OH, B12, folate, copper, zinc

— Calcium, magnesium, phosphorus, albumin

— LFTs (mild transaminitis common, normalizes on GFD)

— TSH (autoimmune thyroid screen)

— HbA1c (T1DM screen)

— INR (if vitamin K malabsorption suspected)

— Symptomatic child + tTG-IgA ≥10× ULN + positive EMA on a separate sample → can diagnose without biopsy

— Adults still require biopsy confirmation in US practice

— Useful only for its negative predictive value — absence rules out celiac (>99% of patients carry one)

— Indicated when: equivocal biopsy, patient already on GFD, screening high-risk groups (e.g., relatives)

Step 3 management: When a vignette asks "next best step" for suspected celiac in an adult still eating gluten, the answer is tTG-IgA + total IgA, not duodenal biopsy and not HLA typing. If the patient is already on a gluten-free diet, the answer flips — order HLA-DQ2/DQ8 first to decide whether a gluten challenge is even worth pursuing.

First-line serology (patient MUST be eating gluten):

If IgA deficient: order IgG-based tests — IgG deamidated gliadin peptide (DGP-IgG) or IgG tTG

Endomysial antibody (EMA-IgA): highly specific (~99%) but operator-dependent, expensive; used as confirmatory when tTG is weakly positive

Avoid: older anti-gliadin antibody tests — poor performance, no longer recommended

Supportive labs to order at diagnosis:

Pediatric pathway (ESPGHAN, increasingly accepted in US):

HLA-DQ2/DQ8 testing:

Diagnostic Workup — Confirmatory Endoscopy and Histology

— Indicated when serology is positive, or when clinical suspicion is high despite negative serology

— Patient must remain on gluten-containing diet (≥3 g gluten/day for ≥6 weeks) before testing

— ≥4 biopsies from distal duodenum (D2/D3) + ≥1–2 from duodenal bulb (D1) — patchy disease is common; bulb-only involvement occurs in ~10%

— Orientation matters: poorly oriented specimens overcall villous atrophy

— Scalloped folds, mosaic mucosal pattern, fissuring, reduced/absent Kerckring folds

— Can be visually normal — biopsy regardless if suspicion is real

— Marsh 0: normal

— Marsh 1: increased intraepithelial lymphocytes (IELs >25/100 enterocytes), normal villi

— Marsh 2: IEL increase + crypt hyperplasia

— Marsh 3a/b/c: partial, subtotal, total villous atrophy — diagnostic of celiac in the right clinical and serologic context

— Compatible histology (Marsh 2 or 3) plus positive serology, or

— Marsh 3 + clinical/histologic response to GFD

— ≥3 g gluten/day (≈2 slices of wheat bread) for 6–8 weeks before retesting serology and biopsy

— Skip if HLA-DQ2/DQ8 negative — celiac essentially excluded

— Don't start GFD before biopsy if diagnosis is uncertain — abolishes diagnostic findings

— Don't rely on tTG alone for definitive adult diagnosis

Board pearl: A patient who started a gluten-free diet on their own and now has negative serologies presents a classic Step 3 trap. Correct sequence: HLA-DQ2/DQ8 testing first — if negative, stop; if positive, perform a formal gluten challenge before repeating serology and biopsy.

Upper endoscopy with duodenal biopsy = gold standard in adults

Biopsy protocol (critical for board questions):

Endoscopic clues (suggestive, not diagnostic):

Modified Marsh classification:

Diagnostic certainty requires:

Gluten challenge (when patient is already gluten-free):

What NOT to do:

Risk Stratification and Management Framework

— Symptom severity: classic malabsorption vs silent disease

— Nutritional deficits: iron, B12, folate, vitamin D, calcium, zinc, copper

— Bone health: DEXA at diagnosis in all adults

— Comorbid autoimmunity: TSH, HbA1c, LFTs

— Refractoriness predictors: older age at diagnosis, HLA-DQ2 homozygosity, persistent villous atrophy despite GFD

— Confirm diagnosis per pathway above

— Referral to registered dietitian with celiac expertise — non-negotiable

— Patient education: cross-contamination, hidden gluten (sauces, medications, communion wafers, beer, oats unless certified GF)

— Replete deficiencies: oral iron, vitamin D3, calcium, B12 if low, folate

— DEXA scan at baseline

— Pneumococcal vaccination (PCV15→PPSV23 or PCV20) — functional hyposplenism risk

— Screen first-degree relatives with tTG-IgA + total IgA

— Symptom + nutrition check at 3–6 months

— tTG-IgA at 6 and 12 months (should fall) and annually thereafter

— Repeat DEXA in 1–2 years if abnormal at baseline

— Repeat biopsy at ~2 years if symptoms persist or serology fails to normalize

— Persistent IBS-type symptoms on strict GFD may respond to low-FODMAP trial

Step 3 management: Celiac disease is fundamentally outpatient longitudinal management — the answer to "next best step" after diagnosis is almost always referral to a dietitian + DEXA + complete micronutrient panel + pneumococcal vaccination + screen first-degree relatives, not a medication.

Confirmed celiac disease → lifelong strict gluten-free diet (GFD) is the cornerstone — no pharmacologic substitute is FDA-approved as first-line

Risk stratification at diagnosis:

Initial management bundle (Step 3 CCS-style orders):

Follow-up cadence:

Address concurrent functional overlay:

Pharmacotherapy and Nutritional Repletion

— Iron deficiency: oral ferrous sulfate 325 mg daily or every other day (better absorbed); IV iron (ferric carboxymaltose, iron sucrose) if severe villous atrophy limits absorption or if oral fails

— Vitamin D: D3 1,000–2,000 IU daily; higher doses (50,000 IU weekly × 8 weeks) if 25-OH-D <20 ng/mL

— Calcium: 1,000–1,200 mg elemental daily (diet + supplement)

— Folate: 1 mg daily until corrected

— Vitamin B12: PO 1,000 mcg daily or IM if neurologic symptoms

— Zinc, copper, magnesium: replete based on levels

— Vitamin K: if INR elevated from malabsorption

— GFD + calcium/vitamin D often restores BMD over 1–2 years

— Bisphosphonate if osteoporosis on DEXA (T ≤ –2.5) or fragility fracture — same indications as general osteoporosis

— Dapsone for dermatitis herpetiformis — controls itch within 24–72 hours (check G6PD before starting; monitor CBC for hemolysis and methemoglobinemia)

— Loperamide for residual diarrhea only after celiac control achieved

— Pancreatic enzyme replacement rarely needed if severe steatorrhea persists despite GFD

— Type I: budesonide (open-capsule formulation), systemic steroids, azathioprine

— Type II: aberrant IEL clone — high lymphoma risk, refer to specialty center; cladribine, autologous stem cell transplant in select cases

Board pearl: Patients with celiac disease have functional hyposplenism and warrant the full pneumococcal vaccine sequence — a frequently missed CCS-style order set point. Do not forget meningococcal and H. influenzae if other splenic dysfunction features (e.g., Howell-Jolly bodies on smear).

There is no first-line pharmacologic therapy — strict lifelong GFD is treatment

Nutritional repletion at diagnosis (replete what's low; don't shotgun supplement):

Bone protection:

Adjunct medications:

Refractory celiac disease (RCD):

Vaccinations: pneumococcal series due to functional hyposplenism; annual influenza; routine adult schedule

Gluten-Free Diet Implementation and Counseling

— Wheat (including spelt, kamut, einkorn, farro, durum, semolina)

— Barley (including malt, malt vinegar, most beers)

— Rye (including triticale)

— Cross-contaminated oats — only certified gluten-free oats are acceptable, and ~5% of celiac patients still react to even pure oats (avenin sensitivity)

— Rice, corn, quinoa, buckwheat, millet, sorghum, teff, amaranth

— All unprocessed meats, fish, eggs, dairy, fruits, vegetables, legumes, nuts

— Distilled spirits (gluten removed in distillation), wine, certified GF beer

— Soy sauce, salad dressings, soups, processed deli meats, gravies

— Communion wafers (low-gluten options available)

— Lip balm, certain medications and supplements (excipients)

— Play-Doh, modeling clays (relevant for children)

— Separate toaster, cutting boards, colanders

— Wash surfaces; dedicated condiment jars (no double-dipping with crumbs)

— Restaurants: communicate clearly; risk highest with fried foods, sauces, pasta water

— GFD products cost 2–3× conventional equivalents

— Connect patients to celiac support organizations and food assistance programs

— Document medical necessity for tax deductions, school lunch accommodations (Section 504 plan)

CCS pearl: Always order a registered dietitian consult at diagnosis — passing self-management to the patient without expert dietary counseling is a Step 3 wrong-answer trap. Strict adherence correlates directly with mucosal healing, normalization of tTG, and reduction in lymphoma risk.

What patients must eliminate:

Safe staples:

Hidden gluten sources to flag:

Cross-contamination prevention:

FDA labeling: "Gluten-free" = <20 ppm gluten — generally safe

Cost and equity considerations:

Lactose intolerance is common at diagnosis due to secondary disaccharidase deficiency; usually resolves with mucosal healing — temporary lactose restriction can ease early symptoms

Special Populations — Elderly and Renal/Hepatic Impairment

— Increasing incidence; often missed because symptoms attributed to "aging gut" or IBS

— Present more often with iron-deficiency anemia, osteoporosis, weight loss than diarrhea

— Higher rate of refractory celiac disease and enteropathy-associated T-cell lymphoma (EATL)

— Slower mucosal healing on GFD (may take 2–5 years vs <2 in younger adults)

— Higher fracture risk — earlier DEXA, lower threshold for bisphosphonate

— Don't anchor on "too old to have new celiac" — diagnose at any age

— Always rule out malignancy (lymphoma, adenocarcinoma) in older adult with new villous atrophy or refractory symptoms — consider CT enterography, capsule endoscopy

— Many tablets contain wheat starch as excipient — verify with pharmacist

— Bisphosphonates may worsen esophagitis in malnourished, debilitated patients

— Celiac disease itself doesn't cause CKD, but IgA nephropathy is associated — check UA at diagnosis

— Adjust iron, vitamin D dosing per renal function

— Avoid magnesium-containing supplements in advanced CKD

— Mild transaminitis at diagnosis is common and normalizes on GFD within 6–12 months

— If LFTs don't normalize, work up for autoimmune hepatitis, PBC, NAFLD — all overrepresented in celiac

— Severe hypoalbuminemia → consider protein-losing enteropathy or refractory disease

Key distinction: Persistent transaminase elevation after 12 months of strict GFD with normalized tTG is not "celiac hepatitis" — it requires workup for autoimmune liver disease (ANA, ASMA, AMA, IgG levels) and possible liver biopsy. Missing AIH in a celiac patient is a classic Step 3 oversight.

Elderly-onset celiac disease (>65 years):

Diagnostic considerations in elderly:

Polypharmacy concerns:

Renal impairment:

Hepatic considerations:

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Undiagnosed/untreated celiac → infertility, recurrent miscarriage, intrauterine growth restriction, low birth weight, preterm delivery

— Mechanism: micronutrient deficiency (folate, iron, zinc), inflammation, possibly antibody-mediated placental effects

— Strict GFD before and during pregnancy normalizes fertility and obstetric outcomes

— Screen women with unexplained infertility or ≥2 miscarriages

— Continue prenatal vitamins; ensure adequate folate (4 mg/day if prior neural tube defect risk)

— Breastfeeding is encouraged; introduction of gluten to infant per standard pediatric guidelines (around 4–6 months, while still breastfeeding, does not prevent celiac but may delay onset)

— Failure to thrive, short stature, delayed puberty, dental enamel defects

— ESPGHAN no-biopsy pathway: symptomatic child + tTG-IgA ≥10× ULN + EMA positive on separate draw + HLA-DQ2/DQ8 positive → diagnose without endoscopy

— Catch-up growth typically robust on GFD; monitor height/weight quarterly

— Routine screening in T1DM at diagnosis and then every 1–3 years

— Adherence is the major challenge — peer pressure, autonomy

— Higher rates of eating disorders; screen routinely

— School accommodations under 504 plan

— Celiac may unmask with recurrent hypoglycemia (impaired carb absorption)

— Initiating GFD may require insulin dose adjustment as absorption normalizes

— Use IgG-based serologies (DGP-IgG, tTG-IgG)

— Increased infection risk; standard vaccination schedule still indicated

Step 3 management: A woman with unexplained recurrent pregnancy loss and iron-deficiency anemia gets tTG-IgA + total IgA as part of her workup — alongside antiphospholipid antibodies, TSH, and uterine imaging. Missing celiac in the infertility workup is a high-yield Step 3 vignette.

Pregnancy:

Pediatric celiac disease:

Adolescents:

Type 1 diabetes patients:

Selective IgA deficiency:

Complications and Adverse Outcomes

— Iron, folate, B12, vitamin D, calcium, zinc, copper deficiencies

— Osteopenia/osteoporosis with fragility fractures

— Short stature, delayed puberty in untreated children

— Functional hyposplenism (Howell-Jolly bodies on smear) → encapsulated organism risk

— Vitamin K deficiency → coagulopathy

— Enteropathy-associated T-cell lymphoma (EATL) — rare but feared; presents with weight loss, abdominal pain, fever in a previously stable celiac patient

— Small bowel adenocarcinoma — markedly increased relative risk

— Non-Hodgkin lymphoma overall increased

— Strict adherence to GFD reduces lymphoma risk toward baseline

— Persistent symptoms + villous atrophy after >12 months of strict GFD

— Type I: polyclonal IELs, treat with budesonide/steroids

— Type II: monoclonal aberrant IEL population — pre-lymphomatous, refer to tertiary center

— Autoimmune thyroid disease, T1DM, autoimmune hepatitis, PBC

— IgA nephropathy, Sjögren syndrome, primary biliary cholangitis

— Addison disease (rare but recognized)

— Gluten ataxia, peripheral neuropathy, encephalopathy

— Some respond to GFD; established cerebellar atrophy may not

— Severe diarrhea, dehydration, electrolyte derangement, metabolic acidosis, hypoalbuminemia

— Usually pediatric; requires inpatient resuscitation and IV steroids

Board pearl: Sudden weight loss, abdominal pain, fever, or new B-symptoms in a previously well-controlled adult with celiac disease → think EATL until proven otherwise. Workup: CT enterography, capsule endoscopy, push enteroscopy, and biopsy of any suspicious lesion. Don't anchor on "noncompliance."

Nutritional/metabolic:

Hematologic:

Malignancy (the headliner Step 3 association):

Refractory celiac disease (RCD):

Associated autoimmune disease (risk rises with later diagnosis):

Neurologic:

Celiac crisis (rare):

When to Escalate Care — Consultation and Inpatient Triage

— Confirming diagnosis (endoscopy with duodenal biopsy)

— Persistent symptoms despite ≥6–12 months of strict GFD with normalized tTG → evaluate for refractory disease

— Suspected complication (stricture, ulcerative jejunitis, lymphoma)

— Pediatric ESPGHAN pathway management

— Persistent severe vitamin D deficiency, refractory osteoporosis

— Comorbid Addison disease or complex multi-autoimmune presentation

— Severe anemia not correcting on GFD + repletion → exclude alternate cause

— Suspected lymphoma

— Celiac crisis (severe diarrhea, dehydration, hypokalemia, metabolic acidosis, hypoalbuminemia) — admit for IV fluids, electrolyte correction, parenteral nutrition if needed, IV methylprednisolone

— Severe symptomatic anemia requiring transfusion

— Acute abdomen — concern for perforation, intussusception, lymphoma complication

— Fragility hip/vertebral fracture

— Hemodynamic instability from celiac crisis

— Severe metabolic derangement (Na, K, glucose) requiring continuous monitoring

— IV NS or LR resuscitation, continuous telemetry

— Replace K, Mg, Ca aggressively

— NPO initially, then GFD diet order (specify "gluten-free" explicitly in EMR)

— IV methylprednisolone 1 mg/kg/day if refractory

— Albumin if severe hypoalbuminemia with edema

— Nutrition consult, GI consult

— DVT prophylaxis, stress ulcer prophylaxis per usual criteria

CCS pearl: When admitting a celiac patient for any reason, explicitly order a gluten-free diet in the EMR — default hospital diets contain gluten and inadvertent exposure is a recognized patient safety event and a Step 3–style transition-of-care error.

Outpatient gastroenterology referral indications:

Dietitian referral: at diagnosis, and re-engage at 6–12 months and whenever adherence falters

Endocrinology referral:

Hematology referral:

Hospitalization indications:

ICU triage:

CCS-style inpatient orders for celiac crisis:

Key Differentials — Other Causes of Villous Atrophy and Malabsorption

— Tropical sprue: travel to tropics, megaloblastic anemia, responds to tetracycline + folate; biopsy looks similar

— Common variable immunodeficiency (CVID): recurrent sinopulmonary infections, low IgG/IgA/IgM, absent plasma cells in lamina propria (vs preserved in celiac)

— Autoimmune enteropathy: severe refractory diarrhea, anti-enterocyte antibodies, often pediatric (IPEX syndrome) or adult-onset; doesn't respond to GFD

— Whipple disease: middle-aged man with arthralgias, weight loss, neurologic symptoms; PAS-positive macrophages, Tropheryma whipplei; treat with ceftriaxone then TMP-SMX

— Eosinophilic gastroenteritis: eosinophilic infiltrate, peripheral eosinophilia

— Olmesartan enteropathy: ARB-induced sprue-like illness; tTG negative; resolves on drug discontinuation

— Giardiasis: travel, daycare, stool antigen positive; villous blunting on biopsy

— NSAID enteropathy

— HIV enteropathy, radiation enteritis, chemotherapy-induced

— Celiac: villous atrophy + crypt hyperplasia + IEL >25/100 + plasma cells preserved

— CVID: villous atrophy + absent plasma cells

— Whipple: PAS+ foamy macrophages in lamina propria

— Giardia: trophozoites visible

— Autoimmune enteropathy: deep crypt apoptosis, anti-enterocyte Ab

— Confirm patient was eating gluten

— Check for IgA deficiency (use IgG-based serology)

— Review medications (olmesartan, NSAIDs, MMF)

— Stool studies (Giardia)

— Quantitative immunoglobulins (CVID)

— HLA-DQ2/DQ8 — if negative, celiac essentially excluded; pursue alternate diagnosis

Key distinction: Seronegative villous atrophy — when biopsy shows celiac-like changes but serologies are negative, HLA testing is the discriminator: HLA-DQ2/DQ8 negative virtually rules out celiac and redirects you to CVID, autoimmune enteropathy, drug-induced sprue, or tropical sprue.

Same-category (villous atrophy mimics):

Differentiating features on biopsy:

Approach to "celiac-like biopsy with negative serology":

Key Differentials — Non-Enteropathy Causes of Similar Symptoms

— Irritable bowel syndrome (IBS): Rome IV criteria; no alarm features, normal labs; symptoms may overlap with non-celiac gluten sensitivity

— Inflammatory bowel disease (Crohn's, UC): bloody diarrhea, elevated CRP/calprotectin, characteristic endoscopic findings

— Microscopic colitis: watery non-bloody diarrhea in older woman, often on NSAIDs/PPIs/SSRIs; normal colonoscopy with lymphocytic or collagenous changes on biopsy; 5–10× association with celiac — biopsy both small bowel and colon if suspected

— Lactose intolerance / FODMAP sensitivity

— Bile acid diarrhea: post-cholecystectomy or ileal disease; responds to cholestyramine

— Small intestinal bacterial overgrowth (SIBO): breath testing; can coexist with celiac

— Chronic pancreatitis / pancreatic insufficiency: steatorrhea, low fecal elastase, calcifications on imaging

— Hyperthyroidism: weight loss, diarrhea, palpitations

— Carcinoid, VIPoma, gastrinoma (rare but classic)

— Occult GI blood loss (colon cancer, peptic ulcer) — colonoscopy + EGD if age-appropriate

— Menorrhagia

— H. pylori gastritis (impairs iron absorption)

— Autoimmune atrophic gastritis (pernicious anemia spectrum)

— NAFLD, viral hepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease, alpha-1-antitrypsin deficiency, drug-induced — celiac is an underappreciated cause and warrants tTG in any cryptogenic LFT elevation

Board pearl: A patient with chronic watery diarrhea, normal endoscopy, and biopsies showing microscopic colitis → also biopsy the duodenum. Microscopic colitis and celiac coexist frequently, and missing the celiac component leaves the patient with persistent symptoms after starting budesonide for the colitis alone.

Causes of chronic diarrhea mimicking celiac:

Causes of refractory iron-deficiency anemia (the celiac-mimicking presentation):

Causes of unexplained transaminitis:

Secondary Prevention and Long-Term Plan

— Confirmed diagnosis documented in problem list

— Registered dietitian appointment scheduled

— Baseline DEXA ordered or completed

— Micronutrient deficiencies identified and repletion prescribed (iron, vitamin D, calcium, folate, B12 as needed)

— Pneumococcal vaccination administered or scheduled (PCV15 + PPSV23, or PCV20 alone)

— Annual influenza, routine adult schedule

— TSH, HbA1c, LFTs at baseline and annually

— First-degree relatives offered tTG-IgA screening

— Bone-protective measures: calcium 1,000–1,200 mg, vitamin D 1,000–2,000 IU, weight-bearing exercise, smoking cessation, limit alcohol; bisphosphonate if osteoporosis

— Medication review for gluten-containing excipients

— Don't forget routine ASCVD prevention — celiac patients may have increased cardiovascular risk from chronic inflammation and untreated dyslipidemia patterns

— Lipid panel may change after GFD (some patients gain weight, LDL rises as absorption normalizes)

— Standard age-appropriate screening (colon, breast, cervical)

— No celiac-specific lymphoma screening recommended in asymptomatic adherent patients

— Women: optimize GFD before conception; ensure adequate folate

— Family planning discussions for autoimmune comorbidity risk

— Celiac Disease Foundation, Beyond Celiac, GIG (Gluten Intolerance Group)

— Mobile apps for restaurant gluten-free options

Step 3 management: "Best long-term intervention to reduce lymphoma risk in celiac disease" → strict adherence to a gluten-free diet — not chemoprevention, not surveillance endoscopy, not annual CT.

The single most important long-term intervention: lifelong, strict gluten-free diet adherence — reduces symptoms, normalizes serology, heals mucosa, restores BMD, and reduces lymphoma risk toward baseline

Discharge / outpatient transition checklist (Step 3–style):

Cardiovascular and metabolic:

Cancer screening:

Reproductive counseling:

Patient resources:

Follow-Up, Monitoring, and Counseling Cadence

— 3–6 months post-diagnosis: clinical symptom check, weight, dietitian re-assessment, review of adherence, repeat any abnormal micronutrient labs

— 6 months: tTG-IgA — should be declining

— 12 months: comprehensive review — CBC, iron studies, vitamin D, B12, folate, TSH, LFTs, tTG-IgA (target normalization), repeat DEXA if baseline abnormal

— Annually thereafter: symptom and adherence assessment, tTG-IgA, CBC, comprehensive metabolic panel, TSH, LFTs, vitamin D

— DEXA: every 1–2 years if abnormal, every 2–5 years if normal

— Indicated if symptoms persist, serology fails to normalize, or in adults to confirm mucosal healing (some centers do routinely; others reserve for clinical indication)

— Persistent villous atrophy on strict GFD = refractory celiac disease workup

— Self-reported adherence is unreliable

— tTG-IgA trajectory is the standard surrogate

— Emerging: urinary/stool gluten immunogenic peptides (GIP) detect recent gluten exposure

— Dietitian-administered standardized questionnaires

— Cross-contamination at home, work, school, travel

— Eating out: dedicated GF menus, allergen communication

— Reading labels every time (formulations change)

— Medication and supplement excipients

— Psychosocial impact: anxiety, depression, eating disorders — screen and refer

— Growth velocity, Tanner staging

— School accommodations

— Mental health screening — adolescents struggle with adherence

Board pearl: A patient whose tTG-IgA does not fall by ≥50% at 6 months and does not normalize by 12 months on a "strict" GFD almost always has ongoing gluten exposure — pursue dietitian re-education and consider GIP testing before labeling them refractory.

Recommended follow-up schedule (US guidelines, AGA/ACG):

Repeat duodenal biopsy at 1–2 years:

Adherence assessment:

Counseling priorities:

Pediatric/adolescent monitoring:

Ethical, Legal, and Patient Safety Considerations

— Hospital admission of a celiac patient: explicitly order "gluten-free diet" in the EMR — default hospital diets contain gluten; inadvertent exposure is a documented adverse event

— Medication reconciliation must include verifying excipients in newly prescribed drugs (some generics contain wheat starch)

— Discharge summary should communicate celiac diagnosis to PCP, including need for ongoing dietitian access, DEXA, vaccinations, family screening

— Standard procedural risks (sedation, bleeding, perforation)

— Important: explain that going gluten-free before biopsy invalidates the test — patients sometimes start GFD on a friend's advice between referral and procedure

— Parental refusal of GFD when biopsy-confirmed celiac in a child: engage social work, document harm of untreated disease (failure to thrive, lymphoma risk), escalate to ethics or child protective services if persistent neglect

— Adolescent autonomy and adherence: shared decision-making, address peer/body image concerns

— Family members may decline screening — respect autonomy after informing them of asymptomatic-but-affected possibility

— HLA testing has implications for blood relatives — discuss before ordering

— Celiac qualifies as a disability under ADA in some contexts — meal accommodations at schools (504 plans), workplaces, prisons, military

— Document medical necessity letters when patients request

— Tax deductibility of GFD cost differential (US: with physician letter)

— GFD is expensive; food-insecure patients face barriers to adherence

— Connect to food assistance, celiac foundations, low-cost GF resources

— Gluten challenge studies require careful informed consent regarding symptom induction and small lymphoma risk over long horizons

Step 3 management: A celiac patient is admitted for pneumonia and develops diarrhea on day 2 — the most likely cause is inadvertent gluten exposure from a non-GFD hospital tray, not C. difficile, and the immediate corrective action is verifying and re-ordering the GFD, then reviewing the medication list for gluten-containing excipients.

Patient safety in transitions of care:

Informed consent for endoscopy:

Pediatric ethics:

Genetic counseling:

Disability and accommodations:

Equity considerations:

Research ethics:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: The Step 3 stem "young woman, iron-deficiency anemia refractory to oral iron, early osteoporosis, bloating" → IgA tTG + total IgA, then duodenal biopsy, then dietitian referral + DEXA + pneumococcal vaccination + screen first-degree relatives. Memorize this sequence — it appears in some form on nearly every exam cycle.

Genetic backbone: HLA-DQ2 (~90%) and HLA-DQ8 (~10%); absence of both has >99% negative predictive value

Best initial test: IgA tTG + total IgA in a patient still eating gluten

Gold standard for adult diagnosis: duodenal biopsy with ≥4 D2/D3 + ≥1–2 bulb samples; Marsh 2–3 + positive serology

Pediatric no-biopsy pathway: tTG-IgA ≥10× ULN + positive EMA on separate sample + symptomatic

Pathognomonic skin manifestation: dermatitis herpetiformis — granular IgA at dermal papillae on DIF; treat with GFD ± dapsone

Iron-deficiency anemia refractory to oral iron in a young adult → celiac until proven otherwise

Unexplained transaminitis → check tTG; normalizes on GFD

Microscopic colitis → 5–10% have concurrent celiac; biopsy duodenum too

Functional hyposplenism → pneumococcal vaccination indicated; Howell-Jolly bodies on smear

Associated autoimmune diseases: T1DM, autoimmune thyroid disease, autoimmune hepatitis, PBC, IgA nephropathy, Addison disease, Sjögren syndrome, Down syndrome, Turner syndrome, Williams syndrome, IgA deficiency

Feared malignancy: enteropathy-associated T-cell lymphoma (EATL); also small bowel adenocarcinoma

Refractory celiac disease type II: monoclonal aberrant IELs, pre-lymphomatous, refer to tertiary center

Olmesartan-induced sprue-like enteropathy: mimics celiac, tTG negative, resolves on discontinuation

Celiac crisis: severe diarrhea, dehydration, electrolyte derangement; pediatric > adult; IV fluids + steroids

Pregnancy: untreated celiac → infertility, miscarriage, IUGR; GFD restores fertility

Bone health: DEXA at diagnosis; calcium + vitamin D; bisphosphonate if osteoporotic

Adherence monitoring: tTG-IgA trajectory; urinary/stool gluten immunogenic peptides (GIP) emerging

Common pitfalls: patient on GFD before biopsy (use HLA testing), IgA deficiency (use IgG serologies), seronegative villous atrophy (rethink differential)

Board Question Stem Patterns

— "32-year-old woman with fatigue, microcytic anemia, ferritin 6, did not respond to 3 months of oral iron…"

— Best next step: IgA tTG + total IgA

— Trap answers: colonoscopy first (not yet — too young without alarms), IV iron (treats symptom not cause), HLA typing (not first-line)

— "Patient started GFD 6 months ago after reading online, serologies now negative, asks how to confirm diagnosis…"

— Best next step: HLA-DQ2/DQ8 testing — if negative, celiac excluded; if positive, formal gluten challenge then serology + biopsy

— "Pruritic vesicles on extensor surfaces, granular IgA on DIF…"

— Diagnosis: celiac disease; treatment: GFD ± dapsone (check G6PD first)

— "Newly diagnosed celiac — what's next?"

— Best answer: dietitian referral + DEXA + micronutrient panel + pneumococcal vaccination + first-degree relative screening

— "Diagnosed 1 year ago, symptoms persist, tTG still elevated…"

— Best next step: dietitian re-evaluation for gluten exposure (most common cause), then consider refractory disease workup

— "Healthy young patient with persistent AST/ALT 80/95, negative viral, alcohol, drugs…"

— Include tTG-IgA in the workup

— "Older woman with chronic watery diarrhea on PPI, colonoscopy normal, random biopsies show collagenous colitis…"

— Also biopsy duodenum / check celiac serology

— "tTG-IgA negative but total IgA also low…"

— Order IgG-based serology (DGP-IgG or tTG-IgG)

— "Stable celiac for 10 years suddenly losing weight, abdominal pain, B symptoms…"

— Workup for EATL with CT enterography, capsule endoscopy

— Inpatient celiac developing diarrhea → check the tray; confirm GFD ordered

Step 3 management: Recognize stems by demographic + complication pattern: young woman + IDA = celiac; child + FTT = celiac; middle-aged adult + transaminitis = celiac in the differential. Then anchor on serology-first sequencing.

Pattern 1 — The classic IDA stem:

Pattern 2 — Already on a gluten-free diet:

Pattern 3 — Dermatitis herpetiformis:

Pattern 4 — Post-diagnosis management bundle:

Pattern 5 — Non-responder on GFD:

Pattern 6 — Unexplained transaminitis:

Pattern 7 — Microscopic colitis crossover:

Pattern 8 — IgA deficiency twist:

Pattern 9 — Refractory/lymphoma:

Pattern 10 — CCS hospital safety:

One-Line Recap

— Diagnose: IgA tTG + total IgA first (patient must be eating gluten); duodenal biopsy (≥4 D2/D3 + bulb samples) confirms; if already gluten-free, use HLA-DQ2/DQ8 to decide whether to pursue gluten challenge; in IgA deficiency use IgG-based serology

— Treat: strict lifelong gluten-free diet + dietitian referral + replete iron, vitamin D, calcium, B12, folate as indicated + DEXA at baseline + pneumococcal vaccination (functional hyposplenism) + screen first-degree relatives with tTG-IgA

— Monitor and protect: tTG-IgA at 6 and 12 months then annually; expect normalization within 12–24 months on strict adherence; persistent symptoms with persistently elevated tTG = ongoing gluten exposure (most common) before labeling refractory; bisphosphonate if osteoporotic; sudden weight loss / B symptoms in stable patient → think enteropathy-associated T-cell lymphoma

— Whenever the stem mentions iron-deficiency anemia refractory to oral iron, unexplained transaminitis, early osteoporosis in a young adult, dermatitis herpetiformis, infertility with autoimmune features, or microscopic colitis — order IgA tTG and total IgA before anything fancier, and remember that on Step 3, the right answer often includes the longitudinal bundle (dietitian, DEXA, vaccinations, family screening), not just the diagnostic test

Board pearl: Strict gluten-free diet is the only intervention proven to normalize mucosa, restore bone density, reverse infertility, and reduce lymphoma risk — no pharmacologic agent currently substitutes for it as first-line therapy in celiac disease.

The core teaching point: Celiac disease is a lifelong gluten-driven autoimmune enteropathy diagnosed by IgA tTG plus total IgA followed by duodenal biopsy in a patient still eating gluten, and managed primarily through strict lifelong gluten-free diet, micronutrient repletion, DEXA-guided bone protection, pneumococcal vaccination, family screening, and serologic monitoring of adherence.

Three-bullet high-yield recap:

Final pearl for the exam: