Penyakit Celiac

01Pathophysiology

Celiac disease is an immune-mediated enteropathy that develops when genetically predisposed individuals ingest gluten, a storage protein found in wheat, barley, and rye. The immunologically active component of gluten is gliadin. After ingestion, gliadin peptides cross the intestinal epithelium and are deamidated by the enzyme tissue transglutaminase (tTG) in the lamina propria. This deamidation increases the binding affinity of gliadin peptides to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells.
Once presented, these modified gliadin peptides activate CD4+ T-helper cells, which drive a robust inflammatory cascade. This results in the release of pro-inflammatory cytokines (including interferon-gamma) and activation of cytotoxic intraepithelial lymphocytes (CD8+ T cells), which directly damage enterocytes. The end result is the hallmark histological triad: villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis.
The damage preferentially involves the proximal small bowel (duodenum and jejunum), because this is where the highest concentration of dietary gluten contacts the mucosa. This anatomical predilection explains the classic pattern of nutrient deficiencies. Iron and folate are absorbed in the duodenum and proximal jejunum, so patients frequently present with iron deficiency anemia and folate deficiency. Calcium and fat-soluble vitamins (A, D, E, K) also depend on proximal absorption, leading to osteoporosis and steatorrhea.
The reason patients develop dermatitis herpetiformis is that IgA antibodies directed against tTG deposit in the dermal papillae of the skin, triggering a granular IgA-mediated inflammatory response. This is considered the cutaneous manifestation of celiac disease, and biopsy of uninvolved perilesional skin showing granular IgA deposits at the dermoepidermal junction is diagnostic.

02Classification and Clinical Manifestation

03Diagnostic Workup

The diagnostic approach begins with serological testing in a patient who is actively consuming gluten. This is a critical point: if the patient has already started a gluten-free diet before testing, both serology and biopsy may be falsely normal. The best initial test is the IgA anti-tTG antibody, which has excellent sensitivity and specificity. You must always order a total serum IgA level concurrently, because selective IgA deficiency occurs in approximately 2-3% of celiac patients, and this will render all IgA-based serological tests falsely negative. In IgA-deficient patients, switch to IgG-based assays (IgG anti-tTG or IgG deamidated gliadin peptide).
If serology is positive, the next step is upper endoscopy with multiple biopsies from the duodenum (at least four from the distal duodenum and at least one from the duodenal bulb). The histological findings are graded using the Marsh classification: Marsh 0 (normal), Marsh I (increased intraepithelial lymphocytes only), Marsh II (added crypt hyperplasia), and Marsh III (added villous atrophy, subdivided into IIIa partial, IIIb subtotal, IIIc total). A Marsh III lesion is the classic finding tested on exams.
HLA typing is not used to diagnose celiac disease but rather to exclude it. If a patient with an equivocal workup is negative for both HLA-DQ2 and HLA-DQ8, you can confidently say they do not have celiac disease. This test is most useful in patients already on a gluten-free diet whose prior workup was incomplete.

04Management and Treatment

The cornerstone of treatment is a lifelong strict gluten-free diet. This means complete avoidance of wheat, barley, and rye in all forms, including hidden sources such as sauces, processed foods, and certain medications. Pure, uncontaminated oats are tolerated by the majority of celiac patients, but cross-contamination during processing is common, so only certified gluten-free oats should be consumed. Referral to a dietitian experienced in celiac disease is strongly recommended at the time of diagnosis.
At diagnosis, patients should be evaluated for nutritional deficiencies. Iron supplementation is given as ferrous sulfate 325 mg (65 mg elemental iron) orally one to three times daily on an empty stomach. Folate is replaced at 1 mg daily. Calcium (1000-1500 mg/day) and vitamin D (at least 1000 IU/day, adjusted based on serum 25-hydroxyvitamin D levels) should be supplemented to address bone loss. A DEXA scan is obtained at diagnosis to assess bone mineral density.
An often-overlooked point is the recommendation for pneumococcal vaccination. Celiac disease is associated with functional hyposplenism, which increases susceptibility to encapsulated organisms. Patients should receive the pneumococcal conjugate and polysaccharide vaccines per current guidelines.
Response to the gluten-free diet is monitored with serial anti-tTG IgA titers, which should decline and eventually normalize within 6 to 12 months. If symptoms persist or serology fails to improve, reassess dietary compliance first (this is the most common reason for treatment failure). If the patient is truly adherent and remains symptomatic with persistent villous atrophy for more than 12 months, the diagnosis of refractory celiac disease is made. Type I refractory disease (polyclonal intraepithelial lymphocytes) responds to corticosteroids. Type II (clonal/aberrant intraepithelial lymphocytes) carries a high risk of progression to enteropathy-associated T-cell lymphoma (EATL) and requires aggressive immunosuppressive therapy and close oncological follow-up.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common trap with celiac disease questions is the IgA deficiency pitfall. A vignette will describe a patient with classic malabsorption symptoms, and the anti-tTG IgA result comes back negative. Students who do not check total serum IgA will incorrectly conclude that celiac disease has been ruled out. The correct next step when serological tests are negative but clinical suspicion remains high is to check a total IgA level. If IgA is low, you must reorder testing using IgG-based assays.
The second common trap involves patients who are already on a gluten-free diet before workup. Serological tests and even biopsies may normalize after weeks to months of gluten avoidance. If a patient has been self-restricting gluten, the correct approach is to perform a gluten challenge (reintroduce gluten for at least 2-4 weeks, ideally 6-8 weeks) before testing. This is a frequently tested concept.
A third high-yield pearl is the association between celiac disease and dermatitis herpetiformis. When the vignette describes a pruritic vesicular rash on the elbows, knees, or buttocks in the setting of GI symptoms, think celiac immediately. The skin biopsy of perilesional (uninvolved) skin showing granular IgA deposits at the dermoepidermal junction on direct immunofluorescence is diagnostic. Treatment of dermatitis herpetiformis includes both a gluten-free diet and dapsone for symptomatic relief.
Finally, always remember the long-term complications. The exam often tests whether students recognize that non-adherence to a gluten-free diet raises the risk of enteropathy-associated T-cell lymphoma and small bowel adenocarcinoma. A patient with known celiac disease who develops new-onset abdominal pain, weight loss, or GI bleeding after years of poor dietary compliance should prompt concern for malignancy.