In a 24‑year‑old man with 20 kg unintentional weight loss over one year, chronic diarrhea, selective immunoglobulin A (IgA) deficiency (IgA 57 mg/dL) and borderline negative tissue transglutaminase immunoglobulin A (tTG‑IgA) (1.0 U), and low libido with erectile dysfunction since age 19, what is the appropriate diagnostic work‑up and initial management?

Diagnostic Work-Up and Management

This patient requires immediate IgG-based celiac serology (specifically IgG deamidated gliadin peptide) because his low total IgA (57 mg/dL) renders the negative tTG-IgA result unreliable and cannot exclude celiac disease. His presentation—45 lb weight loss, chronic diarrhea, and fatigue—is classic for celiac disease, and IgA deficiency occurs 10–15 times more frequently in celiac patients than healthy controls. 1

Critical Diagnostic Error to Avoid

The borderline tTG-IgA of 1.0 appears reassuring but is falsely negative due to selective IgA deficiency (IgA 57 mg/dL, well below normal). 2, 1 Standard IgA-based celiac testing (tTG-IgA, endomysial antibody) cannot be trusted when total IgA is low, as these assays depend on adequate IgA production. 2

Immediate Celiac Disease Work-Up

Step 1: Order IgG-Based Serology Now

• IgG deamidated gliadin peptide (DGP-IgG) is the preferred test in IgA-deficient patients, with 93.6% sensitivity and 99.4% specificity—far superior to tTG-IgG (which has only 40.6–84.6% sensitivity). 1, 3
• Traditional gliadin antibody assays are outdated and should not be used. 1
• Confirm the patient has consumed at least 10 g of gluten daily (approximately 3 slices of bread) for the past 6–8 weeks; insufficient gluten intake is the leading cause of false-negative results. 2, 1

Step 2: Proceed to Duodenal Biopsy

• If DGP-IgG is positive, proceed directly to upper endoscopy with at least 6 biopsies: 1–2 from the duodenal bulb and ≥4 from the second part of the duodenum. 1
• Even if DGP-IgG is negative, strongly consider biopsy given his severe symptoms (45 lb weight loss, chronic diarrhea) because antibody-negative celiac disease accounts for 6.4–7% of cases. 2
• Request evaluation by an experienced GI pathologist to assess for villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (≥25 per 100 enterocytes). 1

Step 3: Consider HLA-DQ2/DQ8 Genetic Testing

• If both DGP-IgG and biopsy are negative but clinical suspicion remains high, order HLA-DQ2/DQ8 testing. 1
• Absence of both alleles has >99% negative predictive value and essentially rules out celiac disease. 1

Evaluation of Low Libido and Erectile Dysfunction

Assess for Hypogonadism Secondary to Malabsorption

• Order testosterone (total and free), LH, FSH, prolactin to evaluate for hypogonadotropic hypogonadism, which can result from chronic malnutrition and weight loss. 2
• Check zinc, vitamin D, vitamin B12, folate, iron studies as micronutrient deficiencies from celiac disease commonly cause sexual dysfunction and fatigue. 2
• Measure thyroid function (TSH, free T4) as autoimmune thyroid disease co-occurs with celiac disease and IgA deficiency. 2, 1

Rule Out Primary Immunodeficiency

• His low IgA (57 mg/dL) warrants evaluation for Common Variable Immunodeficiency (CVID), especially given chronic diarrhea. 4
• Measure total IgG and IgM levels; CVID is defined as IgG <5 g/L plus low IgA or IgM. 4
• Note: One case report documents selective IgM deficiency masking seronegative celiac disease, with IgM normalizing after gluten-free diet. 5

Additional Infectious and Inflammatory Work-Up

Screen for Opportunistic Infections

• Stool testing for Giardia (ELISA preferred, 92% sensitivity) is essential, as IgA-deficient and immunodeficient patients have increased susceptibility to chronic giardiasis. 2, 4
• Send three fresh stool samples for ova, cysts, and parasites to exclude other protozoan infections (amoebiasis). 2
• Consider HIV testing as chronic diarrhea is a common presenting symptom in newly diagnosed HIV, and immunodeficiency complicates the diagnostic picture. 2

Evaluate for Inflammatory Bowel Disease

• If celiac serology and biopsy are negative, consider fecal calprotectin and colonoscopy with ileoscopy to exclude Crohn's disease or ulcerative colitis, which can present with weight loss and chronic diarrhea. 2

Management After Celiac Disease Confirmation

Initiate Strict Gluten-Free Diet

• Start a lifelong gluten-free diet immediately after biopsy confirmation (daily gluten intake <10 mg). 2, 1
• Refer to a registered dietitian experienced in celiac disease management. 6
• Never start a gluten-free diet before completing the diagnostic work-up, as this invalidates subsequent testing. 2, 6

Monitor Response to Treatment

• Use IgG-based antibody tests (DGP-IgG or tTG-IgG) for monitoring dietary compliance at 6 months, 12 months, and annually thereafter—not IgA-based tests. 1
• Persistently positive serology indicates ongoing gluten exposure or poor adherence. 6
• Consider follow-up biopsy at 1–3 years to confirm mucosal healing, especially with severe initial presentation. 6

Address Nutritional Deficiencies

• Supplement identified deficiencies (iron, zinc, vitamin D, B12, folate) aggressively. 6
• Oral iron supplementation is first-line; consider IV iron if severe anemia, intolerance, or profound villous atrophy. 6

Common Pitfalls

• Do not dismiss the low IgA as clinically insignificant—it is the key to understanding why standard celiac testing failed. 1, 4
• Do not rely on tTG-IgG alone when total IgA is low; it has poor diagnostic accuracy (sensitivity 40.6–84.6%, specificity 78.0–89.0%). 1, 3
• Do not order multiple antibody panels simultaneously in low-risk individuals, as this reduces specificity without meaningful sensitivity gains. 6
• Do not forget to verify adequate gluten intake before any serologic or histologic testing. 2, 1

Addressing the Sexual Dysfunction

• If testosterone is low secondary to malnutrition, it should normalize with nutritional rehabilitation after starting a gluten-free diet. 2
• If hypogonadism persists despite weight restoration, consider endocrinology referral for possible testosterone replacement. 2
• Zinc and vitamin D deficiencies specifically impair testosterone production and should be corrected. 2