Treatment Approach for Chronic Diarrhea with Elevated Inflammatory Markers and Normal Calprotectin
This patient requires endoscopic evaluation to rule out inflammatory bowel disease (IBD) despite normal calprotectin, followed by empiric treatment for gastroesophageal reflux disease (GERD) with proton pump inhibitor therapy and consideration of bile acid diarrhea (BAD) as a primary diagnosis.
Diagnostic Interpretation
The stool biomarker pattern reveals a complex inflammatory picture that warrants careful evaluation:
Elevated MMP-9, lactoferrin, beta defensin 2, and eosinophil protein X indicate active intestinal inflammation, though the specific pattern suggests possible eosinophilic or non-classical inflammatory processes rather than typical IBD 1, 2.
Normal calprotectin is reassuring but does not completely exclude IBD, as calprotectin <150 mg/g has a sensitivity of only 81% for IBD when using a 50 mg/g threshold 1.
Low secretory IgA (sIgA) suggests mucosal immune dysfunction, which can occur in chronic inflammation, immunodeficiency states, or functional disorders 2.
Normal fecal fat and elastase effectively rules out pancreatic insufficiency and significant fat malabsorption 1.
Immediate Management Steps
1. Endoscopic Evaluation Required
Proceed with colonoscopy with biopsies from right and left colon (not rectum) to exclude microscopic colitis and assess for IBD 1. The AGA guidelines recommend endoscopic assessment rather than empiric treatment when patients have chronic symptoms with mixed or atypical biomarker patterns 1.
The elevated inflammatory markers (lactoferrin, MMP-9, beta defensin 2, eosinophil protein X) combined with normal calprotectin creates diagnostic uncertainty that requires direct visualization 1.
Eosinophil protein X elevation specifically suggests possible eosinophilic gastroenteritis, which requires tissue diagnosis 2.
2. GERD Treatment Initiation
Begin proton pump inhibitor (PPI) therapy with omeprazole 20-40 mg once daily before breakfast for the acid reflux component 1, 3.
The ACCP guidelines recommend empiric PPI therapy for chronic cough and reflux symptoms, with assessment of response within 1-3 months 1.
Dietary modifications should include: no more than 45g fat per 24 hours, avoiding coffee, tea, soda, chocolate, mints, citrus products (including tomatoes), and alcohol 1.
If symptoms persist after 8 weeks of PPI therapy, consider adding prokinetic therapy or intensifying acid suppression 1.
Common pitfall: Do not assume GERD is ruled out if initial PPI therapy fails—the empiric therapy may not have been intensive enough 1.
3. Bile Acid Diarrhea Evaluation
Test for bile acid diarrhea using serum 7α-hydroxy-4-cholesten-3-one (C4) or SeHCAT scanning if available, rather than empiric treatment 1, 4.
The Canadian Association of Gastroenterology recommends diagnostic testing over empiric bile acid sequestrant therapy in patients with chronic diarrhea, including those with functional diarrhea and IBS-D 1.
Risk factors to assess include: history of cholecystectomy, terminal ileal resection, or abdominal radiotherapy 1, 4.
BAD should be strongly considered given the 3-year duration of diarrhea and normal fat malabsorption studies 1.
4. If BAD Testing is Positive or Unavailable
Initiate cholestyramine 4g once or twice daily with meals as first-line therapy, titrating to 2-12g/day based on symptom response 1, 4.
Cholestyramine achieves clinical response in approximately 70% of patients with confirmed BAD 4.
Alternative bile acid sequestrants (colesevelam, colestipol) can be used if cholestyramine is not tolerated 1, 4.
Monitor for fat-soluble vitamin deficiencies (A, D, E, K) with long-term use, as malabsorption occurs in 20% of patients on prolonged therapy 4.
Additional Diagnostic Considerations
Rule Out Infectious Causes
Test for Giardia using antigen test or PCR 1. The AGA strongly recommends Giardia testing in all patients with chronic diarrhea, as it is readily treatable and common throughout the United States 1.
Assess for Small Intestinal Bacterial Overgrowth (SIBO)
Consider empiric antibiotic trial (rifaximin 550mg three times daily for 14 days) rather than breath testing if SIBO is suspected 1. The British Society of Gastroenterology recommends empiric antibiotics over breath testing due to insufficient evidence for routine hydrogen or methane breath testing 1.
Monitoring Strategy
Reassess symptoms and biomarkers in 2-4 months after initiating treatment 1.
If symptoms improve but biomarkers remain elevated, consider treatment adjustment without repeat endoscopy 1.
If symptoms persist despite maximal medical therapy for GERD (PPI + prokinetic + dietary modification), consider 24-hour esophageal pH monitoring to confirm ongoing reflux and potentially antireflux surgery 1.
For BAD treatment, maintain therapy at the lowest effective dose and consider intermittent, on-demand administration rather than continuous therapy 4.
Critical Caveats
Do not use antidiarrheal agents (loperamide, diphenoxylate) until infectious causes are excluded and if there is any evidence of fever, abdominal tenderness, or colonic dilation 5. These agents are contraindicated in severely ill patients and can precipitate toxic megacolon in inflammatory conditions 5.
Avoid prolonged PPI use beyond what is medically necessary due to risks of Clostridium difficile-associated diarrhea, bone fractures with long-term use, acute tubulointerstitial nephritis, and drug-induced lupus 3.
The low sIgA finding warrants consideration of selective IgA deficiency or common variable immunodeficiency if the patient has recurrent infections, though this is less likely to be the primary cause of diarrhea 2.