What is the best course of treatment for a patient with a 3-year history of chronic diarrhea, recently worsened to include nocturnal episodes, with lab results showing elevated ferritin, high B12, low mean RBC iron, low vitamins D and E, and evidence of intestinal yeast overgrowth, gastritis, and esophagitis, despite normal colonoscopy and negative celiac testing?

Treatment Approach for Chronic Nocturnal Diarrhea with Malabsorption and Intestinal Yeast

This patient requires immediate treatment for bile acid diarrhea with a bile acid sequestrant (cholestyramine or colesevelam), antifungal therapy for documented intestinal yeast overgrowth, and aggressive management of gastroesophageal reflux disease (GERD) to prevent nocturnal aspiration. 1, 2

Immediate Priority: Bile Acid Diarrhea

The nocturnal timing (1-2 hours post-bedtime), watery nature, and laboratory pattern strongly suggest bile acid malabsorption as the primary driver:

• Start cholestyramine 4g once or twice daily or colesevelam 625mg 3 tablets twice daily as first-line therapy for bile acid diarrhea 1, 2
• The British Society of Gastroenterology strongly recommends making a positive diagnosis of bile acid diarrhea with SeHCAT testing or serum 7α-hydroxy-4-cholesten-3-one (C4), but given limited availability in many regions, an empirical trial of bile acid binders is reasonable when clinical suspicion is high 1
• Nocturnal diarrhea is a specific alarm feature suggesting organic disease rather than functional bowel disorder 1, 3
• The elevated stool inflammatory markers (MMP-9, beta-defensin 2, lactoferrin, eosinophil protein X) with normal calprotectin suggest mucosal irritation without frank colitis, consistent with bile acid effects 1

Critical Secondary Issue: Intestinal Yeast Overgrowth

The documented x3 intestinal yeast with low secretory IgA requires antifungal treatment:

• Initiate fluconazole 100-200mg daily for 2-4 weeks to address documented yeast overgrowth 2
• Low secretory IgA predisposes to fungal overgrowth and impairs mucosal defense 2
• The combination of elevated ferritin, high B12, elevated LDH with low mean RBC iron suggests chronic inflammation and possible hemolysis, which can occur with chronic intestinal dysbiosis 1

Address GERD and Nocturnal Aspiration Risk

The esophagitis, gastritis, and nocturnal nasal regurgitation create serious aspiration risk:

• Optimize proton pump inhibitor therapy with twice-daily dosing (e.g., omeprazole 20mg twice daily) taken 30-60 minutes before meals 3
• Elevate head of bed by 6-8 inches and avoid eating within 3 hours of bedtime to prevent nocturnal reflux 3
• The nocturnal diarrhea timing (1-2 hours after lying down) may be partially triggered by reflux-induced vagal stimulation 1

Nutritional Deficiency Correction

The pattern of low vitamins D, E, and low mean RBC iron with normal transferrin saturation suggests fat-soluble vitamin malabsorption:

• Supplement vitamin D 2000-4000 IU daily and vitamin E 400 IU daily to correct documented deficiencies 1
• Consider iron supplementation with vitamin C despite normal CBC, as low mean RBC iron indicates depleted stores 1
• The high ferritin with low mean RBC iron suggests anemia of chronic disease pattern 1

Symptomatic Diarrhea Control

While addressing underlying causes:

• Loperamide 4mg initially, then 2mg after each unformed stool (maximum 16mg/day) for immediate symptom relief 2, 4
• Consider probiotics (Vivomixx or similar high-potency formulation) to restore intestinal microbiome 2

Diagnostic Gaps to Address

Despite extensive workup, critical tests remain missing:

• Serum anti-tissue transglutaminase IgA with total IgA must be performed if not already done, as celiac disease remains the most common small bowel enteropathy and can present with these exact features 1, 3
• Colonoscopy with biopsies from right and left colon (not rectum) to exclude microscopic colitis, which has normal-appearing mucosa but causes watery diarrhea 1, 2
• Consider SeHCAT scan or serum C4 testing if available to confirm bile acid malabsorption before long-term bile acid sequestrant therapy 1, 2
• Small intestinal bacterial overgrowth (SIBO) testing via glucose or lactulose hydrogen breath test, or empiric trial of rifaximin 550mg three times daily for 14 days 1, 2, 3

Common Pitfalls to Avoid

• Do not diagnose functional diarrhea or IBS-D prematurely - nocturnal diarrhea is an alarm feature indicating organic disease, and Rome IV criteria have only 52-74% specificity 1, 2, 3
• Do not miss microscopic colitis - this requires biopsies from normal-appearing mucosa and is a common cause of chronic watery diarrhea 1, 2
• Review all medications - proton pump inhibitors, if already being used, can paradoxically cause diarrhea in some patients, though they are needed here for GERD 1, 3
• The fecal incontinence episodes indicate severe disease requiring aggressive treatment rather than reassurance 1

Treatment Sequence and Monitoring

1. Week 1-2: Start bile acid sequestrant, fluconazole, optimize PPI therapy, elevate bed, begin vitamin supplementation
2. Week 2-4: Add loperamide as needed for breakthrough symptoms, continue antifungal course
3. Week 4-6: Reassess symptom response; if inadequate improvement, pursue missing diagnostic tests (celiac serology, microscopic colitis biopsies, SIBO testing)
4. Ongoing: Monitor vitamin levels every 3 months until normalized, then annually 1

The combination of nocturnal timing, documented yeast overgrowth, low secretory IgA, fat-soluble vitamin deficiencies, and elevated stool inflammatory markers without elevated calprotectin creates a distinct clinical picture requiring this multi-targeted approach rather than single-diagnosis thinking 1, 2.