What could be the cause of worsening chronic diarrhea, including nocturnal episodes, and malabsorption of essential vitamins, such as vitamin D and E, and low normal B vitamins, in a patient with a 3-year history of chronic diarrhea, who experiences exacerbation of symptoms with supplement intake?

Worsening Chronic Diarrhea with Supplement Intolerance: Underlying Malabsorption

This patient's presentation of nocturnal diarrhea, fat-soluble vitamin deficiencies (D and E), and worsening symptoms with supplements strongly indicates an underlying malabsorptive disorder that must be diagnosed before any symptomatic treatment, with celiac disease, pancreatic exocrine insufficiency, and bile acid malabsorption being the most likely culprits. 1, 2

Why Supplements Worsen Diarrhea

The supplements themselves are likely exacerbating diarrhea through several mechanisms related to the underlying malabsorption:

• Osmotic load from unabsorbed supplements: When the intestinal mucosa cannot properly absorb vitamins and minerals, these supplements remain in the intestinal lumen and draw water into the bowel through osmotic forces, worsening diarrhea 3, 4

• Magnesium content: Many multivitamin formulations contain magnesium, which is a well-known cause of chronic diarrhea and accounts for up to 4% of chronic diarrhea cases 1

• Fat-soluble vitamin preparations: The deficiency of vitamins D and E specifically indicates fat malabsorption, and attempting to supplement these in standard formulations requires adequate fat absorption capacity that this patient lacks 5, 3

Critical Diagnostic Imperative

The presence of nocturnal diarrhea is an alarm feature that excludes functional disorders like irritable bowel syndrome and mandates immediate investigation for organic pathology. 2, 6, 7

Mandatory First-Line Testing

The following tests must be completed urgently (within 1-2 weeks):

• Celiac disease serology: Anti-tissue transglutaminase IgA with total IgA level, as celiac disease is the most common small bowel enteropathy and a sensitive indicator of malabsorption, particularly with iron deficiency 1, 8

• Complete blood count: To assess for anemia, which has high specificity for organic disease 1, 7

• Inflammatory markers: C-reactive protein or ESR, as abnormalities have high specificity for organic pathology 1, 2, 7

• Comprehensive metabolic panel: Including calcium, as hypocalcemia can occur with vitamin D malabsorption 1, 7

• Thyroid function tests: TSH is the best predictor for hyperthyroidism, which can cause chronic diarrhea 1, 2

• Fecal calprotectin: To distinguish inflammatory from non-inflammatory causes, with >90% sensitivity for inflammatory bowel disease 2, 7

Essential Endoscopic Evaluation

Upper endoscopy with distal duodenal biopsies is mandatory, regardless of celiac serology results, because antibody-negative celiac disease accounts for 6.4-7% of cases. 6

Full colonoscopy with random biopsies throughout the colon is essential, even if mucosa appears normal, as microscopic colitis can only be detected histologically and commonly presents with nocturnal diarrhea. 6, 7

Most Likely Diagnoses Based on Clinical Pattern

Celiac Disease (Highest Priority)

• The combination of fat-soluble vitamin deficiencies (D and E) with low-normal B vitamins strongly suggests small bowel enteropathy 1, 5
• Iron deficiency is a sensitive indicator of small bowel enteropathy, particularly celiac disease 1
• Nocturnal diarrhea can occur with celiac disease 2
• Treatment: Strict lifelong gluten-free diet if confirmed 6

Pancreatic Exocrine Insufficiency

• Fat-soluble vitamin deficiencies (D and E) are hallmark features of pancreatic insufficiency due to fat malabsorption 5, 3
• Previous pancreatic disease should be specifically sought in the history 1
• Treatment: Pancreatic enzyme replacement therapy (pancrelipase) with meals 9

Bile Acid Malabsorption

• Typically causes postprandial diarrhea but can manifest nocturnally, particularly in diabetics 2, 6
• Should be tested with serum 7α-hydroxy-4-cholesten-3-one if colonoscopy is negative 6, 7
• Treatment: Bile acid sequestrants (cholestyramine or colesevelam) 6

Microscopic Colitis

• Causes secretory diarrhea that can occur at night and follows a relapsing-remitting course 2
• Accounts for 15% of chronic diarrhea cases in older adults 7
• Has entirely normal-appearing mucosa on endoscopy but shows characteristic histologic changes only on biopsy 7
• Treatment: Budesonide is first-line therapy 6

Critical Management Pitfalls to Avoid

• Never diagnose irritable bowel syndrome or initiate IBS treatment in the presence of nocturnal diarrhea without completing the organic disease workup 6, 7

• Do not rely on negative celiac serology alone—duodenal biopsies must be performed regardless of antibody results 6

• Do not skip colonic biopsies even with normal-appearing mucosa—microscopic colitis requires histologic diagnosis 6, 7

• Do not continue vitamin supplementation in standard formulations until the underlying malabsorptive disorder is identified and treated—this will only worsen symptoms 3

Immediate Management Strategy

1. Stop all current vitamin supplements temporarily until diagnosis is established 3

2. Initiate urgent diagnostic workup with blood tests, stool studies, and gastroenterology referral within 2-4 weeks 7

3. Once diagnosis is established, treat the underlying condition first before attempting vitamin repletion 3

4. For fat-soluble vitamin deficiencies, once pancreatic insufficiency or celiac disease is treated, use water-miscible preparations of vitamins D and E if standard formulations remain poorly tolerated 5, 3

5. If pancreatic exocrine insufficiency is confirmed, pancreatic enzyme replacement must be taken with all meals and snacks, with dosing not exceeding 2,500 lipase units/kg/meal or 10,000 lipase units/kg/day to avoid fibrosing colonopathy 9