What is the best course of treatment for a patient with chronic diarrhea, bloating, and mucus in stools, who also has a history of weight loss, acid reflux, nocturnal diarrhea, intermittent rash, eczema, hyperferritinemia, elevated B12, vitamin D deficiency, mildly elevated liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), increased lactate dehydrogenase (LDH), intestinal yeast, and increased inflammatory markers in stool?

Diagnostic Workup and Treatment Approach

This patient requires urgent upper endoscopy with duodenal biopsies to evaluate for celiac disease and other small bowel enteropathies, alongside targeted testing for small intestinal bacterial overgrowth (SIBO), bile acid malabsorption, and inflammatory bowel disease, as the constellation of nocturnal diarrhea, weight loss, elevated inflammatory markers, and abnormal liver enzymes strongly suggests organic pathology rather than a functional disorder. 1

Critical Diagnostic Priorities

Immediate Endoscopic Evaluation Required

• Upper endoscopy with distal duodenal biopsies is mandatory despite any prior negative celiac serology, as antibody-negative celiac disease accounts for 6.4-7% of cases, and the clinical presentation (weight loss, diarrhea, vitamin D deficiency, elevated liver enzymes) is highly suggestive of small bowel enteropathy 1

• The presence of nocturnal diarrhea is an alarm feature that excludes functional disorders like IBS and mandates investigation for organic disease 1

• Duodenal biopsies will also identify other seronegative enteropathies including tropical sprue, collagenous sprue, autoimmune enteropathy, Whipple's disease, and intestinal lymphoma 1

Essential Laboratory Testing

Complete the following blood work immediately:

• Tissue transglutaminase (TTG) IgA and endomysial antibody (EMA) with total IgA level - these have >90% sensitivity/specificity in high-prevalence populations, but if IgA deficient, order IgG-based tests 1

• Fecal calprotectin - elevated levels (>250 μg/g) predict endoscopic inflammation and help distinguish inflammatory bowel disease from functional disorders 1

• Stool studies for ova, cysts, and parasites (three specimens) plus Giardia-specific ELISA - has 92% sensitivity and 98% specificity for giardiasis, which can cause chronic diarrhea with malabsorption 1

• HIV testing - chronic diarrhea is a common presenting symptom in newly diagnosed HIV, and immunodeficiency predisposes to opportunistic infections 1

• Thyroid function tests - hyperthyroidism causes chronic diarrhea through increased gut transit 1

Specific Mechanistic Testing

Based on the clinical presentation, prioritize these investigations:

• SeHCAT scan or serum 7α-hydroxy-4-cholesten-3-one for bile acid malabsorption - particularly relevant given the carnivore diet initially improved symptoms (suggesting fat/bile acid component) and the presence of nocturnal diarrhea 1

• Glucose hydrogen breath test for SIBO - the presence of "intestinal yeast" on labs, bloating, and malodorous characteristics suggest bacterial overgrowth 2

• Colonoscopy with random biopsies - the elevated inflammatory markers, nocturnal diarrhea, and mucus in stools warrant evaluation for inflammatory bowel disease and microscopic colitis 1

Key Clinical Features Demanding Attention

Alarm Features Present

• Nocturnal diarrhea - this symptom specifically excludes IBS and indicates organic pathology requiring aggressive workup 1

• 20-pound weight loss - suggests malabsorption or inflammatory disease, not functional disorder 1

• Elevated liver enzymes (AST/ALT) with high LDH - may indicate celiac disease-associated hepatitis, autoimmune hepatitis, or systemic inflammatory process 1, 3

• Hyperferritinemia with elevated B12 - paradoxically high ferritin and B12 in the setting of chronic diarrhea suggests inflammatory disease (ferritin is an acute phase reactant) rather than simple malabsorption 4

Laboratory Pattern Analysis

The combination of high ferritin, high B12, low vitamin D, and elevated inflammatory markers is atypical for simple malabsorption and suggests:

• Active inflammatory process (ferritin as acute phase reactant) 4
• Possible bacterial overgrowth (elevated B12 from bacterial production) 1
• Fat malabsorption (low vitamin D) 3
• Intestinal inflammation (elevated stool inflammatory markers) 1

Critical Pitfalls to Avoid

Do not make a diagnosis of IBS or functional diarrhea in the presence of:

• Nocturnal symptoms 1
• Significant weight loss 1
• Elevated inflammatory markers 1
• Abnormal liver enzymes 1

Do not rely on negative celiac serology alone - proceed with duodenal biopsies given the high clinical suspicion, as 6.4-7% of celiac disease cases are seronegative 1

Do not overlook medication history - specifically ask about NSAIDs, PPIs, antihypertensives (especially olmesartan), and antibiotics, as these account for up to 4% of chronic diarrhea cases 1

Do not dismiss the "intestinal yeast" finding - while often overdiagnosed, in the context of chronic diarrhea with malabsorption, consider SIBO or immunodeficiency states 1, 2

Empirical Treatment Considerations

While Awaiting Diagnostic Results

• Vitamin D supplementation - address the documented deficiency immediately 3, 4

• Consider empirical trial of rifaximin for presumed SIBO if breath testing unavailable and symptoms suggest bacterial overgrowth (bloating, malodorous stools) 2

• Avoid empirical gluten-free diet before completing celiac workup, as this will invalidate serologic and histologic testing 1

If Bile Acid Malabsorption Confirmed

• Cholestyramine or colesevelam - effective for bile acid diarrhea, which typically presents with post-prandial diarrhea 1

Diagnostic Algorithm Summary

1. Immediate: Upper endoscopy with duodenal biopsies + celiac serology + fecal calprotectin + stool studies for parasites 1

2. Concurrent: HIV test, thyroid function, comprehensive metabolic panel 1

3. If initial workup negative: SeHCAT scan or 7α-hydroxy-4-cholesten-3-one + glucose breath test for SIBO 1, 2

4. If inflammatory markers elevated: Colonoscopy with random biopsies for IBD and microscopic colitis 1

5. Specialist referral: Gastroenterology consultation is warranted given the severity, duration, alarm features, and diagnostic complexity 1

The presence of multiple alarm features (nocturnal diarrhea, weight loss, elevated inflammatory markers, abnormal liver enzymes) makes organic disease highly likely and demands comprehensive evaluation before considering any functional diagnosis 1.