What is the best course of treatment for a 25-year-old male with a history of beta-thalassemia, H. pylori infection, and C. diff infection, presenting with nausea, flatulence, diarrhea, anal pain, and abnormal liver function tests?

Inflammatory Bowel Disease Workup and Treatment

This 25-year-old male with markedly elevated fecal calprotectin (>3500 mg/kg), blood in stool, and chronic gastrointestinal symptoms requires urgent colonoscopy with biopsies to diagnose inflammatory bowel disease (IBD), followed by initiation of appropriate immunosuppressive therapy once infectious causes are excluded.

Immediate Diagnostic Priorities

The stool calprotectin level of >3500 mg/kg is profoundly elevated and strongly indicates active intestinal inflammation, most consistent with IBD rather than functional disorders like IBS 1. This level far exceeds the threshold for distinguishing IBD from IBS and mandates endoscopic evaluation 1.

Required Endoscopic Evaluation

• Colonoscopy with multiple biopsies from all colonic segments and terminal ileum is essential to establish the diagnosis, assess disease extent, and exclude microscopic colitis 1
• The presence of blood streaks in stool, combined with the extremely elevated calprotectin, makes colonoscopy mandatory regardless of age 1
• Biopsies should be obtained even from normal-appearing mucosa to detect microscopic inflammation 1

Exclude Remaining Infectious Causes

Before initiating immunosuppressive therapy, the following must be ruled out:

• Repeat stool testing for C. difficile using two-stage approach: glutamate dehydrogenase EIA or PCR followed by toxin EIA, given his history of prior C. difficile infection and multiple antibiotic courses 1
• Stool culture or multiplex PCR panel for bacterial pathogens (Salmonella, Shigella, Campylobacter, STEC) given the bloody stools 1
• Stool examination for parasites (Giardia, Entamoeba histolytica) using ELISA or PCR, particularly given his history of multiple infections 1

Addressing the Beta-Thalassemia Context

His beta-thalassemia minor complicates the clinical picture but does not explain the severe intestinal inflammation:

• The indirect hyperbilirubinemia (1.5 mg/dL) and mild splenomegaly are consistent with his thalassemia and chronic hemolysis, not acute liver disease 2
• Beta-thalassemia patients have increased prevalence of H. pylori infection and gastrointestinal symptoms, but his H. pylori has been treated 3
• Iron overload from chronic transfusions can cause hepatic fibrosis, but his liver enzymes are only mildly elevated and fatty liver on imaging is more likely related to other factors 4

Treatment Algorithm Once IBD is Confirmed

Step 1: Assess Disease Severity and Extent

Based on endoscopic findings, histology, and clinical parameters:

• Extensive colitis with severe inflammation (suggested by calprotectin >3500): Consider hospitalization for IV corticosteroids (methylprednisolone 40-60 mg daily) 1
• Moderate disease: Oral corticosteroids (prednisone 40 mg daily) with rapid taper over 8-12 weeks 1
• Concurrent initiation of steroid-sparing immunomodulator (azathioprine 2-2.5 mg/kg or anti-TNF therapy) should be considered given the severity 1

Step 2: Nutritional and Symptomatic Management

• Correct any micronutrient deficiencies: Check vitamin B12, folate, vitamin D (already corrected), zinc, and selenium 1
• Avoid NSAIDs and antimotility agents (loperamide), which can precipitate toxic megacolon in active IBD 1
• Dietary modifications: While awaiting endoscopy, a low-residue diet may reduce symptoms, but specific dietary therapy should be individualized after diagnosis 1

Step 3: Address Specific Symptoms

• For acid reflux symptoms: Continue PPI therapy (omeprazole 20-40 mg twice daily) given his fear of eating after 4 PM and reflux symptoms 5
• For anal pain: Evaluate for perianal disease (fissures, fistulas, abscesses) during examination, which would suggest Crohn's disease 1
• For left flank pain: The CT finding of reactive lymph nodes in the right iliac fossa (not left) may represent mesenteric adenitis from active IBD 1

Critical Pitfalls to Avoid

• Do not attribute these symptoms to IBS given the markedly elevated calprotectin, blood in stool, and alarm features 1
• Do not delay colonoscopy while pursuing additional stool testing; these can be done concurrently 1
• Do not start empiric antibiotics for presumed bacterial diarrhea without culture confirmation, as this may worsen IBD and complicate C. difficile testing 1, 6
• Do not assume post-infectious IBS from his prior C. difficile infection when calprotectin is this elevated 1
• Do not use hydrogen breath testing for carbohydrate malabsorption or SIBO, as these are not indicated with typical IBD symptoms and would delay appropriate diagnosis 1

Monitoring After Diagnosis

• Serial fecal calprotectin measurements every 3-6 months to assess treatment response and predict relapse 1
• Complete blood count, liver enzymes, and albumin every 3 months while on immunosuppression 1
• Thiopurine methyltransferase (TPMT) testing before starting azathioprine to prevent severe myelosuppression 1

The combination of extremely elevated calprotectin, visible blood in stool, chronic symptoms, and systemic findings (reactive lymph nodes, mild splenomegaly beyond what thalassemia explains) creates a compelling case for IBD that requires urgent endoscopic confirmation and aggressive treatment 1.