What is the differential diagnosis for a patient with cachectic malabsorption issues, elevated Porphyobilinogen (PBG), and significantly elevated Ferritin levels, indicating potential acute intermittent porphyria and iron overload?

Differential Diagnosis: Cachexia, Malabsorption, Elevated PBG, and Ferritin 1134 ng/mL

Primary Diagnosis to Confirm or Exclude

The combination of elevated porphobilinogen (PBG) with cachexia and malabsorption strongly suggests acute intermittent porphyria (AIP) as the primary diagnosis, while the ferritin elevation of 1134 ng/mL requires differentiation between AIP-associated inflammation versus a concurrent systemic inflammatory condition such as adult-onset Still's disease (AOSD) or hemophagocytic syndrome. 1

Immediate Diagnostic Algorithm

Step 1: Confirm or Exclude Acute Hepatic Porphyria

• Measure urinary ALA and PBG with creatinine on a random urine sample (preferably morning spot urine, protected from light with aluminum foil) 1, 2
• During acute attacks, both ALA and PBG are elevated at least 5-fold above the upper limit of normal (often >10-fold), with PBG/creatinine ratio typically >10 times upper limit of normal 1, 3, 4
• If PBG is significantly elevated (>5-10x upper limit of normal), AIP is confirmed and explains the cachexia and malabsorption through chronic gastrointestinal dysfunction 2, 3
• If both ALA and PBG are normal during symptoms, AHP is effectively ruled out (except for extremely rare ALAD deficiency porphyria where only ALA is elevated) 2, 3, 4

Critical pitfall: Never rely on urine porphyrins alone—this is the most common diagnostic error leading to false positives and false negatives 1, 2, 4

Step 2: Interpret the Ferritin Elevation in Context

The ferritin level of 1134 ng/mL requires careful interpretation based on the PBG results:

If AIP is Confirmed (PBG >5-10x elevated):

• Ferritin 1134 ng/mL represents moderate elevation consistent with acute-phase response during an AIP attack 1, 5
• AIP attacks cause systemic inflammation, autonomic dysfunction, and metabolic derangement that can elevate ferritin 5, 6, 7
• The cachexia and malabsorption are explained by recurrent AIP attacks causing chronic gastrointestinal symptoms and nutritional compromise 5, 8

If AIP is Excluded (Normal PBG and ALA):

• Ferritin 1134 ng/mL with cachexia and malabsorption shifts the differential toward systemic inflammatory conditions:
  • Adult-onset Still's disease (AOSD): Ferritin >1000 ng/mL has 74.7% sensitivity and 88.9% specificity for AOSD versus sepsis 1
  • Measure glycosylated ferritin (GF): If GF ≤20%, this supports AOSD (79.5% sensitivity, 66.4% specificity) 1
  • Check for AOSD clinical features: Quotidian fever, salmon-pink rash, arthritis (especially wrists, knees, ankles), sore throat 1
  • Hemophagocytic lymphohistiocytosis (HLH): Consider if ferritin continues rising with cytopenias, hepatosplenomegaly, or triglyceride elevation
  • Malignancy-associated cachexia: Particularly lymphoma or gastrointestinal malignancy with paraneoplastic ferritin elevation
  • Chronic infection with malabsorption: Including tuberculosis, HIV enteropathy, or chronic parasitic infection

Step 3: Additional Discriminatory Testing

If PBG is elevated (confirming AIP):

• Proceed with genetic testing to identify the specific mutation (HMBS, CPOX, PPOX, or ALAD genes) 1, 2, 4
• Screen first-degree family members once the pathogenic variant is identified 1, 2, 4
• Evaluate for chronic complications: hypertension, chronic kidney disease, hepatocellular carcinoma 5

If PBG is normal (excluding AIP):

• For suspected AOSD: Measure glycosylated ferritin, check inflammatory markers (ESR, CRP), and evaluate for characteristic articular involvement 1
• For suspected HLH: Check soluble IL-2 receptor, triglycerides, fibrinogen, NK cell activity, and bone marrow for hemophagocytosis
• For malignancy: Age-appropriate cancer screening with emphasis on gastrointestinal tract (endoscopy, colonoscopy, CT imaging)
• For chronic infection: HIV testing, tuberculosis screening (QuantiFERON, chest imaging), stool studies for parasites

Key Clinical Discriminators

Features Favoring AIP:

• Recurrent severe abdominal pain without peritoneal signs (paroxysmal nature) 5, 6, 8
• Acute peripheral neuropathy (motor and/or sensory polyneuropathy) 5, 8
• Autonomic dysfunction (tachycardia, hypertension, constipation) 5, 7, 8
• Hyponatremia (often severe and intractable) 5, 6, 8
• Encephalopathy with seizures or psychosis 5, 7, 8
• Female sex and reproductive age (attacks often triggered by hormonal changes) 4, 5

Features Favoring AOSD:

• Quotidian fever pattern (daily temperature spike to ≥39°C) 1
• Salmon-pink evanescent rash (appears with fever) 1
• Arthritis or arthralgias (particularly wrists 69%, knees 61-77%, ankles 46-75%) 1
• Sore throat (non-exudative pharyngitis) 1
• Ferritin >1000 ng/mL with glycosylated ferritin ≤20% 1

Common Diagnostic Pitfalls

• Do not use 24-hour urine collection—random spot urine is sufficient and preferred for PBG/ALA testing 1, 2, 4
• Do not rely on qualitative tests (Watson-Schwartz or Hoesch tests) alone—always use quantitative ALA and PBG measurements 2, 4
• Do not perform genetic testing first—biochemical confirmation with PBG/ALA must precede genetic testing 1, 2, 4
• Do not assume ferritin >1000 ng/mL automatically means AOSD—this level can occur in AIP, sepsis, malignancy, and liver disease 1
• Hemin treatment can normalize PBG levels—if the patient received hemin, PBG may be falsely normal 4

Management Implications Based on Diagnosis

If AIP is confirmed:

• Treat acute attacks with intravenous hemin (preferably into high-flow central vein) 1
• Provide high carbohydrate intake (glucose loading) to suppress ALA synthase 5, 7
• Eliminate precipitating factors (certain medications, alcohol, fasting, hormonal changes) 5
• Address malnutrition with adequate nutrition and fluid therapy during and between attacks 5

If AOSD is confirmed:

• Initiate immunosuppressive therapy (corticosteroids, IL-1 or IL-6 inhibitors) based on disease severity 1
• Monitor for macrophage activation syndrome (a form of secondary HLH) 1