What is the differential diagnosis for a patient presenting with hyperporphyria, severely elevated ferritin, and a malnourished appearance?

Differential Diagnosis: Elevated Porphobilinogen, Severely Elevated Ferritin (1535 μg/L), and Malnutrition

The combination of elevated porphobilinogen with severely elevated ferritin (1535 μg/L) and malnourished appearance most likely represents porphyria cutanea tarda (PCT) with secondary iron overload, though you must immediately measure transferrin saturation to distinguish between hereditary hemochromatosis-associated PCT versus other causes of hyperferritinemia in this context. 1, 2

Immediate Diagnostic Priority

Measure fasting transferrin saturation (TS) immediately—this is the single most important test to determine if true iron overload is present. 1, 3, 4

• If TS ≥45%, suspect primary iron overload (potentially hereditary hemochromatosis coexisting with PCT) and proceed to HFE genetic testing for C282Y and H63D mutations 1, 4
• If TS <45%, iron overload is unlikely and the elevated ferritin represents secondary causes (inflammation, liver disease, malnutrition) 1, 3

Primary Differential Diagnoses

1. Porphyria Cutanea Tarda with Iron Overload (Most Likely)

PCT is strongly associated with iron overload, with 62% of Italian PCT patients demonstrating iron accumulation, and many harbor genetic hemochromatosis genes. 2

• The elevated porphobilinogen directly indicates porphyria, while ferritin 1535 μg/L falls within the typical range for PCT with iron overload 2, 5
• Iron overload in PCT patients frequently results from coexistent HFE hemochromatosis genes (C282Y homozygosity or compound heterozygosity) 2
• HLA-A3 prevalence is significantly higher (p<0.01) in PCT patients with iron overload versus those without 2
• Serum ferritin in PCT correlates with hepatic iron stores rather than hepatocellular necrosis, making it a reliable marker 5

Key diagnostic steps:

• Check for skin photosensitivity, skin fragility, and hyperpigmentation (classic PCT features) 2
• Measure urine porphyrins (uroporphyrin and coproporphyrin will be markedly elevated) 2
• Assess for hepatic disease with ALT, AST, and consider abdominal ultrasound 1, 3
• If TS ≥45%, proceed with HFE genetic testing 4, 2

2. Hereditary Hemochromatosis (Primary Iron Overload)

If transferrin saturation is ≥45%, hereditary hemochromatosis becomes the leading diagnosis requiring immediate genetic confirmation. 1, 4

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE hemochromatosis 1, 4
• Classic presentation includes hepatomegaly, arthralgias (particularly 2nd/3rd metacarpophalangeal joints), and elevated ferritin 3, 4
• Ferritin 1535 μg/L exceeds the 1000 μg/L threshold associated with 20-45% prevalence of cirrhosis in C282Y homozygotes 1, 3
• Critical: Liver biopsy should be considered if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL 1, 3, 4

3. Malnutrition-Related Hyperferritinemia with Liver Disease

The malnourished appearance suggests chronic liver disease, metabolic dysfunction, or inflammatory conditions causing secondary hyperferritinemia. 1

• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome accounts for >90% of outpatient hyperferritinemia cases 1, 4
• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 1
• Viral hepatitis (B or C) causes hyperferritinemia in approximately 50% of patients 1, 3
• Cell necrosis from hepatocellular injury releases ferritin independent of iron stores 1

4. Inflammatory/Rheumatologic Conditions

While less likely given the porphobilinogen elevation, extremely high ferritin can indicate life-threatening inflammatory syndromes. 1, 6

• Adult-onset Still's disease (AOSD) presents with ferritin 4,000-30,000 ng/mL (occasionally up to 250,000 ng/mL) with glycosylated ferritin <20% 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome presents with ferritin >5,000 ng/mL, cytopenias, fever, and multiorgan dysfunction 1, 3
• Your patient's ferritin of 1535 μg/L is below these extreme thresholds, making these diagnoses less likely 6

5. Malignancy

Malignancy was the most frequent cause of markedly elevated ferritin (>1000 μg/L) in one large series (153/627 cases). 6

• Solid tumors, lymphomas, and hepatocellular carcinoma all cause hyperferritinemia 1
• The malnourished appearance raises concern for underlying malignancy 6
• Check for B symptoms (fever, night sweats, weight loss), lymphadenopathy, and hepatosplenomegaly 1

Critical Diagnostic Algorithm

Step 1: Measure transferrin saturation immediately 1, 3, 4

Step 2: Order comprehensive laboratory panel:

• Complete blood count with differential 1, 3
• Complete metabolic panel including ALT, AST, albumin 1, 3
• Inflammatory markers (CRP, ESR) 1, 3
• Urine porphyrins (uroporphyrin, coproporphyrin) 2, 5
• Creatine kinase to evaluate muscle necrosis 3

Step 3: If TS ≥45%:

• Order HFE genetic testing for C282Y and H63D mutations 1, 4
• If C282Y homozygote or C282Y/H63D compound heterozygote with elevated iron stores, diagnosis of HFE hemochromatosis is confirmed 1, 4
• Consider liver biopsy given ferritin >1000 μg/L to assess for cirrhosis 1, 3, 4

Step 4: If TS <45%:

• Focus on secondary causes: liver disease (ultrasound), malignancy screening, nutritional assessment 1, 3
• Treat underlying condition rather than elevated ferritin itself 1, 3

Risk Stratification and Management Implications

Ferritin 1535 μg/L places this patient above the critical 1000 μg/L threshold, which has 100% sensitivity but only 70% specificity for cirrhosis in hemochromatosis patients. 3

• The combination of ferritin >1000 μg/L with elevated liver enzymes and platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1, 3
• Ferritin >1000 μg/L warrants specialist referral (gastroenterology, hematology, or iron overload specialist) regardless of transferrin saturation 3
• If hereditary hemochromatosis is confirmed, initiate therapeutic phlebotomy immediately with target ferritin 50-100 μg/L 3, 4

Common Pitfalls to Avoid

Never use ferritin alone without transferrin saturation to diagnose iron overload—ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 3

Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests—this combination warrants histologic assessment for cirrhosis. 1, 3

**Do not assume iron overload when TS <45%**—in the general population, iron overload is NOT the most common cause of elevated ferritin, with >90% of cases due to inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome. 1, 4

Recognize that the malnourished appearance may reflect chronic liver disease, malignancy, or malabsorption—address nutritional status while pursuing the underlying diagnosis. 6