What further workup and differential diagnoses should be considered for a 44-year-old female with malabsorption, borderline anemia, chronic fatigue, skin rashes, spontaneous bruising, elevated Porphobilinogen (PBG), and elevated ferritin after iron supplementation with Venofer (Iron Sucrose)?

Workup and Differential Diagnosis for Elevated Ferritin with Malabsorption and Elevated PBG

This patient's elevated porphobilinogen (PBG) with skin rashes, spontaneous bruising, and malabsorption strongly suggests an acute porphyria, most likely acute intermittent porphyria (AIP) or variegate porphyria (VP), and the elevated ferritin post-iron supplementation requires immediate cessation of further iron therapy and comprehensive porphyria workup. 1

Immediate Priority: Porphyria Evaluation

The constellation of elevated PBG, skin rashes on sun-exposed areas (face, torso, extremities), spontaneous bruising (photosensitivity manifestation), and chronic fatigue mandates urgent porphyria investigation 1:

• Measure 24-hour urine porphyrins including uroporphyrin I and coproporphyrin I levels 1
• Quantify urinary aminolevulinic acid (ALA) alongside PBG 1
• Check plasma/fecal porphyrins to differentiate between acute intermittent porphyria (elevated urine only) versus variegate porphyria or hereditary coproporphyria (elevated fecal porphyrins) 1
• Measure erythrocyte zinc protoporphyrin (ZnPP) and free protoporphyrin (FPP) 1

The photosensitivity with severe skin manifestations combined with elevated PBG suggests either variegate porphyria or, less likely, congenital erythropoietic porphyria (CEP), though CEP typically presents earlier in life 1.

Addressing the Elevated Ferritin

Stop all iron supplementation immediately 1. The ferritin of 1134 ng/mL after recent IV iron (Venofer) requires interpretation in context 1:

• Measure transferrin saturation (TSAT) to distinguish true iron overload from ferritin elevation due to inflammation or porphyria itself 1, 2
• Check C-reactive protein (CRP) since ferritin is an acute-phase reactant and may be falsely elevated in inflammatory states 1, 2
• Obtain complete iron panel including serum iron, total iron-binding capacity, and transferrin 2, 3

In porphyrias, particularly those with photosensitivity and hemolysis, ferritin can be elevated independent of total body iron stores 1. The British Association of Dermatologists notes that iron overload itself can cause pruritus and skin manifestations 1.

Malabsorption Workup

Given unexplained malabsorption with borderline anemia despite recent IV iron 2, 4:

• Screen for celiac disease with tissue transglutaminase (TTG) antibodies and total IgA level (to exclude IgA deficiency causing false-negative TTG) 1, 2
• Test for Helicobacter pylori via non-invasive testing, as H. pylori can cause iron malabsorption 2, 4
• Consider bidirectional endoscopy (upper endoscopy and colonoscopy) if celiac and H. pylori testing are negative, as recommended for unexplained iron deficiency anemia in adults 2
• Evaluate for inflammatory bowel disease with fecal calprotectin if diarrhea is present 4

The wasted appearance suggests chronic malnutrition requiring assessment of albumin, prealbumin, and fat-soluble vitamins (A, D, E, K) 4.

Hematologic Evaluation

The borderline anemia with spontaneous bruising requires 2, 5:

• Complete blood count with differential and reticulocyte count to assess for hemolysis (elevated reticulocytes) versus defective erythropoiesis 2, 5
• Peripheral blood smear to evaluate red cell morphology for hemolysis, which occurs in some porphyrias 1
• Coagulation studies (PT/INR, aPTT, fibrinogen) to evaluate spontaneous bruising 5
• Vitamin B12 and folate levels as malabsorption can cause combined deficiencies 4

Genetic Disorders of Iron Metabolism

If porphyria is excluded and ferritin remains elevated with low-normal TSAT, consider 1:

• Iron-refractory iron deficiency anemia (IRIDA) due to TMPRSS6 mutations, though this typically presents with very low TSAT and resistance to oral iron 1
• Ferroportin disease (SLC40A1 mutations), which causes elevated ferritin with low-normal TSAT and macrophage iron loading 1
• Genetic testing for TMPRSS6 and SLC40A1 if clinical suspicion warrants 1

However, the elevated PBG makes porphyria far more likely than these rare genetic iron disorders 1.

Key Differential Diagnoses

Primary considerations:

1. Variegate porphyria - explains elevated PBG, photosensitive skin rashes, spontaneous bruising (skin fragility), malabsorption, and can cause elevated ferritin 1
2. Acute intermittent porphyria with secondary complications - elevated PBG with systemic manifestations 1
3. Celiac disease - causes malabsorption, can present with dermatitis herpetiformis (rash), and iron deficiency 1, 2, 4
4. Congenital erythropoietic porphyria - less likely given age of presentation but causes photosensitivity, hemolytic anemia, and elevated uroporphyrins 1

Secondary considerations: 5. Hemochromatosis with concurrent illness - elevated ferritin but would expect high TSAT 1 6. Inflammatory/autoimmune condition causing elevated ferritin as acute-phase reactant 1, 2

Critical Pitfalls to Avoid

• Do not continue iron supplementation with ferritin >500 ng/mL without clear evidence of functional iron deficiency (low TSAT), as this risks iron overload 1
• Do not dismiss elevated ferritin as solely due to recent IV iron - investigate underlying causes 1, 2
• Do not overlook porphyria when PBG is elevated with photosensitive rashes; this is a diagnostic emergency requiring avoidance of porphyrinogenic drugs 1
• Do not assume dietary deficiency alone explains the clinical picture without completing GI evaluation 2
• Ferritin between 100-500 ng/mL in inflammatory states may still represent iron deficiency - use TSAT and CRP for interpretation 1, 2

Recommended Diagnostic Algorithm

1. Urgent porphyria workup (24-hour urine porphyrins, ALA, PBG, plasma/fecal porphyrins) 1
2. Iron studies with inflammation markers (TSAT, serum iron, TIBC, CRP) 1, 2
3. Celiac screening (TTG antibodies, total IgA) 1, 2
4. H. pylori testing 2, 4
5. Hematologic evaluation (CBC with differential, reticulocyte count, peripheral smear, B12, folate) 2, 5, 4
6. If above negative, proceed to endoscopy 2