Background Despite its dramatic cutaneous manifestations, EPP is a systemic disease with multi-organ involvement. In fact, protoporphyrin IX (PPIX) accumulates in multiple sites beside the skin, chiefly the bone marrow and the liver. Therefore, EPP patients display mild hematological alterations and are at risk of developing cholestatic liver disease, which may evolve to liver cirrhosis. Several patients show thrombocytopenia with increased spleen dimensions, which in the presence of hepatic alterations may raise the suspicion of portal hypertension.

Aim To characterize the phenotype of clinically stable EPP from a multi-system perspective.

Methods To test phenotypic correlations, 15 patients were enrolled: liver status, hematology and spleen parameters, and PPIX levels were collected at the same timepoint.

Results Increased spleen dimensions (SplD: bipolar diameter, BP; area-at-hilus, Ah) are common in EPP (7/15). Free PPIX levels predicted liver stiffness (LS, β=0.71, p=0.004), erythropoietin levels (β=0.63, p=0.020), SplD (BP: β=0.76, p=0.001; Ah: β=0.81, p<0.001), and platelet count (β=−0.60, p=0.017); SplD predicted platelet count (BP: β=−0.64, p=0.014; Ah: β=−0.82, p<0.001); when both SplD and PPIX levels were tested, platelet count was significantly correlated to SplD only (Ah: β=−0.95, p=0.008). Spleen stiffness was within normal ranges in all patients and not significantly associated with SplD. Instead, it showed significant correlations with hemoglobin (Hb, β=0.62, p=0.03), hypochromic red blood cell percentage (HypoRBC, β=−0.77, p=0.003), and ferritin (β=0.60, p=0.038). Hb was inversely related to HypoRBC, (β=−0.64, p=0.010). HypoRBC was inversely related to reticulocyte Hb content (β=−0.65, CHr, p=0.008) and mean corpuscular Hb (MCH, β=−0.51, p=0.047). Serum ferritin predicted the iron status of red blood cell lineage (HypoRBC: β=−0.64, p=0.010, CHr: β=0.72, p=0.002), but did not significantly reflect on Hb. Alterations in liver biochemistry were significantly associated with increased LS.

Discussion Taken together, these findings support the following phenotype model: in EPP, hypersplenism is likely an expression of compensatory extramedullary erythropoiesis, independent of protoporphyric hepatopathy; thrombocytopenia may be directly linked to increased spleen dimensions, rather than direct PPIX-driven impairment on platelet production; the erythropoietic drive is directly dependent on the disease activity; HypoRBC, MHC, and CHR could support a diagnosis of iron-restricted erythropoiesis better than serum ferritin or transferrin saturation.

Conclusion Although further studies are needed to confirm these findings, this is the first description of a complex multi-system interplay in protoporphyria. These findings could help better define the phenotype of EPP patients, particularly in the context of protoporphyric hepatopathy with spleen or hematological alterations.