Erythropoietic ProtoPorphyria (EPP) is an autosomal recessive disorder caused by the deficiency of the ferrochelatase (FECH) enzyme resulting in the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes and tissues. EPP is characterized by acute, painful and non-blistering phototoxicity on sun exposure and, in a small proportion of patients, by liver disease with the development of liver failure in 1–5% of cases.

Our clinical vignette describes the case of a 71-year old man who received a diagnosis of low risk myelodysplastic neoplasm with ring sideroblasts in 2018. Due to anemia, erythropoietin (EPO) 40000 U once a week was started. Four years later, he presented to gastroenterology unit because of jaundice, asthenia and nausea. Blood tests revealed an increase in hepatobiliary enzymes and an ultrasound diagnosis of liver cirrhosis was made. Investigating more deeply his past medical history, he reported cholelithiasis and photodermatosis, with painful erythema and edema since childhood, and therefore a form of chronic porphyria was suspected. Erythrocyte protoporphyrins (PP), predominantly metal-free PPIX, resulted markedly increased, spectrofluorimetric plasma scan showed an emission peak at 634 nm and molecular analysis of FECH gene revealed the presence of a pathogenetic variant (c.215dupT) trans to the hypomorphic allele (c.-252A>G, c.68–23C>T and c.315–48T>C), thus confirming the diagnosis of EPP.

During hospitalization, a further increase in serum transaminases, total and conjugated bilirubin and erythrocyte PPIX level concomitantly to EPO administration was observed. For this reason, EPO was interrupted and seven cycles plasma- and erythro-exchange were performed with improvement in liver enzymes and PP levels. Treatment with ursodeoxycholic acid was also promptly started as well as regular blood transfusions to reduce protoporphyrin production by suppressing erythropoiesis. Symptoms improved but, due to liver failure, the patient was transplanted. A year later, due to the worsening of the transfusion need, Luspatercept was started at 1 mg/kg/day every 3-week. Two doses were administered with a good response on Hb levels but, the exponential increase in PP levels (from 15 to 36.8 to 137.5 mg/gHb) and liver enzymes (ALT from 30 to 36 to 168 U/L and AST from 10 to 66 to 99U/L) prompted treatment cessation with subsequently normalization of serum markers.

The treatment with EPO has been already reported to be contraindicated in EPP. Luspatercept acts in the late-stage of erythropoiesis and, unlike EPO, that mainly stimulates the proliferation of erythroid compartment, it improves anemia enhancing erythroid differentiation. To the best of our knowledge, this is the first case of an EPP patient treated with Luspatercept and it suggests that not only EPO but also this drug, can induce exacerbations of EPP phenotype, even in a liver transplant patient.