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. 2023 Jun 15;141(24):2921-2931.
doi: 10.1182/blood.2022018688.

How I treat erythropoietic protoporphyria and X-linked protoporphyria

Rebecca Karp Leaf  1   2 , Amy K Dickey  2   3
Affiliations

How I treat erythropoietic protoporphyria and X-linked protoporphyria

Rebecca Karp Leaf et al. Blood. .

Abstract

Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria caused by reduced expression of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis. The resultant accumulation of protoporphyrin IX leads to severe, painful cutaneous photosensitivity, as well as potentially life-threatening liver disease in a small percentage of patients. X-linked protoporphyria (XLP) is clinically similar to EPP but results from increased activity of δ-aminolevulinic acid synthase 2, the first step in heme biosynthesis in the bone marrow, and also causes protoporphyrin accumulation. Although historically the management of EPP and XLP (collectively termed protoporphyria) centered around avoidance of sunlight, novel therapies have recently been approved or are in development, which will alter the therapeutic landscape for these conditions. We present 3 patient cases, highlighting key treatment considerations in patients with protoporphyria, including (1) approach to photosensitivity, (2) managing iron deficiency in protoporphyria, and (3) understanding hepatic failure in protoporphyria.

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Conflict of interest statement

Conflict-of-interest disclosure: R.K.L. serves as a consultant for Mitsubishi Tanabe, Alnylam Pharmaceuticals, and Recordati Pharmaceuticals. A.K.D. has received research funding from Disc Medicine for other research unrelated to this publication, and serves as a consultant for Alnylam Pharmaceuticals and Recordati Pharmaceuticals.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
The heme biosynthetic pathway. Heme biosynthesis occurs by 8 sequential enzymatic steps. Decreased activity of ferrochelatase, the final enzyme in the pathway, leads to EPP. XLP is caused by gain-of-function mutations in ALAS2, the enzyme that catalyzes the initial step in this pathway within the erythroblast.
Figure 2.
Figure 2.
Cutaneous manifestations of phototoxic reactions in protoporphyria. (A) Mild cutaneous edema during a phototoxic reaction. (B) Severe cutaneous edema with petechiae during a phototoxic reaction. Note: in protoporphyria, visible cutaneous changes may not be present, even during severely painful phototoxic reactions.
Figure 3.
Figure 3.
Production of protoporphyrin and chemical structure. (A) Protoporphyrin is primarily produced within the erythroblast in the bone marrow. Iron enters the cell through the transferrin receptor (TFR) and is converted from the ferric (Fe3+) to the ferrous (Fe2+) form. The formation of heme requires insertion of Fe2+ into protoporphyrin, which is catalyzed by FECH. XLP is caused by gain-of-function variants in ALAS2, and EPP by loss-of-function variants in FECH. (B) Protoporphyrin (depicted in purple) is photoreactive and can cause burning, itching, and pain of the skin. (C) The chemical structure of protoporphyrin (left) and chlorophyl (right) are similar. (D) Plasma protoporphyrin (depicted in purple) enters the liver from plasma and can cause liver damage and protoporphyrin-containing gallstones. PPIX, protoporphyrin IX.
Figure 4.
Figure 4.
Evaluation and treatment algorithm for patients with protoporphyria. CBC, complete blood count; HAV, hepatitis A virus; HBV, hepatitis B virus; PPIX, protoporphyrin IX; ULN, upper limit of normal.
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References

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