The porphyrias: advances in diagnosis and treatment

Abstract

The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.

Figure 1

The human heme biosynthetic pathway. The pathway consists of 8 enzymatic steps: 4 localized in mitochondria and 4 in the cytosol. Only the type III isomers of uroporphyrinogen and coproporphyrinogen are metabolized to heme. Heme is exported from mitochondria for incorporation into cellular hemoproteins and, particularly in liver, exerts feedback regulation on 5-aminolevulinic acid synthase (ALAS1).

Figure 2

Porphyria cutanea tarda. (A-B) Sun-exposed hands of a PCT patient showing areas of atrophy and scarring. (C) Urine from a symptomatic PCT patient and a healthy control in daylight (left) and under ultraviolet light (right). The PCT urine has an orange-red color in daylight that fluoresces red under ultraviolet light.

Figure 3

Congenital erythropoietic porphyria. (A) A severely affected CEP patient who has had multiple sun-induced skin lesions. The cutaneous bullae and vesicles burst and became secondarily infected, leading to bone involvement and resultant loss of facial features and digits. (B) Note his brownish discolored teeth, which fluoresce (erythrodontia) when exposed to ultraviolet light. The erythrodontia is the result of the accumulation of uroporphyrin I and coproporphyrin I in his teeth. (C) Urine from a CEP patient that fluoresces red under ultraviolet light (left) and from a healthy person (right).

Figure 4

Erythropoietic protoporphyria. (A) An EPP patient after sun exposure. Note the reddish and swollen appearance of her face and (B) scarring and thickening of the skin on the dorsum of her hand because of multiple sun/light exposures.