The porphyrias are a group of eight inherited metabolic disorders of heme biosynthesis in which specific patterns of accumulation of heme precursors are associated with characteristic clinical features: acute neurovisceral attacks, skin lesions or both [1]. Each type of porphyria is the result of a specific enzymatic abnormality in the heme biosynthetic pathway (Fig. 1). Delta-aminolevulinic acid (ALA) and/or porphobilinogen (PBG), the initial heme lineage precursors, are overproduced in the porphyrias that cause chronic neuropathy and acute neurovisceral attacks, and porphyrinogens are overproduced in the cutaneous porphyrias [2]. Heme is required for the synthesis of hemoproteins such as hemoglobin, myoglobin, the mitochondrial or microsomal cytochromes, catalase, peroxidase, nitric oxide synthase, prostaglandin endoperoxide synthase, guanylate cyclase and tryptophan dioxygenase, all of which play important roles in oxidation-reduction reactions and oxygen transport [1]. The three terminal enzymes (coproporphyrinogen oxidase [CPO], protoporphyrinogen oxidase [PPOX] and ferrochelatase [FECH]) are associated with the inner mitochondrial membrane in a multienzymatic terminal complex related to the import of iron into mitochondria (Fig. 2) [3]. Zn2+ is also a substrate for the enzyme, and iron deficiency leads to Zinc-Protoporphyrin (PPIX) accumulation, whereas ferrochelatase deficiency leads to free-PPIX accumulation [4], [5]. Although heme is synthesized in every human cell, 80% is produced in erythropoietic cells and 15% in liver parenchymal cells. Heme biosynthesis is differently controlled in these two tissues [6]. ALA synthesis is the most important controlling step for heme formation [4], [6]. The first enzyme, δ-aminolevulinic acid synthase (ALAS; EC 2.3.1.37), is encoded by two genes, one erythroid specific (ALAS2 on the X chromosome) and one ubiquitous (ALAS1 on chromosome 3) [6]. In the liver, newly formed hemoproteins are rapidly turned over in response to current metabolic needs, and the liver ALAS1 is under a negative feedback regulation by the intracellular “uncommitted” heme pool (Fig. 3). Increased hepatic ALAS activity is a secondary phenomenon that results from exposure to several influences (such as drugs, fasting and hormones). This accounts for the especially marked increase in ALA and PBG production and excretion in acute hepatic porphyrias [2].
In erythroid cells, synthesis of the enzymes participating in the formation of heme is regulated during erythroid differentiation by erythropoietin and is finely tuned by iron availability. In these cells, the rate of ALAS2 synthesis is increased only during the period of active heme synthesis and is regulated by iron availability. Ferrochelatase, the final enzyme of heme biosynthesis, and iron, its substrate, also play a significant role in controlling the rate of heme formation in erythroid cells [7].
Spleen and liver macrophages have a special role in degrading heme and recycling iron following phagocytosis of senescent erythrocytes. Heme oxygenase 1 (HO-1, EC 1.14.99.3) is present in especially large amounts in liver and spleen and generates carbon monoxide, biliverdin and iron (Fig. 3). Biliverdin is oxidized to bilirubin and excreted in bile, while the liberated iron is stored as ferritin or is recycled back to the plasma [8].
The porphyrias are generally broadly classified as acute porphyrias and cutaneous porphyrias, based on their clinical presentation (Fig. 4) [9]. Acute intermittent porphyria (AIP) and the rare ALA dehydratase porphyria (ADP) are associated with neuropathy and acute attacks only. Variegate porphyria (VP) and hereditary coproporphyria (HC) are associated with both acute attacks and/or skin lesions. Congenital erythropoietic porphyria (CEP), sporadic and familial porphyria cutanea (PC), erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) present with dermatological symptoms only. Most porphyrias, apart from the sporadic form of porphyria cutanea, are monogenic disorders with an autosomal dominant inheritance and low clinical penetrance. The majority of the individuals who inherit an autosomal dominant porphyria remain asymptomatic throughout life (latent or presymptomatic) but are at risk of chronic liver complications [10]. Accurate diagnosis of clinically overt porphyria requires identification of the unique pattern of overproduction of porphyrin precursors (ALA, PBG) and porphyrins (Uro, Copro, Protoporphyrins) that results from each enzyme deficiency (Table 1). ALA and PBG are excreted only in the urine. Coproporphyrin and uroporphyrin are the predominant porphyrins in normal human urine. Protoporphyrin, a very poorly water-soluble compound, and 70% of coproporphyrin are excreted in feces through the liver, where they may induce cholestasis [11].