Abstract
The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Neurovisceral porphyrias are characterized by acute attacks, in which excessive heme production is induced following exposure to a trigger. An acute attack usually presents with severe abdominal pain, vomiting, and tachycardia. Other symptoms which could appear include hypertension, hyponatremia, peripheral neuropathy, and mild mental symptoms. In severe attacks there could be severe symptoms including seizures and psychosis. If untreated, the attack might become very severe, affecting the peripheral, central, and autonomic nervous system, leading to paralysis, respiratory failure, hyponatremia, coma, and even death. From the biochemical point of view, acute attacks are involved with increased levels of precursors in the heme biosynthetic pathway, up to the deficient step. Of these precursors, aminolevulinic acid (ALA) is considered to be neurotoxic. Treatment is directed to reduce ALA production by reducing the activity of the enzyme aminolevulinate synthase (ALAS)—most effectively by heme therapy. Cutaneous symptoms are a consequence of elevated porphyrins in the blood stream. These porphyrins react to light; therefore sun-exposed areas are affected, producing fragile erosive skin lesions in porphyria cutanea tarda (PCT) or non-scarring stinging and burning symptoms in erythropoietic protoporphyria (EPP). Unlike the most common neurovisceral porphyria, acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) can have cutaneous symptoms as well. Differentiating them from other cutaneous porphyrias is essential for accurate diagnosis, treatment, and patient recommendations.
Highlights
Each type of porphyria is a result of a specific deficiency in one of the enzymes involved in the pathway (Figure 1) and, is characterized by a specific pattern of accumulation of heme precursors and typical clinical manifestations
Regulation of heme synthesis is influenced by erythroid differentiation and erythropoietin and iron availability, while in the liver, ALAS1 is under negative feedback regulation by the intracellular heme pool.[3]
The acute neurovisceral forms are characterized by overproduction of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are porphyrin precursors, at the initial steps of heme synthesis[4,5] (Figure 1), while the cutaneous ones are characterized by accumulation of porphyrins, which are the precursors at the final steps of the synthesis.[6]
Summary
The porphyrias are a group of rare metabolic disorders—either inherited or acquired along the heme biosynthetic pathway.[1,2] Each type of porphyria is a result of a specific deficiency in one of the enzymes involved in the pathway (Figure 1) and, is characterized by a specific pattern of accumulation of heme precursors and typical clinical manifestations. The first step in the synthesis, ALA formation (Figure 1), is the most important site of control. This step is catalyzed by the enzyme ALA synthase (ALAS), which has two subtypes—ALAS1, the ubiquitous one, encoded on chromosome 3, and ALAS2, erythroid-specific, encoded on chromosome X. Regulation of heme synthesis is influenced by erythroid differentiation and erythropoietin and iron availability, while in the liver, ALAS1 is under negative feedback regulation by the intracellular heme pool.[3] This regulatory mechanism is the basis of strategies in treatment and management of porphyria patients. In this review we will summarize the different characteristics of each of the porphyrias: clinical manifestations, diagnosis, and treatment options
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