Porphyria: What Is It and Who Should Be Evaluated?

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.

Figure 1. The Heme Synthesis Pathway: Enzymes Involved in the Pathway and the Associated Porphyrias with the Disruption of Each Specific Enzyme

Main (center) core: Precursors and intermediary products in the heme synthesis pathway. (ALA, aminolevulinic acid; PBG, porphobilinogen; HMB, hydroxymethylbilane; URO III, uroporphyrinogen III; COPRO III, coproporphyrinogen III; PROTO’gen IX, protoporphyrinogen IX; PPIX, protoporphyrin IX; Fe2+, iron.) Left of the core: Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. (ALAS, aminolevulinate synthase; ALAD, aminolevulinic acid dehydratase; HMBS, hydroxymethylbilane synthase; UROS, uroporphyrinogen-III synthase; UROD, uroporphyrinogen decarboxylase; CPOX, coproporphyrinogen oxidase; PPOX, protoporphyrinogen oxidase; FECH, ferrochelatase.) Right of the core: Porphyrias resulting from disruption of enzyme production. (ADP, aminolevulinic acid dehydratase porphyria; AIP, acute intermittent porphyria; CEP, congenital erythropoietic porphyria; PCT, porphyria cutanea tarda; HCP, hereditary coproporphyria; VP, variegate porphyria; EPP, erythropoietic protoporphyria.) The final product, the heme, exerts control over the whole pathway via a negative feedback mechanism on the first enzyme – ALAS (indicated by the circle with the minus symbol).

Figure 2. Diagnosis Algorithm for Acute Neurovisceral Symptoms Leading to Suspicion of Porphyria

* Biochemical markers also detected in the latent phase. ADP, aminolevulinic acid dehydratase porphyria; AIP, acute intermittent porphyria; ALA, aminolevulinic acid; HCP, hereditary coproporphyria; HMBS, hydroxymethylbilane synthase; PBG, porphobilinogen; VP, variegate porphyria.

Figure 3. Diagnosis Algorithm for Porphyria Cutaneous Symptoms

ADP, aminolevulinic acid dehydratase porphyria; AIP, acute intermittent porphyria; CEP, congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria; XLPP, X-linked protoporphyria