Porphyrias: Clinical Evaluation and Interpretation of Laboratory Tests

Abstract

Porphyria is a hereditary enzyme disorder that affects the heme biosynthetic pathway and results in excess accumulation and excretion of porphyrin or porphyrin precursors (Fig. 1). Heme is a functional component of hemoglobin and heme-requiring enzymes, such as the cytochrome P-450 system. The structural constituents of heme are protoporphyrin IX (a tetrapyrrole ring) and iron. Heme production is especially active in developing erythrocytes and in hepatic cells. Clinical Spectrum of Porphyrias.—An enzyme defect in any of the heme biosynthetic steps (Fig. 1) causes excess accumulation of the related substrate porphyrinogen or porphyrinogen-precursor molecule. Disease manifestation depends on the type of the excess porphyrinogen intermediate and related porphyrin. If the excess is of the early precursor molecules (9-aminolevulinic acid [ALA], porphobilinogen [PBG], or both), the manifestations are neuropsychiatrie. These consist of recurrent acute attacks of autonomie dysfunction expressed as abdominal pain, vomiting, constipation, tachycardia, and hypertension in association with psychiatric symptoms, fever, leukocytosis, proximal paresis, paresthesias, and occasionally the syndrome of inappropriate antidiuretic hormone. If the excess is of the distal intermediates (uroporphyrins, coproporphyrins, and protoporphyrins), the manifestations are cutaneous and consist of photosensitivity, blister formation, facial hypertrichosis, and hyperpigmentation. Finally, if the excess is of both the early and the distal porphyrin intermediates, the manifestations are both neuropsychiatrie and cutaneous. Accordingly, the porphyrias are clinically classified by their potential to involve the nervous system or the skin (or both). Three groups have been identified: neural, neurocutaneous, and cutaneous porphyrias. The first two are also known as acute hepatic porphyrias, an indication of the principal site of overproduction of porphyrin. All porphyrias are inherited as autosomal dominant traits except plumboporphyria (PP) and congenital erythropoietic porphyria (CEP), which are inherited as autosomal recessive traits. Neuroporphyrias.—In acute intermittent porphyria (AIP) and PP, the defective enzymes are PBG deaminase and ALA dehydrase, respectively; thus, PBG or ALA (or both) accumulates. Induction of hemoprotein synthesis for the production of catalase and cytochromes, and induction of ALA synthase by fasting, drugs, hormones, or alcohol may result in precipitation of acute attacks. Accordingly, the best treatment is avoidance of these factors. During attacks, a loading dose of carbohydrates may help because glucose prevents induction of ALA synthase by both exogenous and endogenous factors. Two recent randomized studies failed to demonstrate the clinical value of hematin or tin protoporphyrin therapy, even though biochemical remissions were verified.1·2