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The porphyrias are among the most intriguing human diseases. Widely variable, even bizarre in their clinical manifestations, these disorders of porphyrin or porphyrin-precursor metabolism result from aberrations in the control of the heme biosynthetic pathway. Heme is essential for oxygen binding and transport (as in hemoglobin and myoglobin), for electron transport (as in cytochromes), and for monooxygenases such as cytochrome P450. Chlorophyll, a magnesium-chelated porphyrin, is another important tetrapyrrole that is critical for photosynthesis, the specialized energy-storing system found in plants in which the conversion of light energy into stabilized chemical energy is achieved with a sequence of oxidation-reduction reactions. The corrin ring, a cobalt-chelated tetrapyrrole, is a major constituent of vitamin B12, the lack of which results in pernicious anemia. Therefore, porphyrins are ubiquitous and essential biochemical constituents of living beings. The biologic importance of the porphyrins and their iron complexes lies in their capacity to facilitate metabolic reactions, either as oxidative components in the metabolism of steroids, drugs, and environmental chemicals or by enhancing gas exchange, such as oxygen and carbon dioxide, between the environment and the tissues of the body.

Daily synthesis of porphyrins and heme in humans occurs in amounts sufficient to provide for the body's metabolic requirements. The control of heme synthesis is so precise that, under normal circumstances, only microgram quantities or less of pathway intermediates are present in plasma, red blood cells (RBC), urine, and stool (Table 132-1).

Table 132-1 Normal Values of Porphyrins and Porphyrin Precursors in Humans

The porphyrias are a clinically and genetically heterogeneous group of metabolic diseases, which result from an either inherited or acquired dysfunction of enzymes crucial for heme biosynthesis (Fig. 132-1). Heme synthesis is controlled by eight enzymes along the heme biosynthetic pathway. Deficient activity of seven of these eight enzymes can give rise to a specific type of porphyria (Fig. 132-1).13 A gain of function of the first enzyme in the pathway, δ-aminolevulinic acid synthase (ALAS) is responsible for X-linked dominant protoporphyria (XLDPP), a recently recognized type of porphyria.4 Each of these enzymes will be discussed separately below, in the context of the corresponding type ...

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