Mechanisms of phototoxicity in porphyria cutanea tarda and erythropoietic protoporphyria.

The porphyrias are the only group of diseases caused by endogenous phototoxic agents. While patients with erythropoietic protoporphyria and those with porphyria cutanea tarda both have skin lesions on sun-exposed areas, there are differences in their cutaneous manifestations. Based on information discussed in this chapter, the following pathophysiologic mechanisms can be proposed. In porphyria cutanea tarda, photoactivation of the complement system in the presence of uroporphyrin results in activation of dermal mast cells, which release their proteases. This results in dermal-epidermal separation, reflected clinically as skin fragility and vesicles. The interaction between activated mast cells with fibroblasts, the nature of which is still unclear, may contribute to fibrosis and sclerodermoid skin changes. The stimulatory effect of uroporphyrin on collagen biosynthesis by fibroblasts, which occurs independent of irradiation, may be responsible for the sclerodermoid lesions seen at sun-exposed as well as sun-protected areas. In erythropoietic protoporphyria, mast cell activation can occur as the result of complement activation induced by protoporphyrin and irradiation. Protoporphyrin and irradiation may also directly induce the release of preformed and generated mediators from mast cells, a process mediated at least in part by peroxidation. The release of mast cell mediators may account for the erythema, edema, and urticaria observed in patients with erythropoietic protoporphyria upon exposure to sunlight. Interaction of mast cells with fibroblasts, and the direct membrane-damaging effect of protoporphyrin and irradiation on the latter, may contribute to the waxy thickening of skin seen in chronically sun-exposed areas of these patients. There are, however, many unanswered questions. What accounts for the different biological effects of mast cell-derived mediators: dermal-epidermal separation in one, erythema and urticaria in the other? The fragmentation of dermal collagen bundles associated with cleavage beneath the lamina densa, and the hyperpigmentation and hypertrichosis observed in some patients with porphyria cutanea tarda remain unexplained. What is the mechanism of the reduplication of blood vessel basal lamina in the non-sun-exposed areas of both types of patient? Are there any roles for cytokines and epidermal cell-derived eicosanoids? While it is clear that the pathogenesis of cutaneous lesions in porphyria cutanea tarda and erythropoietic protoporphyria involves interactions among inflammatory mediators and various cells in skin, much still needs to be done to further our understanding of their pathophysiology.