Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda - suggestions for a handling programme

Deficiency of the fifth enzyme in haem synthesis, uroporphyrinogen decarbox ylase (UPGD), may give rise to accumulation and excretion of poly-carboxyla ted porphyrins, as well as to clinical manifestations in the form of a phot otoxic skin reaction and liver engagement leading to cirrhosis and hepatoce llular cancer. The cutaneous reaction, presenting as skin fragility and bli sters on areas exposed to sun-porphyria cutanea tarda (PCT)-develops only i n individuals with a remaining hepatic UPGD activity less than 20% of norma l. Experimental results and clinical observation give evidence that PCT is a multifactorial disease. In some individuals a 50% decrease in UPGD activi ty is a consequence of inheritance of an allele with a mutation in the gene programming for the enzyme, but in these gene carriers, as well as in the other patients with overt PCT, the activity of the hepatic enzyme is reduce d below the critical level by the action of specific inhibitors. In the gen eration of the enzyme inhibitors, iron plays a central role by promoting th e formation of reactive oxygen species, a process where a specific class of cytochrome enzymes; cytochrome P450 1A (CYP4501A), participates. The varyi ng individual susceptibility to development of the disease can be discussed in terms of differences in a spectrum of factors that affect the availabil ity of the free form of this element in the liver, or its pathogenic action . In the article the roles of chronic viral infection, alcohol abuse and ex position to polyhalogenated cyclic hydrocarbons are considered in the light of effects on the availability of iron in the liver. Some genetic prerequi sites for susceptibility to PCT-inducing agents are included in a tentative model for the disease, i.e. mutations in the UPGD gene and in the HFE gene affected in haemochromatosis, as well as genetically steered inducibilitie s of the genes programming for CYP4501A and the rate-limiting enzyme in hae m synthesis, 5-aminolevulinate synthase. With the pathogenic model as a bas is the different therapeutic strategies that can be applied are discussed, and suggestions for a handling programme for the patient presenting with PC T put forward.