Deficiency of the fifth
enzyme in
haem synthesis,
uroporphyrinogen decarboxylase (UPGD), may give rise to accumulation and excretion of poly-carboxylated
porphyrins, as well as to clinical manifestations in the form of a phototoxic skin reaction and liver engagement leading to
cirrhosis and
hepatocellular cancer. The cutaneous reaction, presenting as skin fragility and
blisters on areas exposed to sun--
porphyria cutanea tarda (PCT)--develops only in individuals with a remaining hepatic UPGD activity less than 20% of normal. Experimental results and clinical observation give evidence that PCT is a multifactorial disease. In some individuals a 50%, decrease in UPGD activity 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 reduced below the critical level by the action of specific inhibitors. In the generation of the
enzyme inhibitors,
iron plays a central role by promoting the formation of
reactive oxygen species, a process where a specific class of
cytochrome enzymes;
cytochrome P450 1A (CYP4501A), participates. The varying individual susceptibility to development of the disease can be discussed in terms of differences in a spectrum of factors that affect the availability 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 exposition to polyhalogenated
cyclic hydrocarbons are considered in the light of effects on the availability of
iron in the liver. Some genetic prerequisites 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 inducibilities of the genes programming for CYP4501A and the rate-limiting
enzyme in
haem synthesis,
5-aminolevulinate synthase. With the pathogenic model as a basis the different therapeutic strategies that can be applied are discussed, and suggestions for a handling programme for the patient presenting with PCT put forward.