Porphyria cutanea tarda (PCT) arises from a deficiency of
uroporphyrinogen decarboxylase (UROD) in the liver. Several exogenous risk factors are associated with the acquired form of the disease. In Southern Europe, PCT is strongly linked to hepatitis C virus (HCV)
infection to the point that a high prevalence of
viral infection in some geographic areas generated an increase of PCT cases as a complication. In spite of the association, PCT is a rare complication of HCV
infection, thus suggesting the existence of susceptibility factors operating in only some patients. Investigation of liver specimens of PCT patients showed
iron accumulation, which albeit moderate, was higher in comparison with HCV-infected patients without PCT. Measurements of
hepcidin in serum of HCV-infected patients with and without PCT and calculation of
hepcidin/
ferritin ratio were compatible with the hypothesis that HCV induced inadequate response of
hepcidin to
iron accumulation. Administration of direct-acting
antivirals (DAA) to HCV-infected patients with active PCT showed that eradication of the virus was followed by resolution of PCT and rapid disappearance of urinary
porphyrins. This suggests a direct participation of the virus in the oxidative mechanism leading to UROD inhibition. If clinical evolution of HCV- PCT-patients is placed within a time-frame, rapid PCT resolution by DAA is in striking contrast with a long-delay (in most cases of decades) between
viral infection and appearance of overt
porphyria. This could be explained if HCV
infection (a): enhanced an oxidative environment in the vicinity of UROD and (b): facilitated
iron accumulation through hepdicin down-regulation. Thus, only when
iron accumulation reached a threshold, inhibition of UROD attained a critical level. However, the enigma is why only a minority of HCV-infected patients develop PCT. If additional risk factors (i.e.
alcohol abuse) are not concurring, it should be concluded that modifier genes or epigenetic mechanisms related to
iron homeostasis, facilitate
iron progressive accumulation in only a minority susceptible patients.