Porphyria cutanea tarda (PCT) is observed in both sporadic (80%, type I) and familial (20%, type II, autosomal dominant) forms. Nongenetic predisposing factors for PCT include alcohol ingestion, medications (estrogens, tamoxifen, 4-fluorquinolone antimalarial agents), excess iron intake, tobacco smoking, vitamin C depletion, and exposure to hepatotoxic polychlorinated aromatic hydrocarbons. PCT is associated with viral hepatitis (hepatitis B and C, CMV), HIV, sarcoidal hepatitis, hemochromatosis genes (HFE), lupus erythematosus (all forms), abnormal glucose metabolism and hepatic tumors (primary or metastatic), and chronic dialysis for end-stage renal disease (1).
Tong et al describe cases of 3 men with HCV who had resolution of their PCT manifestations months after completing an 8- or 12-week combination regimen of ledipasvir, 90 mg and sofosbuvir, 400 mg (Harvoni). The authors suggest that the impressive improvement in PCT is likely related to the cure of HCV that can be achieved by direct-acting antiviral agents in general and not necessarily only ledipasvir-sofosbuvir combination therapy, as clearance of PCT has also been noted with boceprevir (2).
How does chronic hepatitis C infection (CHC) result in PCT? It probably boils down to an elementary cause – iron.
According to Ryan Caballes, “Although chronic hepatitis C (CHC) is among factors known to increase risk of PCT, it is not clear if the virus, per se, plays a role in the development and pathogenesis of PCT, or whether this association is mainly due to iron overload and/or increased oxidative stress, which often occur in the context of CHC. It has been known for many years that 1) most patients with PCT have some degree of iron overload; 2) iron removal ameliorates porphyrin overproduction and clinical features; and 3) administration of iron produces relapse of PCT. Serum iron indices and iron content of the liver are often elevated in patients with CHC. The precise molecular mechanisms by which iron may influence HCV-induced liver disease are not fully understood. Among several proposed mechanisms are iron-induced immunologic modifications and iron effects on signal transduction and HCV proliferation. Elevated hepatic iron and increased serum iron indices also have been associated with PCT, and iron is known to exert several actions that increase oxidation of porphyrinogens and lead to inhibition of UROD [uroporphyrinogen decarboxylase]. Therefore, iron can be considered as a common factor for the development and progression of both CHC- and PCT- induced liver diseases. Based on these facts, it can be anticipated that patients with iron overload like those with hereditary hemochromatosis (HH) have a higher risk for the development and progression of both CHC- and PCT- induced liver diseases. Indeed, significantly increased frequencies of both C282Y and H63D mutations of HFE in PCT patients have been reported from studies in Northern Europe and the USA. The preponderance of the evidence suggests that patients with CHC who are heterozygous for H63D or C282Y mutations are at a higher risk of severe hepatocellular injury and fibrosis. Therefore, even in patients harboring HFE mutations that cause milder defects in iron homeostasis, it is possible that the presence of HFE mutations leads to the inactivation of UROD through interaction with other factors like HCV infection, which change iron homeostasis in the liver.” (3)
Treatment of PCT focuses on identifying associated maladies, eliminating any predisposing factors if possible, photoprotection, phlebotomies, consideration of erythropoietin in those with end-stage renal disease, or low-dose hydroxychloroquine if phlebotomy is not a viable option. If patients have CHC, the new direct-acting antiviral agents present a golden opportunity to escape PCT’s iron fist.
- Poh-Fitzpatrick M. Porphyrias. In Callen JP, Jorizzo JL (eds). Dermatological Signs of Systemic Disease, fifth edition. Elsevier. Edinburgh, pp 235-242.
- Tong Y, et al. Resolution of porphyria cutanea tarda in patients with hepatitis C following ledipasvir-sofobuvir combination therapy. JAMA Dermatology 2016; 152: 1393-4.
- Ryan Caballes F, et al. Hepatitis C, porphyria cutanea tarda, and liver iron: An Update. Liver Int 2012; 32: 880-93.