Blistering lesions on sun-exposed areas of the skin, especially the backs of the hands, may be due to porphyria cutanea tarda (PCT), an otherwise unapparent disease of the liver. This iron-related disorder is the most common and readily treated form of human porphyria. It is aptly named, because the cutaneous manifestations usually occur in middle or late life. This is the only major form of human porphyria that can develop in the absence of a mutation of an enzyme of the heme biosynthetic pathway. Inherited deficiencies of the other seven enzymes in this pathway cause either X-linked sideroblastic anemia (from a deficiency of the erythroid form of 5-aminolevulinic acid synthase, the first enzyme in the pathway) or the other types of hepatic and erythropoietic porphyrias.1
The enzyme that is deficient in PCT is uroporphyrinogen decarboxylase (UROD, the fifth enzyme in the pathway), which sequentially decarboxylates uroporphyrinogen (which has 8 carboxyl side chains) to yield coproporphyrinogen (with 4 carboxyl groups). The substrate and the intermediate and final products of the reaction are porphyrins in their reduced forms. Uroporphyrinogen and the intermediate porphyrinogens become oxidized in PCT and accumulate in the liver (mostly as uroporphyrin and heptacarboxylporphyrin), and then appear in plasma and urine.2 Photosensitivity results from activation of porphyrins in the skin by long-wave UV light and generation of reactive oxygen species. Pigment changes and scarring are sometimes prominent; facial hypertrichosis can be a major complaint, especially in women.
PCT is an iron-related disorder that develops when a combination of susceptibility factors (multiple, but not the same in all patients)3 interact and lead to a deficiency of UROD specifically in hepatocytes. Iron does not directly inhibit UROD, and may act by promoting oxidative stress. Known or suspected susceptibility factors, which may include a deficiency of ascorbic acid in some patients, are listed in Table 1. Many of these factors, such as iron, alcohol, and hepatitis C, are known to cause liver damage and oxidative stress in hepatocytes, but only a small fraction of individuals who are exposed to or inherit PCT susceptibility factors actually develop the disease. This suggests that particular combinations or additional unknown factors are important. Even though the precise mechanisms whereby multiple factors interact with iron to cause decreased UROD activity remain elusive, iron reduction by repeated phlebotomy is effective regardless of the risk factors present in a particular patient, if the appropriate target ferritin level is achieved.1, 4
|UROD mutations||19% (based on erythrocyte UROD activity)|
|HFE mutations||65% (9% CYP282Y/CYP282Y)|
|Estrogens||73% of females|
|Metabolic and nutritional|
|Excess iron||>95% (stainable iron in hepatocytes)‡|
|Ascorbic acid deficiency||62%§|
A large outbreak of human PCT occurred in eastern Turkey in the 1950s, when a population that was experiencing food shortages consumed seed wheat treated with hexachlorobenzene as a fungicide.5 Smaller outbreaks and individual cases have occurred after exposures to other polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). These chemicals were subsequently shown to cause hepatic UROD deficiency and biochemical features resembling PCT in laboratory animals, and many studies that followed have greatly increased our understanding of this acquired enzyme deficiency (for a detailed review, see Elder2). Uroporphyria can also be induced in rodents by loading with iron and the heme precursor δ-aminolevulinic acid (ALA), as well as an engineered mouse strain with UROD and HFE mutations, the latter causing hepatic iron overload.6 CYP1A2 knockout mice are highly resistant to developing chemical-induced uroporphyria.1, 7–10
The accumulated evidence from numerous studies in animals and hepatocyte cultures points to a mechanism whereby the intermediate uroporphyrinogen is enzymatically oxidized (UROX activity), probably by CYP1A2 and perhaps other cytochrome P450 species to uroporphyrin, which accumulates in liver, and also in the presence of iron to a specific inhibitor of UROD (Fig. 1).2, 11, 12 However, this postulated inhibitor remains to be isolated and characterized. Other potential mechanisms, such as oxidative damage to active site residues, are less favored but have not been excluded.2
It is clear that hepatic UROD activity must be reduced probably to ∼20% of normal in order for PCT to be manifest. The amount of enzyme protein, when measured immunochemically in liver, remains at its genetically determined level, which suggests enzyme inhibition or inactivation.13 Individuals who have an inherited ∼50% deficiency of UROD, which is an autosomal dominant trait with low penetrance, are more susceptible to developing PCT (as listed in Table 1). They are said to have familial (type 2) PCT, which may develop at a younger age, and some have relatives who also have had the disease. But the majority of patients have no UROD mutations and are said to have sporadic (type 1) PCT. With both types, some of the multiple factors listed in Table 1, and probably others not yet known, must have been present to substantially reduce hepatic UROD activity. Types 1 and 2 are usually not distinguishable clinically, except by measuring erythrocyte UROD activity (usually about half-normal on a genetic basis in type 2) or by looking for UROD mutations. Both respond to iron depletion by repeated phlebotomy, which restores hepatic UROD activity to its genetically determined level.13
A deficiency of the antioxidant vitamin ascorbic acid14, 15 and perhaps other antioxidants16 may play a role in some patients with PCT. In this issue of HEPATOLOGY, Gorman and co-workers17 examine the interactions between iron and ascorbic acid in an ascorbate-requiring strain of mice. These investigators have shown previously that ascorbic acid inhibits hepatic UROX activity and impairs the development of uroporphyria in rodents.18, 19
They now report the effects of iron dextran administration on hepatic uroporphyrin accumulation at 2 different levels of ascorbate intake. Their careful experimental design and choice of appropriate doses of ascorbate and iron led to clear and important conclusions. In this model, ascorbate decreased uroporphyrin accumulation except in animals treated with large amounts of iron. Although iron loading negated the beneficial effects of ascorbate, it did not decrease hepatic ascorbate levels. A threshold effect for iron causing uroporphyrin accumulation was observed, which was accounted for by accumulation of iron in hepatocytes rather than in Kupffer cells. Thus, they have made the important observation that the degree of iron overload can greatly influence the effects of ascorbate deficiency and repletion on uroporphyrin accumulation.17
These results have important implications for humans with PCT, who harbor many more types and wider dose ranges of environmental and inherited susceptibility factors. It was reported that PCT patients with low ascorbate levels did not improve when treated with ascorbate.14 But response to ascorbate replacement may be modulated by the degree of iron overload, as in the present study in mice, and possibly other susceptibility factors. Moreover, porphyrin accumulation in liver is massive in PCT, and observation periods of weeks or months may be needed to observe a beneficial response. Therefore, detailed dose-response studies in an appropriate animal model, such as reported here, provide insight that will enlighten future studies in patients with PCT.
A nutritionally adequate intake of ascorbic acid and other nutrients should be assured in PCT patients, but the vitamin should not be used as primary therapy instead of repeated phlebotomy, which is established as highly effective.1 Low-dose hydroxychloroquine or chloroquine can be used when phlebotomy is contraindicated or poorly tolerated.20, 21 Excess alcohol intake, smoking (which induces hepatic CYP1A2), and estrogens should be discontinued. If needed, estrogen can be reintroduced via the transdermal route, which entails less liver exposure, after remission is achieved.22 Hepatitis C is one of the most common susceptibility factors in the United States and many other countries.23, 24 Lengthy and sometimes unsuccessful treatment of this infection may interfere with the highly successful treatment of PCT by repeated phlebotomy, and should generally be postponed for several months until PCT is in remission. It seems likely that risk of chronic liver disease and hepatocellular carcinoma decreases with treatment of PCT, but this is not established.