In our patient, fragile skin and bullae formation on the dorsal side of the hands related to PCT is the presenting symptom of underlying primary hemochromatosis. Hemochromatosis is the most common inherited liver disease and the most common autosomal recessive genetic disorder [4]. From epidemiological point of view there is a clearcut association between PCT and hemochromatosis [5]. The question rises how porphyria, hemochromatosis and/or the hemolytic streptococcal infection can be linked together.
Most patients with heriditary hemochromatosis have a mutation in one of the mentioned HFE genes located on chromosome 6 [6]. Hemochromatosis interferes with the transferrin receptor and causes a clear decrease in the affinity with which the receptor binds transferrin. This interaction also may modulate cellular iron uptake and decrease ferritin levels. When a mutant or nonfunctional variant of the HFE gene is present, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced accumulation of iron in peripheral tissues [7].
The term "porphyria cutanea tarda" originally described the dermatological manifestations of various chronic porphyrias. Its usage now is usually restricted to disorders associated with a deficiency of uroporphyrinogen decarboxylase (UROD). It is UROD that is responsible for an essential step in the heme synthesis pathway: the conversion of uroporhyrinogen III into coproporphyrinogen III [7]. This is reflected in Figure 3.
Iron overload and in particular the cellular modifications of the iron status secondary to hemochromatosis mutations affect the quantity and activity of UROD [8]. Iron, by catalyzing the formation of reactive oxygen species, can enhance uroporphyrin formation by increasing the rate at which uroporphyrinogen is oxidized to uroporphyrin. Iron may also act indirectly to inhibit UROD activity by enhancing the formation of non-porphyrin products of porphyrinogen oxidation that are themselves direct inhibitors of the enzyme. Finally, iron can act to increase urophorphyrin production by inducing δ-aminolevulinic acid synthase, the precursor to uroporphyrinogen, inside the cell [4]. With the deficiency in UROD activity heme precursor uroporphyrinogen accumulates in the skin. This molecule is highly photosensitive, causing blistering and fragility on the UV-exposed skin and subsequent complement activation and histamine release. Since a considerable amount of iron is required to produce symptoms, this type of PCT most often starts in the third decade of life. Secondary causes contributing to the disease, such as alcohol use, excessive iron and vitamin C intake, oral contraceptives and blood transfusions, are often observed and should also be eliminated. From epidemiological point of view PCT and hemochromatosis are also heavily linked together.
The ecthyma caused by group A beta-hemolytic streptococci our patient developed could not be explained by either hemochromatosis or PCT. One report highlights the increased risk of venous leg ulceration in patients with the C282Y mutation [9]. However, given the rapid development of three ulcers, the bacterial cultures that revealed beta-hemolytic streptococci group A and a rapid response to local treatment, a venous origin of the leg ulcerations in this young patient is not likely.
Treatment of PCT is based on recurrent phlebotomies and low-dose (hydroxy)chloroquine. Our patient had an excellent response to these treatments [2, 4, 6]. However, there is evidence that patients that are homozygotes for the C282Y mutation suboptimally respond to (hydroxy)chloroquine therapy in contrast to their heterozygote and wild-type counterparts [6].