Treatment and Management of Variegate Porphyria

Prevention and Treatment of Specific Symptoms

Treating and managing variegate porphyria remains a challenge due to its rarity and difficult diagnosis. Once identified, the first step is to take preventative measures that reduce the occurrence of both erythropoietic and hepatic symptoms. Erythropoietuc ymptoms are handled by wearing protective clothing and limiting exposure to sunlight (Singal, 1993). One can also use sunscreen containing ZnO or TiO2 to reduce UV exposure (Hift, 2003). Avoiding hepatic symptoms involve eliminating exacerbating factors such as fasting, drugs, hormones, and alcohol (Handschin, 2013).

In the event that symptoms present themselves, some treatment options are available. While there is not treatment available for erythropoietic symptoms (Hift, 2003), analgesics can be used to reduce pain and antibiotics if an infection develops (Singal, 1993). During a hepatic attack, patients are first treated with an IV infusion of haem arginate are hematin (Figure 1), both of which are derivatives of heme (Chen, 2009). This has been common practice since the 1980s (Tokola, 1988) and little to no side effects of the treatment are observed. The result of the infusions is inhibition of heme biosynthesis via a negative feedback loop, reducing the amount of excess metabolites in the body (Hanschin, 2013). In addition, patients are often treated with IV infusions of glucose with or without insulin (Chen, 2009). This also inhibits heme biosynthesis by the insulin-induced phosphorylation of FOXO1, preventing it from binding PGC-1α and activating the transcription of ALAS-1 (Handschin, 2013).

Figure 1. Hematin, a oxidized form of heme used to treat hepatic attacks of VP by inhibition of heme biosynthesis. Source: http://www.answers.com/topic/hematin
Figure 1. Hematin, a oxidized form of heme used to treat hepatic attacks of VP by inhibition of heme biosynthesis. Source: http://www.answers.com/topic/hematin

Managing the Global Disease State

Even when patients contracted with VP are not experiencing an acute attack of cutaneous symptoms, work by Ferrer et al. demonstrates these individuals are in a state of oxidative stress. In order to manage this aspect of the disease, they recently looked at the effects of antioxidant vitamins E and C on the redox state of lymphocytes in women with VP. First, they established the basal redox state of VP lymphocytes relative to the control. As in their 2010 study, H­2O2 production was higher in VP cells upon stimulation with phorbol myristate acetate (PMA). Ascorbate and α-tocopherol levels were the same in VP and the control while the antioxidant enzymes catalase and glutathione peroxidase were decreased in VP (Ferrer, 2013). After a six-month period in which both the control and VP patients were given a placebo or a vitamin E and C enriched almond beverage, the redox state of lymphocytes was once again examined. Though the condition had no impact on H2O2 production after stimulation with PMA, ascorbate levels, or catalase and glutathione peroxidase activity, other factors attributable to the disease state had changed significantly (Ferrer, 2013). First, α-tocopherol levels were seen to be elevated. In addition, the redox balance enzymes glutathione reductase and superoxide dismutase were elevated in both the control and VP women treated with the vitamin E and C enriched beverage. The most significant result, however, was the discovery that PPOX mRNA levels in VP women exceeded that of the control after treatment (Figure 2). This is a particularly significant finding as PPOX is the enzyme whose decreased activity results in VP. While this is a preliminary study, it suggests that diets rich in vitamins E and C may be effective at managing the disease state of variegate porphyria.

Figure 2. Expression of PPOX in healthy women (white) and women with VP (black) before treatment, and after six-month administration of a placebo or antioxidant-enriched drink. A # denotes statistical difference between control and VP groups while § indicates a statistical difference between the placebo and treatment groups. Source: Ferrer, 2013.
Figure 2. Expression of PPOX in healthy women (white) and women with VP (black) before treatment, and after six-month administration of a placebo or antioxidant-enriched drink. A # denotes statistical difference between control and VP groups while § indicates a statistical difference between the placebo and treatment groups. Source: Ferrer, 2013.

In addition to managing the redox state of patients with VP, liver transplants have been done in extreme porphyria cases. In 2010, there was report of four known cases, one of which was with a VP patient (Siegesmund, 2010). While the long-term results of the VP patient transplant are not reported, one of the patients that received a liver transplant for acute intermittent porphyria (AIP) had gone four years without an attack in 2010 (Sigesmund, 2010). Though a liver transplant would only be performed in extreme cases, due to the hazards of organ transplants and the demand for organs, this case of AIP suggests this may also be an effective way to treat, or even cure VP. However, due to the nature of VP as a hereditary disorder that produces a catalytically deficient enzyme, curing the disease is only possible with enzyme replacement or gene therapy, neither of which are available for humans at this time.