Porphyrias: a disease grouping by cause, not symptoms

Held biennially, the Porphyrins & Porphyrias conference (P&P) is the world’s largest gathering on the porphyrias – a group of metabolic disorders causing biochemical disruptions in the pathway of the body which synthesizes haem (heme).

As a result of each of these disruptions, the body presents with unique symptoms ranging from skin symptoms and phototoxicity – as those seen in erythropoietic protoporphyria and congenital erythropoietic porphyria – through to acute attacks of abdominal pain, seen most commonly in acute intermittent porphyria. In short, no two porphyrias are clinically identical yet they are discussed as a single group of disorders with a similar cause. As a matter of fact, there are eight variations of porphyrias, each with a specific clinical manifestation of disease.

P&P is a unique conference, reflecting the current scientific thinking on the diseases. The attending experts represent the challenges presented by the porphyrias from both a research and clinical perspective. There are specialists from diverse backgrounds – dermatologists, haematologists, gastroenterologists, photobiologists, metabolic specialists, geneticists and transplant experts, amongst others – attending the conference and tackling both basic research and clinical care for porphyrias. This diversity is clearly reflected in the conference’s program, where a dermatological case study may sit parallel to theoretical discussions of gene therapy.

Fortunately, great progress has been made in recent years to better integrate clinical care for patients with porphyria, and the results of some of these programs were presented or discussed throughout the conference, including the EPNET project and the British and Irish Porphyria Network (BIPNET). The ongoing success and funding of such programs provides physicians with better integrated access to research, while ensuring patients are delivered the highest possible quality of care. A similar initiative has been established in the USA, which has been active in clinical research as well as highlighting the importance of clinical care in the porphyrias.

Although a number of interesting presentations were given across the porphyrias, given our clinical focus it is cutaneous porphyrias, specifically erythropoietic protoporphyria (EPP), which we’ll discuss further.

Prof Dr Jean-Charles Deybach delivered the plenary lecture on EPP, which included highlighting the newly understood X-linked dominant erythropoietic protoporphyria (XLDPP). Despite being clinically similar in that they both cause phototoxicity, rather than being caused by a deficiency like EPP, XLDPP is caused by an activation of a gene leading to overproduction and accumulation of the phototoxic enzyme protoporphyrin IX (PPIX) in the blood. Prof Dr Deybach discussed the possibility of patients with EPP developing gallstones, as well as the rate at which EPP patients suffer liver failure requiring transplant; it is believed that 2-5% of EPP patients incur this failure, but it is impossible to predict in which patients this will occur. This highlighted the need for regular liver tests in EPP, and encouraging patients to be aware of the risk to their liver.

A prevalence study from Denmark showed that the European nation had a relatively high incidence of EPP compared to the rest of Europe with a 2010 prevalence of 1:103,774 individuals (based on a Danish population of 5.5 million). Working from the basis that EPP and XLDPP both cause disturbances in the metabolism of iron, a team from Switzerland showed that the availability of iron in the blood may have an effect on the function of ferrochelatase, the enzyme which is deficient in EPP. Meanwhile a UK based team suggested that mRNA analysis could assist in unraveling some of the still-unknown links in genetic variations in EPP. Both these studies admit that follow up work is required to confirm their theses.

Following the release of a large body of work on EPP from Sweden last year, the same team presented research on liver transplantation in EPP patients across Europe. Following a literature and transplant registry search, the team uncovered 31 patients who had undergone 35 transplants following EPP-induced liver failure across Europe between 1983 and 2008. This study in particular highlighted the risk of EPP patients to phototoxic injury during surgery; that is patients could have an EPP reaction caused by surgical lighting, something seen in 25% of those patients who didn’t have filters fitted to their surgical lights.

A key presentation for Clinuvel was data from our first European and Australian Phase III study of SCENESSE® (afamelanotide) in EPP (CUV017) along with clinical anecdotes from our Phase II study and ongoing compassionate use programs. At the previous P&P conference Phase II results (CUV010) had been presented, so results from this larger study attracted good interest and discussion. Prof Dr Elisabeth Minder presented an overview of EPP before discussing how, numerically, patients responded to treatment. Prof Minder highlighted the seasonality of the drug’s effect in this study and the changes in melanin density in EPP patients throughout the study. Data were also presented on changes to quality of health and quality of life throughout the study where a clear trend, but no statistical significance, could be seen in patients receiving the drug compared to placebo. Questions from the audience focused on the drug’s safety profile, including its longer term use (Prof Dr Minder highlighted that her team had been treating several patients under study and compassionate use protocols for more than 30 months and additional long term use information would come from Italy).

In addition to the main conference, the British Porphyria Association hosted an international patient day, giving patients the opportunity to learn much of the progress from the conference and various patient associations, as well as ask questions directly to experts about their condition. It is always interesting to hear direct discussion between a patient and an expert as everybody learns from such discussions.

Questions and suggested answers on EPP were as follows*:

What can be done to relieve phototoxicity in EPP?

The panel admitted this was difficult and the discussion was quickly assumed amongst the patient group present. It was generally agreed that cooling the sensitive area was important, although one individual suggested that very warm water can provide relief. Both aloe vera and tea tree oil were suggested as possible coolants.

What is the link between EPP and gallstones?

Unlike the ordinary gallstone, which is often full of cholesterol, gallstones in EPP are dark purple and full of protoporphyrin. While it is unlikely that gallstones will cause health problems, it is best that they be removed. Further, there is unfortunately little that can be done to prevent the development of gallstones.

Is there a link between EPP and fatigue?

One of the panel highlighted that the key thing to remember about fatigue is that it is incredibly difficult to explain medically and may not always be linked to EPP (or other porphyrias). The panel agreed that there is a link between EPP and fatigue, but that this may be coincidental, rather than causal.

General discussion

Two other key points were raised during general discussion. The first, a theoretical, discussed the links between EPP and cholesterol levels where more research should be focused to better understand whether EPP may lead to higher cholesterol and the best way to deal with this clinically.

The second discussion focused on clinical care, with a member of the panel emphasising that not all symptoms seen in patients should be directly attributed to porphyria; ‘you’re not immune from other disorders within the population’. In essence, this panel member was encouraging patients to knock out other possible ailments or conditions as causing symptoms before attributing them to porphyria, as this could ultimately lead to better clinical workups and thus better clinical care.

It is always fascinating to attend a conference of this nature and of significant value to those who attend. Clinuvel was proud to be able to provide sponsorship and ongoing support of porphyrias research and understanding. For those who are unaware, we’re in the middle of National Porphyria Awareness Week in the USA and will be highlighting more events on Twitter throughout the week. If you have any questions, feel free to post a comment below or drop us an email to mail@clinuvel.com.

Finally, our thanks to all involved in the P&P conference; we look forward to Porphyrins & Porphyrias 2013 in Luzern, Switzerland!

* Disclaimer: Information presented is designed for educational and informational purposes only. Third parties listed on this sheet have not explicitly endorsed this information. The information provided is not a substitute for professional, medical and health advice. Do not interpret or use this information to diagnose or treat a health problem or disease without consulting a professionally qualified health care provider. Please consult a relevant health care provider if you have any questions or concerns or if you wish to determine the information you are relying on is appropriate for your medical condition/s. Clinuvel Pharmaceuticals Ltd (‘Clinuvel’) does not endorse or attest to the validity or accuracy of any treatments or medications mentioned. Clinuvel makes no representations concerning the efficacy or suitability of any treatments, medications mentioned. Clinuvel has made every effort to ensure the accuracy of information and welcomes your feedback on any information.

Image reference

‘Cardiff April 2010 063′ uploaded to Flickr.com by shining.darkness on April 8, 2010 <http://www.flickr.com/photos/33124746@N04/4529993211/>

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