A public health project supported by the European Commission DGSANCO - Report 2010

European Porphyria NetworkEuropean Porphyria NetworknetEp

Providing better healthcare for patients and their families

European Porphyria NetworkEuropean Porphyria NetworknetEp

European Porphyria NetworkEuropean Porphyria Network

Providing better healthcare for patients and their families

Associate Partners Jean-Charles DeybachAP-HP - Paris - France Pavel Martasek Univerzita Karlova v Praze - Prague - Czech Republic Maria CappelliniUniversita degli Studi di Milano - Milan - Italy Gianfranco BiolcatiInstituti Fisioterapici Ospitalien - Rome - Italy Mike BadmintonCardiff SAS Porphyria Service, NHS Trust - Cardiff - UK Agnieszka LipniackaInstytyt Hematologii I Transfuzjologii - Warsaw - Poland Samantha ParkerOrphan Europe Sarl - Paris - France Felix De RooijErasmus MC Universitair Medisch centrum Rotterdam - Rotterdam - The Netherlands Raili KauppinenHospital District of Helsinki and Uusimaa - Helsinki - Finland Joanne MarsdenKing’s college Hospital - London - UK Sverre SandbergHaukeland University Hospital - Bergen - Norway Pauline Harper Karolinska University Hospital - Stockholm - Sweden Jorge FrankAcademisch Ziekenhaus Maastricht - Maastricht - The Netherlands Jordi ToHospital Clinic I Provincial de Barcelona - Barcelona -Spain Ulrich StoelzelPorphyria Centre Saxony - Saxony - Germany

Collaborating PartnersRafael Salamanca Hospital Universitario 12 de Octubre - Madrid - Spain

Petro Petrides Hem-Onc-Center - Munchen - Germany

Maria Kiss University of Szeged - Szeged - Hungary

Frederic Cotton ULB - Brussels - Belgium

Vivion Crowley St James Hospital - Dublin - Ireland

Elisabeth MinderStadtspital Triemli - Zurich - Switzerland

EAHC Project OfficerGeorgios MargetidisLuxemburg

1. FORWARD 7

2. IntRODuctIOn 9

3. GeneRAl ObjectIve 10

4. GOveRnAnce & MeMbeRSHIP 10

5. WORk PeRFORMeD 11

5.1. Information for patients and healthcare professionals 11

5.2. Selection of drugs for use in patients with an acute porphyria 12

5.3. Diagnostic and clinical quality assessment 16

5.4. Registry 19

6. cOncluSIOnS 23

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Contents

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The characteristics of rare diseases - limited number of patients and scarcity of relevant knowledge and expertise - single them out as an area of especially high European added-value. There is probably no other area in health where collaboration between 27 different national approaches can be as efficient and effective. European reference networks are an initiative of the Commission with the aim of putting in place concrete means of working together on specific conditions to share expertise and provide a basis for cooperation across Europe.

Rare diseases offer a prime example of the benefits of trans-national co-ordination. When diseases are rare, expertise is scarce as well. Certain centres of expertise (also called centres of reference in some Member States) have developed expertise which is widely used by other professionals from their country or even internationally. In some countries these centres are officially recognised but in most they are only established by reputation. The European Commission has decided to prioritise cooperation and knowledge sharing between these centres in the different EU Member States as the most efficient approach for giving patients an opportunity for diagnosis and treatment that may not exist in their country of residence.

Certain principles have been developed regarding European Reference Networks (ERN), including their role in tackling rare diseases or other conditions requiring specialised care, patient volumes and other criteria that such centres should fulfil. ERNs should also serve as research and knowledge networks updating and contributing to the latest scientific results, treating patients from other Member States and ensuring the availability of subsequent treatment facilities where necessary. ERNs should also reflect the need for services and expertise to be appropriately distributed across the enlarged European Union.

Following the procedures of selection in the Health Programme (2008-2013) and previous programmes the Commission is now supporting 10 pilot ERN on rare diseases in the European Union. EPNET (European Porphyria Network) has been one of these useful and very positive examples of this cooperation in the benefit of the patients and the Commission is very happy to have contributed to their development. The experience of these pilot networks will provide valuable source of lessons to be used in the future.

The Commission’s proposals for a directive on patient rights in cross-border healthcare included provisions that would put this European cooperation on a sufficient legal basis to provide for its sustained implementation. It is still unclear when this proposal will be in force but through these tools, Europe will provide a concrete response to the legitimate hopes of patients suffering from a rare disease, including the porphyrias, throughout the EU.

Antoni Montserrat Moliner

Policy Officer for Rare and Neurodevelopmental Diseases Health and Consumers General-Directorate (SANCO)

1. Forward

The porphyrias are a group of rare mainly inherited disorders of the heme biosynthesis pathway. Heme is made by all cells in the body, but is particularly important in the liver and for making haemoglobin in the bone marrow, There are seven main types of porphyria which are usually classified by what type of illness they cause; There are four “acute” porphyrias: acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HC) and a very rare porphyria called ALA dehydratase deficiency porphyria. They are called acute because they usually cause sudden attacks of very severe stomach pain that last for several days. VP and HC may also cause skin symptoms. The other porphyrias, porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP) and the rare congenital erythropoietic porphyria (CEP) (also known as Günther’s disease) affect mainly the skin and do not cause acute symptoms in other organs. The porphyrias may also be classified as hepatic or erythropoietic depending on the organ where the porphyrins accumulate, the liver for the hepatic porphyrias (AIP, HC, VP and PCT), the bone marrow for the erythropoietic porphyrias.

All porphyrias result from partial deficiency of one of the enzymes of heme biosynthesis and, apart from the sporadic form of porphyria cutanea tarda, are inherited in monogenic patterns. Accurate diagnosis of clinically overt (symptomatic) porphyria requires identification of the unique pattern of overproduction of heme precursors that results from each enzyme deficiency.

2. Introduction

The porphyrias are rare conditions affecting about 1 in 20,000 of the EU population. As such, most healthcare professionals have no experience of diagnosing and treating patients. Their clinical management varies between EU countries and there is disparity in the content and accessibility of information for patients and healthcare professionals.

The European Porphyria Network’s (EPNET) mission is to improve the lives of porphyria patients by improving the diagnosis and treatment of these rare conditions. The objective is to provide an effective network of specialist porphyria centres in each country. EPNET began with 20 EU specialist centres collaborating together to develop an up-to-date approach to the diagnosis and management of patients and families with porphyria that conforms to uniform standards.

EPNET is one of the reference network pilot projects funded in 2006 by the European Commission DGSANCO supporting exchange of information and experience on good practice on porphyrias.

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The overall aim of EPNET was to develop a common approach to the diagnosis and clinical management of the porphyrias throughout the EU so that patients, their families and healthcare professionals can benefit from access to evidence-based, consensus-agreed information in their own languages through easily accessible support and to provide not yet available epidemiological data on acute porphyrias to Public Health National and EU Authorities.The EPNET project had four key strategic objectives:1. To provide up-to-date information about all the porphyrias to patients, their families and healthcare professionals in their own languages on a website dedicated to porphyria.2. To provide improved, evidence-based, information about the selection of drugs for use in patients with an acute porphyria.3. To promote better definition and classification of the porphyrias by establishing a European network of diagnostic and clinical advisory centres, each of which conforms to agreed clinical and biological quality criteria.4. To collect and provide epidemiological data about the inherited porphyrias and their main complications at EU level to Public Health Authorities.

3. General Objective

4. Governance &membership

EPNET is a network of expert centres providing specialist testing and clinical advice on all porphyrias. EPNET has expanded from 20 to 32 members in 21 countries (including 4 associate members from outside of Europe). Members are required to submit an annual report of their activity and subscribe to an External Quality Assurance scheme. They are also expected to liaise with their national scientific and patient networks, enter data into the patient registry, and collect information about drug use by their acute porphyria patients. All network members constitute the board. The board meets once a year when possible during the porphyria and porphyrins conference (Rotterdam 2007, Stockholm 2009 & Cardiff 2011). The board is chaired by the coordinator at APHP and it defines the overall direction.

A small executive group (EG) meets more frequently to check project progress against objectives and discuss publications. A part-time network manager and secretary assist the coordinator in the week by week running of EPNET. Each member of the EG has responsibility for one of the four specific project activities: information, drugs, laboratory and registry; working groups for specific tasks have been set-up.

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EPNET will continue to expand the network in 2 ways:

1. Attract new members from underrepresented EU countries: Applicants for EPNET membership will be considered by the board and will be required to provide a specified repertoire of tests to a minimum quality standard, give detailed interpretation of results and expert clinical advice on management Participation in the EPNET EQA scheme is mandatory. Centres that do not fulfill these criteria will be supported by existing members and expected to achieve the full standard within two years of provisional membership.

2. Stimulate national networks in EU countries where they do not exist: Over the last period we have recognised that service provision, data collection and improved quality is facilitated in countries which have formal national networks involving clinicians, scientists and patient groups e.g. British and Irish Porphyria Network (BIPNET) or formal national reference centres e.g. France.

5. Work performed

5.1. Information for patients and healthcare

professionals

Introduction

The internet provides a large amount of accessible health information of variable quality to patients. However they are usually unable to assess the value and quality of these sources. The aim of this workpackage was to develop consensus-agreed information written by international experts on the non-acute porphyrias: porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP) so that information about all porphyrias will be available on a single website. Website information will be provided separately for patients and for healthcare professionals. Information for patients will be translated into the languages of each EPNET partner. Existing consensus agreed information on acute porphyrias; acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) has also been updated.

Methods

Draft information was prepared and circulated to partners with clear deadlines for comments. We used the internal website for repository and progress. Comments were collated and a final draft sent to the steering group. The final English patient information leaflets were circulated to partners for translation and then published on the website.

Findings

Information on the skin porphyrias is available in English, French, German, Italian, Spanish, Polish, Dutch, Swedish, Norwegian and Portuguese. Where funding and or expertise is available, EPNET will translate this patient information into further European languages.

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Link to information on website: http://www.porphyria-europe.org

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Key achievements

• InformationontheskinporphyriasavailableinmainEUlanguages.

• The website has also allowed the exchange of ideas and difficult clinical management issues between porphyria centres

Information has been shared and disseminated in response to individual health issues. An example includes the rapid assessment and dissemination of information regarding the safety of antiviral medication for porphyria patients at the start of the swine flu epidemic.

5.2. Selection of drugs for use in patients with

an acute porphyria

Introduction

This WP focused on improving the evidence-base for information about the selection of drugs for use in patients with an acute porphyria. Patients with one of the acute porphyrias are susceptible to sudden medical crises (pain, nerve damage, sickness and vomiting), which require urgent hospital treatment and can be life threatening. These crises are usually precipitated by one of a number of events, but the main cause is often that they have taken a prescribed medicine. This medicine may be one that has been used safely for many years by all other patients, but triggers an attack only in porphyria patients. A good example of this is a drug called carbamazepine, which is used to successfully treat many thousands of epilepsy sufferers every year. However, if given to a porphyria patient this can provoke an acute crisis, and we therefore advise the patient that they need to use a «safe» alternative. In this context we mean safe for porphyria patients. This is therefore not seen as a reason to restrict the licensing of the medicine, as greater than 99.99% of the population can take it quite safely. There is also no legal obligation to report these interactions in porphyria patients through national pharmacovigilance programmes, and there is therefore no formal collection of this data. For this reason, a crisis in a porphyria patient, if caused by a drug, would not be brought to the attention of the European Medicines Agency (EMA).

Through trial and error and sharing information between doctors who specialise in this field, a limited amount of information has been collected and we now have enough information on some drugs to be able to advise whether they can be prescribed for porphyria patients or not (we call these our “safe drug” and “unsafe drug” lists).

Unfortunately there are many drugs for which information has not been collected, and we face the difficult dilemma in porphyria patients who develop other illnesses (for example high blood pressure, diabetes, cancer) of whether or not we can prescribe drugs, which may improve survival or quality of life, but for which we do not know if they will cause a crisis.

For more serious illnesses (e.g. cancer) we may advise to use the drug, taking a chance with the patients health on the assumption that it is better to treat than not treat. However there are cases where porphyria patients have been denied life saving medication in case this caused an acute crisis. In other conditions, (e.g. diabetes) we might decide that it would be best to use only the old established drugs therefore limiting, possibly unnecessarily, the benefit to the patient of a more modern and efficient drug treatment. This lack of adequate information can therefore lead to increased clinical risk for porphyria patients by limiting their access to the full range of modern, effective treatments.

This work package describes an entirely novel approach to this problem as it proposes to improve the quality of information we have available by contacting porphyria patients and asking them what drugs they have been prescribed, and whether this led to clinical problems or not. This direct clinical information will be added to that which is currently available and made available to the network members via a specific, searchable, website.

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Findings

We have received 5071 reports in total of which in 99.4% drugs have been used safely. There have been 18 reports of drugs causing an attack (0.6%). In total we have received reports on a total of 716 different drugs (as defined by their ATC-codes). In addition we have received 108 reports of the use of herbal medicines.

Overall on the 31st March 2010 there are 805 drugs classified in the drug database.

Country/region

Reports from healthcare professionals

Reports from patient questionnaires

UK 883 125

Sweden 87 1636

Poland 813

Norway 9 584

France 486

Italy 193

Switzerland 192

Spain 63

Methods

Four part-time pharmacists were employed to collect follow-up information on whether drugs were ‘safe’ or ‘unsafe’ in patients with porphyria and their affected asymptomatic relatives. A proforma for data collection was produced and a patient information leaflet developed. The information collected was processed into a report and sent via a web-based data collection to a central database. The information from the reports was collated and the porphrynogenicity of the medications was validated in conjunction with the theoretical and pharmacological markers for triggering the cellular mechanism responsible for an attack. A less detailed direct patient survey was also developed to validate the information collected by the pharmacists.

A searchable database providing improved information on the safety of medicines in the acute porphyrias has been established. Drugs have been classified as :

not porphyrinogenic (NP),

probably not porphyrinogenic(PNP),

possibly porphyrinogenic (PSP),

probably porphyrinogenic (PRP)

porphyrinogenic (P).

The evidence behind the classification is available for each drug in the form of a monograph. In view of variable susceptibility of individual patients it was decided that a minimum of 20 reports of safe use were required to provide sufficient evidence of safety on clinical grounds.

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Drugs reported as causing an attack

The information collected has allowed the confirmation of historical and often anecdotal information that implicated medication in causing acute attacks. Examples are listed in Table 1 and include steroid hormones such as norethisterone and dydrogesterone.

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Generic nameNumber of

Classificationattack reports

Levonorgestrel and estrogen 4 PRP

Desogestrel and estrogen 1 PRP

Norethisterone 2 P

Desogestrel 1 NC

Progesterone 1 PRP

Dydrogesterone 1 P

Chorionic gonadotrophin 1 NC

Clomifene 1 NC

Diclofenac 1 PRPChlorzoxazone, comb excl psycoleptics (also contains dextropropoxiphen)

1 P

Lidocaine 1 PSPDextropropoxiphene, comb excl psycoleptics (also contains phenazone)

1 P

Morphine and antispasmodics (also contains methylscopolamine, codeine, noscapine & papavarine)

1 PSP

Almotriptan 1 PNP

Phenobarbital 1 P

Chlordiazepoxid (Librium) 1 NC

Amitriptyline 1 PRP

Acute attacks have also been reported with agents previously assessed as being not porphyrinogenic. The quality of the supporting clinical information has been assessed and the information made available in the monographs as shown below for gentamicin. This data has been carefully analysed for other factors, such as infection, stress, dehydration and poor nutrition either solely or in combination which may have caused the attack.

Conversely it cannot be assumed from a single report of safe use of medication in an acute porphyria patient that the drug can be safely used.

Table 1: Reports of attacks

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Drug used and reported as uneventful

More than twenty reports were received on fifty one different drugs (Table 2). Although many of these drugs have already been classified as safe (not porphyrinogenic) in the drugs database on theoretical grounds, this valuable clinical information has confirmed that these evaluations are accurate. And this information is now available in the individual drug monographs.

Generic name Number of reports Classification

Paracetamol 423 PNP

Ibuprofen 201 PNP

Amoxicillin/Amoxicillin & enz. inh. 140 NP

Omeprazole 94 NP

Metoprolol 85 NP

Naproxen 81 PNP

Atenolol 72 NP

Amlodipine 59 PNP

Propranolol 46 NP

Phenoxymethylpenicillin 46 NP

Furosemide 45 PNP

Enalapril 45 NP

Diclofenac 44 PRP

Candesartan 42 NP

Fluoxetine 37 NP

Rosuvastatin 31 PNP

Metformin 30 NP

Glucosamine 28 NP

Lisinopril 25 NP

Isosorbide mononitrate 24 NP

Salbutamol 21 NP

Atorvastatin 20 PRP

Budesonide 20 NP

Reclassification of drugs based on EPNET clinical reports

The collection of data has allowed 37 drugs to be reclassified.

Generic name Old Classification New Classification

Omeprazol PSP NP

Amlodipin PRP PNP

Felodipine PRP PNP

Perindopril NC PNP

Nifedipine PRP PNP

Cetirizine PRP NP

Table 2: Examples of drugs

used safely

Table 3:Examples of drugs

classified

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Discrepancies in clinical information.

Two drugs had previously been classified as probably porphyrinogenic and therefore access to this treatment would have been restricted for acute porphyria patients. Although theoretical evidence of risk is strong the clinical reporting has indicated that they have been used safely by 20 or more patients. One of the drugs (diclofenac) was also reported as causing an attack.

Key achievements

• Settingupthesystematiccollectionofclinicalinformationondrugsusedsafely or causing an effect in patients with porphyria

• Collecting5071reportsfrompatientswithanacuteporphyria

• Atotalof805drugshavebeenassessedandthisinformationisavailableona searchable website (www.drugs-porphyria.org).

5.3. Diagnostic and clinical quality

assessment

Introduction

The aims of this work package were to collect data about the European porphyria laboratory workload, to set-up a clinical and analytical external quality assessment (EQA) scheme for the participants, to develop uniform quality standards and to draw up consensus-agreed protocols for porphyria diagnosis and monitoring.

Methods

1. Four EQAS were distributed to all EPNET partners. Blood, urine and faeces samples were tested for HIV, hepatitis B and C and sent frozen to all the participants who analysed the samples with the methods they use, they provide a diagnosis, give information on how they would report the case to the requesting physician and give information about their diagnostic strategies. Feedback reports were given to each participant comparing their results with others.

2. Questionnaires collecting information about lab activities e.g type of analyses they have on their repertoire, number of analyses performed number of diagnosis made, workload, participation in EQAS schemes and accreditation status are sent to all EPNET partners yearly. Questionnaires were sent asking for activity in years 2006, 2007 and 2008. The data were analysed and feed-back reports given to partners.

In addition EPNET has continued to collaborate with the European Molecular Quality Network in an audit of laboratories undertaking molecular diagnosis of porphyria.

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Findings

Activity reports:

The activity reports show that there are great differences between specialist centres. An example of this can be shown in table 4 where the number of analyses is reported:

and in diagram 1 showing the number of individuals investigated and/or request forms received in each country per 100 000 inhabitants. When both are reported, the number of request forms are larger than the number of individuals investigated since several samples may be obtained from the same individual. Overall the figure shows that there is great variation regarding number of people investigated for porphyria in different countries in Europe.

Table 4: Number of analyses

reported by a lab.Urine

Your data 2008

Median Range Number of centres (n)

Your data 2007

ALA* 935 158.5 10 - 1305 32 1173

PBG* 935 280 20 - 1429 32 1173

Total porphyrins* 917 316.5 20 - 1508 28 953

Fractionation of porphyrins* 184 101 12 - 1011 31 257

Faeces

Total porphyrins* 90 4 - 578 23

Fractionation with separation of copro I/III 437 24.5 0 - 437 30 435

Fractionation without separation of copro I/III 15 0 - 182 9

Erythrocytes

Protoporphyrin* 137.5 2 - 860 28

Free and zinc protoporphyrin 377 148 0 - 1177 26 754

Plasma

Plasma scan* 674 171 0 - 1435 31 604

Total plasma porphyrins 3 0 - 57 17

Fractionation of plasma porphyrins 36.5 0 - 887 18

Enzymes

PBG-deaminase 79 45 0 - 489 26 146

Uro-decarboxylase 0 0 0 - 171 15 46

Other* 21 0 - 144 9

DNA TESTING

HMBS-gene 17 15 0 - 397 19 32

UROS-gene 0 0 0 - 3 9

UROD-gene 36 4 0 - 59 15 32

CPOX-gene 1 2 0 - 17 17 2

PPOX-gene 0 5.5 0 - 165 20 7

FECH-gene 4 6 0 - 61 15 2

ALAS1-gene 0 0 - 0 5

ALAS2-gene 1 0 - 30 7

BIOCHEMICAL TESTING All centres 2008:

*Minimum criteria for being a European Specialist Porphyria Centre.

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Criteria for being a specialist porphyria centre have been developed and advice has been given to laboratories to achieve these standards. In general there seems to an improvement in the period evaluated: The reports from the last three years show that in 2006, 22 of 29 laboratories fulfilled all the criteria for being a Porphyria Specialist Centre. In 2007, 25 of 32 laboratories fulfilled the criteria and in 2008, 30 of the 32 laboratories fulfilled all the criteria.

EQAS scheme:

All members have participated in the external quality assessment scheme (EQAS). A typical feedback for one analyte is shown in the diagram 2.

Participants whose results have been “poor” have been offered advice to improve their methods and later surveys can show that an improvement has taken place.

Diagnostic strategies have been reported from each centre – i.e. what analyses would you have analysed in your centre given “this case history”. See example from a feedback report below:

Diagram 1:

Diagram 2:EQAS feedback

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Although there is a rather large variation in analytical results, most laboratories have been able to make a correct diagnosis and there has been an improvement in how the results have been reported to the requesting physician. After the completion of the project, a permanent EQAS scheme for porphyria laboratories has been established and 28 laboratories (8 more than in the original project) will participate (paying a fee) in 2010.

Key achievements

• Establishmentofasystemforannualactivityreportingwithindividualfeedback for all porphyria centres. Centres fulfilling the criteria for being a porphyria specialist centre appear on the website and their annual activity is monitored.

• Establishmentof a sustainable fee-payingEQASscheme forporphyriawith 32 participating laboratories making it possible to monitor analytical and clinical performance at the different centres

• Settingupasystemforaddressingunderperforminglaboratories

5.4. Registry Introduction

The aims of this work package 7 were to determine the incidence of new cases of clinically overt inherited porphyrias in European countries and to estimate the prevalence of selected severe complications of these disorders. The main disorders investigated were the autosomal dominant acute porphyrias: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP); and the autosomal recessive cutaneous porphyrias: erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP). The clinical, biochemical and genetic features of these diseases have recently been reviewed (Puy, H. et al. Lancet 2010;375: 924-37).

Prospective studies of the incidence (new symptomatic cases per year per million inhabitants) of the different inherited porphyrias have not been reported for any European or other country, partly because of the difficulty in obtaining comprehensive information from the large populations that are needed to determine the incidences of such rare diseases.

The amount of health care resources required to support patients with inherited porphyrias and their families is related to the incidence of each disease (management of acute symptoms) and the proportion of newly presenting patients who go on to develop complications (management of chronic disease and late complications). This work package was designed to provide an initial quantitative indication of both these aspects of the clinical management of the porphyrias.

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Methods

A password-protected, CNIL approved central database was established in Paris to function as a European Porphyria Registry. All partners obtained appropriate approval for collection and submission of patient information from their local ethics committees. All information entered into the data base was anonymised. Data was submitted from each participating country either from a single centre tasked with collecting information from the whole country or, for some countries, from centres covering a defined geographical area within their country. To determine incidence, the numbers of newly diagnosed patients identified over a 3 year period were collected. The numbers of patients with one or more of nine rare complications were also collected during the third year of the project. The populations of each country were obtained from the Eurostat website.

Findings

Incidence of porphyria.

Porphyria centres in 16 countries entered information on incidence into the database. The information from 11 countries was judged sufficiently complete (at least 80% of patients identified in most countries for most diseases) to allow determination of the minimum incidence of the acute porphyrias and EPP (Tables 1 and 2). New cases of CEP, hepatoerythropoietic porphyria (HEP) and other inherited porphyrias (5-aminoleavulate dehydratase deficiency, homozygous VP) were very rare (1 per year per 100 million inhabitants or less).

*Data collected for 2 years.

Country Populationmillions AIP HCP VP EPP

Finland 5.35 0.13 0 0.06 -

France 64.71 0.11 0.01 0.12 0.06

Ireland 4.45 0 0 0.16 0.08

Northern Italy 27 0,11 0.03 0.05 0.06

Italy 60.40 - - 0.06 0.07

Netherlands 16.58 0.18 0.02 0.06 0.18

Norway 4.85 0.14 0 0.07 0.36

Poland 38.16 0.16 0 0.01 0.02

Spain 46,09 0.12 0.04 0.04 0.03

Sweden 9.35 0.51 0 0.11 0.18

Switzerland 7.76 0.35 0.04 0.26 0.35

UK 62.04 0.16 0.04 0.08 0.33

All countries 314.39 0.13* 0.02 0.08 0.12

*Excludes Sweden, Switzerland and Italy, apart from northern Italy Data on acute porphyrias was available only for northern Italy

Country code

Type of porphyria Total patientsAIP HCP VP EPP CEP HEP Other

CH 8 1 6 8 1 24

FI 2 0 1 3

FR 22 2 23 12 2 61

IR 2 1 3

IT (N) 9 2 4 5 1 21

IT (S) 7 7 14

NL 9 1 3 9 2 24

NO 2 1 5 1 9

PL* 12 1 2 15

SE 14 3 5 1 23

SP 17 5 5 3 1 31

UK 29 8 14 55 3 0 1 110

Total 124 19 70 112 7 2 4 338

Table 5:Numbers of newly

diagnosed patients identified during the 3 year study period

Table 6:Incidence

(newly diagnosed cases per year

per million inhabitants)

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Acute porphyrias. Table 6 shows that the incidence of AIP is similar in all countries apart from Sweden and Switzerland, in both of which it is significantly higher than in other countries (P < 0.001) The high incidence in Sweden is consistent with previous reports of an increased prevalence caused by a founder effect. After exclusion of these two countries, the incidence for the combined populations (263.88 million) of the other 7 countries and northern Italy is 0.13 per year per million (95% confidence interval: 0.11 – 0.16 per year per million).

The incidence of HCP is similar in all countries (Table 6) with the incidence for the combined population of all countries (314.39 million) being 0.02 per year per million (95% confidence interval: 0.01 – 0.03). The incidence of VP varies more widely between countries but without significant differences between countries. The overall incidence for the total population is 0.08 per year per million (95% confidence interval: 0.06 – 0.09).

The ratio of the incidences of AIP:VP:HCP is 1.00:0.62:0.15 , in countries other than Sweden and Switzerland.

Erythropoietic protoporphyria. The incidences of EPP show a wider variation between countries than the acute porphyrias (Table 6). The explanation for this is unclear. The prevalence of EPP in a particular population is strongly influenced by genetic factors but these are unlikely to provide more than a partial explanation. Other potential contributing factors are differences in clinical awareness of the disease, in diagnostic services, in ascertainment by reporting centres, particularly when these are concerned mainly with the acute porphyrias, and a possible north to south decrease in the incidence of EPP.

Main clinical features of newly diagnosed patients

Table 7 confirms that symptomatic AIP, HCP and VP are commoner in females and shows that in AIP, but not HCP or VP, female patients are diagnosed at an earlier age. When patients with VP are divided into those presenting with an acute attack and those presenting with skin symptoms, there are no significant differences between the sexes with regard to age at diagnosis.

Disease Total Age at diagnosis*

AIP F 94 30, 11-72**

M 30 (24%) 41.5, 22-72

HCP F 12 32.5, 20-79

M 7 (37%) 38, 32-51

VP F 47 40, 17-78

M 22 (32%) 33.5, 20-91

EPP F 56 21, <1-83

M 56 (50%) 20.5, 5-75

*Median, range (yr); **P = 0.002 vs AIP males. Figures in parentheses are % total patients.

The ages in Table 7 are those at diagnosis. The delay between first symptoms and diagnosis was not determined. For most patients with acute porphyrias, the delay is likely to be less than a year though a few patients with repeated attacks of acute porphyria were not diagnosed for several years. Almost all patients in EPP develop symptoms in early childhood, the much later median age at diagnosis is consistent with recent series and reflects the delay in clinical recognition that is currently of feature of this disorder.

Table 7:Age at diagnosis

and sex ratio

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Table 8 shows the clinical presentation and whether the patient was aware of a family history (FH) of porphyria at the time of diagnosis for each porphyria. Clinical presentation was divided into acute symptoms sufficiently severe to require admission to hospital for at least one night, acute symptoms not requiring hospital admission and cutaneous symptoms as the sole or main reason for seeking medical advice. 20% of newly presenting AIP patients did not require admission to hospital; possible explanations include referral to a specialist centre for diagnosis after remission of acute symptoms or less severe clinical symptoms. The proportion of AIP patients who knew that their family had acute porphyria was similar in both groups. Thus there was no evidence that prior diagnosis of porphyria in a family currently leads to clinically less severe presentation through earlier diagnosis and prevention of escalation of symptoms.

Disease/sexAcute

(admitted to hospital)

Acute (no

admission)Cutaneous FH

YesFHNo

FHNot

recorded

AIP/F 75 19 (20%) 40 36 18

AIP/M 24 6 (20%) 13 9 8

HCP/F 8 2 2 (17%) 4 3 5

HCP/M 5 1 1 (14%) 1 3 3

VP/F 6 5 36 (77%) 17 17 13

VP/M 1 3 18 (82%) 5 11 6

EPP/F 56 5 26 25

EPP/M 56 2 28 26

Figures in parentheses are % total patients

Rare complications of porphyria

One hundred and nine patients (88 AIP, 7 VP, 14 EPP) with rare complications were entered into the registry from seven countries.

The rare complications for which information was collected were: repeated attacks of acute porphyria (more than 4 per year); long term (more than one year) treatment to suppress acute attacks; liver transplantation for acute porphyria; complications human hemin therapy (iron overload, venous thrombosis); administration of human hemin during pregnancy; new cases of primary liver cancer (HCC) in acute porphyria presenting during the 3 year study period; severe renal failure in acute porphyria; liver disease in EPP; death from all causes. For several complications, the number of patients entered is as yet too small for analysis.

Primary hepatocellular carcinoma (HCC). HCC is an important complication of acute porphyria. An epidemiological study in Sweden showed that 27% of patients with AIP aged over 50 years developed HCC and AIP in France is associated with a 36-fold increased risk of HCC compared with the general population. However, no prospective studies of the incidence of HCC in acute porphyria have been reported. Fourteen new cases of HCC (10 in women) were identified during the study period in 11 patients with AIP and 3 with VP. All cases were from Sweden except for one each from the Netherlands (AIP), Switzerland (AIP) and the UK (VP). No new case of HCC was reported from France. The confirmation of the much higher incidence of this complication in Sweden is an important outcome of our study that requires further investigation.

Table 8:Clinical presentation

and family history

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Recurrent attacks of acute porphyria. The clinical management of patients with severe recurrent attacks of acute porphyria, which often persist for many years, requires prolonged periods of out-patient and in-patient care, long term treatment with human hemin and/or other drugs and, in some patients, eventual liver transplantation. This work identified 67 patients with this complication, of whom most had been receiving treatment for at least 4 years and 13 had received a liver transplant for acute porphyria. The majority had AIP (64 patients; 53 female, 11 male). Our data confirmed previous reports that severe recurrent acute attacks are mainly a feature of AIP (64 of 67 patients) and are commoner in women (53 females; 11 males) The median ages of females and males with recurrent attacks were 36 years (range 23 -68 years) and 43.5 years (range 17 – 52 years) respectively. The difference between these ages and age at diagnosis (Table 3) was significant only for female patients (P = 0.03).

The estimated percentage of newly diagnosed patients with AIP that will develop severe recurrent acute attacks, based on data from 5 countries, was 8.2% (95% confidence interval: 6.3 – 10.6%) for women and 5.6% (95% confidence interval: 3.2 – 10.9%) for men.

Mortality. Information about 16 patients with porphyria who died during the 3 year study period was returned to the database. Two deaths were unrelated to porphyria. Four patients with EPP died from liver failure. Of the 10 patients who died from acute porphyria (9 AIP, one VP), 7 were caused by HCC, one followed liver transplantation and the cause of death was unrecorded for 2 patients with AIP.

Key achievements

• SettingupaEuropeanporphyriaregistry.

• DeterminingtheincidenceofinheritedporphyriainEurope.

• Providing information about the main demographic and clinical features of inherited porphyria from a prospective study of a large number of patients.

• Collectinginformationaboutrarecomplicationsofporphyria

• Providinginitialevidencethathepatocellularcarcinomaismorecommonasa complication of acute porphyria in Sweden than in other countries.

• Determining the percentage of newly diagnosed patients with acute porphyria who will develop repeated acute attacks and require sustained clinical management.

This project has succeeded beyond expectation in the objective of improving healthcare for patients with porphyria and their families. The network of participating centres is larger than planned for and partners have enthusiastically embraced the principles of widening access to and improving quality of diagnostic and clinical services. Information for patients, families and non-expert clinicians is available in a variety of European languages and there is a commitment of partners to expand this library to include more international languages where possible. Systematic collection and pooling of clinical experience with drug use in acute porphyria has had a major impact on the quality and availability of clinical advice that can be provided to patients. Audit and assessment of the quality of laboratory diagnosis has allowed key diagnostic criteria to be defined and services to be measured against these standards which will enhance quality. Finally, collection of detailed epidemiological data has for the first time allowed incidence data and the level of disease burden to be defined. Finally the project has engendered a momentum and enthusiasm among professionals working in this field to continue the network and build on what has been achieved so far.

6. Conclusion

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