J Inherit Metab Dis

DOI 10.1007/s10545-012-9544-4

ORIGINAL ARTICLE

The incidence of inherited porphyrias in Europe

George Elder & Pauline Harper & Michael Badminton &
Sverre Sandberg & Jean-Charles Deybach

Received: 2 July 2012 / Revised: 10 September 2012 / Accepted: 13 September 2012

# SSIEM and Springer Science+Business Media Dordrecht 2012

Abstract Retrospective estimates of the prevalence of protoporphyria (EPP) was less uniform between countries
porphyrias have been reported but there has been no and, in some countries, exceeded previous estimates.
large scale prospective study of their incidence. The Fourteen new cases of HCC (11 from Sweden) were
European Porphyria Network collected information pro- reported in patients with acute porphyria. Sixty seven
spectively over a 3 year period about the number of patients (3 VP; 64 AIP: 53 females, 11 males) with
newly diagnosed symptomatic patients with an inherited recurrent attacks of acute porphyria were identified. The
porphyria (335 patients from 11 countries). Prevalence estimated percentage of patients with AIP that will de-
was calculated from the incidence and mean disease velop recurrent acute attacks was 3–5 %. In conclusion,
duration. The incidence of hepato-cellular carcinoma the prevalence of symptomatic acute porphyria may be
(HCC) in acute hepatic porphyria and the prevalence of decreasing, possibly due to improved management, whereas
patients with recurrent acute attacks of porphyria were the prevalence of EPP may be increasing due to im-
also investigated. The incidence of symptomatic acute proved diagnosis and its greater recognition as a cause of
intermittent porphyria (AIP) was similar in all countries photosensitivity.
(0.13 per million per year; 95 % CI: 0.10 – 0.14) except
Sweden (0.51; 95 % CI: 0.28–0.86). The incidence ratio Abbreviations
for symptomatic AIP: variegate porphyria: hereditary cop- AIP Acute intermittent porphyria
roporphyria was 1.00:0.62: 0.15. The prevalence of AIP ADP 5-aminolevulinate dehydratase deficiency porphyria
(5.4 per million; 95 % CI: 4.5–6.3) was about half that CEP Congenital erythropoietic porphyria
previously reported. The prevalence of erythropoietic CI Confidence interval
EPNET European Porphyria Network
EPP Erythropoietic protoporphyria
HCC Hepatocellular carcinoma
Communicated by: Robert Steiner
HCP Hereditary coproporphyria
On behalf of the European Porphyria Network (EPNET). EPNET HEP Hepatoerythropoietic porphyria
investigators are listed at the end of the article.
VP Variegate porphyria
G. Elder : M. Badminton (*)
Department of Medical Biochemistry and Immunology,
University Hospital of Wales,
Cardiff CF14 4XW, UK Introduction
e-mail: mike.badminton@wales.nhs.uk

P. Harper Although over 6000 diseases have been classified as rare,

Porphyria Centre Sweden, Karolinska University, information about the prevalence of individual disorders is
Stockholm, Sweden based more often on estimates than on systematic popula-
tion surveys, with the notable exceptions of congenital
S. Sandberg
Norwegian Porphyria Centre (NAPOS), Haukeland abnormalities and those metabolic disorders detected by
University Hospital, neonatal screening (Posada de la Paz et al 2010).
Bergen, Norway The porphyrias are a group of rare disorders of haem
J.-C. Deybach
biosynthesis, all of which are inherited apart from some
Centre Francais des Porphyries, Hopital Louis Mourier, forms of porphyria cutanea tarda (Puy et al 2010). Acute
92701 Colombes CEDEX, France intermittent porphyria (AIP), hereditary coproporphyria

(HCP) and variegate porphyria (VP) are low penetrance
autosomal dominant disorders that have identical acute neu-
rovisceral attacks as their most severe or, for AIP, only
clinical manifestation. In HCP and VP, skin lesions caused
by photosensitisation by porphyrins may occur with acute
attacks or separately. These features are often episodic so
that most patients spend long periods without symptoms.
However, a few develop severe recurrent acute attacks
that persist for years (Puy et al 2010) and may require
liver transplantation for their cure (Dowman et al
2012). Other long term complications include primary
hepatocellular carcinoma (Andersson et al 1996;
Andant et al 2000; Innala and Andersson 2011), chron-
ic renal failure and hypertension (Puy et al 2010).
Acute attacks also occur in the very rare recessive
disorder, 5-aminolevulinate dehydratase deficiency por-
phyria (ADP). All other inherited porphyrias are auto-
somal recessive or X-linked photodermatoses with close to
full penetrance (Puy et al 2010). The recessive disorder,
erythropoietic protoporphyria (EPP), is by far the most com-
mon of these photodermatoses and is characterised by life-
long acute photosensitivity (Holme et al 2006).
Diagnosis of individual porphyrias requires specialist
analysis of porphyrins and porphyrin precursors in ap-
propriate samples (Deacon et al 2006). This allows
appropriate treatment, supported by porphyria clinical
specialists where necessary, to be implemented. Within
Europe, promotion of analytical quality and diagnostic
accuracy is a major objective of the recently estab-
lished network of specialist porphyria centres, the Eu-
ropean Porphyria Network (EPNET) (Aarsand et al
2011; www.porphyria-europe.org).
The health care resources required for the support of
patients with inherited porphyrias and their families will be
related to the prevalence of overt cases of each disease, the
proportion of patients who develop long term complications
and preventive strategies. Much information about the preva-
lence of porphyrias is derived from estimates based on the
clinical experience of specialist porphyria centres (Anderson et
al 2001; Orphanet Report Series 2010; Puy et al 2010), al-
though more systematic studies of individual porphyrias have
been reported from a few countries (Mustajoki and Koskelo
1976; Mustajoki 1980; Went and Klasen 1984; Meissner et al
1987; Kauppinen and Mustajoki 1988; Nordmann et al 1997;
Floderus et al 2002; von und zu Fraunberg et al 2002; Holme et
al 2006; Thunell et al 2006; Schneider-Yin et al 2009; Wahlin
et al 2011). There are no reports of the incidence of the
inherited porphyrias in European or other countries.
Here we describe a prospective survey in European
countries of the incidence and prevalence of inherited
porphyrias and two of their major complications based
on data collected from EPNET-participating porphyria
centres.
J Inherit Metab Dis
Methods
A password-protected, central database, approved by the
Commission nationale de l’informatique et des libertés,
was established in Paris. All information was anonymised;
approval for collection and submission of patient informa-
tion was obtained as appropriate for each country. For most
countries, data were submitted from a single centre tasked
with collecting information from the whole country. The
population of each country was obtained from the Eurostat
website (http://epp.eurostat.ec.europa.eu). For Italy and
Spain, data were submitted from two centres, each covering
a distinct geographical area for which the population could
be estimated. To determine incidence, each centre counted
the number of newly diagnosed symptomatic patients with
an inherited porphyria who presented during a 3 year period
(January 2007 to December 2009). Newly diagnosed symp-
tomatic patients were defined as patients who had not pre-
viously had symptoms diagnosed as being caused by
porphyria, and who presented with either an acute attack
of porphyria or skin lesions shown biochemically to be
caused by porphyria according to currently accepted diag-
nostic criteria (Deacon et al 2006).
For those patients with HCP or VP with acute and cuta-
neous symptoms, the dominant mode of presentation was
recorded. Patients were asked at the time of diagnosis if they
knew whether anyone else in their family had porphyria. No
other information about family history was collected. Por-
phyria cutanea tarda, which is an acquired disorder in the
majority of patients, was not included in the study. For the
autosomal dominant acute porphyrias, information was also
collected by centres about new cases of hepatocellular car-
cinoma that presented during the 3 year study period and
about patients treated during the study period for severe,
recurrent acute porphyria, defined as four or more acute
attacks for one or more years. Prevalence was calculated
using the formula: incidence rate x mean duration of disease
(Posada de la Paz et al 2010). Since there are no published
figures for the mean disease duration of these disorders, we
used 45 years for AIP, 40 years for VP and 77 years for EPP.
These figures were obtained by subtracting the median age
at diagnosis for all patients with AIP (33 years), all patients
with VP (38 years) and the median age of onset for EPP
(1 year) (Holme et al 2006) from an assumed life expectancy
of 78 years for both sexes, since these diseases have little
effect on the life span of most patients (Mustajoki 1980;
Anderson et al 2001; Puy et al 2010).
Data were analysed using Microsoft Excel and Minitab v
13. The significance of differences between quantitative
variables was assessed by the Mann–Whitney test. Confi-
dence intervals were calculated based on the Poisson distri-
bution (Ulm 1990).
P values less than 0.05 indicated significant differences.
J Inherit Metab Dis

Results diagnosis. In EPP, both sexes were equally affected, con-

firming previous reports (Todd 1994; Holme et al 2006).
Table 1 shows the number of newly diagnosed symptomatic Table 2 shows age at diagnosis; age at onset was not
patients identified by 13 centres in 11 countries. Returns reported. Thus, the delay between first symptoms and diag-
from five centres in four other countries were incomplete nosis could not be determined. For the acute porphyrias, the
and are not included. As expected from estimates of preva- delay is likely to be less than a year though a few patients
lence (Anderson et al 2001), AIP, EPP and VP were the with repeated attacks of acute porphyria were not diagnosed
most common porphyrias, together accounting for 91 % of for several years. In EPP, symptoms normally start in early
patients. New cases of CEP, hepatoerythropoietic porphyria childhood, the much later median age at diagnosis (Table 2)
(HEP) and other inherited porphyrias (5-aminolevulinate reflects the delay in clinical recognition that is currently a
dehydratase deficiency porphyria, homozygous VP) were feature of this disorder (Schneider-Yin et al 2000; Holme et
very rare. al 2006; Wahlin et al 2011).
The main characteristics of the patients with AIP, HCP, Not all patients with an acute attack were recorded as
VP or EPP are shown in Table 2. Symptomatic AIP and requiring admission to hospital for their management (Ta-
HCP were more common in females, as reported previously ble 2). Among the 18 % of patients in this category urinary
(Martasek 1998; Hift and Meissner 2005), with this differ- PBG excretion was not significantly lower for UK patients
ence being significant for AIP (P <0.001). VP was also more (median 13.0, range 10.2–213.2) μmol/mmol creatinine, n0
common in females (P00.025), irrespective of the type of 5, vs 52.0, 38.1–177 μmol/mmol, n013; reference range:
presentation. We did not find the equal distribution between less than 1.0 μmol/mmol) or for those from France (median
the sexes of acute attacks of VP that has been reported from 20.7, range 13.4–44.0 μmol/mmol creatinine, n06, vs 28.8,
South Africa (Hift and Meissner 2005) nor were our female 1.5–55.9 μmol/mmol, n 014; reference range: less than
(median age:28, range: 24–61 years) or male patients (me- 1.0 μmol/mmol); numbers from other countries were too
dian age:30, range: 21–63 years) with acute attacks of VP small for statistical analysis. It is likely that the patients who
significantly older than those with AIP. In AIP, but not HCP were not admitted to hospital form a mixed group. Some
or VP, female patients were diagnosed at a younger age (P0 may have had less severe symptoms but the majority were
0.02). In VP, there was no significant difference between the probably referred to a specialist centre for diagnosis after the
sexes with regard to mode of presentation or age at acute phase of the attack.
Among the patients with AIP, HCP or VP, 45–54 % of
those for whom this information was recorded were aware
Table 1 Numbers of newly diagnosed patients with inherited porphy-
rias identified over a 3 year period that the disease ran in their families (Table 2). The overall
percentages may be lower because this information may not
Country Type of porphyria Total always have been recorded for patients without a known
AIP HCP VP EPPa CEP HEP Otherb
family history. In AIP, the proportion of AIP patients who
knew that their family had acute porphyria was similar
Finland 2 0 1 0 0 0 0 3 whether or not hospital admission was required. Only
France 22 2 23 12 2 0 0 61 13 % of EPP patients were recorded as knowing of an
Irish Republic 0 0 2 1 0 0 0 3 affected relative at the time of diagnosis (Table 2); a figure
Italy (Milan) 9 2 4 5 0 1 0 21 that is lower than those reported from retrospective studies
Italy (Rome) NR NR 7 7 0 0 0 14 of large numbers of European families with EPP (Went and
Netherlands 9 1 3 9 0 0 2 24 Klasen 1984; Holme et al 2006).
Norway 2 0 1 5 0 0 1 9 The data in Table 1 were used to calculate the incidence
Polandc 12 0 1 2 0 0 0 15 of each inherited porphyria in 11 countries. Table 3 shows
Spain (Barcelona) 4 0 2 1 1 0 0 8 the incidences of AIP, VP and EPP. The incidence of AIP
Spain (Madrid) 13 5 3 2 0 0 0 23 was significantly higher in Sweden (0.51 per year per mil-
Sweden 14 0 3 5 1 0 0 23 lion) than in the other countries combined (0.12 per year per
Switzerland 5 1 6 8 0 1 0 21 million) (P<0.001). In the nine other countries that reported
United Kingdom 29 8 14 55 3 0 1 110 new cases of AIP, incidences were similar, ranging from
Total 121 19 70 112 7 2 4 335 0.11 to 0.22 per year per million, with an overall incidence
of 0.12 (95 % CI: 0.10 – 0.14). The incidence of VP was
NR no data returned about half that of AIP. Only Switzerland had an incidence
a
Includes XLDPP statistically higher than all other countries combined. The
b
ADP, homozygous VP incidence of EPP varied more widely between countries
c
data collected for 2 years (Table 3), but only Switzerland and the United Kingdom
 J Inherit Metab Dis

Table 2 Characteristics of newly diagnosed patients

Disease/sex Number of patients Age at diagnosis Mode of presentation FH known at diagnosis

Acute (admitted to hospital) Acute (no admission) Cutaneous Yes No Not recorded

AIP/F 92* 30, 11–72** 75 17 (19 %) 40 34 18

AIP/M 29 (24 %) 41.5, 22–72 24 5 (17 %) 12 9 8
HCP/F 12 32.5, 20–79 8 2 2 (17 %) 4 3 5
HCP/M 7 (37 %) 38, 32–51 5 1 1 (14 %) 1 3 3
VP/F 48*** 40, 17–78 6 (13 %) 5 (10 %) 37 (77 %) 18 17 13
VP/M 22 (32 %) 33.5, 20–91 1 (5 %) 3 (14 %) 18 (82 %) 5 11 6
EPP/F 56 21, <1–83 56 5 26 25
EPP/M 56 (50 %) 20.5, 5–75 56 2 28 26

Figures for age at diagnosis are medians and ranges; those in parentheses are % total patients; FH: family history known to patient at diagnosis. *P<
0.001 vs. number of male AIP patients; **P00.020 vs. age at diagnosis for male AIP patients; ***P00.025 vs. number of male VP patients; other
differences were not significant

showed significantly increased incidences by comparison
with the other countries combined. Table 4 shows the prev-
alence and total number of patients with current or past
symptoms of AIP, VP or EPP in each country, calculated
from the incidence data in Table 3.
For the less common inherited porphyrias, the overall
incidence was calculated for the combined population of
the 11 countries (308.5 million). The incidence of HCP
was 0.2 (95 % CI: 0.10–0.30) per year per 10 million. The
combined incidence of CEP, HEP, ADP and homozygous
VP was 0.13 (95 % CI: 0.11–0.16) per year per 10 million
with CEP accounting for just over half of these cases.
We also investigated the frequency of two important
complications of AIP and VP: recurrent acute attacks (Puy
et al 2010) and primary hepatocellular carcinoma (HCC)
(Innala and Andersson 2011). Patients were categorised as
having recurrent acute attacks if they had more than four
acute attacks per year for at least 1 year or were under
treatment to suppress recurrent acute attacks or had
received a liver transplant for recurrent acute porphyria.
We identified 62 patients with this complication, most of
whom had been receiving treatment for more than 4 years.
Most had AIP, consistent with previous reports that the ma-
jority of patients with severe recurrent acute attacks have this
disorder (Hift and Meissner 2005; Puy et al 2010), but three
patients (two females, one male), all from the UK, had VP.
The median ages of females and males with recurrent attacks
of AIP 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 2) was significant only
for female patients (P00.03).
Data from five countries about recurrent attacks of
AIP were judged sufficiently complete to indicate the
minimum prevalence of this complication and are shown

Table 3 The incidence of newly

diagnosed cases of symptomatic Country Population (millions) Incidence (new cases per year per million inhabitants)
AIP, VP and EPP in European
countries AIP VP EPP

Finland 5.4 0.13 (0.02–0.45) 0.06 (0.002–0.35) NCI

France 62.2 0.12 (0.07–0.18) 0.12 (0.08–0.19) 0.06 (0.03–0.11)
Figures in parentheses are 95 % Irish Republic 4.2 NCI 0.16 (0.03–0.57) 0.08 (0.002–0.44)
confidence limits calculated for Northern Italy 27 0.11 (0.05–0.21) – –
the numbers of new cases over
3 years (Table 1). NCI, no new Italy 58.1 – 0.06 (0.03–0.11) 0.07 (0.04–0.12)
cases identified during the study Netherlands 16.7 0.18 (0.08–0.34) 0.06 (0.01–0.24) 0.18 (0.08–0.37)
period. Data for AIP in Italy was Norway 4.7 0.14 (0.02–0.51) 0.07 (0.002–0.39) 0.36 (0.11–0.83)
available only for northern Italy.
Poland 38.5 0.16 (0.08–0.27) 0.01a (<0.001–0..05) 0.03 (0.003–0.09)
UK data for EPP does not in-
clude Scotland Spain 40.5 0.14 (0.08–0.22) 0.04 (0.01–0.10) 0.03 (0.01–0.07)
a
Acute attacks only Sweden 9.1 0.51 (0.28–0.86) 0.11 (0.02–0.32) 0.18 (0.06–0.43)
b
All countries including Swe- Switzerland 7.6 0.22 (0.07–0.51) 0.26 (0.10–0.57) 0.35 (0.15–0.69)
den; if Sweden is excluded the UK 61.1 0.16 (0.11–0.23) 0.08 (0.04–0.13) 0.33 (0.24–0.39)
incidence is 0.12 (95 % CI: All countries 308.05 0.13b (0.11–0.16) 0.08 (0.06–0.10) 0.12 (0.10–0.15)
0.10– 0.14)
J Inherit Metab Dis

Table 4 The calculated prevalence of patients with current or past symptoms of AIP, VP or EPP in European countries

Country Population (millions) Prevalence (cases per million inhabitants) (calculated Total cases in each country (calculated from
from incidence) prevalence)

AIP VP EPP AIP VP EPP

Finland 5.35 5.9 (0.9–20.3) 2.4 (0.08–14.0) – 32 (6–109) 13 (1–75) –

France 62.2 5.5 (3.2–8.1) 4.8 (3.2–7.6) 4.6 (2.3–8.5) 342 (119–504) 299 (199–473) 286 (143–529)
Irish Republic 4.2 – 6.4 (1.2–22.8) 6.2 (0.2–33.9) 27 (5–96) 26 (1–142)
Northern Italy 27 5.0 (2.3–9.5) – – 135 (62–257)
Italy 58.1 – 2.4 (1.2–4.4) 5.4 (3.1–9.2) 139 (70–256) 314 (180–535)
Netherlands 16.7 8.1 (3.6–15.3) 2.4 (0.4–9.6) 13.9 (6.2–28.5) 135 (60–256) 40 (7–160) 232 (104–476)
Norway 4.7 6.3 (0.9–23.0) 2.8 (0.1–15.6) 27.7 (8.5–63.9) 30 (4–108) 13 (1–73) 130 (40–300)
Poland 38.5 7.2 (3.6–12.2) 0.40a (<0.1–2.0) 1.5 (0.2–6.9) 277 (139–470) 15a (1–77) 58 (8–266)
Spain 40.5 6.3 (3.6–9.9) 1.6 (0.4–4.0) 2.3 (0.8–5.4) 255 (146–401) 65 (16–162) 93 (32–219)
Sweden 9.1 23.0 (12.6–38.7) 4.4 (0.8–12.8) 13.9 (4.6–33.1) 209 (115–352) 40 (7–117) 127 (42–301)
Switzerland 7.6 9.9 (3.2–23.0) 10.4 (4.0–22.8) 27.0 (11.6–53.1) 75 (24–175) 79 (30–173) 205 (88–404)
UK 61.1 7.2 (5.0–10.4) 3.2 (1.6–5.2) 25.4 (18.5–30.0) 440 (306–635) 196 (98–318) 1552 (1130–1833)
All countries 308.05 5.9b (5.0–7.2) 3.2 (2.4–4.0) 9.2 (7.7–11.6)

Prevalence was calculated from the data in Table 3 by using the formula: incidence x mean disease duration, assuming this to be 45 years for AIP,
40 years for VP and 77 years for EPP (see text)
a
Acute attacks only
b
All countries including Sweden; if Sweden is excluded the prevalence is 5.4 (95 % CI: 4.5– 6.3)

in Table 5. Severe recurrent acute attacks were more was reported from France. For AIP, the incidence in Sweden
common in AIP and in women (P<0.001). Women with was 0.33 cases per year per million inhabitants (95 % CI: 0.15–
overt AIP were slightly more likely than men to develop 0.63) compared with 0.005 cases per year per million (95 %
this complication, although this difference was not sig- CI: 0.001–0.016 %) in the four other countries combined.
nificant (P00.08). Only three patients with VP and no
patients with HCP and recurrent acute attacks were
reported to the database. Discussion
Fourteen new cases of primary HCC were identified during
the study period in 11 patients with AIP and three with VP. Six Information about the incidence and prevalence of rare dis-
patients (43 %) had latent porphyria. All were aged 60 or more eases, such as the porphyrias, is important for planning
(ten females: median age 76, range 60–83 years; four males: health care and certain types of clinical research, in partic-
median age 83, range 78–91 years). All cases were from ular evaluation of new treatments. Determination of the
Sweden except for one each from the Netherlands (AIP), incidence of a disease across large populations in different
Switzerland (AIP) and the UK (VP). No new case of HCC countries requires precise definition of phenotype, accurate
information about the size of the population within each
Table 5 Recurrent acute attacks in AIP catchment area and identification of all patients within that
area during a fixed time period. Phenotype definition is an
Country Current patients with Percentage
recurrent attacks or of total cases important problem in the acute porphyrias because patients
post-liver transplant may be symptomatic, in remission or have never had symp-
Female Male toms. Previous retrospective estimates of prevalence have
not always distinguished adequately between these catego-
France 15 females; 3 males 5.8 3.7
ries (Anderson et al 2001; Orphanet Report Series 2010). In
Netherlands 1 female; 1 male 1.0 3.1
the cutaneous porphyrias, symptoms range from severe to
Sweden 3 female; 1 male 1.4 2.0
Switzerland 4 females 7.0 –
trivial; family investigations may identify mildly affected
UK 25 females; 3 males 7.5 2.8
relatives who would not have independently sought medical
All 5 countries 48 females; 8 males 5.3 (4.0–6.9) 2.8(1.4–5.4)
advice. Here we counted prospectively only newly diag-
nosed patients who presented to their doctors with either
Total cases are from Table 4, assuming 24 % patients are male (Table 2) an acute attack or skin lesions shown biochemically to be
Figures in parentheses are 95 % confidence intervals caused by an inherited porphyria.

The figures for incidence shown in Table 3 assume
that all new cases of clinically overt porphyria in the
residents of each country or geographical region during
the 3 year study period were reported to the database. It
seems unlikely that this was achieved uniformly. In the
smaller countries with established centralised systems
for the diagnosis of porphyria, ascertainment may have
approached 100 % but, in larger countries with one
national centre, more than one centre or a network of
collaborating centres, the level of ascertainment is less
certain. In general, it would be expected to be higher
for patients with acute attacks since these more often
require specialist management and diagnosis than for the
less severe cutaneous porphyrias that are more likely to
be managed locally. Double counting of patients and
inclusion of non-residents was minimised by the study
design. Our calculation of prevalence (Table 4) from
these incidence figures is also based on assumptions:
that the population is stable, that the incidence of dis-
ease is constant and that, given the lack of any pub-
lished figures, our estimates of mean disease durations
are reasonably accurate.
We found that the incidence of AIP is remarkably similar
in all European countries with the notable exception of
Sweden where the incidence is more than four-fold higher
than the overall incidence for all countries in the study
(Table 3). This high incidence is explained by a founder
effect centred on northern Sweden (Floderus et al 2002).
The prevalence of symptomatic AIP in Sweden has not been
reported but about 900 symptomatic and latent cases have
been identified by family studies giving a prevalence of 100
per million (Floderus et al 2002). We found a prevalence of
23 per million for symptomatic cases which equates to a
penetrance of 23 %, consistent with previous reports of 10–
20 % from the United States (Lamon et al 1979) and 17 %
for patients diagnosed since 1980 in Finland (von und zu
Fraunberg et al 2005) but lower than the 42 % of patients
with clinical manifestations in northern Sweden (Bylesjo et
al 2009). However, a survey of French blood donors found a
minimum population prevalence for the AIP genotype of
one in 1675 donors (Nordmann et al 1997), indicating that
the clinical penetrance of AIP mutations may be about ten-
fold lower than suggested by family studies.
The overall prevalence of 5.4 (95 % CI: 4.5 – 6.3) for
other countries (Table 4) is lower than previous estimates
which range from 10 to 20 per million (Moore et al 1987;
Mustajoki and Koskelo 1976; Schneider-Yin et al 2009; Puy
et al 2010) for clinically overt AIP and much lower than the
50 per million quoted for the United States and most other
countries (Anderson et al 2001) or the 101 per million given
as a consensus figure from the literature by Orphanet
(Orphanet Report Series 2010). However, these higher fig-
ures probably include all individuals with AIP including
J Inherit Metab Dis
those who have never had symptoms. It is not clear why
our prevalence figure is lower than anticipated from the
literature. Our figure is derived from a prospective study
of incidence whereas previous estimates have been retro-
spective and based on the experience of individual specialist
centres. Although our study may not have captured all cases,
the agreement between countries, in most of which diagnos-
tic tests for AIP were restricted to the centres participating in
our survey, suggests that ascertainment was uniformly high.
Derivation of prevalence from incidence assumes that the
ratio between the two is stable for many years. A 60 year
retrospective study in Finland showed that the number of
patients experiencing acute attacks declined with time be-
fore 1989 and this trend may have continued subsequently
(Kauppinen and Mustajoki 1992; von und zu Fraunberg et al
2005); similarly a decrease in acute attacks in VP since 1980
has been noted in South Africa (Hift et al 2004). Thus the
lower prevalence that we found may be consistent with a
decreasing incidence of new acute attacks over the past
decades, probably due to improved family screening and
preventive counselling.
Skin lesions were the dominant presenting symptom in
about 80 % of the patients with VP (Table 2). We did not
record the number of these patients who also had abdominal
pain. In comparison, about 60 % of patients from the UK,
France and South Africa had skin lesions alone with a
further 20 % having both cutaneous and abdominal symp-
toms (Eales et al 1980; Whatley et al 1999; von und zu
Fraunberg et al 2002; Puy et al 2010). In Finland, 84 % of
patients had skin lesions with acute abdominal symptoms in
about 10 % of these (von und zu Fraunberg et al 2002).
Overall, the incidence of VP was about half that of AIP, as
previously reported (Puy et al 2010), and four times greater
than HCP (incidence of AIP to VP to HCP: 1.00:0.62:0.15).
The calculated prevalence was 3.2 (95 % CI: 2.4–4.0)
symptomatic cases per million (Table 4), equivalent to a
total prevalence for symptomatic and latent patients of 8.0
(95 % CI: 6.0–10.0) per million, assuming a disease pene-
trance of 40 % (Hift et al 2004). These figures are in
reasonable agreement with the total prevalences of 13 and
4.3 per million reported for Finland and Switzerland respec-
tively (Mustajoki 1980; Schneider-Yin et al 2009), particu-
larly when the decline in overt cases in Finland since 1980 is
taken into account (von und zu Fraunberg et al 2002);
prevalence data for other European countries has not been
published. However, the significantly higher prevalence for
VP in Switzerland (Table 4) found in our study remains
unexplained; a recent study from that country reported a
prevalence of about 4 per million with symptomatic AIP
being about four times more common (Schneider-Yin et
al 2009).
The incidence and prevalence of the cutaneous porphyria,
EPP, varied between countries with the incidence ranging
J Inherit Metab Dis
from 0.03 to 0.36 per year per million (Table 3). The
prevalence of EPP in a population is strongly influenced
by the frequency of the hypomorphic FECH IVS3-48C
allele (Gouya et al 2006). Allele frequencies for European
countries vary from 11 % (France), 8 % (Sweden), 7 %
(Switzerland), 6.5 % (UK), 5 % (Spain) to 1 % (Italy)
(Wiman et al 2003; Elder et al 2009) and may explain some
of the observed variation in incidence (Table 3). In five
countries, the calculated prevalence (13.9–27.7 per million)
was at least twice that in the other countries (Table 4). In one
of these, the Netherlands, the prevalence that we found
agrees closely with a previous estimate derived from retro-
spective case finding (Went and Klasen 1984). However,
similar retrospective surveys in the UK, Switzerland and
Sweden identified far fewer cases than predicted from our
incidence data with prevalences ranging from 5.6 to7.8 per
million (Murphy et al 1985; Holme et al 2006; Schneider-
Yin et al 2009; Wahlin et al 2011). The most likely expla-
nation for this disparity is an increased rate of diagnosis in
recent years due to increased clinical awareness and the
wider availability of better diagnostic methods. In particular,
patients with mild unexplained photosensitivity are now
more likely to be screened for EPP; such mild cases may
be more frequent in the fair skinned people of northern
Europe. Since the calculation that we used to estimate
prevalence requires that incidence remains stable over the
mean duration of disease, such an increased incidence in
recent years will lead to an over-estimate of disease
prevalence.
In other countries, the incidence of EPP was lower. Our
data hint at a decrease in incidence from north to south in
Europe (Table 3), possibly due in part to changes in skin
pigmentation. Tanning is known to protect against photo-
sensitivity in EPP (Todd 1994) and greater melanin deposi-
tion may mask milder forms of the disease. In addition,
differences in prevalence may, at least for some countries,
reflect differences in the population frequency of deleterious
mutant FECH alleles; large extended families or founder
effects have been reported from Switzerland (Schneider-Yin
et al 2009) and the UK (Whatley et al 2010). Overall, our
findings suggest that the prevalence of EPP may be less
uniform throughout Europe than that of the acute hepatic
porphyrias.
We also investigated the incidence and prevalence in
five countries of two important complications of acute
porphyria. The clinical management of patients with
severe recurrent attacks, which affect less than 10 %
of AIP patients but may persist for many years (Puy et
al 2010), requires prolonged periods of out-patient and
in-patient care. Long term treatment often includes haem
arginate and/or other drugs and, in some patients, liver
transplantation (Dowman et al 2012). Our data confirm
that most patients with this complication are women, as
is the case for uncomplicated acute attacks (Tables 2
and 5). They also provide an evidence-based assessment
of the risk that a newly diagnosed patient with an acute
attack of AIP will have a 3–5 % risk of going on to
have repeated severe acute attacks (Table 5).
An association between hepatocellular carcinoma with-
out cirrhosis and acute hepatic porphyria was first recog-
nised in Scandinavia and subsequently reported from
other European countries (Lithner and Wetterberg 1984;
Kauppinen and Mustajoki 1988; Andersson et al 1996;
Andant et al 2000; Schneider-Yin et al 2009). An epidemi-
ological survey in northern Sweden found an annual inci-
dence of HCC of 0.8 % in AIP gene carriers aged over
54 years of whom 27 % had never had symptoms (Innala
and Andersson 2011). Our prospective survey in five
countries confirm that the incidence of primary HCC as a
complication of acute hepatic porphyria is higher in Sweden
than in other European countries; the incidence in Sweden
being at least eight-fold greater than in any of the other
countries that reported cases. Of the approximately 900
AIP gene carriers of all ages in Sweden (Floderus et al
2002), our data suggest that about 0.3 % will develop
HCC each year; a percentage that is in reasonable agreement
with the 0.8 % reported for gene carriers aged over 54 years.
No new cases of HCC were reported from France although a
previous prospective study identified seven cases among
650 French patients with acute hepatic porphyria fol-
lowed over 7 years (Andant et al 2000). The reason for
the higher rate of HCC in acute hepatic porphyria in
Sweden is uncertain (Deybach and Puy 2011); it is
possible that not all cases in other countries, developing
as they often do in elderly asymptomatic patients, are
reported to porphyria centres but it seems unlikely that
this accounts for more than a small part of the differ-
ence. Annual screening for HCC by ultrasound of
patients with acute hepatic porphyria who are aged over
49 years (Innala and Andersson 2011) or 46 years
(Schneider-Yin et al 2009) has been recommended.
The cost-effectiveness of any such programme outside
Sweden (Innala and Andersson 2011) has yet to be
established, particularly since previous data show that
the risk is not confined to those with overt disease.
Acknowledgements This work was co-funded by the European Com-
mission through its Public Health and Consumer Protection Directorate
(DG SANCO) PHEA programme. Thomas Røraas at the Norwegian
Quality Improvement of Primary Care Laboratories (NOKLUS), Bergen
Norway advised on the statistical analyses of the data.
Competing interest The project was co-funded by the European
Commission through its Public Health and Consumer Protection Di-
rectorate (DG SANCO) PHEA programme. The authors confirm inde-
pendence from the sponsors; the content of the article has not been
influenced by the sponsors.

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EPNET investigators: Jean-Charles Deybach1, Samantha Parker2, Herve
Puy3, Swati Sharma4, Sylvie Simonin5 (France); Sverre Sandberg6, Egil
Støle7, Jørild Villanger Haugen8 (Norway); Frederic Cotton9 (Belgium);
Pavel Martasek10 (Czech Republic); Elisabeth Minder11, Xiaoye
Schneider-Yin12 (Switzerland); Petro E. Petrides13, Ulrich Stolzel14
(Germany); Maria Kiss15 (Hungary); Raili Kauppinen16 (Finland);
Vivion Crowley17, Cindy Darby18 (Ireland); Gianfranco Biocalti19, Maria
Dominica Cappellini20,(Italy); Jorge Frank21, Felix De Rooij22, Paul
Wilson23 (Netherlands); Agnieszka Lipniacka24, Robert Wasilweski25
(Poland); Pauline Harper26, Ylva Floderus27, Christer Andersson28,
Eliane Sardh29, Staffan Wahlin30 (Sweden); Rafael Enriquez de
Salamanca31, Carmen Herrero32, Jordi To-Figueras33 (Spain); Michael
Badminton34, George Elder35, Julian H. Barth36, Joanne Marsden37,
David Rees38,Penny Stein39, Felicity Stewart40, Jacqueline Woolf41
(UK). 1,3,4,5Centre Francais des Porphyries, Hopital Louis Mourier,
92701 Colombes CEDEX; 2Orphan Europe, La Defense, Paris; 6,7,8Nor-
wegian Porphyria Centre (NAPOS), Haukeland University Hospital,
Bergen; 9Centre Belge des Porphyries, Hopital Universitaire Erasme,
Brussels; 10National Laboratory for Porphyric Disease, Charles II Uni-
versity Hospital, Praha 2; 11,12Porphyrie-Referenzlabor, Stadtspital
Triemli, Zurich; 13 Hematology Oncology Center and Ludwig-
Maximilians-University, Munich; 14Porphyria Center Saxony, Medizini-
zinische Klinik II, Klinikum Chemnitz gGmbH, Chemnitz-Dresden.
15
Porphyrin Laboratory, Department of Dermatology and Allergology,
University of Szeged, Szeged; 16Porphyria Research Centre in Finland,
University Central Hospital of Helsinki; Helsinki. 17,18Irish Porphyria
Specialist Centre, St James Hospital, Dublin; 19Struttura Semplice
Dipartimentale Centro per le Porfirie e Malattie Metaboliche Ereditarie,
Istituto San Gallicano, IRCCS, 00144 Rome; 20Fondazione IRCCS Ca
Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano,
Milano; 21Department of Dermatology Euroregional Porphyria Centre,
Maastricht University Medical Centre, Maastricht; 22,23Porphyria Center
Rotterdam, Erasmus Medical Centre, Rotterdam; 24Laboratory of Por-
phyria and 25Department of Disorders of Hemostasis and Internal Med-
icine, Institute of Hematology and Transfusion Medicine, Warsaw;
26,27,29,30
Porphyria Centre Sweden, Karolinska University, Stockholm;
28
Department of Family Medicine, University of Umea, Umea; 31Por-
phyria Unit, Hospital Universtario 12 de Octubre, Madrid; 32,33Porphyria
Unit, Hospital Clinic, University of Barcelona, Barcelona; 34,35,41Depart-
ment of Medical Biochemistry and Immunology, University Hospital of
Wales, Cardiff CF14 4XW; 36Blood Sciences, Leeds General Infirmary,
Leeds LS1 3EX; 37Department of Clinical Biochemistry and 38Depart-
ment of Haematology, Kings College Hospital, London SE5 9RS; 39De-
partment of Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ;
40
Department of Clinical Biochemistry, Salford Royal NHS Foundation
Trust, Salford M6 8HD.