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The Patient - Patient-Centered Outcomes Research

The Patient - Patient-Centered Outcomes Research
Patient Perspective on Acute Intermittent Porphyria with Frequent
Attacks: A Disease with Intermittent and Chronic Manifestations
Amy Simon1 · Farrah Pompilus2 · William Querbes1 · Alex Wei1 · Sara Strzok2 · Craig Penz1 · Desiree Lyon Howe3 ·
Jessica R. Hungate3 · Jae B. Kim1 · Sonalee Agarwal1 · Patrick Marquis2
© The Author(s) 2018
Objective Acute intermittent porphyria is a rare metabolic disorder that affects heme synthesis. Patients with acute intermittent
porphyria may experience acute debilitating neurovisceral attacks that require frequent hospitalizations and negatively
impact quality of life. Although clinical aspects of acute intermittent porphyria attacks have been documented, the experience
of patients is not well known, particularly for those more severely affected patients who experience frequent attacks.
The aim of the present study was to qualitatively characterize the experience of patients with acute intermittent porphyria
who have frequent attacks, as well as the impact of the disease on daily living.
Methods Patients with acute intermittent porphyria who experience frequent attacks were recruited and took part in 2-h
qualitative one-on-one interviews with a semi-structured guide. Interviews were anonymized, transcribed, and coded. The
inductive coding approach targeted textual data related to acute intermittent porphyria attack symptoms, chronic symptoms,
and the impact of the disease. Saturation analysis was conducted to assess whether the research elicited an adequate account
of patients’ experiences.
Results In total, 19 patients with acute intermittent porphyria were interviewed (mean age 40 years; 79% female). Eighteen
patients (95%) experienced both attack and chronic symptoms. Patients described attacks as the onset of unmanageable
symptoms that generally lasted 3–5 days requiring hospitalization and/or treatment. Pain, nausea, and vomiting were considered
key attack symptoms; pain, nausea, fatigue, and aspects of neuropathy (e.g., tingling and numbness) were considered
key chronic symptoms.
Conclusions In this study population of acute intermittent porphyria with frequent attacks, most patients had symptoms
during and between attacks. In these patients, acute intermittent porphyria appears to have acute exacerbations as well as
chronic day-to-day manifestations, and is not just intermittent as its name implies. As a result, patients reported limitations
in their ability to function across multiple domains of their lives on a regular basis and not just during acute attacks.
Electronic supplementary material The online version of this
article (https :// 1-018-0319-3) contains
supplementary material, which is available to authorized users.
* Amy Simon
1 Alnylam Pharmaceuticals, 300 Third Street, Cambridge,
MA 02142, USA
2 Modus Outcomes, Newton, MA, USA
3 American Porphyria Foundation, Houston, TX, USA
A. Simon et al.
Key Points
Acute intermittent porphyria (AIP) is a rare, often mis/
underdiagnosed, inherited metabolic disease characterized
by acute potentially life-threatening attacks and in
some patients, chronic debilitating multi-systemic symptoms
and manifestations that negatively impact patients’
daily functioning and quality of life.
This qualitative research study undertook one-to-one
interviews with 19 patients with AIP to characterize their
symptoms and the impact of the disease burden on their
daily lives.
Patients with AIP having frequent attacks may have both
attack and chronic disease symptoms, suggesting in some
patients, AIP is not just an ‘intermittent’ disease but also
has chronic symptoms, many of which are disabling.
1 Introduction
Acute hepatic porphyrias (AHPs) are a family of rare metabolic
disorders each caused by a deficiency in one of four
enzymes responsible for heme synthesis in the liver. Patients
may experience acute debilitating neurovisceral attacks that
require frequent hospitalizations and negatively impact quality
of life [1–3]. The four AHPs are acute intermittent porphyria
(AIP), δ-aminolevulinic acid dehydratase deficiency
porphyria, hereditary coproporphyria, and variegate porphyria
[1, 2]. Factors such as cytochrome P450-inducing
drugs, dieting, or hormonal changes can induce aminolevulinate
synthase 1, the first and rate-limiting enzyme in the
heme pathway. This can result in accumulation of the neurotoxic
intermediates δ-aminolevulinic acid and porphobilinogen
upstream of the enzyme deficiencies. Patients present
with signs and symptoms that are secondary to widespread
dysfunction across the central, peripheral, and autonomic
nervous system [3, 4].
AIP, the most common type of AHP (~ 80% of cases),
results from a deficiency in hydroxymethylbilane synthase
(porphobilinogen deaminase), the third enzyme in the heme
biosynthetic pathway [Fig. 1 of the electronic supplementary
material (ESM)] [1]. Patients with AIP experiencing attacks
present with highly morbid and potentially life-threatening
symptoms [1–3]. The most commonly reported debilitating
symptoms are diffuse severe pain affecting the abdomen,
back, or limbs; other common attack signs and symptoms
include nausea and vomiting, constipation, hypertension,
motor weakness, insomnia, or anxiety [1–3, 5]. Porphyria
attacks typically last 5–7 days [6], although more severe or
prolonged attacks can occur, potentially causing paralysis,
respiratory failure, and death [7, 8]. AIP attacks can also
lead to frequent hospitalizations [2], long-term use of opioids
[2, 9], and high rates of unemployment [10].
Emerging clinical data indicate that some patients with
AHP have chronic disease manifestations outside of the
attack setting. Natural history studies conducted both in
Sweden and the USA [with manifest AIP in 91 (55%) and
77 (85%) patients, respectively] determined that approximately
20% of patients experienced chronic symptoms [5,
11]. However, a recent multinational natural history study
in an AHP population experiencing recurrent attacks, found
64% of patients experienced symptoms between attacks [12].
Currently, there are no approved pharmacotherapies for
the prevention of attacks or treatment of chronic AIP symptoms.
Treatment is focused on managing attacks, which typically
require urgent medical attention in a healthcare setting,
pain management, and intravenous hemin for attacks. In some
patients, hemin is used off label to prevent recurring attacks;
however, clinical evidence about the efficacy and safety of
chronic prophylactic hemin use is insufficient [2, 13].
Although the clinical aspects of AIP attacks have been
described in the literature [1–3, 5] and some studies have
explored the impact of AIP using quality-of-life tools and
other standard measures [10, 14–16], little qualitative work
has been conducted directly with patients to understand the
overall picture of the disease burden from their perspective.
The aim of the present study was to qualitatively characterize
the experience of patients with AIP who have frequent
attacks, as well as the impact of the disease on daily living.
2 Methods
2.1 Study Design and Procedures
This was a qualitative research study in patients with AIP
using a one-to-one interviewing approach via telephone
with a semi-structured guide (Fig. 2 of the ESM). Concept
elicitation interviews [17] were conducted to obtain information
about the symptoms, impact, treatment experience, and
preferences of patients with AIP. This manuscript reports
patient symptom experience and impact. The research plan
was developed with consideration of the recommendations
and best scientific practices set forth in the US Food and
Drug Administration Patient-Reported Outcome Guidance
[18], the Roadmap to Patient-Focused Outcome Measurement
in Clinical Trials [19], and best practices in qualitative
research [20, 21]. The study was reviewed and approved by
Quorum Review, an independent review board (Institutional
Review Board Tracking No. 31332/1). The study methodology
is summarized in Fig. 3 of the ESM.
Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks
2.2 Study Patients
Eligible patients were aged ≥ 18 years from the USA with
a diagnosis of AIP that was made and/or confirmed by a
porphyria specialist (this was reported by the patient; the
study team did not have access to medical records), and were
recruited in collaboration with the American Porphyria Foundation
(APF) patient advocacy group. Recruiters from the
APF identified and contacted potentially eligible patients
listed in the APF database to participate in the study. Purposive
sampling was implemented to select patients. If patients
were willing to take part, and met the eligibility criteria, they
were contacted by the interviewer (initially via e-mail) to
answer any queries and for patients to provide informed consent.
Patients were then contacted via the phone to discuss
the study and schedule the interview. Patients were informed
that researchers were interested in learning more about the
experience of living with AIP. Patients were eligible if they:
(1) had three or more porphyria attacks (defined as an acute
episode of severe abdominal, back, and/or limb pain that may
also have had associated symptoms such as nausea, vomiting,
poor appetite, palpitations, and problems with mood or
sleep) over the past 12 months, with at least one of the porphyria
attacks requiring hemin treatment, and/or (2) were
currently receiving hemin treatment on a scheduled basis for
prevention of porphyria attacks. At least five patients currently
receiving hemin treatment on a scheduled basis for
prevention of porphyria attacks were targeted in the sample.
Patients were excluded if they had any cognitive impairment
that would prevent them from understanding and answering
questions or if they did not speak English.
A total of 19 patients participated in the study, with an
average age of 49 years and 79% were female (Table 1). The
reported time to AIP diagnosis ranged from < 1 month to
23 years, and within the last 12 months, patients reported
experiencing 0–20 attacks [mean 9.5 (standard deviation)
2.3 Data Collection
Concepts representative of the patients’ experience were
elicited during interviews conducted by trained interviewers
experienced in patient-centered qualitative research. Interviews
were conducted by Farrah Pompilus (research scientist),
Sara Strzok (research manager), and JoAnne Liebeler
(freelance interviewer). All interviewers were female and
have completed National Institutes of Health Protecting
Human Research Participants training. All interviewers
were trained using a qualitative study playbook developed
by Modus Outcomes (the company for which they worked),
which provided a “how to” guide for qualitative research
design, execution, analysis, and reporting to facilitate harmonization
of processes across researchers. Before the
interviews, all interviewers conferred to discuss the interviews,
identify any potential issues with the interview guide,
and ensure consistent interviewing practices. After a small
Table 1 Patient demographics and clinical information
Data are n (%) unless otherwise stated
GED general educational development, SD standard deviation
Characteristic Patients (n = 19)
Age, (years)
Mean (SD) 40 (11)
Range 24–61
Female 15 (79)
Male 4 (21)
Employment status
Not employed 12 (63)
Full-time employment 4 (21)
Part-time employment 3 (16)
Education level
Post-graduate degree 5 (26)
Degree 4 (21)
Some college education 3 (16)
Trade program/certification 3 (16)
High school/GED equivalent 3 (16)
Some high school education 1 (5)
< US$60,000 8 (42)
$US60,000–$100,000 7 (37)
> US$100,000 2 (11)
Not specified 2 (11)
Marital status
Married 11 (58)
Single 4 (21)
Divorced/separated 4 (21)
Time since symptom onset, (years)
< 3 2 (11)
3–10 8 (42)
> 10 9 (47)
Time since porphyria diagnosis, (years)
< 3 5 (26)
3–10 10 (53)
> 10 4 (21)
Taking hemin prophylactically
Yes 11 (58)
No 8 (42)
Reporting chronic symptoms between attacks
Yes 18 (95)
No 1 (5)
Taking pain medication between attacks
Yes 12 (63)
No 7 (37)
A. Simon et al.
set of interviews, the interviewers re-conferred to identify
any discrepancies between them and notes were added to the
interview guide to ensure alignment across the interviewers.
Interviewers employed an open-ended line of questioning,
limiting the potential for bias; however, questions reflected
the specific research goals identified by the researchers prior
to the interviews. Interviews were targeted to last approximately
2 h and repeated interviews were carried out. Field
notes were made during the interviews on printed copies of
the interview guide to help facilitate follow-up probes and
document any non-verbal cues (e.g., changes in tone, sighs,
and laughter). Interviews were audio-recorded, anonymized,
and transcribed. Transcripts were not shared with participants
and they did not provide feedback on the findings. The
sample size for the concept elicitation interviews was based
on the principle of saturation [22]. It was estimated that 20
patients would be necessary to reach saturation. Patients
were compensated for participating in the interviews.
2.4 Data Analysis
Interviews were coded qualitatively by three data coders
[Farrah Pompilus, Sara Strzok, and Caitlyn Gardner (junior
research scientist)] using inductive coding [20] (ATLAS.ti
software, Version 7). Coding was then reviewed by two different
researchers and coding meetings were held to avoid
bias and ensure consistency. Codes were developed by categorizing
data clusters, creating a name for the concepts,
and defining key concepts with clearly delineated boundaries
and attributes. All concepts were created during analysis and
pre-identified themes (attack symptoms, chronic symptoms,
and impact of AIP) were used to help organize the concepts.
Saturation analysis was conducted as follows: the transcripts
were ordered chronologically based on the interview completion
dates and grouped into quintiles. Codes used to characterize
the raw data in the second quintile were compared
with the codes used for the first quintile. This comparison
was repeated for each additional quintile. Saturation was
considered achieved when the cycle of data collection and
analysis produced minimal or no new information, i.e., no
new codes were necessary to describe the raw data [23].
3 Results
All recruited patients participated in the interviews. Saturation
was achieved in terms of impact and attack symptoms,
with the final quintile of interviews generating limited additional
information. However, subsequent chronic symptomfocused
re-analysis of the data indicated that saturation was
achieved for chronic pain but not achieved in terms of nonpain
chronic symptoms.
3.1 Overall Experience of Acute Intermittent
When asked what it is like to have porphyria, patients
reported a high burden of disease, experiences of both attack
and chronic symptoms, and that AIP impacted a number of
different areas of their lives. In total, patients reported 78
unique symptoms attributable to AIP attacks, 35 of which
were also experienced chronically. Pain was usually the first
symptom cited by patients when they were asked to define
porphyria or to describe their symptom experience. Attack
or chronic pain (not mutually exclusive) was reported as the
most bothersome symptom by 13 patients (68%).
“I’ll feel like hot knives stabbing me.”
Nausea was reported as the next most bothersome by
eight patients (42%).
“My nausea is uncontrollable. And I—my body just
doesn’t feel right anymore.”
Other bothersome symptoms reported by two or more
patients included abdominal pain specifically [n = 6 (32%)],
memory loss [n = 4 (21%)], vomiting [n = 3 (16%)], constipation
[n = 2 (11%)], and fatigue [n = 2 (11%)].
3.2 Attack Experience
Attacks were described as extreme incapacitating episodes
characterized by progressive and uncontrollable symptoms
with widespread dysfunction that preclude usual daily activities
(Fig. 1a). Descriptions included:
“Completely unbearable.”
“Something that is beyond my control.”
“I’ll know from experience I need to be hospitalized.”
Attacks generally lasted 3–5 days, required treatment or
hospitalization, and had a long recovery period.
“It will take me a couple of days just to lay in bed and
sleep trying to recover.”
3.3 Attack Symptoms
The most common attack symptom, reported by all participants,
was pain. Patients described attack pain as:
“Stabbing, knife-like”
“Burning, like a fire”
Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks
“I’m more than in tears, like I am literally like crying,
crying, because the pain is just, it’s so bad, it’s like a
stabbing, it’s a burning, it’s a pulling and a twisting,
it’s everything you could imagine, it’s the absolute
worst pain in the world.”
When asked to describe attack pain severity, patients
characterized it as the worst imaginable level of pain, pain
worse than the pain of childbirth or broken bones, or pain
that is incompatible with life.
“Some days I just feel like I hurt so bad that it’s like
I actually will think out loud, like how is porphyria
compatible with life, you know? When you get to that
point where you’re in that much pain, it’s not compatible
with life. You can’t live like that.”
“I’ll lose feelings in my hands and my stomach
will be – it feels like someone’s kicking me in
the stomach. It’s very, very sore and very tender.
And then my liver area will start burning really
badly. I can’t eat because anything that I eat will
come back up. And, I’m dizzy at times and
disoriented and the biggest thing is that it robs
me of my quality of life.” (Patient No. 01)
“… and then the worst days is like being
disemboweled, having a hot pan shoved into
your intestines or into your abdomen while
having your ribs filleted.” (Patient No. 03)
“I had seizures after seizures … about three of
them within about four hours.” (Patient No. 08)
“I had like paralysis also in my legs, and I
couldn’t walk. I mean like I was dragging a leg.
And also I had difficulty breathing. I almost got
put on the ventilator.” (Patient No. 16)
“I describe mine as having the worst flu you
ever had in your life, that whole body ache and
everything else that goes along with it and
multiply that by about a hundred times.”
(Patient No. 02)
“When it’s chronic, it’s something I’m constantly having to manage… there will be pains where I feel
like I’m getting stung by a swarm of bees or something like that. But it doesn’t get to the point where
I’m having to go to the emergency room and vomiting.” (Pain – Patient No. 18)
“You know, I don't really get a whole lot of relief in between attacks. I still experience severe, severe
nausea, especially in the morning when I first wake up.” (Nausea – Patient No. 20)
“It definitely affects me. I get tired very easily and have to take one, two naps a day.”
(Fatigue – Patient No. 04)
“On a pain scale from zero to 10 where you know zero is no pain and 10 is the worst, um, a typical
day you know the headaches are probably around a four to a five.”
(Headaches – Patient No. 03)
“I haven’t been able to – off and on I haven’t been able to feel my hands since November of 2011.
Um, I, I have less or more numbness in my fingers and tingling in my fingers and hand.”
(Neuropathy – Patient No. 07)
Fig. 1 Patients’ descriptions of their: a porphyria attacks and b chronic symptoms
A. Simon et al.
Patients explained that attack pain was “incapacitating,”
rendering them unable to function in their work, social, or
family roles, or to perform basic daily activities.
“I’ll be in so much pain that I won’t be able to move.”
Patients also explained that they knew they were experiencing
an attack when they could no longer control pain at
home and needed to seek help at a hospital or clinic, while
others stated that attack pain is so severe that it cannot be
controlled with pain medication.
“Just so uncontrollable, even with all my medications.”
Attack pain persisted until patients were successfully
treated with medication, or until the end of the attack. Attack
pain occurred in a variety of body locations, abdominal pain
being the most frequent.
“It’s this spearing abdominal pain, like almost like
someone is taking a hot butcher knife and tearing it
through your stomach.”
Other locations included the entire body, stomach, back
and spine, ribs, shoulders, arms, hands, legs, knees, feet,
joints, and head. Further patient experiences describing
attack pain are presented in Table 2.
The second most common attack symptom was nausea,
reported by 16 patients (84%).
“The nausea is what just knocks me out. I mean it
just—literally, I cannot do anything. I get up in the
morning and if the nausea is that bad, I’ll start eating
some toast, trying to at least eat something, because I
can’t go without eating because that makes me sicker.”
The next most common attack symptom was vomiting,
reported by 15 patients (79%).
“You’re like throwing up to the point where like you
want to die, and you’re spitting up bile, and even
though your stomach is completely empty and you’re
like, ‘where is this coming from? I haven’t eaten in
hours. I’ve been throwing up for half a day’. I’m vomiting
foam at that point.”
Another common attack symptom was headache, reported
by ten patients (53%).
“… headaches so bad that they’ve caused me to lose
my sight on numerous occasions.”
The Table in the ESM lists other common attack symptoms
reported by seven or more patients, along with descriptions
and patient experiences. The symptoms experienced
during an attack were described as extending beyond the
period of the attack, leaving residual chronic symptoms and
included two patients whose attack resulted in a coma.
3.4 Chronic Experience
Patients described the chronic experience of AIP as:
“Something I’m constantly having to manage.”
“Almost daily.”
“I don’t get a whole lot of relief in between attacks.”
Eighteen patients (95%) experienced chronic symptoms
(defined as symptoms attributed to AIP experienced between
attacks) with the remaining patient only experiencing symptoms
during attacks. All the symptoms reported chronically
were also reported during an attack, although chronic symptoms
were described as less severe. The chronic symptom
frequency ranged from occasional experiences with pain,
fatigue, or nausea, to daily experiences of a wide range of
symptoms (Fig. 1b). Patients also highlighted that the disease
is not ‘intermittent’ as the name implies.
“My condition seems to be more chronic than it is
“There’s not a week that goes by that I don’t have
[chronic symptoms].”
3.5 Chronic Symptoms
Chronic pain experienced between attacks was often characterized
as sore, dull, aching, throbbing, and/or burning
(Table 2) and was the most frequently reported chronic
symptom, experienced by 17 patients (78%). Chronic pain
was rarely described in the more extreme terms used to characterize
attack pain and was not considered as severe.
“When I’m not having an attack I will experience some
pain, like some joint pain in my knees and also the
neuropathy in my hands. Those are my symptoms that
don’t go away.”
However, some patients characterized more severe peak
episodes of pain outside of an attack as sharp or stabbing.
“… pain level is probably like at a six out of 10, um,
on a daily basis … I would say it feels like you—like
I said, you have like little people in there with barbed
wires, just like fighting.”
Many rated living with pain in the range of 2–6 out of 10
as a “good day” or “typical day” with porphyria, noting that
their perception of pain is different from those who have
never dealt with the degree of pain experienced by those
with AIP.
“I have pain disassociation so that my level of pain is
at a five all the time, which is probably someone else,
a normal person’s 10, because I’m so used to the pain.”
Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks
Table 2 Patients’ descriptions of attack pain and chronic pain
ER emergency room, IV intravenous
Description Severity Duration Location
Attack pain “It’s a real hot feeling like it feels like
there’s hot coals packed in there. And it
feels like someone’s like poking in more
of them, and there’s all this pressure,
you know, like stretching and burning …
And then that like carries on. And then
whenever, oh, and then sometimes also
I’ll feel like hot knives stabbing me.”
(Patient No. 16)
“What would you do if you had what felt
like a rock on fire inside of your abdomen?
Like I mean other than obviously,
you know, you would like, you would
like curl up in the fetal position and cry.”
(Patient No. 06)
“… but the pain I would say right now the
pain is probably well over a 10.” (Patient
No. 12)
“And then the pain just being able to—or
not being able to get out of bed, that sort
of thing, when it gets to that level of
severity.” (Patient No. 15)
“… if I move into a more intensified
attack that’s when the pain is completely
unbearable and I go to the ER and get
morphine through my port and—but it’s
just a Band-Aid. You know, that pain is
just going to relieve it for a few hours.”
(Patient No. 01)
“… the pain is so intense that I can be
taking pain medicine all day long and the
strongest stuff I have and nothing helps.”
(Patient No. 10)
“Usually [the abdominal pain lasts] until
I’m able to get to the hospital and get on
IV pain medicine.” (Patient No. 15)
“So mostly burning in my abdomen, nausea,
then the burning in my abdomen kind of
radiates to my back, like on either side of
my spine, and then I have like shooting,
stabbing, burning pain in my lower
back and down my legs, especially in my
glutes.” (Patient No. 20)
“Attack symptoms are more the horrible
abdominal pain. When I was younger, it
would just be localized to my abdomen.
Now, it will be my back, my legs, my
arms, my abdomen. It’s kind of an all-over
pain.” (Patient No. 17)
Chronic pain “I actually did have to take pain medicine
today because I feel my stomach has a
dull, throbbing feeling.” (Patient No. 10)
“I have like a neuropathy type feeling in
the bottoms of my feet. Um, they go
numb and burn a lot. They hurt.” (Patient
No. 01)
“Mostly it would be like fatigue and, and
backaches. Very noticeable in the morning
when I first wake up. I’m just really
sore.” (Patient No. 09)
“A normal day I feel decent. My pain from
one to 10 on an attack is a 10. But my
pain on a normal day is about a two, a
three.” (Patient No. 08)
“I have pain disassociation so that my
level of pain is at a five all the time,
which is probably someone else—a
normal person’s 10, because I’m so used
to the pain.” (Patient No. 04)
“I’m 38 years old and, you know, putting
in an eight-hour day is something that’s
just not possible for me.” (Patient No.
“Almost every day with the exception of
me being a couple days a month. I would
say about five, four to five days I’m in
pain.” (Patient No. 10)
“I would say 80% of the time I’m symptomatic.”
(Patient No. 18)
“I guess then, throughout the day because
it’s not like my hands are like painful
all day. It just comes and goes.” (Patient
No. 15)
“I have pain all of the time if I don’t
take pain medicine for it. And then it’s
completely controlled with the pain
medicine.” (Patient No. 17)
“Kind of a, a dull burning in the liver area
as well as in the digestive area, colon such
as that.” (Patient No. 01)
“And then I get the pain that radiates
down to my—down my extremities, my
legs and my arms, but it’s not that same
type of pain. Um, it’s really a radiating
pain where you, it’s like tentacles going
down, it feels like, and spreading and so.”
(Patient No. 04)
“I’d have it, you know, in my back, my
arms, my legs.” (Patient Patient No. 17)
A. Simon et al.
Patients reported that chronic pain ranged from manageable
with little impact, to having a significant impact on
day-to-day activities.
“I don’t really sleep well at night at all from the porphyria
because, um, my back hurts and, uh, my feet
hurt and my legs, they hurt a lot.”
Twelve patients (63%) reported taking pain medications
between attacks. Patients who experienced pain outside of
their attacks reported variable frequency and duration of
this pain. Some reported that pain was “constant” unless
alleviated by medication, while others described pain as a
sensation that comes and goes. Chronic pain was reported
in a variety of body locations including the entire body, the
abdomen, stomach, back (particularly lower back), buttocks,
ribs, shoulders, arms, hands, legs, knees, feet, joints, and
head. Patients also reported non-specific nerve and bone
pain that they associated with AIP.
The second most common chronic symptom, reported by
nine patients (47%), was neuropathy. The term was spontaneously
generated by patients, and includes tingling, numbness,
or loss of sensation.
“Nerve pain and nerve sensations because when you
get numbness sometimes there’s nerves that are kind
of alive and other parts that are dead. And it feels like
something is crawling on you. And it’s like a bug is on
your arm or something touches you on the middle of
the night. It wakes you up. I get woken up a lot because
of nerve sensation.”
The next most common chronic symptom was nausea,
reported by seven patients (37%).
“I was nauseated every day and it was like a six to a
seven on the scale.”
Other commonly reported chronic symptoms included
insomnia by six patients (32%).
“There is a days [sic] I somehow I cannot sleep at all,
no matter how, no matter how I am tired.”
Five patients (26%) reported fatigue.
“… it’s so frustrating. You know, you shouldn’t be that
tired. You know, you should be able to live a normal
3.6 Impact of Acute Intermittent Porphyria
on Patients’ Lives
Patients reported AIP as having an impact on a number of
different areas of their lives (Table 3). The most frequently
reported impact was on sleep [n = 18 (95%)], ability to work
[n = 16 (84%)], finances [n = 14 (74%); medical costs or
inability to work], difficulty walking [n = 14 (74%)], and
decreased socialization [n = 12 (63%)]. Patients frequently
reported an impact on sleep from both chronic and attack
“I don’t really sleep well at night at all from the porphyria
because my back hurts and my feet hurt and my
legs, they hurt a lot.”
Table 3 Patients’ descriptions of the impact of acute intermittent porphyria
Topic Exemplar quotes
Sleep “I don’t really sleep well at night at all from the porphyria because my back hurts and my feet hurt and my legs, they hurt a lot. I
don’t know if it’s like restless leg syndrome, but it’s like I keep moving type of thing … I’ll jerk and it wakes me up when I do
sleep, so I have a lot of problems with sleeping. And so when I wake up in the morning I’m always fatigued.” (Patient No. 01)
Social “I think the unpredictability [of] porphyria is frustrating. It’s difficult to make plans far out because of porphyria. I’ve missed
friends’ weddings. I’ve had to cancel trips. Even appointments that day—I think one of the biggest ways that porphyria impacts
your life is that it’s completely unpredictable. There’s no way I could be a reliable employee to somebody because I could not
guarantee that I will be there tomorrow for work.” (Patient No. 06)
Financial “Well of course not being able to work has impacted our finances quite a bit and then the hospital bills have also been impacting
our finances a lot.” (Patient No. 02)
Nutritional “My diet has changed by 80, 90% because I can’t [eat] anything anymore.” (Patient No. 08)
“It hurts to eat … I don’t eat a meal or anything … it’s too painful. So I mostly just kind of eat small things during the day, and I
drink a continuum of sugary liquids all day … I just won’t eat that much substance at all, because it’s too painful to eat … It’s
the digesting later that hurts.” (Patient No. 16)
Lifestyle “So, things that I would want to do—travel, go places—if I get sick and I’m somewhere where they don’t know what—I mean,
very few doctors understand what porphyria is or even how to treat it … That’s a huge concern. So we don’t travel much. It’s,
you know, it limits your life.” (Patient No. 17)
Psychologic “I have to take all these stupid medications, and there’s so much stigma in society about prescription pain meds and stuff nowadays.
So now it’s like this complete shaming process that I’m experiencing, even though I’m in no way addicted to anything.
I’d throw it all away if all this would go away, but I have to now feel like I’m some kind of horrible person because I have pain
and need pain medication. So I get to be shamed every time I go to the pharmacy to get my medicine.” (Patient No. 16)
Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks
The unpredictable nature of attacks and symptoms was
also noted; patients reported never knowing how they
will feel from day to day or when an incapacitating attack
will occur, which impedes attendance at work and social
“It’s completely unpredictable. There’s no way I could
be a reliable employee to somebody because I could
not guarantee that I will be there tomorrow for work.”
Patients highlighted the medical costs of the disease.
“As a matter of fact, I have to make a phone call to
my secondary insurance provider finding out why they
dropped me because I just received a $650,000 bill.”
The wide-ranging psychological impacts included challenging
diagnostic journeys, lack of knowledge of the disease,
not being believed by healthcare professionals, and
being labeled as drug seeking.
“Very few doctors understand what porphyria is or
even how to treat it.”
“I have to take all these stupid medications, and there’s
so much stigma in society about prescription pain
4 Discussion
This qualitative study adds to the understanding of the
patient experience of living with AIP that is characterized
by frequent attacks, describing the wide array of
patient-reported symptoms and the impact of the disease
on patients’ ability to function. Pain was usually the first
symptom cited by patients with AIP when asked to define
porphyria or describe their experience of the disease. It was
the most common and distressing symptom experienced by
patients, both during attacks and chronically. Attacks were
described as extreme events characterized by progressive
and uncontrollable symptoms that preclude usual daily
activities. Other attack symptoms included nausea, vomiting,
headache, memory loss, constipation, weakness, paralysis,
and numbness. Attacks generally lasted 3–5 days, but
the recovery period was long and attack symptoms were
described as extending into residual chronic symptoms.
All but one patient reported chronic symptoms, describing
AIP as something they are constantly having to manage,
with some experiencing daily or almost daily symptoms.
Pain was the most common symptom, experienced by 17
patients (89%), although it was rarely described in the more
extreme terms used to characterize attack pain. This qualitative
research indicates that in this group of patients with
AIP who experience frequent attacks, most also face chronic
disease manifestations and that the disease may not be ‘intermittent’
in character as its name suggests.
The findings regarding chronic symptoms are consistent
with those reported in the EXPLORE natural history study
(NCT02240784), where 65% of 112 patients with AHP
with recurrent attacks (104 with AIP) reported experiencing
chronic symptoms [12], with 46% of patients having these
symptoms on a daily basis (most commonly pain, nausea,
tiredness, and anxiety) [12]. In addition, a high burden of
disease and acute and chronic disease manifestations were
reported by patients with AHP and their care givers at a
patient-focused drug development meeting that was recently
held by the APF and the US Food and Drug Administration
[24]. Lower rates (20 and 18%) of chronic symptoms were
observed in two larger studies (n = 356 and n = 108) of
patients with AHP; however, these studies included patients
with less frequent attacks and patients with no manifest
symptoms of AIP [5, 24, 25].
In assessing the impact of AIP on patients’ lives, aspects
such as symptoms, unpredictability of knowing when the
next attack would come, and treatment factors were shown to
affect work/education, social relationships and roles, leisure
and exercise, diet and nutrition, healthcare and treatment,
free time, ability to travel, and emotional state. Consistent
with findings in an earlier study [9], patients reported that
they were unable to engage in employment at all or as fully
as they would like, with 63% being unemployed. This, along
with healthcare costs, influenced patients’ finances. Overall,
these data support earlier studies that found the disease had
a significant impact on patients’ quality of life [10, 15, 16].
This study has some limitations, including that biochemical
data were not used to confirm porphyria attacks and
that clinical diagnosis, although made by a porphyria specialist,
was self-reported. Some selection bias is inherent
in recruiting patients through a patient organization such
as APF as patients may be more likely to join if they have
worse disease; however, the aim of the study was to obtain a
breadth of patients’ views rather than to assess the frequency
of these symptoms. As all symptoms were self-reported, it
is not possible to conclude that they were the result of AIP,
particularly non-pain and chronic symptoms. Research suggests
patients find attribution of the causes of symptoms
difficult and can be inconsistent in their reporting [26]. The
design of the study therefore means such conclusions are not
possible; however, patients clearly had non-pain and chronic
experiences and they felt these were attributable to AIP and
were consistent with the understanding of AIP symptoms.
Furthermore, the etiology of chronic symptoms in this
sample and in patients with AIP is not entirely clear. It is
not well understood whether symptoms such as chronic
pain or fatigue are caused by irreversible nerve damage
or by ongoing nerve injury from the increased levels of
porphyrin precursors (i.e., δ-aminolevulinic acid and
A. Simon et al.
porphobilinogen). Additionally, non-pain chronic symptom
concepts were continuing to emerge in the final quintile
of interviews, which was not the case for attack symptoms.
While the concept of saturation and at what point
it is possible to conclude that no new insights will occur
are sources of debate among researchers [27], we cannot
conclude that saturation of non-pain chronic symptom
concepts was achieved. Taken together, these data suggest
that we are only beginning to understand the range of
chronic and non-specific symptoms that some people with
severe AIP experience, in addition to disabling attacks,
and the frequency of their occurrence across a range of
disease severities. Further research is warranted to better
understand the full range of disease manifestations that
patients with severe AIP experience.
5 Conclusion
The aim of the present study was to qualitatively characterize
the experience of patients with AIP who experience
frequent attacks, as well as the impact of the disease on daily
living. The findings indicate that in the study population,
the disease is not just ‘intermittent’ as its name implies, but
has chronic manifestations that impact on patients’ lives and
their ability to function. A wide variety of attack and chronic
symptoms were reported that were similar among patients,
with pain being the most frequent symptom both during
attacks and chronically. This qualitative study suggests that
in some patients with AIP who experience frequent attacks,
the disease has acute exacerbations as well as chronic manifestations,
which pervade patients’ lives on a frequent or
even daily basis.
Acknowledgements The authors thank the patients who participated in
this study. The first draft of the manuscript was written by the authors;
editorial support for the preparation of the manuscript was provided
by Adelphi Communications and funded by Alnylam Pharmaceuticals,
Cambridge, MA, USA.
Author Contributions AS, WQ, AW, CP, and SA contributed to the
study design, data interpretation, manuscript development, and review
of this article. JBK contributed to the data interpretation, manuscript
development, and review of this article. FP, SS, and PM contributed
to the study design, data collection, data analysis, data interpretation,
manuscript development, and review of this article. DLH and JRH
contributed to the study design, data collection, manuscript development,
and review of this article.
Compliance with Ethical Standards
Funding This work was supported by Alnylam Pharmaceuticals, Cambridge,
MA, USA. Data collection and analysis were performed by
Modus Outcomes under the direction of the authors.
Conflict of Interest Amy Simon, William Querbes, Alex Wei, Craig
Penz, Jae B. Kim, and Sonalee Agarwal are employees of Alnylam
Pharmaceuticals, which sponsored this study. Farrah Pompilus, Sara
Strzok, and Patrick Marquis are employees of Modus Outcomes and
received funding from Alnylam Pharmaceuticals to conduct the study.
Desiree Lyon Howe and Jessica R. Hungate are employees of the
American Porphyria Foundation.
Data Availability The data that support the findings of this study may
be available on request from the corresponding author (AS), based
on the specific request. The data are not publicly available because
they contain information that could compromise research participant

Open Access This article is distributed under the terms of the Creative
Commons Attribution-NonCommercial 4.0 International License
(, which permits any
noncommercial use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate
if changes were made.

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