The National Organization for Rare Disorders
Nord Guides for Physicians #10
Physician’s Guide
Hereditary
Angioedema
(HAE)
For information about NORD’s programs and services, contact:
National Organization for Rare Disorders (NORD)
PO Box 1968
Danbury, CT 06813-1968
Phone: (203) 744-0100
Tollfree: (800) 999-NORD
Fax: (203) 798-2291
Website: www.rarediseases.org
Email: [email protected]
NORD’s Rare Disease Database and Organizational Database may be
accessed at www.rarediseases.org.
Contents ©2010 National Organization for Rare Disorders®
This booklet is the tenth in a series of free publications for
physicians and other medical professionals. It is NORD’s
hope that patients and their families will benefit from this
and other efforts to enhance awareness of the almost 7,000
rare diseases affecting an estimated 30 million Americans.
What is Hereditary Angioedema (HAE)?
Hereditary Angioedema (HAE) is an autosomal dominant disease characterized
by painful, unpredictable, recurrent attacks of inflammation affecting the
hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation
can be disfiguring, debilitating, or in the case of laryngeal attacks, life-threatening1. Prevalence for HAE is uncertain but is estimated to be approximately 1
case per 50,000 persons without known differences among ethnic groups2 and
is caused by deficient (Type I) or dysfunctional (Type II) levels of C1- Inhibitor
(C1-INH), a naturally occurring molecule that is known to inhibit kallikrein,
bradykinin, and other serine proteases in the blood1,3. If left untreated, HAE
can result in a mortality rate as high as 40% primarily due to upper airway
obstruction3.
As with other autosomal dominant diseases, patients with HAE generally inherit
one normal gene and one abnormal gene (heterozygous). Thus, the child of an
affected parent has a 50% chance of inheriting the abnormal gene. The genetic
defect may also be caused by spontaneous mutations, and it is estimated that
20% to 25% of all HAE cases occur in patients with no family history of the
disease1.
3
Figure 1: Autosomal Dominant Inheritance Pattern
HAE is Autosomal Dominant
Unaffected
Parent
Parent
with HAE
Normal
Allele
Dominant
HAE Allele
Offspring have
50% chance to
inherit HAE
Unaffected
Offspring
Unaffected
Offspring
Offspring
with HAE
Offspring
with HAE
What is the underlying cause of Hereditary
Angioedema (HAE)?
The underlying cause of HAE is the depletion or consumption of C1-inhibitor
(C1-INH), which can occur in two primary ways. Type 1 occurs in 80% to 85% of
patients and is due to a decreased production of C1-INH. Type 2 occurs in 15% to
20% of patients and is due to the production of normal or elevated levels of functionally impaired C1-INH. Circulating C1-INH levels may be normal or elevated, but
the protein remains dysfunctional. Type 1 and Type 2 HAE have been reported in all
races with no sex predominance1. Both types of HAE are similar with regard to
disease severity and manifestation4, and the underlying cause of the disease is a
deficiency in C1 Inhibitor.
C1-INH belongs to a class of protein enzyme inhibitors called serpins (serine protease
inhibitors). Serpins are known as suicide substrates because they inactivate proteases
4
by forming an irreversible bond. C1-INH inhibits multiple processes including the
complement, the fibrinolytic, and the contact systems4. Additionally, C1-INH
inactivates several other proteases5.
Once the complement, contact, and fibrinolytic systems are activated via triggers such
as trauma, medical procedures, or infections, C1-INH is consumed through complex
formation with several factors such as: C1r, C1s, factor XIIa, kallikrein, tissue plasminogen activator and plasmin. In most people, C1-INH regulates these systems by
blocking pathways, preventing the systems from becoming overactive. In HAE
patients, the reduced reserve of C1-INH becomes depleted, leaving the three systems
unopposed resulting in an overproduction of bradykinin. It is believed that bradykinin
mediates vasodilatation, increased vascular permeability, constriction of uterine and
gastrointestinal smooth muscle, constriction of coronary and pulmonary vasculature
and bronchoconstriction5. If C1-INH levels were increased, bradykinin production
would be controlled and balance could be restored.
Figure 2: Pathophysiology of an HAE Attack
Triggers
Factor XIIa
Contact System
C1
C1-INH
Prekallikrein
-IN
H
C1rs
C1
Plasminogen
-IN
-IN
H
C1
Kallikrein
H
Complement
System
HK
C1
Factor XII
Bradykinin
Fibrinolytic
System
Plasmin
Increased vascular
permeability, leading to
angioedema
5
C1-INH
depletion
C4
C2
Pathophysiology of an HAE attack: Triggers such as trauma and infection activate
the complement system. Triggers also activate the contact and fibrinolytic systems.
In a normal person, C1-INH regulates these systems by blocking pathways and
thus preventing the systems from becoming overactive. Patients with HAE have
low reserves of C1-INH. Once reserves are further depleted, the systems will be
unopposed resulting in an over production of bradykinin, which is believed to be
responsible for swelling symptoms.
What is the typical symptomatic presentation
of a Hereditary Angioedema (HAE) attack?
Symptoms of an HAE attack generally present as edema of one or more organ
systems, most commonly affecting the skin, gastrointestinal tract, or respiratory tract.
During skin attacks, the edema is generally non-pitting with poorly defined margins
and typically involves areas of the face such as the lips, eyelids, and tongue. Patients
who experience gastrointestinal attacks typically present with significant abdominal
pain and vomiting, usually resulting from intestinal obstruction1 caused by swelling
in the gut. Gastrointestinal patients may also experience attacks of acute abdominal
pain that can mimic other acute surgical conditions, leading to unnecessary
abdominal surgeries6.
More severe symptoms of HAE include laryngeal and upper respiratory edema that
may lead to respiratory tract compromise and potential death from asphyxiation.
Patients with no previous history of upper airway involvement are still at risk for
asphyxiation as there is no correlation between anatomical location of previous
attacks and likely location of future attacks. In acute laryngeal attacks, death may
result in as quickly as 20 minutes.
An additional morbidity associated with HAE is premature labor in pregnant women
afflicted with the disease. In a study of one kindred, 60% more premature labor was
reported among diagnosed mothers1. It is important that emergency room physicians
become familiar with HAE symptoms as HAE patients account for about 15,000 to
30,000 Emergency Room visits annually7. Emergency departments should have a
protocol for the management of patients with HAE, which should include seeking
the advice of an allergist/immunologist on the plan of treatment. It is also important
6
that allergists work with their patients’ general physicians to ensure that general
physicians are aware of all HAE patients within their practice and that appropriate
treatment plans are in place6.
What is the frequency for patients to experience
Hereditary Angioedema (HAE) attacks?
HAE is unpredictable in nature with substantial variation in the frequency and the age
of onset of attacks. Attack patterns vary with age and may affect a single site or
multiple sites7. Patients with symptomatic HAE generally experience at least one acute
exacerbation per month. Most attacks of HAE last 2 to 5 days, resulting in 20 to 100
days of incapacitation per year. Acute episodes of HAE often occur without warning
and often may be precipitated by a trigger. Common attack triggers include1:
Trauma
Surgery
Anesthesia
Dental procedures
Emotional stress
Menstruation
Oral contraceptive use
Infections
There is little correlation between the symptoms of attack and the type of genetic
defect present, even within the same family6. Furthermore, age and past attack
patterns do not predict the site, severity, or speed of future attacks.
What are the frequent causes for the
misdiagnosis of Hereditary Angioedema (HAE)?
HAE is frequently misdiagnosed and the time lapse between onset of symptoms and
the accurate diagnosis may be 20 years or longer8. In the US, approximately 68% of
patients receive a misdiagnosis before receiving an accurate HAE diagnosis. Patients
are commonly misdiagnosed with allergies, appendicitis, stress disorders, reactions to
insect bites, gastroenteritis, and stomach ulcers before receiving the correct diagnosis
of HAE9.
Adding to the difficulty in accurately diagnosing HAE is the wide variety of presenting
symptoms and variable age range. Approximately half of HAE patients are symptomatic by age 7 and two-thirds are symptomatic by age 13, but it is not uncommon
to see patients present during their fourth or fifth decade of life5. The differential
7
diagnosis of angioedema includes acquired angioedema (AAE), a variety of allergic
reactions, direct histamine release, and drug-induced angioedema. The acquired form
of C1-INH deficiency may be due to a lymphoproliferative disorder such as lymphoma
or autoimmune disease such as lupus, and is usually associated with an older age at
onset with no family history9.
In some patients, recurrent abdominal pain may be their only presenting symptom.
When these HAE symptoms are missed or HAE is misdiagnosed, it can lead to several
extensive evaluations and unnecessary abdominal surgeries for unexplained abdominal pain. This unexplained abdominal pain has been mistaken for acute abdomen
and has led to narcotic dependence psychiatric diagnoses9.
How can Hereditary Angioedema (HAE)
be accurately diagnosed?
The diagnosis of HAE requires a detailed personal and family history, and laboratory
measure of C1-INH, C1-INH activity, and serum C4 levels. Serum C1q levels may be
used to differentiate AAE from HAE. A diagnostic test panel is available through
commercial laboratories and is a highly effective tool in accurately diagnosing HAE.
The combination of low C4 and low C1-INH is 98% specific for C1-INH deficiency
and has a 96% negative predictive value10. In instances of high clinical suspicion
and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated.
Table 1: HAE Diagnosis
Diagnostic Labs
Type 1
C1-INH level
Type 2
Normal or
C1-INH activity
Serum C4 level
Serum C1q level
decreased;
Normal
increased
8
Normal
What is the prognosis for patients with
Hereditary Angioedema (HAE)?
The mortality rate from undiagnosed HAE can be as high as 40% and is primarily
attributed to upper airway obstruction3. Asphyxiation can occur in 20 minutes to 14
hours in patients of any age, and it has occurred in patients with no previous history
of respiratory symptoms1. Therefore, an early and accurate diagnosis of HAE is crucial
to minimize the morbidity and mortality associated with HAE.
The goal for physicians treating HAE patients is to manage their disease proactively to
maintain personal safety and achieve a normal quality of life. During every acute HAE
attack, the patient is at risk of the vicious cycle of bradykinin and C1-INH mediated
pathway activation until appropriate acute treatment (that raises C1-INH serum levels)
is given, or until spontaneous remission occurs. A treatment that actually corrects the
underlying cause of HAE would theoretically be more effective against rebound
angioedema and be more effective at mitigating the severity and longevity of acute
HAE attacks7. A treatment that restores physiological balance by increasing C1-INH
levels has the potential to improve a patient’s quality of life with minimal disruption
in daily activities4.
What are the treatment options
currently available to prevent Hereditary
Angioedema (HAE) attacks?
Cinryze is a C1-esterase inhibitor therapy and the first member in its class to have
been approved by the FDA in the United States for routine prophylaxis of attacks of
spontaneous swelling (angioedema) in adolescents and adults with hereditary
angioedema (HAE). Cinryze is administered in a healthcare setting and could be selfadministered if the patient receives appropriate training from the healthcare provider.
However, it is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions including anaphylaxis to the product. Since hypersensitivity reactions and HAE attacks may have similar symptoms, it is important but could
be challenging to distinguish between the two. Monitoring patients with known risk
factors for thrombotic events is recommended when administering Cinryze. As in
products made with human plasma, Cinryze may contain infectious agents. During
the trials, the commonest adverse effects were upper respiratory tract infections,
sinusitis, rash and headaches11.
9
Another FDA-approved drug, Danazol, is also used for prophylaxis; however, its use is
limited by its contraindications and major side effects. It is contraindicated in patients
who are pregnant, lactating or with impaired hepatic, renal or cardiac functions.
Major side effects include hepatic toxicity and androgenic effects, which are often
irreversible. Other complications include myalgias, cramps, headaches, anxiety, cholesterol abnormalities, persistent hematuria and transaminase elevations12,13. Other
approaches to prevent triggering HAE attacks include avoiding angiotensin-converting
enzyme (ACE) inhibitors and estrogens, as these have been shown to worsen symptoms. Estrogens are thought to decrease expression of ACE, and ACE inhibition acts
synergistically with C1-INH deficiency to increase plasma levels of bradykinin.
What are the treatment options currently
available to treat the symptoms of Hereditary
Angioedema (HAE) attacks?
Proper acute treatment of HAE attacks can be potentially life-saving. The FDA recently
approved Kalbitor, a plasma kallikrein inhibitor to be administered in a healthcare setting via subcutaneous injection to treat sudden attacks of HAE in patients 16 years
and older. The medication has known side effects such as an allergic reaction usually
within 1 hour after receiving Kalbitor with symptoms that can be similar to those of
HAE. Other side effects include headache, nausea, diarrhea, swelling of the nose and
throat, fever and skin irritations. Kalbitor should not be administered to any patient
with known clinical hypersensitivity to it14.
Berinert is another C1-esterase inhibitor approved by the FDA for use in the United
States to treat acute abdominal attacks and facial swelling associated with HAE.
Similar to Cinryze, it is also contraindicated in patients with history of life-threatening
hypersensitivity to C1-esterase inhibitor and is delivered by a healthcare professional.
The most serious adverse effect with Berinert is the increase in severity of pain associated with HAE. Subsequent HAE attacks, headaches, abdominal pain, nausea, muscle
spasms, pain, diarrhea and vomiting are other adverse effects commonly reported
with Berinert15. Treatment with corticosteroids, antihistamines, and epinephrine has
not been proven efficacious in aborting acute attacks16,17. Fresh frozen plasma containing the C1-esterase may help to abort episodes of acute HAE, but fresh frozen
plasma can cause adverse events due to reactions to other plasma components.
A significant aspect of therapy in acute attacks is supportive including pain
10
management and fluid replacement. Intubation or tracheotomy is frequently administered to provide adequate support for attacks associated with severe respiratory compromise1. In the future, however, patients may have more options for treating HAE
attacks. To find clinical trials, go to www.clinicaltrials.gov.
What is the role for diagnostic testing?
With HAE following an autosomal inheritance pattern, it is critically important to
test immediate and extended family members of a newly diagnosed patient as early
as possible. On average, two other immediate family members of an HAE patient
will have HAE. The rate of testing immediate family members in the US is below
the world average with only 37% of immediate family members being tested.
Additionally, on average two members of the extended family of an HAE patient
will have HAE, but only 23% of extended family members are tested for HAE10.
The accurate diagnosis provided by thorough clinical and laboratory evaluation is
essential for appropriate therapy of attacks and management during childhood and
pregnancy. Laboratory confirmation provides the opportunity for family counseling18.
Conclusion
HAE is an autosomal dominant genetic disease whose underlying cause is due
to a deficiency of C1-inhibitor. HAE attacks result in significant morbidity due to
painful, recurrent attacks of inflammation that can be life-threatening when
laryngeal involvement occurs. Since HAE is frequently misdiagnosed for extended
amounts of time, it is critically important that clinicians be aware of the presenting
signs and symptoms associated with the disease. It is equally important that patients
with angioedema of unknown etiology, along with immediate and extended family
members, be adequately tested for HAE. When treating HAE, it is essential that
clinicians understand the underlying cause of HAE i.e. a patient’s deficiency of C1inhibitor. There are newer therapies now available for prophylaxis as well as for treating signs and symptoms at specific anatomical locations associated with HAE that can
improve patient outcomes. Current clinical trials are listed on www.clinicaltrials.gov.
Information about investigational therapies is also available in NORD’s Rare Disease
Database and on the web site of the US Hereditary Angioedema Association.
11
Hereditary Angioedema (HAE) study cases
Case 1
Patient History
A 27-year-old female who was previously diagnosed with HAE presents to the emergency room with a history of cramping lasting over an hour, severe abdominal pain,
and vomiting. She has suffered from recurrent abdominal attacks since the age of 12
and has been taking Danazol for prophylaxis but recently discontinued due to adverse
effects associated with therapy. Her recurrent attacks have been severe enough to
require multiple hospital admissions for fluid replacement and pain control. She has
also experienced laryngeal attacks in the past requiring emergency tracheotomy and
extended hospitalizations.
Outcome
Patient was admitted to the National Institute of Allergy and Infectious Diseases
for evaluation and treatment. She was treated with IV fluids and narcotics and her
symptoms resolved over a period of 48 hours. The attending physician recommended
the initiation of prophylactic therapy.
Conclusion
Although she has endured multiple hospitalizations, emergency respiratory interventions, extended periods of time away from work, and significant impact on her
quality of life, only supportive care can be offered to this patient. She is at a high
risk of symptom recurrence and repeated hospital admissions, and should benefit
from being on a prophylactic treatment for HAE.
Case 2
Patient History
A 31-year-old male with previously diagnosed HAE and a history of facial & laryngeal
attacks presents to the emergency room with labored breathing. The patient had
been on prophylactic Danazol therapy for a number of years, but has since stopped
treatment due to excessive toxicities and continual attacks of HAE. The patient has
been experiencing similar attacks since the age of 10 and has had emergency intervention (i.e. intubation / tracheotomy) on numerous occasions requiring extended
hospital stays and severely impacting quality of life. Although highly educated, this
patient is unable to retain a job due to the extended periods of hospitalization that
render him incapacitated and unable to perform any job-related functions.
12
Outcome
The labored breathing the patient was experiencing continued to worsen upon his
arrival at the hospital and an emergency tracheotomy was performed (intubation
was attempted and failed due to massive airway swelling). The patient went into a
drug-induced coma and remained in intensive care for a period of 8 days. On day 8,
the airway swelling had rescinded, the tracheotomy was removed, and the patient
was sent home.
Conclusion
The impact of disease on this patient’s life has been devastating. Due to the
unpredictable nature of this disease and rapid onset of symptoms, the patient has
been unable to travel or retain steady employment. Additionally, treatment with
Danazol therapy has proven ineffective and highly toxic with the patient continuing
to experience attacks while on therapy. As a result, this patient has continued to rely
on emergency intervention when experiencing laryngeal attacks and could benefit
from newer treatment options now available for managing certain symptoms and
prevention of HAE.
Patient Support and Resources
National Organization for Rare Disorders
55 Kenosia Avenue
PO Box 1968
Danbury, CT 06813-1968
(203) 744-0100
http://www.rarediseases.org
The US Hereditary Angioedema Association
Seven Waterfront Plaza
500 Ala Moana Blvd, Suite 400
Honolulu, HI 96813
(866) 798-5598
http://www.haea.org
Immune Deficiency Foundation
40 West Chesapeake Avenue
Towson, MD 21230
(800) 296-4433
http://www.primaryimmune.org
American Academy of Allergy, Asthma and Immunology
611 East Wells Street
Milwaukee, WI 53202
(414) 272-6071
http://www.aaaai.org
American College of Allergy, Asthma & Immunology
85 West Algonquin Road, Suite 550
Arlington Heights, IL 60005
(847) 427-1200
http://www.acaai.org
NIH/National Heart, Lung and Blood Institute
31 Center Drive MSC 2480
Bethesda, MD 20892-2480
(866) 284-4107
http://www.nhlbi.nih.gov
14
References
1. Nzeako UC, Frigas E, Tremaine WJ. Hereditary
angioedema. Arch Intern Med. 2001;161:2417-2429.
2. Zuraw BL. Hereditary Angioedema. NEJM. 2008;359:
1027-36.
3 Bork K, Siedlecki K, Bosch S, et al. Asphyxiation by laryngeal
edema in patients with hereditary angioedema. Mayo Clin
Proc. 2000;75: 349-354.
4. Frank MM. Hereditary Angioedema: The Clinical Syndrome
and its Management in the United States. Immunol Allergy
Clin N Am 26 (2006) 653-658.
5. Davis AE. The pathophysiology of hereditary angioedema.
Clin Immunol.2005;114:3-9.
6. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor
deficiency: consensus document. Clin Exp Immunol.
2005;139: 379-394.
7. Moore GP, Hurley WT, Pace SA. Hereditary angioedema.
Ann Emerg Med. 1998;17: 1082-1086.
8. Jensen NF, Weiler JM. C1 esterase inhibitor deficiency,
airway compromise, and anesthesia. Anesth Analg.
1998;87:480-488.
9. International survey of patient experience of HAE, Aug-Sept
2004, Double-Helix Development. [Data on file] Lev
Pharmaceuticals.
10. Gompels MM, Lock RJ, Morgan JE, et al. A multicentre
evaluation of the diagnostic efficiency of serological
investigations for C1 inhibitor deficiency. J Clin Pathol.
2002;55:145-147.
11. C1-esterase inhibitor [Human] (Cinryze) [package insert].
New York, NY: Distributed by Lev Pharmaceuticals, Inc;
May 2009.
12. Hosea SW, Frank MM. Danazol in the treatment of
hereditary angioedema. Drugs.1980;19: 370-372.
13. Zurlo JJ, Frank MM. The long-tem safety of danazol in
women with hereditary angioedema. Fertil Steril. 1990;
54: 64-72.
14. Ecallantide (KALBITOR) [medication guide]. Cambridge, MA:
Manufactured for Dyax Corp.
15. C1-esterase inhibitor [Human] (Berinert) [package insert].
Kankakee, IL: Distributed by CSL Behring LLC; October 2009
16. Zuraw BL. Current and future therapy for hereditary
angioedema. Clin Immunol. 2005;114: 10-16.
17. Danocrine (Danazol) [package insert]. New York, NY:
Marketed by Sanofi-Synthelabo Inc; October 2006.
18. Weiler CR, Van Dellen RG. Genetic test indications and
interpretations in patients with hereditary angioedema.
Mayo Clin Proc. 2006;81(7): 958-972.
NORD gratefully
acknowledges
the assistance
of the following
physicians in the
preparation of this
publication:
Sukirti Bagal, MD, MPH
Medical Editor
National Organization for
Rare Disorders (NORD)
Danbury, CT
James W. Baker, MD
Baker Allergy Asthma and
Dermatology Research
Center
Lake Oswego, Oregon
Timothy Craig, DO, FAAAA,
FACOI
Professor of Medicine
and Pediatrics
Pennsylvania State University,
Hershey Medical Center
Marc Riedl, MD, MS
Assistant Professor of
Medicine
Section Head, Clinical
Immunology and Allergy
UCLA – David Geffen
School of Medicine
Los Angeles, CA
Nord Guides for Physicians #10
#1
The Pediatrician’s Guide to
Tyrosinemia Type I
#2
The Pediatrician’s Guide to Ornithine
Transcarbamylase Deficiency…and
other Urea Cycle Disorders
#3
The Physician’s Guide to
Primary Lateral Sclerosis
#4
The Physician’s Guide to
Pompe Disease
#5
The Physician’s Guide to
Multiple System Atrophy
#6
The Physician’s Guide to
Hereditary Ataxia
#7
The Physician’s Guide to Giant
Hypertrophic Gastritis and
Menetrier’s Disease
#8
The Physician’s Guide to Amyloidosis
#9
The Physician’s Guide to
Medullary Thyroid Cancer
#10
The Physician’s Guide to
Hereditary Angioedema (HAE)
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This booklet was made possible by a charitable
contribution from ViroPharma Incorporated.
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increase awareness of rare diseases to facilitate
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and the voluntary health organizations that help people affected by
them, visit NORD’s Web site at
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999-NORD or (203) 744-0100.
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Contact NORD at:
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National Organization for Rare
Disorders (NORD)
PO Box 1968
Danbury, CT 06813-1968
Phone: (203) 744-0100
Tollfree: (800) 999-NORD
Fax: (203) 798-2291