CASE DESCRIPTION
A 16-year-old girl presented to the emergency room with severe
swelling of her left hand and forearm. Her symptoms began 12 h earlier
with left forearm swelling that progressed to the tips of her fingers.
She reported her forearm felt normal, but her hand had a tingling
sensation and she was barely able to move her fingers. She also reported
having had moderately painful abdominal cramps earlier that day. She
denied urticarial or pruritic rashes, respiratory distress, and throat
tightness. During the previous week she had felt stressed because of
schoolwork and also had developed a mild headache, clear rhinorrhea, and
cough. She had never had episodes of swelling in the past.
Family history revealed similar episodes in multiple family
members. The patient's father and 15-yearold sister had histories
of numerous episodes of painful localized edema since childhood. Her
paternal grand-mother, great-grandfather, and great-great-grandfather
died of asphyxiation due to attacks of angioedema and swelling of the
throat. Her mother and 13-year-old brother were healthy.
On examination, the patient appeared well and in no respiratory
distress. Vital signs were stable. Her skin had no rashes. Her left
upper extremity was severely swollen from the midforearm to the
fingertips. Her left hand was cold and capillary refill was mildly
delayed. The patient reported a tingling sensation when her fingers were
superficially palpated. Flexion and extension of her fingers were
greatly reduced. The patient's abdomen was soft but diffusely
tender, without hepatosplenomegaly. There was no swelling of other body
parts. Physical examination results were otherwise unremarkable.
Complete blood count showed mild leukocytosis with neutrophilic
predominance. C-reactive protein was 15 mg/L (reference interval <5
mg/L), C3 was 1170 mg/L (reference interval 830-1770 mg/L), and C4 was
<60 mg/L (reference interval 140-420 mg/L).
DISCUSSION
Angioedema in a patient with positive family history and low C4 is
characteristic of hereditary angioedema (HAE). (2)
HAE, a rare genetic disorder with autosomal dominant inheritance,
is caused by a deficiency of C1 inhibitor (C1-INH). The incidence of HAE
is estimated to be 1 in 10 000 to 1 in 150 000, with no differences
between sexes or ethnicities (1). The disease is characterized by
recurrent episodes of localized subcutaneous or mucosal swelling that
most commonly affect extremities but can also involve the face,
genitals, trunk, tongue, lips, and larynx. Cutaneous attacks can be
temporarily disfiguring but are not dangerous. In addition, patients
with HAE frequently have episodic abdominal pain due to swelling of the
bowel. Abdominal-pain attacks occasionally lead to unnecessary surgery
owing to suspicion of acute abdomen. HAE attacks do not usually involve
urticaria or pruritus, a characteristic that helps in differentiating
HAE from allergic angioedema. However, approximately one-third of HAE
patients may have a nonraised serpiginous rash preceding angioedema
attacks. Episodes are usually self-limited and last 1 to 5 days, having
a gradual onset and gradual resolution. When the larynx is compromised,
however, attacks can lead to asphyxiation and, if not treated in time,
to death. Most attacks are sporadic and do not have a recognizable
inciting factor. Nevertheless, patients report that episodes are
triggered by local trauma or pressure, and in about one-third of cases,
by emotional stress. Other reported triggers are infections, dental
work, surgery, menstruation, pregnancy, oral contraceptives, and
angiotensin-converting-enzyme inhibitors (2). The age at which attacks
begin is variable, with most patients having their first attack in
childhood or adolescence. The frequency of attacks ranges from weekly to
once every few years.
Despite the fact that HAE is frequently classified as an allergic
disease, it is not, and HAE attacks are not mediated by histamine (3).
In 1963, Donaldson and Evans recognized that the concentration of a
serum protein now known as C1-INH was decreased in most RAE patients
(4). Subsequently, more than 190 different mutations of the gene that
encodes C1-INH, serpin peptidase inhibitor, clade G (C1 inhibitor),
member 1 (SERPINGI ), have been described (5). Approximately 25% of
patients have no family history, indicating their disease is
attributable to de novo mutations.
[FIGURE 1 OMITTED]
There are 2 main variants of HAE. Type I, which affects 85% of
patients, is characterized by low C1-INH concentrations attributable to
mutations that lead to no synthesis or failure to secrete the protein.
Type II affects the remaining 15% of patients, who secrete a mutant
nonfunctioning C1-INH protein, and thus have normal or increased
concentrations of C1-INH in plasma. A rare third type has been described
in patients, predominantly women, who have C1-INH concentrations within
the reference interval and normal C1-INH function. This type of HAE may
be due to increased activity of coagulation factor XII (6).
C1-INH is a serpin-type protease inhibitor, active against multiple
plasma proteases. It mimics the substrate of the protease and traps it
by binding covalently to its active site. C1-INH regulates many of the
mediator cascades in serum, most importantly the complement and contact
systems. The complement system consists of proteins that participate in
the humoral immune defenses of the body. It has 3 different pathways
(classical, alternative, and lectin) that differ in their mechanisms of
activation. All 3 pathways converge into a final common pathway at the
level of activation of the complement component C3 and therefore have
the same biologic effects, which include opsonization, lysis of
pathogens or altered host cells, inflammation, and chemotaxis. C1-INH
acts as the primary regulator of the classical complement pathway by
inhibiting C1r and C1s, 2 early components of this pathway. In addition,
C1-INH exerts inhibitory effects on mannose-binding lectin-associated
serine proteases 1 and 2, 2 early enzymes of the lectin pathway (7).
C1-INH has also been reported to be a regulator of the alternative
pathway convertase by binding to C3b, although not through a covalent
bond (8) (Fig. 1).
The contact or kallikrein-kinin system is a network of proteins
that modulate inflammation, blood pressure, coagulation, and pain.
Activated factor XII converts prekallikrein into kallikrein, and the
latter cleaves high-molecular-weight kininogen into bradykinin, which
mediates many of the biologic effects of this system. C1-INH is a major
inhibitor of kallikrein and coagulation factor XII (Fig. 1).
Pathophysiologically, angioedema is caused by postcapillary venule
leakage and edema formation in subcutaneous or mucosal soft tissues.
After years of debate about whether angioedema is caused by activation
of the complement or the contact systems, it is now generally agreed
that bradykinin is probably the only mediator of angioedema attacks in
HAE (9).
DIAGNOSIS OF HAE
RAE is diagnosed by evaluation of C1-INH in serum. Both
quantitative and functional tests are available, which help determine if
a patient has RAE type I or type II. C2 and C4, both early components of
the classical complement pathway, are almost always low in RAE patients,
with C4 being a common screening test for this condition owing to its
widespread availability. Because HAE often involves constant low-grade
spontaneous activation of complement, C4 can also be low when patients
are asymptomatic. C1q, another early complement protein, is within
reference intervals in RAE, but C1q measurement is useful to
differentiate RAE from acquired angioedema, a condition in which C1q is
usually low. Acquired angioedema can be associated with
lymphoproliferative disorders or antibodies against C1-INH and should be
suspected in patients without family history and with symptom onset at
an older age. Genetic testing for the SERPING1 gene can also be done but
is usually unnecessary.
TREATMENT OF HAE
Treatment of HAE can be prophylactic or directed to acute attacks.
Attenuated androgens have been successfully used for prophylaxis.
Adverse side effects restrict their use in children, however, and often
lead to treatment discontinuation, especially in women. For angioedema
attacks no approved treatments are available in the US. New emerging
therapies that should radically change the treatment of HAE include
purified C1-INH, which has been effectively used in Europe for years,
and recombinant C1-INH. FDA clearance for the use of both treatments in
the US is currently being sought. Other promising new therapies that
directly address the pathophysiology of HAE are being tested, including
a kallikrein inhibitor and a bradykinin-receptor antagonist (10).
CASE RESOLUTION
The case patient was observed in the emergency room for a few
hours, during which she experienced gradual decreases in extremity
swelling and abdominal pain. Additional studies showed a C1-INH
concentration of 7 mg/L (reference interval 210-390 mg/L), and a C1-INH
functional assay revealed 38% of normal enzymatic activity (reference
interval >68%). The diagnosis of HAE type I was established.
Subsequent gene sequencing of SERPING1 revealed a nonsense mutation
(Arg472stop). The patient was discharged in good condition and after 48
h the swelling resolved completely. She was instructed to consult the
nearest emergency room for any symptoms of oropharyngeal swelling and to
inform her dentist about her condition. She was also advised against
traveling to remote areas with difficult medical access. In the
following year, she developed 2 new episodes of extremity swelling,
likely triggered by stress and/or viral infections. Because of the
rarity of this patient's attacks and her young age, no prophylactic
treatment was started.
During the last decades, combined clinical and laboratory research
have elucidated the genetic cause and clarified the pathophysiology of
what used to be a mysterious clinical syndrome. This improved
understanding of HAE is now leading to new therapies that target the
mechanisms of disease and likely improve the lives of patients who
suffer from this disease. HAE provides a clear example of how basic
science contributes to the understanding of disease mechanisms and leads
to effective specific therapies.
POINTS TO REMEMBER
* HAE, an episodic swelling disorder of autosomal dominant
inheritance, is caused by deficiency of C1-INH.
* Deficiency of C1-INH causes activation of the complement and
contact system. Bradykinin has been identified as the substance most
likely responsible for the angioedema.
* Clinical manifestations include episodic swelling of extremities,
recurrent abdominal pain, and laryngeal angioedema attacks. The latter
can be life-threatening.
* Diagnosis is confirmed by quantifying and measuring functional
activity of Cl-INH. C4 is a good screening test because it is usually
low in HAE patients.
* Acquired causes of angioedema must be considered in older
patients who do not have a family history of HAE.
Author Contributions: All authors confirmed they have contributed
to the intellectual content of this paper and have met the following 3
requirements: (a) significant contributions to the conception and
design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; and (c) final
approval of the published article.
Authors' Disclosures of Potential Conflicts of Interest: Upon
submission, all authors completed the Disclosures of Potential Conflict
of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: Lynda C. Schneider, Data Safety
Monitoring Board for Dyax.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: Lynda C. Schneider, CSL Behring; Raif S. Geha,
NIH Grant POI-AI-035714.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
References
(1.) Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a
broad review for clinicians. Arch Intern Med 2001;161:2417-29.
(2.) Bowen T, Cicardi M, Bork K, Zuraw B, Frank M, Ritchie B, et
al. Hereditary angiodema: a current state-of-the-art review, VII.
Canadian Hungarian 2007 International Consensus Algorithm for the
Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy
Asthma Immunol 2008;100:530-40.
(3.) Brickman CM, Frank MM, Kaliner M. Urine-histamine levels in
patients with hereditary angioedema (HAE). J Allergy Clin Immunol
1988;82:403-6.
(4.) Donaldson VH, Evans RR. A biochemical abnormality in
hereditary angioneurotic edema: absence of serum inhibitor of C'
1-esterase. Am J Med 1963;35:37-44.
(5.) Kalmar L, Heged0s T, Tordai A. HAEdb--C1 inhibitor gene
mutation database. Available from: http://hae.enzim.hu/. Accessed
February 2008.
(6.) Cichon S, Martin L, Hennies HC, Muller F, Van Driessche K,
Karpushova A, et al. Increased activity of coagulation factor Al
(Hageman factor) causes hereditary angioedema type III. Am J Hum Genet
2006;79:1098-104.
(7.) Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T.
Proteolytic activities of two types of mannosebinding lectin-associated
serine protease. J Immunol 2000;165:2637-42.
(8.) Jiang H, Wagner E, Zhang H, Frank MM. Complement 1 inhibitor
is a regulator of the alternative complement pathway. J Exp Med
2001;194: 1609-16.
(9.) Davis AE 3rd. Hereditary angioedema: a current
state-of-the-art review, III: mechanisms of hereditary angioedema. Ann
Allergy Asthma Immunol. 2008;100:57-12.
(10.) Frank MM, Jiang H. New therapies for hereditary angioedema:
disease outlook changes dramatically. J Allergy Clin Immunol
2008;121:272-80.
(2) Nonstandard abbreviations: HAE, hereditary angioedema; C1-INH,
C1 inhibitor.
Arturo Borzutzky, [1] * Lynda C. Schneider, [1] and Raif S. Geha
[1]
[1] Division of Immunology, Children's Hospital Boston,
Harvard Medical School, Boston, MA.
* Address correspondence to this author at: Children's
Hospital Boston, Division of Immunology, 300 Longwood Avenue, Boston, MA
02115. Fax 617-730-0249; e-mail arturo.borzutzky@childrens.harvard.edu.
Received April 30, 2008; accepted June 12, 2008.
Previously published online at DOI: 10.1373/clinchem.2008.109751
Commentary
Michael M. Frank
In the past 50 years, our understanding of hereditary angioedema
(HAE) has markedly expanded. Although HAE was first defined in general
terms in the 19th century, we now have extensive insight into the
clinical expression, cause, pathophysiology, and treatment of this
disease, so that HAE represents a success story of modern medicine. We
know that emotional stress, trauma, and endocrine factors all can
contribute to disease expression. The disease has unique clinical
symptomatology, and often a diagnosis can be made with clinical history
alone. The observations that the disease can become very severe during
puberty and that estrogens markedly exacerbate symptoms led to the
empirical use of impeded androgens in treatment. In turn, this treatment
led to a major decrease in mortality because patients had fewer
life-threatening airway attacks.
Because HAE is such a rare disease, the diagnosis is often missed
regardless of the characteristic clinical history. Patients often go for
decades without proper diagnosis. When we published our detailed studies
of clinical expression of the disease in 1976, we found that after the
onset of attacks an average of 21 years passed before patients received
a proper diagnosis (1). These patients were at high risk of airway
attacks and asphyxiation. We also noted that approximately 30% of
afflicted relatives of our patients had died of upper-airway edema. More
recently, a pharmaceutical company reported that in European patients 9
years had passed between the onset of attacks and diagnosis. This time
lapse is obviously unacceptable, given the fact that successful
treatment is available, and shows that both physician and patient
education is still desperately needed. As noted in the clinical case
study, new and better therapies for HAE are on the horizon. Even in the
absence of gene therapy, this inherited disease may come to be
considered a minor condition and not a life-threatening illness.
Author Contributions: All authors confirmed they have contributed
to the intellectual content of this paper and have met the following 3
requirements: (a) significant contributions to the conception and
design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; and (c) final
approval of the published article.
Authors' Disclosures of Potential Conflicts of Interest: No
authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
Reference
(1.) Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the
clinical syndrome and its management. Ann Intern Med 1976;84:580-93.
Duke University Medical Center, Durham, NC.
* Address correspondence to the author at: Duke University Medical
Center, DUMC 3010, 445 Sands Bld, Box 3352, Durham, NC, 27710. Fax
919-681-0847; e-mail frank007@mc.duke.edu.
Received July 8, 2008; accepted July 10, 2008.
Previously published online at DOI: 10.1373/clinchem.2008.112300
Commentary
Bruce L. Zuraw
Hereditary angioedema (HAE) is an uncommon disease caused by
mutations in the SERPINGI gene, which codes for the C1-inhibitor
(C1-INH) protein and is transmitted in an autosomal dominant fashion
with high penetrance. Clinical suspicion should be triggered by a
history of recurrent angioedema, as in the patient described in the case
report by Borzutzky et al. Diagnosis requires laboratory confirmation.
Screening patients by measuring the C4 concentration is useful to
exclude the diagnosis of HAE. Even while asymptomatic, HAE patients
almost always have a low C4, and the C4 concentration is invariably low
during attacks. To establish the diagnosis, a decrease in C1-INH
concentration or function must be demonstrated. In the 85% of patients
with type I HAE, the diagnosis can be established by measuring C1-INH
antigenic concentrations. Type II HAE requires demonstration of low
functional activity of C1-INH. The diagnostic sensitivity of this assay
is not ideal, however. Therefore, in rare cases sequencing the SERPINGI
gene is required to establish the diagnosis of Type II HAE. Although
mutations leading to type I C1-INH occur throughout the gene, almost all
type II C1-INH mutations occur near the [Arg.sup.444]-[Thr.sup.445]
reactive center of SERPING1, thereby simplifying the sequencing
strategy.
HAE with normal C1-INH function primarily, but not exclusively,
affects women, and appears to be transmitted in an autosomal dominant
fashion with low penetrance. In some families, individuals with HAE with
normal C1-INH function have a gain-of-function mutation in coagulation
factor XII that may result in enhanced generation of bradykinin. With
current methods it is difficult to confirm a diagnosis of HAE in
patients with normal C1-INH function. In addition to normal C1-INH
function, these patients have C1-INH concentrations within reference
intervals. Sequencing of coagulation XII may confirm the diagnosis, but
in only a subset of patients. Better understanding of the underlying
molecular etiology and diagnostic strategy for this disease is urgently
needed.
Author Contributions: All authors confirmed they have contributed
to the intellectual content of this paper and have met the following 3
requirements: (a) significant contributions to the conception and
design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; and (c) final
approval of the published article.
Authors' Disclosures of Potential Conflicts of Interest: Upon
submission, all authors completed the Disclosures of Potential Conflict
of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: B. Zuraw, Lev Pharmaceuticals, Jerini,
CSL Behring, and Dyax.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: B. Zuraw, NIH, CDC, Lev Pharmaceuticals, and
Pharming.
Expert Testimony: B. Zuraw, Lev Pharmaceuticals.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
Department of Medicine, University of California San Diego, CA.
Address correspondence to the author at: 9500 Gilman Dr., Mailcode 0732,
La Jolla, CA 92093-0732; e-mail bzuraw@ucsd.edu.
Received July 21, 2008; accepted July 28, 2008.
Previously published online at DOI: 10.1373/clinchem.2008.112318