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-year-old sister had histories of numerous episodes of painful localized edema since childhood. Her paternal grandmother, 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).
Angioedema in a patient with positive family history and low C4 is characteristic of hereditary angioedema (HAE).1
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 HAE patients(4). Subsequently, more than 190 different mutations of the gene that encodes C1-INH, serpin peptidase inhibitor, clade G (C1 inhibitor), member 1 (SERPING1), have been described(5). Approximately 25% of patients have no family history, indicating their disease is attributable to de novo mutations.
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
HAE is diagnosed by evaluation of C1-INH in serum. Both quantitative and functional tests are available, which help determine if a patient has HAE type I or type II. C2 and C4, both early components of the classical complement pathway, are almost always low in HAE 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 HAE, but C1q measurement is useful to differentiate HAE 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).
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 C1-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 P01-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.
↵1 Nonstandard abbreviations: HAE, hereditary angioedema; C1-INH, C1 inhibitor.
- © 2008 The American Association for Clinical Chemistry