Hereditary angioedema (HAE) makes up only a small proportion of overall cases of angioedema, but it deserves attention because it can be life-threatening. The term “angioedema” itself indicates the kind of disease it is; “angio” refers to blood or lymph vessels and “edema” refers to vascular swelling.
HAE is inherited in an autosomal dominant manner and is characterized by recurrent episodes of subcutaneous tissue swelling. In addition, swelling can also occur in the oro-pharyngeal mucosa and along the gastrointestinal tract.
When episodes of edema occur, they tend to be self-limiting and nonpruritic. They also have ill-defined margins. An edema attack typically has a slow onset and resolves within 48 to 72 hours. The prevailing theory on how edema occurs is the loss of control over the kallikrein-kinin system (KKS), which results in uncontrolled bradykinin production or signaling.
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“Research developed during the last 2 decades has significantly widened our understanding of HAE pathophysiology and provided meaningful insights into the biological activities exerted by the KKS,” Lera wrote in the Balkan Medical Journal.
Current Understandings of HAE Pathophysiology
The current classification of HAE divides it into those with functional C1 esterase inhibitor (C1-INH) deficiency and those with normal C1-INH. The first type is diagnosed in an estimated 85% of patients, making it the more common form of the disease. In the second form, C1-INH levels are normal but unable to function normally. This is usually the result of mutations near the inhibitor site, causing the protein to be nonfunctional.
“The major functions of C1-INH include inhibition of the following: activated C1r and C1s, activated Hageman factor (XIIa), Hageman factor fragment (XIIf), activated factor XI, tissue plasminogen activator, and activated kallikrein,” Patel and Pongracic wrote in Allergy & Asthma Proceedings.
The KKS, in turn, is a proteolytic cascade that plays a major role in proinflammatory and procoagulant pathways. The important role that the KKS plays in the pathophysiology of HAE is supported by genetic and molecular studies that demonstrate the influence that pathological processes in HAE have on components that control the activation of the KKS. KKS dysfunction leads to the release of bradykinin.
“There has been significant progress in our understanding of pathophysiology of HAE” summarized Sharma and colleagues in Clinical Reviews in Allergy & Immunology. “This is based on two landmark discoveries: (i) identification of [C1-INH] protein deficiency in serum of patients with C1-INH-HAE (Type I and Type II) and (ii) identification of bradykinin (BK) as the main mediator of swelling.”
Bradykinin is the principal mediator of hereditary angioedema and is generated via the contact system, causing the dilation of postcapillary venules and an increase in vascular permeability. In acute attacks, bradykinin levels are significantly elevated. The specific triggers that activate bradykinin remain a subject of debate within academic circles.
Clinical Signs and Symptoms
HAE is often diagnosed during childhood. It is usually suspected if a family member is known to have a history of angioedema. Symptoms may appear in childhood and tend to get progressively worse in adolescence and adulthood.
The most concerning aspect of HAE is that it can result in acute attacks, which can often lead to serious complications. The frequency of attacks is variable; some patients go years without experiencing an attack, while others experience them on a weekly basis.
“Attacks of HAE are the result of localized subcutaneous or submucosal edema that may be spontaneous or triggered by trauma, medical or dental procedures, emotional stress, menstruation, infection, exogenous estrogen replacement therapies, or angiotensin-converting enzyme inhibitors,” Patel and Pongracic wrote.
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Up to half of patients with HAE report experiencing prodromal symptoms. These may include tightness, tingling, or erythema marginatum. Angioedema then worsens over the next day or so and lasts for the next few days. The edema observed during acute attacks is nonpitting, tense, and painful. In 3 out of every 4 patients, cutaneous angioedema of an extremity is the first clinical symptom of an attack.
If visceral edema occurs in the gastrointestinal system, intestinal obstruction, abdominal pain, and vomiting can occur. Upon examination, the abdomen is tender but guarding is absent. Gastrointestinal involvement during an attack often resembles an acute abdomen, which may prompt surgeons to conduct an (unnecessary) exploratory laparotomy in an attempt to understand possible underlying causes.
Arguably, the worst form of an attack is when it involves the oropharynx and larynx, since it can lead to airway obstruction. In the prodrome phase, some patients report feelings of throat tightness, voice changes, or buccal swelling. Eventually, swallowing difficulties and frank stridor can occur. In extreme cases, the patient may die from asphyxiation.
Connecting Pathophysiology and Clinical Indications
Much research is currently being conducted to further our understanding of the genetic and molecular mechanisms underlying HAE. The main problem with the disease can be summarized as edema occurring in painful and sometimes life-threatening locations. Hence, our current understanding of the roles of C1-INH, the KKS, and bradykinin should lead to the discovery of new drugs for treating the main features of this disease.
“In recent years, increasing insight into the pathogenesis of HAE and the access to next-generation sequencing technologies have led to . . . improved diagnostic and therapeutic management of patients,” Lera wrote.
Let us hope this results in a therapeutic breakthrough in the near future.
Sharma J, Jindal AK, Banday AZ, et al. Pathophysiology of hereditary angioedema (HAE) beyond the SERPING1 gene. Clin Rev Allergy Immunol. 2021;60(3):305-315. doi:10.1007/s12016-021-08835-8
Patel G, Pongracic JA. Hereditary and acquired angioedema. Allergy Asthma Proc. 2019;40(6):441-445. doi:10.2500/aap.2019.40.4267
Lera AL. Pathophysiology and underlying mechanisms in hereditary angioedema. Balkan Med J. 2021;38(2):82-88. doi:10.4274/balkanmedj.galenos.2020.2020.10.166