C1 Esterase Inhibitor Deficiency

Etiology

Hereditary angioedema results from excessive production of bradykinin. Bradykinin is a vasodilator that causes the larynx to become engorged and swollen, threatening the airway. Due to this pathway, the swelling is not amenable to antihistamines as it is not a histamine-mediated process. While there are other forms of hereditary angioedema, deficiency or dysfunction in C1 inhibitor is the most common form. C1 inhibitor is an acute phase reactant and a serine protease inhibitor (serpin). Serpins inhibit the steps in the lectin complement pathway as well as kinin-producing pathways. While C1 inhibitor has many functions, its function in the kinin pathway leads to angioedema.[2]

While it is uncertain what causes the initial molecular events leading to this angioedema, it is believed activated factor XII of the coagulation cascade and kallikrein catalyze the cleavage of kininogen, which produces bradykinin. C1 inhibitor usually limits this bradykinin production by inhibiting kallikrein and factor XIIa. Bradykinin is a potent vasodilator due to multifactorial downstream effects on the smooth muscle in blood vessels. This activity, in turn, leads to edema of surrounding tissues and, most importantly, the airway. In individuals with a deficiency of C1 inhibitor, this process proceeds unchecked and leads to gross vasodilation and angioedema.[1]

Epidemiology

Hereditary angioedema has an incidence of approximately 1 in 50000 individuals. While there are nearly 300 pathogenic variants, most are inherited in an autosomal dominant fashion, with approximately 25% of cases arising from de novo mutations. This condition leads to about 15000 to 30000 emergency department visits per year.[1]

Pathophysiology

The most clinically significant sequelae of C1 inhibitor deficiency is the potential for laryngeal edema and subsequent asphyxiation due to angioedema from unchecked bradykinin effects. The pathophysiology of C1 esterase inhibitor deficiency largely stems from the increased bradykinin production. Increased levels of bradykinin then lead to smooth muscle relaxation in the walls of blood vessels which causes edema. If severe enough, the airway can be compromised and effectively swollen closed, preventing air movement into and out of the lungs.[3]

History and Physical

When suspecting C1 esterase deficiency, key historical findings such as a family history for the disease or upper airway swelling may be noted. Additionally, a history of unexplained recurrent episodes of self-limited colicky abdominal pain may be present. History of angioedema without urticaria, pruritus, ACE inhibitor, NSAID, or allergic exposure is highly suggestive as well. Common sites that are affected include the hands and feet as well.[1]

Evaluation

When suspecting C1 esterase inhibitor deficiency, it may present with airway compromise from laryngeal edema or a more benign presentation of unexplained hands and foot swelling. First, care should be taken to ensure the airway is secured; this can be via traditional airway methods but will be made difficult due to airway swelling. Further evaluation should take place on a trial basis of classic allergic airway swelling management (epinephrine, steroids, antihistamines). In the case of C1 inhibitor deficiency, these methods will not work. At this point, a presumptive diagnosis can be made, but for a definitive diagnosis, clinicians can obtain C4 levels. In the case of C1 inhibitor deficiency, C4 levels will be low. Further testing can include C1NH protein levels and function studies for definitive diagnosis.[4]

Treatment / Management

Management of C1 esterase inhibitor deficiency is mostly in response to airway compromise. If only mild symptoms present and the patient has a known diagnosis, it is reasonable to manage conservatively with observation. If more severe symptoms and impending airway compromise are present, a definitive airway is necessary. Presumptive treatment with epinephrine, steroids, and antihistamines is recommended of the undifferentiated patient with airway compromise secondary to laryngeal edema. However, in the setting of C1 esterase inhibitor deficiency, this is ineffective but should be attempted as allergic airway compromise is more common, and these methods have a high reward with relatively little downside.[5](A1)

Specific therapy for C1 esterase inhibitor deficiency with laryngeal edema involves replacing the deficient enzyme. The easiest way is to give human plasma, which contains C1 esterase inhibitor. An initial dose of human plasma is 2 units. C1INH concentrate derived from human plasma may be a therapeutic option. The initial dose is 1500 units.[6]

More specific, less widely used medications include Icatibant and ecallantide. Icatibant is a synthetic bradykinin B2-receptor antagonist, while ecallantide is a recombinant plasma kallikrein inhibitor.[5][6](A1)

Differential Diagnosis

Differential diagnosis in the setting of airway edema includes:

• Anaphylaxis/allergic
• ACE inhibitor-induced edema
• Idiopathic
• Autoimmune disorders
• Superior vena cava syndrome
• Thyroid disorders
• Cheilitis granulomatosa
• Trichinosis 

The possible differentials can broaden when symptoms relate solely to extremity swelling: 

• Lymphedema
• Deep vein thrombosis
• Cellulitis

Prognosis

Depending on the response to therapy, the patient should return to normal health. Occasionally patients are very resistant to therapy and will require intubation. After the acute event and extubation, the patient should have a full recovery. The chance of recurrence, however, is always present.[7]

Complications

The most severe complication is airway compromise requiring intubation or surgical airway; standard airway procedures and protocols should manage this situation.[6]