Basics
Description
- A hereditary and acquired form of recurrent angioedema. The attacks are usually without urticaria.
- Has been classified into a number of types, including
- Hereditary angioedema (HAE) type I (transmitted as autosomal dominant)
- HAE type II (transmitted as autosomal dominant)
- Acquired angioedema (AAE) types I, II, III, and IV
- HAE type I
- Accounts for ~85% of the C1 esterase deficiencies, insufficient levels of normal C1-esterase inhibitor (C1-INH) protein due to a genetic alteration that leads to impairment of messenger RNA (mRNA) transcription or translation and therefore decreased enzyme synthesis. Often thought of as quantitative deficiency.
- HAE type II
- Patients have normal levels of less functional C1-INH. May be thought of as a qualitative deficiency.
- HAE type III
- An estrogen-dependent form; typical clinical features of type I with normal C1-INH level and function and normal C4
- These cases are all female and have dominant mode of inheritance; poorly understood mechanism.
- In acquired deficiency of C1-INH, there appears to be a normal ability to synthesize the enzyme; however, the enzyme is metabolized at an increased rate. This syndrome may be seen in patients with autoimmune diseases or malignancy and usually occurs after the 4th decade of life.
- AAE type I
- Very rare syndrome usually associated with lymphoproliferative (usually B-cell) carcinomas, autoimmune diseases, and paraproteinemias. Because of the other disease processes, complement-activating factors and idiotype-anti-idiotype complexes act to increase consumption of C1-INH.
- AAE type II
- Develops when an autoantibody is produced against the C1-INH protein. When these antibodies adhere to the C1-INH molecule, conformational change occurs, leading to decreased function or enhanced metabolism. This type is often associated with autoimmune disorders.
- AAE type III
- Associated with sex hormones (specifically in pregnancy)
- AAE type IV
- Drug-induced AAE, particularly associated with ACE inhibitors or angiotensin receptor blockers
- AAE forms may be differentiated from HAE by genetic studies and serologically by significantly decreased C1q, C1r, and C1s levels and decreased functional activity of the enzyme in AAE.
Epidemiology
Incidence
1:50,000
Genetics
HAE types I and II are transmitted as autosomal dominant.
Pathophysiology
- C1-INH is a single-chain polypeptide with a molecular weight of 108 kD. The gene has been identified on chromosome 11 (11q12-q13.1). It is involved in the control of vascular permeability.
- C1-INH is a member of the serpin family of serine protease inhibitors produced in the liver.
- This protein inhibits the classic complement pathway by inhibiting activation of C2 and C4. In the fibrinolytic system, C1-INH inhibits formation of plasmin, the activation of C1r and C1s, and the formation of bradykinin from kininogen.
- Deficiency of this enzyme results in activation of the classic complement system along with fibrinolysis and kinin formation, which is felt to participate in the production of angioedema.
- Kinin is known to cause similar histologic lesions to histamine but without pruritus.
- The complement activation leads to production of C2b, a product that also has kinin-like activity, and bradykinin, a vasoactive peptide that may also participate in the formation of angioedema.
Diagnosis
History
- Presentation: Patients with HAE usually present in the 2nd decade of life with angioedema involving the subcutaneous tissues (mostly involving the extremities).
- Attacks can be precipitated by trauma, infection, or pregnancy.
- Timing
- Classically, the edema develops gradually over several hours and increases slowly over 12-36 hours.
- GI effects
- Predominant symptom in 25% of patients
- Patients may experience abdominal attacks with sudden and very severe onset without visible edema.
- Angioedema involving the GI tract may lead to severe pain, vomiting, and diarrhea as well as ascites.
- Secondary to transient edema of small bowel resulting in intestinal obstruction, ascites, and hemoconcentration
- Respiratory complications: 2 of 3 patients will have orofacial or laryngeal swelling.
- Hives: The edema usually occurs without evidence of inflammation; rash resembles urticaria (however, episodes of urticaria have also been documented).
- The variability of clinical manifestations, even among individuals with the same genetic mutation, is striking, implicating nongenetic factors or other genes as possible mediators of clinical presentation.
- Emesis
- Diarrhea
- Hypotension from extravasation of plasma into the skin
- Hemoconcentration
- Azotemia
- CNS complaints, including headache, hemiparesis, and seizures, may be triggered by trauma or stress.
- AAE presents similarly, in the same way but usually in the 4th decade of life; not associated with a familial history.
Physical Exam
Depending on the clinical features, angioedema causes pale, well-demarcated, tense, brawny, nonpruritic, and nonpitting single or multiple localized swellings. These may involve the periorbital tissues, genitalia, face, tongue, lips, larynx, extremities, and GI tract.
Diagnostic Tests & Interpretation
Lab
- C1-INH concentration
- C1-INH activity
- C4 concentration: low serum level
- C4D: cleavage product of C4, low even when C4 is normal
- C1q concentration (usually lower in patients with AAE)
Differential Diagnosis
- IgE mediated
- Episodic angioedema
- Allergic reactions to food and drugs
- Physically induced angioedema
- Hypocomplementemic HAE
- Idiosyncratic
- Lupus erythematosus
- Idiopathic
Treatment
General Measures
- During an acute episode, management focuses on adequate respiratory and fluid resuscitation and the treatment of pain.
- In HAE, acute attacks are treated with replacement of the C1-INH with IV concentrates. Fresh frozen plasma may also be used.
- Recent studies have shown benefit with recombinant human C1-INH for acute attacks and prophylaxis.
- A recent study has demonstrated that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.
- For prophylaxis, androgens (such as danazol and stanozolol) are used in postpubertal patients with HAE of both types. These androgens stimulate the synthesis of C1-INH, and although the level of activity is not normalized, it is increased sufficiently to be clinically efficacious.
- In prepubertal children, androgens are used only in those with severe attacks; purified C1-INH can be used if available. Antifibrinolytics should be used in prepubertal children over androgens.
- Patients should avoid estrogen oral contraceptive pills (OCPs) or use with caution.
- For patients who do not tolerate androgens, tranexamic acid and ε-aminocaproic acid (antifibrinolytic inhibitors or plasmin activity) may be used, although they carry the risk of significant side effects.
- AAE type I patients may respond to epinephrine for reversal of airway compromise.
- AAE type I requires an intensive search for malignancy, although this form of AAE occasionally appears before the development of clinical signs of the malignancy.
- Androgens are also effective in preventing attacks in individuals with this syndrome.
- AAE type II requires immunosuppression to decrease formation of the autoantibody.
- These patients may respond to C1-INH concentrate.
- Androgen treatment has not led to good clinical response.
- Prophylaxis prior to dental procedures or surgery: high-dose danazol
- Potential treatment: plasma kallikrein antagonists, bradykinin antagonists, serine protease inhibitors
- Genetic counseling: Given the autosomal dominant inheritance, family counseling is important.
Inpatient Considerations
Initial Stabilization
Therapy is divided into management of the acute attack, maintenance therapy for HAE, and more specific interventions for those with AAE.
Additional Reading
- Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3)(Suppl):S51-S131. [View Abstract]
- Bernstein J. Hereditary angioedema: validation of the endpoint time to onset of relief by correlation with symptom intensity. Asthma Allergy Proc. 2011;32(1):36-42. [View Abstract]
- Csepregi A, Nemesanszky E. Acquired C1 esterase inhibitor deficiency. Ann Intern Med. 2000;133(10):838-839. [View Abstract]
- Frank MM. Update on preventive therapy (prophylaxis) of hereditary angioedema. Asthma Allergy Proc. 2011;32(1):17-21. [View Abstract]
- Gompels M, Lock R, Abinun M. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139(3):379-394. [View Abstract]
- Riedl MA. Update on the acute treatment of hereditary angioedema. Asthma Allergy Proc. 2011;32(1):11-16. [View Abstract]
- Weiler C, van Dellen R. Genetic tests indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006;81(7):958-972. [View Abstract]
Codes
ICD09
- 277.6 Other deficiencies of circulating enzymes
ICD10
- D84.1 Defects in the complement system
SNOMED
- 82966003 Hereditary angioneurotic edema (disorder)
FAQ
- Q: What are other causes of angioedema?
- A:
- Classic allergic reactions to food and drugs
- Physically induced angioedema
- IgE-mediated episodic angioedema
- Idiosyncratic reactions to nonsteroidal anti-inflammatory and other drugs
- Lupus erythematosus
- Idiopathic causes
- Q: What are the usual precipitating factors in causing reactions?
- A: Recurrent episodes of angioedema, abdominal pain, nausea, and vomiting that occur spontaneously or after local trauma, especially to the upper respiratory tract:
- Vigorous exercise
- Emotional stress
- Menstruation