A. Symptoms

1. Red, warm swelling, usually in head and neck, larynx, and/or extremities
2. Laryngeal swelling may compromise airway leading to stridor
3. Abdominal pain followed by watery diarrhea common in acute attacks
4. Edema is subepithelial and accumulates in areas of loose subcutaneous tissue
5. Angioedema alone is not pruritic
6. Urticaria is present in allergic form

B. Etiology

1. Allergic (Histaminergic) Reactions [1]
   1. Pruritus and cough are often present
   2. Late onset after drug
   3. Prior drug exposure
   4. Nausea / abdominal pain are uncommon
   5. Histamine reactions occur in most cases
   6. Most cases respond to histamine blockade
   7. Bradykinin (BK) does not appear to be involved
2. Side Effect of ACE Inhibitors [1,7,8]
   1. Occurs in ~0.5% of patients on ACE inhibitors
   2. Risk in African Americans may be about 5X higher than overall risk
   3. Likely due to accumulation BK (ACE is a kininase) [1]
   4. Substance P, prostaglandins and/or thromboxanes may be involved [5]
   5. Angiotensin II receptor antagonists can also cause angioedema but much lower risk [8]
   6. The risk of second reaction after primary angioedema is very high [7]
3. Hereditary [2,11]
   [Figure] "The Complement Cascade"
   1. Abnormality of Complement Protein 1 (C1) esterase inhibitor (C1-Inh)
   2. Inherited as autosomal dominant trait in most families
   3. usually presents prior to age 40
   4. Two forms of hereditary C1-Inh dysfunction occur:
   5. Absence (type 1) or Dysfunction (type 2)
   6. Type 1 due to mutation that prevents transcription of C1-inh
   7. Type 2 due to mutation that alters protein sequence and reduces serine protease activity
   8. Control of contact activation and kinin systems through Factor XII and Kallikrein
   9. Blood C4 levels are depressed in acute attacks and should be used for screening
   10. If C4 depressed during attack, then C1q esterase inhibitor level should be obtained
   11. Helicobacter pylori induced inflammation may provoke attacks [12]
   12. 30% of patients with hereditary angioedema had anti-H. pylori Abs [12]
   13. Symptoms include recurrent swelling of subcutaneous and mucous tissues
   14. Gastrointestinal wall swelling may cause abdominal pain
   15. Urticaria is nearly always present
   16. Usually responds to antihistamine treatment
   17. BK levels very high in patients with antihistamine resistant attacks [1]
   18. Epinephrine for severe throat swelling can abort severe attacks
4. Acquired (Autoimmune) C1 Esterase Inhibitor Deficiency [3,10]
   1. Associated with B cell lymphoproliferative disorders (mainly non-Hodgkin's lymphoma) and monoclonal gammopathies [13]
   2. Also found in some autoimmune disorders
   3. Symptoms identical to hereditary form
   4. Usually affects adults or elderly patients
   5. Patients usually present with recurrent angioedema, low levels of C4, and normal C3
   6. Confirm diagnosis by showing low levels of C1q and low C1 esterase inhibitor activity
   7. Androgens (danazol or stanozolol) are often effective
   8. Glucocorticoids may be added or used alone with good effects
   9. Treatment of underlying neoplastic or autoimmune disorders can be effective
   10. Long term androgens can be used to prevent attacks
5. Idiopathic Nonhistaminergic Angioedema [9]
   1. Cutaneous swellings without urticaria
   2. Does not respond to antihistamines
   3. Syndrome may occur in families
   4. Tranexamic acid appears to be effective, but is not readily available (see below)
   5. Likely that BK plays a role

C. Differential Diagnosis [2]

1. C1q Inhibitor Deficiency
2. Allergic (IgE Mediated) Reactions
3. Cold and/or exercise induced angioedema
4. Direct histamine release (anaphylactoid) - morphine, codeine, radiocontrast media
5. Idiopathic
6. Other
   1. NSAID sensitivity
   2. C2 deficiency: Cold urticaria
   3. Hypocomplementemic vasculitis (usually with urticaria)
   4. Serum Sickness
   5. Cutaneous and systemic mastocytosis
   6. C3b inactivator deficiency
   7. Carboxypeptidase B deficiency
   8. Amyloidosis

D. Treatment of Angioedema

1. Acute
   1. Epinephrine
   2. Glucocorticoids and anti-H1-histamines (diphenhydramine)
   3. Monitor airway
   4. Avoid other ACE Inhibitors
   5. Plasma C1-inhibitor concentrate or Fresh-Frozen Plasma (FFP) 4-6 Units
2. C1 Inhibitor Concentrate [4]
   1. Vapor-heating the concentrate inactivates HIV, HBC, and HCV
   2. The vapor concentrate is effective in prevention and treatment of hereditary angioedema
   3. Dose is 25 U/kg iv for prophylaxis or emergent treatment
3. Other agents [4]
   1. Indomethacin, other NSAIDs reduce ACE-I cough but raise diastolic BP
   2. Nifedipine also effective in reducing the cough and resulted in lowering of DBP
   3. Thromboxane antagonist can reduce cough in most patients [5]
   4. Chronic: diphenhydramine (Benadryl®), hydroxazine (Vistaril®, Atarax®)
4. Long Term Therapy of Hereditary and Autoimmune Forms
   1. Attenuated Androgens: Danazol 50-800mg po qd Stanozolol 2-4mg po qd
   2. E-Aminocaproic Acid (EACA; Amikar®) 20-30gm daily may be effective prophylaxis
   3. Amikar® at these doses causes muscle weakness, myolysis, vascular thrombosis
   4. Tranexamic acid (anti-fibrinolytic) no longer available due to oncogenic potential
   5. C1 inhibitor concentrate reduces risk of attacks with no side effects [6]
5. Eradication of Helicobacter Pylori [12]
   1. H. pylori induced inflammation may trigger humoral immune responses
   2. This inflammation could lead to C1-esterase inhibitor depletion triggering angioedema
   3. Eradication of H. pylori reduced angioedema attacks by ~80% in ~50% of patients

References

1. Nussberger J, Cugno M, Cicardi M. 2002. NEJM. 347(8):621
2. Sim TC and Grant JA. 1990. Am J Med. 88(6):657
3. Cicardi M, Bisiani G, Cugno M, et al. 1993. Am J Med. 95(2):169
4. Fogari R, Zoppi A, Tettamanti F, et al. 1992. J Cardiovasc Pharmacol. 19:670
5. Malini PL, Strochhi E, Zanardi M, et al. 1997. Lancet. 350:15
6. Waytes AT, Rosen FS, Frank MM. 1996. NEJM. 334(25):1630
7. Brown NJ, Snowden M, Griffin MR. 1997. JAMA. 278(3):232
8. deShazo RD and Kemp SF. 1997. JAMA. 278(22):1895
9. Cicardi M, Bergamaschini L, Zingale LC, et al. 1999. Am J Med. 106(6):650
10. Markovic SN, Inward DJ, Frigas EA, Phyliky RP. 2000. Ann Intern Med. 132(2):144
11. Walport MJ. 2001. NEJM. 344(14):1058
12. Farkas H, Fust G, Fekete B, et al. 2001. Lancet. 358(9294):1695
13. Fremeaux-Bacchi V, Guinnepain MT, Cacoub P, et al. 2002. Am J Med. 113(3):194