Case Presentation June 25, 2004 H. Henry Li, MD, PhD Institute for Asthma and Allergy

Patient History  52 Y/O, F  Frequent Abdominal pain since early childhood  No vomiting, diarrhea, or skin rash  Evaluation for food allergies, parasite infections, etc. all negative

Patient History  In her 20’s, appendectomy  In her 30’s, ectopic pregnancy  In her 40’s, cholycystectomy  Six exploratory abdominal procedures in 30 year period of time  2 month before the OV, started to have lip and tongue swelling

Laboratory Examination  C1 esterase inhibitor: None detected  C1 esterase inhibitor, functional: None  C4: < 6 mg/dl  Hgb: 9.6,  Iron: 32  g/dl  Ferritin: 10 ng/dl

Family History

Major Features of Hereditary Angioedema  Onset generally in youth  Autosomal dominant inheritance, Incomplete penetrance, de novo mutation  Abdominal pain common  Laryngeal edema relatively common  Urticaria and pruritus absent  C1 inhibitor deficiency

Contact activation pathway leading to bradykinin formation.

 Inhibits C1r and C1s of the complement system  Inhibits activated factor XIIa and kallikrein  An inhibitor of factor XIa and plasmin  Inhibits activation of C1 C1 Inhibitor Functions

Role of C1 inhibitor Trace Factor XIIa Factor XIIFactor XIIa Prekallikrein Kallikrein HK Bradykinin Factor XIIf C1 C4, C2 digestion Surface Inhibited By C1 INH Plasmin Plasminogen

Further Data Regarding C1 INH  Complete acid sequence known; heavily glycosylated  Generation of cDNA clones accomplished, localization to chromosome 11  Deficiency heterogeneous by DNA restriction fragment length polymorphisms  Deficiency frequently associated with autoimmune phenomena  Mechanisms of acquired C1 inhibitor deficiency:  Depletion by complement activation  Contact system activation  Anti-C1 inhibitor antibodies  Anti-idiotypic antibodies

Lab Tests for C1 INH Deficiency  C4 low; C4d/C4 ratio always elevated  C1 inhibitor protein low in about 85% of cases  C1 inhibitor only functionally deficient in about 15%  C1q antigen low in acquired deficiency  Abnormal C1 inhibitor mobility (lower molecular weight) on SDS gel electrophoresis

Treatment of HAE  Patient education very important; test family  No regular medication needed in many cases  Long term prophylactic anabolic androgens and antifibrinolytics  Short term prophylaxis  Symptomatic treatment during attacks

Long Term Prophylaxis  Stanozolol (1-4 mg/day); (more virilizing, less expensive)  Danozol (50 mg qod – 200 mg tid)  Epsilon aminocaproic acid (EACA, Amicar) an option

Short Term Prophylaxis  Fresh frozen plasma, 2 units, 7 hour before procedure  High dose of Danazol/Stanozolol, 7 –10 days before procedure

Treatment of Acute Attacks  Antihistamine, Epinephrine, corticosteroids, limited value  Pain relieve with narcotics  C1 INH infusion  EACA IV  FFP use with care  New medications

Future Treatment Options  C1 esterase inhibitor infusion  Human Concentrates  Transgenic rh C1 INH  Kallikrein inhibitor  Bradykinin receptor blocker