Hereditary Angioedema
Figure 1: A Schematic Diagram Showing the Inhibitory Roles of C1-inhibitor in the Complement, Contact and Fibrinolytic Systems
Complement pathway C1q C1r C1s C1s
Complement protease C1
Activation
High-molecular- weight kininogen
C1INH C1q C1r C1s C1s
Assembly of C3 convertase
+ C1q C1r C1s C1s C1r C4b C2a C1INH = C1-inhibitor. Adapted with permission from Zuraw, 2008.5 C1INH Fibrin degradation C1INH Fibrin Bradykinin + Icatibant
Bradykinin B2 receptor
Cell membrane C1r + C1INH Plasmin
C1INH and ecallantide
Cleaved
high-molecular- weight kininogen
Kallikrein
Factor XIa
+ C1r Contact activation pathway
High-molecular- weight kininogen
Factor XI
C1INH +
Factor XIIa
+ Fibrinolytic pathway Plasminogen + + +
High-molecular- weight kininogen
Kallikrein
Factor XII
C1INH and ecallantide
+
High-molecular- weight kininogen
C1INH Prekalikrein
Table 1: A Summary of Hereditary Angioedema Summary
Cause
People with Hereditary Angioedema Experience Acute Attacks Of Local Swelling (Angioedema)
Prevalence Symptoms
HAE is caused by mutations in the C1INH gene. Low functional levels of C1INH protein in the blood can result in inappropriate production of substances that increase vascular permeability and cause local swelling Estimates range from 1 in 10,000 to 1 in 50,000
Usually begin in childhood or adolescence Acute attacks of local swelling
Early symptoms may occur one to 12 hours before an established attack, e.g. non-itchy rash, fatigue, muscle aches, tingling, headache, peristaltic changes and mood changes
Occur spontaneously or in response to physiological or psychological stress e.g. surgery, trauma, infections or menstruation
Locations of attacks
Frequency of attacks varies between patients from several attacks per week to less than one per year Untreated attacks can last between 48 and 120 hours The location of attacks affects the symptoms: Larynx – obstruction of the airway
Abdomen – abdominal pain, often accompanied by vomiting and diarrhoea
Extremities, face and genitals – disfigurement, disability and pain
C1INH = C1-inhibitor; HAE = hereditary angioedema.
Hereditary Angioedema Treatments Treatments for patients with HAE are commonly divided into treatments that stop a progressing acute attack (on demand) and prophylactic treatments that reduce the occurrence of attacks or prevent the anticipated triggering of an attack. Prophylactic treatment may be appropriate for patients who suffer frequent and severe attacks, or for patients undergoing dental surgery or other procedures that may trigger attacks.11
Treatments for Acute Attacks
Fresh frozen plasma, the first available treatment for acute attacks of HAE,12
was superseded by the use of concentrated C1INH derived from human plasma. The available dose of functional C1INH in fresh frozen plasma is limited by the low concentration (1U/ml), and fresh frozen plasma carries a higher risk of human virus transmission. Since it also contains other active ingredients, it may paradoxically worsen the symptoms of an acute attack.13
Therefore, fresh frozen
plasma should only be considered to treat acute attacks if C1INH or other treatments (see Table 2) are not available.2,11
There are two preparations of plasma-derived C1INH approved for the treatment of acute HAE attacks within Europe, Berinert® and Cetor®/Cebitor®. Recently, regulatory approval of Berinert was extended to many EU countries and it was also approved for the treatment of acute abdominal and facial HAE attacks in the US,14 following the demonstration of the efficacy of 20U/kg in a randomised placebo-controlled trial.15
production of a non-functional C1INH protein. The clinical manifestations of type 1 and 2 HAE are the same. HAE attacks occur when the systems regulated by C1INH are activated inappropriately, producing signalling molecules such as bradykinin that locally increase vascular permeability (see Figure 1).9,10
130
Two new drugs, icatibant (Firazyr®) and ecallantide (Kalbitor®), were recently approved for the treatment of acute attacks in Europe and the US, respectively.16,17
Both drugs should be administered subcutaneously, and both inhibit the activity of pathways involved in HAE attacks. Specifically, ecallantide inhibits kallikrein, decreasing the formation of
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
C2
C4
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84