15
2.3 Pathophysiology: C1-INH Deficiency as
the Fundamental Cause of HAE Symptoms
However, experts have come to believe that the distinction
between HAE-I and HAE-II may be less absolute, and
some individuals may have varying combinations of both
dysfunctional and low plasma levels of C1-INH.
5,24
A third form of HAE has been described, often referred
to as type III HAE. It mainly occurs in women and is not
associated with increased or dysfunctional C1-INH but with
other defects including mutations in the coagulation factor XII
gene. Type III HAE is not addressed in this monograph.
C1-INH is a single-chain glycoprotein that consists of 478
amino acid residues organized into 3 beta-sheets and 8
or 9 alpha-helices. It has an isoelectric point of between
pH 2.7 and 2.8 and its physiological plasma concentration
Genetic Mutation
11q12-13.1
•
Autosomal Dominant
•
de Novo
C1-INH Deficiency
•
Quantitative (HAE-I)
•
Qualitative (HAE-II)
•
Kallikrein-Kinin System
•
Complement System
•
Fibrinolysis
•
Coagulation Cascade
Plasma Cascade
Dysregulation
Vascular Permeability
Angioedema
•
Cutaneous
•
Mucous Membrane
Figure 5 – Pathophysiology of
Hereditary Angioedema
in a healthy human is approximately 270 mg/L. In case of
infections, the plasma level increases up to 2-fold, and for
this reason C1-INH is regarded as an acute phase protein.
C1-INH is mainly produced in the parenchymal cells of the
liver and is present in normal human plasma.
6
Monocytes,
fibroblasts, endothelial cells, and microglial cells are also
sites of normal C1-INH production.
8,26
As mentioned previously, the fundamental cause of HAE
results from a mutation of the
SERPING1
gene, which causes
a quantitative and/or qualitative deficiency of the C1-INH
molecule (Figure 5). This deficiency can result in recurrent,
episodic, nonpitting, circumscribed edema. The angioedema
occurs because of locally increased vascular permeability and
the extravasation of plasma from capillaries or postcapillary
venules into the deeper cutaneous and/or mucosal layers.
10
HAE
