CASE presentation & TOPIC discussion

a presentation of a case seen recently in casualty in our weekly morning meetings, with an indepth discussion of the diagnosis.

1. ANGIOEDEMA:ANGIOEDEMA:
CASE & DISCUSSIONCASE & DISCUSSION

Pathophysiology and ManagementPathophysiology and Management

2. CaseCase
GMGM
68 year old female68 year old female
Presented to the casualty early hours of morning Presented to the casualty early hours of morning
on Saturday 6 April 2013on Saturday 6 April 2013
C/o swelling in mouth and face with increasing C/o swelling in mouth and face with increasing
‘tightening’ of throat, progressively worsening ‘tightening’ of throat, progressively worsening
over last 12hrsover last 12hrs
No new medications, no medical or food allergyNo new medications, no medical or food allergy

3. PMHx:PMHx:
HypertensionHypertension
DMDM
Current breast cancer patient on chemotherapyCurrent breast cancer patient on chemotherapy
Had similar presentation one year ago, treated at Had similar presentation one year ago, treated at
hospital hospital
No known allergiesNo known allergies

4. Social Hx:Social Hx:
Nil of noteNil of note
Surgical historySurgical history: :
Biopsy breast lump 3 years ago.Biopsy breast lump 3 years ago.

5. Meds:Meds:
PerindoprilPerindopril
HCTZHCTZ
SimvastatinSimvastatin
MetforminMetformin
AspirinAspirin
lasixlasix
Chemotherapy (drug names unknown to Chemotherapy (drug names unknown to
patient’s daugther)patient’s daugther)

6. sats 97% R/A, BP 150/90 regular pulsesats 97% R/A, BP 150/90 regular pulse
tachycardiactachycardiac
No stridor No stridor
Edema of lips and mainly of tongueEdema of lips and mainly of tongue
Posterior pharyngeal wall not well visualizedPosterior pharyngeal wall not well visualized
Flexible scope, larynx anatomically normal no Flexible scope, larynx anatomically normal no
oedema or impending airway obstructionoedema or impending airway obstruction

8. DDx:DDx:
AngioedemaAngioedema
Facial lymphedemaFacial lymphedema
Autoimmune (Sjogren’s, SLE)Autoimmune (Sjogren’s, SLE)
HypothyroidismHypothyroidism
SVC syndromeSVC syndrome

9. Management:Management:
Kept in casualty for initial treatmentKept in casualty for initial treatment
Anti hypertensives given with omission of coversylAnti hypertensives given with omission of coversyl
Lasix 20 mg iviLasix 20 mg ivi
Decadron 8 mgDecadron 8 mg
In 5 mins, the tongue almost halved in size and In 5 mins, the tongue almost halved in size and
patient was much more comfortable and not patient was much more comfortable and not
distresseddistressed
Patient then admitted to ward for continuation of Patient then admitted to ward for continuation of
corticosteroids and monitering of vitalscorticosteroids and monitering of vitals
Patient discharged after 24 hours of monitering and Patient discharged after 24 hours of monitering and
getting dexamethasone in the wardgetting dexamethasone in the ward

10. ANGIOEDEMAANGIOEDEMA

11. Definition:Definition:
Rapid nonpitting edema of the dermis, subcutaneous Rapid nonpitting edema of the dermis, subcutaneous
tissue, mucosa and submucosal tissuestissue, mucosa and submucosal tissues

12. Areas of involvement:Areas of involvement:
Face Face
LipsLips
LarynxLarynx
ExtremitiesExtremities
GenitalsGenitals
IntestinesIntestines
If involvement of face/larynx = potentially life-If involvement of face/larynx = potentially life-
threateningthreatening
94% of the time involves structures in the H&N94% of the time involves structures in the H&N

13. Epidemiology:Epidemiology:
10% of Americans have an episode once in their 10% of Americans have an episode once in their
lifetime (20% in south africa)lifetime (20% in south africa)
Higher in hypertensive patients that are on ACE Higher in hypertensive patients that are on ACE
inhibitorsinhibitors
Usually in 3Usually in 3
rdrd
/4/4
thth
decades of life decades of life
M=FM=F
Attacks usually self-limiting and resolve in 24-48 Attacks usually self-limiting and resolve in 24-48
hours hours
Principal cause of mortality is airway compromisePrincipal cause of mortality is airway compromise

14. Basic Pathophysiology:Basic Pathophysiology:
Increased vascular permeability in the Increased vascular permeability in the
submucosal, subcutaneous, and deep dermal submucosal, subcutaneous, and deep dermal
tissues.tissues.
Mediated by vasoactive substances:Mediated by vasoactive substances:
•HistamineHistamine
•BradykininBradykinin
•Products of complement cascade: C3a, C5aProducts of complement cascade: C3a, C5a

15. 5 Main Causes:5 Main Causes:
1.1.Hereditary C1INH deficiencyHereditary C1INH deficiency
2.2.Acquired C1INH deficiencyAcquired C1INH deficiency
3.3.ACE inhibitorsACE inhibitors
4.4.Allergic reactionsAllergic reactions
5.5.IdiopathicIdiopathic

16. Can sub-divide the causes of angioedema by mediators Can sub-divide the causes of angioedema by mediators
involved:involved:
BradykininBradykinin – Induced: – Induced:
Hereditary or acquired C1 inhibitor deficiencyHereditary or acquired C1 inhibitor deficiency
ACE inhibitorsACE inhibitors
HistamineHistamine – Induced: – Induced:
Allergic angioedemaAllergic angioedema
UnknownUnknown
IdiopathicIdiopathic

17. BradykininBradykinin
BradykininBradykinin
Peptide in blood coagulation subsystem Peptide in blood coagulation subsystem
•‘‘contact system’contact system’
Release regulated by C1-INHRelease regulated by C1-INH
Stimulus for production:Stimulus for production:
ToxinsToxins
Injury/inflammationInjury/inflammation
IschemiaIschemia
Viral infectionsViral infections

18. Kinin-Kallikrein SystemKinin-Kallikrein System
High molecular weight kininogen is combined High molecular weight kininogen is combined
with prekallikreinwith prekallikrein
Prekallikrein broken down by factor XIIa to Prekallikrein broken down by factor XIIa to
kallikreinkallikrein
Kallikrein then breaks high molecular weight Kallikrein then breaks high molecular weight
Aminogen to bradykininAminogen to bradykinin
Bradkinin is main mediator of vasopermeabilityBradkinin is main mediator of vasopermeability

19. Kinin-Kallikrein SystemKinin-Kallikrein System
C1-INH inhibits the reaction cascade at two points:C1-INH inhibits the reaction cascade at two points:
Prevents self-activation of factor XII (PreKPrevents self-activation of factor XII (PreKK)K)
Inhibits release of bradykinin from HMW kininogenInhibits release of bradykinin from HMW kininogen

20. BradykininBradykinin

21. BradykininBradykinin
Support for Bradykinin as mediator:Support for Bradykinin as mediator:
Cicardi (2003)Cicardi (2003)

: showed increased levels of : showed increased levels of
bradykinin in affected arms of patientsbradykinin in affected arms of patients
BUT increased bradykinin levels in normal patients BUT increased bradykinin levels in normal patients
taking ACEIs (prolongs survival of bradykinin)taking ACEIs (prolongs survival of bradykinin)

22. ACEi AngioedemaACEi Angioedema
Recently become the leading cause of acquired Recently become the leading cause of acquired
angioedemaangioedema
Corresponds with increasingly widespread use of Corresponds with increasingly widespread use of
ACEi to manage hypertension and CHFACEi to manage hypertension and CHF

23. Renin-Angiotensin-Aldosterone Renin-Angiotensin-Aldosterone
System (RAAS)System (RAAS)

24. ACEi AngioedemaACEi Angioedema
Mechanism:Mechanism:
ACE inhibition:ACE inhibition:
reduces the catabolism of bradykininreduces the catabolism of bradykinin
increase the availability of bradykininincrease the availability of bradykinin
*BUT bradykinin elevated in ALL patients on *BUT bradykinin elevated in ALL patients on
ACEi’s and <1% develop angioedemaACEi’s and <1% develop angioedema

25. ACEi AngioedemaACEi Angioedema
Incidence:Incidence:
Can occur at ANY time during treatment.Can occur at ANY time during treatment.
Most severe episodes occur within the first week Most severe episodes occur within the first week
of treatment.of treatment.
Some reports of incidence AFTER Some reports of incidence AFTER
discontinuation of therapy therefore may have discontinuation of therapy therefore may have
latent effect.latent effect.

26. ACEi AngioedemaACEi Angioedema
Large Trial - Determine Incidence:Large Trial - Determine Incidence:
Omapatrilat Cardiovascular Treatment versus Omapatrilat Cardiovascular Treatment versus
Enalipril (Enalipril (O.C.T.A.V.E.O.C.T.A.V.E.) trial Kostis et al (2004)) trial Kostis et al (2004)
•Double-blinded RCTDouble-blinded RCT
•N = 24,302N = 24,302
•Primary outcome: drug efficacy in cardiac settingPrimary outcome: drug efficacy in cardiac setting
•Secondary outcome – incidence of angioedemaSecondary outcome – incidence of angioedema
•2.17% vs 0.68%2.17% vs 0.68%

27. ACEi AngioedemaACEi Angioedema
Epidemiology:Epidemiology:
More common in Black populations than More common in Black populations than
Caucasian 3:1Caucasian 3:1
Increased risk unrelated to dose, type of ACEi Increased risk unrelated to dose, type of ACEi
or concomitant medicationsor concomitant medications
Increased sensitivity to elevated bradykinin Increased sensitivity to elevated bradykinin
levelslevels

28. ACEi AngioedemaACEi Angioedema
Other Risk Factors:Other Risk Factors:
ImmunocompromisedImmunocompromised
Prior history of idiopathic angioedemaPrior history of idiopathic angioedema
Seafood allergySeafood allergy

29. ACEi AngioedemaACEi Angioedema
Clinical presentation:Clinical presentation:
Wide range of symptoms Wide range of symptoms
•Life-threatening to minor swelling (may not report Life-threatening to minor swelling (may not report
to health-care provider)to health-care provider)
•Can resolve spontaneouslyCan resolve spontaneously
In severe cases:In severe cases:
•Swelling of lips, tongue, post pharynx, eyesSwelling of lips, tongue, post pharynx, eyes
•Dyspnea, dysphagia, dysphonia in up to 20% Dyspnea, dysphagia, dysphonia in up to 20%
patients patients  a/w obstruction a/w obstruction

30. ACEi AngioedemaACEi Angioedema
Treatment: Treatment:
*Difficult to tailor Rx as difficult to determine etiology *Difficult to tailor Rx as difficult to determine etiology
in acute scenarioin acute scenario
ABCs always firstABCs always first
•establish a/westablish a/w
•Tongue edema is NON pitting therefore difficult orotracheal Tongue edema is NON pitting therefore difficult orotracheal
intubationintubation
•May require nasotracheal intubation or trachMay require nasotracheal intubation or trach
Secondary goal = prevent further edemaSecondary goal = prevent further edema

31. ACEi AngioedemaACEi Angioedema
Treatment:Treatment:
Antihistamines often used, but ~ no effectAntihistamines often used, but ~ no effect
Corticosteroids – minimal/no benefitCorticosteroids – minimal/no benefit
Epinephrine – works in non-specific manner Epinephrine – works in non-specific manner
(vasoconstriction of leaky blood vessels)(vasoconstriction of leaky blood vessels)
FFP (likely the effect of functional kininase II – FFP (likely the effect of functional kininase II –
breaks down bradykinin)breaks down bradykinin)

32. ACEi AngioedemaACEi Angioedema
Currently NO diagnostic test to determine who Currently NO diagnostic test to determine who
is at riskis at risk

33. ARB AngioedemaARB Angioedema
Links have been made with ARBs and angioedemaLinks have been made with ARBs and angioedema
Highly variable results depending on the studyHighly variable results depending on the study
Controversial evidence for triggering angioedemaControversial evidence for triggering angioedema
ARBs not supposed to be involved in kinin metabolismARBs not supposed to be involved in kinin metabolism
Seen in patients who previously developed angioedema Seen in patients who previously developed angioedema
with ACEiwith ACEi

34. ARB AngioedemaARB Angioedema
Also present in patients who never received Also present in patients who never received
ACEi’sACEi’s
Unknown mechanism Unknown mechanism
Unknown incidenceUnknown incidence

35. ARB AngioedemaARB Angioedema
Cicardi et al (2004):Cicardi et al (2004):
2 of 26 patients with ACEi induced angioedema 2 of 26 patients with ACEi induced angioedema
also had angioedema when placed on an ARBalso had angioedema when placed on an ARB
Effect disappeared upon w/drawl of the ARBEffect disappeared upon w/drawl of the ARB
Recommendations: use ARBs cautiously in Recommendations: use ARBs cautiously in
patients w/ history of ACEi angioedemapatients w/ history of ACEi angioedema

36. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Rare (1:50 000-1:150 000)Rare (1:50 000-1:150 000)
Autosomal dominantAutosomal dominant
No ethnic or sexual prediliction No ethnic or sexual prediliction
Individuals affected = commonly heterozygous Individuals affected = commonly heterozygous
Disorder of C1 inhibitor (C1INH)Disorder of C1 inhibitor (C1INH)

37. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Genetics - C1INH:Genetics - C1INH:
C1 inhibitor – heavily glycosylated serine protease C1 inhibitor – heavily glycosylated serine protease
inhibitorinhibitor
Chromosome 11q11-13.2Chromosome 11q11-13.2
Single dysfunctional allele results in diseaseSingle dysfunctional allele results in disease

38. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
C1INH:C1INH:
Only regulator of classical complement pathway Only regulator of classical complement pathway
activationactivation
Involved in:Involved in:
Contact system (XII and kallikrein)Contact system (XII and kallikrein)
Complement cascade (C1r,C1s, MASP 2)Complement cascade (C1r,C1s, MASP 2)
Intrinsic coagulation cascade (XI, plasmin, tPA)Intrinsic coagulation cascade (XI, plasmin, tPA)
Low levels C1INH OR dysfunctional C1INH = Low levels C1INH OR dysfunctional C1INH =
HAEHAE

39. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
2 types of HAE:2 types of HAE:
Type IType I (85%) (85%)
low levels of C1INH and functional deficiencylow levels of C1INH and functional deficiency
Type IIType II (15%) (15%)
Normal protein concentration but functional defectNormal protein concentration but functional defect

40. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Diagnosis – Type I or II:Diagnosis – Type I or II:
Measure C1INH antigen and functional levelsMeasure C1INH antigen and functional levels
Type I – values <50% normalType I – values <50% normal
Not specific asNot specific as::
absolute C1INH level is NOT correlated with freq absolute C1INH level is NOT correlated with freq
or degree of symptomsor degree of symptoms

41. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Epidemiology:Epidemiology:
Onset of attacks usually w/in 2Onset of attacks usually w/in 2
ndnd
decade of life decade of life
Time of onset to diagnosis 3-8 yearsTime of onset to diagnosis 3-8 years

42. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Clinical Presentation:Clinical Presentation:
Repeated episodes of edema (NON pruritic and Repeated episodes of edema (NON pruritic and
NON pitting):NON pitting):
FaceFace
Extremities Extremities
Genitals Genitals
Intestines (w/ pain, N/V/D)Intestines (w/ pain, N/V/D)
Larynx (less common) Larynx (less common)
**Combination and migratory attacks common**Combination and migratory attacks common

43. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Clinical Presentation:Clinical Presentation:
Laryngeal edemaLaryngeal edema
Usually in 3Usually in 3
rdrd
decade of life decade of life
Lifetime incidence of 70% Lifetime incidence of 70%
Retrospective review (Bork, 2000): 40% pt’s lost Retrospective review (Bork, 2000): 40% pt’s lost
family member to asphyxiationfamily member to asphyxiation

44. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Clinical Presentation:Clinical Presentation:
Erythema marginatum and macular rash in Erythema marginatum and macular rash in
SOME patientsSOME patients
***NO urticaria***NO urticaria
Swelling increases over 24 hours then subsides Swelling increases over 24 hours then subsides
over next 24-72 hoursover next 24-72 hours
Frequency, duration and severity of symptoms Frequency, duration and severity of symptoms
VARIABLE even w/in same familyVARIABLE even w/in same family

45. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Clinical Presentation:Clinical Presentation:
Recognized triggers:Recognized triggers:
OCP (Estrogen – containing)OCP (Estrogen – containing)
MensesMenses
TraumaTrauma
InfectionInfection
Stress Stress
Dental surgery(trigger for laryngeal attack)Dental surgery(trigger for laryngeal attack)

46. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Labs:Labs:
1) C1INH - low levels, or elevated levels of 1) C1INH - low levels, or elevated levels of
dysfunctional C1 esterase inhibitor (detected by dysfunctional C1 esterase inhibitor (detected by
an immune assay).an immune assay).
2) Between attacks, low levels of C4 are noted.2) Between attacks, low levels of C4 are noted.

47. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Economic/Burden:Economic/Burden:
Untreated patients lose up to 100-150 work Untreated patients lose up to 100-150 work
days/yeardays/year
Morbidity ~50%Morbidity ~50%

48. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Diagnostic Criteria:Diagnostic Criteria:
A) A) Clinical:Clinical:
Self-limited, angioedema without urticaria, Self-limited, angioedema without urticaria,
recurrent and >12 hoursrecurrent and >12 hours
Self-remitting abdo pain without clear organic Self-remitting abdo pain without clear organic
etiology, recurrent and >6hrsetiology, recurrent and >6hrs
Recurrent laryngeal edemaRecurrent laryngeal edema

49. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Diagnostic Criteria:Diagnostic Criteria:
B) B) Laboratory:Laboratory:
C1INH<50% at 2 sep determinations with C1INH<50% at 2 sep determinations with
patient at basal conditionpatient at basal condition
C1INH function <50% C1INH function <50%
Mutation in C1INH gene altering protein Mutation in C1INH gene altering protein
syn/functionsyn/function
*low C4 not mentioned in criteria although part of *low C4 not mentioned in criteria although part of
initial w/uinitial w/u

50. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Supportive treatment:Supportive treatment:
Laryngeal edema:Laryngeal edema:
Prudent use ETT intubationPrudent use ETT intubation
Monitored setting until resolution of attackMonitored setting until resolution of attack
Steroids/antihistamines NOT usefulSteroids/antihistamines NOT useful
Adrenaline nebs may decrease the vascular Adrenaline nebs may decrease the vascular
component of edema but doesn’t change the component of edema but doesn’t change the
underlying processunderlying process

51. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Supportive treatment:Supportive treatment:
Intestinal edema:Intestinal edema:
Aggressive replacement fluid losses (3Aggressive replacement fluid losses (3
rdrd
spacing spacing
and V/D)and V/D)
Pain managementPain management
Non-sedating anti-emeticsNon-sedating anti-emetics
Avoid interventional procedures unless unusual Avoid interventional procedures unless unusual
s/s (hematemesis, hematochezia)s/s (hematemesis, hematochezia)

52. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Established Pharmacologic Treatments:Established Pharmacologic Treatments:
ProphalaxisProphalaxis::
1)1)Androgen derivativesAndrogen derivatives
2)2)Antifibrinolytic agentsAntifibrinolytic agents
Acute attacks:Acute attacks:
3) FFP (replacement)3) FFP (replacement)
4) Purified C1INH (not available in SA)4) Purified C1INH (not available in SA)

53. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Mechanism of action:Mechanism of action:
1) Androgens (Danazol)1) Androgens (Danazol)
Stimulate hepatocytes and other cells to secrete Stimulate hepatocytes and other cells to secrete
more C1INHmore C1INH
2) Antifibrinolytics (2) Antifibrinolytics (Transexamic acid)Transexamic acid)
Inhibits fibrinolysis and reduces consumption of Inhibits fibrinolysis and reduces consumption of
C1INHC1INH

54. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Mechanism of action:Mechanism of action:
3) FFP3) FFP
Replaces C1INH missing/dysfunctional in Replaces C1INH missing/dysfunctional in
recipientrecipient
4)4)Purified C1INHPurified C1INH
Replaces C1INHReplaces C1INH

55. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Recent Study (CSL Behring):Recent Study (CSL Behring):
The The I.M.P.A.C.TI.M.P.A.C.T. trial (International Multi-centre . trial (International Multi-centre
Prospective Angioedema C1-inhibitor TrialsProspective Angioedema C1-inhibitor Trials
Phase III study conducted in N America and EuropePhase III study conducted in N America and Europe
Comparing human pasteurized C1-INH vs placebo for Comparing human pasteurized C1-INH vs placebo for
speed of relief of symptomsspeed of relief of symptoms
Studying patients with acute abdominal or facial HAEStudying patients with acute abdominal or facial HAE

56. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Future Therapies:Future Therapies:
2 Treatments Under Investigation:2 Treatments Under Investigation:
•DX-88DX-88
•Bradykinin Antagonist – IcatibantBradykinin Antagonist – Icatibant

57. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
DX-88DX-88
binds and inhibits proteolytic activity of binds and inhibits proteolytic activity of
kallikrein kallikrein
300x more specific than C1INH300x more specific than C1INH
Lumry et al (2006) showed successful Lumry et al (2006) showed successful
resolution symptoms in all 215 attacks treated resolution symptoms in all 215 attacks treated
with DX-88with DX-88

58. Kinin-Kallikrein SystemKinin-Kallikrein System

59. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Bradykinin antagonist – IcatibantBradykinin antagonist – Icatibant
 potent, selective bradykinin receptor antagonistpotent, selective bradykinin receptor antagonist
Bork et al (2007) showed treatment considerably Bork et al (2007) showed treatment considerably
shortened duration of attacks compared with shortened duration of attacks compared with
untreated attacks (1.0 hr vs several hrs)untreated attacks (1.0 hr vs several hrs)

60. Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)
Resolution after attack - not well understoodResolution after attack - not well understood
Theories:Theories:
1)1)Consumption of available substrates for Consumption of available substrates for
kallikreinkallikrein
2)2)Removal of triggerRemoval of trigger

61. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
2 Types:2 Types:
1)1)Type I (AAE-I)Type I (AAE-I)
•associated with other diseases, most commonly B-associated with other diseases, most commonly B-
cell lymphoproliferative disorderscell lymphoproliferative disorders
1)1)Type II (AAE-II)Type II (AAE-II)
• an autoimmune process (autoantibody directed an autoimmune process (autoantibody directed
against the C1 inhibitor molecule (C1-INH). against the C1 inhibitor molecule (C1-INH).

62. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
Pathophysiology:Pathophysiology:
1)1)AAE-IAAE-I
•assoc disorders (usually lymphoproliferative assoc disorders (usually lymphoproliferative
malignancies, most common – B cell lymphoma) malignancies, most common – B cell lymphoma)
•produce complement-activating factors, antibodies, produce complement-activating factors, antibodies,
or other immune complexesor other immune complexes
•destroy C1-INH functiondestroy C1-INH function

63. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
PathophysiologyPathophysiology
2)2)AAE-IIAAE-II
•normal C1-INH molecule is synthesized in normal C1-INH molecule is synthesized in
adequate amountsadequate amounts
•subpopulation of B cells secretes autoantibodies to subpopulation of B cells secretes autoantibodies to
the C1-INH moleculethe C1-INH molecule
•autoantibody binds to the reactive center of C1-autoantibody binds to the reactive center of C1-
INH and its regulatory capacity is INH and its regulatory capacity is
diminished/destroyed.diminished/destroyed.

64. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
EpidemiologyEpidemiology
Rare (150 cases reported in the literature)Rare (150 cases reported in the literature)
?M=F??M=F?
Race?Race?
Onset most common after 4Onset most common after 4
thth
decade of life decade of life

65. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
Clinical presentation:Clinical presentation:
*no family history (distinguish from HAE)*no family history (distinguish from HAE)
PainlessPainless
Non-pruritic Non-pruritic
Non-pitting Non-pitting
Usually not assoc with urticariaUsually not assoc with urticaria
Edema of the skin and subcutaneous tissuesEdema of the skin and subcutaneous tissues

66. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
Labs:Labs:
AAE-I and AAE-II AAE-I and AAE-II
Low C1-INH levels Low C1-INH levels
Low C1q levels (except 1 reported case) Low C1q levels (except 1 reported case)
Low C4 levels Low C4 levels
Low C2 levels Low C2 levels
AAE-II - Positive immunoblot assay findings for 95-AAE-II - Positive immunoblot assay findings for 95-
kd C1-INH cleavage product kd C1-INH cleavage product

67. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
Management:Management:
Supportive (airway)Supportive (airway)
Androgens Androgens
may be beneficial in AAE-I but are of no value in may be beneficial in AAE-I but are of no value in
AAE-IIAAE-II
AntifibrinolyticsAntifibrinolytics
more effective for long-term prophylaxis in those more effective for long-term prophylaxis in those
with AAE.with AAE.

68. Acquired Angioedema (AAE)Acquired Angioedema (AAE)
Management:Management:
Immunosuppressive therapyImmunosuppressive therapy
Direct toward decreasing autoantibody production Direct toward decreasing autoantibody production
may be of value in patients with AAE-IImay be of value in patients with AAE-II

69. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria

70. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Reactions are induced by histamine and Reactions are induced by histamine and
mediated by IgEmediated by IgE
IgE mediated hypersensitivity reactionIgE mediated hypersensitivity reaction
Reaction with allergen induces the release of Reaction with allergen induces the release of
histamine and other mediatorshistamine and other mediators
Result: vasodilatation and edemaResult: vasodilatation and edema

71. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria

72. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Biochemistry:Biochemistry:
Dependent on presence IgE molec sp to Dependent on presence IgE molec sp to
proteins in causative agentproteins in causative agent
IgE molec bind to patients mast cellsIgE molec bind to patients mast cells
Trigger rxn upon re-exposure to antigenTrigger rxn upon re-exposure to antigen

73. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Inciting Agents:Inciting Agents:
MedicationsMedications
FoodsFoods
Latex Latex
Environmental (includes insect bites)Environmental (includes insect bites)

74. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Clinical Presentation:Clinical Presentation:
Highly variableHighly variable
Depends on:Depends on:
 prev sensitizationprev sensitization
type of allergentype of allergen
+/- urticaria+/- urticaria
(pruritic)(pruritic)

75. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Clinical Presentation:Clinical Presentation:
Often seen in patients with other allergic Often seen in patients with other allergic
conditions:conditions:
Atopic dermatitisAtopic dermatitis
Allergic rhinitis Allergic rhinitis
Asthma Asthma

76. Allergic Angioedema/UrticariaAllergic Angioedema/Urticaria
Management:Management:
As always, airway firstAs always, airway first
AAE does respond to:AAE does respond to:
SteroidsSteroids
H1 and H2 blockersH1 and H2 blockers
subcutaneous epinephrinesubcutaneous epinephrine
antihistamines. antihistamines.

77. Management AngioedemaManagement Angioedema