A case of pain…
A case of pain…
Alan Chan, MD
Med-peds resident
Diagnosed with Hereditary Angioedema type I, not started on therapy due to patient preference
Definition
Angioedema – self limited local swelling of the skin
Urticaria or hives – flushing, generalized itching, near syncope, hypotension with mast cell activation
History
First described and Autosomal Dominant inheritance pattern realized by Sir William Osler in 1888.
Protein defect described in 1963 by Donaldson and Evans.
Types of familial angioedema
Type I – absence of one allele with resulting decreased expression of C1-inh in plasma – most cases (85%) – labs shows low antigenic protein and functional activity
Type II – expression of a dysfunctional protein – normal level, but low function
Suggested type III – normal levels and function, estrogen dependent
Acquired type of Angioedema
typically older
Type I - may be from B cell malignancies, and rheumatologic disorders, autoimmune
Immune complexes that are formed more in these diseases thought to consume C1 esterase inh
Type II – autoAb (IgG, IgA, or IgM) against C1 INH produced, bind and inactivate it.
Can result in inactivation of C1-INH
Idiopathic Angioedema
Defined as >= 3 episodes of recurrent angioedema in 1 yr period with no apparent cause
Estimated to effect up to 20% of people at some point in life.
Up to ½ have urticaria – not seen in other types
ACE inhibitor induced AE
Also seen in antibiotics, narcotics, NSAIDs, ARBs (losartan)
Class effect
Hapten hypothesis from allergic standpoint may explain the urticaria more than the angioedema.
ACE substrate on angiotensin I and BK; excess of latter causes effect
Usually onset within 1st week, and can be a few years out from 1st use.
Background
Incidence is about 1/50,000
Typically symptoms begin in childhood, although diagnosis delayed average of 10 years.
As many as 20-25% are spontaneous mutation
Labs
Patient S. O.
C4 9 (14-40)
C1 inhibitor antigenic protein 15 (19-37)
C1 inhibitor functional level 60 (nl is >=60)
Onset
Typically in childhood, worsen in puberty, and unpredictable severity
Attacks typically have a prodrome, like a “tingling” sensation
Skin - Erythematous rash, nonpruritic
Random swelling – hands, arms, feet, abdomen, face
Usually no fever, or leukocytosis
Shift of fluids in abdominal attacks can cause hypotension
Involvement of airways – risk of asphyxiation
Risks
Typically attacks without trigger, but some may be local trauma such as dental work and stress
Pregnancy seems to have decreased attack frequency – total circulating C1-INH increases.
Attacks reported associated with oral contraceptive use and menstruation.
C1 Inhibitor function, a serine protease
(like a1 antitrypsin, antithrombin)
Inactivation of Factors XIIa (Hageman) , XIIf, and XIa
Direct ininhibition of activated kallikrein
Contact system
C1 inhibitor suggested to inactivated 90% of factor XIIa and its metabolite XIIf, and almost half of kallikrein
Kallikrein cleaves HMW kininogens and bradykinin release
Also cleaves plasminogen to active plasmin, which cleaves factor XII
Factor XII undergoes some autoactivation
Short term treatment
use C1 inh replacement, FFP. Latter is controversial because it has contact proteins that could promote bradykinin release
Prophylaxis (prior to dental work) – C1 inh, or androgen (takes days), or FFP 1-12 hr before
C1 inh replacement (Cinryze and Berinert P) – very expensive!
Antifibrinolytics (EACA, TA) – thought to inhibit plasmin activation – sparing effect. Not FDA approved.
C1 INH - seem to work based on one study with 11 pts, and another with 125 pts.
FFP – case reports of efficacy.
Long term
Avoid triggers including drugs, estrogen meds, tamoxifen, ACEI
17a – androgens (danazol and stanozolol), to increase C1 INH, C4, and C2 levels – thought to increase aminopeptidase P (inactivates kinins), increase hepatic production of C1 INH.
Doses can be adjusted to as low as danazol 200 mg 3 days a week.
Androgens
These attenuated androgens contraindicated in pregnancy, childhood.
Antifibrinolytic agents
Used in pediatrics (before Tanner V puberty), but not as affective.
Only EACA available in US.
Also used in acquired angioedema.
Common side effects - muscle cramps, myalgia, elevated CK
New agents
Ecallantide, kallikrein inhibitor (Kalbitor).
Developed by novel unmet medical needs company. Also for use in CV surgery to reduce blood loss during on-pump procedures like bypass.
Originally for inflammation and oncology indications.
Icatibant (Firazyr), bradykinin receptor antagonist, approved only in Europe.
References
Weis M. Clinical Review of HAE: Diagnosis and Management. Postgraduate Medicine 2009; 121(6): 113-120.
Nzeako UC, Frigas E, Tremaine WJ. Hereditary Angioedema. Arch Intern Med. 2001; 161: 2417-2429.
Zuraw B. Hereditary Angioedema. NEJM. 2008; 359: 1027-36.
Bowen T, Cicardi M, Frank M. Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008; 100(Suppl 2): S30-40.
Frank MM, Jiang H. New therapies for hereditary angioedema: Disease outlook changes dramatically. J Allergy Clin Immunol. 2008; 121(1); 272-80.
Uptodate articles accessed 2/20/2010. Diagnosis of hereditary and acquired angioedema (C1 inhibitor disorders)
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