Hereditary Angioedema

Hereditary AngioedemaWe have previously discussed Chronic Recurrent Abdominal Pain. Certainly, this is not a sensational topic, yet it is one that is encountered often and can not only derail your shift, but may also obscure our view of the true underlying, etiology.  As is always the case, our job is to remain vigilant for the subtle presentation of the serious condition, while remaining reasonable in our approach to evaluation.  Most often, this challenge is accomplished by honing our curiosity and obtaining a thoughtful history and physical exam.  With these “simple” and elegant tools, perhaps we can discover a cause of recurrent abdominal pain, like Hereditary Angioedema!

 

Hereditary Angioedema: Basics

  • Inherited in an Autosomal Dominant fashion!
    • Although can occur de novo.
    • There may be a delay in diagnosis in those without a family history. [Nada, 2015]
  • Due to Protein C1-Inhibitor inactivity or inadequate activity. [MacGinnitie, 2014]
    • C1-Inhibitor is a protease that inhibits (you guessed it) C1.
      • C1 is the 1st component in the classical complement cascade.
      • C1-Inhibitor also inhibits other enzymes (kallikrein, Factors XI and XII, and tissue plasminogen activator).
    • Low Protein C1-Inhibitor activity leads to increased levels of bradykinin (due to increased kallikrein activity).
    • Increased bradykinin leads to increased vascular permeability and, thus, edema.

 

Hereditary Angioedema: Presentation

  • Typically presents in childhood. [Christiansen, 2015]
    • Median age of 1st swelling – 11 years
    • Median age of diagnosis – 19 years
      • Those who develop symptoms earlier seem to have longer delays in diagnosis.
      • Those who develop symptoms earlier seem to have more morbidity.
  • Characterized by recurrent attacks.
    • Attacks resolve slowly, usually over 2-5 days.
    • Non-pruritic swelling.
    • Often painful swelling.
  • Attacks can be triggered stress and trauma.
  • Causes symptoms through swelling (angioedema) of the:
    • Intestinal tract 
      • Maybe the only location involved.
      • Can mimic surgical process (like appendicitis). [Rubinstein, 2014]
      • Can make diagnosis a challenge (and is why we are discussing it now).
      • Can lead to delayed diagnosis.
    • Skin
      • May develop preceding altered sensation/tingling of the skin.
      • May develop erythema marginatum (non-pruritic, flat red eruption with central clearing).
      • Hives are not a part of hereditary angioedema, but can occur concurrently.
    • Upper Airway
      • Obviously, this is the most dangerous.
      • Those who have yet to be correctly diagnosed with hereditary angioedema are at greater risk for asphyxiation. [Bork, 2012].
    • Also can involve other regions:
      • Esophagus
      • Kidneys
      • Brain
      • Pancreas

 

Hereditary Angioedema: Diagnosis

  • History of recurrent attacks and family history are important!
  • C4 levels are low at all times in the majority of patients. [MacGinnitie, 2014]
  • C1-Inhibitor level and activity level can also be obtained.

 

Hereditary Angioedema: Treatment

  • Since the edema is bradykinin mediated, it will not respond to antihistamines, corticosteroids, or epinephrine. [Christiansen, 2015; MacGinnitie, 2014]
  • Often patients and families will come to the ED with their own specialized medications.
    • Look them up to re-familiarize yourself with that child’s medications.
    • Call the child’s allergist / immunologist early in the management course.
  • “Fancy Meds” (things that I always have to look up again)
    • C1-Inhibitor replacement
      • Two versions exist:
        • Purified-plasma C1-Inhibitor (Berinert or Cinryze)
        • Recombinant C1-Inhibitor (Ruconest)
      • Augments C1-Inhibitor levels.
      • Can be self administered at home. [Kreuz, 2012]
      • Can be used for prophylaxis as well as acute therapy. [Schneider, 2012; Martiez-Saguer, 2010]
      • Often used as 1st line therapy in pediatric patients. [Craig, 2015]
    • Kallikren Inhibitor
      • Ecallantide (Kalbitor)
      • Given SubCutaneously!
      • For acute therapy and typically given by health care providers. [MacGinnitie, 2013]
    • Bradykinin Receptor Antagonist
      • Icatibant (Firazyr)
      • Given SubCutaneously!
      • Can be self-administered.
  • Other options
    • Antifibrinolytics
      • Tranexamic Acid (TXA) and Epsilon-Aminocaproic Acid
    • Fresh Frozen Plasma
    • Attenuated androgens

 

Moral of the Morsel

  • Certainly we will encounter many more cases of chronic recurrent abdominal pain that are due to idiopathic or benign entities, but keeping Hereditary Angioedema on our differential will allow us look for the clues that may help positively impact that child’s life.
  • Additionally, it is a good thing to keep in mind the pathophysiology when considering therapies for children that have known Hereditary Angioedema (the typical allergic reaction medications won’t work). Thankfully, the parents/patients often come with their own medications!

 

References

Nanda MK1, Elenburg S2, Bernstein JA3, Assa’ad AH4. Clinical features of pediatric hereditary angioedema. J Allergy Clin Immunol Pract. 2015 May-Jun;3(3):392-5. PMID: 25609346. [PubMed] [Read by QxMD]

Christiansen SC1, Davis DK2, Castaldo AJ2, Zuraw BL3. Pediatric Hereditary Angioedema: Onset, Diagnostic Delay, and Disease Severity. Clin Pediatr (Phila). 2015 Nov 18. PMID: 26581355. [PubMed] [Read by QxMD]

Craig TJ1, Schneider LC1,2,3, MacGinnitie AJ1,2,3. Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review. Pediatr Allergy Immunol. 2015 Sep;26(6):537-44. PMID: 26111105. [PubMed] [Read by QxMD]

Lumry W1, Soteres D2, Gower R3, Jacobson KW4, Li HH5, Chen H6, Schranz J6. Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema. Pediatr Allergy Immunol. 2015 Nov;26(7):674-80. PMID: 26171584. [PubMed] [Read by QxMD]

MacGinnitie AJ1. Pediatric hereditary angioedema. Pediatr Allergy Immunol. 2014 Aug;25(5):420-7. PMID: 24313851. [PubMed] [Read by QxMD]

Rubinstein E1, Stolz LE, Sheffer AL, Stevens C, Bousvaros A. Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency. BMC Gastroenterol. 2014 Apr 9;14:71. PMID: 24712435. [PubMed] [Read by QxMD]

Schneider L1, Hurewitz D, Wasserman R, Obtulowicz K, Machnig T, Moldovan D, Reshef A, Craig TJ. C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies. Pediatr Allergy Immunol. 2013 Feb;24(1):54-60. PMID: 23173714. [PubMed] [Read by QxMD]

MacGinnitie AJ1, Davis-Lorton M, Stolz LE, Tachdjian R. Use of ecallantide in pediatric hereditary angioedema. Pediatrics. 2013 Aug;132(2):e490-7. PMID: 23878046. [PubMed] [Read by QxMD]

Farkas H1, Zotter Z, Csuka D, Szabó E, Nébenfűhrer Z, Temesszentandrási G, Jakab L, Varga L, Harmat G, Karádi I. Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor–a long-term survey. Allergy. 2012 Dec;67(12):1586-93. PMID: 23025435. [PubMed] [Read by QxMD]

Bork K1, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol. 2012 Sep;130(3):692-7. PMID: 22841766. [PubMed] [Read by QxMD]

Kreuz W1, Rusicke E, Martinez-Saguer I, Aygören-Pürsün E, Heller C, Klingebiel T. Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema. Transfusion. 2012 Jan;52(1):100-7. PMID: 21756262. [PubMed] [Read by QxMD]

Martinez-Saguer I1, Rusicke E, Aygören-Pürsün E, von Hentig N, Klingebiel T, Kreuz W. Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. Transfusion. 2010 Feb;50(2):354-60. PMID: 19788511. [PubMed] [Read by QxMD]

Sean Fox

I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renown educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.

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