Updated: 10/22/2018

Hereditary Angioedema

Review Topic
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  • A 15-year-old boy is rushed to the emergency department by his mother due to increased difficulty with breathing. His mother says that he does not have a food allergy and that this has happened to him before after undergoing a dental procedure. She reports that in the father's side of the family, they suffer from these episodes of swelling but usually self resolve. On physical exam, the patient has swelling of the lips, tongue, and skin around the face and arms. He is immediately sedated and subsequently intubated and treated for anaphylaxis which does not improve his symptoms. Laboratory testing is significant for decreased C4 and C1 inhibitor levels as well as normal C1q levels.
  • Clinical definition
    • hereditary C1 inhibitor deficiency that leads to recurrent angioedema without urticaria or pruritus
      • triggers include
        • physical
          • dental work
          • surgery
          • intubation
        • medical
          • angiotensin-converting enzyme (ACE) inhibitors
          • tamoxifen
          • estrogen-containing medications (e.g., hormone replacement therapy and oral contraceptives)
  • Epidemiology
    • incidence
      • 0.001%-0.003% of the general population
    • demographics
      • typically begins in childhood and worsens during puberty
    • location
      • skin, upper airway, and gastrointestinal tract
    • risk factors
      • family history
  • Pathophysiology
    • pathobiology
      • C1 inhibitor deficiency (hereditary angioedema type I) or dysfunction (hereditary angioedema type II) results in
        • unchecked bradykinin production
          • C1 inhibitor inhibits kallikrein and active factor XII, which is involved in the cleavage of high molecular weight kininogen into bradykinin
        • decreased serum C4 levels
          • due to increased C1 complex cleavage of C4 in the absence or dysfunction of C1 inhibitor
  • Genetics
    • inheritance pattern
      • autosomal dominant
  • Associated conditions
    • possibly associated with an increased incidence of autoimmune disease
  • Prognosis
    • variable
      • after the attack occurs, they may recur throughout the patient's life
        • attack frequency can be reduced with appropriate therapy
  • Symptoms
    • prodromal symptoms
      • fatigue
      • nausea and/or other gastrointestinal symptoms
      • flu-like symptoms
    • angioedema without urticaria or pruritus affecting the
      • skin
        • swelling of the extremities, face, and genitals
          • can affect any area
      • upper airway
        • swelling of the lips, tongue, uvula, soft palate, and larynx
      • gastrointestinal
        • bowel wall edema resulting in
          • gastrointestinal colic, nausea, vomiting, and/or diarrhea
  • Physical exam
    • skin
      • erythema marginatum may be seen
    • upper airway
      • voice changes or horseness
      • stridor
      • shortness of breath
    • gastrointestinal
      • abdominal tenderness
      • ascites
      • signs of small bowel obstruction
  • Labs
    • ↓ C4 and C2 levels
    • normal C1q levels
    • C1 inhibitor levels
      • low level (hereditary angioedema type I)
      • normal level (hereditary angioedema type II)
  • Drug-induced anaphylaxis
  • Contact dermatitis
  • Atopic dermatitis
  • Superior vena cava syndrome
  • Conservative
    • securing airway, breathing, and circulation
      • indication
        • for the treatment of acute attacks of angioedema
          • it is difficult to differentiate anaphylaxis and angioedema
            • epinephrine, corticosteroids, and antihistamines are not effective in hereditary angioedema
  • Medical
    • plasma-derived C1 inhibitor
      • indication
        • acute treatment of herediatry angioedema
        • short-term prophylaxis in patients with hereditary angioedema who will be exposed to a trigger (e.g., dental procedures and surgery)
        • long-term prophylactic treatment of hereditary angioedema
      • other medications that can be used in the acute treatment of hereditary angioedema includes
        • plasma kallikrein inhibitorn (ecallantide) 
        • bradykinin receptor antagonist
    • attenuated androgens (e.g., danazol)
      • indication
        • for long-term prophylactic treatment of hereditary angioedema
  • Asphyxiation can result in death
  • ≥ 30% mortality in patients with laryngeal angioedema
    • can present with decreased inspiratory and expiratory rate and should be treated promptly w/epinephrine (histaminergic angioedema) 

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Questions (2)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2

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