Updated: 7/25/2019

Hereditary Angioedema

Topic
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Questions
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Evidence
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Snapshot
  • A 23-year-old woman with past medical history of multiple allergies leading to facial swelling presents with marked difficulty breathing, abdominal pain, and swelling of the face and neck. On physical exam, her extremities are also noted to be markedly swollen (picture). She is immediately sedated for intubation to maintain patency of airway. Chart review reveals newly-started ACE-inhibitor. She is given epinephrine, fluids, and fresh frozen plasma.
Introduction

  • Disorder of complement, causing angioedema
  • Genetics
    • autosomal dominant
  • Pathogenesis
    • C1 esterase inhibitor deficiency  
      • C1 esterase inhibitor inhibits kallikrein-kinin pathway
        • remember kallikrein activates bradykinin
        • bradykinin
          • ↑ vasodilation
          • ↑ permeability
          • ↑ pain
    • ACE-inhibitors are contraindicated
      • ACE inactivates bradykinin
      • ACE-inhibitors allows ongoing bradykinin, causing angioedema
  • Epidemiology
    • attacks begin during childhood
  • Risk factors
    • family history of angioedema
    • family history of those contraindicated with ACE-inhibitors
    • autoimmune conditions
Presentation
  • Symptoms/physical exam
    • recurrent episodes of angioedema without urticaria
      • as opposed to anaphylaxis, which typically has urticarial
      • angioedema of the face, oropharynx, extremities, or abdomen
      • angioedema of GI tract
        • severe abdominal pain
        • GI upset
      • worst at 24 hours
      • resolves over 48-72 hours
    • often preceded by prodrome
      • fatigue
      • flu-like symptoms
    • not responsive to epinephrine (epi-pen) or antihistamines
Evaluation
  • Best initial test
    • ↓ C4 and C2 levels
    • if C4 are normal, C1 inhibitor deficiency is unlikely
  • To confirm diagnosis if ↓ C4
    • ↓ C1 inhibitor antigenic levels
    • ↓ C1 inhibitor functional levels
Differential Diagnosis
  • Anaphylaxis
  • Allergic angioedema
  • Facial cellulitis
  • SVC syndrome
Treatment
  • Anaphylaxis presents very similarly to angioedema and often cannot be differentiated immediately in an emergency room setting
    • therefore, patients are often initially treated with medications for anaphylaxis given urgent, life-threatening nature of anaphylaxis
      • epinephrine
      • fluid replacement
      • anti-histamines
  • Assess airway, even after administering treatment
    • intubate if necessary
  • As soon as possible, especially if epinephrine and anti-histamines are not effective, administer medications for hereditary angioedema
    • plasma-derived C1 inhibitor
    • recombinant human C1 inhibitor
    • fresh frozen plasma if above are not available
Prognosis, Prevention, and Complications
  • Prognosis
    • mortaliy >30% in those with laryngeal angioedema
    • angioedema is unpredictable
  • Complications
    • small bowel obstruction
    • compartment syndrome
    • death by asphyxiation
 

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Questions (3)
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
Volume  
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
Urine  
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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(M1.IM.74) A 47-year-old male presents to the emergency department with facial swelling and trouble breathing. These symptoms began this morning and progressively worsened over the past several hours. Vital signs are as follows: T 37.7, HR 108, BP 120/76, RR 20, and SpO2 96%. Physical examination reveals nonpitting swelling of the face, hands, and arms as well as edema of the tongue and mucus membranes of the mouth and pharynx. The patient reports several episodes of mild facial swelling that occurred during childhood between the ages of 5-18, but he does not recall seeing a physician or receiving treatment for this. His medical history is otherwise negative, except for mild hypertension for which his primary care physician initiated lisinopril 2 weeks ago. This patient most likely has which of the following underlying abnormalities? Review Topic

QID: 106671
1

MHC class I deficiency

11%

(4/38)

2

Defective lysosomal storage proteins

8%

(3/38)

3

Lack of NADPH oxidase

0%

(0/38)

4

Defect in cytoskeletal glycoprotein

3%

(1/38)

5

Deficiency of C1 esterase inhibitor

68%

(26/38)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(M1.IM.21) A 23-year-old female presents to the emergency room with diffuse swelling. Her boyfriend is especially concerned because her face has begun to swell (Figure A). Her tongue is also swollen and she is beginning to have trouble breathing. If her symptoms are due to a congenital syndrome and not a medication side effect, which of the following would be true regarding this patient's disease? Review Topic

QID: 104232
FIGURES:
1

Caused by deficiency in C1 esterase inhibitor

62%

(31/50)

2

Caused by deficiency in C3

12%

(6/50)

3

Caused by deficiency in C5-C8

8%

(4/50)

4

Caused by deficiency in decay accelerating factor

4%

(2/50)

5

Danazol is contraindicated in this disease as it may worsen symptoms

6%

(3/50)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 1
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