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Difficulty: MediumImmunologic and Inflammatory Processes

A 28-year-old man is brought to the emergency department due to a 2-hour history of progressive swelling of his face, lips, and tongue, along with severe, crampy abdominal pain and nausea. He denies any recent changes in diet, insect stings, or new environmental exposures. He has no itching or skin rash. His temperature is 37.1 C (98.8 F), blood pressure is 110/70 mm Hg, pulse is 92/min, and respirations are 18/min. Physical examination shows pronounced, nonpitting edema of the lips and tongue, but no urticaria. Bowel sounds are hyperactive. The patient states that a similar, milder episode occurred when he was 15 years old following a tooth extraction. He takes no daily medications and has no known allergies. Initial treatment with intramuscular epinephrine, intravenous diphenhydramine, and corticosteroids is administered, but his condition remains unchanged 45 minutes later. Laboratory studies reveal a significantly decreased serum C4 level and a normal C3 level. Which of the following is the most likely primary mechanism mediating this patient's current symptoms?

  1. Unregulated cleavage of high-molecular-weight kininogenAnswer
  2. B
    Cross-linking of surface IgE on tissue mast cells
  3. C
    Decreased enzymatic degradation of endogenous bradykinin
  4. D
    Deposition of circulating immune complexes and classical complement activation
  5. E
    Autoantibody-mediated consumption of C1q and C1 inhibitor

Answer

Unregulated cleavage of high-molecular-weight kininogen
This patient's presentation of recurrent, nonpitting edema without urticaria, accompanied by crampy abdominal pain, lack of response to epinephrine, and a low C4 level is highly characteristic of hereditary angioedema (HAE). HAE is an autosomal dominant disorder caused by a deficiency or dysfunction of C1 inhibitor (C1-INH). C1-INH is a serine protease inhibitor that normally inactivates C1r and C1s in the classical complement pathway, as well as kallikrein and coagulation factor XIIa in the contact activation pathway. In the absence of functional C1-INH, kallikrein becomes unregulated and excessively cleaves high-molecular-weight kininogen to produce bradykinin. Bradykinin is a potent vasodilator that increases vascular permeability, leading to the characteristic angioedema. Because the reaction is driven by bradykinin rather than histamine, it does not respond to standard anaphylaxis treatments (epinephrine, antihistamines, corticosteroids) and is not associated with urticaria. The unregulated C1s also continuously cleaves C4, making a low C4 level an excellent screening test for HAE.

Step-by-Step Solution

1
Analyze the clinical presentation and medication history.
The patient has isolated angioedema without urticaria or pruritus, and gastrointestinal involvement (abdominal pain), without taking any medications.
This helps rule out histamine-mediated allergic reactions (which typically feature urticaria) and medication-induced angioedema (e.g., ACE inhibitors).
2
Evaluate the response to initial therapy and laboratory findings.
The condition did not improve with epinephrine, antihistamines, or corticosteroids. Labs show low C4 and normal C3.
Lack of response to epinephrine confirms the edema is not histamine-mediated. A low C4 with normal C3 is the hallmark screening finding for C1 inhibitor deficiency.
3
Identify the underlying immunopathologic mechanism.
The patient has hereditary angioedema (HAE) due to C1 inhibitor deficiency. C1 inhibitor normally downregulates kallikrein. Its absence leads to uninhibited kallikrein, which cleaves high-molecular-weight kininogen into bradykinin.
Connecting the diagnosis to the molecular mechanism answers the question.

Key Concept

Hereditary angioedema is caused by C1 inhibitor deficiency, leading to unregulated kallikrein activation and excessive production of bradykinin from high-molecular-weight kininogen. It presents with angioedema without urticaria and a low C4 level.
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Topics

Immunologic and Inflammatory Processes

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