IgE level, C4 C1 Inhibitor antigen. If low C1 inhibitor antigen, check, C1q Antigen. If normal C1 inhibitor antigen, check C1 Inhibitor function by Chromogenic assay (100 % sensitivity). If all normal, check fXII mutation.
For now check,
IgE level, C4 level, C1 Inhibitor antigen C1q antigen C1 inhibitor functional assay by Chromogenic assay (100 % sensitive)
Note: First thing in an evaluation of a patient with Angiodema is to evaluate if it is - Histamine Mediated
- Occurs acutely, resolves in 24-48 hr
- Due to mast-cell granulation or in some cases with no evidence of mast cell granulation
- Mast-Cell granulation often associated with urticaria, flushing, generalized pruritus, bronchospasm, throat tightness, and/or hypotension
- Non-mast cell mediated angioedema occurs alone or with urticaria, but is not accompanied by respiratory or circulatory symptom
- Glucocorticoids do not inhibit mast cell degranulation but probably act by suppressing a variety of contributing inflammatory mechanisms.
- Bradykinin Mediated
- Occurs gradually (24-36 hr), and resolves in 2-4 days
- Not associated with Urticaria, Bronchospasm, or other symptoms of Allergic Reactions
- eg. ACEI
- Ref: uptodate
Illustrates how C1 Inhibitor absence can cause increased production of BK by 4 different effect.
HAE - Angiodema is a swelling of subcutaneous and submucosal tissue
- HAE Is Bradykinin mediated, and not histamine mediated. Note: Non-heridetary HAE may be mediated by histamines (see above in the classification)
- Can cause acute abdominal pain; hand swelling; and of course airway involvement
- Mostly a pediatric condition
- Case fatality is often in the patient with no prior establised diagnosis
- 3-5 hr delay is typical. From onset of symptoms to
- Screening is done by: C4 test (note: Normal in Type 3)
- C1H antigen is tested.
- If normal, functional assay is done.
- Pathophysiology
- Osler first identified it 80 yrs back
- Kallikarin prevents the formation of Pre-bradykini to Bradykinin
- 3 types (mostly AD)
- Type 1 (C1 INH deficiency)
- Type 2 (C1 INH FUNCTIONAL deficiency)
- Type 3 ( a/k/a HAE with normal C1 INH
- 2 Types of C 1 INH Functional Assay
- ELISA assay (Can miss some patients)
- Chromogenic assay (100 % sensitivity). Hence, is a better test.
- They do not agree all the time
- Epidemiology
- Unclear
- 1 in 80,000
- Autosomal Dominent
- Stress, Infection, Estrogen, ACEI all can trigger HAE flare. Progesterone does not trigger or exacerbate it. Hence, avoid OCP containing estrogen. All of these triggers increase Bradykinin production.
- Emotional Stress: Not clear how it causes worsening of the symptoms.
- Treatment Strategy:
- For acute attacks
- On demand treatment is necessary for all breakthrough attack
- All attacks are eligible for treatment; any delay can cause poor outcomes. Earlier you treat, better the outcome
- Approach 3 approach (Pathophysiology will help better explain this)
- Replace c1 Inh
- Plasma kallikranin inhibitor
- Block Bradykinin action
- Prophylactic treatment
- Not clear who are the patients who will benefit from prophylactic treatment
- Attenuated Androgen (not useful for pregnancy and peads)
- C1-INH (IV access, risk for post-thrombosis and infection; hypersensitivity reactions)
- Prophylactic medication may decrease facial swelling, but does not reduce the laryngeal attacks. Hence, acute treatment strategy should be ready.
- No preferred drugs for acute or prophylactic treatment except for children or pregnant patients.
- Note: Routine dose FDA approved maximum dose of anti-histamines often used for Uritcaria may not be enough to say the mechanism of swelling to be Bradykinin mediated process. Guidelines hence, even in the absence of much evidence, do stress on the need to use High Dose Anti-histamines; unto 4 times
HAE with Normal C1 INH (difficult to diagnose) - C1 INH level, and function is all normal in these patient population
- Compare and contrast
- HAE with C1N: Extremity = Abdomen > Face
- HAE with normal C1INH: Face > Extremity > Abdomen
- There is a variation in the frequency of tongue swelling as well.
- Recurrent Angiodema without concomitant Urticaria
- and Normal C4 and C1H inhibitor
- Lack of response of antihistamines
Clinical Question:
65 yo F presents with recurrent symptoms of skin lesion, and throat discomfort. No syncope, airway compromise, or anaphylaxis. No prurutis. She has diffi culty in swallowing. Patient has not had this in the past. No family history is present. Is taking Lisinopril for 15 yrs. Patient has not had any fever, lymphadenopathy, or joint pain. No prior history of abdominal pain or cramps as well. Her mother also has had SLE. These lesions are equally painful as well. Hgb, WBC, Plt is normal. ESR is normal at 15. CRP is slightly increased 1.7 . Albumin is 4. UA with microscopy was not done. Following were the clinical findings.
C4 is low. What is the diagnosis? - Hereditory C1 Inh angioedema.
- Acquired C1 Inh angioedema
- Mast Cell Disease
- Ig E mediated allergy.
- Serum Sickness
- Urticarial vasculitis.
- SLE
Urticaria is characterized by raised, erythematous, and extremely pruritic lesion. They typically appear in one area, and resolve over the course of several hours, and then reappear elsewhere. Individual lesion may enlarge, and develop central pallor before fading.
What is the difference between Angioedema and Urticaria pathophysiologically?
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