Definitions

Angioedema: subcutaneous and/or submucosal swelling; mainly skin, GI tract, upper airways; secondary to sudden and localized vascular permeability and vasodilation

Mechanisms

Probably other mechanisms involved that we don't know about. Mainly two categories we know of however:

1. Histamine mediated
2. Bradykinin mediated. Short half-life (17), metabolized mainly by ACE, but also by neutral endopeptidase (NEP or Neprilysin); secondarily things like DPP4

• So things like Entresto might cause it too, or things like DPP4 i (particularly sitagliptin)
• TpA can also cause it, 2% of patients

Categories

Mast cell mediated angioedema

Usually allergic: Food, NSAIDS, insect stings, urticaria associated

Can be:

• CSU (with or without hives), also called idiopathic histaminergic angioedema or idiopathic mast cell mediated angioedema
  • Distinction: histaminergic mediated => should respond to continuous antihistamines; mast cell mediated => doesn't respond to antihistamines but does to omalizumab
  • Can also have delayed pressure urticaria/angioedema which may last up to 72h and can be associated with burning/pain, usually 4-6 hours AFTER pressure stimulus
• It can be pruritc and/or painful
• Interestingly, most of these are not life threatening; ie not going to obstruct upper airway

RE: CSU - 10% have ONLY angioedema. 50% only hives; 40% both hives and angioedema

Regardless:, in terms of treatment:

• anti IgE is quite helpful for BOTH urticaria and angioedema

Bradykinin mediated - HAE type I and II

Epid: any race/gender Pathophys: deficiency in C1-INH amount or function

Presentation: Usually has non-pitting circumscribed painful edema; if upper airway CAN be life threatening Also can have abdomina pain from bowel wall edema, almost mimicking bowel wall edema

Triggers: Trauma Menstration Surgical procedures Medications: estrogen, ACEi Stress Infection Pregnancy

PEARL: Can develop a non-urticarial rash that can occur almost like a prodrome in any place, may be hours/days before the attack

HAE type III - normal C1-INH and C4

RARE. Most are type I around 85%; the rest is type II, ; global study some canada specific data shows there's more tpye III but ? overdiagnose or innapropiate?

Diagnostic criteria:

• Episodic angioedema without urticaria (abdominal pain COUNTS!) if they get a CT scan during that time its very helpful
• Normal C1-INH and C4
• Family history OR relevant genetics for this condition (there are a few)
  • FXII mutation - mainly women affected, depends on high estrogen exposure; classically appears when starting OCPs or becoming pregant; for men half are symptomatic
  • PLG-HAE; median age 20, mainly face and tongue swelling
  • 4 more ... then unknown
• Other causes excluded

Acquired angioedema

Similar to HAE I or II but usually later in life it presents It is very rare though autoantibodies to or consumption of normal C1-INH ie associated with lymphoproliferative disorders, MGUS, AI diseases similar triggers to HAE

Note: C1q depending on the province can be quite hard to actually order Also note the 50% cutoff for the C1-INH level and function; the test is quite fragile and there often has be shipping towards special labs; if not handled properly you can have slightly low C1 even in a normal person You also need at least 2 abnormal values at least 1 mo apart

ACEi mediated

only 0.1 to 0.7% of patients commonly involves the mouth Bradykinin mediated 66% occurs within first 3 months of therapy, but afterwards the remaining % could occur up to YEARs later there is a washout period even after stopping; can occur up to 1-2 months after stopping

Bradkinin or non mast cell mediated

Normal c1h, not responsive to antihistamines or anti IgE, doesn't meet criteria for HAE III we call it bradykinin (idiopathic Bradykinin mediated angioedema) if responsive to typical treatments such as TXA, C1 in, Icatibant if not responsive; idiopathic non mast cell (which is a big umberlla term otherwise)

Angioedema differential

Throat symptoms:

• VCD, GERD, post nasal drip

• SVC syndrome

• Orofacial granulomatosis

• Morbus morbihan

• systemic capillary leak syndrmoe

• Eosinophilic disorders

Trick: palpate the tongue; should be like a pancake, thi If you trigger gag reflex the tongue; if tognue togally retacts you're good

Cases

macro

To add to macro:

HAE I or II Treatment of acute attacks

• ie Berinent, Firazyr

pearl: study from germany on deaths phase 1 2 3 1 first sx 2 dyspnea 3 about to die if tx stage 1 then good outcome otherwise poor. treat EARLY.

Prophylaxis if more frequent attacks not specific threhosld but funded if 3x in a month or any SEVERE attack life-threatening etc

procedures does require surgical or dental procedures, she will need prophylactic therapy with C1 inhibitor to prevent angioedema attack.

triggers We reviewed that there are certain medications that she will need to avoid as they interfere with bradykinin metabolism and could precipitate life-threatening angioedema attacks. These include: ACE inhibitors, Neprilysin inhibitors, DPP-4 inhibitors and Estrogens. She does not currently have indications for any of these medications.

HPI: ACEi or NSAIDs Exposures, triggers (foods, hormones, stress, meds, trauma) duration, speed of swelling, relation to exposure timing location of swelling when was the first episode abdo pain, systemic symptoms, rashes, arthralgias, vitiligo family history Urticaria

• Work up: C3/C4, C1-INH level and function, C1q; SPEP, CBC, Cr, Calcium/Albumin

We have advised the importance of avoiding stress, limiting alcohol, and no NSAID use In the interim, we will start empiric treatment with second generation antihistamines; undifferentiated angioedema may still be mast-cell mediated.

• Rx: Blexten 40mg PO BID

*** confirmed HAE => acute mgment: C1-INH concentrate (Berinert), Bradykinin receptor antagonist Icatibant (FIRAZYR®), plasma kallikrein inhibition Lanadelumab (TAKHZYRO®), present to ED => long term prophylaxis: C1-INH, ?androgrens but AEs

*** AAE ACEi supportive care, avoid ACEi and Entresto, ARBs ok in a pinch

rough

classification

with or without urticaria with comes down to chronic vs acute without some down to AAE and HAE AAE might be: NSAID, ACEi HAE has its own classifaciotns into type I II and III with their own epid, ie. II is 15, I is 85%, and III is something?

this is the old way of classication but if you look at the new DANCE criteria it is a bit different

Pathophys

Depends but the old school thought is bradykinin mediated vs histmaine mediated where pro bradykinin can happenw tih c1est def vs something else (ie impaired degration with ACEi)

triggers possible can vary