Angioedema hereditary 1D84.1

Osler, 1888

Historical outline and new classification: Knowledge of rare genetic diseases, such as hereditary angioedema (HAE), has evolved rapidly in parallel with the development of new molecular tools. The deficiency of C1 esterase inhibitor (C1-INH) has been known since the 1960s as the main cause of HAE (HAE-C1-INH) and was of fundamental importance for the pathogenetic and pathophysiological understanding of the various angioedemas. These findings led to a dichotomous division of angioedema into acquired, histamine-mediated angioedema without C1-INH deficiency and non-histamine-mediated angioedema. For this group, bradykinin was identified as the main cause of the tendency to oedema. This bradykinin group is both drug-induced (inhibition of the renin-angiotensin system by ACE inhibitors with increased production of bradykinin/frequent occurrence) and hereditary (rare occurrence) due to mutations in genes that control the bradykinin system.

The genetic deficiency of C1-INH is caused by autosomal dominant mutations in the SERPING1 gene, which codes for the C1 esterase inhibitor (C1-INH). The prevalence is 1:50,000. The lack of inhibitory effect on the kallikrein-kinin system (plasma kallikrein and factor XIIa) is decisive for the aetiopathogenesis of C1-INH deficiency, which in turn leads to an increased bradykinin release and a tendency to oedema. In HAE type I, there is a C1-INH deficiency with reduced plasma levels (C1-INH concentration is in the interval <50% with a further drop during relapse activity). In HAE type II, on the other hand, C1-INH is dysfunctional. The C1-INH concentration is normal or even elevated, while the activity is <30% of the norm.

In 2000, hereditary angioedema with normal C1-INH was described for the first time almost exclusively in women. This type was designated HAE type III. Oestrogens (contraceptives, pregnancy and hormone substitutes) were identified as triggers and amplifiers. Mutations in the F12 gene were first diagnosed in HAE type III in 2006.

It later became apparent that HAE type III is not a unitary entity. In the last three years, advanced next-generation sequencing techniques have led to the identification of mutations in five other new genes in addition to the F12 gene mutation, which have been linked to the hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin) and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

Hereditary angioedema is a rare, genetically heterogeneous inherited disorder characterized by recurrent episodes of fluid accumulation outside the blood vessels, resulting in rapid, potentially life-threatening swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airways.

Incidence: 2-4/100,000 inhabitants/year.

The C1 esterase inhibitor (C1-INH) belongs to the serpin family of serine esterases and regulates various signal transduction pathways of the complement system, intravascular coagulation and the contact system of blood coagulation. In the case of hereditary angioedema (HAE), C1-INH deficiency can lead to edema formation in both systems.

However, the peptide bradykinin appears to play the central role in the blood coagulation contact system. Bradykinin causes an increase in nitric oxide, epoprostenol and endothelium-derived hyperpolarizing factor via its B2 receptor. This results in vasodilation with increased fluid leakage from the vessels and edema formation. At the same time, contractions of the smooth muscles are triggered (cramps and pain). Normally, the release of bradykinin is limited by the effect of C1-INH. A C1-INH deficiency leads to increased bradykinin release.

Type I and II:

• Described is autosomal dominant inheritance with incomplete penetration of mutations of the C1 inhibitor gene (C1-INH) localized to gene locus 11q12-q13.1. In about 80% of cases there is an inherited C1 esterase inhibitor deficiency, 20% of patients have a defective C1 esterase inhibitor.
• The main symptoms are angioedema of the skin and colicky abdominal complaints. In addition to the usual trigger factors, oral contraceptives and pregnancy can also trigger the disease. For all types, surgical interventions (e.g. dental treatment), infections or stress can also trigger flare-ups.

Usually first appearing in childhood, often up to the 5th or later around the age of 15. A third peak of frequency is found in the 3rd decade of life (21-30 years). Rarely beyond the age of 50. No gender preference.

Face, extremities (especially arms, more rarely legs), genitals; also lips, tongue, abdomen Life threatening: swelling of the larynx.

Triggered mostly by minor trauma, infectious diseases involving the oropharynx or menses/pregnancy due to decrease in functional_{C1-INH activity}.

• Prodromes: Fatigue, headache, malaise, vomiting.
• Integument: Slowly (over hours) developing, localized, skin-colored to markedly faded, nonpruritic, body-warm to cool skin and mucosal edema of variable size and doughy to coarse consistency.
• Regression after hours to 2 days.
• No accompanying urticaria!
• Extracutaneous manifestations: Abdominal colic is characteristic. Misrecognition of clinical symptoms may lead to misdiagnosis and even surgical intervention.
• The development of laryngeal edema is less common than allergy-induced angioedema, but can lead to life-threatening obstruction.
• Direct triggers may include: stress, infections, minor trauma, dental work, menstruation, oral contraceptives (progesterone-only preparations appear to have a beneficial effect on HAE).

Type I: Decreased_{C1-esterase inhibitor} in blood serum (< 30% of normal), C1-Inh function decreased; decreased total complement or C4.

Type II: High levels of a dysfunctional_{C1-esterase inhibitor}; C1-INH function decreased (with commercial test systems, substrate conversion can be observed by color change due to lack of_C1-esterase inhibition). C1-INH conc. normal, C4 decreased

DD: nC1-INH-HAE (HAE types III - VIII): Normal_C1 and C4. C1-IHF function normal, C1-INH conc normal/slightly elevated; detection of mutations in F-12 (factor XII), ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

Edema in the subcutis. Non-specific pattern.

Laboratory, molecular genetic analysis in patients with a blanched family history.

Hereditary angioedema is suspected when:

Main symptoms

• Swelling attacks that develop (slowly) over hours
• C1 inhibitor function/concentration decreased
• No concomitant urticaria
• Painful abdominal colic (pain, nausea, vomiting - CT/ sonography: wall-thickened sections of GI tract, ascites)
• positive family history
• first manifestation between 1-20 years (rarely 20-30 years)

Secondary symptoms

• Prodromi (fatigue, malaise, muscle pain)
• antihistamines are ineffective
• Laryngeal edema (>50% of HAE patients)
• Triggering factors (previous infections, ACE inhibitors, dental treatments, hormonal contraceptives)

Acute therapy (adults and children):

• _{C1-INH concentrate}: Inject highly purified_{C1-INH concentrate}(e.g. Berinert P) 500 IU (10 ml) slowly i.v., in severe cases 1000 IU (20 ml) to max. 10,000 IU. Clinical improvement 20-30 min. after short infusion; check the C4 concentration in the blood as a therapy progress control (increasing). If i.v. therapy is not possible for technical reasons, the preparation can also be effectively administered s.c..
• Icatibant (Firazyr®) is a synthetically produced decapeptide (protein fragment) approved by the EMA for the symptomatic treatment of acute attacks of hereditary angioedema in adults with C1 esterase inhibitor deficiency. This peptide is the most potent antagonist of the bradykinin B2 receptor to date and is available as a pre-filled syringe for subcutaneous injection (recommended dose: 30 mg s.c.). Caution. Inflammatory reactions at the injection site should be noted (redness, swelling, itching, pain).

Alternative therapy

• Fresh plasma infusions, frozen plasma (500 ml), and lyophilized, clotting-active human plasma.
• Antifibrinolytics: Antifibrinolytics are the second choice (therapeutic success presumably through inhibition of plasmin activation): tranexamic acid (e.g. Ugurol) 1.5-2.0 g/day i.v. or epsilon-aminocaproic acid (e.g. Amicar) 8-10 g/day i.v. under close coagulation control. Complications of these drugs are thromboembolism, myositis and peliosis hepatis.

Drugs not yet approved in Europe:

• Ecallantide: A genetically engineered biopharmaceutical consisting of 60 amino acids, effective as an inhibitor of the enzyme kallikrein. In a clinical trial (EDEMA3) of 36 patients with hereditary angioedema, ecallantide performed better than placebo. Another study of 255 patients is available.
• Rhucin (recombinant C1-INH) is a C1 inhibitor derived from transgenic rabbits by recombinant DNA technology to compensate for C1-INH deficiency (analogous mechanism of action to Berinert). Not approved to date.
• Ecallantide (trade name Kalbitor; highly specific kallikrein inhibitor). Orphan drug designation in Europe.

Long-term therapy (> 1 episode/month; therapy of acute attacks not sufficiently effective/available):

• Lanadelumab (Takhzyro®) is a subcutaneous (every 14 days) recombinant human monoclonal antibody (IgG1-kappa light chain antibody) directed against active kallikrein in blood plasma. The drug has been approved for prophylaxis in patients aged twelve years and older in the EU since 2019.
• Androgens (no approval): In severe course, long-term prophylaxis with stanazol or danazol (e.g. Danadrol; available via international pharmacy) 3 times/day 100 mg (increase up to 600 mg/day possible), after 6 months reduction to 2 times/day 100 mg, after another 6 months alternating 100 and 200 mg/day. Aim for the lowest effective maintenance dose (Milan protocol). Alternatively, start with a low dosage, increase dosage until effective dose is reached (Budapest Protocol). Androgen derivatives promote the expression of male sexual characteristics and lead to masculinization (virilization) of the female organism. There is also a risk of kidney and liver dysfunction. Therefore, close monitoring of the course parameters is necessary. In rare cases, long-term hormone therapy can lead to liver carcinoma. In this respect, this therapy option should be reconsidered. Patients could benefit from a dose reduction or discontinuation of androgen prophylaxis if attacks that occur are controlled with an acute therapy (which can be controlled by the patient) with C1-INH or Icatibant.
• Progestogens: In type III, prophylaxis with progesterone may be successful.

Berotralstat, ^Orladeyo®: Oral prophylaxis of HAE for adolescents from 12 years of age and adults. 1 time daily 150 mg

Anabolic steroids with androgenic residual potency show good results, e.g. Danazol (e.g. Danazol-ratiopharm Kps.) in an initial dose of 1-3 times/day 1 Kps. à 200 mg p.o. The long-term medication is usually 200 mg/day, possibly further reduction to 2 times/week 50 mg p.o. Caution! Virilization in women! Long-term prophylaxis is also possible with Stanazol. Glucocorticoids and antihistamines generally show no therapeutic efficacy, but are often used in the acute phase due to differential diagnostic difficulties.

Case history 1:

• EA: 31-year-old woman with HAE III. First bulky swellings of face and extremities in LJ 17 with crampy abdominal pain and vomiting. Attacks last about 1-3 days and do not respond to corticosteroids or antihistamines.
• FA: Mother and maternal cousin also suffer from recurrent facial and extremity swelling without response to corticosteroids and antihistamines. Severe attack with laryngeal edema 3 years ago. In recent years recurrences at shorter intervals and with increasing severity.
• Diagnostics: Exclusion of all possible diseases (porphyrins, cryoglobulins, ANA, RF, ACE, histamine in plasma, routine laboratory o.B., no evidence of sensitization against drugs or externals). Normal_{C1 esterase inhibitor}; normal function.
• Tried therapy with danazol 600 mg/day p.o., no further attacks thereafter. Dose reduction at 2-week intervals to 50 mg p.o. 2 times/week as maintenance dose. Pat. has been free of attacks for 2 years!
• Side effects of therapy: weight gain, mild acne papulopustulosa, amenorrhea after cessation of oral contraception, mild hyperandrogenemia.

Casuistry 2:

• One patient showed the following laboratory findings:
• C1-inhibitor protein: 5.6 mg/dL (normal value: 15-35 mg/dL).
• C1-inhibitor function: 1% (normal value 70-130%)
• C4 protein: 10.0 mg/dL (normal value 20-50 mg/dL)
• additional: leukocytosis and elevated CK
• Diagnosis: C1 inhibitor deficiency, presence of hereditary angioedema (type I).

Case report 3:

• A 35-year-old patient comes from a large family in which 10 other members besides him suffer from hereditary angioedema. The first clinical symptoms appeared in him at the age of 27 years. Since then, angioedema had occurred 25 times on the skin, 2 times on the scrotum, and 12 times in the gastrointestinal tract. Gastrointestinal symptoms manifested as colicky pain. The diagnosis was made in 1993. Danazol therapy was refused by the patient. Since 1994, the patient has been treated as an outpatient. Due to severe upper abdominal complaints with repeated vomiting inpatient admission. C1-INH activity: 6%; C1-INH protein: normal, C4: 2mg/dl. Administration of 30 mg Icatibant s.c..30 min later complete regression of pain. 3 hrs later still mild fatigue and some dizziness. After 1 month, acute angioedema of lips and chin region. 2 h later after renewed Icatibant administration (dosage as above) the swelling conditions had largely regressed.

1. Banerji A et al (2017) Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med 376:717-728.
2. Bork K et al (2003) Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Internal Med 163: 1229-1235
3. Bork K et al (2009) Hereditary angioedema caused by missense mutations in the factor XII gene: Clinical features, trigger factors and therapy. J Allergy Clin Immunol 124: 129-134
4. Giardino F et al (2015) Use of subcutaneous C1-INH for acute theapy and prophylaxis of a child with HAE. Ped All Immunol 26: 296-297
5. Krause K et al (2010) Successful treatment of hereditary angioedema with the bradykinin B2 receptor anatagonist Icatibant. JDDG 8: 272-274
6. Magerl M et al (2012) Diagnosis and exclusion of hereditary angioedema. Dermatologist 63: 567-572
7. Maurer M et al (2011) Long-term prevention of hereditary angioedema with androgen derivatives: critical evaluation and possible alternatives. JDDG ):99-108
8. Nzeako UC et al (2001) Hereditary angioedema a broad review for clinicians. Arch Internal Med 161: 2417-2429
9. Nzeako UC et al (2002) Hereditary angioedema as a cause of transient abdominal pain. J Clin Gastroenterol 34: 57-61
10. Osler W (1888) Hereditary angioneurotic oedema. On J Med Sci 95: 362-367
11. Treudler R (2010) Allergic diseases in pregnant women. dermatologist 61: 1027-1033
12. Weiler JM et al (2002) Does heparin prophylaxis prevent exacerbations of hereditary angioedema? J Allergy Clin Immunol 109: 995-1000