Chronic angioedema. Three relevant cases

ALLERGOL. ET IMMUNOPATHOL., 1998;26(4):195-198

CLINICAL CASES

Chronic angioedema. Three relevant cases

A. Sánchez Palacios, F. Schamann Medina and J. A. García Marrero

Allergy Unity. Hospital Insular. Las Palmas de Gran Canaria, Spain.

---

SUMMARY

Three cases of clinical angioedema are reported in which the etiopathogenetic involvement of qualitative and quantitative complement disorders was demonstrated. The first patient had a functional deficit in C₁ inhibitor, the second had a decrease in CH50, and the third, a reduction in the C_1q, C₃, and C₄ fractions. The cases are interesting because of occasional difficulties in the causal diagnosis, the severity of the symptoms, which can include laryngeal edema, and, finally, the favorable outcome achieved with correct medication, which did not include antihistamines or steroids.

The clinical picture of hereditary angioedema is characterized by the familial occurrence of the process, although this apparently was absent in these cases. Two patients experienced laryngeal edema and none had abdominal manifestations.

The treatment of choice for angioedema of these characteristics is antifibrinolytic agents, which achieve good results in 70% of the patients. Epsilon-aminocaproic acid and tranexamic acid inhibit the formation of plasmin and fragments of the Hageman factor, thus inhibiting kallikrein and bradykinin production. The androgens danazol and estanazol have been used since the 1970s, and estanazol proved to be very effective in two of our patients.

Key words: Familial angioedema. Hereditary angioedema. Quincke''s edema. C₁-esterase inhibitor. Danazol. Tranexamic acid.

Allergol et Immunopathol 1998;26:195-198.

---

INTRODUCTION

Pathogenesis for urticaria and angioedema is generally thought to involve the release of several potentially vasoactive mediators. The main non-cytotoxic mechanism known for histamine release requires the combination of antigen with IgE antibodies together with basophils or hystic mastocytes (1, 2).

Of the acid metabolites, prostaglandin D₂, a vasolidator, and synthetic leucotrienes C and D (3) may increase vascular patency. These may have a synergic action in the skin (4).

The mastocytes or basophils also release one or more enzymes capable of causing local release of calidine or bradicinine; among these is an enzyme similar to calicreine (5).

We present three patients who showed a similar course involving angioedema and quantitative alterations in the complement. Two of the patients responded favorably to androgens and antifibrinolytics.

CASE DESCRIPTIONS

First Case Report

A 23-year-old patient with no family or personal history of atopia, presented acute, generalized urticarical eruption, after eating different foods (paella with seafood and anchovies, preserved meat, spicey sauces, dried fruit and chocolate). On one occasion the patient required admission for generalized edema with difficulty breathing and for aphonia with swollen throat.

Anamnesis and physical examination were unremarkable. Complementary cutaneous tests for habitual pneumoallergens and different foods were negative. Complement fraction C₃: 97 mg/dl (normal values 85/193); complement C₄: 18 (normal values 12/36). Evaluation of C_1s gene inactivation (C₁ esterase inhibitor): less than 10% (reference values 80/135%) = 5 mg/dl (normal value: 16 ± 6 mg/dl).

Second case

A 32-year-old male professional basketball player with positive atopic family background and a personal history of surgically treated osteopathy. He presented at our Unit with generalized angioedema of no apparent cause.

Anamnesis was unremarkable. Physical examination showed edema in the lower lip. Cutaneous tests for pneumoallergens and habitual foods were negative. Serum immunoglobulins: IgG: 1320 mg/dl; IgM: 262 mg/dl; IgA: 175 mg/dl. Complement: C₃: 145; C₄: 23, 39.

Determination of C₁ esterase inhibitor: 32.5 mg/dl = 40% C_1s gene inactivation. Total IgE: 72.8 (specific IgE using RAST: no antibodies compared to

Dermatophagoides (egg white, cow''s milk and lactic albumin). Hemogram and laboratory values were normal.

Third case

Female patient, 57, admitted to the internal medicine service for facial angioedema. Our Unit was involved in the etiologic study.

Of note in the family background was a daughter diagnosed as presenting chronic vulgar pemphigus. Her own personal history included surgery for

thyroid nodule 10 years ago. She had frequent migraines.

For 6 months prior to admission she presented facial swelling and dyspnea which resolved spontaneously and with corticoids, accompanied at times by swellings on the head and arms unrelated to any external factors, at times with different foods. Physical examination was unremarkable. Other complementary examinations: Stool sample: negative. Hepatitis B virus markers: positivity of anti-HBS and anti-HBc IgG. Routine plasma biochemistry and urinary system: normal. Urine culture: negative. IgG, IgM, C_e and C₄: normal. IgA: 317 (normal to 150). Esterase inhibitor C₁: 140%. Thoracic radiography, abdominal and gynecologic echography: no pathologic findings.

Habitual pneumoallergen and food tests were negative. The patient underwent a series of provocation tests with additives of tartracine, sodium benzoate and salicylates.

The patient was released with an exclusion diet and symptomatic treatment. She was readmitted for bilateral and facial edema accompanied by pain in the right frontal area. Radiography a diffuse blurred area showed in the right maxilary sinus.

She was studied at another center where complementary tests were carried out: blood test: complement fractions: C₃: 153; C₄: 23; C₁ inhibitor: 30 mg/dl; activity: 1, inhibitor: 1. 1. Histamine release tests for tartracin: negative. Stool sample: negative. Oxyurea: negative. Radiography of the sinus showed thickening of the mucosa of the right maxilary sinus. Cutaneous tests for habitual pneumoallergens: negative. Drug tests (salicylate, butazolidine, dipyrone, aminopyrine): negative. No pathologic findings were found and the condition was attributed to emotional factors and the family situation.

The patient has been seen at our unit on an outpatient basis for relapses of cutaneous angioedema. Within the complementary examinations subsequently carried out, determination of C₁ esterase inhibitor (18-02-94): 35.2; C₃: 82 and C₄: < 8 were significant. Danazol and tranexamic acid were administered and the patient improved.

DISCUSSION

Our first patient had normal values for fractions C₃ and C₄, but C₁ esterase inhibitor activity was lower than 10%.

Hereditary angioedema (HAE) is characterized by the absence or functional deficit of C₁INH with two genetic varieties. The first has C₁ INH levels which are reduced or un detectable (85% of the cases). In the second, normal or raised levels are functionally inactive (6). In our first patient we have no antecedents of the disease in her genealogy. A dominant autosomic hereditary process affects heterozygotics subjects; 20% of patients do not present background evidence of the disease, suggesting therefore that the appearance of the condition may be due to a genetic mutation (7).

In our second patient C₃, C₄ and C₁ INH levels were within normal limits and only a reduction in CH 50 was found.

Our third case of angioedema presents an etiology with multiple factors (salicylates, benzoates, emotion, sinus disease), which in the course of the disease led to a decrease of C₃ and C₄.

Hereditary angioedema was first described by Osler in 1888 who studied five generations of a familiy (8). In 1962, Landerman (9) related genetic deficiency with an inhibitor of coagulation.

The clinical characteristics include family history although none of our three patients had relatives affected by the disease.

Facial edema was found in all three case. Laryngeal edema was detected in the first and third case. Abdominal localization was not detected in any of our patients, in contrast to other cases describe (10).

The circulating immune complexes (CiC-C_1q) were diminished in the third case described. In these subjects, lupus erythema, rectal carcinoma, some forms of lymphoma or xanthomatosis and diffuse lipemia (12) have been described.

In table I, the patients'' clinical and analytical data are shown.

Table I
Clinical and analytical data of our patients
Common Symptoms*	HAE	Patient 1	Patient 2	Patient 3
Family History	YES	NO	NO	NO
Facial Edema	YES	YES	YES	YES
Laryngeal Edema	YES	YES	NO	YES
Visceral Edema	YES	NO	NO	YES
Urticaria	NO	YES	NO	NO
Atopia	NO	NO	NO	NO
High IgE levels	NO	NO	NO	NO
Low C1 INH	YES	YES	NO	NO
Low C4	YES	NO	NO	YES
Low C3	NO	NO	NO	YES
Low C1g	NO	NO	NO	YES
Low CH50	YES	NO	YES	­
CIC**	YES	­	­	YES
Concommitant disease	NO	NO	NO	NO
* HAE: Hereditary Angioedema. **CIC: Circulating immune complexes.

Treatments of choice in these types of angioedema, with a 70% success rate, are antifibrinolytic agents such as epsilonaminocaproic and tranexamic acid.

In the 1960s, androgens began to be used in treatment, and danazol and stanazolol are currently the most commonly used. In our first patient, the latter was given. The second patient, still under study, in the most specific components of the complement are responding to steroids and antihistamines. Our third patient progressed favorably with tranexamic acid and danazol.

In table II, we present the treatment regime of HAE.

Table II
Treatment regime of Hereditary Angioedema
ACUTE EPISODES
1. With glottic involvement:
	­ Tranexamic acid: 500 mg intravenous (1 ampule Amchafibrinr) and/or ­ C1 inactivator (Behring): 3000 - 6000 intravenous units (1-2 ampules), or ­ Fresh plasma: 2 units (if intravenous C1 INH is not available), and ­ Tracheotomy if required.
2. Without glottic involvement:
	­ Double dosage of tranexamic acid if already administered. ­ If not administered, tranexamic acid: 500 mg/8 h orally (Amchafibrinr. ­ In case of abdominal pain: analgesics and spasmolytics.
SHORT-TERM PROPHYLAXIS (surgical interventions, etc.).
	­ C1 inactivator (Behring): 3000 - 6000 intravenous units (1-2 ampules) one hour prior to intervention or ­ Fresh plasma: 2 units (if intravenous C1 INH is not available).
MAINTENANCE
	­ Tranexamic acid: 500 mg/12 h (Amchafibrinr: 1 comp./12 h) and adjust according to results. ­ Danazol: 200 mg/24 h (Danatrolr: 1 comp./24 h), increasing to 400 mg/24 h and increasing to 200-400 mg on alternate days. ­ Stanazolol: 0.5-2 mg/taken every three days (Winstrolr: comp. 2 mg). ­ Attempt treatment every three days. ­ General measures: avoid "stress", trauma, dietary transgressions, etc.

From the cases described in the literature and our clinical case experience here, we offer these practical conclusions:

1. Hereditary angioedema may develop through acquisition, as most cases lack a family background of the disease.

2. It may be associated with urticaria or atopic disease.

3. Some patients without hereditary antecedents and low C₄, C₁ INH, may have adenocarcinomas or lymphomas. Normal leves of C_1q in family angioedema would rule this out.

4. Suspicion of the disease may be confirmed by laboratory test of C₄, C₁ INH, CH 50 and CIC.

5. Given the danger of laryngeal edema, the patients require intravenous administration of fresh plasma or concentrated C₁ INH. The therapeutic dose of androgens varies for each individual.

---

RESUMEN

Se presentan tres casos de angioedema crónico, en cuya etiopatogenia se demostraron alteraciones cualitativas o cuantitativas del complemento. En el primer paciente se encontró un déficil funcional del C₁ inhibidor, en el segundo una disminución de CH50 y en el tercero, descenso de las fracciones C_1q, C₃ y C₄. El interés de los casos reside en la dificultad del diagnóstico etiológico en ocasiones, en la gravedad de los síntomas, a veces con presentación de edema laríngeo y, por último, en la evolución favorable con la medicación adecuada, sin antihistamínicos ni esteroides.

El cuadro clínico del angioedema hereditario se caracteriza por la incidencia familiar del mismo proceso, aunque este hecho no parecía existir en los casos aquí presentados. El edema laríngeo se presentó en dos de los casos y ninguno de ellos tuvo manifestaciones abdominales.

El tratamiento de elección, en el angioedema de estas características, son los agentes antifibrinolíticos, con un 70% de buenos resultados. El ácido epsilon-aminocaproico y el tranexámico inhiben la formación de plasmina y la formación de fragmentos del factor Hageman, inhibiendo por tanto la producción de calicreína y bradicinina. Los andrógenos danazol y estanazolol se usan desde la década de los 70, habiendo sido muy eficaz éste último en dos de los pacientes que se presentan en esta revisión.

Palabras clave: Angioedema familiar. Angioedema hereditario. Edema de Quincke. Inhibidor de la C₁-esterasa. Danazol. Ácido tranexámico.

---

REFERENCES

1. Ishizaka K, Debermardo R, Tomioka H, et al. Identification of basophil granulocytes as a site of allergic histamine release. J. Immunol 1972;180:1000.

2. Tomioka H, Shizaka K. Mechanisms of passive sensitization. II. Presence of receptors for IgE in monkey mast cells. J. Immunol 1971;107-971.

3. Orange RP, Austen KF. Immunologic and pharmacologic receptor control of the release of chemical mediators from human lung. In Ishizaka K, and Kayton DH, jr, editors. The biological role of the immunoglobulin E system. Bethesda, MD, 1972, National Institutes of Health, US Department of Health, Education and Welfare.

4. Soter NA, Lewis RA, Corey EJ, Austen KF. Local effects of synthetic leucotrienes (LTC₄, LTD₄, LTE₄ and LTB₄) in human skin, J. Invest Dermatol 1983;80:115.

5. Proud D, MacGlashan DW, Newball HH, et al. Immunoglobulim E-mediated release of a kininogenase from purified lung mast cells. Am Rev Respir Dis 1985;132:405.

6. Rosen FS, Charache P, Pensky J, et al. Hereditary angioneurotic edema. Two genetic variants. Science 1965;148: 957-8.

7. Senent Sánchez E, Gozalo Reques F. Alergología. Pregrado. Edit. Luzan; 1985;348.

8. Osler W. Angio-neurotic oedema, in Osler W (ed). The principles and practice of medicine, ed. 4. Edinburgh-London, Young G. Pentland 1901, pp. 1140-1141.

9. Landerman NS. Hereditary angioneurotic edema. J. Allergy Clin Immunol 1962;33:316-29.

10. Fabiani JE, Simking GO, Leoni J, Squiquera L, Mathov E. Hereditary angioedema. Polymorphism. Annals of Allergy 1985;55:830-4.

11. Jaffe CJ, Atkinson JP, Gelfand JA, et al. Hereditary angioedema. The use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. J Allergy Clin Immunol 1975;55:386-93.

12. Donaldson VH, Hess EV, Mac Adams, AS. Lupus erythematosus like disease in three unrelated women with hereditary antioneurotic oedema. Ann Intern Med 1977;86: 312-7.

Correspondence:

A. Sánchez Palacios

Allergy Unity; Hospital Insular

C/. Dr. Pasteur, s/n.

35016 Las Palmas de Gran Canaria, Spain