Acquired angioedema associated with rectal carcinoma and its response to danazol therapy Acquired angioedema treated with danatol Steven H. Cohen, M.D., Susan M. Koethe, Ph.D., Franklin Kozin, M.D., Glenn Rodey, M.D., John A. Arkins, M.D., and Jordan N. Fink, M.D. Milwaukee,
Wis.
Cases of the acquired form of angioedema have been recognized as a separate entity since 1972. Previously reported cases have been related to various hematologic malignancies. We have recently studied a patient with rectal carcinoma who manifests a complement pattern compatible with the acquired form of angioedema. No previous personal or family history of allergic disease or angioedema was present. Because the episodes of angioedema were laryngeal in location and required emergency intubation to maintain an adequate airway, a trial qf danazol prophylaxis, which has been shown to be effective in hereditary angioedema, was undertaken. His beneficial response to this form of therapy is also documented.
The acquired form of angioedemahas been recognized since 1972. Patients with this variant have a complement profile different from the hereditary form, in that the first component of complement is reduced in addition to the second and fourth components and CT INH level.*-” Such patients usually have an underlying lymphoproliferative diseasesuch as lymphosarcoma’ or leukemia.g-‘l We have studied a patient with the acquired form of angioedema, presumably related to a proved adenocarcinomaof the rectum, without evidenceof hematologic malignancy. Furthermore, the patient’s response to danazol has been followed and is reported.
Considerable knowledge concerning hereditary angioedema (HAE) has been accumulated since Osler’s’ first description in 1888. Recent discoveries have defined much of the pathophysiology of HAE. These include the finding of nonfunctioning CT esterase inhibitor (CT INH),* low absolute CT INH levels,2*3 and the activation of Cl by plasmin during trauma.4 Various modes of therapy, primarily with antifibrinolytic agents,j* 6 have been based on the pathophysiology. Current studies suggestthat an androgen derivative, danazol, may offer a more specific approach to therapy as demonstrated by both biochemical and clinical improvement,’
CASE REPORT
The patient,a 69-year-old retired white man, was first hospitalized with acute laryngeal edema in March, 1975. The episode developed over several hours and no specific stimulus could be identified. On examination, the uvula and posterior pharynx were markedly edematous and auscultation of the chest revealed coarse rhonchi. No wheezing or stridor was noted. The white blood count was 14,200 cell/ mm3 with a normal differential count. The patient was intubated and received subcutaneous epinephrine, intramuscular diphenhydramine, and intravenous cotticosteroids. Within 36 hr the angioedema subsided and the endotracheal tube was removed. The family history was negative for allergic diseases,
From the Allergy and Rheumatology Sections, Department of Medicine, and the Department of Pathology, The Medical College of Wisconsinandthe Milwaukee County Medical Complex. Supportedby a National ResearchService Award Grant (SHC) AI 7006 from the National Institute of Allergy and Infectious Diseasesand by the Department of Pathology ResearchFunds. Abstract presented at the Thirty-fourth Annual Meeting of the American Academy of Allergy, Phoenix, Ariz., March I, 1978. Received for publication March 22, 1978. Accepted for publication June 9, 1978. Reprint requeststo: Steven H. Cohen, M.D., Milwaukee County Medical Complex, 8700 West Wisconsin Ave., Milwaukee, WI 53226.
0091-6749/78/100217+05$00.5010
0 1978 The C. V. Mosbv
Co.
Vol. 62, No. 4, pp. 217-221
218
Cohen et al.
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1978
r360,000
0 i’ a 4’
-300,000 - 240,000
- 180,000 -120,000
t 1976
;z ; -g i g $ P
t
1977
FIG. 1. Changes in CT INH, C4, and Ci levels before and after danazol therapy: (1) 2/2/77 danazol begun at 200 mg 3 times daily; (2) 2/18/77 danazol reduced to 200 mg 2 times daily; (3) 312177 danazol reduced to 200 mglday for maintenance. Laboratory normal values: C4, 12 to 72 mgldl; Ci INH, 15 to 35 mgldl; Ci titration, 190,000 to 340,000 U/ml.
including urticaria or angioedema, and the patient had no personal allergic history. Skin tests to various food antigens were negative. The patient remained well until 10 mo later when the laryngeal edema recurred. Again, no specific etiology could be determined. Presentation, immediate therapy, and laboratory findings were similar to those of the initial episode. The hospital course was identical to that of the first admission, except for the finding of occult blood in the stool. The only abnormality on proctoscopy examination was a polyp at I6 cm which was biopsied and found to be adenomatous. A third spontaneous episode of acute laryngeal edema occurred 4 wk later. The episode was similar to the others, but intubation was not necessary. At that time the CT INH level was found to be diminished and a complement profile revealed depressed CH,*, C4, and Ci and normal C3 levels (Fig. I). Repeat pmctoscopy, barium enema, and air contrast studies were performed. At this time, a previously missed lesion was seen at 5 cm and biopsy demonstrated an adenocarcinoma. The radiographic studies revealed no other lesions. Several attempts at fulguration were unsuccessful, tumor being found in the margins of pathologic specimens, and abdomin-transsacral resection was subsequently undertaken. At the time of surgery, the abdomen was carefully explored and no evidence of metastatic disease was found. Complement profile during an asymptomatic period continued to be abnormal (Fig. I ). The patient continued symptom-free for II mo until the most recent attack of angioedema in January, 1977. This occurred over a 45min period without a precipitating event. Examination and therapy were identical to the previous episodes; complement component levels continued to be
abnormal. No evidence for recurrent carcinoma could be documented by physical examination, laboratory studies, barium studies of the gastrointestinal tract, or bone scintigraphy . Because of the potentially lethal nature of his attacks, danazol, 200 mg 3 times daily, was statted. Complement levels returned to normal within 2 wk and the CT INH level became elevated (Fig. 1). The patient has moved to another city, been well, and has had no attacks in 16 mo of follow-up on danazol. His weight has been stable after an initial increase of 3 to 5 kg. No evidence of recurrent or metastatic tumor has been noted.
MATERIALS AND METHODS Blood samples were obtained by venipuncture, allowed to clot for I hr at room temperature and then 1 hr at 0” C, and centrifuged; the serum was isolated and frozen at -80” C until studied. Methods for preparing veronal-buffered saline (containing 0.1% gelatin, 0.0005 M Ca*+, and 0.00015 M mg*+ [GVBZ+]), dextrose-vemnal-buffered saline (containing gelatin and the same concentrations of Ca2+ and Mg2+ [DGVB~+]), and 0.04 M ethylenediaminetetracetate (EDTA) buffer were as described by Nelson and associates.i2 Sheep erythmcytes were coated with antisheep hemolysin made in rabbits (EA)13 and were used in an assay modified from the method of Schulman14 for measurement of total hemolytic complement (CH,,). The procedure used to measure the functional activity of the first component of complement (Cl ) has been described by Borsos and coworkers.lJ C4 and C3 protein levels were measured by radial immunodiffusion (RID) with commercially prepared RID plates (Meloy Laboratories, Inc., Springfield, Va., and
VOLUME NUMBER
62 4
Behring Diagnostics, Somerville, N. J.), which was incorporatedinto 1.5% agamse(Fischer Scientific, Chicago, Ill.) as described by Allison.”
RESULTS OF THERAPY Our patient experienced two potentially life-threatening attacks of laryngeal edema before the diagnosis of rectal carcinoma was established. Despite adequate surgical therapy and absence of demonstrable local or metastatic recurrence, a subsequent episode of laryngeal edema occurred. No other specific inciting event, such as trauma, could be determined. Because of the nature of the attacks, a trial of danazol was undertaken. Within 14 days, CT INH levels were above normal and C4 levels were within normal limits (Fig. 1). The dose of danazol was titrated over the elsuing months by monitoring the complement and Cl INH levels. The patient subsequently moved and a serum sample sent to our laboratory revealed that the complement and CT INH levels had returned to predanazol treatment values. Increasing the danazol dose to 600 mg daily did not change these laboratory parameters. Despite this, he remains well, free from further attacks of angioedema, and without evidence of recurrent malignancy.
DISCUSSION The hereditary form of angioedema is characterized by episodic swelling of various areas of the body including abdominal viscera, extremities, face, and airways. Episodes may be precipitated by trauma or emotional stress but also may occur without apparent provocation. 4, I7 The underlying etiology of this disease is thought to be a deficiency in the inhibitor of the first component of complement, either because of low absolute levels of CT INH or presence of a nonfunctioning protein.2 The other classical laboratory finding is that of a lowered C4 level due to the uninhibited activation of Cl and its subsequent activation of C4 and C2. In 1972, Caldwell and associates* demonstrated an association between lymphosarcoma and an abnormal complement profile. These investigators detected lowered levels of the first, fourth, and second components of complement, as well as the CT INH, in 2 patients. One patient experienced episodes of angioedema. The features discriminating this syndrome from hereditary angioedema included negative past histories, absence of any complement system abnormalities in other family members, and a low level of Cl. Subsequent to this report, the acquired form of angioedema complement pattern was described in patients with chronic lymphocytic leukemia,Q lympho-
Acquired angioedema treated with danazol
219
proliferative disorder,” and diffuse normolipemic plane xanthomatosis (usually associated with hematologic malignancy).” Three of the 5 patients reported had clinically apparent episodes of angioedema, and all had the associated complement pattern with negative family evaluation. Although laryngeal involvment was reported, them were no deaths due to the angioedema. Until recently, therapy of hereditary angioedema generally has been unsatisfactory. Acute episodes of life-threatening laryngeal edema have been treated with corticosteroids, epinephrine, antihistamines, and/or tracheostomy or tracheal intubation in order to support vital functions until the attack spontaneously subsides, usually within 24 to 72 hr. The first attempts at prevention were noted by Spaulding18 in 1960, who found testosterone to be effective in reducing the frequency of attacks. Masculinization and anecdotal reports of failure, however, prevented this therapy from being widely used. His observations have subsequently been confirmed in a double-blind study by Sheffer and co-workers. lQ Knowledge of the action of plasmin in activating C 1, especially in trauma, and the blocking effect of epsilon aminocaproic acid (EACA) of this plasmin function have led to its use prophylactically. However, since long-term use of EACA or its analogue, tranexamic acid, is associated with thrombosis, phlebitis, and muscle necrosis with enzyme changes, these drugs have been used primarily in the immediate operative and postoperative period.*O A recent study by Gelfand and colleagues’ using the androgen derivative, danazol, has improved the potential for prophylaxis of potentially fatal angioedema. These investigators demonstrated a prompt and significant rise in CT INH levels as well as C4 levels during therapy. Side effects of the drug were minor and were felt to be more tolerable than angioedema. The exact mechanism of the CT INH increase in response to androgen is unknown, although it has been suggested that the drug acts to increase the level of Ci INH production.‘, *i The current case report is the first symptomatic case of the acquired form of angioedema associated with a gastrointestinal carcinoma. Hauptmann and associates** used danazol to treat a patient with acquired CT INH deficiency associated with lymphoma. The patient had the typical complement profile but had no attacks of angioedema. The patient showed normalization of CT INH levels within 20 days but the other complement levels remained unchanged. We have noted a similar response to danazol in a patient with chronic lymphocytic leukemia.23
220 Cohen et al.
The relationship betweenmalignancy and abnormal complement component levels in acquired angioedemais obscure. It is possible that continuous tissue damage from a locally expanding lesion might activate plasmin with subsequentCl, and then C4 and C2, activation. Since CT INH forms a stoichiometric complex with CT, thus blocking the action of Ci on C4 and C2,24 the formation and clearance of this CT-CT INH complex may explain the low Ci and Ci INH value in some such patients. Since studies have shown that danazol acts to increase the level of C’T INH, one might expect an even lower level of Cl rather than the rise we have observed. This would be basedon larger amounts of CT INH present to bind stoichiometrically with activated Cl, We can only speculate then that danazol in some way was able to reduce the effect of the initiating event in Cl activation. We cannot prove that the episodesof angioedema are specifically related to the adenocarcinoma.After the last episode, the evaluation allowed by the patient showed no biochemical or x-ray evidence of metastatic disease.Further follow-up over the past 16 mo shows no physical evidence that the tumor has reoccurred. Evaluation for a sourceof hematologic malignancy during previous admissions including bone marrow aspiration and bone marrow biopsy were not diagnostic. In the Ci INH-deficient patient with the lymphoproliferative disorder described by Schreiber and associates,lo the patient’s own lymphocytes were shown to both activate Cl and bind the CT INH. We could find no evidence of this type of activity associated with Ficoll-Hypaque-isolated lymphocytes from our patient. We ate left with a tissue-proved cancer and an acquired form of angioedemathat has been described in association with malignancy. In summary, a patient with the acquired form of CT INH deficiency associated with carcinoma of the rectum is described. Becauseof the life-threatening nature of his attacks, a trial of danazol therapy was undertaken. On therapy, complement and C’i INH levels rapidly returned to normal, as has been shown in patients with the hereditary form of angioedema. This points to the importance of Ci INH and C4 determinations in patients who lack a family history suggesting the inherited disease. If these determinations are abnormal, pointing to acquired angioedema, these patients should be evaluated carefully for evidence of malignant disease.The responseto therapy with danazol suggeststhat the complement and Cl INH levels may return to normal and that further attacks of angioedemamay be prevented.
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1978
We wish to acknowledge the excellent technical assistance of Zita Jendrzejczak, M.L.T. (ASCP), Barbara Niemczycki, M.T. (ASCP), Ann McDonald, M.T. (ASCP), Linda Henick, M.T. (ASCP), Ginny Olsen, M.T. (ASCP), and Natlie Russell, C.L.L. (ASCP). We also wish to acknowledge Mrs. Anita Balistreri for her secretarial skills. REFERENCES
I. Osler, W.: Hereditary angioneuroticedema,Am. J. Med. Sci. 95~362-367, 1888. 2. Rosen, F. S., Charache, P., Pensky, J., et al.: Hereditary angioneurotic edema:Two genetic variants, Science 148:957958, 1965. 3. Donaldson, V. H., and Evans, R. R.: A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of Cl esterase,Am. J. Med. 35:37-44, 1963. 4. Frank, M. M., Gelfand, J. A., and Atkinson, J. P.: Hereditary angioedema:The clinical syndromeand its management,Ann. Intern. Med. 84:580-593, 1976. 5. Frank, M. M., Sergent, S. S., Kane, M. A., et al.: Epsilon aminocaproic acid therapy of hereditary angioneuroticedema: A double blind study, N. Engl. J. Med. 286:808-812, 1972. 6. Sheffer, A. L., Austen, K. F., and Rosen, F. S.: Tranexamic acid therapy in hereditary angioneurotic edema, N. Engl. J. Med. 282452-454, 1972. 7. Gelfand, J. A., Sherins, R. J., Alling, D. W., et al.: Treatment of hereditary angioedemawith danazol: Reversal of clinical and biochemical abnormalities, N. Engl. J. Med. 295:14441448, 1976. 8. Caldwell, J. R., Ruddy, S., Shur, P. H., et al.: Acquired CT inhibitor deficiency in lymphosarcoma, Clin. Immunol. Immunopathol. 1:39-52, 1972. 9. Day, N. K., Winfield, J. B., Gee, T., et al.: Evidence for immune complexes involving anti-lymphocyte antibodies associated with hypocomplementaemiain chronic lymphocytic leukaemia (CLL), Clin. Exp. Immunol. 26: 189-195, 1976. 10. Schreiber, A. D., Zweiman, B., Atkins, P., et al.: Acquired angioedemawith lymphoproliferative disorder: Association of Cl inhibitor deficiency with cellular abnormality, Blood 48~567-580, 1976.
1I. Jordan, R. E., McDuffie, F. C., Good, R. A., et al.: Diffuse normolipaemic plane xanthomatosis: An abnormal complement component profile, Clin. Exp. Immunol. l&407-415, 1974.
12. Nelson, R. A., Jensen, J., Gigli, I., et al.: Methods for the separation, purification and measurementof the nine componentsof hemolytic complementin guinea pig serum, Immunochemistry3:111-135, 1966. 13. Mayer, M. M.: In Kabat, E. A., and Mayer, M. M., editors: Experimental immunochemistry,ed. 2, Springfield, Ill., 1961, Charles C. Thomas, Publisher, p 149. 14. Schuhnan, N. R.: Immunoreactionsinvolving platelets. I. A steric and kinetic model for formation of a complex from a human antibody, quinidine as a haptene, and platelets and for the fixation of complement by the complex, J. Exp. Med. 107:665-696, 1958.
15. Borsos, T., Rapp, H. J., and Walz, U. L.: Action of the first component of complement: Activation of C’ I to C’ la in the hemolytic system, J. Immunol. 92: 108-112, 1964. 16. Allison, A. C.: In Williams, C. A., and Chase, M. W.,
VOLUME NUMBER
17.
IS.
19.
20.
Acquired
62 4
editors: Methods in immunology and immunochemistry, ed. I, New York, 1971, Academic Press, Inc., p 217. Landerman, N. S.: Hereditary angioneurotic edema. I. Case reports with a review of the literature, J. ALLERGY 33~316 329, 1962. Spaulding, W. B.: Methyltestosterone therapy for hereditary episodic edema (hereditary angioneurotic edema), Ann. Intern. Med. X%739-745, 1960. Sheffer, A. L., Fearon, D. T., and Austen, K. F.: Methyltestosterone therapy in hereditary angioedema, Ann. Intern. Med. 86~306-308, 1977. Pence, H. L., Evans, R., Guernsey, L. H., et al.: Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema, J. ALLERGY CLM. IMMUNOL. 53:298-302, 1974.
angioedeme
treated
with danazol
2 1. Rosse, W. F., Logue, G. L., and Silberman, H. R.: The effect of synthetic androens on the clinical course of Cl esterase inhibitor (Cl INH) levels in hereditary angioneurotic edema (HANE), Chn. Res. 24:482A, 1976. 22. Hauptmann, G., Mayer, S., Lang, J., et al.: Treatment of acquired CT inhibitor deficiency with danazol. Ann. Intern. Med. 87~577-578, 1977. 23. Cohen, S. H., and Koethe, S. M.: Danazol and CT esterase inhibitor deficiency, Ann. Intern. Med. 88:429, 1978. 24. Gigli, I., Ruddy, S., and Austen, K. F.: The stoichiometric measurement of the serum inhibitor of the first component of complement by the inhibition of immune hemolysis, J. Immunol. 100: 1154-l 164, 1968.
. Information
221
for authors
Most of the provisions of the Copyright Act of 1976 becameeffective on January 1, 1978. Therefore, all manuscriptsmust be accompaniedby the following statement,signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscriptentitled (title of article)‘to The C. V. Mosby Company in the evertt the work is published. The author(s) warrants that the article is original, is not under consideration by anotherjournal, and hasnot beenpreviously published:” Authors will be consulted, when possible, regarding republication of their material.
Wis.
Cases of the acquired form of angioedema have been recognized as a separate entity since 1972. Previously reported cases have been related to various hematologic malignancies. We have recently studied a patient with rectal carcinoma who manifests a complement pattern compatible with the acquired form of angioedema. No previous personal or family history of allergic disease or angioedema was present. Because the episodes of angioedema were laryngeal in location and required emergency intubation to maintain an adequate airway, a trial qf danazol prophylaxis, which has been shown to be effective in hereditary angioedema, was undertaken. His beneficial response to this form of therapy is also documented.
The acquired form of angioedemahas been recognized since 1972. Patients with this variant have a complement profile different from the hereditary form, in that the first component of complement is reduced in addition to the second and fourth components and CT INH level.*-” Such patients usually have an underlying lymphoproliferative diseasesuch as lymphosarcoma’ or leukemia.g-‘l We have studied a patient with the acquired form of angioedema, presumably related to a proved adenocarcinomaof the rectum, without evidenceof hematologic malignancy. Furthermore, the patient’s response to danazol has been followed and is reported.
Considerable knowledge concerning hereditary angioedema (HAE) has been accumulated since Osler’s’ first description in 1888. Recent discoveries have defined much of the pathophysiology of HAE. These include the finding of nonfunctioning CT esterase inhibitor (CT INH),* low absolute CT INH levels,2*3 and the activation of Cl by plasmin during trauma.4 Various modes of therapy, primarily with antifibrinolytic agents,j* 6 have been based on the pathophysiology. Current studies suggestthat an androgen derivative, danazol, may offer a more specific approach to therapy as demonstrated by both biochemical and clinical improvement,’
CASE REPORT
The patient,a 69-year-old retired white man, was first hospitalized with acute laryngeal edema in March, 1975. The episode developed over several hours and no specific stimulus could be identified. On examination, the uvula and posterior pharynx were markedly edematous and auscultation of the chest revealed coarse rhonchi. No wheezing or stridor was noted. The white blood count was 14,200 cell/ mm3 with a normal differential count. The patient was intubated and received subcutaneous epinephrine, intramuscular diphenhydramine, and intravenous cotticosteroids. Within 36 hr the angioedema subsided and the endotracheal tube was removed. The family history was negative for allergic diseases,
From the Allergy and Rheumatology Sections, Department of Medicine, and the Department of Pathology, The Medical College of Wisconsinandthe Milwaukee County Medical Complex. Supportedby a National ResearchService Award Grant (SHC) AI 7006 from the National Institute of Allergy and Infectious Diseasesand by the Department of Pathology ResearchFunds. Abstract presented at the Thirty-fourth Annual Meeting of the American Academy of Allergy, Phoenix, Ariz., March I, 1978. Received for publication March 22, 1978. Accepted for publication June 9, 1978. Reprint requeststo: Steven H. Cohen, M.D., Milwaukee County Medical Complex, 8700 West Wisconsin Ave., Milwaukee, WI 53226.
0091-6749/78/100217+05$00.5010
0 1978 The C. V. Mosbv
Co.
Vol. 62, No. 4, pp. 217-221
218
Cohen et al.
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1978
r360,000
0 i’ a 4’
-300,000 - 240,000
- 180,000 -120,000
t 1976
;z ; -g i g $ P
t
1977
FIG. 1. Changes in CT INH, C4, and Ci levels before and after danazol therapy: (1) 2/2/77 danazol begun at 200 mg 3 times daily; (2) 2/18/77 danazol reduced to 200 mg 2 times daily; (3) 312177 danazol reduced to 200 mglday for maintenance. Laboratory normal values: C4, 12 to 72 mgldl; Ci INH, 15 to 35 mgldl; Ci titration, 190,000 to 340,000 U/ml.
including urticaria or angioedema, and the patient had no personal allergic history. Skin tests to various food antigens were negative. The patient remained well until 10 mo later when the laryngeal edema recurred. Again, no specific etiology could be determined. Presentation, immediate therapy, and laboratory findings were similar to those of the initial episode. The hospital course was identical to that of the first admission, except for the finding of occult blood in the stool. The only abnormality on proctoscopy examination was a polyp at I6 cm which was biopsied and found to be adenomatous. A third spontaneous episode of acute laryngeal edema occurred 4 wk later. The episode was similar to the others, but intubation was not necessary. At that time the CT INH level was found to be diminished and a complement profile revealed depressed CH,*, C4, and Ci and normal C3 levels (Fig. I). Repeat pmctoscopy, barium enema, and air contrast studies were performed. At this time, a previously missed lesion was seen at 5 cm and biopsy demonstrated an adenocarcinoma. The radiographic studies revealed no other lesions. Several attempts at fulguration were unsuccessful, tumor being found in the margins of pathologic specimens, and abdomin-transsacral resection was subsequently undertaken. At the time of surgery, the abdomen was carefully explored and no evidence of metastatic disease was found. Complement profile during an asymptomatic period continued to be abnormal (Fig. I ). The patient continued symptom-free for II mo until the most recent attack of angioedema in January, 1977. This occurred over a 45min period without a precipitating event. Examination and therapy were identical to the previous episodes; complement component levels continued to be
abnormal. No evidence for recurrent carcinoma could be documented by physical examination, laboratory studies, barium studies of the gastrointestinal tract, or bone scintigraphy . Because of the potentially lethal nature of his attacks, danazol, 200 mg 3 times daily, was statted. Complement levels returned to normal within 2 wk and the CT INH level became elevated (Fig. 1). The patient has moved to another city, been well, and has had no attacks in 16 mo of follow-up on danazol. His weight has been stable after an initial increase of 3 to 5 kg. No evidence of recurrent or metastatic tumor has been noted.
MATERIALS AND METHODS Blood samples were obtained by venipuncture, allowed to clot for I hr at room temperature and then 1 hr at 0” C, and centrifuged; the serum was isolated and frozen at -80” C until studied. Methods for preparing veronal-buffered saline (containing 0.1% gelatin, 0.0005 M Ca*+, and 0.00015 M mg*+ [GVBZ+]), dextrose-vemnal-buffered saline (containing gelatin and the same concentrations of Ca2+ and Mg2+ [DGVB~+]), and 0.04 M ethylenediaminetetracetate (EDTA) buffer were as described by Nelson and associates.i2 Sheep erythmcytes were coated with antisheep hemolysin made in rabbits (EA)13 and were used in an assay modified from the method of Schulman14 for measurement of total hemolytic complement (CH,,). The procedure used to measure the functional activity of the first component of complement (Cl ) has been described by Borsos and coworkers.lJ C4 and C3 protein levels were measured by radial immunodiffusion (RID) with commercially prepared RID plates (Meloy Laboratories, Inc., Springfield, Va., and
VOLUME NUMBER
62 4
Behring Diagnostics, Somerville, N. J.), which was incorporatedinto 1.5% agamse(Fischer Scientific, Chicago, Ill.) as described by Allison.”
RESULTS OF THERAPY Our patient experienced two potentially life-threatening attacks of laryngeal edema before the diagnosis of rectal carcinoma was established. Despite adequate surgical therapy and absence of demonstrable local or metastatic recurrence, a subsequent episode of laryngeal edema occurred. No other specific inciting event, such as trauma, could be determined. Because of the nature of the attacks, a trial of danazol was undertaken. Within 14 days, CT INH levels were above normal and C4 levels were within normal limits (Fig. 1). The dose of danazol was titrated over the elsuing months by monitoring the complement and Cl INH levels. The patient subsequently moved and a serum sample sent to our laboratory revealed that the complement and CT INH levels had returned to predanazol treatment values. Increasing the danazol dose to 600 mg daily did not change these laboratory parameters. Despite this, he remains well, free from further attacks of angioedema, and without evidence of recurrent malignancy.
DISCUSSION The hereditary form of angioedema is characterized by episodic swelling of various areas of the body including abdominal viscera, extremities, face, and airways. Episodes may be precipitated by trauma or emotional stress but also may occur without apparent provocation. 4, I7 The underlying etiology of this disease is thought to be a deficiency in the inhibitor of the first component of complement, either because of low absolute levels of CT INH or presence of a nonfunctioning protein.2 The other classical laboratory finding is that of a lowered C4 level due to the uninhibited activation of Cl and its subsequent activation of C4 and C2. In 1972, Caldwell and associates* demonstrated an association between lymphosarcoma and an abnormal complement profile. These investigators detected lowered levels of the first, fourth, and second components of complement, as well as the CT INH, in 2 patients. One patient experienced episodes of angioedema. The features discriminating this syndrome from hereditary angioedema included negative past histories, absence of any complement system abnormalities in other family members, and a low level of Cl. Subsequent to this report, the acquired form of angioedema complement pattern was described in patients with chronic lymphocytic leukemia,Q lympho-
Acquired angioedema treated with danazol
219
proliferative disorder,” and diffuse normolipemic plane xanthomatosis (usually associated with hematologic malignancy).” Three of the 5 patients reported had clinically apparent episodes of angioedema, and all had the associated complement pattern with negative family evaluation. Although laryngeal involvment was reported, them were no deaths due to the angioedema. Until recently, therapy of hereditary angioedema generally has been unsatisfactory. Acute episodes of life-threatening laryngeal edema have been treated with corticosteroids, epinephrine, antihistamines, and/or tracheostomy or tracheal intubation in order to support vital functions until the attack spontaneously subsides, usually within 24 to 72 hr. The first attempts at prevention were noted by Spaulding18 in 1960, who found testosterone to be effective in reducing the frequency of attacks. Masculinization and anecdotal reports of failure, however, prevented this therapy from being widely used. His observations have subsequently been confirmed in a double-blind study by Sheffer and co-workers. lQ Knowledge of the action of plasmin in activating C 1, especially in trauma, and the blocking effect of epsilon aminocaproic acid (EACA) of this plasmin function have led to its use prophylactically. However, since long-term use of EACA or its analogue, tranexamic acid, is associated with thrombosis, phlebitis, and muscle necrosis with enzyme changes, these drugs have been used primarily in the immediate operative and postoperative period.*O A recent study by Gelfand and colleagues’ using the androgen derivative, danazol, has improved the potential for prophylaxis of potentially fatal angioedema. These investigators demonstrated a prompt and significant rise in CT INH levels as well as C4 levels during therapy. Side effects of the drug were minor and were felt to be more tolerable than angioedema. The exact mechanism of the CT INH increase in response to androgen is unknown, although it has been suggested that the drug acts to increase the level of Ci INH production.‘, *i The current case report is the first symptomatic case of the acquired form of angioedema associated with a gastrointestinal carcinoma. Hauptmann and associates** used danazol to treat a patient with acquired CT INH deficiency associated with lymphoma. The patient had the typical complement profile but had no attacks of angioedema. The patient showed normalization of CT INH levels within 20 days but the other complement levels remained unchanged. We have noted a similar response to danazol in a patient with chronic lymphocytic leukemia.23
220 Cohen et al.
The relationship betweenmalignancy and abnormal complement component levels in acquired angioedemais obscure. It is possible that continuous tissue damage from a locally expanding lesion might activate plasmin with subsequentCl, and then C4 and C2, activation. Since CT INH forms a stoichiometric complex with CT, thus blocking the action of Ci on C4 and C2,24 the formation and clearance of this CT-CT INH complex may explain the low Ci and Ci INH value in some such patients. Since studies have shown that danazol acts to increase the level of C’T INH, one might expect an even lower level of Cl rather than the rise we have observed. This would be basedon larger amounts of CT INH present to bind stoichiometrically with activated Cl, We can only speculate then that danazol in some way was able to reduce the effect of the initiating event in Cl activation. We cannot prove that the episodesof angioedema are specifically related to the adenocarcinoma.After the last episode, the evaluation allowed by the patient showed no biochemical or x-ray evidence of metastatic disease.Further follow-up over the past 16 mo shows no physical evidence that the tumor has reoccurred. Evaluation for a sourceof hematologic malignancy during previous admissions including bone marrow aspiration and bone marrow biopsy were not diagnostic. In the Ci INH-deficient patient with the lymphoproliferative disorder described by Schreiber and associates,lo the patient’s own lymphocytes were shown to both activate Cl and bind the CT INH. We could find no evidence of this type of activity associated with Ficoll-Hypaque-isolated lymphocytes from our patient. We ate left with a tissue-proved cancer and an acquired form of angioedemathat has been described in association with malignancy. In summary, a patient with the acquired form of CT INH deficiency associated with carcinoma of the rectum is described. Becauseof the life-threatening nature of his attacks, a trial of danazol therapy was undertaken. On therapy, complement and C’i INH levels rapidly returned to normal, as has been shown in patients with the hereditary form of angioedema. This points to the importance of Ci INH and C4 determinations in patients who lack a family history suggesting the inherited disease. If these determinations are abnormal, pointing to acquired angioedema, these patients should be evaluated carefully for evidence of malignant disease.The responseto therapy with danazol suggeststhat the complement and Cl INH levels may return to normal and that further attacks of angioedemamay be prevented.
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1978
We wish to acknowledge the excellent technical assistance of Zita Jendrzejczak, M.L.T. (ASCP), Barbara Niemczycki, M.T. (ASCP), Ann McDonald, M.T. (ASCP), Linda Henick, M.T. (ASCP), Ginny Olsen, M.T. (ASCP), and Natlie Russell, C.L.L. (ASCP). We also wish to acknowledge Mrs. Anita Balistreri for her secretarial skills. REFERENCES
I. Osler, W.: Hereditary angioneuroticedema,Am. J. Med. Sci. 95~362-367, 1888. 2. Rosen, F. S., Charache, P., Pensky, J., et al.: Hereditary angioneurotic edema:Two genetic variants, Science 148:957958, 1965. 3. Donaldson, V. H., and Evans, R. R.: A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of Cl esterase,Am. J. Med. 35:37-44, 1963. 4. Frank, M. M., Gelfand, J. A., and Atkinson, J. P.: Hereditary angioedema:The clinical syndromeand its management,Ann. Intern. Med. 84:580-593, 1976. 5. Frank, M. M., Sergent, S. S., Kane, M. A., et al.: Epsilon aminocaproic acid therapy of hereditary angioneuroticedema: A double blind study, N. Engl. J. Med. 286:808-812, 1972. 6. Sheffer, A. L., Austen, K. F., and Rosen, F. S.: Tranexamic acid therapy in hereditary angioneurotic edema, N. Engl. J. Med. 282452-454, 1972. 7. Gelfand, J. A., Sherins, R. J., Alling, D. W., et al.: Treatment of hereditary angioedemawith danazol: Reversal of clinical and biochemical abnormalities, N. Engl. J. Med. 295:14441448, 1976. 8. Caldwell, J. R., Ruddy, S., Shur, P. H., et al.: Acquired CT inhibitor deficiency in lymphosarcoma, Clin. Immunol. Immunopathol. 1:39-52, 1972. 9. Day, N. K., Winfield, J. B., Gee, T., et al.: Evidence for immune complexes involving anti-lymphocyte antibodies associated with hypocomplementaemiain chronic lymphocytic leukaemia (CLL), Clin. Exp. Immunol. 26: 189-195, 1976. 10. Schreiber, A. D., Zweiman, B., Atkins, P., et al.: Acquired angioedemawith lymphoproliferative disorder: Association of Cl inhibitor deficiency with cellular abnormality, Blood 48~567-580, 1976.
1I. Jordan, R. E., McDuffie, F. C., Good, R. A., et al.: Diffuse normolipaemic plane xanthomatosis: An abnormal complement component profile, Clin. Exp. Immunol. l&407-415, 1974.
12. Nelson, R. A., Jensen, J., Gigli, I., et al.: Methods for the separation, purification and measurementof the nine componentsof hemolytic complementin guinea pig serum, Immunochemistry3:111-135, 1966. 13. Mayer, M. M.: In Kabat, E. A., and Mayer, M. M., editors: Experimental immunochemistry,ed. 2, Springfield, Ill., 1961, Charles C. Thomas, Publisher, p 149. 14. Schuhnan, N. R.: Immunoreactionsinvolving platelets. I. A steric and kinetic model for formation of a complex from a human antibody, quinidine as a haptene, and platelets and for the fixation of complement by the complex, J. Exp. Med. 107:665-696, 1958.
15. Borsos, T., Rapp, H. J., and Walz, U. L.: Action of the first component of complement: Activation of C’ I to C’ la in the hemolytic system, J. Immunol. 92: 108-112, 1964. 16. Allison, A. C.: In Williams, C. A., and Chase, M. W.,
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editors: Methods in immunology and immunochemistry, ed. I, New York, 1971, Academic Press, Inc., p 217. Landerman, N. S.: Hereditary angioneurotic edema. I. Case reports with a review of the literature, J. ALLERGY 33~316 329, 1962. Spaulding, W. B.: Methyltestosterone therapy for hereditary episodic edema (hereditary angioneurotic edema), Ann. Intern. Med. X%739-745, 1960. Sheffer, A. L., Fearon, D. T., and Austen, K. F.: Methyltestosterone therapy in hereditary angioedema, Ann. Intern. Med. 86~306-308, 1977. Pence, H. L., Evans, R., Guernsey, L. H., et al.: Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema, J. ALLERGY CLM. IMMUNOL. 53:298-302, 1974.
angioedeme
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with danazol
2 1. Rosse, W. F., Logue, G. L., and Silberman, H. R.: The effect of synthetic androens on the clinical course of Cl esterase inhibitor (Cl INH) levels in hereditary angioneurotic edema (HANE), Chn. Res. 24:482A, 1976. 22. Hauptmann, G., Mayer, S., Lang, J., et al.: Treatment of acquired CT inhibitor deficiency with danazol. Ann. Intern. Med. 87~577-578, 1977. 23. Cohen, S. H., and Koethe, S. M.: Danazol and CT esterase inhibitor deficiency, Ann. Intern. Med. 88:429, 1978. 24. Gigli, I., Ruddy, S., and Austen, K. F.: The stoichiometric measurement of the serum inhibitor of the first component of complement by the inhibition of immune hemolysis, J. Immunol. 100: 1154-l 164, 1968.
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221
for authors
Most of the provisions of the Copyright Act of 1976 becameeffective on January 1, 1978. Therefore, all manuscriptsmust be accompaniedby the following statement,signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscriptentitled (title of article)‘to The C. V. Mosby Company in the evertt the work is published. The author(s) warrants that the article is original, is not under consideration by anotherjournal, and hasnot beenpreviously published:” Authors will be consulted, when possible, regarding republication of their material.
