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Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives
Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives Marco Cicardi, M.D., Luigi Bergamaschini, M.D., Antonietta Tucci, M.D., Angelo Agostoni, M.D., Giulio Tornaghi, M.D., Guido Coggi, M.D.,* Roberto Colombi, M.D., * and Giuseppe Viale, M.D.* Milan, ltal~
I7u-Alkylated androgens are highly effecth’e in preventing attacks in HAE patients. These drugs, however, seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumors. In order to assess the risk-benefit balance of the long-term therap> with androgen derivatives, a follow-up inl,estigation was performed in 13 HAE patients. The results of this study indicate that long-term treatment (15 to 47 mo) with low doses c!f‘danazol or stanozolol does not induce significant hepatic damage detectable by laboratory tests or live, biopsy. However. the limited number of patients, although in a rather long period qf observation, still suggests a careful control and the use qf minimal e#ecti\,c doses. (J ALLERGY
CLINIMMUNOL72:294-298, 1983.)
The effectiveness of androgen derivatives in reversing the clinical picture and the inherited deficiency of Cl-INH in patients with HAE has been clearly demonstrated.‘-’ We have shown previously that only 17a-alkylated androgens are effective in such a treatment.x Nevertheless, treatment with these drugs is associated with significantly high risk of hepatic damage, ranging from cholestasis and peliosis hepatis to hepatocellular or vascular neoplasia, both benign and malignant. Such undesirable effects have been observed in patients receiving relatively high doses for myelofibrosis, aplastic anemia, hypogonadism, endometriosis, and transsexuality.9-‘X Moreover, it has been suggestedIfi that liver biopsy appears to be a more reliable tool for detection of early hepatic damage than serologic laboratory tests. In our case-list,‘” because of the severity of their symptoms, 28% of the patients required a permanent prophylactic treatment with 17a-alkylated androgen derivatives (danazol or stanozolol). The lack of substantial information on
From the Department of Clinical Medicine and the *Department of Pathology, University of Milan, Italy. Supported in part by C.N.R. Rome, grant CT81,00502,04. Received for publication Nov. 24, 1982. Accepted for publication March 28, 1983. Reprint requests: Marco Cicardi, M.D., Clinica Medica VII, Ospedale San Paolo, Via di Rudini, 8, 20142 Milano, Italy.
294
the actual hazardousness of long-term low dosages (even on alternate days), its high effectiveness on the clinical picture (leading the patient to refuse the withdrawal), the potentially high mortality rate of untreated HAE, and, finally, the perspective of indefinite treatment prompted us to a follow-up investigation based on both serologic tests and liver biopsy in order to assess the risk-benefit balance of long-term
Abbreviations used HAE: Hereditary angioedema C I-INH: Inhibitor of the first component of human complement SCOT: Serum glutamic-oxaloacetic transaminase SGPT: Serum glutamic-pyruvic transaminase AP: Alkaline phosphatase y-GT: Gamma glutamyltransferase LDH: Lactic dehydrogenase AFP: Alphafetoprotein p-CHS: Pseudo-cholinesterase PT: Prothrombin time PTT: Partial thromboplastin time Creatinekinase CK: HB,Ag: Hepatitis B surface antigen Blood urea nitrogen BUN: PAS: Para-aminosalicyclic acid
VOLUME
72
NUMBER
3
Liver in hereditary angioedema
295
FIG. 1. Ultrastructural examination of the liver shows the presence of giant mithocondria. (Uranyl acetate-lead citrate; x 11,900.)
therapy with androgen derivatives. We describe the results of such an investigation in this report. MATERIAL
AND METHODS
Thirteen patients, who gave written approval, were admitted to this study. Their age ranged from 28 to 59 years. The diagnosis was established on the basis of the clinical history. the low serum levels of Cl-INH (<40% of the normal values), C4 (<60% of the normal values) immunochemically assayed,‘!’ and the low enzymatic activity of C I -1NH (<40% of the normal values) measured according to the method of Lachmann et al.zo Normal values for C I-INH and C4 have been published elsewhere.2’ Four patients belonged to the HAE variant showing low Cl-INH activity with normal antigenic levels.2’ At the time of the study all but two of the patients (patients 6 and I I who were taking danazol) were receiving stanozolol. The medium daily dose taken by each patient during the whole treatment period ( 15 to 47 mo) is reported in Table I. The drugs were taken in alternate periods (usually 5 days on, 5 days off). Each patient was examined for serum hepatic parameters (SGOT, SGPT, bilirubin, y-GT, LDH, AFP, pCHS, HBsAg, protein electrophoresis), coagulation tests (PT, PTT, platelets), renal function (BUN, creatinine, electrolytes, urine analysis), CK, sedimentation rate, blood cells’ count. Liver scintiscan with SBmT~was performed in each pa-
tient. Percutaneous liver biopsy was performed with a Trucut needle (Travenol Laboratories) in 1I patients. Biopsies could not be performed on patients 9 and 13 for technical reasons. For electron microscopy, samples were immediately cut in small blocks, fixed in glutaraldehyde, postfixed in osmium, and embedded in paraffin. For light microscopy, samples were fixed in formalin and embedded in paraffin. Four-micrometer sections were stained with hematoxylineosin, PAS, PAS-diastase, Gomori reticulin stain, Masson trichromic, long Ziehl-Neelsen stain, and orcein. Sternberg’s peroxidase-antiperoxidase technique using specific antisera was performed for HBsAg.‘:’
RESULTS The more relevant findings are collected in Table I. Clinical
and laboratory
evaluation
All the patients were free from HAE symptoms while receiving treatment. As already reported,x only negligible side effects, which did not require the withdrawal of the treatment, were observed with both drugs. Only patient 11 preferred the treatment with danazol because of a higher amount of water retention with stanozolol. A moderate increment in serum transaminases was
296 Cicardi et al.
J. ALLERGY
TABLE I. Hepatic function and morphologic androgen derivatives (danazollstanozolol)
data in 13 HAE patients
Dana201 treatment Patient No.
Duration
Stanozolol
Medium dose (mglday)
Duration (mo)
treatment
2 2
13 25
11 22
26 27
5 3
20 43
16 32
-
27
2
39
48
100 300 200 200
I5 30 28 19 4
2 3 2 3 4
IO 7 9 12 IO 45
14 13 I6 I9 9 66
300 150
30 17
3 1
10 20 <28
12 17 <30
M F
28 51
30 30
1.50 150
17 17
3 4
M F
59 59
15 -
400 -
5
F
48
6 7 8 9 10 II
F F M F F F
37 43 45 48 42 39
39 17 19 28
12 M 13 F Normal value
32 31
17 27
1
with
SGPT W/L)
Age (yr)
2
treatment
SGOT (W/L)
Sex
(mo)
on long-term
CLIN IMMUNOL. 1983 SEPTEMBER
Medium dose hglday)
Neg = negative.
found in three patients (Nos. 2, 5, 11); patient 11 also showed an increment in -y-GT and conjugated bilirubin. No deviation from the normal mean was reported for all the other parameters. Five patients (patients 1, 2, 5, 8, 11) had an increase in liver size as shown at scintiscan. No areas of deficient colloid uptake could be observed in any of the subjects. Histologic
findings
Seven cases were completely negative. Patient 2 had a clinical picture consistent with the diagnosis of chronic persistent hepatitis; the immunohistochemical search for HBsAg was, nevertheless, negative. Patient 11 showed a marked steatosis that was accompanied by the presence of lipogranulomas. This patient, whose hepatic laboratory tests were also abnormal, is a carrier of a type IIa dysiipidemia. Two of the remaining patients (Nos. 4 and 5) showed small degrees of liver involvement (slight cholestasis and small areas of intralobular necrosis). Ultrastructural
findings
The ultrastructural pictures did not show significant abnormalities. However, a rather constant finding (nine patients) was the presence of scattered giant mitochondria (Fig. 1) and of biliary pigments.
DISCUSSION The hepatotoxic effects of long-term therapy with androgen derivatives have been described in several reports.24, 25Duration of treatment and dose seem of major importance in the genesis of such abnormalities.‘0T ” However, a critical dose in relation to the total amount administered has not been established. On the basis of these data, the long-term treatment that our patients must receive, although with low doses, has raised justified concern about its potential risk. Our study has shown that the majority of patients has normal liver. The only abnormalities often encountered were the ultrastructural finding of giant mitochondria and intracanalicular bile pigments. Such a finding can not be considered as specific or as cell injury’“; however, their high frequency could relate them to the drugs. With regard to patient 2 (chronic persistent hepatitis) and patient 11 (marked steatosis with hepatic enzymes abnormalities in a dyslipidemic woman), we would rather consider these findings as incidental but a relationship to the therapy cannot be excluded. Laboratory and morphological evidence of mild hepatic involvement has been found also in patients 4 and 5. We would like to add that all laboratory and histologic abnormalities were minimal and found
VOLUME NUMBER
72 3
Liver in hereditary
angioedema
297
Bilirubin AFP Imgldl)
y-GT (IUlml)
Total
84 69
II 13
0.14 0.15
0.02 0.05
Neg Neg
2230 1616
27 39
88 101
15 12
0.30 0.25
0.20 0.10
Neg Neg
2330 1454
26 34
81
13
0.30
0.20
Neg
1500
25
69 67 51 103 73 81
8 15 14 15 9 101
0.30 0.15 0.30 0.50 0.40 1.20
0.20 0.10 0.25 0.30 0.20 0.70
Neg Neg Neg Nets Neg Neg
2450 3300 2863 2165 3446 3014
I2 24 43 42 10 19
85 87 cl78
11 15 <28
0.40 0.15 Cl.0
0.15 0.05 co.3
Neg Neg
2756 1760 >1400
17 16 <70
Conjugated
whereas there were no signs of more significant diseases in the form of severe cholestasis, vascular abnormalities, or tumor production. In addition, all the patients with some degree of liver involvement were neither those treated at higher doses nor those receiving therapy with androgen derivatives for a longer time. Although the present group of HAE patients receiving long-term treatment with androgen derivatives has shown no significant negative effects to date, it remains possible that these will appear at a later date. The use of such drugs has to be limited to very severe cases (two or more attacks a month), carefully establishing, on a clinical basis, the minimal effective dose. in only
a minority
of the patients,
REFERENCES I. Gelfand JA, Sherins RJ, Ailing DW, Frank MM: Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 293~1444, 1976. 2. Pitts JS, Donaldson VH, Forristal J, Waytt RJ: Remission induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentration of Cl inhibitor and the fourth and second component of complement. J Lab Clin Med 92:501, 1978. 3. Spaulding WB: Methyltestosterone therapy for hereditary episodic edema. Ann Intern Med 86306, 1960. 4. Davis PS, Davis FB, Charache P: Long-term therapy of hereditary angicedema (HAE). Johns Hopkins Med J 135:391,1974.
pCHS (W/L)
Histologic
findings
Negative Chronic persistent hepatitis Negative Slight steatosis; scattered cholestasis Small areasof intralobular necrosis Negative Negative Negative Not done Negative Marked steatosis; lipogranulomas Negative Not done
5. Sheffer AL, Fearon DT, Austen KF: Methyltestosterone therapy in hereditary angioedema. Ann Intern Med 86:306, 1977. 6. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angicedema. J ALLERGY CLIN IMMKJNOL 64:275, 1979. 7. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effect of stanozolol therapy for hereditary angioedema. J ALLERGY CLIN IMMUNOL 6&181, 1981. 8. Agostoni A, Cicardi M, Martignoni GC, Bergamaschini L, Marasini B: Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J ALLERGY CLIN IMMUNOL 65:75, 1980. 9. Leonard-Johnson FR, Feagler JR, Lemer KG, et al: Association of androgenic anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273, 1972. 10. Farrel GC, Joshua VE, Uren RF, Baird PJ, Perkins RW, Kronenberg H: Androgen induced hepatoma. Lancet 1:430, 1975. 11. Sweeney EC, Evans DJ: Hepatic lesions in patients treated with synthetic anabolic steroids. J Clin Pathol 29:626, 1976. 12. Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM: Liver damage from long-term methyltestosterone. Lancet 2:261, 1977. 13. Sale GE, Lemer KG: Multiple tumours after androgen therapy. Arch Pathol Lab Med 101:600, 1977. 14. Goodman MA, Laden AMJ: Hepatocellular carcinoma in association with androgen therapy. Med J Aust 1:220, 1977. 15. Paradinas FJ, Bull TB, Westaby D, Murray-Lyon IM: Hyperplasia and prolapse of hepatocytes into hepatic veins during long-term methyltestosterone therapy: possible relationships of these changes to the development of peliosis hepatis and liver turnours. Histopathology 1:225, 1977.
298
Cicardi
J ALLERGY
et al
16. Falk H. Thomas LB. Popper H, lshak KG: Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 2: 1120. 1979. 17. Nadell J. Kosek J: Peliosis hepatis. Twelve cases associated with oral androgen therapy. Arch Path01 Lab Med 101:405, 1977. 18. Chopra S. Edelstein A, Raymond SK, Zimelman AP, Lacson A. Neiman RS: Peliosis hepatis in hematologic diseases. Report of two cases. JAMA 240: 11.53, 1978. 19. Cicardi M, Bergamaschini L, Marasini B, Boccassini G, Tucci A. Agostoni A: Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 28448. 1982. 20. Lachman PJ, Hobart MJ, Aston WP: Complement technology. In Weir MD, editor: Handbook of experimental immunology. Oxford, 1973. Blackwell Scientific Publications, pp. l-23. 21. Agostoni A. Marasini B, Cicardi M, Martignoni GC, Brenna
22.
23.
24. 25.
CLIN. IMMUNOL. SEPTEMBER 1983
0: Studio mediante dosaggio enzimatico e immunochimico dell’inibitore della Cl esterasi in 50 pazienti affetti da angioedema ereditario. Boll 1st Sieroter Milan 56: I, 1977. Rosen FS, Charge P, Pensky J, Donaldson VH: Hereditary angioneurotic edema: two genetic variants. Science 148:957, 1965. Huang S: Immunocytochemic demonstration of hepatitis-B viral antigen, In De Lellis R, editor: Diagnostic immunochemistry. New York, 1981, Masson Publishing USA Inc, pp. 325-36. Pearson K, Zimmerman MJ: Danazol and liver damage. Lancet 1:645, 1980. Hosea SW. Santaella ML, Brown EJ. Berger M, Katusha K, Frank MM: Long-term therapy of hereditary angioedema with danazol. Ann Intern Med 93:809, 1980.
I7u-Alkylated androgens are highly effecth’e in preventing attacks in HAE patients. These drugs, however, seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumors. In order to assess the risk-benefit balance of the long-term therap> with androgen derivatives, a follow-up inl,estigation was performed in 13 HAE patients. The results of this study indicate that long-term treatment (15 to 47 mo) with low doses c!f‘danazol or stanozolol does not induce significant hepatic damage detectable by laboratory tests or live, biopsy. However. the limited number of patients, although in a rather long period qf observation, still suggests a careful control and the use qf minimal e#ecti\,c doses. (J ALLERGY
CLINIMMUNOL72:294-298, 1983.)
The effectiveness of androgen derivatives in reversing the clinical picture and the inherited deficiency of Cl-INH in patients with HAE has been clearly demonstrated.‘-’ We have shown previously that only 17a-alkylated androgens are effective in such a treatment.x Nevertheless, treatment with these drugs is associated with significantly high risk of hepatic damage, ranging from cholestasis and peliosis hepatis to hepatocellular or vascular neoplasia, both benign and malignant. Such undesirable effects have been observed in patients receiving relatively high doses for myelofibrosis, aplastic anemia, hypogonadism, endometriosis, and transsexuality.9-‘X Moreover, it has been suggestedIfi that liver biopsy appears to be a more reliable tool for detection of early hepatic damage than serologic laboratory tests. In our case-list,‘” because of the severity of their symptoms, 28% of the patients required a permanent prophylactic treatment with 17a-alkylated androgen derivatives (danazol or stanozolol). The lack of substantial information on
From the Department of Clinical Medicine and the *Department of Pathology, University of Milan, Italy. Supported in part by C.N.R. Rome, grant CT81,00502,04. Received for publication Nov. 24, 1982. Accepted for publication March 28, 1983. Reprint requests: Marco Cicardi, M.D., Clinica Medica VII, Ospedale San Paolo, Via di Rudini, 8, 20142 Milano, Italy.
294
the actual hazardousness of long-term low dosages (even on alternate days), its high effectiveness on the clinical picture (leading the patient to refuse the withdrawal), the potentially high mortality rate of untreated HAE, and, finally, the perspective of indefinite treatment prompted us to a follow-up investigation based on both serologic tests and liver biopsy in order to assess the risk-benefit balance of long-term
Abbreviations used HAE: Hereditary angioedema C I-INH: Inhibitor of the first component of human complement SCOT: Serum glutamic-oxaloacetic transaminase SGPT: Serum glutamic-pyruvic transaminase AP: Alkaline phosphatase y-GT: Gamma glutamyltransferase LDH: Lactic dehydrogenase AFP: Alphafetoprotein p-CHS: Pseudo-cholinesterase PT: Prothrombin time PTT: Partial thromboplastin time Creatinekinase CK: HB,Ag: Hepatitis B surface antigen Blood urea nitrogen BUN: PAS: Para-aminosalicyclic acid
VOLUME
72
NUMBER
3
Liver in hereditary angioedema
295
FIG. 1. Ultrastructural examination of the liver shows the presence of giant mithocondria. (Uranyl acetate-lead citrate; x 11,900.)
therapy with androgen derivatives. We describe the results of such an investigation in this report. MATERIAL
AND METHODS
Thirteen patients, who gave written approval, were admitted to this study. Their age ranged from 28 to 59 years. The diagnosis was established on the basis of the clinical history. the low serum levels of Cl-INH (<40% of the normal values), C4 (<60% of the normal values) immunochemically assayed,‘!’ and the low enzymatic activity of C I -1NH (<40% of the normal values) measured according to the method of Lachmann et al.zo Normal values for C I-INH and C4 have been published elsewhere.2’ Four patients belonged to the HAE variant showing low Cl-INH activity with normal antigenic levels.2’ At the time of the study all but two of the patients (patients 6 and I I who were taking danazol) were receiving stanozolol. The medium daily dose taken by each patient during the whole treatment period ( 15 to 47 mo) is reported in Table I. The drugs were taken in alternate periods (usually 5 days on, 5 days off). Each patient was examined for serum hepatic parameters (SGOT, SGPT, bilirubin, y-GT, LDH, AFP, pCHS, HBsAg, protein electrophoresis), coagulation tests (PT, PTT, platelets), renal function (BUN, creatinine, electrolytes, urine analysis), CK, sedimentation rate, blood cells’ count. Liver scintiscan with SBmT~was performed in each pa-
tient. Percutaneous liver biopsy was performed with a Trucut needle (Travenol Laboratories) in 1I patients. Biopsies could not be performed on patients 9 and 13 for technical reasons. For electron microscopy, samples were immediately cut in small blocks, fixed in glutaraldehyde, postfixed in osmium, and embedded in paraffin. For light microscopy, samples were fixed in formalin and embedded in paraffin. Four-micrometer sections were stained with hematoxylineosin, PAS, PAS-diastase, Gomori reticulin stain, Masson trichromic, long Ziehl-Neelsen stain, and orcein. Sternberg’s peroxidase-antiperoxidase technique using specific antisera was performed for HBsAg.‘:’
RESULTS The more relevant findings are collected in Table I. Clinical
and laboratory
evaluation
All the patients were free from HAE symptoms while receiving treatment. As already reported,x only negligible side effects, which did not require the withdrawal of the treatment, were observed with both drugs. Only patient 11 preferred the treatment with danazol because of a higher amount of water retention with stanozolol. A moderate increment in serum transaminases was
296 Cicardi et al.
J. ALLERGY
TABLE I. Hepatic function and morphologic androgen derivatives (danazollstanozolol)
data in 13 HAE patients
Dana201 treatment Patient No.
Duration
Stanozolol
Medium dose (mglday)
Duration (mo)
treatment
2 2
13 25
11 22
26 27
5 3
20 43
16 32
-
27
2
39
48
100 300 200 200
I5 30 28 19 4
2 3 2 3 4
IO 7 9 12 IO 45
14 13 I6 I9 9 66
300 150
30 17
3 1
10 20 <28
12 17 <30
M F
28 51
30 30
1.50 150
17 17
3 4
M F
59 59
15 -
400 -
5
F
48
6 7 8 9 10 II
F F M F F F
37 43 45 48 42 39
39 17 19 28
12 M 13 F Normal value
32 31
17 27
1
with
SGPT W/L)
Age (yr)
2
treatment
SGOT (W/L)
Sex
(mo)
on long-term
CLIN IMMUNOL. 1983 SEPTEMBER
Medium dose hglday)
Neg = negative.
found in three patients (Nos. 2, 5, 11); patient 11 also showed an increment in -y-GT and conjugated bilirubin. No deviation from the normal mean was reported for all the other parameters. Five patients (patients 1, 2, 5, 8, 11) had an increase in liver size as shown at scintiscan. No areas of deficient colloid uptake could be observed in any of the subjects. Histologic
findings
Seven cases were completely negative. Patient 2 had a clinical picture consistent with the diagnosis of chronic persistent hepatitis; the immunohistochemical search for HBsAg was, nevertheless, negative. Patient 11 showed a marked steatosis that was accompanied by the presence of lipogranulomas. This patient, whose hepatic laboratory tests were also abnormal, is a carrier of a type IIa dysiipidemia. Two of the remaining patients (Nos. 4 and 5) showed small degrees of liver involvement (slight cholestasis and small areas of intralobular necrosis). Ultrastructural
findings
The ultrastructural pictures did not show significant abnormalities. However, a rather constant finding (nine patients) was the presence of scattered giant mitochondria (Fig. 1) and of biliary pigments.
DISCUSSION The hepatotoxic effects of long-term therapy with androgen derivatives have been described in several reports.24, 25Duration of treatment and dose seem of major importance in the genesis of such abnormalities.‘0T ” However, a critical dose in relation to the total amount administered has not been established. On the basis of these data, the long-term treatment that our patients must receive, although with low doses, has raised justified concern about its potential risk. Our study has shown that the majority of patients has normal liver. The only abnormalities often encountered were the ultrastructural finding of giant mitochondria and intracanalicular bile pigments. Such a finding can not be considered as specific or as cell injury’“; however, their high frequency could relate them to the drugs. With regard to patient 2 (chronic persistent hepatitis) and patient 11 (marked steatosis with hepatic enzymes abnormalities in a dyslipidemic woman), we would rather consider these findings as incidental but a relationship to the therapy cannot be excluded. Laboratory and morphological evidence of mild hepatic involvement has been found also in patients 4 and 5. We would like to add that all laboratory and histologic abnormalities were minimal and found
VOLUME NUMBER
72 3
Liver in hereditary
angioedema
297
Bilirubin AFP Imgldl)
y-GT (IUlml)
Total
84 69
II 13
0.14 0.15
0.02 0.05
Neg Neg
2230 1616
27 39
88 101
15 12
0.30 0.25
0.20 0.10
Neg Neg
2330 1454
26 34
81
13
0.30
0.20
Neg
1500
25
69 67 51 103 73 81
8 15 14 15 9 101
0.30 0.15 0.30 0.50 0.40 1.20
0.20 0.10 0.25 0.30 0.20 0.70
Neg Neg Neg Nets Neg Neg
2450 3300 2863 2165 3446 3014
I2 24 43 42 10 19
85 87 cl78
11 15 <28
0.40 0.15 Cl.0
0.15 0.05 co.3
Neg Neg
2756 1760 >1400
17 16 <70
Conjugated
whereas there were no signs of more significant diseases in the form of severe cholestasis, vascular abnormalities, or tumor production. In addition, all the patients with some degree of liver involvement were neither those treated at higher doses nor those receiving therapy with androgen derivatives for a longer time. Although the present group of HAE patients receiving long-term treatment with androgen derivatives has shown no significant negative effects to date, it remains possible that these will appear at a later date. The use of such drugs has to be limited to very severe cases (two or more attacks a month), carefully establishing, on a clinical basis, the minimal effective dose. in only
a minority
of the patients,
REFERENCES I. Gelfand JA, Sherins RJ, Ailing DW, Frank MM: Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 293~1444, 1976. 2. Pitts JS, Donaldson VH, Forristal J, Waytt RJ: Remission induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentration of Cl inhibitor and the fourth and second component of complement. J Lab Clin Med 92:501, 1978. 3. Spaulding WB: Methyltestosterone therapy for hereditary episodic edema. Ann Intern Med 86306, 1960. 4. Davis PS, Davis FB, Charache P: Long-term therapy of hereditary angicedema (HAE). Johns Hopkins Med J 135:391,1974.
pCHS (W/L)
Histologic
findings
Negative Chronic persistent hepatitis Negative Slight steatosis; scattered cholestasis Small areasof intralobular necrosis Negative Negative Negative Not done Negative Marked steatosis; lipogranulomas Negative Not done
5. Sheffer AL, Fearon DT, Austen KF: Methyltestosterone therapy in hereditary angioedema. Ann Intern Med 86:306, 1977. 6. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angicedema. J ALLERGY CLIN IMMKJNOL 64:275, 1979. 7. Sheffer AL, Fearon DT, Austen KF: Clinical and biochemical effect of stanozolol therapy for hereditary angioedema. J ALLERGY CLIN IMMUNOL 6&181, 1981. 8. Agostoni A, Cicardi M, Martignoni GC, Bergamaschini L, Marasini B: Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J ALLERGY CLIN IMMUNOL 65:75, 1980. 9. Leonard-Johnson FR, Feagler JR, Lemer KG, et al: Association of androgenic anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273, 1972. 10. Farrel GC, Joshua VE, Uren RF, Baird PJ, Perkins RW, Kronenberg H: Androgen induced hepatoma. Lancet 1:430, 1975. 11. Sweeney EC, Evans DJ: Hepatic lesions in patients treated with synthetic anabolic steroids. J Clin Pathol 29:626, 1976. 12. Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM: Liver damage from long-term methyltestosterone. Lancet 2:261, 1977. 13. Sale GE, Lemer KG: Multiple tumours after androgen therapy. Arch Pathol Lab Med 101:600, 1977. 14. Goodman MA, Laden AMJ: Hepatocellular carcinoma in association with androgen therapy. Med J Aust 1:220, 1977. 15. Paradinas FJ, Bull TB, Westaby D, Murray-Lyon IM: Hyperplasia and prolapse of hepatocytes into hepatic veins during long-term methyltestosterone therapy: possible relationships of these changes to the development of peliosis hepatis and liver turnours. Histopathology 1:225, 1977.
298
Cicardi
J ALLERGY
et al
16. Falk H. Thomas LB. Popper H, lshak KG: Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 2: 1120. 1979. 17. Nadell J. Kosek J: Peliosis hepatis. Twelve cases associated with oral androgen therapy. Arch Path01 Lab Med 101:405, 1977. 18. Chopra S. Edelstein A, Raymond SK, Zimelman AP, Lacson A. Neiman RS: Peliosis hepatis in hematologic diseases. Report of two cases. JAMA 240: 11.53, 1978. 19. Cicardi M, Bergamaschini L, Marasini B, Boccassini G, Tucci A. Agostoni A: Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 28448. 1982. 20. Lachman PJ, Hobart MJ, Aston WP: Complement technology. In Weir MD, editor: Handbook of experimental immunology. Oxford, 1973. Blackwell Scientific Publications, pp. l-23. 21. Agostoni A. Marasini B, Cicardi M, Martignoni GC, Brenna
22.
23.
24. 25.
CLIN. IMMUNOL. SEPTEMBER 1983
0: Studio mediante dosaggio enzimatico e immunochimico dell’inibitore della Cl esterasi in 50 pazienti affetti da angioedema ereditario. Boll 1st Sieroter Milan 56: I, 1977. Rosen FS, Charge P, Pensky J, Donaldson VH: Hereditary angioneurotic edema: two genetic variants. Science 148:957, 1965. Huang S: Immunocytochemic demonstration of hepatitis-B viral antigen, In De Lellis R, editor: Diagnostic immunochemistry. New York, 1981, Masson Publishing USA Inc, pp. 325-36. Pearson K, Zimmerman MJ: Danazol and liver damage. Lancet 1:645, 1980. Hosea SW. Santaella ML, Brown EJ. Berger M, Katusha K, Frank MM: Long-term therapy of hereditary angioedema with danazol. Ann Intern Med 93:809, 1980.