Australas J. Dermatol 1992; 33: 35-38



Hereditary angioedema is a rare disorder which is associated with an inherited deficiency of the inhibitor of the activated first component of complement. Genetic transmission occurs in an autosomai dominant manner Affected patients are heterozygotes, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor.' We describe two cases ofC, esterase inhibitor deficiency occurring in a mother and daughter in whom the symptoms appeared to be related to the menstrual cycle or the taking of the oral contraceptive pill. Although both features have been mentioned in the literature, to the best of our knowledge premenstrual exacerbations have not been documented previously. We examined the likely basis of hormonally exacerbated hereditary angioedema. Key words: hereditary angioedema, Ci esterase inhibitor deficiency, hormonal influences, oral contraceptive pill. 0.04 g/L. She had ceased Stanozolol for no apparent reason. On review in September 1988 she was noted to be well with no further attacks while taking Stanozolol. She was lost to follow-up until December 1989 when she presented to dermatology outpatients complaining of weekly attacks involving erythema and swelling of her feet. Ci esterase inhibitor level (quantitative level) was 0.09 g/L and her functional level was less than 23 u/ml (normal range 70-130 u/ml). C3 was 1.30 g/L and C4 0.04 g/L. She had been on the oral contraceptive pill, Femodene since November 1988 for dysmenorrhoea. Femodene was stopped and she was reviewed three months later. The frequency of the attacks subsided to only one attack each month since ceasing the oral contraceptive pill. She remained stable until January 1991 when she presented with a further attack of recurrent hereditary angioedema (HAE) involving the neck, throat area and tongue as well as the left arm and left side of her neck. She had recommenced the same oral contraceptive pill two months earlier, again for dysmenorrhoea. Furthermore she had ceased her Stanozolol four months previously, noting an initial decrease in attacks but later increasing frequency of attacks up to one each month. The swelling and erythema settled within hours of admission to the ward. No FFP was required. Stanozolol was restarted at 5 mg twice daily and she was advised to continue taking the


Case 1 K.B., a 15 year old female first presented in June 1988 following a sudden episode of swelling in the left arm and shoulder, subsequently extending to the neck and back. An upper respiratory tract infection with a sore throat for two to three days preceded this attack. Her voice became high pitched and dysphagia occurred. A strong family history of angioedema affecting her mother and younger sister was noted. Episodes of angioedema had occurred since the age of two years but symptoms became more frequent around puberty. Examination revealed soft swelling of the left forearm, upper arm, shoulder and left side of the neck. No facial swelling was evident and pharyngeal and laryngeal involvement had apparently settled by the time she was examined. She was transfused 2 units of fresh frozen plasma. The oedema settled and she made an uneventful recovery and was discharged two days later. Prior to discharge she was commenced on Stanozolol 5 mg twice daily. On follow-up in July 1988, her Ci esterase inhibitor level was 0.06 g/L, C3 0.99 g/L and C4 Jennifer Yip, MM, MBBS. Dermatology Fellow. William J. Cuncliffe, FRCP, MD. Consultant Dermatologist. Department of Dermatology, The General Infirmary at Leeds, Leeds, England. Address for correspondence: Dr Jennifer Yip, Dermatology Centre, Lidcombe Hospital, Joseph St, Lidcombe, NSW 2141.



tiiedication even in the absence of sytnptoms. The oral contraceptive pill was ceased.

hereditary form was transmitted in an autosomal dominant manner. Briefly, there are 3 distinct syndromes of Ci esterase inhibitor deficiency which occur in humans and are associated with recurrent angioedema:

Case 2

J.B., mother of K.B., initially presented at the age of 35 years in 1980 with a 20 year history of rectirrent abdominal pain, swelling of the hands and feet occurring every two months with symptoms lasting up to one year. Her Ci esterase inhibitor level was noted to be less than 25% of normal levels. Cj was L50 g/L and C4 less than 5g/L. The patient herself had noted that while on the oral contraceptive pill the attacks were more severe and frequent, with extensive erythema of the chest in addition to abdominal pain. She was commenced on Danazol 200 mg daily and the oral contraceptive pill stopped. Her acute attacks with abdominal pain subsided but she continued to experience oedema and erythema of the chest and back, particularly in the latter part of the menstrual cycle and premenstrually. She has been regularly reviewed for almost eleven years and she remained well with only occasional mild attacks, often premenstrually. Her dose of Danazol had been reduced to 200 mg on alternate days as she was experiencing some weight gain. She has had two pregnancies in 1972 and 1976 during which she did not experience any increase in symptoms. Furthermore she denied any exacerbations of her angioedema during pregnancy and childbirth. Interestingly, her younger daughter, R.B. presented in June 1990 at the age of 14 with attacks since childhood occurring every six to eight weeks with swelling, rash and occasional abdominal pain. She was noted to have a Ci esterase inhibitor level below 25% of the normal range at the age of four years. She was on no medication when seen in June 1990. Her functional Ci esterase inhibitor level at this stage was less than 22. Her CA was noted to be 0.6 g/L. She was given Terfenidine 120 mg bd since and has remained symptom-free.

Hereditary Angioedema

In Type I or classical form of hereditary angioedema there is a deficiency of the functionally active Ci esterase inhibitor. In Type II or functionally deficient form of hereditary angioedema normal or even elevated levels of Ci esterase inhibitor protein occur but there is synthesis of a functionally impaired inhibitor Ci protein. Acquired Ci esterase inhibitor protein deficiency

Low or absent levels of Ci esterase inhibitor protein occur but there is normal or slightly increased synthesis of the inhibitor protein. Most are associated with benign or malignant lymphoproliferative disorders or B cell abnormalities with autoantibody production." Acquired Ci esterase inhibitor deficiency

Autoantibodies against the C, esterase inhibitor occur with the latter being of lower molecular weight than that of normal controls. This may be associated with the hereditary or the acquired form of angioedema. The anti-Ci inhibitor antibodies prevent the binding of Ci inhibitor to activated CiS. In vitro studies of the patients' serum reveal degradation of 105,000 dalton Ci inhibitor into the inactive 96,000 dalton molecule, caused by activated CiS.' Our observations confirm the recent findings that hormonal influences can modify disease activity."'" In both cases the initial attacks either occurred or worsened around puberty. Interestingly, in male patients with HAE no association with puberty has been documented in the literature so far. In women with HAE a high frequency of severe attacks associated with oedema has been observed under increasing oestrogen levels at puberty, with aggravation of their symptoms during the menstrual period." In contrast, our patient's symptoms were noted to be worst premenstrually. Others have reported a significant improvement in symptoms in the postmenopause period or after ovariectomy and hysterectomy.'^ Similar symptoms due to giant urticaria and idiopathic angioedema (both non-hereditary


The clinical syndrome of angioedema was first described by Milton^ (1892) and Quinke^ (1882). It was initially given the name angioneurotic oedema by Strubing in 1885 as it was thought that the nervotJS system participated in the development of the oedema. Osier" (1885) described a familial form of angioedema occurring in an American family and proposed that the 36


forms of angioedema), have been reported to occur during the menstrual cycle particularly perimenstrually, although symptoms have been observed throughout the whole menstrual cycle.' We believe Cqse 2 is the first report in the literature of hereditary angioedema exacerbated premenstrually. Frank et al" reported a significant increase in attacks during the menstrual period in five out of twelve patients. The reason for this phenomenon is not known. A possible explanation is the sudden change in hormonal levels, particularly progesterone, which steeply diminishes premenstrually. Symptoms occurring in patients with the non-hereditary form of angioedema have been noted to decrease or disappear during pregnancy, lactation and the use of the oral contraceptive pill. During pregnancy and lactation amenorrhoea, progesterone levels are relatively constant.' There appear to be few reports in the literature concerning the effects of the oestrogen containing oral contraceptive pill on hereditary angioedema. In Case 1 the patient's symptoms were exacerbated by the use of the oral contraceptive pill and the first symptoms were noted to occur shortly after institution of the pill. On cessation of this medication, symptoms improved. Serious attacks of hereditary angioedema in patients taking oral contraceptives have been reported in the literature."' Oestrogen containing oral contraceptives are thought to cause a significant reduction in Ci-INH in the serum while the contraceptive is being taken,"" Administration of a progesterone-only containing pill has led to improvement of symptoms in one patient with HAE known to be exacerbated by the oestrogen containing oral contraceptive pill. However others have found therapeutic doses of progesterone to have no effect on the symptoms.'" Farah et a/" described two cases of progesterone inducecj urticaria occurring at the middle and the premenstrual parts of the cycle. Although these patients were thought to have normal levels of Ci-INH, it is interesting to note that in both cases relief was obtained after use of anti-ovulatory agents. The significance of a mild deficiency of Ci-INH in normal women taking oral contraceptives is uncertain. However the consequences appear to be serious when Ci-INH levels were initially deficient as Case 1 demonstrated. Furthermore the use of the anti-androgen, cyproterone acetate as a contraceptive has recently been implicated in the development of recurrent

angioedema in female patients with normal C,-INH function.'Although Case 2 did not appear to have a worsening of her symptoms during pregnancy, others have reported an exacerbation of symptoms particularly during the first and second trimesters.'' Symptoms have been noted to lessen by the third trimester and during the delivery. In most cases, neither the trauma of the delivery or an episiotomy has resulted in oedema of the vulva." However Postnikoff and Pritzker"* reported a fatal case of extensive perineal oedema 48 hours after a vaginal delivery and episiotomy. Although the alpha-2 macroglobulin fraction to which Ci-INH belongs is increased physiologically during pregnancy, a quantitative increase in Ci-INH does not occur.'" Danazol, a synthetic derivative of 17-alphaethinyl testosterone is a weak androgen with no estrogenic or progestational activity. At very high doses, it produces a dose-dependent reduction of serum gonadotropins, resulting in a concomitant decrease of the primary sex hormone. Plasma luteinizing hormone remains essentially unchanged but follicular stimulating hormone remains consistently in the low normal range. Plasma estradiol levels decrease significantly, particularly after four weeks of therapy. Plasma progesterone levels remain much unchanged from pretreatment levels." No data appears to be available on the hormonal changes associated with the lower doses of Danazol required in HAE. However it is interesting to speculate that these hormonal changes and the lack of pituitary suppression that Danazol produces may be associated with a direct local action on d-INH activity. This effect may be mediated by circulating oestrogens in patients with hormonally exacerbated HAE. Danazol has been shown to increase C)-INH levels 3 to 4.5 times, frequently to normal levels, and C4 levels to 15 times that of pretreatment levels. These increased levels were observed after only one week of therapy and fell rapidly after the drug was discontinued.' In summary, we recommend that oestrogen containing contraceptives should be avoided in known cases of hereditary angioedema. Current evidence suggests that even progesterone-only contraceptives may precipitate attacks of nonhereditary forms of angioedema, and safety in hormonally exacerbated hereditary angioedema has not been assessed. Finally, cyclic premenstrual attacks as well as exacer,bations during the 37


menstrual period can occur in these patients Antihistamine can also be of use in known cases of HAE as our third patient, R.B. demonstrated. REFERENCES ' Hadjiyannaki K, Lachmann PJ. Hereditary angioedema: a review with particular reference to pathogenesis and treatment. Ctin Altergy 1971; 1: 221-33. ^ Milton JL. On giant urticaria. Edinburgh Medicat Journal 1876; 22: 513. ' Quinke H. Uberakutes umschriebenes Hautodem. Monatshefte fur Praktische Dermatologie 1882; 1: 129. •* Osier N. Hereditary angioneurotic edema. Amer J Med Set 1888; 95: 362. ' Gelfand JA, Sherins RJ, Ailing DW, Frank M. Treatment of hereditary angioedema with Danazol. New Eng J Med 1976; 295: 1444-48. ' Sheffer AL, Austen KF, Rosen FS, Fearon DT. Acquired deficiency of the inhibitor of the first component of complement: Report of five additional cases with commentary on the syndrome. J Allergy Clin Immunol 1985; 75: 640-46. ' Malbran A, Hammer CH, Frank M, Fries LF. Acquired angioedema: Observations on the mechanism of action of autoantibodies directed against Ci esterase inhibitor. J Allergy Clin Immunol 1988; 81: 1199-1204.


Hakansson OM. Menstruation-related angioedema treated with tranexamic acid. Acta Obstet Gynecol Scand 1988; 67: 571-72. Gordon EM, Ratnoff OD, Saito H et al. Rapid fibrinolysis, augmented Hagemann factor (factor XII) titers, and decreased Ci esterase inhibitor titers in women taking oral contraceptives. J Lab Clin Med 1980; 96: 762-69. Bockers M, Bork K. Kontrazeption und Schwangerschaft beim hereditaren Angioodem. Dtsch Med Wschr 197; 112: 507-509. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Int Med 1976; 84: 580-93. Atkinson JP. Diagnosis and management of hereditary angioedema. Ann Allergy 1979; 42: 348. Farah FS, Shbaklu Z. Autoimmune progesterone urticaria. J Allergy Clin Immunol 1971; 48: 257-61. Pichler WJ, Lehner R, Spath PJ. Reccurent angioedema associated with hypogonadism or anti-androgen therapy. Ann Altergy 1989; 63: 301-305. Stiller RJ, Kaplan BM, Andreoli JW. Hereditary angioedema and pregnancy. Obstet and Gynec 1984; 64: 133. Postnikoff M, Pritzker KPH. Hereditary angioneurotic edema. An unusual case of maternal mortality. J Eorens Sci 1979; 24: 473. Wood GP, Wu CH, Flickinger GL, Mikhail G. Hormonal changes associated with Danazol therapy. Obstet and Gynec 1975; 45: 302-4.

Hormonally exacerbated hereditary angioedema.

Hereditary angioedema is a rare disorder which is associated with an inherited deficiency of the inhibitor of the activated first component of complem...
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