What Cause of Puzzling Hormonally Related Symptoms?

I suspect that my patient has hereditary angioedema (HAE). During her lastpregnancy 2 years earlier, she had severe preeclampsia.

I suspect that my patient has hereditary angioedema (HAE). During her lastpregnancy 2 years earlier, she had severe preeclampsia. After delivery, shehad persistent, severe migraine-like headaches that were accompanied by facialand lip swelling. Her symptoms seemed to improve after she started takingcetirizine.
However, now that her menses have returned (she was amenorrheic whilebreast-feeding), she has severe headaches and swelling of the lips, hands, and feet,both at mid cycle and during her periods. Occasionally, she has upper airwaystridor and irritable bowel syndrome (IBS)-like symptoms. She has a positiveantinuclear antibody titer of 1:160, speckled. All complement levels and erythrocytesedimentation rate are normal.
Could HAE be responsible for my patient's symptoms?

Recurrent angioedema is commonly seen in various conditions.1 In manypatients, angioedema is associated with urticaria, which may indicate achronic idiopathic condition, an IgE-mediated response to an allergen,or induced direct histamine release from mast cells. Recurrent angioedemawithout urticaria may result from these pathologic mechanismsas well as other causes, such as hereditary or acquired C1-inhibitor deficiencyor a reaction to angiotensin-converting enzyme inhibitors.2

Role of hormones. The role of estrogen in HAE has been debated. An increasein attacks has been reported during menstruation,3,4 and oral contraceptiveshave been linked to greater frequency and severity of attacks.3,5,6 Estrogenreplacement therapy has also precipitated attacks.7 Although HAE usuallytakes a benign course during pregnancy,3,8 case reports have described an increasein the incidence and severity of attacks.9-12 Androgens-particularlydanazol and stanozolol-have been shown to decrease the severity and frequencyof attacks.13-15

Clinical manifestations. Swelling of the face, lips, and feet; upper airwaystridor; and IBS symptoms are consistent with HAE. The disorder can affectany part of the body but most commonly involves the extremities, trunk, face,throat, and abdominal viscera, where it causes pain. HAE has also been associatedwith urinary tract infections in women, an increase in spontaneous abortionsand premature labor and, more frequently, heartburn and rheumaticcomplaints.16

The initial episode of HAE typically occurs early in life; more than 50% ofpatients experience their first attack before age 10.3,4,8 The initial presentationhere was much later, but this does not rule out HAE.

Making the diagnosis. Your patient's symptoms responded to an antihistamine.However, adrenaline, antihistaminic agents, and corticosteroids haveno role or benefit in patients with HAE.8

Three distinct forms of HAE have been identified based on complementlevels and activity:

  • Type I is characterized by absent or decreased C1-inhibitor antigenic levelsand decreased functional activity.17
  • In type II, C1-inhibitor antigenic levels are normal but functional activity ismarkedly reduced.18
  • More recently, a third type of HAE has been described.19 In type III, whichappears to affect only women, C1-inhibitor activity is normal. The mediatorof this form of HAE has not been identified but has been postulated as a vasoactiveproduct of an X-linked gene. Like types I and II, type III respondsneither to corticosteroids nor toantihistamines.

In short, the evidence regardinga diagnosis of HAE in this clinical scenariois conflicting. A response to cetirizine,which implicates histamine,strongly militates against this diagnosis.Thus, the likely causes are an IgE-mediated responseto an allergen, an induced direct histamine release frommast cells, or a chronic idiopathic condition.

-Paul McGlinchey, MD
  Physician in Cardiology/General Internal Medicine
  Royal Victoria Hospital
  Northern Ireland

REFERENCES:1. Greaves M, Lawlor F. Angioedema: manifestations and management. J AmAcad Dermatol. 1991;25:146-154.
2. Giannoccaro PJ, Wallace GJ, Higginson LAJ, Williams WL. Fatal angioedemaassociated with enalapril. Can J Cardiol. 1989;5:335-336.
3. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndromeand its management. Ann Intern Med. 1976;84:580-593.
4. Cicardi M, Bergamaschini L, Marasini B, et al. Hereditary angioedema: anappraisal of 104 cases. Am J Med Sci. 1982;284:2-9.
5. Winnewisser J, Rossi M, Spath P, Purgi H. Type I hereditary angio-oedema.Variability of clinical presentation and course within two large kindreds. J InternMed. 1997;241:39-46.
6. Gordon EM, Ratnoff OD, Saito H, et al. Rapid fibrinolysis, augmented Hagemanfactor (Factor XII) titers and decreased C1 esterase inhibitor titers inwomen taking oral contraceptives. J Lab Clin Med. 1980;96:762-769.
7. McGlinchey PG, McCluskey DR. Hereditary angioedema precipitated byestrogen replacement therapy in a menopausal woman. Am J Med Sci. 2000;320:212-213.
8. Donaldson VH, Rosen FS. Hereditary angioneurotic edema: a clinical survey.Pediatrics. 1966;37:1017-1027.
9. Stiller RJ, Kaplan BM, Andreoli JW. Hereditary angioedema and pregnancy.Obstet Gynaecol. 1984;64:133-135.
10. Chibber G, Cohen A, Lane S, et al. Immunoblotting of plasma in a pregnantpatient with hereditary angioedema. J Lab Clin Med. 1990;115:112-121.
11. Chappatte O, DeSwiet M. Hereditary angioneurotic oedema and pregnancy.Case reports and review of the literature. Br J Obstet Gynaecol. 1988;95:938-942.
12. McGlinchey PG, Golchin K, McCluskey DR. Life-threatening laryngealoedema in a pregnant woman with hereditary angioedema. Ulster Med J. 2000;69:54-57.
13. Frank M. Effect of sex hormone on the complement-related clinical disorderof hereditary angioedema. Arthritis Rheum. 1979;22:1295-1299.
14. Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedemawith danazol. Reversal of clinical and biochemical abnormalities. NEngl J Med. 1976;95:1444-1448.
15. Pitts JS, Donaldson VH, Forristal J, Wyatt RJ. Remissions induced in hereditaryangioneurotic edema with an attenuated androgen (danazol): correlation betweenconcentrations of C1-inhibitor and the fourth and second components ofcomplement. J Lab Clin Med. 1978;92:501-507.
16. Nielsen EW, Gran JT, Straume B, et al. Hereditary angio-oedema: new clinicalobservations and autoimmune screening, complement and kallikrein-kininanalyses. J Intern Med. 1996;239:119-130.
17. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneuroticedema: absence of serum inhibitor of C1-esterase. Am J Med. 1963;35:37-44.
18. Rosen FS, Charache P, Pensky J, Donaldson VH. Hereditary angioneuroticedema: two genetic variants. Science. 1965;148:957-958.
19. Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema withnormal C1-inhibitor activity in women. Lancet. 2000;356:213-217.