What Cause of Puzzling Hormonally Related Symptoms?

March 1, 2006

Volume 42 - Issue 3 - March 2002

 

I suspect that my patient has hereditary angioedema (HAE). During her last pregnancy 2 years earlier, she had severe preeclampsia. After delivery, she had persistent, severe migraine-like headaches that were accompanied by facial and lip swelling. Her symptoms seemed to improve after she started taking cetirizine.
However, now that her menses have returned (she was amenorrheic while breast-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 airway stridor and irritable bowel syndrome (IBS)-like symptoms. She has a positive antinuclear antibody titer of 1:160, speckled. All complement levels and erythrocyte sedimentation rate are normal.
Could HAE be responsible for my patient's symptoms?
—MD

Recurrent angioedema is commonly seen in various conditions.1 In many patients, angioedema is associated with urticaria, which may indicate a chronic idiopathic condition, an IgE-mediated response to an allergen, or induced direct histamine release from mast cells. Recurrent angioedema without urticaria may result from these pathologic mechanisms as well as other causes, such as hereditary or acquired C1-inhibitor deficiency or a reaction to angiotensin-converting enzyme inhibitors.2

Role of hormones. The role of estrogen in HAE has been debated. An increase in attacks has been reported during menstruation,3,4 and oral contraceptives have been linked to greater frequency and severity of attacks.3,5,6 Estrogen replacement therapy has also precipitated attacks.7 Although HAE usually takes a benign course during pregnancy,3,8 case reports have described an increase in the incidence and severity of attacks.9-12 Androgens-particularly danazol( and stanozolol(-have been shown to decrease the severity and frequency of attacks.13-15

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

The initial episode of HAE typically occurs early in life; more than 50% of patients experience their first attack before age 10.3,4,8 The initial presentation here 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 have no role or benefit in patients with HAE.8

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

 

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

 

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

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

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3. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84:580-593.
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