Consider a 12-year-old female patient who for the first time in her life has developed a “severe allergic reaction,” according to her caretaker. Her lips and tongue are swollen, she appears to be in acute distress, and the caretaker is visibly nervous.
“What happened?” you ask. Both the girl and the caretaker confirm nothing out of the ordinary occurred recently. She was not stung by any insects, she has not tried any new food, she was not exposed to any chemicals or detergents, and they have not traveled recently. There are no new pets in the house, she has not had other animal contacts, and she is not on any new medications.
The caretaker has given her a double dose of antihistamines that the patient takes occasionally for seasonal allergies, with no improvement noted. The patient has a history of recurrent colicky abdominal pain that lasts on average 2 days for the past year.
Allow me to leave a brief disclaimer before proceeding. The details mentioned above describe a real patient; however, outcomes for the different paths below are purely hypothetical. The clinic I worked at the time was on an island and did not have the capacity to manage this case so she was referred to the mainland for management. In a resource-rich setting, the story would go something like the ones seen in the paths below.
Spotting Unique Characteristics of Angioedema
Upon physical examination, you notice something interesting about this patient’s swelling. There was no obvious trigger, and the patient does not complain of itching. Additionally, there are no wheals, no wheezing is heard on pulmonary auscultation, and the patient does not appear flushed.
You call the patient’s only living parent, her father, and he is alarmed. His voice cracks when he says he is on his way. He explains that the patient’s deceased mother had similar episodes throughout her life before dying in a car accident 9 years ago. She would refuse to get treatment for the episodes because they would always resolve after taking antihistamines for 2-3 days.
Taking all this into account, what is the next step?
Reaching a Differential Diagnosis
Anaphylaxis and hereditary angioedema (HAE) are 2 good differential diagnoses at this point. Edema without wheals, flushing, or pruritus is interesting, suggesting that the mechanism of fluid extravasation is not dependent on histamine and other vasoactive compounds released by degranulating mast cells and basophils. The patient’s physical examination findings and family history are clues that her edema might be due to a hereditary disease.
Angioedema is not itchy and does not present with urticaria. Erythema marginatum is an evanescent, nonpruritic macular rash that has been described as a prodromal symptom in HAE due to functional C1-inhibitor (C1-INH) deficiency and should not be confused with urticaria when present.1 Erythema marginatum has not been described in HAE with normal C1-INH.2
Test your knowledge about treating HAE in women
Additionally, treatment with antihistamines, corticosteroids, or epinephrine would have no effects on swelling due to HAE—a hallmark characteristic.1 The patient’s history of chronic colicky abdominal pain lasting an average of 2 days might be due to gastrointestinal (GI) involvement. Combined with a positive family history, it appears this patient is likely suffering from an HAE attack.
Laboratory testing for C4 levels and quantitative and functional C1-INH levels are ordered after ensuring the patient’s airways are patent and she is hemodynamically stable.
Read more about the full spectrum of HAE symptoms
Patients with HAE fall into 1 of 2 categories: HAE due to C1-INH deficiency (HAE-C1INH) or HAE with normal C1-INH (HAE-nl-C1INH), which is sometimes referred to as type 3 HAE. Let’s explore 2 possible paths forward from this point, and discuss sex-specific factors associated with each diagnosis.
Laboratory testing reveals C4 levels and C1-INH function and serum levels are low.
In this path, the patient has type 1 HAE-C1INH due to mutations in the SERPING1 gene leading to truncated or misfolded C1-INH proteins that are not secreted efficiently. Patients with this type of HAE have low plasma levels of C1-INH and low C1-INH function. If a patient has type 2 HAE-C1INH, laboratory testing would reveal low C4 levels and low C1-INH function; however, serum antigenic levels of C1-INH would be normal.
This is the most baffling path; our patient’s C4 levels, C1-INH function, and C1-INH serum levels are normal.
HAE-nl-C1INH almost exclusively affects women.1 There are 4 well-documented mutations associated with this condition. These mutations affect the F12, ANGPT1, PLG, or KNG genes. Defects to these genes may not be detected in some patients with HAE-nl-C1INH and they are classified as HAE-unknown.1
HAE-nl-C1INH is a challenging diagnosis and it is preferable that an expert in angioedema be present to evaluate the patient and render their clinical judgment. The required clinical criteria for HAE-nl-C1INH are:1
- A history of recurrent angioedema in the absence of concomitant urticaria and no concomitant use of medication known to cause angioedema
- Documented normal or near normal C4, C1-INH antigen, and C1-INH function
- At least one of the following:
- Demonstration of a mutation associated with the disease
- A positive family history of recurrent angioedema and documented lack of efficacy of high-dose antihistamine therapy (ie, cetirizine at 40 mg/d or the equivalent) for at least 1 month or an interval expected to be associated with 3 or more attacks of angioedema, whichever is longer.
Our patient is debuting with cutaneous findings that clinically match angioedema (no urticaria), and she is not on any medication known to cause angioedema. However, at this point, she does not technically meet the first criterion due to lack of recurrence—although one may argue that her recurrent abdominal pain is likely due to GI HAE attacks. This is impossible to determine retrospectively, and this debate would require input from a seasoned expert in HAE.
Let’s proceed assuming our expert consultant agrees that she meets the first criterion. The second criterion was met during our initial workup. Genetic testing would be a reasonable next step to determine if she carries any known genetic mutations to meet the third criterion.
Read more about the types of hereditary angioedema
Let’s also take a step back and analyze this patient’s family history further by asking the living parent a very important question: “Did the patient’s mother’s facial swelling improve rapidly with antihistamines?”
“Not really. Sometimes she would take 3 or 4 pills a day and after about 3 days or so the swelling would go away. So, I guess they didn’t work rapidly like you said, but they must have been doing something because it would always go away after a few days, which is why she never wanted to see a doctor about it,” he responds.
In retrospect, this appears to meet the last criteria in our list above. Our patient’s parents believed that antihistamines were effective in treating the deceased mother’s facial edema; however, this likely is not the case. HAE attacks are usually self-limiting. Typically, angioedema worsens over the first 24 hours and then slowly resolves within 48 to 72 hours.3 It is probable that the patient’s mother’s facial swelling would have resolved with or without oral antihistamines.
Read about the diagnostic workup for HAE
Supporting findings for HAE-nl-C1INH include a history of rapid and durable response to a bradykinin-targeted medication and predominant documented visible angioedema. In patients with predominant abdominal symptoms, evidence of bowel wall edema can be documented by computed tomography (CT) or magnetic resonance imaging (MRI) and is also a supporting finding.1 HAE-nl-C1INH has a tendency to involve the face, tongue, and oropharynx over other body parts and seldomly presents with multisystem involvement.2
Considerations for Women With HAE
There are a few considerations that physicians need to make when caring for patients with HAE-C1INH types 1 and 2 (both types referred to as HAE for simplicity) and HAE-nl-C1INH who are female.
Puberty and Menstruation
Puberty worsens the disease course of HAE in 62% of female patients and may be the precipitating factor for an initial attack.3,4 HAE attacks have been also been triggered by menses and ovulation in 35% and 14% of patients, respectively.4
The age of presentation of our patient coinciding with puberty is an important consideration. It’s worth noting that our patient’s recurrent abdominal pain may be the result of GI involvement. It is reasonable to believe that the length of the attacks and their self-limiting nature suggest GI attacks preceding her current cutaneous event.
Pregnancy may be an exacerbating factor for patients with all types of HAE and has been shown to worsen the disease course in 38% of patients.1,4 However, 30% of patients reported improvement and 32% reported no change.4 An uneventful previous pregnancy is not a predictor of future disease activity in later pregnancies.1
Two known risk factors for HAE during pregnancy are a history of symptomatic HAE early in life and carrying a fetus with HAE-C1INH.5 The GI tract is the most frequently involved site during pregnancy, possibly due to mechanical triggers such as the stretching of the gravid uterus and fetal movements. During pregnancy, abdominal pain may be due to an HAE attack or other obstetric complications, and prompt investigation is usually warranted.1
Overall, pregnancy has a positive prognosis and most studies of pregnant patients with HAE report a mild aggravation of the disease, with severe life-threatening events occurring extremely rarely.6 HAE does not increase the risk of premature birth, spontaneous abortion, or cesarean delivery.1 C1-INH is first-line therapy during pregnancy due to its favorable safety profile as documented by numerous case reports and observational studies.1
Read more about HAE therapies
Vaginal delivery is well tolerated in HAE-C1INH and attacks during labor are uncommon (6-8%).5 Prophylaxis for HAE is not indicated during vaginal delivery; however, the obstetrician and attending medical personnel should be made aware of the patient’s condition and have on-demand access to medications in the unlikely event of an acute attack. If the decision is made to use forceps or vacuum assistance during delivery, a prophylactic dose of plasma-derived C1INH (pdC1INH) is recommended before the procedure.1 It is reasonable to consider prophylaxis with pdC1INH in patients with a history of severe attacks, genital attacks secondary to trauma, or frequent attacks during the third trimester.
Like with HAE-C1INH, pregnancy may improve, worsen, or have no effect on the disease course of HAE-nl-C1INH. Patient surveys show that 12% of women in this group debut with HAE attacks during their first pregnancy. Furthermore, 28% reported worsening of existing symptoms, 40% reported no symptom change, and 20% reported symptom improvement.2 Vaginal delivery is also well tolerated in HAE-nl-C1INH, and the indications for delivery are identical to those listed above for HAE-C1INH.1
Exposure to estrogen-containing oral contraceptives (OCs) and hormone replacement therapy are known exacerbating factors in both HAE-C1INH and HAE-nl-C1INH.3 It may be the trigger for the first HAE attack in up to two-thirds of women.3 Combined OCs worsen disease activity in 80% of women.
Conversely, 64% experience improvement on progestin-only pills.4 Some patients have managed to completely stop long-term prophylaxis after switching to progestin-only OCs.5 Antigonadotrophic agents like lynestrenol, nomegestrol, and chlormadinone acetate are more effective than low-dose progestin-only pills (L-norgestrel, norgestrienone, and desogestrel).5 Progestin-only pills are also first-line for emergency contraception. Intrauterine devices are also well tolerated, and placement does not require routine prophylaxis.
Some patients remain symptomatic after menopause, suggesting that estrogen may not be the sole exacerbating factor in females.2 One study found that 55% of patients experience no change in symptoms. Meanwhile, 32% of patients worsened after menopause and 13% experienced improvement.4
In the general population, vasomotor symptoms of menopause are treated with estrogen-containing hormonal therapy—a contraindication in women with HAE. In these patients, progesterone and progestins are alternatives.5
Our Patient’s Outcome
In a possible conclusion to Path 2, the patient would be tested for factor XII, plasminogen, angiopoietin-1, and kininogen mutations. Genetic testing could be positive for the p.Thr309Lys mutation to the F12 gene. This is the most common type of F12 mutation and is thought to enhance susceptibility to excessive activation of the contact system which in turn overproduces bradykinin.1 A discussion would be initiated with the patient and her family, taking into consideration the topics discussed above, and a treatment plan devised.
- Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. The Journal of Allergy and Clinical Immunology: In Practice. 2021;9(1):132-150.e3. doi:10.1016/j.jaip.2020.08.046
- Riedl MA. Hereditary angioedema with normal C1-INH (HAE type III). J Allergy Clin Immunol Pract. 2013;1(5):427-432. doi:10.1016/j.jaip.2013.06.004
- Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Supplements and Featured Publications. 2013;19(7 Suppl).
- Bouillet L, Longhurst H, Boccon-Gibod I, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol. 2008;199(5):484.e1-4. doi:10.1016/j.ajog.2008.04.034
- Banerji A, Riedl M. Managing the female patient with hereditary angioedema. Womens Health (Lond). 2016;12(3):351-361. doi:10.2217/whe.16.6
- González-Quevedo T, Larco JI, Marcos C, et al. Management of pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency. J Investig Allergol Clin Immunol. 2016;26(3):161-167. doi:10.18176/jiaci.0037