An Approach to the Diagnosis and Treatment of HAE
HAE Australasia is committed to providing the patient community with support and information that sets the standard for the diagnosis and treatment of HAE.
The Australasian Society of Clinical Immunology and Allergy (ASCIA) is the peak professional body of Clinical Immunology and Allergy Specialists in Australia and New Zealand. They have prepared a Position Paper on treating hereditary angioedema see the Position Paper here(link is external).
From this they have prepared a Treatment Plan see the Mangement Plan(link is external)
Clinical Characteristics indicating HAE as a Potential Diagnosis
The patient may or may not report a family history because up to 25 percent of new HAE cases result from de novo mutations. Age of onset is variable ranging from early childhood to adult; frequency worsening around puberty. Attacks may be preceded or accompanied by a non-pruritic, flat, erythematous mottling or erythema marginatum. Attacks are prolonged, typically increasing over the first 24 hours then slowly subsiding over the next 48-72 hours before full resolution is achieved. Hereditary Angioedema does not respond to treatment with adrenaline, antihistamines, or corticosteroids.
Scientists recognize two forms of disease, but it is important for the clinician to note they are symptomatically indistinguishable. Type I HAE is characterized by low quantitative/antigenic and functional levels of C1-Inhibitor and affects about 85% of patients. Type II HAE affects the other 15% of patients whose tests reveal normal or elevated quantitative/antigenic levels of protein which is dysfunctional and results in a low C1-Inhibitor functional value.
Results should be confirmed by repeat testing before making a definitive diagnosis of HAE, since delay in processing or refrigeration can result in artificially low results especially in the C1 INH functional assay.
Patients may be diagnosed with hereditary angioedema with normal C1-INH when they have isolated angioedema with a positive family history and normal levels of C4 and C1-INH, no history of use of ACE-inhibitors or other drugs suspected to cause bradykinin-mediated angioedema and no response to antihistamines, steroids, or adrenaline. (If there is no family history the appropriate diagnosis is idiopathic non-histaminergic angioedema).
The clinical features differ in some ways from those of classic HAE: the swelling episodes are more likely to commence in adult life; the symptoms are less frequent and they usually affect the skin, tongue, lips and abdomen more than other areas; the symptoms are more common in women; exogenous oestrogen is a risk factor. A number of rare genetic mutations have been described including mutations in factorXII, angiopoietin 1 and the plasminogen genes.
There are no randomised controlled trials to guide treatment in these cases but evidence from case series suggests that icatibant and C1-INH concentrate may be effective as on-demand treatment to terminate acute attacks.
HAE patients experience recurrent episodes of swelling in the hands, feet, face, gastrointestinal tract, genitals, and larynx (throat) that can last from two to five days. The frequency of and severity of attacks varies dramatically among patients, and even among those within the same family. Nearly half the patients have more than one attack per month, but many suffer attacks infrequently.
HAE-related swelling is non-whealing and non-pruritic with ill defined margins, and generally remains unrelieved by antihistamines and corticosteroids. About 25 percent of HAE patients experience a non-pruritic erythematous rash or a tingling feeling that often occurs during the attack prodrome.
Swelling involving the feet and hands is extremely uncomfortable, and often prevents patients from being able to participate in normal daily routines. Gastrointestinal attacks produce severe abdominal pain, nausea, vomiting, and diarrhea caused by swelling in the intestinal wall. This symptom is a distinguishing feature of HAE because abdominal pain is rarely seen in other types of angioedema. Hypovolemia can occur from a combination of fluid loss, plasma extravasation, and vasodilation, and can progress into hypovolemic shock.
Approximately one third of patients with undiagnosed HAE undergo unnecessary surgery during abdominal attacks because the symptoms mimic a surgical emergency.
Laryngeal oedema is the most significant feature of HAE, because swelling can close the airway and cause death by asphyxiation. Surveys of HAE patients reveal that approximately 50 percent experienced at least one laryngeal episode in their lives. Before effective prophylactic therapy became available, the mortality rate for airway obstruction was reportedly as high as 30 percent.
Often no precipitating factor can be discerned but recognised triggers include stress, infection, trauma, surgery, dental treatment, oral contraceptives, hormone replacement therapy, pregnancy and ACE inhibitors.
Treatment of HAE
Treatment of acute attacks
- Berinert® brand of C1-inhibitor has been approved for treating acute abdominal, facial or laryngeal HAE attacks. Berinert® is delivered intravenously
- Cinryze® brand of C1-inhibitor is also approved for use in treating acute attacks, it is reconstituted and delivered intravenously.
- Firazyr® brand of bradykinin receptor antagonist has been approved for treating acute HAE attacks in patients 2 years and older. Firazyr® is delivered by subcutaneous injection and is approved for self-administration. Available in New Zealand
- Icatibant (Cipla) generic brand of bradykinin receptor antagonist approved for treating acute HAE attacks in patients 2 years and older. Icatibant is delivered by subcutaneous injection and is approved for self-administration. Available in Australia.
HAE does NOT respond to the drugs employed in treating other forms of urticaria/angioedema such as antihistamines, adrenaline, and corticosteroids.
Maintaining airway patency is the primary concern for patients with laryngeal edema. If the airway is threatened, the patient should be intubated by an experienced physician. In addition, the capability for emergency tracheostomy should be readily available. Because gastrointestinal edema usually involves severe pain, frequent vomiting, and the potential for hypotension, therapy should include aggressive fluid replacement and pain management.
Short-term prophylactic therapy is imperative to prevent attacks of angioedema when the patient is at high risk of swelling, particularly before expected trauma such as surgery or dental procedures.
Daily high dose androgen therapy (600-800mgs of danazol) was recommended for at least four days prior to surgery and two days afterward.
or Berinert® 20U/kg or Cinryze® 1,000U 1 to 6 hours prior to the surgery.
Some patients experience only infrequent and mild attacks and therefore require no long-term therapy. Clinicians generally recommend long-term therapy for patients who experience more than one attack per month, or who believe that the disease significantly interferes with their life style.
Drugs historically available for long-term therapy have been the attenuated androgens danazol and the antifibrinolytic drug tranexamic acid.
- The dose of anabolic androgens used to treat HAE should be titrated down to find the lowest dose that prevents attacks. A reasonable starting dose for danazol is 100 to 200 mg/day
- The side effects of anabolic androgens are dose related, with the most important side effects being hepatotoxicity and virilization. Patients taking anabolic androgens should have their liver enzymes checked every six months. Since hepatic adenomas have been reported as a consequence of anabolic androgens liver and spleen ultrasonography should be done yearly.
- Tranexamic acid is thought to be less effective than danazol but with fewer side-effects. The dosage is 30-50mg/kg daily divided over 2-3 doses. It may be suitable for children over two years of age.
C1-INH concentrate (Cinryze®) is an intravenous product approved for routine prevention of angioedema attacks in adults and adolescents with frequent debilitating attacks of HAE, who are intolerant to, or insufficiently protected by oral therapy.
It is essential the treatment approach be uniquely tailored to the needs of each HAE patient.
For further information and clarification see the Professional Papers(link is external)
DISCLAIMER: The information, including opinions and recommendations, contained in this document is for educational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis or treatment.