Angioedema – Hereditary and Acquired

Are You Confident of the Diagnosis?

The procedure for angioedema is closely related to that for urticaria (see chapter on Chronic Spontaneous Urticaria.)

  • What to be alert for in the history

Of all the diagnostic procedures, the most important is to obtain a thorough history, including all possible eliciting factors and significant aspects of the nature of the angioedema. Questions should be asked regarding the following items:

  • Time of onset of disease

  • Frequency and duration of wheals

  • Diurnal variation

  • Occurrence in relation to weekends, holidays, and foreign travel

  • Shape, size, and distribution of wheals

  • Associated subjective symptoms of lesion, e.g. itch, pain

  • Family and personal history regarding urticaria, atopy

  • Previous or current allergies, infections, internal diseases, or other possible causes

  • Psychosomatic and psychiatric diseases

  • Surgical implantations and events during surgery

  • Gastric/intestinal problems (stool, flatulence)

  • Induction by physical agents or exercise

  • Use of drugs (NSAIDs, injections, immunizations, hormones, laxatives, suppositories, ear and eye drops, and alternative remedies)

  • Observed correlation to food

  • Relationship to the menstrual cycle

  • Smoking habits

  • Type of work

  • Hobbies

  • Stress (eustress and distress)

  • Quality of life related to urticaria and emotional impact

  • Previous therapy and response to therapy

  • Characteristic findings on physical examination

The second step is the physical examination of the patient. This should include a test for dermographism where indicated by history (NB: antihistamine therapy should be discontinued for at least 2-3 days).

Angioedema is characterized by:

  • Sudden, pronounced swelling of the lower dermis and subcutis

  • Occasionally pain rather than itching

  • Frequent involvement below mucous membranes

  • Resolution slower than for wheals that can take up to 72 hours

  • Expected results of diagnostic studies

Intense and costly general screening programs are not suggested in cases where the angioedema occurs with wheals (Figure 1). If wheals are not present, then angioedema must be excluded.

Figure 1.

Diagnostic algorithm for the differential diagnosis of angioedema

  • Diagnosis confirmation

Histamine-related angioedema. In histamine-induced angioedema accompanying urticaria, the diagnostic procedures are identical to those for urticaria. It has to be remembered that angioedema can be part of chronic urticaria even if presenting without wheals, as well as of physical urticaria, especially dermographic, delayed pressure urticaria, and cold urticaria.

Hereditary or acquired angioedema. If angioedema is not associated with urticaria, both hereditary and acquired angioedema can be present (see Figure 1). Acquired angioedema can be:

  • Associated with reduced C1 esterase inhibitor (C1-INH);

  • Drug-induced, mostly with ACE inhibitor intake;

  • Histamine dependent (and regarded as a manifestation of urticaria without wheals)

Hereditary angioedema (HAE) is divided into three distinct subtypes:

  • Hereditary angioedema type I: reduced production of C1-INH.

  • Hereditary angioedema type II: sufficient production of C1-INH but function is decreased.

  • Hereditary angioedema type III: mutation in factor XII. Affects only women. Estrogen dependent.

All patients in which hereditary angioedema type I or II are suspected should be assessed for a decrease of C4, C1 INH protein and C1 INH function levels. In some patients these are only lower directly after an attack. For hereditary angioedema type III currently no routine test is available.

Who is at Risk for Developing this Disease?

Histamine-related angioedema and angioedema in chronic spontaneous urticaria

Histamine-related angioedema and angioedema in chronic spontaneous urticaria can occur as an isolated symptom or in combination with recurrent wheals. In addition, many chronic spontaneous urticaria patients suffer from wheals without angioedema.

More patients with wheals and angioedema still suffer after 1 year as compared to patients who exhibit only wheals (64%-70% vs 43%-48%). In addition, many chronic spontaneous urticaria patients suffer from wheals without angioedema. More patients with wheals and angioedema still suffer after 1 year as compared with patients who exhibit only wheals (64-70% vs. 43-48%).

In addition, the prognosis for the duration of symptoms seems to be even worse in patients who only develop angioedema. For example, Kozel et al demonstrated that 80% of patients with angioedema without recurrent wheals were still affected after 12 months.

In general, most studies found that around 30%-50% of chronic spontaneous urticaria patients suffer from angioedema with or without wheals. Lower figures (20%) in Japan might point towards cultural and/or ethnic differences. Although the current guidelines state that chronic spontaneous urticaria in some patients is characterized by angioedema without wheals, some observations indicate that angioedema alone may be another disease. Future studies will have to address this question.

Hereditary and acquired nonhistaminergic angioedema

The most frequent form of nonhistamine-mediated acquired angioedema is bradykinin-induced and associated with the intake of ACE-inhibitors. Since this is not a drug allergy, bug related to the pharmacological properties of ACE-inhibitors, the symptoms depend on an increased bradykinin release and thus can occur sporadically only and happen to be seen already in a few weeks after first intake in some patients, but in others only after more than a year.

Another form of acquired nonhistaminergic angioedema is associated with a reduced function of C1-INH and often associated with neoplasia, or, more frequently, with lymphoproliferative diseases. In rare cases infections have been described in association with acquired angioedema. Symptoms can precede the neoplasia by months or even years.

This form of acquired angioedema can be caused by Anti-C1-INH autoantibodies, which recognize epitopes around the reactive centre of the C1-INH molecule and rendering the protein functionally inactive.

Hereditary angioedema is an autosomal dominant disease with either reduced levels of C1-INH or reduced function of C1-INH. Therefore, all children of HAE patients need to be screened as early as possible, since severe and even fatal reactions have been reported already in early childhood. In addition, there is a rare form of hereditary angioedema seen in women only. This type of HAE (type III) is associated with mutations in the Factor-XII and estrogen dependent.

A rare form of episodic angioedema is observed in Gleich’s syndrome. In this case, angioedema is associated with a peripheral blood eosinophilia.

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

Angioedema can occur as part of the disease urticaria with or without accompanying wheals based on mast cell-dependent histamine release. This is the most frequent form of angioedema. The differential diagnoses are non-histamine mediated types of angioedema that usually occur without wheals. The most frequent forms are ACE-inhibitor induced angioedema and hereditary or acquired angioedema based on C-esterase H1 inhibitor deficiency. A rare group of hereditary angioedemas is independent of H1-esterase inhibitor deficiency and mainly affects women.

Systemic Implications and Complications

In principle, for histamine-induced angioedema with accompanying urticaria there is a risk that angioedema may develop in the oral pharynx, but fatal cases have not been observed. In theory, there is also a risk for all other histamine-mediated forms of anaphylactic reactions (loss of blood pressure or unconsciousness). However, this too is not described in the literature. In case of acute or chronic spontaneous urticaria, it may, of course, happen, in cases where a true IgE-mediated food allergy is responsible for the wheals. In case of acute or spontaneous urticaria, other histamine-mediated forms of anaphylactic reactions may happen.

In cases of severe angioedema, angioedema of the oral pharynx, or a drop in blood pressure, it is warranted to take patients as inpatients for observation since, especially in angioedema, although antihistamines and corticosteroids will be able to stop the additional swelling, the resorption of the already existing interstitial fluid will take its time (up to 72 hours).

In all cases of known hereditary or acquired angioedema, as well as ACE-inhibitor induced bradykinin-dependent angioedema, there is a danger of severe and fatal reactions. In cases in which angioedema affects the oral pharynx or larynx, as well as internal organs (often presenting with severe abdominal pain), immediate treatment as described below needs to be initiated.

Treatment Options

Hereditary angioedema

In HAE, therapeutic options are either treatment of acute angioedema, which is especially warranted in those cases that only rarely involve episodes of angioedema, with prophylactic treatment as a second option. In addition, it is warranted to use short-term prophylactic treatment if possible triggering factors such as dental procedures or surgical procedures are planned for the patient.

Acute therapy is certainly required in all life-threatening episodes. Possible treatment options include fresh frozen plasma, which is least specific but available worldwide; concentrate of the human C1-INH; and a specific bradykinin antagonist (icatibant).

While the first two options replace the missing C1-INH activity, the third option actively stops the cascade at the level of the effect of bradykinin. Due to this mode of action, icatibant is also useful in nonhereditary bradykinin-induced angioedema. such as ACE-inhibitor angioedema. Other advantages of icatibant are that it can be stored at room temperature, can be given subcutaneously and is licensed for home treatment in Europe.

Short-term prophylaxis

Short-term prophylaxis is widely accepted as useful, although none of the available drugs are licensed. The question of whether the costly medication should be used prior to surgery or dental procedures depends on the history of the patient and on the procedure itself. Thus, in procedures with little trauma or in areas of the body where angioedema wouldn’t be dangerous (e.g., extremities), it may be sufficient to have C1-INH concentrate at hand or icatibant available.

Short-term prophylaxis can also be offered using danazol, which needs to be administered from 5 days before until 2 days after the procedure at a dosage of 2.5-10 mg/kg daily (not during the first two trimesters of pregnancy). Another synthetic androgen is stanazol, which can also be used for this purpose. Both drugs increase the production of C1-INH in the liver.

Before larger surgical procedures, especially in the area of the throat, it is useful to administer C1-INH concentrate 1-1.5 hours before the start of the procedure at a dose of 500 units for each 50 kg of body weight (Note also that intubation poses a considerable risk for the patient).

Long-term prophylaxis

In those HAE patients who have frequently recurring and/or severe attacks, long-term prophylactic management can help to reduce frequency and severity of symptoms. For decades, androgen derivatives such as danazol have been used for this purpose and these drugs have the advantage of being administered orally. However, the effect is highly variable and the doses need to be adjusted according to the C1-INH levels. The mode of action is an increased synthesis of C1-INH in the liver.

The consensus recommendation for the use of danazol suggests starting with a dosage of 200 mg once daily. However, the many known side effects of androgens may pose a problem for patients, especially women. Close monitoring of side effects is thus essential and apart from clinical examination, laboratory controls of blood count, liver enzymes, serum lipids, creatine kinase, and urine analysis need to be performed at least twice a year. In addition, it is recommended to use ultrasound diagnostics for the liver once yearly. To reduce the side effects, the dosages should preferably be adjusted to dosages below 200 mg/day. Many patients experience a good efficacy with only 50 mg/day.

Histamine-related angioedema

Apart from the prophylactic treatment described above especially acute attacks need immediate treatment. Certainly those with life-threatening implications such as attacks effecting the upper airways and throat immediate treatment is mandatory in all other attacks with large angioedema causing dysfunction or pain especially those involving a face, neck, or internal organs from the abdomen on-demand treatment should be considered.

In acute attacks treatment can be effectively delivered by C1-INH concentrate, ecallantide or icatibant (in those countries where these drugs are not available solvent detergent treated plasma (SDP) or fresh frozen plasma should be used instead). Especially with a development of icatibant as bradykinin antagonist the treatment of acute attacks can also be delivered by the patient himself as this drug is applied subcutaneously.

Diagnosis and treatment of histamine-induced forms of angioedema follows the algorithm for treatment of urticaria. See Figure 2.

Figure 2.

Algorithm for treatment of urticaria

Optimal Therapeutic Approach for this Disease

Histamine-related angioedema

Modern nonsedating antihistamines should be prescribed. Dosage should be increased to fourfold in case of nonresponding patients. Especially in recurrent forms of angioedema happening, for instance, every other week, where eliciting factors could not be determined, prophylactic treatment with non-sedating antihistamines is warranted.

Nonhistamine-mediated angioedema

Unlike histamine-mediated angioedema, there is no clear “optimal” approach for all patients with this disease, since its severity is highly variable. As extensively discussed in the section above, on-demand, short-term and long-term prophylaxis are the possible treatments which can be offered. The final decision depends on the patient’s needs and on the availability of these drugs in the different areas of the world.

Patient Management

Patient quality of life in angioedema, as in urticaria, is severely affected and management of the disease should therefore be prompt. There should be close collaboration between patient and physician. Triggering factors should be avoided. It is important to tell the patient that the disease is benign and treatable – even if the underlying cause cannot be found in all cases.

In the majority of patients with histamine-mediated angioedema, symptomatic pharmacologic treatment is possible with new-generation antihistamines, with a very low adverse effect profile and good patient compliance. In nonresponding patients, higher dosages (up to fourfold) and alternative medication should be tried. See also the chapter on chronic spontaneous urticaria for other treatment options that have been described in small case series or case reports, or which have not been added to the treatment algorithm because they either have very high costs (eg, immunoglobulin) or are associated with a higher incidence of adverse events.

Patient management is especially important in hereditary angioedema. In addition to the essential disease management components listed above (correct diagnosis, short- and long-term prophylaxis), physicians must consider the effect of the disease on the patients’ quality of life. Impaired effectiveness at work and school is common, and attention should be paid to mental health effects, most commonly depression.

These patients are clearly at a potentially lethal risk and need very good consultation regarding the possible triggering factors, implications for their children, including the offer of an early checkup to see if the mutation is present, and (if appropriate) a good counseling and home treatment with emergency drugs.

While icatibant is licensed in Europe for home subcutaneous application, many patients in the past also have learned how to administer intravenous C1-INH concentrate, which can be life-saving; eg, when a patient travels to or works in a remote area. Since this is a chronic, lifelong disease, it is useful to have a collaboration with one of the specialist centers interested in the disease.

Prednisone and other immunomodulatory drugs (Plaquenil, methotrexate, cyclosporine, thyroid hormone) have all been proven useless in C1-INH dependent angioedema, as well as in acquired.

Unusual Clinical Scenarios to Consider in Patient Management

Especially in HAE, patients often go undiagnosed, since in some patients the symptoms only present as noncutaneous angioedema with, e.g., abdominal pain. Several patients have unnecessarily undergone surgery in the past due to incorrect diagnosis.

Patients with acquired angioedema specifically due to new onset C1 inhibitor deficiency should be evaluated closely for an underlying lymphoma due to the high prevalence of splenic marginal zone lymphoma in these patients.