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Synonyms and related keywords: hereditary angioedema, C1 inhibitor deficiency, C1 esterase inhibitor deficiency, HAE, oedema, complement deficiency induced angioedema, angioneurotic edema, acquired angioedema, AAE, complement component 1 inhibitor deficiency, laryngeal edema, Quincke's disease

Background

Hereditary angioedema (HAE) is an inherited disease caused by low levels of the plasma protein C1 inhibitor (C1-INH). Acquired angioedema (AAE) is caused by a consumption of C1-INH (for various reasons) that leads to low levels of this protein (see Angioedema). Deficiencies in this protein allow unchecked activation of the classic complement pathway and other biochemical systems. Patients can present with any combination of cutaneous angioedema, severe abdominal pain, or acute airway obstruction. Prior to the development of effective therapy, the mortality rate was 20-30%. Although preventable and treatable, the complications of this disease do not respond well to the usual therapies for angioedema; therefore, establishment of the correct diagnosis is critical.

Pathophysiology

C1-INH is a member of the serpin family of proteases, as are alpha-antitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited. Although synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood, but, since patients respond clinically to androgen therapy serum levels of C1-INH increase, it is believed that androgens may stimulate C1-INH synthesis. All C1-INH deficient patients are heterozygous; half the normal level of C1-INH is not believed sufficient to prevent attacks.

Although named for its action on the first component of complement (C1 esterase), C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, PTA, and kallikrein. Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s. Without C1-INH, unchecked activation of C1, C2, and C4 occur before other inhibitors (C4-binding protein and factor I) can halt the cascade.

The actual factor or factors responsible for the edema formation remain somewhat controversial. Researchers have demonstrated activation of the kinin system and increased bradykinin concentration associated with clinical flares. Bradykinin is an important inflammatory mediator that causes neutrophil chemotaxis, capillary dilation, and smooth muscle relaxation, and it has been linked to other forms of angioedema. In an animal model of C1-INH deficiency, bradykinin antagonists prevent capillary leakage. Others implicate C2 kinin, a metabolite of C2b, as the active agent in the presence of plasmin.

Frequency

United States

Although urticaria and angioedema are common problems that affect nearly 20% of the population, HAE is a rare disorder. It accounts for approximately 2% of clinical angioedema cases and occurs in approximately 1 in 50,000 persons. It affects whites, African Americans, and all other ethnic groups.

Mortality/Morbidity

• Although rare, HAE is a disease with potentially catastrophic consequences for those affected. These effects include acute respiratory compromise and unnecessary abdominal surgery, both of which can be prevented by appropriate therapy. Prior to the development of effective therapy, the mortality rate was 20-30%.
• Laryngeal edema is the major source of HAE-related mortality, and case series indicate that more than half the patients with HAE develop involvement in this area. The clinical condition may deteriorate rapidly following the development of angioedema, progressing from mild discomfort to complete airway obstruction within a span of a few hours. The pharyngeal swelling is often difficult to visualize, and progression of the disease can be best evaluated by asking the patient if the attack is progressing. Difficulty with secretions and a change in the tone of the patient's voice are good measures of progression. C1-INH is not needed for intact immune function, and patients with HAE have no increase in the incidence or severity of infections. Other biochemical pathways in which C1-INH is active, such as those for fibrinolysis and clotting, also function relatively normally without it. Unlike other forms of angioedema, histamine is not involved in the pathogenesis of HAE.

Race

No racial predilection is recognized.

Sex

As an autosomal dominant inheritable genetic disorder, no single sex predominates.

Age

The onset of HAE usually occurs during adolescence.

History

Patients typically report episodic attacks that begin during adolescence, although many patients present when they are children. Attacks in childhood are usually mild. Attacks are often preceded (1-2 hours before swelling begins) by a prodrome associated with a tingling in the area that will swell. Trauma precipitates attacks in about one third of patients. The trauma is usually pressure rather than sharp trauma. Patients who stand in one spot for long periods may have foot swelling; patients who used a lawn mower may have hand swelling. In some cases, infections may trigger attacks. However, most attacks have no clear inciting event. The frequency of attacks varies greatly among affected individuals and in the same individual, with some experiencing weekly episodes, while others might go longer than a year between attacks.

• Cutaneous edema is the most common and most noticeable symptom. Patients first notice tightness or tingling of the skin followed by the development of angioedema that evolves over several hours. In some patients, attacks are preceded by the development of an erythematous, nonraised, and nonpruritic rash, known as erythema marginatum. The angioedema typically resolves over 1-3 days.
• Laryngeal edema is the most feared complication of hereditary angioedema (HAE) and can cause an immediate life-threatening emergency. Case series indicate that more than half the patients with HAE develop involvement in this area at some time during their lives. The injection of lidocaine (Xylocaine) into the gums for the purpose of dental work is a common precipitant, but laryngeal edema can be spontaneous. The clinical condition may deteriorate rapidly, progressing through mild discomfort to complete airway obstruction over a period that is usually measured in up to 4 hours. Soft tissue edema can be readily seen when it involves the throat and uvula. This may rapidly progress to difficulty swallowing secretions, a change in the tone of the voice, and airway obstruction and may require emergency intubation or tracheostomy to ensure an adequate airway.
• Less common presentations reflect edema at other sites. Scrotal swelling is fairly common in males. Occasionally, urinary obstruction is observed.
• The peripheral angioedema of HAE usually involves the upper and lower extremities and oropharynx. Not associated with urticaria, the lesions are nonpitting and usually nonerythematous.
• The abdominal pain associated with HAE is caused by edema of the mucosa of any portion of the gastrointestinal tract. The intensity can approximate that of an acute abdomen, often resulting in unnecessary surgery. Either constipation or diarrhea can be noted. The gastrointestinal edema generally follows the same time course to resolution as cutaneous attacks.
• Two genetic types of HAE result in essentially the same phenotypic expression. The C1 inhibitor (C1-INH) gene is located on chromosome 11 in the p11-q13 region. Restriction endonuclease techniques demonstrate that multiple mutations can result in the affected phenotype. The inheritance is autosomal dominant with incomplete penetrance. Those who inherit the abnormal gene can have a clinical spectrum ranging from asymptomatic to severely affected.
• • Type 1 is the most common form and accounts for approximately 85% of cases. Synthesis of C1-INH is blocked at the site of the faulty allele but occurs at the normal allele. The result is transcription of the normal protein, yielding quantitative serum concentrations of C1-INH that are approximately 10-40% of normal.

  • Type 2 HAE accounts for approximately 15% of cases. Because of a mutation near the active site of the inhibitor, nonfunctional C1-INH is synthesized by the abnormal gene. The normal gene appears to synthesize near-normal levels of the inhibitor protein. Whereas patients with type I HAE have depressed serum levels of C1-INH, patients with type II HAE have either normal or increased concentrations of the protein.

  • A clinical syndrome resembling HAE that affects only women has been described and termed type 3 HAE. In this condition, no abnormalities of complement or of C1-INH levels have been described.

• Patients with HAE have a propensity to develop autoimmune disease. This may range from inflammatory bowel disease to systemic lupus erythematosus (SLE) to thyroiditis and should be considered if the patient's symptoms are suggestive of one of these problems.

Physical

See History. When patients present with acute attacks of HAE, they may appear severely ill. The first priority in the evaluation is to ensure an adequate airway. Abdominal pain is often the presenting symptom and is treated with narcotics. Patients may have intravascular fluid loss, which must be replaced. With severe attacks, patients can develop hypotension, owing to sequestration of fluid in the extravascular space. They should not be febrile if HAE is their only active problem.

Causes

Hormonal fluctuations play a role in HAE, and the surges that occur during adolescence are associated with the usual presentation of the disease at that age.

• Women often have attacks during menses, but attacks may be less frequent during the later stages of pregnancy. Both estrogen and antiandrogen therapy have been described as precipitators of attacks.
• In most cases, the cause of an individual attack is unknown. In some cases, trauma or emotional stress has precipitated attacks.

Other Problems to be Considered

Acquired angioedema and allergic angioedema.

Usually, the swelling is not confused with the swelling of rheumatic disease. However, in occasional cases when the swelling surrounds a joint and movement of the joint becomes difficult, this difference becomes more difficult to distinguish.

Lab Studies

• The results of most routine laboratory tests performed on patients with hereditary angioedema (HAE) are usually normal. Patients typically do not have increased erythrocyte sedimentation rates or eosinophilia; if either is present, the clinician should consider a coexisting or different diagnosis.
• During attacks, patients can demonstrate hemoconcentration or prerenal azotemia, both of which reflect intravascular volume loss. The white blood cell count is not increased during attacks.
• The screening tests for HAE are serum C4 and C1-INH levels. The C4 concentration is almost always decreased during attacks and is usually low between attacks. The concentrations of C3 and C1q are normal in patients with HAE, regardless of the clinical status of their disease. During attacks, the total serum hemolytic complement (CH50) is typically decreased, but it returns to normal with recovery. Because a deficiency in any of several components of complement can cause a decrease in CH50, a decreased value is not a particularly helpful finding (ie, low positive predictive value). Keep in mind that patients can have C1 inhibitor (C1-INH) that is antigenically present but is nonfunctional. Therefore, functional tests may be useful. Unfortunately, functional testing has a high error rate.

Imaging Studies

• Imaging studies are usually unrevealing, but mechanical bowel obstruction is occasionally observed during attacks of gastrointestinal edema. Ultrasonographic examination of the abdomen of a patient with gastrointestinal edema may show edema within the intestinal wall but may be unrevealing.

Histologic Findings

Very few histologic studies have been performed. Histologically, the angioedema of HAE is indistinguishable from other types of angioedema. Typically, perivascular mononuclear cell infiltrate and dermal edema similar to that seen with chronic urticaria or angioedema of other types are observed.

Medical Care

Medical treatment consists of prophylaxis, management of acute attacks, and prophylactic therapy in situations where attacks may occur (see Medication). During attacks, patients may require respiratory support. They also may require large amounts of intravenous fluids to maintain hemodynamic stability. None of the currently available therapies reliably terminate acute attacks. Subcutaneous epinephrine may provide some benefit in some patients.

Surgical Care

Episodes of laryngeal edema may necessitate emergent procedures to maintain the patient's airway. Because surgical or dental procedures can precipitate attacks, preventive measures should be considered prior to elective procedures. The C1 inhibitor (C1-INH) levels of patients can be boosted prior to procedures by the use of anabolic steroids for a week or, more reliably, with fresh frozen plasma (FFP) infusions.

Consultations

Primary care physicians who are unfamiliar with hereditary angioedema (HAE) may want to consult an allergist or immunologist to aid with the diagnosis and management of these patients. Once the diagnosis of HAE is made, patients and their families may benefit from discussions with a genetic counselor.

Diet

No particular dietary restrictions are necessary.

Activity

Activity is not limited with HAE, but advise patients to try to avoid activities that bring them many hours away from possible emergency treatment.

In Europe, purified C1 inhibitor (C1-INH) is available for treatment of acute attacks; it is not available in the United States. As discussed above, FFP or attenuated androgen is given prophylactically prior to surgery. Since therapy of acute attacks is relatively unsatisfactory, drug prophylaxis is the mainstay of therapy.

Drug Category: Blood products

These agents are used to improve the clinical aspects of the disease.

Drug Name	Fresh frozen plasma
Description	Infuse prior to airway manipulation (eg, dental cleaning) to prevent angioedema. Administering 2 units of FFP sustains complement control and prevents development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.
Adult Dose	2 U IV infusion prior to airway manipulation or surgery
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; fluid overload
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Risk of administering FFP during an active attack of angioedema involves feeding into complement consumption, thus increasing extent of involvement; viral contamination and infection are possible but unlikely due to prescreening; ineffective in patients with factor IX inhibitors; may induce an anamnestic response

Drug Category: Androgens

Some agents in this class may increase levels of C4 component of complement.

Drug Name	Danazol (Danocrine)
Description	Reduces attack frequency in most patients. As a prophylactic drug approach, dose is adjusted to lowest dose that controls symptoms.
Adult Dose	600 mg PO qd; gradually reduce to maintenance dose, which varies from patient to patient; most patients' attacks are controlled on 100-200 mg/d
Pediatric Dose	Not established; avoid use of androgens in children if possible
Contraindications	Documented hypersensitivity
Interactions	Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine and cyclosporine levels
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in seizure disorders and renal, hepatic insufficiency; monitor hyperlipidemia; may cause transaminase elevations; methylated androgens cause peliosis hepatis under rare circumstances and liver function tests should be followed; all androgens tend to cause elevations in cholesterol and LDL and a fall in HDL

Drug Name	Stanozolol (Winstrol)
Description	Reduces intolerable frequent attacks, especially involving the airway. No longer available in the US.
Adult Dose	6 mg PO qd; gradually reduce to maintenance dose of 2 mg PO qod
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; nephrosis, breast or prostate cancer
Interactions	Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur

Drug Category: C1-inhibitor concentrates

These concentrates are used in the acute treatment of angioedema.

Drug Name	C1-inhibitor concentrate
Description	Pending approval. Provides concentrated C1-inhibitor during an acute attack. Long-term use not recommended pending study results of infectious transmission of blood-borne pathogens (eg, HIV, slow viruses, hepatitis).
Adult Dose	500-1000 U IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not yet approved for this indication

Drug Category: Hemostatic agents

These agents are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

Drug Name	Aminocaproic acid (Amicar)
Description	Lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity. Widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. Can be used PO/IV. Described here is the use of this agent in treatment of hereditary angioedema in adults and children.
Adult Dose	About 7 g/d PO/IV divided q6h
Pediatric Dose	Syrup: 50-100 mg/kg PO q6h
Contraindications	Documented hypersensitivity; thrombosis diathesis; myositis; evidence of active intravascular clotting process
Interactions	Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Usually only indicated if definite diagnosis of hyperfibrinolysis made; caution in cardiac, hepatic, or renal disease; since aminocaproic acid can be fatal in patients with disseminated intravascular coagulation (DIC) or hypercoagulable state, important to differentiate between hyperfibrinolysis and disseminated intravascular coagulation; thrombi that form during treatment are not lysed and effectiveness is uncertain

Further Inpatient Care

• Inpatient care for patients with angioedema is based on providing patient support during an attack. Protection of the airway is of foremost concern and should be handled in cooperation with physicians capable of performing emergent intubation or tracheostomy, if required. Future use of C1 inhibitor (C1-INH) concentrate may provide another option in the emergent care of these patients.
• Once recovery is achieved, proper referral for education and long-term management should be arranged.

Further Outpatient Care

• Outpatient management should focus on prophylaxis and patient education.

In/Out Patient Meds

• Preventative therapy with attenuated androgens is usually the initial mode of treatment. Therapy should be minimized, balancing the severity of the disease with the severity of adverse effects. The specific drug most commonly used is danazol. All attenuated androgens are useful in treatment.
• A discussion of future plans, such as pregnancy, should be routine. The positive and negative aspects of androgen therapy should be discussed openly.
• Anticipatory guidance with respect to oral surgery or any major procedure that will involve airway instrumentation should be stressed during follow-up care.

Complications

• Airway obstruction can complicate episodes of laryngeal edema.

Prognosis

• Prognosis has improved over the past 20 years, with fewer adverse effects, both short-term and long-term, from judicious use of androgens. The addition of C1-INH concentrate will greatly enhance the emergent care of these patients.

Patient Education

• Educate patients about possible triggering factors of their attacks. Advise patients of the autosomal dominant inheritance pattern of hereditary angioedema (HAE) and that they should anticipate that 50% of their children will be affected. However, phenotypic expression of the condition may vary significantly within families.

Medical/Legal Pitfalls

• Hereditary angioedema (HAE) is a treatable disease; however, the agents used to treat more common forms of angioedema are not effective. The diagnosis of HAE should be considered when angioedema is not associated with urticaria or when cutaneous or laryngeal attacks do not respond to the usual therapy. Once the diagnosis has been made, efforts should be made to prevent attacks associated with dental and surgical procedures.

Special Concerns

• Other types of angioedema without urticaria, referred to as acquired angioedema (AAE), can complicate the process of diagnostic evaluation. As with patients with HAE, those with AAE have decreased C1 inhibitor (C1-INH) activity and experience the same spectrum of clinical disease. However, the 2 conditions differ in several respects. Acquired angioedema is caused by (1) an autoantibody to the C1-INH that prevents its function, (2) marked utilization of the normal C1 inhibitor by high levels of antigen-antibody complexes, or (3) factors formed by lymphoid tumors that destroy C1-INH activity. In general, these patients have low levels of C1q, which distinguishes them from HAE patients, who have normal levels of the protein.