Introduction
Over the years, research has been uncovering more and more rare diseases, especially genetic disorders. Hereditary Angioedema (HAE) is one of such rare disorders of the blood that causes a disfiguring swelling of a part of the body, particularly the face, larynx, extremities, abdomen, and genitalia. It may range from a simple painful swelling of an extremity to asphyxiation from laryngeal involvement. Diagnosis and prognosis of this condition depends on a heightened sense of awareness of the symptoms of the disease by the managing clinician and the availability of effective interventions.
HAE is known to occur in people with a deficiency of a particular enzyme (C1-esterase inhibitor) responsible for regulating the complex processes and biochemical reactions that occur during the body’s response to a foreign invader, particularly during coagulation and inflammation. When this inhibitor does not do what it is supposed to do, biochemical imbalances result leading to the formation of bradykinin which causes an increase in vascular permeability and a rush of fluid into the interstitial spaces. The end result of this is edema.
C1-esterase inhibitor deficiency has been found out to be caused by an autosomal-dominantly inherited mutation of the C1-inhibitor gene, although some few cases arise from spontaneous mutations in this gene coding for the C1-inhibitor protein (Gower 9). This has led to the classification of HAE into two types: HAE type I and type II. Type I accounts for most cases (85%) and is characterized by low levels of both antigenic and functional C1-esterase inhibitor caused by deficiencies in the amounts produced. On the other hand, type II which accounts for the remaining 15% is characterized by elevated or normal levels of the antigenic C1-inhibitor with reduced levels of the functional C1-inhibitor (Lumry 104). However, a third type has recently been isolated when a research revealed that out of 10 families with the disease, 36 women but no male was affected (Bork 1). The unique feature of this third type of HAE is that individuals have normal levels of C1-inhibitor yet with the classical features of the disease.
Natural History
The natural course of the disease usually follows a typical pattern in most patients. The first signs of the disease are evident during childhood or during the teen years, then gradually gets worse as pubertal developments supervene, and then persist throughout the individual’s lifetime (Lumry 105). For instance, a study has shown the mean age of disease onset to be 11.2 years with more than 50% first occurring before the age of 10 (Bork 2).
The disease is usually caused when the individual comes in contact with any of the identified triggering factors, which have been found to be diverse. It has been found out that exposure to cold, minor injuries, standing or sitting for prolonged periods, consumption of certain foods, drugs (particularly angiotensin-converting enzyme inhibitors), hormones, and emotional stress (Lumry 105). The use of oral contraceptives containing estrogen or hormone replacement therapy has been found to trigger or worsen clinical symptoms in a lot of women leading to the assumption that the manifestation of the disease in these women is estrogen-dependent (Bork 2). Also, the use of angiotensin-converting enzyme inhibitors in cases of hypertension or cardiac failure is associated with cases of people with HAE resulting from C1-inhibitor deficiency.
The pathophysiology of HAE is typical. Contact with any of the triggers above initiates any or both of the complement and coagulation cascades. The end result of these cascades is bradykinin, which is an inducer of increased vascular permeability. In a normal individual, C1-inhibitor is meant to regulate these pathways and control the amounts of bradykinin produced. However, when there is a deficiency of this inhibitor, levels of bradykinin shoot up, and there is an increased binding of bradykinin to the appropriate receptors on endothelial cells, leading to increased permeability and edema (Johnston 30).
Like the natural course of HAE, the occurrence of the clinical symptoms of this disease is quite consistent. The cardinal features include skin edema which is commonly described as “episodic, localized, non-urticarial, non-pitting, subcutaneous”, mucosal edema involving the gastrointestinal tract and the airways, particularly the larynx (Gower 9). Swelling of the skin is the most typical feature of the disease and it involves more of the upper limbs than the lower limbs. Involvement of the face, genitals, upper trunk and cervical region are rare, in descending order. Also, unlike most causes of superficial subcutaneous edema (nephrotic syndrome for instance), the edema found in HAE does not pit and is not associated with pruritus. In severe cases of skin edema, there may be formation of blisters and compartment syndromes.
HAE also affects the mucosa of the gastrointestinal tract, leading to the occurrence of abdominal pain which is usually recurrent in most cases. The intensity of the pain varies from mild abdominal discomfort to serious colicky pain followed by nausea and vomiting and/or passage of loose watery stools. Severe bowel edema has been associated with hypovolemic shock occurring from third space fluid losses, vasodilation, and plasma extravasation (Lumry 106).
Laryngeal edema is a rare but fatal feature of HAE. It constitutes about 0.9% of all HAE episodes but mortality could be as much as 30% (Farkas 715). It occurs very commonly during childhood and has the risk of being confused with other causes of laryngeal edema such as acute epiglottitis or bronchial asthma. The distinguishing factor is that laryngeal edema from HAE is unresponsive to corticosteroids, antihistamines and epinephrine which are the standard medications for the other causes. Laryngeal edema ranges from mild in which all the patient has is voice changes or hoarseness and dysphagia, to aphonia and severe asphyxiation with complete respiratory obstruction.
Other features of HAE include headaches, blurred vision, disorientation, chest pain, dyspnea, dysuria, bladder spasm, pain and swelling of muscles and joints, etc.
Incidence/Prevalence
The effects of HAE are quite significant. It has been estimated that every 1 in 10,000 to 1 in 150,000 people are affected worldwide. In the United States, the exact prevalence of the disease is uncertain, but it has been estimated at 1 in 50,000 (Johnston 28). This means that there are as many as 6000 cases of HAE in the United States alone. The theoretical rarity of the condition may not be too far from the fact that there is frequently a long delay between the period of onset of the disease and the time a definitive diagnosis is made. As a result of this, misdiagnoses and mismanagement are not too uncommon. In the pediatric age bracket, the estimated prevalence has been put between 1 in 10,000 and 1 in 50,000 live births (Farkas 714).
Every year, HAE accounts for as much as 30,000 visits to the emergency rooms with most patients presenting with laryngeal edema. Also, as much as 45% of all the patients presenting with symptoms of HAE are subsequently hospitalized as in-patients (Gower 9). There does not seem to be any correlations between HAE and race or gender, although it tends to be more common in women than men (Johnston 28).
Diagnosis
The diagnosis of HAE stems largely from the clinical history, examination and laboratory investigations. The classical presentation of non-pitting subcutaneous edema with the absence of pruritus and other urticarial lesions suggests HAE. Also, the significance of recurrent attacks of colicky pain and episodes of laryngeal edema further indicates the diagnosis. Again, a family history of similar symptoms indicates HAE, although absence of family history does not rule out HAE because up to 25% of patients have spontaneous mutations of the C1-inhibitor gene (Lumry 108).
The definitive diagnosis is made from laboratory investigations with measurement of the levels of factor C4 and C1-inhibitor as the first step in the investigative algorithm developed by (Lumry 108). Measurement of the levels of these factors is considered as a relatively cost-effective, sensitive and specific test for HAE in individuals. Prenatal genetic testing has been carried out on fetuses of affected parents with varying results.
Treatment
The aims of treatment of patients with HAE is to resuscitate individuals with severe attacks, slow the progression of the disease, reduce the number and severity of attacks, increase the period of time between attacks, and improve their quality of life. Because of the disparities in the clinical presentations of patients with this disease, it is recommended that management be individualized and based on interactions between the physician and the patient.
The treatment is based on three approaches: treatment of acute edema, short-term prophylaxis, and long-term prophylaxis. For the acute treatment, the pharmacologic options include replacement therapy with human or recombinant C1-esterase inhibitor, Ecallantide, and/or Icatibant, all of which are in use worldwide (Gower 12). The use of C1-esterase inhibitor infusions rapidly increases the levels of functional C1-inhibitor to normal or close to normal levels. The use of Icatibant (bradykinin B2-receptor antagonist) is associated with reversal of increased vascular permeability and reduced vasodilation and extravasation. Ecallantide is an inhibitor of kallikrein, thereby preventing the conversion of high-molecular-weight kininogens (HMWK) to bradykinin. However, in the United States, only two medications have been approved for the treatment of acute attacks: Berinert, which is a plasma-derived C1-inhibitor, and Kalbitor, which is a form of ecallantide – a kallikrein inhibitor (Johnston 33).
Short-term prophylaxis is commonly used in patients at risk of acute attacks such as patients going in for dental, surgical or medical procedures. There is much support for the use of C1-esterase inhibitor for short-term prophylaxis, although other drugs such as antifibrinolytics, attenuated androgens, icatibant (Johnston 35) and fresh frozen plasma (FFP) can be used (Gower 12). In the US, only C1-inhibitor concentrates (Cinryze) and Danazol (an attenuated androgen) have been approved by the FDA for routine prophylaxis, whether short-term or long-term (Johnston 35).
Other newer forms of therapy such as Firazyr, which is a bradykinin antagonist, and Rhucin, a recombinant C1-esterase inhibitor, are still under investigations in the US. The use of epinephrine, FFP and antifibrinolytics has been associated with questionable efficacies against acute attacks although their use may attenuate future attacks. Also, the use of antihistamines and corticosteroids has been proven to have no benefits in patients with HAE, because HAE is not a type of hypersensitivity reaction.
Conclusion
HAE is a rare genetic disorder which may have fatal consequences if not appropriately diagnosed and treated effectively. There are various treatment options, depending on the type of disease and presentation of the illness which can go a long way in terminating acute attacks, slowing the disease progression, and improve the overall quality of life of affected individuals.
Works Cited
Bork, Konrad. “Diagnosis and Treatment of Hereditary Angioedema with Normal C1 Inhibitor.” Allergy, Asthma & Clinical Immunology 6.15 (2010): 1-8. Web. 25 Feb. 2014.
Farkas, Henriette, et al. “Management of Hereditary Angioedema in Pediatric Patients.” Pediatrics 120.3 (2007): 713-722. Web. 25 Feb. 2014.
Gower, Richard G., et al. “Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies.” WAO Journal 4.2 (2011): S9–S21. Web. 25 Feb. 2014.
Johnston, Douglas T. “Diagnosis and Management of Hereditary Angioedema.” J Am Osteopath Assoc 111.1 (2011):28-36. Web. 25 Feb. 2014
Lumry, William. “Overview of Epidemiology, Pathophysiology, and Disease Progression in Hereditary Angioedema.” Am J Manag Care 19.7 (2013): S103-S110. Web. 25 Feb. 2014.
