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Hereditary Angioedema

HAE

Hereditary angioedema (HAE) is an autosomal dominant disorder that involves a defect in the C1-INH protein.

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Presentation

A detailed history concerning angioedema should be done. The following should warrant suspicion of HAE [9] [10]:

  • Family history of HAE
  • Reccurent angioedema that is non-responsive to antihistamine, glucocorticoid or epinephrine and produces various cutaneous sensations an hour prior to attack (prodromal)
  • Onset of symptoms during childhood
  • Recurrent abdominal pain
  • Occurrence of difficulty of breathing

The most frequent presentation is asymmetric, non-pitting, cutaneous swelling [1]. The sites of predilection are the face, genitalia, buttocks, and extremities. The most common site of swelling in the face is the periorbital area and the lips [1]. There are prodromal signs (e.g. tingling sensation) in the affected area several hours prior to swelling. The swelling is self-limiting and resolves in 12 to 36 hours [1]. There is no discoloration in the affected site after the attack has elapsed. GI involvement of HAE may present with or without nausea and vomiting [1]. The abdominal pain is severe and mimics the presentation of a surgical abdomen.

Laryngeal edema is the most severe presentation of HAE. Complete upper airway obstruction may commence without immediate medical attention. Progressive upper airway obstruction warrants immediate emergency intubation. In the pediatric population, frequent GI disturbances are common; therefore, it is an unreliable symptom to consider HAE. Flat, erythematous, non-pruritic lesions occur as a prodromal sign to angioedema. This is also known as erythema marginatum and is observed in 42 to 58% of cases [11].

Swelling
  • Cutaneous swelling and abdominal pain attacks caused by gastrointestinal wall swelling are common symptoms in HAE, whereas laryngeal swelling is rare.[ncbi.nlm.nih.gov]
  • The most serious manifestation is a laryngeal attack associated with upper airway swelling.[ncbi.nlm.nih.gov]
  • HAE symptoms overlap with other conditions that cause swelling. An accurate diagnosis is therefore crucial when considering therapy. Recently approved treatments for HAE swelling attacks include C1 esterase inhibitor concentrate and ecallantide.[ncbi.nlm.nih.gov]
  • The most common site of swelling in the face is the periorbital area and the lips. There are prodromal signs (e.g. tingling sensation) in the affected area several hours prior to swelling.[symptoma.com]
  • Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. Itchiness does not typically occur.[en.wikipedia.org]
Pain
  • M. aged 21, transported to emergency after being wakened from sleep by severe, acute abdominal pain. The pain was non-radiating, colic, and associated with flatulence, nausea and vomiting.[ncbi.nlm.nih.gov]
  • Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis.[ncbi.nlm.nih.gov]
  • We describe a 6-year-old boy who presented with recurrent severe abdominal pain accompanied by an elevation in pancreatic enzyme levels, without subcutaneous or cutaneous angioedema.[ncbi.nlm.nih.gov]
  • The same can be said for abdominal pain which mimics surgical abdomen and may result in superfluous surgical management. Peripheral swelling limits functionality of the patient.[symptoma.com]
  • Severities were aggravated by activity and his headache had shown recent progression with abdominal pain.[ncbi.nlm.nih.gov]
Fatigue
  • The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood.[ncbi.nlm.nih.gov]
  • Dagen & Craig (2010) documented that “the most common identifiable prodromal symptoms include unusual fatigue, rash on arms or legs and muscle aches” (p. 3).[haecanada.org]
  • […] urticaria as opposed to anaphylaxis, which typically has urticarial angioedema of the face, oropharynx, extremities, or abdomen angioedema of GI tract severe abdominal pain GI upset worst at 24 hours resolves over 48-72 hours often preceded by prodrome fatigue[step1.medbullets.com]
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • These may include: Extreme fatigue Muscle ache Tingling Headache Belly pain Hoarseness Mood changes Triggers Although you may not be able to tell what your triggers are, common ones include: Stress or anxiety Minor injury or surgery Illnesses such as[webmd.com]
Mucosal Edema
  • The lack or non-functionality of said inhibitors leads to activation of an inflammatory cascade, which result in cutaneous and mucosal edema.[ncbi.nlm.nih.gov]
  • One of the products is bradykinin which promotes tissue swelling and mucosal edema of the airways and GI tract. Reccurent angioedema without pruritus characterizes the disorder. Advances in treatment decreased the mortality rate of HAE.[symptoma.com]
  • Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria. Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.[emedicine.medscape.com]
  • "Thumbprinting" and a stacked coin appearance, also signs of mucosal edema, may also be seen on radiographs.[archinte.ama-assn.org]
Malaise
  • Fatigue, malaise, irritability, hyperactivity, mood changes, and nausea are other preceding factors [ 21 , 24 ]. The severity of HAE is variable and usually unpredictable.[intechopen.com]
  • […] non-pruritic, nonpainful angioedema in the subcutis or submucosa Throat Glottal edema, laryngeal edema starting with swallowing difficulties, voice changes, Abdomen hoarseness, dyspnea, in Vomiting, colicky pain, extreme cases suffocation diarrhea, malaise[slideshare.net]
Hoarseness
  • Symptoms include: Airway blockage -- involves throat swelling and sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the hands, arms, legs, lips, eyes, tongue, throat, or genitals Swelling of the intestines -- can[medlineplus.gov]
  • Symptoms Symptoms include: Airway blockage -- involves throat swelling and sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the hands, arms, legs, lips, eyes, tongue, throat, or genitals Swelling of the intestines[ufhealth.org]
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • These may include: Extreme fatigue Muscle ache Tingling Headache Belly pain Hoarseness Mood changes Triggers Although you may not be able to tell what your triggers are, common ones include: Stress or anxiety Minor injury or surgery Illnesses such as[webmd.com]
Stridor
  • Pruritus, urticaria, and bronchospasm do not occur, but laryngeal edema may be present, causing stridor (and sometimes death). Swelling resolves within about 1 to 3 days of onset.[msdmanuals.com]
  • Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation.[rarediseases.org]
  • Mild/moderate angioedema episodes Present with: Swelling of the peripheries Mild/moderate abdominal pain Severe angioedema episodes Present with: Stridor or respiratory distress due to laryngeal oedema Other signs of potential airway compromise eg hoarse[rch.org.au]
  • Symptoms/signs of respiratory distress - eg, stridor, dyspnoea, fear of suffocation, anxiety/agitation; the patient may grasp his/her throat with the thumb and index fingers (the universal choking sign).[patient.info]
Pleural Effusion
  • Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema. Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al.[emedicine.medscape.com]
  • effusions rarely may be seen Abdominal ultrasonography or computed tomography scanning: Edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid may be found See Workup for more detail.[emedicine.medscape.com]
  • Transient pleural effusions, sometimes with cough and mild pleuritic chest pain, can also occur. 9 Gastrointestinal tract symptoms of HAE, caused by visceral edema, result in varying degrees of intestinal obstruction.[archinte.ama-assn.org]
Dyspnea
  • The aim of this case report is to describe the lifesaving use of a novel C1-INH protein concentrate in a patient with mild-to-moderate dyspnea caused by swelling of the upper airway (larynx) and tongue.[ncbi.nlm.nih.gov]
  • 3. recurrent, recurrent, non-pruritic, nonpainful angioedema in the subcutis or submucosa Throat Glottal edema, laryngeal edema starting with swallowing difficulties, voice changes, Abdomen hoarseness, dyspnea, in Vomiting, colicky pain, extreme cases[slideshare.net]
Voice Alteration
  • Episodes of peripheral swelling only usually do not require treatment, but stanozolol (up to 6 mg/day) can be given during an attack. 78 Involvement of the upper airway usually begins slowly; voice alteration and dysphagia will precede total airway obstruction[pubmedcentral.nih.gov]
Abdominal Pain
  • Accurate and timely diagnostics of acute abdominal pain, a common emergency, is crucial in decreasing unnecessary surgical interventions. We present the case of a patient, Xh.[ncbi.nlm.nih.gov]
  • We describe a 6-year-old boy who presented with recurrent severe abdominal pain accompanied by an elevation in pancreatic enzyme levels, without subcutaneous or cutaneous angioedema.[ncbi.nlm.nih.gov]
  • Severities were aggravated by activity and his headache had shown recent progression with abdominal pain.[ncbi.nlm.nih.gov]
  • We report a case of a 9-year-old boy with a spontaneous mutation causing HAE, diagnosed after a life-threatening episode of angioedema of the head and upper respiratory tract after a 5-year history of recurrent skin swellings and abdominal pain leading[ncbi.nlm.nih.gov]
  • Abdominal pain, angioedema, bradykinin, C1 inhibitor, hereditary, inherited, swelling.[ncbi.nlm.nih.gov]
Nausea
  • The clinical signs may range from subtle, diffuse abdominal pain and nausea, to overt peritonitis.[ncbi.nlm.nih.gov]
  • The pain was non-radiating, colic, and associated with flatulence, nausea and vomiting. The family history was negative regarding Angioedema, which decreases but does not exclude the possible appearance of hereditary Angioedema.[ncbi.nlm.nih.gov]
  • He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain.[ncbi.nlm.nih.gov]
  • CASE REPORT A 17-year-old Hispanic female patient with past medical history of HAE, presented with a 4-day history of episodic abdominal pain, worsening during the last 2 days with associated nausea, vomiting, and bright red blood per rectum.[ncbi.nlm.nih.gov]
  • Other side effects patients experienced during clinical studies include: headache nausea diarrhea These are not all the possible side effects of RUCONEST.[ruconest.com]
Vomiting
  • Gastrointestinal symptoms are also common and may include abdominal pain, vomiting, and diarrhea. However, pancreatic involvement is rare and has been reported only in a few adults with previously diagnosed HAE.[ncbi.nlm.nih.gov]
  • The pain was non-radiating, colic, and associated with flatulence, nausea and vomiting. The family history was negative regarding Angioedema, which decreases but does not exclude the possible appearance of hereditary Angioedema.[ncbi.nlm.nih.gov]
  • CASE REPORT A 17-year-old Hispanic female patient with past medical history of HAE, presented with a 4-day history of episodic abdominal pain, worsening during the last 2 days with associated nausea, vomiting, and bright red blood per rectum.[ncbi.nlm.nih.gov]
  • Case Presentation A 6-year-old boy with an unremarkable family history presented to the Pediatric Surgery Department with complaints of abdominal pain, nausea, and vomiting, without fever.[pediatrics.aappublications.org]
  • If the intestinal tract is affected abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction.[en.wikipedia.org]
Diarrhea
  • Gastrointestinal symptoms are also common and may include abdominal pain, vomiting, and diarrhea. However, pancreatic involvement is rare and has been reported only in a few adults with previously diagnosed HAE.[ncbi.nlm.nih.gov]
  • The most common adverse drug reactions are injection site reactions, upper respiratory infections, headache, rash, muscle pain, dizziness, and diarrhea. "HAE attacks are painful, debilitating, and potentially life threatening.[medscape.com]
  • Other side effects patients experienced during clinical studies include: headache nausea diarrhea These are not all the possible side effects of RUCONEST.[ruconest.com]
  • Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
Severe Abdominal Pain
  • Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling.[ncbi.nlm.nih.gov]
  • A 45-year-old womon presented with a 10-year history of recurrent severe abdominal pain. Abdominal computed tomography revealed remarkable submucosal edema of the ileum.[ncbi.nlm.nih.gov]
  • In March 2007, she began suffering from severe abdominal pain due to intestinal edema. After treatment with C1-INH concentrate, her symptoms disappeared.[ncbi.nlm.nih.gov]
  • We describe a 6-year-old boy who presented with recurrent severe abdominal pain accompanied by an elevation in pancreatic enzyme levels, without subcutaneous or cutaneous angioedema.[ncbi.nlm.nih.gov]
  • A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier.[nejm.org]
Lip Swelling
  • Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
  • Melkersson–Rosenthal syndrome, which was diagnosed in 4 patients, is a rare idiopathic noncaseating granulomatous condition characterized by lip swelling (or other oro facial form of edema), facial nerve palsy and stable lingua plicata. 37 The symptoms[doi.org]
Edema of the Tongue
  • Physical examination reveals nonpitting swelling of the face, hands, and arms as well as edema of the tongue and mucus membranes of the mouth and pharynx.[step1.medbullets.com]
Hypotension
  • […] agonist terbutaline (Brethaire, Brethine) has been shown to be more effective at controlling urticaria than placebo. [6] However, efficacy is low for urticaria and angioedema; therefore, it is seldom used for treatment of angioedema. [6] Patients with hypotension[emedicine.com]
  • It leads to an increase in vascular permeability by binding to the B2 receptor on the vascular endothelial cells, and this in turn causes the development of edema, ascites, and hypotension [ 25 , 26 ].[intechopen.com]
  • Allergy attacks are rapid in onset, there is generally a recognisable allergen, and will be associated with a superficial itch, a generalised rash with raised wheals, respiratory wheeze, abdominal pain and possibly hypotension.[rcemlearning.co.uk]
  • With severe attacks, patients can develop hypotension, owing to sequestration of fluid in the extravascular space. Physical signs of hereditary angioedema (HAE) include overt, noninflammatory swelling of the skin and mucous membranes.[emedicine.medscape.com]
  • Antifibrinolytics also may have efficacy for HAE, but these agents have been associated with a variety of adverse effects, including nausea and diarrhea, postural hypotension, fatigue, enhanced thrombosis, retinal changes, and teratogenicity. 8, 22, 23[the-hospitalist.org]
Chest Pain
  • Transient pleural effusions, sometimes with cough and mild pleuritic chest pain, can also occur. 9 Gastrointestinal tract symptoms of HAE, caused by visceral edema, result in varying degrees of intestinal obstruction.[archinte.ama-assn.org]
Myalgia
  • Antifibrinolytic agents are reserved for patients who cannot tolerate anabolic steroids or other forms of prophylactic therapy. 12,13 Side effects associated with these agents include myalgias, fatigue, and coagulation disorders.[clevelandclinicmeded.com]
  • The most frequent adverse effects of the 17α‐alkylated androgens are menstrual irregularities, changes in libido, hirsutism, acne, changes in mood, weight gain, myalgia, erythrocytosis, increased blood pressure, and abnormalities in lipid profiles [ 51[intechopen.com]
  • […] who did not respond or responded suboptimally to androgen therapy may respond to adminstration of antifibrinolytic agents. 23 After an initial oral loading dose of 5 g, typical dosages effective for management of HAE have ranged from 7 to 10 g/d. 9 Myalgia[archinte.ama-assn.org]
Swelling of Hand
  • Head: swelling of the eyelids, lips, facial skin, headaches, dizziness Genital organs: swelling of the external genital organs Arms and legs: swellings on hands, feet, arms and legs; normal sequences of movement are restricted, walking impeded In mast[aha.ch]
Urticaria
  • It manifests as painless, nonpruritic, nonpitting episodic swelling of the subcutaneous tissues, gastrointestinal, and upper respiratory tracts in the absence of urticaria. An attack typically takes 24 h to peak and resolves over 48-72 h.[ncbi.nlm.nih.gov]
  • Tabs Content Clinical Overview Diagnosis Indications for Testing Recurrent angioedema in the absence of urticaria of Subcutaneous tissues Systemic organs Mouth, larynx, or pharynx Family history of angioedema Unexplained episode of laryngeal edema Laboratory[arupconsult.com]
  • The differential diagnosis should include acquired angioedema (see this term), intestinal occlusion syndrome and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria.[web.archive.org]
  • Abstract Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria.[ncbi.nlm.nih.gov]
Chronic Urticaria
  • The Role of the Coagulation Pathways in Recurrent Angioedema Previous studies reported infraclinical modifications of the homeostasis in chronic urticaria, recurrent idiopathic angioedema and hereditary angioedema.[centerwatch.com]
  • BSACI guidelines for the management of chronic urticaria and angio-oedema.Clin Exp Allergy. 2007 May;37(5):631-50.[gpnotebook.co.uk]
  • Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol 1989 ; 84 : 66 -71. 32. Kaplan AP. Clinical practice. Chronic urticaria and angioedema.[doi.org]
  • However, chronic urticaria usually responds to treatment with antihistamines and glucocorticoids, while hereditary angioedema does not respond to these therapies.[clinicaladvisor.com]
  • urticaria/angioedema - Preface ANNALS-OF-ALLERGY-ASTHMA-AND-IMMUNOLOGY.[malattierare.regione.veneto.it]
Skin Edema
  • Skin edema is nonpitting, with ill-defined margins, and most commonly affects areas of the face, extremities, and genitals. Facial areas typically involved are the lips, eyelids, and tongue.[archinte.ama-assn.org]
Facial Swelling
  • In the cases reported, after initiation of combined contraceptives, patients presented with facial swelling with airway involvement (laryngeal edema) and abdominal pain.[ncbi.nlm.nih.gov]
  • Critical Essential Core Tested Community Questions (2) (M1.IM.74) A 47-year-old male presents to the emergency department with facial swelling and trouble breathing.[step1.medbullets.com]
  • swelling as compared to swellings of the extremities and sex bias.[genedx.com]
  • swelling [ more ] 0000282 Intestinal edema 0005225 Intestinal obstruction Bowel obstruction Intestinal blockage [ more ] 0005214 Laryngeal edema 0012027 Percent of people who have these symptoms is not available through HPO Abnormality of the larynx[rarediseases.info.nih.gov]
  • In 2009, FDA approved Berinert, to treat acute abdominal attacks and facial swelling associated with HAE in adults and adolescents. It is a protein product derived from human plasma, and is manufactured by CSL Behring, Inc.[rarediseases.org]
Facial Edema
  • A 42-year-old Japanese man with hereditary angioedema suffered accidental trauma to his jaw in Shizuoka Prefecture, Japan, which gradually caused facial edema.[ncbi.nlm.nih.gov]
  • She had a 14-year history of ongoing lip and facial edema sometimes necessitating emergency department visitation.[ncbi.nlm.nih.gov]
  • edema Facial puffiness Facial swelling [ more ] 0000282 Intestinal edema 0005225 Intestinal obstruction Bowel obstruction Intestinal blockage [ more ] 0005214 Laryngeal edema 0012027 Percent of people who have these symptoms is not available through[rarediseases.info.nih.gov]
  • Signs and Symptoms Approximate number of patients (when available) Angioedema Very frequent (present in 80%-99% of cases) Ascites Occasional (present in 5%-29% of cases) Facial edema Occasional (present in 5%-29% of cases) Intestinal edema Occasional[web.archive.org]
  • Facial edema and oral mucuous membrane swelling may be present. The abdomen may be distended and tender to palpation, and bowel sounds are often diminished. Abdominal attacks often lead to unnecessary imaging and surgical exploration.[clinicaladvisor.com]
Neck Swelling
  • Individuals with Hereditary Angioedema may be present with: Swelling of the face, legs, arms, and genitalia Neck swelling leading to airway obstruction and deepening of the voice Protruding belly due to excessive fluid, which can cause signs and symptoms[dovemed.com]
Hunger
  • In the early days there was a hunger for any information on PID and a desperate need for clinics with the expertise and specialists to diagnose and treat PID patients.[pia.org.uk]
  • By JEN GUNTER Well Photo Credit Illustration by Celia Jacobs Outrunning Hunger Intense exercise may change the way certain neurons influence our appetite and metabolism.[nytimes.com]
Urinary Retention
  • Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria. Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.[emedicine.medscape.com]
Anuria
  • Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria. Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.[emedicine.medscape.com]
Headache
  • He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain.[ncbi.nlm.nih.gov]
  • The most common adverse drug reactions are injection site reactions, upper respiratory infections, headache, rash, muscle pain, dizziness, and diarrhea. "HAE attacks are painful, debilitating, and potentially life threatening.[medscape.com]
  • The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache.[ncbi.nlm.nih.gov]
  • Other side effects patients experienced during clinical studies include: headache nausea diarrhea These are not all the possible side effects of RUCONEST.[ruconest.com]
  • The most common side effects of FIRAZYR include: redness, bruising, swelling, warmth, burning, itching, irritation, hives, numbness, pressure, or pain at the injection site fever too much of an enzyme called transaminase in your blood dizziness nausea headache[firazyr.com]
Tingling
  • The rash is characterized by red rings that appear on the trunk and appendages as part of a prodrome that may also include a tingling sensation in the area where swelling will occur. 7 Reproduced with permission from the US Hereditary Angioedema Association[jaoa.org]
  • It is sometimes preceded by a tingling or burning sensation a few hours before the attack. Tummy ache Tummy ache occurs because the lining of the stomach and intestines become swollen.[symptoma.com]
  • […] children) Most frequent cause of death is airway obstruction secondary to laryngeal edema Presence of autoimmune diseases (especially glomerulonephritis ) is higher in these patients Typical and predictable course Many attacks, preceded by prodrome (tingling[arupconsult.com]
Irritability
  • Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis.[ncbi.nlm.nih.gov]
  • The most common side effects of FIRAZYR include: redness, bruising, swelling, warmth, burning, itching, irritation, hives, numbness, pressure, or pain at the injection site fever too much of an enzyme called transaminase in your blood dizziness nausea[firazyr.com]
  • Hereditary angioedema (HAE) is a rare disease that is often misdiagnosed because its symptoms mimic those of several common conditions, such as allergic reaction, acute appendicitis, gallbladder attack, submucosal abdominal tumor, diverticulitis, and irritable[allabouthae.ca]
  • Abdominal attacks are also confused with appendicitis or irritable bowel syndrome .[discoverhae.com]
  • Due to the nature of the disease, swelling can also occur in the intestines, causing various types of episodic and unpredictable abdominal pain, which may be confused with irritable bowel syndrome, inflammatory bowel disease, gynecological conditions[health.ucsd.edu]
Seizure
  • Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema. Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al.[emedicine.medscape.com]
  • Others 9, 16, 17 have reported seizures and hemiparesis. These symptoms are thought to be caused by local cerebral edema and consequent cerebral hypoperfusion, caused by the acute HAE episode.[archinte.ama-assn.org]
Ataxia
  • Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported. Cases of painful muscle swelling and unilateral hip or shoulder involvement have also been cited.[emedicine.medscape.com]

Workup

Newborn screening for HAE is not advisable. Complement protein levels erratically increase and reach the normal value at 1 year of age [12]. The best time to screen for HAE is after 1 year of age.

Complement testing

Measurements of C4, C1-INH, C1-INH functional activity, and C1q are laboratory test to diagnose HAE. The C4 is the single best screening test to detect HAE [13]. Uncontrolled C1 activity permanently depletes the C4 stores in all types of HAE. The levels decrease further during acute episodes. However, the C4 level is not highly specific or sensitive for diagnosis of HAE [14].

The C1-INH level and functional activity distinguishes the three types of HAE. The C1-INH level is low due to innate deficiency in type 1 HAE [14] [15]. The C1-INH level is normal but dysfunctional in type 2 HAE due to a mutation in the protein [14] [15]. Both C1-INH level and functional activity is normal for type 3 HAE because the defect lies in a mutation not related to the C1-INH protein.

The C1q level distinguishes HAE from acquired angioedema. All types of HAE will have normal C1q levels [15] [16]. Acquired angioedema will present will low C1q levels because the autoantibodies attach to both the C1-INH and C1q rendering them inactive.

C4 Decreased
  • […] the absence of urticaria of Subcutaneous tissues Systemic organs Mouth, larynx, or pharynx Family history of angioedema Unexplained episode of laryngeal edema Laboratory Testing Initial testing Complement 1 esterase inhibitor (C1-INH), complement 4 (C4[arupconsult.com]
Pleural Effusion
  • Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema. Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al.[emedicine.medscape.com]
  • effusions rarely may be seen Abdominal ultrasonography or computed tomography scanning: Edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid may be found See Workup for more detail.[emedicine.medscape.com]
  • Transient pleural effusions, sometimes with cough and mild pleuritic chest pain, can also occur. 9 Gastrointestinal tract symptoms of HAE, caused by visceral edema, result in varying degrees of intestinal obstruction.[archinte.ama-assn.org]

Treatment

On-demand treatment

Early treatment of acute attacks is warranted because the symptoms are debilitating and severely painful as a result of uncontrolled pro-inflammatory chemical release and nociceptive receptor stimulation. Upper airway obstruction should be treated immediately to avoid asphyxiation [17]. The same can be said for abdominal pain which mimics surgical abdomen and may result in superfluous surgical management. Peripheral swelling limits functionality of the patient. HAE attacks are treated with C1-INH, kallikrein inhibitor, or bradykinin receptor antagonist [18].

  • C1-INH

Administration of C1-INH concentrate resolves the underlying cause [19]. The concentrate restores activity regulation of the complement, clotting, fibrinolytic, and kinin systems. The result is reduction of bradykinin, factor XII, and eicosanoid derivative levels that cause angioedema.

  • Kallikrein inhibitor

Kallikrein’s function of cleaving HMWK to bradykinin is inhibited and prevents edema progression during attacks [20]. The only commercial kallikrein inhibitor available is ecallantide [21]. The medication is administered by subcutaneous injection. A 30 mg dose is indicated for HAE patients ≥ 16 years old for acute attacks [18] [21].

  • Bradykinin receptor antagonist

The synthetic peptide icatibant competitively binds at the bradykinin B2 receptors to inhibit the effects of bradykinin. It is administered subcutaneously with a recommended dose of 30mg for on-demand treatment [18]. A side effect of transient erythema, wheal, pruritus, or burning sensation may occur at the site of administration [22].

Short-term prophylaxis

Dental, minor, and major surgical procedures may trigger acute attacks of HAE due to physical trauma and/or emotional stress [23]. The site of attack is often near the site of surgery [18]. This poses an increased risk of upper airway obstruction for dental procedures.

C1-INH concentrate is the first line drug for short-term prophylaxis. 10 to 20 units/ kilogram of body weight should be given 1 to 6 hours prior to procedure [18]. Androgens such as danazol, stanozolol are a viable alternative if risk of attack is low. Prophylaxis starts 5 days prior to 2 days post-procedure. The recommended dose for danazol is 2.5-10 mg/kilogram/day with a maximum dose of 600mg. Stanozol’s recommended dose is 4-6 mg/day [18].

Prophylactic treatment

Prophylactic long-term treatment with Danazol is necessary if patients are afflicted with frequent and/or severe episodes.

Prognosis

The main concern lies with laryngospasm or laryngoedema. Both should be treated immediately with administration of C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist treatment. Progressive obstruction of the upper airways warrants intubation to avoid asphyxia. Abdominal and cutaneous attacks should be treated on demand as well since there is uncontrolled cascade of pro-inflammatory chemicals that evoke severe pain.

Etiology

HAE is an autosomal dominant disorder that involves a defect in the C1-INH protein. The deficient or dysfunctional protein cannot fulfill its function of regulating the release of bradykinin. Bradykinin produces venodilation and edema, laryngospasm and gastrointestinal (GI) disturbances, and cytokine and eicosanoid pathway derivative release. Some attacks may be triggered by trauma, psychological stress situations (Christmas, weddings, etc.), menstruation, ovulation and infectious diseases.

Epidemiology

  • The offspring of a person with HAE has a 50% chance of inheriting the disorder due to its autosomal dominant pattern of inheritance.
  • The ratio of C1-INH deficiency occurrence is 1 in every 50,000 persons [2]. 
  • De novo mutation of the C1-INH occurs in 20-25% of HAE [3].
  • The onset of symptoms occurs between 5-11 years of age in 50% of HAE patients [1].
Sex distribution
Age distribution

Pathophysiology

The C1-INH is a protein involved in the regulation of the complement, clotting, fibrinolytic, and kinin systems. The defect in C1-INH regulation with HAE allows spontaneous activation of complements C1, C2, and C4, kallikrein, factor XII, mannose-binding lectin associated proteases (MASP) 1 and 2, plasmin and factor XI [1]. Of the activated systems involved, it is the uncontrolled stimulation of the kinin system that primarily evokes angioedema [4].

HAE is a type of bradykinin-mediated angioedema due to a deficiency or dysfunction of the C1-INH gene. Uncontrolled activity of factor XII (Hageman Factor) activates pre-kallikrein into kallikrein. Kallikrein then cleaves the high molecular weight-kininogen (HMWK) to produce the vasoactive polypeptide bradykinin [1].

Excess in bradykinin promotes increased vascular permeability, venodilation and increased nitric oxide synthesis, smooth muscle contraction in airways and gastrointestinal (GI) tract, pain stimulation, and stimulation of various cytokines and eicosanoid derivatives release [1]. The result is the clinical picture of HAE. Increased permeability and venodilation [5] [6] leads to localized edema involving the deep layer of the dermis and subcutaneous tissue. Recurrent GI symptoms and laryngospasm may occur as a result of bradykinin-induced smooth muscle contraction. Pain and swelling arises from increased release of eicosanoid pathway products and cytokines.

Types of HAE

  • Type 1 (null)

It is transmitted in an autosomal dominant genetic pattern and constitutes 85% of HAE [1]. The available protein is low antigenicity and functional levels.

  • Type 2 (dysfunctional)

Mutations result in a dysfunctional protein. C1-INH is secreted in adequate amount and normal in terms of antigenicity. However, the function of the protein is impaired leading to angioedema.

  •  Type 3 (factor XII mutation)

Type 3 HAE is very rare. The recent theory is a factor XII mutation causes angioedema [7]. The mutation allows factor XII to activate kallikrein. Kallikrein in turn produces excessive amounts of bradykinin. The diagnosis of type 3 HAE necessitates a family history of angioedema [8] since the genetic defect of the disease is still inconclusive.

Prevention

The disease itself is not preventable as it is autosomal dominant in origin in majority of cases. A person with HAE should avoid using angiotensin converting enzyme (ACE) inhibitors to prevent acute attacks. ACE inhibitors suppress bradykinin dehydrogenase activity [1] thereby promoting bradykinin accumulation.

Women with HAE should be cautious with the hormonal replacement therapy or oral contraceptive (OCP) use. High levels of estrogen increase the levels of factor XII [24] available and decrease both C1-INH [25] and ACE [25] [26] levels. As a consequence, bradykinin accumulation occurs.

Summary

Angioedema is a well-demarcated, localized, nonpitting edema that may involve the deep dermis, subcutaneous or submucosal tissue [1]. Edema may also occur at the mucosal lining of the upper airways and the gastrointestinal (GI) tract. Angioedema may be inherited with an autosomal dominant trait known as hereditary angioedema (HAE). The main cause of HAE is a defect in C1 inhibitor (C1-INH) protein [1]. This protein is mainly responsible for regulation of complement, kinin, clotting, and fibrinoltyic pathway activities. Defect or dysfunction of C1-INH impairs the regulation of the aforementioned systems. As a result, excessive products by the various systems circulate in the bloodstream. One of the products is bradykinin which promotes tissue swelling and mucosal edema of the airways and GI tract. Reccurent angioedema without pruritus characterizes the disorder.

Advances in treatment decreased the mortality rate of HAE. Treatment with C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist regulates the level of bradykinin in the body; hence, life-threatening complications such as upper airway obstruction secondary to laryngeal edema are prevented.

Patient Information

Hereditary angioedema (HAE) is a type of rare inherited disorder that typically involves localized swelling of various body parts. A patient with the disease can pass it on to his/her child 50% of the time.

HAE is due to a defect in an important protein, C1 inhibitor (C1-INH), of the body. This protein regulates the release of bradykinin, a chemical that evokes multiple bodily reactions including increase in blood flow, leakiness of blood vessels, and release of chemicals that cause pain and tissue swelling. The protein defect allows accumulation of bradykinin. Thus, it imposes its uncontrolled effects on the body that result in angioedema.

Symptoms

  • Swelling of various body parts

Swelling usually involves the face, buttocks, reproductive organs, and limbs. The lips and skin surrounding the eyes are the areas that usually get swollen in the face. The typical characteristic of swelling is asymmetric that does not blanch under pressure. It is sometimes preceded by a tingling or burning sensation a few hours before the attack.

  • Tummy ache

Tummy ache occurs because the lining of the stomach and intestines become swollen. The tummy ache is often described as severe in pain and mistaken for a disease that warrants immediate surgery.

  • Difficulty of breathing

Bradykinin causes swelling of the upper airways. It often presents as difficulty of breathing. This warrants immediate medical attention to prevent suffocation from a complete upper airway obstruction.

Treatment

Treatment involves three drugs that prevent the accumulation of bradykinin– C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist. C1-INH concentrate administration is the treatment of choice for acute attacks of HAE because it solves the underlying problem which is a defect in C1-INH.

Intubation is necessary for patients who are at risk for complete airway obstruction.

Prevention

The disease per se is not preventable since it is an inherited disorder.

The use of drugs such as angiotensin converting enzyme (ACE) inhibitor and oral contraceptive pills should be avoided by HAE patients. These drugs trigger acute attacks of HAE by promoting accumulation of bradykinin in the body.

References

Article

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  3. Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009; 5: 1153–1158.
  4. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. Sep 4 2008; 359(10):1027-36.
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  9. Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol.2010; 5:24.
  10. Caballero T, Baeza ML, Cabañas R, Campos A, Cimbollek S. et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis. J Investig Allergol Clin Immunol. 2011; 5:333–347.
  11. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol.2010; 5:18. 
  12. Nielsen EW, Johansen HT, Holt J, Mollnes TE. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res. 1994; 5:184–187.
  13. Karim Y, Griffiths H, Deacock S. Normal complement C4 values do not exclude hereditary angioedema.J Clin Pathol. 2004; 5:213–214. 
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Last updated: 2019-07-11 20:56