Hereditary Angioedema Type 1
HAE Type 1
Hereditary angioedema type 1 is an autosomal dominant disease characterized by C1 esterase inhibitor deficiency and the onset of edema, abdominal pain and erythema marginatum.
Presentation
Clinical features of HAE are largely indistinguishable across all types, but type 1 is characterized by a prodromal period in which a nonpruritic, nonpitting rash appears and is known as erythema marginatum [1] [3]. Soon after, the rapid onset of edema of the extremities, face, and/or the upper airway (angioedema) occurs and is considered to be the hallmark of HAE [3] [4]. Abdominal pain and cramping that may be quite severe develop concomitantly and diffuse tenderness is noted during physical examination as a result of profound gastrointestinal angioedema [4]. These symptoms are recurrent and occur in an unpredictable and abrupt fashion, but in the majority of cases, attacks spontaneously resolve within 12-72 hours, although therapy is frequently necessary [6]. It must be noted that urticaria is never a part of the clinical presentation of HAE and its presence universally excludes HAE as an underlying cause of symptoms [3].
Entire Body System
Swelling
- Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
- In addition to abdominal swelling and pain, people often experience nausea, which can be accompanied by vomiting. Attacks of HAE in the throat are the most dangerous because swelling that closes off the airway may be life threatening.[berinert.com]
- Hereditary angioedema type III is characterized primarily by skin swellings (predominantly facial) and abdominal attacks. Additional symptoms that may occur are tongue swellings, laryngeal edemas and swellings of the soft palate.[genedx.com]
- Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
Pain
- Hereditary angioedema type 1 is an autosomal dominant disease characterized by C1 esterase inhibitor deficiency and the onset of edema, abdominal pain and erythema marginatum.[symptoma.com]
- "The first symptoms I feel are usually sharp abdominal pains." –BERINERT patient[berinert.com]
- The horrific abdominal pain started when I was twelve. Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.org]
- FDA-regulated Device Product: No Keywords provided by Centogene AG Rostock: Angioedema, Hereditary Biomarker Additional relevant MeSH terms: Edema Abdominal Pain Angioedema Angioedemas, Hereditary Laryngeal Edema Signs and Symptoms Pain Neurologic Manifestations[clinicaltrials.gov]
- Puffiness in the feet and hands can be painful and make it hard to go about your daily life. Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
Fatigue
- Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.com]
- Numerous side-effects have been reported, including reduced efficacy when used for a prolonged period of time, affected growth and development in children, weight gain, menstrual changes, depression, fatigue, hypertension and many other, but the benefit[symptoma.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]
- The exact initiating mechanism(s) is unknown but stress (including mental stress, fatigue), trauma, infection, and increased estrogen states can be triggers.[pediatriceducation.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]
Leg Swelling
- The diagnosis of bilateral lower leg swelling secondary to enlarged local reactions to bug bites was made. The family was educated about large local reactions and given the proper dosing for diphenhydramine to use for the pruritus.[pediatriceducation.org]
Respiratoric
Hoarseness
- A 34-year-old female patient presented to the hospital complained of swollen and painful legs, flatulence, palpebral and labial edema, dyspnea, dysuria, frequent herpetic infections of mouth and nose, subfebrile body temperature and was hoarse.[signavitae.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]
- Voice changes - high-pitched, hoarse, rough or with a resonant, 'barky' cough or unable to speak.[patient.info]
Stridor
- […] swelling of the lips, tongue, uvula, soft palate, and larynx gastrointestinal bowel wall edema resulting in gastrointestinal colic, nausea, vomiting, and/or diarrhea Physical exam skin erythema marginatum may be seen upper airway voice changes or horseness stridor[medbullets.com]
- 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.[merckmanuals.com]
- 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]
Dyspnea
- A 34-year-old female patient presented to the hospital complained of swollen and painful legs, flatulence, palpebral and labial edema, dyspnea, dysuria, frequent herpetic infections of mouth and nose, subfebrile body temperature and was hoarse.[signavitae.com]
- Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
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[jcp.bmj.com]
Gastrointestinal
Abdominal Pain
- Hereditary angioedema type 1 is an autosomal dominant disease characterized by C1 esterase inhibitor deficiency and the onset of edema, abdominal pain and erythema marginatum.[symptoma.com]
- Brief Summary: Development of a new MS-based biomarker for the early and sensitive diagnosis of hereditary angioedema disease type 1 from the blood C1 Esterase Inhibitor Deficiency Angio-Oedema of Lips Angio-Oedema of Tongue Abdominal Pain Laryngeal Edema[clinicaltrials.gov]
- Swelling of the intestines may also occur, which can cause debilitating abdominal pain. Swelling of mucous membranes of the mouth, tongue, or throat from HAE can be life-threatening due to obstruction of the airway.[health.ucsd.edu]
- "The first symptoms I feel are usually sharp abdominal pains." –BERINERT patient[berinert.com]
- Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
Nausea
- Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.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]
- Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
- At 29 weeks of gestation, she was admitted to our emergency ward mainly complaining of nausea and vomiting; she received an injection of hC1- INH and her symptoms were resolved.[omicsonline.org]
Vomiting
- Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.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]
- Abdominal swelling usually involves pain, vomiting and diarrhea. Symptoms usually appear early in life, most often by age 13 and may increase in severity after puberty.[angioedemacenter.com]
- Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
Diarrhea
- Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
- Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.org]
- Abdominal swelling usually involves pain, vomiting and diarrhea. Symptoms usually appear early in life, most often by age 13 and may increase in severity after puberty.[angioedemacenter.com]
- Swelling of the skin (note that above symptoms may occur before swelling begins) Extreme fatigue or tiredness Headache Muscle aches Tingling in the skin Abdominal or belly pain (may be extreme enough to lead to surgical exploration) Nausea and vomiting Diarrhea[medicinenet.com]
Severe Abdominal Pain
- The clinical presentation includes the appearance of erythema marginatum (non-pitting and non-pruritic rash), recurrent attacks of angioedema that may involve any part of the body and severe abdominal pain and cramping.[symptoma.com]
- abdominal pain, or acute airway obstruction.[ijdvl.com]
- Episodes involving the intestinal tract cause severe abdominal pain, nausea, and vomiting. Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway.[ghr.nlm.nih.gov]
- It should therefore be limited to patients with laryngeal involvement or with severe abdominal pain. 7 However, a study using C1 inhibitor concentrate that was vapor-heated (to destroy the viral contaminants) showed a vast decrease in the time to resolution[mdmag.com]
Jaw & Teeth
Lip Swelling
- Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
- Six months after the accident he developed acute onset bilateral facial swelling, lip swelling, and difficulty breathing.[hoajonline.com]
Cardiovascular
Hypotension
- 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]
- When urticaria, generalized pruritus, or hypotension is present, the mast cell system is usually involved. In these cases, internal and external triggers (ie, foods, drugs, insects) should be sought.[mdmag.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]
- Stanozolol (Winstrol) Usual doses Adults: 2 mg/day Children 6–12 yr: 0.5–2 mg/day Children 0.5–1 mg/day Yes Yes Yes Yes No Antifibrinolytics Epsilon aminocaprioic acid (EACA) or Amicar 1–2 g by mouth 3x daily Hypercoagulability Muscle cramps Postural hypotension[clevelandclinicmeded.com]
Skin
Erythema
- Hereditary angioedema type 1 is an autosomal dominant disease characterized by C1 esterase inhibitor deficiency and the onset of edema, abdominal pain and erythema marginatum.[symptoma.com]
- Figure 2: Erythema of both thighs and left forearm.[omicsonline.org]
- The serpiginous, nonpruritic rash of erythema marginatum, which precedes an attack of hereditary angiodema in one-third of patients.[jaoa.org]
- Reticulate erythema: A prodrome in hereditary angioedema. Br J Dermatol 1979;101:549-52. [ PUBMED ] 3. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioedema. Am J Med 1963;35:37-44. [ PUBMED ] 4.[e-ijd.org]
- A subset of patients also note erythema marginatum at the onset of an attack. True urticaria and pruritis are typically absent.[clinicaladvisor.com]
Musculoskeletal
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]
- Adverse events were reported by nearly 80% of patients on danazol therapy and included weight gain, menstrual irregularities, female virilization, acne, headache, depression, and myalgia.[link.springer.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]
Swelling of Hand
- Figure 1: Hand swelling (left hand). She was referred to our obstetric outpatient ward for the care of pregnancy. At 18 weeks of pregnancy, she had an episode of abdominal pain and GI tract edema was suspected.[omicsonline.org]
Face, Head & Neck
Facial Swelling
- swelling as compared to swellings of the extremities and sex bias.[genedx.com]
- Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
- Six months after the accident he developed acute onset bilateral facial swelling, lip swelling, and difficulty breathing.[hoajonline.com]
Facial Edema
- 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]
Psychiatrical
Hunger
- Attacks are frequently accompanied by prodromal symptoms, including nonspecific complaints of irritability, aggressiveness, fatigue, or hunger[ 15 ].[link.springer.com]
Neurologic
Tingling
- Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.com]
- You may also experience skin tingling or tightness.[health.ucsd.edu]
- 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]
- 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]
Headache
- 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]
- All impeded androgens have many potentially important side effects, including masculinization, headaches, lack of libido or increased libido, hair gain or loss, liver function abnormalities, myopathy, and lipid abnormalities.[clinicaladvisor.com]
- Upper respiratory infection, sinusitis, rash, and headache were the most commonly reported adverse reactions[ 34 ].[link.springer.com]
- The other episodes were laryngeal edema (0.9%); edema of the soft palate (0.6%); tongue swellings (0.3%); headache episodes (0.7%); episodes affecting urinary bladder (0.3%), chest (0.2%), muscles (0.4%), joints (0.1%), kidneys (0.1%), and esophagus ([aaaai.org]
Irritability
- Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.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]
- Firazyy is a 10 amino acid peptide which causes local irritation, but otherwise has not been associated with serious side effects thus far. It is approved for self-administration subcutaneously.[clinicaladvisor.com]
- Attacks are frequently accompanied by prodromal symptoms, including nonspecific complaints of irritability, aggressiveness, fatigue, or hunger[ 15 ].[link.springer.com]
Urogenital
Urinary Retention
- The genitourinary tract may also be involved, causing acute urinary retention, often with hematuria. Patients also often experience headaches, although the reason for this remains unclear. Angioedema itself is not known to cause a febrile illness.[mdmag.com]
Workup
The combination of recurrent angioedema and gastrointestinal attacks, as well as positive family history, should be highly suggestive of HAE, but laboratory tests are necessary to confirm the diagnosis. Very low levels of C4 and C1-INH in serum are definite indicators of type I HAE and their values should be obtained at rest and during attacks, but persistently low C4 serum levels are observed in these patients [3] [4].
Serum
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]
Treatment
HAE is not responsive to antihistamines, corticosteroids, or epinephrine, suggesting that other agents have to be used in the acute setting, but in prophylaxis as well. Recombinant or human C1-INH, icatibant (a bradykinin B2-receptor antagonist that is able to reverse profound vascular permeability and reduce extravasation of fluid) or ecallantide (human plasma kallikrein inhibitor) are first-line therapy for acute attacks [1], while danazol, stanozolol, and oxandrolone are androgens used for both short-term and long-term prophylaxis [1]. Numerous side-effects have been reported, including reduced efficacy when used for a prolonged period of time, affected growth and development in children, weight gain, menstrual changes, depression, fatigue, hypertension and many other [1], but the benefit of prophylactic treatment substantially outweighs the risks for their appearance [1]. Androgens are contraindicated in pregnant women, however, and antifibrinolytics (tranexamic or aminocaproic acid) are used as alternatives in that particular setting [7]. HAE, regardless of the type, is unpredictable and a sudden onset of attacks can be provoked by daily-life situations (eg. stress). For this reason, patients are instructed and trained for self-administration of therapy, the primary reason being the reduction of complications that can occur as a result of treatment delay [7].
Prognosis
The diagnosis is often made late, as isolated reports have shown that recognition of HAE may take between 8-22 years after the first attack [1]. Having in mind the fact that life-threatening laryngeal edema and asphyxiation has been reported in these patients, a strong clinical suspicion must exist when patients present with symptoms suggestive of HAE.
Etiology
Mutations involving genes responsible for C1-INH production is the cause of HAE type I [4]. Specifically, serine (or cysteine) peptidase inhibitor (SERPIN) genes located on chromosome 11 code for C1-INH and more than 450 missense, nonsense, deletions, or insertion mutations have been described in the literature [3].
Epidemiology
Stress, trauma, infections, menstruation, pregnancy, use of estrogen-containing agents and angiotensin-converting enzyme inhibitors have been proposed as risk factors and potential triggers [1].
Pathophysiology
C1-INH is an enzyme responsible for suppression of the C1 complement system and in its absence, this pathway activates factors XIIa, XIIf, XIa and kallikrein, the precursor of bradykinin, which is considered to be the main mediator of the symptoms in HAE [5].
Prevention
Prevention of acute attacks is the most important part of long-term management, primarily because adequate therapy may substantially reduce the frequency of symptom occurrence. Prophylaxis prior to stressful situations or procedures that may trigger an attack (such as invasive medical or dental procedures, but also emotional stress induced by daily-life situations) is pivotal for preventing angioedema and other associated symptoms.
Summary
Hereditary angioedema (HAE) is a rare genetic disease that affects approximately 1 in 50,000 individuals and is classified into three types [1]. Type 1 accounts for the majority of HAE patients (85%) and is distinguished by the deficiency of C1 esterase inhibitor (C1-INH) due to genetic mutations of C1-INH producing gene located on chromosome 11 [1]. HAE type 1 is transmitted by an autosomal dominant pattern of inheritance [2], and numerous risk factors have been proposed, including stress (eg. weddings, Christmas, etc.), trauma, infection and menstruation [1]. The clinical presentation includes the appearance of erythema marginatum (non-pitting and non-pruritic rash), recurrent attacks of angioedema that may involve any part of the body and severe abdominal pain and cramping [4]. The diagnosis is made by determining very low levels of C4 and C1-INH in serum [3]. Treatment with androgens, antifibrinolytics, bradykinin receptor antagonists or C1-INH concentrate has shown good results and their prophylactic use (both short-term and long-term) is one of the key measures in preventing attacks [3].
Patient Information
Hereditary angioedema (HAE) is a familial disorder in which genetic mutations cause a rash, generalized swelling of the face and the extremities and profound abdominal pain accompanied by cramping. There are three distinct types and type 1 is distinguished by the deficiency of C1-esterase inhibitor (C1-INH), an enzyme responsible for regulation of numerous functions in the immune and coagulation system. It is by far the most common subtype, but the cause of mutations responsible for its development remains unknown. Various precipitating events have been established, including emotional stress, trauma, pregnancy and use of estrogen and angiotensin-converting enzyme drugs. The clinical presentation involves a sudden onset of marked swelling of the subcutaneous tissue preceded by a rash that does not itch and remains at the level of the skin (erythema marginatum), while profound abdominal pain, cramping, and tenderness on palpation are constitutive symptoms as well. In rare cases, swelling of the larynx may cause life-threatening asphyxiation, which is why early diagnosis through laboratory detection of low C1-INH in serum and prompt use of recombinant C1-INH and several other drugs are vital. Prevention of attack can be achieved through the use of androgen drugs - danazol, stanozolol or oxandrolone, prior to potentially stressful events.
References
Article
- Gower RG, Busse PJ, Aygören-Pürsün E, et al. Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies. World Allergy Organ J. 2011;4(2):S9-S21.
- Lei WT, Shyur SD, Huang LH, Kao YH, Lo CY. Type I hereditary angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J Allergy Immunol. 2011;29(4):327-331.
- Henao MP, Kraschnewski JL, Kelbel T, Craig TJ. Diagnosis and screening of patients with hereditary angioedema in primary care. Ther Clin Risk Manag. 2016;12:701-711.
- Khan DA. Hereditary angioedema: Historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10.
- Banerji A. Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc. 2011;32(6):403-407.
- Miranda AR, de Ue APF, Sabbag DV, Furlani W de J, de Souza PK, Rotta O. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. An Bras Dermatol. 2013;88(4):578-584.
- Caballero T, Canabal J, Rivero-Paparoni D, Cabañas R. Management of hereditary angioedema in pregnant women: a review. Int J Womens Health. 2014;6:839-848.