Hereditary angioedema

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Hereditary angioedema (HAE)
Other namesHereditary angioneurotic edema (HANE), [1] familial angioneurotic edema [2]
Swollen hand during a hereditary angioedema attack..jpg
Swollen right hand during a hereditary angioedema attack.
Specialty Hematology
Symptoms Recurrent attacks of severe swelling [3]
Usual onsetChildhood [3]
DurationAttacks last a few days [3]
TypesType I, II, III [3]
Causes Genetic disorder (autosomal dominant) [3]
Diagnostic method Measuring C4 and C1-inhibitor levels. [2]
Differential diagnosis Intestinal obstruction, other types of angioedema [2]
Prevention C1 inhibitor [1]
Treatment Supportive care, medications [1]
Medication C1 inhibitor, ecallantide, icatibant [1]
Prognosis 25% risk of death if airway involved (without treatment) [2]
Frequency~1 in 50,000 [3]

Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. [3] The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. [3] If the intestinal tract is affected, abdominal pain and vomiting may occur. [1] Swelling of the airway can result in its obstruction and trouble breathing. [1] Without preventive treatment, attacks typically occur every two weeks and last for a few days. [3]

Contents

There are three main types of HAE. [3] Types I and II are caused by a mutation in the SERPING1 gene, which encodes the C1 inhibitor protein, and type III now called HAE with Normal C1 esterase(HAE nl C1). Six known mutations are described in the literature under the type 3 HAE. [4] The result is increased levels of bradykinin, which promotes swelling. [3] The condition may be inherited in an autosomal dominant manner or occur as a new mutation. [3] Triggers for an attack may include minor trauma or stress, but attacks often occur without any obvious preceding event. [3] Diagnosis of types I and II is based on measurement of C4 and C1-inhibitor levels. [2]

Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur. [1] During an attack, supportive care such as intravenous fluids and airway support may be required. [1] C1 inhibitor medications can be used for both prevention and treatment, while ecallantide and icatibant can be used to treat acute attacks. [1]

HAE affects approximately 1 in 50,000 people. [3] The condition is typically first noticed in childhood. [3] Type I and II affects females and males equally, [5] while type III affects females more often than males. [2] When the airway is involved, without treatment, the risk of death is about 25%. [2] With treatment, outcomes are generally good. [2] The condition was first described in 1888 by Canadian physician William Osler. [6]

Signs and symptoms

People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract. [7]

Swelling involving the respiratory and gastrointestinal systems can cause significant risk and distress. Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction. [7] [8] Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration. [8]

Some people may experience prodromal symptoms, including tingling, fatigue or weakness at the site of impending edema with one third of people experiencing an erythematous rash (erythema marginatum) as the prodromal symptom. [7] Urticaria is usually not seen in hereditary angioedema, as compared to other causes of angioedema such as histamine induced symptoms. [7]

Genetics

Because HAE is an autosomal dominant disease, there is no sex difference in transmission and both sexes are equally likely to receive the mutated gene from their parents. The autosomal dominant inheritance pattern with regards to hereditary angioedema requires receipt of only one copy of the mutated C1 inhibitor gene to have symptomatic disease. [9] [10] [11] [12] Further, hereditary angioedema with C1 inhibitor deficiency types 1 and 2 have complete penetrance, meaning all of those who inherit the dysfunctional gene will have symptomatic disease. However, hereditary angioedema with normal C1 inhibitor levels (Type 3 disease) has incomplete penetrance, and men may be asymptomatic carriers despite inheriting a mutated gene. [7]

With regards to the mutations in the SERPING1 gene that is seen in hereditary angioedema types 1 and 2 (hereditary angioedema with C1 inhibitor deficiency), 75% of the cases are due to an autosomal dominant inheritance of a mutated gene and 25% of cases are due to de novo mutations of the egg or sperm, or early in embryological development. [7] Hereditary angioedema type 3 (hereditary angioedema with normal C1 inhibitor levels) is associated with mutations in genes for Factor XII, angiopoietin 1, plasminogen or kininogen 1. [7]

Pathophysiology

The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the plasma contact system. However, in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of bradykinin B1 receptor and bradykinin B2 receptor on endothelial cells (cells lining blood vessels). [7] This activation leads to vascular endothelial cadherin (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to actin cytoskeleton contraction and increased pore size of the vascular endothelial cells. Adherens junctions are also reduced due to bradykinin B1 and B2 receptor activation and vascular endothelial growth factor (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema. [7] The bradykinin B1 receptor (unlike the B2 receptor) is slowly and only partially desensitized after binding the bradykinin agonist, thus remaining constitutively active long after initial bradykinin exposure which can explain the protracted swelling seen in hereditary angioedema as compared to other causes of angioedema. [7]

Diagnosis

Complement tests
C4 (C) FB (A) C3 CH50 Conditions
·↓↓↓ PSG, C3 NeF AA
↓·↓· HAE, C4D
···↓ TCPD
↓·/↓↓↓ SLE
↑↑↑↑ inflammation

Recognizing HAE is often difficult due to the wide variability in disease expression, with the diagnosis often delayed for years. [7] The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When HAE is misdiagnosed as an allergy it is most commonly treated with steroids, epinephrine or anti-histamines, drugs that are usually ineffective in treating a HAE episode. [7] Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other HAE patients report that their abdominal pain was wrongly diagnosed as psychosomatic or malingering. [7]

HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized. [13]

Types

There are three types of hereditary angioedema (HAE). HAE types I and II are both caused by a deficiency of complement C1-inhibitor (C1-INH), a plasma protein that is an important inhibitor of several serine proteases, specially of the complement system and the contact activation/kallikrein-kinin pathway, but also the fibrinolytic system. [14] [15] [16]

In HAE type I, there is a quantitative C1-inhibitor deficiency, antigenic as well as functional C1-inhibitor levels in plasma are decreased. This type accounts for approximately 85% of HAE cases with C1-inhibitor deficiency. [7]

In HAE type II, there is a qualitative deficiency, with normal - sometimes even elevated - C1-inhibitor protein levels, but decreased functional C1-inhibitor measurements. This type is seen in approximately 15% of HAE cases with C1-inhibitor deficiency. [16] [17]

C1-inhibitor deficiency is caused by mutations of the SERPING1 gene, the gene encoding complement C1-inhibitor. More than 700 different mutations have been described. [17] The SERPING1 gene shows a considerable tendency for de novo mutations. As a result, it is not uncommon to observe patients with primary recurrent angioedema attacks and C1-inhibitor deficiency where both parents are unaffected. [18]

Another type of hereditary angioedema, originally named HAE type III, has been observed. [19] [20] [21] In contrast to HAE types I and II, this type of the disease is characterized by normal C1-inhibitor measurements. Thus, the term "hereditary angioedema with normal C1-inhibitor" is now generally used for this HAE type. Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema. [7]

Hereditary angioedema with normal C1-inhibitor is a genetically heterogeneous disorder. Several molecular subtypes have been identified. A first subtype, identified in 2006, is caused by mutations of the F12 gene encoding coagulation factor XII (also known as Hageman factor). [22] [23] All four mutations known so far, the two originally described missense mutations in exon 9 as well as the two additional, very rare mutations described later, affect the proline-rich region of coagulation factor XII. [22] [23] [20] An accelerated activation of the kallikrein-kinin system appears to represent the pathomechanism through that the F12 mutations cause angioedema. [24]

Clinical manifestation of hereditary angioedema due to a F12 mutation occurs preferably, but not exclusively in female mutation carriers. The remarkable estrogen-sensitivity is a characteristic feature of the HAE type caused by a F12 mutation. For example, estrogen-containing oral contraceptives play an important role in triggering angioedema attacks. Exacerbation of symptoms during pregnancy is also a common observation. [25] [21] Hereditary angioedema due to Factor XII dysfunction is the most common subtype of type III angioedema. [7]

A second molecular subtype of HAE with normal C1-inhibitor is caused by a mutation of the plasminogen gene, namely a rare missense mutation within the kringle 3 domain of plasminogen, resulting in a novel type of dysplasminogenemia. [26] The mutation creates a new lysine-binding site within the kringle 3 domain and alters the glycosylation of plasminogen. [26] The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen. [27] Tongue swellings are a very frequent and characterizing symptom in patients with hereditary angioedema due to a plasminogen mutation. [26] [21]

Very rare observations have suggested that mutations of the following genes may also be responsible for the development of hereditary angioedema with normal C1-inhibitor: angiopoietin 1 [HAE with an angiopoietin 1 (ANGPT1) mutation]; myoferlin [HAE with a myoferlin (MYOF) mutation]; kininogen 1 [HAE with a kininogen 1 (KNG1) mutation]; and heparan sulfate-glucosamine 3-sulfotransferase 6 [HAE with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation]. [23] [21]

However, for a large proportion of cases with hereditary angioedema with normal C1-inhibitor the genetic cause remains unknown. [7]

Prevention

Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes. [28] [29]

Long-term

People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of pdC1INH in many parts of the world; bradykinin receptor antagonists (icatibant) in Europe; kallikrein inhibitors (ecallantide and lanadelumab) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa) in Europe. Tranexamic acid has been shown to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events. [30]

In 2018, the US Food and Drug Administration (FDA) approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people twelve years of age and older. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II. [31] [32]

Berotralstat was approved in the US in December 2020, for the prevention of attacks of hereditary angioedema in people twelve years of age and older. [33] [34]

Short-term

Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days. [35]

Management

The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor. [36]

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in the EU since 1979. Several C1 inhibitor treatments are available in the US and two C1 inhibitor products are available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the US FDA in 2009 for acute attacks. Cinryze, which is nanofiltered, was approved by the FDA in 2008 for prophylaxis. Ruconest is a recombinant C1 inhibitor approved in the US and the EU that does not carry the risk of infectious disease transmission due to human blood-borne pathogens. [37] [ unreliable medical source? ]

The medication ecallantide inhibits plasma kallikrein and was approved by the FDA in the United States for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in the EU and the US. [37] [ unreliable medical source? ] [38]

In February 2023, the FDA approved the expanded use of lanadelumab (Takhzyro) to prevent attacks of hereditary angioedema in children aged 2 to 12 years of age. [39]

The experimental gene therapy BMN 331 can also be used to prevent the disorder by targeting the SERPING1 gene with adeno-associated virus.

Prognosis

About 25% of those affected die in the first two decades of life, mainly due to lack of treatment. [40]

Epidemiology

Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year. [41] [42]

Society and culture

There are national associations for HAE patients and their families in a number of countries around the world. Many of these national associations are members of the global organization Hereditary Angioedema International (HAEI). HAEI raises awareness about hereditary angioedema as well as facilitating coordination of research regarding the condition. [43]

Each year on 16 May, HAEi and the HAE community raise awareness of HAE with the international HAE day. [44] [45]

Research

Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.[ citation needed ]

In October 2010, the European Medicines Agency authorized conestat alfa (brand name Ruconest), a C1-inhibitor for the treatment of acute angioedema attacks. [46]

Icatibant (marketed as Firazyr) is a selective bradykinin receptor antagonist, was authorized in the EU in July 2008, [47] [48] and was approved in the US in August 2011. [38] After initial borderline results this drug was shown to be effective in phase III trials. [49] Cinryze, a C1 esterase inhibitor, was approved by the FDA in October 2008. [50] [51]

Sebetralstat, an oral plasma kallikrein inhibitor, provided faster times to beginning of symptom relief, reduction in attack severity, and complete attack resolution compared to placebo when given as on-demand treatment to people twelve years of age or older., [52] raising the possibility of a “pill-in-pocket” preventive approach to HAE attacks.

The investigational antisense oligonucleotide donidalorsen significantly reduced hereditary angioedema attack rates and improved patient-reported quality of life when administered 80 mg subcutaneously every 4 or 8 weeks. [53] The drug selectively binds to prekallikrein messenger RNA (mRNA) and degrades it by means of ribonuclease H1, which results in the reduced production of prekallikrein protein, a key precursor in the kallikrein–kinin cascade.

Based CRISPR/Cas9 technology, a potential one-time gene editing therapy known as NTLA-2002 is also being developed for the treatment of HAE. NTLA-2002 is designed to prevent HAE attacks by inactivating the kallikrein B1 (KLKB1) gene, which encodes for prekallikrein, the kallikrein precursor protein. [54]

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Antithrombin</span> Mammalian protein found in Homo sapiens

Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.

<span class="mw-page-title-main">Bradykinin</span> Chemical compound

Bradykinin (BK) (from Greek brady- 'slow' + -kinin, kīn(eîn) 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.

<span class="mw-page-title-main">Niemann–Pick disease</span> Medical condition

Niemann–Pick disease (NP), also known as acid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A/B, and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM). NP type C is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM.

<span class="mw-page-title-main">Plasmin</span> Enzyme in human blood that degrades clots and other proteins

Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.

<span class="mw-page-title-main">Angioedema</span> Disease characterized by rapid swelling

Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.

High-molecular-weight kininogen is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

<span class="mw-page-title-main">C1-inhibitor</span> Mammalian protein found in humans

C1-inhibitor is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

<span class="mw-page-title-main">Icatibant</span> Pharmaceutical drug

Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication from the ACE inhibitor class.

<span class="mw-page-title-main">Complement deficiency</span> Medical condition

Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one of the complement system proteins. Because of redundancies in the immune system, many complement disorders are never diagnosed. Some studies estimate that less than 10% are identified. Hypocomplementemia may be used more generally to refer to decreased complement levels, while secondary complement disorder means decreased complement levels that are not directly due to a genetic cause but secondary to another medical condition.

Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.

<span class="mw-page-title-main">Acquired C1 esterase inhibitor deficiency</span> Medical condition

Acquired C1 esterase inhibitor deficiency, also referred to as acquired angioedema (AAE), is a rare medical condition that presents as body swelling that can be life-threatening and manifests due to another underlying medical condition. The acquired form of this disease can occur from a deficiency or abnormal function of the enzyme C1 esterase inhibitor (C1-INH). This disease is also abbreviated in medical literature as C1INH-AAE. This form of angioedema is considered acquired due to its association with lymphatic malignancies, immune system disorders, or infections. Typically, acquired angioedema presents later in adulthood, in contrast to hereditary angioedema which usually presents from early childhood and with similar symptoms.

<span class="mw-page-title-main">BioCryst Pharmaceuticals</span> American pharmaceutical company

BioCryst Pharmaceuticals, Inc. is an American pharmaceutical company headquartered in Durham, North Carolina. The company is a late stage biotech company that focuses on oral drugs for rare and serious diseases. BioCryst's antiviral drug peramivir (Rapivab) was approved by FDA in December 2014. It has also been approved in Japan, Korea, and China.

Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody that targets plasma kallikrein (pKal) in order to promote prevention of angioedema in people with hereditary angioedema. Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema attacks. Lanadelumab is the first treatment for hereditary angioedema prevention made by using cells within a lab, not human plasma.

<span class="mw-page-title-main">Contact activation system</span> Activation of coagulation cascade

In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate the coagulation cascade by cleaving and activating factor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.

<span class="mw-page-title-main">Berotralstat</span> Medication

Berotralstat, sold under the brand name Orladeyo, is a medication used to prevent attacks of hereditary angioedema (HAE) in people aged twelve years and older.

BMN 331 is an experimental gene therapy for hereditary angioedema, delivered by adeno-associated virus type 5 and targeting the SERPING1 gene.

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