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Hereditary Angioedema (C1 Esterase Inhibitor Deficiency)

Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema (HAE), also known as C1 esterase inhibitor (C1-INH) deficiency, is an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder characterized by recurrent episodes of severe swelling Swelling Inflammation ( angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema). Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema commonly affects the limbs, face, intestinal tract, and upper airway Airway ABCDE Assessment. Swelling Swelling Inflammation in the airway Airway ABCDE Assessment can restrict breathing and lead to a life-threatening airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction. Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema has 3 subtypes distinguished by their underlying etiologies and levels of C1 inhibitor C1 inhibitor An endogenous 105-kda plasma glycoprotein produced primarily by the liver and monocytes. It inhibits a broad spectrum of proteases, including the complement C1r and the complement C1s proteases of the classical complement pathway, and the mannose-binding protein-associated serine proteases. C1-inh-deficient individuals suffer from hereditary angioedema types I and II. Angioedema in the blood. Management includes treatment with danazol Danazol A synthetic steroid with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties. Danazol has been used in the treatment of endometriosis and some benign breast disorders. Antiestrogens, kallikrein inhibitors, and C1-INHs. Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema is self-limiting Self-Limiting Meningitis in Children, but may be fatal if the airway Airway ABCDE Assessment becomes compromised.

Last updated: Sep 19, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema (HAE) is a hereditary condition featuring recurrent episodes of swelling Swelling Inflammation ( angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema), usually of the mucosa of the respiratory and gastrointestinal (GI) systems, without urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) or itching.

Epidemiology

  • Worldwide incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 
    • 1 in 50,000–150,000 people
    • Represents 2% of clinical angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
    • No difference in prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency between genders
    • No difference in prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency between ethnic groups
    • 75% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present by 15 years of age
  • Emergency department (ED) visits due to HAE: 15,000–30,000/year

Etiology

Genetic mutations Genetic Mutations Carcinogenesis are the cause of HAE:

  • Inherited mutations in the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics for the C1 esterase inhibitor (C1-INH): mapped to 11q12-13.1
  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disease
  • Transmission: 50% probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of transmission to children of either gender Gender Gender Dysphoria

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Pathophysiology and Types

The basic pathophysiology of swelling Swelling Inflammation in HAE has to do with the overproduction of bradykinin.

HAE type I HAE type II HAE type III
Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency 80%–85% of cases 15%–20% Very rare; usually in women
Cause Reduced secretion Secretion Coagulation Studies of C1-INHs Production of non-functional C1-INH
  • Normal C1-INH levels
  • Unclear cause; contact with estrogens and hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins, such as oral contraceptives
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in F12 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, which encodes for a protein involved in blood clotting (disease-causing gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 5q35.2-35.3)
Pathophysiology Excess production of inflammatory anaphylatoxins Anaphylatoxins Serum peptides derived from certain cleaved complement proteins during complement activation. They induce smooth muscle contraction; mast cell histamine release; platelet aggregation; and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from the strongest to the weakest is C5a, C3a, C4a, and C5a des-arginine. Innate Immunity: Barriers, Complement, and Cytokines that affect the flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure of body fluids between the vascular system and body tissues Excess production of inflammatory anaphylatoxins Anaphylatoxins Serum peptides derived from certain cleaved complement proteins during complement activation. They induce smooth muscle contraction; mast cell histamine release; platelet aggregation; and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from the strongest to the weakest is C5a, C3a, C4a, and C5a des-arginine. Innate Immunity: Barriers, Complement, and Cytokines that affect the flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure of body fluids between the vascular system and body tissues
  • Increased activity of the enzyme kininogenase, which leads to a rise in levels of bradykinin
  • Other patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with mutations in F12, encode defective protein functioning in blood coagulation

Clinical Presentation

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HAE have recurrent attacks:

Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema attack

  • Cutaneous symptoms:
    • Swelling Swelling Inflammation of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions in non-dependent areas
    • Seen most commonly on face and genitals
    • Swelling Swelling Inflammation increases over 24 hours and subsists over the following 48 hours.
  • GI symptoms:
    • Symptoms of colic, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Often preceded by prodromal symptoms of fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, hunger, irritability, and rash Rash Rocky Mountain Spotted Fever
  • Airway Airway ABCDE Assessment symptoms:
    • Swelling Swelling Inflammation of the lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, uvula Uvula A fleshy extension at the back of the soft palate that hangs above the opening of the throat. Peritonsillar Abscess, or palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
    • Early symptoms may include voice changes, sore throat Sore throat Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis, and “barky” cough
    • Severe episodes may cause airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction and suffocation.
    • More than ½ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will experience airway Airway ABCDE Assessment symptoms.

Triggers

  • Illness:
    • Upper respiratory infection Upper respiratory infection Rhinitis
    • H. pylori H. pylori A spiral bacterium active as a human gastric pathogen. It is a gram-negative, urease-positive, curved or slightly spiral organism initially isolated in 1982 from patients with lesions of gastritis or peptic ulcers in Western Australia. Helicobacter pylori was originally classified in the genus campylobacter, but RNA sequencing, cellular fatty acid profiles, growth patterns, and other taxonomic characteristics indicate that the micro-organism should be included in the genus Helicobacter. It has been officially transferred to Helicobacter gen. Helicobacter infection
  • Trauma:
  • Medication:
    • ACE inhibitors ACE inhibitors Truncus Arteriosus 
    • Tamoxifen Tamoxifen One of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium. Antiestrogens
    • Some hormone replacement medications

Diagnosis

History and physical exam

Recognizing HAE is often difficult due to a wide variability in disease expression: 

  • May be similar to other types of angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema resulting from allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency or other medical conditions 
  • HAE should be considered if the patient presents with:
    • Recurrent angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema (without urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives))
    • Recurrent episodes of abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Laryngeal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Positive family history Family History Adult Health Maintenance of angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema

Laboratory testing

Blood tests often used to confirm the diagnosis:

  • Serum complement factor 4 (C4): most reliable and cost-effective screening Screening Preoperative Care test
  • C1-INH antigenic protein
  • C1-INH functional level (if available)
Table: Common lab findings in HAE based on types
Type of angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema without urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) C1-INH protein C1q C4 & C2
HAE type I Normal
HAE type II N or ↑ (but dysfunctional) Normal
Acquired angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema with C1-INH deficiency (type I)
Acquired angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema with C1-INH deficiency (type II)

Management

There is no chronic preventive treatment; management focuses on treating attacks based on specific symptoms:

  • Medications used in all acute attacks as soon as symptoms start:
    • C1-INHs: 1st-line treatment:
      • Concentrates from human plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products
      • Recombinant forms
    • Bradykinin B2-receptor antagonist
    • Kallikrein inhibitors (available in the United States only)
  • Airway Airway ABCDE Assessment symptoms:
    • Airway management Airway management An airway, breathing, and circulation (ABC) assessment is the mainstay for evaluating and treating critically ill individuals. The airway assessment helps identify individuals with potential obstruction of the airway, which may benefit from airway management techniques to ensure adequate ventilation and oxygenation. Airway Management
    • Intubation Intubation Peritonsillar Abscess should be considered early.
  • GI symptoms:
  • Cutaneous symptoms: usually with medication only
  • Preventative therapy: C1-INH is often administered 1–1.5 hours before surgery.

References

  1. Nordenfelt, P., Nilsson, M., Björkander, J., Mallbris, L., Lindfors, A., & Wahlgren, C.F. (2016). Hereditary Angioedema in Swedish Adults: Report From the National Cohort. Acta Derm Venereol. May;96(4):540-5. doi: 10.2340/00015555-2274. PMID: 26540175.
  2. Bork, K., Meng, G., Staubach, P., & Hardt, J. (2006). Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med. Mar;119(3):267-74. doi: 10.1016/j.amjmed.2005.09.064. PMID: 16490473.
  3. Bork, K., Frank, J., Grundt, B., Schlattmann, P., Nussberger, J., & Kreuz, W. (2007). Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. Jun;119(6):1497-503. doi: 10.1016/j.jaci.2007.02.012. Epub 2007 Apr 5. PMID: 17418383.

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