Hereditary Angioedema (C1 Esterase Inhibitor Deficiency)

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

Pathophysiology and Types

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

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 Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy, and “barky” cough
  • Severe episodes may cause airway Airway ABCDE Assessment 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:
  • Intubation Intubation Peritonsillar Abscess
  • Dental work
  • Piercings
• 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 Abdominal Pain Acute Abdomen 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)

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 Airway ABCDE Assessment management
  • Intubation Intubation Peritonsillar Abscess should be considered early.
• GI symptoms:
  • Supportive care and close monitoring
  • Rehydration Rehydration Dengue Virus may be necessary.
  • Monitor for signs of intestinal occlusion from swelling Swelling Inflammation.
• Cutaneous symptoms: usually with medication only
• Preventative therapy: C1-INH is often administered 1–1.5 hours before surgery.