C1 inhibitor deficiency is a rare medical condition that can lead to serious, recurrent episodes of swelling. This disorder involves a protein, C1 inhibitor (C1-INH), which regulates various bodily processes, including inflammation and blood vessel function. Early recognition and management are important for reducing the frequency and severity of swelling attacks.
Understanding C1 Inhibitor Deficiency
C1 inhibitor (C1-INH) is a protein that controls several systems, including the complement system, the kinin-kallikrein system, and parts of the coagulation and fibrinolytic pathways. C1-INH blocks proteins like plasma kallikrein and activated factor XII (factor XIIa), which produce bradykinin. Bradykinin increases vascular permeability, causing fluids to leak from blood vessels into tissues and leading to swelling.
When C1-INH is deficient or not working correctly, these systems become overactive, leading to uncontrolled inflammation and swelling. This leads to excess bradykinin production, causing fluid leakage and edema. The deficiency can manifest in two primary forms: hereditary angioedema (HAE) and acquired angioedema (AAE).
Hereditary angioedema (HAE) is a genetic disorder inherited in an autosomal dominant pattern. It is primarily caused by mutations in the SERPING1 gene, which instructs the body to make the C1-INH protein. These genetic changes can lead to either low levels of C1-INH (Type I HAE, about 85% of cases) or the production of a dysfunctional C1-INH protein despite normal or even elevated levels (Type II HAE, about 15% of cases).
Acquired angioedema (AAE) is a rarer condition that develops later in life, in adults over 40, without familial predisposition. AAE is often associated with other underlying medical conditions, such as lymphoproliferative disorders (e.g., non-Hodgkin’s lymphoma) or autoimmune diseases (e.g., systemic lupus erythematosus). In AAE, the immune system may produce antibodies that target and consume C1-INH, or the underlying condition may increase protein consumption.
Recognizing the Signs
C1 inhibitor deficiency causes recurrent swelling, known as angioedema. The swelling is non-itchy and non-pitting, distinguishing it from allergic reactions that involve hives. It can affect the skin, gastrointestinal tract, and upper airway.
Skin swelling occurs on the face, lips, tongue, hands, feet, and genitals. Gastrointestinal swelling can cause severe abdominal pain, nausea, vomiting, and diarrhea, sometimes mistaken for other abdominal conditions. Attacks usually resolve within one to three days if untreated.
Swelling of the upper airway, including the mouth, throat, and larynx, can interfere with breathing and become life-threatening. Patients may experience a gasping sound, hoarseness, or difficulty speaking. Prompt medical attention is necessary for airway swelling.
Attacks can be unpredictable, but certain factors may trigger them. Triggers include physical or psychological stress, minor injuries (e.g., dental procedures), viral infections, and certain medications like ACE inhibitors. Some patients experience prodromal symptoms, such as fatigue, flu-like symptoms, indigestion, or a tingling sensation, before swelling begins.
Diagnosis and Treatment Approaches
Diagnosing C1 inhibitor deficiency involves clinical evaluation and specific blood tests. A thorough family history is important, particularly for suspected hereditary angioedema, as about 75% of HAE cases have a family history. Doctors suspect the condition when recurrent swelling occurs without hives, itching, or apparent cause.
Blood tests confirm the diagnosis. A low level of complement factor 4 (C4) is a screening test for C1-INH deficiency, as C4 levels are low in untreated cases. If C4 is low, further tests measure the C1-INH protein level and its functional activity. For Type I HAE, both C1-INH protein levels and function are low, while in Type II HAE, C1-INH protein levels may be normal or elevated, but its function is impaired. For acquired angioedema, C1q levels are often decreased, which can help differentiate it from hereditary forms.
Treatment focuses on managing acute attacks and preventing future episodes. For acute attacks, treatments reduce swelling duration and severity. Options include plasma-derived human C1-INH concentrate, which replaces the deficient protein, and recombinant C1-INH. Other acute treatments include bradykinin receptor antagonists, such as icatibant, which block the effects of bradykinin, and kallikrein inhibitors, like ecallantide or lanadelumab, which reduce bradykinin production. These treatments are administered intravenously or subcutaneously, with some allowing for self-administration.
Long-term prophylactic treatment prevents attacks. Attenuated androgens, such as danazol, can be used to increase C1-INH levels, although these may have side effects and are not typically recommended for children or women. Plasma-derived C1-INH concentrate can also be given as regular infusions for prevention. Newer options include kallikrein inhibitors like lanadelumab, a monoclonal antibody that targets plasma kallikrein. Individualized treatment plans are developed based on the patient’s specific condition and attack frequency, with emergency preparedness being a significant aspect of management.