Acquired C1 esterase inhibitor deficiency

It is estimated that the worldwide prevalence of AAE ranges from 1 person in every 10,000 people are affected to 1 case in every 150,000 people. However, it is thought that this disease prevalence could be higher due to diagnostic oversight and the shared symptoms of acquired angioedema with similar diseases. This disease tends to affect males and females equally. Additionally, individuals with acquired angioedema usually develop symptoms in their fourth decade of life or older. Of note, Saini reports the difficulty of diagnosing angioedema accurately due to certain challenges. These obstacles include the lack of awareness about angioedema presentation and potentially higher than expected worldwide prevalence. More challenges include the similarities to paraneoplastic disorders that often require higher priority of care, the evolution of symptoms over time, and mild cases might be attributed to medication use or allergic reactions from an individual's existing medical history. As a result, accurate diagnosis of AAE can take several months, which can delay targeted and specific treatment. == Causes ==

There are various disease comorbidities associated with acquired C1 esterase inhibitor deficiency, including: Lymphoproliferative disorders and lymphatic malignancies • Lymphoproliferative disorders, such as monoclonal gammopathy of undetermined significance (MGUS) and non-Hodgkin lymphoma are associated with acquired angioedema. In cohort studies, MGUS is considered one of the most common disorders associated with AAE. Additionally, through retrospective case studies performed in France, Gobert et al. found that non-Hodgkin lymphoma was associated with 48% of cases in a sample size of 92 cases of acquired angioedema. • Multiple myeloma (MM) is a malignant plasma cell disorder that progresses from MGUS. MM is characterized by elevated monoclonal paraprotein in addition to end organ damage, such as kidney failure. • Lymphoplasmacytic lymphoma (also known as Waldenström macroglobulinemia) is a B cell malignancy with hematologic changes that affect the lymphatic system. Some of the clinical manifestations seen in this lymphoma are anemia, hyperviscosity syndrome, and neuropathy. The autoantibody component involved in SLE has been investigated and is thought to be associated with angioedema manifestations. This vasculitis is associated with certain comorbidities including asthma, rhinosinusitis, and eosinophilia (blood cells responsible for activating immune responses and downstream signals in inflammation). • Hepatitis B viral infection (HBV) is a transmissible DNA virus that can potentially lead to liver injury. In a series of cases studies with patients reporting symptoms of angioedema, some of these individuals were found to have positive markers of HBV. Metabolic disorders • Xanthomatosis is a systemic metabolic disorder marked by fatty deposits in the presence of hypercholesterolemia, or high cholesterol. Idiopathic causes • Idiopathic etiology is considered when well-understood and known causes are excluded after a thorough medical evaluation. == Pathophysiology ==

The C1 esterase inhibitor (C1-INH) enzyme plays a role in the classical pathway of the complement cascade, which is a component of the immune system response that acts to protect the human body from a variety of foreign substances. As shown in the figure above, the complement cascade starts with the C1q protein which binds to an antibody-antigen complex that arises during an immune response to an invading substance. When the complex is signaled for activation or turned on, then downstream proteins in the complement cascade are activated, including complement component 2 (C2), complement component 3 (C3), and complement component 4 (C4). When these particular enzymes such as C3 and C4 are activated, their subsequent signals lead to an inflammatory response that involves localized edema, or swelling. The role of C1-INH is to regulate and control the activities of the complement cascade, such that complement proteins remain in check and do not lead to unnecessary activity. When there is a deficiency of C1-INH due to one of the previously mentioned causes, then the complement cascade remains continuously activated and can lead to potentially life-threatening swelling. == Clinical Presentation ==

Acquired angioedema presents as mucosal swelling on external and/or internal surfaces of the body. Typical areas of swelling include the face, arms, and legs, while internally some individuals have swelling of the tongue and upper airways. In contrast to hereditary angioedema, there tend to be fewer symptoms of the abdomen or gastrointestinal tract, but symptoms of nausea, vomiting, and diarrhea have been seen in acquired angioedema. Although this condition appears similar to other skin conditions in which swelling occurs, acquired angioedema does not lead to itchy skin (pruritus) or hives (urticaria). == Diagnosis ==

Acquired angioedema is diagnosed through a supportive clinical examination usually in addition to laboratory evaluation. Using the diagnostic approach mentioned here and in the figure shown above, acquired angioedema is categorized into subtypes for targeted management. The following subtypes include AAE-I, AAE-II, sex-hormone dependent AAE, and drug-induced AAE. == Management ==

Treatment of acquired angioedema is separated into two main parts. First controlling acute symptoms during angioedema attacks is crucial for preventing and lowering the risk of mortality. In life-threatening situations, including cases of oral and pharyngeal swelling, it is important to manage these symptoms and to protect the airways to lower the risk of mortality. Typical treatments for anaphylaxis and allergic reactions, such as epinephrine, corticosteroids, and antihistamines, are often used in acute cases of AAE with variable resolution. C1-INH concentrates are available in intravenous (IV) and intramuscular (IM) methods of delivery. C1-INH concentrate therapy has shown considerable efficacy (or effect) in acute and prophylactic treatments of hereditary angioedema but has varying levels of efficacy in AAE. For prophylaxis, clinicians focus on controlling underlying disorders, such as those mentioned under causes, that could be contributing to AAE pathophysiology. Beyond controlling comorbidities, angioedema is usually managed through medications to prevent attacks and to reduce the number of attacks. C1-INH concentrate can be used to replace deficient or abnormal C1-INH enzyme with considerable efficacy. The following list of medical therapies have been used for prophylaxis, including androgens, tranexamic acid, and monoclonal antibody such as rituximab. These agents all have varying roles, efficacy, and potential risks through their use. == Prognosis ==

The evaluation of acquired angioedema usually prompts an investigation into the underlying cause. As mentioned in the causes section, malignancy or autoimmune disorders are the more common causes, which must be further explored and considered for treatment if found in an individual. Prognosis depends on the underlying disorder, which may be found at the time of initial diagnosis or through ongoing monitoring. Additionally, successful treatment of the underlying disorder has been observed in some cases to resolve acquired angioedema from partial to complete remission. == See also ==