An Integrative Medicine Approach to Angioedema

Experiencing swelling of the face, lips, tongue, or airway can be a very scary experience, especially when you have angioedema. This condition causes swelling in the tissues beneath the inner layer of your skin (dermis) or the layer below a mucous membrane as liquid leaks out from small blood vessels. 

Around 20% to 25% of people in the U.S. experience at least one episode of angioedema and/or hives during their lives. Overall, women are more commonly impacted by angioedema than men. An estimated 1 out of 50,000 people have the hereditary form of angioedema. 

This swelling can be difficult to live with and is conventionally managed with medications like steroids, epinephrine, and targeted therapies (depending on the cause). An integrative functional medicine approach can be used to evaluate some of the underlying factors contributing to angioedema in order to help manage triggering episodes. A personalized approach incorporating nutrition, lifestyle, and targeted supplementation can improve quality of life and help bring the body back into balance. 

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What is Angioedema?

Angioedema occurs when a trigger causes a reaction that leads to fluid leaking rapidly out of small blood vessels. This fluid fills the tissues beneath the inner layer of skin (dermis) or below a mucous membrane, causing swelling. 

The non-pitting, asymmetric swelling that occurs in angioedema can happen in any part of the body but most commonly impacts the face, lips, tongue, larynx, genitalia, and extremities. When the airway is impacted, it can cause a life-threatening medical emergency that requires urgent intervention. 

In addition to non-pitting swelling in the skin, other symptoms of angioedema include redness of the skin tone and a burning sensation. There is usually no itching and no lesions that weep or blister (in contrast to acute eczema). 

In hereditary forms of angioedema, swelling can also occur within the gastrointestinal tract, causing severe abdominal pain, nausea, vomiting, and diarrhea. 

There are several classes of common triggers of angioedema. The most common triggers for angioedema are allergic reactions and ACE inhibitor medications (ACEIs) that are usually used to manage high blood pressure or heart issues or non-steroidal anti-inflammatory agents (NSAIDs) like ibuprofen and naproxen. 

When angioedema occurs due to an allergic trigger such as food (especially fish, shellfish, tree nuts, peanuts), medications, latex, and insect stings, the swelling typically begins within a few minutes of exposure and may be accompanied by hives (urticaria), diarrhea, coughing, wheezing, conjunctivitis (eye redness), and nasal inflammation (rhinitis). 

Your immune system has cells, known as mast cells, in the skin and other organs that degranulate and release mediator chemicals, including histamine, when triggered. Allergic angioedema occurs due to direct activation and degradation of these mast cells that occurs when allergens bind and cross-link high-affinity IgE receptors. This causes the release of inflammatory mediators, including histamine, into the dermis, triggering the leaking of fluid from blood vessels. 

Vibratory angioedema is swelling that occurs when exposed to repeated vibrations. This can occur with activities like riding a motorcycle, running, jogging, vigorous massage, or other activities.

Unlike allergic angioedema, non-allergic angioedema (including hereditary angioedema, acquired angioedema, and angioedema associated with medications) involves an increase in bradykinin and complement-derived mediators that cause fluid to leak out from the blood vessels, similarly leading to localized skin swelling. 

Acquired angioedema or acquired C1 inhibitor deficiency can occur as a paraneoplastic disorder associated with lymphatic malignancies or due to an autoimmune condition where antibodies are produced to C1 esterase inhibitor (C1-INH). This protease inhibitor normally helps to regulate and inhibit a part of your immune system known as the complement system. The complement system is a group of almost 60 proteins in the blood and on the surface of some cells that work with your immune system to remove foreign substances and protect you from infections. 

There are also hereditary forms of angioedema (HAE). Types I and II HAE occur due to autosomal dominantly-transmitted heterogeneous mutations of the C1-INH gene, causing a missing or dysfunctional product. This results in characteristically low C4 levels and bradykinin accumulation that causes angioedema. In hereditary angioedema, swelling may come on spontaneously or be triggered by trauma or stress.

Importance of Lab Testing in Integrative Medicine for Angioedema

A detailed medical history exploring triggers and accompanying symptoms can help pinpoint the type and cause(s) of angioedema in order to guide personalized management for swelling. In addition, functional medicine laboratory testing can help uncover underlying factors contributing to angioedema. 

Allergy Testing 

Since food allergies are a common cause of IgE-mediated reactions that can lead to angioedema, testing for food allergies and sensitivities can help with identifying triggers. Precision Point's P88 Dietary Antigen Test can be used to evaluate IgE, IgG, IgG4, and C3d reactions to 88 of the most common foods to identify food allergies and sensitivities.

Environmental allergies can also be evaluated.

For a comprehensive look at various allergens, the LRA Basic 144 Panel offers comprehensive food and environmental sensitivity testing to detect delayed hypersensitivities to commonly consumed foods, environmental chemicals, additives and preservatives, molds, and color additives.

Complement Testing

Measuring levels of complement factor 4 (C4) can help to distinguish between different types of angioedema. Low levels of C4 level can be seen with acquired angioedema and types I and II hereditary angioedema. To then distinguish between these causes of angioedema, a CI INH level and function can be measured, which will typically be <30% of normal in type 1 hereditary angioedema and acquired angioedema. If the C1q level is also low, this suggests acquired angioedema as the cause.

Comprehensive Stool Test

Comprehensive stool testing can help provide an evaluation of some of the common underlying contributors of inflammation that may make the body more reactive and sensitive to allergens and histamine. The GI-MAP with Zonulin from Diagnostic Solutions provides insights into microbial imbalances, inflammation, digestion, immune function, and zonulin, a marker associated with a leaky gut.

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Conventional Treatments for Angioedema

Conventionally, angioedema is managed with various approaches depending on the cause. Various medications for swelling are used to manage angioedema as well as address angioedema complications. It is important to remove any identified triggers and be sure that the airway is properly maintained if tongue or laryngeal swelling is occurring. 

For allergic angioedema, antihistamines, oral corticosteroids, and injectable epinephrine are used to calm the reaction. Antihistamines, often in high doses, are standard management for allergic angioedema in the acute phase and are also used prophylactically. In more severe cases, or if the airway is at risk of being threatened, a short course of oral steroids and epinephrine may be needed. 

There are medications available to help manage episodes of HAE as well as to address acute HAE angioedema. Traditionally, compounded androgens, like danazol and stanozolol, or antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, were used for HAE prophylaxis. Newer options have been introduced with fewer side effects, including plasma-derived C1 INH concentrate and plasma kallikrein inhibitor.

Integrative Medicine Perspective on Angioedema

While acute episodes of angioedema often require urgent medical intervention, a holistic approach to angioedema looks at the whole person and individualizes a plan of care to reduce triggers and help manage future episodes of angioedema. Diet, supplementation, and integrative therapies can be used to reduce exposure to triggers and improve mild symptoms. 

Dietary Insights to Reduce Angioedema

Reducing inflammation throughout the body can help reduce reactivity and the chance for angioedema to develop. Especially with allergic angioedema, a nutrient-dense anti-inflammatory diet that eliminates all foods to which you are allergic and/or sensitive, as well as high-histamine foods, helps to remove triggers. 

Exclude dietary triggers of swelling that can contribute to inflammation like high-fat red and processed meats, ultra-processed foods, refined grains, sugary foods and beverages, and alcohol to help support gut health and reduce overall inflammation while instead focusing on low-histamine fruits, vegetables, whole grains, legumes, herbs, and spices. 

Stress and Angioedema

Emotional stress and anxiety are common triggers and aggravators of angioedema episodes. Studies show that when people with angioedema experience stress, levels of bradykinin increase, which may increase disease severity. 

Incorporating meaningful stress management and mind-body practices helps you relax and cope with daily life stressors to avoid triggering swelling episodes. Regularly practicing techniques like yoga, tai chi, prayer, breathwork, and time in nature can help you minimize the impacts of chronic stress. 

Natural and Alternative Treatments to Reduce Angioedema

An integrative approach incorporates natural treatments and complementary therapies for skin issues like angioedema. Herbal remedies can help to reduce allergic reactions and the impacts of histamine, and an individualized supplementation regimen can help to restore deficient nutrient levels, support gut health, and work synergistically with an anti-inflammatory diet to balance inflammation. 

Plants, herbs, vitamins, and nutrients like vitamin C, DAO, goldenseal, licorice root, quercetin, and probiotics support the body in managing inflammation and histamine levels. 

For example, vitamin C can help to support DAO levels to aid in the breakdown of histamine. To avoid further triggering mast cells, opt for vitamin C, which is produced without fermentation. Oral supplementation with diamine oxidase (DAO) can also be used before meals to support the breakdown of histamine in the gut and help manage histamine-related symptoms.

Goldenseal (Hydrastis canadensis) is a plant that may help address many of the symptoms of allergic reactions and histamine overwhelm, including stomach pain, diarrhea, and reduced appetite. It is important to discuss if this supplement is appropriate for you with your doctor since goldenseal interacts with several medications, including blood thinners and cyclosporine, and may also lower blood sugar. 

Licorice root (Glycyrrhiza glabra) is another natural remedy that may help reduce inflammation involved with allergic reactions and support the immune system. Licorice should not be used if you have high blood pressure, erectile dysfunction, edema, heart failure, hormone-sensitive cancers (such as breast, prostate, ovarian, or uterine cancer), diabetes, kidney disease, liver disease, low potassium, or if you are taking corticosteroids.

Quercetin is a polyphenol flavonoid that may help inhibit histamine production and pro-inflammatory mediators to help manage allergic reactions. It can help to stabilize the membranes of mast cells and reduce the release of histamine to help manage allergic angioedema. ‍

The microbes in your gut play important roles in modulating inflammation, allergies, and reactivity and in breaking down histamine. Therefore, bringing greater balance to the gut microbiome can help manage inflammation and swelling. Targeted supplementation with probiotics can be guided by functional medicine testing and focused on strains such as Bifidobacterium adolescentis, Bacteroides thetaiotaomicron, Bacteroides fragilis, and Lactobacillus rhamnosus that may help break down histamine and manage allergic reactions.

Other natural remedies for angioedema include acupuncture and homeopathy. 

In Traditional Chinese Medicine, angioedema is classified as Feng Zhen, characterized by wind heat with liver, kidney, and spleen deficiency. Acupuncture alone or in combination with cupping has been shown to help manage allergic histamine reactions, such as angioedema and hives, by rebalancing the body and managing allergic reactivity. 

Apis mellifica is a homeopathic remedy that is traditionally used for angioedema, hives, and other allergic reactions. It has been studied to help manage recurrent cases of angioedema and manage allergic reactions and swelling.

Future Research in Integrative Medicine for Angioedema

While current treatments aim to manage episodes of swelling and improve the quality of life for people with angioedema, the condition can be difficult to live with and cause a lot of distress and disability. Therefore, new treatments and research are ongoing to look for innovative ways to address this condition. 

As more is learned about the genetics behind various forms of HAE, multiple new therapies are being investigated to target C1 esterase inhibitor deficiency. New approaches to drug delivery, such as subcutaneous C1 esterase inhibitor concentrates and continuous pumps to deliver preventive medications, offer promise for managing swelling episodes in those with this condition. 

In addition, as the understanding of genetic forms of angioedema evolves, medications targeting kallikrein have been developed. The kallikrein-kinin, or bradykinin-forming pathway, plays key roles in vasodilation, blood coagulation, and fibrinolysis. Type I and II HAE are primarily caused by the overproduction of bradykinin due to genetic mutations that lead to C1INH dysfunction or deficiency. Type III HAE, or hereditary angioedema with normal C1INH, is thought to be caused by excessive bradykinin formation with defective endothelial cells. Emerging treatment strategies target this physiology with monoclonal antibody inhibitors of kallikrein, oral kallikrein inhibitors, RNA-targeted antisense against pre-kallikrein, and gene therapy.

This condition can be very stressful to live with and is, in turn, triggered by emotional stress. During stress, cortisol is secreted, which impacts immune responses in a way that may increase bradykinin, potentially increasing the risk of angioedema episodes. Yoga and other mindfulness practices can inhibit the paraventricular nuclei of the hypothalamus to reduce ACTH production from the anterior pituitary gland. In turn, this may reduce cortisol secretion from the adrenal glands. 

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Summary

Angioedema causes swelling in the dermis below the surface of the skin that can impact any part of the body, including the face, tongue, and airway. Since it can cause debilitating and even life-threatening impacts, a comprehensive, patient-centered integrative approach to angioedema can complement conventional approaches to care and individualize a management plan to each person’s needs. 

Angioedema commonly occurs due to an allergic reaction to a food, insect sting, or latex that causes mast cells to degranulate and release histamine, making blood vessels leak into the skin. It can also occur due to a reaction to ACEI or NSAID medications or as part of a paraneoplastic syndrome. More rarely, angioedema is due to a hereditary mutation in genes impacting the complement system that impacts immune system functioning. 

While acute intervention is often needed with severe angioedema or swelling that threatens the airway, in many cases, a functional and integrative approach can evaluate underlying factors that may contribute to this swelling in order to improve quality of life. Diet, supplements, and integrative therapies can help manage episodes of swelling and bring the body into better balance.