What is Angioedema?
Angioedema is a medical condition where you have swelling in the skin or just beneath it. This can affect different parts of the body such as lips, face, neck, and extremities as well as inside the mouth, throat, and gut. It can become life-threatening when it affects the throat, while intestinal angioedema, swelling in the stomach area, can be painful and can seem like a serious stomach problem.
It was first recognized in 1882 by Quincke, and in 1888, Osler described a specific type that can be inherited (hereditary angioedema). In 1963, Donaldson and his team highlighted the role of a certain protein, called C1 inhibitor, in angioedema.
Angioedema can be classified into two major types:
The first type is acquired, which means it develops during your lifetime for various reasons including:
– Allergic reactions, which is called histaminergic angioedema, often associated with severe allergic reactions or anaphylaxis.
– Non-allergic reactions, or non-histaminergic angioedema, which can show up on its own or with a rash called urticaria.
– Drug-induced, caused by certain medicines like angiotensin-converting enzyme inhibitors (a type of blood pressure medication) and non-steroidal anti-inflammatory drugs, which are commonly used painkillers.
– Complement-mediated, which is linked to a shortage of the C1-inhibitor protein.
– Idiopathic, which means the cause is unknown. This can further be grouped into histaminergic and non-histaminergic.
The second type is hereditary, which means you inherit it from your parents. This type involves a deficiency in C1-Inhibitor and can be further classified into:
– Type 1: Here, the body lacks the C1-inhibitor protein.
– Type 2: In this, the C1-inhibitor protein is present but does not work properly.
What Causes Angioedema?
Hereditary angioedema is a condition that you inherit from your parents. It happens because of changes, or mutations, in a specific gene responsible for producing a protein known as C1-inhibitor. These changes are passed down through families in what’s known as an autosomal dominant pattern. This means you only need to get the abnormal gene from one of your parents to inherit the disease.
On the other hand, angioedema can sometimes be acquired due to a variety of factors. This might include conditions where the body produces too many lymph cells (lymphoproliferative disorders), autoimmune conditions where the body attacks its own tissues, cancer (neoplastic), infections, or even as a side effect of certain medications (drug-induced).
Risk Factors and Frequency for Angioedema
According to a past study, angioedema is the second most common reason for hospitalization after asthma in New York State. Among these hospitalizations for angioedema, 42% were African Americans. An inherited version of this condition, hereditary angioedema, is rarer and affects 1 in 50,000 individuals. It has been found to impact females more severely than males, according to a study conducted in Sweden.
- Angioedema is the second most common cause of hospital visits, after asthma, in New York State.
- African Americans make up 42% of these hospital visits due to angioedema.
- There’s a rarer type – hereditary angioedema, which affects 1 out of every 50,000 people.
- A Swedish study revealed that hereditary angioedema affects females more severely than males.
Signs and Symptoms of Angioedema
Angioedema, which is characterized by noticeable swelling under the skin, can be chronic, or it can come on quickly. Symptoms often involve various bodily systems and may include skin reactions, like hives, redness, and itching, respiratory problems like trouble breathing, and gastrointestinal issues like abdominal pain and vomiting. These occur within an hour of exposure to the allergen and can last anywhere from one to two days. This type of angioedema is often caused by drugs, certain foods, latex, or insect stings.
There is also bradykinin-mediated angioedema, which differs from histaminergic angioedema. This type:
- Does not include hives
- Is typically more severe and lasts longer
- Is associated with abdominal symptoms
There is also a type of angioedema that is related to ACE inhibitors. This type often shows up without any hives or itching and is common in African-Americans. This reaction often develops within the first week of being exposed to the ACE inhibitor.
Some other types of angioedema include one that is caused by nonsteroidal anti-inflammatory drugs (NSAIDs), which often results in hives and facial swelling. Another is hereditary angioedema, which typically starts in childhood or young adulthood, worsens at puberty, and results in occurring bouts of swelling or abdominal pain. This type of angioedema can also have noticeable symptoms like a rash. An attack usually peaks within one day and resolves within two to three days.
Another type, acquired angioedema with C1 inhibitor deficiency, presents very similarly to hereditary angioedema, but in this case, the deficiency is often due to an underlying disorder, which results in an overproduction of bradykinin.
If you go to the emergency room with angioedema, you can expect medical professionals to carefully monitor your vital signs and level of consciousness. They will likely also thoroughly examine your skin, head, neck, respiratory system, and abdomen.
- Monitoring of oxygen levels
- Monitoring of heart function
Testing for Angioedema
When you visit the emergency room because of an unexpected swelling in the skin (termed “angioedema”), the first step doctors take is to know more details about any specific medications you’re on, and your family’s health history. In addition, they’ll perform some blood tests to help identify the cause of this swelling.
Two key blood tests they’ll use include tests for ‘C4’ and ‘tryptase.’ Here is why these tests are important:
– C4 test: Helps the doctor detect ‘hereditary angioedema,’ a rare genetic disorder that causes episodes of swelling.
– Tryptase test: Used primarily when a severe allergic reaction (anaphylaxis) is suspected along with swelling. This test is particularly helpful when carried out during an acute swelling episode.
Keep in mind that the tryptase level is usually normal in case of hereditary angioedema one and two but will be increased during an allergic reaction or in other disorders linked with angioedema.
In addition to blood tests, a flexible fiberoptic laryngoscopy (a procedure that allows your doctor to look at your throat) might be done to see if the swelling involves your tongue or voice box, especially if you’re showing symptoms related to the head, neck, or upper airway.
It’s vital for the doctor to clearly distinguish whether the swelling is caused by histamine (a chemical involved in allergic reactions) or bradykinin (a chemical that widens blood vessels). This knowledge can be lifesaving, as these two types of swelling are often treated differently.
If your doctor suspects hereditary angioedema, the blood tests may reveal certain patterns. For instance:
– Hereditary angioedema type 1: The blood test will show low function and levels of ‘C1 inhibitor’ (a protein that helps control inflammation) and a low level of component C4.
– Hereditary angioedema type 2: The test will show low function of ‘C1 inhibitor’ and a low level of C4, but the level of ‘C1 inhibitor’ may be normal or high.
To confirm these conditions, the doctor will likely repeat the blood tests.
In the cases of acquired deficiency of ‘C1 inhibitor’ (a condition that’s not inherited but arises due to the formation of antibodies that deplete ‘C1 inhibitor’), a blood test would show low levels of ‘C1 inhibitor’ and another protein called ‘C1q.’
Treatment Options for Angioedema
Angioedema is a condition that causes swelling beneath the skin. There are different types, and treatment depends on the specific type you have. Two main types are histaminergic angioedema and bradykinin-mediated angioedema.
For histaminergic angioedema, the swelling is often treated with antihistamines, corticosteroids, and a medication called epinephrine. However, bradykinin-mediated angioedema often doesn’t respond to these therapies.
For a type of angioedema that is inherited, known as hereditary angioedema, emergency treatment may involve keeping the airway open with a tube or through surgical intervention. Early treatment is important, and various medications, like a C1 inhibitor concentrate, ecallantide which is a Kallikrein inhibitor, or icatibant, a bradykinin-receptor antagonist might be used. Icatibant is particularly effective and can be used at home.
In cases where high-risk procedures are necessary, short-term prevention or ‘prophylaxis’ might be applied to help protect individuals. For long-term prevention, C1 inhibitor is commonly used first, with androgens as a second option.
For hereditary angioedema that is caused by mutations in a specific gene (F12), treatment involves avoiding triggers like certain medications, using a plasma-derived C1 inhibitor for sudden attacks, and preventing attacks with medications like progestins, tranexamic acid, and danazol.
There’s a type of acquired angioedema related to a medication called an angiotensin-converting enzyme (ACE) inhibitor. Treating this involves using antihistamines, epinephrine, and glucocorticoids, and stopping the use of the ACE inhibitor. It’s crucial that the patient doesn’t use any ACE inhibitors in the future.
For angioedema caused by a deficiency in C1 inhibitors, a majority of cases have no symptoms and respond to a type of treatment called immunochemotherapy. For sudden attacks, icatibant and plasma-derived C1 inhibitor concentrate might be used, and prevention can be achieved with a drug called rituximab, sometimes along with chemotherapy and spleen removal.
In special instances, like during pregnancy, certain treatments are recommended due to their safety for the mother and baby, such as plasma-derived nano-filtered C1-inhibitor, or in emergencies, bradykinin receptor antagonist Icatibant. For children, safe doses are set based on weight, and medications like C1 esterase inhibitor and Icatibant are well-tolerated.
Concurrent use of certain medications should be monitored closely, and in cases of severe allergies that cause difficulty swallowing, liquid steroids might be used. For a rare condition known as idiopathic non-histaminergic acquired angioedema, which is resistant to antihistamines, a drug called omalizumab might be used.
What else can Angioedema be?
There are several conditions that could be mistaken for angioedema due to similarities in symptoms. These include:
- Acute contact dermatitis
- Drug rash with eosinophilia and systemic symptoms
- Dermatomyositis
- Morbus Morbihan disease
- Superior vena cava syndrome
- Hypothyroidism
- Subcutaneous emphysema (air trapped under the skin)
- Orofacial granulomatosis (swelling and sores in the face and mouth)
- Hypocomplementemic urticarial vasculitis syndrome (rash with inflammation of the blood vessels)
- Clarkson’s disease (fluid accumulation causing swelling)
- Gleich’s syndrome (rash, eosinophilia, and swelling)
- Cluster headaches
- Idiopathic edema (unexplained swelling)
Furthermore, sudden onset of isolated swelling can sometimes be mistakenly diagnosed as angioedema, while hereditary angioedema caused by a C1 inhibitor deficiency can be wrongly diagnosed as familial Mediterranean fever, a genetic disorder causing recurring fevers and inflammation.
What to expect with Angioedema
Histaminergic angioedema, a type of swelling caused by an allergic reaction, usually begins within an hour of exposure to the allergen and may last for one to two days.
Hereditary angioedema, an inherited condition that causes occasional swelling, is not very common and is often not diagnosed correctly due to several reasons. One reason is that some patients’ family medical history is unknown. Another reason is that the disease sometimes only affects the digestive system and does not cause swelling on the skin.
For people with type 1 and 2 angioedema related to a deficiency in the C1 inhibitor protein, their symptoms can actually be worse than those in people with an angioedema condition caused by the deficiency in the same protein, but it is acquired and not inherited.
Possible Complications When Diagnosed with Angioedema
Some severe side effects could occur such as the blockage of the airway leading to fatality. Also, there can be a sudden swelling of the larynx, pharynx, and tongue. In some cases, asphyxiation can occur which could result in death. Certain conditions like hereditary angioedema (a genetic disorder that causes episodes of swelling) may also lead to inflammation of the pancreas. Doctors should carefully monitor patients who are on angiotensin-converting enzyme inhibitors and exhibit signs of unstable heart rate after treatment with a protein called the recombinant tissue plasminogen inhibitor.
Severe Side Effects:
- Blockage of the airway leading to death
- Sudden swelling of larynx, pharynx, and tongue
- Death from asphyxiation
- Hereditary angioedema leading to inflammation of the pancreas
- Unstable heart rate in patients on certain medications after receiving recombinant tissue plasminogen inhibitor treatment
Preventing Angioedema
If you have been diagnosed with Hereditary angioedema, learning how to manage your condition can help ease any fears you might have about self-administering injections under your skin, also known as subcutaneous injections.
Every patient will get personal training on how to plan and schedule their injections to ensure effective treatment. If you’re a parent or caregiver, you’ll also receive training on important skills such as:
- Choosing the right location for the injection on the body,
- Maintaining cleanliness to prevent infection (aseptic technique),
- Preparing the needle or syringe for the subsequent step,
- Administering the C1 inhibitor injection under the skin.
In the initial months of your treatment, regular follow-up visits with your healthcare provider will be necessary to monitor your progress and adjust your treatment plan as needed.
We also advise patients keep a record book for their treatment, where they can log any necessary information. This book should also include details about any unexpected episodes or worsening of symptoms from Hereditary angioedema. Timely reporting of these situations can help your doctor manage your condition in the best possible way.
