What is Hereditary Angioedema?
Hereditary angioedema (HAE) is a genetic condition that happens when there’s a shortage or abnormal function of a protein called C1-inhibitor. So, instead of referring to this condition as type 1, 2, or 3 HAE, it’s now more accurately called by what causes it. The types include HAE due to a deficiency of C1-inhibitor (type 1), HAE due to a malfunctioning C1-inhibitor (type 2), and HAE where the C1-inhibitor is normal. Even though the ways to diagnose each type are unique, they all have similar symptoms, mainly swelling (angioedema).
The rest of this explanation will focus on type 1 and 2 HAE. The type of HAE that has a normal C1-inhibitor is not part of this discussion because diagnosing it can be complex due to its various types, lack of specific testing methods for most cases, and absence of treatments approved by the Food and Drug Administration (FDA).
What Causes Hereditary Angioedema?
Type I Hereditary Angioedema (HAE), or HAE with deficient C1-inhibitor, is a condition caused by a lack of a specific substance in the body, called the C1 inhibitor. You can think of C1 inhibitor as a type of bodyguard that stops certain enzymes from going out of control in our body.
This C1 inhibitor is part of a larger group of proteins known as the serpin superfamily. It primarily helps to control several other proteins involved in our immune system and blood clotting process. When there’s a shortage of this C1 inhibitor due to some changes or mutations in a gene named SERPING1, it can lead to Type 1 HAE.
Scientists have found more than 150 different kinds of such changes in the SERPING1 gene among patients with HAE. These changes can cause the C1 inhibitor protein to be made in a wrong or incomplete way, and hence it cannot be secreted or released from the cells as needed. This lack of enough C1 Inhibitors results in Type 1 HAE.
In a different version of HAE, called Type 2 (HAE with a dysfunctional C1-inhibitor), mutations in the same SERPING1 gene cause the C1 inhibiting protein to be produced and secreted normally but it doesn’t function as it should. Therefore, in type II HAE, the levels of C1 Inhibitor in the blood can be normal or even higher than normal, but the protein doesn’t do its job properly.
Risk Factors and Frequency for Hereditary Angioedema
Angioedema, a condition that can cause sudden swelling beneath the skin, is estimated to affect 1 in every 50,000 people. It usually shows up in the first 20 years of a person’s life, which is earlier than another type of angioedema that arises due to a deficiency in the C1-inhibitor protein—this typically occurs after the age of 40. If there’s a family history of angioedema, it can guide doctors towards a diagnosis. However, it’s worth noting that 25% of angioedema cases result from new spontaneous mutations, meaning they can occur without a previous family history. After a child’s first birthday, biological tests tend to be quite accurate in diagnosing angioedema, so genetic testing isn’t usually required.
Signs and Symptoms of Hereditary Angioedema
The symptoms of this condition can differ in terms of severity, where they show up, and how long they last. They primarily affect the respiratory system, skin, and digestive system. In the digestive system, blocked bowels can cause discomfort. Skin experiences swelling which can distort its shape and cause discomfort, especially if severe. However, it’s not itchy. The major concern associated with this condition is the swelling of the upper airways, which could potentially cause choking. Thankfully, this only happens in 1 to 3% of cases.
These episodes can last from 2 to 5 days, generally getting worse before they begin to fade away, even without treatment. In about 40% of cases, certain triggers, like injury, infections, stress, or procedures, can be identified. Symptoms like a rash – known as erythema marginatum – occur before the majority of the attacks, but it’s hard to tell how accurately this predicts an incoming attack. Other triggers may include ACE inhibitors and estrogens.
Testing for Hereditary Angioedema
If your doctor suspects Hereditary Angioedema (HAE), a condition which causes swelling in various body parts, they will likely run several tests. The C4 test is commonly done initially as a screening tool. If the results of this test indicate HAE, your doctor will confirm the diagnosis with additional tests: these measure the amount of a protein called C1-inhibitor in your body and how well it’s functioning.
There are three types of HAE distinguished by these tests. In type 1 HAE, both the amount of C1-inhibitor and its function are low. In type 2 HAE, the function is low but there is a normal or even high amount of this protein. However, the protein is defective and doesn’t work as intended. Type 3 HAE is trickier: all the tests return normal results and it seems to be linked with an amplified activity of Factor 12, which plays a role in blood clotting, and possibly other unknown causes. Those cases likely result in swelling due to an overproduction of a substance called bradykinin.
There’s another test, the C1q, usually reserved for late-onset disease to rule out acquired angioedema, a similar condition that is not inherited. This is warranted because in most cases of acquired angioedema with deficient C1-inhibitor, C1q levels are low, but in HAE they are not.
In these cases, swellings result from an overproduction of bradykinin, however, certain medications like Angiotensin-converting enzyme inhibitors (commonly known as ACE inhibitors) can also cause swelling. In these cases, the swelling is due to a decrease in the overall breakdown of bradykinin in the body.
Treatment Options for Hereditary Angioedema
Unlike other forms of swelling, angioedema does not respond to common treatments such as antihistamines, corticosteroids, or adrenaline. Angioedema needs specific medications to reduce the level of a substance, bradykinin, which is the primary cause of swelling. These medications either block production of bradykinin or stop its effects.
There are three main ways to use these medications: to treat a flare-up of angioedema, to prevent a probable flare-up in the short-term, and to prevent flare-ups over the long-term. The types of drugs used for these include ecallantide, icatibant, plasma-derived C1-inhibitor, or a lab-made version of C1-inhibitor. Your doctor might also consider giving you fresh frozen plasma, which includes components your body needs to manage bradykinin, but only if none of the above-mentioned drugs are accessible.
Because ecallantide and icatibant don’t stay active in your body for long, they don’t work well in preventing flare-ups. The C1-inhibitor, either derived from plasma or made in a lab, can replace impaired or deficient C1-inhibitors in the body. Given its longer activity period, it can be used for treating flare-ups & as a short and long-term preventive measure. The lab-made version of C1-inhibitor has similar usefulness.
There are other methods that used to be more common but aren’t favored as much now. This includes the use of antifibrinolytics and androgens. Androgens stimulate the production of C1-inhibitor and are good at preventing attacks but don’t help during an attack. Although effective in the short-term, androgens have limitations for long-term use due to their side effects which include high cholesterol, obesity, masculine traits in females, and mood changes.
The antifibrinolytics tranexamic acid and aminocaproic acid aren’t very effective. Nonetheless, other medications can be used for long term prevention of attacks. These include lanadelumab, berotralstat (both kallakrein inhibitors), and androgens and tranexamic acid (although these are used more sparingly).
Another important part of managing angioedema is avoiding any known triggers, as well as estrogen and ACE-inhibitors, substances known to increase the likelihood of attacks. Treatment plans should include long-term prevention, pre-procedure therapy, a plan to treat flare-ups, and a backup treatment plan. Regular reassessments are crucial to determine the effectiveness of the treatment and to reduce discomfort. Most patients are also taught self-treatment techniques to better manage their condition and improve their quality of life.
What else can Hereditary Angioedema be?
Hereditary angioedema (swelling beneath the skin’s surface) is driven by bradykinin, while other types of angioedema can be driven by histamine or other processes. These different causes of angioedema are managed differently, so it’s important to identify which type is present. Unfortunately, no test can help doctors make a definite distinction between histamine-driven and bradykinin-driven angioedemas. However, each type has different characteristics that can help guide diagnosis and treatment.
Histamine-Mediated Angioedema:
- This type of angioedema, driven by histamine, often comes with hives and itching. Triggers could include viruses, medication, food, and sometimes it might be caused by an autoimmune response.
- Most cases begin rapidly and respond quickly to treatments like antihistamines, adrenaline, or steroids.
- In some instances, the angioedema is resistant to treatment and more aggressive therapies such as omalizumab or cyclosporine are necessary.
- Typically, this type of angioedema doesn’t involve significant abdominal pain. It will usually cause the skin to quickly swell up and then clear up just as fast.
- It can sometimes come with symptoms of a severe allergic reaction known as anaphylaxis.
Bradykinin-Mediated Angioedema:
- This includes hereditary angioedema, acquired angioedema, and angioedema caused by a medicine called an angiotensin-converting enzyme inhibitor.
- It typically doesn’t come with itching or hives.
- This type of angioedema develops more slowly than the histamine-mediated type and can last longer, especially if left untreated. About 50% of cases involve the abdomen.
- Lastly, a key sign of bradykinin-driven angioedema is that it usually doesn’t respond to treatment with adrenaline, antihistamines, and corticosteroids.