Hereditary Angioedema Type I Triggered by Dental Treatment: A Case Report and Review of the Literature

Case report

A 29-year-old male was initially referred to the oral medicine department at Guy's Hospital, London for patch testing to exclude an allergy to dental materials. The patient described an episode of upper lip swelling (Figure 1) with extension towards the cheeks and throat, which commenced the same day following a crown preparation and impressions. The patient reported previous episodes of spontaneous swelling of the hands (precipitated by application of pressure, for example increased grip on the steering wheel) and feet, associated with features of a rash of 3 years' duration (Figure 2). He experienced four previous episodes of facial and genital swelling. Previous therapies trialled included antihistamines and oral corticosteroids, with no improvement documented.

The patient was otherwise fit and well with an allergy to penicillin noted. He did not smoke and rarely consumed alcohol. On initial examination, the hands were visibly swollen. There was no lip swelling. Intraorally, all soft tissues were healthy.

A series of haematological investigations were undertaken including a full blood count, complement C3 and C4, C1-INH function and immunoglobulin E (IgE) level. Eosinophils and IgE levels were within normal range. Complement C4 was 0.02 g/L (reference range 0.1–0.4 g/L) and C1-INH function was <31% (reference range 85–99%). This prompted a referral to the immunology department, where a diagnosis of type 1 HAE was made, possibly due to a de novo mutation. All family members were subsequently screened and found to be negative for the same mutation. Treatment recommended for an acute swelling, particularly affecting the head and neck region, includes a slow intravenous injection of C1-INH 1500 units in a hospital setting. Additionally, subcutaneous icatibant 30 mg (self-administered by the patient to the abdomen) during an acute episode of angioedema was also recommended for this patient. Prophylactic use of attenuated androgen, danazol, was offered.

Discussion

HAE is a rare condition characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Type 1 HAE, an autosomal-dominant disorder, is caused by a deficiency in C1-INH due to a mutation in the SERPING1 gene. This results in low plasma levels of functional and antigenic C1-INH. This differs from type 2 HAE, where antigenic C1-INH levels are in the normal or even high range – it is the production of dysfunctional C1-INH that results in oedemic attacks due to the reduced presence of functional C1-INH.⁵ C1-INH also interferes with the cleavage to C4 as part of the complement pathway, therefore a low C1-INH also results in low C4 levels in the blood, which is an effective screening tool. Patients with low functional C1-INH, C4 levels and antigenic C1-INH are most likely to have type I HAE.⁵ Patients with low functional C1-INH, low C4 levels but with normal or raised antigenic C1-INH are diagnosed with type 2 HAE.⁵ Type 3 is caused by a mutation in the Factor XII gene resulting in normal C1-INH levels, and is associated with women taking therapeutic oestrogen.⁵

C1-INH is responsible for regulating a number of physiological responses. It inhibits the activation and cleavage of prekallikrein to kallikrein by its action on factor XIIa and also directly inhibits activated kallikrein, which is required for the cleavage of high-molecular weight kininogen into bradykinin leading to angioedema.⁵ This process may be initiated from minor tissue injury, such as from dental procedures. Therapeutic approaches target C1-INH by restoring these levels, or by inhibiting the co-products of the pathway. Danazol and stanozolol are attenuated androgens and both work by physically increasing the liver's production of C1-INH.⁶ They belong to a class of anabolic steroids and involve careful tapering regimens, making them more appropriate for administration prophylactically in the long term, but not for acute attacks. Anti-fibrinolytics such as ε-aminocaproic acid and tranexamic acid work by inhibiting plasmin activity, which directly regulates the complement pathway but also prevents the release of further vasoactive proteins, which in turn decreases further tissue inflammation.⁷ Fresh frozen plasma (FFP) transfusions have been used historically to aid increasing the volume of complement components in human plasma. However, due to their associated safety risks including anaphylaxis, viral transmission and transfusion-related lung injury, it appears safer to use C1-INH concentrates.⁸ Advances have also been made in the development of new treatments for HAE. Icatibant is a synthetic protein used to inhibit bradykinin B2 receptors and thus decrease the activity of bradykinin.⁹ It can be self-administered subcutaneously, unlike alternatives such as ecallantide. Ecallantide acts on a different pathway by inhibiting kallikrein; however, due to its potent response and risk of anaphylaxis, it can only be administered subcutaneously by a medical professional.¹⁰

Dental interventions have the ability to trigger an acute episode of angioedema (Table 1). In some situations, these can be fatal with the possibility of death being a conceivable consequence.^4,11,12 The various interventions include: extractions, orthognathic surgery, pulp extirpations, bridge placement, crown preparations, restorations, scaling and intra-oral biopsies.^{4,11,12,13,14,15,16,17,18,18,20,21,22} Time of onset of angioedema following a dental procedure varies between patients, from as quickly as 30 seconds to up to 2 days following treatment; therefore all patients must be informed of the signs and symptoms, and the need to seek urgent care. The gender was often undocumented in the cases described in Table 1, and therefore it was difficult to ascertain whether HAE was more predominant in a particular gender. The age of the patients was also often not documented, but from those where it was included, it ranged from 18 to 63 years. Management strategies used varied widely between studies and included corticosteroids, danazol, subcutaneous epinephrine, antihistamines, intravenous C1-INH and FFP (Table 1).

If a patient is identified as being at risk of angioedema, liaising with the patient's general medical practitioner as well as their immunologist will ensure the best pathway of care. Treatment in a hospital setting with close clinical observation may be necessary. The immunologist will be able to advise on prophylactic management prior to dental interventions to reduce the risk of significant angioedema. Prophylactic regimens quoted in the literature include C1-INH 500 units, 1000 units or 1500 units given before dental treatment.^15,18,21 Bork et al compared patients who received prophylactic C1-INH to patients who did not, and concluded that prophylactic treatment significantly reduces the risk of symptoms following an extraction.¹⁸ Other preventive treatment methods mentioned include the use of FFP, anti-fibrinolytic drugs, such as tranexamic acid, androgen derivatives and anabolic steroids.¹⁷ Jaffe et al showcased that if FFP is transfused one day before surgery it has the potential to raise the levels of C4 and C1-INH.²³

Hormonal influences are also thought to trigger an attack, therefore the use of contraceptives containing oestrogen and hormone replacement therapy is not advised.²⁴ ACE inhibitors have the ability to induce angioedema by blocking the degradation of bradykinin.²⁵

As this case demonstrates, because patients may present undiagnosed, it is important to undertake a complete and thorough medical history enquiring about a history of repeated swellings affecting the face and extremities. Furthermore, oral hygiene instruction, dietary advice and regular visits to a general dental practitioner should be encouraged in patients with a known diagnosis of HAE to prevent the need for future operative dental interventions, which have the potential to trigger an acute attack.

Angioedema versus anaphylaxis

Some signs and symptoms of angioedema and anaphylaxis can overlap; however, it is important to differentiate between the two conditions.

NICE guidelines have outlined three criteria that make a diagnosis of anaphylaxis more likely:²⁷

The diagnosis of anaphylaxis is further strengthened by a known exposure to an allergen including food, medication or venom.

Typically, anaphylaxis is a systemic process whereas angioedema occurs in a localized site. Anaphylaxis can occur with or without angioedema. A sense of impending doom along with urticaria may be present during an anaphylactic attack, while the swellings associated with angioedema tend to be non-pruritic.

However, as we have shown in our literature review, HAE also has the potential to cause an airway swelling leading to airway compromise and death, thus urgent care for either angioedema or anaphylaxis is advised.

Although HAE is a rare phenomenon, it should be included in the differential diagnosis of patients presenting with recurrent episodes of facial swelling. Prompt recognition and effective treatment is critical due to the risk of fatal laryngeal attacks. While dental extractions tend to be the most common dental precipitant, our literature review showed a wide variety of other interventions, including pulp extirpations, bridge placement, crown preparations, restorations, scaling and intra-oral biopsies that have the potential to trigger an episode.