“When you hear hoofbeats, think horses not zebras” — Dr. Theodore Woodward
For the dental practitioner encountering a patient with a complaint of orofacial edema (swelling) following dental treatment, several routine possibilities come to mind. Common things being common, the differential diagnosis is often rightly limited to the most likely suspects of trauma, infection, or allergy.As Dr. Woodward intones, the laws of probability suggest that it is prudent to consider these familiar issues first. However, rare diseases may mimic or present similarly to common diseases, resulting in an apparent “medical mystery”.
Such diagnostic dilemmas can be disconcerting for both the patient and the dentist providing care. The purpose of this article is to provide a basic introduction of two rare medical syndromes, Hereditary Angioedema (HAE) and Acquired Angioedema (AAE), which may present as orofacial swelling following dental treatment. These syndromes are the result of the abnormal function of a classical complement pathway regulatory inhibitor, C1-esterase inhibitor (C1-INH).1 Although generally benign conditions, knowledge of these disorders is of critical importance to the dental community as dental treatment is a known trigger for angioedema episodes. 2 These acute attacks may become life-threatening if the ensuing swelling involves airway structures. Edema of the larynx can progress rapidly to asphyxiation, as evidenced by several case reports of death following tooth extraction. 3
Although awareness of these conditions in the medical and dental communities is poor, the clinical features of C1-esterase inhibitor (C1-INH) disorders have been documented for more than a century. 4 It was not until 1963, however, that the specific biochemical defect was isolated, 5 giving rise to the description of two main syndromes: Hereditary Angioedema (HAE), and the even rarer form of Acquired Angioedema (AAE).6 Although there are multiple classifications and sub-classifications based on the underlying etiology, the manifestations of the C1-INH disorders are clinically indistguishable. 7 Features include relapsing and self-limited episodes of swelling of various body sites, typically the face, intestinal walls, and larynx, leading to transient disfigurement, colicky abdominal pain, and airway obstruction. 8 Edema episodes may occur spontaneously and unexpectedly, with triggering events varying widely among those affected. 2
Epidemiology
HAE is an autosomal dominant disorder associated with a mutation of the C1-inhibitor gene and is therefore presents with a familial history in approximately 75% of cases, the remaining 25% arising from spontaneous mutation.9 This hereditary form most commonly presents within the first two decades of life, beginning at school age or early adolescence.7 Unfortunately, these signs and symptoms may only be recognized retrospectively, as the edema episodes may be attributed to other causes. In contrast, the acquired form typically occurs at an older age and is often associated with an underlying pathology which may include autoimmune disorders and malignancies. 10 The estimated prevalence of HAE has been reported as 1:50,000,11 although it has been suggested this number may be closer to 1:10,00012 due to frequent misdiagnosis and subsequent under-reporting. A recent large clinical review found AAE to be approximately ten times rarer than HAE. 13
Ge neral Pathophysiology
The clinical features of HAE and AAE are due to the absence, decrease, or malfunction of a serum inhibitor in the classical complement cascade known as C1-esterase inhibitor (C1-INH).1 C1-INH prevents excessive complement activation of the inflammatory fluid phase (edema), and its abnormality results in an inability to regulate complement activation. Without this “off switch” there is an unchecked and excessive generation of pro-inflammatory mediators: the acute attacks of edema are therefore believed to be the result of the unopposed downstream activation of vasoactive substances that cause dilatation and increased permeability of capillaries and venules. 7 This loss of vascular integrity allows fluid to move into deeper cutaneous and mucosal tissue spaces, producing the characteristic edema.
While the exact pathophysiology remains incompletely understood, it is important to note that histamine and other mast-cell mediators typical of allergic edema are not involved, accounting for the general ineffectiveness of antihistamines, corticosteroids, and epinephrine in the management of acute attacks. 2 The edema produced in HAE and AAE has been linked to the release of kinins: as a potent inducer of vascular permeability, bradykinin, among other substances, has been implicated in attack generation. 1 Activation of these substances leads to vascular leakage, which accounts for the typical non-puritic, non-urticarious, and non-erythematous edema of HAE and AAE in contrast to the traditional histamine-associated itchy wheal and flare presentation of allergic edema (Table 1).
Risk Assessment
In light of recent data which estimates mortality rates from acute attacks of hereditary angioedema are as high as 13%,1 it is prudent to consider aggressively investigating any angioedema of an unknown etiology that follows dental treatment. Although edema may present minutes to hours following a precipitating event, most swelling occurs 12-24 hours post-operatively with symptom-free periods from 1-48 hours. 3 Swelling may first appear subtle, usually asymmetrical and localized to only a small area, for example, the lip, with progression to diffuse bilateral edema over the span of several hours (Fig. 1). Additionally, signs and symptoms may not be limited to the oral area: a history of intraabdominal swelling and peripheral edema in the absence or in addition to orofacial swelling may also suggest a diagnosis of HAE or AAE. 14 Oral surgical procedures carry a known risk, 2,3,15 although even minor or “non-invasive” procedures, such as intraoral impressions16 and oral radiologic procedures15 may be triggers, depending on the individual’s propensity for attacks. Additional triggers relevant to the dental environment include oral trauma, oral infectious diseases, psychological stress or excitement, exposure to cold and prolonged sitting or standing. 1,3 Although previous dental treatment may have occurred without an overt attack, this suggests but does not guarantee dental treatment in future will not precipitate a life-threatening edema episode.3 Conversely, some patients with serum markers for C1-INH deficiency may never experience angioedma. 7 A diagnosis of HAE or AAE should be considered if trauma, infection, and allergy are ruled to be unlikely, especially if there is a history of similar previous episodes.
If an edema attack following dental treatment due to HAE or AAE is suspected, airway assessment is essential and prompt referral to a medical centre is prudent for continued monitoring and supportive care, such as early intubation or tracheostomy in the case of airway compromise. 17 Although most attacks spontaneously resolve within 72 hours, 8 severe or prolonged attacks may require the use of specific intravenous therapies such as C1-esterase inhibitor replacement, antithrombolytics (tranexamic acid), plasma products (fresh frozen plasma), and attenuated androgens (danazol).12 Following an acute episode, patients with suspected HAE or AAE should be referred for blood tests which screen for characteristic surface antigens in order to facilitate diagnosis. 2
Screening From Patient History
Due to the routine nature of dental care and standard preoperative medical history, dentists have an excellent opportunity to screen patients and promote awareness within the hea
lthcare community, as well as the ability to intervene with potentially lifesaving diagnosis and treatment. Clinical features that distinguish angioedema due to C1-esterase inhibitor deficiency from general- ized edema due to cardiovascular, renal, and liver disease include 1) relatively rapid onset from minutes to hours, 2) asymmetric distribution, 3) non-gravity dependent distribution, and 4) involvement of the lips, larynx, and bowel. Established guidelines exist which recommend referral for laboratory diagnostic screening for suspected HAE or AAE based on patient history1,2 (Table 2). These patients may present with a preoperative medical history of extensive GI investigations without definitive diagnosis, vague diagnoses (i. e. irritable bowel syndrome), or possibly emergent operative procedures (i. e. surgical resection for ischemic bowel) due to frequent presentations of severe abdominal pain. 18 Finally, dental treatment providers should consider asking all patients if they have a history of skin swelling as part of their routine preoperative medical history. 3
Recognition and appropriate treatment for both HAE and AAE remains an ongoing challenge within the healthcare community.7 This article is presented from the perspective of the complaint of orofacial edema of unknown etiology following dental treatment. It does not include the general management of patients with existing HAE or AAE, who may require short-term pharmacological prophylaxis2 before dental treatment or additional investigations due to chronic use of long-term prophylactic medications before undergoing routine dental treatment. 19 Swelling in the orofacial area is not limited to HAE or AAE, but can also include other rare causes such as lymphadema, hypothyroidism, autoimmune disorders, and drug-induced angioedema from ACEinhibitors or angiotensin-II receptor blockers. 1
Although smartly stated, the emphasis of Dr. Woodward’s axiom regarding “common disorders” should not lull us into a false sense of security, for when zebras run, they too make hoofbeats. Basic knowledge of atypical causes of common clinical presentations is important for all dentists to render the best patient care possible.
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Dr. Carilynne Yarascavitch is a graduate of the Masters in Dental Anaesthesia Program at the University of Toronto and is a clinical instructor at the Paediatric Anaesthesia Surgicentre at the Faculty of Dentistry. She maintains a part-time general practice in St. Catharines, Ontario and may be reached at 905-935-4066 or c.yarascavitch@dentistry.utoronto.ca.Dr. Yarascavitch became interested in raising awareness in the dental community on this topic after her mother was diagnosed with HAE in 2006.
Oral Health welcomes this original article.
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Acute attacks may become life threatening if the ensuing swelling involves airway structures
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Edema of the larynx can progress rapidly to asphyxiation
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A diagnosis of HAE or AAE should be considered if trauma, infection, and alergy are ruled to be unlikely
