Case Description. The authors reviewed the literature, focusing on the pathogenesis, clinical signs and treatment of HAE. They also provided case reports of four patients who died from laryngeal edema induced by tooth extraction. In patients with HAE, dental surgery—including tooth extraction—may be followed by self-limiting edema episodes, including lip swelling, facial swelling, tongue edema and laryngeal edema with upper airway obstruction. Preoperative prophylaxis has been performed with attenuated androgens, fresh frozen plasma, C1NH concentrate and antifibrinolytics. The four patients described underwent tooth extraction, which, after a symptom-free latency of four to 30 hours, provoked laryngeal edema. Three of the patients died of asphyxiation the night after surgery, and the fourth died on the second night. In three of the patients, laryngeal edema had not occurred previously.

Clinical Implications. Before undergoing dental surgery, patients with a history of recurrent angioedema should be evaluated for C1NH deficiency. If it is present, they are at risk of developing life-threatening laryngeal edema.

Patients with hereditary angioedema due to C1 inhibitor deficiency may develop facial swelling, life-threatening laryngeal edema and other symptoms after dental surgery.

	HEREDITARY ANGIOEDEMA DUE TO C1 INHIBITOR DEFICIENCY

TOP ABSTRACT HEREDITARY ANGIOEDEMA DUE TO... CASE REPORTS DISCUSSION CONCLUSIONS REFERENCES

 
Pathophysiology. HAE first was described clinically by Quincke³ and Osler.⁴ Classical HAE is a well-defined autosomal dominant disease caused by an inherited deficiency of functional C1NH. Donaldson and Evans⁵ discovered the underlying defect in 1963. The defective C1NH gene produces either no C1NH (HAE type I) or a dysfunctional C1NH (HAE type II). In HAE type I, which represents 85 percent of patients, plasma levels of C1NH are 5% to 30 percent of normal values; in HAE type II, plasma levels of C1NH are normal or elevated. The two forms are clinically indistinguishable.

C1NH is a member of the protein superfamily of serine protease inhibitors, or serpins, and C1NH protein gene is assigned to chromosome 11 in the subregion q11.2-q13. More than 100 different C1NH gene mutations have been described in HAE, including missense and nonsense mutations, large deletions, and frameshift and splice-site mutations.^6,7 The exact pathomechanism of angioedema development is not completely clear. The low C1NH concentration activates the kallikrein-kinin system, the early part of the classical complement pathway and even the fibrinolytic system, with the release of vasoactive peptides such as bradykinin considered to be most important (Figure 1). Another type of HAE that is not associated with C1NH deficiency and that has been observed only in females recently was described and named HAE type III.⁸ Two other families with this disease also have been reported.^9,10

View larger version (21K): [in this window] [in a new window]   Figure 1. Plasma kinin-forming cascade, indicating the steps inhibitable by C1 inhibitor, or C1NH. Evidence strongly suggests that bradykinin is involved in the development of symptoms in patients with hereditary angioedema due to C1NH deficiency. Bradykinin is generated from high-molecular-weight kininogen by kallikrein; the activation of prekallikrein to kallikrein is mediated by activated factor XII.

Clinical symptoms. Classical HAE due to C1NH deficiency is clinically characterized by relapsing, self-limiting edema episodes at various body sites—most often the subcutaneous tissue, wall of the intestine and larynx. The recurrent edema attacks appear as

– skin swelling, most frequently affecting the lips, face (Figure 2), hands and feet; urticaria is not a clinical symptom;

– abdominal pain attacks with or without nausea, vomiting and ascites;

– episodes of upper airway obstruction.

View larger version (119K): [in this window] [in a new window]   Figure 2. Typical facial swelling in a patient with hereditary angioedema due to C1 inhibitor deficiency.

All edema episodes are self-limiting, last for one to seven days and are followed by a disease-free interval. The frequency and severity of the clinical symptoms are highly variable from patient to patient and even in the same patient. Most of these edema episodes occur spontaneously, without a recognizable external trigger; patients do not know when the next swelling will occur, which organ will be affected or how severe the clinical symptoms will be.

Factors provoking edema episodes. In HAE due to C1NH deficiency, most edema episodes occur spontaneously and unexpectedly. Some swelling, however, is provoked by triggers such as infectious diseases, drug treatment, psychological stress and local trauma occurring after dental surgery and general anesthesia.

In several case reports of patients with HAE due to C1NH deficiency, it was found that dental surgery may provoke episodes of angioedema.^15–22 Dental surgery may be followed by lip swelling, facial swelling, tongue edema and laryngeal edema with upper airway obstruction (that is, laryngeal edema without associated facial swelling). Lip swelling may progress to facial swelling, and facial swelling may progress to laryngeal edema. Several cases of primary or secondary—with or without lip or facial swelling—laryngeal edema after dental surgery have been reported.^16,20–22 Even abdominal swelling and peripheral angioedema secondary to tooth extraction have been reported.^19,21

In patients with HAE type I and type II, not all dental surgery procedures, including tooth extraction, are followed by an edema episode.¹⁹ Systematic studies on how often angioedema attacks subsequent to dental surgery occur in those patients are lacking.

Diagnosing HAE. Diagnosis of HAE type I or type II is based on the occurrence of typical clinical symptoms (mostly skin swelling and abdominal pain attacks), positive family history (though spontaneous mutations with negative family history may occur) and laboratory findings (low C1NH concentration and function in HAE type I and normal or even increased C1NH protein levels in plasma and low C1NH function in HAE type II). Differential diagnosis of laryngeal edema and skin swelling includes allergic or nonallergic adverse drug reactions secondary to local anesthetics (not recurrent, no change of affected body sites, latency between exposure and clinical signs usually of a short duration) and other types of recurrent angioedema (Box). Lip or facial swelling also are clinical symptoms of Melkersson-Rosenthal syndrome; if the disease is full-blown, lip swelling (cheilitis glandularis) and facial swelling are permanent. In the early stage of the disease, however, the symptoms may be transitory and recurrent and might be confused with recurrent angioedema. Lip swelling in cheilitis glandularis is not recurrent and no other body sites are affected.^23,24

Treatment of acute edema episodes in HAE due to C1NH deficiency. C1NH concentrate is effective in preventing and treating acute attacks of HAE including laryngeal edema.^25–29 It is rapidly effective in laryngeal edema,²⁹ usually acting within 30 to 60 minutes, and it is effective in treating abdominal pain attacks and skin angioedema. The available preparations are virus-inactivated concentrates from pooled human plasma. Transmissions of infectious agents have not been reported since the introduction of viral inactivation steps. The concentrate is expensive, however, and is not available in some countries, including the United States. Fresh frozen plasma, or FFP, which is available in the United States, also is effective and can be used if C1NH concentrate is not obtainable. FFP, however, has a number of adverse effects, including urticaria, anaphylactic shock and hemolysis, and it can transmit infectious agents as it is not virally inactivated. Depending on the state of respiratory distress, using further emergency measures, such as intubation or cricothyrotomy, may become necessary to keep the upper airways open. Corticosteroids and antihistamines are not effective.

Long-term prophylaxis. Long-term prophylactic treatment may be performed with attenuated androgens, tranexamic acid and C1NH concentrate. Attenuated androgens such as danazol or stanozolol reduce the number of HAE attacks considerably.^13,30,31 However, a number of side effects, which include weight gain, menstrual irregularities or virilization in women, and arterial hypertension, may limit their use.^32,33 Recently, hepatocellular adenoma and liver cell carcinoma have been reported in patients with HAE who were taking danazol.^34–37 Therefore, despite the proven efficacy in preventing HAE attacks, treatment with attenuated androgens cannot be recommended routinely to all patients.

Antifibrinolytic agents also may be used for continuous prophylactic treatment of HAE. For example, -aminocaproic acid is effective but has various side effects such as thrombosis. Tranexamic acid can be used instead, but its efficacy is lower than that of androgens.³¹ Furthermore, antifibrinolytic agents have the risk of causing thromboembolic events. C1NH concentrate also has been found to be effective in long-term prophylaxis of HAE.³⁸ The listed risks limit the use of these drugs as lifelong prophylactic standard treatment.

Identifying patients at risk of experiencing angioedema attacks. Before performing dental surgery, dentists should ask patients about their history of skin swelling. If angioedema episodes occurred, patients should be asked whether they have been diagnosed with HAE due to C1NH deficiency. If patients report skin swelling with or without a positive family history and the type of their angioedema disease is not known and had not been classified, an allergist should perform an evaluation before surgery.

Before performing dental surgery, dentists should ask patients about their history of skin swelling.

Dentists should inform patients with known HAE due to C1NH deficiency that dental surgery might trigger edema episodes, including laryngeal edema. They should be informed that these edemas may occur directly after the dental procedure or after a symptom-free interval lasting from one hour to one or two days.

Prophylaxis before dental surgery in patients with HAE due to C1NH deficiency. Since there is a risk of developing angioedema and possibly experiencing life-threatening attacks, using preoperative treatment to lower the risks has been attempted. Available information, however, is limited to case reports or small patient studies. Further, as mentioned previously, even without preoperative prophylaxis only some patients with HAE have edema attacks after dental surgery. Patients who undergo dental surgery more than once may develop edema episodes after one or more tooth extractions but not after others. Therefore, it is difficult to assess the efficacy of the regimen recommended for edema prophylaxis until studies with larger numbers of patients are available.

Preoperative prophylaxis before dental surgery has been performed with FFP, antifibrinolytics, attenuated androgens and C1NH concentrate. FFP has been used in a number of patients for prophylaxis before dental surgery.^{16,19,39–42} In some patients, edema attacks occurred despite pretreatment with FFP.^16,19,42 Antifibrinolytics such as -aminocaproic acid⁴³ and tranexamic acid^44,45 also have been used for preoperative prophylaxis in some patients. Since tranexamic acid is less effective in long-term prophylactic treatment of HAE, typical prophylactic treatment for dental surgery focuses on attenuated androgens and C1NH concentrate. In patients with known HAE due to C1NH deficiency, prophylaxis for dental surgery with attenuated androgens has been shown to be effective in many patients,^18,19,21 though some patients have developed swelling.^16,46

C1NH concentrate has been used for prophylaxis in only a few patients.⁴⁷ Since the risk of experiencing angioedema attacks secondary to dental surgery cannot be avoided completely by preoperative prophylaxis, it is important to inform the patient about the possibility that an angioedema attack might occur, about the clinical symptoms of laryngeal edema and about what to do in case a laryngeal edema occurs (inject C1NH concentrate if available, calling an emergency physician or ambulance or both).

	CASE REPORTS

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We report on four patients with HAE who died from laryngeal edema occurring four to 30 hours after a tooth extraction. The patients were treated in different dental offices.

Case 1. A 30-year-old woman had experienced recurrent skin swelling, relapsing abdominal pain attacks and laryngeal edema since she was 11 years old. When she was 25 years old, C1NH deficiency was confirmed (plasma C1NH concentration 1.2 milligram per deciliter; normal range, or nr, 15 to 35 mg/dL; C1NH function 6 percent, nr 70 to 130 percent; C4 4 mg/dL, nr 20 to 50 mg/dL), and she was diagnosed with HAE. Her two sons, aged 18 months and four years, both were confirmed as having C1NH deficiency; her mother and sister also had recurrent skin swelling, abdominal attacks and plasma C1NH deficiency. Thirty hours after a tooth extraction performed under local anesthesia (lidocaine and epinephrine), the patient began to feel a lump in her throat (at 6 p.m.). Shortly after midnight, she awoke with a feeling of tightness in her throat and a deep voice. Because of increasing dyspnea, the emergency physician was called and the increasing dyspnea suggested to him an allergic glottic edema. This assumption led him to treat the patient with intravenous steroids and antihistamines. Use of ventilation via mask and oxygen therapy also was unsuccessful. The progressing dyspnea led to the referral of the patient to the hospital, where she died of asphyxiation at 5 a.m.

In all four patients, the symptoms of laryngeal edema began when they had returned home from the dentist.

Case 2. A 27-year-old woman had experienced recurrent skin swelling of the face and extremities and recurrent abdominal colic pain attacks since she was 10 years old. She did not have a history of laryngeal edema, but four hours after a tooth extraction she developed lip swelling that spread to the tongue after a further four hours. The patient awoke at 3 a.m. with swollen lips, tongue and throat; severe dyspnea; and a hoarse voice. Intubation by the emergency physician was unsuccessful due to massive swelling, and the patient died of asphyxiation at 3:30 a.m. The diagnosis of HAE had not been established, though two other family members had been affected by the same symptoms. The mother and son of the patient subsequently were found to have a C1NH deficiency (mother, C1NH concentration 4.0 mg/dL, C1NH function 8 percent and C4 6.2 mg/dL; son, C1NH concentration 4.8 mg/dL, C1NH function 1 percent and C4 6.0 mg/dL).

Case 3. A 46-year-old man had experienced recurrent angioedema of the skin and abdominal colic pain since he was 12 years old; laryngeal edema had never occurred. Three other family members also had these symptoms, including one daughter with HAE type II due to a functional C1NH deficiency (C1NH concentration 42.0 mg/dL, C1NH function 6.2 percent and C4 2.0 mg/dL). Despite his family history, the patient refused to consult a physician. At midnight, seven hours after a tooth extraction was performed under local anesthesia, the patient awoke with a lump in his throat and had difficulty swallowing. Three hours later, his voice became hoarse and then progressed to total loss; he experienced no lip or facial swelling. Around 5 a.m., the patient informed his family of his symptoms of progressive dyspnea and died of asphyxiation approximately 45 minutes later, before the emergency physician arrived.

Case 4. A 32-year-old woman had had recurrent skin swelling and abdominal pain attacks since she was 19 years old, but she had no history of laryngeal edema. Nine hours after a tooth extraction, she developed facial swelling, and seven hours later, at 4 a.m., she died of asphyxiation. The diagnosis of HAE due to C1NH deficiency was not known in the patient at that time; later the diagnosis of HAE type I was established in three other family members with similar symptoms.

	DISCUSSION

TOP ABSTRACT HEREDITARY ANGIOEDEMA DUE TO... CASE REPORTS DISCUSSION CONCLUSIONS REFERENCES

 
Case comments. These cases demonstrate what can occur secondary to dental surgery when the history of recurrent angioedema is not considered seriously, the disease is not recognized, and the upper airway obstruction is not properly treated.

In one patient, the diagnosis of HAE due to C1NH deficiency had been established before her death. The diagnosis was not established in the other patients, and they had no history of laryngeal edema. In all four patients, the symptoms began when they had returned home from the dentist. The interval between tooth extraction and the beginning of the laryngeal edema ranged from four to 30 hours. All of the fatal laryngeal edema episodes occurred at night, and the patients died in the early hours of the morning. None had received C1NH concentrate, which has a rapid effect in laryngeal edema of HAE due to C1NH deficiency.²⁹ An emergency cricothyrotomy, which might have been lifesaving, was not performed.

In 1960, two patients with HAE died from asphyxiation after undergoing dental extractions.⁴⁸ One was a 20-year-old woman who had four teeth extracted. Eleven hours later, she died of asphyxiation. Five years later, her 28-year-old brother died 14 hours after undergoing extraction of a molar. Another patient mentioned by Winnewisser and colleagues⁴⁹ died during the night after dental surgery.

Preventive measures. Patients with HAE, their relatives, the general physician and the dentist need to have a high degree of awareness that a life-threatening laryngeal edema might occur after a symptom-free latency period subsequent to dental surgery. If symptoms of beginning laryngeal edema develop, an emergency physician or ambulance must be called as early as possible. Patients with HAE must be informed sufficiently and prepared for these possible sequelae.

Acute angioedema after dental surgery in patients with other types of recurrent angioedema. Most reports of patients with a previous recurrent angioedema who develop new edema episodes after dental procedures involve patients with HAE due to C1NH deficiency (HAE type I and type II). These patients obviously are at the greatest risk. Angioedema attacks in patients with HAE type III after dental surgery have not been reported.

Another type of recurrent angioedema can occur as a side effect of angiotensin-converting enzyme, or ACE, inhibitors. The benefits of these drugs in the management of hypertension, congestive heart failure and other conditions have led to an increase in their use over the past 10 years. Therefore, ACE inhibitor–induced angioedema also has become frequent. It has been reported that two patients who received ACE inhibitors developed angioedema attacks after dental surgery.^50,51 There are no reports on the risk of dental surgery in patients with other types of recurrent angioedema such as idiopathic angioedema or urticaria-related angioedema.

	CONCLUSIONS

TOP ABSTRACT HEREDITARY ANGIOEDEMA DUE TO... CASE REPORTS DISCUSSION CONCLUSIONS REFERENCES

 
Patients with hereditary angioedema due to C1NH deficiency may develop facial swelling, life-threatening laryngeal edema and other symptoms after dental surgery. The four fatal cases reported in his article demonstrate the risk of dental extraction in patients with this disease. Patients with HAE due to C1NH deficiency who have not been diagnosed are at the greatest risk. Therefore, before performing dental surgery, dentists should ask all patients about previous swelling episodes. Patients with a positive history of angioedema should be examined, and the angioedema should be classified. In HAE due to C1NH deficiency, awareness that laryngeal edema may occur within two days after tooth extraction and after a symptom-free interval must be emphasized, not only to at-risk patients but to their relatives and attending physicians.

View larger version (124K): [in this window] [in a new window]   Dr. Bork is a professor, Universitäts-Hautklinik, Langenbeckstr. 1, 55131 Mainz, Germany, e-mail "bork{at}hautklinik.klinik.uni-mainz.de". Address reprint requests to Dr. Bork.

View larger version (136K): [in this window] [in a new window]   Dr. Barnstedt is a resident, Department of Dermatology, Johannes Gutenberg-University, Mainz, Germany.