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Delayed Diagnosis of Hereditary Angioedema
CASE REPORT
Delayed Diagnosis of Hereditary Angioedema Zahida Khan Maskatia, MD and Frank M. Orson, MD
Abstract: Hereditary angioedema (HAE) is a rare and potentially fatal disease that is important to recognize early. It is usually associated with low levels or impaired function of C1 inhibitor, which is involved in several inflammatory pathways. The treatment of HAE is very different from other causes of angioedema, emphasizing the importance of early and accurate diagnosis. The authors report the case of a patient who had symptoms starting in his teens but was not diagnosed until the age of 57 years. They also review the consequences of delayed diagnosis of HAE. Key Indexing Terms: Hereditary angioedema; Diagnosis; C1 inhibitor. [Am J Med Sci 2010;340(1):82–83.]
H
ereditary angioedema (HAE) is a rare autosomal dominant disorder that is characterized by recurrent episodes of painless nonpruritic angioedema, which can affect the subcutaneous tissues (such as the extremities, genitals and buttocks), abdominal organs and upper airway. Typically, symptoms begin in childhood and persist throughout life, but HAE can be fatal if left untreated. Most cases are associated with low levels or impaired function of C1 inhibitor (C1-INH), which is a serine protease inhibitor that affects several inflammatory pathways. Type I HAE, which compromises approximately 85% of cases, is characterized by low levels and reduced functional tests of C1-INH. Type II HAE, on the other hand, is characterized by a dysfunctional inhibitor and is associated with normal or elevated C1-INH protein levels but reduced functional tests of C1-INH.1–3 A third type of HAE has been described as well, which involves normal C1-INH antigen and functional levels. It was originally identified as an estrogen dependent form found only in women, but more recently, it has also been diagnosed in men.4 Some of these patients have a mutation in coagulation factor XII, which may cause increased generation of bradykinin.5 Although typically diagnosed early in life, we report the case of a patient who had symptoms starting in his teens but was not diagnosed until the age of 57 years. We also review the consequences of delayed diagnosis of HAE.
CASE REPORT A 57-year-old man was evaluated in Immunology clinic for angioedema. He had a history of recurrent nonpruritic swelling of his extremities, genitals and neck for as long as he could remember, with each episode lasting about 4 days. He suffered about 4 to 5 episodes a year. He had come to his local emergency department several times in the past decade with complaints related to extremity pain and swelling. More recently, his symptoms had become more frequent and severe, and he required admission to an intensive care unit 2 times in the few months before Immunology evaluation for throat swelling, although he did not require intubation.
From the Baylor College of Medicine (ZKM, FMO), Houston, Texas; and Departments of Medicine and Immunology (FMO), Veterans Affairs Medical Center, Houston, Texas. Submitted December 14, 2009; accepted in revised form March 19, 2010. Correspondence: Zahida Khan Maskatia, MD, Baylor College of Medicine (ZKM, FMO), Houston, TX 77030 (E-mail: [email protected]).
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In addition to swelling, the patient had also been suffering brief attacks of abdominal pain, vomiting and diarrhea for the past 7 years. He could not identify any triggers and suffered about 1 episode a year. Previous colonoscopies and radiographic studies had been normal, but recently, the patient had such severe pain that he went to his local hospital, where a computed tomography scan revealed bowel edema, and an urgent laparotomy was recommended for possible Crohn disease. The patient refused this intervention, and his symptoms improved with supportive care alone. Of note, the patient’s father had a long history of swelling of his hands, feet and throat but was never formally diagnosed. No other family members were known to be affected. The patient’s other medical problems included mild obstructive sleep apnea with secondary chronic mild erythrocytosis, diabetes mellitus, depression, allergic rhinitis and arthritis. His medications include glyburide/metformin, lovastatin, metoprolol, ranitidine, loratadine and aspirin. He had no known drug allergies. Physical examination at the time of evaluation in clinic showed stable vital signs, with no apparent swelling of the oral mucosa, extremities or genitalia. Examination also revealed clear breath sounds, regular heart rate without murmurs and a soft and nontender abdomen. Laboratory tests showed a decreased serum C1-INH antigen level of 14 mg/dL (normal, 21–39 mg/dL) or approximately 66% of normal. C1-INH function was 51% of normal on the initial laboratory test and undetectable when checked again a few weeks later. The C4 level was also reduced at 8.72 mg/dL (normal, 16 –38 mg/dL), whereas C3 level was normal at 175 mg/dL (range, 79 –152 mg/dL). A diagnosis of type I HAE was made, and the patient was started on prophylactic treatment with danazol. He has not reported any attacks since the starting of treatment.
DISCUSSION It is important to recognize HAE early to avoid potentially fatal outcomes, and the disease should be suspected on clinical grounds in most cases. HAE attacks are often preceded by a prodrome associated with tingling, and many also involve a macular nonpruritic rash known as erythema marginatum. Most cases have no clear inciting event, but trauma or stress can precipitate attacks. As an example, the injection of procaine hydrochloride into the gums for the purpose of dental work is a common precipitant, and HAE should be considered if mouth swelling occurs after dental work. The subcutaneous swelling of HAE is painless and nonpruritic and usually lasts for 24 to 72 hours.6 Affected areas can include the subcutaneous tissues (such as the extremities, genitals and buttocks), abdominal organs and upper airway, which may result in obstruction. Diagnostic clinical criteria for HAE are evolving, with the most recent consensus stating that the diagnosis of HAE is supported by 2 laboratory measurements revealing C1-INH concentration and/or function to be ⬍50% of normal, in conjunction with a low C4.3 Our patient met the criteria for HAE, but his case was unusual in that he had an extremely delayed
The American Journal of the Medical Sciences • Volume 340, Number 1, July 2010
Delayed Diagnosis of Hereditary Angioedema
diagnosis, with about 40 years from the onset of symptoms to the diagnosis. This is considerably longer than average time to diagnosis. In 1977, it was reported that time between the onset of symptoms and the diagnosis was 22 years.6 In 2005, it had improved considerably but was still reported to be more than 10 years in 1 study from Spain.7 More recently in 2007, data collected from more than 1000 patients in Europe found an average of 15 years between the onset of symptoms and diagnosis of HAE.8 Late diagnosis of HAE is detrimental, because it carries a risk of death from laryngeal obstruction if not treated properly. In fact, our patient finally had a severe episode with laryngeal edema, which precipitated evaluation by the Immunology service and eventually lead to his diagnosis. Early diagnosis of HAE is also important because some commonly used medications should not be prescribed to these patients. For example, angiotensin-converting enzyme inhibitors should be avoided in patients with a high risk of angioedema from whatever diagnosis (eg, allergic hypersensitivity to insect stings, idiopathic- or exercise-induced anaphylaxis or acquired angioedema or HAE).9 Angiotensin receptor blockers similarly increase the risk of anaphylactic episodes, although less so than angiotensin-converting enzyme inhibitors. Thus, it is critical to educate both the patients and their primary care providers regarding this potential problem. The mainstays of allergic angioedema treatment (including antihistamines, epinephrine and steroids) are not effective in HAE. This emphasizes the importance of accurate diagnosis for appropriate treatment. For acute HAE attacks, C1-INH concentrate is first-line therapy.10,11 This has been available for decades in Europe and other countries and was recently approved by the U.S. Food and Drug Administration for HAE attacks. In cases where C1-INH concentrate is not available, fresh frozen plasma or antifibrinolytic agents can be used for acute attacks.12 For prophylaxis, attenuated androgens (which increase production of the normal C1-INH from the unaffected chromosome) and antifibrinolytics are often used. If these are ineffective, C1-INH replacement protein can be used.13,14 In addition to risk of death from improper treatment, timely diagnosis of HAE patients is important, because these patients tend to use medical resources more frequently until their diagnosis is established, leading to increased health care costs. The results of an online survey that were published in 2004 found that HAE patients averaged 4.7 visits to the emergency department per year, with almost one quarter of patients treated for anaphylaxis.15 Studies have also found patients with abdominal attacks associated with undiagnosed HAE often undergo unnecessary surgery, similar to our patient who almost did.16 Earlier diagnosis can prevent the disability that accommodates people during and after episodes of HAE.
© 2010 Lippincott Williams & Wilkins
For all of these reasons, more efforts are needed to increase awareness of HAE and improve timely diagnosis and treatment. REFERENCES 1. Davis AE III. C1 inhibitor and hereditary angioneurotic edema. Annu Rev Immunol 1988;6:595– 628. 2. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992;71:206 –15. 3. Agostoni A, Aygoren-Pursun E, Binkley K, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(3 suppl):S51–131. 4. Binkley KE, Davis A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000;106:546 –50. 5. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286 –9. 6. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;84:580 –93. 7. Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005;94:498 –503. 8. Zingale LC, Bork K, Farkas H, et al. The European Register of Hereditary Angioedema: experience and Preliminary Results. J Allergy Clin Immunol 2007;119:S276. 9. Ricketti AJ, Cleri DJ, Ramos-Bonner LS, et al. Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment. Ann Allergy Asthma Immunol 2007;98:397– 401. 10. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996;334:1630 – 4. 11. Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004;114:629 –37. 12. Prematta M, Gibbs JG, Pratt EL, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007;98:383– 8. 13. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008;100:153– 61. 14. Langston D, Weiner J, Fary W. C1-esterase inhibitor concentrate prevents upper airways obstruction in hereditary angio-oedema. Med J Aust 1994;164:383. 15. Huang S. Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc 2004;25:127–31. 16. Bowie KJ, Scarupa M, Li H. Unnecessary abdominal surgeries secondary to undiagnosed hereditary angioedema. J Allergy Clin Immunol 2007;119:S276.
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Delayed Diagnosis of Hereditary Angioedema Zahida Khan Maskatia, MD and Frank M. Orson, MD
Abstract: Hereditary angioedema (HAE) is a rare and potentially fatal disease that is important to recognize early. It is usually associated with low levels or impaired function of C1 inhibitor, which is involved in several inflammatory pathways. The treatment of HAE is very different from other causes of angioedema, emphasizing the importance of early and accurate diagnosis. The authors report the case of a patient who had symptoms starting in his teens but was not diagnosed until the age of 57 years. They also review the consequences of delayed diagnosis of HAE. Key Indexing Terms: Hereditary angioedema; Diagnosis; C1 inhibitor. [Am J Med Sci 2010;340(1):82–83.]
H
ereditary angioedema (HAE) is a rare autosomal dominant disorder that is characterized by recurrent episodes of painless nonpruritic angioedema, which can affect the subcutaneous tissues (such as the extremities, genitals and buttocks), abdominal organs and upper airway. Typically, symptoms begin in childhood and persist throughout life, but HAE can be fatal if left untreated. Most cases are associated with low levels or impaired function of C1 inhibitor (C1-INH), which is a serine protease inhibitor that affects several inflammatory pathways. Type I HAE, which compromises approximately 85% of cases, is characterized by low levels and reduced functional tests of C1-INH. Type II HAE, on the other hand, is characterized by a dysfunctional inhibitor and is associated with normal or elevated C1-INH protein levels but reduced functional tests of C1-INH.1–3 A third type of HAE has been described as well, which involves normal C1-INH antigen and functional levels. It was originally identified as an estrogen dependent form found only in women, but more recently, it has also been diagnosed in men.4 Some of these patients have a mutation in coagulation factor XII, which may cause increased generation of bradykinin.5 Although typically diagnosed early in life, we report the case of a patient who had symptoms starting in his teens but was not diagnosed until the age of 57 years. We also review the consequences of delayed diagnosis of HAE.
CASE REPORT A 57-year-old man was evaluated in Immunology clinic for angioedema. He had a history of recurrent nonpruritic swelling of his extremities, genitals and neck for as long as he could remember, with each episode lasting about 4 days. He suffered about 4 to 5 episodes a year. He had come to his local emergency department several times in the past decade with complaints related to extremity pain and swelling. More recently, his symptoms had become more frequent and severe, and he required admission to an intensive care unit 2 times in the few months before Immunology evaluation for throat swelling, although he did not require intubation.
From the Baylor College of Medicine (ZKM, FMO), Houston, Texas; and Departments of Medicine and Immunology (FMO), Veterans Affairs Medical Center, Houston, Texas. Submitted December 14, 2009; accepted in revised form March 19, 2010. Correspondence: Zahida Khan Maskatia, MD, Baylor College of Medicine (ZKM, FMO), Houston, TX 77030 (E-mail: [email protected]).
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In addition to swelling, the patient had also been suffering brief attacks of abdominal pain, vomiting and diarrhea for the past 7 years. He could not identify any triggers and suffered about 1 episode a year. Previous colonoscopies and radiographic studies had been normal, but recently, the patient had such severe pain that he went to his local hospital, where a computed tomography scan revealed bowel edema, and an urgent laparotomy was recommended for possible Crohn disease. The patient refused this intervention, and his symptoms improved with supportive care alone. Of note, the patient’s father had a long history of swelling of his hands, feet and throat but was never formally diagnosed. No other family members were known to be affected. The patient’s other medical problems included mild obstructive sleep apnea with secondary chronic mild erythrocytosis, diabetes mellitus, depression, allergic rhinitis and arthritis. His medications include glyburide/metformin, lovastatin, metoprolol, ranitidine, loratadine and aspirin. He had no known drug allergies. Physical examination at the time of evaluation in clinic showed stable vital signs, with no apparent swelling of the oral mucosa, extremities or genitalia. Examination also revealed clear breath sounds, regular heart rate without murmurs and a soft and nontender abdomen. Laboratory tests showed a decreased serum C1-INH antigen level of 14 mg/dL (normal, 21–39 mg/dL) or approximately 66% of normal. C1-INH function was 51% of normal on the initial laboratory test and undetectable when checked again a few weeks later. The C4 level was also reduced at 8.72 mg/dL (normal, 16 –38 mg/dL), whereas C3 level was normal at 175 mg/dL (range, 79 –152 mg/dL). A diagnosis of type I HAE was made, and the patient was started on prophylactic treatment with danazol. He has not reported any attacks since the starting of treatment.
DISCUSSION It is important to recognize HAE early to avoid potentially fatal outcomes, and the disease should be suspected on clinical grounds in most cases. HAE attacks are often preceded by a prodrome associated with tingling, and many also involve a macular nonpruritic rash known as erythema marginatum. Most cases have no clear inciting event, but trauma or stress can precipitate attacks. As an example, the injection of procaine hydrochloride into the gums for the purpose of dental work is a common precipitant, and HAE should be considered if mouth swelling occurs after dental work. The subcutaneous swelling of HAE is painless and nonpruritic and usually lasts for 24 to 72 hours.6 Affected areas can include the subcutaneous tissues (such as the extremities, genitals and buttocks), abdominal organs and upper airway, which may result in obstruction. Diagnostic clinical criteria for HAE are evolving, with the most recent consensus stating that the diagnosis of HAE is supported by 2 laboratory measurements revealing C1-INH concentration and/or function to be ⬍50% of normal, in conjunction with a low C4.3 Our patient met the criteria for HAE, but his case was unusual in that he had an extremely delayed
The American Journal of the Medical Sciences • Volume 340, Number 1, July 2010
Delayed Diagnosis of Hereditary Angioedema
diagnosis, with about 40 years from the onset of symptoms to the diagnosis. This is considerably longer than average time to diagnosis. In 1977, it was reported that time between the onset of symptoms and the diagnosis was 22 years.6 In 2005, it had improved considerably but was still reported to be more than 10 years in 1 study from Spain.7 More recently in 2007, data collected from more than 1000 patients in Europe found an average of 15 years between the onset of symptoms and diagnosis of HAE.8 Late diagnosis of HAE is detrimental, because it carries a risk of death from laryngeal obstruction if not treated properly. In fact, our patient finally had a severe episode with laryngeal edema, which precipitated evaluation by the Immunology service and eventually lead to his diagnosis. Early diagnosis of HAE is also important because some commonly used medications should not be prescribed to these patients. For example, angiotensin-converting enzyme inhibitors should be avoided in patients with a high risk of angioedema from whatever diagnosis (eg, allergic hypersensitivity to insect stings, idiopathic- or exercise-induced anaphylaxis or acquired angioedema or HAE).9 Angiotensin receptor blockers similarly increase the risk of anaphylactic episodes, although less so than angiotensin-converting enzyme inhibitors. Thus, it is critical to educate both the patients and their primary care providers regarding this potential problem. The mainstays of allergic angioedema treatment (including antihistamines, epinephrine and steroids) are not effective in HAE. This emphasizes the importance of accurate diagnosis for appropriate treatment. For acute HAE attacks, C1-INH concentrate is first-line therapy.10,11 This has been available for decades in Europe and other countries and was recently approved by the U.S. Food and Drug Administration for HAE attacks. In cases where C1-INH concentrate is not available, fresh frozen plasma or antifibrinolytic agents can be used for acute attacks.12 For prophylaxis, attenuated androgens (which increase production of the normal C1-INH from the unaffected chromosome) and antifibrinolytics are often used. If these are ineffective, C1-INH replacement protein can be used.13,14 In addition to risk of death from improper treatment, timely diagnosis of HAE patients is important, because these patients tend to use medical resources more frequently until their diagnosis is established, leading to increased health care costs. The results of an online survey that were published in 2004 found that HAE patients averaged 4.7 visits to the emergency department per year, with almost one quarter of patients treated for anaphylaxis.15 Studies have also found patients with abdominal attacks associated with undiagnosed HAE often undergo unnecessary surgery, similar to our patient who almost did.16 Earlier diagnosis can prevent the disability that accommodates people during and after episodes of HAE.
© 2010 Lippincott Williams & Wilkins
For all of these reasons, more efforts are needed to increase awareness of HAE and improve timely diagnosis and treatment. REFERENCES 1. Davis AE III. C1 inhibitor and hereditary angioneurotic edema. Annu Rev Immunol 1988;6:595– 628. 2. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992;71:206 –15. 3. Agostoni A, Aygoren-Pursun E, Binkley K, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(3 suppl):S51–131. 4. Binkley KE, Davis A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000;106:546 –50. 5. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286 –9. 6. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;84:580 –93. 7. Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005;94:498 –503. 8. Zingale LC, Bork K, Farkas H, et al. The European Register of Hereditary Angioedema: experience and Preliminary Results. J Allergy Clin Immunol 2007;119:S276. 9. Ricketti AJ, Cleri DJ, Ramos-Bonner LS, et al. Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment. Ann Allergy Asthma Immunol 2007;98:397– 401. 10. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996;334:1630 – 4. 11. Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004;114:629 –37. 12. Prematta M, Gibbs JG, Pratt EL, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007;98:383– 8. 13. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008;100:153– 61. 14. Langston D, Weiner J, Fary W. C1-esterase inhibitor concentrate prevents upper airways obstruction in hereditary angio-oedema. Med J Aust 1994;164:383. 15. Huang S. Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc 2004;25:127–31. 16. Bowie KJ, Scarupa M, Li H. Unnecessary abdominal surgeries secondary to undiagnosed hereditary angioedema. J Allergy Clin Immunol 2007;119:S276.
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