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Congenital angiotensin-converting enzyme deficiency presenting as recurrent angioedema of upper airway in adult life
Congenital angiotensin-converting enzyme deficiency presenting as recurrent angioedema of upper airway in adult life ANEKAL B. SREERAM, MD, and JACQUELYNNE P. COREY, MD, FACS,Chicago, Illinois
A n g i o e d e m a is a life-threatening ccndition. Single or r e c u r r e n t attacks should be thoroughly investig a t e d for d e t e r m i n a t i o n of the cause, which will help in t r e a t m e n t of the patient. T h e case in our discussion was thoroughly e x a m i n e d and led to an extremely rare diagnosis of congenital angiotensinconverting e n z y m e ( A C E ) deficiency first seen as r e c u r r e n t a n g i o e d e m a of the u p p e r airway in adult life. CASE REPORT
A 51-year-old female registered nurse with a life-long histo~ of suspected allergies to food and inhalant allergens was referred to the ear, nose, and throat allergy clinic because of episodes of angioedema occurring off and on for the previous 3 years and getting worse during the last year. Episodes described by the patient included periorbital and facial swelling with redness, tightness in the throat, and difficulty swallowing. Occasionally, swelling of the hands, joint pains, and muscle aches accompanied these episodes. The patient had had a course of immunotherapy 20 years previously. Precipitat ing factors for the episodes of angioedema included humid atmospheric conditions, springtime, and coffee intake. The patient lives in a well-maintained 20-year-old apartment with a wall airconditioner used in summer. She has no pets at home, nor does she have any workplace exposure to animals. She noticed in the past that housecleaning increased her chances of having the symptoms. In the allergy history, it was noted that the patient had hay fever and asthma as a child. She was tested in childhood and found to be allergic to molds, hay, cheese, mushrooms, and milk. She had some delayed skin reaction to the shots after 1 year of immunotherapy. No known drug allergies were reported by the patient. The medieal history of the patient included hyperten-
sion, hypothyroidism, and hypercholesterolemia. The only surgery that she erer had was a laminectomy done in 1960. She was taking medications including prednisone, Chlortrimetron (chlorpheniramine maleate), Corgard (nadolol), Mevacor (lovastatin), Zantac (ranitidine), and Synthroid (levothyroxine sodium). She had never been given any ACE inhibitors. The patient's family history included clinically suspected allergies in her mother and grandmother. The patient's mother had recently been diagnosed as having Bartter's syndrome. The patient is a nonsmoker, rarely drinks alcohol, and usually consumes four cups of coffee per day. The findings on physical examination were essentially normal, and the results of the otolaryngologic examination were normal except for a large soft palate and mild deviated nasal septum. The laboratory data can be summarized as follows. Allergy screening (by radioallergosorbent test) was negative, with a low IgE level of 16 KU/L (normal, 19.4 to 79.3 KU/L). Radioallergosorbent test screening was done for 10 common allergens, including Candida albicans, white ash tree, house dust mite, timothy grass, giant ragweed,
Aspergillus fumigatus, Altemaria altemata, Hernintho.sporium halodes, and cat dander (Table 1). The complete blood cell count was normal. The erythrocyte sedimentation rate was raised to 26 mm/hour (normal, 0 te 12 mm/hour). The ACE level was low at 5 U/L (normal, 8 to 52 U/L). The antinuclear antibody, complement C4, CH50, and C1 esterase inhibitor levels were all normal. A barium swallow was performed to evaluate the dysphagia. It showed mild reflux esophagitis. No evidence of Bartter's syndrome was found in our patient. This, as described by Bartter et al., ~ consists of hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemia. Repeated ACE levels were still below the normal level of 8 to 52 U/L. DISCUSSION
From the University of Chicago. Received for publication June 2, 1994; revision receivecl Oct. 4, 1994; accepted Oct. 7, 1994. Reprint requests: J. Corey, MD, FACS, University of Chicago, 5841 S. Mawland Ave.-MC 1035, Chicago, IL 60637. OTOLARYNGOLHEADN~CKSUR~ 1995;112:421-3. Copyrigh~ © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$3.00 + 0 23/1/61112
A brief review of clinical pharmacolo~ ~of ACE [nhibitors and the remn-angiotensin aldosterone system will be useful in u n d e r s t a n d i n g the subsequent discussion. Renin, an enzyme p r o d u c e d by the kidneys, is released into the circulation, w h e r e it acts on a p l a s m a glob'alin substrate to p r o d u c e angiotensin I, a relatively w e a k vasoconstrictor d e c a p e p tide. Angiotensin I is then converted by A C E , pro42t
422
Otolaryngology Head and Neck Surgery March t995
SREERAMand COREY
Renin (Kidneys)
'Table t. Results of allergy tests
I
Method and test name
/ N substrate ........................ > Angiotensin I
Class
Result
Plasma globulin renin
\
Angiotensin converting enzyme (ACE)~-------> Lungs Angiotensin II / ~
Vas~oconstriction
~ Renal salt and water retention
Total IgE Immunocap RAST, alternate scoring method f2 Milk m5 C, albicans tl 5 White ash tree d2 Dermatophagoides farinae g6 Timothy grass w3 Giant ragweed m3 A. fumigatus m6 A. alternata m8 H, halodes el Cat dander
-
16,0 kU/L
0 0 0
39.2% 35.3% 31.7% 23.3% 27.2% 40.4% 29.9% 50.7% 25.5% 23.8%
0 0 0 0 0 0 0
REF REF REF REF REF REF REF REF REF REF
RAST,Radioallergosorbenttest,
Fig. 1. Clinical pharmacology of ACE inhibitors.
duced in the lung parenchyma, to angiotensin II, an octapeptide and an extremely powerful vasoconstrictor. Angiotensin II is also a strong stimulator of the adrenal cortex to produce aldosterone, which by its renal mechanism causes sodium and fluid retention in plasma 2,3 (Fig. 1). Acute, localized, noninflammatory edema was first described by Quincke 4in 1882. In 1885 Strubing5 coined the word angioedema. Both of these clinicians theorized that the underlying mechanism for edema was increased vascular permeability.60sler 7 reported the hereditary form of this disorder in 1888. More recently, Landerman8has described two types of hereditary angioedema: 1. Hereditary angioneurotic edema is described as a rare autosomal-dominant disorder characterized by recurrent attacks of circumscribed edema involving the skin, pharynx, larynx, and gastrointestinal tract, often precipitated by minor trauma. The disease is caused by a hereditary C1 esterase inhibitor deficiency. The mechanism of edema is due to uncontrolled activation of complement pathway, and C1 esterase inhibitor prevents this uncontrolled activation.8 2. Hereditary allergic angioneurotic edema, in contrast, represents a Gel & Coombs type I hypersensitivity reaction. 6 It occurs in patients with a family history of allergy, including urticaria, eczema, hay fever, or asthma. 6 It is usually possible to demonstrate the allergen responsible for the event on extensive allergy workup. Our patient was thoroughly tested for allergies and C1 esterase deficiency, with negative results.
Our patient saw a consulting endocrinologist, who did not believe that she had Bartter's syndrome. However, we found that our patient had very low ACE levels but had never received ACE inhibitors in the past. A search of the literature showed that congenital ACE deficiency is a very rare condition. Two cases of congenital ACE deficiency were described by Shingtomi et al. 9 in a 57-year-old mother and her 29-year-old daughter. The clinical-biochemical presentation of these cases was that of hyperkalemia. Both also exhibited subnormal plasma aldosterone levels in the face of elevated plasma renin activity. Similar biochemical abnormalities were reported by Patressi et al. 1°in a patient known to have factor XII deficiency. Davidai et al. 11 have reported two children of the same family having congenital unresponsiveness to adrenocorticotropic hormone stimulation. However, there has been no reference to this problem occurring as recurrent angioedema of the upper airway as in our case. There are, however, a number of references to acquired angioedema with use of ACE inhibitors. Thompson and Frable 12 reported 36 cases of angioedema caused by ACE inhibitors at the Medical College of Virginia Hospitals between 1984 and 1991. In a previous study from our institution, published in 1992, Jain et al. ~~found that trauma to the upper airway in the past predisposed to development of secondary angioedema from the use of ACE inhibitors. Suggestions for treatment of acute angioedema related to ACE deficiency include emergency administration of subcutaneous 1 : 1000 epinephrine in 0.5-ml doses up to a maximum of three doses. 14The use of epinephrine is advocated because these pa-
Otolaryngo~ogy Head and Neck Surgery Volume 112 Number 3
tients r e s p o n d poorly to steroids. This should be d o n e cautiously, with monitoring, especially in elderly or hypertensive patients and in patients with a cardiac history. 14 If the airway b e c o m e s c o m p r o mised or there is a p o o r response to epinephrine injection, intubation or t r a c h e o s t o m y taust be considered. Portable self-administered epinephrine kits are available for patient use and can be used in an e m e r g e n c y situation. 14Patients should be instructed to seek medical help immediately if they n e e d m o r e than two shots to relieve their symptoms or if they have an incomplete response or no response in symptoms. A m o r e cautious a p p r o a « h is to advise that they p r o c e e d to the nearest e m e r g e n c y departm e n t immediately after self-administration of epinephrine. SUMMARY
In summary, a rare case of congenital A C E deficiency is presented. This disorder is of concern to the otolaryngologist because the patient in question had episodes of recurrent u p p e r airway angioedema. M a n a g e m e n t of a n g i o e d e m a generally consists o f self-administered epinephrine because these patients r e s p o n d poorly to steroids. REFERENCES
1. Bartter FC, Pronove P, Gill JR, et al. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. Am J Med 1962;33:811-27.
SREERAM and COREY 423
2. Katzung BG. Basic and clinical pharmacology. Norwalk, Conn.: Appleton and Lange. 1989:134-9. 3. Guyton AC. Textbook of medical physiotogy. 1!th ed. Philadelphia, Pa.: WB Saunders Co., 1991:21t-20. 4. Quincke H. Über Akutes umschriebenes Hautodern. Monatschr Prakt Dermatol 1882;1:129-31. 5. Strubing P. Über Akutes angioneurotisches Oedem. Ztschr Klin Med 1885;9:381-96. 6. Jarvis BL, Corey JP. Acute uvular edema, case reports. Ear Nose Throat J 1988;67:665-9. 7. Osler W. Hereditary angioneurotic edema. Am J Med Sci 1888;95:362-7. 8. Landerman NA. Hereditary angioneurotic edema. J Allergy Clin Irnmunol 1962;33:316-29. 9. Shingtomi S, Ojima M, Ueno S, et at. Two adult familial cases of selective hypoaldosteronism due to insufficiency of conversion of corticosterone to aldosterone. Endocr J 1986;33: 786-94. 10. Patressi GM, Mantero F, Fallo F, et al. Captopril induced changes on active and inactive renin in a patient with congenital factor XII defieiency. Res Exp Med (Berlin) 1985; 185:2t7-20. 11. Davidai G, Kahana L, Hochberg Z. Glomerular failure in congenital adrenocortical unresponsiveness to ACTH. Clin Endocrinol (Oxf) 1984;20:515-20. 12. Thompson T, Frable MA. Drug induced, life threatening angioedema revisited. Laryngoscope 1993;103:10-2. 13. Jain M, Armstrong L, Hall J. Predisposition to and late onset of upper airway obstruction following angiotensin-converting enzyme inhibitor therapy. Chest 1992;102:871-4. 14. Arky R. Physicians desk reference. 48th ed. Mont-~ale, NJ.: Medical Economics Data Production Company, 1994:1594-6, 1718-9, 2314-7.
A n g i o e d e m a is a life-threatening ccndition. Single or r e c u r r e n t attacks should be thoroughly investig a t e d for d e t e r m i n a t i o n of the cause, which will help in t r e a t m e n t of the patient. T h e case in our discussion was thoroughly e x a m i n e d and led to an extremely rare diagnosis of congenital angiotensinconverting e n z y m e ( A C E ) deficiency first seen as r e c u r r e n t a n g i o e d e m a of the u p p e r airway in adult life. CASE REPORT
A 51-year-old female registered nurse with a life-long histo~ of suspected allergies to food and inhalant allergens was referred to the ear, nose, and throat allergy clinic because of episodes of angioedema occurring off and on for the previous 3 years and getting worse during the last year. Episodes described by the patient included periorbital and facial swelling with redness, tightness in the throat, and difficulty swallowing. Occasionally, swelling of the hands, joint pains, and muscle aches accompanied these episodes. The patient had had a course of immunotherapy 20 years previously. Precipitat ing factors for the episodes of angioedema included humid atmospheric conditions, springtime, and coffee intake. The patient lives in a well-maintained 20-year-old apartment with a wall airconditioner used in summer. She has no pets at home, nor does she have any workplace exposure to animals. She noticed in the past that housecleaning increased her chances of having the symptoms. In the allergy history, it was noted that the patient had hay fever and asthma as a child. She was tested in childhood and found to be allergic to molds, hay, cheese, mushrooms, and milk. She had some delayed skin reaction to the shots after 1 year of immunotherapy. No known drug allergies were reported by the patient. The medieal history of the patient included hyperten-
sion, hypothyroidism, and hypercholesterolemia. The only surgery that she erer had was a laminectomy done in 1960. She was taking medications including prednisone, Chlortrimetron (chlorpheniramine maleate), Corgard (nadolol), Mevacor (lovastatin), Zantac (ranitidine), and Synthroid (levothyroxine sodium). She had never been given any ACE inhibitors. The patient's family history included clinically suspected allergies in her mother and grandmother. The patient's mother had recently been diagnosed as having Bartter's syndrome. The patient is a nonsmoker, rarely drinks alcohol, and usually consumes four cups of coffee per day. The findings on physical examination were essentially normal, and the results of the otolaryngologic examination were normal except for a large soft palate and mild deviated nasal septum. The laboratory data can be summarized as follows. Allergy screening (by radioallergosorbent test) was negative, with a low IgE level of 16 KU/L (normal, 19.4 to 79.3 KU/L). Radioallergosorbent test screening was done for 10 common allergens, including Candida albicans, white ash tree, house dust mite, timothy grass, giant ragweed,
Aspergillus fumigatus, Altemaria altemata, Hernintho.sporium halodes, and cat dander (Table 1). The complete blood cell count was normal. The erythrocyte sedimentation rate was raised to 26 mm/hour (normal, 0 te 12 mm/hour). The ACE level was low at 5 U/L (normal, 8 to 52 U/L). The antinuclear antibody, complement C4, CH50, and C1 esterase inhibitor levels were all normal. A barium swallow was performed to evaluate the dysphagia. It showed mild reflux esophagitis. No evidence of Bartter's syndrome was found in our patient. This, as described by Bartter et al., ~ consists of hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemia. Repeated ACE levels were still below the normal level of 8 to 52 U/L. DISCUSSION
From the University of Chicago. Received for publication June 2, 1994; revision receivecl Oct. 4, 1994; accepted Oct. 7, 1994. Reprint requests: J. Corey, MD, FACS, University of Chicago, 5841 S. Mawland Ave.-MC 1035, Chicago, IL 60637. OTOLARYNGOLHEADN~CKSUR~ 1995;112:421-3. Copyrigh~ © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$3.00 + 0 23/1/61112
A brief review of clinical pharmacolo~ ~of ACE [nhibitors and the remn-angiotensin aldosterone system will be useful in u n d e r s t a n d i n g the subsequent discussion. Renin, an enzyme p r o d u c e d by the kidneys, is released into the circulation, w h e r e it acts on a p l a s m a glob'alin substrate to p r o d u c e angiotensin I, a relatively w e a k vasoconstrictor d e c a p e p tide. Angiotensin I is then converted by A C E , pro42t
422
Otolaryngology Head and Neck Surgery March t995
SREERAMand COREY
Renin (Kidneys)
'Table t. Results of allergy tests
I
Method and test name
/ N substrate ........................ > Angiotensin I
Class
Result
Plasma globulin renin
\
Angiotensin converting enzyme (ACE)~-------> Lungs Angiotensin II / ~
Vas~oconstriction
~ Renal salt and water retention
Total IgE Immunocap RAST, alternate scoring method f2 Milk m5 C, albicans tl 5 White ash tree d2 Dermatophagoides farinae g6 Timothy grass w3 Giant ragweed m3 A. fumigatus m6 A. alternata m8 H, halodes el Cat dander
-
16,0 kU/L
0 0 0
39.2% 35.3% 31.7% 23.3% 27.2% 40.4% 29.9% 50.7% 25.5% 23.8%
0 0 0 0 0 0 0
REF REF REF REF REF REF REF REF REF REF
RAST,Radioallergosorbenttest,
Fig. 1. Clinical pharmacology of ACE inhibitors.
duced in the lung parenchyma, to angiotensin II, an octapeptide and an extremely powerful vasoconstrictor. Angiotensin II is also a strong stimulator of the adrenal cortex to produce aldosterone, which by its renal mechanism causes sodium and fluid retention in plasma 2,3 (Fig. 1). Acute, localized, noninflammatory edema was first described by Quincke 4in 1882. In 1885 Strubing5 coined the word angioedema. Both of these clinicians theorized that the underlying mechanism for edema was increased vascular permeability.60sler 7 reported the hereditary form of this disorder in 1888. More recently, Landerman8has described two types of hereditary angioedema: 1. Hereditary angioneurotic edema is described as a rare autosomal-dominant disorder characterized by recurrent attacks of circumscribed edema involving the skin, pharynx, larynx, and gastrointestinal tract, often precipitated by minor trauma. The disease is caused by a hereditary C1 esterase inhibitor deficiency. The mechanism of edema is due to uncontrolled activation of complement pathway, and C1 esterase inhibitor prevents this uncontrolled activation.8 2. Hereditary allergic angioneurotic edema, in contrast, represents a Gel & Coombs type I hypersensitivity reaction. 6 It occurs in patients with a family history of allergy, including urticaria, eczema, hay fever, or asthma. 6 It is usually possible to demonstrate the allergen responsible for the event on extensive allergy workup. Our patient was thoroughly tested for allergies and C1 esterase deficiency, with negative results.
Our patient saw a consulting endocrinologist, who did not believe that she had Bartter's syndrome. However, we found that our patient had very low ACE levels but had never received ACE inhibitors in the past. A search of the literature showed that congenital ACE deficiency is a very rare condition. Two cases of congenital ACE deficiency were described by Shingtomi et al. 9 in a 57-year-old mother and her 29-year-old daughter. The clinical-biochemical presentation of these cases was that of hyperkalemia. Both also exhibited subnormal plasma aldosterone levels in the face of elevated plasma renin activity. Similar biochemical abnormalities were reported by Patressi et al. 1°in a patient known to have factor XII deficiency. Davidai et al. 11 have reported two children of the same family having congenital unresponsiveness to adrenocorticotropic hormone stimulation. However, there has been no reference to this problem occurring as recurrent angioedema of the upper airway as in our case. There are, however, a number of references to acquired angioedema with use of ACE inhibitors. Thompson and Frable 12 reported 36 cases of angioedema caused by ACE inhibitors at the Medical College of Virginia Hospitals between 1984 and 1991. In a previous study from our institution, published in 1992, Jain et al. ~~found that trauma to the upper airway in the past predisposed to development of secondary angioedema from the use of ACE inhibitors. Suggestions for treatment of acute angioedema related to ACE deficiency include emergency administration of subcutaneous 1 : 1000 epinephrine in 0.5-ml doses up to a maximum of three doses. 14The use of epinephrine is advocated because these pa-
Otolaryngo~ogy Head and Neck Surgery Volume 112 Number 3
tients r e s p o n d poorly to steroids. This should be d o n e cautiously, with monitoring, especially in elderly or hypertensive patients and in patients with a cardiac history. 14 If the airway b e c o m e s c o m p r o mised or there is a p o o r response to epinephrine injection, intubation or t r a c h e o s t o m y taust be considered. Portable self-administered epinephrine kits are available for patient use and can be used in an e m e r g e n c y situation. 14Patients should be instructed to seek medical help immediately if they n e e d m o r e than two shots to relieve their symptoms or if they have an incomplete response or no response in symptoms. A m o r e cautious a p p r o a « h is to advise that they p r o c e e d to the nearest e m e r g e n c y departm e n t immediately after self-administration of epinephrine. SUMMARY
In summary, a rare case of congenital A C E deficiency is presented. This disorder is of concern to the otolaryngologist because the patient in question had episodes of recurrent u p p e r airway angioedema. M a n a g e m e n t of a n g i o e d e m a generally consists o f self-administered epinephrine because these patients r e s p o n d poorly to steroids. REFERENCES
1. Bartter FC, Pronove P, Gill JR, et al. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. Am J Med 1962;33:811-27.
SREERAM and COREY 423
2. Katzung BG. Basic and clinical pharmacology. Norwalk, Conn.: Appleton and Lange. 1989:134-9. 3. Guyton AC. Textbook of medical physiotogy. 1!th ed. Philadelphia, Pa.: WB Saunders Co., 1991:21t-20. 4. Quincke H. Über Akutes umschriebenes Hautodern. Monatschr Prakt Dermatol 1882;1:129-31. 5. Strubing P. Über Akutes angioneurotisches Oedem. Ztschr Klin Med 1885;9:381-96. 6. Jarvis BL, Corey JP. Acute uvular edema, case reports. Ear Nose Throat J 1988;67:665-9. 7. Osler W. Hereditary angioneurotic edema. Am J Med Sci 1888;95:362-7. 8. Landerman NA. Hereditary angioneurotic edema. J Allergy Clin Irnmunol 1962;33:316-29. 9. Shingtomi S, Ojima M, Ueno S, et at. Two adult familial cases of selective hypoaldosteronism due to insufficiency of conversion of corticosterone to aldosterone. Endocr J 1986;33: 786-94. 10. Patressi GM, Mantero F, Fallo F, et al. Captopril induced changes on active and inactive renin in a patient with congenital factor XII defieiency. Res Exp Med (Berlin) 1985; 185:2t7-20. 11. Davidai G, Kahana L, Hochberg Z. Glomerular failure in congenital adrenocortical unresponsiveness to ACTH. Clin Endocrinol (Oxf) 1984;20:515-20. 12. Thompson T, Frable MA. Drug induced, life threatening angioedema revisited. Laryngoscope 1993;103:10-2. 13. Jain M, Armstrong L, Hall J. Predisposition to and late onset of upper airway obstruction following angiotensin-converting enzyme inhibitor therapy. Chest 1992;102:871-4. 14. Arky R. Physicians desk reference. 48th ed. Mont-~ale, NJ.: Medical Economics Data Production Company, 1994:1594-6, 1718-9, 2314-7.