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Hyperammonemic Coma Due to Proteus Infection
0022-534 7/85/1345-0972$02.00/0 Vol. 134, November Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Williams & Wilkins Co.
HYPERAMMONEMIC COMA DUE TO PROTEUS INFECTION JOSEPH R. KUNTZE, ALAN C. WEINBERG
AND
THOMAS E. AHLERING
From the Division of Urology, University of Southern California/Chi/,dren's Hospital of Los Angeles, Los Angeles, California
ABSTRACT
Hyperammonemic coma without liver disease or associated deficiencies in urea cycle enzymes is rare. We report a case and discuss the pathophysiological findings of hyperammonemic coma secondary to Proteus mirabilis urinary tract infection. Hyperammonemic encephalopathy is a widely reported clinical syndrome that can be the end result of a number of pathophysiological disturbances. 1 Most hyperammonemic states represent the sequelae of acquired cirrhosis due to alcohol, hepatitis or Reyes' syndrome. 1' 2 Failure of the liver to detoxify normal amounts of endogenously produced ammonia plus portacaval shunting, either surgically created or subsequent to obstructive liver disease, allows ammonia to bypass the liver and elevate serum ammonia levels. Congenital deficiencies of the urea cycle enzymes can be responsible for high levels of serum ammonia. 3 We present a third and less common mechanism of hyperammonemic encephalopathy, that is an increase in ammonia load due to absorption of ammonia from the urinary tract infected with a urease-producing organism. CASE REPORT
A 27-month-old black boy was seen in the emergency room with emesis for 36 hours and 12 hours of increasing lethargy. Medical history was pertinent for the prune belly syndrome. The patient required loop cutaneous ureterostomies because of urosepsis when he was 6 months old. He did well and, subsequently, underwent staged urinary tract reconstruction, including bilateral ureteral reimplantation, excision of a urachal diverticulum and closure of the ureterostomies. Physical examination at hospitalization was remarkable only for the stigmas of the prune belly syndrome and lethargy. The patient was afebrile. Laboratory data revealed normal serum electrolytes and a bicarbonate of 17 mEq/1., urea nitrogen 20 mg./dl. and creatinine 1.0 mg./dl. Hemoglobin was normal and white blood count was elevated to 10,400 with 16 per cent bands. Urinalysis revealed many white and red blood cells, and many bacteria. Urine pH was 9. In the emergency room the serum ammonia level was 251 /Lg./dl. (normal less than 75 /Lg./ dl.). Six hours later in the intensive care unit the boy became comatose and the serum ammonia level had increased to 308 /Lg./dl. Liver function tests were normal. The patient was treated with gentamicin and ampicillin, and a Foley catheter was placed. Blood and spinal fluid cultures yielded no organisms. Urine culture yielded Proteus mirabilis. Twelve hours after the Foley catheter was placed (18 hours after hospitalization) the mental status began to improve and the ammonia level decreased to 240 /Lg./dl. The next afternoon, 24 hours after hospitalization, the serum ammonia level had decreased to 90 /Lg./dl. and the boy had awakened from the coma. The patient was discharged from the hospital after 3 days without incident. Complete metabolic diagnostic studies for the hyperammonemic state were normal, including lumbar puncture evaluation of serum amino acids, Krebs cycle enzymes and tricarboxylic acid cycle enzymes, serum and urine toxicology screening, and determination of Accepted for publication July 2, 1985.
urine orotic, keto and methylmalonic acids. The urine has remained sterile on antibiotic suppression. DISCUSSION
Ammonia is a by-product of nitrogen metabolism and is excreted by the kidney after conversion to urea in the liver. The lower gastrointestinal tract normally is the major source of ammonia, the result of hydrolysis of nitrogenous waste by the enteric flora. 3• 4 The ammonia is absorbed and transported via the portal vein to the liver. Therefore, patients with liver disease and portacaval shunting are the most frequent victims of hyperammonemic encephalopathy. Hyperammonemic coma also has been described in patients wth ureterosigmoidostomies, all of whom had concomitant liver disease. 6- 9 Hyperammonemic coma in the absence of liver disease or enzyme deficiency is rare. To our knowledge, this condition has been reported to be secondary to urinary tract infection on 4 occasions. 10- 13 Urea excreted in the urine in the presence of urease-producing organisms is hydrolyzed to produce ammonia. As a result the urine pH increases to 8 to 9. In aqueous solution ammonia exists in equilibrium with ammonium. The pKa of this reaction (ammonia + water - ammonium + hydroxide ion-) is 9.15 and, thus, in an alkaline environment one would expect equal amounts of ammonia and ammonium. 14 The ammonia is electrically neutral and lipid soluble, and readily crosses the bladder mucosa and, thereby, gains access to the blood stream. 11• 15 The venous drainage of the bladder bypasses the liver and the ammonia is not detoxified. The serum ammonia levels then increase and encephalopathy may develop. Urinary tract infections due to P. mirabilis are common and these patients have been shown to excrete up to twice the amount of ammonia that is absorbed from the gastrointestinal tract daily. 16 The explanation for the rarity of hyperammonemia appears to revolve around the additional requirement for large urine residual volumes. Of the 4 reported cases 2 had the prune belly syndrome, 1 had massive ureteral and bladder outlet obstruction secondary to ureteroceles, and 1 had an occult neurogenic bladder with residual urine volumes of 1,100 cc. These patients and ours had capacious urine volumes, urine pH values of 8 to 9 and urinary infections due to ureaseproducing organisms. The upper urinary tract diversion had protected our patient against large residual urine volumes. When the cutaneous ureterostomies were closed 1 month before this episode the patient was exposed to large volumes of residual urine. The P. mirabilis infection produced large amounts of ammonia in an alkaline environment, which resulted in the hyperammonemic state. This mechanism was demonstrated by Drayna and associates, who found that manipulation of residual urine volumes in a patient with urease-producing urinary tract infection led to predictable and reproducible changes in urine pH and ammonia levels. 1° Correction of the high residual urine volumes with intermittent catheterization eliminated- the hyperammonemic problem.
972
DlJE TO PTUYTEUS tNFECTI01'J
tract infection the coexistence of ,,,,1,uc,m"·· a urine infection with ureaseproducing organisms and an elevated pH. Understanding this mechanism should aid the clinician in how to predict, correct and prevent this unusual presentation of hyperammonemic coma. Although the elimination of high urinary residuals or infection is the ideal treatment, perhaps use of acetohydroxamic acid, 16 a urease inhibitor, would present a theoretical method of controlling this problem in a chronic fashion should catheterization and/or eradication of infection not be feasible. REFERENCES 1. Walker, C. 0. and Schenker, S.: Pathogenesis of hepatic encepha-
2.
3. 4.
5.
lopathy-with special reference to the role of ammonia. Amer. J. Clin. Nutr., 23: 619, 1970. Lockwood, A.H., McDonald, J.M., Reiman, R. E., Gelbard, A. S., Laughlin, J. S., Duffy, T. E. and Plum, F.: The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest., 63: 449, 1979. Hsia, Y. E.: Inherited hyperammonemic syndromes. Gastroenterology, 67: 347, 1974. Wolpert, E., Phillips, S. F. and Summerskill, W. H. J.: Ammonia production in the human colon. Effects of cleansing, neomycin and acetohydroxamic acid. New Engl. J. Med., 283: 159, 1970. McDermott, W. V., Jr.: Diversion of urine to the intestines as a factor in ammoniagenic coma. New EngL J. Med., 256: 460, 1957.
97.3
6. Silberrr1an) R.: Ammonia intoxication u:reterosigrnoidostomy in a patient with liver disease. Lancet, 937, 1958. 7. Egense, J. and Schwartz, M.: Recurrent hepatic coma following ureterosigmoidostomy. Scand. J. Gastroent., suppl., 7: 149, 1970. 8. Mortensen, E., Lyng, G. and Juhl, E.: Ammonia induced coma after ureterosigmoidostomy. Lancet, l: 496, 1972. 9. Mounger, E. J. and Branson, A. D.: Ammonia encephalopathy secondary to ureterosigmoidostomy: a case report. J. Urol., 108: 411, 1972. 10. Drayna, C. J., Titcomb, C. P., Varma, R. R. and Soergel, K. H.: Hyperammonemic encephalopathy caused by infection in a neurogenic bladder. New Engl. J. Med., 304: 766, 1981. 11. Samtoy, B. and DeBeukelaer, M. M.: Ammonia encephalopathy secondary to urinary tract infection with Proteus mirabilis. Pediatrics, 65: 294, 1980. 12. Ullman, M. A., Haecker, T. A. and Medani, C. R.: Hyperarnmonemic encephalopathy and urinary obstruction. New Engl. J. Med., 304: 1564, 1981. 13. Sinha, B. and Gonzalez, R.: Hyperammonernia in a boy with obstructive ureterocele and Proteus infection. J. Urol., 131: 330, 1984. 14. Bromberg, P.A., Robin, E. D. and Forkner, C. E., Jr.: The existence of ammonia in blood in vivo with observations on the significance of the NH4 +-NH3 system. J. Clin. Invest., 39: 332, 1960. 15. Pitts, R. F.: Renal regulation of acid-base balance. In: Physiology of the Kidney and Body Fluids, 3rd ed. Chicago: Year Book Medical Publishers, Inc., chapt. 11, pp. 217-234, 1974. 16. Griffith, D. P., Gibson, J. R., Clinton, C. W. and Musher, D. M.: Acetohydroxamic acid: clinical studies of a urease inhibitor in patients with staghorn renal calculi. J. Urol., 119: 9, 1978.
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Williams & Wilkins Co.
HYPERAMMONEMIC COMA DUE TO PROTEUS INFECTION JOSEPH R. KUNTZE, ALAN C. WEINBERG
AND
THOMAS E. AHLERING
From the Division of Urology, University of Southern California/Chi/,dren's Hospital of Los Angeles, Los Angeles, California
ABSTRACT
Hyperammonemic coma without liver disease or associated deficiencies in urea cycle enzymes is rare. We report a case and discuss the pathophysiological findings of hyperammonemic coma secondary to Proteus mirabilis urinary tract infection. Hyperammonemic encephalopathy is a widely reported clinical syndrome that can be the end result of a number of pathophysiological disturbances. 1 Most hyperammonemic states represent the sequelae of acquired cirrhosis due to alcohol, hepatitis or Reyes' syndrome. 1' 2 Failure of the liver to detoxify normal amounts of endogenously produced ammonia plus portacaval shunting, either surgically created or subsequent to obstructive liver disease, allows ammonia to bypass the liver and elevate serum ammonia levels. Congenital deficiencies of the urea cycle enzymes can be responsible for high levels of serum ammonia. 3 We present a third and less common mechanism of hyperammonemic encephalopathy, that is an increase in ammonia load due to absorption of ammonia from the urinary tract infected with a urease-producing organism. CASE REPORT
A 27-month-old black boy was seen in the emergency room with emesis for 36 hours and 12 hours of increasing lethargy. Medical history was pertinent for the prune belly syndrome. The patient required loop cutaneous ureterostomies because of urosepsis when he was 6 months old. He did well and, subsequently, underwent staged urinary tract reconstruction, including bilateral ureteral reimplantation, excision of a urachal diverticulum and closure of the ureterostomies. Physical examination at hospitalization was remarkable only for the stigmas of the prune belly syndrome and lethargy. The patient was afebrile. Laboratory data revealed normal serum electrolytes and a bicarbonate of 17 mEq/1., urea nitrogen 20 mg./dl. and creatinine 1.0 mg./dl. Hemoglobin was normal and white blood count was elevated to 10,400 with 16 per cent bands. Urinalysis revealed many white and red blood cells, and many bacteria. Urine pH was 9. In the emergency room the serum ammonia level was 251 /Lg./dl. (normal less than 75 /Lg./ dl.). Six hours later in the intensive care unit the boy became comatose and the serum ammonia level had increased to 308 /Lg./dl. Liver function tests were normal. The patient was treated with gentamicin and ampicillin, and a Foley catheter was placed. Blood and spinal fluid cultures yielded no organisms. Urine culture yielded Proteus mirabilis. Twelve hours after the Foley catheter was placed (18 hours after hospitalization) the mental status began to improve and the ammonia level decreased to 240 /Lg./dl. The next afternoon, 24 hours after hospitalization, the serum ammonia level had decreased to 90 /Lg./dl. and the boy had awakened from the coma. The patient was discharged from the hospital after 3 days without incident. Complete metabolic diagnostic studies for the hyperammonemic state were normal, including lumbar puncture evaluation of serum amino acids, Krebs cycle enzymes and tricarboxylic acid cycle enzymes, serum and urine toxicology screening, and determination of Accepted for publication July 2, 1985.
urine orotic, keto and methylmalonic acids. The urine has remained sterile on antibiotic suppression. DISCUSSION
Ammonia is a by-product of nitrogen metabolism and is excreted by the kidney after conversion to urea in the liver. The lower gastrointestinal tract normally is the major source of ammonia, the result of hydrolysis of nitrogenous waste by the enteric flora. 3• 4 The ammonia is absorbed and transported via the portal vein to the liver. Therefore, patients with liver disease and portacaval shunting are the most frequent victims of hyperammonemic encephalopathy. Hyperammonemic coma also has been described in patients wth ureterosigmoidostomies, all of whom had concomitant liver disease. 6- 9 Hyperammonemic coma in the absence of liver disease or enzyme deficiency is rare. To our knowledge, this condition has been reported to be secondary to urinary tract infection on 4 occasions. 10- 13 Urea excreted in the urine in the presence of urease-producing organisms is hydrolyzed to produce ammonia. As a result the urine pH increases to 8 to 9. In aqueous solution ammonia exists in equilibrium with ammonium. The pKa of this reaction (ammonia + water - ammonium + hydroxide ion-) is 9.15 and, thus, in an alkaline environment one would expect equal amounts of ammonia and ammonium. 14 The ammonia is electrically neutral and lipid soluble, and readily crosses the bladder mucosa and, thereby, gains access to the blood stream. 11• 15 The venous drainage of the bladder bypasses the liver and the ammonia is not detoxified. The serum ammonia levels then increase and encephalopathy may develop. Urinary tract infections due to P. mirabilis are common and these patients have been shown to excrete up to twice the amount of ammonia that is absorbed from the gastrointestinal tract daily. 16 The explanation for the rarity of hyperammonemia appears to revolve around the additional requirement for large urine residual volumes. Of the 4 reported cases 2 had the prune belly syndrome, 1 had massive ureteral and bladder outlet obstruction secondary to ureteroceles, and 1 had an occult neurogenic bladder with residual urine volumes of 1,100 cc. These patients and ours had capacious urine volumes, urine pH values of 8 to 9 and urinary infections due to ureaseproducing organisms. The upper urinary tract diversion had protected our patient against large residual urine volumes. When the cutaneous ureterostomies were closed 1 month before this episode the patient was exposed to large volumes of residual urine. The P. mirabilis infection produced large amounts of ammonia in an alkaline environment, which resulted in the hyperammonemic state. This mechanism was demonstrated by Drayna and associates, who found that manipulation of residual urine volumes in a patient with urease-producing urinary tract infection led to predictable and reproducible changes in urine pH and ammonia levels. 1° Correction of the high residual urine volumes with intermittent catheterization eliminated- the hyperammonemic problem.
972
DlJE TO PTUYTEUS tNFECTI01'J
tract infection the coexistence of ,,,,1,uc,m"·· a urine infection with ureaseproducing organisms and an elevated pH. Understanding this mechanism should aid the clinician in how to predict, correct and prevent this unusual presentation of hyperammonemic coma. Although the elimination of high urinary residuals or infection is the ideal treatment, perhaps use of acetohydroxamic acid, 16 a urease inhibitor, would present a theoretical method of controlling this problem in a chronic fashion should catheterization and/or eradication of infection not be feasible. REFERENCES 1. Walker, C. 0. and Schenker, S.: Pathogenesis of hepatic encepha-
2.
3. 4.
5.
lopathy-with special reference to the role of ammonia. Amer. J. Clin. Nutr., 23: 619, 1970. Lockwood, A.H., McDonald, J.M., Reiman, R. E., Gelbard, A. S., Laughlin, J. S., Duffy, T. E. and Plum, F.: The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest., 63: 449, 1979. Hsia, Y. E.: Inherited hyperammonemic syndromes. Gastroenterology, 67: 347, 1974. Wolpert, E., Phillips, S. F. and Summerskill, W. H. J.: Ammonia production in the human colon. Effects of cleansing, neomycin and acetohydroxamic acid. New Engl. J. Med., 283: 159, 1970. McDermott, W. V., Jr.: Diversion of urine to the intestines as a factor in ammoniagenic coma. New EngL J. Med., 256: 460, 1957.
97.3
6. Silberrr1an) R.: Ammonia intoxication u:reterosigrnoidostomy in a patient with liver disease. Lancet, 937, 1958. 7. Egense, J. and Schwartz, M.: Recurrent hepatic coma following ureterosigmoidostomy. Scand. J. Gastroent., suppl., 7: 149, 1970. 8. Mortensen, E., Lyng, G. and Juhl, E.: Ammonia induced coma after ureterosigmoidostomy. Lancet, l: 496, 1972. 9. Mounger, E. J. and Branson, A. D.: Ammonia encephalopathy secondary to ureterosigmoidostomy: a case report. J. Urol., 108: 411, 1972. 10. Drayna, C. J., Titcomb, C. P., Varma, R. R. and Soergel, K. H.: Hyperammonemic encephalopathy caused by infection in a neurogenic bladder. New Engl. J. Med., 304: 766, 1981. 11. Samtoy, B. and DeBeukelaer, M. M.: Ammonia encephalopathy secondary to urinary tract infection with Proteus mirabilis. Pediatrics, 65: 294, 1980. 12. Ullman, M. A., Haecker, T. A. and Medani, C. R.: Hyperarnmonemic encephalopathy and urinary obstruction. New Engl. J. Med., 304: 1564, 1981. 13. Sinha, B. and Gonzalez, R.: Hyperammonernia in a boy with obstructive ureterocele and Proteus infection. J. Urol., 131: 330, 1984. 14. Bromberg, P.A., Robin, E. D. and Forkner, C. E., Jr.: The existence of ammonia in blood in vivo with observations on the significance of the NH4 +-NH3 system. J. Clin. Invest., 39: 332, 1960. 15. Pitts, R. F.: Renal regulation of acid-base balance. In: Physiology of the Kidney and Body Fluids, 3rd ed. Chicago: Year Book Medical Publishers, Inc., chapt. 11, pp. 217-234, 1974. 16. Griffith, D. P., Gibson, J. R., Clinton, C. W. and Musher, D. M.: Acetohydroxamic acid: clinical studies of a urease inhibitor in patients with staghorn renal calculi. J. Urol., 119: 9, 1978.