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Hyperammonemic Encephalopathy: A Complication Associated with the Prune Belly Syndrome
0022 .. 534 7/89 /14, 2 '2 ~()361$02. 00 /0 'THE JGURI'.JAL OF UROLOG-i Copyright© 1989 Dy AiviERICAN UROLOGICAL Assocu-..ri'ION,
Vol. 142,
Printed in
HYPERAMJ\AONEMIC ENCEPHALOPATHY: COIVIPLICATION ASSOCIATED WITH THE PRUNE BELLY SYNDROME DAVID A. DIAMOND, ANNE BLIGHT
AND
PHILIP G. RANSLEY
From the Division of Urology, Department of Surgery, University of Massachusetts Medical Center, Worcester, Massachusetts, and The Great Ormond Street Hospital for Sick Children and The Institute of Urology, London, England
ABSTRACT
Hyperammonemic encephalopathy in the urological patient is a rare but grave condition. In the pediatric urological population it has been associated with massively dilated upper tracts and urinary infection with urea-splitting organisms. We report 2 cases of hyperammonemic encephalopathy in association with the prune belly syndrome. Both patients presented comatose with markedly elevated serum ammonia levels and Proteus mirabilis urinary tract infection. Intravenous antibiotics and catheter drainage resulted in dramatic reversal of the encephalopathy. The pathophysiology of hyperammonemic encephalopathy in association with the prune belly syndrome and a review of the literature are presented. (J. Ural., 142: 361-362, 1989) Hyperammonemic encephalopathy is a grave condition that usually is associated with hepatic dysfunction. We report 2 cases of hyperammonemic coma in children with the prune belly syndrome and Proteus mirabilis urinary tract infection in the absence of demonstrable liver disease. The pathophysiology of hyperammonemic encephalopathy in the prune belly syndrome is discussed. CASE REPORTS
Case 1. D. H., a 4-year-old boy, had the prune belly syndrome. As a neonate the patient was noted to void well and an excretory urogram (IVP) and diethylenetriaminepentaacetic acid renal scan demonstrated dilated but nonobstructed upper tracts. A voiding cystourethrogram demonstrated a large bladder without reflux and without urethral obstruction. During the next 4 years the patient did well until an Escherichia coli urinary tract infection developed that was treated successfully with oral trimethoprim-sulfamethoxazole. An IVP when he was 4 years old demonstrated dilated but nonobstructed upper tracts with a large capacity bladder. Within 1 week of these radiological studies mental status changes and violent behavior developed. The patient was hospitalized in an obtunded state but responsive to He was distended bladder. The bladder afebrile and had an was catheterized because of a large residual urine which was remarkable for numerous white cells and bacteria microThe urine was 9.0. Serum creatinine (normal 0.4 to blood urea nitrogen (BUN) 7 to and white blood count (normal 4.3 to 10.3 thousand per mm. Serum glutamic oxaloacetic and pyruvic transaminases, alkaline phosphatase and bilirubin, direct and total were normal. Emergency computerized tomography (CT) of the head was unremarkable. The patient was placed on a ventilator, with catheter drainage and parenteral antibiotics. Serum ammonia level was determined by the glutamate dehydrogenase enzyme technique using a Boehringer kit with photometric analysis in the ultraviolet range, and was 316 µg./ dl. (normal 15 to 55 µg./dl.). This level reached a peak of 368 µg./dL within 24 hours of hospitalization. Urine culture yielded greater than 10 6 P. mirabilis and blood culture was negative. By day 2 the serum ammonia level had decreased to 73 µg./dl. and by day 3 it had decreased to within normal limits at 33 µg./ dl. The mental status gradually improved and the patient was Accepted for publication January 23, 1989. 361
extubated on hospital day 3. Resolution of the sensorium was believed to be complete by day 7. Case 2. A.-G., a boy with the prune belly syndrome, as a neonate underwent an IVP and diethylenetriaminepentaacetic acid renal scan, which demonstrated dilated but nonobstructed upper tracts. A voiding cystourethrogram was remarkable for moderate reflux on the left side and reasonable urethral drainage. Serum creatinine as a neonate was 0.5 mg./dl. Because of the reflux status the patient was managed on suppressive antibiotics. The patient did well until he was 2 years old, when he presented comatose with a temperature of 38C. The creatinine was 0.6 mg./dl., BUN 12 mg./dl. and white blood count 18,600. He was mildly acidotic with a serum bicarbonate of 17 mg./dl. (normal 24 to 32 mmol./l.). Serum glutamic oxaloacetic and pyruvic transaminases, alkaline phosphatase and bilirubin, direct and total were normal. Urinalysis was remarkable for numerous white cells and bacteria microscopically, and a dipstick pH of 9.0. An emergency CT scan and lumbar puncture were unremarkable and electroencephalography demonstrated diffuse slowing. The patient was treated with catheter drainage and parenteral antibiotics. The serum ammonia level was 110 µg./dl. Urine culture was remarkable for greater than 106 P. mirabilis and blood culture was negative. On catheter drainage and parenteral antibiotics the serum ammonia decreased to 28 µg./dL within 48 and he became awake and communicative. The mental status normalized by 5. A followup radiological evaluation demonstrated poor a vesicoslower tract emptying that ultimately was relieved tomy. DISCUSSION
In man plasma ammonia is metabolized by l of 2 mechanisms: 1) ammonia may combine with glutamic acid to form glutamine (in a detoxification process) or 2) the ammonia that reaches the liver enters the Krebs-ornithine-urea cycle to be converted to urea, which is excreted by the kidneys. 1 Hyperammonemic coma usually is associated with altered hepatic metabolism of ammonia. Therefore, patients with liver disease, an acquired or congenital deficiency of hepatic enzymes of the Krebs urea cycle, Reye's syndrome or portocaval shunts are at particular risk. Hyperammonemic coma is a rare finding in the absence of liver disease. 2 Hyperammonemic coma has been reported in 5 patients with the prune belly syndrome and urinary tract infection with P. mirabilis. 3 - 5 The prune belly syndrome is the most common
.362
DIAMOND, BLIGHT AND RANSLEY
term for congenital absence or deficiency of the abdominal musculature accompanied by a large hypotonic bladder, dilated and tortuous ureters and bilateral cryptorchidism. 6 All 5 reported patients had markedly dilated urinary tracts. Only 1 patient had evidence of bladder outflow obstruction. If all of these patients had normal liver enzyme studies, why should they have been at risk for hyperammonemic coma? In solution, ammonia exists in equilibrium as the ammonium ion (NH4 +) or the free base (NHa). The free base (NHa) is lipid soluble and rapidly permeates all cell membranes, in contrast to the charged ammonium ion (NH4+). At a urine pH of 7.4, 1 per cent of the molecules exist as NH3 but at a urine pH of 9, 50 per cent of the molecules exist as NH3 • 4 In the alkaline urine that results when urea-splitting organisms infect the urinary tract, the free base (NHa) diffuses from the urinary tract into the blood stream, where it is converted to the poorly permeable ammonium ion (NH4+) in a process known as diffusion trapping.7 The combination of a massive ammonia load and an alkaline urine, both due to the urea-splitting infection, result in an elevated peripheral blood ammonia level. In all 5 prune belly syndrome patients with hyperammonemic coma there was urinary infection with a urea-splitting organism, resulting in an enormous release of ammonia and an alkaline urine. The massively dilated collecting systems produced an increased surface area through which ammonia could be absorbed. Although rare, hyperammonemic encephalopathy currently
is a well documented complication of the prune belly syndrome. Patients with the prune belly syndrome and urea-splitting urinary tract infections should be treated aggressively. If neurological symptoms develop in a prune belly syndrome patient a urea-splitting urinary tract infection should be suspected and a serum ammonia level should be obtained immediately. REFERENCES
1. Podolsky, D. K. and Isselbacher, K. J.: Derangements of hepatic metabolism. In: Harrison's Principles of Internal Medicine, 11th ed. Edited by E. Braunwald, K. J. Isselbacher, R. G. Petersdorf, J. D. Wilson, J.B. Martin and A. S. Fauci. New York: McGrawHill Book Co., vol. 2, chapt. 244, pp. 1309-1315, 1987. 2. Conn, H. 0. and Atterbury, C. E.: Cirrhosis. In: Diseases of the Liver, 6th ed. Edited by L. Schiff and E. R. Schiff. Philadelphia: J.B. Lippincott Co., chapt. 20, pp. 725-864, 1987. 3. Kuntze, J. R., Weinberg, A. C. and Ahlering, T. E.: Hyperammonemic coma due to proteus infection. J. Urol., 134: 972, 1985. 4. Samtoy, B. and DeBeukelaer, M. M.: Ammonia encephalopathy secondary to urinary tract infection with Proteus mirabilis. Pediatrics, 65: 294, 1980. 5. Ullman, M. A., Haecker, T. A. and Medani, C. R.: Hyperammonemic encephalopathy and urinary obstruction. New Engl. J. Med., 304: 1564, 1981. 6. Osler, W.: Congenital absence of the abdominal muscles, with distended and hypertrophied urinary bladder. Bull. Johns Hopkins Hosp., 12: 331, 1901. 7. Orloff, J. and Berliner, R. W.: The mechanism of the excretion of ammonia in the dog. J. Clin. Invest., 35: 223, 1956.
Vol. 142,
Printed in
HYPERAMJ\AONEMIC ENCEPHALOPATHY: COIVIPLICATION ASSOCIATED WITH THE PRUNE BELLY SYNDROME DAVID A. DIAMOND, ANNE BLIGHT
AND
PHILIP G. RANSLEY
From the Division of Urology, Department of Surgery, University of Massachusetts Medical Center, Worcester, Massachusetts, and The Great Ormond Street Hospital for Sick Children and The Institute of Urology, London, England
ABSTRACT
Hyperammonemic encephalopathy in the urological patient is a rare but grave condition. In the pediatric urological population it has been associated with massively dilated upper tracts and urinary infection with urea-splitting organisms. We report 2 cases of hyperammonemic encephalopathy in association with the prune belly syndrome. Both patients presented comatose with markedly elevated serum ammonia levels and Proteus mirabilis urinary tract infection. Intravenous antibiotics and catheter drainage resulted in dramatic reversal of the encephalopathy. The pathophysiology of hyperammonemic encephalopathy in association with the prune belly syndrome and a review of the literature are presented. (J. Ural., 142: 361-362, 1989) Hyperammonemic encephalopathy is a grave condition that usually is associated with hepatic dysfunction. We report 2 cases of hyperammonemic coma in children with the prune belly syndrome and Proteus mirabilis urinary tract infection in the absence of demonstrable liver disease. The pathophysiology of hyperammonemic encephalopathy in the prune belly syndrome is discussed. CASE REPORTS
Case 1. D. H., a 4-year-old boy, had the prune belly syndrome. As a neonate the patient was noted to void well and an excretory urogram (IVP) and diethylenetriaminepentaacetic acid renal scan demonstrated dilated but nonobstructed upper tracts. A voiding cystourethrogram demonstrated a large bladder without reflux and without urethral obstruction. During the next 4 years the patient did well until an Escherichia coli urinary tract infection developed that was treated successfully with oral trimethoprim-sulfamethoxazole. An IVP when he was 4 years old demonstrated dilated but nonobstructed upper tracts with a large capacity bladder. Within 1 week of these radiological studies mental status changes and violent behavior developed. The patient was hospitalized in an obtunded state but responsive to He was distended bladder. The bladder afebrile and had an was catheterized because of a large residual urine which was remarkable for numerous white cells and bacteria microThe urine was 9.0. Serum creatinine (normal 0.4 to blood urea nitrogen (BUN) 7 to and white blood count (normal 4.3 to 10.3 thousand per mm. Serum glutamic oxaloacetic and pyruvic transaminases, alkaline phosphatase and bilirubin, direct and total were normal. Emergency computerized tomography (CT) of the head was unremarkable. The patient was placed on a ventilator, with catheter drainage and parenteral antibiotics. Serum ammonia level was determined by the glutamate dehydrogenase enzyme technique using a Boehringer kit with photometric analysis in the ultraviolet range, and was 316 µg./ dl. (normal 15 to 55 µg./dl.). This level reached a peak of 368 µg./dL within 24 hours of hospitalization. Urine culture yielded greater than 10 6 P. mirabilis and blood culture was negative. By day 2 the serum ammonia level had decreased to 73 µg./dl. and by day 3 it had decreased to within normal limits at 33 µg./ dl. The mental status gradually improved and the patient was Accepted for publication January 23, 1989. 361
extubated on hospital day 3. Resolution of the sensorium was believed to be complete by day 7. Case 2. A.-G., a boy with the prune belly syndrome, as a neonate underwent an IVP and diethylenetriaminepentaacetic acid renal scan, which demonstrated dilated but nonobstructed upper tracts. A voiding cystourethrogram was remarkable for moderate reflux on the left side and reasonable urethral drainage. Serum creatinine as a neonate was 0.5 mg./dl. Because of the reflux status the patient was managed on suppressive antibiotics. The patient did well until he was 2 years old, when he presented comatose with a temperature of 38C. The creatinine was 0.6 mg./dl., BUN 12 mg./dl. and white blood count 18,600. He was mildly acidotic with a serum bicarbonate of 17 mg./dl. (normal 24 to 32 mmol./l.). Serum glutamic oxaloacetic and pyruvic transaminases, alkaline phosphatase and bilirubin, direct and total were normal. Urinalysis was remarkable for numerous white cells and bacteria microscopically, and a dipstick pH of 9.0. An emergency CT scan and lumbar puncture were unremarkable and electroencephalography demonstrated diffuse slowing. The patient was treated with catheter drainage and parenteral antibiotics. The serum ammonia level was 110 µg./dl. Urine culture was remarkable for greater than 106 P. mirabilis and blood culture was negative. On catheter drainage and parenteral antibiotics the serum ammonia decreased to 28 µg./dL within 48 and he became awake and communicative. The mental status normalized by 5. A followup radiological evaluation demonstrated poor a vesicoslower tract emptying that ultimately was relieved tomy. DISCUSSION
In man plasma ammonia is metabolized by l of 2 mechanisms: 1) ammonia may combine with glutamic acid to form glutamine (in a detoxification process) or 2) the ammonia that reaches the liver enters the Krebs-ornithine-urea cycle to be converted to urea, which is excreted by the kidneys. 1 Hyperammonemic coma usually is associated with altered hepatic metabolism of ammonia. Therefore, patients with liver disease, an acquired or congenital deficiency of hepatic enzymes of the Krebs urea cycle, Reye's syndrome or portocaval shunts are at particular risk. Hyperammonemic coma is a rare finding in the absence of liver disease. 2 Hyperammonemic coma has been reported in 5 patients with the prune belly syndrome and urinary tract infection with P. mirabilis. 3 - 5 The prune belly syndrome is the most common
.362
DIAMOND, BLIGHT AND RANSLEY
term for congenital absence or deficiency of the abdominal musculature accompanied by a large hypotonic bladder, dilated and tortuous ureters and bilateral cryptorchidism. 6 All 5 reported patients had markedly dilated urinary tracts. Only 1 patient had evidence of bladder outflow obstruction. If all of these patients had normal liver enzyme studies, why should they have been at risk for hyperammonemic coma? In solution, ammonia exists in equilibrium as the ammonium ion (NH4 +) or the free base (NHa). The free base (NHa) is lipid soluble and rapidly permeates all cell membranes, in contrast to the charged ammonium ion (NH4+). At a urine pH of 7.4, 1 per cent of the molecules exist as NH3 but at a urine pH of 9, 50 per cent of the molecules exist as NH3 • 4 In the alkaline urine that results when urea-splitting organisms infect the urinary tract, the free base (NHa) diffuses from the urinary tract into the blood stream, where it is converted to the poorly permeable ammonium ion (NH4+) in a process known as diffusion trapping.7 The combination of a massive ammonia load and an alkaline urine, both due to the urea-splitting infection, result in an elevated peripheral blood ammonia level. In all 5 prune belly syndrome patients with hyperammonemic coma there was urinary infection with a urea-splitting organism, resulting in an enormous release of ammonia and an alkaline urine. The massively dilated collecting systems produced an increased surface area through which ammonia could be absorbed. Although rare, hyperammonemic encephalopathy currently
is a well documented complication of the prune belly syndrome. Patients with the prune belly syndrome and urea-splitting urinary tract infections should be treated aggressively. If neurological symptoms develop in a prune belly syndrome patient a urea-splitting urinary tract infection should be suspected and a serum ammonia level should be obtained immediately. REFERENCES
1. Podolsky, D. K. and Isselbacher, K. J.: Derangements of hepatic metabolism. In: Harrison's Principles of Internal Medicine, 11th ed. Edited by E. Braunwald, K. J. Isselbacher, R. G. Petersdorf, J. D. Wilson, J.B. Martin and A. S. Fauci. New York: McGrawHill Book Co., vol. 2, chapt. 244, pp. 1309-1315, 1987. 2. Conn, H. 0. and Atterbury, C. E.: Cirrhosis. In: Diseases of the Liver, 6th ed. Edited by L. Schiff and E. R. Schiff. Philadelphia: J.B. Lippincott Co., chapt. 20, pp. 725-864, 1987. 3. Kuntze, J. R., Weinberg, A. C. and Ahlering, T. E.: Hyperammonemic coma due to proteus infection. J. Urol., 134: 972, 1985. 4. Samtoy, B. and DeBeukelaer, M. M.: Ammonia encephalopathy secondary to urinary tract infection with Proteus mirabilis. Pediatrics, 65: 294, 1980. 5. Ullman, M. A., Haecker, T. A. and Medani, C. R.: Hyperammonemic encephalopathy and urinary obstruction. New Engl. J. Med., 304: 1564, 1981. 6. Osler, W.: Congenital absence of the abdominal muscles, with distended and hypertrophied urinary bladder. Bull. Johns Hopkins Hosp., 12: 331, 1901. 7. Orloff, J. and Berliner, R. W.: The mechanism of the excretion of ammonia in the dog. J. Clin. Invest., 35: 223, 1956.