Noncirrhotic hyperammonemia causing relapsing altered mental status Chibuzo Clement Odigwe, MD, Binod Khatiwada, MD, Christopher Holbrook, MD, Ifeoma Sylvia Ekeh, MD, Chukwuemeka Uzoka, MD, Isaac Ikwu, MD, and Bishwas Upadhyay, MD
Hyperammonemia is a recognized cause of encephalopathy. However, it is commonly seen in patients with liver disease. The clinical entity of noncirrhotic hyperammonemia is now being increasingly recognized. We report a man who presented to our hospital with relapsing altered mental status later diagnosed as noncirrhotic hyperammonemia.
O
ne of the most common causes of emergency room presentation is an acute or progressive deterioration in mental status. In most cases, a careful history, physical examination, and some basic investigation may suggest the cause. However, in some patients, the cause may not be readily obvious, thus presenting a clinical dilemma. In the case of altered mental status of unknown etiology, the differential diagnosis is wide and includes toxic-metabolic, traumatic, functional, vascular, and infectious causes. The syndrome of noncirrhotic or nonhepatic hyperammonemia, by which we mean raised blood ammonia levels in the setting of normal liver function, is an increasingly recognized and reported cause of altered mental status (1–5). Although it is not very common, it is important for clinicians to be aware of this entity, since the timely diagnosis requires a high index of suspicion, particularly in predisposed patients, and the therapeutic outcome is good if well managed.
CASE PRESENTATION A 69-year-old Hispanic man was brought to our hospital with complaints of a progressive deterioration in mental status of about 1 week duration. He was having some difficulty finding appropriate words, and this was said to be maximal on the day of presentation. He was repeating words incomprehensibly. He was severely ataxic and unable to walk, which he could do prior to the onset of symptoms. There was no history of headache, chest pain, or seizure. He did not complain of numbness or tingling in any part of his body. His appetite was normal, although he was constipated in the preceding days. He had had previous admissions for recurrent upper gastrointestinal bleeds and bacteremias. He had an unresectable pancreatic cancer for which he received some radiotherapy and chemotherapy with 5-fluorouracil in the past. He also had hyperlipidemia, hypertension, coronary artery disease, and valvular heart disease, for which he had a bioprosthetic aortic valve replacement. 472
His medications included ferrous gluconate, fish oil plus cholecalciferol, fluticasone inhaler, furosemide, hydrocodoneacetaminophen, metoprolol, pancrelipase, pantoprazole, potassium chloride, senna, simvastatin, and sucralfate. He had no known drug or food allergies. He lived at home with his wife and had a support network of their children and several family friends. His blood pressure was 161/93 mm Hg; heart rate, 67 beats per minute; respiratory rate, 16 breaths per minute; oral temperature, 97.9°F; and oxygen saturation, 99% on room air. His body mass index was 19.4 kg/m2. He was alert to name only and was able to follow simple commands. He had no pronator drift in the upper extremities, and power was grade 2/5 in the lower limbs. He had no tremors. Pinprick sensation was normal on both upper and lower extremities. There were no gaze palsies and his speech was not slurred but he had perseveration. He had a nontender, nonpulsatile firm mass in the epigastric region that was about 5 cm × 4 cm with ill-defined borders. His initial laboratory values appear in the Table. A computed tomography scan of the brain was negative for hemorrhage, edema, or mass effect, and the ventricles were normal in size. There was mild generalized atrophy and subtle scattered white matter with low density consistent with subtle chronic ischemic changes. His chest radiograph did not suggest any consolidation, pneumothorax, or pleural effusion. The patient slowly improved over the next 2 days on conservative management with fluids and his medications, but then deteriorated again, becoming lethargic and completely nonverbal within 24 hours. He never had a fever or oxygen desaturation. An electroencephalogram showed mild generalized slowing, and left anterior temporal sharp waves suggested underlying cortical hyperexcitability. The differential diagnosis was expanded, and we checked urine toxicology studies, antinuclear antibody, serum vitamin B12, thyroid-stimulating hormone, rapid plasma reagin, and serum thiamine; all were within normal limits. From the Department of Medicine, St. Joseph Hospital, 2900 North Lake Shore Drive, Chicago, Illinois. Dr. Upadhyay is currently with the Department of Medicine, University of Nevada, Reno. Corresponding author: Chibuzo Clement Odigwe, MD, Department of Medicine, St. Joseph Hospital, 2900 North Lake Shore Drive, Chicago, IL 60657 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2015;28(4):472–474
Table. Initial laboratory values Test White blood cell
(×109/L)
(×109/L)
Result
Normal range
4.9
4.0–10
254
150–350
Hemoglobin (g/dL)
8.4
14–17
Mean cell volume (fL)
83.6
80–100
Serum creatinine (mg/dL)
0.8
0.7–1.3
Blood urea nitrogen (mg/dL)
17
8–20
Platelet count
Blood glucose (mg/dL)
115
70–100
Lactic acid (mmol/L)
2.44
0.67–1.8
Albumin (g/dL)
2.8
3.5–5.5
Sodium (mEq/L)
145
136–145
Potassium (mEq/L)
3.5
3.5–5.0
Chloride (mEq/L)
110
98–106
Bicarbonate (mEq/L)
21
23–28
Ionized calcium (mmol/L)
1.16
1.1–1.35
Aspartate transaminase (units/L)
28
0–35
Alanine transaminase (units/L)
17
0–35
Alkaline phosphatase (units/L)
132
36–92
Erythrocyte sedimentation rate (mm/h)
61
0–22
The serum ammonia level was 123 umol/L (normal, 10–40 umol/L). The patient was treated with lactulose enema, and within 1 hour his mental status improved dramatically. He had no recollection of the prior events. Repeat serum ammonia estimation after about 12 hours was 49 umol/L. He remained at his baseline for a further 48 hours and was discharged home with the addition of lactulose to his home medications. He continued to follow up with his primary care doctor as an outpatient. DISCUSSION Hyperammonemia refers to an increase in the level of ammonia in the blood. Ammonia is a normal constituent of all body fluids, and the body excretes excess ammonia as urea following synthesis in the liver by the enzymes commonly referred to as urea cycle enzymes. Ammonia in humans is generated by bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine nucleotide cycle, and amino acid transamination in skeletal muscle and other metabolic processes in the kidneys and the liver. If ammonia accumulates in the blood, it can cross the blood-brain barrier and result in the neurological disorders associated with hyperammonemia (1). Primary causes of hyperammonemia include congenital enzymopathies in the urea cycle, such as deficiencies of ornithine transcarbamoylase and argininosuccinate lyase. These disorders can lead to varying degrees of hyperammonemia depending on the enzyme affected and on whether the genetic deficiency is heterozygous or homozygous. Secondary hyperammonemia occurs commonly in the presence of hepatic disorders leading October 2015
to portosystemic encephalopathy, but can occur in the absence of hepatic dysfunction in disorders like Reye’s syndrome, ureterosigmoidostomy, and infection in a neurogenic bladder. Drug toxicity as a result of disruption of mitochondrial pathways by drugs like cyanide, carbamazepine, valproic acid, iron, and cytotoxics can also cause secondary hyperammonemia, and this is thought to be the main mechanism by which nonhepatic or noncirrhotic hyperammonemia can occur in people exposed to these drugs (2, 4–9). Common chemotherapeutic agents that have been implicated in the syndrome of nonhepatic/noncirrhotic hyperammonemia include cytarabine, vincristine, amsacrine, etoposide, L-asparaginase, cyclophosphamide, and 5-fluorouracil in various combinations. On the other hand, hyperammonemia is also known to be a rare complication of malignancies with and without chemotherapy (4). It has been reported as complicating acute leukemias, multiple myeloma, and solid organ tumors. Recently, chemotherapeutic regimens for pancreatic cancer like FOLFIRINOX have also been implicated. Development of splenorenal shunts can manifest with hyperammonemia as well (10). Noncirrhotic hyperammonemia as a cause of altered mental status remains a diagnosis of exclusion. In our patient, the elevated blood ammonia level and the rapid resolution of symptoms coupled with the reduction of his blood ammonia level led us to suspect that hyperammonemia may have accounted for his presentation. His clinical presentation and subsequent clinical course were similar to those of patients described in prior case reports of noncirrhotic/nonhepatic hyperammonemia (2–8). The exact cause of hyperammonemia in our patient was not certain. He had an unresectable pancreatic malignancy, and there was a remote history of administration of 5-fluorouracil as part of his treatment (5). 5-Fluorouracil is one of the chemotherapeutic agents that have been implicated as a cause of nonhepatic/noncirrhotic hyperammonemia (6, 11). We are also unable to completely exclude any minor or subclinical infection in the few days prior to his presentation. Minor infections like pharyngitis have been reported to lead to a slightly more catabolic state and trigger hyperammonemia, particularly in people with partial deficiencies in urea cycle enzymes (1). Plans for further workup included an evaluation for urea cycle enzyme deficiency in view of reports of partial deficiencies becoming clinically apparent in people in middle age (1). The syndrome of noncirrhotic or nonhepatic hyperammonemia has also been described in association with gastric bypass surgery. A report by Fenves et al (3) described the case of 5 women who lapsed into coma and died in spite of treatment with lactulose, antibiotics, nutritional repletion, and supportive care. The diagnosis of hyperammonemia may be challenging and requires a high index of suspicion. However, it should be considered when a clear cause of altered mental status is not obvious after basic investigations. As an initial step, it is advisable to exclude hypo- or hyperglycemia, azotemia, liver failure, electrolyte imbalance, sepsis, structural and vascular pathologies like stroke, and central nervous system involvement by cancers.
Noncirrhotic hyperammonemia causing relapsing altered mental status
473
Thereafter, the evaluation can be expanded to consider less common etiologies. 1. 2.
3.
4.
5.
474
Crisan E, Ramachandran TS, eds. Hyperammonemia. Medscape. Available at http://emedicine.medscape.com/article/1174503; last updated April 21, 2014. LaBuzetta JN, Yao JZ, Bourque DL, Zivin J. Adult nonhepatic hyperammonemia: a case report and differential diagnosis. Am J Med 2010;123(10):885–891. Fenves A, Boland CR, Lepe R, Rivera-Torres P, Spechler SJ. Fatal hyperammonemic encephalopathy after gastric bypass surgery. Am J Med 2008;121(1):e1–e2. Hawkes ND, Thomas GA, Jurewicz A, Williams OM, Hillier CE, McQueen IN, Shortland G. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J 2001;77(913):717–722. Weng TI, Shih FF, Chen WJ. Unusual causes of hyperammonemia in the ED. Am J Emerg Med 2004;22(2):105–107.
6.
Nott L, Price TJ, Pittman K, Patterson K, Fletcher J. Hyperammonemia encephalopathy: an important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 2007;48(9):1702–1711. 7. Vivekanandan S, Nayak SD. Valproate-induced hyperammonemic encephalopathy enhanced by topiramate and phenobarbitone: a case report and an update. Ann Indian Acad Neurol 2010;13(2):145–147. 8. Labib PL, Wing S, Bhowmik A. Transient hyperammonaemia in a patient with confusion: challenges with the differential diagnosis. BMJ Case Rep 2011 Sep 4;2011. 9. Pegg EJ, Zaman F. Sodium valproate-related hyperammonaemic encephalopathy. BMJ Case Rep 2014 Apr 10;2014. 10. Rogal SS, Hu A, Bandi R, Shaikh O. Novel therapy for non-cirrhotic hyperammonemia due to a spontaneous splenorenal shunt. World J Gastroenterol 2014;20(25):8288–8291. 11. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75(3):464–465.
Baylor University Medical Center Proceedings
Volume 28, Number 4
Hyperammonemia is a recognized cause of encephalopathy. However, it is commonly seen in patients with liver disease. The clinical entity of noncirrhotic hyperammonemia is now being increasingly recognized. We report a man who presented to our hospital with relapsing altered mental status later diagnosed as noncirrhotic hyperammonemia.
O
ne of the most common causes of emergency room presentation is an acute or progressive deterioration in mental status. In most cases, a careful history, physical examination, and some basic investigation may suggest the cause. However, in some patients, the cause may not be readily obvious, thus presenting a clinical dilemma. In the case of altered mental status of unknown etiology, the differential diagnosis is wide and includes toxic-metabolic, traumatic, functional, vascular, and infectious causes. The syndrome of noncirrhotic or nonhepatic hyperammonemia, by which we mean raised blood ammonia levels in the setting of normal liver function, is an increasingly recognized and reported cause of altered mental status (1–5). Although it is not very common, it is important for clinicians to be aware of this entity, since the timely diagnosis requires a high index of suspicion, particularly in predisposed patients, and the therapeutic outcome is good if well managed.
CASE PRESENTATION A 69-year-old Hispanic man was brought to our hospital with complaints of a progressive deterioration in mental status of about 1 week duration. He was having some difficulty finding appropriate words, and this was said to be maximal on the day of presentation. He was repeating words incomprehensibly. He was severely ataxic and unable to walk, which he could do prior to the onset of symptoms. There was no history of headache, chest pain, or seizure. He did not complain of numbness or tingling in any part of his body. His appetite was normal, although he was constipated in the preceding days. He had had previous admissions for recurrent upper gastrointestinal bleeds and bacteremias. He had an unresectable pancreatic cancer for which he received some radiotherapy and chemotherapy with 5-fluorouracil in the past. He also had hyperlipidemia, hypertension, coronary artery disease, and valvular heart disease, for which he had a bioprosthetic aortic valve replacement. 472
His medications included ferrous gluconate, fish oil plus cholecalciferol, fluticasone inhaler, furosemide, hydrocodoneacetaminophen, metoprolol, pancrelipase, pantoprazole, potassium chloride, senna, simvastatin, and sucralfate. He had no known drug or food allergies. He lived at home with his wife and had a support network of their children and several family friends. His blood pressure was 161/93 mm Hg; heart rate, 67 beats per minute; respiratory rate, 16 breaths per minute; oral temperature, 97.9°F; and oxygen saturation, 99% on room air. His body mass index was 19.4 kg/m2. He was alert to name only and was able to follow simple commands. He had no pronator drift in the upper extremities, and power was grade 2/5 in the lower limbs. He had no tremors. Pinprick sensation was normal on both upper and lower extremities. There were no gaze palsies and his speech was not slurred but he had perseveration. He had a nontender, nonpulsatile firm mass in the epigastric region that was about 5 cm × 4 cm with ill-defined borders. His initial laboratory values appear in the Table. A computed tomography scan of the brain was negative for hemorrhage, edema, or mass effect, and the ventricles were normal in size. There was mild generalized atrophy and subtle scattered white matter with low density consistent with subtle chronic ischemic changes. His chest radiograph did not suggest any consolidation, pneumothorax, or pleural effusion. The patient slowly improved over the next 2 days on conservative management with fluids and his medications, but then deteriorated again, becoming lethargic and completely nonverbal within 24 hours. He never had a fever or oxygen desaturation. An electroencephalogram showed mild generalized slowing, and left anterior temporal sharp waves suggested underlying cortical hyperexcitability. The differential diagnosis was expanded, and we checked urine toxicology studies, antinuclear antibody, serum vitamin B12, thyroid-stimulating hormone, rapid plasma reagin, and serum thiamine; all were within normal limits. From the Department of Medicine, St. Joseph Hospital, 2900 North Lake Shore Drive, Chicago, Illinois. Dr. Upadhyay is currently with the Department of Medicine, University of Nevada, Reno. Corresponding author: Chibuzo Clement Odigwe, MD, Department of Medicine, St. Joseph Hospital, 2900 North Lake Shore Drive, Chicago, IL 60657 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2015;28(4):472–474
Table. Initial laboratory values Test White blood cell
(×109/L)
(×109/L)
Result
Normal range
4.9
4.0–10
254
150–350
Hemoglobin (g/dL)
8.4
14–17
Mean cell volume (fL)
83.6
80–100
Serum creatinine (mg/dL)
0.8
0.7–1.3
Blood urea nitrogen (mg/dL)
17
8–20
Platelet count
Blood glucose (mg/dL)
115
70–100
Lactic acid (mmol/L)
2.44
0.67–1.8
Albumin (g/dL)
2.8
3.5–5.5
Sodium (mEq/L)
145
136–145
Potassium (mEq/L)
3.5
3.5–5.0
Chloride (mEq/L)
110
98–106
Bicarbonate (mEq/L)
21
23–28
Ionized calcium (mmol/L)
1.16
1.1–1.35
Aspartate transaminase (units/L)
28
0–35
Alanine transaminase (units/L)
17
0–35
Alkaline phosphatase (units/L)
132
36–92
Erythrocyte sedimentation rate (mm/h)
61
0–22
The serum ammonia level was 123 umol/L (normal, 10–40 umol/L). The patient was treated with lactulose enema, and within 1 hour his mental status improved dramatically. He had no recollection of the prior events. Repeat serum ammonia estimation after about 12 hours was 49 umol/L. He remained at his baseline for a further 48 hours and was discharged home with the addition of lactulose to his home medications. He continued to follow up with his primary care doctor as an outpatient. DISCUSSION Hyperammonemia refers to an increase in the level of ammonia in the blood. Ammonia is a normal constituent of all body fluids, and the body excretes excess ammonia as urea following synthesis in the liver by the enzymes commonly referred to as urea cycle enzymes. Ammonia in humans is generated by bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine nucleotide cycle, and amino acid transamination in skeletal muscle and other metabolic processes in the kidneys and the liver. If ammonia accumulates in the blood, it can cross the blood-brain barrier and result in the neurological disorders associated with hyperammonemia (1). Primary causes of hyperammonemia include congenital enzymopathies in the urea cycle, such as deficiencies of ornithine transcarbamoylase and argininosuccinate lyase. These disorders can lead to varying degrees of hyperammonemia depending on the enzyme affected and on whether the genetic deficiency is heterozygous or homozygous. Secondary hyperammonemia occurs commonly in the presence of hepatic disorders leading October 2015
to portosystemic encephalopathy, but can occur in the absence of hepatic dysfunction in disorders like Reye’s syndrome, ureterosigmoidostomy, and infection in a neurogenic bladder. Drug toxicity as a result of disruption of mitochondrial pathways by drugs like cyanide, carbamazepine, valproic acid, iron, and cytotoxics can also cause secondary hyperammonemia, and this is thought to be the main mechanism by which nonhepatic or noncirrhotic hyperammonemia can occur in people exposed to these drugs (2, 4–9). Common chemotherapeutic agents that have been implicated in the syndrome of nonhepatic/noncirrhotic hyperammonemia include cytarabine, vincristine, amsacrine, etoposide, L-asparaginase, cyclophosphamide, and 5-fluorouracil in various combinations. On the other hand, hyperammonemia is also known to be a rare complication of malignancies with and without chemotherapy (4). It has been reported as complicating acute leukemias, multiple myeloma, and solid organ tumors. Recently, chemotherapeutic regimens for pancreatic cancer like FOLFIRINOX have also been implicated. Development of splenorenal shunts can manifest with hyperammonemia as well (10). Noncirrhotic hyperammonemia as a cause of altered mental status remains a diagnosis of exclusion. In our patient, the elevated blood ammonia level and the rapid resolution of symptoms coupled with the reduction of his blood ammonia level led us to suspect that hyperammonemia may have accounted for his presentation. His clinical presentation and subsequent clinical course were similar to those of patients described in prior case reports of noncirrhotic/nonhepatic hyperammonemia (2–8). The exact cause of hyperammonemia in our patient was not certain. He had an unresectable pancreatic malignancy, and there was a remote history of administration of 5-fluorouracil as part of his treatment (5). 5-Fluorouracil is one of the chemotherapeutic agents that have been implicated as a cause of nonhepatic/noncirrhotic hyperammonemia (6, 11). We are also unable to completely exclude any minor or subclinical infection in the few days prior to his presentation. Minor infections like pharyngitis have been reported to lead to a slightly more catabolic state and trigger hyperammonemia, particularly in people with partial deficiencies in urea cycle enzymes (1). Plans for further workup included an evaluation for urea cycle enzyme deficiency in view of reports of partial deficiencies becoming clinically apparent in people in middle age (1). The syndrome of noncirrhotic or nonhepatic hyperammonemia has also been described in association with gastric bypass surgery. A report by Fenves et al (3) described the case of 5 women who lapsed into coma and died in spite of treatment with lactulose, antibiotics, nutritional repletion, and supportive care. The diagnosis of hyperammonemia may be challenging and requires a high index of suspicion. However, it should be considered when a clear cause of altered mental status is not obvious after basic investigations. As an initial step, it is advisable to exclude hypo- or hyperglycemia, azotemia, liver failure, electrolyte imbalance, sepsis, structural and vascular pathologies like stroke, and central nervous system involvement by cancers.
Noncirrhotic hyperammonemia causing relapsing altered mental status
473
Thereafter, the evaluation can be expanded to consider less common etiologies. 1. 2.
3.
4.
5.
474
Crisan E, Ramachandran TS, eds. Hyperammonemia. Medscape. Available at http://emedicine.medscape.com/article/1174503; last updated April 21, 2014. LaBuzetta JN, Yao JZ, Bourque DL, Zivin J. Adult nonhepatic hyperammonemia: a case report and differential diagnosis. Am J Med 2010;123(10):885–891. Fenves A, Boland CR, Lepe R, Rivera-Torres P, Spechler SJ. Fatal hyperammonemic encephalopathy after gastric bypass surgery. Am J Med 2008;121(1):e1–e2. Hawkes ND, Thomas GA, Jurewicz A, Williams OM, Hillier CE, McQueen IN, Shortland G. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J 2001;77(913):717–722. Weng TI, Shih FF, Chen WJ. Unusual causes of hyperammonemia in the ED. Am J Emerg Med 2004;22(2):105–107.
6.
Nott L, Price TJ, Pittman K, Patterson K, Fletcher J. Hyperammonemia encephalopathy: an important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 2007;48(9):1702–1711. 7. Vivekanandan S, Nayak SD. Valproate-induced hyperammonemic encephalopathy enhanced by topiramate and phenobarbitone: a case report and an update. Ann Indian Acad Neurol 2010;13(2):145–147. 8. Labib PL, Wing S, Bhowmik A. Transient hyperammonaemia in a patient with confusion: challenges with the differential diagnosis. BMJ Case Rep 2011 Sep 4;2011. 9. Pegg EJ, Zaman F. Sodium valproate-related hyperammonaemic encephalopathy. BMJ Case Rep 2014 Apr 10;2014. 10. Rogal SS, Hu A, Bandi R, Shaikh O. Novel therapy for non-cirrhotic hyperammonemia due to a spontaneous splenorenal shunt. World J Gastroenterol 2014;20(25):8288–8291. 11. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75(3):464–465.
Baylor University Medical Center Proceedings
Volume 28, Number 4
