Hyperammonemia in a child with short bowel syndrome: urea cycle disorder or complication of altered gastrointestinal function?
Biochemical/Metabolic and Therapeutics
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Introduction
Hyperammonemia is an acute condition frequently encountered in the field of biochemical genetics and can result from a variety of underlying etiologies. While many of these etiologies are inborn errors of metabolism, hyperammonemia can result from acquired pathologies such as non-genetic liver damage, infections, and medications. Elevated ammonia levels have also been recognized in adult patients who have undergone bariatric surgery or have short bowel syndrome, thought to be related to a combination of catabolism from decreased intake, malabsorption of nutrients (including urea cycle intermediates and essential amino acids required for anabolism), and altered intestinal microbiota. However, to our knowledge, this phenomenon has not before been demonstrated in the pediatric population.
Case Presentation
Here we present a 4-year old male with a history of short bowel syndrome secondary to malrotation with volvulus as an infant, G-tube dependence, episodes of D-lactic acidosis, and esophageal strictures who presented to the hospital with headaches, emesis, and progressive lethargy and was found to be hyperammonemic with a peak ammonia level of 397 umol/L.
Diagnostic Workup
Subsequent biochemical laboratory work-up included urine organic acids, plasma amino acids, plasma carnitine, plasma acylcarnitine profile, and vitamin B12 level. Urine organic acids were significant for massively elevated urine orotic acid of 133.5 mmol/mol Cr as well as elevated 3-OH-isovaleric acid, 3-OH-propionic acid, methylcitric acid, methylmalonic acid, tiglyglycine, propionylglycine, and 3-methylcrotonylglycine. Plasma amino acids were globally low but plasma arginine (7 umol/L) and plasma citrulline (5 umol/L) were disproportionately decreased. Total carnitine (22 umol/L) and free carnitine (12 umol/L) were low and the acylcarnitine profile was significant for elevated propionylcarnitine (6.92 umol/L). Vitamin B12 was decreased (128 pg/mL). The orotic aciduria and low plasma arginine and citrulline were concerning for a urea cycle disorder, particularly for Ornithine Transcarbamylase (OTC) Deficiency. The remainder of his abnormal urine organic acids and elevated plasma propionylcarnitine were thought to be related to vitamin B12 deficiency. Molecular testing via a hyperammonemia gene panel was negative.
Treatment and Management
Initial management of the patient’s hyperammonemia consisted of rifaximin, lactulose, 10% dextrose at 1.5 times maintenance rate, intralipids 1g/kg/day, and an IV ammonia scavenger. He was later transitioned to an enteral ammonia scavenger and supplementation with enteral citrulline. In regards to his dietary management, original enteral protein goals were 1.5g/kg/day in order to balance the need for low protein with a potential urea cycle disorder and malabsorption from short bowel syndrome. However, plasma amino acid levels remained low until TPN was initiated and the amino acid concentration in the TPN alone was increased to 1g/kg/day.
Outcome and Follow-Up
Since this time, the patient has not had any further episodes of hyperammonemia and his nutritional status has greatly improved on the recommended daily intake (RDI) of protein for age, TPN, citrulline, and the enteral ammonia scavenger. Due to concerns for liver injury from long-term TPN use, his GI team has recently been working on decreasing his TPN and incorporating essential amino acids into his enteral intake with close monitoring. He has undergone evaluation for liver and small bowel transplant and is due for follow-up evaluation this year.
Discussion
Since the patient has done so well on TPN receiving the RDI of protein for age and his genetic testing was negative, it brings into question as to whether the hyperammonemia and orotic aciduria could have been nutritional as opposed to an inborn error of metabolism. There are currently no CLIA approved labs that can offer OTC enzyme testing on liver tissue to confirm a diagnosis of OTC deficiency. He has been enrolled in a research study that offers long read of the OTC gene to look at introns and promotors for pathogenic variants.
Conclusion
In summary, a 4-year old male with a history of short bowel syndrome developed significant hyperammonemia that was originally attributed to an inborn error of metabolism based on the results of his biochemical work-up, but may instead be secondary to the nutritional consequences of short bowel syndrome given his so far negative molecular testing and his clinical improvement on TPN and the RDI of protein for age. If this is the case, he would be the youngest patient reported in the literature to demonstrate this phenomenon.
Hyperammonemia is an acute condition frequently encountered in the field of biochemical genetics and can result from a variety of underlying etiologies. While many of these etiologies are inborn errors of metabolism, hyperammonemia can result from acquired pathologies such as non-genetic liver damage, infections, and medications. Elevated ammonia levels have also been recognized in adult patients who have undergone bariatric surgery or have short bowel syndrome, thought to be related to a combination of catabolism from decreased intake, malabsorption of nutrients (including urea cycle intermediates and essential amino acids required for anabolism), and altered intestinal microbiota. However, to our knowledge, this phenomenon has not before been demonstrated in the pediatric population.
Case Presentation
Here we present a 4-year old male with a history of short bowel syndrome secondary to malrotation with volvulus as an infant, G-tube dependence, episodes of D-lactic acidosis, and esophageal strictures who presented to the hospital with headaches, emesis, and progressive lethargy and was found to be hyperammonemic with a peak ammonia level of 397 umol/L.
Diagnostic Workup
Subsequent biochemical laboratory work-up included urine organic acids, plasma amino acids, plasma carnitine, plasma acylcarnitine profile, and vitamin B12 level. Urine organic acids were significant for massively elevated urine orotic acid of 133.5 mmol/mol Cr as well as elevated 3-OH-isovaleric acid, 3-OH-propionic acid, methylcitric acid, methylmalonic acid, tiglyglycine, propionylglycine, and 3-methylcrotonylglycine. Plasma amino acids were globally low but plasma arginine (7 umol/L) and plasma citrulline (5 umol/L) were disproportionately decreased. Total carnitine (22 umol/L) and free carnitine (12 umol/L) were low and the acylcarnitine profile was significant for elevated propionylcarnitine (6.92 umol/L). Vitamin B12 was decreased (128 pg/mL). The orotic aciduria and low plasma arginine and citrulline were concerning for a urea cycle disorder, particularly for Ornithine Transcarbamylase (OTC) Deficiency. The remainder of his abnormal urine organic acids and elevated plasma propionylcarnitine were thought to be related to vitamin B12 deficiency. Molecular testing via a hyperammonemia gene panel was negative.
Treatment and Management
Initial management of the patient’s hyperammonemia consisted of rifaximin, lactulose, 10% dextrose at 1.5 times maintenance rate, intralipids 1g/kg/day, and an IV ammonia scavenger. He was later transitioned to an enteral ammonia scavenger and supplementation with enteral citrulline. In regards to his dietary management, original enteral protein goals were 1.5g/kg/day in order to balance the need for low protein with a potential urea cycle disorder and malabsorption from short bowel syndrome. However, plasma amino acid levels remained low until TPN was initiated and the amino acid concentration in the TPN alone was increased to 1g/kg/day.
Outcome and Follow-Up
Since this time, the patient has not had any further episodes of hyperammonemia and his nutritional status has greatly improved on the recommended daily intake (RDI) of protein for age, TPN, citrulline, and the enteral ammonia scavenger. Due to concerns for liver injury from long-term TPN use, his GI team has recently been working on decreasing his TPN and incorporating essential amino acids into his enteral intake with close monitoring. He has undergone evaluation for liver and small bowel transplant and is due for follow-up evaluation this year.
Discussion
Since the patient has done so well on TPN receiving the RDI of protein for age and his genetic testing was negative, it brings into question as to whether the hyperammonemia and orotic aciduria could have been nutritional as opposed to an inborn error of metabolism. There are currently no CLIA approved labs that can offer OTC enzyme testing on liver tissue to confirm a diagnosis of OTC deficiency. He has been enrolled in a research study that offers long read of the OTC gene to look at introns and promotors for pathogenic variants.
Conclusion
In summary, a 4-year old male with a history of short bowel syndrome developed significant hyperammonemia that was originally attributed to an inborn error of metabolism based on the results of his biochemical work-up, but may instead be secondary to the nutritional consequences of short bowel syndrome given his so far negative molecular testing and his clinical improvement on TPN and the RDI of protein for age. If this is the case, he would be the youngest patient reported in the literature to demonstrate this phenomenon.