Differential diagnosis includes posterior reversible encephalopathy syndrome, seizure activity, metabolic and hepatic encephalopathy, and diffuse hypoxic-ischemic injury [ 66 ]. Exclusion of an overlapping effect of hypoxic injury or seizure activity on imaging findings may be difficult, but very symmetric involvement of cingulate and insular gyri favor a toxic encephalopathy [ 66 ]. Acute treatments of hyperammonemia are geared towards lowering the blood ammonia level and manage seizures, cerebral edema, and elevated intracranial pressure.
Continuing treatments may target the specific etiology of hyperammonemia such as inborn errors of metabolism and vary with the condition. Nonabsorbable disaccharides, which decrease intestinal ammonia production and absorption, are an established first-line therapy for hepatic encephalopathy and the mainstay of treatment for chronic encephalopathy; however, they do not affect mortality [ 70 ]. Antibiotics that decrease enteric ammonia production by reducing the amount of urease-producing bacteria are another treatment option.
Neomycin, an antibiotic and glutaminase inhibitor, has been FDA approved for use in acute hepatic encephalopathy but is also commonly used with lactulose as off-label treatment for chronic encephalopathy [ 71 ]. Rifaximin, a nonabsorbable antibiotic derivative, is used as first-line or in addition to nonabsorbable disaccharides in acute or chronic encephalopathy [ 72 ]. Sodium benzoate or sodium phenyl acetate enhances alternative pathways of ammonia metabolism and subsequent excretion via urine [ 33 ].
Emergent hemodialysis can be used to rapidly, though temporarily, decrease serum ammonia, with conventional hemodialysis offering the highest ammonium clearance rate of all dialysis methods [ 73 ]. Data and practices of management for elevated ICP and cerebral edema are largely available from observations in fulminant hepatic failure and may not apply to isolated hyperammonemia. Usual management includes hyperosmolar agents and propofol sedation [ 74 ].
While mannitol used to be the mainstay of therapy despite doubts about efficacy [ 75 ], hypertonic saline has gained more attention [ 76 ]. For medically refractory intracranial hypertension, decompressive craniectomy can be considered for a potential positive outcome [ 77 ].
ICP monitoring and transcranial Doppler sonography may be used to assist in diagnosis and monitoring of treatment effect [ 78 ], but ICP monitoring has been shown to have potential detrimental effects in absence of mortality benefit [ 79 ]. Introduction of a diet with a favorable calorie-to-nitrogen ratio and restriction of exogenous protein is a supporting measure [ 80 ].
L-Carnitine plays a critical role in the intermediary metabolism of fatty acids and their transport across mitochondrial membranes and has been shown to be of use in treatment of inborn errors of metabolism [ 81 ]. Supplementation with L-carnitine in urea-cycle disorders may lower the frequency of attacks [ 82 ].
While primary treatment for valproic acid induced hyperammonemia is withdrawal of the drug and limitation of potentiating drugs such as phenobarbital and phenytoin [ 83 ], treatment of valproic acid induced hyperammonemia with L-carnitine has been reported to improve both symptoms and survival [ 84 ].
L-Ornithine-L-aspartate increases muscle ammonia metabolism and has been shown to be beneficial in clinically manifest hepatic encephalopathy [ 85 ]. Arginine, the immediate precursor of ornithine, can serve as treatment of hyperammonemia in urea-cycle disorders by replenishing the urea-cycle substrates [ 86 ]. Liver transplantation is an important treatment modality in urea-cycle disorders, with high survival rates that are superior to survival in liver transplantation for other diseases [ 87 ].
Portosystemic shunts may be obliterated surgically or by interventional radiological techniques but, depending on the type, may also require liver transplantation [ 88 ]. Several case reports have described acute onset of hyperammonemia due to late-onset inborn errors of metabolism in previously healthy adolescents or adults.
The majority of these cases are fatal [ 89 — 92 ]. Panlaqui et al. Mahmood and Nugent describe a year-old woman with late-onset OTC deficiency unmasked by gastrointestinal hemorrhage, presenting with encephalopathy [ 94 ]. Wendell et al. U-King-Im et al. Unlike our patient, these four described patients all had severe systemic disease or hepatic failure, namely, 1 status after heart-lung transplantation with multiple organ dysfunction and sepsis, 2 fulminant acute hepatic failure, 3 severe sepsis in setting of chronic cirrhosis, and 4 severe sepsis in a hepatic transplant patient with hepatorenal syndrome.
All four patients had MRI findings delineating the characteristic findings of hyperammonemia. Only one patient had a good outcome [ 66 ]. Rosario et al. We therefore present a novel and unique case of an adult with late-onset OTC deficiency, with very severe clinical manifestation and very high ammonia levels, as well as extensive MRI findings characteristic for hyperammonemic encephalopathy.
Our case highlights that extensive imaging findings can be reversible in late-onset OTC deficiency and that outcome can be excellent if correctly diagnosed and aggressively and rapidly treated. Hyperammonemia should be considered in the differential diagnosis for encephalopathy and seizures, especially in presence of MRI findings of bilateral symmetric involvement of insular and cingulate cortices.
In absence of hepatic dysfunction, hyperammonemia can be caused by increased ammonia production or decreased ammonia excretion. Aggressive management with ammonia-lowering measures, cerebral edema, and increased intracranial pressure is warranted. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Ruby Upadhyay, 1 Thomas P. Bleck, 2 and Katharina M. Academic Editor: Piotr K.
Received 13 Jul Accepted 28 Aug Published 21 Sep Abstract Purpose. Background Ammonia is a highly potent neurotoxin well known for its implication in hepatic encephalopathy [ 1 ]. Case Presentation A year-old male business manager with past medical history of hypertension, diabetes mellitus, and intermittent sinusitis was transferred to our tertiary care center for progressive encephalopathy and concern for nonconvulsive status epilepticus.
Figure 1. MRI of the brain a DWI sequence, b FLAIR sequence on day 3 after presentation, showing extensive areas of restricted diffusion with associated FLAIR hyperintensity involving bilateral temporal lobes, bilateral insular, bilateral frontal, and parietal regions in cortical and subcortical areas and diffuse mild effacement of the cerebral sulci.
Figure 2. EEG on hospital day 3, showing theta frequency slowing and artifacts from spontaneous horizontal and vertical eye movements but no triphasic activity and no epileptiform activity. Table 1. References P. Cichoz-Lach and A.
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Hoffman, W. Nyhan, J. Zschocke, S. UCDs are usually difficult to recognize because many of these patients are frequently ill for other reasons, such as sepsis, acute pancreatitis, trauma, or other acute diseases.
Plasma ammonia determination is carried out in venous or arterial blood collected in chilled tubes with ammonia-free sodium heparin or EDTA tubes placed on ice. An elevated plasma ammonia level is associated with normal blood glucose levels. A normal anion gap suggests UCDs because hyperammonemia associated with hyperglycemia and an abnormal anion gap are found in organic acidemias a different inborn error of metabolism.
Plasma and urine must be frozen for future diagnostic tests to identify the specific enzyme deficiency. The following are the conditions that may induce hyperammonemia in partial UCDs:.
Hyperammonemia may damage the brain by a variety of mechanisms. The most important mechanism is brain edema, probably induced by disruption of the aquaporin system membrane water channels and brain electrolyte homeostasis. The central feature of hyperammonemia-induced encephalopathy is an increase in astrocytes glutamine synthesis, and swelling of astrocytes in response to the osmotic effect of glutamine accumulation, resulting in increased intracranial pressure [ 11 ].
A recent study using N -ammonia positron emission tomography suggested that the magnitude of the flux of ammonia from the blood into intracellular glutamine in the brain is primarily correlated with blood ammonia concentrations [ 12 ]. In infancy, brain damage in acute hyperammonemia is similar to that seen in hypoxic-ischemic situations, with white matter disruption and lacunar infarcts.
Brain damage due to hyperammonemia may result in seizures and coma [ 13 ]. Subclinical seizures are common in acute hyperammonemia and may be considered in the treatment of these conditions. In many cases, modern imaging techniques may provide information related to the extent and intensity of brain injury. However, routine neurological images may not detect brain damage [ 14 ].
Newer technologies, such as magnetic resonance spectroscopy, diffusion tensor imaging, and functional magnetic resonance may provide information about the many types of neurological damage seen in UCDs. Renal replacement therapy RRT allows efficient removal of toxic metabolites, minimizing the duration of the metabolic disturbance. The use of RRT has changed since the studies of Donn et al. Currently, the choice of treatment for hyperammonemia is hemodialysis or continuous RRT, or even both modalities as early as possible [ 16 — 18 ].
The clearance of ammonia and other low-molecular-weight toxins is much greater with hemodialysis than with other RRTs [ 16 , 17 , 19 ]. Hemodialysis is the first-line therapy for the initial treatment of hyperammonemia in UCDs. Because ammonia is a gas, its rapid removal by hemodiafiltration is not associated with osmotic problems, and no special care must be taken to avoid dialysis disequilibrium syndrome [ 17 , 18 ].
Peritoneal dialysis is not effective for this purpose and should not be used. However, clinical evaluation is the best parameter to be used for discontinuation of dialysis. Patients with severe encephalopathy from acute hyperammonemia may completely recover unless prolonged cerebral edema results in cerebral damage [ 11 ].
The patient was weaned from the respirator and became completely awake. Rebound hyperammonemia with clinical worsening may also occur, requiring further dialysis. In our patient, discontinuation of hemofiltration was accompanied by deterioration in the patient's mental status. Any oral or parenteral protein administration must be immediately discontinued when hyperammonemia is detected.
Sodium phenylacetate and sodium benzoate, or sodium phenylbutyrate, are available for intravenous or oral administration. The basis for use of these drugs was established by Brusilow et al. Alternative pathway treatment diverts nitrogen from the urea cycle to alternative routes of excretion. Sodium phenylacetate combines with glutamine, producing phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys and sodium benzoate conjugates with glycine, producing sodium hippurate, which is also excreted by the kidneys [ 21 ].
Arginine administration in patients without a definitive diagnosis of the specific type of UCD is also important because ornithine transcarbamylase OTC is the most common type of late-onset UCDs [ 2 , 20 , 22 ]. Low plasma arginine levels observed in patients with OTC deficiency may also be related to increased vascular thrombosis [ 23 ].
In our patient, we administered sodium benzoate 3 g and arginine 3 g every 4 h via a nasogastric tube, maintaining plasma ammonia levels within the normal range. Recently, it was found that glycerol phenylbutyrate, which has excellent pharmacokinetics, controls plasma ammonia, improving executive function in adult and pediatric patients [ 24 ].
Restriction of protein intake for a period of 24 to 48 h and administration of calories from glucose and fat are important in patients on hemodialysis or hemofiltration for the prevention of an excessive catabolic state.
Maintenance of adequate plasma levels of essential amino acids is also necessary to avoid the catabolic state. Low-dose continuous infusion of insulin with glucose may be used to potentially alleviate the catabolic state. Liver transplantation is considered only in patients with recurrent hyperammonemia or in those resistant to conventional medical therapy.
The decision for liver transplantation is also based on the extent of brain and liver damage. The elevation in plasma ammonia concentrations is the main alteration in UCDs.
Quantitative plasma amino acid concentrations are used to determine specific enzyme deficiency in UCDs Table 1. Plasma levels of citrulline can be used to evaluate the type of UCD and to separate proximal from distal urea cycle defects.
Plasma citrulline levels are absent or present in trace amounts in CPS-1 deficiency and in low, or even normal, concentrations in late onset of OTC deficiency.
Plasma citrulline levels are present in high concentrations tenfold in argininosuccinic acid synthetase deficiency. Moderate elevation in plasma citrulline levels is seen with argininosuccinic acid lyase deficiency, accompanied by an elevation in argininosuccinic acid in plasma and urine Table 1.
Plasma concentrations of arginine are reduced in every type of UCD, except in arginase deficiency elevation five to sevenfold. In late onset or in partial enzyme defects, arginine concentrations may be normal.
Plasma concentrations of glutamine, asparagine, and alanine are elevated in UCDs. Urinary orotic acid concentrations are also elevated in arginase deficiency and in citrullinemia type 1 deficiency Table 1.
Diagnosis may be further refined by enzyme analysis in appropriate tissues as follows: liver biopsy CPS-1, N -acetyl glutamate synthetase, and OTC deficiencies ; red blood cells arginase deficiency ; and fibroblasts skin biopsy, argininosuccinic acid synthetase and argininosuccinic acid lyase deficiencies.
There are several genetic tests available for the diagnosis of UCDs. In late-onset hyperammonemia, DNA testing for OTC deficiency should be the first test for evaluation because this is the most common type of late-onset UCD, and many mutations have been described in this condition.
Recently, a more sophisticated DNA mutation analysis has been introduced, which allows identification of variants in most coding genes [ 25 ]. Several disorders disturbing liver function may mimic UCDs. These include hepatic encephalopathy in patients with advanced liver disease, vascular bypass of the liver, valproic acid or cyclophosphamide poisoning, herpes simplex infection, and gastrointestinal bacterial overgrowth.
In the last two conditions, the plasma ammonia levels are usually moderately elevated. A number of inborn errors of metabolism may also cause hyperammonemia:. Citrin deficiency CTLN2 is a late-onset disorder characterized by recurrent periods of hyperammonemia, delirium, irritability, and liver fatty infiltration, but there is no hepatic dysfunction.
Citrin is an aspartate glutamate transporter across the mitochondrial membrane [ 2 ]. Citrin deficiency leads to a decrease in cytoplasmic aspartate, limiting the activity of the enzyme argininosuccinic acid synthase [ 2 ]. Diagnosis of this alteration is based on findings of hyperammonemia and increased plasma concentrations of citrulline and arginine.
SLC25A13 is a gene mutated in patients with citrin deficiency. Ornithine translocase deficiency is a rare disease that results in hyperornithinemia, homocitrullinuria, and hyperammonemia, similar to those in UCDs.
A reduction in ornithine transport into the mitochondria results in orotic aciduria and deficiency of urea synthesis. In this situation, plasma levels of ornithine are high and can be reduced by a low-protein diet. Citrin deficiency and hyperammonemia may be included in UCDs as transporter defects.
Therefore, UCDs is related to eight defects, with deficiencies in six enzymes and two transporters. Hyperammonemia in an acutely ill patient can cause irreversible neurological damage, or even death, if not recognized.
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