-
Clinical Journal of the American... Oct 2016Hyperammonemia is an important cause of cerebral edema in both adults with liver failure and children with inborn errors of metabolism. There are few studies that have... (Review)
Review
Hyperammonemia is an important cause of cerebral edema in both adults with liver failure and children with inborn errors of metabolism. There are few studies that have analyzed the role of extracorporeal dialysis in reducing blood ammonia levels in the adult population. Furthermore, there are no firm guidelines about when to implement RRT, because many of the conditions that are characterized by hyperammonemia are extremely rare. In this review of existing literature on RRT, we present the body's own mechanisms for clearing ammonia as well as the dialytic properties of ammonia. We review the available literature on the use of continuous venovenous hemofiltration, peritoneal dialysis, and hemodialysis in neonates and adults with conditions characterized by hyperammonemia and discuss some of the controversies that exist over selecting one modality over another.
Topics: Adult; Ammonia; Brain Diseases; Humans; Hyperammonemia; Infant, Newborn; Renal Replacement Therapy
PubMed: 27197910
DOI: 10.2215/CJN.01320216 -
Revista de Gastroenterologia de Mexico... 2019Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by... (Review)
Review
Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by two enzymes: glutaminase or glutamine synthetase. The first produces ammonia and the second detoxifies the ammonia, which is why treatments are aimed at glutaminase inhibition or glutamine synthetase activation. At present, we know that both enzymes are found not only in the liver, but also in the muscle, intestine, kidney, and brain. Therefore, current treatments can be directed at each enzyme at different sites. Awareness of those potential treatment sites makes different options of approach possible in the patient with hepatic encephalopathy, and each approach should be personalized.
Topics: Ammonia; Enzyme Activators; Enzyme Inhibitors; Glutamate-Ammonia Ligase; Glutaminase; Hepatic Encephalopathy; Humans; Hyperammonemia
PubMed: 31014748
DOI: 10.1016/j.rgmx.2019.02.004 -
European Journal of Pediatrics Jan 2011Hyperammonemia is a life-threatening condition which can affect patients at any age. Elevations of ammonia in plasma indicate its increased production and/or decreased... (Review)
Review
Hyperammonemia is a life-threatening condition which can affect patients at any age. Elevations of ammonia in plasma indicate its increased production and/or decreased detoxification. The hepatic urea cycle is the main pathway to detoxify ammonia; it can be defective due to an inherited enzyme deficiency or secondary to accumulated toxic metabolites or substrate depletion. Clinical signs and symptoms in hyperammonemia are unspecific but they are mostly neurological. Thus, in any unexplained change in consciousness or in any unexplained encephalopathy, hyperammonemia must be excluded as fast as possible. Any delay in recognition and start of treatment of hyperammonemia may have deleterious consequences for the patient. Treatment largely depends on the underlying cause but is, at least in pediatric patients, mainly aimed at establishing anabolism to avoid endogenous protein breakdown and amino acid imbalances. In addition, pharmacological treatment options exist to improve urea cycle function or to remove nitrogen, but their use depend on the underlying disorder. To improve the prognosis of acute hyperammonemia, an increased awareness of this condition is probably more needed than anything else. Likewise, the immediate start of appropriate therapy is of utmost importance. This review focuses on a better understanding of factors leading to ammonia elevations and on practical aspects related to diagnosis and treatment in order to improve clinical management of hyperammonemia.
Topics: Amino Acids; Ammonia; Child; Diagnosis, Differential; Humans; Hyperammonemia; Practice Guidelines as Topic; Prognosis
PubMed: 21165747
DOI: 10.1007/s00431-010-1369-2 -
Annals of Hepatology 2022Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%-40% of patients with cirrhosis will present... (Review)
Review
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%-40% of patients with cirrhosis will present overt HE during their lifetime. While the pathophysiology of HE is not entirely understood, three critical factors have been identified: hyperammonaemia, systemic inflammation and oxidative stress by glutaminase gene alterations. Minimal HE is defined by the presence of signs of cognitive abnormalities in a patient without asterixis or disorientation; it can only be diagnosed with neuropsychological or psychometric tests. The diagnosis of overt HE is based on clinical examination with clinical scales. Currently, only overt HE should be routinely treated. The aims of treatment in an acute episode should be to improve the mental status, identify and treat the precipitating factor, reduce duration and limit consequences. Treatment strategies are targeted at reducing ammonia production and/or increasing its elimination. Even though minimal HE has negative effects on the patient's quality of life and effects on prognosis, indications for treatment are still controversial. There are still many unanswered questions regarding the pathophysiology and management of HE. We should also endeavor to develop more accurate and objective diagnostic methods for overt HE that would permit early detection and help improve outcomes on quality of life and economic burden.
Topics: Humans; Hepatic Encephalopathy; Quality of Life; Liver Cirrhosis; Hyperammonemia; Psychometrics
PubMed: 36115576
DOI: 10.1016/j.aohep.2022.100757 -
Journal of the American Board of Family... 2007The use of valproic acid (VPA) (also known as Depakote, Depakene, and others) frequently results in elevated plasma ammonia. In some people, hyperammonemia may be... (Review)
Review
The use of valproic acid (VPA) (also known as Depakote, Depakene, and others) frequently results in elevated plasma ammonia. In some people, hyperammonemia may be clinically significant, resulting in hyperammonemic encephalopathy, which may be severe. Valproic acid-induced hyperammonemic encephalopathy may occur in people with normal liver function, despite normal doses and serum levels of VPA. We describe 2 cases of valproic acid-induced hyperammonemic encephalopathy in patients with supratherapeutic VPA levels, although the condition has been described in people with normal VPA levels. With the increasing indications and off-label uses of VPA, family physicians should be aware of this potential complication of VPA and check ammonia levels in patients taking VPA who present with alterations in mental status. Treatment with L-carnitine may be beneficial in reducing ammonia levels.
Topics: Antimanic Agents; Bipolar Disorder; Cognition Disorders; Coma; Female; Humans; Hyperammonemia; Middle Aged; Neurotoxicity Syndromes; Stress Disorders, Post-Traumatic; Valproic Acid
PubMed: 17823470
DOI: 10.3122/jabfm.2007.05.070062 -
Nature Reviews. Nephrology Aug 2020Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common... (Review)
Review
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
Topics: Arginine; Carnitine; Child; Child, Preschool; Continuous Renal Replacement Therapy; Delphi Technique; Diet, Protein-Restricted; Humans; Hybrid Renal Replacement Therapy; Hyperammonemia; Infant; Infant, Newborn; Parenteral Nutrition; Peritoneal Dialysis; Phenylacetates; Phenylbutyrates; Practice Guidelines as Topic; Renal Dialysis; Sodium Benzoate; Urea Cycle Disorders, Inborn; Vitamin B Complex
PubMed: 32269302
DOI: 10.1038/s41581-020-0267-8 -
Journal of Inherited Metabolic Disease Nov 2019
Topics: Animals; Congresses as Topic; Disease Models, Animal; History, 20th Century; History, 21st Century; Humans; Hyperammonemia; International Cooperation; Japan; Mice; Mice, Transgenic; Switzerland; Urea Cycle Disorders, Inborn
PubMed: 31769067
DOI: 10.1002/jimd.12179 -
Orphanet Journal of Rare Diseases May 2012Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core... (Review)
Review
Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.
Topics: Child; Child, Preschool; Diagnosis, Differential; Dietary Proteins; Humans; Hyperammonemia; Infant; Infant, Newborn; Neonatal Screening; Practice Guidelines as Topic; Prenatal Diagnosis; Urea Cycle Disorders, Inborn
PubMed: 22642880
DOI: 10.1186/1750-1172-7-32 -
Annals of Clinical and Translational... Sep 2019Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable...
OBJECTIVE
Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild-to-moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model.
METHODS
We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E-IMD databases.
RESULTS
Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L-citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification-based guidance of therapeutic decision-making based on residual enzymatic ASS1 activity in the future.
INTERPRETATION
Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity-adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system.
Topics: Animals; Argininosuccinate Synthase; COS Cells; Chlorocebus aethiops; Citrulline; Citrullinemia; Genotype; Humans; Hyperammonemia; Models, Theoretical; Mutation; Phenotype; Prognosis; Severity of Illness Index
PubMed: 31469252
DOI: 10.1002/acn3.50886 -
Human Mutation Dec 2017Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or... (Comparative Study)
Comparative Study
Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140 out of 358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95 out of 140 subjects identified causative variants in 84% of the alleles. The missense variants identified in our patients and others previously reported (n = 92) were expressed in CHO cells. Carnitine transport was impaired by 73 out of 92 variants expressed. Prediction algorithms (Polyphen-2, SIFT) correctly predicted the functional effects of expressed variants in about 80% of cases. These results indicate that mutations in the coding region of the SLC22A5 gene cannot be identified in about 16% of the alleles causing primary carnitine deficiency. Prediction algorithms failed to determine the functional effects of amino acid substitutions in this transmembrane protein in about 20% of cases. Therefore, functional studies in fibroblasts remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency.
Topics: Amino Acid Substitution; Animals; Biological Transport; CHO Cells; Cardiomyopathies; Carnitine; Cricetinae; Cricetulus; DNA Mutational Analysis; Exons; Fibroblasts; Gene Frequency; Genetic Variation; Humans; Hyperammonemia; Hypoglycemia; Muscular Diseases; Mutation; Mutation, Missense; Solute Carrier Family 22 Member 5
PubMed: 28841266
DOI: 10.1002/humu.23315