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Cellular and Molecular Neurobiology Nov 2022Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations... (Review)
Review
Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.
Topics: Ammonia; Fatty Acids; Humans; Hyperammonemia; Infant, Newborn; Metabolic Diseases; Urea
PubMed: 34665389
DOI: 10.1007/s10571-021-01156-6 -
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 -
Current Opinion in Infectious Diseases Jun 2022Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients.... (Review)
Review
PURPOSE OF REVIEW
Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients. Growing evidence suggests hyperammonemia syndrome is associated with systemic infections caused by urease-producing organisms, namely Ureaplasma spp., an organism unable to grow with routine culturing techniques. This review will summarize the epidemiology and clinical manifestations of hyperammonemia syndrome, as well as diagnostic and management strategies once hyperammonemia syndrome is suspected.
RECENT FINDINGS
Hyperammonemia syndrome is being described in increasing frequency in the solid organ transplant population. Morbidity and mortality, even with treatment, is high once hyperammonemia syndrome occurs. Surveillance studies indicate the prevalence of lung donor colonization with Ureaplasma spp. is high, suggesting screening and treatment may be of benefit. Antibiotic resistance is common, and rapid diagnostics can facilitate appropriate antimicrobial therapy in the peri-transplant period.
SUMMARY
Hyperammonemia syndrome is most commonly seen in lung transplant recipients and has a high mortality rate once it occurs. Screening for Ureaplasma spp. should be considered in all lung transplant donors.
Topics: Humans; Hyperammonemia; Immunocompromised Host; Syndrome; Transplant Recipients; Ureaplasma; Ureaplasma Infections
PubMed: 35665721
DOI: 10.1097/QCO.0000000000000828 -
Pediatric Nephrology (Berlin, Germany) Feb 2012Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high... (Review)
Review
Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high concentrations, ammonia is toxic. Endogenous ammonia intoxication can occur when there is impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms and signs, including significant central nervous system (CNS) abnormalities. Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis, and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis, and treatment of hyperammonemia.
Topics: Amino Acids; Argininosuccinic Aciduria; Brain; Citrullinemia; Diagnosis, Differential; Humans; Hyperammonemia; Synaptic Transmission; Urea Cycle Disorders, Inborn
PubMed: 21431427
DOI: 10.1007/s00467-011-1838-5 -
Pediatric Clinics of North America Apr 2018The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins... (Review)
Review
The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins required to convert toxic ammonia into urea and to produce arginine and citrulline. The clinical manifestations of these disorders are mostly the result of acute or chronic hyperammonemia, which affects the central nervous system. Affected individuals can also develop hepatic dysfunction. These disorders can present at any age from the immediate newborn to later in life. Early diagnosis and treatment are key to improving outcomes.
Topics: Ammonia; Emergency Treatment; Humans; Hyperammonemia; Infant; Infant, Newborn; Urea; Urea Cycle Disorders, Inborn
PubMed: 29502911
DOI: 10.1016/j.pcl.2017.11.004 -
Orphanet Journal of Rare Diseases Mar 2015Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a... (Review)
Review
BACKGROUND
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.
METHODS
A systematic review of publications reporting patients with HHH syndrome was performed.
RESULTS
We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.
CONCLUSIONS
This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Topics: Aging; Humans; Hyperammonemia; Mutation; Origin Recognition Complex; Ornithine; Protein Conformation; Urea Cycle Disorders, Inborn
PubMed: 25874378
DOI: 10.1186/s13023-015-0242-9 -
Expert Opinion on Pharmacotherapy Aug 2014Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that is seen in patients with liver failure. The pathogenesis of HE is not entirely understood,... (Review)
Review
INTRODUCTION
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that is seen in patients with liver failure. The pathogenesis of HE is not entirely understood, but several hypotheses have emerged and persisted during the years. Despite the many prevalent hypotheses, most of the existing evidence point to ammonia as the main culprit behind primary and secondary symptoms making it the center of potential therapeutic options for the treatment of HE. Most treatments of hyperammonemia target the organs and metabolic processes involved in ammonia detoxification.
AREAS COVERED
This article provides a review of the current targets of therapy as well as the drugs used for hyperammonemia treatment.
EXPERT OPINION
Lactulose and rifaximin have a proven role as measures to use for secondary prophylaxis and are the mainstay of current therapy. The use of molecular adsorbent recirculating system in patients with severe HE has been proven to be efficacious, but through mechanisms that appear to be independent of ammonia. The main challenge that faces the further development of treatments for HE is finding appropriate end points, and the next step would be to provide evidence of the effectiveness of established treatments and define the role of emerging new treatments.
Topics: Ammonia; Animals; Gastrointestinal Agents; Hepatic Encephalopathy; Humans; Hyperammonemia; Lactulose; Rifamycins; Rifaximin; Sorption Detoxification
PubMed: 25032885
DOI: 10.1517/14656566.2014.931372 -
Transplant Infectious Disease : An... Dec 2022Hyperammonemia syndrome (HS) is a rare post-transplant complication associated with high morbidity and mortality. Its incidence appears to be higher in lung transplant... (Review)
Review
BACKGROUND
Hyperammonemia syndrome (HS) is a rare post-transplant complication associated with high morbidity and mortality. Its incidence appears to be higher in lung transplant recipients and its pathophysiology is not well understood. In addition to underlying metabolic abnormalities, it is postulated that HS may be associated with Ureaplasma or Mycoplasma spp. lung infections. Management of this condition is not standardized and may include preemptive antimicrobials, renal replacement, nitrogen scavenging, and bowel decontamination therapies, as well as dietary modifications.
METHODS
In this case series, we describe seven HS cases, five of whom had metabolic deficiencies ruled out. In addition, a literature review was performed by searching PubMed following PRISMA-P guidelines. Articles containing the terms "hyperammonemia" and "lung" were reviewed from 1 January 1997 to 31 October 2021.
RESULTS
All HS cases described in our center had positive airway samples for Mycoplasmataceae, neurologic abnormalities and high ammonia levels post-transplant. Mortality in our group (57%) was similar to that published in previous cases. The literature review supported that HS is an early complication post-transplant, associated with Ureaplasma spp. and Mycoplasma hominis infections and of worse prognosis in patients presenting cerebral edema and seizures.
CONCLUSION
This review highlights the need for rapid testing for Ureaplasma spp. and M. hominis after lung transplant, as well as the necessity for future studies to explore potential therapies that may improve outcomes in these patients.
Topics: Humans; Meta-Analysis as Topic; Lung Transplantation; Hyperammonemia; Ureaplasma
PubMed: 36039822
DOI: 10.1111/tid.13940 -
Transplant International : Official... 2022Hyperammonemia after lung transplantation (HALT) is a rare but serious complication with high mortality. This systematic review delineates possible etiologies of HALT... (Review)
Review
Hyperammonemia after lung transplantation (HALT) is a rare but serious complication with high mortality. This systematic review delineates possible etiologies of HALT and highlights successful strategies used to manage this fatal complication. Seven biomedical databases and grey literature sources were searched using keywords relevant to hyperammonemia and lung transplantation for publications between 1995 and 2020. Additionally, we retrospectively analyzed HALT cases managed at our institution between January 2016 and August 2018. The systematic review resulted in 18 studies with 40 individual cases. The mean peak ammonia level was 769 μmol/L at a mean of 14.1 days post-transplant. The mortality due to HALT was 57.5%. In our cohort of 120 lung transplants performed, four cases of HALT were identified. The mean peak ammonia level was 180.5 μmol/L at a mean of 11 days after transplantation. HALT in all four patients was successfully treated using a multimodal approach with an overall mortality of 25%. The incidence of HALT (3.3%) in our institution is comparable to prior reports. Nonetheless, ammonia levels in our cohort were not as high as previously reported and peaked earlier. We attributed these significant differences to early recognition and prompt institution of multimodal treatment approach.
Topics: Ammonia; Cohort Studies; Humans; Hyperammonemia; Lung Transplantation; Retrospective Studies
PubMed: 35620675
DOI: 10.3389/ti.2022.10433 -
Journal of Investigative Medicine High... 2022Elevated ammonia levels lead to cerebral edema, encephalopathy, seizures, coma, and death. Hyperammonemia is primarily associated with liver disease; however, there are... (Review)
Review
Elevated ammonia levels lead to cerebral edema, encephalopathy, seizures, coma, and death. Hyperammonemia is primarily associated with liver disease; however, there are rare cases without liver disease. Noncirrhotic hyperammonemia is primarily due to increased production and/or decreased elimination of ammonia. We present a rare case of a 35-year-old female with severe acute noncirrhotic hyperammonemia associated with gram-negative septic shock and a suspected undiagnosed partial urea cycle enzyme deficiency. She had elevated blood and urine amino acid levels speculated to be due to an underlying urea cycle defect, which was unmasked in the setting of septic shock with urea splitting bacteria leading to severely elevated ammonia levels. Ammonia levels were rapidly corrected with hemodialysis, as other conventional treatments failed. We highlight the importance of considering noncirrhotic causes of hyperammonemia in patients with elevated ammonia levels and intact liver function. Prompt treatment should begin with reducing the catabolic state, nitrogen scavenging, replacing urea cycle substrates, decreasing intestinal absorption, and augmented removal of ammonia with renal replacement therapy.
Topics: Adult; Ammonia; Female; Humans; Hyperammonemia; Liver Diseases; Shock, Septic; Urea
PubMed: 35596541
DOI: 10.1177/23247096221101855