Hyperammonemia: Description, Causes and Risk Factors:The presence of ammonia or some of its compounds in the blood, thought to be formed from the decomposition of urea; it usually results in subnormal temperature, weak pulse, gastroenteric symptoms, and coma.HyperammonemiaAmmonia metabolism involves primarily five organs — the gut, kidney, muscle, liver, and brain. Ammonia is produced mostly in the gut, but also in the kidneys and muscle. Within the GI tract, ammonia is a byproduct of protein digestion and bacterial metabolism. Within the kidney, ammonia is essential for the renal handling of acid. Ammonium is synthesized from glutamine in the proximal tubule and ultimately is concentrated in the medullary interstitium, where it is either released into the systemic circulation or used to facilitate the excretion of protons. Renal ammonia production is dynamic and increases with alterations in renal acid-base status changes and with GI bleeding. Finally, skeletal muscle can also produce ammonia, usually during seizures or with intense exercise.This condition is typically caused by two factors. It may be a result of processes that raise production of ammonia. Hyperammonemia, resulting from decreased ammonia elimination, can occur due to medicinal side effects as well as the onset of conditions like:Fulminant hepatic failure (FHF).
  • Portosystemic shunting (PSS).
  • Inborn error of metabolism (IEM).
In adults, acute hyperammonemia is most commonly caused due to fulminant hepatic failure. Every year, approximately 2,000 cases of this condition are found to result from liver failure.Types:Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by reduced activity of any of the enzymes in the urea cycle.
  • Secondary hyperammonemia is caused by inborn errors of intermediary metabolism characterised by reduced activity in enzymes that are not part of the urea cycle (e.g. .Propionic acidemia, Methylmalonic acidemia) or dysfunction of cells that make major contributions to metabolism (e.g. hepatic failure).
  • Idiopathic hyperammonemia (IHA) is a medical condition in which increased levels of ammonia are disproportional to liver dysfunction without the presence of an inherited metabolic disorder. Other conditions that may elevate ammonia production involve herpes infection, multiple myeloma, urinary diversion or infection with organisms that split urease enzyme. A person is unlikely to suffer from this condition unless there is some type of defect in the metabolic conversion system. In newborns, the defect often results from genetic defects. In older adults, however, the defect mostly occurs due to a diseased liver. However, onset of genetic disorders of the urea cycle in a growing number of adults is also being seen as a reason.
Risk Factors:Some drugs disrupt the urea cycle and give rise to hyperammonemia.
  • Certain physiologic stressors cause stress and arouse hyperammonemia in sufferers of metabolic disorders. These agents include dietary changes, fever, Pneumonia, Pregnancy, infection with urease-splitting organisms, GI bleeding and upper respiratory tract illnesses.
Symptoms:The specific physical symptoms of hyperammonemia are very few in number. Certain medical researchers have, however, identified some discomforting symptoms like:Dehydration. Patients of this syndrome are also found to develop fontanelles that are larger than normal. Fontanelles are soft spots on the skull surface of babies where the bone has not had a complete formation as yet.Diagnosis:The following tests should be performed after a patient is found to be hyperammonemic:Arterial blood gas analysis: This study determines acid-base status; respiratory alkalosis strongly suggests a urea cycle defect; it is the result of hyperventilation due to stimulation of the central respiratory drive.
  • Urinary orotic acid tests: The level is increased markedly in OTC deficiency and mildly in other enzyme deficiencies except for CPS/NAGS deficiency, in which it is decreased mildly.
  • Urinary ketone tests: Presence of ketosis indicates an organic acidemia.
  • Plasma and urinary organic acid tests: These levels screen for the presence of an organic acidemia that may be causing the hyperammonemia.
  • Enzyme assays: Assays performed on tissue specimens obtained by percutaneous liver biopsy can determine diagnosis in cases of CPS, NAGS, and OTC deficiency. Enzyme assays are also performed on red blood cells (for arginase deficiency), fibroblast from skin biopsy (argininosuccinate synthetase (ASS), Argininosuccinate lyase (ASL), and hyperornithinemia, hyperammonemia, and homocitrillinemia (HHH)), and intestinal mucosa (CPS, OTC). Enzyme analysis has largely been replaced by genetic analysis. It is still indicated in selected cases with negative genetic testing or if genetic testing is not available.
Serum amino acid tests
  1. Glutamine and alanine levels are increased in all urea cycle defects except for arginase deficiency.
  2. Citrulline level is decreased mildly in CPS/NAGS and OTC deficiencies but increased markedly in AS deficiency and moderately in AL deficiency.
  3. Arginine level is increased markedly in arginase deficiency but decreased mildly in all the other enzyme deficiencies of the urea cycle.
  4. Argininosuccinic acid level is increased markedly in AL deficiency.
DNA mutation analysis is the method of choice in confirming the diagnosis of UCD as it is clinically available for all genes of the urea cycle.Heterozygote identification in OTC-deficient pedigrees
  • Allopurinol loading test: This test establishes the carrier status of women at risk for OTC deficiency. After a loading dose of allopurinol, urinary orotidine excretion is measured; it is increased greatly in carriers.
  • DNA analysis: Several techniques are available to determine the presence of a mutation at the OTC locus.
Antenatal diagnosis: All urea cycle defects can be diagnosed antenatally by different techniques including, DNA analysis on chorionic villus or amniotic fluid cells, measurements of amniotic fluid metabolites or enzyme activities in the amniotic cells, chorionic villi, fetal liver, and fetal erythrocytes.Imaging:Neuroimaging: CT or MRI of the brain may show cerebral edema in acute hyperammonemia. The classic MR finding in patients with chronic liver disorders is hyperintense signal in the globus pallidum on T1 weighted images due to increased tissue concentration of manganese.
  • MR spectroscopy: This shows an elevated glutamine/glutamate peak coupled with decreased myoinositol and choline signals.[18, 19]
Treatment:Several treatments are appropriate for all patients with hyperammonemia, while some treatments are reserved for those with hyperammonemia that is thought to be related to an IEM (inborn error of metabolism). Often, therapy must be given empirically, as the diagnosis of IEM can take weeks to months.For both types of patients, initial treatment must focus on the management of ICH, which is a condition that is associated with increased morbidity and mortality. Usually, hyperammonemia in adults is associated with cerebral edema, decreased cerebral metabolism, and increases in cerebral blood flow. The management of these patients entails the reduction of cerebral edema and cerebral blood flow. However, in some patients cerebral blood flow may be reduced; in these patients, drugs that lower cerebral blood flow and cerebral perfusion pressure must be avoided. Unfortunately, placement of intracranial pressure monitoring is associated with complications, and management may need to be performed empirically. Given the dynamic changes in cerebral blood flow, there is controversy about which management strategy is most appropriate.Intravenous sodium phenylacetate and sodium benzoate are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylacetate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylacetate conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys. A preparation containing sodium phenylacetate and sodium benzoate is available under the trade name Ammonul. Acidification of the intestinal lumen using lactulose can decrease ammonia levels by protonating ammonia and trapping it in the stool. This is a treatment for hepatic encephalopathy. Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 ?mol/L) should begin with hemodialysis if it is otherwise medically appropriate and tolerated.NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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