Urea cycle defect hyperammonemia
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The document summarizes urea cycle defects and hyperammonemia. It discusses that defects in any of the six urea cycle enzymes or two transporters can cause toxic buildup of ammonia in the blood. Specific urea cycle disorders are described including ornithine transcarbamylase deficiency and N-acetylglutamate synthase deficiency. Treatment focuses on removing ammonia through hemodialysis or drug therapy, and maintaining a protein-restricted diet to prevent further ammonia production. Long-term management requires monitoring amino acid intake and considering liver transplantation.
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Urea cycle defect hyperammonemia
- 1. Addis Ababa University School of Medicine Department of Biochemistry Title: Urea Cycle Defect-Hyperammonemia Ayetenew Abita June, 2017 1
- 2. Presentation Outline • Introduction – Source of Ammonia – Urea cycle – Toxicity of Ammonia • Defects of Urea Cycle – Hyperammonemia type I – Hyperammonemia type II – Hyperammonemia type III – Citrllinemia – Arginosuccinic aciduria – Hyperargininemia • Defect in Ornithine and Citrulline translocase . • Pathophysiology of urea cycle defects • Treatment options • Summary • Reference 2
- 3. Introduction • Every amino acid contains at least one amino group. • Therefore every amino acid degradation pathway has a key step where the amino group is removed. • In short amino acid catabolism generates ammonia. 3
- 4. Source of Ammonia 1. bacterial hydrolysis of urea 2. nitrogenous compounds in the intestine 3. the purine-nucleotide degradation 4. amino acid transamination in skeletal muscle 5. metabolic processes in the kidneys and liver 4
- 5. UREA CYCLE • First metabolic pathway to be elucidated by Krebs & Henseleit since 1932. • Is the sole source of endogenous production of arginine, ornithine, and citrulline. • Is the principal mechanism for the clearance of waste nitrogen resulting from protein turnover. • Is the principal mechanism for the metabolism of other nitrogenous metabolic compounds such as adenosine monophosphate. 5
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- 7. Hyperammonemia • Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterized by an excess of ammonia in the blood . • Hyperammonemia may be acquired or congenital • Acquired hyperammonemia is usually caused by diseases that result in acute liver failure such as; – Chronic hepatitis B – chronic hepatitis C, and – excessive alcohol consumption are common causes of cirrhosis. • The physiologic consequences of cirrhosis include shunting of blood from the liver to the inferior vena cava, resulting in decreased filtration of blood and removal of nitrogen-containing toxins by the liver, and then hyperammonemia. 7
- 8. Urea Cycle Defect • Urea cycle disorders (UCD) result from inherited deficiencies in the six enzymes of the urea cycle pathway (CPS1, OTC, ASS1, ASL, ARG, and NAGS). • The urea cycle also depends on two transporters (Two transporters: Ornithine and Citrulline translocase. • Abnormalities in these transporters and urea cycle enzymes results hyperammonemia (accumulation of highly toxic substance in the body). 8
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- 10. Cont’d Hereditary deficiency of any of the Urea Cycle enzymes leads to hyperammonemia - elevated [ammonia] in blood. Elevated ammonia is toxic, especially to the brain. Other metabolites of urea cycle accumulate depending on specific enzyme defect. The clinical symptoms: Vomiting, lethargy, irritability, ataxia, and metal retardation. If not treated immediately after birth, severe mental retardation results. Total lack of any Urea Cycle enzyme is lethal. 10
- 11. Toxicity of Ammonia • The binding of ammonia in the synthesis of glutamate causes an out flow of α- ketoglutarate from TCA cycle , with decrease formation of ATP energy and deteriorates the activity of cells. • Ammonium ion caused alkalization of blood plasma. This increases the affinity of hemoglobin for oxygen ( Boher effect ), the hemoglobin does not release oxygen to the capillaries , resulting cells hypoxia occurs. • The accumulation of free ammonium ion in the cytosol affects the membrane potential and intracellular enzyme s work- it competes with ion pumps, Na+ and K+. 11
- 12. Toxicity of Ammonia • The producing ammonia transform glutamic acid to glutamine, an osmotically active substance. This leads to water retention in the cells and the swelling that causes swelling of tissues. – In the case of nervous tissue it can cause brain swelling , comma and death. • The use of α-ketoglutarte and glutamate to neutralize the ammonia causes a decrease synthesis of GABA inhibitory neurotransmitter of the nervous system. 12
- 13. Hyperammonemia type I • Carbamoyl phosphate synthetase I deficiency (CPS1 deficiency) • It is the most severe of the urea cycle disorders. • Individuals with complete CPS1 deficiency rapidly develop hyperammonemia in the newborn period. • Children who are successfully rescued from crisis are chronically at risk for hyperammonemia. 13
- 14. Metabolic Derangement of HAT-I • Deficiency of carbamoyl synthetase I (CPS-I ) regulatory enzyme for urea cycle leading to; – Accumulation of ammonia in the blood – Pass through BBB – Elevated level of glutamine and alanine in blood plasma . 14
- 15. Hyperammonemia type II Ornithine transcarbamylase deficiency Carbamoyl phosphate will not condense with ornitine to form cirulline . Cause ammonia to accumulate in the blood Absence of OTC activity in males is as severe as CPS1 deficiency. The only recessive x-linked encoded enzyme . 15
- 16. Metabolic Derangement of HAT-II • Deficiency of Ornithine transcarbamylase enzyme for urea cycle leading to; –Accumulation of ammonia in the blood –Accumulation of orotic acid –Pass through BBB –Elevated level of glutamine and alanine in blood plasma . 16
- 17. Hyperammonemia type III • Hyperammonemia type III refers to a urea cycle disorder inherited as an autosomal recessive trait – due to N-acetyl glutamate synthase deficiency • which results in a reduced activity of carbamoyl phosphate synthetase I –and resulting subsequent accumulation of neurotoxic ammonia. 17
- 18. Metabolic Derangement in HAT III • Deficiency of NAGS lead to low level of N- acetyl glutamate which is allostric activator of regulatory enzyme for urea cycle (CPS-I ) leading to; –Accumulation of ammonia in the blood –Pass through BBB –Elevated level of glutamine and alanine in blood plasma . 18
- 19. Treatment Hyperammonemia type III • Therapy of HAT3 comprises the immediate treatment of hyperammonemia and long-term prevention of renewed increases in blood ammonia levels by daily administration of carbamoyl glutamate. – this a structural analogue of N-acetyl-glutamate, may activate CSPI and thus compensates for NAGS deficiency. • Although the affinity of N-acetyl-glutamate to CPSI is higher, this compound has poor pharmacokinetic properties. • Furthermore, a restriction of dietary protein intake to less than 3 g/kg/day may be necessary, especially during metabolic crises. 19
- 20. Treatment Hyperammonemia type III • Emergency treatment of hyperammonemia is not specific for HAT3 and may comprise the following measures • Prevent any further intake of proteins for up to 36 hours • Fluid therapy, intravenous application of dextrose (possibly plus insulin) and Intra lipids • Provide L-arginine, L-citrulline and nitrogen scavenger medication. • If at all possible, patients known to suffer from HAT3 should not be treated with drugs that possibly induce a hyperammonemia crisis. 20
- 21. Ornithine Translocase Deficiency • Mutations in the SLC25A15 gene cause ornithine translocase deficiency. • Ornithine translocase deficiency is an inherited disorder that causes ammonia to accumulate in the blood Frequency Ornithine translocase deficiency is a very rare disorder. Fewer than 100 affected individuals have been reported worldwide 21
- 22. Citrulline Translocase Deficiency • The citrin gene (SLC25A13) codes for mutation leads to citrulline translocase deficiency. – Leading to transport impairment from mitochondria to cytosol and resulting amonia to accumulate – hyperammonemia • The gene loci for classic citrullinemia and for citrin deficiency reside on separate chromosomes. 22
- 23. Citrllinemia • Citrulline is the resultant product of the condensation reaction that occurs during normal function of the ornithine transcarbamylase reaction. • Under normal circumstances, citrulline is condensed with aspartic acid to form argininosuccinic acid (ASA), which is a reaction mediated by the argininosuccinic acid synthase enzyme. • ASA synthase deficiency leads to accumulation of citrulline, a condition known as citrullinemia. 23
- 24. Arginosuccinic aciduria • Argininosuccinic aciduria (ASL deficiency ) present with rapid-onset hyperammonemia in the newborn period. • Some affected individuals develop chronic hepatic enlargement and elevation of transaminases. • Liver biopsy shows enlarged hepatocytes, which may over time progress to fibrosis, the etiology of which is unclear. • Affected individuals can also develop trichorrhexis nodosa, a node-like appearance of fragile hair that usually responds to arginine supplementation. • Affected individuals who have never had prolonged coma nevertheless have been reported to have significant developmental disabilities. 24
- 25. Hyperargininemia • Arginase: Ammonia and arginine accumulates • Arginase deficiency (hyperargininemia, ARG deficiency) is not typically characterized by rapid- onset hyperammonemia, however, some individuals present earlier with more severe symptoms. • Affected individuals develop progressive spasticity and can also develop tremor, ataxia, and choreoathetosis. Growth is also affected . 25
- 26. Treatment Technique • Acute Treatment – Hemodialysis – Sodium benzoate and sodium phenylacetate to scavenge excess ammonia – Caloric supplementation – Glucose, intralipids • Complete protein restriction for 24-48 hours • Nutrition Interventions – Protein adjustment to account for severity, age, growth rate, and individual preferences without any extra – Supplemental arginine for most – May use essential amino acid mixture to replace natural sources – 25-30% of protein intake should be essential amino acids 26
- 27. Treatment Technique • Nutrition Concerns –Amino acid intake must be balanced –Adequate energy intake –Continuous monitoring • Adjunct therapies –Liver transplantation –Alternative pathway therapy 27
- 28. Summary • Any defect in urea cycle enzyme deficiency results hyperammonemia • Hyperammonemia results disturbance of biochemical pathways. – Will cause several complication like respiratory alkalosis, mental retardation and etc • Glutamine and alanine levels are increased in case of HAT3, CPSI deficiency, and ornithine transcarbamylase, with the latter urea cycle disorders being much more common than NAGS deficiency. 28
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- 30. Reference Ari Auron & Patrick D., 2011 , Brophy Hyperammonemia in review: pathophysiology, diagnosis,and treatment, Pediatr Nephrol , EDUCATIONAL REVIEW, DOI 10.1007/s00467-011-1838-5 Walker V (2009) Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diab Obes Metab 1(9):823– 385 Tizianello A, Deferrari G, Garibotto G, Robaudo C, Acquarone N, Ghiggeri GM (1982) Renal ammoniagenesis in an early stage of metabolic acidosis in man. J Clin Invest 69(1):240–250 Windmueller HG, Spaeth AE (1980) Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. J Biol Chem 255:107–112 Singh RH (2007) Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 30:880–887 Cooper AJ, Plum P (1987) Biochemistry and physiology of brain ammonia. Physiol Rev 67:440–519 30
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Editor's Notes
- Urea Cycle Disorders: is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic substance, and is not removed from the body.
- Impaired capacity to excrete nitrogen in the form of urea Cascade of enzymatic reactions which converts ammonia to urea can be blocked Or a depletion of an amino acid essential to the function of the cycle can result Causing hyperammonemia. The urea cycle ( See Differential Diagnosis) Five catalytic enzymes: Carbamoylphosphate synthetase I (CPS1) Ornithine transcarbamylase (OTC) Argininosuccinic acid synthetase (ASS1) Argininosuccinic acid lyase (ASL) Arginase (ARG) A cofactor-producing enzyme: N-acetyl glutamate synthetase (NAGS)
- Urea Cycle Disorders Appear to be unaffected at birth In a few days develop vomiting, respiratory distress, and coma. Symptoms mimic other illnesses Untreated results in death
- N-Acetylglutamate synthase – very rare autosomal recessive, lethargy, poorly-controlled breathing rate or body temperature, seizures, coma, hyperammonemia, increased serum alanine and glutamine urine orotic acid within reference range. Treatment is low protein intake. Carbamoylphosphate synthetase – rare, autosomal recessive, early-onset lethargy, seizures, hyperammonemia, serum ammonia concentrations are usually 10-20 times higher than reference range. Treatment is reduced protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Ornithine transcarbamoylase – rare, X-linked recessive, early- or late-onset, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased urine orotic acid, enzyme assays. Treatment is restricted protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Argininosuccinate synthetase – rare, autosomal recessive, two forms (type I more common than II). Type I lethargy, poor feeding, vomiting, seizures, and loss of consciousness, type II confusion, restlessness, memory loss, abnormal behaviors (such as aggression, seizures, and coma, hyperammonemia, increased serum citrulline, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is restricted protein diet and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Argininosuccinate lyase – rare, autosomal recessive, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased serum and urine argininosuccinic acid, increased serum citrulline, glutamine, alanine, and lysine, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is low-protein diet, arginine supplementation and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. Arginase – very rare (least common urea cycle defect), autosomal recessive, delayed development, protein intolerance, spasticity, hyperammonemia (sometimes), assay for erythrocyte arginase activity. Treatment is low-protein diet and administration of oral sodium benzoate or sodium phenylbutyrate to reduce ammonia concentration when appropriate.
- MRS. In OTC deficiency, biochemical markers of brain injury resulting from hyperammonemia that can be measured quantitatively on 1H MRS include increased glutamine levels and depletion of myoinositol.
- In arginase deficiency, diffusion tensor imaging (DTI ) demonstrates additionally decreased fiber density reflecting the predilection of corticospinal tracts to brain injury corresponding to the spastic diplegia observed in this disorder.
- Serum ammonia concentration elevation is usually the first identified laboratory abnormality in most of the urea cycle disorders. Quantitative plasma amino acid analysis can be used to arrive at a tentative diagnosis. (As the liver is not fully mature at birth, affected newborns often have plasma amino acid concentrations that are quite different from those in older children and adults.) Plasma concentration of citrulline helps discriminate between the proximal and distal urea cycle defects, as citrulline is the product of the proximal enzymes (OTC and CPS1) and a substrate for the distal enzymes (ASS1, ASL, ARG). Plasma citrulline is either absent or present only in trace amounts in neonatal-onset CPS1 deficiency and OTC deficiency and present in low to low-normal concentrations in late-onset disease. A tenfold elevation in plasma citrulline concentration is seen in ASS deficiency. A more moderate (~2- to 5-fold) increase in plasma citrulline concentration is seen in ASL deficiency, which is also associated with high levels of argininosuccinic acid (ASA) in plasma and urine. ASA is normally absent [Summar 2001, Summar & Tuchman 2001]. Plasma concentration of arginine may be reduced in all urea cycle disorders except ARG deficiency, in which it is elevated five- to sevenfold; however, in partial enzyme defects, it may be normal. Note: Plasma concentrations of glutamine, alanine, and asparagine, which serve as storage forms of waste nitrogen, are frequently elevated. Urinary orotic acid is measured to distinguish CPS1 deficiency from OTC deficiency. It is normal or low in CPS1 deficiency and significantly elevated in OTC deficiency. Note: Urinary orotic acid excretion can also be increased in argininemia (ARG deficiency) and citrullinemia type I (ASS1 deficiency). Molecular genetic testing is used for diagnosis, carrier detection, and prenatal diagnosis for all six UCDs (see Table 2). It has supplanted measurement of enzyme activity as the definitive diagnostic test. Enzyme activity. If molecular testing is uninformative, the following disorders can be diagnosed by assay of enzyme activity: CPS1 deficiency, OTC deficiency, or NAGS deficiency: liver biopsy ARG deficiency: red blood cells ASS1 deficiency and ASL deficiency: fibroblasts
- Newborn Screening Current extended newborn screening panels using tandem mass spectrometry detect abnormal concentrations of analytes associated with ASS1 deficiency, ASL deficiency, and arginase deficiency; however, the sensitivity and specificity of such screening for these disorders is unknown. Some newborn screening programs are investigating methods to detect OTC deficiency and the proximal urea cycle defects. Some caveats regarding newborn screening for urea cycle defects: CPS1 deficiency, OTC deficiency, and NAGS deficiency currently cannot be reliably detected. Although hyperargininemia (i.e., arginase deficiency) has been detected by these methods, newborn screening cannot be expected to reliably detect all cases. Even in UCDs detectable by newborn screening, neonates are often symptomatic prior to availability of the screening results; thus a high level of clinical suspicion on the part of healthcare providers is necessary.
- Mode of Inheritance Deficiencies of CPS1, ASS1, ASL, NAGS, and ARG are inherited in an autosomal recessive manner. OTC deficiency is inherited in an X-linked manner.