Ammonia metabolism, disorders

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

Patients snffering from metabolic disorders such as phenylketonuria (PKU), branched-chain ketoaciduria (maple syrup urine disease, MSUD), nrea and ammonia disorders or glycogen storage disease reqnire formulations manufactured specifically for each disease (Elsas Acosta, 2006). (Appendix 15.1). 

Because of the high selectivity and sensitivity of the postcolumn fluorescence detection of histidine with OPA, the present HPLC method is applicable to a specific and rapid assay of histidine in human semm, blood, and urine after simple pretreatment. A recent paper demonstrated that the postcolumn detection with OPA was applicable to the simultaneous assays of histidine and its major metabolites cis- and frawi-urocanic acids) in human stratum corneum. " The postcolumn detection system was also applicable to the flow injection analysis (FIA) method for the assay of histidine in semm and urine. The FIA method enabled us to determine histidine in blood after pretreatment of the sample with A-ethylmaleimide (masking reagent of glutathione).These methods are useful in the diagnosis of histidinanemia, one of hereditary metabolic disorders characterized by a virtual deficiency of histidine ammonia-lyase. 

Figure 47-SO The major metabolic pathways for the use of ammonia by the hepatocyte. Solid bars indicate the sites of primary enzyme defects in various metabolic disorders associated with hyperammonemia /) carbamyl phosphate synthetase I, (2) ornithine transcarbamylase, (3) argininosuccinate synthetase, (4) argininosuccinate lyase, (5) arginase, (6) mitochondrial ornithine transport, (7) propionyi CoA carboxylase, (fi) methylmalonyl CoA mutase, (9) L-lysine dehydrogenase, and (10) N-acetyl glutamine synthetase. Dotted lines indicate the site of pathway activation (+) or inhibition ( ). (From Flannery OB, Hsia YE, Wolf 6. Current status of /lyperommofiemjo syndromes. Hepatology 1982 2 495-506,)...

The acquired causes of hyperammonemia are advanced liver disease and renal failure. Severe or chronic liver failure (as occurs in fiilminant hepatitis and cirrhosis, respectively) leads to a significant impairment of normal ammonia metabolism. Reye s syndrome, which is primarily a central nervous system disorder with minor hepatic dysfunction, is also associated with hyperammonemia. Hepatic en-... 

Bachmann C, Colombo JP. Acid-base status and plasma glutamine in patients with hereditary urea cycle disorders. In Soeters PB, Wilson )HP, Meijer AJ, eds. Advances in ammonia metabolism and hepatic encephalopathy, 1st ed. Amsterdam Elsevier, 1988 72-8. 

The determination of plasma ammonia is of great importance both for the diagnosis and for the treatment of hereditary metabolic disorders of the urea cycle. The level is always raised in these conditions since the other mechanisms for regulating blood ammonia mentioned above are not able by themselves to keep the ammonia level within normal limits. 

The goals of nutrition management are to prevent the accumulation of ammonia, normalize plasma amino acids, and promote normal growth and development (Box 15.2). The treatment of UCD differs from other metabolic disorders with respect to protein intake. In UCD total protein is... 

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some covalent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. 

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

Also, respiratory distress with lung disorders osteomalacia on anti-convulsants metabolic acidosis/ coma in renal deficiency/diabetic nephropathy ammonia poisoning with cirrhosis hypo-potassium enhanced trough levels of cyclosporine. 

A description of acid-base balance involves an accounting of the carbonic (H2C03, HCOh COa", and CO2) and noncar-bonic acids and conjugate bases in terms of input (intake plus metabolic production) and output (excretion plus metabolic conversion) over a given time interval. The acid-base status of the body fluids is typically assessed by measurements of total CO2 plasma pH and PCO2, because the bicarbonate/carbonic acid system is the most important buffering system of the plasma. Occasionally, measurement of total titratable acid or base, or other acid and base analytes (e.g., lactate and ammonia [NH3]) is necessary to determine the etiology of an acid-base disorder. 

Animal and human studies have shown that an elevated concentration of ammonia (hyperammonemia) exerts toxic effects on the central nervous system. There are several causes, both inherited and acquired, of hyperammonemia. The inherited deficiencies of urea cycle enzymes are the major cause of hyperammonemia in infants. The two major inherited disorders are those involving the metabolism of the dibasic amino acids lysine and ornithine and those involving the metabolism of organic acids, such as propionic acid, methylmalonic acid, isovaleric acid, and others (see Chapter 55). 

The fasting venous plasma ammonia concentration is useful in the differential diagnosis of encephalopathy when it is unclear if encephalopathy is of an hepatic origin. It is especially helpful in diagnosing Reye s syndrome and the inherited disorders of urea metabolism. However, it is not a useful test to use in patients with laiown liver disease. 

Valproic acid (2-propyl-n-pentanoic acid, VP A) is an anticonvulsant widely used in the treatment of various epileptic disorders. It has been known that VPA administration caused severe hepatic dysfunction similar to Reye s syndrome in a small number of patients. Deaths from hepatotoxicity were also reported. VPA affects carnitine and ammonia levels and other metabolic parameters related to fatty acid oxidation. The potential hepatotoxicity by VPA is caused by its unsaturated metabolites, such as 4-en-... 

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