Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This contribution presents data from the literature as well as our own results concerning the mechanisms of hepatic encephalopathy (HE). 1. Blood chemistry: In patients with liver cirrhosis, the plasma levels of ammonia, phenylalanine, tyrosine, phenolic acids, and octopamine correlated with the stages of HE. Methionine and free tryptophan concentrations were increased only in stages 2-4. Further, branched chain amino acids were below the normal range. Experimental findings in animals elucidated some mechanisms of these changes. 2. Effects of administered substances: With ammonia, methionine, methanethiol, tryptophan, phenolic substances, and fatty acids central nervous disturbances were observed. 3. Interactions: Anemia, methanethiol, and fatty acids favored ammonia toxicity. Alkalosis diminished cerebral symptoms. 4. Neurotransmitters: HE was accompanied by an enhanced turnover of serotonin and by increased amounts of false neurotransmitters (like octopamine) in the brain. 5. Oxydative brain metabolism: Disorders of cerebral oxygen and glucose utilization were mainly documented in cases of long term HE with EEG alterations. 6. Structural changes of the brain: Most of them are irreversible.
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PMID:[Pathogenesis of hepatic encephalopathy (author's transl)]. 1 66

Tyrosine (Tyr), tyrosine hydroxylase (TH), tryptophan (Trp), serotonin (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were assayed spectrofluorometrically and radioenzymatically in various regions of post-mortem brains of human patients with hepatic, uremic, and diabetic coma, liver cirrhosis without coma, and hepatic coma treated with parenteral administration of L-valine, a branched-chain amino acid. The results were as follows: In both hepatic and diabetic coma Tyr was increased as compared to non-comatose cirrhosis and controls, while TH acitivity was within normal limits, indicating sufficient oxygen supply of the brain in both types of coma. Brain DA showed a mild decrease in all types of metabolic coma. Brain Trp was not considerably changed in non-comatose cases of liver cirrhosis and after L-valine treatment of hepatic encephalopathy, but was significantly increased in hepatic coma, with highest elevation in the brainstem tegmentum. Both 5-HT and 5-HIAA were not significantly changed in non-comatose cirrhosis, while a general increase with prevalence for the brainstem was obvious in all types of metabolic coma. After L-valine treatment of hepatic coma, 5-HT levels were usually decreased below control values, while 5-HIAA levels were at or below controls. These results in human post-mortem brains confirm previous CSF and brain findings in experimental and human hepatic and uremic encephalopathies, indicating derangement of brain monoamine neurotransmitter metabolism which is attributed to imbalance of aromatic and branched-chain amino acids in plasma and brain. Increased cerebral 5-HT turnover, particularly in the ascending serotonergic brainstem systems, due to derangement of brain uptake of Trp is suggested to represent an important biochemical substrate of disorders of consciousness in hepatic failure and other types of metabolic encephalopathies. Clinical improvement of hepatic encephalopathy and of the underlying neurotransmitter derangements by administration of L-valine and the possible role of this competitive amino acid on intermediary metabolism and ammonia detoxification are discussed.
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PMID:Brain monoamines in hepatic encephalopathy and other types of metabolic coma. 3 73

It is proposed that severe impairment of liver function in cirrhosis or portacaval shunt results in unrestricted entry of insulin into the peripheral circulation. The ensuing high level of insulin promotes excessive removal of the branched-chain aminoacids by muscle, thereby lowering the plasma levels of these aminoacids. In consequence, the competitive action of the branched-chain aminoacids on the entry of tryptophan into the brain is reduced, more tryptophan enters the brain, and serotonin is synthesised in excess, thus facilitating hepatic coma.
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PMID:Insulin, plasma aminoacid imbalance, and hepatic coma. 4 85

A histochemical study was carried out on orcein-positive hepatocellular material in 111 cases, 27 of which were stained positively by orcein. Orcein-positive material was very frequently found in protracted viral hepatitis and in chronic active hepatitis, as well as in other liver diseases with or without cholestasis; it was absent in liver cirrhosis. In all the cases considered the orcein-positive material was mainly formed of proteins, rich in amino acids with sulfhydryl and disulphide radicals, tryptophan and, to a lesser extent, of NH2 alpha amino acids. The orcein-positive substance was apparently carbohydrate-free. The presence of copper was also confirmed.
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PMID:Histochemical study of orcein-positive hepatocellular material in paraffin sections of liver biopsy samples in the course of various liver diseases. 9 Nov 88

The concentrations of tryptophan in serum and CSF, as well as that of 5-HIAA in CSF were investigated in various group of patients. Those with hepatic cirrhosis have normal total serum tryptophan. However, because of the low concentration of serum albumin the percentage of nonalbumin-bound tryptophan is elevated about 50 percent above the mean control value. By contrast tryptophan in the CSF was increased by 50 to over 800 percent. This suggests that there is also an increase in brain tryptophan and serotonin in the cirrhotic patients. No significant difference was found for the concentrations of tryptophan in CSF of patients in coma and those not in coma. Patients with hepatic coma had an elevated concentration of 5-HIAA in the lumbar CSF which may reflect the increase in this compound and in serotonin reported by Jellinger and Riederer (1977). However, following treatment with probenecid in order to block the egress of 5-HIAA from the CSF, the concentration of 5-HIAA in relation to that of probenecid was not significantly different for the group with hepatic coma as compared with the control group.
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PMID:Tryptophan in hepatic coma. 29 Jul 43

Many pathways of essential neutral amino acid metabolism in the CNS are influenced by precursor availability. Since the delivery of circulating amino acids to brain cells is primarily controlled by the rate of amino acid transport through the blood-brain barrier (BBB), pathways of brain amino acid metaboliransport system. The Km of BBB transport is in the 0.1--0.6 mM range, which approximates the physiologic plasma levels and forms the basis of the unusual sensitivity of the brain to competition effects on neutral amino acid transport. Unlike the brain, the Km of amino acid transport into other organs is in the 1--10 mM range or greater, which frees these tissues from competition effects in the physiologic range of plasma amino acids. Tryptophan circulates 80--90% bound to albumin; however, the capacity/affinity ratio of the BBB neutral amino acid transport system exceeds the capacity/affinity ratio of albumin binding of tryptophan, which enables the carrier to strip tryptophan off albumin as it traverses the brain capillary. The activity of the BBB neutral amino acid transport system is probably not modulated by insulin, but is influenced by changes in thyroid hormone status; the transport system is also induced in states of hepatic encephalopathy and this induction process is the primary cause of the increased brain tryptophan and serotonin levels in cirrhosis.
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PMID:The role of blood-brain barrier transport of tryptophan and other neutral amino acids in the regulation of substrate-limited pathways of brain amino acid metabolism. 38 9

Encephalopathic patients with cirrhosis of the liver consistently showed elevated levels of the aromatic amino acids, phenylalanine, tyrosine and free tryptophan as well as methionine in serum, whereas levels of the branched chain amino acids, valine, leucine and isoleucine, were depressed. Comatose patients with fulminant hepatitis had markedly elevated levels of all amino acids, the results being greatly different from those of cirrhotic patients. Molar ratios of (valine + leucine + isoleucine)/(phenylalanine + tyrosine) decreased both in cirrhotics with and without encephalopathy and in cases with fulminant hepatitis. Infusion of a commercially available L-amino acid solution in a cirrhotic patient induced a strikingly abnormal aminogram documented in hepatic encephalopathy. Therefore, effects of branched chain amino acid infusion on the deranged amino acid pattern were primarily studied for the purpose of improvement in hepatic encephalopathy by normalization of serum amino acid patterns. Elevated levels of the aromatic amino acids and methionine could be apparently depressed in a cirrhotic patient by this type of infusion but not in a case of fulminant hepatitis probably because of the poor utilization of these amino acids in severely impaired liver.
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PMID:Serum amino acids in hepatic encephalopathy--effects of branched chain amino acid infusion on serum aminogram. 52 13

The effect of varying dietary protein content on the daily rhythms in plasma neutral amino acid concentrations was studied in patients with chronic cirrhosis. For two consecutive 5-day periods, subjects consumed diets containing either 0 or 75 g of protein per day. Blood samples were drawn at 4-hr intervals on the 4th and 5th days of each dietary period. For most of the neutral amino acids, the changes in plasma concentration associated with time of day or with variations in dietary protein content were similar to those observed previously in normal subjects. Ingestion of the protein-free diet caused significant reductions in the daytime level of all amino acids studied, except for tryptophan, the concentration of which did not change during the 24-hr period. Ingestion of the 75-g protein diet caused plasma levels of most of theamino acids to increase slightly during the day; these increments were not statistically significant for tryptophan, tyrosine, leucine, and methionine. The absolute plasma concentrations of most of the neutral amino acids were also in the normal range; exceptions included methonine, tyrosine, and phenylalanine, whose plasma levels were significantly elevated above normal valves. The plasma ratios of tryptophan, tyrosine, and phenylalanine concentrations to the sum of the concentrations of other large neutral amino acids increased during the day uhen the protein-free diet was ingested; this effect was moderated by the addition of protein to the food. The plasma ratios for the branched-chain amino acids were depressed below normal; those for tyrosine, phenylalanine, and methionine were significantly increased. The plasma tryptophan ratio was within the normal range. These findings provide a basis for anticipating that the uptake from blood into brain of several of the large neutral amino acids may be modified in patients with chronic cirrhosis.
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PMID:Diurnal variations in plasma neutral amino acid concentrations among patients with cirrhosis: effect of dietary protein. 57 62

To clarify the involvement of tryptophan in the pathogenesis of hepatic coma, plasma and cerebrospinal fluid (CSF) tryptophan was studied in three patient groups (hepatic coma, stable cirrhosis, and control). An assessment of free fatty acids, some of the amino acids reported to compete with tryptophan for brain uptake, and albumin was also made. The data demonstrated that, whereas the elevated CSF tryptophan levels in cirrhotic patients compared to controls may have been attributable to decreased plasma branched chain amino acids, the elevated CSF tryptophan levels in hepatic coma compared to stable cirrhotic patients were probably attributable to increased plasma free tryptophan concentrations. Associated with the elevated plasma free tryptophan in coma patients was an increase in plasma free fatty acids and a marked decrease in serum albumin levels. Of all the amino acids investigated in the CSF, only tryptophan was significantly increased in patients in hepatic coma compared to cirrhotic patients not in coma.
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PMID:Tryptophan and hepatic coma. 62 Aug 92

In rats after portacaval anastomosis (an animal model of chronic liver disease), transport of tryptophan and other members of the large neutral amino acid group from blood to brain was markedly enhanced. Increased transport activity was apparently restricted to the neutral amino acid transport system, since brain uptake of glucose, inulin, and tyramine was unaffected while blood-brain arginine transport was significantly reduced. These results strikingly confirm the hypothesis that carrier-mediated blood-brain transport is the limiting factor determining the availability of the neutral amino acids to the brain. The encephalopathy associated with cirrhosis may be the result of abnormal neurotransmitter metabolism and neurotransmission secondary to increased neutral amino acid transport activity and an increased brain content of members of the neutral amino acid group.
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PMID:Blood-brain neutral amino acid transport activity is increased after portacaval anastomosis. 66 19


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