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)

Toxic protein metabolites are assumed to play an important role in the multifactorial pathogenesis of hepatic encephalopathy (HE). To investigate this, we examined the serum levels of free amino acids, free phenols and indoles in 100 healthy adults, and in 124 liver cirrhotics with HE and 80 without HE. We found a significant increase in free serum phenols and indican already in liver cirrhosis without portal hypertension (PH) and HE. In stage III and IV HE large amounts of p-hydroxy-phenyl lactic acid were detected, which was not the case in cirrhotics without HE. In HE the increase in free serum phenols and indican was much higher than that of the mother substances tyrosine and tryptophan. The quotient BCAA/AAA was decreased significantly already in PH without HE. In addition to the increased formation by intestinal bacteria, a diminished oxidative capacity of the cirrhotic liver seems to be one of the main causes of the increased serum levels of toxic protein metabolites in HE.
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PMID:The role of protein metabolism in 204 liver cirrhotics with and without hepatic encephalopathy. II. Amino acids, free phenols and indoles. 372 89

Tryptophan is considered to be one of the agents involved in the pathogenesis of hepatic encephalopathy. In our study, we evaluated tryptophan metabolism in liver disease. A bolus of 1.5 g of L-tryptophan was administered intravenously to 14 patients with noncirrhotic liver disease, 40 patients with liver cirrhosis, and 8 healthy volunteers. As pharmacokinetic parameters, the half life, clearance, and volume of distribution of free and total tryptophan were determined using a biexponential formula. In addition, the activity of liver tryptophan pyrrolase, the key enzyme of tryptophan metabolism, was measured in liver biopsy specimens of 15 patients with noncirrhotic liver disease, 8 patients with cirrhosis of the liver, and 4 patients with histologically normal livers. Healthy subjects and patients with noncirrhotic liver disease both showed similar results in measured and calculated data. In contrast, patients with cirrhosis revealed significant alterations of the pharmacokinetic parameters of free and total tryptophan: the half-life was increased by 195% and 176%, the clearance was decreased by 73% and 34%, respectively, and the activity of tryptophan pyrrolase was decreased by 22%. The tryptophan transfer in cirrhosis amounted to only 0.75 +/- 0.03 g per 24 h compared with 2.6 +/- 0.34 g per 24 h in healthy individuals. The findings demonstrate that patients with cirrhosis show a marked reduction in their ability to metabolize tryptophan. This should be taken into account in the oral and parenteral nutrition of those patients.
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PMID:[Tryptophan metabolism in liver diseases: a pharmacokinetic and enzymatic study]. 374 17

The tolerance to exogenous fats has been evaluated in patients with liver cirrhosis. A three-stage lipid clearance test with continuous infusion (3 hr) of a triglyceride emulsion, Intralipid, was performed on 10 patients with well compensated liver cirrhosis and 10 normolipidemic volunteers. During the infusion, blood samples were collected for the measurement of particulate triglycerides (TG) by nephelometry; samples were also collected for total TG, free fatty acids (FFA) and free tryptophan (TRP) determinations. Plasma endogenous triglycerides were calculated as the total minus exogenous, particulate, TG. The fractional removal rate (K2) and the maximal clearing capacity (K1) for exogenous TG were lower in patients than in controls, though a significant difference (p less than 0.05) was found only for K1. Endogenous TG and FFA showed a comparable rise in patients and controls during Intralipid infusion. A significant increase in free TRP was noted in cirrhotics upon maximal infusion rate. It is concluded that: in patients with well compensated liver cirrhosis the maximal clearing capacity (K1) for exogenous TG is impaired. Nonetheless, moderate amounts of fat may be removed at a normal rate from the bloodstream; a normal synthesis rate of exogenous TG may be maintained even in a severely damaged liver; considering the possible role of free TRP in the pathogenesis of hepatic encephalopathy (HE), the use of large amounts of lipids should be discouraged in patients with decompensated liver cirrhosis, or even avoided in those with impending or overt HE.
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PMID:Exogenous lipid clearance in compensated liver cirrhosis. 379 49

Changes in amino acid concentrations in plasma during a 100 g oral glucose tolerance test were investigated in patients with liver cirrhosis and in healthy controls. In the controls, almost all amino acid concentrations reached a nadir about 3 hours after glucose loading, then returned to initial levels after 6 hours. Immunoreactive insulin levels reached a peak about 30 minutes after loading, then decreased gradually, reaching initial levels after 6 hours. In the controls, the decrease ratios, defined as maximum decrease during the 3 hours after loading/initial concentration in plasma, were 0.607 and 0.554 for isoleucine (Ile) and leucine (Leu) respectively and 0.382 for valine (Val) which is significantly lower than for Ile or Leu. A similar tendency was recognized in patients with liver cirrhosis. The initial concentration of tyrosine (Tyr) and phenylalanine (Phe) in liver cirrhosis was significantly higher and their decrease ratios were significantly lower than in controls. Though no difference was observed between initial concentrations of tryptophan (Trp) in controls and liver cirrhosis patients, the decrease ratio of Trp in liver cirrhosis was lower (0.061) than that of controls (0.279) (p less than 0.001). The value, t-Trp/BCAA + AAA, i.e. total Trp concentration (mmol/l)/concentration (mmol/l) of branched chain amino acids (BCAA, Ile + Leu + Val) plus aromatic amino acids (AAA, Tyr + Phe), which is known to correlate with the brain Trp concentration of rats (Fernstrom, J. D. & Wurtman, R. J. (1972) Science 178, 414-416), changed significantly from 9.6 +/- 2.4 (mean +/- 1 SD) at the initiation to 12.9 +/- 3.3 at 3 hours after loading in controls (p less than 0.001), and in liver cirrhosis it changed from 10.3 +/- 1.9 to 15.8 +/- 3.1 (p less than 0.001).
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PMID:Changes in plasma amino acids during the oral glucose tolerance test and the effect of these changes on hepatic encephalopathy. 389 65

S9 fraction pools of liver biopsy samples, collected from 129 patients in two consecutive studies, were comparatively assayed for their ability to activate aflatoxin B1 (AFB1) and a tryptophan pyrolysate product (Trp-P-2) in a miniaturized Salmonella mutagenicity test system. Metabolic activation was not affected to a significant extent by most of the monitored variability factors, such as sex, alcohol, cigarette smoking and liver histology (minimal changes, chronic persistent (CPH) or active (CAH) hepatitis, CAH steatosis, or cirrhosis). Conversely, a significant enhancement of activation was observed for AFB1 in cases of mild CAH and especially for Trp-P-2 in hepatitis B virus carriers, irrespective of their histologic diagnosis.
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PMID:Metabolic activation of hepatocarcinogens in chronic hepatitis B. 393 46

Cytochrome P450 levels are often low in the cirrhotic liver but the reason for this has not been established. Because changes in heme metabolism may reduce hepatic levels of cytochrome P450, the relationship of heme turnover to cytochrome P450 levels has been examined in rats with cirrhosis. Cirrhosis was produced by repeated carbon tetrachloride inhalation. In animals with cirrhosis, hepatic microsomal cytochrome P450 content was significantly less (32%) than in controls. Heme synthesis was assessed by measuring the activity of mitochondrial delta-amino-levulinic acid synthetase and also by determining the incorporation (within 30 min) of radiolabeled delta-aminolevulinic acid into the microsomal heme fraction. Both these parameters were normal in rats with CCl4-induced cirrhosis. In addition, the activity of microsomal heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin, was not altered. Cytochrome P450 heme degradation was then determined directly by injecting radiolabeled delta-aminolevulinic acid and measuring radioactivity in CO-binding particles (microsomes incubated with protease to remove cytochrome b5) prepared at various times thereafter. By this method, the degradation rate of cytochrome P450 heme did not differ between rats with cirrhosis and controls. Finally, the availability of hepatic heme for formation of hemoproteins was deemed to be satisfactory in cirrhotic liver because tryptophan pyrrolase saturation was comparable with controls, and also because heme administered in vivo did not enhance hepatic clearance of the cytochrome P450 substrate antipyrine. The failure to find defective heme biosynthesis or accelerated heme breakdown and the evidence that heme is available in amounts that do not restrict hemoprotein formation indicate that aberrant heme metabolism is not the cause of low cytochrome P450 levels in this rat model of cirrhosis.
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PMID:Hepatic heme metabolism and cytochrome P450 in cirrhotic rat liver. 400 1

Oral tryptophan loading tests were performed on patients with cirrhosis of the liver before and after treatment with an oral antibiotic practically unabsorbed from the gastrointestinal tract. After antibiotic therapy, neuropsychiatric manifestations evoked by the oral administration of tryptophan were reduced in duration by about 50% and in severity as well despite a slightly enhanced elevation of serum total and free tryptophan levels, compared to pre-treatment loading tests. The urinary indican output also showed a significantly greater decrease in the post-treatment test (p less than 0.05) whereas no appreciable difference was observed in urinary 5-hydroxy-indoleacetic acid excretion between the pre- and post-treatment tests. The data suggest that neuropsychiatric manifestations seen following oral administration of tryptophan may be attributed to intestinal tryptophan metabolites rather than to this aromatic amino acid itself and/or its metabolites in the brain.
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PMID:Tryptophan metabolism in liver cirrhosis: influence of oral antibiotics on neuropsychiatric symptoms. 620 23

Fasting serum levels of total and free tryptophan, and free fatty acids and albumin, were measured and compared by blood biochemical analysis in patients with hepatobiliary disease and neuropsychiatric symptoms. The serum total tryptophan level tended to be elevated in patients with chronic active hepatitis, hepatic coma and obstructive jaundice, but not significantly. The serum free tryptophan level was significantly elevated in patients with chronic active hepatitis, liver cirrhosis, primary hepatocellular carcinoma and obstructive jaundice. The free tryptophan level was related to the decreased serum albumin level and elevated serum free fatty acid levels, which seems to indicate a connection with liver parenchymal function. The level, however, seemed not to correlate with neuropsychiatric symptoms.
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PMID:Clinical evaluation of serum levels of tryptophan in hepatobiliary disease. 624 22

Free tryptophan in plasma was separated by centrifugation through an Amicon ultrafiltration membrane cone. The value obtained without control of pH was found to be lower than that obtained with control of pH by an improved method ( Hijikata et al. (1981) Anal. Biochem. 118, 10-16). For determination of the total tryptophan concentration in the plasma, high performance liquid chromatography (HPLC) was better than the method of Denckla Dewey as modified by Bloxam & Warren ( (1974) Anal. Biochem. 60, 621-625), as judged on the basis of sensitivity, recovery rate and coefficient of variance. The total tryptophan concentration in the plasma determined by HPLC was lower than that determined by the Bloxam & Warren method. The total tryptophan concentration (t-Trp), free tryptophan concentration (f-Trp) and f-Trp/t-Trp ratio were 55.8 +/- 10.2 mumol/l, 11.6 +/- 1.5 mumol/l and 0.211 +/- 0.03 (mean +/- 1 SD) respectively, in healthy subjects (controls). No significant difference was observed between the values of controls and those of patients with liver cirrhosis, hepatocellular carcinoma, liver cirrhosis with hepatocellular carcinoma and hepatic encephalopathy of liver cirrhosis without bleeding. But in liver cirrhosis with bleeding, free tryptophan concentration (f-Trp, 48.0 +/- 23.3 mumol/l, p less than 0.001) and f-Trp/t-Trp ratio (0.645 +/- 0.289, p less than 0.001) were significantly higher than those of controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determination of free tryptophan in plasma and its clinical applications. 633 Feb 73

The metabolic effects of a protein-rich meal were studied for 3 h in 10 controls and in 20 cirrhotic patients. After protein ingestion, blood glucose did not vary significantly. Insulin and glucagon levels rose in controls and, more markedly, in cirrhotics. Aromatic amino acids and tryptophan increased more in cirrhotics as a result of their decreased liver function. Similarly, branched-chain amino acids increased by 153 +/- 14 nmol/ml X min (mean +/- SE) in controls and by 259 +/- 27 nmol/ml X min in cirrhotics (p less than 0.02), in the presence of a markedly increased insulin response. Branched-chain amino acid metabolism mainly occurs in skeletal muscle under insulin control; in cirrhosis, it might be reduced as a consequence of insulin resistance. To support this hypothesis, the effects of the protein meal were compared with those of an oral glucose load in 15 cirrhotic patients. Branched-chain amino acid response to protein ingestion significantly correlated with blood glucose response to oral glucose (r = 0.714), and with insulin resistance during the glucose tolerance test, when assessed by the insulinogenic index (r = 0.628). Similarly, in 8 patients, increased branched-chain amino acid response also correlated with the index of tissue sensitivity to insulin obtained by means of the glucose clamp technique during continuous insulin infusion (r = -0.809). We conclude that liver cirrhosis is characterized by an abnormal branched-chain amino acid response to protein ingestion, which matches the well-known intolerance to oral glucose. Both alterations are possibly due to decreased peripheral insulin activity on substrates.
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PMID:Plasma amino acid response to protein ingestion in patients with liver cirrhosis. 634 56


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