Antipyrine clearance and response to interferon therapy in chronic hepatitis.
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Antipyrine↗
Biomedical subjects
G Marchesini
Publications and source records attributed to G Marchesini.
Glutathione kinetics in normal man and in patients with liver cirrhosis.
BACKGROUND/AIMS: The dynamics of glutathione in plasma has always been studied by bolus injections. Data are available suggesting that the low plasma levels of cirrhosis are due to decreased production in glutathione-producing tissues, mainly the liver. We aimed to measure the kinetics of glutathione during controlled steady-state conditions, and to determine the reasons for its reduced plasma levels in advanced cirrhosis. METHODS: The plasma clearance of glutathione was measured in six control subjects and in ten patients with cirrhosis during a 2-step infusion study, producing steady-state levels approximately 5 and 10 times basal values. The plasma disappearance curve after infusion stop was used to determine the apparent volume of distribution and half-life of glutathione, and the estimated basal appearance rate. RESULTS: The clearance of glutathione did not reject 1st-order kinetics, i.e., it was concentration-independent, and was nearly doubled in cirrhosis. The half-life of exogenous glutathione was not different, whereas the volume of distribution was larger in cirrhosis, in the same range as extracellular water. The endogenous basal appearance rate of glutathione was reduced by 50%, and correlated with liver function, measured by routine and dynamic tests. CONCLUSIONS: The data confirm that the primary defect responsible for reduced glutathione in liver disease is a reduced production, possibly related to hepatocyte dysfunction and a block along the pathway of methionine metabolism.
Adult↗
Effect of lactulose on carbohydrate metabolism and diabetes mellitus.
BACKGROUND: Unabsorbable disaccharides, by reducing transit time and possibly glucose absorption, are expected to affect carbohydrate metabolism. AIM: To test the effects of a preparation containing fibre and lactulose in the form of biscuits on glucose and insulin levels in obesity. METHODS: In 10 obese patients glucose and insulin were measured in the fasting state and in response to a meal during two consecutive days on a strictly controlled diet; on one day a total of 11 biscuits (10 g dietary fibre, 2 g raw fibre +8.2 g lactulose) were randomly substituted for an equicaloric part of a diet. RESULTS: Glucose and insulin in response to breakfast and to lunch were blunted by dietary fibre and lactulose, without any trend towards post-meal hypoglycaemia. Average day-time glucose decreased by 0.53 +/- SD 0.28 mmol/L, and insulin by 74.6 +/- 45.2 pmol/L. Plasma amino acids were higher during supplementation, ruling out malabsorption as a cause of glucose flattening. CONCLUSION: Because of the rationale of the preparation, good compliance of patients, and significant results in short-term experiments, the association of fibre and lactulose deserves more careful evaluation in long-term clinical studies.
Blood Glucose↗
Uncertainty in liver function assessment on the basis of single-point galactose concentration.
The uncertainty in liver function assessment based on single-sample galactose levels after galactose injection, in comparison to the standard procedure using the galactose elimination capacity (GEC), was assessed in 905 tests performed in a wide range of liver functions. The 45-min galactose levels significantly correlated with GEC, the correlation being better in subjects with a good liver function. In cirrhosis, the prediction using the 60-min galactose value was better than when the 45-min value was used. In the whole series, the 95% confidence interval of GEC predicted by 45-min galactose was as large as +/- 1.55mg x kg(-1) x min(-1) as absolute value, corresponding to a range from -41 to +47% of measured GEC. In cirrhosis, the 95% confidence interval was +/- 1.42 mg x kg(-1) x min(-1) and between -40 and +46% of measured GEC. The 60-min values were more predictive, but in Child class C patients the average error was 0.42 mg x kg(-1) x min(-1) (95% confidence interval -0.64 to +1.49, corresponding to -39 to +76% of measured GEC). The uncertainty was maintained within +/- 10% of measured values only in 50% of the tests. We conclude that the single-point galactose test introduces a considerable error, mainly in patients with more advanced liver disease, which may bias the decision-making process.
Analysis of Variance↗
Efficacy of a surveillance program for early detection of hepatocellular carcinoma.
BACKGROUND: Contrasting data have so far been reported on the utility and efficacy of screening patients with cirrhosis for early detection of hepatocellular carcinoma (HCC). The goal of this study was to evaluate the efficacy of a regular ultrasonographic and laboratory follow-up for the early detection of small HCC, and to identify parameters correlated with a higher risk of developing HCC. METHODS: One hundred and sixty-four consecutive patients with liver cirrhosis living in Emilia Romagna, Italy, were enrolled in the period 1989-1991. All patients underwent clinical, biochemical, and ultrasonographic evaluations at entry and at 3- and 6-month intervals during follow-up. RESULTS: By April 1995, 34 patients had developed HCC. In 76% of the patients, ultrasonography identified HCC when it was still single and small (< 4 cm). At discriminant, logistic regression and univariate analyses, sex and the entry concentration of alkaline phosphatase, alpha-fetoprotein, gamma-glutamyl transpeptidase, and albumin were associated with a higher risk of developing HCC, whereas at multivariate analysis (Cox's model), only sex and the entry concentration of alkaline phosphatase, albumin, and alpha-fetoprotein were independently and significantly related to the appearance of HCC. CONCLUSIONS: A regular ultrasonographic follow-up, timed at 3- to 6-month intervals according to the risk of HCC development in patients with cirrhosis, allows the detection of liver carcinoma at an early stage in a high proportion of patients, possibly improving the prognosis of the disease.
Adult↗
Transamination of methionine after loading in patients with cirrhosis.
BACKGROUND/AIMS: An impaired methionine degradation along the transsulfuration pathway has been widely described in cirrhosis. Evidence has been provided that methionine can also be degraded via a transamination pathway, leading to formation of methanethiol and its metabolites, protein-S-SCH3 (a mixed disulphide of blood proteins and methanethiol), alpha-ketomethylthiobutyrate and X-S-SCH3 (a mixed disulphide of a thiol with an unknown component X and methanethiol). This pathway seems to be of little importance in normal subjects, even after methionine loading, but its role in the presence of an acquired transsulfuration defect has never been tested. METHODS: We measured the plasma concentration of methanethiol metabolites in six normal subjects and 11 patients with cirrhosis receiving a primed-continuous infusion of L-methionine, at rates able to increase plasma methionine to levels approximately 20 times basal concentrations. RESULTS: Before methionine infusion, the sum of transamination metabolites was similar in the two groups (0.29 +/- SD 0.07 mumol/l in controls and 0.45 +/- SD 0.22 in patients with cirrhosis). During methionine infusion and after the end of infusion, there was a progressive increase of transamination metabolites, which reached values approximately 10 times basal concentrations, with no difference between groups. CONCLUSIONS: We conclude that transamination cannot represent a quantitatively important exit for excess methionine in subjects with cirrhosis, in the presence of an acquired block along the transsulfuration pathway.
Galactose↗
Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study. AISF Group for the Study of Liver Transplantation. Associazione Italiana per lo Studio del Fegato.
AIMS/METHODS: The present study aimed to examine whether the galactose elimination capacity can be used to predict the survival of patients with advanced liver disease. We studied 194 patients with cirrhosis, belonging to Child class B and C, for 2 years each. RESULTS: The overall probability of survival was 79% at 6 months, 72% at 1 year and 62% at 2 years. Variables significantly associated with the duration of survival, as assessed by univariate analysis, were the Child-Pugh score, presence of ascites, size of esophageal varices, prothrombin time, albumin, bilirubin, urea, creatinine, glucose and galactose elimination capacity. By a multivariable analysis, only Pugh score (p = 0.005), creatinine (p < 0.001), varices (p = 0.001) and galactose elimination capacity (p < 0.001) were independent predictors of mortality. The galactose elimination capacity was even more sensitive when the end-point was limited to deaths due to liver failure and hepatorenal syndrome. A new score obtained by summing the Pugh score with a score derived from galactose elimination capacity was quite simple and accurate for predicting survival. CONCLUSIONS: The quantitative measurement of liver function as the galactose elimination capacity could be of use to identify patients with cirrhosis and probable short survival who might benefit most from urgent transplantation.
Adolescent↗
Transdermal nitroglycerin in cirrhosis. A 24-hour echo-Doppler study of splanchnic hemodynamics.
BACKGROUND/AIMS: The present study was aimed to evaluate the 24-hour effect of transdermal nitroglycerin on splanchnic hemodynamics in cirrhotic patients. METHODS: Hemodynamic parameters (blood velocity and resistance indexes) were determined by means of pulsed echo-Doppler, a non-invasive method which proved to be useful to evaluate the effects of drugs on splanchnic vessels. Nine patients with biopsy-proven liver cirrhosis were studied. They were kept on a standard diet divided into 3 meals served at 8, 12 a.m. and 6 p.m. Echo-Doppler measurements were determined for 2 consecutive days at 7, 8, 9, 12 a.m, 1, 3, 6, 7, 9, 12 p.m. and again at 7 a.m. A transdermal nitroglycerin tape, capable of releasing 15 mg of the drug in 24 h, was applied to the skin of the chest at 7 a.m. of the second day. RESULTS: After nitroglycerin mean portal blood velocity and flow significantly decreased by 18 and 22%. Similarly superior mesenteric artery velocity decreased, while resistance indexes increased. ANOVA analysis showed a significant effect of the drug on superior mesenteric artery and portal flow, while the effect on hepatic artery flow and renal indexes were low. CONCLUSIONS: This study shows that nitroglycerin, given as transdermal long-acting system, significantly influences portal hemodynamics in liver cirrhosis. Its use, favoured by easy administration, may be proposed for long-term clinical studies to test its efficacy in preventing gastrointestinal bleeding.
Administration, Cutaneous↗
Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis.
Zinc deficiency is common in cirrhosis and has been involved in the altered nitrogen metabolism. In this study, we measured the effects of zinc supplementation on the dynamics of amino acid-derived urea synthesis in cirrhosis with mild or latent encephalopathy. The hepatic conversion of amino acids into urea was studied in eight patients with advanced cirrhosis under controlled conditions of substrate availability (continuous alanine infusion), before and after 3-month oral zinc sulfate supplementation (600 mg/d). Eight more patients, matched for hepatocellular failure and encephalopathy, served as controls. Plasma zinc levels were reduced in all patients and returned to normal after oral zinc. The alanine-stimulated urea nitrogen synthesis rate in relation to alpha-amino-N concentration--the functional hepatic nitrogen clearance--increased by 25% after zinc supplementation, i.e., more urea was produced at any alpha-amino-N concentration. Basal and alanine-induced glucagon decreased by 50%, and the ammonia response to alanine decreased by 30%. Psychometric tests improved, as did routine and dynamic liver function tests and the Child-Pugh score. Also, the plasma concentration of lipid peroxides was reduced by zinc. No significant changes were observed in the control group. Our data indicate that long-term oral zinc speeds up the kinetics of urea formation from amino acids and ammonia. Changes in the hormonal drive and/or the antioxidant activity of zinc might be involved in the general improvement in liver function, whereas the beneficial effects on encephalopathy might stem from decreased ammonia.
Administration, Oral↗
The course of galactose elimination capacity in patients with alcoholic cirrhosis: possible use as a surrogate marker for death.
There is increasing interest for the use of surrogate end points in the evaluation of treatments in patients with liver disease, but adequate validation is seldom available. This study aimed to describe the different course of galactose elimination capacity in patients with alcoholic cirrhosis who continued to drink or abstained from alcohol consumption during follow-up, and to validate changes in galactose elimination as a surrogate end point for death from liver-related causes. Forty-five patients with alcoholic cirrhosis (22 who continued drinking throughout the study period, and 23 who stopped drinking and were abstinent throughout the study period) were retrospectively selected among patients who had galactose elimination capacity measured at 6-month intervals. During follow-up 10 drinkers and 3 abstainers died of liver-related causes (P = .025). Abstainers showed a transient improvement in galactose elimination capacity, followed by a decrease. Continuous drinkers showed a reduction from the beginning. According to Cox's regression analyses, persistent alcohol abuse and galactose elimination capacity were separately related to the risk of death, but, when a time-dependent model was fitted containing galactose elimination capacity and persistent alcohol abuse, only the former remained significant. This implies that variations in the risk of death occurring as a consequence of abstinence from alcohol consumption may be predicted from changes in galactose elimination capacity, and that the mechanisms through which abstinence influences survival are strictly linked to the mechanisms responsible for the changes in the test. Because of the strict association of decrease in galactose elimination capacity and short survival, as proved in several series, this observation represents adherence to the criteria requested for adequacy of a surrogate end point. In conclusion, in alcoholic cirrhosis the decrease in galactose elimination capacity is an adequate surrogate end point for death from liver-related causes, which is worth testing in other conditions and in response to other treatments.
Alcoholism↗
Evaluation of a new endoscopic index to predict first bleeding from the upper gastrointestinal tract in patients with cirrhosis.
The aim of this study was to prospectively evaluate the usefulness of the Italian Liver Cirrhosis Project (ILCP) classification of esophageal varices, together with the gastric features of portal hypertension, in predicting the first upper gastrointestinal bleeding in cirrhosis. The efficiency of these endoscopic parameters in predicting bleeding was also compared with the efficiency of the North Italian Endoscopic Club (NIEC) index. Three hundred forty-four cirrhotic patients with esophageal varices but without any previous bleeding were enrolled in the study. The following endoscopic parameters of esophageal varices were recorded: location, size, occupancy, blue tone, and red color signs. Gastric varices were graded as absent or present, while congestive gastropathy was considered as absent, mild to moderate, or severe. All patients were followed until the first upper gastrointestinal bleeding and/or death, or for at least 24 months. No patient received any treatment to prevent bleeding. Sixty-five patients bled from the upper gastrointestinal tract during the study. Univariate analysis showed that all endoscopic parameters were predictors of bleeding. According to multivariate analysis (Cox's model), size, gastric varices and congestive gastropathy were the only independent predictors of bleeding, and the following prognostic index (PI) was developed: PI = (size x 0.0395) + (congestive gastropathy x 0.878) + (gastric varices x 0.705). This index, which was validated using a split-sample technique, and which appears to be superior to the NIEC index in predicting bleeding, may be useful in decision making for primary prophylaxis.
Adult↗
The galactose elimination capacity test: a study of the technique based on the analysis of 868 measurements.
OBJECTIVES: Our objective in this study was to analyze the correspondence of galactose concentration-on-time-decay curve to theoretical assumptions and the confidence limits of the determination of galactose elimination capacity. METHODS: We analyzed a retrospective series of 868 galactose elimination tests, performed on subjects with and without liver disease. Zero-order kinetics of galactose elimination was tested by comparison of the residual variance of linear regression with that obtained after quadratic transformation. The uncertainty in determination of galactose elimination capacity was calculated on the regression line by computing the 95% confidence limits of the estimate. RESULTS: The time-course of galactose concentration suggested an initial uneven distribution, and the first (20-min) data point deviated significantly from the regression. The galactose decay curve in plasma rejected linearity in 13% of tests; after exclusion of the first data-point, linearity was rejected in only 3% of cases. The 95% confidence interval of galactose elimination capacity was on average +/- 16%, but in individual tests it was as large as +/- 60-80%. The uncertainty of the test was not affected by linearity. It was larger, with poor fitting of the experimental data on the regression of galactose concentration on time, low number of data points, and low galactose elimination. It was maintained within +/- 20% only when residual variance was > or = 2% of total variance (nearly 50% of tests). CONCLUSION: The methodology for the determination of galactose elimination capacity leads to considerable uncertainty as to the final result, which must be considered whenever the test is used for clinical purposes in the decision-making process. It tends to be larger in patients with advanced disease and can be accurately calculated so as to contribute to a proper evaluation of the test result.
Adolescent↗
Thyroid volume in type 1 diabetes patients without overt thyroid disease.
An association between insulin-dependent diabetes mellitus (type 1) and thyroid diseases has long been reported, but the morphological evaluation of the thyroid in type 1 diabetes patients without overt thyroid disease has always been limited to physical examination. Ultrasonography of the thyroid gland was performed in 45 patients with type 1 diabetes without overt thyroid disease, to study thyroid volume and the prevalence of thyroid nodules. Data were compared with those obtained in 45 age- and sex-matched control subjects residing in the same area. In the patients, thyroid volume had increased on average by 46%; 35% of male and 32% of female patients had a thyroid volume exceeding the 95% confidence limits of the matched controls. The prevalence of thyroid nodules was only slightly raised. On average, free thyroxine was increased in the presence of normal triiodothyronine levels. Four patients were frankly hyperthyroid. The patients also showed a higher prevalence of thyroid-microsomal antibodies, but the thyroid hormone status was not different in relation to thyroid volume, nor was thyroid volume in relation to the presence of autoantibodies. Patients with type 1 diabetes without overt thyroid disorders may have morphological, ultrasonographically detectable alterations of the thyroid gland, the expression of a possible involvement of the thyroid in an autoimmune disorder not limited to the islet cells.
Adolescent↗
Effects of beta-blockade on hepatic conversion of amino acid nitrogen and on urea synthesis in cirrhosis.
beta-Blockers are widely used to prevent gastrointestinal hemorrhage in cirrhosis. The metabolic effects of treatment are scarcely studied: hepatic function reportedly does not change significantly, but beta-adrenoceptors have been reported to regulate protein and amino acid metabolism. We studied hepatic nitrogen metabolism in response to constant alanine infusion in seven patients with cirrhosis before and 7 to 10 days after treatment with oral propranolol (60 to 100 mg/d). Beta-blockade was effective: it decreased heart rate by 25%, abolished orthostatic tachycardia, and reduced portal blood flow by 20%. Alanine-stimulated urea nitrogen synthesis rate (UNSR) was higher in patients with propranolol treatment, without any difference in aminonitrogen concentration. The kinetics of hepatic conversion of amino acid nitrogen into urea--ie, functional hepatic nitrogen clearance (FHNC)--increased by 30%, from (mean +/- SD) 17.0 +/- 4.1 to 22.0 +/- 6.6 L/h (P < .01). Increased urea production during alanine infusion resulted in negative nitrogen exchange even at the peak of alpha-aminonitrogen concentration. Basal insulin level was only slightly reduced during propranolol treatment, whereas the insulin response to alanine was significantly blunted. No differences in glucagon and cortisol were demonstrated. Epinephrine and norepinephrine levels were high-normal and did not vary after treatment. Increased urea production and stimulation of hepatic nitrogen clearance during beta-blockade may be mediated by relative hypoinsulinemia or by direct involvement of beta-adrenoceptors in the control of nitrogen metabolism, possibly by regulation of amino acid uptake and release in peripheral tissues.
Aged↗
Functional hepatic flow and Doppler-assessed total hepatic flow in control subjects and in patients with cirrhosis.
Functional hepatic flow and total hepatic flow were determined by non-invasive techniques in 32 patients with cirrhosis and in 32 paired control subjects. Functional hepatic flow was measured by the hepatic clearance of D-sorbitol, while total hepatic flow was determined by pulsed echo-Doppler, as the sum of portal and hepatic arterial blood flow. Functional hepatic flow was significantly reduced in patients with cirrhosis (927 +/- 314 vs. 1287 +/- 315; p < 0.0001), while total hepatic flow was slightly increased (1511 +/- 540 vs. 1261 +/- 321 in controls; p = 0.028). In control subjects functional hepatic flow significantly correlated with total hepatic flow (r = 0.823; p < 0.001), while no correlation was observed in cirrhosis. Functional hepatic flow and the difference between total hepatic flow and functional hepatic flow significantly correlated with the Child-Pugh score in patients with cirrhosis. The data obtained in control subjects support the measurement of functional hepatic flow and total hepatic flow by non-invasive techniques. The finding that in cirrhosis functional hepatic flow is significantly decreased, while Doppler-assessed total hepatic flow is preserved or even increased, confirms that a relevant part of blood flowing through the liver is diverted by intrahepatic shunts. The simultaneous assessment of these two parameters by non-invasive techniques may be proposed as a reliable tool for the study of functional shunting of cirrhosis.
Adult↗
Physical examination of the liver: is it still worth it?
OBJECTIVES: The aim of this study was to evaluate the actual role of physical examination of the liver in normal subjects and in cirrhotic patients. METHODS: One hundred healthy subjects and 100 patients with liver cirrhosis underwent a physical and an ultrasonographic evaluation of the liver by independent operators. Physical examination was performed by means of percussion and palpation to determine total liver span, liver span below the costal margin, and liver consistency. Total liver span, liver span below the costal margin, and liver volume were also determined by means of ultrasonography. RESULTS: The agreement between physical and ultrasonographic assessment of the liver span below the costal margin was poor in controls (chance corrected agreement index = 0.13) and excellent in patients (chance corrected agreement index = 0.93). Physical and ultrasonographic total liver span were correlated in patients with cirrhosis (r = 0.592) but not in controls (r = 0.205). Echo-measured liver span significantly correlated with the actual volume of the organ in both groups, whereas physical liver span significantly correlated with liver volume in cirrhosis but not in controls. The difference between actual liver volume and the value predicted by liver span was large. The cirrhotic liver was slightly reduced in size in comparison with that of healthy subjects and differed by an increase in consistency and a thickened edge. CONCLUSIONS: The bedside examination of the liver does not provide any accurate information regarding the actual volume of the organ. Its major role remains to define the characteristics of lower edge, mainly consistency, which may help in clinical diagnosis. Liver volume proved to predict prognosis in patients with cirrhosis, but its measurement needs quantitative, reproducible methods, which can be obtained only by imaging techniques.
Case-Control Studies↗
Hepatic lidocaine metabolism and liver histology.
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Humans↗
Hepatic conversion of amino-nitrogen to urea in thyroid diseases. II. A study in hyperthyroid patients.
Conflicting data have been reported on the influence of thyroid hormones on hepatic nitrogen metabolism and on liver metabolic activity. We studied the urea-nitrogen synthesis rate (UNSR) and the kinetics of the process of hepatic amino-nitrogen to urea-nitrogen conversion in response to constant alanine infusion (ie, the functional hepatic nitrogen clearance [FHNC]) in five hyperthyroid female patients before and after the achievement of a stable euthyroid status. In the same patients, galactose elimination capacity and antipyrine clearance were also measured as quantitative indices of hepatic function. The basal urea synthesis rate was nearly doubled in hyperthyroid patients (35.6 +/- 8.5 mmol.h-1 v 17.6 +/- 7.7 in euthyroid patients, P < .05) and increased linearly with increasing alpha-amino-nitrogen (alpha-AN) concentrations in both conditions. The urea synthesis rate during alanine infusion was still higher by approximately 30 mmol.h-1 in hyperthyroid subjects. The FHNC, calculated as the slope of the linear relation between the UNSR in each time interval and the corresponding average alpha-AN concentration, was not different (hyperthyroidism, 30.6 +/- 7.2 L.h-1; euthyroidism, 28.5 +/- 4.4; normal values > 25). The hepatic microsomal and cytosolic activities (antipyrine clearance and galactose elimination) were normal in hyperthyroid patients and did not change significantly after therapy. Our data show that the hepatic nitrogen metabolism of hyperthyroid patients is characterized by an upregulation of amino-nitrogen catabolism and loss of the sparing mechanism at low plasma amino acid levels, without any change in different metabolic activities.
Adult↗