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[The utility of quantitative 99mTc-GSA liver scintigraphy in the evaluation of hepatic functional reserve: comparison with 99mTc-PMT and 99mTc-Sn colloid].

Using data from 17 patients with liver cirrhosis and 3 patients with fatty liver, we have compared the utility of 3 hepatic imaging agents in the evaluation of hepatic functional reserve. Evaluated here were 99mTc-galactosyl human serum albumin (GSA) which is a new ligand for hepatic binding protein, 99mTc-N-pyridoxyl-5-methyl tryptophan (PMT) of a hepatobiliary agent, and 99mTc-Sn colloid. In each patient, we performed these 3 imaging studies within a week and also examined hepatic function tests (indocyanine green test, hepaplastin test, choline-esterase, etc). In each imaging study, serial images and dynamic data were obtained after the injection of 99mTc-GSA (185 MBq/3 mg), 99mTc-PMT (185 MBq), or 99mTc-Sn colloid (185 MBq). Using the obtained dynamic data, we analyzed the liver kinetics of the 3 agents based on 1 compartment model with 3 parameters (hepatic clearance, hepatic excretion rate, non-specific volume of distribution). From fitting the liver and heart data to this model, three unknown parameters were determined. Patlak plot was also applied in order to estimate liver uptake rate. Both curve fitting and Patlak plot could determine appropriate parameters in every study. In 99mTc-GSA, a nonlinear 3 compartment model was also applied in order to estimate hepatic blood flow, liver receptor density, and affinity of receptor-GSA binding separately. Using the obtained parameters, we analyzed the correlations between the parameters and the results of hepatic function tests. In all of the parameters, those obtained from 99mTc-GSA imaging showed the most significant statistical correlation with the results of hepatic function tests. From the present results, 99mTc-GSA imaging was concluded to be the best for evaluation of hepatic functional reserve.

Adult

Postischemic ATP levels predict hepatic function 24 hours following ischemia in the rat.

Hepatic function was assessed by the aminopyrine breath test (ABT) in male Sprague Dawley rats 24 h after partial hepatic ischemia. ABT decreased progressively to 26.3 (p less than 0.05) and 19.7% of dose (p less than 0.05) after 90 and 120 min of ischemia, respectively. ABT at 24 h after injury was correlated to the concentration of ATP in the ischemic lobes 1 h after the onset of reperfusion (r2 = 0.971) but not to ALT activity in plasma at 1 h (r2 = 0.391). We conclude that postischemic ATP levels are a better index of subsequent hepatic function than ALT.

Adenosine Triphosphate

[Relation of hepatic protein synthesis and hepatic functional mass in obstructive jaundiced rats].

In obstructive jaundiced rat, the change of hepatic functional mass assessed by [14C]-aminopyrine breath test (ABT) and galactose tolerance test (GaTT) and hepatic protein synthesis measured by [14C]-leucine incorporation into hepatic protein fraction were investigated. Bile duct ligation (BDL) for 5 and 14 days was followed by choledocho-duodenal fistula as the relief of obstruction. Hepatic functional mass measured by ABT and GaTT revealed a remarkable decrease at 5 and 14 days after BDL without differences in grades. These depressed values returned to the preoperative ones in 10 to 20 days after the relief of obstruction. On the contrary, hepatic protein synthesis was reciprocally enhanced after BDL. After the relief of obstruction the enhancement of hepatic protein synthesis was prolonged and then returned to the normal level in 20 days. These data suggested that in obstructive jaundice hepatic protein synthesis was stimulated by several stress and continued to be enhanced even after the relief of obstruction. These enhancement of hepatic protein synthesis would induce to decrease hepatic functional mass.

Aminopyrine

Actinomycin D blocks the hepatic functional albumin mRNA increase in aminonucleoside-nephrotic rats.

Hepatic functional albumin-mRNA was measured in the following groups of rats: (a) puromycin aminonucleoside (PAN)-nephrotic rats, (b) PAN-nephrotic rats treated with actinomycin D prior to sacrifice, (c) control rats, and (d) control rats treated with actinomycin D. Albumin mRNA was translated in an mRNA-dependent cell-free system from rabbit reticulocyte lysate. Albumin-mRNA increased about 2-fold in PAN-nephrotic rats. This increase was abolished in vivo in PAN-nephrotic rats treated with actinomycin D. Albumin mRNA was not significantly modified in control rats treated with actinomycin D. These data suggest that the increased level of hepatic functional albumin mRNA observed in PAN-nephrotic rats in vivo was due mainly to the increased rate of albumin gene transcription.

Albumins

[Hepatic functional reserve and tumor size as prognostic factors in patients with primary liver cancer undergoing non-surgical therapy].

A prognostic study on 119 patients with primary liver cancer undergoing nonsurgical therapy was carried out to evaluate the relevance of hepatic functional reserve and tumor size to their cumulative survival rates. All patients were classified into the three groups of Child's classification (A, B and C) according to their hepatic functional reserve and were also divided into the five groups according to their tumor size. The cumulative survival rates of all patients at 1, 2, 3, 4 and 5 years after the diagnosis were 50.9, 28.3, 18.8, 13.5 and 6.7%, respectively. The cumulative survival rates of group V whose tumor occupied more than 40% of the liver area were significantly lower than those of the other tumor-size-groups. The survival rates of Child's group A were significantly higher than those of group B and C. But in those patients who were classified into group V according to their tumor size, there was no significant difference in their survival rates among the three groups of Child's classification. These results suggest that hepatic functional reserve as well as tumor size is an important prognostic factor in patients with primary liver cancer. But if the cancer once develops greater than 40% of the liver area, hepatic functional reserve diminishes in value as a prognostic factor.

Antineoplastic Agents

Effect of combined ethinyl estradiol and norgestrel oral contraceptives on hepatic functions of albino rats.

The effect of two different doses of ethinyl estradiol and norgestrel combined oral contraceptives (OCs) on hepatic functions of albino rats was studied for a period of six months. Combined OCs treatment caused an increase in glycogen, RNA, total lipids, triglycerides, cholesterol and free fatty acids contents of liver and liver microsomes and decreased the liver weight/body weight ratio and phospholipid contents. Liver aminotransferase activities were elevated in the OCs treated animals whereas alkaline phosphatase activity remained unchanged. The biochemical changes were found to be dose dependent. Thus the present study has shown that the combined OCs treatment for six months is associated with altered hepatic functions. The possible mechanism of such an alteration of hepatic functions on OCs treatment is discussed.

Animals

Acute effects of acetylsalicylic acid on renal and hepatic function in normal humans.

The effect of a single oral dose (1 g) of acetylsalicylic acid (ASA) on renal function and hepatic enzymes as well as prothrombin time was studied in two series of experiments on normal human volunteers. Radioimmunoassay of albumin and beta 2-microglobulin excretion rates in urine revealed a statistically significant increase in both beta 2-microglobulin and albumin excretion rates within 2 h after dosage. Hepatic enzymes were not influenced by a single dose of ASA, while a statistically significant reduction in prothrombin time was registered. High-pressure liquid chromatography was used for measuring serum levels of ASA and salicylic acid (SA). Peak levels of 500 mumol/l and 150 mumol/l for SA and ASA, respectively, were found.

Adolescent

Changes in hepatic functional reserve after transcatheter embolization of hepatocellular carcinoma. Assessment by maximal removal rate of indocyanine green.

To clarify the influence of transcatheter arterial embolization (TAE) on hepatic function, the maximal removal rate of indocyanine green (ICG-Rmax), which represents the hepatic functional reserve, and the plasma disappearance rate of indocyanine green (k-ICG) were measured serially before and after 15 TAE procedures performed on 13 hepatocellular carcinoma (HCC) patients with underlying hepatic diseases. Compared to the values before TAE, ICG-Rmax values did not change or gradually decreased during 4 weeks in seven of the 13 patients but markedly decreased in the remaining six by as much as 50% during the first week. k-ICG values remained almost unchanged at any time after TAE. Albumin and prothrombin time were serially measured before and after 24 TAE procedures performed on 21 HCC patients with underlying hepatic diseases in whom no plasma products had been used for therapy. Albumin decreased by up to 75% in one of the 21 patients during the first week but did not change or gradually decreased in 20 of the 21 patients. Prothrombin time showed no obvious changes. This study showed that prominent changes occurred in ICG-Rmax, i.e., in the hepatic functional reserve, after TAE.

Aged

Expression of fetal and neonatal hepatic functions by mouse hepatoma-rat hepatoma hybrids.

In order to analyze the mechanisms implicated in the expression of differentiated functions during development, we have studied ten hybrid clones arising from fusion of cells of a mouse hepatoma characterized by the expression of only fetal hepatic functions with those of a rat hepatoma which express, like adult hepatocytes, a set of neonatal as well as fetal hepatic functions. The cells of most hybrid clones contain one set of chromosomes of each parent and coexpress the hepatic functions common to both parents. Among the hepatic proteins characteristic of only one parental line, some continue to be expressed while others are extinguished. The three functions out of the eight examined which are subject to extinction are expressed uniquely by the rat parental cells and appear only near or at birth during normal liver development. These results suggest that regulatory mechanisms (whose final effect is negative) operate in fetal cells to inhibit the expression of differentiated functions limited to a later stage of development.

Animals

Renal and systemic hemodynamics in experimental cirrhosis in rats: relation to hepatic function.

The onset of sodium retention in the phenobarbital and carbon tetrachloride model of cirrhosis in the rat is preceded by a linear decrease in hepatic function as measured by the aminopyrine breath test. Sodium retention occurs when liver function decreases below a critical threshold. Changes in systemic hemodynamics may be responsible for initiating the development of renal sodium retention. The objective of this study was to investigate the relationship between hepatic function and systemic and renal hemodynamics of experimental cirrhosis in rats maintained on a constant salt diet. Cirrhosis was induced in phenobarbital-treated rats by weekly administration of carbon tetrachloride. The aminopyrine breath test served as a measure of hepatic function. Three groups of animals were studied to evaluate the contribution of changes in systemic and renal hemodynamics to the onset of sodium retention: a group with sodium retention and aminopyrine breath test results just below the critical threshold, a group without sodium retention and aminopyrine breath test results just above the critical threshold and a phenobarbital-treated control group. In each group, urinary sodium excretion, renal plasma flow, glomerular filtration rate, mean arterial pressure and arterial and renal venous plasma renin activities were determined. A progressive, significant reduction in mean arterial pressure was seen, comparing controls with the other two groups. No differences in renal plasma flow were observed between the three groups, but glomerular filtration rate and filtration fraction were slightly reduced in the sodium-retaining group compared with the non-retaining group and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyrine

Effect of intrahepatically implanted islets of Langerhans on hepatic function in the rat.

Diabetes mellitus is satisfactorily controlled in the rat by hepatic implantation of isolated, isologous pancreatic islets. The transplanted islets appear to be viable for at least 6 months after implantation, and hepatic function studies (serum bilirubin, alkaline phosphatase, glutamic-oxalacetic transaminase, prothrombin time) and microscopic examination indicate that they do not interfere with hepatic function.

Alkaline Phosphatase

Recommendations for the investigation of abnormal hepatic function in asymptomatic workers.

Occupational medicine programs use medical surveillance tests to measure physiologic parameters that may be affected by workplace exposures. Surveillance tests can detect early detrimental changes before workers manifest recognizable symptoms. Hepatic function testing is one type of surveillance test used to monitor workers exposed to hepatotoxins. However, a significant proportion of these test reports return showing abnormal hepatic function without a readily apparent etiology. Follow-up investigation of abnormal liver enzyme tests is a commonly encountered problem in occupational medicine clinics. The algorithm proposed in this paper will outline a systematic approach for investigating abnormal hepatic function tests from asymptomatic workers.

Alcohol Drinking

Functional hepatic imaging with receptor-binding radiopharmaceutical: clinical potential as a measure of functioning hepatocyte mass.

Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Technetium-99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin (TcGSA) is a newly developed analog ligand to ASGP-R. Fourteen human subjects were studied: three normal volunteers, one with chronic hepatitis, 6 with liver cirrhosis, and 4 with hepatocellular carcinoma associated with liver cirrhosis. The receptor index parameter (LHL15), was obtained from the liver and heart time-activity data as the ratio of radioactivity of the liver over that of the liver plus heart at 15 min after intravenous injection of 1 mg of TcGSA. Means +/- standard deviations of LHL15 in normal volunteers (3 cases), patients with mild (4 cases), moderate (2 cases), and severe liver damage (5 cases) were 0.933 +/- 0.006, 0.789 +/- 0.045, 0.723 +/- 0.033, and 0.488 +/- 0.094, respectively. The difference between the mean values of each group was statistically significant (P less than 0.05). LHL15 correlated well with classical indicators for hepatic functional capacity such as serum albumin level, serum bilirubin level, prothrombin time, ICG R15 or Child-Turcotte criteria score. Our preliminary experiences of high correlations of TcGSA functional imaging data with clinical data suggest that the dynamic data using this receptor-binding radiopharmaceutical provides invaluable information with regard to liver function, and thus, the TcGSA study is potentially a noninvasive practical tool to measure functioning hepatocyte mass.

Asialoglycoprotein Receptor

[Analysis of the clinical effect of Adelavin infusion during enflurane anesthesia on post-operative hepatic function].

The protective effect of Adelavin, which is made of liver essence, for maintaining postoperative hepatic function was analysed in 85 patients who had enflurane anesthesia. The patients who showed hepatic dysfunction preoperatively were excluded from this trial. Adelavin was infused at a speed of 0.1 mg.kg-1.hr-1 during anesthesia. The group who had upper abdominal surgery in the Adelavin group showed significantly lower incidence of postoperative hepatic dysfunction. The group who had only enflurane anesthesia in the Adelavin group showed significantly lower incidence of postoperative hepatic dysfunction. These results suggest that the Adelavin infusion has a significant protective effect on hepatic function after enflurane anesthesia.

Anesthesia, Inhalation

Kinetics of disopyramide in decreased hepatic function.

The elimination kinetics of disopyramide was studied in 9 patients with decreased hepatic function (DHF) due to histologically verified cirrhosis of the liver, and in 11 patients with ischaemic heart disease (IHD). Disopyramide 100 and 150 mg was given intravenously as a bolus to the patients with IHD and DHF, respectively, followed by a continuous infusion of disopyramide 0.3 (DHF group) and 0.4 mg X min-1 (IHD group) until steady-state was achieved. A significant (p less than 0.001) positive correlation between the percentage unbound and total serum concentration of disopyramide was demonstrated in both groups. The percentage of unbound disopyramide at a total serum concentration of 5.9 mumol X l-1 was 45.5% and 19.4% in the DHF and IHD groups, respectively. A negative correlation (r = -0,751, p less than 0.05, and r = -0.827, p less than 0.01 in the IHD and DHF patients, respectively) between the free fraction of disopyramide and alpha 1-acid glycoprotein was observed. The serum concentration of alpha 1-acid glycoprotein, the major binding protein of disopyramide, was significantly lower in the patients with DHF. The clearance of unbound disopyramide and its total volume of distribution and half-life were significantly lower in the DHF patients. No difference in total elimination clearance could be demonstrated. The clinical implication of the present findings appear to be that the dosage of disopyramide should be reduced by 25% when it is given intravenously to patients with decreased hepatic function.

Adult

Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function.

The [Arg8]vasopressin (AVP) receptor expressed by human hepatocytes was characterized, and compared with the rat hepatic V1a vasopressin receptor subtype. In addition to determining the pharmacological profile of the human receptor, the cellular responses to AVP were measured in human and rat hepatocytes by assaying glycogen phosphorylase alpha activity and DNA synthesis. Marked differences were observed between human and rat hepatocytes regarding vasopressin receptors and the intracellular consequences of stimulation by AVP. Data presented in this paper demonstrate the following, (i) Vasopressin V1a receptors are present in low abundance on human hepatocytes. (ii) Species differences exist between human and rat V1a receptors with respect to the affinity of some selective antagonists. (iii) AVP-stimulated glycogen phosphorylase a activation in human hepatocytes was approx. 5% of that observed in rat cells. (iv) In contrast with rat hepatocytes, DNA synthesis in human cells in culture was not stimulated by AVP. It is concluded that vasopressin plays only a minor role in the regulation of human hepatic function. Furthermore, conclusions drawn from observations made with AVP and its analogues on rat hepatic function cannot be directly extrapolated to the human situation.

Animals

Hepatic function and portal hemodynamics in patients with liver cirrhosis.

We investigated the distribution of portal blood flow per kilogram of body weight (PBF/BW) in 112 healthy volunteers and 90 patients with liver cirrhosis using an ultrasonic Doppler duplex system. The PBF/BW in healthy volunteers showed a log-normal distribution, while the distribution was irregular and showed two peaks in patients with cirrhosis. This irregular distribution was thought to reflect their complex physiopathological state. We next analyzed the relationship between PBF/BW and the data from hepatic function tests (serum albumin, total bilirubin, indocyanine green 15-min retention rate, and indocyanine green plasma disappearance rate) in 48 patients with liver cirrhosis. The patients were divided into four groups according to their portal blood flow: group A with a hepatofugal or stagnant portal blood flow, group B with a hepatopetal PBF/BW of less than 12 ml/min/kg, group C with a hepatopetal PBF/BW of 12 or more but less than 20 ml/min/kg, and group D with a hepatopetal PBF/BW of 20 ml/min/kg or more. Among patients with cirrhosis, group A showed the worst results in hepatic function tests, group D the second worst, and group C the best. The effective hepatic blood flow was thought to have decreased because of the development of extrahepatic portosystemic shunts in the patients in groups A and B, whereas it decreased because of the development of intrahepatic shunts in patients in group D. The results of hepatic function tests deteriorated as a consequence of the decrease in the effective hepatic blood flow.

Adult

Hepatic function and indocyanine green clearance during and after prolonged anaesthesia with propofol.

We have studied the effects of propofol on hepatic function and clearance of indocyanine green (ICG) in 13 consecutive patients undergoing prolonged plastic and reconstructive surgery. Hepatic function was assessed using serum concentrations of liver-specific glutathione-S-transferase (GST). There were no significant changes in GST activity or plasma clearance of ICG throughout the study.

Adult