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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

Autoantibodies and immunoglobulins in patients with alcoholic cirrhosis. Relation to measurements of hepatic function and hemodynamics.

In order to evaluate the possible relation between hepatic function and hemodynamics and the increased humoral immune response of cirrhotic patients, titres of antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) and concentrations of immunoglobulin (Ig) G, A and M were determined in 74 consecutive patients with alcoholic liver cirrhosis. Patients showed significantly (p less than 0.05) increased prevalences of ANA and SMA and concentrations of Ig G, A and M when compared to controls. No significant correlations were found between titres of ANA or SMA and hepatic scan score, galactose elimination capacity, indocyanine green clearance, hepatic blood flow and wedged-to-free hepatic vein pressure. Hepatic scan score correlated directly (rho = 0.38, p less than 0.05) to IgA concentrations; wedged-to-free hepatic vein pressure correlated directly to IgG concentrations (rho = 0.35, p less than 0.05) and to IgM concentrations (rho = 0.42, p less than 0.01). No other significant correlations were found between Ig concentrations and variables of hepatic function or hemodynamics.

Adult

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

Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function.

By use of computed tomography measurements, preoperative estimations of the safe limits of hepatic resection have been attempted in 38 patients with primary hepatocellular carcinoma who underwent hepatectomies of varying degrees. Twenty eight (73.7%) of these 38 patients had cirrhosis. Preoperative computed tomography estimations of volume of liver and hepatocellular carcinoma have been compared with measured volume of the resected specimens. The average differences between the estimated and actual volumes of resected liver and hepatocellular carcinoma were within 10% and 7%, respectively. To quantify the extent of hepatectomy, the "parenchymal hepatic resection rate" (formula: see text) was provided. As an indicator of functional impairment of the liver, the retention rate 15 minutes after an intravenous injection of indocyanine green dye (ICG) at 0.5 mg/kg (ICG R15) was used. A close correlation was observed between the parenchymal hepatic resection rate and ICG R15 relative to the patients' outcome, indicating their potential use in the prediction of the safe limits of hepatectomy and the probable development of posthepatectomy liver failure.

Carcinoma, Hepatocellular

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

Compromised hepatic function in dogs treated with anticonvulsant drugs.

Hepatic function tests were performed on 48 dogs that had been given primidone, phenytoin, or a combination of anticonvulsant drugs for 6 months or longer. Except for histories of seizures, 44 of the dogs were healthy at the time the tests were performed. Abnormal test results were observed most frequently in dogs given only primidone and in dogs given combinations of anticonvulsant drugs. The test results that were abnormal most often were those for alanine transaminase and alkaline phosphatase activities, and sulfobromophthalein excretion. The dosage of anticonvulsant drug was found to modify certain test results. Statistically significant positive correlations were found between the dosage of primidone and serum alanine transaminase activity and between the dosage of phenytoin and serum alkaline phosphatase activity. Four of the dogs were examined because of signs of weakness and anorexia and 2 also had ascites. Three of the 4 dogs were euthanatized 2 to 49 days after admission with clinical signs compatible with hepatic failure, and cirrhosis of the liver was confirmed at necropsy. The fourth dog died at home and was not necropsied. Four of the remaining 44 dogs that apparently were healthy at the time of examination had abnormalities in hepatic biochemical test results that were comparable with those in the 4 dogs with clinical illness. We concluded that, although results of hepatic biochemical tests frequently may be abnormal in dogs given anticonvulsant drugs long-term, severe hepatic injury is observed less often.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

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

Risk factors before hepatectomy, hepatic function after hepatectomy and computed tomographic changes as indicators of mortality from hepatic failure.

The mortality rate from hepatic failure after extensive resection should be negligible in the presence of normal results from preoperative liver function tests in patients without pre-existing hepatitis and cirrhosis. Despite conventionally acceptable results from preoperative hepatic function tests in 56 patients undergoing extensive hepatic resection for tumours (47 metastatic, six hepatomas and three adenomas), however, five patients died of hepatic failure. Among the many preoperative and intraoperative risk factors studied, the important factors in the group with hepatic failure were very high levels of serum alkaline phosphatase (p less than 0.05) in the presence of normal levels of bilirubin and large tumor, preoperative administration of chemotherapy, the presence of hepatomas rather than metastatic carcinoma (p = 0.083) and intraoperative blood loss of greater than 5,000 milliliters (p = 0.03). The patients receiving preoperative chemotherapy or those with hepatoma showed a minimal rise of alkaline phosphatase (p less than 0.03) and a minimal regeneration of liver on computed tomographic (CT) scan after hepatic resection. In the group with hepatic failure, a consistent postoperative pattern of increasing bilirubin with normal or subnormal alkaline phosphatase levels corresponded with lack of regeneration of liver on repeated CT scans. Conversely, the pattern of decreasing bilirubin with reciprocal increase in alkaline phosphatase corresponded with hepatic regeneration on CT scan in the group of survivors. Thus, we observe that alkaline phosphatase is a good indicator of hepatic regeneration in the absence of jaundice in patients after hepatectomy. To avoid postoperative hepatic failure, we recommend more discriminant tests than conventional hepatic function tests in patients with large tumors associated with high alkaline phosphatase levels, preoperative chemotherapy and hepatoma even without pre-existing cirrhosis or hepatitis.

Adult

Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function.

Etoposide (VP16) pharmacokinetics was investigated in three groups of cancer patients: a control group of 18 patients with renal and hepatic function tests in the normal range; a group of 8 patients with renal insufficiency; and a group of 15 patients with abnormal hepatic function. In the control group plasma clearance (Clp), volume of distribution (Vd), and elimination half-life (t1/2 beta) of VP16 were, respectively, 22.8 +/- 1.0 (SE) ml/min/m2, 11.4 +/- 0.8 liters/m2, and 5.6 +/- 0.4 h. In patients with renal insufficiency Clp was 12.8 +/- 1.1 ml/min/m2, Vd was 20.8 +/- 4.9 liters/m2, and t1/2 beta was 19.2 +/- 4.7 h. A statistically significant correlation (P = 0.0000001) was found between VP16 Clp and creatinine clearance. In 12 of 15 patients with abnormal liver tests Clp, Vd, and t1/2 beta were, respectively, 27.9 +/- 2.7 ml/min/m2, 12.4 +/- 1.5 liters/m2, and 5.4 +/- 0.6 h and are thus similar to those of the control group. In the other three cases with abnormal liver function VP16 plasma levels were very low. In these cases VP16 t1/2 beta values were similar (5.1, 4.4, and 5.1 h) whereas Clp values (320, 87, and 96 ml/min/m2) and Vd values (142, 33, and 42 liters/m2) were much larger than in controls. These results suggest that VP16 doses should be reduced in patients with renal function impairment but not necessarily in patients with liver impairment. The high VP16 Vd and Clp values found in a subset of patients with liver impairment require further elucidation.

Adult