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In vivo estimates of hepatic binding protein concentration: correlation with classical indicators of hepatic functional reserve.

Hepatic binding protein (HBP) is a hepatic cell surface receptor specific for asialoglycoprotein. In vivo estimates of HBP concentration ([HBP]) were compared to classical indicators for hepatic functional reserve to clarify the validity of [HBP] in estimating the hepatic functional reserve in 30 humans. Estimates of [HBP] were obtained based on kinetic analysis of liver and blood time-activity data resulting from the hepatic clearance of a single injection of technetium-99m galactosyl-neoglycoalbumin, which is a synthetic analog radioligand specific to HBP. Estimates of [HBP] ranged 0.054 to 0.720 microM. Estimates of [HBP] in normal volunteers were 0.668 +/- 0.050 microM, whereas that in liver cirrhosis were 0.188 +/- 0.112 microM. The difference between the mean values of [HBP] estimates was statistically significant (p = 0.0001). Good correlations were observed between [HBP] and prothrombin time (r = 0.625, p = 0.0002), serum albumin level (r = 0.687, p = 0.0001), serum cholinesterase level (r = 0.764, p = 0.0001), indocyanine green plasma disappearance rate (r = 0.602, p = 0.0024), and Child-Turcotte classification score (Pugh's modification) (r = -0.797, p = 0.0001). We concluded that excellent correlations of [HBP] with classical indicators for hepatic functional reserve suggest potential value of [HBP] as a sensitive measure of functioning hepatocyte mass.

Adult

Effect of valproic acid on hepatic function.

Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.

Adolescent

Evaluation of hepatic function using the pharmacokinetics of a therapeutically administered drug. Application to the immunosuppressant cyclosporin.

A method is presented for the simultaneous estimation of functional hepatic blood flow and intrinsic clearance. The method uses pharmacokinetic data of a therapeutically employed drug and one of its primary metabolites following intravenous and oral administration of the parent compound. When the disposition of the drug is linear, this method can cope with complicated dosage regimens commonly confronted in clinical data. The feasibility of the method was demonstrated in 10 patients who had undergone liver transplantation and were receiving cyclosporin in the immediate postoperative period. Mean hepatic blood flow was estimated to be 0.89 (95% CI: 0.62 to 1.23) L/h/kg and intrinsic cyclosporin clearance as 0.60 (95% CI: 0.49 to 0.72) L/h/kg. Apart from the hepatic parameters, bioavailability and the fraction of the dose absorbed, a detailed pharmacokinetic description of the parent drug and the elimination pharmacokinetics of a primary metabolite are provided. This information not only allows optimisation of individual therapy, but also may be used to compare absorption properties of different pharmaceutical formulations.

Administration, Oral

Effects of experimental hepatic artery embolization on hepatic function.

The hepatic artery was embolized with Gelfoam in 12 dogs to evaluate the effect of embolization on hepatic function. Liver function studies, including SGPT, alkaline phosphatase, BSP test, and bilirubin, were done serially over a 6 week period following the embolization. Eleven of the 12 embolized dogs survived the 6 week experimental period. Hepatic artery embolization caused some liver damage; however, recovery occurred by 6 weeks. These results suggest a possible therapeutic role for hepatic artery embolization in patients with massive hepatic bleeding or hemobilia who are not surgical candidates and who would require hepatic lobectomy or dearterialization to control the bleeding.

Animals

Study on some hepatic functions and prevalence of hepatitis B surface antigenaemia in Egyptian children with schistosomal hepatic fibrosis.

Several different hepatic parenchymal lesions, including chronic hepatitis and cirrhosis, have been increasingly reported in children with schistosomal hepatic fibrosis (SHF) despite the known mesenchymal nature of the disease. The prevalence of persistent hepatitis (B) surface (HBs) antigenaemia and some hepatic functions have been determined in 52 children with SHF as well as in 100 age-matched healthy children. High prevalence of chronic HBs antigenaemia (58 per cent) has been demonstrated in children with SHF, but only in 2 per cent of the normal children. This denotes that children with SHF represent a dangerous reservoir for hepatitis B infection to the community. Serum alanine transferase (ALT) was higher than normal in 58 per cent of HBS seropositive patients and in none of the seronegative patients. This points to the risk of continual hepatic parenchymal injury to the HBs seropositive patients with schistosomiasis.

Adolescent

Effects of fasting on hepatic function in ponies.

Hepatic function was measured, using sulfobromophthalein sodium (BSP) in fed and fasted ponies. In the 1st experiment, single injections of BSP were administered, and the rate of removal of BSP from plasma was determined. Fasting decreased the rate of BSP removal from plasma, as indicated by increased half-time (t 1/2). In the 2nd experiment, BSP was infused for 5 hours, and its clearance from plasma was determined. Fasting decreased BSP clearance. In the 3rd experiment, BSP was infused consecutively at 2 dose rates, and maximal excretion and hepatic storage were determined. Although fasting did not affect maximal excretion, it decreased hepatic storage. Thus, results in the 3 experiments indicated a decreased hepatic clearance of BSP during fasting.

Animals

Effects of quinestrol on hepatic function in the rat.

Hepatic function in female rats given 200 microgram of quinestrol every 15 days for up to 210 days was studied. Prolonged treatment with quinestrol affected liver weight, serum cholestrol levels, biliar flux, and bromosulphthalein test, but these parameters tended toward control levels after 30 days of treatment. Quinestrol failed to affect alkaline phosphatase, oxalacetic and pyruvic transaminases and the concentration of bilirubin in serum and bile. The effects of quinestrol on hepatic function are similar to the effects of other estrogen derivatives.

Alkaline Phosphatase

[Hepatic protein synthesis rate as an index of hepatic functional reserve in human liver].

Hepatic protein synthesis rate (HPS) in human livers were measured to evaluate hepatic functional reserve. HPS of 34 patients who underwent operations were studied and were divided into 4 groups. Normal liver (n = 7), obstructive jaundice (n = 9), liver cirrhosis (n = 8) and other hepatic dysfunction (n = 10). HPS in normal liver was 6.9 +/- 3.0 nmol/mg wet wt./10 min. HPS in obstructive jaundice liver was 17.1 +/- 10.3, and HPS in liver cirrhosis was 47.5 +/- 17.8. There were significant differences among these three groups. HPS correlated well with cholinesterase (r = -0.6533, P less than 0.01) and ICGR15 (r = 0.7315, P less than 0.01). In 15 patients who received hepatectomy, relations between HPS and postoperative complication were studied. There were no complications in patients whose HPS were less than 20 nmol/mg wet wt./10 min. in major hepatic resection and in patient whose HPS were less than 40 in a segmentectomy. Even if HPS were elevated, the operations were safe in subsegmentectomy and partial hepatectomy. So HPS would be one of the good indices to evaluate hepatic functional reserve.

Biopsy, Needle

Effect of portacaval transposition on hepatic function in dogs with obstruction to the hepatic venous outflow.

Complete hepatic venous outflow obstruction (COB) in dogs resulted in impairment of hepatic function and cellular injury. Thus both the serum albumin concentration and the plasma clearance of indocyanine green (ICG) were reduced, whilst serum glycoproteins, aminotransferases and alkaline phosphatase levels were increased. Partial outflow block (POB)resulted in less severe functional changes although a significant decrease in serum albumin was also observed. The changes in liver function in dogs with portacaval transposition (PCT) and COB were generally similar to those in dogs with COB alone. However, the increases in serum enzyme activities and the decrease in plasma clearance of ICG were greater in the group with PCT. A late improvement in the clearance of ICG in dogs with COB and PCT was probably related to retrograde portal flow. When the hepatic lesion was only moderate (POB) PCT had little effect on either the liver function tests or plasma clearance of ICG, although no improvement in function was observed. It is concluded that PCT has no beneficial effect on dogs with either severe or moderate hepatic lesion and may cause further functional deterioration.

Alkaline Phosphatase

Nicardipine infusion improved hepatic function but failed to reduce hepatic venous pressure gradient in patients with cirrhosis.

We investigated the effects of nicardipine on systemic and splanchnic hemodynamics and on liver function in 16 patients with cirrhosis and portal hypertension. Patients received a continuous infusion of 0.3 mg/min of nicardipine (n = 10) and a control infusion (n = 6). No significant changes were observed after a control infusion. In contrast, systemic vasodilatation, evidenced by a significant fall in mean arterial pressure (-14%, p less than 0.01) and systemic vascular resistance (-30%, p less than 0.01), increased heart rate (+8%, p less than 0.01) and cardiac output (+21%, p less than 0.01), and increased hepatic blood flow (+43%, p less than 0.01) were observed at 60 min after a continuous infusion of nicardipine. Although nicardipine improved hepatic function (intrinsic clearance from 0.29 +/- 0.13 to 0.33 +/- 0.15 L/min, p less than 0.05), portal pressure evaluated by hepatic venous pressure gradient was not reduced significantly (from 16.3 +/- 4.9 to 15.1 +/- 5.7 mm Hg; NS). We conclude that a continuous infusion of nicardipine improves liver function but has no beneficial effect on portal pressure in patients with cirrhosis.

Adult

[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

[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

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