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Biomedical subjects

K Einarsson

Publications and source records attributed to K Einarsson.

At least 73 records · Page 4Linked to original sources
PubMed1990

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia.

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.

Adult↗
PubMed1990

Quantitative ultrastructural studies of gall bladder epithelium in gall stone free subjects and patients with gall stones.

The present study aimed at a further evaluation of the role of glycoproteins in the formation of cholesterol gall stones in man. An electron microscopic morphometric study of the gall bladder epithelium was performed in six gall stone free subjects and 12 gall stone patients. Six of the gall stone patients were treated with ursodeoxycholic acid three weeks before cholecystectomy. The number and the volume density of the mucin containing secretory granules, were not significantly increased in gall stone patients compared with gall stone free subjects. Treatment with ursodeoxycholic acid did not affect the number or volume density of the secretory granules. Thus, these results do not give evidence for that the degree of cholesterol saturation influences mucin content in the gall bladder wall of man. A major new finding was that gall stone patients had a markedly reduced total lysosome area and volume density of lysosomes compared with gall stone free subjects, a finding which may be related to a decreased intracellular degradation of protein and/or mucin.

Adult↗
PubMed1990

Studies with the haeme oxygenase inhibitor Sn-protoporphyrin in patients with primary biliary cirrhosis and idiopathic haemochromatosis.

Sn(tin4+)-protoporphyrin, a potent competitive inhibitor of haeme oxygenase, the rate limiting enzyme in the degradation of haeme to bile pigments, was given intravenously to six patients with primary biliary cirrhosis and to four patients with idiopathic haemochromatosis. Serum bilirubin concentrations decreased in all patients after administration of 1-2 mumol/kg body weight of the metalloporphyrin, given in two doses eight to 24 hours apart. This reduction lasted approximately four to five days after injection of the compound. Excretion of endogenous haeme in bile increased (mean increase approximately two to threefold) in parallel with the decrease in serum bilirubin concentrations in both patient groups, and the highest biliary haeme concentrations were found during the first 48 hours after treatment. Sn-protoporphyrin was cleared rapidly from plasma with a half-life of 3.4 hours. Biliary bilirubin concentrations decreased (mean decrease, 49%) in the haemochromatosis patients after Sn-protoporphyrin administration. No decrease in biliary bilirubin concentrations could be detected in the primary biliary cirrhosis patients under the same conditions. Thus, Sn-protoporphyrin treatment resulted in a decrease in serum bilirubin concentrations and an increase in biliary haeme excretion in patients with haemochromatosis and primary biliary cirrhosis, as has previously been shown in normal subjects. The results indicate that the synthetic haeme analogue inhibits haeme oxidation activity in the two patient groups studied, as it does in normal people and in experimental animals. The lack of effect of Sn-protoporphyrin on biliary bilirubin excretion in primary biliary cirrhosis may be related to a differently affected hepatic clearance system or to a different distribution of tissue bilirubin pools in this condition.

Adult↗
PubMed1990

Decreased concentrations of deoxycholic acid in serum of uraemic patients with diarrhoea.

The fasting peripheral serum concentrations of cholic acid, chenodeoxycholic acid, deoxycholic acid and ursodeoxycholic acid were determined in a total of 32 patients with uraemia. Eighteen of the patients suffered from diarrhoea. A highly accurate and specific mass-fragmentographic technique with high sensitivity was used to measure the concentrations of the individual bile acids. The total amount of bile acids was normal in the two groups of patients. Patients with diarrhoea had 50% lower concentrations of deoxycholic acid than a corresponding group of healthy subjects. It is suggested that the low level of deoxycholic acid may contribute to diarrhoea in these patients.

Adult↗
PubMed1990

Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.

To characterize the metabolic regulatory response to interruption of the enterohepatic circulation of bile acids, we examined the effects of cholestyramine treatment on the rate-limiting steps in cholesterol biosynthesis (HMG-CoA reductase) and bile acid production (cholesterol 7 alpha-hydroxylase) as well as on the heparin-sensitive binding of low density lipoproteins (LDL) (reflecting LDL receptor expression) in human liver. Altogether, 18 normolipidemic patients with uncomplicated cholesterol gallstone disease were treated with cholestyramine (8 g b.i.d.) for 2-3 weeks prior to cholecystectomy, and another 34 cholesterol gallstone patients served as untreated controls. Cholestyramine treatment stimulated cholesterol 7 alpha-hydroxylase more than sixfold, and increased both HMG-CoA reductase activity (552 +/- 60 pmol/min per mg protein vs 103 +/- 9 pmol/min per mg protein) and LDL receptor expression (6.1 +/- 0.8 ng/mg protein; n = 6 vs 2.2 +/- 0.3 ng/mg protein; n = 7). Moreover, there was a good correlation between HMG-CoA reductase activity and LDL receptor binding (rs = +0.71; n = 13), suggesting a simultaneous stimulatory effect to compensate for the increased hepatic cholesterol catabolism due to bile acid depletion caused by cholestyramine. Further evidence for this assumption was the finding of a significant relationship between cholesterol 7 alpha-hydroxylase activity and both LDL receptor expression (rs = +0.77; n = 13) and HMG-CoA reductase activity (rs = +0.76; n = 46). We conclude that in human liver a parallel stimulation of cholesterol synthesis and LDL receptor expression occurs in response to stimulation of bile acid synthesis.

Adult↗
PubMed1990

Apparent lack of conversion of sitosterol into C24-bile acids in humans.

The metabolic fate of intravenously administered [4-14C]sitosterol was studied in two healthy subjects. In marked contrast to the results of a previous investigation with [22,23-3H]sitosterol, no detectable labeled C24-bile acid products appeared in bile. The first and rate-limiting step in the conversion of cholesterol into bile acids is catalyzed by the liver microsomal cholesterol 7 alpha-hydroxylase. When incubated with human liver microsomes, no detectable 7 alpha-hydroxylation of sitosterol could be demonstrated. This was the case also when using liver microsomes from two subjects treated with cholestyramine, in which case the rate of 7 alpha-hydroxylation of cholesterol was increased three- to sixfold. In order to bypass the rate-limiting step, the metabolic fate of 3H-labeled 7 alpha-hydroxysitosterol was studied in two volunteers. In this case there was a significant conversion into acid products in bile (18-32% excreted in bile during the first 17 h). Although part of the labeled products had chromatographic properties similar to those of cholic acid and chenodeoxycholic acid, further analysis showed that none of the products was identical to chenodeoxycholic acid and only traces at the most could be identical to cholic acid. The results suggest that healthy human subjects, in similarity with other mammalian species studied, have little or no capacity to convert sitosterol into the normal C24-bile acids.

Adult↗
PubMed1989

Activation of rat liver cytosolic phosphatidic acid phosphatase by nucleoside diphosphates.

Phosphatidic acid phosphatase (EC 3.1.3.4) was purified 30-fold by ammonium sulfate fractionation and hydroxyapatite chromatography from the soluble fraction of rat liver. ADP was found to stimulate the enzyme activity with half-maximal stimulation at 0.2 mM. Similar effects were seen when ADP was replaced by GDP or CDP. In contrast, ATP inhibited the enzyme; half-maximal inhibition observed at 0.2 mM. Again, the degree of inhibition did not differ when GTP or CTP replaced ATP. Thus, the structure of the base part of the nucleotide was not critical for mediating these effects. The positions of the phosphate groups in the nucleotide structure were however found to be of importance for the enzyme activity. Variations in the structure of the phosphate ester bound at the 5'-position had a pronounced effect on phosphatidic acid phosphatase activity. The effect of nucleotides depended on pH, and the inhibition by ATP was more pronounced at pH levels lower than 7.0, whereas the stimulatory effect of ADP was virtually the same from pH 6.0 to pH 8.0. The enzyme showed substrate saturation kinetics with respect to phosphatidic acid, with an apparent Km of 0.7 mM. Km increased in the presence of ATP, whereas both apparent Vmax and Km increased in the presence of ADP, suggesting different mechanisms for the action of the two types of nucleotides. The results indicated that physiological levels of nucleotides with a diphosphate or a triphosphate ester bound at the 5'-position of the ribose moiety influenced the activity of phosphatidic acid phosphatase. The possibility is discussed that these effects might be of importance for the regulation of triacylglycerol biosynthesis.

Adenosine Diphosphate↗
PubMed1989

Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity.

The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.

Adult↗
PubMed1989

Biliary excretion of iron and ferritin in idiopathic hemochromatosis.

The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

Adult↗
PubMed1989

Effects of somatostatin on hepatic bile formation.

Somatostatin is a peptide that has anticholeretic properties in the dog. The purpose of the present work was to investigate if somatostatin is an anticholeretic agent in humans also. The effects of intravenous infusion of somatostatin on hepatic bile flow and biliary electrolytes and secretion of biliary lipids were studied in 7 patients with complete biliary drainage who had been operated on for choledocholithiasis. Somatostatin, 250 microgram/h, was found to decrease the hepatic bile secretion by approximately 30%. The peptide also reduced the outputs of bile acids, cholesterol, and phospholipids and the outputs of sodium, potassium, and chloride. The concentrations of the biliary lipids were not significantly changed. Somatostatin inhibited the erythritol clearance in the 2 patients studied by approximately 25%. The present study thus provides evidence that somatostatin inhibits bile formation in humans. It appears as if the reduction in bile production is mainly due to decreased canalicular bile flow. It is possible that this effect of somatostatin is attributable to inhibition of bile acid synthesis or of transport-secretion of bile acids, or both.

Adult↗
PubMed1989

Unsatisfactory effect of cyclosporin A treatment in Crohn's disease: a report of five cases.

Five patients with chronic continuous Crohn's colitis were treated with peroral Cyclosporin A (CyA) for 3 months in an open, uncontrolled pilot trial. The CyA dose was 10 mg kg-1 d-1 the first month of study, and thereafter 5 mg kg-1 d-1. Three of the patients initially showed some response to the treatment with decreases in the Crohn's disease activity index, but subsequently deteriorated. In one patient the condition was unchanged and another clearly worsened. Increases in serum creatinine levels were noted in three patients, and all of these also had decreased 51Cr-EDTA clearance indicating impaired renal function. Hypertrichosis and hyperaesthesia were also noted as side-effects. This study does not support the use of CyA in the short-term treatment of Crohn's disease in the colon.

Adult↗
PubMed1989

Increased oxidoreduction of deoxycholic acid in cholecystectomised patients.

The extent of oxidoreduction of deoxycholic acid in the enterohepatic circulation was studied in seven healthy subjects and seven patients after cholecystectomy. (12 beta-3H) Deoxycholic acid was given orally together with (24-14C) labelled bile acid. The rate of oxidoreduction of the 12 alpha-hydroxyl group of deoxycholic acid was calculated from the decay in ratio between 3H and 14C. In spite of a normal proportion of deoxycholic acid and other secondary bile acids in bile, patients after cholecystectomy had more than two-fold higher degree of oxidoreduction of the 12 alpha-hydroxyl group than healthy controls. The high extent of oxidoreduction is probably because of an increased exposure of the bile acid pool to intestinal bacteria and may have physiological implications.

Adult↗
PubMed1989

Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma.

To assess if and by which mechanisms pharmacological estrogen treatment induces gallstone disease, we examined patients with recently diagnosed prostatic cancer randomly allocated to estrogen therapy (n = 37) or orchidectomy (n = 35). According to gallbladder ultrasonography, after 1 yr new gallstones had developed in 5 of 28 estrogen-treated patients, compared with 0 of 26 orchidectomized patients (P = 0.03). Estrogen therapy for 3 mo increased the relative concentration of cholesterol and cholesterol saturation of bile by approximately 30% (n = 10). Serum LDL cholesterol was reduced by approximately 40%, and its relative change related inversely to that of bile cholesterol (Rs = -0.77). There were no changes in biliary or serum lipids after orchidectomy (n = 9). Secretion rates of biliary lipids were measured with a duodenal perfusion technique. Patients on chronic estrogen therapy (n = 5) had approximately 40% higher biliary excretion rates of cholesterol than age-matched controls (n = 7). Phospholipid secretion was also higher, but no difference in bile acid secretion was found. We conclude that an increased hepatic secretion of cholesterol results in increased cholesterol saturation of bile and an enhanced rate of gallstone formation during estrogen treatment. The changes in bile cholesterol seem to be related to the induced changes in serum lipoprotein metabolism.

Aged↗
PubMed1989

Serum concentrations of unconjugated and conjugated cholic acid in portal venous and systemic venous blood of fasting man.

The fasting concentrations of unconjugated and conjugated cholic acid were determined in the peripheral venous serum of 15 healthy subjects, eight patients with ileal resection and six patients with known bacterial overgrowth of the upper small intestine. In addition, the estimated hepatic uptake of unconjugated and conjugated cholic acid was determined in 15 gallstone patients undergoing cholecystectomy. A highly accurate and specific mass-fragmentographic technique with high sensitivity was used. The proportion of unconjugated cholic acid averaged 34% in the healthy subjects. The estimated fractional hepatic uptake of unconjugated cholic acid was lower than that of conjugated cholic acid, 71% and 87%, respectively (means). Patients with ileal resection had an increased proportion of unconjugated cholic acid in their peripheral venous serum, 49% (mean). The patients with bacterial overgrowth of the upper small intestine also displayed a high proportion of unconjugated cholic acid, 63% (mean). It is suggested that determination of the proportion of unconjugated cholic acid in peripheral venous blood may possibly be used for detection of bacterial contamination of the upper small intestine.

Adult↗
PubMed1989

Restriction fragment length polymorphism analysis of T-cell receptor genes in inflammatory bowel disease.

The etiology of inflammatory bowel disease is still unknown, but autoimmune phenomena are thought to play an important role. However, only a weak association between HLA or immunoglobulin allotypes and inflammatory bowel diseases has been noted. Recently, DNA markers (restriction fragment length polymorphism (RFLP) pattern) of T-cell receptor gene allotypes have been reported and shown to be linked to susceptibility to autoimmune disease. We investigated the T-cell receptor RFLP pattern in inflammatory bowel diseases. No linkage to the constant region alpha- and beta-chain markers was observed, and no differences in the frequencies of 'genoallotypes' was found between patients and normal blood donors.

Colitis, Ulcerative↗