Biomedical subjects

K Einarsson

Publications and source records attributed to K Einarsson.

At least 109 records · Page 6Linked to original sources

PubMed1986

Ursodeoxycholic acid treatment in humans: effects on plasma and biliary lipid metabolism with special reference to very low density lipoprotein triglyceride and bile acid kinetics.

Ursodeoxycholic acid reduces biliary saturation with cholesterol and may induce dissolution of cholesterol gallstones in man. In order to characterize the effects of this potentially useful bile acid on plasma lipid metabolism, we determined lipoprotein levels and very low density lipoprotein (VLDL) triglyceride kinetics in six hypertriglyceridaemic and three normolipidaemic subjects before and after 4-6 weeks of ursodeoxycholic acid treatment at a daily dose of 15 mg kg-1 body weight. The plasma levels of low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol were not significantly affected by therapy. Nor were the plasma level and apparent formation of VLDL triglycerides changed. In five subjects, the effects of a low dose (7.5 mg kg-1 body weight day-1 for 4-6 weeks) of ursodeoxycholic acid on biliary lipid composition and kinetics of cholic acid and chenodeoxycholic acid were determined. The relative concentration of cholesterol in bile was reduced to the same level as during treatment with a high dose of ursodeoxycholic acid. The synthesis rates of bile acids were not suppressed with ursodeoxycholic acid. It is concluded that, unlike chenodeoxycholic acid, ursodeoxycholic acid does not suppress endogenous bile acid production. The efficiency at lower doses, and the lack of effects on plasma lipid metabolism, may make ursodeoxycholic acid a more attractive alternative for clinical attempts of gallstone dissolution.

Adult↗

PubMed1986

Studies of the human liver insulin receptor in noninsulin-dependent diabetes mellitus.

The insulin binding characteristics and the structural components of the insulin receptor were studied in the purified liver plasma membranes from seven patients with noninsulin-dependent diabetes (NIDDM) and seven control subjects. In comparison to the controls, diabetic subjects had a 65% reduction in plasma insulin levels in response to an oral glucose load. Specific insulin binding by liver membranes from diabetic patients was, however, twofold greater than the binding activity by membranes from control subjects. This alteration resulted largely from an increase in the number of insulin receptors and a modest increase in receptor binding affinity. Holo (nonreduced) receptor species of similar molecular weights were detected by an affinity labeling technique in the two membrane preparations and sulfhydryl reduction demonstrated an insulin binding subunit of 125,000 mol wt. Overall, these results show that the hepatic insulin resistance of NIDDM cannot be explained by a deficiency in insulin binding.

Diabetes Mellitus, Type 2↗

PubMed1986

Evidence against in vitro modulation of rat liver cholesterol 7 alpha-hydroxylase activity by phosphorylation-dephosphorylation: comparison with hydroxymethylglutaryl CoA reductase.

The activity of cholesterol 7 alpha-hydroxylase in rat liver microsomes was investigated under conditions favourable for phosphorylation-dephosphorylation. The enzyme activity was similar in the presence or absence of sodium fluoride during preparation. Preincubation with ATP and magnesium did not affect the enzyme activity. Cholesterol 7 alpha-hydroxylase was inhibited by alkaline phosphatase, but this inhibition was similar also after inactivation of the phosphatase. Under similar conditions, rat hepatic hydroxymethylglutaryl CoA reductase activity was clearly modulated in agreement with phosphorylation-dephosphorylation. The absence of such a modulation of cholesterol 7 alpha-hydroxylase argues against involvement of phosphorylation-dephosphorylation in the regulation of this enzyme.

Animals↗

PubMed1986

Biliary colic without evidence of gallstones: diagnosis, biliary lipid metabolism and treatment.

Fifteen patients with history of biliary colic, induceable by cholecystokinin, but normal oral cholecystogram and ultrasonogram were studied prior to and after cholecystectomy. Fasting duodenal bile, obtained preoperatively after administration of cholecystokinin, and gallbladder bile obtained at operation were analyzed. The lipid composition as well as the cholesterol saturation were within the range seen in gallstone-free subjects. The total lipid concentration of gallbladder bile was normal, whereas that of duodenal bile was reduced by about 50%, indicating a less efficient gallbladder emptying. In 10 of the 15 patients, the analysis of the excised gallbladder displayed macro- or microscopic abnormalities; two patients had cholesterol gallstones. At re-examination 9-27 months after the operation, 12 of the patients were completely symptom-free and two patients reported a clear improvement while on still had unchanged symptoms. It is concluded that cholecystectomy is the treatment to prefer in patients with "acalculous" biliary pain, induceable by cholecystokinin.

Adult↗

PubMed1986

Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by isotope dilution-mass spectrometry.

The present work describes an accurate assay of the rate-limiting enzyme in bile acid synthesis, the cholesterol 7 alpha-hydroxylase, in human liver. The assay is based on isotope dilution-mass spectrometry, and endogenous microsomal cholesterol is used as the only substrate for the enzyme. Operative liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In ten gallstone patients, the enzyme activity of the microsomal fraction averaged 9.6 +/- 1.4 (mean +/- SEM) pmol X min-1 X mg protein-1 corresponding to a daily synthesis of about 0.5 mmol of bile acids. Three cholestyramine-treated patients displayed a four-fold higher enzyme activity. No evidence was obtained supporting the concept that the cholesterol 7 alpha-hydroxylase is modulated by phosphorylation-dephosphorylation.

Bile Acids and Salts↗

PubMed1986

Oxidoreduction of different hydroxyl groups in bile acids during their enterohepatic circulation in man.

The extent of oxidoreduction of the 3 alpha-, 7 alpha- and 12 alpha-hydroxyl groups in bile acids during the enterohepatic circulation in man was studied with the use of [3 beta-3H]-labeled deoxycholic acid and cholic acid, [7 beta-3H]-labeled cholic acid, and [12 beta-3H]-labeled deoxycholic acid and cholic acid. Each [3H]-labeled bile acid was given per os to healthy volunteers, together with the corresponding [24-14C]-labeled bile acid. The rate of oxidoreduction was calculated from the decrease in the ratio between 3H and 14C in the respective bile acid isolated from duodenal contents collected at different time intervals after administration of the labeled bile acids. The mean fractional conversion rate was found to be 0.29 day-1 for the 3 alpha-hydroxyl group in deoxycholic acid (n = 2), 0.18 day-1 for the 12 alpha-hydroxyl group in deoxycholic acid (n = 6), 0.09 day-1 for the 3 alpha-hydroxyl group in cholic acid (n = 3), 0.05 day-1 for the 7 alpha-hydroxyl group in cholic acid (n = 2), and 0.03 day-1 for the 12 alpha-hydroxyl group in cholic acid (n = 2). The extent of oxidoreduction of the 12 alpha-hydroxyl group in [12 beta-3H]-labeled deoxycholic acid given to two patients operated with subtotal colectomy and ileostomy was markedly reduced (less than 20% of normal).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Influence of age on secretion of cholesterol and synthesis of bile acids by the liver.

Supersaturation of bile with cholesterol predisposes to the development of cholesterol gallstones. To identify the factors determining cholesterol saturation of bile, we analyzed the lipid composition of stimulated duodenal bile in 60 healthy subjects of various ages (31 men and 29 women) who were not obese and were free of gallstones. A positive correlation between age and cholesterol saturation of bile was found (P less than 0.001). To analyze the relation between age and cholesterol saturation, we studied the rates of hepatic secretion of biliary lipids and the kinetics of cholic acid and chenodeoxycholic acid in 22 and 18 of the subjects, respectively. Age was positively correlated with the cholesterol secretion rate (r = 0.48) and negatively correlated with bile acid synthesis (r = -0.60) and the size of the cholic acid pool (r = -0.54). We conclude that cholesterol saturation of bile increases with age as a consequence of enhanced hepatic secretion of cholesterol and decreased bile acid synthesis. These findings may explain why age is a risk factor for the development of cholesterol gallstones.

Adult↗

PubMed1985

Biliary lipid output and bile acid kinetics in cholesterol gallstone disease. Evidence for an increased hepatic secretion of cholesterol in Swedish patients.

Sweden has one of the highest incidences of gallstone disease in the Western world. It is therefore important to characterize the mechanisms responsible for the formation of cholesterol gallstones in this population. In the present study, we have determined the kinetics of the two primary bile acids, cholic acid and chenodeoxycholic acid, and the hepatic secretion rates of the biliary lipids in 21 normolipidemic, nonobese gallstone patients (13 with functioning and 8 with nonfunctioning gallbladder) and in 23 healthy controls. The cholesterol saturation of fasting gallbladder bile averaged 110% in the gallstone patients with functioning gallbladder and 82% in the controls. The pool sizes of cholic acid and chenodeoxycholic acid were reduced by about 40% in the two groups of gallstone patients, whereas the rates of synthesis were close to normal. The fractional catabolic rate of both bile acids was increased in both groups of gallstone patients. The gallstone patients with functioning gallbladder had an increased (about 50%) cholesterol secretion but normal bile acid and phospholipid secretion rates. In the gallstone patients with nonfunctioning gallbladder the secretion rates of biliary lipids were not significantly different from those of the controls. The ratio between cholesterol and bile acids was about 50% higher in the gallstone patients with functioning gallbladder than in the controls or in those with nonfunctioning gallbladder. The results indicate that the hepatic secretion of cholesterol is an important determinant for the development of saturated gallbladder bile in Swedish gallstone patients.

Adult↗

PubMed1985

Serum concentrations of ursodeoxycholic acid in portal venous and systemic venous blood of fasting humans as determined by isotope dilution-mass spectrometry.

The fasting concentrations of ursodeoxycholic acid were determined in peripheral and portal venous serum of untreated (n = 12) and ursodeoxycholic acid-treated (n = 7) patients undergoing cholecystectomy. The levels of ursodeoxycholic acid were also determined in peripheral venous serum of 9 healthy subjects before and during treatment with ursodeoxycholic acid. Ursodeoxycholic acid, as well as cholic, chenodeoxycholic, and deoxycholic acids, were analyzed by a highly specific method based on isotope dilution-mass spectrometry. The fasting peripheral venous serum concentration of total (unconjugated plus conjugated) ursodeoxycholic acid averaged 0.14 mumol/L in the untreated gallstone patients and 0.19 mumol/L in the healthy subjects. The corresponding value in portal venous serum was 0.44 mumol/L. Treatment with ursodeoxycholic acid raised the level of this bile acid about 25-fold in portal as well as in peripheral venous serum. The proportion of unconjugated ursodeoxycholic acid was 34% in portal and 49% in peripheral venous serum of treated subjects. The mean hepatic uptake of ursodeoxycholic acid was calculated to be about 60% both in untreated and treated subjects. This uptake was significantly lower than that of cholic acid (83%). The hepatic uptake of ursodeoxycholic acid also tended to be lower than that of chenodeoxycholic acid (68%). This was mainly due to a lower hepatic uptake of unconjugated ursodeoxycholic acid (34%) compared with unconjugated chenodeoxycholic acid (49%). The relatively low hepatic uptake of unconjugated ursodeoxycholic acid explains why serum levels of the administered bile acid are higher during treatment with ursodeoxycholic acid than during treatment with chenodeoxycholic acid. Our results also give evidence that the hepatic uptake of ursodeoxycholic acid cannot be saturated under physiologic conditions.

Adult↗

PubMed1985

Glucagon receptor of human liver. Studies of its molecular weight and binding properties, and its ability to activate hepatic adenylyl cyclase of non-obese and obese subjects.

The glucagon receptor and the adenylyl cyclase system of human liver membranes were studied in six non-obese and six obese subjects who had elevated insulin and plasma glucagon levels. Analysis of specific glucagon binding by the method of Scatchard demonstrated a linear (monocomponent) plot with a dissociation constant of 2-3 nM, and the binding at low hormone concentrations was sensitive to guanosine triphosphate (GTP). The molecular weight of the glucagon receptor was 63,000 D as determined by an affinity labeling procedure and sodium dodecyl sulfate gel electrophoresis. Affinity labeling of this structure was specific for glucagon and inhibited by GTP. Glucagon stimulated the production of cyclic adenosine monophosphate (cAMP) by human membranes with half-maximal activation elicited by 6 nM hormone. The human cyclase system required GTP to facilitate an optimal glucagon response. NaF (10 mM) also activated the cyclase system and produced the same magnitude of response as maximum glucagon activation. A comparison of the liver adenylyl cyclase system of non-obese and obese subjects was made using glucagon (5 nM and 1 microM) and NaF (10 mM). No significant differences in cAMP production were noted between the two groups, regardless of the agent used to activate the enzyme. These findings agree with the glucagon binding studies that showed similar amounts of binding activity in the membranes from the two groups. Also, there was no influence of either age or sex of the subjects on the adenylyl cyclase response. In conclusion, human liver membranes contain a glucagon receptor and an adenylyl cyclase system that correspond closely to the well-studied system in animal liver. This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder.

Adenylyl Cyclases↗

PubMed1985

Hydrogen concentration in expired air analyzed with a new hydrogen sensor, plasma glucose rise, and symptoms of lactose intolerance after oral administration of 100 gram lactose.

A rapid breath hydrogen analyzer to detect lactose malabsorption is described. After ingestion of a lactose solution the patient expires into a mouthpiece attached to a hydrogen sensor at 30-min intervals for 3 1/2 h. The hydrogen of the expired air causes a voltage change that can be transformed into ppm from a calibration curve. A tolerance test with a load of 100 g lactose was performed in 43 consecutive patients with various gastrointestinal disturbances, referred to the laboratory for the commonly used lactose tolerance test based on plasma glucose measurements. Eleven patients developed symptoms of lactose intolerance during the test. Biopsy specimens from the distal duodenum or proximal jejunum showed partial villous atrophy in one, in whom celiac disease with lactose intolerance was diagnosed; the other 10 had normal specimens. In nine of them lactose intolerance was diagnosed and confirmed by observation for months on a lactose-poor diet. The 10th patient (H.P.L.) did not improve on such a diet. He also showed pronounced symptoms of intolerance during a test with monosaccharides (glucose + galactose). His intestinal disease remained undiagnosed. The 11 patients with symptoms of intolerance and 3 patients without symptoms during the lactose load showed a flat plasma glucose curve after drinking the lactose solution--that is, a maximum rise of the glucose concentration of 1.5 mmol/l. One of the symptom-free patients dropped out and could not be observed, another did not improve on a lactose-poor diet, and the third noticed a favorable effect of the diet on stool consistency but not on other abdominal symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Plasma disappearance of 14C-glycocholic acid as a test of liver dysfunction. Relation to liver histology.

The present study was undertaken to evaluate the clinical usefulness of determining the plasma disappearance of 14C-glycocholic acid in the diagnosis of hepatic disease. This test was compared with the sulfobromophthalein test in 8 control subjects and 46 patients with abnormal liver histology (15 with fatty liver, 20 with alcoholic liver cirrhosis, 6 with primary biliary cirrhosis, and 5 with chronic hepatitis). The best distinction between controls and patients with liver disease was obtained by using the ratio between the plasma radioactivities at 45 and 2 min. However, even then, the 14C-glycocholic acid test had a very low sensitivity for the four groups of patients (0, 60, 50, and 40%, respectively) compared with the sulfobromophthalein test (73%, 90%, 67%, and 100% respectively). The lower sensitivity of the 14C-glycocholic acid test may be explained by the assumption that the clearance of a radioactive tracer dose is more dependent on liver blood flow than on liver function. This test is thus of little clinical value in separating patients with and without normal hepatic histology.

Adult↗

PubMed1984

Effect of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia.

Treatment with hypolipidaemic drugs such as clofibrate increases secretion of biliary cholesterol and induces supersaturation of bile, leading to an increased risk of gallstone formation. Ciprofibrate is a phenoxyisobutyrate derivative with lipid-lowering effects in hyperlipoproteinaemia. We analysed serum lipid levels and biliary lipid composition and cholesterol saturation of gallbladder bile in nineteen hyperlipoproteinaemic patients before and after 6 weeks treatment with ciprofibrate, 100 mg daily. In addition, hepatic secretion rates of biliary lipids were determined in eight of the patients. Ten of the patients were also studied after 1 year of treatment. Short-term treatment reduced the serum cholesterol levels by about 20% (P less than 0.001) and the serum triglycerides by about 40% (P less than 0.001). The relative cholesterol concentration and cholesterol saturation of bile were not significantly increased for the group as a whole, nor in patients with familial hypercholesterolaemia (n = 9), or with other types of hyperlipidaemia (n = 10). During treatment, however, fourteen patients had saturated bile compared with nine before treatment. An increase in cholesterol saturation was the consequence of an increased hepatic secretion of cholesterol whereas the secretion rates of bile acids and phospholipids were unaffected. After 1 year of treatment the serum lipid concentrations were reduced to about the same level as after 6 weeks, whereas biliary lipid composition and cholesterol saturation had returned to pre-treatment values. In contrast to clofibrate ciprofibrate exerts hypolipidaemic effects without consistently increasing the relative cholesterol concentration in bile. In some patients it leads to a transient rise in cholesterol saturation of gallbladder bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Triglyceride metabolism in human liver: studies on hepatic phosphatidic-acid phosphatase in obese and non-obese subjects.

According to current concepts, soluble phosphatidic-acid phosphatase, converting phosphatidic acid into a diglyceride, is a rate-limiting enzyme in the hepatic biosynthesis of triglycerides. The present paper is the first report on this enzyme in human liver. The enzyme activity was assayed in ammonium sulphate precipitates of cytosol obtained from human liver biopsies. The activity was stimulated by preincubation with alkaline phosphatase and inhibited by Mg-ATP, suggesting that phosphorylation-dephosphorylation may be of some importance for the expression of the activity of the enzyme. When assayed under optimal conditions, the activity obtained in liver biopsies from normal-weight gallstone patients averaged 12.8 +/- 2.0 nmol min-1 (mg protein)-1 (mean +/- SEM) (n = 17). The enzyme activity was slightly higher in liver biopsies from morbidly obese subjects 16.4 +/- 2.8 nmol min-1 (mg protein)-1 (n = 14). The difference between the two groups of subjects was probably in part sex-dependent and was not statistically significant. A similar small and insignificant difference between the two groups of subjects was found when the enzyme activity was assayed in the maximally stimulated state--i.e. after incubation with alkaline phosphate. These findings suggest that an increased capacity of the soluble phosphatidic-acid phosphatase is not of major importance for the increased triglyceride synthesis known to occur in obesity. Other factors (i.e. availability of substrate and cofactors) may be of greater importance.

Adult↗

PubMed1984

3-hydroxy-3-methylglutaryl coenzyme A reductase in human liver microsomes: active and inactive forms and cross-reactivity with antibody against rat liver enzyme.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the rate-limiting step in cholesterol biosynthesis, exists in one active (dephosphorylated) and one inactive (phosphorylated) form in liver microsomes obtained from several animal species. The present study was undertaken in order to determine a) whether the human enzyme also exists in active and inactive readily interconvertible forms; b) whether the large inter-individual variation in HMG-CoA reductase activity observed in normal man can be explained by variations in the activation state of the enzyme; and c) to characterize the reactivity of antibodies raised against rat liver HMG-CoA reductase with the intact human microsomal enzyme. HMG-CoA reductase activity, assayed in microsomes prepared in the presence of 50 mM NaF, was only 17 +/- 3% of the activity observed in microsomes prepared from the same liver in the absence of fluoride. Preincubation of microsomes prepared in NaF with alkaline phosphatase resulted in a tenfold increase of enzyme activity, while the activity of microsomes prepared without fluoride was increased also (by about 45%) with this treatment. On the other hand, the activated enzyme could be inactivated by incubation of microsomes with Mg-ATP. In eleven normal weight, normolipidemic gallstone patients, the HMG-CoA reductase activity determined in microsomes prepared without NaF ("standard procedure") reflected well both the "expressed" activity (in microsomes prepared with NaF) and the "total" (fully activated) enzyme activity; correlation coefficients were +0.80 and +0.84, respectively. Preincubation of human liver microsomes with rabbit antiserum against partially purified HMG-CoA reductase from rat liver resulted in a 72 +/- 6% inhibition of enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗

PubMed1984

Effects of substance P and somatostatin on taurocholate-stabilized and CCK- or secretin-induced choleresis in the anesthetized dog.

Eleven anesthetized dogs were provided with a common bile duct fistula, and the gallbladder was excluded. After stabilization of the bile flow by intravenous infusions of taurocholate, various peptides were administered intravenously. Substance P (SP) decreased the output of hepatic bile, bile acids, sodium, potassium, and bicarbonate by about 50%. When SP was superimposed on cholecystokinin (CCK)- or secretin-induced choleresis, all CCK-induced effects were abolished, whereas SP had a less pronounced anticholeretic effect when choleresis was induced by secretin. Somatostatin (SST) decreased the output of hepatic bile, bile acids, sodium, potassium, and bicarbonate by about 25%. SST had no inhibitory effect on CCK- or secretin-induced choleresis. It is suggested that the principal mode of action of SST on bile flow is indirect by inhibiting the release of choleretic hormones, whereas SP is suggested to act directly on the hepatocytes.

Animals↗

PubMed1984

Effect of ursodeoxycholic acid treatment on intestinal absorption of triglycerides in man.

The aim of the present study was to evaluate whether treatment with ursodeoxycholic acid (UDCA) may affect the absorption of dietary fat in man. Fifteen healthy subjects volunteered for the study. They were treated with UDCA in a daily dose of 15 mg/kg body weight for 4 weeks. Before and during treatment fat absorption was measured with a 14C-triolein breath test. In addition, fasting serum bile acids were measured in 11 of the subjects. The maximum specific activity of 14CO2 was not significantly changed during the treatment period. However, the cumulative output of 14CO2 during a 6-h period was decreased by about 25% (p less than 0.03). Several subjects with decreased outputs also lost 1-2 kg of body weight during the study period. UDCA treatment raised the serum level of this bile acid from 0.18 +/- 0.11 mumol/l to 5.98 +/- 1.08 mumol/l. The concentrations of the other bile acids were not significantly changed. It is suggested that UDCA treatment may in some patients be associated with an impaired fat absorption. Whether this effect is of any clinical importance remains to be elucidated.

Adult↗

PubMed1983

Bile acid metabolism in hypothyroid subjects: response to substitution therapy.

Bile acid kinetics and biliary lipid composition were determined in ten hypothyroid patients before and after treatment with L-thyroxine. Hypothyroid patients had normal synthesis rates of cholic acid and chenodeoxycholic acid. Hormone treatment, which lowered plasma cholesterol by about 35%, stimulated the formation of chenodeoxycholic acid by about 40% but did not significantly change the synthesis of cholic acid or total primary bile acids. The mean relative biliary concentration of deoxycholic acid was decreased from 30% to 19% and that of chenodeoxycholic acid was concomitantly increased. Cholesterol saturation of bile was decreased by treatment in six of the patients, but the mean value before treatment (135 +/- 13%) was not significantly different from that obtained after treatment (108 +/- 9%). It is suggested that the hypocholesterolaemic effect of thyroid hormones is not primarily due to an increased degradation of cholesterol to bile acids. Similar to what is observed in heterozygous familial hypercholesterolaemia, the defective receptor mediated degradation of plasma low density lipoproteins in hypothyroidism is thus apparently associated with a quantitatively normal catabolic rate of cholesterol to bile acids.

Aged↗