FK 506 improves recovery of bile secretion following orthotopic liver transplantation in man.
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Azathioprine↗
Biomedical subjects
K Einarsson
Publications and source records attributed to K Einarsson.
Cholesterol metabolism in liver and gallbladder mucosa of patients with cholesterolosis.
The objective of this study was to investigate possible pathogenetic factors for cholesterolosis. Liver tissue, gallbladder mucosa, and gallbladder bile were collected in patients with cholesterol gallstones (GS) (14 patients with and 14 patients without cholesterolosis) and gallstone-free (GSF) subjects (11 with and 21 without cholesterolosis) undergoing cholecystectomy. In cholesterolosis, the gallbladder mucosa was characterized by a fivefold increase in esterified cholesterol and normal content of free cholesterol. The hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, governing cholesterol synthesis, and acyl coenzyme A: acyltransferase activity, catalyzing the esterification of cholesterol, were similar in patients with and without cholesterolosis. Also in the gallbladder mucosa, the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity was similar in patients with and without cholesterolosis. The acyl coenzyme A: acyltransferase activity of the gallbladder mucosa was increased in the GSF subjects with cholesterolosis. The nucleation time of gallbladder bile was shorter in the GSF subjects with cholesterolosis compared with the time of those without cholesterolosis. Occurrence of cholesterol crystals, lipid composition, and cholesterol saturation of gallbladder bile were not significantly influenced by the absence or presence of cholesterolosis. The study has confirmed that cholesterolosis is associated with a several-fold increased level of esterified cholesterol. The data suggest that patients with cholesterolosis have normal hepatic cholesterol formation and esterification. The local synthesis of cholesterol in the gallbladder mucosa seems to be normal. A positive correlation was obtained between the cholesterol saturation of bile and the content of esterified cholesterol in the gallbladder mucosa in the whole series of patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Bile↗
Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism.
A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.
Adult↗
Effect of ursodeoxycholic acid on hepatic cholesterol metabolism.
Oral administration of ursodeoxycholic acid (UDCA) renders bile unsaturated with cholesterol by reducing the hepatic output of cholesterol. Theoretically, several mechanisms may be of importance. In the present overview, the effect of treatment with UDCA on hepatic cholesterol metabolism is evaluated, in particular the influence on hepatic cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity, bile acid synthesis, 7 alpha-hydroxylation of cholesterol, and esterification of cholesterol--acyl coenzyme A: cholesterol acetyltransferase (ACAT) activity. It is apparent that UDCA treatment does not inhibit the hepatic HMG CoA reductase activity. Neither is ACAT activity or the cholesteryl ester content changed by UDCA. The catabolism of cholesterol to bile acids is unaffected or slightly increased during administration of UDCA. It is concluded that a stimulated degradation of cholesterol to bile acids may partly explain the decrease in hepatic secretion of cholesterol obtained during UDCA administration. It is suggested that the reduction in cholesterol absorption from the intestine seen during UDCA therapy may also be of importance.
Acyl Coenzyme A↗
Hepatic esterification rate of cholesterol and biliary lipids in human obesity.
Obesity is often associated with an increased hepatic secretion rate of cholesterol and saturated gallbladder bile. In order to evaluate the role of hepatic esterification of cholesterol in this phenomenon, we assayed the activity of acyl CoA:cholesterol acyl transferase (ACAT), which catalyzes the esterification of cholesterol, in liver microsomes obtained from 19 morbidly obese patients without gallstones undergoing vertical banded gastroplasty. Gallbladder bile was obtained and analyzed for lipid composition, cholesterol saturation, nucleation time, and occurrence of cholesterol crystals. Fourteen non-obese gallstone-free subjects undergoing cholecystectomy because of suspected polyp or adenomyoma in the gallbladder served as controls. The hepatic content of esterified cholesterol was increased by about 70% in the obese patients (P < 0.05). Still, the mean levels of the ACAT activity were equal in the obese and non-obese patient groups (11 +/- 1 and 11 +/- 2 pmol/min per mg protein, respectively). When exogenous cholesterol was added to the assay system, the activity was increased markedly in both groups. The ACAT activity was higher in obese patients with steatosis of the liver compared with those displaying normal liver morphology (12 +/- 1 vs 8 +/- 1 pmol/min per mg, P < 0.05). Obese patients did not have significantly more saturated gallbladder bile than the non-obese controls (84 +/- 7 and 77 +/- 8%, respectively). They had a normal nucleation time and their gallbladder bile did not contain any cholesterol crystals. We conclude that obese patients without gallstones usually have a normal esterification rate of cholesterol in the liver. Steatosis of the liver was associated with increased ACAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Serum 7 alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid malabsorption in patients with diarrhoea: correlation to SeHCAT test.
The synthesis of bile acids is regulated by a homeostatic mechanism in which bile acids returning to the liver from the intestine inhibit their own synthesis. Serum concentrations of the bile acid intermediate 7 alpha-hydroxy-4-cholesten-3-one reflect the rate of bile acid synthesis whereas bile acid malabsorption can be determined by the SeHCAT test. This study was done to evaluate the correlation between the two tests in humans. Twenty eight patients with chronic diarrhoea were included in the study. Fasting serum was collected for the determination of 7 alpha-hydroxy-4-cholesten-3-one, and on the same day the gamma emitting bile acid analogue SeHCAT was given orally and its fractional catabolic rate assessed by repeated external counting over the upper abdomen during the next seven days. There was a highly significant positive correlation between the two tests (Rs = 0.80, p < 0.001). The results show a close relation between intestinal loss and hepatic synthesis of bile acids and imply that analysis of 7 alpha-hydroxy-4-cholesten-3-one in serum should now be evaluated as a possible convenient method for assessing bile acid malabsorption in patients with diarrhoea.
Adult↗
7 alpha-hydroxylation of 27-hydroxycholesterol in human liver microsomes.
Human liver microsomes were found to catalyze 7 alpha-hydroxylation of 27-hydroxycholesterol at a rate of up to about 0.2 nmol/mg protein per min. The product of the reaction, 5-cholestene-3 beta, 7 alpha, 27-triol, was identified by means of combined gas chromatography-mass spectrometry. Liver microsomes from two patients with an upregulated cholesterol 7 alpha-hydroxylase, did not have higher 7 alpha-hydroxylase activity towards 27-hydroxycholesterol than those from untreated patients, suggesting that the 7 alpha-hydroxylase active towards 27-hydroxycholesterol is not the same as that active towards cholesterol. The mitochondrial fraction of liver from untreated patients and patients treated with cholestyramine, had negligible 7 alpha-hydroxylase activity towards 27-hydroxycholesterol less than 0.01 nmol/mg protein per min). The results are in accord with the possibility that there is a pathway to bile acids in human liver in which the first step is a 27-hydroxylation of cholesterol.
Adult↗
Cholesterol metabolism in human gallbladder mucosa: relationship to cholesterol gallstone disease and effects of chenodeoxycholic acid and ursodeoxycholic acid treatment.
The objective of this study was to investigate cholesterol metabolism in human gallbladder mucosa, especially in relation to hepatic cholesterol metabolism, gallstone disease and treatment with bile acids. Gallbladder mucosa and liver tissue samples were collected in 44 patients undergoing cholecystectomy; 30 had cholesterol gallstones and the rest were stone free. Ten of the gallstone patients were treated with chenodeoxycholic acid and eight received ursodeoxycholic acid, with a daily dose of 15 mg/kg body wt, for 3 wk before surgery. The 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, governing cholesterol synthesis, was considerably lower in the gallbladder mucosa than in liver tissue (28 +/- 6 and 120 +/- 40 pmol/min/mg protein). The acyl coenzyme A:acyltransferase activity in the gallbladder mucosa catalyzing the esterification of cholesterol was, on the other hand, several times higher than corresponding activity in the liver (92 +/- 23 and 11 +/- 2 pmol/min/mg protein). In the presence of exogenous cholesterol, the acyl coenzyme A:acyltransferase activity increased about twofold in the gallbladder mucosa. The acyl coenzyme A:acyltransferase activity of the gallbladder mucosa from untreated gallstone patients was not stimulated further by the addition of exogenous cholesterol. Otherwise, there were no significant differences in acyl coenzyme A:acyltransferase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities in the gallbladder mucosa of gallstone patients compared with gallstone-free controls. Treatment with chenodeoxycholic and ursodeoxycholic acids did not affect the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity of the gallbladder mucosa but reduced the acyl coenzyme A:acyltransferase activity by 60% to 65%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Hepatic cholesterol metabolism in estrogen-treated men.
Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.
Aged↗
Somatostatin does not block the effect of vasoactive intestinal peptide on bile secretion in man.
The effects of intravenously administered somatostatin and vasoactive intestinal peptide (VIP) on bile secretion were studied in 10 patients with complete biliary fistulas. The two peptides were administered both separately and simultaneously. During the infusion of vasoactive intestinal peptide, bile secretion increased by 85%, whereas during somatostatin infusion it decreased by 40%. When the peptides were administered together, the VIP-induced choleretic effect was not reduced by somatostatin. Vasoactive intestinal peptide infusion increased bicarbonate concentration and output, whereas somatostatin had the opposite effect. The output of chloride also increased following vasoactive intestinal peptide infusion but decreased following somatostatin infusion. The concentration of chloride was unaffected by somatostatin whereas it was decreased by vasoactive intestinal peptide. The output of bile acids was unaffected by vasoactive intestinal peptide and decreased by somatostatin infusion, whereas total lipid concentration increased during somatostatin infusion and decreased when vasoactive intestinal peptide was added. It is concluded that, in man, somatostatin acts on the bile acid-dependent canalicular bile secretion and also, to some extent, on the ductular secretion, whereas vasoactive intestinal peptide acts strictly at the ductular level. The effects of the two peptides on bile secretion are independent of each other.
Adult↗
Protracted cholestasis probably induced by oral contraceptive.
The case of a patient with intrahepatic cholestasis, probably induced by an oral contraceptive agent, is reported. Initially, early primary biliary cirrhosis was suspected, but this diagnosis could not be verified either clinically or by immunological tests. Re-examination and re-evaluation of the liver biopsy revealed some eosinophilia and sinusoidal dilatation, changes indicative of drug-induced liver injury. The cholestasis gradually disappeared as indicated both biochemically and histologically, but the elevation of serum alkaline phosphatase levels persisted for some 10 years after termination of drug therapy. Oral contraceptive agent-induced jaundice or cholestasis is generally reported to disappear when the drug is stopped, and we are unaware of similar cases in the literature with a protracted course such as that described here. Still, the circumstances of this patient suggest that a correlation between the oral contraceptive agent and the hepatic reaction is most likely, and we consider it important that colleagues pay attention to this possibility.
Adult↗
HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.
The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.
Blotting, Southern↗
Comparison of the proportion of unconjugated to total serum cholic acid and the [14C]-xylose breath test in patients with suspected small intestinal bacterial overgrowth.
The proportion of unconjugated to total cholic acid in fasting serum and the 1-gram [14C]-xylose breath test were determined in 36 patients with suspected bacterial overgrowth of the small intestine. Twenty-two patients had an abnormal [14C]-xylose breath test, indicating bacterial overgrowth. The proportion of unconjugated to total cholic acid was significantly higher in the patients with an abnormal breath test compared with those displaying a normal breath test (47 +/- 5% vs 16 +/- 3%). A good correlation was obtained between the proportion of unconjugated to total cholic acid and the breath test (r = 0.63, n = 36). Provided the [14C]-xylose breath test is reliable as a test of bacterial overgrowth, determination of the proportion of unconjugated to total cholic acid in fasting serum had a sensitivity of 73% and a specificity of 94%. It is suggested that determination of the proportion of unconjugated to total cholic acid in peripheral venous blood may be useful as a simple screening test for detection of bacterial contamination of the upper small intestine provided the patients do not have bile acid malabsorption.
Adult↗
12 alpha-hydroxylase activity in human liver and its relation to cholesterol 7 alpha-hydroxylase activity.
Interruption of the enterohepatic circulation by cholestyramine causes a several-fold increase in bile acid synthesis, reflected in a stimulation of cholesterol 7 alpha-hydroxylase activity; the synthesis of cholic acid being stimulated to a greater extent than chenodeoxycholic acid. It is not known if this preferential increase in cholic acid is due to an increase of the 12 alpha-hydroxylase activity. The present study aimed at investigating the 12 alpha-hydroxylase activity and its relation to cholesterol 7 alpha-hydroxylase activity in liver microsomes of patients with different levels of cholesterol 7 alpha-hydroxylase activity. Liver biopsies were obtained from four gallstone-free patients, and seven untreated and two cholestyramine-treated gallstone patients undergoing cholecystectomy, and four patients with Crohn's disease undergoing intestinal resection. The combined group of cholestyramine-treated and ileum-resected patients had four times higher cholesterol 7 alpha-hydroxylase activity and two times higher 12 alpha-hydroxylase activity than the other patients. A positive correlation was obtained between cholesterol 7 alpha-hydroxylase activity and 12 alpha-hydroxylase activity (r = +0.69; n = 16). These results indicate that the increased ratio between the synthesis of cholic acid and chenodeoxycholic acid during cholestyramine treatment is due to a compensatory increase of the 12 alpha-hydroxylase activity.
Adult↗
Metabolic effects caused by exclusion of intestinal segments.
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Adaptation, Physiological↗
The plasma level of 7 alpha-hydroxy-4-cholesten-3-one reflects the activity of hepatic cholesterol 7 alpha-hydroxylase in man.
Circulating levels of 7 alpha-hydroxy-4-cholesten-3-one have been compared with activities of the rate-limiting enzyme in bile acid synthesis, microsomal cholesterol 7 alpha-hydroxylase, measured in liver biopsies obtained from patients undergoing surgery for gallstone disease. Some patients were treated with cholestyramine or bile acids prior to operation in order to alter the feed-back inhibition of the enzyme. The levels of the sterol were similar in untreated patients and in patients treated with ursodeoxycholic acid (median concentration 17 and 13 ng/ml, respectively), and so were the activities of the enzyme (median activity 7.0 and 5.5 pmol/min/mg protein, respectively). The sterol levels and enzyme activities were significantly increased in patients treated with cholestyramine (91 ng/ml and 45 pmol/min/mg protein) and decreased in patients treated with chenodeoxycholic acid (less than 2.0 ng/ml and 0.7 pmol/min/mg protein). There was a strong positive correlation (r = 0.90, P less than 0.00001) between levels of 7 alpha-hydroxy-4-cholesten-3-one in plasma and the activities of cholesterol 7 alpha-hydroxylase in the whole patient group. The results show that analysis of 7 alpha-hydroxy-4-cholesten-3-one in plasma is a sensitive and convenient method to determine relative rates of bile acid production in man.
Adult↗
[Effect of pravastatin on hepatic cholesterol metabolism].
BACKGROUND: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. METHODS: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. RESULTS: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (p less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (p less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; p less than 0.001). The expression of LDL receptors was increased by 180 percent (p less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A: cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. CONCLUSIONS: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.
Adult↗
Effects of bezafibrate on hepatic cholesterol metabolism.
The influence of bezafibrate treatment on hepatic cholesterol metabolism was studied in rats and in humans. The activities of the three key enzymes involved in cholesterol metabolism [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-coenzyme A: cholesterol acyltransferase (ACAT)] were suppressed by bezafibrate treatment in rats, but only the ACAT activity was significantly decreased when the activity was related to total liver weight. In humans, HMG-CoA reductase activity was increased about twice in the treated normolipidemic gallstone patients. In contrast, the concentration of lathosterol in serum decreased, indicating depression of the cholesterol synthesis. The increase in HMG-CoA reductase activity may be a compensatory effect of an inhibition of some other enzymes in the synthesis of cholesterol, as in vitro study on liver microsomes excluded a direct inhibitory effect of bezafibrate on HMG-CoA reductase. The ACAT activity was not significantly changed, and the cholesterol 7 alpha-hydroxylase activity was decreased by 55-60% compared with controls. The LDL-receptor-binding activity was unaffected by bezafibrate treatment.
Animals↗