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Biomedical subjects

G T Everson

Publications and source records attributed to G T Everson.

At least 19 recordsLinked to original sources
PubMed1995

Course of thrombocytopenia of chronic liver disease after transjugular intrahepatic portosystemic shunts (TIPS). A retrospective analysis.

Thrombocytopenia associated with chronic liver disease presents a difficult management issue. Most reports conclude that portocaval and distal splenorenal shunts do not improve platelet counts in this setting. The response of thrombocytopenia after transjugular intrahepatic portosystemic shunt placement has not been studied. All platelet counts of 21 patients undergoing intrahepatic shunt placement were determined retrospectively to accumulate values at one month prior to procedure, weekly for the first month after the procedure, and monthly thereafter to six months. Comparison of pre- and postshunt platelet means showed a significant increase in counts in patients with a postshunt portal pressure gradient < 12 mm Hg, with the increment evident by one week after the procedure. This response was not seen when preshunt thrombocytopenia was used as the lone variable. This study suggests that the transjugular intrahepatic portosystemic shunt may improve the thrombocytopenia associated with liver cirrhosis when these pressure gradients are attained.

Adult↗
PubMed1995

Possible idiopathic thrombocytopenic purpura associated with natural alpha interferon therapy for chronic hepatitis C infection.

We report the case of a 41-yr-old male with chronic hepatitis C who developed severe thrombocytopenia on interferon alfa-n3 therapy. The patient was enrolled in a multi-center trial of interferon alfa-n3 in the treatment of chronic hepatitis C. In the 10th wk of therapy, he presented with gingival bleeding and a petechial rash. Complete blood count demonstrated WBC 5,800/mm3. Hgb 16.3 g/dl, Hct 45.5%, and platelet count 6,000/mm3. Interferon was withdrawn, and he was admitted to intensive care and was treated with platelet transfusion, intravenous steroids, and intravenous immunoglobulin. His platelet counts returned to 157,000/mm3 in 7 days and remained normal on a tapering dose of prednisone. Bone marrow biopsy/aspirate demonstrated numerous megakaryocytes. Stored plasma was negative for development of specific high-titer anti-platelet antibody. We suggest that the clinical findings and response to therapy are consistent with interferon-induced idiopathic thrombocytopenic purpura.

Adult↗
PubMed1994

Characteristics and regulation of bile salt synthesis and secretion by human hepatoma HepG2 cells.

Bile salt uptake, synthesis and secretion by the human hepatoma-derived cell line HepG2 were studied. The cells transported and secreted bile salts largely by means of passive mechanisms. The cells synthesized and secreted the normal human primary bile salts. The ratio of cholate to chenodeoxycholate was 1.5:1. The degree of conjugation, about 35%, was lower than normal, and the glycine-to-taurine ratio was abnormal (4.5:1). This was not due to amino acid deficiency in the medium. Contrary to the report of others, little 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid was secreted. This was confirmed by gas chromatography-mass spectrometry. The total rate of synthesis was about 33% that of normal liver. The specific activity of bile salts synthesized from [3H]mevalonate was about 20 times higher than that of the cellular cholesterol derived from the same precursor. The regulation of bile salt synthesis by two compounds that could alter the precursor pool of cholesterol was studied. After a 24-hr incubation in serum-free medium, the compound 25(OH)cholesterol inhibited the rate of bile salt synthesis compared with control values, possibly by depleting the intracellular free cholesterol pool. Surprisingly, however, progesterone, which inhibits cholesterol esterification and should have expanded this pool, also inhibited bile salt synthesis under those conditions. The effect of these compounds on the level of mRNA for cholesterol 7 alpha-hydroxylase was also determined by Northern-blot analysis. The cholesterol 7 alpha-hydroxylase mRNA was 3.7 kb, similar to that in the rat. The incubation of cells in 25(OH)cholesterol or progesterone, as above, resulted in a decreased level of mRNA. The reduction was proportional to the reduction in bile salt synthesis, suggesting that these compounds act at a pretranslational level. Taken together, these results suggest that our particular subclone of HepG2 cells will be useful for studies of the regulation of bile salt synthesis, but not of transport, by human liver-derived tissue.

Bile Acids and Salts↗
PubMed1994

Sodium retention does not occur at a critical threshold of liver function in alcoholic cirrhosis.

Sodium retention is triggered in rats with experimental liver injury at a critical threshold of liver function. We compared liver function and sodium retention in serially studied patients with alcoholic cirrhosis to determine whether a similar threshold exists in human beings. Antipyrine, caffeine, and cholic acid clearance were measured in 35 men with alcoholic liver disease. Nineteen patients were evaluated on two or more occasions; between studies, 28 remained in sodium balance (group NN), six spontaneously developed sodium retention and ascites formation (group NY), and seven spontaneously lost ascites (group YN). A threshold between patients with and without sodium retention did not exist for any of the clearance measurements. Indeed, values overlapped widely between the two groups. Antipyrine and cholate clearance were significantly reduced in patients with sodium retention, but caffeine clearance was similar in the two groups. Antipyrine and caffeine clearance declined significantly between the first and second study in group NY; cholate clearance did not change. No significant differences were observed between studies in group YN. In several patients of this group, liver function worsened as ascites spontaneously resolved. Impaired liver function commonly but not invariably accompanies sodium retention in patients with cirrhosis. A threshold at which sodium retention occurs or resolves does not exist.

Antipyrine↗
PubMed1992

Effects of psyllium hydrophilic mucilloid on LDL-cholesterol and bile acid synthesis in hypercholesterolemic men.

The goal of the current study was to determine the mechanism of the hypocholesterolemic effect of psyllium using a randomized, double-blind, crossover design. Twenty males (age 44 +/- 4 yr, weight 79 +/- 10 kg) with moderate hypercholesterolemia (total 265 +/- 17 mg/dl, low density lipoprotein (LDL) 184 +/- 15 mg/dl) were studied at baseline (B) and after randomization to receive a 40-day course of 15 g/day of either psyllium (Ps) or placebo (Pl) (cellulose). After a washout period (11 +/- 2 days), subjects were crossed over to the other fiber treatment for an additional 40 days and restudied. Intestinal cholesterol absorption, cholesterol synthesis in isolated peripheral blood mononuclear cells, bile acid kinetics, gallbladder motility, and intestinal transit were measured at each study period. Psyllium lowered LDL cholesterol (x:184 (B), 169 (Ps), and 179 (Pl) mg/dl; Ps vs. B,Pl: P less than 0.004, P less than 0.02), decreased relative cholesterol absorption (x:51 (B), 45 (Ps), and 49 (Pl) %; Ps vs. B,Pl: P less than 0.03, P less than 0.03), did not alter absolute cholesterol absorption, and increased the fractional turnover of both chenodeoxycholic acid (x:0.176 (B), 0.203 (Ps), and 0.170 (Pl) day-1; Ps vs. B,Pl: P less than 0.0001, P less than 0.01) and cholic acid (x:0.303 (B), 0.411 (Ps), and 0.301 (Pl) d-1; Ps vs. B, Pl: P less than 0.006, P less than 0.002). Bile acid synthesis increased in subjects whose LDL cholesterol was lowered by more than 10% (Ps vs. B: 1304 +/- 489 vs 992 +/- 307 mumol/day, P less than 0.006; Ps vs. PI: 1304 +/- 489 vs. 914 +/- 321 mumol/day, P less than 0.0002). We conclude that psyllium lowers LDL cholesterol primarily via stimulation of bile acid synthesis.

Adult↗
PubMed1992

Gastrointestinal motility in pregnancy.

The gallbladder and gut should be viewed as hormonally responsive organs the normal physiology of which may be altered by the hormones of pregnancy. The gallbladder enlarges and empties sluggishly in response to meals during pregnancy. Small bowel transit is slowed, and the resting pressure of the lower esophageal sphincter is reduced. All these effects are reversed by delivery; motility reverts toward normal in the postpartum period. The rapid return of normal motility suggests that the effects of pregnancy are hormonally related. Most studies have demonstrated that progesterone, not estrogen, may be the hormone responsible. Although incompletely defined, one mechanism of the effects of pregnancy on motility may be progesterone-induced inhibition of the mobilization of intracellular calcium within smooth muscle cells.

Cholelithiasis↗
PubMed1991

Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats.

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated.

Alkaline Phosphatase↗
PubMed1991

Bile acid synthesis in cultured human hepatoblastoma cells.

Biosynthetic pathways to bile acids have been studied in HepG2 cells, a well-differentiated human hepatoblastoma cell line. Cholesterol metabolites, in total 29, were isolated from culture media and cells by liquid-solid extraction and anion-exchange chromatography and were identified by gas-liquid chromatography-mass spectrometry. The production rates/concentrations of cholic acid (CA) and chenodeoxycholic acid (CDCA) in media from control cells were 71 and 74 ng/10(7) cells/h, respectively. Major bile acid precursors were 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA), 7 alpha, 12 alpha-dihydroxy-3-oxo-4-cholestenoic acid, 7 alpha-hydroxy-3-oxo-4-cholenoic acid, and 7 alpha, 12 alpha-dihydroxy-3-oxo-5 beta-cholanoic acid, their concentrations being 60, 30, 23, and 10 ng/10(7) cells/h, respectively. These and nine other isolated intermediates formed essentially complete metabolic sequences from cholesterol to CA and CDCA. The remaining steroids were metabolites of the intermediates or autooxidation products of cholesterol. These findings and the observed effect of dexamethasone on production rates suggest that in HepG2 cells the major biosynthetic pathways to primary bile acids start with 7 alpha-hydroxylation of cholesterol and oxidation to 7 alpha-hydroxy-4-cholesten-3-one followed by hydroxylation at either the 26 or 12 alpha position. CDCA is formed by the sequence of 26-hydroxylation, oxidation, and degradation of the side chain and A-ring reduction. CA is formed by the sequence of 12 alpha-hydroxylation, 26-hydroxylation, oxidation, and degradation of the side chain and reduction of the A-ring. An alternative pathway to CA included A-ring reduction of the intermediate 7 alpha, 12 alpha-dihydroxy-3-oxo-4-cholestenoic acid to form THCA prior to side chain cleavage. These pathways are not limited to HepG2 cells but may also be important in humans.

Bile Acids and Salts↗
PubMed1991

Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism.

Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.

Adult↗
PubMed1991

Effects of specific inhibition of sterol biosynthesis on the uptake and utilization of low density lipoprotein cholesterol by HepG2 cells.

Treatment of HepG2 cells in lipoprotein-deficient media with 4,4,10 beta-trimethyl-trans-decal-3 beta-ol (TMD) abolished the incorporation of [3H]acetate into cholesterol with concomitant accumulation of squalene 2,3(S)-oxide and squalene 2,3(S):22(S),23-dioxide, indicating a specific inhibition of oxidosqualene cyclase. The activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was affected in a biphasic manner, being inhibited by 30% at low concentrations of TMD and stimulated by 30% at concentrations that completely shut down oxidosqualene cyclase. Treatment with TMD (greater than 20 micrograms/ml) doubled the specific binding and internalization of low density lipoproteins (LDL) and also enhanced their degradation to a degree comparable to that produced by lovastatin, a well-known inhibitor of HMG-CoA reductase. The enhanced binding of LDL to HepG2 cells appeared to occur as a result of an increase in the number of binding sites with no change in their binding affinity for the lipoprotein. At concentrations that completely inhibited cholesterol biosynthesis, TMD did not affect the ability of LDL-derived cholesterol to stimulate cholesterol esterification by seven- to tenfold or to stimulate bile acid secretion to a lesser degree. However, TMD treatment inhibited overall bile acid secretion by 75-85%. The compound had no inhibitory effect on the rates of secretion of either apolipoprotein B or of cholesterol by HepG2 cells into the culture medium. These data demonstrate that a specific inhibition of the sterol branch of isoprenoid biosynthetic pathway in hepatic cells by TMD is sufficient to induce the expression of LDL receptors and that the cholesterol delivered by LDL is available for normal metabolic purposes of the cell.

Cell Line↗
PubMed1991

Plasma glucagon concentration in cirrhosis is related to liver function but not to portal-systemic shunting, systemic vascular resistance, or urinary sodium excretion.

We tested the hypothesis that increased plasma glucagon concentration resulting from portal-systemic shunting or liver dysfunction causes arterial vasodilation and thereby stimulates sodium retention in cirrhosis. Twenty-seven studies were performed in patients with alcoholic liver disease, 11 of whom had ascites. Liver function was quantitated as the elimination rate of antipyrine, caffeine, and stable isotopes of cholic acid administered both orally (2,2,4,4-2H) and intravenously (24-13C). Portal-systemic shunt fraction was calculated as the ratio of the intravenous and oral clearances of the isotopes of cholic acid. Cardiac output was measured by using Doppler echocardiography. Plasma glucagon concentration was increased in patients with ascites when compared with that in patients without ascites (474 +/- 180 pg/ml vs 245 +/- 120 pg/ml, p = 0.0007) but was unrelated to urinary sodium excretion, heart rate, mean arterial pressure, cardiac output, and systemic vascular resistance (r = -0.48, 0.35, -0.13, 0.18, and 0.22, respectively). Plasma glucagon concentration correlated with the half-lives of all model compounds (r = 0.58, p = 0.002; r = 0.62, p = 0.0008; r = 0.62, p = 0.001; and r = 0.64, p = 0.0005; for caffeine, antipyrine, oral and intravenous cholic acid, respectively) but not with shunt fraction (r = 0.14). Increased plasma glucagon concentration in cirrhosis is probably a result of diminished hepatic clearance. However, increased plasma concentration of glucagon does not appear to cause a hyperdynamic circulatory state or sodium retention.

Glucagon↗
PubMed1991

Gallbladder function in gallstone disease.

The gallbladder should be viewed as a hormonally responsive organ whose normal physiology may be altered by conditions ranging from intestinal disease to pregnancy. Disorders or conditions characterized by altered gallbladder motility predispose persons to gallstone formation. Recent studies of gallbladder sludge and the gallbladder motility of gallstone patients suggest that localized processes within the gallbladder may be critically important in gallstone formation. No unifying disturbance of motility characterizes gallstone patients, perhaps because mechanisms of gallstone formation are many and diverse.

Bile↗
PubMed1990

Substrate stimulation of 7 alpha-hydroxylase, an enzyme located in the cholesterol-poor endoplasmic reticulum.

We examined the role of cholesterol in altering the activity of the microsomal cytochrome P-450 enzyme, cholesterol-NADPH:oxygen oxidoreductase (cholesterol 7 alpha-hydroxylase). Liposomes were used to deliver cholesterol to hepatic microsomes. Formation of 7 alpha-hydroxycholesterol was quantitated by isotope dilution/gas chromatography-mass spectrometry. As the liposomal cholesterol/phospholipid molar ratio increased, 7 alpha-hydroxylase activity increased, whereas the activity of another microsomal cytochrome P-450 enzyme, ethylmorphine N-demethylase, decreased. To determine if the degree of stimulation was affected by the endogenous activity (without liposomes), microsomes, from rats fed chow alone or chow containing cholestyramine, taurocholate, or cholesterol were challenged with cholesterol-enriched liposomes. The degree of stimulation was dependent upon the endogenous activity: cholestyramine-fed much greater than cholesterol = chow control greater than taurocholate-fed. To determine if cholesterol stimulates 7 alpha-hydroxylase by increasing membrane viscosity, microsomes were incubated with liposomes having the same cholesterol/phospholipid molar ratio as microsomes, but different viscosities. Dipalmitoylphosphatidylcholine (high viscosity) liposomes increased microsomal viscosity and decreased 7 alpha-hydroxylase activity. In contrast, dioleoylphosphatidylcholine (low viscosity) liposomes decreased microsomal viscosity and increased enzyme activity. Since greater viscosity inhibits 7 alpha-hydroxylase, cholesterol cannot stimulate the enzyme by increasing membrane viscosity. The data suggest that cholesterol stimulates production of 7 alpha-hydroxycholesterol by providing substrate.

1,2-Dipalmitoylphosphatidylcholine↗