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Biomedical subjects

J W Marks

Publications and source records attributed to J W Marks.

At least 37 records · Page 2Linked to original sources
PubMed1986

The effect of diet on bile acid kinetics and biliary lipid secretion in gallstone patients treated with ursodeoxycholic acid.

Effects of specific dietary alterations in patients with radiolucent gallstones treated with ursodeoxycholic acid (UDCA, 750 mg at bedtime) were investigated. Patients were allocated randomly to one of four diets: standard (500 mg cholesterol/day), low-cholesterol (250 mg/day), added-bran (30 g/day), or substituted medium-chain triglycerides (MCT) oil (20% of fat). Dietary intake and good compliance were verified by computerized analysis of dietary diaries. Bile-acid kinetics (26 patients) or secretion of biliary lipids (23 other patients) were determined at enrollment and at 6 and 9 mo, respectively, during treatment. Although MCT further decreased the UDCA-induced decrease in the synthesis of chenodeoxycholic acid, it did not lessen desaturation of bile. Otherwise, compared to the standard diet, no experimental diet significantly altered the UDCA-induced increase of the pools of total bile acids and UDCA or the UDCA-induced decrease in synthesis of bile acids and in biliary secretion or saturation of cholesterol. If these dietary manipulations facilitate dissolution of gallstones by UDCA, they do so by other mechanisms.

Adult↗
PubMed1985

Effect of dietary cholesterol on biliary lipids in patients with gallstones and normal subjects.

The purpose of this study was to determine the effect of dietary cholesterol on biliary lipids in subjects with and without gallstones. Twelve patients with asymptomatic gallstones (six men, six women) were assigned diets containing 500, 750, and 1000 mg cholesterol daily for 3-wk periods in random sequence. Seven healthy women similarly were assigned diets containing 500 and 1000 mg cholesterol daily. With increasing dietary cholesterol in patients with gallstones, biliary saturation indices and molar percents of cholesterol and phospholipids increased significantly while molar percent of biliary bile acids decreased significantly. With increasing dietary cholesterol in healthy women, the biliary saturation index and molar percent of cholesterol increased significantly; the mean saturation index exceeded unity on the diet containing 1000 mg cholesterol daily. In conclusion, augmented dietary cholesterol for brief periods increased biliary cholesterol saturation in subjects with and without gallstones.

Bile↗
PubMed1984

Lack of correlation between serum lipoproteins and biliary cholesterol saturation in patients with gallstones.

It has been suggested that elevated serum lipoprotein cholesterol levels may be a determinant of biliary cholesterol saturation and cholesterol gallstone disease. The aim of this study was to correlate serum lipoprotein cholesterol and apolipoprotein levels with biliary cholesterol saturation in patients with gallstones who participated in the National Cooperative Gallstone Study. Baseline serum lipoprotein and biliary lipid levels were studied in 181 of these patients before they received treatment for dissolution of their gallstones. Neither low- or high-density lipoprotein cholesterol nor apolipoprotein levels correlated with biliary cholesterol saturation. This study, therefore, does not support the concept that serum lipoproteins are a determinant of biliary cholesterol saturation. It is possible, however, that a significant effect of lipoprotein levels is obscured by the greater effects of more important determinants of biliary cholesterol saturation.

Adult↗
PubMed1984

Major issues in the organization and implementation of the National Cooperative Gallstone Study (NCGS).

The National Cooperative Gallstone Study (NCGS) was a cooperative, randomized, controlled trial of a drug, chenodiol, for the medical dissolution of gallstones. The design and procedures of the NCGS were complex, having developed as a result of extensive involvement of many experts in the field of gallstone disease and biliary lipids. During the design and implementation of the protocol, many important issues required consideration and resolution. The aim of this article is to review these issues and the deliberations surrounding their resolution and provide personal conclusions and recommendations that may be helpful to other investigators involved in cooperative, controlled trials.

Chenodeoxycholic Acid↗
PubMed1984

Low-dose chenodiol to prevent gallstone recurrence after dissolution therapy.

Chenodiol is a safe and effective agent for the medical dissolution of gallstones in selected patients; however, after dissolution and cessation of treatment, gallstones recur. This study was done to determine the recurrence rate after successful medical treatment and cessation of chenodiol therapy; compare the efficacy and safety of low-dose chenodiol, as compared to placebo, for prophylaxis against recurrence; and identify factors predictive of recurrence. In a randomized, double-blind fashion, 53 patients with gallstone dissolution received either chenodiol, 375 mg/d, or placebo, for at least 2 years. Standardized oral cholecystograms were done at 6 months, 1 year, and then yearly thereafter. Routine laboratory testing was done every 6 months. The cumulative rate of recurrence (life-table) was 27% in patients followed for up to 3.5 years. Chenodiol, 375 mg/d, was ineffective in preventing the recurrence of gallstones. No demographic, clinical, roentgenographic, or biochemical characteristics were predictive of recurrence.

Aged↗
PubMed1984

Additional chenodiol therapy after partial dissolution of gallstones with two years of treatment.

During the National Cooperative Gallstone Study, therapy with chenodiol, 750 or 375 mg/d, for 2 years resulted in confirmed, complete gallstone dissolution in 14% and 5% of patients, respectively, and partial dissolution (greater than 50%) in 27% and 18%. The present study was done to determine the frequency with which complete dissolution occurs in patients having partial dissolution of gallstones who receive additional therapy. Eighty-six of one hundred thirty-eight eligible patients continued to receive 750 mg/d (61 patients) or 375 mg/d (25 patients) of chenodiol for 1 year. Patients whose oral cholecystogram at the end of the year showed further (greater than 50%) dissolution continued to receive chenodiol, (28 patients at 750 mg/d and 11 patients at 375 mg/d) for a second year (total duration of therapy, 4 years). A final oral cholecystogram was taken at the end of the fourth year. Complete dissolution occurred in 23% and 16% of patients receiving chenodiol, 750 or 375 mg/d, respectively, for an additional 1 or 2 years.

Chenodeoxycholic Acid↗
PubMed1984

Cyclic nucleotides and glycoproteins during formation of cholesterol gallstones in prairie dogs.

Male prairie dogs received in standard diets either 0.08% cholesterol (control, n = 30) or 1.2% cholesterol (lithogenic, n = 31). Animals were killed at days 2-4, 7, 10, 21, and 39 to determine the temporal sequence of changes in mucosal cyclic adenosine 3':5'-monophosphate in the gallbladder and of cholesterol saturation, glycoproteins, cholesterol crystals, and gallstones in bile of prairie dogs fed a cholesterol-rich lithogenic diet. Glycoprotein concentration in bile in the lithogenic group was significantly elevated compared to controls on all days of death. Saturation of bile and formation of cholesterol crystals occurred only in the lithogenic group, detected first after 7 days of feeding. Gallstones were found in the lithogenic group only. Elevation of cyclic adenosine 3':5'-monophosphate in the mucosa of gallbladders was found in the lithogenic group only, beginning at day 10. In summary, increased glycoproteins in bile preceded cholesterol saturation and crystallization which, in turn, preceded increased mucosal cyclic adenosine 3':5'-monophosphate.

Animals↗
PubMed1984

Intermittency of cholesterol crystals in duodenal bile from gallstone patients.

The detection of cholesterol crystals in duodenal bile is of clinical value in the diagnosis of cholesterol gallstone disease; however, not all patients with cholesterol gallstones have crystals detected in their duodenal bile, thus limiting the value of examination of duodenal bile. The aims of this study were to (i) determine whether the lack of crystals in some patients with cholesterol gallstones was due to (a) the intermittent presence of crystals, (b) spontaneous crystal dissolution, or (c) changes in dietary cholesterol intake; (ii) determine whether incubation of duodenal bile for 24 h would result in crystal formation. Sixteen patients with radiolucent gallstones each underwent three duodenal biliary drainages. Thirty-one percent of patients had crystals in all three bile specimens, 12% in two specimens, 25% in one specimen, and 32% in no specimen. One of 31 specimens with small numbers of crystals initially had no crystals at 24 h, and five specimens initially devoid of crystals developed crystals by 24 h. Despite a significant increase in biliary cholesterol saturation index with increasing cholesterol intake, the prevalence of crystals in bile did not increase in gallstone patients. No crystals were identified in 18 specimens from normal subjects examined initially or in the 15 specimens that were examined after 24 h. We conclude that the intermittent presence of cholesterol crystals in duodenal bile is probably not due to dissolution of crystals or varying dietary cholesterol intake and that the frequency with which crystals are found increases with incubation. Determination of the diagnostic value of multiple duodenal biliary drainages or incubation of bile in patients with normal oral cholecystograms or gallbladder ultrasonograms, however, will require examinations of large numbers of patients.

Bile↗
PubMed1982

Enrichment of bile with tauroursodeoxycholic acid and biliary cholesterol saturation in hamsters.

Three groups of golden Syrian hamsters were fed equimolar amounts of taurine-conjugated ursodeoxycholic acid (TUDCA) or unconjugated ursodeoxycholic acid (UDCA) with or without excess taurine for 2 wk. They also received a lithogenic diet composed of standard rodent chow containing ethynylestradiol and increased cholesterol. Bile was obtained from the gallbladder after ketamine anesthesia and analyzed for biliary lipids. The percentage of biliary UDCA was higher with TUDCA (38.5 +/- 3.7) than with UDCA plus taurine (26.5 +/- 2.0, P less than 0.01). The glycine-to-taurine ratio of biliary UDCA conjugates was lower with TUDCA (0.9 +/- 0.1) than with UDCA plus taurine (2.1 +/- 0.2, P less than 0.01) and was highest with UDCA without taurine (4.1 +/- 0.1, P less than 0.01). Biliary cholesterol (molar percentage) and the cholesterol saturation indices with or without correction for UDCA-rich bile were significantly lower with TUDCA than with unconjugated UDCA with or without added taurine. In conclusion, administration for 2 wk of TUDCA, compared with an equimolar amount of unconjugated UDCA plus taurine, produced in the bile of hamsters a higher percentage of UDCA, a lower glycine-to-taurine ratio of UDCA conjugates, and a lower saturation index before and after adjustment for UDCA-rich bile.

Animals↗
PubMed1982

Pretreatment biliary lipid composition in white patients with radiolucent gallstones in the National Cooperative Gallstone Study.

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Adult↗
PubMed1981

Sulfation of lithocholate as a possible modifier of chenodeoxycholic acid-induced elevations of serum transaminase in patients with gallstones.

Chenodeoxycholic acid (CDC), through its metabolite, lithocholic acid (LC), is hepatotoxic in certain species. The cause of elevations of serum transaminase in 25% of humans ingesting CDC, however, is unknown, but also may be due to LC. Because efficient hepatic sulfation of LC may protect against hepatic injury, the aim of this study was to determine if sulfation of LC might modify CDC-induced elevations of transaminase. Pretreatment sulfation fraction (SF) was estimated in 63 randomly selected patients with gallstones in a double-blind randomized trial of CDC, 750 mg/d, 375 mg/d, or placebo; in 27 of these, SF was repeated at 1 or 2 yr. In four other patients, the SF was measured at 2 yr only. Serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were determined monthly for 3 mo and then every 3 or 4 mo; an elevation of transaminase was defined as > 150% of the normal upper limit in asymptomatic patients. 10 muCi of (3)H-glyco-LC (sp act 84 mCi/mol) was ingested 10-12 h before fasting duodenal biliary drainage. Bile acids in bile were separated by thin-layer chromatography. The SF was estimated as a percentage of total radioactivity (scintillation counting) in sulfated glyco-LC. The standard deviation for replicate SF determinations (n = 311) was 2.1% The pretreatment SF (mean 60.7+/-1.7 SEM) correlated inversely with age (r = 0.336, P < 0.005) and directly with the obesity index (r = 0.495, P > 0.001), but was independent of sex. The SF, remeasured at 1 or 2 yr, did not change significantly with time or CDC. Among CDC-treated patients, elevations of transaminase occurred in 75% of patients with a SF < 45% vs. 11% with a SF > 45% (P < 0.001). In conclusion, a SF < 45% occurred in patients with gallstones who had a high probability of developing elevated serum transaminase when treated with CDC. Thus, sulfation of lithocholate may modify CDC-induced elevations of serum transaminase.

Aged↗
PubMed1981

Treatment of choledocholithiasis with oral chenodeoxycholic acid.

The aim of this study was to conduct a controlled trial of oral chenodeoxycholic acid in the management of radiolucent choledocholithiasis. Thirteen patients were randomized in double-blind fashion to receive either 750 mg/day of chenodeoxycholic acid (CDCA) or a placebo. After 4 months, those who had the placebo were administered CDCA; those who had received CDCA and showed a 25% or more decrease in the size of stones (evaluated blindly) received CDCA for an additional 4 months. Five of the 13 patients did not complete the study; four (one initially placebo and three CDCA) because acute biliary symptoms mandated operative intervention and one (initially placebo, then CDCA) because of asymptomatic elevations of the serum transaminase levels. Patients who were withdrawn from the study had significantly larger stones (P less than 0.02) (mean largest diameter, 11.4 mm +/- 1.6 SEM) than those who completed the study (6.5 +/- 0.5). Of the eight patients who completed the study, two of the three who received CDCA initially for 6 to 8 months experienced complete disappearance of stones; all five patients who took the placebo failed to show dissolution, and one of these subsequently had dissolution of stones after 8 months of CDCA. Biliary lipid analyses during treatment showed bile unsaturated with respect to cholesterol in the three patients whose stones dissolved with CDCA therapy. In conclusion, a patient with partial dissolution of stones and unsaturated bile after 4 months of CDCA probably will have complete dissolution of stones after 6 to 8 months of CDCA.

Administration, Oral↗
PubMed1980

Reflux gastritis syndrome: mechanism of symptoms.

Despite numerous observations indicating the deleterious effect of refluxed intestinal contents upon the stomach, the mechanism of injury and symptoms in the reflux gastritis syndrome is unclear. Much speculation has centered around the role of bile acids in the production of symptoms and histologic damage. Accordingly, the aims of our study were (a) to determine whether administration of autologous intestinal contents into the stomach can produce the symptoms of the reflux gastritis syndrome, (b) to measure and conpare the concentrations of bile acids in upper intestinal contents of postsurgical patients with and without the syndrome, and (c) to determine whether artificial bile acid solutions can reproduce the symptoms reported by the patients. Eleven patients with reflux gastritis syndrome and 10 asymptomatic postgastric surgery patients were evaluated. Autologous intestinal contents obtained after cholecystokinin injection and normal saline were infused in a random, double-blind fashion into the stomach of the patients. Determinations for total and individual bile acids, as well as the bile acid conjugated/unconjugated and glycine/taurine ratios were made on aliquots of upper intestinal contents of symptomatic and asymptomatic patients. Finally, saline and two artificial bile acid solutions with bile acid compositions similar to those of upper intestinal contents from symptomatic and asymptomatic patients were infused in random, double-blind fashion into the stomach of 8 patients from each group. Positive symptom responses to autologous intestinal contents were found in 10 of 11 symptomatic patients and only 2 of 10 asymptomatic patients (P < 0.01), both of whom showed positive responses to both autologous intestinal contents and saline. No symptomatic patients had a positive response to saline. Symptomatic patients had bile acid concentrations significantly greater (P < 0.001) than asymptomatic patients. A positive response to artificial bile acid solution infusion was found in only 1 symptomatic patient. It is concluded that (a) symptoms of the reflux gastritis syndrome are reproduced by gastric infusion of upper intestinal contents and (b) bile acids alone are not responsible for the production of symptoms.

Adult↗
PubMed1980

Biliary lipid synthesis and secretion in gallstone patients before and during treatment with chenodeoxycholic acid.

The interrelationships between biliary lipid secretion and the hepatic activities of the rate-limiting enzymes for bile acid and cholesterol synthesis have not been investigated in patients with gallstones before and during desaturation therapy. Liver biopsies for enzyme assays and biliary lipid secretion measurements were performed in 12 patients with gallstones before chenodeoxycholic acid therapy and in nine of these patients at 9 months of therapy. Six nongallstone control patients underwent only the lipid secretion measurements. In the patients with gallstones before treatment, all of whom had saturated bile, increased cholesterol secretion correlated directly with increased HMGCoAR activity, whereas bile acid and phospholipid secretion rates were significantly lower than in controls. During desaturation in response to chenodeoxycholic acid, biliary cholesterol and phospholipid secretion rates decreased significantly, and bile acid secretion was unchanged. Concomitantly, both HMGCoAR and cholesterol 7alpha-hydroxylase activities decreased significantly, but the correlation between HMGCoAR and cholesterol secretion was lost. Furthermore, no correlation was found between cholesterol 7alpha-hydroxylase activity and bile acid secretion during therapy. Enzyme assays were performed on single liver samples obtained at the same time of day but 48 hr before the lipid secretion measurements. That correlations between data obtained under these conditions are valid remains to be proved. In conclusion, the mechanism of biliary cholesterol saturation in patients with gallstones probably is related primarily to increased hepatic cholesterol synthesis, whereas desaturation during chenodeoxycholic acid therapy involves altered relationships among hepatic enzyme activities and biliary lipid secretions.

Bile Acids and Salts↗
PubMed1979

Gallstone dissolution--a progress report.

Cholesterol gallstone formation occurs in three stages. First, the bile must be saturated with cholesterol, thereby allowing cholesterol crystals to form. Then, nucleation and growth of the gallstone can occur, although little is known about these latter two stages. Therapy for dissolution of gallstones is directed at desaturating the bile. Chenodeoxycholic acid (CDCA), the most extensively tested agent, is successful in dissolving 60 per cent of radiolucent gallstones; however, long-term safety remains to be demonstrated. Ursodeoxycholic acid (UDCA), the 7 beta epimer of CDCA, is a promising agent for cholesterol gallstone dissolution, but it, other potential agents, and dietary manipulations require more extensive study. An important problem, the prevention of recurrence of gallstones after dissolution, also needs resolution. Medical dissolution probably will be applicable as an alternative to cholecystectomy for most patients with radiolucent gallstones, but the specific relative indications remain to be determined. A variety of modalities, both medical and surgical, are being used for the treatment of retained or reformed bile duct stones. These include T-tube infusions, oral CDCA, and extraction either through the T-tube tract or after endoscopic papillotomy. Further studies, including controlled trials, are necessary to determine the relative indications for these methods.

Animals↗