Natural history of biliary stones.
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Cholelithiasis↗
Biomedical subjects
H Y Mok
Publications and source records attributed to H Y Mok.
Chronology of cholelithiasis. Dating gallstones from atmospheric radiocarbon produced by nuclear bomb explosions.
We investigated the natural history of cholelithiasis in 59 samples of stones from the gallbladder or common bile duct in 15 patients, using as a tracer for the timing of stone formation the 14C released into the environment during nuclear weapons testing. The ages of the stones were correlated with the dates of onset of symptoms and with other clinical data. None of 11 symptomatic patients had symptoms or complications until at least two years (mean +/- SD, 8.0 +/- 5.1 years) after stone formation began. There was a lag time of 11.7 +/- 4.6 years between initial stone formation and cholecystectomy. The growth rates of stones from 11 symptomatic patients and 4 asymptomatic patients were similar (2.6 +/- 1.4 and 2.6 +/- 1.1 mm per year). Studies of two stones retrieved from the common bile duct showed that one had the same age as a cholecystic stone; the other, removed two years after cholecystectomy, apparently grew in the common bile duct. The long latency period between the formation of gallstones and the onset of symptoms indicates that interruption of the natural progression of gallstone disease is potentially possible with medical therapy.
Carbon Radioisotopes↗
Ultrasonic absorption in myoglobin and other globular proteins.
The ultrasonic absorption of myoglobin has been measured by the resonance and pulse-echo techniques as a function of pH. The absorption at a given frequency can be separated into pH-dependent and pH-independent contributions. Like other proteins, two peaks at pH 3 and 11.5 are observed which can be accounted for a proton-transfer reactions of the side-groups. In addition, the absorption undergoes a large increase within a small range of 0.2 pH unit at pH around 4, when denaturation of myoglobin occurs, indicating that the absorption is sensitive to the overall protein conformation. To elucidate the origin of the pH-independent component, the absorptions of several other globular proteins at neutral pH are also measured. The absorptions of these proteins exhibit a linear correlation with their isothermal compressibilities, suggesting that the pH-independent component is related to volume fluctuations of protein molecules. The activation energy of 4 kcal/mol found for this relaxation is consistent with such an interpretation.
Chymotrypsinogen↗
Current status of medical treatment of gallstones.
Medical dissolution of gallstones is feasible and has worked in clinical practice. Cholelithiasis is both common and a cause of significant morbidity nationally. Thus, to readdress the question posed in the introduction, should there be a more aggressive detection of populations at risk to consider prophylactic or early treatment of gallstones, one has to consider the following. Is it cost effective to treat people with asymptomatic stones when one half of gallstones detected at autopsy have not caused trouble in life? Will the reduction of one health hazard create other hazards, such as colonic cancer? Is it improving the quality of the patient's life after successful treatment to have the person return every year for ultrasound or radiologic check-ups for recurrence of gallstones? We feel that despite the low morbidity and mortality of elective surgery, medical dissolution of gallstones is a viable alternative, but, as with most medical decisions, the pros and cons of any therapy for cholelithiasis will ultimately be a decision based on the physician, the patient, and the situation. On the basis of what has been discussed in this review, the approach to treatment should involve a rational understanding of all alternatives.
Bile Duct Diseases↗
Effects of rifampin on biliary lipids in humans.
Because the action of rifampin induces hepatic microsomal enzymes, a study was carried out in four patients to determine whether this drug alters the composition of biliary lipids. Several different measurements were made while patients were both on and off rifampin therapy for various infective processes. These measurements included multiple determinations of lipid composition of gallbladder bile, the relative proportions f individual bile acids, and kinetics of cholic acid and chenodeoxycholic acid. In all four patients, the saturation of gallbladder bile increased during rifampin treatment, and the bile consistently became supersaturated. The relative portions of chenodeoxycholic acid and cholic acid were essentially unchanged by treatment, but total synthesis of bile acids increased in three tested patients with rifampin therapy. These results indicate that rifampin increases saturation of bile with cholesterol, but this increase is not due to a reduction in bile acid production.
Adult↗
Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man.
The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones.
Absorption↗
Effects of cimetidine on biliary lipids in patients with reflux esophagitis.
In 14 patients with reflux esophagitis previously treated with antacids, the effects of addition of cimetidine on biliary lipids were studied. Each subject served as his own control, but no placebo medication was used. It was found that cimetidine (300 mg p.o. q.i.d.), over a 6-mo period of therapy, did not significantly alter lipid composition of fasting gallbladder bile, biliary lipid secretions, bile acid pool size, and its internal composition. In addition to detailed biliary studies, other observations were also made. Symptomatically, most of the patients responded favorably to cimetidine, and 9 of the 14 patients reported virtual elimination of bothersome symptoms while taking this medication. Concomitant with symptomatic improvement, daily antacid requirement was significantly reduced. Lower esophageal sphincter pressure was unaffected by cimetidine. No significant side effects were noted in this series of patients.
Aged↗
Cholesterol and bile acid absorption during bile acid therapy in obese subjects undergoing weight reduction.
One of the potential complications of bile acid therapy for gallstone disease is the promotion of intestinal absorption of cholesterol, thereby increasing the influx of cholesterol in body pools. To determine whether bile acid feeding is associated with an increased absorption of intestinal cholesterol, absorption measurements were made in 8 obese subjects given chenodeoxycholic acid (CCDA) or Bilron (750 mg/day). The bile acids were given in random order, separated by control periods, in patients undergoing weight reduction. Absorption of cholesterol (mass and percent) and of bile acids were determined by a technique of combined measurements of biliary lipid secretion and fecal steroid excretion. Our data showed that during treatment with either bile acid, a marked increase in pool size and hepatic secretion of bile acids occurred. However, despite an increased flux of bile acids through the intestinal tract, there was no significant increase in cholesterol absorption as compared to control periods. Absorption rates during administration of the two bile acids were approximately the same. Furthermore, plasma cholesterol concentrations were stable throughout both control and treatment periods. Bile acid absorption remained highly efficient (greater than 96%) during all periods, even with administration of exogenous bile acids.
Adult↗
Kinetics of the enterohepatic circulation during fasting: biliary lipid secretion and gallbladder storage.
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Bile Acids and Salts↗
Relapse of pseudomembranous colitis after vancomycin therapy.
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Administration, Oral↗
Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia.
Measurements of transport of triglycerides (TG) in very low density lipoproteins (VLDL) were carried out in 59 patients by injection of radioactive glycerol, determinations of specific activities of VLDL-TG for 48 h thereafter, and treatment of the data by multicompartmental analysis. The patients were divided into three groups: normal weight (89-120% ideal weight), mildly obese (120-135% ideal weight), and markedly obese (135% ideal weight). They had varying levels of VLDL-TG ranging from normal to markedly elevated. In many subjects, there was a positive correlation between concentrations and transport of VLDL indicating that overproduction of VLDL-TG contributed to hypertriglyceridemia. In others, and particularly in several markedly obese subjects, transport rates were greatly increased without significant hypertriglyceridemia, suggesting that they had enhanced capacity to clear TG. In all groups, however, there were patients whose degree of hypertriglyceridemia seemed out of proportion to their transport rates. This finding and the fact that many patients have increased secretion of VLDL-TG without elevated plasma TG suggests that both overproduction of VLDL-TG and insufficient enhancement of clearance contributed to the development of hypertriglyceridemia.The data showed a poor correlation between transport rates determined by our multicompartment analysis and single-exponential analysis used previously by other investigators (r = 0.46); this comparison was not improved by segregating patients according to their degree of obesity. Although two conversion pathways (fast and slow synthetic paths) were required to fit the data, there was no correlation between transport rates and the ratio of the two pathways. Also, despite the known pathway of conversion of VLDL to low density lipoprotein, no correlation was found between VLDL-TG transport rates and estimated low density lipoprotein-cholesterol concentrations.
Biological Transport↗
Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphalipoproteinemia and fasting chylomicronemia.
A new kindred with asymptomatic hypobetalipoproteinemia is reported. The proband, age 67, differs from previously described cases in several respects: (a) unusually low levels of low density lipoprotein (LDL) cholesterol (4-8 mg/dl); (b) normal triglyceride levels; (c) low levels of high density lipoprotein; (d) mild fat malabsorption; and (e) a defect in chylomicron clearance. On a high-carbohydrate diet his plasma triglyceride levels, instead of rising, actually fell. Turnover of triglycerides in very low density lipoproteins (VLDL) was low (2.8 mg/kg per h). Fractional catabolic rate of LDL protein was just above the normal range (0.655/d) but net turnover was <10% of normal (0.65 mg/kg per d). The half-life of his chylomicrons was 29 min, five times the normal value. Postheparin lipoprotein lipase activity was normal and apolipoprotein C-II, the activator protein for lipoprotein lipase, was present and functional. Apolipoprotein C-III(1), however, was not detected in the VLDL fraction, a finding previously reported in patients with abetalipoproteinemia. Fecal excretion of cholesterol was almost twice normal; total sterol balance was increased by congruent with40%. The unusual features in the proband that distinguish him from previously described cases and from his affected first-degree relatives suggested that, in addition to the basic gene defect affecting LDL metabolism, he might have a second abnormality affecting clearance of chylomicrons and VLDL. The ratio of apolipoprotein E(3) to E(2) in his VLDL fraction was 0.93, just below the lower limit of normal, suggesting heterozygosity for E(3) deficiency. Whether or not this contributes to his hypertriglyceridemia remains to be established.
Adult↗
Effects of continuous and intermittent feeding on biliary lipid outputs in man: application for measurements of intestinal absorption of cholesterol and bile acids.
Hepatic outputs of biliary lipids can be measured by intestinal perfusion techniques, either during constant infusion of liquid formula into the duodenum or through-out a 24-hour period during which time three meals are given along with an overnight fast. The purpose of this study was to compare these two methods for estimating secretion of biliary lipids. In 21 subjects, mean hourly outputs measured during continuous feeding were highly comparable to those during intermittent feeding, showing that the constant infusion technique gave valid estimations of overall daily secretion rates of biliary lipids. On the other hand, the intermittent mode of feeding showed phasic changes of outputs and composition of biliary lipids in response to feeding and fasting apart from total outputs over 24 hours. However, it takes longer to complete and requires the use of a meal marker. By combining the intestinal perfusion technique with measurements of fecal excretion of neutral steroids and bile acids, this method may be used to estimate absorption of cholesterol and bile acids from the intestine. Thus, these measurements allow quantification of a number of parameters of the enterohepatic circulation.
Adult↗
Bilary lipid metabolism in obesity. Effects of bile acid feeding before and during weight reduction.
Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.
Adult↗
Cholesterol and bile acid metabolism in moderately advanced, stable cirrhosis of the liver.
We have selected for this study a well-defined group of patients with moderately advanced but compensated alcoholic cirrhosis. They were well-nourished and had no ascites, varices, azotemia, or encephalopathy. Liver biopsy showed little or no necrosis and inflammation despite wide-spread fibrosis. Serum bilirubin, transaminase, alkaline phosphatase, albumin and globulins were essentially normal. Biochemical evidence for liver disease was restricted to modest elevation of BSP retention, gamma GTP, serum bile acid concentrations, and urinary bile acid excretion. Except for changes in the interrelationships among the three biliary lipids, they were generally spared the abnormalities of sterol metabolism described in other patients with more advanced, more active liver disease. Thus, striking abnormalities in the metabolism of cholesterol and bile acids probably require severe reductions in functioning hepatocellular mass, major portal-systemic shunting, high disease activity, or all three to become manifest.
Adult↗
Effects of interruption of enterohepatic circulation on biliary lipid secretion in man.
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Bile↗
Plant sterols as cholesterol-lowering agents: clinical trials in patients with hypercholesterolemia and studies of sterol balance.
We have evaluated the efficacy of plant sterol preparations from two different sources and in two different physical forms in lowering the plasma cholesterol of a total of 46 patients with type II hyperlipoproteinemia when given in addition to appropriate diet therapy. In addition, the mechanisms of the hypocholesterolemic effect were investigated in 7 patients by a sterol balance technique. The maximal mean cholesterol lowering in response to any preparation was 12 percent, although it was much greater in some individual patients. Sterol balance data showed that plant sterols inhibit cholesterol absorption with maximal negative cholesterol balance in adults at a dose of 3 g/day of a tall oil sterol suspension. Interestingly, maximal plasma cholesterol reduction in the adult outpatients on this preparation was seen at the same dose level. Since the tall oil sterol suspension is relatively palatable and is poorly absorbed, it has potential value as an adjunct to dietary therapy in patients with mild hypercholesterolemia for whom long-term drug therapy is deemed advisable.
Cholesterol↗
Colestipol, clofibrate, and phytosterols in combined therapy of hyperlipidemia.
Studies were carried out to determine effects of combined chemotherapy in patients with hyperlipidemia. In one study, 14 patients were treated first with colestipol and then with the combination of colestipol and clofibrate. In a second study, six patients were given clofibrate followed by addition of phytosterols. The following measurements were made in most patients: (1) plasma lipid concentrations, (2) fecal excretions of neutral steroids and bile acids, and (3) lipid composition of gallbladder bile. In six patients of the first study, hepatic secretion rates of biliary lipids and pool sizes of bile acids were also estimated. In the first study, colestipol alone caused a marked increase in fecal bile acids that resulted in a sizable decrease in plasma cholesterol concentrations (average 21 percent). In several patients, however, triglycerides were increased somewhat by colestipol. Despite interruption of the enterohepatic circulation of bile acids, the bile acid pool was not reduced, since a compensatory increase took place in bile acid synthesis. Also, except in one patient who developed gallstones following institution of colestipol, saturation of gallbladder bile with cholesterol was not markedly increased by this drug alone. Addition of clofibrate frequently produced a further decrement in plasma cholesterol, and the mild hypertriglyceridemia induced by colestipol was reversed. However, colestipol plus clofibrate usually caused a striking increase in saturation of gallbladder bile. Previous studies have shown that clofibrate causes a flux of cholesterol from tissue pools by simultaneously decreasing cholesterol synthesis and increasing its excretion. To further increase cholesterol excretion, phytosterols, which block cholesterol absorption, were added to clofibrate in the second study. Although phytosterols did not cause a further reduction in plasma cholesterol in these particular patients, they nevertheless greatly enhanced cholesterol excretion.
Adult↗