The monoglyceride pathway of fat absorption in man.

The absorption of fat was studied in five male subjects with cannulation of the thoracic duct in the neck by the administration of doubly labeled monoglycerides, or triglyceride as well as labeled free glycerol or labeled free oleic acid, by gastric or duodenal intubation.Total recoveries of the administered glyceride radioactivity from the lymph lipids ranged from 35 to 53% for the glycerol label (tritium) and from 35 to 57% for the fatty acid label ((14)C). The recovery of administered radioactive free glycerol in lymph lipids was only 4.1%, even when given in mixture with bile salts, fatty acid, and monoglyceride.A comparison of the isotope ratios of the two components (glycerol and fatty acid) of the lymph glycerides with the ratios of these components of the original meal glyceride showed little change during the initial period of fat absorption, indicating that the doubly labeled monoglycerides passed into the lymph intact. During the later part of the period of major fat absorption, the ratios in lymph lipids changed due to loss of glycerol representation, indicating monoglyceride hydrolysis and portal venous diversion of free glycerol. Confirmation of the intact nature of 2-monoglyceride during absorption was made by analyzing the amount and position of the labeled fatty acid in the lymph triglycerides. The percentage of labeled fatty acid in the various positions of the lymph triglycerides was virtually identical with that of the meal during the initial period of fat absorption and then changed reflecting isomerization of fatty acids and subsequent complete hydrolysis of the glycerides.The 2-monoglyceride pathway appears to be the major route of fat absorption for man during normal digestion and absorption of dietary triglyceride.

Bile salt regulation of fatty acid absorption and esterification in rat everted jejunal sacs in vitro and into thoracic duct lymph in vivo.

This study was performed to investigate whether the malabsorption of fat in the blind loop syndrome is due to the presence of free bile acids or to a deficiency of conjugated bile salts produced by bacterial degradation of normal bile salts, as well as to learn something of the mechanisms by which bile salts might regulate fat absorption. In the everted gut sac of the rat in vitro, conjugated bile salts were necessary for maximal rates of fatty acid esterification to triglycerides, whereas free bile acids inhibited this process even in the presence of physiologically normal or higher concentrations of conjugated bile salts. In contrast, in the living animal the addition of similar or higher concentrations of free bile acids to infusions of fatty acids in taurocholate micellar solutions produced no reduction in the amount of fatty acid absorbed into lymph or the amount of fatty acid esterified into lymph triglyceride. Both in vitro and in the living animal, reduction in the conjugated bile salt concentration reduced both the rate of fatty acid uptake by the intestine and the esterification into triglycerides. It is concluded that the steatorrhea of the blind loop syndrome or other conditions in which upper intestinal stasis allows bacterial proliferation is not due to presence of increased gut luminal concentrations of free bile acids, but rather is a consequence of lowered concentrations of conjugated bile salts.

Alanine aminotransferase: a clinical and regulatory tool for detecting liver injury-past, present, and future.

Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean? Not what it is too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better.

Monitoring for hepatotoxicity: what is the predictive value of liver "function" tests?

Drug-induced liver injury (DILI) is a major reason drugs fail during development or are withdrawn from the market. The ability to predict, detect, and avoid DILI through appropriate patient selection and effective monitoring has proved to be an elusive goal. Many approved drugs have labeling recommendations for serum enzyme monitoring intended to detect and prevent hepatotoxicity, but such monitoring is often seen as inconvenient, uncomfortable, costly, and inefficient by both patients and doctors, and thus monitoring recommendations are poorly followed, if at all. This review considers whether monitoring works to prevent DILI, whether monitoring recommendations are derived from data or opinions, and whether any better alternatives exist.

Emergency measurement of stat, timed, serum ethanol levels for medical management.

Because of a general impression that a substantial proportion of emergency medical problems requiring treatment or hospitalization was caused by unsuspected alcohol consumption, a study to question that impression was done on a population of urban emergency service patients. We evaluated blood samples taken from these patients for routine determinations for many reasons other than suspicion of alcohol use or abuse. Abnormalities in results of serum ethanol concentrations were found more frequently than abnormalities of concurrently determined serum electrolytes, urea nitrogen, or glucose. The frequency of abnormalities found was ethanol, 42%; carbon dioxide, 35%; glucose, 34%; chloride, 32%, sodium, 21%; potassium, 20%; and urea nitrogen, 13%. The high incidence of serum ethanol elevations in such hospital emergency service patients and the considerable potential usefulness of ethanol levels in diagnosis and management of a wide variety of medical problems suggest that determinations of stat, timed, serum ethanol concentrations are often indicated as an emergency study for urban populations.

Granulocyte function and levels of immunoglobulins and complement in patients admitted for withdrawal from alcohol.

Chronic alcoholics who had been drinking heavily until admission for withdrawal from alcohol were studied to determine their level of granulocyte function, immunoglobulin concentration, and complement system activity. Although most had some mild derangement in results of liver function tests, serum albumin concentrations were normal, and there was no clinical evidence of malnutrition or cirrhosis. Granulocyte adherence was slightly depressed in two subjects (52.4% and 54.1%; normal, 76.0% +/- 12%), although mean adherence for the group was normal. Mean chemotaxis was significantly below normal (2,103 vs. 7,943 counts per min), and the impairment was related to a defect or inhibitor in the serum of patients. Phagocytic activity was less than half that of control subjects in two alcoholics, but mean values were not depressed. Bactericidal activity was normal in all. Serum concentrations of immunoglobulins and total hemolytic complement activity were above the normal range for the group. The general inhibition of chemotaxis or the occasional defects in other granulocyte functions may contribute to the difficulty that alcoholics have with infection.

In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids.

The rate of decrease of gallstone diameter appeared to be linear with oral bile acid treatment time, as estimated by inspection of graphic data of individual patient serial oral cholecystograms. A theoretical basis for this model was derived. The hypothesis of diameter decrease proportional to treatment time was tested with data from 223 patients with radiolucent gallbladder stones up to 20 mm in diameter treated with 7-8 or 14-15 mg.kg-1.day-1 of either ursodiol or chenodiol for 1 year, followed up after 3, 6, and 12 months of treatment. Linearity of individual sets of data points was tested by mathematical and statistical methods, including polynomial curve fitting, linear regression analysis, quadratic vs. linear analyses of covariance, and prediction of 12-month stone size by linear extrapolation from diameters at 0 and 6 months. Most patients (greater than 70%) had rates of gallstone diameter decrease that were almost linear with treatment time, independently of different dissolution rates on a given regimen. Additional treatment time needed may be estimated from cholecystograms or ultrasonograms performed before treatment and after several months.

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study.

We investigated the effects of once-daily oral administration of 10 mg/kg ursodeoxycholic acid (generic name, ursodiol) on elevated serum enzyme activities, bilirubin, cholesterol, bile acids and symptoms in patients with primary sclerosing cholangitis. A 30-mo, open-label, pilot trial was designed to cover four periods: (a) 3 mo of pretreatment observation (period 1), (b) 6 mo on ursodiol (period 2), (c) 3 mo withdrawal of treatment (period 3) and (d) 18 mo of extended retreatment (period 4). Diagnosis was confirmed by cholangiography and liver biopsy specimens. We enrolled 12 patients with persistently elevated pretreatment alkaline phosphatase and gamma-glutamyltransferase levels (at least twice the upper limit of normal), and observed them for a median of 37 mo. Significant reductions in serum total cholesterol levels and in serum enzyme activities indicating cholestasis and hepatocellular injury occurred during ursodiol treatment in both treatment periods 2 and 4 and relapsed with treatment interruption in period 3. Elevated serum bilirubin and symptoms of disabling fatigue, pruritus and diarrhea were improved by ursodiol. Improvements have continued after 2 yr of treatment in 10 patients (1 patient had a transplantation after he relapsed on withdrawal of ursodiol therapy; another died of postoperative complications of colon resection for carcinoma). No other cases of clinical deterioration were observed in the retreatment period. The longer term reductions of alkaline phosphatase, transaminases, bilirubin and cholesterol after 2 yr of treatment were even greater than the initial reductions after 6 mo of treatment. These results justify initiation of larger, controlled clinical trials, with serial morphological evaluations of the liver and biliary tree.

Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs). DESIGN: 6-month randomized, double-blind, placebo-controlled trial. SETTING: 664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada. PATIENTS: 8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993. INTERVENTION: Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day. MEASUREMENTS: Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy). RESULTS: Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% CI, 0.364 to 0.982; P = 0.049]) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months. CONCLUSIONS: In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.

Effect of long-term treatment with ursodiol on clinical and biochemical features and biliary bile acid metabolism in patients with primary biliary cirrhosis.

The effect of ursodiol on the clinical and biochemical features, serum, urinary, and biliary bile acids was investigated over a 2-yr treatment period in 14 patients with primary biliary cirrhosis (stages II-IV). Pruritus and fatigue improved, and alkaline phosphatase and liver transferases declined significantly in all patients during therapy. In four patients, less inflammation was noted by liver biopsy after 2 yr, but histology of disease did not change. Serum and urinary bile acids were increased several-fold before treatment, with cholic acid predominating. Ursodiol accounted for 30% of biliary bile acids after administration (gallstone subjects approximately 50%), and was conjugated with glycine and taurine in a ratio of 7.3:1. However, in the endogenous bile acids, the ratio increased from 1.2:1 to only 2.1:1. About 6% unconjugated bile acids were secreted into the bile (healthy controls < 1%). Thus, in patients with primary biliary cirrhosis, a larger fraction of free bile acids and a higher proportion of taurine-conjugated bile acids are secreted into the bile, compared with healthy controls. Ursodiol improves symptoms and histology with lower biliary enrichment with this bile acid.