The effect of deoxycholate ingestion, 750 mg per day, on bile acid kinetics, biliary bile acid composition, and biliary lipid secretion was studied in 7 healthy volunteers. Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantitated by a duodenal perfusion technique during a 24-hr period which included three liquid meals and an overnight fast. Biliary bile acid composition was assessed by coupled gas chromatography-mass spectrometry. After deoxycholic acid ingestion, biliary bile acids became composed of predominantly deoxycholyl conjugates, and deoxycholic acid pools increased 4-fold. Both chenodeoxycholic and cholic acid pools decreased, and daily synthesis of each of the primary bile acids was inhibited by 50%. Total bile acid pools did not change in any consistent manner. Daily bile acid secretion increased slightly during deoxycholic acid ingestion, and recycling frequency varied reciprocally with the total bile acid pool both before and during deoxycholic acid treatment. Deoxycholic acid ingestion caused no change in either the daily secretion of cholesterol or lecithin, or the cholesterol saturation of fasting-state bile, which remained unsaturated throughout the study. SGOT levels increased to 4 times the upper limits of normal in 2 of 7 subjects, but these levels promptly returned to normal when deoxycholate feeding was stopped. Serum cholesterol levels decreased in every subject (average 15%) during deoxycholic acid administration. No evidence for a direct role of deoxycholate in the pathogenesis of cholesterol cholelithiasis was obtained in these studies.

A double blind, randomized, controlled trial has been conducted in 11 Veterans Administration hospitals during a 49-month period to compare the relative efficacies of immune serum globulin (ISG) and an albumin placebo for the prevention of post-transfusion hepatitis (PTH). A total of 2204 patients, of whom 1094 received ISG, participated in the study. The results indicate that ISG significantly reduced the incidence of icteric type non-B hepatitis only (inferred to be also type non-A hepatitis). Adverse reactions were rare, and the ISG did not significantly alter the incubation period or duration of the disease. The data suggest, however, that a similar reduction in type non-A, non-B hepatitis would have occurred had commercial blood been excluded from use. Analysis of the 241 patients who developed hepatitis indicates that type B hepatitis constituted less than 20% of the cases each year of the study. Furthermore, the efficacy of the ISG, manufactured in 1944, against apparent type non-A, non-B hepatitis suggests that this overlooked disease has existed from at least that time. Host- and transfusion-related factors that might have modified the development of PTH were examined. The use of commercial blood was observed to be the most important risk factor. It is concluded that the PTH incidence can be most effectively reduced by eliminating commercial donor blood, and continuing to screen volunteer donors for hepatitis B surface antigen (HBsAg) by sensitive procedures. Of prime importance is the need to define the agent(s) responsible for type non-A, non-B hepatitis.

The high speed supernatant fluid prepared from rat intestinal mucosa was subjected to ion-exchange chromatography on diethlaminoethyl-cellulose eluted with a linear gradient of sodium chloride (0 to 0.27 M). Assay of eluted fractions for Phe-Gly hydrolase activity revealed four distinct peaks of enzyme activity. These cytosol enzymes have been designated I, II, III, and IV in order of their elution from the column. Examination of the substrate specificity of the four enzymes by use of 20 mM peptide concentrations indicated the most discriminating substrates for the four enzymes were Leu-Gly-Gly, His-Met, Ser-Phe, and leucine amide, respectively. The mean distribution of the recovered peptide hydrolase activities against these substrates among the four enzymes I, II, III, and IV was 96.1, 1.4, 1.7, and 0.8%, respectively, for Leu-Gly-Gly; 0.6, 96.4, 2.4, and 0.6% for His-Met; 0, 0, 95.8, and 4.2% for Ser-Phe; and 20.8, 19.8, 5.6, and 53.8% for leucine amide. Ion-exchange chromatography resulted in increases in specific activity of 19-, 19-, 46-, and 3.5-fold for enzymes I, II, III, and IV, respectively. The activity of all four enzymes, but especially III and IV, were stabilized by the presence of 150 muM dithioerythritol. Activity of each of the four enzymes was decreased 79 to 100% by 1mM ethylenediaminetetraacetate, HgCl2, 1, 10-phenanthroline, or 0.5 mM p-hydroxymercuribenzoate, except that the activity of enzyme I was decreased only 15% by ethylenediaminetetraacetate. No significant activation of the partially purified enzymes occurred in the presence of 500 muM Zn++, Co++, or Mg++. The four enzymes exhibited distinct pH profiles with optima at 7.5, 7.5, 8.5, and 8.0 for enzymes I, II, III, and IV, respectively. Molecular weights of the four enzymes determined by gel filtration on Sephadex G-200 were 58,500, 74,000, 97,500, and 113,000, respectively. All four enzymes lost more than 85% of their activity after 1 hr at temperatures of 50 degrees C or higher in sodium phosphate buffer, pH 7.0. The Km values determined with the most specific substrates for each enzyme were 0.76, 0.44, 3.82, and 8.3 mM for enzymes I, II, III, and IV, respectively. Recent evidence suggests that a significant amount of some small peptides are absorbed intact and hydrolyzed by cytosol peptide hydrolases. Adequate understanding of the function and control of these intracellular enzymes requires knowledge of the characteristics and substrates specificity of individual enzymes. The study described here demonstrates the presence of at least four cytosol peptide hydrolases with distinct substrate specificities. Substrates almost exclusively hydrolyzed by each of three of the enzymes, and therefore suitable for assay of each of these enzymes in the presence of the others, have been identified.

Both as the result of liver disease and of alcoholism per se, chronic alcoholics develop infertility, sterility, gonadal atrophy, hypoandrogenization, and feminization. The hypothalamic-pituitary abnormalities associated with alcoholism include hyperprolactenemia-increased estrogen-stimulated neurophysin levels, suppressed secretion of plasma gonadotropins, and loss of gonadotropin reserve. Several of the possible mechanisms potentially responsible for the development of these endocrine abnormalities have been discussed. The rational for suspecting that alcohol might interfere with either vitamin A metabolism of alter the redox state of the testes, thus affecting germ cell proliferation and steroidogenesis, has been presented. A possible mechanism for the sexual changes observed in chronic alcoholic men has been proposed. Much work remains to be done in this area before a complete understanding of the pathogenesis of these phenomena is obtained. The omission of any consideration of the effects of alcohol on sexual function in women is an admission of gross ignorance greatly in need of rectification. The necessity for couching a description of even the natural history of the syndrome in alcoholic men in conditional terms is a reflection of the limited state of the art. Nevertheless, it behooves the gastroenterologist, who is frequently called upon to be the primary physician for alcoholic men, to keep abreast of the nongastrointestinal medical consequences of alcohol addiction so that they can be recognized early and incorporated into long range medical planning designed to care for the chronic alcoholic patient.

Extremely deficient levels of alpha-1-antitrypsin (ALPHA1AT) predispose such deficient individuals to the development of emphysema and cirrhosis. Protease inhibitor (Pi) typing has clarified that the inherited deficiency is codominant. A glycoprotein with antigenic characteristics of alpha1AT is found in the endoplasmic reticulum of the hepatocytes of individuals with PiZ phenotype. No therapy is available except liver transplantation. Although biochemical advances in defining the nature of alpha1AT deficiency are progressing, the pathogenesis of the liver disease remains an enigma.

Ultrasound is high frequency mechanical vibration. As far as is presently known, there are no harmful effects of ultrasound at the energy levels used in currently available commercial ultrasonic scanners. Ultrasonic studies are independent of organ function, are painless, and require nor special preparation. Ultrasonic scanning is useful in the diagnosis of pancreatic disease, especially in the detection of complications of pancreatitis such as pancreatic abscess or pseudocyst, and in diagnosing pancreatic carcinoma. Gallstones and dilation of the biliary tree can be detected ultrasonically even when the patient is jaundiced. Primary liver tumors and hepatic metastases can often be demonstrated. Intraabdominal abscesses are better investigated by ultrasound than by any other means currently available. Ultrasonic scanning also provides a sensitive means of detecting ascites. Ultrasonic control of needle placement has been suggested for pancreatic and liver biopsy, for aspiration of intraabdominal fluid collections, and for percutaneous transhepatic cholangiography. Ultrasonic B-mode scans provide undistorted images of cross sections through the abdomen which can be used in radiotherapy planning to localize tumor masses and to place kidney shields accurately. Organ volumes can be estimated from a set of ultrasonic B-mode scans without any assumptions being made as to the shape of the organ.

A patient with post-traumatic seizure disorder developed lymphadenopathy, exfoliative dermatitis, and hepatic failure while on diphenylhydantoin therapy and died in hepatic coma. Autopsy disclosed massive hepatic necrosis. The clinical and pathological pictures are similar to the six previously reported cases of diphenylhydantoin-induced hepatic necrosis, with the exception of the time of onset of hepatic failure, which is explained. The cause of such hepatotoxicity is unknown, although hypersensitivity is postulated. It appears that studies of liver function in patients receiving diphenylhydantion are indicated to assess the true indicence of hepatocellular injury.

A primate model is described that permits separate but simultaneous sampling of both bile and pancreatic fluid without altering the normal enterohepatic circulation. Simultaneous biliary and pancreatic dose response curves are presented to contrast the production of bile with both pancreatic flow and the secretion of pancreatic protein and bicarbonate. The data show that in the cholecystectomized animal both cholecystokinin and secretin increase bile flow at doses that produce appropriate submaximal responses from the pancreas. Both these hormones, therefore, are physiologically important in regulating flow. Further, over a wide dose range (0.2 to 2.3 U per kg) secretion has the major effect on bile flow, and pancreatic flow, and pancreatic bicarbonate secretion, whereas cholyecystokinin has the major effect on pancreatic protein secretion.

The plasma fractional disappearance rate of indocyanine green (kICG, min-1) and the absolute hepatic ICG removal rate (VICG, mg per kg per min) were determined in 26 patients with Gilbert's syndrome (GS) and 19 normal control volunteers following intravenous administration of doses of 0.5, 2.0, 3.5, and 5.0 mg per kg of dye. The diagnosis of GS was based on studies of radiobilirubin kinetics in all cases and liver biopsy in 22 cases. The patients were further classified into 3 subgroups, based on patterns of sulfobromophthalein (BSP) kinetics, as follows: GS I (15 patients) had normal BSP metabolism; GS II (5 patients) had a defect in BSP metabolism beyond the stage of initial hepatic uptake; and GS III (6 patients) had a defect in the initial hepatic uptake of BSP (Gastroenterology 63:472-481, 1972). Both kICG and VICG were significantly reduced, compared to normal controls, in the GS III group with defective BSP uptake, but did not differ significantly from normal in the GS I and GS II groups. Michaelis-Menten analysis of the data indicated that VMAX for ICG uptake in the GS III group (1.2 +/- 0.6 mg per min per kg) was significantly reduced compared to the previously established normal value of 3.6 +/- 0.6 mg per min per kg; (P less than 0.01). For the total population of 26 patients with Gilbets' syndrome, there was a highly significant correlation (r= 0.77, P less than 0.01) between kICG and lambda21BSP, the fractional hepatic uptake rate for BSP. These studies confirm previous work indicating that patients with Gilbert's syndrome constitute a heterogeneous population with regard to defects in hepatic organic anion transport, some of the defects not being attributable to glucuronyl transferese deficiency. Future studies of Gilbert's syndrome must take into account the existence of these subgroups, since they may have different underlying pathogenetic mechanisms.

A patient with long-standing Crohn's disease of the large and small intestine was found to have extensive gastric metaplasia of the ileum. Most metaplastic glands were of the pyloric type, but numerous oxyntic glands with parietal and chief cells were also seen. By immunofluorescence the chief cells contained both the group I and group II pepsinogens, while the pyloric gland cells contained only the group II pepsinogens. Gastric-containing or other endocrine cells were not detected in the metaplastic pyloric and oxyntic glands. The latter findings are consistent with the concept expressed by Pearse that the endocrine and exocrine cells of the gastrointestinal mucosa may originate from different precursor elements during embryogenesis.

Mouse gallbladder epithelial cells were studied with the electron microscope during fasting and refeeding. Morphometric data were obtained from randomly selected epithelial cells of normal starved (12, 24, and 48 hr) and refed (12 hr) mice. Deprivation of food significantly diminishes the volume density of the mucinous secretory granules by about 70% after 48 hr of fasting. Upon refeeding, this secretory granule parameter increases significantly ( 2.5 times). Stereological measurements were also performed on nuclei, mitochondria, and lysosomes, but no major morphometric changes were observed in these organelles. The findings suggest that a basal secretion of mucin granules occur in the mouse gallbladder, irrespective of the animal's nutritional state and that this discharge during starvation exceeds the formation of new granule material. The findings are discussed in relation to effects of fasting and refeeding on other secretory cell systems.

The possibility that microtubules might be involved in intestinal lipoprotein formation or secretion was studied by determining the effect of colchicine, a known microtubule inhibitor, on intestinal lipid absorption. The effect of colchicine (0.5 mg per 100 g) in the lymphatic absorption of [14C]oleic acid was studied in rats with indwelling mesenteric lymph cannulas. Colchicine-treated animals showed a marked delay as well as a decrease in the lympatic absorption of [14C]oleic acid. Chylomicrons from colchicine-treated animals showed no difference in apoprotein content when examined on sodium dodecyl sulfate polyacrylamide gels. Micellar lipid absorption was next studied from in situ jejunal loops in animals pretreated with colchicine. Colchicine administration was associated with a 3-fold increase in residual mucosal lipid when compared with controls. Thin layer chromatography of residual lipid demonstrated that residual lipid was largely present as triglyceride, suggesting that the impairment in lipid transport induced by colchicine was at a site distal to triglyceride resynthesis. Electron microscopic examination of intestine from colchicine-treated animals revealed that most residual lipid was present within the endoplasmic reticulum and Golgi in numerous particles the size of chylomicrons (0.2 to 0.4 mu). These results suggest that the impairment in lipid transport induced by colchicine is distal and, in part, may represent an "exit block". These results suggest a possible role for microtubules in intestinal lipid transport. However, further studies are required to demonstrate directly the participation of microtubules in chylomicron secretion.