Hydration and nutrition at the end of life: a systematic review of emotional impact, perceptions, and decision-making among patients, family, and health care staff.

BACKGROUND: Decrease in oral intake, weight loss, and muscular weakness in the last phases of a terminal illness, particularly in the context of the cachexia-anorexia syndrome, can be an important source of anxiety for the triad of patient, family, and health staff. METHODS: The present literature review examines the emotional impact of reduced oral intake as well as perceptions and attitudes toward assisted nutrition and hydration for terminally ill patients(1) at the end of life, among patients, family, and health care staff. We have identified the ways in which emotional and cultural factors influence decision-making about assisted nutrition and hydration. RESULTS: Lack of information and misperceptions of medically assisted nutrition and hydration can play a predominant role in the decision to begin or suspend nutritional or hydration support. CONCLUSIONS: Our literature review reveals that these social, emotional, and clinical misperception elements should be considered in the decision-making processes to help the triad develop functional forms of care at this final stage of life. Copyright © 2011 John Wiley & Sons, Ltd.

The mechanisms of and the interrelationship between bile acid and chylomicron-mediated regulation of hepatic cholesterol synthesis in the liver of the rat.

Hepatic cholesterol synthesis is controlled by both the size of the bile acid pool in the enterohepatic circulation and by the amount of cholesterol reaching the liver carried in chylomicron remnants. These studies were undertaken to examine how these two control mechanisms are interrelated. When the size of the pool was systematically varied, the logarithm of the rate of hepatic cholesterol synthesis varied in an inverse linear fashion with the size of the taurocholate pool between the limits of 0 and 60 mg of bile acid per 100 g of body weight. The slope of this relationship gave the fractional inhibition of cholesterol synthesis associated with expansion of the taurocholate pool and was critically dependent upon the amount of cholesterol available for absorption from the gastrointestinal tract. Furthermore, the degree of inhibition of cholesterol synthesis in the liver seen with taurocholate feeding was reduced by partially blocking cholesterol absorption with beta-sitosterol even though the bile acid pool was still markedly expanded. In rats with diversion of the intestinal lymph from the blood, a five-fold expansion of the taurocholate pool resulted in only slight suppression of the rate of hepatic cholesterol synthesis, and even this inhibition was shown to be attributable to small amounts of cholesterol absorbed through collateral lymphatic vessels and (or) to a fasting effect. Similarly, the infusion of either taurocholate or a combination of taurocholate and taurochenate into rats with no biliary or dietary cholesterol available for absorption caused no suppression of hepatic cholesterol synthesis. Finally, the effect of changes in the rate of bile acid snythesis on hepatic cholesterol synthesis was examined. The fractional inhibition of cholesterol synthesis found after administration of an amount of cholesterol sufficient to raise the hepatic cholesterol ester content by 1 mg/g equalled only --0.36 when bile acid snythesis was increased by biliary diversion but was --0.92 when bile acid synthesis was suppressed by bile acid feeding. It is concluded that (a) bile acids are not direct effectors of the rate of hepatic cholesterol synthesis, (b) most of the inhibitory activity seen with bile acid feeding is mediated through increased cholesterol absorption, and (c) bile acids do have an intrahepatic effect in that they regulate hepatic cholesterol synthesis indirectly by altering the flow of cellular cholesterol to bile acids.

Regulation of biliary cholesterol secretion. Functional relationship between the canalicular and sinusoidal cholesterol secretory pathways in the rat.

The functional interrelationship between biliary cholesterol secretion, sinusoidal lipoprotein cholesterol secretion and bile salt synthesis was studied in the rat. Diosgenin, fructose, and colestipol in the diet were used to, respectively, influence biliary cholesterol output, VLDL production and bile salt synthesis. In the acute bile fistula rat, biliary cholesterol output was 700% increased by diosgenin and 50% decreased by fructose. In the rats fed both diosgenin and fructose, biliary cholesterol secretion was increased only by approximately 200%, whereas biliary bile salts and phospholipid outputs were unchanged. In the isolated perfused liver, VLDL-cholesterol output was 50% reduced by diosgenin alone, but was unchanged following feeding of diosgenin plus fructose. However, the livers of rats fed diosgenin plus fructose exhibited a 700% increase in VLDL-triglyceride production and a 200% increase in VLDL-cholesterol output. A significant reciprocal relationship between VLDL-cholesterol secretion and the coupling ratio of cholesterol to bile salts in bile was observed. Colestipol added to the diet maintained both sinusoidal and biliary cholesterol outputs within the normal range. In the chronic bile fistula rat, colestipol increased bile salt synthesis by 100% while diosgenin and fructose diets had no effect. Similarly, the addition of fructose to the colestipol diet did not decrease bile salt synthesis. These data suggest a reciprocal relationship between biliary cholesterol secretion and hepatic secretion of cholesterol as VLDL particles. The free cholesterol pool used for bile salt synthesis seems functionally unrelated to the pool from which VLDL-cholesterol and biliary cholesterol originate. These findings support the idea that metabolic compartmentalization of hepatic cholesterol is a major determinant of the quantity of cholesterol available for recruitment by the bile salt-dependent biliary cholesterol secretory mechanism.

Regulation of biliary cholesterol secretion in the rat. Role of hepatic cholesterol esterification.

Although the significance of the enterohepatic circulation of bile salts in the solubilization and biliary excretion of cholesterol is well established, little is known about the intrahepatic determinants of biliary cholesterol output. Studies were undertaken to elucidate some of these determinants in the rat. Feeding 1% diosgenin for 1 wk increased biliary cholesterol output and saturation by 400%. Bile flow, biliary bile salt, phospholipid and protein outputs remained in the normal range. When ethynyl estradiol (EE) was injected into these animals, biliary cholesterol output decreased to almost normal levels under circumstances of minor changes in the rates of biliary bile salt and phospholipid outputs. Similarly, when chylomicron cholesterol was intravenously injected into diosgenin-fed animals, biliary cholesterol output significantly decreased as a function of the dose of chylomicron cholesterol administered. Relative rates of hepatic cholesterol synthesis and esterification were measured in isolated hepatocytes. Although hepatic cholesterogenesis increased 300% in diosgenin-fed animals, the contribution of newly synthesized cholesterol to total biliary cholesterol output was only 19 +/- 9%, compared with 12 +/- 6% in control and 15 +/- 5% in diosgenin-fed and EE-injected rats. The rate of oleate incorporation into hepatocytic cholesterol esters was 30% inhibited in diosgenin-fed rats. When EE was injected into these animals, the rate of cholesterol esterification increased to almost 300%. To investigate further the interrelationship between hepatic cholesterol esterification and biliary cholesterol output, we studied 21 diosgenin-fed rats. Six of them received in addition EE and 10 received chylomicron cholesterol. The relationships between biliary cholesterol output as a function of both microsomal acyl-CoA:cholesterol acyltransferase (ACAT) activity and hepatic cholesterol ester concentration were significantly correlated in a reciprocal manner. From these results it is concluded that the size of the biliary cholesterol precursor pool can be rapidly modified through changes in the activity of the hepatic ACAT.

Mechanism and kinetic characteristics of the uncoupling by plant steroids of biliary cholesterol from bile salt output.

In male Wistar rats fed diets containing different plant steroids, including sitosterols, diosgenin, digitonin and saponin from gypsophila, biliary cholesterol secretion significantly increased 50% to 300%, whereas biliary bile salt and phospholipid showed minor changes. Both cholesterol and phospholipid outputs were coupled to biliary bile salt output in a curvi-linear relationship which could be fitted by rectangular hyperbolae, in the animals fed with different plant steroids. The theoretical maximal biliary cholesterol output significantly increased by 200% in sitosterol-fed rats and 500% in diosgenin-fed animals. No changes were found in the kinetic characteristics of biliary phospholipid outputs. Adding 2% cholesterol to the diosgenin diet abolished the increment of biliary cholesterol output induced by the plant steroid. The intraperitoneal injection of 45 mumol/kg body wt per day (3 days) diosgenin, a C27-sapogenin, and 65 mumol/kg body wt. per day (3 days) tomatidin, a C27-alkaloid, incorporated in phosphatidylcholine-taurocholate liposomes significantly increased biliary cholesterol output by 70%. These experiments indicated that the plant steroid-induced biliary cholesterol output was independent of the inputs of cholesterol from the diet and from hepatic cholesterogenesis modified by the plant steroid. It was apparent that the profound changes of biliary cholesterol secretion were the consequence of direct effects of the steroids on the intrahepatocytic regulatory mechanisms of biliary cholesterol secretion. This novel effect appears to be a universal characteristic of plant steroids, since it can be elicited by sitosterols, C27-sapogenins, C27-alkaloids, and saponins of the cholanic and beta-amirinic group.

Bile acid pool changes and regulation of cholate synthesis in experimental diabetes.

The effect of alloxan-diabetes and insulin treatment in bile acid pool size and composition, bile acid secretion and cholic acid synthesis was investigated in the rat. The size of the cholate pool was significantly increased 4 days after diabetes induction. It reached a constant size three times that of control animals after 2 weeks of diabetes. Changes in bile acid pool size and secretion were directly dependent of the insulin deficiency state since they were reversed by insulin treatment and were not influenced by the caloric intake of the animal nor the pharmacologic effect of alloxan. Biliary cholate secretion was also 3-fold increased in diabetic rats and it accounted for more than 80% of the total bile acids compared to 60% in the control group. The calculated daily rate of cholate synthesis was increased in diabetic rats and the circadian rhythm of cholate synthesis was abolished in this condition. Therefore, it was shown that the negative feedback mechanism that regulates bile acid snythesis was deleted in diabetes. This mechanism was partially restored after 2 weeks of insulin treatment. These studies demonstrated that bile acid metabolism was profoundly changed in alloxan-diabetic rats and suggested that insulin may play an important role in the regulation of bile acid snythesis and intestinal absorption.

Rate constants for the uptake of cholesterol from various intestinal and serum lipoprotein fractions by the liver of the rat in vivo.

The increase in the mass of cholesterol esters in the liver was used to estimate hepatic net uptake rates of cholesterol from various serum and intestinal lipoprotein fractions. Initial uptake rates equalled essentially zero for high density serum lipoproteins and for large chylomicrons while administration of both low density serum lipoproteins and smaller chylomicrons produced a significant increase in hepatic cholesterol ester levels. The rate of uptake of both serum lipoprotein fractions did not change over a 5 h interval after injection: in contrast, the rates of uptake of the intestinal fractions increased 10-25-fold during this interval. Circulation of large chylomicrons in functionally eviscerated rats markedly increased the rate of hepatic cholesterol uptake when these metabolized lipoproteins were reinjected into recipient animals. Uptake of cholesterol from intestinal lipoproteins was essentially a linear function of the amount of chylomicrons administered to the animals and was independent of the level of circulating serum cholesterol and the rate of hepatic cholesterogenesis. These observations are consistent with the view that the liver is capable of taking up cholesterol from chylomicron remnants and, at significantly lower rate, low density serum lipoproteins.

Reversal of progesterone-induced biliary cholesterol output by dietary cholesterol and ethynylestradiol.

The significant increment of biliary cholesterol output induced by the subcutaneous injection of 40 mg/kg body wt. of progesterone to male rats was reversed either by feeding a 1% cholesterol diet or by injecting three daily doses of 2 mg/kg ethynylestradiol. These last two experimental manipulations significantly decreased biliary cholesterol saturation from 44 +/- 4% (progesterone) to 30 +/- 3% (progesterone +1% cholesterol diet) and 23 +/- 0.5% (progesterone + ethynylestradiol) under circumstances of minor changes in the rates of biliary bile salt and phospholipids outputs. The rate of the microsomal acyl-CoA:cholesterol acyltransferase and the concentration of microsomal cholesterol esters significantly increased more than 100% in both cholesterol-fed and estradiol-injected rats. The rate of biliary cholesterol output was reciprocally correlated with both microsomal cholesterol ester concentration of livers (r = -0.47, P less than 0.01) and the activity of the hepatic acyl-CoA:cholesterol acyltransferase (r = -0.58, P less than 0.005) in a series of rats injected with progesterone, with progesterone +1% cholesterol diet and with progesterone + estradiol. No correlation was found between the rate of biliary cholesterol output and the concentration of microsomal free cholesterol. These experiments demonstrate the existence of a close and reciprocal relationship between the rate of biliary cholesterol output and the rate at which the liver esterifies cholesterol.

Isolation and partial characterization of cholesterol pronucleating hydrophobic glycoproteins associated to native biliary vesicles.

Cholesterol is transported both in unilamellar phosphatidylcholine vesicles and in bile salts-mixed micelles in native bile. The vesicular carrier of biliary lipids apparently has a well defined protein profile with a potent cholesterol crystallization-promoting activity. This study was conducted to identify and further characterize these vesicular proteins and to test the effect of isolated vesicular proteins on the cholesterol crystal formation in supersaturated model bile. The results confirmed that proteins are a constant component of highly purified biliary vesicles both in hepatic and gallbladder bile. Immunoglobulins (IgA, IgG and IgM) and albumin are associated to the purified hepatic biliary vesicles. Furthermore, four different hydrophobic glycoproteins with a molecular mass of 130, 114, 86, and 62-67 kDa were isolated. These glycoproteins showed no reactivity with anti-human whole serum or anti-immunoglobulin antibodies, suggesting that these proteins are biliary-specific. Isolated 130, 114 and 62-67 kDa vesicular glycoproteins significantly decreased the cholesterol nucleation time in artificial model bile. We concluded that some, but not all, vesicular-bound hydrophobic glycoproteins have cholesterol pronucleating activity and they may be involved in the pathogenesis of cholesterol gallstone disease.

Cholesterol crystallization-promoting activity of aminopeptidase-N isolated from the vesicular carrier of biliary lipids.

Different hydrophobic glycoproteins are associated to native biliary vesicles, which are the major carrier of biliary cholesterol. Some of these proteins promote cholesterol crystallization, a key step in cholesterol gallstone formation. This study was specifically conducted to identify the 130 kDa biliary vesicle-associated glycoprotein and to determine its in vitro effect on the cholesterol crystal formation time. The 130 kDa vesicular glycoprotein was identified as aminopeptidase-N by amino acid sequencing and specific enzymatic assay. Polyclonal antibodies raised against aminopeptidase-N allowed us to determine its concentration in human hepatic bile, which varied from 17.3 to 57.6 micrograms/ml. Aminopeptidase-N showed a concentration-dependent cholesterol crystallization activity when it was added to supersaturated model bile at a concentration range usually found in native bile. Because of this promoting effect on in vitro cholesterol crystal formation, we suggest that biliary aminopeptidase-N may play a critical role in the pathogenesis of cholesterol gallstone disease.

Mutagenic activity in stones from a patient with a congenital choledochal cyst.

A 12-year-old boy presenting a congenital choledochal cyst complicated with stones and chronic recurrent cholangitis was subjected to surgery for cyst resection with a Roux-Y hepatojejunostomy. Potential carcinogenic factors were looked for in the cyststones using the Salmonella typhimurium plate test of Ames. High mutagenic activity was found in the stone extract incubated with the TA 98 tester strain, but not with the TA 100 strain. The test was negative with stone extracts obtained from seven patients operated on for chronic gallbladder disease. This study demonstrates the presence of a mutagenic chemical in the biliary tree of a patient with a clinical condition commonly associated with biliary tract cancer.

Apolipoprotein E polymorphism in patients with acute pancreatitis.

We have shown that patients with previous acute pancreatitis (AP) may have an abnormal catabolism of chylomicron remnants (CMR). Because apoprotein E (Apo E) genetic polymorphism has an important influence on CMR clearance, we compared frequency distribution of Apo E phenotypes in 52 patients with AP, 109 patients with gallstones, and 110 control subjects. Apo E phenotypes were detected by isoelectric focusing and immunoblotting. After adjusting for differences in age and gender, fasting triglyceride level was comparable between the study groups. The frequency distribution of Apo E phenotypes was not different between the three study groups and it was in Hardy-Weinberg equilibrium. The gene frequency for Apo E2 was 0.212, 0.273, and 0.243 in AP, gallstone, and control group, respectively. For Apo E3 it was 0.701, 0.627, and 0.674, and for Apo E4 0.090, 0.100, and 0.083 in the same groups, respectively. Differences were not statistically significant (chi 2). In conclusion, the abnormal catabolism of CMR in patients with AP is not attributable to Apo E polymorphism. An alternative explanation may be sought in the activity of the recently identified hepatocytic Apo E receptor [LDL-related receptor protein (LRP)].

Uptake of dodecanedioic acid by isolated rat liver.

The uptake of dodecanedioic acid (C12); a dicarboxylic acid with 12 carbon atoms, was studied in the isolated perfused rat liver. Fifty mumol of C12 were injected as a bolus into the perfusing liver solution. The concentration of C12 in perfusate samples taken over 2 h from the beginning of the experiments were analyzed by high performance liquid chromatography. An in vitro experimental session was performed to determine the binding curve of C12 to defatted bovine serum albumin. These data were then used to compute the perfusate C12 free fraction. The number of binding sites on the albumin molecule was equal to 4.29 +/- 0.21 (S.E.), while the affinity constant was 6.33 +/- 0.87 x 10(3). M-1. Experimental values of perfusate C12 concentration versus time were individually plotted and fitted to a monoexponential decay for each liver perfused. The predicted C12 concentration at time zero averaged 0.354 +/- 0.0375 mumol/ml. Prom this value the apparent volume of distribution of C12 was obtained and corresponded to 153.02 +/- 14.56 ml. The disappearance rate constant from the perfusate was 0.0278 +/- 0.0030 min-1. The C12 half life was 26.6 +/- 2.3 min. The mean hepatic clearance from the perfusate was 4.08 +/- 0.38 ml/min. In conclusion, C12 is quickly taken up by the liver so that in about 100 min it was completely cleared from the perfusate.

Mutagenic substances in red and white wine in Chile, a high risk area for gastric cancer.

Chilean home-made and commercial wines were analyzed for the presence of mutagenic substances using the Salmonella mutagenicity test with preincubation. Strains TA98 and TA100 were used in the absence and in the presence of S9 mix. 90% of red wines from a total of 30 samples and 54% of white wines from a total of 22 were found to be mutagenic. In all cases, S9 mix did not affect the mutagenicity of the samples. At least in one case, more than one mutagen was present, since the mutagenicity with TA98 could be selectively inactivated without affecting that with TA100. This study supports the hypothesis that wine consumption may be an important risk factor for upper gastrointestinal cancer, particularly for adenocarcinoma of the stomach, which is highly prevalent in Chile.

Discovery of the hepatic canalicular and intestinal cholesterol transporters. New targets for treatment of hypercholesterolemia.

Arteriosclerosis and cholesterol cholelithiasis are characterized by abnormal regulation of cholesterol trafficking and solubilization, and subsequent development of the arteriosclerotic plaque in the artery walls and gallstone formation in the gallbladder, respectively. Cholesterol metabolism is controlled by many complex polygenetic - environmental interactions that contribute to the regulation of serum lipoprotein cholesterol levels and biliary cholesterol and bile acids secretion, which constitute the only pathway for sterol elimination from the organism. Much of our understanding of cholesterol metabolism has arisen from studies of the pathways controlling cholesterol synthesis and the uptake and degradation of LDL and HDL lipoproteins. Recently, two new members of the ABC transporter family (ABCG5 and ABCG8 heterodimers) have been discovered in the apical pole of the enterocyte and in the canalicular membrane of hepatocytes. Experiments in genetically engineered mice have demonstrated that ABCG5/G8 represent the physiological canalicular transporter of biliary cholesterol and the intestinal secretory mechanism of absorbed dietary plant sterols. Interestingly, mutation of ABCG5 and or ABCG8 genes in man causes sitosterolemia, a rare genetic disease characterized by massive absorption of plant sterols and premature arteriosclerosis. The potential pharmacological manipulation of biliary cholesterol secretion represents another important therapeutic target to treat hypercholesterolemia, if this manipulation is simultaneously accompanied by measures aimed to avoid gallbladder cholesterol crystallization. The best theoretical drug should decrease serum lipoprotein cholesterol levels, increase biliary cholesterol secretion and fecal elimination and favoring at the same time gallbladder emptying to prevent gallstone formation.

Risk factors and pathogenesis of cholesterol gallstones: state of the art.

The aim of this article is to present an update of selected aspects of the pathogenesis and risk factors of cholesterol gallstones, a highly prevalent Western disease. The etiology of cholesterol cholelithiasis is considered to be multifactorial, with interaction of genetic and environmental factors. Mechanisms of cholesterol lithogenesis include biliary cholesterol hypersecretion, supersaturation and crystallization, stone formation and growth, and bile stasis within the gallbladder. Each of these various steps could be under genetic control and/or be influenced through intermediate pathogenic steps linked to a variety of environmental factors.

[Cancer of the gallbladder in Chile]. / Cáncer de la vesícula biliar en Chile.

This issue of the Revista brings two articles relayed to gallbladder cancer (GC), a highly prevalent cancer among Chileans. The first papaer relates to therapy for Stage II NO GC. Authors from Universidad de la Frontera corroborate the bad results usually obatined with adjunct chemotheraphy and radiotheraphy, associated to a second operation. The second paper discusses the negative influences that the new Xth Edition of the International Classification of Diseases might have on GC control. This cancer appears now with a dramatic 100% decrease in mortality rate in the last 3 years, associated to a simultaneous increase of the digit related to biliary tract cancer of "undefined orgin", which in the great majority of cases truly corresponds to GC throughout the world. This involuntary bias could have a strong negative effect on health policy makers, because health resources will not be derived to perform more cholecystectomies needed to significantly decrease the number of gallbladders at risk. This is a major issue for the Chilean health system, since GC represents the first cause of deaths due to cancer among Chilean women.

[Dentistry and seropositivity. Therapeutic protocol]. / Odontoiatria e sieropositività. Protocollo terapeutico.

The Authors wanted to give a basis for oral hygiene in order to reduce gingival bleed in risk patients. The experimental study tested for 21 days 63 people ex addicts divided into 3 groups: 4 periodontal probings with the Ainamo e Bay method. The statistical calculus showed an improvement in the group that had been using 3 garglings a day for 7 days and afterwards 1 gargling a day for 7 days with clorexidina glucosed 8 ml in 80 ml water for 60 seconds. It is necessary to remind risk patients of the importance of removing the plaque through brushing, without having too confidence in the garlings.

Ultracentrifugal isolation of vesicular carriers of biliary cholesterol in native human and rat bile.

We have utilized ultracentrifugation of native bile-Metrizamide density gradients to isolate a vesicular transport system of biliary lipids in both man and rat. We identified vesicular structures by electron microscopy. Fresh bile specimens were obtained from bile fistula rats (unsaturated bile) and from patients 1 week after bile duct surgery (supersaturated bile). Metrizamide was dissolved in bile (33% w/v), and continuous density gradients were performed with undiluted bile (density limits = 1.020 to 1.300 gm per ml). The relative distribution of biliary cholesterol, phospholipid and bile salt was studied as a function of the density of the fractions. Approximately 50% of total rat biliary cholesterol and between 61 and 90% of human biliary cholesterol was concentrated in the lightest fractions of the gradients (density less than 1.060 gm per ml). In contrast, less than 20% of bile salts was present in fractions with densities lower than 1.060 gm per ml. The highest amounts of bile salts and phospholipids of the bile-Metrizamide density gradients were found in the density range of 1.075 to 1.100 gm per ml in both human and rat bile. More than 80% of biliary proteins was found in fractions with densities greater than 1.075 gm per ml, and only 2% was found in the cholesterol-rich fraction with density less than 1.060 gm per ml in both species. When bile salt concentration was raised in rat bile from 38 to 97 mM by adding taurocholate, the low density cholesterol-rich fraction almost disappeared. Electron microscopy of negatively stained preparations of the fractions with density less than 1.060 gm per ml showed 40 to 120 nm vesicles, which were not apparent in the other fractions. Similar vesicles were demonstrated also in fresh rat bile and within the canaliculi after acute depletion of the bile salt pool (biliary bile salt concentration of 3.45 mM; total biliary lipid concentration of 0.25 gm%). The structure of these vesicles was shown in thin sections of liver specimens. They appeared as internal cavities surrounded by a single, continuous 6-nm-thick bilayer. These studies demonstrate that a high proportion of biliary cholesterol is transported in vesicles in human supersaturated native bile and that vesicular carriers are also responsible for the transport of a significant amount of biliary cholesterol in unsaturated rat bile. The presence of vesicles in unsaturated hepatic bile strongly supports the thesis that biliary lipids may be secreted as vesicles from the hepatocyte into the canaliculi.