Effect of sodium benzoate on blood ammonia response to oral glutamine challenge in cirrhotic patients: a note of caution

OBJECTIVE: The administration of sodium benzoate provides an alternative pathway for the disposal of waste nitrogen and this substance has been used to treat patients with urea cycle defects and more recently cirrhotics with hepatic encephalopathy. The aim of the study was to assess the ammonia-lowering effect of benzoate in cirrhotic patients without overt hepatic encephalopathy. METHODS: Glutamine challenge, a method to induce an increase of blood ammonia, was performed in six cirrhotics before and after 5 days of benzoate treatment (10 microg/day). Number Connection Test and Posner's Attention Test were also performed before and after benzoate treatment. RESULTS: Blood ammonia increased after the glutamine load both before (from 66 +/- 12 microg/dl to 123 +/- 34 microg/dl and 179 +/- 53 microg/dl after 30 and 60 min, respectively; ANOVA p = 0.0004) and after benzoate treatment (from 102 +/- 27 microg/dl to 185 +/- 49 microg/dl and 250 +/- 39 microg/dl after 30 and 60 min, respectively; ANOVA p = 0.00001). However, after benzoate treatment, the basal values (102 +/- 27 vs 66 +/- 12 microg/dl; p = 0.01) and peak increments of ammonia (166 +/- 56 microg/dl vs 102 +/- 40 microg/dl; p = 0.04) were significantly higher than before. The Number Connection test and the Posner's test were not altered by benzoate treatment. CONCLUSIONS: Benzoate increased both the basal and post-glutamine ammonia levels. These results confirm what has already been observed in experimental animals and suggest a note of caution in the use of sodium benzoate in cirrhotic patients.     

Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients

We compared the effect of lactulose or lactitol on the fecal flora of 21 cirrhotic patients without hepatic encephalopathy. All were treated with an individualized disaccharide dose to achieve and maintain two semiliquid bowel movements per day. Stool pH and fecal flora were determined before and 10 days after stabilizing the cathartic effect. Increased counts of lactobacilli were obtained with both treatments. This increase, which was related to the decreased stool pH, was more constant with lactulose. In addition, lactitol decreased certain proteolytic bacteria such as enterococci and enterobacteria. Both total aerobic and anaerobic bacterial counts showed little quantitative variations with either treatment.     

Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy

BACKGROUND/AIMS: We assessed the usefulness of oral glutamine challenge (OGC) and minimal hepatic encephalopathy in evaluating risk of overt hepatic encephalopathy in cirrhotic patients.METHODS: Minimal hepatic encephalopathy (MHE) was inferred using neuro-psychological tests. Venous ammonia concentrations were measured pre- and post-60 min (NH(3)-60m) of a 10 g oral glutamine load. Receiver-operating-characteristic curve analysis indicated a pathological glutamine tolerance cut-off value of NH(3)-60m >128 microg/dl. RESULTS: In healthy control subjects (n=10) ammonia concentrations remained unchanged but increased significantly in cirrhotic patients (from 70.41+/-45.2 to 127.43+/-78.6; P<0.001). In multiple logistic regression analysis, altered OGC was related to Child-Pugh (odds ratio, OR=7.69; 95% confidence interval, CI=1.72-33.3; P<0.01) and MHE (OR=5.45; 95% CI=1.17-25.4; P<0.05). In the follow-up 11 patients (15%) developed overt hepatic encephalopathy (HE). In multivariate analysis OGC (OR=14.5; 95% CI=1.26-126.3) and MHE (OR=1.56; 95% CI=1.02-21.9) were independently related with HE in the follow-up. Patients with MHE and altered OGC showed significantly higher risk of overt HE in the follow-up (60%) than patients without MHE and normal OGC (2.8%) (Log rank test=21.60; P<0.0001). CONCLUSIONS: A pathological OGC in patients with MHE appears to be a prognostic factor for the development of overt hepatic encephalopathy, whereas a normal OGC in patients without MHE could exclude risk of overt HE.     

Plasma somatostatin response to an oral mixed test meal in cirrhotic patients.

Ten patients with non-alcoholic cirrhosis and ten control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Plasma somatostatin, blood glucose, plasma insulin, C-peptide and glucagon were determined before and 15, 30, 45, 60, 90, 120 and 180 min after the start of the meal. Basal somatostatin levels in patients (31.9 +/- 1.8 ng/l) were significantly higher (p less than 0.01) than in controls (12.5 +/- 0.9 ng/l). The time-course of the somatostatin secretory response after the meal was similar in the two groups, but the increase, evaluated as incremental area above baseline, was significantly smaller (p less than 0.01) in cirrhotics (804 +/- 134 ng/l per min) than in controls (1482 +/- 149 ng/l per min). Data indicate that elevated basal plasma somatostatin concentrations in cirrhosis may be consequent to elevated gastrointestinal and/or pancreatic secretion, whereas the blunted somatostatin response to the mixed test meal may derive from the hyperinsulinemia which occurs in the postprandial period.     

Effect of oral calcium on blood pressure response in salt-loaded borderline hypertensive patients

To clarify the mechanism of the antihypertensive effect of oral calcium loading, we studied the effect of low versus high calcium intake on salt-induced blood pressure elevations in patients with borderline hypertension. After a 7-day period of dietary salt restriction (50 meq/day), 27 patients were placed on a high salt (300 meq/day), low calcium (250 mg/day) diet for 7 days; 14 of these patients were given 2,160 mg/day of supplementary calcium (Ca group), and 13 patients were given placebo (non-Ca group). With a high salt intake, the percent increase in mean blood pressure was smaller in the Ca group than in the non-Ca group (+2.85 +/- 1.22% vs. +8.63 +/- 1.66%, respectively, p less than 0.01). The Ca group showed a smaller weight gain (p less than 0.05) and a greater urinary excretion of sodium (p less than 0.005) than the non-Ca group. In the Ca group, but not in the non-Ca group, high salt intake resulted in an increase in intraerythrocyte magnesium content (p less than 0.01), which was correlated inversely with the salt-induced changes in mean blood pressure (r = -0.54, p less than 0.05). While the increase in cellular magnesium was greater in the Ca group, the changes in red blood cell sodium and sodium/potassium ratio were not different between the two groups. The results suggest that oral calcium supplementation may prevent a rise in blood pressure in patients on a high salt, low calcium diet by attenuating the sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of inhaled glutathione on airway response to 'Fog' challenge in asthmatic patients

OBJECTIVE: We report on the effect of glutathione, an antioxidant compound on the airway response to the ultrasonically nebulised distilled water (UNDW, 'fog') challenge. METHODS: 12 subjects with mild-to-moderate bronchial asthma underwent double-blind, cross-over pretreatment, administered 30 min earlier, in a randomised order with inhaled glutathione (G) (600 mg), sodium cromoglycate (SCG) (20 mg) and placebo (P), followed by the challenge. RESULTS: After P pretreatment UNDW challenge caused a mean 20.41% decrease in FEV-1 (p < 0.05), after G, a mean 6.04% fall in FEV-1 (p = n.s.), and after SCG a mean 5.99% fall in FEV-1 (p = n.s.). CONCLUSIONS: G significantly attenuated 'fog'-induced falls in FEV-1 (p < 0.001 compared with P) and showed a protective effect on UNDW-induced bronchoconstriction. Copyright Copyright 1999 S. Karger AG, Basel     

The effect of mannitol infusion on the response to diuretic therapy in cirrhotic patients with ascites

GOALS: A good response to diuretics is obtained initially in the treatment of cirrhotic ascites. However, unresponsiveness to therapy and various complications may develop with disease progression. This makes obligatory the search for new treatment methods that may be alternative to standard diuretics. In our study, we investigated the effect of mannitol infusion on current therapies in patients with cirrhotic ascites who were using diuretic treatment. BACKGROUND: Thirty cirrhotic patients with ascites who were using diuretic treatment were included in the study. The patients were randomly divided into two groups; a dose of 100-mL 20% mannitol was administered to the first group, and 100-mL 5% dextrose solution was administered to the second group. The patients' urinary volumes and serum and urine electrolyte levels (sodium, potassium) were determined before and after the test. RESULTS: In the mannitol group, a significant increase in urinary volume was observed (p < 0.05). However, in the control group no significant differences in urinary sodium excretion were observed after the test (p > 0.05). In the mannitol group, a concomitant increase in urinary volume and sodium excretion was observed in eight cases (53%). The urinary sodium excretions and serum sodium levels before the test were significantly lower in patients who responded to mannitol than in patients who did not respond (p = 0.001 and p = 0.04, respectively). CONCLUSIONS: As a result, short-term mannitol therapy makes a significant contribution to diuretic therapy in approximately half of cases with cirrhotic ascites. The results we obtained suggest that mannitol may be a useful alternative in the treatment of ascites.     

Regional blood flow and the localisation of lymphoblasts in the small intestine of the mouse: effect of an elemental diet

To test the hypothesis that food antigens influence the in vivo migration of lymphoblasts to the small intestine, the effect of an elemental diet (Vivonex) on the distribution of lymphoblasts within the small intestine of mice has been examined. Viable lymphoblasts from the mesenteric nodes of conventionally fed animals were labelled in vitro and given intravenously to recipient mice fed either a standard diet or elemental diet. The localisation of these cells within the small intestine was altered in the animals fed the elemental diet but only in the distal half of the small intestine. The relationship of the localisation of blast cells to the delivery of cardiac output along the small intestine was examined by assessing cell localisation in conjunction with the distribution of an isotopic indicator (86RbC1). The results show that the pattern of localisation of lymphoblasts within the small intestine is related to the probability that they will be delivered to different regions by the blood stream. Therefore, the alterations in blast localisation in the small intestine of animals of the elemental diet can be viewed as a consequence of changes in the perfusion of the distal small intestine. These results do not support the concept that antigens directly influence the efficiency with which blast cells migrate into the intestinal mucosa.     

Effect of isopropamide on response to oral cimetidine in patients with Zollinger-Ellison syndrome

Patients with Zollinger-Ellison syndrome whose gastric acid secretion or symptoms were not controlled by cimetidine in conventional dosage were selected for studies of responsiveness of their acid secretion to increasing doses of cimetidine, used either alone or in combination with a long-acting anticholinergic agent, isopropamide iodide. Results indicate that in the group as a whole the suppression achieved with a 900-mg dose of cimetidine was not significantly better than that achieved with a 300-mg dose, although in individual cases this did not hold true. In individuals the combination of cimetidine and isopropamide was generally more effective in suppressing acid secretion than cimetidine alone, used either in the same dose as in the combination or in the next highest possible dosage. This was also true in the group as a whole, where combined therapy showed significant advantage over either drug alone in controlling acid secretion, in the third, fourth, and fifth hours following administration of the drugs. The data suggest that in the minority of patients not controlled by cimetidine 300–600 mg q6hper os, addition of isopropamide (20–40 mg/day) may be preferrable to further increasing the dose of cimetidine.This work was presented to the Annual Meeting of the American Gastroenterological Association, and has been published in abstract form: Gastroenterology 76(5):1198, 1979.     

Effect of an oral branched chain amino acid‐enriched snack in cirrhotic patients with sleep disturbance

Aim: Sleep is closely related to physical and mental health. Sleep disturbance is reported in patients without encephalopathy. We examined the relationship among cirrhotic symptoms, laboratory data and sleep disturbances. Next, we examined the influence of a branched chain amino acid (BCAA) supplement on sleep disturbance in cirrhotic patients. Methods: We investigated a total of 21 patients at Nagasaki University Hospital from January to June 2009. We constructed questionnaire items for the evaluation of cirrhotic symptoms. The items, as major symptoms of cirrhotic patients, were as follows: hand tremor, appetite loss, muscle cramp of foot, fatigue, decreased strength, anxiety, abdominal fullness, abdominal pain and a feeling of low energy. We used the Epworth Sleepiness Scale (ESS) for the evaluation of daytime hypersomnolence. Energy supplementation with a BCAA snack was performed as a late evening snack (LES). All patients were assessed at the time of entry into the study, and at 4 and 8 weeks. Results: It was found that BCAA snack, taken p.o. as an LES, improved the ESS for cirrhotic patients without encephalopathy. This beneficial result was recognized in the short term, 4 weeks after beginning of treatment. This study demonstrated the utility of BCAA supplementation for cirrhotic patients with sleep disturbance. However, the cirrhotic symptom‐related score was positively relation with the Child–Pugh score at the time of patient entry, and we were unable to identify the item that related to ESS. Conclusion: A BCAA snack is a useful drug for cirrhotic patients who do not have any overt encephalopathy, but who suffered from sleep disturbance.     

The hypotensive effect of oral nitroglycerin on portal venous pressure in patients with cirrhotic portal hypertension

Abstract Nitroglycerin was administered orally to seven patients with cirrhosis and portal hypertension, to determine whether portal venous pressure (PVP) may be lowered without the systemic effects associated with its intravenous or sublingual use. PVP was measured via direct cannulation of the portal vein transhepatically using a Chiba needle. PVP decreased from 29 (s.d. = 4) to 22.7 (s.d. = 3.7) mmHg (22% mean fall) following 1.2 mg nitroglycerin with onset 7–15 min following ingestion, and the response persisted for up to 150 min. This was not associated with headache in any patient. Although a decrease in blood pressure was seen in most patients, this temporally followed the fall in PVP suggesting that it was a secondary response. Sublingual nitroglycerin was given to two patients without change in PVP yet both experienced severe headache. These findings support the hypothesis that oral nitroglycerin is delivered differentially to the portal venous bed with differential effects on PVP. Further studies are needed to evaluate this agent and this strategy for their potential role in long-term control of portal pressure.     

Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture

Background: Background: Cirrhotic patients frequently undergo various medical procedures, such as diagnostic gastrointestinal endoscopy, without taking breakfast. The aim of the present study was to clarify the effect of longer fasting (>12 h) on energy metabolism, and to test whether supplementation of an oral branched-chain amino-acid-enriched nutrient mixture (BCAA mixture), which contains various nutrients in addition to BCAA, could improve the catabolic state. Methods: Metabolic measurement was performed in 30 cirrhotic patients and 13 normal subjects, using indirect calorimetry. Results: Compared with that in the normal subjects, the respiratory quotient (RQ) was significantly lower after an overnight fast in the cirrhotic patients, indicating accelerated fat oxidation and a catabolic state. In addition, RQ in cirrhotic patients (n= 7) decreased rapidly with longer fasting, whereas that in the normal subjects (n= 5) showed relatively stable values. These results indicate that special care should be taken with medical procedures that are carried out in patients who have fasted. The effect of oral glucose, a carbohydrate-rich snack (rice ball), and the BCAA mixture (each, 210 kcal) on RQ was studied in 6 normal subjects and 6 patients with liver cirrhosis after an overnight fast. Supplementation of the carbohydrate-rich snack and the BCAA mixture (210 kcal each) elevated RQ and blood glucose levels to a similar degree in the cirrhotic patients. Oral administration of glucose (210 kcal) led to significantly greater elevation of blood glucose levels than the other snacks, which may be unfavorable for cirrhotic patients, who frequently have glucose intolerance. In the 30 cirrhotic patients, supplementation with the BCAA mixture in the late evening significantly improved RQ in the early morning. Conclusions: Carbohydrate-rich meals are used as a late evening snack in cirrhotic patients, but our study indicates that supplementation with a BCAA mixture can also be used to reduce fat oxidation in the early morning, with results similar to those with carbohydrate-rich snacks. Received: June 8, 2001 / Accepted: November 30, 2001     

Effect of metoclopramide on transmural oesophageal variceal pressure and portal blood flow in cirrhotic patients

This study was undertaken to evaluate the effect of metoclopramide on transmural oesophageal variceal pressure and portal blood flow in cirrhotic patients. Sixteen cirrhotics were randomly assigned to metoclopramide (10 mg i.v.) or saline. Metoclopramide significantly decreased transmural variceal pressure (15.7% decrease, p less than 0.05 vs. basal value). In order to evaluate if the metoclopramide-induced drop in transmural variceal pressure was due to an effect on portal haemodynamics, we also measured, by means of real time and pulsed Doppler ultrasonography, portal vein diameter, mean velocity of portal flow, and portal venous flow. No significant change was observed before and after metoclopramide. In conclusion, metoclopramide, which increases lower oesophageal sphincter pressure, significantly decreases transmural variceal pressure in cirrhotic patients. However, it does not have any effect on portal haemodynamics.     

Metabolism of oral glucose in children born small for gestational age: evidence for an impaired whole body glucose oxidation

Epidemiological studies indicate that intrauterine growth restriction confers an increased risk of developing type 2 diabetes mellitus in subsequent life. Several studies have further documented the presence of insulin resistance in young adults or adolescent children born small for gestational age. Since most studies addressed postpubertal individuals, and since puberty markedly affects energy metabolism, we evaluated the disposal of oral glucose in a group including mainly prepubertal and early pubertal children with intrauterine growth restriction and in healthy age- and weight-matched control children. All children had an evaluation of their body composition by skinfold thickness measurements. They were then studied in standardized conditions and received 4 consecutive hourly loads of 180 mg glucose/kg body weight to reach a near steady state. Energy expenditure and substrate oxidation were evaluated during the fourth hour by indirect calorimetry. Compared to both age- and weight-matched children, children born small for gestational age had lower stature. Their energy expenditure was not significantly decreased, but they had lower glucose oxidation rates. These results indicate that metabolic alterations are present early in children born small for gestational age, and are possibly related to alterations of body composition.     

Acute effect of propranolol and isosorbide-5-mononitrate administration on renal blood flow in cirrhotic patients

Background—Propranolol andisosorbide-5-mononitrate (ISMN) are increasingly used in theprophylaxis of variceal haemorrhage in cirrhosis. However, recentstudies have suggested that these drugs may compromise renal function,possibly by reducing renal blood flow.
Aims—To assess the acute effects of propranololand ISMN on renal blood flow and other haemodynamic parameters incirrhosis.
Patients and methods—Twenty six cirrhoticpatients were given either 80 mg propranolol, 20 mg ISMN, or acombination of the two drugs. Unilateral renal blood flow (RBF), azygosblood flow (AZBF), hepatic venous pressure gradient (HVPG), meanarterial pressure (MAP), and heart rate (HR) were recorded prior to and one hour after drug administration.
Results—Propranolol caused a reduction in HR(p<0.005), AZBF (p<0.01), and HVPG (p=0.05), but no change in MAP orRBF (454.1(77.3) versus 413.9 (60.3) ml/min). ISMN reduced MAP(p<0.005) and HVPG (p<0.01), but had no effect on HR, AZBF, or RBF(302.5(49.4) versus 301.7 (58.8) ml/min). Combined treatment reduced MAP (p<0.005), AZBF (p<0.05), and HVPG (p=0.002), but HR and RBF (419.2 (62.6) versus 415.1 (61.1) ml/min) remained unchanged.
Conclusions—Despite the anticipated changes inother haemodynamic parameters, acute propranolol and/or ISMNadministration did not reduce RBF. These drugs do not seem tocompromise RBF in cirrhosis.

Keywords:cirrhosis; portal hypertension; renal blood flow; propranolol; nitrates

     

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene × environment interaction approach

Aims/hypothesis  Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. Methods  We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. Results  The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. Conclusions/interpretation  Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.