Macronutrient oxidation in liver disease.
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Biomedical subjects
Publications and source records attributed to M Merli.
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Zinc deficiency is common in cirrhosis and may be involved in the alteration of ammonia metabolism. Rats with carbon tetrachloride-induced cirrhosis have high plasma ammonia and low serum and tissue zinc levels. We used this model to examine the effects of oral zinc supplementation on activities of plasma ammonia and liver ornithine transcarbamylase (a key enzyme in the urea cycle). These parameters were examined in two consecutive experiments. Each experiment included two groups of rats treated with carbon tetrachloride; one group received zinc in the drinking water during the induction of cirrhosis, and another served as a control group. Regardless of zinc supplementation, all carbon tetrachloride-treated rats exhibited similar micronodular cirrhosis, with similar histological appearance and liver function impairment. Cirrhotic rats without zinc supplementation showed high plasma ammonia and low serum and hepatic zinc levels and reduced liver ornithine transcarbamylase activity. Serum, hepatic zinc and liver ornithine transcarbamylase activity increased significantly in the zinc-supplemented group, and these rats' plasma ammonia levels became normal. Plasma ammonia level was significantly inversely correlated with liver ornithine transcarbamylase activity and positively correlated with serum and hepatic zinc content. Our results suggest that zinc deficiency may modify hepatic ornithine transcarbamylase activity and, therefore, ammonia disposal.
Mild to moderate fat malabsorption is frequently present in patients with liver cirrhosis. We investigated the influence of lactulose or lactitol treatment on fecal fat excretion in 18 patients with liver cirrhosis. All patients were Child Pugh class A or B and had not taken any therapy that could have affected intestinal absorption in the previous months. The dose of lactulose or lactitol was individually adjusted to maintain two semiliquid bowel movements per day. Steatorrhea was determined before and after a minimum of 7 days, when the cathartic effect was stabilized. Treatment with nonabsorbable disaccharides induced mild to moderate steatorrhea in 50% of patients. No differences were observed between the effects of lactulose and lactitol, but fecal fat excretion exceeded 10 g/day in two patients taking lactulose. These findings indicate that treatment with nonabsorbable disaccharides may increase fecal fat excretion in patients with liver cirrhosis. This factor should be taken into consideration when a cirrhotic patient has to take these drugs for a long time.
The effect of short-term oral zinc supplementation (zinc sulfate 600 mg/day) on hepatic encephalopathy, was assessed in a double-blind, crossover trial. Fifteen cirrhotic patients with stable, chronic hepatic encephalopathy were randomized to receive either oral zinc or a placebo for 10 days. Following a two-week washout period, these were crossed over to the alternate treatment. Conn's index, which comprises the evaluation of the mental state, asterixis, number connection test, EEG record, and plasma ammonia, was used to score the degree of hepatic encephalopathy, both at the beginning and end of each treatment period. Serum zinc was significantly raised after oral zinc administration and reached the levels observed in cirrhotics without hepatic encephalopathy. Despite this, however, no modification in the parameters included in Conn's index were observed. In conclusion, this study failed to confirm that short-term oral zinc supplementation improves chronic hepatic encephalopathy.
The basal energy production rate was measured using indirect calorimetry in 25 stable cirrhotic patients and 10 controls of comparable age. The endogenous substrate oxidation was also calculated by measuring urinary nitrogen excretion. The energy production rate was similar in cirrhotic patients and controls. The origins of liver disease and the degree of liver damage did not seem to influence the energy production rate. On the other hand, in cirrhotic patients, as in controls, a significant correlation was present between the energy production rate and parameters of body size, such as body weight and fat-free mass. As a consequence, cirrhotic patients with poor nutritional status, with a reduced fat-free mass, showed a lower energy production rate. The measured energy production rate was compared with the resting energy expenditure estimated by formulas commonly used in healthy individuals. The good agreement found between the measured energy production rate and calculated energy expenditure suggests that these formulas may be applied to stable cirrhotic patients in clinical practice. In cirrhotic patients, the oxidation of endogenous fat is the main contributor to basal energy production rate. The fat oxidation rate does not appear to be influenced by the hormonal pattern found in the cirrhotic patients. However, a significant correlation was present between fat oxidation and plasma free fatty acid levels. This confirms that the prevalent fat use in cirrhotic patients is supported by the greater availability of fat-derived substrates.
Insulin action on carbohydrate metabolism is known to be reduced in liver cirrhosis. However, little is known about the effect of insulin on free fatty acid (FFA) metabolism in these patients. To investigate this aspect we performed a two-step insulin euglycemic clamp in 11 cirrhotic patients and 6 controls. Insulin was infused at 0.25 mU/Kg min from 0 to 100 min and at 1 mU/Kg from 100 to 200 min. The FFA lowering capacity of insulin was studied during the first step; the glucose metabolizing capacity (M) was evaluated during the second step. In the cirrhotic patients, the M value was lower than in controls (3.91 +/- 0.48 vs 7.75 +/- 1.09 mg/kg/min, respectively). During the low insulin infusion, FFA and glycerol plasma levels were decreased in both groups. However, the ability of insulin to suppress plasma FFA and glycerol was lower in cirrhotics than in controls. In fact, at 100 min, FFA were 50% of basal values in cirrhotics and 20% in controls (p less than 0.01), while glycerol plasma levels decreased to 70% of basal values in patients and to 56% in controls. The slope of the linear regression obtained between Ln-FFA concentrations vs time was significantly less in cirrhotic patients than in controls (p less than 0.001). In addition, a positive correlation was found between the M value (r = 0.70; p less than 0.01) and the slope of the Ln-FFA in each patient. These findings suggest that in cirrhotic patients the effects of insulin on both FFA and glucose metabolism are reduced.
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.
A continuous intravenous infusion of L-leucine (300 mumols min-1) was given to 12 healthy females over a 2 1/2 h period. Arterial plasma concentrations of amino acids and the keto acids of the branched-chain amino acids (BCAA) were measured. In six subjects muscle biopsies were taken before and at the end of the infusion for determination of intracellular (i.c.) free amino acid concentrations, and leg exchange of amino acids was measured. During infusion the plasma level of leucine rose sixfold. Approximately 40% of the infused amount was taken up by muscle. Of this, half was accumulated intracellularly, where the free leucine concentration increased from basal 190 +/- 22 to 580 +/- 110 mumols l-1 ICW (intracellular water) at the end of infusion. The concentrations of most other amino acids, above all the other BCAA and the aromatic amino acids, decreased, by 17-48% in the i.c. pool and by 17-79% in plasma. The plasma level of ketoisocaproic acid (KIC), the keto acid of leucine, increased in parallel with that of leucine. The concentration of keto valine, ketoisovaleric acid (KIV), decreased by 75%, whereas the keto acid of isoleucine, ketomethylvaleric acid (KMV), was unchanged. Leg release of alanine decreased significantly, whereas the exchange of other amino acids were unchanged. Taken together, decreased i.c. and plasma concentrations but unchanged leg exchange of tyrosine and phenylalanine suggest i.c. accumulation of protein. It can be calculated that approximately 40% of the leucine taken up by muscle was accumulated in the intracellular free pool, some 20% could have been incorporated into protein and 40% was probably oxidized.
Cirrhotic patients often present muscle and adipose tissue depletion as well as reduced visceral protein concentration. Impaired absorption of nutrients may contribute to this altered nutritional status. To verify this hypothesis fecal fat excretion, intestinal mucosal function evaluated by means of the combined sugar oral load test, and intestinal clearance of alpha-1-Antirypsin were studied in 25 cirrhotic patients with clinical and biochemical signs of liver insufficiency and with portal hypertension. About 50% of the patients showed clinical evidence of malnutrition. Three of the 12 well-nourished, and 8 of the 13 malnourished patients presented significant steatorrhoea. Cirrhotics showed no impairment in mediated malabsorption and in passive permeability, as plasma D-xylose/3-O-methyl-glucose concentration and urinary lactulose/L-rhamnose excretion ratios were within the normal range. An increased value of alpha-1-Antitrypsin clearance was found only in two patients. These findings indicate that fat malabsorption is frequent in cirrhotic patients, particularly when malnourished, and does not depend on the presence of mucosal intestinal damage.
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The effect of lactitol, a new non-absorbable disaccharide, in the treatment of chronic hepatic encephalopathy was assessed in 14 cirrhotic patients with non-selective portosystemic anastomosis in a randomized, cross-over study. At the time of inclusion, all patients showed alterations in mental state, and/or psychometric performance, and in the electroencephalogram. Moreover, 10 out of 14 patients suffered from recurrent episodes of hepatic encephalopathy in the 12 months prior to the study. Patients were randomly treated for two consecutive periods of six months with either lactitol or lactulose. The PSE index was calculated to quantify the neuro-psychiatric impairment. Twelve patients completed the study. The patients required a daily dose of 38.2 g +/- 19 of lactulose or 36.3 g +/- 5 of lactitol to produce two semi-soft stools per day. No deterioration in the mental state or in the other neuro-psychiatric parameters were observed, neither during lactitol nor during lactulose therapy. During the study, mild episodes of recurrent encephalopathy occurred in 60% of the patients taking lactulose, and in 25% of the patients taking lactitol, the difference not being significant (X = 1.54, p = 0.21). Flatulence, the major side-effect noted during the study, was present in 7 of the 12 patients during lactulose treatment, and in 2 patients during lactitol treatment; one patient on lactitol complained of nausea. The side effects which occurred during lactitol of the dosage, while those occurring during lactitol appeared when the dosage was higher than 40 g. Lactitol may be considered at least as effective as lactulose in the treatment of chronic hepatic encephalopathy.
Recurrent episodes of hepatic encephalopathy (HE) frequently occur in surgically shunted cirrhotic patients. The prevention of these episodes is based mainly on the long-term use of lactulose. Recently, lactitol, a nonabsorbable disaccharide similar to lactulose, has been proposed as an alternative in the management of HE. It has the advantage of being better tolerated and producing a more predictable catharsis. The effects of the two agents were compared in a controlled randomized study lasting six months involving 31 cirrhotic patients with portal-systemic shunt, of whom 40% experienced HE. The PSE index (mental state, EEG, asterixis, Raitan test, and ammonia) was assessed in each patient on entry to the study and every three months during treatment. Episodes of HE, side effects, and the patients' comments on efficacy, tolerability, and palatability were recorded. The dose required to induce two bowel movements per day was 48 +/- 25 ml of lactulose syrup and 36 +/- 7 g of lactitol. During the study, the number of patients who had an episode of HE and the PSE index was similar in both groups. The patients judged lactitol better from the point of view of palatability. Meteorism and flatulence, experienced by patients treated with lactulose, was not reported by the lactitol group. We concluded that lactitol is as effective as lactulose in the long-term prevention of episodes of HE in cirrhotics with portal-systemic shunt and may be better tolerated.
Two patients with malignant airway obstruction and acute respiratory insufficiency were given emergency treatment with yttrium aluminum garnet (YAG) laser tissue vaporization under local anesthesia only. A mixture of oxygen and helium was administered to reduce the respiratory distress. This case emphasizes the rapidity and effectiveness of YAG laser treatment via fiberoptic bronchoscopy under local anesthesia in the management of acute malignant airway obstructions.
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The goal of this study was to evaluate the presence of extrahepatic damage and the uniformity and reversibility of the histological findings in CCl4-induced liver cirrhosis in the rat. To verify these findings rats were sacrificed 2 and 10 weeks after a treatment consisting of ten intragastric doses of CCl4, administered weekly. All treated rats developed an irreversible micronodular cirrhosis with no damage to the brain, kidney and pancreas. Moreover, rats sacrificed 2 weeks after the last CCl4 dose showed a number of functional alterations usually observed in man. In particular, low branched chain/aromatic amino acids (BCAA/AAA) plasma ratio, high ammonia, low zinc and high insulin with normal blood glucose were obtained.
The circadian periodicity of plasma amino acids (AA) was explored using Cosinor analysis. Six healthy subjects eating a standard diet (30 Kcal and 1 g of protein/Kg of body weight) were studied. Plasma samples for AA determination were taken at 07:00, 11:00, 15:00, 17:00, 21:00 and 24:00. The majority of AA showed an increment in the evening samples. This 24-h variability led to a circadian rhythmicity for all AA, except for taurine, threonine, glutamate, alanine, cystine, and total tryptophan. On average, the fluctuation was approximately 15% of the mesor and the acrophase timing was between 17:00 and 22:00.
The effect of fructose-1,6-diphosphate (FDP) on the recovery of post-arrest cardiac performance was assessed in isolated rabbit heart preparations subjected to cold ischemic cardioplegic arrest (CICA). Twenty-eight hearts were perfused with Krebs-Henseleit (KHBS) solution followed by 40 minutes of CICA. After CICA normothermic reperfusion with KHBS was restarted. The experimental preparations were divided in four groups of seven hearts each: one group served as control and the other three were perfused with KHBS supplemented with FDP (500 mg/l) given before CICA, after CICA or at both study points. Left ventricular end-diastolic pressure, left ventricular systolic pressure, dP/dt and perfusion pressure were measured at different pre- and post-arrest phases. Time analysis of recovery was also performed. The results demonstrated that FDP supplied prior to and after CICA: prevents the ventricular wall rigidity induced by the ischemic arrest, improves cardiac contractile force both in the basal condition and after cardioplegia, reduces the perfusion pressure, reduces the time to recovery of cardiac contractility. Our findings in the isolated rabbit heart are consistent with published data suggesting FDP may limit the impairment of cardiac dynamics induced by ischemia and improve the recovery after cardiac arrest.