Polyunsaturated Fatty Acid Deficiency in Liver Cirrhosis: Its Relation to Associated Protein-Energy Malnutrition (Preliminary Report)

Plasma fatty acids (FA) from C14:0 to C22:6 omega 3 were measured in five healthy subjects and in 27 patients with liver cirrhosis. According to the assessment of triceps skinfold, mid-arm muscle circumference, and serum albumin concentration, patients were prospectively included in three groups: group A (n = 7) with acceptable nutritional status (including good nutrition and mild malnutrition), group B (n = 10) with moderate malnutrition, and group C (n = 10) with severe malnutrition. Plasma levels of total FA, saturated FA, linoleic acid, and omega 6 greater than 18C and omega 3 greater than 18 polyunsaturated fatty acids (PUFA) were lower in cirrhotics than in controls. Linoleic:arachidonic ratio was increased and delta 5-desaturation precursors:products ratio did not change, suggesting a reduction in delta 6-desaturase and/or C18-C20 elongase activities. In addition, a stepwise fall in plasma levels of all but saturated FA was found as the nutritional status worsened, suggesting that, in cirrhosis, impairment in PUFA biosynthesis is related to the severity of associated malnutrition. Since PUFA have important biological functions as components of cell membranes and precursors of eicosanoids, the results reported here may open new perspectives in the understanding of the cirrhosis-malnutrition relationship.     

Malnutrition-related polyunsaturated fatty acid changes in plasma lipid fractions of cirrhotic patients.

Cirrhotic patients have both impaired liver function and nutritional derangement. In fact, the prevalence of protein-energy malnutrition (PEM) is very high in these patients. The aim of the present study was to elucidate whether the nutritional status in cirrhosis could be an additional factor that would affect levels of plasma lipids. Plasma lipid phosphorus, cholesterol, and triglycerides (TG), and fatty acid profiles in plasma and plasma fractions were determined in 50 healthy subjects and 92 patients with liver cirrhosis. The cirrhotic patients were prospectively included in three groups according to the result of nutritional assessment: group 1 (n = 38), acceptable nutritional status (including well-nourished and mildly malnourished patients); group 2 (n = 29), moderate PEM; and group 3 (n = 25), severe PEM. The main findings of this study were that the decrease in plasma cholesterol and linoleic, dihomo-gamma-linolenic, and arachidonic acid levels of cirrhotic patients was related to the degree of PEM. Cholesteryl esters (CE) appeared to be the most sensitive indicator of lipid changes in cirrhosis. We consider that the role of malnutrition in the changes observed for polyunsaturated fatty acid (PUFA) profiles in plasma lipids of cirrhotic patients may be of major importance, since severe malnourished subjects exhibited the lowest levels of those compounds. Dietary supplementation of both essential fatty acids (EFA) and long-chain PUFA in adequate amounts to the cirrhotic patient might be of importance in the management of the disease.     

Spider angiomas in Patients with liver Cirrhosis:Role of vascular endothelial growth factor and basic fibrobalast growth factor

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated with spider angiomas in patients with liver cirrhosis.METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls.RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (L22±13 vs. 71±11 pg/mL, P=0.003for VEGF; 5.1±0.5 vs. 3.4-±0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185±28 vs. 90±10 pg/mL, P=0.003 for VEGF;6.8±1.0 vs. 4.1±0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95 % confidence interval [CI]=2.02-21.79, P=0.002; OR=4.35, 95 % CI=1.35-14.01,P=0.014; OR=5.66, 95 % CI=1.72-18.63, P=0.004, respectively).CONCLUSION: Plasma VEGF and bFGF are elevated in patients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.     

ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child-Turcotte-Pugh score and the Model for End-Stage Liver Disease score

Aim: Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in accumulation of unusually large von Willebrand factor multimers and platelet thrombi formation. Our aim was to evaluate whether ADAMTS13:AC is a prognostic marker in patients with liver cirrhosis. Methods: Plasma ADAMTS13:AC and its related parameters were examined in 108 cirrhotic patients. Results: ADAMTS13:AC decreased as the severity of liver disease increased (means: controls 100%, Child A‐cirrhotics 79%, Child B‐cirrhotics 63%, and Child C‐cirrhotics 31%). ADAMTS13:AC markedly decreased in the cirrhotics with hepatorenal syndrome, refractory ascites and hepatic encephalopathy. The cumulative survival time was the shortest (median: 4.5 months) in the cirrhotics with severe to moderate ADAMTS13:AC deficiency (<3–25%), followed by those with mild ADAMTS13:AC deficiency (25–50%), and was the longest in those with normal activity (>50%). In contrast, based on the Child‐Turcotte‐Pugh (CTP) score, Child C‐cirrhotics had the worst survival, but the survival probabilities did not differ between Child A and B cirrhotics. Based on the Model for End‐Stage Liver Disease (MELD) score, the survival was the worst for the cirrhotics in the fourth quartile, but it was not different among cirrhotics in the first three quartiles. Cox proportional‐hazards regression analysis showed that ADAMTS13:AC and serum albumin were independent factors affecting the survival. Conclusions: ADAMTS13:AC concomitantly decreases as the functional liver capacity decreases. This activity may be a useful prognostic marker that is equal or superior to the CTP score and the MELD score to predict not only the short‐term prognosis but also the long‐term survival of the cirrhotic patients.     

Elevated bound leptin correlates with energy expenditure in cirrhotics

BACKGROUND & AIMS: Leptin, found to be elevated in patients with liver cirrhosis, may contribute to the inadequate energy expenditure and malnutrition associated with a negative prognosis for these patients. Our aim was to characterize leptin components and their relationships to body composition, resting energy expenditure (REE), and substrate use in patients with posthepatic liver cirrhosis. METHODS: Using specific radioimmunoassays, we measured free leptin and bound leptin in 27 cirrhotics and 27 matched control subjects. In the cirrhotic group, body composition and REE were determined. RESULTS: Free leptin was not different in cirrhotics and control subjects and was related to body mass index (controls: r = 0.34, P < 0.05; cirrhotics: r = 0.55, P < 0.005) and to fat mass (cirrhotics: r = 0.76, P < 0.0001). Bound leptin was significantly higher in cirrhotic subjects than in controls (P < 0.001) and was related to REE x fat-free mass(-1) (r = 0.57, P < 0.005) or to the difference between measured and estimated REE (r = 0.55, P < 0.005). CONCLUSIONS: Free leptin reflects fat mass in controls and cirrhotics. Increased serum leptin in cirrhotics is a result of increased bound leptin serum concentrations, which are positively related to energy expenditure. Moreover, bound leptin may be a useful marker for inadequate energy expenditure in patients with liver cirrhosis.     

Spider angiomas in patients with liver cirrhosis： Role of vascular endothelial growth factor and basic fibroblast growth factor

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated with spider angiomas in patients with liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122 +/- 13 vs. 71 +/- 11 pg/mL, P=0.003 for VEGF; 5.1 +/- 0.5 vs. 3.4 +/- 0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185 +/- 28 vs. 90 +/- 10 pg/mL, P=0.003 for VEGF; 6.8 +/- 1.0 vs. 4.1 +/- 0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95 % confidence interval [CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01, P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated in patients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.     

Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease

OBJECTIVES: To investigate the clinical utility and the intra-observer and inter-observer variability of Doppler ultrasound assessment of the hepatic and portal vessels along with measurement of spleen size in the diagnosis of chronic liver disease and cirrhosis. METHODS AND MATERIALS: Ultrasound measurements of portal vein diameter (PVD), portal vein velocity (PVV), hepatic arterial resistance index (HARI), hepatic vein profile (HVP), and spleen size were obtained in 49 controls and 45 patients with liver disease (23 with primary biliary cirrhosis, 22 with hepatitis C) by two experienced observers, who each performed three blinded measurements of each variable. Control values were derived from normal hospital workers. Percutaneous liver biopsies in 41 of the patients showed cirrhosis (14 patients), moderate/severe fibrosis (13 patients), and early disease (14 patients). RESULTS: Seventy-one percent of cirrhotic patients had splenomegaly (> 13.6 cm). The spleen size was significantly larger in cirrhotics (16.0 cm) than in non-cirrhotics (13.0 cm, P < 0.009) and healthy controls (10.7 cm, P < 0.00005), and was the only independent predictor of cirrhosis, with a threshold of 15 cm predicting cirrhosis with a specificity of 98%, positive predictive value of 93%, sensitivity of 57% and negative predictive value of 80%. HVP was abnormal in 76.9% of cirrhotics, 57.7% of non-cirrhotics and 2.1% of controls (P < 0.04). However, the mean PVV, PVD and HARI were no different between controls and patients or between cirrhotic and non-cirrhotic liver disease. There was significant inter-observer variability for PVV, but intra-observer and inter-observer variability was acceptable for the other measurements. CONCLUSIONS: Splenomegaly size and abnormal HVP are useful predictors of chronic liver disease and cirrhosis, and both can be measured reliably and reproducibly. However, Doppler measurements of PVV, PVD and HARI are not useful in distinguishing patients with chronic liver disease from normal controls.     

Elevated growth hormone levels and insulin resistance in patients with cirrhosis of the liver

Carbohydrate intolerance is frequently seen in patients with hepatic cirrhosis. To study the role of the counter regulatory hormones, glucagon, cortisol and growth hormone in this disease, these hormones were measured in 11 patients with hepatic cirrhosis and six controls during a 4-hour oral glucose tolerance test (OGTT) and in five normal and cirrhotic subjects during steady-state plasma insulin and glucose concentrations (SSPGI) achieved with the euglycemic clamp technique. Fasting plasma glucose was 103 +/- 4.3 mg/dl in cirrhotics and 88 +/- 3.3 mg/dl in controls (p less than 0.001). Immunoreactive insulin (IRI) was 24.3 microU/ml in cirrhotics and 12.7 +/- 2.2 microU/ml in controls (p less than 0.001); immunoreactive glucagon (IRG) was 263 +/- 30 pg/ml in cirrhotics and 122 +/- 17.5 pg/ml in controls (p less than 0.001); serum growth hormone (GH) was 4.4 +/- 0.9 ng/ml in cirrhotics and 0.5 +/- 0.1 ng/ml in controls (p less than 0.001). During OGTT, the 2-hour glucose concentration was 201 +/- 9.7 mg/dl in cirrhotic subjects and 147 +/- 10.0 mg/dl in controls (p less than 0.001). IRG levels were suppressed by 20% of basal values in patients with cirrhosis, while controls showed 10% suppression after an oral glucose load. At 60 minutes, the serum GH was 14.7 +/- 3.9 ng/ml in cirrhotics and 0.3 +/- 0.1 ng/ml in controls (p less than 0.001). The normal suppressive effect of hyperglycemia on GH secretion in controls was sharply contrasted by a paradoxical elevation of serum GH in the cirrhotic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastric acid secretion and gastrin and gastric inhibitory polypeptide release in cirrhotic patients

Gastric acid secretion, incidence of gastric mucosal lesion, and gut hormone responses were studied in 24 patients with liver cirrhosis. Gastric acid output in these subjects showed normal acidity and was nearly similar to that in patients with gastric ulcer. The incidence of gastric mucosal lesion was high, especially in patients whose plasma disappearance rate of indocyanine green was low. Plasma levels of both gastric and gastric inhibitory polypeptide were higher in cirrhotic patients than in control subjects both in the fasting state and after the ingestion of a test meal. Gel chromatography of the postprandial plasma of cirrhotics showed a higher immunoreactivity at the second peak than in controls. This is because cirrhotics have a higher percentage of authentic gastric inhibitory polypeptide, although the elution patterns were similar in both groups. It is suggested that impairment of extraction of some molecular components of both gastric and gastric inhibitory polypeptide may occur in the cirrhotic liver.     

Study of fluidity of low density lipoproteins from liver cirrhotic patients

BACKGROUND AND AIM: Liver disease is accompanied by major quantitative and qualitative modifications in plasma lipoprotein metabolism. Alterations in plasma lipoprotein composition and a lower susceptibility to in vitro peroxidation of low density lipoprotein (LDL) and erythrocyte membranes have been observed in liver cirrhosis. The main objective of the present work was to investigate LDL chemical composition and fluidity in liver cirrhosis using the fluorescence polarization (Pf) of the 1,6-diphenyl-1,3,5-hexatriene (DPH) probe. METHODS AND RESULTS: The chemical composition of LDL was studied in 12 cirrhotic patients and 22 controls by conventional methods and its fatty acid composition by gas chromatography. LDL fluidity was determined by measuring the DPH Pf values. A decrease in molecular order was demonstrated by the significant (p < 0.05) decrease in Pf values in the cirrhotics. Modifications in LDL fluidity are correlated with its composition. A significant increase in triglyceride content (p < 0.05), and significant increases in triglyceride/protein and triglyceride/phospholipid ratios were observed in the cirrhotics. CONCLUSIONS: Our results demonstrate that the higher LDL fluidity of cirrhotic patients may be due to an increased triglyceride content.     

Renal function impairment induced by change in posture in patients with cirrhosis and ascites.

The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 greater than p greater than 0.05), aldosterone and noradrenaline concentrations (p less than or equal to 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (sigma delta) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patient's tubular rejection fraction of sodium and sodium excretion were related to sigma delta aldosteronaemia (r = -0.72; p less than 0.01), but no longer to sigma delta plasma noradrenaline.     

Pancreatic beta-cell function in cirrhotic patients with and without overt diabetes. C-peptide response to glucagon and to meal

To study the role of pancreatic beta-cell function in glucose intolerance and frank diabetes that sometimes develops in cirrhosis, the C-peptide response to a bolus IV injection of 1 mg of glucagon was measured in nine controls and in two groups of patients with cirrhosis. The first group comprised nine subjects with normal or high-normal fasting plasma glucose and no glycosuria; five of them had impaired glucose tolerance. The second group consisted of eight cirrhotics in whom frank diabetes had developed six to 48 months after the diagnosis of cirrhosis. They were characterized by fasting plasma glucose greater than 140 mg/dL and permanent glycosuria. No differences in the degree of liver impairment or portal-systemic shunting were observed between the two groups. Plasma glucose response to glucagon was similarly reduced in cirrhotic subjects. Basal C-peptide was high normal in patients with cirrhosis, and significantly increased in nondiabetic subjects. By contrast peak C-peptide levels and total C-peptide responses to glucagon were low normal in cirrhotics and significantly reduced in patients with cirrhosis and diabetes. In 14 patients the C-peptide response to a standard meal was also measured. It was significantly reduced in patients with cirrhosis and diabetes (six cases), as compared to cirrhotic subjects without diabetes. Peak C-peptide after IV glucagon significantly correlated with peak C-peptide after the meal (r = .927), or total C-peptide response to meal (r = .871). Impaired insulin secretion may add to insulin resistance in patients with liver cirrhosis, leading to the development of frank diabetes, characterized by fasting hyperglycemia and glycosuria.     

Resistance to insulin suppression of plasma free fatty acids in liver cirrhosis

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.     

The effect of glucagon on free plasma amino acids in cirrhotics and healthy controls

The effect on free plasma amino acids before and after infusion of 1 mg glucagon was studied at rest after an overnight fast in seven patients with compensated liver cirrhosis and in seven healthy controls. Total aminoacidaemia in cirrhotic patients is significantly higher than in controls. Elevated basal levels in cirrhotics are found particularly in tyrosine, citrulline, tryptophane, threonine, phenylalanine, and methionine whereas ornithine and serine levels are decreased. Save for the redox couple cystine-cysteine which increases, glucagon elicits an decrease in most amino acids that is proportionate to their initial level. Total aminoacidaemia decreases in controls and cirrhotics by 14.6 and 9.1 per cent respectively. Serum ammonia level rises significantly in both groups, urea increases only in controls, uricaemia remains virtually unchanged.     

Gastric and gall bladder emptying of a mixed meal are not coordinated in liver cirrhosis--a simultaneous sonographic study.

BACKGROUND AND AIM: An impaired contractility has been suggested as a contributor to the increased incidence of gallstones in liver cirrhosis, but the few studies on gall bladder emptying in cirrhotics offered contradictory results. Ingestion of a meal triggers the physiological pathway of gall bladder emptying; therefore, it was decided to analyse postprandial kinetics by investigating simultaneously the rates of gastric and gall bladder emptying of a mixed meal in patients with liver cirrhosis. METHODS: Gastric and gall bladder emptying were measured using ultrasound techniques after a solid-liquid meal (14 g fat, 425 kcal) in 24 patients with liver cirrhosis and in 12 controls. None of the subjects had gall bladder disease. Sequential changes in cross sectional area of the gastric antrum and in gall bladder volume were represented as a monoexponential process after the test meal. Cirrhotic patients were analysed according to the severity of disease (Child classes). The presence of portal gastropathy was assessed by endoscopy. Differences between groups were assessed using the two tailed Student's t test for unpaired observations and the correlations by linear regression (Pearson's coefficient). RESULTS: It was found that gastric emptying after the solid-liquid meal was delayed in cirrhotic patients compared with controls. Gall bladder emptying was significantly diminished in cirrhotic patients: the area under curve was greater in Child A (p = 0.01), Child B (p = 0.04), and Child C (p = 0.014) cirrhotics compared with controls. No correlation was found between the variables of gastric and gall bladder emptying. Gall bladder refilling began earlier in cirrhotics than in controls, before completion of gastric emptying. CONCLUSIONS: These results indicate the lack of coordination between gastric and gall bladder emptying in liver cirrhosis. They also support the hypothesis that diminished gall bladder contractility might contribute to the increased gallstone formation in liver cirrhosis.     

Elevated plasma ammonia level in hepatic cirrhosis: role of glucagon

Elevated plasma ammonia level in hepatic cirrhosis has been attributed to a lack of conversion of enteric ammonia into urea or to its entry into systemic circulation via portasystemic shunting, or to both. It is exaggerated by excessive protein intake. Because hyperglucagonemia is well documented in cirrhosis and a protein meal is an effective glucagon secretagogue, plasma glucose, insulin, glucagon, and ammonia levels were determined in 50 cirrhotic patients after an overnight fast. Effects of a protein meal were also assessed in 20 of these patients. Plasma glucose was normal and remained unaltered after a protein meal. Insulin, glucagon, and ammonia levels were elevated, but only in patients with advanced liver dysfunction. Ammonia levels correlated significantly with glucagon (r = 0.61, p less than 0.001), but not with insulin or glucose levels. Insulin and glucagon levels rose after a protein meal in all patients and controls; whereas a significant rise in the ammonia level occurred only in decompensated cirrhotics. Elevation of the ammonia level was significantly correlated with fasting glucagon (r = 0.54, p less than 0.05), as well as with glucagon response (r = 0.65, p less than 0.01), but not with basal insulin or insulin response. Furthermore, the rise in ammonia level occurred too early to be accounted for by enteric generation. Finally, direct effects of glucagon administration on plasma glucose and serum ammonia were examined in 15 cirrhotic patients. Glucose response was significantly blunted in cirrhotic patients as compared with normal subjects, whereas serum ammonia rose promptly but only in cirrhotics, with maximum rise being noted in cirrhotic patients with advanced liver dysfunction. This study, therefore, suggests that hyperglucagonemia may contribute significantly to hyperammonemia in hepatic cirrhosis.     

The effect of an eucaloric high carbohydrate diet on circulating levels of glucose, fructose and non-esterified fatty acids in patients with cirrhosis.

Twelve cirrhotic patients and six controls were fed an eucaloric high carbohydrate (CHO) diet for 3 days. Fasting serum triglyceride (TG), non-esterified fatty acids (NEFA), glucose, insulin and glycerol were estimated daily. On the 3rd day of the study we measured NEFA, glucose, insulin, and fructose every 45 min from 07:45 h until 19:45 h, and then every 4 h until 07:45 h the next day. The patients were divided into two groups of six on the basis of plasma lecithin-cholesterol acyltransferase (LCAT) activity: group A cirrhotics (with good liver function--LCAT activity: 40.6-65.7 nmol.ml-1.h-1; mean 48.5), and group B (poor liver function--LCAT: 23.7-32.3; mean 27.4). On the high CHO diet there was an increase in the fasting serum TG with a peak after 2 or 3 days. The increase in serum TG in controls was greater (p less than 0.01) than in either group of cirrhotics. In the controls and in group A most of the extra TG was carried in VLDL; in group B only 39% of the TG increment was found in VLDL. Fasting NEFA fell with 3 days of CHO feeding in the control group (p less than 0.01); they were unchanged in group A, and rose in group B to a significantly higher level than in controls (p less than 0.01). During day 3 when a high CHO diet was fed plasma NEFA levels fell in cirrhotics, and for most of the day the mean NEFA concentration in group B patients was significantly (p less than 0.05) lower than in normals. On day 3 glucose and fructose levels rose after each meal--much more in cirrhotics than in controls (and more in group B than in group A), and for most of the day they were significantly higher in group B patients as compared to the controls (glucose p less than 0.01, fructose p less than 0.001). Our results supported the hypothesis that plasma NEFA would be lower following high CHO meals in cirrhotics than in controls. This suggests that a high NEFA utilisation, which occurs in fasting cirrhotics, is not present throughout the day. Following a CHO meal, we suggest that tissues derive energy directly from the dietary sugars which are present in high concentration during the period of absorption and that this reduces the post prandial requirement for NEFA.     

Temazepam Clearance Unaltered in Cirrhosis

The kinetics of a single oral dose of the benzodiazepine hypnotic temazepam was evaluated in nine patients with biopsy-proven cirrhosis and in seven healthy controls matched for age and sex. Peak serum temazepam concentrations were reached later in cirrhotics than in controls (2.9 versus 0.6 h after dosage; p less than 0.05), indicating slower temazepam absorption in patients with cirrhosis. Temazepam volume of distribution was smaller in cirrhotics compared to controls, and elimination half-life shorter (10.6 versus 14.6 h). However, these differences were not significant. There were no significant differences between cirrhotics and controls in clearance of total temazepam (1.03 versus 1.03 ml/min/kg), clearance of unbound temazepam (27 versus 31 ml/min/kg), or free fraction in serum (3.9 versus 3.5% unbound). In two cirrhotic patients who received 20 mg of temazepam daily for 8 days, the extent of accumulation was consistent with the dosage interval relative to the elimination half-life, and was similar to the accumulation profile in healthy volunteers. Thus the onset of temazepam hypnotic activity may be delayed in cirrhotic patients, but the rate of elimination and the extent of accumulation are not altered compared to healthy persons of similar age and sex.     

Intestinal permeability in liver cirrhosis.

OBJECTIVE: To determine the changes in intestinal permeability in liver cirrhosis and to investigate whether intestinal permeability relates to the stage and aetiology of cirrhosis or existence of spontaneous bacterial peritonitis (SBP). DESIGN: A prospective study of intestinal permeability in patients with cirrhosis. SETTING: Gastroenterology and Nuclear Medicine Departments of Ege University Hospital. PARTICIPANTS: Intestinal permeability was assessed in 44 consecutive patients with cirrhosis and 10 healthy volunteers by measuring 24 h urine excretion of (99m)technetium diethyl triamine penta-acetic acid (99mTc DTPA). Cases with an associated disease, impaired renal function, continuing alcohol consumption and drug intake which is known to have an effect on intestinal permeability were excluded. MAIN OUTCOME MEASURES: Comparisons of 24 h urine excretion of 99mTc DTPA were made between the groups of cirrhotics and controls, different grades of cirrhosis (according to Child-Pugh criteria), alcoholic and non-alcoholic cirrhotics and cirrhotic patients with and without SBP. RESULTS: Patients with cirrhosis excreted 99mTc DTPA significantly more than controls (11.56 +/- 8.96% in cirrhotics and 4.30 +/- 1.49% in controls, P < 0.0001). There was no relationship of 24 h urine excretion of the tracer with the grade and aetiology of cirrhosis (12.20 +/- 9.47%, 11.41 +/- 9.84%, and 11.09 +/- 8.42%, in Child A, B, and C groups and 8.45 +/- 6.57% and 12.05 +/- 9.25% in alcoholic and non-alcoholic cirrhotics, respectively). No significant difference was found between cirrhotic patients with and without SBP in terms of excretion of the administered dose of 99mTc DTPA (9.98 +/- 9.47% and 12.20 +/- 8.82%, respectively). CONCLUSIONS: This study shows that intestinal permeability increased in cirrhotic patients regardless of the grade and aetiology of disease. The presence of SBP does not seem to be due to increased intestinal permeability.     

Frequency of upper gastrointestinal lesions in patients with liver cirrhosis

The frequency of gastroduodenal lesions has been investigated in 142 patients with liver cirrhosis of various degrees of severity and in 63 patients with mild liver disease (controls) in whom liver biopsy excluded nodular regeneration. Cirrhotic patients were subdivided in three groups according to the Pugh modification of the Child-Turcotte criteria. Although the frequency of peptic ulcer was not different, gastroduodenal erosions were observed more frequently in cirrhotics than in controls (29.6% vs 11.1%, P<0.01 ). The occurrence of erosions was related to the severity of the disease: in Child A and B patients their frequency was 21 and 26% respectively, but rose to 48.4 (15 of 31 vs 7 of 63 in controls, P<0.001 ) in the Child C group. Both mild and severe gastroduodenitis occurred more frequently, although not significantly, in patients with liver cirrhosis. All together one or more endoscopic lesions were observed in almost 60% of cirrhotics but only in 25.4% of controls (P<0.001 ). In conclusion, our data do not show an increased prevalence of peptic ulcer in cirrhotic patients; in contrast, liver cirrhosis is significantly associated with the endoscopic finding of gastroduodenal erosions, especially in the more advanced stages of the disease. These findings would suggest a cautious use, in cirrhotic patients, of drugs which may damage the gastroduodenal mucosa; moreover, longterm administration of antacids or of other drugs with a protective effect on gastroduodenal mucosa might be taken into consideration for Child C patients.