Role of endotoxaemia in hyperdynamic circulation in rats with extrahepatic or intrahepatic portal hypertension

This study investigated the role of endotoxaemia in the development of hyperdynamic circulation observed in rats with extrahepatic (high collateralization) or intrahepatic (low collateralization) portal hypertension. Compared with sham-operated rats, decreased mean arterial pressure and systemic vascular resistance were detected on days 1, 4 and 14 following partial portal vein ligation. By day 1, the cardiac index of portal vein-ligated rats was similar to that of sham-operated rats and progressively increased, thereafter, reaching statistically higher values on days 4 and 14. No differences in plasma endotoxin levels were found between portal vein-ligated and sham-operated rats throughout the observation period. Both carbon tetrachloride-induced cirrhotic rats with and without ascites had a higher cardiac index and lower systemic vascular resistance than those of control rats, and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma endotoxin levels were higher in cirrhotic rats with ascites (8.6±2.0 pg/mL; P < 0.01) than those of control rats (2.2±0.3 pg/mL) and cirrhotic rats without ascites (2.4±0.6 pg/mL). These results suggest that factors other than endotoxaemia play a role in the development of hyperdynamic circulation observed in rats with extrahepatic portal hypertension and cirrhotic rats without ascites, but that endotoxaemia may contribute to the maintenance of hyperdynamic circulation found in cirrhotic rats with ascites. The severity of liver disease may be a more important factor than the presence of portosystemic shunting for the development of endotoxaemia in portal hypertensive states.     

Intestinal glutamine and ammonia metabolism during chronic hyperammonaemia induced by liver insufficiency.

During liver insufficiency, besides portasystemic shunting, high arterial glutamine concentrations could enhance intestinal glutamine consumption and ammonia generation, thereby aggravating hyperammonaemia. To investigate this hypothesis, portal drained viscera (intestines) fluxes and jejunal tissue concentrations of ammonia and glutamine were measured in portacaval shunted rats with a ligated bile duct, portacaval shunted, and sham operated rats, seven and 14 days after surgery, and in normal unoperated controls. Effects of differences in food intake were minimised by pair feeding portacaval shunted and sham operated with portacaval shunted rats with biliary obstruction. At both time points, arterial ammonia was increased in the groups with liver insufficiency. Also, arterial glutamine concentration was raised in all operated groups compared with normal unoperated controls. At both time points, ammonia production by portal drained viscera was reduced in portacaval shunted rats with biliary obstruction, portacaval shunted, and sham operated rats compared with normal unoperated controls, and no major differences were found between these operated groups. At day 7 in all operated groups glutamine uptake by portal drained viscera was lower than in normal unoperated controls, but no major differences were found at day 14. These experiments show that ammonia generation by portal drained viscera remains unchanged in rats with chronic liver insufficiency despite alterations in arterial glutamine concentrations and intestinal glutamine uptake. The hyperammonaemia seems to be mainly determined by the portasystemic shunting.     

Rifaximin, but not growth factor 1, reduces brain edema in cirrhotic rats

AIM: To compare rifaximin and insulin-like growth factor (IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS: Rats with CCl₄-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups: Cirrhosis; Cirrhosis + IGF-1; Cirrhosis + rifaximin; Controls; Controls + IGF-1; and Controls + rifaximin. An oral glutamine-challenge test was performed, and plasma and cerebral ammonia, glucose, bilirubin, transaminases, endotoxemia, brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS: Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups, and improved some liver function parameters (bilirubin, alanine aminotransferase and aspartate aminotransferase). These effects were associated with a significant reduction in cerebral water content. Blood and cerebral ammonia levels, and area-under-the-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals. By contrast, IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION: By reducing gut bacterial overgrowth, only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema, alterations associated with hepatic encephalopathy.     

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.     

Post-feeding hyperammonaemia in patients with transjugular intrahepatic portosystemic shunt and liver cirrhosis: role of small intestinal ammonia release and route of nutrient administration

BACKGROUND: Hyperammonaemia is a pathogenetic factor for hepatic encephalopathy that may be augmented after a transjugular intrahepatic portosystemic shunt (TIPS). Experimental data suggest that hyperammonaemia may be caused to a large extent by metabolism of small intestinal enterocytes rather than colonic bacteria. AIMS: To evaluate if ammonia release and glutamine metabolism by small intestinal mucosa contribute to hyperammonaemia in vivo in patients with liver cirrhosis. METHODS: Using TIPS to examine mesenteric venous blood, we measured mesenteric venous-arterial concentration differences in ammonia and glutamine in patients with liver cirrhosis before, during, and after enteral (n = 8) or parenteral (n = 8) isonitrogenous infusion of a glutamine containing amino acid solution. RESULTS: During enteral nutrient infusion, ammonia release increased rapidly compared with the post-absorptive state (65 (58-73) v. 107 (95-119) micromol/l after 15 min; mean (95% confidence interval)) in contrast with parenteral infusion (50 (41-59) v. 62 (47-77) micromol/l). This resulted in a higher portal ammonia load (29 (21-36) v. 14 (8-21) mmol/l/240 minutes) and a higher degree of systemic hyperammonaemia (14 (11-17) v. 9 (6-12) mmol/l/240 minutes) during enteral than parenteral infusion. The mesenteric venous-arterial concentration difference in glutamine changed from net uptake to release at the end of the enteral infusion period (-100 (-58 to -141) v. 31 (-47-110) micromol/l) with no change during parenteral nutrition. CONCLUSIONS: These data suggest that small intestinal metabolism contributes to post-feeding hyperammonaemia in patients with cirrhosis. When artificial nutrition is required, parenteral nutrition may be superior to enteral nutrition in patients with portosystemic shunting because of the lower degree of systemic hyperammonaemia.     

Preservation of portal pressure improves growth and metabolic profile in the male portacaval-shunted rat

The portacaval anastomosis (PCA) rat model and human cirrhosis have many metabolic and nutritional abnormalities in common, such as growth retardation, hepatic and gonadal atrophy, and hyperammonemia. The severity of these abnormalities is variable and may be related to a number of factors, including portal pressure, portosystemic shunting, dietary intake, and how efficiently food is used. Therefore, this rat model was used to study these variables with the intent of gaining insights for improving the management of portal hypertension and malnutrition in human cirrhosis. A nonsuture end-to-side PCA (N = 100) or sham surgery (N = 71) was performed in 100 male rats. Four weeks after surgery, body and organ weights, food intake, serum ammonia, and serum amino acids were measured at death. In a subgroup of rats, (sham 7; PCA 34) portal venous pressure, degree of portosystemic shunting, and organ and body weights were obtained at death. Growth, liver weight, and testes weight were decreased, ammonia levels were higher, and the ratios of branched chain to aromatic amino acid (BCAA/AAA) were lower in the PCA group compared to the sham animals (P < 0.05). Since spleen weights correlated with portal pressure (P = 0.01), the PCA animals were then divided into those with preserved and those with low portal pressures based on spleen weight. The PCA group with preserved portal pressure had better growth, larger livers and testes, lower serum ammonia, and higher BCAA/AAA levels than the PCA group with low portal pressure; improvements associated with normal amounts of food intake and better food efficiency than the low pressure animals (P < 0.05 or better). Sham animals had no portosystemic shunting, while 100% shunting occurred in both PCA groups regardless of the portal pressure. In conclusion, preservation of portal pressure after portacaval anastomosis provides metabolic and nutritional benefits, which are independent of portosystemic shunting and associated with normal dietary intake and better preserved food efficiency.     

Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis

BACKGROUND AND AIMS: We previously reported the effect of Helicobacter pylori eradication on hyperammonaemia in patients with liver cirrhosis. However, the role of H pylori as a cause of hyperammonaemia is controversial. We developed an animal model with liver cirrhosis and investigated the effect of H pylori infection on hyperammonaemia. MATERIALS AND METHODS: Five week old male Mongolian gerbils were inoculated orally with broth culture of H pylori. Forty eight gerbils were divided into four groups. Gerbils not inoculated with H pylori were fed a commercial rodent diet (group A) or a choline deficient diet (group C). Gerbils inoculated with H pylori were fed the commercial rodent diet (group B) or the choline deficient diet (group D). Blood ammonia levels of the femoral vein and portal vein were measured 30 weeks later. RESULTS: All gerbils fed the choline deficient diet developed liver cirrhosis with fatty metamorphosis. The survival rate of group D was significantly lower than that of the other groups. Systemic and portal blood ammonia levels in group D were significantly higher than those in the other groups. CONCLUSIONS: H pylori infection induces hyperammonaemia in gerbils with liver cirrhosis.     

Refractory hepatic encephalopathy in a patient with hypothyroidism: Another element in ammonia metabolism

Hepatic encephalopathy(HE) remains a diagnosis of exclusion due to the lack of specific signs and symptoms. Refractory HE is an uncommon but serious condition that requires the search of hidden precipitating events(i.e.,portosystemic shunt) and alternative diagnosis. Hypothyroidism shares clinical manifestations with HE and is usually considered within the differential diagnosis of HE. Here,we describe a patient with refractory HE who presented a large portosystemic shunt and post-ablative hypothyroidism. Her cognitive impairment,hyperammonaemia,electroencephalograph alterations,impaired neuropsychological performance,and magnetic resonance imaging and spectroscopy disturbances were highly suggestive of HE,paralleled the course of hypothyroidism and normalized after thyroid hormone replacement. There was no need for intervention over the portosystemic shunt. The case findings support that hypothyroidism may precipitate HE in cirrhotic patients by inducing hyperammonaemia and/or enhancing ammonia brain toxicity. This case led us to consider hypothyroidism not only in the differential diagnosis but also as a precipitating factor of HE.     

Transjugular intrahepatic portosystemic shunt for treatment of bleeding ectopic varices with portal hypertension

PURPOSE: In the setting of hepatic failure and portal hypertension, hemorrhage from stomal and rectal varices is a well-described problem. It has recently been suggested that transjugular intrahepatic portosystemic shunting may be useful in the therapy of bleeding from parastomal or anorectal varices in patients unresponsive to conservative therapy. METHODS: We retrospectively review our institution's experience of five patients with parastomal varices and seven patients with anorectal varices who underwent transjugular intrahepatic portosystemic shunting for hemorrhage refractory to conservative management between 1994 and 1998. RESULTS: The study group consisted of four Child's A, five Child's B, and three Child's C patients. The mean age of the patients was 60.3 (range, 37-85) years. Mean follow-up was 15 (range, 5-27) months. The mean portosystemic pressure gradient before transjugular intrahepatic portosystemic shunting was 17.4+/-3.1 mm Hg. After transjugular intrahepatic portosystemic shunting, the mean portosystemic pressure gradient was reduced to 5.8+/-1.8 mm Hg (P<0.05). Transjugular intrahepatic portosystemic shunting were successful in complete resolution of bleeding in all patients. Three patients had encephalopathic changes after transjugular intrahepatic portosystemic shunting. Two patients died within 30 days of transjugular intrahepatic portosystemic shunting of causes unrelated to the procedure. Four patients required shunt revision within one year of placement. CONCLUSION: The transjugular intrahepatic portosystemic shunting procedure is an effective modality in the therapy of cirrhotic patients with bleeding stomal or anorectal varices unresponsive to conservative management. There is an acceptable procedure-related morbidity and mortality.     

Oral glutamine challenge and magnetic resonance spectroscopy in three patients with congenital portosystemic shunts

BACKGROUND/AIMS: Congenital portosystemic shunts are rare abnormalities of liver vasculature that can cause neurological symptoms, probably secondarily to the effects of the metabolism of ammonia in the brain. Our aim was to investigate the relationship between capillary blood ammonia after oral glutamine challenge and magnetic resonance spectroscopy in three patients with congenital portosystemic shunts. METHODS: Neuropsychological tests, oral glutamine challenge and magnetic resonance spectroscopy were performed at baseline and after 6 months of follow-up in three patients with congenital portosystemic shunts. The results were compared to those obtained in a group of six cirrhotic patients with prior episodes of hepatic encephalopathy and healthy controls. RESULTS: Patients with congenital portosystemic shunts exhibited abnormalities of neuropsychological tests, magnetic resonance spectroscopy and a response to the oral glutamine challenge similar to those observed in patients with cirrhosis. The intensity of the rise of brain glutamine was correlated to the area under the curve of ammonia after the oral glutamine challenge (R=0.72). CONCLUSIONS: Neurological manifestations of patients with congenital portosystemic shunts are mediated through similar mechanisms that are involved in the pathogenesis of hepatic encephalopathy. The area under the curve appears to be the better parameter that defines the response to the oral glutamine challenge.     

Correlation between hemodynamic parameters of the portal circulation in cirrhotic patients

The aim was to study the relationships between portal hemodynamic parameters in cirrhotic patients. Portal hemodynamics was assessed by scintisplenoportography and sonography, and the measurement of portohepatic gradient. Gradient between wedged and free hepatic venous pressures was 2.71 +/- 0.90 kPa (SD), and extrahepatic shunting was 49 +/- 31 p. 100 (SD) in 27 cirrhotic patients. Intrahepatic shunting was present in 17 p. 100 out of 23 cirrhotics. Portal blood flow was 0.582 +/- 0.196 l/min (SD) and hepatic resistance to portal blood flow was 4.84 +/- 2.62 kPa/l/min (SD). Portal blood flow correlated neither with the pressure gradient, nor with portosystemic shunting. The pressure gradient was significantly correlated with portal systemic shunting (r = 0.64, p less than 0.001). Hepatic resistance to portal blood flow was significantly (p less than 0.05) correlated with portal systemic shunting, however the value of the correlation coefficient was low (r = 0.433). The pressure gradient and portosystemic shunting were higher in patients with large esophageal varices than in those with small ones (respectively t = 2.665, p less than 0.02 and t = 3.00, p less than 0.01). Hemodynamic pattern was not correlated with the degree of hepatocellular failure, as assessed by the Child-Pugh index. In conclusion this study provides further evidence for the forward theory of portal hypertension in human liver cirrhosis.     

Propranolol decreases portal pressure without changing portocollateral resistance in cirrhotic rats

Propranolol decreases portal pressure by reducing portal blood inflow. Studies in rats with prehepatic portal hypertension due to portal vein stenosis (a model with extensive portosystemic shunting) have shown that propranolol increases the portocollateral resistance, which hinders the fall in portal pressure. The present study examined the effects of propranolol on splanchnic and systemic hemodynamics in rats with portal hypertension due to cirrhosis of the liver, a model which is characterized by mild portosystemic shunting. Two groups of rats with CCl4-induced cirrhosis were studied: the propranolol group (n = 8), which received a propranolol infusion of 2 mg per 15 min, and controls (n = 9), which received a placebo (saline) infusion. Hemodynamic measurements were done using radiolabeled microspheres. Propranolol-treated rats had significantly lower cardiac output (-31%) and heart rate (-26%) than controls (p less than 0.001). Hepatic artery flow was not modified by propranolol. Propranolol caused splanchnic vasoconstriction, manifested by increased splanchnic resistance (+57%) and by a significant fall in portal blood inflow (4.8 +/- 0.4 vs. 6.3 +/- 0.5 ml per min.100 gm in controls, p less than 0.05). In contrast with rats with prehepatic portal hypertension, propranolol did not increase portal resistance in cirrhotic rats [2.0 +/- 0.2 vs. 2.0 +/- 0.1 mmHg per ml per min.100 gm body weight (not significant)]. Hence, the fall in portal pressure (-19%) was expected from the decrease in portal inflow (-24%). These results suggest that increased portal resistance in rats with prehepatic portal hypertension may represent an intrinsic effect of propranolol on the portocollateral vessels, since beta-blockade does not modify portal vascular resistance in cirrhosis.     

Magnetic resonance images of the globus pallidus in patients with idiopathic portal hypertension: a quantitative analysis of the relationship between signal intensity and the grade of portosystemic shunt

BACKGROUND AND AIM: To elucidate a quantitative relationship between hyperintensity of the globus pallidus on T1-weighted magnetic resonance images (MRI) and portosystemic shunt (PSS) in portal hypertension. METHODS: Fifteen patients with idiopathic portal hypertension (IPH) and 44 patients with liver cirrhosis (LC) underwent brain MRI to asses signal intensity at the globus pallidus and Doppler sonography to examine the blood flow volume of PSS. Blood manganese (Mn) levels were examined in 36 patients and neuropsychological tests were performed in 15 patients without overt hepatic encephalopathy. RESULTS: Pallidal hyperintensity on MRI was more prominent in patients with IPH than in patients with LC. There was no correlation between MRI pallidal hyperintensity and the severity of liver dysfunction or hepatic encephalopathy. The grade of hyperintensity correlated well with the grade of PSS. The correlation was stronger in patients with IPH than in patients with LC. The plasma ammonia level and whole blood Mn level significantly correlated with MRI pallidal hyperintensity, but blood Mn level showed a stronger correlation than plasma ammonia. CONCLUSION: Hyperintensity of the globus pallidus on T1-weighted MRI correlated with the development of PSS independent of liver cell function. This brain image should be an index of the grade of PSS rather than a landmark of chronic liver failure.     

Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia

AIM: To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS: Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS: The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 ± 1.7 mmHg, ammonia + vehicle: 6.8 ± 1.0 mmHg, saline + ciclosporin: 3.1 ± 0.5 mmHg, saline + vehicle: 3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression.CONCLUSION: Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.     

Transjugular intrahepatic portosystemic shunt (TIPS) augments hyperinsulinemia in patients with cirrhosis

BACKGROUND/AIMS: Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance. METHODS: To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS). RESULTS: Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS. CONCLUSION: Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.     

Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic rats after injection of the Liver Growth Factor.

BACKGROUND/AIMS: Most substances used in experimental models of cirrhosis are chosen either as protectors of lipid peroxidation, as antifibrogenic agents or as vitamins, among others. In this report, we analyze the improvement produced, in established cirrhosis (CCl4 plus phenobarbital) in rats, by intraperitoneal injection of Liver Growth Factor, a hepatic mitogen with activity both in vivo and in vitro. METHODS: Following confirmation of CCl4-induced cirrhosis, Liver Growth Factor (4.5 microg per ratx2 injections/week for 3 weeks) was administered to one group of rats (Cirr+LGF). The remaining rats (Cirr) received saline. The groups were compared in terms of serum enzymes, tissue damage, total liver collagen, collagenase activity, microsomal enzyme activities, splanchnic and systemic hemodynamics and portosystemic shunting. RESULTS: Treatment of rats presenting CCl4-induced cirrhosis with Liver Growth Factor decreased serum aminotransferase levels and increased levels of serum albumin and total protein. The Liver collagen content was lower in rats treated with Liver Growth Factor (2.96 vs. 4.32 mg/g liver, p<0.01). Microscopic studies revealed that the livers of rats receiving Liver Growth Factor showed decreases in fibrosis, necrosis and inflammatory infiltration, as well as a recovery of architectural integrity. Liver function was improved after treatment with Liver Growth Factor, as indicated by the rate constant for elimination of aminopyrine, which increased from 0.0063 to 0.0170 (p<0.05). This increase was accompanied by a higher total amount of cytochrome P-450 as well as of certain P-450 isoenzymes, especially those that are hormone-dependent, such as P-450 3A. The improved liver histology and function observed in Cirr+LGF rats was associated with decreases in portal pressure (14.4 vs. 9.4 mm Hg, p<0.01) and portosystemic shunting (55.8 vs. 11.5%, p<0.01), as well as increases in mean arterial pressure and systemic vascular resistance, and a reduction in ascites. CONCLUSIONS: Administration of the hepatic mitogen, Liver Growth Factor, to CCl4-cirrhotic rats decreased liver collagen and reorganized the hepatic extracellular matrix, resulting in an improvement in liver function, reduced portal pressure and amelioration of ascites.     

Inflammatory change of fatty liver induced by intraportal low‐dose lipopolysaccharide infusion deteriorates pancreatic insulin secretion in fructose‐induced insulin‐resistant rats

Background: This study tested whether subacute inflammatory change of fatty liver induced by portal endotoxaemia is detrimental to pancreatic insulin secretion in fructose‐fed rats (FFRs) with fatty liver. Methods: Rats were randomly assigned into two groups with a regular or fructose‐enriched diet for 8 weeks. Rats, after fructose feeding for 4 weeks, were further divided into three subgroups: on fructose diet alone, on fructose diet combined with intraportal saline or lipopolysaccharide (LPS) infusion (n=8 per group) for the next 4 weeks. In another set of experiments, the liver and pancreatic tissues were obtained for histological examination in these four groups. Pancreatic insulin secretion was evaluated by in vivo hyperglycaemic clamp study. Results: Fasting plasma insulin concentrations and homoeostasis model assessment‐insulin resistance, an insulin resistance score, were significantly increased in FFRs but failed to change in rats with LPS treatment. The 4‐week intraportal LPS infusion significantly increased circulating aspartate transaminase, alanine transaminase and C‐reactive protein levels but did not alter endotoxin levels in FFRs. The increased white blood cell count was also noted in rats after intraportal LPS infusion for 2 and 4 weeks. The attenuated first‐phase and second‐phase insulin responses in FFRs shown in hyperglycaemic clamp were further deteriorated in those with intraportal LPS infusion. Increased histopathological scores of liver and pancreas shown in FFRs were further increased in those combined with portal endotoxaemia. Conclusion: This study demonstrates that the chronic subacute inflammatory change of fatty liver induced by mild portal endotoxaemia could deteriorate insulin secretion in a rodent model of metabolic syndrome and fatty liver.     

Effects of hyperammonaemia on brain function

Neuropsychiatric symptoms of hyperammonaemia include alterations of mood and personality, cognitive impairment, ataxia, convulsions and coma. The nature and severity of CNS dysfunction depend upon the aetiology and degree of hyperammonaemia, its acuteness of onset and the age of the patient. Neuropathological studies reveal Alzheimer type II astrocytosis in the adult hyperammonaemic patient, whereas hyperammonaemia in the infant resulting from congenital urea cycle disorders or Reye syndrome is accompanied by cerebral atrophy, neuronal loss and cerebral oedema. Several electrophysiological and biochemical mechanisms have been proposed to explain the deleterious effects of ammonia on CNS function. Such mechanisms include direct effects of the ammonium ion on excitatory and inhibitory neurotransmission and a deficit in cerebral energy metabolism due to ammonia-induced inhibition of α-ketoglutarate dehydrogenase. In addition, ammonia has been shown to interfere with normal processes of uptake, storage and release of various neurotransmitters. Ammonia disrupts monoamine storage, inhibits the high-affinity uptake of glutamate by both astrocytic and neuronal elements and activates 'peripheral-type' benzodiazepine receptors leading to the potential synthesis of neuroactive steroids in brain. On the basis of these actions, it has been proposed that ammonia disrupts neuron-astrocyte trafficking of amino acids and monoamines in brain. The increased formation of brain glutamine in hyperammonaemic syndromes could be responsible for the phenomenon of brain oedema in these disorders. Therapies aimed at either decreasing ammonia production in the gastrointestinal tract or increasing ammonia removal by liver or skeletal muscle are the mainstay in the prevention and treatment of the CNS consequences of hyperammonaemia. New therapeutic approaches aimed at correction of the neurotransmitter and cerebral energy deficits in these syndromes could hold promise for the future.     

L-Carnitine in the treatment of mild or moderate hepatic encephalopathy

Hepatic encephalopathy (HE) is one of the major complications of cirrhosis. Experimental and clinical findings observed in liver, muscle and brain have provided new insights into the ammonia mechanism of action. L-Carnitine (LC), inducing ureagenesis, may decrease blood and brain ammonia levels. 120 patients meeting inclusion criteria were randomized either to a treatment for 60 days with LC or placebo (2 g twice a day). Previous studies have reported a significant protective effect of LC in mice and rats, which is associated with a significant reduction of blood and brain ammonia concentration, suggesting an action of LC either at peripheral or central sites. Results of our study show a protective effect of LC in ammonia-precipitated encephalopathy in cirrhotic patients. Either in subjects with HE 1 or 2 we observed a significant reduction at day 30 and more markedly at day 60 of treatment. A significant therapeutic effect of LC was also observed in the NCT-A, which is an accepted and reliable psychometric test for the assessment of mental function in cirrhotic patients with HE.     

Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: influence of the extent of portal-systemic shunting

The present study investigated whether, in rats with portal hypertension due to cirrhosis of the liver induced by carbon tetrachloride, blood volume restitution following a hemorrhage produces an increase of portal pressure beyond control values, as observed in rats with prehepatic portal hypertension. Since carbon tetrachloride-induced cirrhosis caused mild portal-systemic shunting, in some of the cirrhotic rats (12 of 29 rats) portal-systemic shunting was enhanced by a transient (4 days) partial constriction of the portal vein, which was removed 1 week prior to the study. After baseline measurements of portal pressure and arterial pressure, 15 ml per kg of blood were withdrawn at a rate of 0.3 ml per min and reinfused 15 min later. After blood reinfusion, portal pressure and arterial pressure were measured again, and cardiac output, regional blood flows and portal-systemic shunting were determined using radioactive microspheres. Portal-systemic shunting was 78 +/- 11% of total blood flow in the cirrhotic rats that had temporary portal vein constriction, but only 5 +/- 2% (p less than 0.001) in those that did not. Blood volume restitution in low-portal-systemic shunting rats did not produce any significant modification in splanchnic or systemic hemodynamics. However, in rats with high portal-systemic shunting, blood volume restitution produced a significant increase in portal pressure (from 9.9 +/- 0.9 to 13.5 +/- 0.9 mmHg, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)