Rat CCl4‐induced cirrhosis plus total portal vein ligation: a new model for the study of hyperammonaemia and brain oedema

Introduction: Animal models used to study hyperammonaemic disorders related to chronic liver disease are unsatisfactory. These animals only develop hyperammonaemia and brain oedema when fed with diets supplemented with amonium acetate. Aim: To develop a novel experimental model of hyperammonaemia and brain oedema in CCl₄‐induced cirrhosis in rats. Methods: Four groups were studied: rats with sham intervention (S), rats with total portal vein ligation (TPVL), cirrhotic rats (LC), and cirrhotic rats with TPVL (LC+TPVL). When ascites was diagnosed, oral glutamine challenge (OGC) test was performed. Blood, liver, lungs and brain samples were collected to quantify liver function parameters, plasmatic and cerebral ammonia, endotoxaemia, liver and brain histology, brain oedema and portosystemic shunting degree. Results: LC+TPVL rats showed a significant increase in portosystemic shunting when compared with LC group and a significant derangement in liver function when compared with TPVL group. These alterations resulted in a significant increase in plasmatic and brain ammonia concentrations and a higher plasmatic endotoxaemia as compared with others. Similarly, the area under OGC curve was significantly increased in LC+TPVL group as compared with the others, and correlates with portal shunting. Low‐grade brain oedema was only observed in LC+TPVL group. All cirrhotic groups showed liver regeneration nodules and type‐II Alzheimer astrocytes Conclusion: LC+TPVL reproduce the main alterations – portosystemic shunting, plasmatic and cerebral hyperammonaemia and low‐grade brain oedema – observed in cirrhotic patients with hepatic encephalopathy.     

Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction

BACKGROUND/AIMS: Previous studies reported decreased serum IGF-1 levels in cirrhosis. We aimed to correlate GH-stimulated IGF-1 responses with both MELD and Child-Pugh scores and determine the impact of portal hypertension and nutrition on IGF-1 responses. METHODS: Fifty-three patients (56+/-2 yrs) with cirrhosis were enrolled. Serum IGF-1 levels were measured by RIA before and 24h after a single injection of GH (0.06 mg/kg). RESULTS: Compared to controls, basal IGF-1 levels were significantly decreased in patients with cirrhosis (17.3+/-6.3 vs 13.6+/-5.1, P<0.001). Increments in IGF-1 levels were significantly lower in cirrhotic patients (controls: 133% vs 49% in MELD score <10, 38% in MELD score 11-18, and 13% in MELD score 19-24, p<0.001). 37% of patients had blunted IGF-1 responses. Increments in IGF-1 levels correlated with albumin (r=0.6), portal congestive index (r=0.4), and MAMC (r=0.25). By multivariate analysis, only CP (OR 5.7) and MELD scores (OR 4.5) accurately differentiated between blunted or non-blunted IGF-1 responses and not portal hypertension (OR 0.9) or malnutrition (OR 1.35). CONCLUSIONS: Cirrhosis is associated with low IGF-1 levels and an attenuated response to exogenous GH. These findings correlate better with the extent of hepatic dysfunction rather than the presence of portal hypertension or malnutrition.     

Oral bile acids reduce bacterial overgrowth,bacterial translocation,and endotoxemia in cirrhotic rats

Experiments were performed to test whether conjugated bile acid administration would decrease bacterial overgrowth, bacterial translocation, and endotoxemia in ascitic cirrhotic rats. Cholylsarcosine, a deconjugation-dehydroxylation resistant and cholylglycine, a deconjugation-dehydroxylation susceptible bile acid were used. Rats with CCl(4)-induced cirrhosis and ascites were fed cholylsarcosine, cholylglycine (both at 70 mg/kg/d), or placebo for 2 weeks. Healthy rats, as controls, were treated similarly. In cirrhotic rats receiving placebo, bile secretion from an acute biliary fistula was lower than in healthy rats (27.2 +/- 6.5 vs. 53.0 +/- 3.1 microL/kg/min; mean +/- SE, P<.05). The administration of conjugated bile acids to cirrhotic rats normalized bile secretion (cholylsarcosine, 51.8 +/- 6.29; cholylglycine, 52.72 +/- 8.9 microL/kg/min). Total ileal bacterial content was 6-fold higher in ascitic cirrhotic rats than in healthy rats. Conjugated bile acid administration reduced bacterial content to normal levels. Bacterial translocation was less in cirrhotic animals receiving conjugated bile acids (cholylsarcosine, 33%; cholylglycine, 26%) than in animals receiving placebo (66%). Endotoxemia was decreased in cirrhotic rats by conjugated bile acid feeding (cholylsarcosine, 0.098 +/- 0.002; cholylglycine 0.101 +/- 0.007 EU/mL) compared with placebo (0.282 +/- 0.124, P <.001). Survival was greater in animals receiving conjugated bile acids (cholylsarcosine, 10/15; cholylglycine, 11/15; placebo, 5/15). In conclusion, the administration of conjugated bile acids to ascitic cirrhotic rats increased bile acid secretion, eliminated intestinal bacterial overgrowth, decreased bacterial translocation, decreased endotoxemia, and increased survival. Oral conjugated bile acids may be useful in preventing bacterial translocation, endotoxemia, and spontaneous bacterial perotonitis in cirrhotic patients.     

Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis

BACKGROUND/AIMS: Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats. METHODS: Twenty-nine Sprague-Dawley rats with cirrhosis induced by CCl(4) and ascites received Lactobacillus johnsonii La1 10(9)cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage. RESULTS: Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05). CONCLUSIONS: Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis.     

Endotoxemia, Encephalopathy, and Mortality in Cirrhotic Patients

Endotoxemia without sepsis was detected with a chromogenic Limulus assay in 36 of 39 (92.3%) cirrhotic patients and was absent in seven healthy volunteers. In 11 patients who underwent elective portasystemic shunt, portal vein endotoxemia was higher than inferior vena caval: p less than 0.05, systemic endotoxin levels did not change, compared to preoperative levels, on the 1st, 2nd, and 3rd postoperative days, attendant to an uneventful recovery. In 21 patients in hepatic encephalopathy after esophagogastric hemorrhage, systemic endotoxemia was higher than in well-compensated cirrhotics: p less than 0.001; it was higher in deep than in light coma: p less than 0.05; it was higher in those who died than in those who survived: p less than 0.001. Endotoxin levels showed a positive correlation with serum bilirubin: r = 0.59, p less than 0.001, and a negative correlation with prothrombin activity: r = -0.59, p less than 0.001. These data show endotoxemia without sepsis is a constant finding in cirrhosis and increasing levels of endotoxemia are associated with hepatic failure, encephalopathy, and death.     

Inflammation:A novel target of current therapies for hepatic encephalopathy in liver cirrhosis

Hepatic encephalopathy(HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrumof manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The antiinflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE.     

Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.     

Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial.

Preliminary data suggest that rifaximin a new non-absorbable rifamycin-derivate, has beneficial effects on chronic portal systemic encephalopathy (PSE). To compare the efficacy and safety of rifaximin vs neomycin in the treatment of the hyperammoniemic state of PSE, 30 cirrhotic patients with grade I to III of PSE were randomly allocated to one of two groups: group A (15 patients) receiving rifaximin (400 mg/8h) and group B (15 patients) neomycin (1gr/8h). The duration of treatment was 21 consecutive days. Age, sex, hepatic and renal function, level of PSE, EEG and number connection test were similar in both groups. A significant decrease in blood ammonia levels was observed at the end of the treatment period in both groups; moreover rifaximin produced an earlier reduction of blood ammonia levels. The neuropsychic syndrome related to the PSE improved in both groups without significant difference. No side effects attributable to therapy were observed in the rifaximin group. These results indicate that, rifaximin is at least as effective as neomycin in the achievement and maintenance of low blood ammonia levels in cirrhotics with chronic PSE.     

Role of intestinal bacterial overgrowth and intestinal motility in bacterial translocation in experimental cirrhosis.

BACKGROUND: Intestinal bacterial overgrowth (IBO) is related to small bowel motility and has been involved in the pathogenesis of bacterial translocation (BT) in experimental models, and both overgrowing gut flora and translocating bacteria to mesenteric lymph nodes are common features in cirrhosis. OBJECTIVES: The aims of this study were to analyze cecal aerobic bacteria and intestinal transit in cirrhotic rats, and their relationship with BT, evaluating the role of intestinal bacterial overgrowth and small bowel dismotility in the development of BT in experimental cirrhosis. MATERIAL AND METHODS: We included twenty-seven male Sprague-Dawley rats with carbon tetrachloride-induced cirrhosis without ascites and ten controls. Cultures of mesenteric lymph nodes (MLN), peripheral and portal blood, liver, spleen and cecal samples were carried out. Small intestinal transit was determined in ten cirrhotic rats and in ten control rats. RESULTS: The prevalence of bacterial translocation was 56%. Total cecal aerobic bacteria count was significantly higher in cirrhotic rats than in control rats (p < 0.001). Cirrhotic rats with translocated bacteria had higher total aerobic intestinal counts than culture-negative MLN bacteria (p < 0.05). The prevalence of total intestinal bacterial overgrowth in cirrhotic animals was 67%, and 0% in control animals (p < 0.001). According to BT, total IBO was more frequent in cirrhotic rats with BT versus those without BT (93 vs. 33%) (p < 0.001). Of the translocating bacteria, 95.6% were found to be overgrown in the cecum. The small-intestinal transit was slower in cirrhotic rats (60.5 +/- 12.7 cm vs. 81.2 +/- 5.7 cm) than in control animals (p < 0.001). CONCLUSIONS: These results suggest that the increase of intestinal aerobic bacteria in experimental cirrhosis is associated with translocation. In addition, IBO is frequent in cirrhotic rats, and is supposed to play an important role in the development of BT. Impaired motility of the small intestine is a common feature in cirrhosis and may be implicated in the pathogenesis of IBO.     

Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis

OBJECTIVES: The significance of small intestinal bacterial overgrowth in patients with cirrhosis is not fully understood and its diagnostic criteria are not uniform. We examined the association of small intestinal bacterial overgrowth with spontaneous bacterial peritonitis and compared various microbiological criteria. METHODS: Jejunal secretions from 70 patients with cirrhosis were cultivated quantitatively and classified according to various definitions. Clinical characteristics of patients were evaluated and the incidence of spontaneous bacterial peritonitis was monitored during a 1-yr follow-up. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony-forming units/ml jejunal secretions, was present in 61% of patients. Small intestinal bacterial overgrowth was associated with acid-suppressive therapy (p = 0.01) and hypochlorhydria (p < 0.001). Twenty-nine patients with persistent ascites were observed. Six episodes of spontaneous bacterial peritonitis occurred after an average 12.8 wk. Occurence of spontaneous bacterial peritonitis correlated with ascitic fluid protein concentration (p = 0.01) and serum bilirubin (p = 0.04) but not with small intestinal bacterial overgrowth (p = 0.39). Its association with acid-suppressive therapy was of borderline significance (hazard ratio = 7.0, p = 0.08). CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is associated with acid-suppressive therapy and hypochlorhydria, but not with spontaneous bacterial peritonitis. The potential role of acid-suppressive therapy in the pathogenesis of spontaneous bacterial peritonitis merits further studies.     

Sleep apnoea syndrome and early stage cirrhosis: a pilot study

OBJECTIVES: Hepatic encephalopathy in patients with end-stage liver cirrhosis is associated with alterations in sleep patterns. Cirrhosis may also affect pulmonary function and it might be involved in the development of obstructive sleep apnoea syndrome (OSAS) in patients with ascites. We carried out a study to evaluate the presence of OSAS in cirrhotic patients without evidence of ascites (early stage cirrhosis). METHODS: We investigated 20 patients with Child A or B cirrhosis (19 and one, respectively) and 10 non-cirrhotic patients with chronic viral hepatitis (disease control group). All subjects were interviewed and underwent a thorough physical examination, a full polysomnographic study and a pulmonary function testing by spirometry. Serum samples were also obtained in order to determine the liver function tests. RESULTS: The presence of OSAS and inverted sleep patterns was similar in cirrhotic patients and disease controls. However, significant correlations were revealed between age and hypopnoeas per hour of sleep; age and the Apneas/Hypopneas Index (AHI); age and FEV1/FVC; gamma-glutamyl transpeptidase and FEV1/FVC; and total bilirubin and total sleep time. CONCLUSIONS: Early stage cirrhosis is not associated with sleep disorders and OSAS. However, total bilirubin levels might be a useful laboratory marker for early assessment of disturbance in sleep patterns and therefore of subclinical hepatic encephalopathy in Child A cirrhosis.     

内毒素受体、内毒素血症与肝硬化

内毒素在肝脏内可激活Kupffer细胞,合成和释放多种细胞因子和炎症介质,使肝细胞受损,其作用机制主要是通过Kupffer细胞上的内毒素受体启动宿主免疫反应和效应功能。肝硬化患者因多种原因引起肠道菌群生长过度和菌群易位,可导致内毒素血症;反之,内毒素本身又可加重肝脏损伤。因此,通过改变肝硬化患者的肠道微生态,调节肠道菌群,可减少肠道内毒素的产生,防止内毒素血症的发生,减轻肝脏损伤,延缓肝硬化的进程。     

Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia

OBJECTIVES: Systemic endotoxemia has been implicated in various pathophysiological sequelae of chronic liver disease. One of its potential causes is increased intestinal absorption of endotoxin. We therefore examined the association of small intestinal bacterial overgrowth with systemic endotoxemia in patients with cirrhosis. METHODS: Fifty-three consecutive patients with cirrhosis (Child-Pugh group A, 23; group B, 18; group C, 12) were included. Jejunal secretions were cultivated quantitatively and systemic endotoxemia determined by the chromogenic Limulus amoebocyte assay. Patients were followed up for 1 yr. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony forming units per milliliter of jejunal secretions, was present in 59% of patients and strongly associated with acid suppressive therapy. The mean plasma endotoxin level was 0.86 +/- 0.48 endotoxin units/ml (range = 0.03-1.44) and was significantly associated with small intestinal bacterial overgrowth (0.99 vs 0.60 endotoxin units/ml, p = 0.03). During the 1-yr follow-up, seven patients were lost to follow up or underwent liver transplantation and 12 patients died. Multivariate Cox regression showed Child-Pugh group to be the only predictor for survival. CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is common and associated with systemic endotoxemia. The clinical relevance of this association remains to be defined.     

Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites

Bacterial translocation appears to be an important mechanism in the pathogenesis of spontaneous infections in cirrhosis. Cirrhotic patients are commonly treated with beta-adrenoceptor blockers, but the impact of this treatment in the factors promoting bacterial translocation has not been investigated. This study was aimed at investigating in cirrhotic rats with ascites the effect of propranolol on intestinal bacterial load, transit, and permeability of the bowel and on the rate of bacterial translocation. Bacterial translocation to mesenteric lymph nodes and intestinal bacterial overgrowth, permeability (urinary excretion of (99m)Tc-diethylenetriaminepentaacetic acid [(99m)Tc-DTPA]), and transit (geometric center ratio of (51)Cr) were assessed in 29 rats with carbon tetrachloride (CCl(4)) cirrhosis and 20 controls. These variables were then measured in 12 placebo- and in 13 propranolol-treated ascitic cirrhotic rats. Bacterial translocation was present in 48% of the cirrhotic rats and in none of the controls. Cirrhotic rats with intestinal bacterial overgrowth had a significantly higher rate of translocation and slower intestinal transit than those without it. Among the 15 rats with overgrowth and a (99m)Tc-DTPA excretion greater than 10%, 15 had translocation and 2 had bacterial peritonitis. Only 1 of the 14 rats with either intestinal overgrowth or a (99m)Tc-DTPA excretion greater than 10% presented translocation. Compared with the placebo group, propranolol-treated animals had significantly lower portal pressure, faster intestinal transit, and lower rates of bacterial overgrowth and translocation. In ascitic cirrhotic rats, bacterial translocation results from intestinal overgrowth and severe damage to gut permeability. In this setting, intestinal overgrowth is associated with intestinal hypomotility. Propranolol accelerates the intestinal transit, decreasing the rates of bacterial overgrowth and translocation.     

Intestinal mucosal oxidative damage and bacterial translocation in cirrhotic rats

BACKGROUND: Bacterial translocation plays an important role in the pathogenesis of spontaneous bacterial peritonitis mainly due to intestinal bacterial overgrowth. Alterations in the functional integrity of the intestinal barrier caused by an increased production of free radical metabolites as a consequence of portal hypertension could also facilitate bacterial translocation in cirrhotic rats. OBJECTIVE: The aim of the study was to determine intestinal mucosal lipid peroxidation and neutrophil infiltration and their relationship with portal hypertension and bacterial translocation in cirrhotic rats. DESIGN: Eighteen male Sprague-Dawley rats with cirrhosis induced by carbon tetrachloride, administered by gavage, and eight control rats were included in the study. METHODS: Samples of jejunum, ileum and caecum were obtained by laparotomy for the determination of malondialdehyde and myeloperoxidase as indexes of lipid peroxidation and neutrophil infiltration, respectively. Samples of ascitic and pleural fluids, mesenteric lymph nodes and ileal stools were obtained for the culture of microoganisms. RESULTS: The concentration of malondialdehyde was significantly higher in ileal and caecal, but not in jejunal mucosa, in cirrhotic rats, mainly in those with ascites (P< 0.01), as compared to control rats (P< 0.01), and in cirrhotic rats with bacterial translocation compared to those without bacterial translocation (P< 0.01). No differences between groups were observed in the concentrations of myeloperoxidase in jejunum, ileum or caecum. A direct correlation between ileal malondialdehyde and portal pressure was observed (P< 0.01). CONCLUSIONS: Cirrhotic rats, particularly those with ascites and bacterial translocation, show increased malondialdehyde levels in ileal and caecal mucosa. These results suggest that mucosal oxidative damage in ileum and caecum could favour bacterial translocation in cirrhotic rats.     

The prevalence of atherosclerosis in cirrhotic patients: assessment of two aspects of atherosis and sclerosis

Aim: In general, cirrhotic patients are known to have a low prevalence of cardiovascular disease. Cirrhosis is often accompanied by diabetes mellitus, while blood pressure and serum cholesterol levels are low in liver cirrhosis. We examined the atherosclerosis of patients with chronic liver disease by two phases of atherosis "lipid deposition" and sclerosis "arterial fibrosis." Methods: Atherosis was assessed by carotid intima-media thickness and the ratio of the systolic blood pressure at the ankle to the average systolic blood pressure at the right arm (ankle brachial pressure index), while sclerosis was evaluated by brachial ankle pulse wave velocity. Results: There were no significant differences in intima-media thickness and ankle brachial index among grades of cirrhosis. Brachial ankle pulse wave velocity decreased closely as the severity of cirrhosis progressed (F = 4.90, P < 0.05). In univariate analysis, brachial ankle pulse wave velocity was correlated with systolic blood pressure, age, total bilirubin, albumin, prothrombin time, retention rate of indocyanine green at 15 min, blood ammonia, branched chain amino acids/tyrosine molar rate and fasting blood sugar. Multiple regression analysis showed that systolic blood pressure and total bilirubin were independent factors for the inhibition of vascular sclerosis progression. Conclusion: Although no difference in atherosis between cirrhotic patients and healthy controls was found, vascular sclerosis was decreased with the severity of cirrhosis through hypotension and hyperbilirubinemia.     

Clinical and laboratory differentiation of cirrhosis and extrahepatic portal venous obstruction in children

BACKGROUND AND AIM: Differentiation between cirrhosis and extrahepatic portal venous obstruction (EHPVO) in children presenting with features of portal hypertension is important for cost-effective management and proper resource utilization. We undertook this study to differentiate clinical and laboratory features between these two groups of patients. METHODS: Clinical features and laboratory parameters at presentation of children with portal hypertension and cirrhosis of the liver were analyzed. The variables analyzed were age at presentation, duration of symptoms, incidence and frequency of upper gastrointestinal (GI) bleeding, encephalopathy, jaundice, ascites, splenomegaly, and presence of dilated abdominal veins. The laboratory parameters studied were hemoglobin, prothrombin time, serum bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. Two groups were compared using appropriate statistical methods; and the differentiating features were analyzed using logistic regression analysis. RESULTS: Of the total of 120 cases, cirrhosis was diagnosed in 28.3% and EHPVO in 71.6%. Children with EHPVO, in comparison to cirrhosis, had significantly higher frequency of upper GI bleeding (61.6%vs 14.7%), increased number of previous bleeding episodes (2.7 +/- 0.5 vs 1.2 +/- 0.4), longer duration of symptoms (25.7 +/- 4.6 vs 12.3 +/- 3 months) and a lower frequency of jaundice (2%vs 76.4%). Low hemoglobin (6.4 +/- 2.7 g/dL) and preserved liver functions characterized by normal bilirubin, albumin levels and prothrombin time were observed in EHPVO cases. Cirrhosis patients had higher hemoglobin (8.8 +/- 2.8 g/dL) and abnormal liver function tests. CONCLUSION: Presence of UGI bleeding and the absence of jaundice are 97.5% accurate in predicting diagnosis of EHPVO.     

Cerebral vascular resistance assessed by transcranial color Doppler ultrasonography in patients with chronic liver diseases

BACKGROUND AND AIM: Cerebral hemodynamic derangement is well known in patients with liver cirrhosis. The advent of transcranial Doppler enables a non-invasive observation of cerebral hemodynamics. To evaluate the clinical usefulness we examined cross-sectionally and longitudinally cerebral hemodynamic parameters in patients with cirrhosis. METHODS: The subjects of the cross-sectional study were 117 patients with cirrhosis, 15 patients with chronic hepatitis and 25 healthy controls. The longitudinal study included 26 cirrhotic patients without encephalopathy, and 27 cirrhotic patients with encephalopathy. The pulsatility and resistive indices of the right middle cerebral artery were used as parameters of cerebral hemodynamics. RESULTS: Cerebral pulsatility and resistive indices were significantly higher in patients with cirrhosis (1.05 +/- 0.23, P < 0.0001 and 0.63 +/- 0.07, P < 0.0001, respectively) than in the controls (0.75 +/- 0.11 and 0.55 +/- 0.05, respectively) and patients with chronic hepatitis (0.81 +/- 0.11 and 0.52 +/- 0.05, respectively). Cerebral pulsatility and resistive indices were significantly related with the severity of liver cirrhosis. Patients with encephalopathy had higher cerebral pulsatility and resistive indices than patients without encephalopathy. In the longitudinal studies, cerebral pulsatility and resistive indices were changed in parallel with the severity of cirrhosis and encephalopathy. Cerebral pulsatility and resistive indices were significantly correlated with the blood ammonia level and serum levels of bilirubin and albumin. CONCLUSION: These cross-sectional and longitudinal studies showed that cerebral vascular resistance indices measured by using transcranial Doppler were increased in association with the severity of cirrhosis and encephalopathy. Cerebral pulsatility and resistive indices are real-time and useful parameters to assess and monitor cirrhotic patients.     

Value of regional cerebral blood flow in the evaluation of chronic liver disease and subclinical hepatic encephalopathy

AIMS: Regional changes in cerebral blood flow in patients with chronic hepatitis, cirrhosis and subclinical hepatic encephalopathy were investigated in the present study using single photon emission computed tomography (SPECT). METHODS: Twenty patients with cirrhosis, 11 patients with chronic hepatitis, and nine healthy controls were included in the study. Cerebral SPECT were obtained for all patients. The percentages of cerebral blood flow of 14 regions to the cerebellar blood flow were determined. Only the patients with cirrhosis underwent psychometric evaluation: visual evoked potentials (VEP) measurements and electroencephalogram (EEG) recordings along with blood levels of albumin, bilirubin, and ammonia were measured and prothrombin time was determined in cirrhotic patients. These patients were classified according to the Child-Pugh classification. RESULTS: Among cirrhotic patients, six had abnormal results in VEP studies, 11 in psychometric tests and with six in EEG evaluation. Any abnormality in psychometric tests and/or VEP studies is taken as the main criterion; subclinical hepatic encephalopathy was detected in 12 of 20 patients. According to SPECT results in patients with subclinical encephalopathy, a statistically significant decrease in cerebral blood flow in right thalamus and nearly significant decrease in left thalamus were observed. Regional blood flow was significantly higher in the frontal lobes of patients with cirrhosis when compared with healthy controls. Similarly, cerebral blood flow in frontal and cingulate regions was significantly higher in patients with chronic hepatitis than in healthy controls. There was no relationship between cerebral blood flow and blood levels of ammonia or Child-Pugh score, in cirrhotic patients. CONCLUSION: Significant changes in cerebral blood flow may be present in chronic liver diseases and the authors suggest that the measurement of changes in cerebral blood flow might be useful in detecting subclinical hepatic encephalopathy.     

Cirrhosis and endotoxin decrease urea synthesis in rats

Aim: In patients with cirrhosis, endotoxemia is frequent and the vitally important capacity for urea synthesis is impaired. The patients' mortality of infection is markedly increased, which could be related to adverse metabolic effects of endotoxins. The effects of endotoxins on in vivo urea synthesis and on urea cycle genes during cirrhosis are unknown. Methods: We examined the effects of a low dose of 0.5 mg/kg ip lipopolysaccharide (LPS) on the basal urea nitrogen synthesis rate (UNSR), the capacity of urea nitrogen synthesis (CUNS), liver tissue mRNA levels of urea cycle enzyme genes, and on the metabolic liver function measured by the galactose elimination capacity (GEC) in rats with cirrhosis induced by bile duct ligation and in control animals. Results: LPS and cirrhosis + LPS decreased UNSR by 40% (P < 0.05). Cirrhosis and LPS each tended to decrease CUNS and cirrhosis + LPS decreased CUNS by 40% (P < 0.05). Cirrhosis and LPS each decreased the mRNA level of the gene for the flux-generating urea cycle enzyme carbamoyl phosphate synthetase (CPS) and the mRNA for the rate-limiting urea cycle enzyme arginine succinate synthetase (ASS) (P < 0.05). Cirrhosis + LPS left the mRNA level of CPS unchanged and decreased that of ASS (P < 0.05). The GEC did not differ among the study groups. Conclusion: Endotoxemia in rats with experimental cirrhosis markedly impaired the ability of the animals' livers to synthesize urea, suggesting a pathophysiological mechanism underlying the severe consequences of endotoxemia in human cirrhosis.