Pathological bacterial translocation in cirrhosis: pathophysiology,diagnosis and clinical implications

Bacterial translocation (BT) is defined by the passage of viable indigenous bacteria from the intestinal lumen to mesenteric lymph nodes (MLNs) and other territories, and its diagnostic criteria rely on the isolation of viable bacteria in MLNs. Small intestinal overgrowth, increased intestinal permeability and immunological alterations are the main factors involved in its pathogenesis. BT is obviously difficult to identify in patients with cirrhosis, and alternative methods have been proposed instead. Bacterial DNA detection and species identification in serum or ascitic fluid has been proposed as a reliable marker of BT. Bacterial products, such as endotoxin, or bacterial DNA can translocate to extra‐intestinal sites and promote an immunological response similar to that produced by viable bacteria. Therefore, pathological BT plays an important role in the pathogenesis of the complications of cirrhosis, not only in infections, but by exerting a profound inflammatory state and exacerbating the haemodynamic derangement. This may promote in turn the development of hepatorenal syndrome, hepatic encephalopathy and other portal hypertension‐related complications. Therapeutic approaches for the prevention of BT in experimental and human cirrhosis are summarized. Finally, new investigations are needed to better understand the pathogenesis and consequences of translocation by viable bacteria (able to grow in culture), or non‐viable BT (detection of bacterial fragments with negative culture) and open new therapeutic avenues in patients with cirrhosis.     

Relationships between the severity of cirrhosis and haemodynamic values in patients with cirrhosis

Abstract The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post-necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pugh's A patients (13.6 ± 4.8 mmHg and 6.2 ± 1.6 L/min, mean ± s.d.) were significantly lower than in both Pugh's B (16.8 ± 4.3 mmHg and 7.3 ± 2.1 L/min) and Pugh's C (18.8 ± 5.5 mmHg and 7.4 ± 2.3 L/min) patients ( P < 0.01), respectively. In contrast, the systemic vascular resistance in Pugh's A patients (1232 ± 369 dyn/s per cm⁵) was significantly higher than in both Pugh's B (1016 ± 345 dyn/s per cm⁵) and Pugh's C (935 ± 234 dyn/s per cm⁵) patients ( P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pugh's score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pugh's score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 ± 4.0, 17.0 ± 4.8 and 18.0 ± 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.     

Rifaximin has minor effects on bacterial composition,inflammation, and bacterial translocation in cirrhosis: A randomized trial

Background and Aim

Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo‐controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis.

Methods

Fifty‐four out‐patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end‐stage liver disease score 12 (± 3.9). Patients received rifaximin 550‐mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real‐time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing.

Results

Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell‐derived factor 1‐α, transforming growth factor β‐1, and high sensitivity C‐reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin.

Conclusion

Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).     

Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis

Aim: Bacterial translocation (BT) to mesenteric lymph nodes (MLN) in cirrhosis has been linked to impaired host defence. Phagocytosis by polymorphonuclear leucocytes (PMNLs) is the primary event in the killing of bacteria but has not been investigated in relation to the presence of BT. Methods: Mesenteric lymph nodes were harvested sterile and assessed for BT by culture techniques. Study groups included ascitic cirrhotic rats (LC), healthy controls (Con) as well as portal‐vein‐ligated (PVL) rats 2 days (acute PVL with and without norfloxacin) or 3 weeks after surgery (chronic PVL). PMNLs were isolated from systemic blood and the capacity to phagocytose opsonized Escherichia coli was evaluated by FACS analysis. Results: No BT was observed in Con and chronic PVL animals but 11/20 LC (55%) and six out of six acute PVL (100%) presented with BT. In the presence of BT, PMNL from PVL as well as LC rats showed significantly increased phagocytic activity as compared with controls. In contrast, PMNL from animals without BT, whether PVL or LC, exhibited phagocytic activity similar to those from control rats. The number of PMNLs involved in the phagocytic process was significantly increased only in portal‐hypertensive rats with but not without BT as compared with controls. Norfloxacin did prevent BT in acute PVL animals, thereby correcting the increase in phagocytic capacity in PMNL. Conclusions: Cirrhosis per se is not associated with alterations of the phagocytic capacity of PMNL. The occurrence of BT, however, increases the phagocytic capacity of PMNL, being observed likewise in prehepatic portal hypertension, indicating an in vivo‘priming’ of PMNL by BT independent of cirrhosis.     

Presence of Bacterial Infection in Bleeding Cirrhotic Patients Is Independently Associated with Early Mortality and Failure to Control Bleeding

Bacterial infection is strongly associated with gastrointestinal bleeding in cirrhotic patients and seems to be related with the failure to control bleeding. The aims of this study were to assess the influence of infections on the failure to control bleeding and death in cirrhotic patients without antibiotic prophylaxis. Ninety-one consecutive bleeding cirrhotic patients were analyzed. Bleeding was managed using somatostatin with sclerotherapy for active bleeding. Screening for bacterial infection (analysis and culture of blood, urine, ascitic and other fluids, together with chest radiography) was made at time 0 and when clinical signs suggested infection. The cause of bleeding was variceal in 72 (79%) patients. Failure to control bleeding occurred in 24 (26%) patients, and 10 (11%) of the patients died. Compared with the group without infection, failure to control bleeding (65% vs 15%; P < 0.001) and mortality (40% vs 3%; P < 0.001), were observed more frequently in patients with infection. Multivariate analysis showed that bacterial infection (OR = 9.7; P < 0.001) and the presence of shock (OR = 3.5; P < 0.05) were independently associated with failure to control bleeding. Bacterial infection (OR = 12.6; P < 0.01), encephalopathy (OR = 6.9; P < 0.05), and shock (OR = 5.8; P < 0.05) were identified as predictive of death. In conclusion, in bleeding cirrhotic patients bacterial infection is associated with failure to control bleeding as well as mortality.     

The free portal pressure in awake patients with and without cirrhosis of the liver

ABSTRACT— The free portal pressure was measured by percutaneous transhepatic catheterization of the portal vein in 106 patients with cirrhosis of the liver and in 19 patients without liver disease and with normal portography. Patients with cirrhosis had a median portal pressure of 38 cmH₂O and patients without liver disease had a median portal pressure of 16 cmH₂O. Among the cirrhotic patients the free portal pressure showed no relationship to etiology of cirrhosis, ascites, variceal bleedings or extrahepatic shunting. The median portal pressure was significantly higher in patients with (40 cmH₂O) than without (30 cmH₂O) gastroesophageal varices (p<0.01). The pressure was not related to the size of the varices.     

Vascular,hemodynamic and renal effects of low‐dose losartan in rats with secondary biliary cirrhosis

Background: In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to α1‐adrenoceptor agonists. Recently, the angiotensin II type 1‐receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to α1‐adrenoceptor agonists. Methods: We studied, in rats with secondary biliary cirrhosis and sham‐operated rats, the effect of 0.5 and 10 mg losartan/kg × day on aortic responsiveness to α1‐adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. Results: In cirrhotic rats, 10 mg losartan/kg × day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg × day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. Conclusions: In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to α1‐adrenoceptor agonists.     

肝硬化诊治思路:经典与拓展

肝硬化是我国最严重的公共卫生问题之一。对失代偿期肝硬化患者及时进行病因治疗,延缓其发展,一直是实用而有效的经典策略。高质量或创新的诊疗其实就蕴含在这些平凡的细致工作中。门静脉高压本质上是血管疾病,及时解除门静脉系统压力是防止疾病进展和各种严重并发症的关键。治疗决策需要在对门静脉高压全局有全面了解的基础上做出,微创技术是完成智慧策略的重要手段。     

Underlying mechanism of portal hypertensive gastropathy in cirrhosis: A hemodynamic and morphological approach

Background and Aim:  Portal hypertensive gastropathy (PHG) is an important cause of bleeding in patients with cirrhosis associated with portal hypertension. Histologically, the condition is characterized by dilation of the mucosal and submucosal vessels of the stomach; however, its mechanisms remain unclear. The aim of the present cross-sectional study was to evaluate the role of portal and systemic hemodynamic features, humoral factors and hepatocellular function in the development and severity of PHG in patients with cirrhosis.
Methods:  Forty-six patients with cirrhosis of different etiologies underwent endoscopy. Portal hypertension was evaluated by hepatic venous pressure gradient (HVPG). The gastric mucosa was analyzed using two diagnostic methods: endoscopy according to the McCormack criteria and histological by histomorphometric analysis.
Results:  The prevalence of PHG according to the endoscopic and histomorphometric methods was 93.4% and 76.1%, respectively. There were no statistically significant differences in HVPG measurements between the patients with mild (16.0 ± 5.9 mmHg) and severe PHG (16.9 ± 6.5 mmHg; P  = 0.80) or between patients who did not have (15.2 ± 8.0 mmHg) and those who had PHG (16.3 ± 5.7 mmHg). No correlation was found between the presence or severity of PHG and systemic vascular resistance index ( P  = 0.53 and 0.34, respectively), Child–Pugh classification ( P  = 0.73 and 0.78, respectively) or glucagon levels ( P  = 0.59 and 0.62, respectively).
Conclusions:  The present data show no correlation between the presence or the severity of PHG and portal pressure, Child–Pugh classification or systemic hemodynamics, suggesting that other factors may be involved in the physiopathology of PHG, such as local gastric mucosal factors or other underlying factors.     

门静脉高压症血流动力学改变的发病机理

门静脉高压症（PHT）与肝内循环、体循环和门体侧支循环的血流动力学改变有关。肝内阻力增加和高动力循环侧支血管的扩张在门静脉高压的发病机理中起到了重要作用。不同严重程度的肝硬化均存在能广泛影响人体的血流动力学紊乱。门静脉高压和高动力循环是肝硬化患者发病和死亡的主要原因。而血管结构重塑和血管新生是治疗门静脉高压症的重要目标。     

Lack of hepatic benefit by oxygen inhalation during vasopressin infusion in patients with cirrhosis

Vasopressin has been found to impair hepatic function in patients with cirrhosis. The aim of this study was to investigate whether oxygen inhalation could improve hepatic function during vasopressin infusion. Vasopressin (0.3 iu/min) was infused into eight patients with cirrhosis for 50 min. During the first 30 min they were ventilated by room air and for the following 20 min by oxygen (approximate 50% of FiO2). The extra oxygen inhalation caused a typical increase in arterial (+7%, P less than 0.01), portal venous (+8%, P less than 0.05), and hepatic venous (+9%, P less than 0.01) oxygen content. No effect was noted in arterio-hepatic venous and portal venous-hepatic venous oxygen content difference in comparison with the values after vasopressin alone. The hepatic perfusion remained unchanged. These results suggest that the extra oxygen did not increase hepatic oxygen uptake. Similarly, intrinsic clearance of indocyanine green did not improve. It is concluded that oxygen supplement in this setting has no hepatic benefit in patients with cirrhosis.     

Patients with stable uncomplicated cirrhosis have normal neutrophil function

BACKGROUND: Neutrophil function has been reported to be abnormal in patients with cirrhosis. In order to evaluate the relative contribution of hepatocellular dysfunction and portalsystemic shunting of blood to these abnormalities, neutrophil function was studied in 18 patients with cirrhosis and portal hypertension. Nine patients, with extrahepatic portal hypertension (EPH) caused by portal vein thrombosis, who had no clinical, biochemical or histologic evidence of liver disease were also studied. METHODS: Superoxide generation, phagocytosis, degranulation, leukotriene B4 release, candidacidal activity and quantitative and qualitative expression of the cell surface adhesive marker CD11b/CD18 were measured in these patients as well as in age- and gender-matched controls. RESULTS: Patients with cirrhosis were found to have a small but statistically significant decrease in the expression of the CD18 component of MAC1 in N-formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils (P = 0.04). No significant differences were found between either of the two patient groups and the control group for any of the other parameters of neutrophil function tested. CONCLUSIONS: These were unexpected findings in the light of data published elsewhere, which indicate impaired neutrophil function in patients with cirrhosis. The study suggests that patients with stable, uncomplicated cirrhosis and patients with EPH have normal neutrophil function.     

Effect of anaemia on haemodynamics in patients with cirrhosis

BACKGROUND: It has been suggested that increased blood haemoglobin attenuates splanchnic vasodilatation in portal-hypertensive rats by nitric oxide inactivation. However, the haemodynamic effect of anaemia in cirrhotic patients of varying severity has been rarely discussed. The aim of this study was to evaluate the influence of anaemia on systemic and splanchnic haemodynamics in cirrhotic patients of differing severity. METHODS: Two hundred and twenty-five cirrhotic patients were included in this study. All biochemical and haemodynamic results were utilized for analysis. Anaemia was defined as a haemoglobin level below the cut-off value of 12 g/dL, which might best predict low systemic vascular resistance. RESULTS: Compared with non-anaemic patients, anaemic patients had decreased mean arterial pressure (90 +/- 1 vs 95 +/- 1 mmHg, P = 0.002), and decreased systemic vascular resistance (1022 +/- 25 vs 1227 +/- 30, P < 0.0001), and increased cardiac index (4.3 +/- 0.1 vs 3.8 +/- 0.1 L/min per m2, P < 0.0001) and increased hepatic venous pressure gradient (16.7 +/- 0.5 vs 14.4 +/- 0.6 mmHg, P = 0.006). Haemoglobin concentration exerted an influence on the degree of vasodilatation in cirrhotic patients, with Child-Pugh's A class (but not in Child-Pugh's B and C classes), and in patients without ascites (but not in patients with ascites). CONCLUSIONS: It was concluded that anaemia has a negative effect on hyperdynamic circulation in patients with early cirrhosis which is not observed in patients with advanced cirrhosis.     

Relationship between degree of portal hypertension and liver histologic lesions in patients with alcoholic cirrhosis

The relationship between the degree of portal hypertension and histologic liver lesions was studied in a group of 84 patients with histologically proven alcoholic cirrhosis. The degree of portal hypertension was evaluated by the gradient between wedged and free hepatic venous pressures. Five histologic lesions were quantified: liver cell necrosis, Mallory bodies, neutrophilic infiltrate, fibrosis, and fatty infiltration. The gradient between wedged and free hepatic venous pressures was significantly correlated with the degree of liver cell necrosis and the degree of neutrophilic infiltrate. The stepwise regression analysis showed that only liver cell necrosis has a significant and independent correlation for the degree of portal hypertension. The value for the gradient between wedged and free hepatic venous pressures was significantly higher in patients with (N=48) than in those without (N=36) acute alcoholic hepatitis (19.4±0.8 and 16.5±0.7 mmHg, respectively). Thus, histologic liver lesions observed in acute alcoholic hepatitis may play a role in the risk of complications of portal hypertension in patients with alcoholic cirrhosis.     

Hyperglucagonaemia in cirrhotic patients and its relationship to the severity of cirrhosis and haemodynamic values

Plasma glucagon concentrations were measured in 160 cirrhotic patients (Pugh's grade A in 52 patients, Pugh's grade B in 64 patients and Pugh's grade C in 44 patients). These values were compared with plasma glucagon concentrations in 57 age and sex-matched healthy subjects. Systemic and portal haemodynamic measurements, effective renal plasma flow and creatinine clearance were recorded for each patient. Plasma glucagon levels were significantly increased in cirrhotic patients compared with healthy subjects. In addition, plasma glucagon levels were higher in cirrhotic patients with ascites than in those without ascites and were increased in relation to the severity of cirrhosis as assessed by Pugh's score. Multiple linear regression found that only Child-Pugh's score was estimated to be an independent predictor of hyperglucagonaemia in cirrhotic patients. However, in patients with different degrees of oesophageal varices and in patients without oesophageal varices, plasma glucagon concentrations were no different among the different groups of patients, but were still higher than plasma glucagon concentrations in healthy subjects. In contrast, plasma glucagon levels were negatively correlated with mean arterial pressure and systemic vascular resistance. The results of the present study suggest that impairment of liver function plays, in part, a role in increased plasma glucagon levels observed in patients with cirrhosis. In addition, these data support the hypothesis that hyperglucagonaemia may contribute, at least in part, to the pathogenesis of peripheral arterial vasodilatation in cirrhosis with portal hypertension.