The current pathogenic theory of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites suggests that repeated episodes of bacterial translocation (BT) from intestinal lumen to mesenteric lymph nodes followed by systemic seeding are the key steps for the final development of infectious events. However, most of the episodes of systemic bacterial circulation remain undetected. Therefore, we investigated the hypothetical presence of bacteria in blood and/or ascitic fluid (AF) from patients with cirrhosis and sterile (culture negative) AF by means of bacterial DNA (bactDNA) detection and identification. Twenty-eight consecutively admitted patients with cirrhosis and presence of AF were included in the study. BactDNA was detected using a polymerase chain reaction (PCR)-based method. The corresponding bacteria were identified by nucleotide sequencing of purified PCR products. BactDNA was detected simultaneously in blood and AF in 9 patients (32.1%). DNA sequencing allowed the identification of Escherichia coli (n ‫؍‬ 7) and Staphylococcus aureus (n ‫؍‬ 2). In all cases, the similarity between the sequence found in AF and blood indicated that the bactDNA present in both locations originated from a single clone (single translocation event). Child-Pugh score and basic hemodynamic, clinical, endoscopic, and biochemical characteristics were similar among patients with or without the presence of bactDNA. In conclusion, we have detected bactDNA in serum and AF in 32% of all patients studied, and this likely represents single clone episodes of translocation and systemic seeding. E. coli is the most frequently identified bacteria. (HEPATOLOGY 2002;36:135-141.)

Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n 5 21) or absence of bacterial DNA (n 5 34). Bacterial-DNA(1) patients had significantly lower mean arterial pressure (P 5 0.002) and systemic vascular resistance (P 5 0.03) than bacterial-DNA(2) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(1) as compared with bacterial-DNA(2) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. Conclusion: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction. (HEPATOLOGY 2010;52:2044-2052 P ortal hypertension is a serious consequence of cirrhosis that can result in life-threatening complications with increased mortality and morbidity.1 The primary factor in the pathophysiology of portal hypertension is increased intrahepatic resistance to portal-collateral blood flow. Portal hypertension is further aggravated by increased portal venous inflow, caused by splanchnic vasodilation. Moreover, insufficient nitric oxide (NO) availability in the hepatic microcirculation is considered an important factor that contributes to increase the hepatic vascular resistance. Because of this, the cirrhotic liver, unlike the normal liver, cannot vasodilate in response to a volume flow load such as that caused by meals, which results in abrupt postprandial increases in portal pressure, a concept known as intrahepatic endothelial dysfunction. [2][3][4][5]

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We tested the hypothesis that the presence of bacterial DNA (bactDNA) in ascitic fluid and serum is associated with decreased survival in patients with cirrhosis. In a prospective, multicenter study, we analyzed the clinical evolution of 156 patients with cirrhosis and ascites (first or recurrence) with lower than 250 polymorphonuclear cells (PMN)/ L, negative ascites bacteriological culture, and absence of other bacterial infections being admitted for evaluation of largevolume paracentesis, according to the presence of bactDNA at admission. Survival, causes of death, and successive hospital admissions were determined during a 12-month follow-up period. BactDNA was detected in 48 patients. The most prevalent identified bactDNA corresponded to Escherichia coli (n ‫؍‬ 32/48 patients, 66.6%). Patients were followed for 12 months after inclusion and in this period 34 patients died: 16 of 108 (15%) From the

Bacterial infections and severity of associated inflammatory reaction influence prognosis in patients with advanced cirrhosis. We compared the innate immune response to bacterial DNA (

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL؉HD). Six groups were studied: sham, sham pair-fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL؉HD. The BDL؉HD rats were made hyperammonemic via an ammonia-containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL؉HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL؉HD rats showed activation of the inflammatory system. BDL؉HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo-inositol, and a significant increase in the level of brain water. In coordination tests, BDL؉HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL؉HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). H epatic encephalopathy (HE) is a severe neuropsychiatric complication in both acute and chronic liver failure. Although the pathophysiology of this disorder is incompletely understood, there is agreement on the important role of neurotoxins in its development, especially ammonia. 1 Neuropathologically, HE in chronic liver disease is characterized by astrocytic rather than neuronal changes. 2 Histopathology studies of brain sections from patients with cirrhosis who died in hepatic coma show the presence of changes known as Alzheimer type II astrocytosis. These astrocytes display a specific characteristic of swollen cytoplasm containing a large pale nucleus, with prominent nucleolus and patches of heterochromatin associated with the nuclear envelope. 2 Recently, a new pathophysiological hypothesis has been developed, emphasizing the role of low-grade brain edema in the pathogenesis of HE in chronic liver disease. 3 Following this theoretical model, the presence of a lowgrade astrocyte swelling could have important functional consequences despite the absence of clinically overt increases of intracranial pressure. 3

Bacterial translocation is currently considered the main pathogenic mechanism leading to spontaneous bacterial peritonitis in patients with advanced cirrhosis and ascites. However, to the authors' knowledge there is no information regarding the characteristics of this process in humans. The goals of the current study were to pursue partially identified bacterial DNA in blood (what the authors consider molecular evidence of bacterial translocation) through its relative quantification in a 72-hour study period by using real-time polymerase chain reaction (PCR). A consecutive series of 17 patients with advanced cirrhosis and culture-negative, nonneutrocytic ascites were studied. Therapeutic paracentesis was performed at the time of admission, and blood samples were obtained at baseline and every 8 hours in a 3-day period. S pontaneous bacterial peritonitis (SBP) is a severe infection developing in patients with advanced cirrhosis, in the absence of any intraabdominal, surgically treatable source of infection. 1 It is considered to be the final consequence of repeated episodes of bacterial translocation (BT) from the intestinal lumen and eventual arrival of bacteria in the ascitic fluid (AF). However, the predisposition to develop a SBP episode is related to its intrinsic bactericidal properties. [2][3][4] BT is an incompletely understood process by which intestinal bacteria can cross the epithelial wall, thereby reaching mesenteric lymph nodes and other organs. 5 BT has been studied extensively in cirrhotic rats, 6,7 but for obvious reasons it is difficult to study its incidence in patients with cirrhosis. 8 We recently reported the presence of bacterial DNA (BactDNA) in blood and AF in roughly 40% of patients with cirrhosis and culture-negative, nonneutrocytic ascites 9 and, although more experimental work is needed to confirm our hypothesis, the data available to date may represent molecular evidence of BT. This method allows the study of BT in patients without clinical evidence of infection, thus becoming a useful tool with which to investigate the steps preceding a fully developed infection.To our knowledge, to date it is not known whether bacteria translocate as the result of a "single pulse" event or, conversely, bacteria continuously are crossing the intestinal wall, and what is the rate of bacterial clearance from the systemic circulation. Although we previously reported that Escherichia coli is the most prevalent bacteria found to cause episodes of BT at the time of admission, 9 we do not know whether this finding may be different in the following hours or days.Therefore, the objectives of the current investigation were to explore the temporal pattern of BactDNA clear-

In our study, administration of a small amount of fluid during the initial 24 h was not associated with a poor outcome. The need for a great amount of fluid during the initial 24 h was associated with a poor outcome; therefore, this group of patients must be carefully monitored.