Alterations in the gut microbiome after transjugular intrahepatic portosystemic shunt in patients with hepatitis B virus-related portal hypertension.

BACKGROUND: Gut microbiota (GM) affects the progression and response to treatment in liver diseases. The GM composition is diverse and associated with different etiologies of liver diseases. Notably, alterations in GM alterations are observed in patients with portal hypertension (PH) secondary to cirrhosis, with hepatitis B virus (HBV) infection being a major cause of cirrhosis in China. Thus, understanding the role of GM alterations in patients with HBV infection-related PH is essential. AIM: To evaluate GM alterations in patients with HBV-related PH after transjugular intrahepatic portosystemic shunt (TIPS) placement. METHODS: This was a prospective, observational clinical study. There were 30 patients (with a 100% technical success rate) recruited in the present study. Patients with esophagogastric variceal bleeding due to HBV infection-associated PH who underwent TIPS were enrolled. Stool samples were obtained before and one month after TIPS treatment, and GM was analyzed using 16S ribosomal RNA amplicon sequencing. RESULTS: One month after TIPS placement, 8 patients developed hepatic encephalopathy (HE) and were assigned to the HE group; the other 22 patients were assigned to the non-HE group. There was no substantial disparity in the abundance of GM at the phylum level between the two groups, regardless of TIPS treatment (all, P > 0.05). However, following TIPS placement, the following results were observed: (1) The abundance of Haemophilus and Eggerthella increased, whereas that of Anaerostipes, Dialister, Butyricicoccus, and Oscillospira declined in the HE group; (2) The richness of Eggerthella, Streptococcus, and Bilophila increased, whereas that of Roseburia and Ruminococcus decreased in the non-HE group; and (3) Members from the pathogenic genus Morganella appeared in the HE group but not in the non-HE group. CONCLUSION: Intestinal microbiota-related synergism may predict the risk of HE following TIPS placement in patients with HBV-related PH. Prophylactic microbiome therapies may be useful for preventing and treating HE after TIPS placement.

Isolated gastric varices secondary to abdominal tuberculosis mimicking lymphoma: a case report.

BACKGROUND: Abdominal tuberculosis (TB) rarely presents with abdominal masses and rarely causes isolated gastric varices. CASE PRESENTATION: We report a case of isolated gastric varices secondary to abdominal TB mimicking lymphoma. A 42-year-old woman without any history of liver disease presented with melena and mild abdominal pain. Upon admission to the hospital, laboratory investigations revealed a hemoglobin level of 76 g/L. Gastroduodenoscopic examination showed isolated gastric fundal varices with red color signs. Abdominal contrast-enhanced computed tomography (CECT) revealed non-enhanced masses of soft-tissue density in the lesser omental and the retropancreatic areas, multiple para-aortic lymph nodes, and multiple small hypodense splenic lesions. Positron emission tomography-CT showed hypermetabolic [F-18]2-fluoro-2-deoxyglucose activity involving multiple regional lymph nodes and the bone marrow, suggestive of lymphoma. Bone marrow biopsy revealed no abnormality. Histopathological examination of a CT-guided biopsy specimen showed granulomatous inflammation with necrosis and microorganisms that stained positive with acid-fast stains. Abdominal CECT showed a decrease in the size of the lesser omental and peripancreatic masses, as well as the para-aortic lymph nodes after 4-month anti-TB therapy. CONCLUSIONS: TB should be considered among the differential diagnoses in patients with abdominal masses, isolated gastric varices, and regional lymphadenopathy. Prompt and definitive diagnosis of abdominal TB requires a coordinated approach involving laboratory tests, radiological examination, and invasive procedures for optimal decision making and management.

MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis.

MircoRNA's (miR) have been recognised as important modulators of gene expression and potential biomarkers. However, they have been rarely investigated in bio fluids apart from blood. We investigated the association of miR-125b and miR-155 with complications of cirrhosis. Ascites was prospectively collected from patients with cirrhosis undergoing paracentesis at our department. miR's were determined in the supernatant using qPCR and normalized by SV-40. Clinical parameters were assessed at paracentesis and during follow-up. 76 specimens from 72 patients were analysed. MiR's were not associated to age, sex or aetiology of cirrhosis. MiR-125b levels differed between patients with low and high MELD score, and miR-125b levels showed an inverse correlation to serum creatinine (r2 = -0.23; p = 0.05). MiR-155 was elevated in patients with spontaneous bacterial peritonitis (SBP) (n = 10; p = 0.04). MiR-155 levels differed between patients with and without 30-day survival (p = 0.02). No association of ascites levels of investigated miR's to size of varices, episodes of gastrointestinal bleeding or hepatorenal syndrome was observed. While miR-125b levels in ascites seem to be associated with liver and renal dysfunction, miR-155 might be implicated in local immune response in SBP.

Gut microbiota-related complications in cirrhosis.

Gut microbiota plays an important role in cirrhosis. The liver is constantly challenged with commensal bacteria and their products arriving through the portal vein in the so-called gut-liver axis. Bacterial translocation from the intestinal lumen through the intestinal wall and to mesenteric lymph nodes is facilitated by intestinal bacterial overgrowth, impairment in the permeability of the intestinal mucosal barrier, and deficiencies in local host immune defences. Deranged clearance of endogenous bacteria from portal and systemic circulation turns the gut into the major source of bacterial-related complications. Liver function may therefore be affected by alterations in the composition of the intestinal microbiota and a role for commensal flora has been evidenced in the pathogenesis of several complications arising in end-stage liver disease such as hepatic encephalopathy, splanchnic arterial vasodilatation and spontaneous bacterial peritonitis. The use of antibiotics is the main therapeutic pipeline in the management of these bacteria-related complications. However, other strategies aimed at preserving intestinal homeostasis through the use of pre-, pro- or symbiotic formulations are being studied in the last years. In this review, the role of intestinal microbiota in the development of the most frequent complications arising in cirrhosis and the different clinical and experimental studies conducted to prevent or improve these complications by modifying the gut microbiota composition are summarized.

[Esophageal varices and dyspnea. A clinicopathological conference report]. / Ruokatorven laskimolaajentumat ja hengenahdistus.

A young man who had moved from India to Finland was extensively examined for abdominal complaints. The findings included large esophageal varices, open portal vein and enlarged lymph nodes. The large spleen was excised. The diagnosis did not become clear from laboratory investigations. After ten years the patient was repeatedly examined to reveal the cause of esophageal varices and abdominal complaints. Autoimmune pancreatitis and cholangitis were suspected after 23 years from the initial symptoms. In the end, the most plausible explanation for the patient's mixed disease was tuberculosis. Sarcoidosis was another disease that came into question.

Role of prophylactic antibiotics in cirrhotic patients with variceal bleeding.

Bacterial infections are common in cirrhotic patients with acute variceal bleeding, occurring in 20% within 48 h. Outcomes including early rebleeding and failure to control bleeding are strongly associated with bacterial infection. However, mortality from variceal bleeding is largely determined by the severity of liver disease. Besides a higher Child-Pugh score, patients with hepatocellular carcinoma are particularly susceptible to infections. Despite several hypotheses that include increased use of instruments, greater risk of aspiration pneumonia and higher bacterial translocation, it remains debatable whether variceal bleeding results in infection or vice versa but studies suggest that antibiotic prophylaxis prior to endoscopy and up to 8 h is useful in reducing bacteremia and spontaneous bacterial peritonitis. Aerobic gram negative bacilli of enteric origin are most commonly isolated from cultures, but more recently, gram positives and quinolone-resistant organisms are increasingly seen, even though their clinical significance is unclear. Fluoroquinolones (including ciprofloxacin and norfloxacin) used for short term (7 d) have the most robust evidence and are recommended in most expert guidelines. Short term intravenous cephalosporin (especially ceftriaxone), given in a hospital setting with prevalent quinolone-resistant organisms, has been shown in studies to be beneficial, particularly in high risk patients with advanced cirrhosis.

Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial.

BACKGROUND: Probiotics, by altering gut flora, may favourably alter portal haemodynamics in patients with cirrhosis. AIM: To investigate the effect of probiotics on portal pressure in patients with cirrhosis. METHODS: Randomized double-blind placebo-controlled trial conducted in G.B. Pant Hospital, New Delhi. A total of 94 cirrhotic patients having large oesophageal varices without history of variceal bleeding were randomized to three treatment groups and given 2 months' treatment with propranolol plus placebo, propranolol plus antibiotics (norfloxacin 400 mg BD) or propranolol plus probiotic (VSL#3, 900 billion/day) randomly assigned in 1:1:1 ratio. Outcome measures were change in Hepatic venous pressure gradient (HVPG): Response rate (Percentage of patients having a decrease from baseline of ≥20% or to ≤12 mm Hg) and changes from baseline; biochemical markers of inflammation: changes from baseline. RESULTS: Adjunctive probiotics increased the response rate compared with propranolol alone (58% vs. 31%, P = 0.046), similar to adjunctive antibiotics (54%). The mean fall in HVPG was greater with either adjunctive probiotics (3.7 mm Hg vs. 2.1 mm Hg, P = 0.061) or adjunctive antibiotics (3.4 mm Hg) than with propranolol alone. Both adjunctive therapies were associated with greater decreases in TNF-α levels (in both peripheral and hepatic venous blood) that resulted from propranolol-only treatment. No clinically relevant between-group differences were observed in the type or frequency of adverse events. CONCLUSIONS: Adjunctive probiotic (VSL#3) improved the response rate to propranolol therapy and was safe and well tolerated in patients with cirrhosis. Adjunctive probiotic therapy merits further study for reduction in portal pressure.

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.

[Bacterial endotoxinemia and risk of hemorrhage from oesophageal varicose veins in patients with liver cirrhosis].

This work was designed to substantiate the necessity of estimating serum bacterial endotoxin levels in patients with liver cirrhosis (LC) for the prognostication of the risk of bleeding from oesophageal varices. The prospective cohort study included 90 patients with LC and clinical signs of portal hypertension. Total endotoxin of Gram-negative bacteria was measured by the activated particle method. The intensity of endotoxemia was estimated using the end-point turbidimetric test (variant of LAL test). Pronounced endotoxemia was associated with acute bleeding from oesophageal varices. Its severity in the patients with the history of hemorrhage was higher than in the absence of this complication. The endotoxin level in the range from 0 to 4 ng/ml suggested low probability of hemorrhage; its risk increased significantly at the endotoxin level in excess of 4.1 ng/ ml. It is concluded that the severity of endotoxemia in LC patients correlates with the degree of oesophageal vein dilation and hemorrhage, the endotoxin level of 4 ng/ml being a reliable diagnostic criterion for the associated risks.

Antibiotic prophylaxis in variceal hemorrhage: timing, effectiveness and Clostridium difficile rates.

AIM: To investigate if antibiotics administered within 8 h of endoscopy reduce mortality or increase the incidence of Clostridium difficile infection (CDI). METHODS: A 2-year retrospective analysis of all patients who presented with first variceal hemorrhage was undertaken. The primary outcome measure was 28-d mortality. Secondary outcome measures were 28-d rebleeding rates and 28-d incidence of CDI. All patients were admitted to a tertiary liver unit with a consultant-led, 24-h endoscopy service. Patients received standard care including terlipressin therapy. Data collection included: primary and secondary outcome measures, timing of first administration of intravenous antibiotics, etiology of liver disease, demographics, endoscopy details and complications. A prospective study was undertaken to determine the incidence of CDI in the study population and general medical inpatients admitted for antibiotic therapy of at least 5 d duration. Statistical analysis was undertaken using univariate, non-parametric tests and multivariate logistic regression analysis. RESULTS: There were 70 first presentations of variceal hemorrhage during the study period. Seventy percent of cases were male and 65.7% were due to chronic alcoholic liver disease. In total, 64/70 (91.4%) patients received antibiotics as prophylaxis during their admission. Specifically, 53/70 (75.7%) received antibiotics either before endoscopy or within 8 h of endoscopy [peri-endoscopy (8 h) group], whereas 17/70 (24.3%) received antibiotics at > 8 h after endoscopy or not at all (non peri-endoscopy group). Overall mortality and rebleeding rates were 13/70 (18.6%) and 14/70 (20%), respectively. The peri-endoscopy (8 h) group was significantly less likely to die compared with the non peri-endoscopy group [13.2% vs 35.3%, P = 0.04, odds ratio (OR) = 0.28 (0.078-0.997)] and showed a trend towards reduced rebleeding [17.0% vs 29.4%, P = 0.27, OR = 0.49 (0.14-1.74)]. On univariate analysis, the non peri-endoscopy group [P = 0.02, OR = 3.58 (1.00-12.81)], higher model for end-stage liver disease (MELD) score (P = 0.02), presence of hepatorenal syndrome [P < 0.01, OR = 11.25 (2.24-56.42)] and suffering a clinical episode of sepsis [P = 0.03, OR = 4.03 (1.11-14.58)] were significant predictors of death at 28 d. On multivariate logistic regression analysis, lower MELD score [P = 0.01, OR = 1.16 (1.04-1.28)] and peri-endoscopy (8 h) group [P = 0.01, OR = 0.15 (0.03-0.68)] were independent predictors of survival at 28 d. The CDI incidence (5.7%) was comparable to that in the general medical population (5%). CONCLUSION: Antibiotics administered up to 8 h following endoscopy were associated with improved survival at 28 d. CDI incidence was comparable to that in other patient groups.

Tipsitis: incidence and outcome-a single centre experience.

INTRODUCTION: Infection of transjugular intrahepatic portosystemic stent shunt (TIPSS) called 'Tipsitis' has been reported but appears unusual. We report here our experience of patients who were diagnosed to have Tipsitis at our centre. METHODS: Retrospective single centre study. Patients identified from a dedicated data base. Patients with TIPSS with otherwise unexplained sustained bacteraemia were included. RESULTS: Over 14 years of age, of 785 patients with TIPSS, eight (1%) had Tipsitis. Indication for TIPSS: variceal bleed, seven; refractory ascites, one. Child-Pugh score: 8.3 (1.4). Seven patients had overlapping stents in situ. Duration to Tipsitis: 21.6 (7.1) months. At diagnosis, TIPSS was occluded in four and patent in three. Tipsitis developed within 2 weeks of shunt interventions in two patients and was owing to development of bilio-venous fistula in one. The organisms identified were: Lactobacillus rhamnosus, Escherichia coli, Enterobacter cloacae, Enterococcusfaecium and Staphylococcus aureus. Median duration of antibiotic therapy: 3 (0.3-3) months. Symptoms initially resolved in all but one. Symptoms recurred in three and this was related to premature cessation of antibiotics in two. Five patients died at a median 1.3 (0.3 to 33) months after Tipsitis with Tipsitis contributing to death in three. CONCLUSION: Tipsitis is a rare but serious problem. It should be suspected in patients with TIPSS and unexplained sustained bacteraemia. Shunt interventions, where TIPSS is inserted for variceal bleed, and use of overlapping shunts at TIPSS insertion may be risk factors for its development. Prolonged antibiotics are usually required but Tipsitis may recur despite apparently successful treatment.

Proton pump inhibitors in cirrhosis: tradition or evidence based practice?

Proton pump inhibitors (PPI) are very effective in inhibiting acid secretion and are extensively used in many acid related diseases. They are also often used in patients with cirrhosis sometimes in the absence of a specific acid related disease, with the aim of preventing peptic complications in patients with variceal or hypertensive gastropathic bleeding receiving multidrug treatment. Contradicting reports support their use in cirrhosis and evidence of their efficacy in this condition is poor. Moreover there are convincing papers suggesting that acid secretion is reduced in patients with liver cirrhosis. With regard to Helicobacter pylori (H pylori) infection, its prevalence in patients with cirrhosis is largely variable among different studies, and it seems that H pylori eradication does not prevent gastro-duodenal ulcer formation and bleeding. With regard to the prevention and treatment of oesophageal complications after banding or sclerotherapy of oesophageal varices, there is little evidence for a protective role of PPI. Moreover, due to liver metabolism of PPI, the dose of most available PPIs should be reduced in cirrhotics. In conclusion, the use of this class of drugs seems more habit related than evidence-based eventually leading to an increase in health costs.

[Bacterial infection and its relation to the genesis and course of varicose hemorrhage]. / Bakteriální infekce ve vztahu ke vzniku a prubehu varikózního krvácení.

Acute hemorrhage from esophageal varices due to portal hypertension is a frequent and serious complication of liver cirrhosis. Bacterial infection may be one of the factors influencing such hemorrhage. Endotoxins may increase portal tension and at the same time result in primary hemostasis disorder, thus becoming one of the causes of hemorrhage. The authors of the paper compared the incidence of bacterial infection in 53 patients with varicose hemorrhage due to portal hypertension with 62 patients with liver cirrhosis and portal hypertension without varicose hemorrhage. At least one pathogen was found in considerable 61.1% of the total of patients in the liver cirrhosis group, while the difference between the two groups was but insignificant. No statistically significant difference was found between the group of patients with hemorrhage and those without hemorrhage in terms of presence of bacterial infection in hemoculture, urine, throat, faeces and ascites, nor was there a difference in the etiology of the G+ bacteria, G- bacteria or fungi and yeast infectious agents in the hemoculture, urine, throat, faeces and ascites in either of the groups. No statistically significant difference was found in comparing the patients with a recurrence of hemorrhage (or with mortality) and with infection with those without recurrence of hemorrhage. Bacterial infection was more often found in patients with a recurrence of hemorrhage (75%) as compared with those without any recurrence (52%), and also in patients who died bacterial infection was proven more often than in those who survived (61.9% vs. 58.1%, respectively). There was no difference in morbidity or recurrence of hemorrhage between the patients treated with norfloxacin and ampicilin/sulbactam. No statistically significant difference was recorded between the 1st and 5th day in terms of decrease in bacterial infection. A significant difference was found in the urine etiological agent, where a significant increase in the share of fungal and yeast urine infection (p = 0.011) was recorded after the application of the therapy, as well as a drop in urine infection caused by the G- bacterial agent (p = 0.057).

[Factors participating in development of bleeding varices in portal hypertension. Part I: bacterial infection and comparison of intravenous and peroral antibiotics effects--a randomised study]. / Faktory podílející se na vzniku varikózního krvácení pri portální hypertenzi-- I. cást: bakteriální infekce a porovnání úcinnost intravenózního a perorálního podání antibiotik--randomizovaná studie.

An acute bleeding from oesophageal varices as a result of portal hypertension is a frequent and at the same time serious complication of cirrhosis of the liver. One of factors influencing this bleeding can be a bacterial infection. Endotoxines can increase portal pressure and so participate in development of bleeding and simultaneously deteriorate a patient's prognosis. An antibiotic treatment is a part of a treatment algorithm, however what antibiotics to administer and in what manner is unclear. A group of 46 patients who were admitted to a hospital for an acute bleeding from varices has been compared in the study to 48 cirrhosis patients hospitalised for other reasons. An infection incidence was high in both groups (63.0 % vs. 54.2 %), bleeding patients had more often positive hemoculture (17.3 % vs. 8.6 %), and statistically significantly more often positive findings in throat swab culture (36.9 % vs. 17.3 %, p = 0.04) which is an evidence of an increased pathology colonisation of these patients. Bleeding patients were randomised for peroral norfloxacin administration (n = 25) or an intravenous administration of a combination of ampicilin and sulbactam (n = 21). There was no difference in survival of both groups. Due to a high number of bacterial infections antibiotics administration has been indicated in these patients. Intravenous administration is probably of the same effect as peroral administration.

Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension.

OBJECTIVE: Altered small bowel motility and a high prevalence of small intestinal bacterial overgrowth (SIBO) has been observed in patients with liver cirrhosis. Our aim was to explore the relationship between motility abnormalities, portal hypertension, and SIBO. METHODS: Twenty-four patients with liver cirrhosis were included. Twelve had portal hypertension (PH) and 12 had liver cirrhosis (LC) alone. Child-Pugh score was the same in the groups. Antroduodenojejunal pressure recordings were performed, and noninvasive variceal pressure measurements were undertaken. Thirty-two healthy volunteers served as a reference group. Bacterial cultures were obtained from jejunal aspirates. RESULTS: The PH group had a higher proportion of individual pressure waves that were retrograde in the proximal duodenum during phase II (52% vs 13% vs 8% of propagated contractions; p < 0.001) as well as postprandially (49% vs 18% vs 13%; p < 0.01) compared with LC and controls, respectively. Long clusters were more common in PH than in controls (9.1 +/- 2.1 vs 4.9 +/- 0.8; p < 0.05), and a higher motility index in phase III in the proximal and distal duodenum was seen in the PH as compared with the other groups. The mean variceal pressure was 21 +/- 1 mm Hg. Motor abnormalities were not correlated to the level of variceal pressure. Thirty-three percent of the patients in the PH group but none in the LC group had SIBO. CONCLUSIONS: Abnormal small bowel motility and SIBO is common in patients with liver cirrhosis with concomitant portal hypertension. Portal hypertension per se might be significantly related to small bowel abnormalities observed in patients with liver cirrhosis.