Bacterial DNA Translocation Is Associated With Overt Hepatic Encephalopathy and Mortality in Patients With Cirrhosis.

INTRODUCTION: Data on the relationship between bacterial translocation, hepatic encephalopathy (HE), and mortality are scarce. This study aimed to assess the association between bacterial DNA (bactDNA) translocation, inflammatory response, ammonia levels, and severity of HE in patients with cirrhosis, as well as the role of bactDNA translocation in predicting mortality. METHODS: Cirrhotic patients without bacterial infection were prospectively enrolled between June 2022 and January 2023. Grading of HE was classified by the West Haven Criteria and Psychometric Hepatic Encephalopathy Score ≤ -5. RESULTS: Overall, 294 cirrhotic patients were enrolled, with 92 (31.3%) and 58 (19.7%) having covert and overt HE, respectively. BactDNA translocation was detected in 36.1% of patients (n = 106). Patients with overt HE had more bactDNA translocation and higher serum lipopolysaccharide-binding protein (LBP), tumor necrosis factor-α, interleukin-6 (IL-6), and ammonia levels than those without HE. Patients with detectable bactDNA had higher white cell counts and serum LBP and IL-6 levels than those without. By contrast, bactDNA, serum LBP, and soluble CD14 levels were comparable between patients with covert HE and those without HE. The multivariate Cox regression analysis revealed that bactDNA translocation (hazard ratio [HR] = 2.49, 95% confidence interval [CI]: 1.22-5.11), Model for End-Stage Liver Disease score (HR = 1.12, 95% CI: 1.09-1.16), age (HR = 1.05, 95% CI: 1.000-1.002), and baseline IL-6 (HR = 1.001, 95% CI: 1.000-1.002) were independent factors associated with 6-month mortality. DISCUSSION: Apart from hyperammonemia, bactDNA translocation is a possible factor associated with overt HE in cirrhotic patients. BactDNA translocation and IL-6 are independent factors associated with 6-month mortality.

Microbiome: Emerging Concepts in Patients with Chronic Liver Disease.

The gut microbiome is an exciting new area of research in chronic liver disease. It has shown promise in expanding our understanding of these complicated disease processes and has opened up new treatment modalities. The aim of this review is to increase understanding of the microbiome and explain the collection and analysis process in the context of liver disease. It also looks at our current understanding of the role of the microbiome in the wide spectrum of chronic liver diseases and how it is being used in current therapies and treatments.

Long-Term Effect of Rifaximin with and without Lactulose on the Active Bacterial Assemblages in the Proximal Small Bowel and Faeces in Patients with Minimal Hepatic Encephalopathy.

BACKGROUND: Gut microbiota play an essential role in the pathogenesis of hepatic encephalopathy (HE). Treatment strategies are directed to modulate intestinal microbiota profiles and their function by the administration of the non-absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin, which are required for long terms, but little is known on their long-term effect on gut microbiota composition and function. AIM: To characterize the active bacterial assemblages in duodenum and faeces in patients with minimal HE (MHE) before, during and after long-term therapy with rifaximin. METHODS: We analysed the microbiota composition in 5 patients with liver cirrhosis and MHE treated either with rifaximin 550 mg bid alone continuously for a period of 3 months or combined with lactulose 30-60 mL daily for 3 months. In addition to clinical assessments of HE, biopsies from duodenum and stool samples were analysed for their specific bacterial community applying NGS after RNA isolation before treatment, after 3 months of treatment and 3 months after the end of treatment. RESULTS: All 5 patients had a significant improvement of their MHE. Bacterial communities were different and distinct in duodenal samples and faeces. No statistically significant changes were found in the bacterial community profile at the different time points. CONCLUSION: Rifaximin therapy with and without lactulose over a period of 3 months does not affect the bacterial community composition. The improvement of HE with rifaximin is lasting also after the end of treatment and therefore a prolonged effect on microbiota metabolic function is suggested.

Clinical impact of microbiome in patients with decompensated cirrhosis.

Cirrhosis is an increasing cause of morbidity and mortality. Recent studies are trying to clarify the role of microbiome in clinical exacerbation of patients with decompensated cirrhosis. Nowadays, it is accepted that patients with cirrhosis have altered salivary and enteric microbiome, characterized by the presence of dysbiosis. This altered microbiome along with small bowel bacterial overgrowth, through translocation across the gut, is associated with the development of decompensating complications. Studies have analyzed the correlation of certain bacterial families with the development of hepatic encephalopathy in cirrhotics. In general, stool and saliva dysbiosis with reduction of autochthonous bacteria in patients with cirrhosis incites changes in bacterial defenses and higher risk for bacterial infections, such as spontaneous bacterial peritonitis, and sepsis. Gut microbiome has even been associated with oncogenic pathways and under circumstances might promote the development of hepatocarcinogenesis. Lately, the existence of the oral-gut-liver axis has been related with the development of decompensating events. This link between the liver and the oral cavity could be via the gut through impaired intestinal permeability that allows direct translocation of bacteria from the oral cavity to the systemic circulation. Overall, the contribution of the microbiome to pathogenesis becomes more pronounced with progressive disease and therefore may represent an important therapeutic target in the management of cirrhosis.

[Helicobacter pylori infection: from gastric to systemic disease]. / Manifestazioni extragastriche dell'infezione da Helicobacter pylori.

H. pylori infection, through a chronic stimulation of the immune system and the occurrence of molecular mimicry mechanisms, is responsible for the majority of the gastroduodenal diseases and also for some extragastric disorders, including sideropenic anemia and idiopathic thrombocytopenic purpura; other diseases are under investigation.

[Prevalence and role of Helicobacter pylori infection in some gastroduodenal and hepatic complications in cirrhotic patients]. / Prevalenta si rolul infectiei cu Helicobacter pylori in determinarea unor complicatii gastroduodenale si hepatice la pacientii cu ciroza hepatica.

It has been clearly established that Helicobacter pylori (H. pylori) infection plays a pivotal role in the pathogenesis of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and gastric lymphoma MALT (mucosa-associated lymphoid tissue) in the general population, but data regarding the prevalence and the role of H. pylori infection in liver cirrhosis are conflicting. Most serological studies estimated a high prevalence of H. pylori infection in patients with liver cirrhosis; however, when other methods (urea breath test, histology, culture, rapid urease test) were used, the overall H. pylori prevalence was similar to that in controls. Although the prevalence of both gastric ulcer (GU) and duodenal ulcer (DU) is higher in cirrhotic patients than in general population, the relationship between H. pylori infection and peptic ulcer in cirrhosis remains controversial. Our data regarding peptic ulcer prevalence in cirrhotic patients are in agreement with previous studies that suggest an increased prevalence of both GU and DU. The incidence of bleeding peptic ulcer is high in cirrhotic patients and carries an increased risk of complications or death in these patients and therefore eradication of H. pylori infection might be as effective in preventing ulcer relapse and bleeding as it is in noncirrhotic ulcer patients. Hepatic encephalopathy is a frecquent complication of liver cirrhosis, and it is widely accepted that ammonia plays a major role in its pathogenesis. The ammonia production by H. pylori urease does not increase blood ammonia levels during cirrhosis, and eradication of H. pylori infection does not affect hepatic encephalopathy status.

Alterations in intestinal microbial flora and human disease.

PURPOSE OF REVIEW: To highlight the evidence supporting the role of altered commensal gut flora in human disease. While the contribution of the indigenous gut microbial community is widely recognized, only recently has there been evidence pointing to indigenous flora in disease. RECENT FINDINGS: This review discusses recent evidence pointing to the role of altered commensal gut flora in such common conditions as irritable bowel syndrome and inflammatory bowel disease. Recent studies document the intricate relationship between the vast population of microbes that live in our gut and the human host. Since increased intestinal permeability and immune activation are consequences of an altered host-gut microbial relationship, what are the clinical effects of this shift in relationship? SUMMARY: We focus on the example of an abnormal expansion of gut microbial flora into the small bowel or small intestinal bacterial overgrowth and discuss the effects of bacterial overgrowth on the human host in acute pancreatitis, bacterial gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and fibromyalgia and burn injury. The identification of the underlying role of altered commensal gut microbiota in these and other human diseases could lead to novel diagnostic and therapeutic strategies that would improve clinical outcome.

Helicobacter pylori is not a risk factor for hepatic encephalopathy.

BACKGROUND: Helicobacter pylori infection has been described as a risk factor for hepatic encephalopathy in patients with chronic liver disease although the topic remains controversial. AIMS: To determine whether Helicobacter pylori infection is an independent predictive factor for encephalopathy in patients with liver cirrhosis. METHODS: Clinical, epidemiological, analytical and nutritional parameters of 205 patients were collected. Helicobacter pylori infection was determined by serology. Encephalopathy (grade II or higher) was clinically assessed during follow-up. The relationship between each parameter and encephalopathy was analysed by Kaplan-Meier curves and the Log rank test. The most significant parameters underwent multivariate analysis by Cox regression. RESULTS: Twenty-five variables were related to encephalopathy in the bivariate analysis. Multivariate analysis selected five independent factors: previous bouts of encephalopathy (Odds ratio 3.79; 95% confidence interval 1.94-7.38), albumin (Odds ratio 0.86; 95% confidence interval 0.80-0.92), tricipital skin fold (Odds ratio 0.79; 95% confidence interval 0.66-0.95) chronic pulmonary disease (Odds ratio 2.78, 95% confidence interval; 1.31-5.92), and on-going alcoholism (Odds ratio 2.62; 95% confidence interval 1.16-5. BB). CONCLUSIONS: Helicobacter pylori is not an independent risk factor for hepatic encephalopathy.

[The importance of Helicobacter--beyond the stomach too]. / Die Bedeutung des Helicobacter--auch jenseits des Magens.

The discovery of H. pylori as causative agent for peptic ulcers was a milestone in gastroenterology. Apart from peptic ulcer, H. pylori may play a role in the pathogenesis of coronary heart disease, rheumatoid arthritis, Sjoegren's syndrome and hepatic encephalopathy. These associations are still controversial and need further studies. Other strains (H. bilis, H. hepaticus, H. rappani, H. pullorum) may cause chronic hepatobiliary diseases or diarrhea. The possible role of such strains in carcinogenesis is very interesting and should be further explored.

Helicobacter pylori and the liver: any relationship?

Helicobacter pylori infection is being correlated to a number of human diseases, among which also those of the liver. From a clinical point of view, 4 "areas of interest" for the suggested correlation can be identified: 1. Helicobacter pylori and portal hypertension-related congestive gastropathy in cirrhotics. There are, in the literature, at least 7 studies confirming that the microorganism has no role in causing or worsening the disease. 2. Helicobacter pylori and duodenal ulcer in cirrhotic patients. Apparently, in the cirrhotic patient, the microorganism has no role in causing duodenal ulcer. 3. Helicobacter pylori, ammonia production and hepatic encephalopathy. In this case, there are at least three studies showing that Helicobacter pylori infection increases the risk of developing encephalopathy in the cirrhotic patient, this being a somewhat expected finding. 4. Helicobacter pylori infection in chronic liver disease and its diagnosis. Evidence in the literature suggests: a) that hypertensive gastropathy might not represent a favourable environment for Helicobacter pylori thus making the diagnostic sensitivity of the biopsy lower than expected, and b) that even serological diagnosis might provide data of difficult interpretation, as shown in non alcoholic cirrhosis and, by our own group, in primary biliary cirrhosis. More intriguing are the data generated with respect to the potential capacity of Helicobacter pylori and Helicobacter pylori-like bacteria such as, in particular, Helicobacter hepaticus to damage the liver by producing toxins with a granulating effect on liver cell lines which, in vivo, through the portal tract, might reach the liver, thus causing hepatocellular damage. The point has been addressed by a number of investigators and autoimmune mechanisms have also been suggested. In summary, from the clinical point of view, some evidence suggests that Helicobacter pylori infection might be relevant in the pathogenesis of hepatic encephalopathy in cirrhosis. The data being generated with respect to a direct hepatotoxicity are, at present, stimulating but only speculative.

Fulminant hepatic failure caused by tuberculosis.

A 54 year old Asian woman developed fulminant hepatic failure followed by renal failure. Because of a past history of possible tuberculosis, she was given antituberculous drugs. The chest x ray was normal. A transjugular liver biopsy showed caseating necrosis, granulomas, and acid fast bacilli indicative of miliary tuberculosis. Despite full supportive therapy, her condition deteriorated and she died. Postmortem examination showed widespread miliary tuberculosis; culture confirmed the presence of Mycobacterium tuberculosis. Tuberculosis causes fulminant hepatic failure rarely and only three cases have been described. In this, as with the other cases, hyponatraemia and hepatomegaly were features at presentation. This is the first report of treatment being given before death.

The complete nucleotide sequence of a pre-core mutant of hepatitis B virus implicated in fulminant hepatitis and its biological characterization in chimpanzees.

Hepatitis B virus (HBV) with an in-frame stop codon within the pre-core region of the virus genome caused fulminant hepatitis in two individuals. Serum from a chronically infected patient who was the source of the virus was inoculated into three chimpanzees at dilutions of 10(-1), 10(-3), and 10(-7). All three chimpanzees developed acute hepatitis B with relatively high peak values of liver enzymes in their serum. The complete nucleotide sequence of virus DNA recovered from the chimpanzee serum by enzymatic amplification was identical with that from the human serum. By comparing the sequence of this strain (HT) with that of 32 published HBV genomes, changes in nucleotides and predicted amino acids that were rarely or never found in other HBV isolates were identified. Thirteen such nucleotides were found within the cis-acting regulatory elements, of which 6 were within the enhancer II-core promoter region. Twenty-four rare or unique changes in amino acids were found in open reading frames, of which 15 occurred in the region that spanned the 3' half of the X gene, through the pre-core/core gene, to the 5' end of the polymerase gene. Thus, an HBV pre-core stop mutant implicated in fulminant hepatitis is highly infectious, induces severe hepatitis in chimpanzees, and possesses significant genetic variation from reported HBV isolates.

[Mutation in core and pre-core amino acid sequences of hepatitis B virus correlate with fulminant and severe hepatitis].

Infection with hepatitis B virus leads to a wide spectrum of liver injury, including self-limited acute hepatitis, fulminant hepatitis and chronic hepatitis with progression to cirrhosis or acute exacerbation to liver failure, as well as, an asymptomatic chronic carrier state. To investigate why an extreme immunological attack occurs in fulminant hepatitis and severe exacerbation, the entire precore and core region were sequenced in 13 subjects. No significant change was noted in the 6 self-limited acute hepatitis patients. In contrast, clustering changes in a small segment of core codons #84 to #99 were found in all 7 fulminant and severe exacerbation patients. These data suggest that this mutation clustering region may play an important role in the pathogenesis, and such mutations appear to be related to severe liver damage.

Significance of anti-pre-S antibodies in patients with fulminant hepatic failure.

Anti-pre-S antibody was tested in 38 sera from patients with fulminant hepatitis (positive for HBsAg and/or IgM anti-HBc) using a specific solid phase enzyme linked immunosorbent assay (ELISA). Anti-pre-S activity was detected in 50 percent sera samples positive for HBsAg but negative for IgM anti-HBc. There were 12.5% sera positive for both HBsAg as well as IgM anti-HBc and 75% sera negative for HBsAg but positive for IgM anti-HBc. The prevalence of HBV-specific DNA-polymerase activity was high in all the three groups whereas anti-HBs positivity was low. Anti-pre-S activity was observed both in the presence as well as in the absence of DNA-polymerase activity. High-anti-pre-S level in fulminant hepatitis B patients was assumed to be implicated in the fast clearance of HBsAg from circulation.