Minimal hepatic encephalopathy (MHE) is an important disorder that may seriously impair daily functioning and quality of life in patients with cirrhosis. Treatment with lactulose is of benefit. The possible role of synbiotics (probiotics and fermentable fiber) has not been assessed. We screened 97 consecutive cirrhotic patients without overt hepatic encephalopathy for MHE using the number connection test and measurement of brainstem auditory evoked potentials. MHE, defined by abnormality on at least one test modality, was present in 58 (60%) patients. Fifty-five of these patients with MHE were randomized to receive a synbiotic preparation (n ‫؍‬ 20), fermentable fiber alone (n ‫؍‬ 20), or placebo (n ‫؍‬ 15) for 30 days. Cirrhotic patients with MHE were found to have substantial derangements in the gut microecology, with significant fecal overgrowth of potentially pathogenic Escherichia coli and Staphylococcal species. Synbiotic treatment significantly increased the fecal content of non-urease-producing Lactobacillus species at the expense of these other bacterial species. Such modulation of the gut flora was associated with a significant reduction in blood ammonia levels and reversal of MHE in 50% of patients. Synbiotic treatment was also associated with a significant reduction in endotoxemia. The Child-Turcotte-Pugh functional class improved in nearly 50% of cases. Treatment with fermentable fiber alone was also of benefit in a substantial proportion of patients. In conclusion, treatment with synbiotics or fermentable fiber is an alternative to lactulose for the management of MHE in patients with cirrhosis.

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Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor ␣ (TNF-␣) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-␣ in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-␣, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-␣ production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-␣ levels, and in vitro TNF-␣ production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-␣, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-␣ and sTNFR levels. In vitro TNF-␣ production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-␣ levels were further increased and in vitro TNF-␣ production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-␣ and sTNFR levels in cirrhosis.

Up-regulation of peripheral blood monocyte expression of TLR2 and TLR4 occurs in patients with chronic hepatitis C. Increased monocyte expression of TLR2, but not of TLR4, correlates significantly with both increased circulating TNF-alpha levels and hepatic necroinflammatory activity in this disorder.

Persistent infection with hepatitis B virus (HBV) likely depends on viral inhibition of host defenses.We report that chronic hepatitis B e antigen-positive HBV infection is associated with a significant reduction in peripheral blood monocyte expression of Toll-like receptor 2, a key component of innate immunity, thereby providing a mechanism by which wild-type HBV may establish persistent infection.Mechanisms by which hepatitis B virus (HBV) establishes persistent infection remain unclear, although viral inhibition of host defenses is likely to be important. Most studies of the immunological aspects of persistent HBV infection have focused on adaptive immunity, with little research on the innate immune response to HBV (5). One of the key components of the innate immune response is the family of Toll-like receptors (TLRs), evolutionarily conserved pattern recognition receptors (1). Activation of TLRs by various motifs common to microorganisms, known as pathogen-associated molecular patterns, triggers the release of inflammatory mediators such as tumor necrosis factor alpha (TNF-␣) (6). Recent studies have shown that some viruses suppress TLR-mediated immune mechanisms, thereby disabling an important aspect of the host's antiviral defenses (2-4). The expression of TLRs in patients with HBV and any functional consequences of disturbed TLR expression in this group have not previously been investigated.We studied 17 consecutive noncirrhotic patients with chronic HBV infection (hepatitis B surface antigen positive, as measured by reverse passive hemagglutination [Serodia-HBs; Fujirebio Inc., Japan]) and ongoing viral replication (median HBV DNA level, 1.5 ϫ 10 3 copies/ml; range, 210 to 1.62 ϫ 10 9 copies/ml, as measured by reverse transcription-PCR and, when serum levels were Ͻ2,000 copies/ml, using the Cobas Amplicor HBV Monitor test [Roche]). Nine (53%) patients were hepatitis B e antigen (HBeAg) positive, and eight (47%) patients were HBeAg negative, as determined using the Abott Axsym HbE 2.0 assay (Abbott Laboratories, Illinois). No patient had clinical or laboratory evidence of other infection or immunodeficiency that may have confounded the interpretation of TLR levels. The HBeAg-positive and HBeAg-negative groups were comparable in terms of gender (ratios of males to females, 7/2 and 6/2, respectively), age (median of 35 years and range of 21 to 55 years and median of 40 years and range of 18 to 56 years, respectively), Ishak histological activity index (median of 4 and range of 2 to 6 and median of 4 and range of 2 to 6, respectively), and histological stage (median of 2 and range 1 of 3 and median of 2 and range of 1 to 3, respectively). Thirty-two asymptomatic, age-and sex-matched subjects with negative viral serology, normal liver function tests, and no history of liver disease or immunodeficiency served as controls. Cell surface staining was performed on whole blood using anti-TLR2 and anti-TLR4 (eBioscience) and anti-CD14 (Becton Dickinson) monoclonal antibodies. After red cell lysis, monocytes were gat...

In patients who develop liver damage following moderate paracetamol overdose in the order of 5-10 g daily, recent fasting and nutritional impairment have been identified as key precipitants. Hepatotoxicity caused by paracetamol at recommended dosage, in the absence of exposure to enzyme-inducing drugs, has recently been described as an idiosyncratic phenomenon. The possible importance of fasting and malnutrition in this setting is uncertain. We report a severely malnourished 53-year-old woman who developed severe hepatotoxicity whilst receiving paracetamol at recommended dosage (4 g daily) following a period of fasting, in the absence of enzyme-inducing agents. Subsequent paracetamol exposure up to 2.6 g daily thrice weekly, in the setting of ongoing malnutrition and fasting as before, did not lead to recurrent liver damage. These findings indicate that paracetamol-related liver damage occurring within recommended dosage guidelines can be a dose-dependent rather than necessarily idiosyncratic phenomenon, at least in the setting of recent fasting and severe malnutrition.

Increased prevalence of LM in the elderly is mostly due to clinically non-apparent SIBO, rather than mucosal factors. The lactulose breath hydrogen test cannot be relied upon to identify elderly subjects with SIBO, even in those without an anatomical predisposition.

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