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Background & Aims: Dietary changes can modulate gut microbiota and interact with cirrhosis. Our prior study demonstrated that microbial diversity was higher in cirrhotics from Turkish vs the USA, which was associated with lower risk of 90‐day hospitalizations. We aimed to define gut microbial functional and metabolomic changes to increase insight into benefits of the Mediterranean compared to Western diets. Methods: In all, 139 Turkish (46 controls/50 compensated/43 decompensated) and 157 American subjects (48 controls/59 compensated/50 decompensated) were studied. Turkish subjects consumed a modified Mediterranean diet with daily fermented milk intake, whereas Americans consumed a Western diet. Predicted gut microbial functionalities and plasma metabolomics were compared between/within countries. Correlation network differences between microbiota and metabolites in cirrhotics from Turkey vs the USA were evaluated. Results: Predicted microbial function showed lower amino acid, bioenergetics and lipid pathways, with functions related to vitamin B, glycan, xenobiotic metabolism, DNA/RNA synthesis, in cirrhotics from Turkey compared to the USA. Plasma metabolomics demonstrated higher relative lactate levels in Turkey vs the USA. The metabolite changes in decompensated cirrhosis, compared to controls, showed similar trends in Turkey and the USA, with reduced lipids and phosphocholines. Phosphocholines were significantly lower in patients hospitalized in 90 days (P =.03). Correlation networks in cirrhotics demonstrated linkage differences between beneficial taxa, Blautia and Oscillispira, and lactate and unsaturated lipids, in Turkey compared to American patients. Conclusions: A modified Mediterranean diet was associated with altered plasma metabolomics and beneficially alters microbiota functionality and correlations compared to Western diet in cirrhosis. These altered diet‐microbial interactions could potentially affect the 90‐day hospitalization risk. [ABSTRACT FROM AUTHOR]

Background & Aims Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. Methods Conventionally housed C3H/HeH ( CH) and C3H/HeH germ-free ( GF) mice were administered a 200 mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 h was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using 1H- NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ ( LPS-r) mice were assessed to determine the contribution of LPS/ TLR4 signalling. Results Baseline glutathione levels were significantly reduced ( P = 0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Interindividual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH ( P = 0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 h (cross-validated anova P = 1 × 10-22). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. Conclusion Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/ LPS signalling. [ABSTRACT FROM AUTHOR]

Aim: Hepatic lipid is important in the pathogenesis and progression of hepatitis C-related liver disease. Polyunsaturated fatty acids have been shown to reduce viral replication in cell culture. Proton magic angle spinning magnetic resonance spectroscopy (1H MAS MRS) enables metabolic analysis of intact tissue. The aim was to examine the relationship between hepatic lipid composition by metabolic profiling of liver tissue at baseline and treatment response to pegylated-Interferon alfa2 and Ribavirin. Methods: Baseline liver biopsy samples from 31 patients with chronic hepatitis C were analyzed histologically and by 1H MAS MRS. Indices of lipid composition were derived and partial least squares discriminant analysis with cross-validation was used to predict treatment outcome. Results: Of 31 patients, 14 achieved sustained virological response (SVR). Lipid polyunsaturation (median (IQR)) was higher in SVR (3.41% (2.31)) than in treatment failure (TF) (2.15% (1.51)), P = 0.02. Lipid saturation was lower in SVR (85.9% (3.39)) than TF (86.7% (2.17)), P = 0.04. The total lipid content was lower in SVR (1.54% (0.81)) than TF (2.72% (3.47)), P = 0.004. Total choline to lipid ratio was higher in SVR (11.51% (9.99)) than TF (7.5% (6.82)), P = 0.007. Cross-validation correctly predicted the SVR group in 13 of 14 samples with 1 sample misclassified, and the TF group in all 17 samples. Conclusions: Lipid polyunsaturation was greater and total lipid lower in those with SVR, compared with TF. Metabolic profiling of intact liver biopsy samples predicted SVR with high accuracy. Hepatic lipid composition may impact on treatment success. [ABSTRACT FROM AUTHOR]

Khan SA, Thomas HC, Toledano MB, Cox IJ, Taylor-Robinson SD. p53 mutations in human cholangiocarcinoma: a review. Liver International 2005: 25: 704–716. © Blackwell Munksgaard 2005 The reported mortality from intrahepatic bile duct tumours is increasing markedly in industrialised countries, for reasons that remain unknown. Inactivation of the tumour suppressor gene p53, is the commonest genetic abnormality in human cancer and has been implicated in the genesis of cholangiocarcinoma in various immunohistochemical and molecular epidemiological investigations, including gene sequencing studies. The structure and function of p53 and its role in linking cancer to specific carcinogens by way of mutational signatures is reviewed. The findings of previous p53 studies and their relevance in human cholangiocarcinoma are summarised. [ABSTRACT FROM AUTHOR]

Khan SA, Cox IJ, Hamilton G, Thomas HC, Taylor-Robinson SD.In vivoandin vitronuclear magnetic resonance spectroscopy as a tool for investigating hepatobiliary disease.Liver International DOI: 10.1111/j.1478-3231.2004.0966.x.© Blackwell Munksgaard 2005Nuclear magnetic resonance (NMR) spectroscopy is a non-invasive technique, which allows the study of cellular biochemistry and metabolism. It is a diverse research tool, widely used by biochemists to investigate pathophysiological processesin vitroand, more recently, by physicians to determine disease abnormalitiesin vivo. This article reviews the basics of the NMR phenomenon and summarises previous research on the hepatobiliary system using both laboratory-based and clinical methodologies. The role of proton and phosphorus-31 (31P) NMR spectroscopy in the study of malignant and non-malignant liver disease and studies of bile composition are discussed.In vivotechniques (magnetic resonance spectroscopy, MRS) can be performed as an adjunct to standard MR examination of the liver. Although still primarily a research tool, thein vivotechnique provides non-invasive biochemical information on disease severity and holds promise in its use to gauge response to treatment regimens. [ABSTRACT FROM AUTHOR]

The aim of this study was to obtain 1H MR spectra using magic angle spinning (MAS) techniques from punch biopsies (<20 mg) of preinvasive and invasive cervical disease and to correlate the spectral profiles with sample classification on the basis of histopathology. Tissue samples were obtained at colposcopic examination, during local treatment of cervical intraepithelial neoplasia (CIN) or at hysterectomy. 1H MAS MRS was performed at 25°C while spinning the sample at 4.5 kHz. After measurement, the tissue was immersed in formalin and the pathology determined. Histological examination after 1H MAS MRS defined 27 samples with squamous cell carcinoma (SCC), 12 with CIN and 39 with only normal tissue. The standardized integrals of the lipid, choline and creatine regions of the spectra were significantly higher in SCC than in normal or CIN tissue. There was no obvious difference in the standardized integral of the region 4.15-3.5 ppm. The acyl fatty acid side-chain length was longer or less unsaturated in SCC than in normal tissue. Normal tissue from patients with SCC showed significantly higher triglycerides than normal tissue from patients with benign uterine disease but significantly lower triglycerides than SCC tissue. 1H MAS MRS of the uterine cervix ex vivo may be used to differentiate non-invasive from invasive cervical lesions, increase interpretation of in vivo MRS and provide insights into tumor biology. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In vivo 31P magnetic resonance spectroscopy (MRS) provides direct biochemical information on hepatic metabolic processes. To assess in vivo changes in hepatic 31P MRS in liver transplant candidates, we studied 31 patients with cirrhosis of varying aetiology; 14 with compensated cirrhosis (Pugh's score <7) and 17 with decompensated cirrhosis (Pugh's score <8). Underlying cellular abnormalities were characterised using in vitro 31P MRS and electron microscopy. In vitro spectra were obtained from liver extracts, freeze-clamped at recipient hepatectomy, from all subjects. Electron microscopy of liver tissue was also performed in 17 cases. Relative to nucleotide triphosphates, elevations in phosphomonoesters and reductions in phosphodiesters were observed in vivo with worsening liver function. In vitro spectra showed elevated phosphoethanolamine and phosphocholine, and reduced glycerophosphorylethanolamine and glycerophosphorylcholine, mirroring the in vivo changes, but no distinction was noted between compensated and decompensated cirrhosis. With electron microscopy, functional decompensation was associated with reduced endoplasmic reticulum in parenchymal liver disease, but elevated levels in biliary cirrhosis. We conclude that in vivo spectral abnormalities in cirrhosis are consistent with alterations in phospholipid metabolism and quantity of endoplasmic reticulum. However, in individual patients the biopsy results do not always mirror in vivo findings. [ABSTRACT FROM AUTHOR]

The article discusses a report published within the issue by Ignasi Barbam Nicolas Chatauret and David Garcia-Dorado on grading hepatic encephalopathy and monitoring the effects of therapeutic hypothermia in rats.

Nuclear magnetic resonance (NMR) spectroscopy is a non-invasive technique, which allows the study of cellular biochemistry and metabolism. It is a diverse research tool, widely used by biochemists to investigate pathophysiological processes in vitro and, more recently, by physicians to determine disease abnormalities in vivo. This article reviews the basics of the NMR phenomenon and summarises previous research on the hepatobiliary system using both laboratory-based and clinical methodologies. The role of proton and phosphorus-31 ((31)P) NMR spectroscopy in the study of malignant and non-malignant liver disease and studies of bile composition are discussed. In vivo techniques (magnetic resonance spectroscopy, MRS) can be performed as an adjunct to standard MR examination of the liver. Although still primarily a research tool, the in vivo technique provides non-invasive biochemical information on disease severity and holds promise in its use to gauge response to treatment regimens., (Copyright Blackwell Munksgaard 2005)