Gabriel Perlemuter

Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis.

Liver steatosis, which involves accumulation of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride‐rich very low density lipoproteins (VLDL). Core expression led to reduction in microsomal triglyceride transfer protein (MTP) activity and in the particle size of nascent hepatic VLDL without affecting accumulation of MTP and protein disulfide isomerase. Hepatic human apolipoprotein AII (apo AII) expression in double‐core/apo AII transgenic mice diminished intrahepatic core protein accumulation and abrogated its effects on VLDL production. Apo AII and HCV core colocalized in human HCV‐infected liver biopsies, thus testifying to the relevance of this interaction in productive HCV infection. Our results lead us to propose a new patho‐physiological animal model for induction of viral‐related steatosis whereby the core protein of HCV targets microsomal triglyceride transfer protein activity and modifies hepatic VLDL assembly and secretion.—Perlemuter, G., Sabile, A., Letteron, P., Vona, G., Topilco, A., Chrétien, Y., Koike, K., Pessayre, D., Chapman, J., Barba, G., Bréchot, C. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral‐related steatosis FASEB J. 16, 185–194 (2002)

Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice

Objective Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice. Design Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the ‘responder’, developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a ‘non-responder’, was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD. Results Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels. Conclusions Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.

Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease

FibroTest has been validated as a biomarker of fibrosis in patients with chronic viral hepatitis, with a similar prognostic value as biopsy. The aim of the study was to compare the diagnostic and prognostic values of FibroTest versus the recently patented biomarkers, FibrometerA, and Hepascore. A total of 218 consecutive patients with ALD and available liver biopsy examination were included. Biomarkers were compared using univariate area under the ROC curves (AUROC) and multivariate analysis (logistic regression and Cox). The median follow‐up was 8.2 years. Eighty‐five patients died, including 42 deaths related to liver complications. The diagnostic values of FibrometerA and Hepascore did not differ from that of FibroTest for advanced fibrosis (all AUROC = 0.83 ± 0.03) and cirrhosis (FibroTest and FibrometerA = 0.94 ± 0.02, Hepascore = 0.92 ± 0.02), and were significantly greater than those of nonpatented biomarkers (APRI, Forns, FIB4; P < 0.01). In multivariate analysis the most significant was FibroTest (P = 0.001), without independent diagnostic value for FibrometerA (P = 0.19), and Hepascore (P = 0.40). The prognostic values of FibroTest (AUROC for survival or non liver disease‐related death = 0.79 ± 0.04), FibrometerA (0.80 ± 0.04), Hepascore (0.78 ± 0.04), did not differ from that of biopsy fibrosis staging (0.77 ± 0.04). In multivariate analysis the most significant were FibroTest (P = 0.004) and biopsy (P = 0.03), without independent prognostic values for FibrometerA (P = 0.41) and Hepascore (P = 0.28). In patients with alcoholic liver disease, FibrometerA and Hepascore did not improve the diagnostic and prognostic values of FibroTest. (HEPATOLOGY 2009;49:97‐105.)

Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease

Objective There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH). Design We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied. Results A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4+T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions. Conclusions Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation.

Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model

BACKGROUND/AIMS Alcohol consumption accelerates the appearance of liver fibrosis and hepatocellular carcinoma in patients with chronic hepatitis C virus (HCV) infection, but the mechanisms of these interactions are unknown. We therefore investigated the effects of chronic ethanol consumption in HCV core protein-expressing transgenic mice. METHODS Ethanol was progressively added (up to 20%) to the drinking water that was given ad libidum. RESULTS In vivo fatty acid oxidation was not inhibited by ethanol consumption and/or HCV core expression. Both chronic ethanol consumption and HCV core expression decreased hepatic lipoprotein secretion and caused steatosis, but had no additive effects on lipoprotein secretion or steatosis. However, chronic ethanol consumption and HCV core protein additively increased lipid peroxidation and acted synergistically to increase the hepatic expression of transforming growth factor-beta (TGF-beta) and, to a less extent, tumor necrosis factor-alpha (TNF-alpha). CONCLUSIONS HCV core protein expression and chronic alcohol consumption have no effects on in vivo fatty acid oxidation and do not additively impair hepatic lipoprotein secretion, but additively increase hepatic lipid peroxidation and synergistically increase hepatic TNF-alpha and TGF-beta expression. These effects may be involved in the activation of fibrogenesis and the development of hepatocellular carcinoma in patients cumulating alcohol abuse and HCV infection.

Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases

Chronic intestinal pseudoobstruction (CIPO) is a rare syndrome that may occur in association with connective tissue diseases (CTD). Effective management is a major challenge. We report 3 cases in which subcutaneous octreotide was efficacious in the treatment of digestive symptoms in CIPO. In 2 of the 3 cases, previous treatment with domperidone, cisapride, or erythromycin had been unsuccessful. All 3 patients underwent a regimen of oral antibiotics along with octreotide to stimulate small bowel motility. The effects of octreotide were evident within 48 hours after the first injection in all patients. In 2, the efficacy seemed to decrease after 1 week and 6 months respectively, but increasing the dosage led to another remission. CIPO in CTD is a severe condition that can evolve regardless of the underlying disease activity. Octreotide appears to be efficacious in improving both clinical symptoms and manometric patterns. When its therapeutic effect diminishes, increasing the dosage can be useful.

Chronic intestinal pseudo-obstruction in systemic lupus erythematosus

Background/Aims—Chronic intestinal pseudo-obstruction (CIPO) reflects a dysfunction of the visceral smooth muscle or the enteric nervous system. Gastrointestinal manifestations are common in systemic lupus erythematosus (SLE) but CIPO has not been reported. Features of CIPO are reported in five patients with SLE. Methods—From 1988 to 1993, five patients with SLE or SLE-like syndrome were hospitalised for gastrointestinal manometric studies. CIPO was the onset feature in two cases. Antroduodenal manometry (three hours fasting, two hours fed) was performed in all patients, and oesophageal manometry in four. Results—Intestinal hypomotility associated with reduced bladder capacity and bilateral ureteral distension was found in four patients and aperistalsis of the oesophagus in three. Treatment, which consisted of high dose corticosteroids, parenteral nutrition, promotility agents, and antibiotics, led to remission of both CIPO and urinary abnormalities in all cases. Antroduodenal manometry performed in two patients after remission showed increased intestinal motility. One patient died, and postmortem examination showed intestinal vasculitis. Conclusions—CIPO in SLE is a life threatening situation that can be reversed by treatment. It may be: (a) a complication or onset feature of the disease; (b) secondary to smooth muscle involvement; (c) associated with ureteral and vesical involvement; (d) the result of intestinal vasculitis.

Biliary obstruction caused by portal cavernoma: a study of 8 cases

BACKGROUND/AIMS Biliary obstruction secondary to portal cavernoma is a rare and little-known entity. From 1985 to 1994, we observed eight cases of portal cavernoma compressing the biliary tract. We report here the features of biliary involvement in these cases of portal cavernoma including the circumstances of diagnosis, biliary tract morphology, liver pathology and the efficiency of various treatments. METHODS AND RESULTS The causes of portal vein obstruction were portal vein thrombosis in one case, peritonitis in another, omphalitis in two cases, portal vein catheterization in one case and unknown in two cases. The portal cavernoma was revealed through esophageal varices ruptures in four patients. The mean time from portal cavernoma diagnosis to biliary involvement was 8 years (range 0-21). Six patients had acute cholangitis, one of whom revealed portal vein obstruction. All the patients had abnormal liver function tests. Imaging techniques (transparietal abdominal ultrasonography and abdominal computed tomography scan [n = 8], endosonography [n = 5] and endoscopic retrograde cholangiography [n = 7]) showed in all cases an extraluminal obstacle, laminating the common bile duct. Pathologic examination of the liver showed secondary biliary cirrhosis in one patient, periportal and perisinusoidal fibrosis in another and no abnormalities in three other cases. Three patients were treated by endoscopic sphincterotomy but cholangitis persisted in two cases, leading to death in one. One patient who underwent a splenorenal shunt was symptom-free 60 months after surgery. Balloon endoscopic dilatation of the common bile duct, performed in one case, led to normalization of liver biological tests. The patients with abnormal liver pathology were treated by propranolol and ursodesoxycholic acid. No complication had occurred after 6 and 24 months of follow-up. CONCLUSIONS In conclusion, eliminating biliary obstruction seems to be essential in providing the best change of survival for patients when biliary obstruction becomes symptomatic. In cases of abnormal liver pathology, associating propranolol with ursodesoxycholic acid would seem to be useful.

Increase in liver antioxidant enzyme activities in non‐alcoholic fatty liver disease

Abstract: Aims: Steatosis may increase oxidative stress, which is counteracted by cellular enzymatic (cytosolic and mitochondrial superoxide dismutases (Cu/Zn‐SOD and Mn‐SOD), glutathione peroxidase (GPx), catalase) and non‐enzymatic antioxidant systems. We aimed to determine, in patients with non‐alcoholic fatty liver disease (NAFLD), the level of antioxidant defenses (1) in liver biopsies, to demonstrate the existence of oxidative stress; (2) in erythrocytes and plasma, to determine whether their antioxidant defenses reflect liver oxidative stress.

Cryptogenetic multifocal ulcerous stenosing enteritis: an atypical type of vasculitis or a disease mimicking vasculitis

BACKGROUND/AIMS Cryptogenetic multifocal ulcerous stenosing enteritis (CMUSE) is a rare disease whose origin is unknown. The aim of this study was to describe the clinical spectrum of CMUSE, to determine the origin and pathophysiology of the disease, and to propose a treatment strategy. METHODS A total of 220 French gastroenterology departments were contacted to review patients with unexplained small bowel strictures. Of 17 responses, 12 corresponded to a diagnosis of CMUSE. These patients were hospitalised between 1965 and 1993 and their medical records were reviewed. RESULTS All patients (mean age 42.1 (4.4) years) had intestinal and five had extraintestinal symptoms (peripheral neuropathy, buccal aphthae, sicca syndrome, polyarthralgia, Raynauds phenomenon, arterial hypertension). One patient had heterozygous type I C2 deficiency (28 base pair gene deletion). Two to 25 (mean 8.3 (1.9)) small intestine strictures were found. Stenoses of the large jejunoileal arteries were observed on two and aneurysms on three of five mesenteric angiograms. Despite surgery, symptoms recurred in seven of 10 patients and strictures in four. Steroid therapy was effective but caused dependence. One untreated patient died. Small bowel pathology showed superficial ulceration of the mucosae and submucosae, and an inflammatory infiltrate made of neutrophils and eosinophils. CONCLUSIONS CMUSE is an independent entity characterised by steroid sensitive inflammation of the small bowel which often recurs after surgery. CMUSE may be related to a particular form of polyarteritis nodosa with mainly intestinal expression or with an as yet unclassified vasculitis.