Nonalcoholic steatohepatitis

El fetge gras no alcohòlic es caracteritza per unes lesions hepàtiques semblants a les de la malaltia hepàtica alcohòlica, que comprèn des de l'esteatosi simple i l'esteatohepatitis amb canvis inflamatoris i fibrosi fins a la cirrosi. És una malaltia cada vegada més freqüent que s'associa amb l'obesitat, la diabetis i la dislipèmia, i és probablement el component hepàtic d'una síndrome metabòlica. La seva patogènesi no és ben coneguda, però la resistència a la insulina i l'augment d'àcids grassos lliures al fetge hi tenen un paper fonamental, en provocar un estrès oxidatiu i activar els mecanismes responsables de la inflamació, la necrosi i la fibrosi. El diagnòstic s'ha de fer mitjançant una biòpsia del fetge, la qual també permet establir la gravetat de les lesions. A part del tractament dels factors associats, l'esteatohepatitis no alcohòlica no té un tractament establert, tot i que s'estan assajant fàrmacs que milloren la resistència a la insulina i d'altres amb acció antioxidant. Els resultats d'alguns estudis pilot són esperançadors, encara que falten estudis controlats, amb grups mes grans de malalts i que valorin els canvis histològics.Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition whose symptoms and pathology resemble those of alcohol-induced liver injury. NAFLD includes fatty liver, steatohepatitis (NASH) with inflammatory changes and fibrosis, and cirrhosis. NAFLD is usually seen in association with obesity, diabetes, hypertension, and hypertriglyceridemia, as the hepatic component of a metabolic syndrome. Most NAFLD patients are asymptomatic and usually present with mild elevations in aminotransferases. The diagnosis should be established by liver biopsy. The natural history of this disease is not well defined, but progression to cirrhosis and hepatocellular carcinoma is well recognized in some patients. The pathogenesis is not well known but the accumulation of fat in the liver is probably related to insulin resistance, which leads to altered free fatty acid metabolism. The progression from NAFLD to NASH and cirrhosis is less clear but increasing evidence suggests that oxidative stress may enhance proinflammatory and profibrogenic cytokines and that this leads to mitochondrial dysfunction followed by development of inflammation, necrosis, and fibrosis. There is no established treatment for NASH, and current therapies are focused on correcting the insulin resistance or reducing oxidative stress. Although the results of some recent pilot studies are promising, prospective, randomized studies with clearly defined histological endpoints are needed

Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the −308 and −627 positions in the TNF-α and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS TNF-α −308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 −627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (ORcombined data=3.2 (95% confidence intervals (CI) 1.8–4.5); pcorr=10−5). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (ORcombined data=3.2 (95% CI 1.2–9.0); pcorr=0.006 ). There was no difference in the −627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (ORcombined data=3.8, pcorr=10−6 v ORcombined data=3.2, pcorr=10−5 vORcombined data =3.41, pcorr=10−4, respectively). CONCLUSIONS This study identified a significant association between possession of the TNF2 allele, a G→A substitution at position −308 in the TNF-α promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 −627 promoter polymorphism and PSC

Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion

During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH + I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH + I/R. © 2010 Macmillan Publishers Limited.This work was supported by the Ministerio de Educación y Ciencia (project grant SAF 2005-00385; project grant manager BFU2009-07410) (Madrid, Spain) and the Ministerio de Sanidad y Consumo (project grant PIO60021) (Madrid, Spain). Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is supported by the Instituto de Salud Carlos III (Spain).Peer Reviewe