Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness.

Patients with severe alcoholic hepatitis (SAH) not responding to glucocorticoid therapy have higher mortality, though they do not differ in their baseline clinical characteristics and prognostic scores from those who respond to therapy. We hypothesized that the baseline hepatic gene expression differs between responders (R) and non-responders (NR). Baseline liver transcriptome was compared between R and NR in Indian (16 each) and French (5 NR, 3 R) patients with SAH. There were differentially expressed genes (DEGs) between NR and R, in Indian (1106 over-expressed, 96 under-expressed genes) and French patients (65 over-expressed, 142 under-expressed genes). Indian NR had features of hepatocyte senescence and French NR exhibited under-expression of genes involved in cell division, indicating a central defect in the capacity of hepatocytes for self-renewal in both populations. Markers of hepatic progenitor cell proliferation were either very few (Indian patients) or absent (French patients). No DEGs were enriched in inflammatory pathways and there were no differences in nuclear receptor subfamily 3 group C member 1 (NR3C1) transcript expression and splicing between NR and R. Our results reveal that baseline hepatic transcriptome is reflective of subsequent glucocorticoid non-response and indicate impaired regenerative potential of the liver as an underlying phenomenon in NR.

Peripheral intrahepatic cholangiocarcinoma occurring in patients without cirrhosis or chronic bile duct diseases: epidemiology and histopathology of distant nontumoral liver in 57 White patients.

BACKGROUND/AIM: Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized. PATIENTS AND METHODS: We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease. RESULTS: High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%). CONCLUSION: This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease.

Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.

BACKGROUND & AIMS: A recent genome-wide association study identified genetic polymorphism (rs738409 C>G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD. METHODS: Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patient's phenotype. RESULTS: The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.12-2.11 p = 0.008) and was, among ALD patients, significantly associated with steatosis (p = 0.048), fibrosis (p = 0.001), and greater risk of cirrhosis (p = 0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR = 2.08; 95% CI = 1.15-3.77; p = 0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p = 0.03) and negatively correlated with the hepatic venous pressure gradient (r = -0.41, p = 0.006). CONCLUSIONS: In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD.

Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China.

BACKGROUND: Fatty liver disease (FLD) is increasingly recognized as one of the most common chronic liver diseases in China. This study aimed to investigate the prevalence and risk factors of FLD in Chengdu, Southwest China, and to provide a relevant basis for the prevention and intervention of FLD. METHODS: Altogether 9094 subjects (4721 men and 4373 women) of over 18 years old who had received a medical checkup in the West China Hospital of Sichuan University between January and December 2007 were evaluated for FLD. FLD was diagnosed by ultrasonography. Body mass index (BMI), height, body weight, blood pressure, fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TCh), alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured using routine laboratory methods. RESULTS: The overall prevalence of FLD was 12.5%, which was more than 3-fold higher in males than in females (18.9% vs. 5.7%, X2=359.624, P<0.001). The prevalence increased with age in females and males of less than 50 years. The prevalence of alcoholic, suspected alcoholic, and non-alcoholic FLD was 2.6%, 3.6%, and 6.3%, respectively. Multiple logistic regression analyses showed that 10 factors (male sex, age, BMI, FPG, hypertension, TG, TCh, HDL-C, LDL-C, and ALT abnormalities) were closely related to FLD. In heavy drinkers, obesity increased the risk of FLD by 23.78-fold (95% CI, 10.22-55.33), but heavy drinking was only associated with a 2-fold (95% CI, 1.50-2.66) increased risk in obese subjects. CONCLUSIONS: The prevalence of FLD among a health-checkup population in Chengdu, Southwest China was lower than the published for other areas of China. FLD in Chengdu adults was found to be closely associated with sex, age, BMI, and other metabolic syndrome features.