IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Genetic background may affect liver damage in patients with non-alcoholic fatty liver disease (NAFLD). The main outcomes of the study were to assess whether IL28B rs12979860 and rs8099917 polymorphisms, together with PNPLA3 rs738409 C>G polymorphism, are associated with lobular inflammation and fibrosis, in NAFLD patients. METHODS: One hundred sixty consecutive NAFLD patients were assessed by liver biopsy (Kleiner score); anthropometric, and biochemical and metabolic features were included. IL28B rs12979860 C>T, IL28B rs8099917 G>C, and PNPLA3 rs738409 C>G single nucleotide polymorphisms were tested. RESULTS: Seventy-four (46.2%) patients had IL28B rs12979860 CC polymorphism, compared with 72 (45%) and 14 (8.8%) with TC and TT variants, respectively. PNPLA3 rs738409 CC polymorphism was present in 47 (29.4%) patients, compared with 79 (49.4%) and 34 (21.3%) with CG and GG variants, respectively. Multivariate logistic regression analysis showed that age (OR 1.043, 95% CI 1.012-1.075, p=0.007), triglycerides (OR 1.005, 95% CI 1.000-1.010, p=0.04), hyperuricemia (OR 5.027, 95% CI 1.839-13.742, p=0.002), IL28B rs12979860 TT/TC (OR 0.219, 95% CI 0.101-0.472, p<0.001), and steatosis grade (OR 1.704, 95% CI 1.048-2.773, p=0.03) were independently linked to moderate-severe lobular inflammation. Finally, IL28B rs12979860 CC was associated with severe fibrosis (F3-F4) on univariate analysis, even if only older age (OR 1.064, 95% CI 1.026-1.104, p=0.001), high HOMA (OR 1.213, 95% CI 1.068-1.377, p=0.003), and lobular inflammation (OR 3.181, 95% CI 1.438-7.036, p=0.004), remained associated in multivariate logistic regression analysis. CONCLUSIONS: In NAFLD patients, IL28B rs12979860 CC genotype, together with PNPLA3 rs738409 GG, is associated with the severity of liver damage.

Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.

UNLABELLED: 25-Hydroxyvitamin D (25[OH]D) can potentially interfere with inflammatory response and fibrogenesis. Its role in disease progression in chronic hepatitis C (CHC) and its relation with histological and sustained virological response (SVR) to therapy are unknown. One hundred ninety-seven patients with biopsy-proven genotype 1 (G1) CHC and 49 healthy subjects matched by age and sex were consecutively evaluated. One hundred sixty-seven patients underwent antiviral therapy with pegylated interferon plus ribavirin. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. Tissue expression of cytochrome (CY) P27A1 and CYP2R1, liver 25-hydroxylating enzymes, were assessed by immunochemistry in 34 patients with CHC, and in eight controls. The 25(OH)D serum levels were significantly lower in CHC than in controls (25.07 +/- 9.92 microg/L versus 43.06 +/- 10.19; P < 0.001). Lower levels of 25(OH)D were independently linked to female sex (P = 0.007) and necroinflammation (P = 0.04) by linear regression analysis. CYP27A1, but not CYP2R1, was directly related to 25(OH)D levels (P = 0.01), and inversely to necroinflammation (P = 0.01). Low 25(OH)D (odds ratio [OR], 0.942; 95% confidence interval [CI], 0.893-0.994) and cholesterol (OR, 0.981; 95%CI, 0.969-0.992) levels, older age (OR, 1.043; 95%CI, 1.002-1.085), high ferritin (OR, 1.003; 95%CI, 1.001-1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014-4.929) were independently associated with severe fibrosis (F3-F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. CONCLUSION: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy.

Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis.

UNLABELLED: Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium-large (>or=F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996-0.999) and a high HOMA-IR score (OR, 1.296; 95%CI, 1.018-1.649), not with LSM (OR, 1.009; 95%CI, 0.951-1.070). It is noteworthy that nine of ten patients with medium-large EVs had a platelet/spleen ratio of less than 792 or an HOMA-IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996-1.000), high HOMA-IR score (OR, 1.373; 95%CI, 1.014-1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects. CONCLUSIONS: In patients with Child A HCV cirrhosis, two simple, easy-to-get tests, namely the platelet/spleen ratio and insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, significantly predict the presence of EV, outweighing the contribution given by transient elastography.