Daniela Cabibi

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

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 μg/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. (HEPATOLOGY 2010.)

Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection.

OBJECTIVES:Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV).METHODS:Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis.RESULTS:Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of ≥3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422–6.098), low platelets (OR 0.994, 95% CI 0.981–0.999), low cholesterol (OR 0.987, 95% CI 0.976–0.998), high ferritin (OR 1.002, 95% CI 1.001–1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463–4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) (P = 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other (P = 0.42).CONCLUSIONS:In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.

Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index

Background  Liver stiffness measurement (LSM) using transient elastography (TE) is used to stage fibrosis in patients with liver disease, diagnostic reliability and the factors affecting its performance in patients with non‐alcoholic fatty liver disease (NAFLD) are incompletely understood.

Carotid atherosclerosis and chronic hepatitis C: A prospective study of risk associations

There are contrasting results in studies of cardiovascular risk in patients with genotype 1 chronic hepatitis C (G1 CHC). We evaluated the prevalence of carotid atherosclerosis compared with a control population in order to assess the potential association between atherosclerosis, host and viral factors, and liver histological features. In all, 174 consecutive biopsy‐proven G1 CHC patients were evaluated by anthropometric and metabolic measurements and 174 patients attending an outpatient cardiology unit were used as controls. Intima‐media thickness (IMT) and carotid plaques, defined as focal thickening of >1.3 mm at the level of common carotid, were evaluated using ultrasonography. All G1 CHC biopsies were scored by one pathologist for staging and grading, and graded for steatosis. Carotid plaques were found in 73 (41.9%) G1 CHC patients compared with 40 (22.9%) control patients (P < 0.001). Similarly, G1 CHC patients had a greater IMT compared with control patients (1.04 ± 0.21 versus 0.90 ± 0.16; P < 0.001). Multivariate logistic regression analysis showed that older age (odds ratio [OR] 1.047, 95% confidence interval [CI]: 1.014‐1.082, P = 0.005), and severe hepatic fibrosis (OR 2.177, 95% CI: 1.043‐4.542, P = 0.03), were independently linked to the presence of carotid plaques. In patients ≤55 years, 15/67 cases with F0‐F2 fibrosis (22.3%) had carotid plaques, compared with 11/21 (52.3%) with F3‐F4 fibrosis (P = 0.008). By contrast, in patients >55 years the prevalence of carotid plaques was similar in those with or without severe fibrosis (25/43, 58.1% versus 22/43, 51.1%; P = 0.51). Conclusion: Severe hepatic fibrosis is associated with a high risk of early carotid atherosclerosis in G1 CHC patients. (HEPATOLOGY 2012)

Hyperuricemia is associated with histological liver damage in patients with non‐alcoholic fatty liver disease

Aliment Pharmacol Ther 2011; 34: 757–766

Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1.

Metabolic factors have been associated with liver damage in patients with genotype 1 chronic hepatitis C (G1 CHC). We tested visceral adiposity index (VAI), a new marker of adipose dysfunction in G1 CHC, patients to assess its association with host and viral factors and its link to both histological findings and sustained virological response (SVR). Two hundred thirty‐six consecutive G1 CHC patients were evaluated by way of liver biopsy and anthropometric and metabolic measurements, including insulin resistance (IR), homeostasis model assessment (HOMA), and VAI using waist circumference, body mass index, triglycerides, and high‐density lipoprotein cholesterol. All biopsies were scored by one pathologist for staging and grading and graded for steatosis, which was considered moderate to severe if ≥30%. Multiple linear regression analysis revealed that VAI score was independently associated with higher HOMA score (P = 0.009), log10 hepatitis C virus RNA levels (P = 0.01), necroinflammatory activity (P = 0.04), and steatosis (P = 0.04). Multiple logistic regression analysis revealed that IR (OR 3.879, 95% CI 1.727‐8.713, P = 0.001), higher VAI score (OR 1.472, 95% CI 1.051‐2.062, P = 0.02), and fibrosis (OR 2.255, 95% CI 1.349‐3.768, P = 0.002) were linked to steatosis ≥30%. Logistic regression analysis revealed that older age (OR 1.030, 95% CI 1.002‐1.059, P = 0.03), higher VAI score (OR 1.618, 95% CI 1.001‐2.617, P = 0.04), and fibrosis (OR 2.608, 95% CI 1.565‐4.345, P < 0.001) were independently associated with moderate to severe necroinflammatory activity. No independent associations were found between VAI score and both fibrosis and SVR. Conclusion: In G1 CHC patients, higher VAI score is independently associated with both steatosis and necroinflammatory activity and has a direct correlation with viral load. (HEPATOLOGY 2010.)

BRAFV600E mutation and p27kip1 expression in papillary carcinomas of the thyroid ≤1 cm and their paired lymph node metastases

BRAFV600E mutation and p27kip1 expression have been introduced as novel indicators that may predict prognosis in different tumors, as well as in papillary thyroid carcinomas.

The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease

In nonalcoholic fatty liver disease, the influence of severity of steatosis on liver stiffness measurement (LSM) is poorly studied and still debated. We assessed the impact of steatosis severity and its ultrasonographic (US) sign, severe bright liver echo pattern, on LSM values and on transient elastography accuracy for the diagnosis of liver fibrosis in a cohort of consecutive patients with nonalcoholic fatty liver disease. Patients (n = 253) were assessed by clinical, US, and histological (Kleiner score) features. Transient elastography was performed using the M probe. Among patients with low amounts of fibrosis (F0‐F1 and F0‐F2), median LSM values, expressed in kilopascals, were significantly higher in subjects with severe steatosis (≥66% at liver biopsy) compared to those without (F0‐F1 6.9 versus 5.8, P = 0.04; F0‐F2 7.4 versus 6.0, P = 0.001) as well as in patients with severe bright liver echo pattern on US compared to their counterparts (F0‐F1 7.3 versus 5.6, P = 0.001; F0‐F2 7.6 versus 6.0, P < 0.001). In subjects without significant fibrosis (F0‐F1) and without severe fibrosis (F0‐F2), a higher rate of false‐positive LSM results was observed in patients with steatosis ≥66% compared to those without (F0‐F1 23.6% versus 14.9%, F0‐F2 33.3% versus 13.2%) and in patients with severe bright liver echo pattern on US (F0‐F1 22.2% versus 15.4%, F0‐F2 28.8% versus 15.6%) compared to their counterparts. Conclusions: In patients with nonalcoholic fatty liver disease, the presence of severe steatosis, detected by histology or by US, should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2015;62:1101‐1110)

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.

Visceral adiposity index is associated with significant fibrosis in patients with non‐alcoholic fatty liver disease

Aliment Pharmacol Ther 2012; 35: 238–247