Paolo Sorrentino

Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis

BACKGROUND/AIMS Liver iron deposits are frequent in patients with non-alcoholic steato-hepatitis (NAFLD), but their role is not well defined. To investigate the effect of liver iron excess on the prevalence of hepatocellular carcinoma (HCC) in patients with NASH-related cirrhosis. METHODS Hepatic iron was measured retrospectively with a semiquantitative method in liver biopsies of 153 patients with NASH-related cirrhosis: 51 with HCC and 102 controls without HCC, matched for age, sex and stage of liver disease. The corrected total iron score (0-60) was the sum of three scores: the hepatocytic iron score (0-36), sinusoidal iron score (0-12), and portal iron score (0-12), multiplied by 3/3, 2/3, or 1/3 depending on the localisation of the iron in the nodules. RESULTS Conditional logistic regression analysis showed that iron deposits (corrected total iron score>0) were more frequent in HCC patients than in controls. The median corrected total iron score was significantly higher in HCC patients than in controls. The liver iron overload was sinusoidal. CONCLUSIONS Iron deposition in the liver was more frequent in patients with NASH-related cirrhosis with HCC than in HCC-free controls. Liver iron overload may be associated with development of HCC in patients with NASH-related cirrhosis.

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation.

Metabolic factors involved in the therapeutic response of patients with hepatitis C virus-related chronic hepatitis

Background:  The purpose of the present paper was to investigate the factors possibly involved in the failure of pegylated interferon (Peg IFN) plus ribavirin treatment at standard dosage in hepatitis C virus (HCV) 1b patients, with chronic hepatitis.

The HOX gene network in hepatocellular carcinoma

Liver organogenesis and cancerogenesis share common mechanisms. HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Less is known about the involvement of HOX genes with liver cancerogenesis. The comparison of the HOX gene network expression between nontumorous livers and hepatocellular carcinomas (HCCs) highlights significant differences in the locus A HOX genes, located on chromosome 7, with a consistent overexpression of HOXA13 mRNA thus validating this gene deregulation as a feature of HCC. HOXA13 is a determinant of gut primordia and posterior body structures. Transcriptome analysis of HCC/nontumorous liver mRNAs, selected on the basis of HOXA13 overexpression, recognizes a set of deregulated genes. The matching of these genes with previously reported HCC transcriptome analysis identifies cell‐cycle and nuclear pore‐related HCC phenotype displaying poor prognosis. HOXA13 and HOXA7 homeoproteins share a consensus sequence that physically links eIF4E nuclear bodies acting on the export of specific mRNAs (c‐myc, FGF‐2, vascular endothelial growth factor (VEGF), ornithine decarboxylase (ODC) and cyclin D1). We report the protein–protein interaction between HOXA13 and eIF4E in liver cancer cells and the deregulation of eIF4E mRNA and protein in cell cycle/nuclear pore HCC group phenotype and in T4 stage HCCs, respectively. Thus, transcriptional and post‐transcriptional HOXA13 deregulation is involved in HCC possibly through the mRNA nuclear export of eIF4E‐dependent transcripts.

Histopathology of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

Incidence of hypertension in individuals with different blood pressure salt-sensitivity: results of a 15-year follow-up study

Objective To evaluate the incidence of hypertension and the rate of decline in renal function in a sample of 47 Olivetti Heart Study (OHS) participants whose blood pressure (BP) salt-sensitivity and renal tubular sodium handling had been assessed in 1987–88. Methods During the 2002–04 OHS follow-up examination, medical history, physical examination and blood and urine sampling were performed in 36 of the 47 participants to the baseline study (age 60 ± 6 years; average follow-up = 15.1 ± 0.6 years). The renal length was measured in 23 participants by kidney ultrasonography. Based on the baseline salt-sensitivity evaluation, the subjects were classified into a lower salt-sensitivity (LSS, n = 20) and a higher salt-sensitivity group (HSS, n = 16). Results In comparison with the LSS group, HSS participants had a significantly higher incidence of hypertension (87.5 versus 50.0%, P = 0.02), a higher glomerular filtration rate (median, first to fourth quartile: 81.9, 72.3–95.2 versus 72.3, 59.9–81.2 ml/min; P = 0.03) and greater kidney length (median, first to fourth quartile: 68.2, 63.3–72.1 versus 61.9, 58.7–62.7 mm/m of height; P = 0.003). The incidence of hypertension remained significantly higher in HSS individuals after adjustment for age, intercurrent changes in body mass index and baseline blood pressure on low sodium diet (P = 0.04). Conclusion Our findings indicate that individuals with higher BP salt-sensitivity have a higher rate of incident hypertension and suggest an altered renal tubular sodium handling involving a trend to increased glomerular filtration rate and blood pressure over time as a possible mechanism.

Frontal Behavioural Inventory in the differential diagnosis of dementia.

Objective –  To evaluate diagnostic properties of the Frontal Behavioural Inventory (FBI) in patients suffering from different forms of dementia.

Predicting Fibrosis Worsening in Obese Patients With NASH Through Parenchymal Fibronectin, HOMA-IR, and Hypertension

OBJECTIVES:Few published studies have examined the results obtained from repeat liver biopsies in obese patients with nonalcoholic fatty liver disease (NAFLD). The progressive form of this disease may be largely limited to a subgroup of NAFLD patients with nonalcoholic steatohepatitis (NASH). The presence of intralobular fibronectin (Fn) and other variables was investigated in relation to subsequent fibrosis progression.METHODS:In this prospective study, 271 obese patients admitted to the hospital with NAFLD and abnormal liver enzymes were scheduled to undergo a repeat liver biopsy at least 5 years after the initial biopsy. After excluding cirrhotic patients, basal biopsy specimens obtained from patients who underwent a second liver biopsy were stained with antibodies against Fn. The progression of fibrosis in the follow-up sample was correlated with the amount of Fn and other clinicopathological variables.RESULTS:We obtained a second liver biopsy from 149 patients after a median time of 6.4 years. Of these, 132 showed suitable Fn staining for semi-quantitative assessments. In all, 44 out of 83 patients (53%) with basal NASH showed fibrosis progression by at least one stage in the second liver biopsy. The amount of Fn (odds ratio=14.1; P<0.001), a diagnosis of hypertension (odds ratio=4.8; P=0.028), and homeostasis model assessment parameter of insulin resistance (HOMA-IR) scores (>8, odds ratio=1.9; P=0.004) were independent predictive factors of worsening fibrosis.CONCLUSIONS:A semi-quantitative assessment of the amount of parenchymal Fn present at an early stage in obese patients with NASH is valuable for predicting the progression of fibrosis. Similarly, lobular Fn deposition may be a sensitive and early indicator of active fibrogenetic processes in the liver. Hypertension and higher HOMA-IR scores are other clinical independent risk factors that predict the progression of fibrosis.

Preservation of nutritional-status in patients with refractory ascites due to hepatic cirrhosis who are undergoing repeated paracentesis.

Background and Aim:  Refractory ascites in liver‐cirrhosis is associated with a poor prognosis. We performed a prospective study to investigate whether aggressive nutritional‐support could improve outcomes in cirrhotic patients.

Mental status impairment in patients with West Haven grade zero hepatic encephalopathy: the role of HCV infection

BackgroundIn patients with cirrhosis, subclinical hepatic encephalopathy, which negatively affects the activity of daily living, is often unidentified. In a multicenter observational study, we investigated the possibility of detecting minimal neurological changes consistent with subclinical hepatic encephalopathy by using the Trail Making Test in a cohort of patients with liver cirrhosis at hospital admission.MethodsSeventy-seven consecutive patients with liver cirrhosis were studied (mean age, 69.5 ± 9.1; 95% confidence interval, 67.5–71.6 years). In all patients, possible encephalopathy was investigated according to the West Haven criteria. All those free of any sign of encephalopathy (West Haven 0) were also studied by the Trail Making Test forms A and B. The Child-Pugh score was determined in all patients, and results were compared with the West Haven stage. Exclusion criteria were use of benzodiazepine, beta adrenergic blockers, alcohol, or antiepileptic drugs, or coexistence of depression, dementia, Parkinson’s disease, or chronic or acute cerebral vasculopathy.ResultsOf the 77 patients, 44 (57.1%, 23 men and 21 women) had West Haven score 0, but among these, 26 (59.1%) were diagnosed with mental impairment likely linked to minimal hepatic encephalopathy. Severity of liver disease correlated with the presence of likely minimal hepatic encephalopathy, because the prevalence of abnormal Trail Making Test results increased from 22.2% in Child-Pugh A, to 63.4% and 74.0% in Child-Pugh B and C, respectively.ConclusionsThe investigation of patients with cirrhosis by the West Haven test is not sufficient to identify subclinical forms of encephalopathy. The Trail Making Test (a simple, inexpensive test) in our series evidenced poor psychometric performance in more than half of the patients who were free of manifest encephalopathy. Subclinical hepatic encephalopathy was present mostly in patients with HCV-related cirrhosis. Detecting minimal hepatic encephalopathy in patients with cirrhosis may help improve their quality of life.