The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] ‫؍‬ 1.77; 95% CI ‫؍‬ 1.21-2.58; P ‫؍‬ .0032) and the oral glucose insulin sensitivity (OR ‫؍‬ 0.53; CI ‫؍‬ 0.33-0.87; P ‫؍‬ .0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD. (HEPATOLOGY 2004;39:179 -187.) N onalcoholic fatty liver disease (NAFLD) is growing in importance, causing in a wide spectrum of hepatic injury, ranging from fatty liver to steatohepatitis and cirrhosis. 1 Whereas pure fatty liver has a benign clinical course, nonalcoholic steatohepatitis (NASH) is a recognized cause of progressive liver fibrosis that eventually leads to cirrhosis, liver failure, and hepatocellular carcinoma. 2-4 NAFLD and NASH are the two most common chronic liver diseases in Western countries, with an estimated prevalence in the general population of 10% to 20% and 2% to 3%, respectively. 2,5-7 A two-hit theory 8 has been proposed to explain the progression from simple steatosis to NASH, fibrosis, or cirrhosis. The first hit is represented by excessive hepatic fat accumulation primarily owing to insulin resistance and is supported by the close relation observed between NAFLD and several features of the metabolic syndrome (visceral obesity, type II diabetes mellitus, and dyslipidemia). 9 -11 The second hit is related mainly to increased intrahepatic oxidative stress, which promotes hepatic fibrosis through the production of reactive oxygen sp...

Summary The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion‐transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle‐thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen‐positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty‐four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4–107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.

BackgroundRecent advances in the management of thalassemia have significantly improved life expectancy and quality of life of patients with this hemoglobinopathy, with a consequent increase in their reproductive potential and desire to have children. Design and MethodsWe describe the methods of conception and delivery, as well as the course and outcome of pregnancy including transfusions, iron overload and chelation in 46 women with thalassemia major (58 pregnancies) and in 11 women with thalassemia intermedia (17 pregnancies). Conception was achieved after gonadotrophin-induced ovulation in 33 of the women with thalassemia major and spontaneously in all of those with thalassemia intermedia. ResultsAmong the women with thalassemia major, 91% of the pregnancies resulted in successful delivery of 45 singleton live-born neonates, five sets of twins and one set of triplets. No secondary complications of iron overload developed or worsened during pregnancy. When considering only the singleton pregnancies, the proportion of babies with intrauterine growth retardation did not differ from that reported in the general Italian population. The high prevalence of pre-term births (32.7%) was mostly related to multiple pregnancies and precautionary reasons. Pregnancy was safe in most women with thalassemia major or intermedia. However, women with thalassemia intermedia who had never previously been transfused or who had received only minimal transfusion therapy were at risk of severe alloimmune anemia if blood transfusions were required during pregnancy. ConclusionsProvided that a multidisciplinary team is available, pregnancy is possible, safe and usually has a favorable outcome in patients with thalassemia. In women with hypogonadotropic hypogonadism, gonadal function is usually intact and fertility is usually retrievable.Key words: pregnancy, thalassemia major, thalassemia intermedia, hypogonadism, assisted reproduction.Citation: Origa R, Piga A, Quarta G, Forni GL, Longo F, Melpignano A, and Galanello R. Pregnancy and β-thalassemia: an Italian multicenter experience. Haematologica. 2010; 95:376-381. doi:10.3324/haematol.2009 This is an open-access paper.Pregnancy and β β-thalassemia: an Italian multicenter experience

Objective To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. Methods We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. Results In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. Interpretation Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.

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