Lucia Brodosi

Six score systems to evaluate candidates with advanced cirrhosis for orthotopic liver transplant: Which is the winner?

Many prognostic systems have been devised to predict the outcome of liver transplantation (LT) candidates. Today, the Model for End‐Stage Liver Disease (MELD) is widely used for organ allocation, but it has shown some limitations. The aim of this study was to investigate the performance of MELD compared to 5 different score models. We evaluated the prognostic ability of MELD, modified Child‐Turcotte‐Pugh, MELD‐sodium, United Kingdom MELD, updated MELD, and integrated MELD in 487 candidates with cirrhosis for LT at the Bologna Transplant Centre, Bologna, Italy, between 2003 and 2008. Calibration analysis by Hosmer‐Lemeshow test, calibration curves, and concordance c‐statistics (area under the receiver operating characteristic curve [AUC]) were calculated at 3, 6, and 12 months. Actual cumulative survival curves, taking into account the event of interest in the presence of competing risk, were obtained using the best cutoffs identified by AUC. For each score, the Hosmer‐Lemeshow test revealed a good calibration. Integrated MELD showed calibration curves closer to the line of perfect predicting ability, followed by MELD‐sodium at 3 months and modified Child‐Turcotte‐Pugh at 6 months. MELD‐sodium AUCs at 3 and 6 months (0.798 and 0.765, respectively) and integrated MELD AUC at 6 months (0.792) were better than standard MELD (P < 0.05). Actual survival curves showed that these 2 scores were able to identify the patients with the highest drop‐out risk. In conclusion, MELD‐sodium and integrated MELD were the best prognostic models to predict drop‐out rates among patients awaiting LT. Liver Transpl 16:964‐973, 2010.

Long-term weight loss maintenance for obesity: a multidisciplinary approach.

The long-term weight management of obesity remains a very difficult task, associated with a high risk of failure and weight regain. However, many people report that they have successfully managed weight loss maintenance in the long term. Several factors have been associated with better weight loss maintenance in long-term observational and randomized studies. A few pertain to the behavioral area (eg, high levels of physical activity, eating a low-calorie, low-fat diet; frequent self-monitoring of weight), a few to the cognitive component (eg, reduced disinhibition, satisfaction with results achieved, confidence in being able to lose weight without professional help), and a few to personality traits (eg, low novelty seeking) and patient–therapist interaction. Trials based on the most recent protocols of lifestyle modification, with a prolonged extended treatment after the weight loss phase, have also shown promising long-term weight loss results. These data should stimulate the adoption of a lifestyle modification-based approach for the management of obesity, featuring a nonphysician lifestyle counselor (also called “lifestyle trainer” or “healthy lifestyle practitioner”) as a pivotal component of the multidisciplinary team. The obesity physicians maintain a primary role in engaging patients, in team coordination and supervision, in managing the complications associated with obesity and, in selected cases, in the decision for drug treatment or bariatric surgery, as possible more intensive, add-on interventions to lifestyle treatment.

Virus-Specific Immune Response in HBeAg-Negative Chronic Hepatitis B: Relationship with Clinical Profile and HBsAg Serum Levels

Background & Aims The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV. Methods Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNγ ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay. Results The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients. Conclusions Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

Bone marrow derived stem cells for the treatment of end-stage liver disease

End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell (BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.

NASH: A glance at the landscape of pharmacological treatment.

The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis. This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet medical needs. Several compounds are in the pipeline of pharmaceutical industries and are being studied in phase II trials, but only a few (obeticholic acid, elafibranor) have started phase III trials. This concise review is intended to offer a systematic analysis of the most promising therapeutic intervention in NASH. In conclusion, there is reasonable expectation that drug may help curb the burden of NASH, and we look forward to obtaining solid data on their long-term safety and effectiveness. However, we should not forget that behavioral interventions remain a mandatory background treatment, able to stop disease progression in compliant overweight/ obese patients, with results that compare favorably with - and add to - the beneficial effects of drug treatment.

A new prognostic model to predict dropout from the waiting list in cirrhotic candidates for liver transplantation with MELD score <18

The model for end‐stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD < 18 awaiting LT, finding prognostic variables to identify a high dropout risk.

Pathophysiology of Nonalcoholic Fatty Liver Disease: Lifestyle-Gut-Gene Interaction.

Background: The accumulation of fat droplets in the hepatic parenchyma is driven by several factors, synergistically acting to increase triglyceride flow to the liver (diet and metabolic factors, endotoxemia from gut microbiota, genetic factors). Key Messages: In the presence of unhealthy lifestyles and behavioral factors, leading to enlarged adipose tissue and insulin resistance (IR), both lipolysis and de novo lipogenesis are expected to increase the risk of hepatic lipid depots, in association with high calorie (either high-fat or high-carbohydrate) diets. The gut microbiota may also be involved via obesity, IR and hepatic inflammation generated by gut-derived toxic factors. Finally, several data also support a primary role of genetic factors. A few gene polymorphisms have also been associated with the risk of nonalcoholic fatty liver disease development and nonalcoholic steatohepatitis progression to more fibrosis and advanced liver disease. In a few cases (e.g., patatin-like phospholipase domain-containing 3/adiponutrin), steatosis carries a high risk of both liver disease and cardiovascular morbidity/mortality; in other cases (e.g., transmembrane 6 superfamily 2 human gene), dissociation has been observed between the increased risk of liver disease versus cardiovascular disease. Conclusions: A variable interplay between the genetic background and the metabolic milieu is the likely physiopathologic mechanism involved in individual cases, which must be considered for implementing effective treatment strategies.

NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its prevalence is increasing in relation to the epidemics of obesity and type 2 diabetes mellitus, via non-alcoholic fatty liver disease (NAFLD). Unhealthy lifestyles associated with metabolic disorders are per se risk conditions for NAFLD progression, and specific gene polymorphisms may also favor oncogenesis, particularly in the presence of advanced fibrosis or cryptogenic cirrhosis. However, NAFLD-associated HCC may also develop in non-cirrhotic NAFLD and is frequently diagnosed at a more advanced tumor stage, compared with virus/alcohol-related HCC. This highlights the need for screening programs and long-term surveillance for earlier HCC detection in patients with metabolic risk factors, a policy hindered by the large number of cases at risk, with costs unaffordable by National health systems. New screening tools and cost-utility studies are eagerly awaited to develop more appropriate programs for early detection and treatment of NAFLD-associated HCC.

An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects on weight loss and surrogate markers

BACKGROUND & AIMS Interventions aimed at lifestyle changes are pivotal for the treatment of non-alcoholic fatty liver disease (NAFLD), and web-based programs might help remove barriers in both patients and therapists. METHODS In the period 2010-15, 716 consecutive NAFLD cases (mean age, 52; type 2 diabetes, 33%) were treated in our Department with structured programs. The usual protocol included motivational interviewing and a group-based intervention (GBI), chaired by physicians, dietitians and psychologists (five weekly meetings, n = 438). Individuals who could not attend GBI entered a web-based intervention (WBI, n = 278) derived from GBI, with interactive games, learning tests, motivational tests, and mail contacts with the center. The primary outcome was weight loss ≥10%; secondary outcomes were alanine aminotransferase within normal limits, changes in lifestyle, weight, alanine aminotransferase, and surrogate markers of steatosis and fibrosis. RESULTS GBI and WBI cohorts had similar body mass index (mean, 33 kg/m2), with more males (67% vs. 45%), younger age, higher education, and more physical activity in the WBI group. The two-year attrition rate was higher in the WBI group. Healthy lifestyle changes were observed in both groups and body mass index decreased by almost two points;the 10% weight target was reached in 20% of WBI cases vs. 15% in GBI (not significant). In logistic regression analysis, after adjustment for confounders and attrition rates, WBI was not associated with a reduction of patients reaching short- and long-term 10% weight targets. Liver enzymes decreased in both groups, and normalized more frequently in WBI. Fatty liver index was reduced, whereas fibrosis remained stable (NAFLD fibrosis score) or similarly decreased (Fib-4). CONCLUSION WBI is not less effective than common lifestyle programs, as measured by significant clinical outcomes associated with improved histological outcomes in NAFLD. eHealth programs may effectively contribute to NAFLD control. LAY SUMMARY In patients with non-alcoholic fatty liver disease, participation in structured lifestyle programs may be jeopardized by job and time constraints. A web-based intervention may be better suited for young, busy patients, and for those living far from liver units. The study shows that, following a structured motivational approach, a web-based, interactive intervention coupled with six-month face-to-face meetings is not inferior to a standard group-based intervention with respect to weight loss, adherence to healthy diet and habitual physical activity, normalization of liver enzymes, and stable surrogate markers of fibrosis.