Malnutrition independently predicts mortality at 18 months in patients hospitalised for Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2).

RATIONALE: To investigate the association between malnutrition and patient outcome following hospitalisation for Corona Virus Disease 2019 (COVID-19). METHODS: In April 2020, 268 adult patients (235 included in the follow-up) hospitalised for COVID-19 infection were evaluated for malnutrition risk and diagnosis using modified Nutritional Risk Screening 2002 and modified Global Leadership Initiative on Malnutrition criteria (GLIM), respectively. An 18-month follow-up was carried out to assess the incidence and the associated risk factors for death and re-hospitalization. RESULTS: The outcome was unknown for 33patients. Death occurred in 39% of the 235 patients included in the follow-up. The risk of death was independently associated with malnutrition risk or diagnosis of malnutrition, whereas the male sex showed a protective association. The Kaplan-Meier survival curves showed that patients with diagnosis of malnutrition had lower survival rate. The re-hospitalization rate was 31% and was negatively associated with BMI≥25, and positively associated with length of hospitalisation for COVID-19 and with cancer comorbidity. CONCLUSIONS: In hospitalized patients for SARS-CoV-2 disease, both malnutrition risk (p =0.050) and diagnosis of malnutrition (p=0.047 with modified GLIM and C-reactive protein > 0.5 mg/dL ; p=0.024 with modified GLIM and C-reactive protein > 5 mg/dL) were predictive risk factors for mortality, whereas male sex was associated with lower risk of death. Overweight at time of hospitalization and the length of hospitalisation were respectively protective and risk factor for re-hospitalization after discharge.

Management of Diabetes in Candidates for Liver Transplantation and in Transplant Recipients.

Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.

Management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease is a very common medical condition, driven by a combination of genetic and lifestyle factors, ultimately producing a severe chronic liver disease and increased cardiovascular risk. Most people are asymptomatic for a long time, and their daily life is unaffected, leading to difficulty in identifying and managing people who slowly progress to non-alcoholic steatohepatitis (NASH), NASH-cirrhosis, and eventually hepatocellular carcinoma. Despite advances in the understanding of pathogenic mechanisms and the identification of liver fibrosis as the strongest factor in predicting disease progression, no specific treatments have been approved by regulatory agencies. Outside controlled trials, treatment is generally limited to lifestyle intervention aimed at weight loss. Pioglitazone remains the drug of choice to reduce progression of fibrosis in people with diabetes, although it is often used off-label in the absence of diabetes. Vitamin E is mainly used in children and may be considered in adults without diabetes. Several drugs are under investigation according to the agreed targets of reduced NASH activity without worsening of fibrosis or improving fibrosis without worsening of NASH. Anti-inflammatory, anti-fibrotic agents and metabolism modulators have been tested in either phase III or phase IIb randomized controlled trials; a few failed, and others have produced marginally positive results, but only a few are being tested in extension studies. The development of non-invasive, easily repeatable surrogate biomarkers and/or imaging tools is crucial to facilitate clinical studies and limit liver biopsy.

Lifestyle Changes for the Treatment of Nonalcoholic Fatty Liver Disease - A 2015-19 Update.

BACKGROUND: Lifestyle interventions aimed at weight loss have been associated with improved liver enzymes, reduced intrahepatic triglyceride content, and improved histology (including reduced fibrosis stage). OBJECTIVE: To revise the evidence on the beneficial effects of lifestyle changes accumulated since 2015, following the publication of the pivotal Cuban experience with histologic outcome. METHODS: A PubMed search covering the period 2015 to July 2019 was carried out. All retrieved references were analyzed and double-checked by authors. RESULTS: 20 new studies were identified; in addition, two relevant studies provided new evidence. Thirteen studies were classified as randomized, controlled studies, three as proof-of-concept/pilot studies, four as cohort observational studies. In an attempt to maintain a closer contact between participants and the treatment center, a study implemented regular phone calls, another an e-mail service, a third was based on text messages, and finally, a study was totally web-based. Notably, the web-based treatment, accessed following intense motivational interviewing, was not less effective than a standard group-based behavior program. CONCLUSION: Lifestyle changes should form the basis of any NAFLD intervention. Information technology provides the opportunity to expand treatment, bypassing job and time constraints in younger patients, and to maintain long-term contact between patients and therapists in the NAFLD population.

Moderate Alcohol Intake in Non-Alcoholic Fatty Liver Disease: To Drink or Not to Drink?

Nonalcoholic fatty liver disease (NAFLD) is defined by hepatic steatosis in the presence of alcohol intake within safe limits, defined by guidelines of scientific associations (usually 20 g or 2 units/day in women, 30 g or 3 units in men). The diagnosis is usually followed by medical counseling of total abstinence, in order to prevent disease progression. This policy has been challenged by epidemiological studies, suggesting that the risk of liver disease and disease progression is lower in modest drinkers than in total abstainers. We revised the literature on the effects of modest alcohol intake on disease burden. Epidemiological data may suffer from several potential biases (recall bias for retrospective analyses, difficulties in the calculation of g/day), limiting their validity. Prospective data suggest that NAFLD patients with regular alcohol intake, although within the safe thresholds, are at higher risk of liver disease progression, including hepatocellular carcinoma; a detrimental effect of modest alcohol drinking is similarly observed in liver disease of viral etiology. Alcohol intake is also a risk factor for extrahepatic cancers, particularly breast, oral, and pharyngeal cancers, with gender difference and no floor effect, which outweigh the possible beneficial effects on cardiovascular system, also derived from retrospective studies. Finally, the negative effects of the calorie content of alcohol on dietary restriction and weight loss, the pivotal intervention to reduce NAFLD burden, should be considered. In summary, the policy of counseling NAFLD patients for alcohol abstinence should be maintained.

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.

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.

Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial.

BACKGROUND: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissue injury. AIM: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+ stem/progenitor cells in patients with end-stage liver disease. METHODS: Autologous CD133+ stem/progenitor cells, mobilized with granulocyte-colony stimulating factor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery starting from 5×10(4)/kg up to 1×10(6)/kg. RESULTS: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 were enrolled, 14 mobilized an adequate number of CD133+ stem/progenitor cells and 12 were reinfused. No severe adverse events related to the procedure were reported. MELD score significantly worsened during mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function was observed 2 months after reinfusion (MELD 19.5 vs. 16; P=0.045). Overall, 5 patients underwent liver transplantation within 12 months from reinfusion and 2 died because of progressive liver failure. CONCLUSIONS: CD133+ stem/progenitor cells reinfusion in patients with end-stage liver disease is feasible and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-C patients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapy may be a "bridge to transplant" approach for these patients.

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.

Alopecia universalis after discontinuation of pegylated interferon and ribavirin combination therapy for hepatitis C: a case report.

For the last decade, the combination therapy of pegylated interferon (Peg-IFN) plus ribavirin (RBV) has been considered as the standard of care treatment for chronic hepatitis C virus (HCV) infection. However, it has been associated with an increased incidence of many adverse cutaneous reactions and emergence of autoantibodies or even autoimmune diseases. We report a case of irreversible alopecia universalis (AU) with complete hair loss extended to the whole body, which started after discontinuation of Peg-IFN/RBV combination therapy for chronic HCV infection. In conclusion, this case represents an uncommon presentation of a common disease. Physicians must be aware of the potential adverse reactions of an antiviral therapy containing IFN, which might occur even after the discontinuation, and fully inform the patient at the beginning of his treatment course. We hope that interferon-free regimens will utterly supplant interferon-based therapy for most or all HCV patients avoiding the emergence of autoimmune manifestations.