RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

Metformin and the Liver: Unlocking the Full Therapeutic Potential.

Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.

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.

Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) may progress to advanced liver disease (AdvLD). This study characterized comorbidities, healthcare resource utilization (HCRU) and associated costs among hospitalized patients with AdvLD due to NASH in Italy. METHODS AND RESULTS: Adult nonalcoholic fatty liver disease (NAFLD)/NASH patients from 2011 to 2017 were identified from administrative databases of Italian local health units using ICD-9-CM codes. Development of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), or liver transplant (LT) was identified using first diagnosis date for each severity cohort (index-date). Patients progressing to multiple disease stages were included in >1 cohort. Patients were followed from index-date until the earliest of disease progression, end of coverage, death, or end of study. Within each cohort, per member per month values were annualized to calculate all-cause HCRU or costs(€) in 2017. Of the 9,729 hospitalized NAFLD/NASH patients identified, 97% were without AdvLD, 1.3% had CC, 3.1% DCC, 0.8% HCC, 0.1% LT. Comorbidity burden was high across all cohorts. Mean annual number of inpatient services was greater in patients with AdvLD than without AdvLD. Similar trends were observed in outpatient visits and pharmacy fills. Mean total annual costs increased with disease severity, driven primarily by inpatient services costs. CONCLUSION: NAFLD/NASH patients in Italy have high comorbidity burden. AdvLD patients had significantly higher costs. The higher prevalence of DCC compared to CC in this population may suggest challenges of effectively screening and identifying NAFLD/NASH patients. Early identification and effective management are needed to reduce risk of disease progression and subsequent HCRU and costs.

Stress Hyperglycemia and Complications Following Traumatic Injuries in Individuals With/Without Diabetes: The Case of Orthopedic Surgery.

PURPOSE: Hyperglycemia in trauma patients may stem from metabolic response to stress, both in the presence and the absence of underlying diabetes. We aimed to test the association of stress hyperglycemia with risks of adverse events subjects undergoing orthopedic surgery. PATIENTS AND METHODS: In a prospective observational study, we enrolled 202 consecutive patients with hyperglycemia at hospital admission for trauma injuries requiring orthopedic surgery. Based on history, diabetes was present in 183, and 13 more were defined as unknown diabetes on the basis of HbA1c ≥48mmol/mol. Stress hyperglycemia was defined in subjects with/without diabetes by a stress hyperglycemia ratio (SHR) >1.14, calculated as admission glucose/average glucose, estimated from glycosylated hemoglobin. Logistic regression analysis was used to calculate the risk of post-surgery adverse events associated with different states of hyperglycemia, after correction for demographic and clinical confounders. RESULTS: Stress hyperglycemia was diagnosed, either as superimposed to diabetes (54/196 cases, 27.6%) as well as in the 6 cases without diabetes. At least one complication was recorded in 68 cases (33.7%), the most common being systemic infection (22.8% of cases). In the total cohort, stress hyperglycemia, irrespective of the presence of diabetes, increased the risk of adverse events (any events, odds ratio [OR], 4.43; 95% confidence interval [CI], 2.11-9.30), cardiovascular events (OR, 7.09; 95% CI, 2.47-19.91), systemic infections (OR, 4.21; 95% CI, 1.97-9.03) and other adverse events (OR, 6.30; 95% CI, 1.41-28.03), after adjustment for confounders; hospital stay was much longer. The same was true when the analysis was limited to the diabetes cohort or by comparing pure stress hyperglycemia vs diabetes without stress hyperglycemia. CONCLUSION: The study highlights the importance of stress hyperglycemia for adverse events in the setting of orthopedic surgery following trauma injuries. This condition requires stricter management, considering the much longer length of hospital stay and higher costs.

Searching food during the night: the role of video-polysomnography in the characterization of the night eating syndrome.

OBJECTIVES: To describe the video-polysomnographic (VPSG) features of the night eating syndrome (NES), exploring the existence of potential subtypes. METHODS: In this study, 20 consecutive patients with NES according to the most recent diagnostic criteria underwent an overnight VPSG. None of them presented with a sleep-related eating disorder (SRED). VPSG recordings were reviewed identifying all eating episodes. For each episode, eating latency (time delay from awakening to food intake), eating duration (time between eating onset to eating offset) and sleep latency after eating offset (time delay from eating offset to sleep) were calculated. Total episode duration was considered as the time between awakening and sleep latency after eating offset. RESULTS: Ten patients fulfilled the A1 core criterion for NES (evening hyperphagia with consumption of at least 25% of the daily caloric intake after the evening meal); within this group, eight patients also fulfilled the A2 criterion (at least two episodes of nocturnal eating per week) and were thus included in the evening hyperphagia (EH) subgroup. The remaining 10 patients satisfied only the A2 core criterion for NES, constituting the nocturnal ingestion (NI) subgroup. We recorded 20 eating episodes, seven in the EH group and 13 in the NI group. In the EH subgroup, three eating episodes occurred before sleep onset, one after an awakening from non-rapid eye movement (NREM) stage 1 sleep, two from NREM stage 2 and one from REM sleep. All 13 NI episodes occurred after an awakening from sleep (1 from NREM stage 1 sleep, 8 from NREM stage 2 and four from NREM stage 3). In EH patients, eating latency, total episode duration and sleep latency after eating offset were significantly longer than in NI patients. CONCLUSION: Our VPSG data from a case series of 20 patients referred to our center for nocturnal eating indicate potential different NES subtypes. This distinction may have an impact on patients' treatment and follow-up.

The Effect of Lutein on Eye and Extra-Eye Health.

Lutein is a carotenoid with reported anti-inflammatory properties. A large body of evidence shows that lutein has several beneficial effects, especially on eye health. In particular, lutein is known to improve or even prevent age-related macular disease which is the leading cause of blindness and vision impairment. Furthermore, many studies have reported that lutein may also have positive effects in different clinical conditions, thus ameliorating cognitive function, decreasing the risk of cancer, and improving measures of cardiovascular health. At present, the available data have been obtained from both observational studies investigating lutein intake with food, and a few intervention trials assessing the efficacy of lutein supplementation. In general, sustained lutein consumption, either through diet or supplementation, may contribute to reducing the burden of several chronic diseases. However, there are also conflicting data concerning lutein efficacy in inducing favorable effects on human health and there are no univocal data concerning the most appropriate dosage for daily lutein supplementation. Therefore, based on the most recent findings, this review will focus on lutein properties, dietary sources, usual intake, efficacy in human health, and toxicity.

Expected benefits and motivation to weight loss in relation to treatment outcomes in group-based cognitive-behavior therapy of obesity.

PURPOSE: We aimed to determine cognitive drivers, expected to play a role in target reach and/or attrition in obesity programs. METHODS: We recorded the expected benefits of weight loss, weight targets, primary motivation for weight loss, perceived treatment needs, readiness and self-confidence to be successful and a battery of psychopathology questionnaires in 793 subjects with obesity (68% women; mean age 48.7; 46% obesity class III) enrolled into a group-based cognitive-behavioral treatment program. Their relevance on attrition and successful weight loss outcome were tested by logistic regression analysis. RESULTS: The expected benefits of weight loss scored very high in all physical, psychological and social areas, with differences between genders. Attrition rate was 24, 41 and 65% at 6-, 12-, and 24-month follow-up. Average weight loss was 5.8 ± 7.1 kg (- 4.8%) at 6 months, with 17% of cases (32% of continuers) maintaining weight loss > 10% at 24 months. After adjustment for confounders, attrition was reduced by concern for present health, motivation/consciousness of the importance of physical activity and need for support; treatment discontinuation was favored by concern for body image, by expectations for drug treatment or bariatric surgery, and by high-challenging weight loss targets. Male gender, higher BMI and concern for present health predicted weight loss > 10%, whereas concern for body appearance was associated with lower probability of attaining the desired weight loss targets. CONCLUSION: A more precise definition of needs and expectations might help tailor treatment to individual patients, but attrition rates and target reach remain difficult to predict. LEVEL OF EVIDENCE: Level V, descriptive studies.

Long-term treatment of severe obesity: are lifestyle interventions still an option?

INTRODUCTION: Following lifestyle intervention programs based on dietary restriction and habitual physical activity, weight loss, however large, is reported to peak within six months. Despite maintenance protocols, only few cases continue to lose weight thereafter. The majority of cases regain weight and adherence to lifestyle changes are fostered by long-term contact with a supportive team. In general, surgical procedures are reported to produce much larger weight loss and to impact more favorably on long-term weight loss maintenance. Areas covered: We performed a PubMed search on lifestyle modification studies, focusing on the role of behavior programs for the long-term management of obesity in comparison with surgical procedures. Behaviorally-achieved weight loss outcomes can be improved by integrating standard behavior therapy with self-regulation cognitive skills, motivational interviewing and/or phone/internet-based recall systems. Expert commentary: Clinically-important long-term weight loss is achievable by behavior therapy in a small proportion of subjects with obesity, however severe, through personalized programs associating lifestyle modification interventions, with procedures aimed at developing commitment and responsibility skills. A new area of research is the integration of cognitive-behavior therapy with bariatric (metabolic) surgery, either pre- or post-operatively, to exploit long-term adherence to healthy diet and habitual physical activity.

Undernutrition, risk of malnutrition and obesity in gastroenterological patients: A multicenter study.

AIM: To investigate the prevalence of undernutrition, risk of malnutrition and obesity in the Italian gastroenterological population. METHODS: The Italian Hospital Gastroenterology Association conducted an observational, cross-sectional multicenter study. Weight, weight loss, and body mass index were evaluated. Undernutrition was defined as unintentional weight loss > 10% in the last three-six months. Values of Malnutrition Universal Screening Tool (MUST) > 2, NRS-2002 > 3, and Mini Nutritional Assessment (MNA) from 17 to 25 identified risk of malnutrition in outpatients, inpatients and elderly patients, respectively. A body mass index ≥ 30 indicated obesity. Gastrointestinal pathologies were categorized into acute, chronic and neoplastic diseases. RESULTS: A total of 513 patients participated in the study. The prevalence of undernutrition was 4.6% in outpatients and 19.6% in inpatients. Moreover, undernutrition was present in 4.3% of the gastrointestinal patients with chronic disease, 11.0% of those with acute disease, and 17.6% of those with cancer. The risk of malnutrition increased progressively and significantly in chronic, acute and neoplastic gastrointestinal diseases in inpatients and the elderly population. Logistical regression analysis confirmed that cancer was a risk factor for undernutrition (OR = 2.7; 95%CI: 1.2-6.44, P = 0.02). Obesity and overweight were more frequent in outpatients. CONCLUSION: More than 63% of outpatients and 80% of inpatients in gastroenterological centers suffered from significant changes in body composition and required specific nutritional competence and treatment.

Muscle uncoupling protein 3 expression is unchanged by chronic ephedrine/caffeine treatment: results of a double blind, randomised clinical trial in morbidly obese females.

UNLABELLED: Ephedrine/caffeine combination (EC) has been shown to induce a small-to-moderate weight loss in obese patients. Several mechanisms have been proposed, among which an increased thermogenic capacity of skeletal muscle consequent to the EC-induced up-regulation of uncoupling protein 3 (UCP3) gene expression. We did a parallel group double-blind, placebo-controlled, 4-week trial to investigate this hypothesis. Thirteen morbidly obese women (25-52 years of age, body-mass index 48.0±4.0 kg/m2, range 41.1-57.6) were randomly assigned to EC (200/20 mg, n = 6) or to placebo (n = 7) administered three times a day orally, before undergoing bariatric surgery. All individuals had an energy-deficit diet equal to about 70% of resting metabolic rate (RMR) diet (mean 5769±1105 kJ/day). The RMR analysed by intention to treat and the UCP3 (long and short isoform) mRNA levels in rectus abdominis were the primary outcomes. Body weight, plasma levels of adrenaline, noradrenaline, triglycerides, free fatty acids, glycerol, TSH, fT4, and fT3 were assessed, as well as fasting glucose, insulin and HOMA index, at baseline and at the end of treatments. Body weight loss was evident in both groups when compared to baseline values (overall -5.2±3.2%, p<0.0001) without significant differences between the treated groups. EC treatment increased the RMR (+9.2±6.8%, p = 0.020), differently from placebo which was linked to a reduction of RMR (-7.6±6.5%, p = 0.029). No significant differences were seen in other metabolic parameters. Notably, no changes of either UCP3 short or UCP3 long isoform mRNA levels were evident between EC and placebo group. Our study provides evidence that 4-week EC administration resulted in a pronounced thermogenic effect not related to muscle UCP3 gene expression and weight loss in morbidly obese females under controlled conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02048215.

Hospitalization rates and cost in severe or complicated obesity: an Italian cohort study.

BACKGROUND: The economic and social costs of obesity are estimated to be considerable, particularly for inpatient care. The aim of this study was to compare the hospitalization rates of individuals with severe (body mass index [BMI] ≥40 kg/m2) or complicated (BMI ≥30 kg/m2) obesity with those of the general population in two regions of Northwest Italy, and to describe absolute costs of hospitalization and their determinants. METHODS: Between 1996 and 2002, 6,516 patients who were admitted for the first time to a hospital offering a nutritional rehabilitation programme for obesity were enrolled and followed-up (mean follow-up time: 7.3 years). Standardized hospitalization rates (SHRs) were computed by sex for all-cause and cause-specific hospitalization. The general population of the two regions was used as the reference population. The annual cost of hospitalization was estimated for the study cohort only at the individual level, and its association with different determinants was assessed using a multivariable linear model for longitudinal data. RESULTS: SHRs of the study cohort versus the general population increased for all-cause hospitalization (males: 3.53, 95% CI 3.45-3.61; females: 3.22, 95% CI 3.18-3.26) as well as for most obesity-related conditions. The absolute median annual cost of hospitalization was 2,436 euros for males and 2,293 euros for females. Older age at cohort enrolment, BMI ≥40 kg/m2, waist circumference above the median (males: 1.26 metres; females: 1.13 metres), and the presence of co-morbidities, such as cardiovascular diseases, respiratory diseases, cancer, diseases of the musculoskeletal system and connective tissue, and mental disorders, significantly increased the absolute median annual costs of hospitalization. CONCLUSIONS: The economic consequences of high hospitalization rates in obese individuals are relevant. Reducing the occurrence of co-morbidities among obese persons may be one important goal, not only for clinical reasons, but also from a public health point of view.

Sporadic mutations in melanocortin receptor 3 in morbid obese individuals.

Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3-6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2+/-5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4+/-2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects.

Comparative long-term mortality after laparoscopic adjustable gastric banding versus nonsurgical controls.

BACKGROUND: To compare the mortality rate of obese patients treated by laparoscopic gastric banding (LAGB) with the mortality rate of matched obese patients observed at medical centers. The net effect of bariatric surgery on total mortality is still controversial. Gastric bypass has been shown to reduce the relative risk of death, but similar data with LABG are still lacking. METHODS: The surgical series was composed of 821 patients with a body mass index (BMI) >40 kg/m(2) consecutively treated with LAGB at Padova University, Italy. The reference group was composed of 821 gender-, age-, and BMI-matched patients selected from a sample of 4681 adults with a BMI >40 kg/m(2) observed at 6 Italian medical centers not using surgical therapy. RESULTS: The mean follow-up was 5.6 +/- 1.9 and 7.2 +/- 1.2 years in the surgical and reference group, respectively. The vital status was known in 97.6% of the surgical group (8 deaths) and in 97.4% of the reference group (36 deaths). In the surgical group, the percentage of excess weight loss was 39.8% +/- 17.9% 1 year after LAGB and 37.2% +/- 23.8% 5 years after LAGB. The rate of late revisional surgery was 12.2%. Survival was estimated using the Kaplan-Meier method, and the differences between the 2 groups were evaluated using the log-rank test. The survival rate was significantly greater in the surgical group (P = 0.0004). On multivariate Cox analysis, the 5-year relative risk of death in the surgical group, adjusted for gender, age, and baseline BMI, was 0.36 (95% confidence interval 0.16-0.80). CONCLUSION: LAGB was associated with a 0% operative mortality rate and 40% stable excess weight loss. LAGB patients had a 5-year 60% lower risk of death than comparable morbidly obese patients.

Psychological distress in morbid obesity in relation to weight history.

BACKGROUND: Very few data are available on psychological distress in morbidly obese subjects in relation to the history of their weight. In subjects with childhood obesity, psychological distress might be better than in adult-onset obesity, because of progressive adaptation to the social stigma. METHODS: Psychological distress was tested in relation to BMI at age 20 years (BMI-20), weight history and somatic co-morbidities in 632 treatment-seeking, morbidly obese participants from the QUOVADIS cohort (130 men, 502 women; mean age 45.5 years). The number of dieting attempts/year, BMI increase and cumulative BMI loss since age 20 were calculated as weight cycling parameters. The Symptom Check List-90 (SCL-90), the Psychological General Well-Being (PGWB), the Binge-Eating Scale, and the ORWELL-97 questionnaire were used to score psychometry and health-related quality of life (HRQL). Complications were quantitatively assessed by a modified Charlson's score. RESULTS: BMI-20 was normal in 35% of cases and >35 kg/m2 in only 14%. Psychometric scores were not different in relation to BMI-20, when corrected for age, with the exception of the General Health scale of PGWB, showing a greater distress in subjects with normal BMI-20. In most cases, the prevalence of pathological results of questionnaires showed a J-shaped curve, with participants with normal BMI-20 or those with Class II-III obesity in early adulthood having the highest prevalence of psychological/psychiatric distress and poor HRQL. Weight cycling was a risk factor for binge-eating, depression and interpersonal sensitivity in SCL-90, whereas somatic co-morbidities adversely affected most SCL-90 and all PGWB scales. CONCLUSION: Weight cycling and somatic co-morbidities, but not age of onset of obesity, are the main factors negatively influencing psychological health in treatment-seeking, morbidly obese subjects.