Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Metabolic syndrome and cardiovascular risk after liver transplantation: a single-center experience.

Excessive weight gain, hypertension, hyperlipidemia, and diabetes are frequently observed among orthotopic liver transplantation (OLT) patients. These alterations, which are probably multifactorial in origin, contribute to posttransplantation metabolic syndrome (PTMS), which increases the risk of cardiovascular events. We assessed the prevalence of PTMS (diagnosed according to modified NCEP Adult Treatment Panel III criteria) in 156 OLT patients undergoing regular follow-up after transplantation (median 68 months; range, 6 to 234 months). Several pre- and post-OLT data were collected to identify the factors associated with the presence of PTMS which was found in 28% of cases. The only independent predictive factors for PTMS were diabetes mellitus and patients who were overweight or obese before-OLT. The prevalence of PTSM was lower among patients on tacrolimus immunosuppression. In our population, 21% of patients showed a high cardiovascular risk score with a 4% incidence of cardiovascular events, which was higher among subjects with PTMS. Close follow-up is mandatory to prevent the development of PTMS mainly among overweight and diabetic patients before transplantation.

Impact of anti-hepatitis B core-positive donors in liver transplantation: a survival analysis.

INTRODUCTION: The current shortage of organs for liver transplantation (OLT) requires expansion of the donor pools. A possible approach to this problem may be the use of donors positive for antibody against hepatitis B core antigen (anti-HBc). However, it is not clear whether recipients who receive anti-HBc-positive livers show worse survival. The aim of this study was to retrospectively analyze the patient and graft survivals of two groups of OLT recipients according to the anti-HBc status of their respective donors. METHODS: We stratified 133 patients into group 1 (n = 120; anti-core-negative donors) versus group 2 (n = 13; anti-core-positive donors). RESULTS: Comparing the two groups by univariate analysis, there was no significant differences with regard to recipient, donor, or transplant characteristics. Group 2 showed worse 5-year patient (46.2% vs 72.0%; P = .006) and graft survivals (38.5% vs 68.4%; P = .003). After adjustment for several risk factors for post-OLT death and graft failure, there was no significant difference between patients who received anti-core-positive versus anti-core-negative donors, in terms of patient and graft survivals, particularly only after adjustment for Model for End-stage Liver Disease (MELD) degree of severity. CONCLUSION: The use of anti-HBc-positive donors resulted in worse post-OLT patient and graft survival rates. Unlike the results obtained in the United States, we did not find possible confounders in our results, excluding MELD ≥ 20. However, due to the small size of our cohort, future prospective multicenter studies are required to clarify the safety of anti-core-positive grafts.

Bone disorders in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: An important complication of chronic liver disease is osteodystrophy, which includes osteoporosis and the much rarer osteomalacia. Both conditions are associated with significant morbidity through fractures resulting in pain, deformity, and immobility. Liver transplantation may further deteriorate bone metabolism. The aim of the present study was to investigate the frequency and severity of hepatic osteodystrophy among patients with liver cirrhosis who were referred for liver transplantation. We also evaluated modifications in bone metabolism after liver transplantation. MATERIALS AND METHODS: We recruited 35 consecutive patients with chronic liver disease who were undergoing assessment for transplantation over a 1-year period. Bone mass in the total skeleton and proximal hip was evaluated using a dual-energy X-ray absorptiometry device (Lunar Prodigy Advance, GE Healthcare, USA). According to World Health Organization recommendations, osteoporosis was defined as a T score < -2.5 and osteopenia as T score between -1 and -2.5. RESULTS: We enrolled in the study 35 patients, including 8 females and 27 males of overall mean age of 57 +/- 7, who showed a viral etiology (57%) or alcohol etiology (28%), Child-Pugh 8.7 +/- 2.3. The overall prevalence of osteodystrophy was 40% (26% osteopenia and 14% osteoporosis). No difference was evident according to gender, severity of liver disease (Child-Pugh, Model for End-stage Liver Disease), or origin of liver disease. A subgroup of 10 transplanted patients reached 3-month follow-up, showing total body T score with a significant decrease after 3 months while femoral T scores tended to decrease insignificantly. CONCLUSIONS: This study revealed a high prevalence of low bone mineral density among cirrhotic patients before liver transplantation. We suggest that both bone mineral density and biochemical examinations should be considered to be routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.

Immune-mediated liver dysfunction after antiviral treatment in liver transplanted patients with hepatitis C: allo or autoimmune de novo hepatitis?

BACKGROUND: The recurrence of hepatitis C after liver transplantation is extremely frequent. Antiviral therapy combining pegylated-interferon with ribavirin is therefore increasingly used in these patients. It has been recently reported, however, that during antiviral treatment a hepatic immune-mediated liver dysfunction, similar to "de novo" autoimmune hepatitis, may develop in a few transplanted patients. PATIENTS AND METHODS: Three patients, treated with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C after liver transplantation, developed an aggressive hepatitis with clinical, biochemical, and histological features similar to those of autoimmune hepatitis. RESULTS: In all three patients, a liver enzymes increase was evident after hepatitis C virus-RNA had become undetectable. Diagnosis of "de novo" autoimmune hepatitis was proposed, based on the presence of high-titre circulating autoantibodies and liver histology features. Following the introduction of a steroid therapy, clinical and biochemical parameters progressively improved. Hepatitis C virus infection, however, relapsed after a few months in all the patients. CONCLUSIONS: Following liver transplantation, antiviral therapy with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C may be associated, in a few patients, with severe immune-mediated graft dysfunction similar to autoimmune hepatitis.

Incidence of fungal infections in a solid organ recipients dedicated intensive care unit.

UNLABELLED: Invasive fungal infections are a significant cause of morbidity and mortality for patients undergoing solid organ transplantation. Our aim was to evaluate the incidence of invasive fungal infections in solid organ recipients within a dedicated intensive care unit (ICU). MATERIALS AND METHODS: From May 2002 to May 2005, 278 patients undergoing solid organ transplantation (105 liver, 142 kidney, 20 lung, 2 combined liver-kidney, 9 combined pancreas-kidney) were admitted to our posttransplant intensive care unit. We retrospectively analyzed data obtained from the ICU stay. Fungal infection was defined by positivity of normally sterile biological samples and by elevated positivity of normally non sterile biological samples. We did not consider superficial fungal infections and asymptomatic colonizations. RESULTS: Forty-six patients (16.5%) developed a fungal infection; at least one mycotic agent was isolated from each patient. Candida albicans was the most common pathogen, isolated from 71 % of infected patients (33 of 46). Infected patients showed a mortality rate of 35%, while that for non infected recipients was 3.5%. Total length of ICU stay was the most significant risk factor among infected patients (30.26 days vs 5.04 days P < .0001). Mean time between transplantation and first positive samples was 6.17 days (SD 8.88). CONCLUSION: Fungal infections in solid organ transplant patients are a major issue because of their associated morbidity and mortality. Candida albicans was the most common pathogen and total length of ICU stay was the most important risk factor.

Intractable pruritus in patients with hepatitis C virus.

Intractable pruritus is one of the most common symptoms of chronic liver disease, especially experienced by patients with prolonged cholestasis. It can become the most distressing symptom in patients affected by chronic liver disease, causing a reduction in quality of life, interfering with daily activities, and leading to sleep deprivation or contributing to psychological disturbances up to suicide ideation. Therefore, pruritus that does not respond to medical therapy is an indication for liver transplantation. We treated nine patients with hepatitis C virus affected by intractable pruritus with the molecular adsorbent recirculating system. In each patient, liver function, renal function, and hemodynamic variables were evaluated before and after the treatment. Before undergoing the treatment each patient underwent abdominal ultrasound or computed tomography scan to exclude organic causes for pruritus. We observed a decrease in total bilirubin, creatinine, and bile acids together with a significant improvement in Visual Analog Scale for staging of pruritus in all the patients. Due to the small number of patients the results were not significant.

Patency of anastomoses after bilio-intestinal bypass: radioisotope demonstration.

BACKGROUND: Bilio-intestinal bypass (BIB) is effective for the treatment of refractory obesity. BIB permits bile flow into the non-functional jejunum, whereas food transit occurs via the remaining intestine. We used the radioisotope method of 99mTc-Hida cholescintigraphy (HC) in the follow-up of patients. METHODS: 21 patients were studied 3 months to 3 years after BIB with HC. After 3 hours acquisition, images were reviewed by two independent observers. Regions of interest (ROIs) were drawn on images: liver parenchyma, cholecysto-jejunal anastomosis (CC), choledochus (COL). Radioactivity taken up by liver was compared with radioactivity of CC and COL. % radioactivity passing through CC (%CC) and through COL (%COL) were determined. The final parameter, -COL, indicates the radioactive bile which does not pass through the choledochus. RESULTS: Anastomoses were found patent a few months to 3 years after operation. -COL showed linear correlation with the decrease in cholesterolemia and in body weight in the 1st year after BIB. CONCLUSIONS: HC shows passage of radioactive bile through anastomoses and provides semiquantitative evaluation of bile flux diversion. Bile flux towards the gallbladder and non-functional jejunal limb far exceeds flux directed towards the duodenum via the choledochus.

[Recent studies on the pathogenesis of cholelithiasis: the role of the gallbladder epithelium]. / Recenti studi sulla patogenesi della colelitiasi: il ruolo dell'epitelio della colecisti.

The abnormalities of gallbladder epithelial function involved in cholesterol gallstone pathogenesis are: 1) the impaired biliary lipid absorption and 2) an increased secretion of mucin gel. We developed a model of isolated in vitro intra-arterially perfused gallbladder and showed that the normal gallbladder epithelium absorbs high amounts of biliary cholesterol and phosphatidylcholine in a proportion determined by their molar ratio in the bile which enters the lumen. This physiological lipid absorption continuously reduces biliary cholesterol molar percentage in the gallbladder lumen and protects from gallstone formation by inhibiting cholesterol crystal precipitation. On the opposite, in the presence of cholesterol gallstone disease, even if the gallbladder epithelium is hyperplastic and hypertrophic, it absorbs cholesterol and phosphatidylcholine less efficiently and cholesterol crystal precipitation is favoured. Indirect evidence exists that the impaired gallbladder lipid absorption in cholesterol gallstone disease is not caused by inflammation and is not secondary to the presence of stones. The impaired mucosal function could be the consequence of excessive chronic enrichment of hepatic bile which enters the gallbladder. The mucin gel is the only biliary protein with an established pathogenetic role in cholesterol gallstone disease. The mucin gel is thought to favour gallstone formation by promoting cholesterol crystal precipitation and aggregation.

Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile.

BACKGROUND & AIMS: The role of the gallbladder in gallstone pathogenesis is still unclear. We examined the effects of gallbladder mucosal lipid absorption on lipid composition and cholesterol crystallization in bile. METHODS: The in vitro-isolated, intra-arterially perfused gallbladder model was used (1) to compare the absorption rates of lipids from standard bile by gallbladders obtained from 7 patients with cholesterol gallstones and 6 controls; and (2) to measure the microscopic cholesterol crystal detection time in cholesterol-enriched pig bile before and after lipid absorption by the pig gallbladder. RESULTS: Control gallbladders, but not cholesterol gallstone gallbladders, significantly reduced cholesterol (P < 0.02) and phospholipid (P < 0.01) and increased bile salt (P < 0.01) molar percentages in bile over a 5-hour period by efficient and selective cholesterol and phospholipid absorption. A histomorphometric study of the epithelial cells showed significantly higher values for nuclear density (P < 0.01) and nuclear (P < 0.05) and cytoplasmic (P < 0.05) areas in the cholesterol gallstone than the control group. Sequential microscopy of cholesterol-enriched pig bile showed significantly shorter cholesterol filament (P < 0.01) and typical cholesterol plate (P < 0. 02) detection times before than after exposure of bile to the gallbladder lipid absorption. CONCLUSIONS: In cholesterol gallstone disease, the human gallbladder epithelium loses its capacity to selectively and efficiently absorb cholesterol and phospholipids from bile, even if it is hyperplastic and hypertrophic. This epithelial dysfunction eliminates the positive effect that the normal gallbladder exerts on cholesterol solubility in bile and might be a pathogenetic cofactor for cholesterol gallstone formation.

Plasma lipoproteins affect rate of cholesterol absorbed from bile by gallbladder: preliminary data.

BACKGROUND: The excessive accumulation of cholesterol absorbed from bile by the gallbladder impairs its contractility and favours gallstone formation. The total low plasma and high density lipoprotein cholesterol concentrations are associated with gallstone disease. AIMS: To investigate the effect of plasma lipoproteins on gallbladder cholesterol and phosphatidylcholine absorption from bile and to establish whether cholesterol absorption is Brefeldin A-sensitive. METHODS: Gallbladder mucosa lipid absorption rates were measured using: 1) in vitro isolated intra-arterially perfused pig gallbladder model with and without plasma lipoproteins perfusing the vascular tree; 2) human gallbladder fragments mounted in Ussing chambers with plasma lipoproteins at different concentrations in the serosal side; 3) pig gallbladder fragments mounted in Ussing chambers in the presence and absence of Brefeldin A. RESULTS: Total lipoproteins and high density lipoprotein significantly increased the release of biliary cholesterol and phosphatidylcholine in plasma and significantly decreased the tissue accumulation of cholesterol absorbed from bile. The scavenger effect of plasma lipoproteins on cholesterol absorbed from bile was concentration dependent. Brefeldin A did not influence gallbladder absorption of biliary cholesterol. CONCLUSIONS: Biliary cholesterol is absorbed by gallbladder mucosa via a Brefeldin-insensitive pathway and is removed by plasma lipoproteins.

[Brief treatment with thymopentin as adjuvant in vaccination for hepatitis B: controlled study in patients on periodic hemodialysis]. / Trattamento breve con timopentina come adiuvante nella vaccinazione anti-epatite B: studio controllato in pazienti sottoposti ad emodialisi periodica.

Eleven hemodialysis patients (9 M, 2 F, aged 65 +/- 20 yrs) (Group A) were treated with thymopentin (TP-5) 50 mg as adjuvant therapy to HB vaccination, with 3 weekly administrations, the week before and the two following the first dose of Pasteur vaccine, 5 micrograms. The percentage of patients developing a sufficient antibody titer (20 mUI/ml) after 4 vaccine doses was not statistically different from that obtained among control groups B and C. The age- and sex- matched controls received the same vaccine schedule without adjuvant. The percentages were as follows: Group A 54.5%, Group B 63.6%, Group C 60%. No local or systemic side effects were encountered after the TP-5 administration. The authors suggest that a short TP-5 treatment as an adjuvant therapy to HB vaccination is not effective in patients maintained on hemodialysis.

Reduced protection against hepatitis B virus following vaccination in patients with type 1 (insulin-dependent) diabetes.

Twenty patients with well controlled Type 1 (insulin-dependent) diabetes of at least 10 years duration and 47 control subjects were vaccinated against the hepatitis B virus using the Hevac B vaccine. The vaccine was administered into the deltoid region on three occasions at intervals of 1 month. Thereafter a fourth dose was given to subjects still negative for antibody to hepatitis B surface antigen (HbsAb). The median rise of HbsAb titres was 230 mIU/ml in normal subjects and 50 mIU/ml in diabetic patients (p less than 0.001). Eight patients (40%) failed to reach HbsAb titres above 30 mIU/ml, the level considered to give optimal protection against the infection, whereas only one normal control subject failed to reach this level. Five patients (25%) showed no response despite a fourth dose of the vaccine. There was an increased frequency of HLA-DR7 in low responders and a decreased (less than 1.5) helper/suppressor lymphocyte ratio. Diabetic patients are thus less likely to mount a protective antibody response following vaccination against hepatitis. Since hepatitis B surface antigen is reported to be considerably more common in diabetic patients than control subjects, infection with hepatitis B virus may have a greater risk of chronicity in diabetes.

Cellular detection of HBsAg by immunofluorescence in liver of HBsAg positive and negative subjects.

Demonstration of direct immunofluorescence of HBsAg in the cytoplasm and the nucleus of hepatocytes. The study is based on 77 patients: 32 clinically healthy carriers and 45 patients with acute or chronic hepatitis.