Direct Single-Operator Cholangioscopy and Intraductal Ultrasonography in Patients with Indeterminate Biliary Strictures: A Single Center Experience.

The evaluation of biliary strictures poses a challenge due to the low sensitivity of standard diagnostic approaches, but the advent of direct single-operator cholangioscopy (DSOC) has revolutionized this paradigm. Our study aimed to assess the diagnostic performance of DSOC and DSOC-targeted biopsies, intraductal ultrasound (IDUS), and standard brush cytology in patients with indeterminate biliary strictures (IBS). We reviewed patients who underwent advanced diagnostic evaluation for IBS at our endoscopy unit from January 2018 to December 2022, all of whom had previously undergone at least one endoscopic attempt to characterize the biliary stricture. Final diagnoses were established based on surgical pathology and/or clinical and radiological follow-up spanning at least 12 months. A total of 57 patients, with a mean age of 67.2 ± 10.0 years, were included, with a mean follow-up of 18.2 ± 18.1 months. The majority of IBS were located in the distal common bile duct (45.6%), with malignancy confirmed in 35 patients (61.4%). DSOC and IDUS demonstrated significantly higher accuracies (89.5% and 82.7%, respectively) compared to standard cytology (61.5%, p < 0.05). Both DSOC visualization and IDUS exhibited optimal diagnostic yields in differentiating IBS with an acceptable safety profile.

An Ontology-Based Decision Support System for Tailored Clinical Nutrition Recommendations for Patients With Chronic Obstructive Pulmonary Disease: Development and Acceptability Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic condition among the main causes of morbidity and mortality worldwide, representing a burden on health care systems. Scientific literature highlights that nutrition is pivotal in respiratory inflammatory processes connected to COPD, including exacerbations. Patients with COPD have an increased risk of developing nutrition-related comorbidities, such as diabetes, cardiovascular diseases, and malnutrition. Moreover, these patients often manifest sarcopenia and cachexia. Therefore, an adequate nutritional assessment and therapy are essential to help individuals with COPD in managing the progress of the disease. However, the role of nutrition in pulmonary rehabilitation (PR) programs is often underestimated due to a lack of resources and dedicated services, mostly because pneumologists may lack the specialized training for such a discipline. OBJECTIVE: This work proposes a novel knowledge-based decision support system to support pneumologists in considering nutritional aspects in PR. The system provides clinicians with patient-tailored dietary recommendations leveraging expert knowledge. METHODS: The expert knowledge-acquired from experts and clinical literature-was formalized in domain ontologies and rules, which were developed leveraging the support of Italian clinicians with expertise in the rehabilitation of patients with COPD. Thus, by following an agile ontology engineering methodology, the relevant formal ontologies were developed to act as a backbone for an application targeted at pneumologists. The recommendations provided by the decision support system were validated by a group of nutrition experts, whereas the acceptability of such an application in the context of PR was evaluated by pneumologists. RESULTS: A total of 7 dieticians (mean age 46.60, SD 13.35 years) were interviewed to assess their level of agreement with the decision support system's recommendations by evaluating 5 patients' health conditions. The preliminary results indicate that the system performed more than adequately (with an overall average score of 4.23, SD 0.52 out of 5 points), providing meaningful and safe recommendations in compliance with clinical practice. With regard to the acceptability of the system by lung specialists (mean age 44.71, SD 11.94 years), the usefulness and relevance of the proposed solution were extremely positive-the scores on each of the perceived usefulness subscales of the technology acceptance model 3 were 4.86 (SD 0.38) out of 5 points, whereas the score on the intention to use subscale was 4.14 (SD 0.38) out of 5 points. CONCLUSIONS: Although designed for the Italian clinical context, the proposed system can be adapted for any other national clinical context by modifying the domain ontologies, thus providing a multidisciplinary approach to the management of patients with COPD.

Metformin and Hepatocellular Carcinoma Risk Reduction in Diabetic Patients with Chronic Hepatitis C: Fact or Fiction?

BACKGROUND: Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC. AIM: the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy. METHODS: A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome. RESULTS: Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET. CONCLUSION: according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.

The Endoscopic Retrograde Cholangiopancreatography and Endoscopic Ultrasound Connection: Unity Is Strength, or the Endoscopic Ultrasonography Retrograde Cholangiopancreatography Concept.

Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are both crucial for the endoscopic management of biliopancreatic diseases: the combination of their diagnostic and therapeutic potential is useful in many clinical scenarios, such as indeterminate biliary stenosis, biliary stones, chronic pancreatitis and biliary and pancreatic malignancies. This natural and evident convergence between EUS and ERCP, which by 2006 we were calling the "Endoscopic ultrasonography retrograde colangiopancreatography (EURCP) concept", has become a hot topic in the last years, together with the implementation of the therapeutic possibilities of EUS (from EUS-guided necrosectomy to gastro-entero anastomoses) and with the return of ERCP to its original diagnostic purpose thanks to ancillary techniques (extraductal ultrasound (EDUS), intraductal ultrasound (IDUS), cholangiopancreatoscopy with biopsies and probe-based confocal laser endomicroscopy (pCLE)). In this literary review, we retraced the recent history of EUS and ERCP, reported examples of the clinical applicability of the EURCP concept and explored the option of performing the two procedures in only one endoscopic session, with its positive implications for the patient, the endoscopist and the health care system. In the last few years, we also evaluated the possibility of combining EUS and ERCP into a single endoscopic instrument in a single step, but certain obstacles surrounding this approach remain.

Who Should Not Be Surveilled for HCC Development after Successful Therapy with DAAS in Advanced Chronic Hepatitis C? Results of a Long-Term Prospective Study.

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed a long-term prospective cohort study on F3-F4 HCV-positive patients achieving Sustained Virologic Response (SVR) after DAAs treatment in order to identify patients who can safely suspend surveillance. Methods: 1000 patients with HCV-positive aCLD obtaining SVR by DAAs from January 2015 to December 2017 were divided into four groups according to baseline elastographic, ultrasonographic, clinical and biochemical features: (1) Group 1: 324 patients with Liver Stiffness Measurement (LSM) ≥ 9.5 ≤ 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (2) Group 2: 133 patients with LSM ≥ 9.5 ≤ 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5 (3) Group 3: 158 patients with LSM > 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (4) Group 4: 385 patients with LSM > 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5. FIB-4 and APRI scores were calculated at baseline and at SVR achievement. Each patient was surveiled twice-yearly by ultrasound for a median follow-up of 48 months. Results: among Group 1 patients, 1/324 (0.3%) developed HCC (0.09/100 patients/year [PY]), compared to 6/133 (4.5%) Group 2 patients (1.22/100 PY, p = 0.0009), 10/158 (6.3%) Group 3 patients (1.68/100 PY, p = 0.0001), 54/385 (14.0%) Group 4 patients (4.01/100 PY, p < 0.0001). HCC incidence was significantly lower in Group 2 compared to Group 3 (p = 0.004) and in Group 3 compared to Group 4 (p = 0.009). HCC risk fell in patients showing a decrease of FIB-4/APRI scores. Conclusions: the risk of HCC occurrence is negligible in about 90% of HCV-positive patients with baseline LSM ≥ 9.5 ≤ 14.5 kPa plus FIB-4 < 3.25 and APRI < 1.5 achieving SVR. Among this particular subset of patients, FIB-4/APRI scores may represent an accurate and inexpensive tool to distinguish patients not needing long-term HCC surveillance.

Incidence, risk and protective factors of symptoms after colonoscopy.

BACKGROUND: Few studies focused on minor adverse events which may develop after colonoscopy. AIMS: To investigate the incidence and factors associated to post-colonoscopy symptoms. METHODS: This is a prospective study conducted in 10 Italian hospitals. The main outcome was a cumulative score combining 10 gastrointestinal (GI) symptoms occurring the week following colonoscopy. The analyses were conducted via multivariate logistic regression. RESULTS: Of 793 subjects included in the analysis, 361 (45.5%) complained the new onset of at least one GI symptom after the exam; one symptom was reported by 202 (25.5%), two or more symptoms by 159 (20.1%). Newly developed symptoms more frequently reported were epigastric/abdominal bloating (32.2%), pain (17.3%), and dyspeptic symptoms (17.9%). Symptoms were associated with female sex (odds ratio [OR]=2.54), increasing number of symptoms developed during bowel preparation intake (OR=1.35) and somatic symptoms (OR=1.27). An inverse association was observed with better mood (OR=0.74). A high-risk profile was identified, represented by women with bad mood and somatic symptoms (OR=8.81). CONCLUSION: About half of the patients develop de novo GI symptoms following colonoscopy. Improving bowel preparation tolerability may reduce the incidence of post-colonoscopy symptoms, especially in more vulnerable patients.

Determinants of symptom burden related to bowel preparation for colonoscopy.

BACKGROUND: Symptoms developing during bowel preparation are major concerns among subjects who refuse the procedure. AIMS: We aimed to explore the determinants of symptoms occurring during preparation among patients undergoing elective colonoscopy. METHODS: This is a prospective multicenter study conducted in 10 Italian hospitals. A multidimensional approach collecting socio-demographic, clinical, psychological and occupational information before colonoscopy through validated instruments was used. Outcome was a four-category cumulative score based on symptoms occurring during preparation, according to the Mayo Clinic Bowel Prep Tolerability Questionnaire, weighted by intensity. Missing values were addressed through multiple imputation. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multivariate logistic regression models. RESULTS: 1137 subjects were enrolled. Severe symptoms were associated with female sex (OR=3.64, 95%CI 1.94-6.83), heavier working hours (OR=1.13, 95% CI=1.01-1.25), previous gastrointestinal symptoms (OR=7.81, 95% CI 2.36-25.8 for high score), somatic symptoms (OR=2.19, 95% CI=1.06-4.49 for multiple symptoms), day-before regimen (OR=2.71, 95%CI 1.28-5.73). On the other hand, age ≥60 years (OR=0.10, 95% CI 0.02-0.44) and good mood (p=0.042) were protective factors. A high-risk profile was identified, including women with low mood and somatic symptoms (OR=15.5, 95%CI 4.56-52.7). CONCLUSIONS: We identified previously unreported determinants of symptoms burdening bowel preparation and identified a particularly vulnerable phenotype. Symptoms during preparation especially impact heavier working activity.

Predictors of adverse events after endoscopic ultrasound-guided through-the-needle biopsy of pancreatic cysts: a recursive partitioning analysis.

BACKGROUND AND STUDY AIMS : Endoscopic ultrasound-guided through-the-needle biopsy (TTNB) of pancreatic cystic lesions (PCLs) is associated with a non-negligible risk for adverse events (AEs). We aimed to identify the hierarchic interaction among independent predictors for TTNB-related AEs and to generate a prognostic model using recursive partitioning analysis (RPA). PATIENTS AND METHODS : Multicenter retrospective analysis of 506 patients with PCLs who underwent TTNB. RPA of predictors for AEs was performed and the model was validated by means of bootstrap resampling. RESULTS : Mean cysts size was 36.7 mm. Most common diagnoses were intraductal papillary mucinous neoplasm (IPMN, 45 %), serous cystadenoma (18.8 %), and mucinous cystadenoma (12.8 %). Fifty-eight (11.5 %) AEs were observed. At multivariate analysis, age (odds ratio [OR] 1.32, 1.09-2.14; p = 0.05), number of TTNB passes (OR from 2.17, 1.32-4.34 to OR 3.16, 2.03-6.34 with the increase of the number of passes), complete aspiration of the cyst (OR 0.56, 0.31-0.95; p = 0.02), and diagnosis of IPMN (OR 4.16, 2.27-7.69; p < 0.001) were found to be independent predictors of AEs, as confirmed by logistic regression and random forest analyses. RPA identified three risk classes: high-risk (IPMN sampled with multiple microforceps passes, 28 % AEs rate), low-risk (1.4 % AE rate, including patients < 64 years with other-than-IPMN diagnosis sampled with ≤ 2 microforceps passes and with complete aspiration of the cyst) and middle-risk class (6.1 % AEs rate, including the remaining patients). CONCLUSION : TTNB should be selectively used in the evaluation of patients with IPMN. The present model could be applied during patient selection as to optimize the benefit/risk of TTNB.

Impact of Macroscopic On-Site Evaluation (MOSE) on Accuracy of Endoscopic Ultrasound-Guided Fine-Needle Biopsy (EUS-FNB) of Pancreatic and Extrapancreatic Solid Lesions: A Prospective Study.

This is a prospective and comparative study including 76 consecutive patients performing EUS-FNB for pancreatic and extrapancreatic solid lesions, randomized by alternate allocation to macroscopic on-site evaluation (MOSE) (40 patients) or to a conventional technique (40 patients), with three passes each. MOSE samples were differentiated into score 0: no visible material, score 1: only necrotic or haematic material, score 2: white core tissue ≤ 2 mm, or score 3: white core tissue > 2 mm. The conventional technique consisted in pushing all the needle content into a test tube for evaluation by the pathologist. In both groups, a 22-25 Gauge Franseen-tip needle (Acquire, Boston Scientific Co., Natick, MA, USA) was used. The study evaluated the diagnostic accuracy and adequacy of MOSE compared to the conventional technique and whether MOSE could optimize the number of passes during EUS-FNB. Results: The analysis was performed on 76 patients (38 MOSE, 38 conventional). The overall diagnostic adequacy was 94.7% (72/76) and accuracy was 84.2% (64/76). The diagnostic accuracy was similar in the two groups: MOSE 86.8% (33/38 lesions), vs. conventional 81.6%, 31/38 lesions, p = 0.76). Regarding diagnostic adequacy, the MOSE technique was 97.4% (111/114 passes) compared to 92.1% (105/114 passes) with the conventional technique, p = 0.06. The accuracy increased according to the MOSE score evaluation: it was 43.5%, 65.5% and 78.3% in patients with score 1, score 2, and score 3, respectively. Moreover, if in the first two passes the MOSE score was 2 or 3, the accuracy was 82.6% (20/23), and upon adding a third pass, the accuracy increased to 87% (20/23), which was not significantly different from the general accuracy of the MOSE samples (86.8%) (p = 0.86). Conclusions: The MOSE score showed a comparable diagnostic accuracy to the conventional technique. However, MOSE allows endoscopists to perform an inspective evaluation of the material, tends to perform better than the conventional technique in terms of diagnostic adequacy, and may potentially reduce the number of passes.

Screening and surveillance of oesophageal varices in patients with HCV-positive liver cirrhosis successfully treated by direct-acting antiviral agents.

BACKGROUND & AIMS: limited evidence is available to guide hepatologists regarding endoscopic surveillance of oesophageal varices (EV) in Hepatitis C Virus (HCV)-positive cirrhotic patients achieving a sustained virologic response. To address these issues, we conducted a long-term prospective study on 427 HCV-positive cirrhotic patients successfully treated by Direct Antiviral Agents (DAAs). METHODS: Patients were divided into two groups according to their baseline Baveno VI status: Group 1 (92, 21.5%, favourable Baveno VI status) and Group 2 (335, 78.5%, unfavourable Baveno VI status). Each patient underwent baseline endoscopy and was endoscopically monitored for a median follow-up of 65.2 months according to Baveno VI recommendations. RESULTS: About 4.3% of Group 1 patients showed baseline EV compared with 30.1% of Group 2 patients (p < .0001). No patients belonging to Group 1 without baseline EV developed EV at follow-up endoscopy compared with 6.5% in Group 2 patients (p = .02); 69/107 (64.5%) patients with baseline EV showed small varices. During the endoscopic follow-up, EV disappeared/improved in 36 (33.6%), were stable in 39 (36.4%) and worsened in 32 (29.9%) patients, all belonging to Group 2 (p = .001). Improvement in Baveno VI status was observed in 118/335 (35.2%, p < .0001) of Group 2 patients and among those without pre-therapy EV, none developed EV throughout the follow-up. CONCLUSIONS: HCV-positive cirrhotic patients cured by DAAs showing baseline favourable Baveno VI status and no worsening during follow-up can safely avoid endoscopic screening and surveillance. Patients having unfavourable Baveno VI status without baseline EV who improve their status may suspend further endoscopic surveillance.

The impact of direct-acting antiviral treatment on glycemic homeostasis in patients with chronic hepatitis C.

INTRODUCTION: There is robust epidemiological evidence suggesting the link of chronic hepatitis C virus (HCV) infection with type 2 diabetes mellitus (DM). Viral clearance achieved by direct acting antiviral agents (DAAs) has been associated to significant improvements in glycometabolic control but data on the long-term effect of sustained virological response (SVR) on diabetic disease are limited. The aim of this review is to evaluate the influence of SVR after DAA-based therapy on insulin resistance (IR) and DM incidence in non-diabetic patients, on the glycemic homeostasis in diabetic patients and on their long-term hepatic and metabolic outcomes. EVIDENCE ACQUISITION: An electronic search of Embase, PubMed, MEDLINE, Ovid and the Cochrane Database of Systematic Reviews was performed for papers regarding the effect of DAA-induced SVR on the glycometabolic control and clinical outcomes of HCV-positive diabetic patients up to September 30, 2020. EVIDENCE SYNTHESIS: Among non-diabetic patients, a significant reduction in the risk of IR and DM was reported by the vast majority of the studies; the glycometabolic control significantly improved in diabetic patients during and immediately after the end of antiviral treatment. However, whether this beneficial effect is long lasting is still matter of debate. Furthermore, at variance with data obtained during the Interferon era, DM does not seem to be an unfavorable predictive factor of hepatocellular carcinoma in cured patients. CONCLUSIONS: A favorable influence of DAA-induced SVR on IR and DM incidence and on glycemic control is reported by several studies. However, the long-term biochemical, metabolic and clinical impact of this endocrine benefit remains largely unknown.

Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents.

BACKGROUND AND AIMS: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.

Differential diagnosis of pancreatic cysts: A prospective study on the role of intra-cystic glucose concentration.

BACKGROUND: The accuracy and costs of current diagnostic methods in the differential diagnosis of pancreatic cystic lesions still has ample room for improvement. AIMS: The aim of the study was to confirm the diagnostic yield of intracystic glucose in the diagnosis of pancreatic cyst subtypes. METHODS: We prospectively recruited all patients who underwent Endoscopic Ultrasound with Fine Needle Aspiration of pancreatic cyst at our Institution. RESULTS: Fifty-six patients were included in the study. We found that intracystic glucose concentration < 50 mg/dL was significantly more sensitive than a concentration of Carcinoembryonic Antigen > 192 ng/mL (93.6% vs 54.8%; p = 0.003) for the diagnosis of mucinous cysts. In terms of specificity, the two markers were not different (96% vs 100%; p = 1). Regarding the diagnosis of non-mucinous cysts, intracystic glucose concentration ≥ 50 mg/mL showed higher sensitivity than Carcinoembryonic Antigen level < 5 ng/mL (96% vs 72%) although a statistical significance could not be reached (p = 0.07). The two markers were not statistically different in terms of specificity (93.6% vs 87.1%; p = 0.62). CONCLUSION: Given its diagnostic performance and ease of measurement, intracystic glucose may replace Carcinoembryonic Antigen in the differential diagnosis of mucinous versus non-mucinous pancreatic cysts.

Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis. We undertook this study to elucidate the interplay between macrophage activation, insulin resistance (IR) in target organs/tissues and hepatic damage. METHODS: In 40 non-diabetic patients with biopsy-proven NAFLD we assessed: i) endogenous glucose production (EGP), glucose clearance and indexes of IR in the adipose tissue (Adipo-IR and Lipo-IR) and in the liver (Hep-IR) by tracer infusion ([6,6-2H2]glucose and [2H5]glycerol); ii) macrophage activity (by soluble sCD163) and iii) hepatic expression of CD163 (hCD163). RESULTS: We found that sCD163 levels paralleled both the plasma free fatty acid (FFA) levels and lipolysis from adipose tissue. Consistently, sCD163 significantly correlated with adipose tissue IR (Adipo-IR: r = 0.32, p = 0.042; Lipo-IR: r = 0.39, p = 0.012). At multiple regression analysis, sCD163 levels were associated with FFA levels (rp = 0.35, p = 0.026). In vitro exposure of human monocyte-derived macrophages to palmitate enhanced sCD163 secretion. Conversely, sCD163 did not correlate with EGP or with Hep-IR. In the liver, hCD163 positively correlated with sCD163 (r = 0.58, p = 0.007) and the degree of steatosis (r = 0.34, p = 0.048), but not with EGP or Hep-IR (r = -0.27 and r = 0.11, respectively, p >0.10, both). CONCLUSIONS: Our findings suggest a link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, possibly in response to FFA overflow and independent of obesity and diabetes. Conversely, our findings do not support a link between activated hepatic macrophages and glucose metabolism (EGP or Hep-IR). The relationship between adipose tissue IR and hepatic macrophages should be considered to define therapeutic targets for NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis in the insulin resistant state. This study provides in vivo support for a possible link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, most likely in response to free fatty acid overflow and independent of obesity and diabetes.