Negative impact of the pandemic on hospital admissions, morbidity and early mortality for acute cirrhosis decompensation.

INTRODUCTION: The global pandemic has diverted resources away from management of chronic diseases, including cirrhosis. While there is increasing knowledge on COVID-19 infection in liver cirrhosis, little is described on the impact of the pandemic on decompensated cirrhosis admissions and outcomes, which was the aim of this study. METHODS: A single-centre, retrospective study, evaluated decompensated cirrhosis admissions to a tertiary London hepatology and transplantation centre, from October 2018 to February 2021. Patients were included if they had an admission with cirrhosis decompensation defined as new-onset jaundice or ascites, infection, encephalopathy, portal hypertensive bleeding or renal dysfunction. RESULTS: The average number of admissions stayed constant between the pre-COVID-19 (October 2018-February 2020) and COVID-19 periods (March 2020-February 2021). Patients transferred in from secondary centres had consistently higher severity scores during the COVID-19 period (UK Model for End-Stage Liver Disease 58 vs 54; p=0.007, Model for End-Stage Liver Disease-Sodium 22 vs 18; p=0.006, EF-CLIF Acute Decompensation (AD) score 55.0 vs 51.0; p=0.055). Of those admitted to the intensive care without acute-on-chronic liver failure, there was a significant increase in AD scores during the COVID-19 period (58 vs 48, p=0.009). In addition, there was a trend towards increased hospital readmission rates during the COVID-19 period (29.5% vs 21.5%, p=0.067). When censored at 30 days, early mortality postdischarge was significantly higher during the COVID-19 period (p<0.001) with a median time to death of 35 days compared with 62 days pre-COVID-19. DISCUSSION: This study provides a unique perspective on the impact that the global pandemic had on decompensated cirrhosis admissions. The findings of increased early mortality and readmissions, and higher AD scores on ICU admission, highlight the need to maintain resourcing for high-level hepatology care and follow-up, in spite of other disease pressures.

A novel smartphone scleral-image based tool for assessing jaundice in decompensated cirrhosis patients.

BACKGROUND AND AIM: Serum bilirubin is an established marker of liver disease. Reliable tools for non-invasive assessment of jaundice in cirrhosis patients, at risk of clinical decompensation, are highly desirable. While smartphone-based imaging has been described in neonatal jaundice, it has not been investigated in advanced cirrhosis patients. METHODS: We included 46 hospitalized patients with acute cirrhosis decompensation and jaundice. Scleral images using an Android smartphone were taken to derive "Scleral Color Values (SCV)," which were matched with same day serum bilirubin measurements. In 29 patients, repeat SCV and bilirubin measurements were performed over time. We analyzed the relationship of SCV and its dynamics with serum bilirubin, clinical scores, and patient outcomes. RESULTS: Of 46 patients, 26 (57%) had alcoholic hepatitis as the decompensation precipitant. Seven patients died during admission; a further 12 following hospital discharge. SCV had an excellent linear correlation with serum bilirubin (rho = 0.90, P < 0.001); changes in SCV and serum bilirubin across different time points, were also closely associated (rho = 0.77, P < 0.001). SCV correlated significantly with CLIF Consortium Acute Decompensation score (rho = 0.38, P < 0.001) and grade of Acute-on-Chronic Liver Failure (rho = 0.42, P = 0.039). SCV was higher in patients who died, however, not significantly (86.1 [IQR 83.0-89.7] vs 82.3 [IQR 78.5-83.3], P = 0.22). The associations of SCV with clinical parameters mirrored those of serum bilirubin. CONCLUSION: Smartphone-based assessment of jaundice shows excellent concordance with serum bilirubin and is associated with clinical parameters in acute cirrhosis decompensation. This approach offers promise for remote assessment of cirrhosis patients at-risk of decompensation, post hospital discharge.

Evaluation of CirrhoCare® - a digital health solution for home management of individuals with cirrhosis.

BACKGROUND & AIMS: Individuals with cirrhosis discharged from hospital following acute decompensation are at high risk of new complications. This study aimed to assess the feasibility and potential clinical benefits of remote management of individuals with acutely decompensated cirrhosis using CirrhoCare®. METHODS: Individuals with cirrhosis with acute decompensation were followed up with CirrhoCare® and compared with contemporaneous matched controls, managed with standard follow-up. Commercially available monitoring devices were linked to the smartphone CirrhoCare® app, for daily recording of heart rate, blood pressure, weight, % body water, cognitive function (CyberLiver Animal Recognition Test [CL-ART] app), self-reported well-being, and intake of food, fluid, and alcohol. The app had 2-way patient-physician communication. Independent external adjudicators assessed the appropriateness of CirrhoCare®-based decisions. RESULTS: Twenty individuals with cirrhosis were recruited to CirrhoCare® (mean age 59 ± 10 years, 14 male, alcohol-related cirrhosis [80%], mean model for end-stage liver disease-sodium [MELD-Na] score 16.1 ± 4.2) and were not statistically different to 20 contemporaneous controls. Follow-up was 10.1 ± 2.4 weeks. Fifteen individuals showed good engagement (≥4 readings/week), 2 moderate (2-3/week), and 3 poor (<2/week). In a usability questionnaire, the median score was ≥9 for all questions. Five CirrhoCare®-managed individuals had 8 readmissions over a median of 5 (IQR 3.5-11) days, and none required hospitalisation for >14 days. Sixteen other CirrhoCare®-guided patient contacts were made, leading to clinical interventions that prevented further progression. Appropriateness was confirmed by adjudicators. Controls had 13 readmissions in 8 individuals, lasting a median of 7 (IQR 3-15) days with 4 admissions of >14 days. They had 6 unplanned paracenteses compared with 1 in the CirrhoCare® group. CONCLUSIONS: This study demonstrates that CirrhoCare® is feasible for community management of individuals with decompensated cirrhosis with good engagement and clinically relevant alerts to new decompensating events. CirrhoCare®-managed individuals have fewer and shorter readmissions justifying larger controlled clinical trials. IMPACT AND IMPLICATIONS: As the burden of cirrhosis grows worldwide, increasing demands are being placed on limited healthcare resources, necessitating the adoption of more sustainable care models that allow for at-home patient management. The CirrhoCare® management system was developed to fill this care gap, deploying a novel combination of hardware, apps, and algorithms, to monitor and intervene in individuals at risk of new decompensation. This study highlights the possibility of reducing hospital readmissions for cirrhosis by optimising specialist community care, reducing the need for interventions such as paracentesis, while providing a more sustainable care pathway that is acceptable to patients. However, given the pilot and non-randomised nature of this study, the outcomes require further validation in a larger randomised controlled trial, to assess both clinical effectiveness and cost-effectiveness. Moreover, the data generated will also facilitate data modelling and further research to refine the CirrhoCare® algorithms to increase their detection sensitivity and utility.

Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and is rapidly emerging as the leading cause of liver-related morbidity and mortality. Macrophages play an essential role in the development and progression of NAFLD. AREAS COVERED: In this review, we provide an update on recent studies of drugs, which directly or indirectly affect macrophages in NAFLD, and discuss the implication of macrophage biomarkers to monitor the disease stage and progression/regression. EXPERT OPINION: There is an unmet need for a better understanding of disease pathogenesis from hepatic fat accumulation to disease progression with inflammation and fibrosis. We expect that future research will uncover additional objects/pathways as treatment targets. We speculate that this will involve better characterization of the gut microbiome, damage-associated molecular patterns (DAMPS) or molecules and pathways involved in the development of DAMPS, and advanced molecular biology studies including single-cell sequencing of macrophage subpopulations. In addition, we speculate that studies focusing on pharmaceuticals that improve insulin resistance, diminish the metabolic syndrome, and reduce fibrosis will prevail.

Macrophage activation marker sCD163 is associated with liver injury and hepatic insulin resistance in obese patients before and after Roux-en-Y gastric bypass.

BACKGROUND: Macrophages are associated with metabolic complications to obesity including fatty liver disease and impaired hepatic and muscle insulin sensitivity (IS). Bariatric surgery induces weight loss and improves IS. We investigated associations between the macrophage activation marker soluble (s)CD163, alanine-aminotransferase (ALT), and IS before and after Roux-en-Y Gastric Bypass (RYGB). METHODS: We analyzed sCD163 from 10 type 2 diabetes (T2D) and 10 obese patients with normal glucose tolerance (NGT) undergoing RYGB for associations with hepatic, adipose tissue, and muscle IS and ALT after 1-week, 3, and 12 months postoperatively. IS was evaluated by hyperinsulinemic-euglycemic clamp in combination with glucose tracer technique. RESULTS: Preoperative sCD163 correlated with ALT (r = 0.58, p = 0.007) and tended to associate inversely with hepatic (r = -0.39, p = 0.1) and adipose tissue (r = -0.39, p = 0.09), but not muscle IS. Following RYGB, sCD163 decreased significantly in all patients. The decrease in sCD163 during the first 3 months correlated inversely with the improvement of hepatic IS (r = -0.65, p = 0.01) and tended to be associated with changes in muscle IS (r = -0.45, p = 0.09). After 3 months sCD163 remained associated with ALT (r = 0.75, p < 0.001) and inversely with hepatic IS (r = -0.39, p = 0.1), but not muscle or adipose tissue IS. One year after RYGB, sCD163 correlated with ALT (r = 0.61, p = 0.007), but not with hepatic, adipose tissue, or muscle IS. CONCLUSION: Macrophage activation is associated with liver injury and hepatic IS in obese patients. Improvements in these measures correlate during the first 3 months following RYGB, supporting a link between macrophages and hepatic IS in severe obesity and diabetes.

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Risk and Outcome of Venous and Arterial Thrombosis in Patients With Cirrhosis: A Danish Nation-wide Cohort Study.

BACKGROUND AND AIMS: Cirrhosis affects hemostasis, but its effects across the spectrum of thromboses remain poorly understood. We examined risks and outcomes of venous and arterial thrombosis. APPROACH AND RESULTS: We used nation-wide Danish health care registries to identify outpatients with cirrhosis and a sex- and age-matched comparison cohort without cirrhosis from the general population. Patients with cirrhosis and comparators were followed until they had a venous thromboembolism (VTE), acute myocardial infarction (AMI), or ischemic stroke (IS) or died. We computed absolute risks and HRs of thrombosis and compared outcomes after thrombosis. We included 5,854 patients with cirrhosis (median Model for End-Stage Liver Disease score, 9; interquartile range, 7-13), and their risk of any of the thrombotic events was 0.8% after 1 year and 6.3% after 10 years. They were more likely than the 23,870 matched comparators to have a VTE (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.5-2.6) or IS (aHR, 1.7; 95% CI, 1.3-2.3), but not AMI (aHR, 0.7; 95% CI, 0.5-0.9). Among patients with cirrhosis, decompensation increased the risk of AMI, but not the other thromboses. Following thrombosis, patients with cirrhosis had higher 90-day mortality than comparators (after VTE: 17% vs. 7%; after AMI: 27% vs. 5%; after IS: 10% vs. 7%) and were less likely to receive antithrombotic treatment. CONCLUSIONS: Patients with cirrhosis had an increased risk of VTE and IS, but not AMI. Among patients with cirrhosis, decompensation increased the risk of AMI, exclusively. Mortality after thrombosis was higher in patients with cirrhosis than in other patients. These findings are relevant for decisions about antithrombotic prophylaxis in patients with cirrhosis.

Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy?

INTRODUCTION: Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus. Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis. AREAS COVERED: We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages. EXPERT OPINION: Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.

Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis.

Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.

Liver-related effects of chronic hepatitis C antiviral treatment.

More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.

Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis.

Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.

Macrophage Markers Do Not Add to the Prediction of Liver Fibrosis by Transient Elastography in Patients With Metabolic Associated Fatty Liver Disease.

Background and Aims: Non-invasive fibrosis staging is essential in metabolic associated fatty liver disease (MAFLD). Transient elastography (TE) is a well-established method for liver fibrosis assessment. We have previously shown that the macrophage marker sCD163 is an independent predictor for fibrosis in MAFLD. In the present study we tested whether the combination of macrophage markers and TE improves fibrosis prediction. Methods: We measured macrophage markers soluble (s)CD163 and mannose receptor (sMR) in two independent cohorts from Italy (n = 141) and Sweden (n = 70) with biopsy-proven MAFLD and available TE. Results: In the Italian cohort, TE and sCD163 showed similar moderate associations with liver fibrosis (rho = 0.56, p < 0.001 and rho = 0.42, p < 0.001, respectively). TE had an area under the Receiver Operating Characteristics curve (AUROC, with 95% CI) for fibrosis; F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.81 (0.73-0.89), F4 = 0.95 (0.90-1.0). sCD163 also predicted fibrosis well [F ≥ 2 = 0.71 (0.63-0.80), F ≥ 3 = 0.82 (0.74-0.90), F4 = 0.89 (0.76-1.0)]. However, combining sCD163 and TE did not improve the AUROCs significantly [F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.85 (0.78-0.92), F4 = 0.97 (0.93-1.0)]. In the Swedish cohort, TE showed a closer association with fibrosis (rho = 0.73, p < 0.001) than sCD163 (rho = 0.43, p < 0.001) and sMR (rho = 0.46, p < 0.001). TE predicted fibrosis well [F ≥ 2 = 0.88 (0.80-0.97), F ≥ 3 = 0.90 (0.83-0.97), F4 = 0.87 (0.78-0.96)], whereas sCD163 did not (best AUROC 0.75). sMR showed a better prediction [F ≥ 2 = 0.68 (0.56-0.81), F ≥ 3 = 0.82 (0.71-0.92), F4 = 0.79 (0.66-0.93)], but the addition of sMR did not further improve the prediction of fibrosis by TE. Conclusion: In these cohorts of MAFLD patients, TE was superior to macrophage markers for fibrosis prediction and in contrast to our hypothesis the addition of these markers to TE did not improve its predictive capability.

Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C.

Sofosbuvir-based direct-acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy-one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir-based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8 mg/L, P < .0001), whereas the change in sMR was more subtle (0.37 vs 0.30 mg/L, P < .0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3 kPa, P < .0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P < .0001), suggestive of fibrosis regression. The GEC improved at follow-up (all: 1.74 vs 1.98 mmol/min), mainly at 12 weeks post-treatment, both in patients with cirrhosis (n = 56) and those with advanced liver fibrosis (n = 15) (P < .001). The CRT improved at one-year follow-up (1.86 vs 2.09, P = .04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.

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.

Macrophage markers soluble CD163 and soluble mannose receptor are associated with liver injury in patients with paracetamol overdose.

The macrophage activation markers, soluble CD163 (sCD163) and soluble mannose receptor (sMR), are associated with liver disease severity and prognosis. We aimed to investigate macrophage activation reflected by sMR and sCD163 in patients with mild and severe paracetamol (PCM) intoxication and effects of antidote treatment in patients and healthy controls. We measured sMR and sCD163 levels by in-house enzyme-linked immunosorbent assays in two independent prospective cohorts of PCM overdosed patients: 49 patients with early mild PCM overdose from Aarhus University Hospital and 30 patients with severe acute liver injury included at the Royal Infirmary of Edinburgh. Furthermore, we investigated sMR and sCD163 in 14 healthy controls during N-acetylcysteine treatment. Within the mild PCM cohort, patients with elevated alanine transaminase on admission had significantly higher levels of sCD163 compared with patients with normal alanine transaminase (2.92[2.00-5.75] versus 1.29[1.02-1.69] mg/L, p = .009), whereas sMR showed no significant difference. In patients with acute liver injury, both markers were markedly higher compared to the mild PCM cohort (sCD163: 10.73[5.79-14.62] versus 1.34[1.06-1.96], p < .001; sMR: 0.80[0.63-1.14] versus 0.18[0.14-0.25], p < .001). Antidote treatment significantly reduced sCD163 levels in both PCM overdosed patients and healthy controls. In conclusion, macrophage activation assessed by the levels of sMR and sCD163 is associated with the degree of liver injury in patients with PCM intoxication and is ameliorated by antidote treatment, suggesting macrophage involvement in PCM-induced liver injury.

Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects.

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant liver disease, and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis (NASH) to fibrosis, subsequent cirrhosis, end-stage liver failure, and liver cancer with a potential need for liver transplantation. NAFLD and NASH are closely related to obesity, metabolic syndrome, and type 2 diabetes (T2D). The role of gut hormones, especially glucagon-like peptide 1 (GLP-1), is important in NAFLD. Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2D. Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. In the present review, we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways. We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients. The specific focus was liver histopathology as assessed by the invasive liver biopsy. Additionally, we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.

The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.

Macrophage Markers Are Poorly Associated With Liver Histology in Children With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: We have previously demonstrated associations between the macrophage activation marker soluble (s)CD163 and histology of nonalcoholic fatty liver disease (NAFLD) in adults, and elevated sCD163 levels in children with obesity with NAFLD. Macrophage activation has, however, not been investigated in children with biopsy-proven NAFLD, which was the objective of the present study. METHODS: We used in-house enzyme-linked immunosorbent assays to measure sCD163 and the novel macrophage marker soluble mannose receptor (sMR) in a cross-sectional (n = 155) pediatric NAFLD cohort, and a cohort of NAFLD children (n = 36) undergoing a randomized trial by the probiotic VSL#3. We included 56 healthy nonobese children for comparison. RESULTS: Levels of sCD163 and sMR were higher in both of the NAFLD cohorts compared with controls (P < 0.001). In the cross-sectional cohort, sCD163 only showed trends toward association with ballooning (rho = 0.14, P = 0.08) and portal inflammation (rho = 0.17, P = 0.08). sMR showed similar associations with liver histology. In the VSL#3 cohort, sCD163 correlated inversely with steatosis (rho = -0.35, P = 0.04), and lobular (rho = -0.57, P < 0.001) and portal inflammation (rho = -0.38, P = 0.02); sMR was not associated with any histological scores. Neither sCD163 nor sMR changed significantly during intervention, and without association with NAFLD resolution. CONCLUSIONS: The macrophage activation markers sCD163 and sMR showed poor associations with liver histology in 2 different cohorts of children with biopsy-proven NAFLD, and none of the markers decreased during successful intervention. These results are in contrast with studies of adult NAFLD and may suggest a possibility of different roles for macrophages in the pathogenesis of adult and pediatric NAFLD.