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.

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.

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.

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.

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.

Rapid and persistent decline in soluble CD163 with successful direct-acting antiviral therapy and associations with chronic hepatitis C histology.

BACKGROUND AND AIM: Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163-levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS: We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first-generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS: Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION: sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response.

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.

Soluble CD163 and mannose receptor associate with chronic hepatitis B activity and fibrosis and decline with treatment.

BACKGROUND AND AIM: Liver macrophages are activated in chronic hepatitis B virus (CHB) infection and play a pivotal role in hepatic inflammation and fibrosis. However, their role during antiviral treatment is unclear. The soluble (s) macrophage activation markers, sCD163 and mannose receptor (sMR), are released during liver damage, and their serum levels reflect liver disease severity and portal hypertension. We aimed to investigate associations between sCD163 and sMR and histopathological activity and fibrosis and changes in sCD163, sMR, and hepatic CD163-expression following antiviral treatment in CHB patients. METHODS: We assessed Ishak histological necroinflammatory activity and fibrosis scores in liver biopsies from 254 CHB patients and serially in 71 patients before and after nucleoside-analogue treatment. Liver CD163-expression was semi-quantitatively determined by immunohistochemistry and serum sCD163 and sMR measured by enzyme-linked immunosorbent assays. RESULTS: Before treatment, the mean levels of sCD163 and sMR were 3.57 (SD 1.72) mg/L and 0.35 (0.12) mg/L. sCD163 and sMR increased with histological inflammatory activity (sCD163: r = 0.46, P < 0.00001; sMR: r = 0.48, P < 0.00001) and correlated positively with fibrosis (sCD163: OR 1.16, 95% CI:1.03-1.31; sMR: OR 1.34, 95% CI:1.13-1.59); both were markers of fibrosis independent of other biochemical parameters and risk factors. Antiviral treatment significantly reduced sCD163 (3.76 [1.46] vs 2.31 [0.95], P < 0.00001), sMR (0.37 [0.1] vs 0.29 [0.07], P < 0.00001) and hepatic CD163-expression (P = 0.0002). CONCLUSION: The macrophage activation markers sCD163 and sMR were associated with activity and fibrosis in liver biopsies from CHB patients. Both serum markers decreased with antiviral treatment, along with decreased hepatic CD163 expression.

High burden of coronary atherosclerosis in patients with cirrhosis.

BACKGROUND: Population studies report increased cardiovascular mortality in patients with cirrhosis. Coronary artery disease may be a trait of end-stage liver disease, but whether it is frequent or extensive in cirrhosis in general is unknown. Thus, we aimed to assess the prevalence and extent of coronary artery disease in unselected cirrhosis patients. MATERIALS AND METHODS: Using coronary computed tomography angiography, we investigated 52 patients from all Child-Pugh classes and aetiologies of cirrhosis without known cardiac disease for presence and severity of coronary artery disease in a cross-sectional design. Persons referred with new-onset chest pain served as controls. RESULTS: The prevalence of coronary artery disease was not significantly different between cirrhosis patients and controls (77% vs. 65%, P=0·19). However, cirrhosis patients had a markedly higher coronary artery calcification (Agatston) score than controls (120 [interquartile range, 0-345] vs. 5 [interquartile range, 0-86] HU, P=0·001). Likewise, patients with cirrhosis had a higher prevalence of extensive (≥5 coronary segments involved; 45% vs. 18%, P=0·01) and multivessel coronary disease (≥2 vessels involved; 75% vs. 53%, P=0·02). Furthermore, the total plaque volume whether noncalcified or calcified was higher in cirrhosis (117 [interquartile range, 0-310] vs. 36 [interquartile range, 0-148] mm3 , P=0·02). CONCLUSION: Coronary artery disease is equally prevalent in patients with cirrhosis and subjects with new-onset chest pain, but cirrhosis patients have more extensive and severe disease including several coronary high-risk features associated with myocardial ischaemia and a poor clinical outcome. The potential of preventive measures for coronary artery disease in cirrhosis needs attention.

Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease.

OBJECTIVE: Liver macrophages play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163), a macrophage-specific biomarker, reflects disease activity in the range of liver diseases. The impact of lifestyle intervention on sCD163 in adult NAFLD patients has not been investigated. MATERIAL AND METHODS: We assessed 126 NAFLD patients participating in a lifestyle intervention study for sCD163 concentrations at baseline, after the three-month intervention period, and at long-term follow-up after 12 and 24 months. RESULTS: The median sCD163 concentration at baseline was 2.59 mg/L (IQR = 1.78-3.63 mg/L). There was a significant decrease in sCD163 from baseline to three months follow-up (-0.64 mg/L, p < .001) with no difference between the four study groups (p = .6). At 12 and 24 months follow-up, the sCD163 concentrations had returned to baseline level (p = .3 and p = .1). Baseline sCD163 correlated with liver biomarkers and metabolic variables. There was a significantly greater decrease in sCD163 in patients who had a decrease in alanine aminotransferase (ALT) compared with patients with unchanged or increased ALT (-0.76 mg/L vs. -0.41 mg/L, p = .02), and in patients with a decrease in HOMA-IR compared with individuals with no decrease (-0.86 mg/L vs. -0.55 mg/L, p = .03). CONCLUSION: sCD163 is associated with markers of liver necro-inflammation and glucose homoeostasis in NAFLD. Participation in a lifestyle intervention programme resulted in a significant reduction in sCD163. Our data support the utility of sCD163 as a biomarker for monitoring the efficacy of therapeutic interventions in NAFLD.

The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Macrophage activation plays a key pathogenic role in experimental non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of steatohepatitis (NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s)CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients' morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin-18 (CK-18) to explore a link between macrophage activation and apoptosis. METHODS: sCD163 associations with biochemical and histological measures of NAFLD were investigated in two independent cohorts of 157 Australian and 174 Italian NAFLD patients, with liver biopsies graded for NAFLD severity, steatosis and fibrosis. sCD163 and CK-18 were measured by enzyme-linked immunosorbent assay. RESULTS: In both cohorts sCD163 increased in parallel with the patients' morphological disease grading, being independently associated with the Kleiner fibrosis score (P < 0.001). A high sCD163 predicted advanced fibrosis {F ≥ 3; Australian cohort: area under receiver-operating characteristics curve 0.77 [95% confidence interval (CI): 0.76-0.87], Italian cohort: 0.80 (95% CI: 0.72-0.88)}. In both groups, sCD163 was independently associated with CK-18 (P < 0.001). CONCLUSION: Soluble CD163 reflecting macrophage activation is associated with morphological features of NAFLD suggesting their involvement in the pathogenesis of NAFLD, NASH and particularly fibrosis. An independent association between sCD163 and cytokeratin-18 suggests that apoptosis may contribute to macrophage activation in NAFLD/NASH.

Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma.

BACKGROUND: Tumor associated macrophages are present in hepatocellular carcinoma (HCC) and associated with a poor prognosis. The aim of the present study was to investigate the levels and dynamics of soluble (s)CD163, a specific macrophage activation marker, in patients with HCC. METHODS: In a cohort from Australia, we studied 109 HCC patients, 116 patients with chronic liver disease (CLD), and 52 healthy controls. We examined associations between baseline sCD163 and parameters of HCC severity as well as overall and progression-free survival. In a cohort of 42 Danish HCC patients, we measured sCD163 at baseline and 1, 4 and 12 weeks after ablative treatment. RESULTS: In the Australian cohort, median sCD163 was similarly increased in HCC (5.6[interquartile range 3.5-8.0] mg/L) and CLD (6.1[3.6-9.6] mg/L) patients as compared to controls (2.0[1.5-2.7] mg/L, p < 0.001). sCD163 correlated with Child-Pugh and MELD scores in both HCC and CLD patients. Patients with high sCD163 levels had shorter progression-free survival (p < 0.001), but not overall survival (p = 0.15). In the Danish cohort, patients with HCC progression at 12 weeks had an increase in sCD163. There was no association between sCD163 and HCC size, number, vascular invasion or metastasis in any of the cohorts. CONCLUSIONS: We confirmed increased sCD163 levels in CLD and HCC patients associated with Child-Pugh and MELD scores and portal hypertension, but not with HCC size and number, or metastasis. As a novel finding, baseline sCD163 appeared to predict a rapid HCC progression, as sCD163 increased during follow-up in HCC patients who showed progression.

Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C.

UNLABELLED: Macrophages are involved in inflammation and liver fibrosis and soluble (s)CD163 is a specific marker of activated macrophages. We investigated associations between sCD163 and biochemical and histological parameters of inflammatory activity and fibrosis in 551 patients with chronic hepatitis C virus (HCV) and 203 patients with chronic hepatitis B virus (HBV) before antiviral treatment. Scheuer histological scores of activity and fibrosis were obtained. Clinical, biochemical, and metabolic parameters were recorded. We measured sCD163 by enzyme-linked immunosorbent assay (ELISA). Soluble CD163 was higher in patients with HCV compared to HBV (3.6 [interquartile range (IQR) 2.5-5.4] versus 2.4 [IQR 1.8-3.6] mg/L, P < 0.001). sCD163 was associated with fibrosis stages for both HCV (odds ratio [OR] 1.49, 95% confidence interval [CI]: 1.38-1.61) and HBV (OR 1.32, 95% CI: 1.17-1.49) patients, with highest levels in patients with advanced fibrosis and cirrhosis. sCD163 was a marker of fibrosis independent of other biochemical parameters and known risk factors. We created two novel sCD163-based fibrosis scores, CD163-HCV-FS and CD163-HBV-FS, which showed areas under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI: 0.74-0.83) and 0.71 (95% CI: 0.62-0.79), respectively, for significant fibrosis. Compared to existing fibrosis scores, CD163-HCV-FS was significantly superior to the aspartate aminotransferase (AST) to platelet ratio index (APRI) for all fibrosis stages and to FIB-4 for significant fibrosis, but CD163-HBV-FS was not. CONCLUSION: sCD163 levels are increased in patients with chronic viral hepatitis, reflecting macrophage activation. Increased sCD163 is associated with the severity of disease and predicts fibrosis. A sCD163-based fibrosis score, CD163-HCV-FS, is superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with HCV infection.

Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery.

BACKGROUND AND AIMS: Macrophages play an important role in non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163) is a specific marker of macrophage activation. We aimed to measure sCD163 in morbidly obese patients with varying degrees of NAFLD before and after bariatric surgery (BS). METHODS: Demographic, clinical, and biochemical data, and plasma sCD163 measured by enzyme-linked immunosorbent assay, of 196 patients were collected preoperatively and 3, 6, and 12 months after BS leading to significant weight loss. Peroperative liver biopsies were assessed for the NAFLD Activity Score (NAS), Kleiner fibrosis score, and the fatty liver inhibition of progression (FLIP) algorithm. In a subset, CD163 immunohistochemistry and real-time quantitative polymerase chain reaction for CD163 mRNA were performed. RESULTS: sCD163 was higher in patients with NAS ≥ 5 compared with those with NAS < 5 (2.4(2.0-3.1) vs 1.9(1.5-2.3) mg/L, P < 0.001) and in patients with bridging fibrosis (F ≥ 3) compared with lower fibrosis stages (2.6(2.0-4.9) vs 2.0(1.5-2.4) mg/L, P = 0.001). Preoperative sCD163 was independently associated with both the NAS (P = 0.002) and the fibrosis score (P = 0.024). sCD163 decreased after BS and was greatly reduced after 12 months, more rapidly so in patients with NAS ≥ 5 (P < 0.001) and non-alcoholic steatohepatitis (NASH) according to the FLIP algorithm (P = 0.03). Immunohistochemistry showed CD163-positive macrophages aligning fat-laden hepatocytes and forming microgranulomas in patients with NASH. CD163 mRNA expression did not vary with NAS. CONCLUSION: sCD163 increased in parallel with the severity of NAFLD in morbid obesity, indicating macrophage activation. BS reduced sCD163 even in patients with severe liver injury and fibrosis, suggesting full reversibility of macrophage activation associated with improved insulin sensitivity.

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.

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.