Hepatic recompensation according to Baveno VII criteria is linked to a significant survival benefit in decompensated alcohol-related cirrhosis.

BACKGROUND & AIMS: Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the subsequent survival in patients with decompensated alcohol-related cirrhosis. METHODS: The rate of recompensation was evaluated in patients with decompensated alcohol-related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function. RESULTS: Two hundred and four abstinent patients with decompensated alcohol-related cirrhosis (age: 57.2 [IQR:50.1-63.7] years; 75.0% male; median MELD: 15 [IQR:11-19]) and a median HVPG of 20 (IQR:18-24) mmHg were included. During a median follow-up of 24.4 (IQR:10.9-50.4) months, 37 patients (18.1%) achieved abstinence-induced recompensation. Lower baseline HVPG, lower Child-Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver-related mortality (adjusted HR: 0.091 [95% CI: 0.012-0.677]; p = .019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 [95% CI: 0.084-1.878]; p = .245), yet this finding did not reach statistical significance and requires further investigation. CONCLUSIONS: Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG-characterised patients with decompensated alcohol-related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver-related mortality.

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis.

BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING: Innovative Medicines Initiative 2.

The impact of transmembrane 6 superfamily 2 (TM6SF2) rs58542926 on liver-related events in patients with advanced chronic liver disease.

BACKGROUND & AIMS: Genetic factors such as the transmembrane 6 superfamily 2 (TM6SF2) rs58542926 single nucleotide variant(SNV) modulate the susceptibility for (advanced) chronic liver disease ([A]CLD). However, the impact of this variant in patients who have already progressed to ACLD is unknown. METHODS: The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement. RESULTS: Mean HVPG was 15±7 mmHg and mean UNOS MELD (2016) 11±5 points. Viral hepatitis (n = 495, 53%) was the most common cause of ACLD, followed by alcohol-related (ARLD; n = 342, 37%) and non-alcoholic fatty liver disease (NAFLD; n = 101, 11%). While 754 (80%) patients harboured the TM6SF2 wild-type (C/C), 174 (19%) and 10 (1%) patients had one or two T-alleles. At baseline, patients with at least one TM6SF2 T-allele had more pronounced portal hypertension (HVPG: 16±7 vs. 15±7 mmHg; p = 0.031), higher gamma-glutamyl transferase levels (123 [63-229] vs. 97 [55-174] UxL-1; p = 0.002), and more commonly hepatocellular carcinoma (17% vs. 12%; p = 0.049). Harbouring the TM6SF2 T-allele was associated with the composite endpoint hepatic decompensation/liver transplantation/liver-related death (SHR: 1.44 [95%CI: 1.14-1.83]; p = 0.003). This was confirmed in multivariable competing risk regression analyses that were adjusted for severity of portal hypertension and hepatic dysfunction at baseline. CONCLUSION: The TM6SF2 variant modulates liver disease progression beyond the development of ACLD, as it modifies the risks of hepatic decompensation and liver-related death, independently of baseline liver disease severity.

Alpha-1 antitrypsin Pi∗Z allele is an independent risk factor for liver transplantation and death in patients with advanced chronic liver disease.

Background & Aims: Alpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi∗Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi∗Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion. Methods: A total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi∗Z/Pi∗S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks. Results: Viral hepatitis was the most common etiology (44%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi∗Z and Pi∗S variants, respectively. Pi∗Z carriers had more severe portal hypertension (HVPG: 19±6 vs.15±7 mmHg; p <0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1±1.9 vs. 6.5±1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi∗S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi∗Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi∗MZ genotype (adjusted subdistribution hazard ratio: ≈1.56 vs. Pi∗MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi∗S carriers had no increased risk of events. Conclusion: Genotyping for the Pi∗Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease-modifying treatments in Pi∗Z allele carriers with ACLD. Lay summary: Alpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect.

Systemic inflammation is linked to liver fibrogenesis in patients with advanced chronic liver disease.

BACKGROUND & AIMS: Experimental evidence indicates that systemic inflammation (SI) promotes liver fibrogenesis. This study investigated the potential link between SI and fibrogenesis in patients with advanced chronic liver disease (ACLD). METHODS: Serum biomarkers of SI (CRP, IL-6, procalcitonin [PCT]) and extracellular matrix (ECM) turnover (i.e., fibrogenesis/fibrolysis) were analysed in 215 prospectively recruited patients with ACLD (hepatic venous pressure gradient [HVPG] ≥6 mm Hg) undergoing hepatic vein catheterization. Patients with non-elective hospitalization or bacterial infection were excluded. Histological alpha-smooth muscle actin (α-SMA) area was quantified on full biopsy scans by automated morphometric quantification in a subset of 34 patients who underwent concomitant transjugular liver biopsy. RESULTS: Histological α-SMA proportionate area correlated with enhanced liver fibrosis (ELF) score (Spearman's ρ = 0.660, p < .001), markers of collagen formation (PRO-C3, ρ = 0.717, p < .001; PRO-C6, ρ = 0.526, p = .002) and tissue inhibitor of metalloproteinases-1 (TIMP1; ρ = 0.547, p < .001), indicating that these blood biomarkers are capable of reflecting the dynamic process of ECM turnover. CRP, IL-6 and PCT levels correlated with ELF, biomarkers of collagen synthesis/degradation and TIMP1, both in compensated and decompensated patients. Multivariate linear regression models (adjusted for HVPG) confirmed that CRP, IL-6 and PCT were independently linked to markers of liver fibrogenesis and ECM turnover. CONCLUSION: Systemic inflammation is linked to both liver fibrogenesis and ECM turnover in ACLD and this association is not confounded by the severity of liver disease, as evaluated by HVPG. Our study confirms experimental data on the detrimental impact of SI on ECM deposition and fibrosis progression in a thoroughly characterized cohort of patients with ACLD.

Current treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of pathologies ranging from non-alcoholic fatty liver (NAFL), characterized by simple steatosis without inflammation, to non-alcoholic steatohepatitis (NASH), characterized by steatosis of the liver accompanied by inflammation and hepatocyte ballooning, which can lead to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Apart from lifestyle modifications such as weight loss, a Mediterranean diet and physical activity, only a few NAFLD-specific pharmacological treatment options such as Vitamin E and Pioglitazone are considered by current international guidelines. However, recently randomized controlled trials with GLP-1 agonists, FXR and PPAR ligands as well as other agents have been published and may expand the therapeutic armamentarium for NAFLD in the near future. Finally, knowledge about treating complications of end-stage liver disease due to NASH becomes an increasingly important cornerstone in the treatment of the broad disease spectrum of NAFLD. In this review, we summarize currently available and future treatment options for patients with NAFLD that may help internal medicine specialists treat the complete clinical spectrum of this highly prevalent liver disease.

Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH.

BACKGROUND & AIMS: Previous single-cell RNA-sequencing analyses have shown that Trem2-expressing macrophages are present in the liver during obesity, non-alcoholic steatohepatitis (NASH) and cirrhosis. Herein, we aimed to functionally characterize the role of bone marrow-derived TREM2-expressing macrophage populations in NASH. METHODS: We used bulk RNA sequencing to assess the hepatic molecular response to lipid-dependent dietary intervention in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single-cell sequencing were applied to functionally characterize the role of TREM2+ macrophage populations in NASH. RESULTS: We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in the circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels were superior to traditionally used laboratory parameters for distinguishing between different fatty liver disease stages in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2+ macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis. CONCLUSIONS: Our study highlights the functional properties of bone marrow-derived TREM2+ macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH. LAY SUMMARY: Our study defines the origin and function of macrophages (a type of immune cell) that are present in the liver and express a specific protein called TREM2. We find that these cells have an important role in protecting against non-alcoholic steatohepatitis (a progressive form of fatty liver disease). We also show that the levels of soluble TREM2 in the blood could serve as a circulating marker of non-alcoholic fatty liver disease.

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death.

BACKGROUND & AIMS: Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects. METHODS: In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF-responders' (as defined by a ≥5% decrease in VWF) versus 'VWF-non-responders.' RESULTS: There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG. CONCLUSIONS: Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.

Clinical Course of Porto-Sinusoidal Vascular Disease Is Distinct From Idiopathic Noncirrhotic Portal Hypertension.

BACKGROUND & AIMS: Porto-sinusoidal vascular disease (PSVD) was recently proposed as novel clinical entity characterized by typical histological changes with or without portal hypertension (PH) in the absence of cirrhosis. Thus, we aimed to describe clinical characteristics and the outcome of PSVD patients and to compare these to patients meeting traditional idiopathic non-cirrhotic portal hypertension (INCPH) criteria. METHODS: Patients undergoing liver biopsy (baseline) ±hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 2000-2019 were screened for PSVD and INCPH criteria. RESULTS: 91 patients were diagnosed with PSVD of which 28 (30.8%) also fulfilled INCPH criteria (INCPH+/PSVD+). Specific histological and specific clinical PH signs were found in 72 (79.1%) and 54 (59.3%) patients, respectively. INCPH+/PSVD+ showed higher Child-Pugh-scores (7±2 vs 6±1 points; P = .002) and a higher prevalence of decompensation (57.1% vs 28.6%; P = .009) than INCPH-/PSVD+ patients. Importantly, hepatic decompensation after three years (3Y) occurred in 11.2% of PSVD patients with specific clinical signs of PH, while no decompensation occurred in patients with only specific histological or with unspecific clinical/histological signs (P = .002). When categorizing by INCPH definition, 3Y decompensation was 13.4% in INCPH+/PSVD+ and 3.8% in INCPH-/PSVD+ (P = .120). While overall mortality was similar in INCPH+/PSVD+ (n = 6; 21.4%) and INCPH-/PSVD+ (n = 10; 15.9%) patients (P = .558), liver-related mortality tended to be higher in INCPH+/PSVD+ (6.9%) than in INCPH-/PSVD+ (0%; P = .078). CONCLUSION: Novel PSVD criteria facilitate diagnosis. Compared to INCPH, clinical course of PSVD patients is more favorable. Importantly, specific signs of PH including varices and collaterals are associated with hepatic decompensation and mortality.

Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease.

OBJECTIVE: Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors. DESIGN: Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study. RESULTS: 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added. CONCLUSION: In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

Placental growth factor levels neither reflect severity of portal hypertension nor portal-hypertensive gastropathy in patients with advanced chronic liver disease.

BACKGROUND & AIMS: Experimental data indicates that placental growth factor (PLGF) is involved in the pathophysiology of portal hypertension (PH) due to advanced chronic liver disease (ACLD). We investigated serum levels of PLGF and its "scavenger", the receptor soluble fms-like tyrosine kinase-1 (sFLT1, or sVEGFR1), in ACLD patients with different severity of PH and portal-hypertensive gastropathy (PHG). METHODS: PLGF and sVEGFR1 were measured in ACLD patients with hepatic venous pressure gradient (HVPG) ≥6 mmHg (n = 241) and endoscopic evaluation of PHG (n = 216). Patients with pre-/posthepatic PH, TIPS, liver transplantation and hepatocellular carcinoma were excluded. RESULTS: Thirty-two (13%) patients had HVPG 6-9 mmHg, 128 (53%) 10-19 mmHg and 81 (34%) ≥20 mmHg; 141 (59%) had decompensated ACLD (dACLD). PLGF (median 17.2 vs. 20.8 vs. 22.4 pg/mL; p = 0.002), sVEGFR1 (median 96.0 vs. 104.8 vs. 119.3 pg/mL; p < 0.001) levels increased across HVPG strata, while PLGF/sVEGFR1 ratios remained similar (0.19 vs. 0.20 vs. 0.18 pg/mL; p = 0.140). The correlation between PLGF and HVPG was weak (Rho = 0.190,95%CI 0.06-0.31; p = 0.003), and the PLGF/sVEGFR1 ratio did not correlate with HVPG (p = 0.331). The area-under-the-receiver operating characteristics (AUROC) for PLGF to detect clinically significant PH (CSPH;i.e. HVPG ≥ 10 mmHg) yielded only 0.688 (0.60-0.78; p < 0.001). When compared to ACLD patients without PHG, PLGF levels (20 without vs. 21.4 with mild vs. 17.1 pg/mL with severe PHG, respectively; p = 0.005) and PLGF/sVEGFR1 ratios (0.20 vs. 0.19 vs. 0.17; p = 0.076) did not increase with mild and severe PHG. CONCLUSION: While PLGF levels tended to increase with severity of PH, the PLGF/sVEGFR1 ratio remained stable across HVPG strata. Neither PLGF nor the PLGF/sVEGFR1 ratio had diagnostic value for prediction of CSPH. The severity of PHG was also not associated with stepwise increases in PLGF levels or PLGF/sVEGFR1 ratio.

Prevalence of anti-Hepatitis E antibodies and impact on disease severity in non-alcoholic fatty liver disease.

AIM: In most immune-competent individuals, hepatitis E (HEV) infections appear silent. It is unclear whether past HEV infections deteriorate disease severity in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Patients with biopsy-proven NAFLD and data on anti-HEV immunoglobulin M (HEV-IgM) and anti-HEV IgG antibodies (HEV-IgG) were included. The NAFLD activity score (NAS) was used to grade and stage all liver biopsy samples. The HEV-IgG prevalence was compared to a healthy cohort of 997 subjects. RESULTS: One hundred sixty-seven patients with NAFLD were included with the following characteristics: age, 50 ± 13 years; NAS ≤4, 89 (53.3%); NAS 5-8, 78 (46.7%); cirrhosis, 16 (9.6%). Two patients (1.2%) were HEV-IgM-positive, however HEV polymerase chain reaction remained negative and no signs of acute hepatitis were seen. Forty-four patients (26.3%) were HEV-IgG-positive and they were significantly older (55 ± 10 years vs. 48 ± 13 years, P < 0.001) and predominantly men (31 [70.5%] vs.13 [29.5%], P = 0.022). Distribution across NAS (P = 0.610) was not different. However, HEV-IgG-positive patients were significantly more often found with cirrhosis (8 [18.2%] vs. 8 [6.5%], P = 0.024) and liver stiffness values >10 kPa (14 [58.2%] vs. 29 [43.3%], P = 0.026). Multivariable analyses revealed age (odds ratio [OR], 1.054 [1.022-1.086]) and male sex (OR 2.77 [1.27-6.04]) associated with HEV-IgG positivity. Presence of diabetes (OR 3.86 [1.18-12.59]), higher aspartate aminotransferase levels (OR, 1.02 [1.006-1.033]), and HEV-IgG seropositivity (OR 3.52 [1.11-11.13]) were independently linked to cirrhosis. Finally, HEV-IgG positivity was not independently associated with NAFLD patients in a case-control study including healthy subjects. CONCLUSIONS: Prevalence of anti-HEV-IgG antibodies in patients with NAFLD is linked to age and male sex. Furthermore, previous HEV infection was an independent risk factor for cirrhosis. Whether this finding is causal or solely associative is unclear and should be elucidated in future studies.

Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality.

BACKGROUND & AIMS: Distinct prognostic stages of advanced chronic liver disease (ACLD) are defined by severity of portal hypertension (PH) and the presence/absence of clinical complications. We characterised the degree of liver dysfunction, PH, and systemic inflammation across the distinct prognostic stages and assessed their relative impact on decompensation and mortality. METHODS: A single-centre, prospective cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement between 01/2017 and 08/2019 were classified into 6 prognostic stages: mild PH (HVPG 6-9 mmHg, S0), clinically significant PH (HVPG ≥10 mmHg without varices, S1), presence of varices (S2), history of variceal bleeding (S3), first non-bleeding decompensation (S4), and further decompensation (S5). The model for end-stage liver disease (MELD), C-reactive protein (CRP), and IL-6 levels were assessed in relation to their predictive value for decompensation and death. RESULTS: Among 168 ACLD patients 78 had compensated (cACLD, S0 = 13; S1 = 21; S2 = 44) and 90 had decompensated (dACLD, S3 = 10; S4 = 58; S5 = 22) disease. MELD increased across all stages (p <0.001), whereas HVPG mostly increased within cACLD substages. Significant increases in CRP and IL-6 levels were only noted across dACLD substages. IL-6 was an independent predictor of decompensation at 1-year follow-up in cACLD (hazard ratio [HR] 1.06, 95% CI 1.01-1.10; p = 0.013). In dACLD patients, IL-6 levels predicted death/transplantation after 1-year of follow-up (HR 1.02, 95% CI 1.01-1.03; p = 0.004). CONCLUSION: HVPG progression occurs mostly in cACLD patients, whereas systemic inflammation, as reflected by IL-6 levels, only increases substantially across dACLD stages. IL-6 levels correlate with the risk of first decompensation in cACLD and of death/transplantation in dACLD patients. LAY SUMMARY: Patients with advanced chronic liver disease (ACLD; i.e. liver cirrhosis) have a certain risk of mortality according to their stage of disease. Progression of disease is greatly influenced by increased pressure in the portal venous system (i.e. portal hypertension) and occurrence of clinical complications (i.e. decompensation). Our study demonstrates that systemic inflammation markedly increases across highest disease stages, and the inflammation biomarker IL-6 in blood may specifically indicate risk of disease progression in patients with ACLD. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT03267615).

Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes.

OBJECTIVE: Systemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality. DESIGN: Biomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression. RESULTS: Our study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17-24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: -2 (IQR -19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: -16 (-30;+3)% vs Child-B: -2 (-16;+16)% vs Child-A: +3 (-7;+13)%, p<0.001) and of CRP (Child-C: -26 (-56,+8)% vs Child-B: -16 (-46;+13)% vs Child-A: ±0 (-33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman's ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49-0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356-0.883), p=0.013). CONCLUSION: NSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death.

Vitamin A levels reflect disease severity and portal hypertension in patients with cirrhosis.

BACKGROUND AND AIMS: The liver plays a key role in the storage, metabolism and homeostasis of fat-soluble vitamins. We investigated the relation of Vitamin(Vit)A/D/E serum levels with severity of liver disease and portal hypertension (PHT). METHODS: VitA/D/E serum levels were assessed in 234 patients with advanced chronic liver disease (ACLD, i.e. hepatic venous pressure gradient [HVPG] ≥ 6 mmHg). Patients with hepatocellular carcinoma, pre-/post-hepatic PHT, TIPS or liver transplantation were excluded. RESULTS: Most patients were male (n = 153; 65%) with a median age of 57.6 (49.7-64.5) years. Thirty-two (14%) patients had HVPG 6-9 mmHg, 66 (28%) 10-15 mmHg, and 136 (58%) ≥ 16 mmHg, respectively. VitD deficiency (25-OH-vitamin-D <50 nmol/L) was found in 133 (57%) with higher prevalence in Child-Turcotte-Pugh (CTP)-C: 85% vs. B: 66% vs. A: 47% (p < 0.001). VitD levels displayed significant but weak correlations with hepatic dysfunction and PHT. VitE levels were normal in 227 (97%) patients and displayed no relevant association with hepatic dysfunction or PHT. Only 63 (27%) patients had normal (>1.05 µmol/L) VitA levels, while 58 (25%) had mild (0.70-1.04 µmol/L), 71 (30%) moderate (0.35-0.69 µmol/L), and 42(18%) severe(<0.35 µmol/L) VitA deficiency. VitA correlated with HVPG (Rho = -0.409), CTP score (Rho = -0.646), and serum bile acid levels (Rho = -0.531; all p < 0.001). The prevalence of decompensated ACLD (dACLD) continuously increased with severity of VitA deficiency (no: 40% vs. mild: 51% vs. moderate: 67% vs. severe: 91% had dACLD; p < 0.001). CTP score (per point; OR 2.46; 95%CI 1.80-3.37; p <0.001), age (per year; OR 0.95; 95%CI 0.92-0.98; p = 0.001) and elevated bile acid levels(>10 µmol/L; OR 3.62; 95%CI 1.61-8.14; p = 0.002) were independently associated with VitA deficiency. CONCLUSION: VitA and VitD but not VitE deficiencies are highly prevalent in ACLD. VitA deficiency strongly correlates with hepatic dysfunction, PHT and bile acid levels and is associated with decompensated ACLD. TRIAL REGISTRATION NUMBER: NCT03267615.

Comparison of the diagnostic quality of aspiration and core-biopsy needles for transjugular liver biopsy.

BACKGROUND: Liver biopsy remains essential for the diagnostic work-up of patients with liver disease. AIMS: To evaluate aspiration vs. core-biopsy needles for transjugular liver biopsy (TJLB) in patients undergoing hepatic venous pressure gradient (HVPG) measurements. METHODS: 84 patients undergoing TJLB between 06/2017 and 12/2018 were prospectively included. Liver biopsy specimens were systematically evaluated for quantitative and qualitative criteria such as number of portal tracts, sample length and fragmentation. RESULTS: In direct comparison of paired TJLB specimens (n=35), core-biopsy samples were significantly longer (median 12 vs. 9mm, p=0.012), tended to contain more portal tracts (median 8 vs. 6, p=0.064) and were less fragmented (p<0.001), which resulted in better confidence for liver fibrosis assessment (p=0.035). However, a superior quality in terms of less fragmentation of core-biopsy specimens (p<0.05) was only confirmed in patients with HVPG ≥10mmHg or liver stiffness measurement >40kPa. In contrast, the aspiration needle provided significantly longer samples in patients with HVPG <10mmHg (median 21 vs. 12mm, p=0.007) or with liver stiffness measurement <20kPa (median 21 vs. 11mm, p=0.025). CONCLUSION: In patients with HVPG ≥10mmHg, we recommend to performed TJLB using core-biopsy needles, while the aspiration needle provides high quality liver biopsy specimens in patients with HVPG <10mmHg.

Non-invasive detection of portal hypertension by enhanced liver fibrosis score in patients with different aetiologies of advanced chronic liver disease.

BACKGROUND AND AIMS: The enhanced liver fibrosis (ELF) score comprises serum markers of fibrogenesis and matrix remodelling and was developed to detect liver fibrosis, however, it may also be useful for the non-invasive detection of portal hypertension (PHT). METHODS: ELF score and its single components (TIMP1/PIIINP/HA) were analysed in 201 patients with advanced chronic liver disease (ACLD; ie hepatic venous pressure gradient (HVPG) ≥6 mm Hg). Patients with pre-/post-hepatic PHT, hepatocellular carcinoma beyond Milan criteria, and history of TIPS implantation or liver transplantation were excluded. RESULTS: ELF and its single components correlated with HVPG in the overall cohort: ELF: r = .443, TIMP1: r = .368, PIIINP:r = .332, and HA:r = .419 (all P < .001). The strength of the correlation between ELF and HVPG decreased in higher HVPG strata: 6-9 mm Hg:r = .569(P = .004), 10-19 mm Hg:r = .304 (P = .001) and ≥20 mm Hg:r = -.023(P = .853). Area under the receiver operating characteristics (AUROC) of ELF score to detect clinically significant PHT (CSPH; HVPG ≥ 10 mm Hg) was 0.833. Importantly, HA alone yielded an AUROC of 0.828. Detection of CSPH in strictly compensated ACLD (cACLD) patients was less accurate: AUROC: 0.759 (P < .001). CSPH was ruled-in by ELF ≥ 11.1 with a PPV of 98% (sensitivity: 61%/specificity: 92%/NPV:24%), but CSPH could not be ruled-out. ELF score had a low AUROC of 0.677 (0.60-0.75; P < .001) for the diagnosis of high-risk PHT (HRPH; HVPG ≥ 20mm Hg) and, thus, HRPH could not be ruled-in by ELF. However, ELF < 10.1 ruled-out HRPH with a NPV of 95% (sensitivity: 97%/specificity: 26%/PPV: 39%). CONCLUSION: The ELF score correlates with HVPG at values <20 mm Hg. An ELF ≥ 11.1 identifies patients with a high probability of CSPH, while an ELF < 10.1 may be used to rule-out HRPH.

Novel reliability criteria for controlled attenuation parameter assessments for non-invasive evaluation of hepatic steatosis.

BACKGROUND: There is conflicting evidence regarding reliability criteria for the controlled attenuation parameter (CAP; a marker for hepatic steatosis [HS]). Thus, we assessed the diagnostic performance of CAP according to different reliability criteria based on real-world data from an academic centre. METHODS: Patients undergoing measurement of CAP and liver biopsy (±6 months) at the Medical University of Vienna were included. HS was assessed according to SAF score. RESULTS: In total 319 patients were included. The main aetiologies were non-alcoholic fatty liver disease (NAFLD, n = 177, 55.5%), viral hepatitis (n = 49, 15.4%), and alcoholic liver disease (ALD, n = 29, 9.1%). Histological steatosis and fibrosis stages were: S0: 93 (29.2%), S1: 100 (31.3%), S2: 67 (21.0%), and S3: 59 (18.5%); F0/F1: 150 (47.0%), F2: 47 (14.7%), and F3/F4: 122 (48.3%). In the overall cohort, the area under the receiver operating characteristic curve (AUC) of CAP was 0.843 (95% confidence interval [CI]: 0.798-0.887) for diagnosing HS ≥ S1), 0.789 (95%CI: 0.740-0.839) for ≥S2, and 0.767 (95%CI: 0.712-0.823) for S3. CAP corrections as suggested by Karlas et al. did not improve the diagnostic performance. Importantly, the AUC of CAP for HS ≥ S1 was numerically highest in patients with CAP-IQR/median<0.10 or <0.20 (obtained in 37.9% and 74.9%), in whom CAP also had better diagnostic performance, as compared with patients not meeting these criteria. Moreover, it was substantially higher in 288 (90.3%) patients with CAP-IQR/median<0.3: 0.856 (95%CI: 0.809-0.903) vs. patients not meeting this criterion (0.530 [95%CI: 0.309-0.751]). In contrast, the previously suggested reliability criterion of CAP-IQR<40 dB/m was not associated with an improved diagnostic performance for HS≥S1 (0.866 [95%CI: 0.812-0.920] vs. 0.799 [95%CI: 0.717-0.881]) and was only obtained in 199 (62.4%) patients. CONCLUSION: CAP-IQR/median<0.1, <0.2, and <0.3 identify reliable measurements for diagnosing any hepatic steatosis (≥S1). Importantly, CAP-IQR/median<0.3 has a considerably higher applicability in clinical practice, as compared with the previously suggested CAP-IQR<40 dB/m criterion.

Non-invasive diagnosis of cirrhosis and long-term disease monitoring by transient elastography in patients with Wilson disease.

BACKGROUND & AIMS: The value of liver stiffness measurement (LSM) by transient elastography (TE) for non-invasive fibrosis staging and disease monitoring has not been established in patients with Wilson disease (WD). METHODS: Liver stiffness measurement by TE and non-invasive fibrosis scores (APRI, FIB-4) were analysed from 188 WD patients with liver biopsy (LBX). Longitudinal LSM was performed in 128 (68.1%) patients. RESULTS: One hundred and eighty-eight patients (mean age: 35 ± 14 years, 54.8% women; 27.1% with histological cirrhosis) were studied. Forty-four[23.4%] patients were recently diagnosed with WD, while 144[76.6%] were previously diagnosed (>1 year between LBX and LSM). Overall, LSM (11.3 vs 6.1 kPa, P < .001), APRI (0.72 vs 0.38, P < .001) and FIB-4 (1.54 vs 0.89, P < .001) were higher in cirrhotic than in non-cirrhotic patients. This was even more pronounced in recently diagnosed patients (35.2 kPa vs 6.4 kPa, P < .001). Accuracy for diagnosing cirrhosis at an LSM cut-off ≥9.9 kPa was better in recently diagnosed (PPV: 74%, NPV: 100%) vs previously diagnosed (PPV: 53%, NPV: 82%) patients. Recently diagnosed patients had higher Area Under the Curve (AUC) for APRI (0.79 vs 0.61) and FIB-4 (0.84 vs 0.65) than previously diagnosed patients. At APRI <1.5 and FIB-4 <3.25 cirrhosis was ruled out with a specificity of 93% and 95% respectively. During a median follow-up of 46 (24-66) months, only 5.9% (5/85) of non-cirrhotic WD patients showed progression to cirrhotic LSM values, while 30.8% (4/13) of cirrhotic WD patients showed LSM suggestive of cirrhosis regression. CONCLUSION: TE-based LSM ≥9.9 kPa accurately identifies cirrhosis in WD patients. Next to TE-LSM <9.9 kPa, APRI <1.5 and FIB-4 <3.25 values assist to non-invasively rule out cirrhosis. LSM remains stable in most non-cirrhotic patients on WD therapy, while one-third of cirrhotic patients present clinically relevant decreases in LSM.

Anemia and iron deficiency in compensated and decompensated cirrhosis: Prevalence and impact on clinical outcomes.

BACKGROUND AND AIM: Iron deficiency anemia (IDA)is the leading cause of anemia worldwide. Data on prevalence and clinical impact of anemia in cirrhosis are scarce. Aim was to report on the following:(i) prevalence of anemia and IDA in cirrhosis and (ii) its possible impact on clinical outcomes. METHODS: Consecutive cirrhotic patients from a prospective registry study were included. Anemia was defined as hemoglobin concentration ≤ 12 g/dL. IDA was defined as Hb ≤ 12 g/dL + transferrin-saturation < 20%. Follow up for hepatic decompensation and mortality started with study inclusion and terminated in December 2017. A retrospective validation cohort of 1244 patients was used to validate our findings. RESULTS: Two hundred forty-two patients with compensated (n = 53 [21.9%]) and decompensated (n = 189 [78.1%]) cirrhosis were included. Anemia was present in 128 patients (52.9%); of those, 63 (49.2%) had IDA. Prevalence of anemia increased with Child-Pugh Score (CPS; A: 26.5%, B: 59.2%, C: 69%; P < 0.001) and with decompensated cirrhosis(62.4% vs 18.8%, P < 0.001). Within anemic patients, a higher proportion of patients in CPS A/B vs C (73% vs 35%; P = 0.025) and in compensated cirrhosis (80% vs 46.6%; P = 0.043) were found with IDA. Model for End-Stage Liver Disease (MELD) scores were significantly lower in patients with IDA (14.4 vs 17.9 non-ID-anemia; P = 0.005). Similar results were found in the validation cohort: median MELD (16[8-28]non-IDA vs 12 [7-23] IDA; P < 0.001) and within anemic patients IDA was more common in patients with MELD <15 (58%) versus >15 (24%, P < 0.001). Anemia was associated with a significant risk for hepatic decompensation and/or mortality both in the validation (aSHR: 1.65, P = 0.008) and in the derivation cohort (aSHR: 2.11, P < 0.001) and an independent risk factor for hepatic decompensation and/or mortality in compensated patients (aHR: 4.91, P = 0.004). CONCLUSION: Anemia is highly prevalent in cirrhosis. In compensated cirrhosis, CPS A/B, and low MELD, IDA seems to be the most likely reason for anemia. Furthermore, anemia is associated with a significant risk for hepatic decompensation or mortality during long-term follow up.