Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Prevalence and Natural History of Segmental Colitis Associated With Diverticulosis.

INTRODUCTION: We assessed the prevalence and clinical outcomes of segmental colitis associated with diverticulosis (SCAD) in patients with newly diagnosed diverticulosis. METHODS: A 3-year international, multicenter, prospective cohort study was conducted involving 2,215 patients. RESULTS: SCAD diagnosis was posed in 44 patients (30 male patients; median age: 64.5 years; prevalence of 1.99%, 95% confidence interval, 1.45%-2.66%). Patients with SCAD types D and B showed worse symptoms, higher fecal calprotectin values, needed more steroids, and reached less likely complete remission. DISCUSSION: Although SCAD generally had a benign outcome, types B and D were associated with more severe symptoms and worse clinical course.

Artificial-intelligence-based decision support tools for the differential diagnosis of colitis.

BACKGROUND: Whereas Artificial Intelligence (AI) based tools have recently been introduced in the field of gastroenterology, application in inflammatory bowel disease (IBD) is in its infancies. We established AI-based algorithms to distinguish IBD from infectious and ischemic colitis using endoscopic images and clinical data. METHODS: First, we trained and tested a Convolutional Neural Network (CNN) using 1796 real-world images from 494 patients, presenting with three diseases (IBD [n = 212], ischemic colitis [n = 157], and infectious colitis [n = 125]). Moreover, we evaluated a Gradient Boosted Decision Trees (GBDT) algorithm using five clinical parameters as well as a hybrid approach (CNN + GBDT). Patients and images were randomly split into two completely independent datasets. The proposed approaches were benchmarked against each other and three expert endoscopists on the test set. RESULTS: For the image-based CNN, the GBDT algorithm and the hybrid approach global accuracies were .709, .792, and .766, respectively. Positive predictive values were .602, .702, and .657. Global areas under the receiver operating characteristics (ROC) and precision recall (PR) curves were .727/.585, .888/.823, and .838/.733, respectively. Global accuracy did not differ between CNN and endoscopists (.721), but the clinical parameter-based GBDT algorithm outperformed CNN and expert image classification. CONCLUSIONS: Decision support systems exclusively based on endoscopic image analysis for the differential diagnosis of colitis, representing a complex clinical challenge, seem not yet to be ready for primetime and more diverse image datasets may be necessary to improve performance in future development. The clinical value of the proposed clinical parameters algorithm should be evaluated in prospective cohorts.

Influence of NOD2 risk variants on hepatic encephalopathy and association with inflammation, bacterial translocation and immune activation.

BACKGROUND: Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM: To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS: This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS: Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS: The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.

Costs of a structured early detection program for advanced liver fibrosis and cirrhosis: insights on the "plus" of Check-up 35.

BACKGROUND: The implementation of an early detection program for liver cirrhosis in a general population has been discussed for some time. Recently, the effectiveness of a structured screening procedure, called SEAL (Structured Early detection of Asymptomatic Liver cirrhosis), using liver function tests (AST and ALT) and APRI to early detect advanced fibrosis and cirrhosis in participants of the German "Check-up 35" was investigated. METHODS: This study identifies the expected diagnostic costs of SEAL in routine care and their drivers and reports on prevailing CLD etiologies in this check-up population. The analysis is based on theoretical unit costs, as well as on the empirical billing and diagnostic data of SEAL participants. RESULTS: Screening costs are mainly driven by liver biopsies, which are performed in a final step in some patients. Depending on the assumed biopsy rates and the diagnostic procedure, the average diagnostic costs are between EUR 5.99 and 13.74 per Check-up 35 participant and between EUR 1,577.06 and 3,620.52 per patient diagnosed with fibrosis/cirrhosis (F3/F4). The prevailing underlying etiology in 60% of cases is non-alcoholic fatty liver disease. DISCUSSION: A liver screening following the SEAL algorithm could be performed at moderate costs. Screening costs in routine care depend on actual biopsy rates and procedures, attendance rates at liver specialists, and the prevalence of fibrosis in the Check-up 35 population. The test for viral hepatitis newly introduced to Check-up 35 as once-in-a-lifetime part of Check-up 35 is no alternative to SEAL.

Prognostic performance of the 'DICA' endoscopic classification and the 'CODA' score in predicting clinical outcomes of diverticular disease: an international, multicentre, prospective cohort study.

OBJECTIVE: To investigate the predictive value of the Diverticular Inflammation and Complication Assessment (DICA) classification and to develop and validate a combined endoscopic-clinical score predicting clinical outcomes of diverticulosis, named Combined Overview on Diverticular Assessment (CODA). DESIGN: A multicentre, prospective, international cohort study. SETTING: 43 gastroenterology and endoscopy centres located in Europe and South America. PARTICIPANTS: 2215 patients (2198 completing the study) at the first diagnosis of diverticulosis/diverticular disease were enrolled. Patients were scored according to DICA classifications. INTERVENTIONS: A 3-year follow-up was performed. MAIN OUTCOME MEASURES: To predict the acute diverticulitis and the surgery according to DICA classification. Survival methods for censored observation were used to develop and validate a novel combined endoscopic-clinical score for predicting diverticulitis and surgery (CODA score). RESULTS: The 3-year cumulative probability of diverticulitis and surgery was of 3.3% (95% CI 2.5% to 4.5%) in DICA 1, 11.6% (95% CI 9.2% to 14.5%) in DICA 2 and 22.0% (95% CI 17.2% to 28.0%) in DICA 3 (p<0.001), and 0.15% (95% CI 0.04% to 0.59%) in DICA 1, 3.0% (95% CI 1.9% to 4.7%) in DICA 2 and 11.0% (95% CI 7.5% to 16.0%) in DICA 3 (p<0.001), respectively. The 3-year cumulative probability of diverticulitis and surgery was ≤4%, and ≤0.7% in CODA A; <10% and <2.5% in CODA B; >10% and >2.5% in CODA C, respectively. The CODA score showed optimal discrimination capacity in predicting the risk of surgery in the development (c-statistic: 0.829; 95% CI 0.811 to 0.846) and validation cohort (c-statistic: 0.943; 95% CI 0.905 to 0.981). CONCLUSIONS: DICA classification has a significant role in predicting the risk of diverticulitis and surgery in patients with diverticulosis, which is significantly enhanced by the CODA score. TRIAL REGISTRATION NUMBER: NCT02758860.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.

BACKGROUND & AIMS: Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. METHODS: SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. RESULTS: A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰). CONCLUSIONS: The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. REGISTRATION: DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program.

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients.

Knowledge on the immunogenicity of vector-based and mRNA-vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2-specific T cells and antibodies were analyzed in 40 transplant recipients and 70 controls after homologous or heterologous vaccine-regimens. Plasmablasts and SARS-CoV-2-specific CD4 and CD8 T cells were quantified using flow cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. The two vaccine types differed after the first vaccination, as IgG and neutralizing activity were more pronounced after mRNA priming (p = .0001 each), whereas CD4 and CD8 T cell levels were higher after vector priming (p = .009; p = .0001). All regimens were well tolerated, and SARS-CoV-2-specific antibodies and/or T cells after second vaccination were induced in 100% of controls and 70.6% of transplant recipients. Although antibody and T cell levels were lower in patients, heterologous vaccination led to the most pronounced induction of antibodies and CD4 T cells. Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2-specific IgG- and T cell levels. While antibodies were only detected in 35.3% of patients, cellular immunity was more frequently found (64.7%) indicating that assessment of antibodies is insufficient to identify COVID-19-vaccine responders. In conclusion, heterologous vaccination seems promising in transplant recipients, and combined analysis of humoral and cellular immunity improves the identification of responders among immunocompromised individuals.

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptosis. We identify RIPK1 and caspase-8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL-induced RIPK1-independent apoptosis, HOIP presence, but not its activity, is required for preventing necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC also promotes TRAIL-induced activation of NF-κB and, consequently, the production of cytokines, downstream of FADD, caspase-8 and cIAP1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation.

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

Volume-Function Analysis (LiMAx Test) in Patients with HCC and Cirrhosis Undergoing TACE-A Feasibility Study.

BACKGROUND: Transarterial chemoembolization (TACE) is an important therapy for hepatocellular carcinoma (HCC) in cirrhosis. In particular in advanced cirrhosis, post-TACE hepatic failure liver (PTHF) failure may develop. Currently, there is no standardization for the periinterventional risk assessment. The liver maximum capacity (LiMAx) test assesses the functional liver capacity, but has not been investigated in this setting. AIMS: The aim of this study was to prospectively evaluate periinterventional LiMAx and CT volumetry measurements in patients with cirrhosis and HCC undergoing repetitive TACE. METHODS: From 06/2016 to 11/2017, eleven patients with HCC and cirrhosis undergoing TACE were included. LiMAx measurements (n = 42) were conducted before and after each TACE. Laboratory parameters were correlated with the volume-function data. RESULTS: The median LiMAx levels before (276 ± 166 µg/kg/h) were slightly reduced after TACE (251 ± 122 µg/kg/h; p = 0.08). This corresponded to a median drop of 7.1%. Notably, there was a significant correlation between LiMAx levels before TACE and bilirubin (but not albumin nor albumin-bilirubin [ALBI] score) increase after TACE (p = 0.02, k = 0.56). Furthermore, a significantly higher increase in bilirubin in patients with LiMAx ≤ 150 µg/kg/h was observed (p = 0.011). LiMAx levels at different time points in single patients were similar (p = 0.2). CONCLUSION: In our prospective pilot study in patients with HCC and cirrhosis undergoing multiple TACE, robust and reliable LiMAx measurements were demonstrated. Lower LiMAx levels before TACE were associated with surrogate markers (bilirubin) of liver failure after TACE. Specific subgroups at high risk of PTHF should be investigated. This might facilitate the future development of strategies to prevent occurrence of PTHF.

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury.

BACKGROUND AND AIMS: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4-/- mice with deficiency of the hepatobiliary phospholipid transporter. METHODS: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4-/- (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. RESULTS: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. CONCLUSIONS: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.

Predictive Power of Liver Maximum Function Capacity Test in Transjugular Intrahepatic Portosystemic Shunt Patients: A Pilot Study.

BACKGROUND: Transjugular intrahepatic shunt (TIPSS) is placed in patients with variceal bleeding, refractory ascites, and for other indications. Postprocedural liver function-associated complications (LFAC), including hepatic encephalopathy (HE) and liver failure, represent a major setback. Current methods to predict complications are insufficient. OBJECTIVES: We investigated in a pilot study of patients prior TIPSS placement whether the risk of LFAC correlates with the functional reserve of the liver, as assessed by liver maximum function capacity (LiMAx) test. METHODS: Prospectively we included patients prior TIPSS placement between June 2016 and November 2017 at Saarland University Medical Center. LiMAx was conducted before and after TIPSS placement. Patients with HE prior TIPSS, as well as other factors predisposing to HE, including concomitant sedative drugs, current bacterial infections and sepsis, were excluded. Overt HE (OHE), LiMAx, and laboratory values were assessed before and after TIPSS placement. Data were analyzed in multivariate regression and AUROC models. RESULTS: Mean age was 60 ± 8 years. Patients (n = 20) were mainly men (65%), and presented predominantly with Child-Pugh class B (90%). Indications for TIPSS were most commonly refractory ascites or recurrent variceal bleeding. In total, 40% of the patients developed LFAC after TIPSS placement. Expectedly, LiMAx decreased and serum bilirubin increased after TIPSS. LiMAx drop ≥20% was the only parameter predicting the development of LFAC after TIPSS in multivariate regression and AUROC analysis. CONCLUSIONS: In multivariate regression models and AUROC analysis, a drop in LiMAx predicted the development of LFAC after TIPSS placement. Additional larger studies assessing OHE and early liver failure separately are warranted.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.