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1.
Hepatology ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33786862

RESUMO

Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed due to complications of portal hypertension (PH) or infections. Von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. We determined whether addition of vWF-Ag and CRP to the MELD-Na score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in 2 independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (N=269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na: 0.764, MELD-Na+CRP: 0.790, MELD-Na+vWF: 0.803, MELD-Na+CRP+vWF-Ag: 0.824). Results were confirmed in an independent validation cohort (N=129, AUC: MELD-Na: 0.677, MELD-Na+CRP+vWF-Ag: 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, while CRP closely, and MELD-independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSION: The addition of vWF-Ag and CRP - reflecting central pathophysiological mechanisms of PH, bacterial translocation and inflammation, that are all drivers of mortality on the waiting list for LT - to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

2.
FASEB J ; 35(4): e21217, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33715236

RESUMO

The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) is a critical link between cellular energy demand and translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not affect T cell fate decision, activation, or T effector cell generation; however, the magnitude of T cell responses in murine in vivo models of T cell activation was markedly reduced. This impairment was global, as all T helper cell subsets were similarly sensitive to loss of AMPK which resulted in reduced T cell accumulation in peripheral organs and reduced disease severity in pathophysiologically as diverse models as T cell transfer colitis and allergic airway inflammation. T cell receptor repertoire analysis confirmed similar clonotype frequencies in different lymphoid organs, thereby supporting the concept of a quantitative impairment in clonal expansion rather than a skewed qualitative immune response. In line with these findings, in-depth metabolic analysis revealed a decrease in T cell oxidative metabolism, and gene set enrichment analysis indicated a major reduction in ribosomal biogenesis and mRNA translation in AMPK-deficient T cells. We, thus, provide evidence that through its interference with these delicate processes, AMPK orchestrates the quantitative, but not the qualitative, manifestation of primary T cell responses in vivo.

3.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672787

RESUMO

Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3-PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout (DKO) mice lacking both Mgl and Pnpla3; DKO mice were compared to Mgl-/- after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of Mgl and Pnpla3 resulted in weight gain on a chow diet; when challenged by HFD, DKO mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to Mgl-/-.DKO mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the DKO mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. Pnpla3 deficiency aggravates the effects of Mgl deletion on steatosis and inflammation in the liver under HFD challenge.

4.
J Autoimmun ; 119: 102610, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33621930

RESUMO

CD4+ T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4+ T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-deficient CD4+ T cells downregulated genes associated with leukocyte extravasation. In vitro, HDAC1-deficient CD4+ T cells displayed aberrant morphology and migration on surfaces coated with integrin LFA-1 ligand ICAM-1 and showed an impaired ability to arrest on and to migrate across a monolayer of primary mouse brain microvascular endothelial cells under physiological flow. Moreover, HDAC1 deficiency reduced homing of CD4+ T cells into the intestinal epithelium and lamina propria preventing weight-loss, crypt damage and intestinal inflammation in adoptive CD4+ T cell transfer colitis. This correlated with reduced expression levels of LFA-1 integrin chains CD11a and CD18 as well as of selectin ligands CD43, CD44 and CD162 on transferred circulating HDAC1-deficient CD4+ T cells. Our data reveal that HDAC1 controls T cell-mediated autoimmunity via the regulation of CD4+ T cell trafficking into the CNS and intestinal tissues.

5.
Hepatology ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570776

RESUMO

BACKGROUND & AIMS: Manual histologic assessment is currently the accepted standard for diagnosing and monitoring disease progression in nonalcoholic steatohepatitis (NASH), but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APPROACH & RESULTS: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We utilize samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histologic features in NASH including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a new heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment (DELTA) Liver Fibrosis score, which measured anti-fibrotic treatment effects that went undetected by manual pathological staging and was concordant with histologic disease progression. CONCLUSIONS: Our ML method has shown reproducibility, sensitivity, and was prognostic for disease progression demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of novel therapies.

6.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632708

RESUMO

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.

7.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632710

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term 'fatty liver hepatitis' first appeared in 1962, it was in 1980 that the term 'non-alcoholic steatohepatitis' (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.

8.
Pathologe ; 42(2): 155-163, 2021 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-33575886

RESUMO

BACKGROUND: COVID-19 is considered a systemic disease. A severe course with fatal outcome is possible and unpredictable. OBJECTIVES: Which organ systems are predominantly involved? Which diseases are predisposed for a fatal course? Which organ changes are found with lethal outcome? MATERIALS AND METHODS: Data from published autopsy studies (28 cases by our group) with respect to organ changes and possible cause of death. RESULTS: The most severe alterations are found in the lungs by diffuse alveolar damage as a symptom of an acute respiratory distress syndrome (ARDS), in part with fibrosis. Thrombosis of small- to mid-sized pulmonary arteries is associated with hemorrhagic lung infarction. Frequent complications are bacterial pneumonias and less frequently fungal pneumonias by aspergillus. Pulmonary thromboembolism is found in 20-30% of lethal courses, also in the absence of deep venous thrombosis. Intestinal involvement of COVID-19 can be associated with intestinal ischemia, caused by shock or local thrombosis. In most cases, the kidneys display acute tubular injury reflecting acute renal failure, depletion of lymphocytes in the lymph nodes and spleen, and hyperplastic adrenal glands. The liver frequently reveals steatosis, liver cell necrosis, portal inflammation, and proliferation of Kupffer cells. Important preexisting diseases in autopsy studies are arterial hypertension with hypertensive and ischemic cardiomyopathy and diabetes mellitus but large population-based studies reveal increased risk of mortality only for diabetes mellitus not for arterial hypertension. CONCLUSIONS: Alterations of the pulmonary circulation with pulmonary arterial thrombosis, infarction, and bacterial pneumonia are important and often lethal complications of COVID-19-associated ARDS. Findings from autopsy studies have influenced therapy and prophylaxis.


Assuntos
Trombose , Autopsia , Humanos , Pulmão
10.
Pathol Res Pract ; 217: 153305, 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33285423

RESUMO

Autopsies on COVID-19 have provided deep insights into a novel disease with unpredictable and potentially fatal outcome. A standardized autopsy procedure preferably with an in-situ technique and systematic tissue processing is important. Strict safety measures include personal protective equipment with a standardized protocol for dressing and undressing, usage of FFP-3 masks and minimization of aerosol production. The use of an airborne infection isolation (AIIR) room is preferred. Viral RNA analysis using swabs from throat, both lungs and other organs provides information on cross-organ viral dynamics. To correctly determine the full extent of pathological organ changes an adequate processing procedure is of the utmost importance. Systematic dissection and processing of the lungs revealed pulmonary infarction caused by thrombosis and thromboembolism and bacterial bronchopneumonia as the most frequent cause of death. Fungal pneumonia (aspergillus) was found in one case. The quality of the tissue was sufficient for histopathological and immunohistochemistry analyses in all cases. Viral RNA from throat or lung swabs was detectable post mortem in 89 % of the cases and could also be detected from paraffin-embedded tissue by real-time PCR. Complete COVID-19 autopsies including extensive histopathological studies and viral RNA analysis require approximately three times more human and technical resources and time compared to standard non-COVID autopsies. Autopsies on COVID-19 are feasible, present a manageable risk, while following a strict protocol, and provide novel insights into disease pathogenesis and the clinician with important feedback.

11.
Hepatol Int ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289910

RESUMO

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.

12.
Liver Int ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33290614

RESUMO

BACKGROUND & AIMS: Portal hypertension (PH) and sarcopenia are common in patients with advanced chronic liver disease (ACLD). However, the interaction between PH and sarcopenia and their specific and independent impact on prognosis and mortality has yet to be systematically investigated in patients with ACLD. METHODS: Consecutive patients with ACLD and hepatic venous pressure gradient (HVPG) ≥10mmHg with available CT/MRI imaging were included. Sarcopenia was defined by transversal psoas muscle thickness (TPMT) at <12mm/m in men and <8mm/m in women at the level of the third lumbar vertebrae. Hepatic decompensation and mortality was recorded during follow-up. RESULTS: Among 203 patients (68% male, age:55±11, MELD:12[9-15]) Sarcopenia was observed in 77 (37.9%) and HVPG was ≥20mmHg in 98 (48.3%). There was no correlation between TPMT and HVPG (r=0.031, p=0.66), median HVPG was not different between patients with vs. without sarcopenia (p=0.211). Sarcopenia was significantly associated with first/further decompensation both in compensated (SHR:3.05, p=0.041) and in decompensated patients (SHR: 1.86, p=0.021). Furthermore, sarcopenia (SARC) was a significant predictor of mortality irrespective of HVPG (HVPG<20-SARC: SHR:2.25, p=0.021; HVPG ≥20-SARC: SHR:3.33, p=0.001). On multivariate analysis adjusted for age, HVPG, and MELD, sarcopenia was an independent risk factor for mortality (aHR: 1.99, 95% confidence intervall: 1.2-3.3, p=0.007). CONCLUSION: Sarcopenia has a major impact on clinical outcomes both in compensated and in decompensated ACLD patients. The presence of sarcopenia doubled the risk for mortality independently from the severity of PH.

13.
Wien Klin Wochenschr ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33270161

RESUMO

BACKGROUND: Portal hypertension (PH) causes severe complications in patients with liver cirrhosis, such as variceal bleeding and ascites; however, data on the knowledge and perceptions on guideline recommendations for the management of varices and the use of albumin is scarce. METHODS: We designed two structured surveys on (i) the management of varices and (ii) the use of albumin for Austrian physicians of specialized Gastro-Intestinal (GI) centers. The interviewed physicians were confronted spontaneously and provided ad hoc responses to the questionnaire. RESULTS: In total, 158 surveys were completed. Interestingly, many specialists (30%) would recommend a follow-up gastroscopy after 1 year in patients with compensated cirrhosis without varices (i.e., overtreatment). For small varices, 81.5% would use non-selective beta blockers (NSBB) for primary prophylaxis (PP). For PP in patients with large varices, endoscopic band ligation (EBL) plus NSBB was preferred by 51.4% (i.e., overtreatment). Knowledge on the indication criteria for early TIPS (transjugular intrahepatic portosystemic shunt) was reported by 54.3%, but only 20% could report these criteria correctly. The majority (87.1%) correctly indicated a preference to use NSBB and EBL for secondary prophylaxis (SP). The majority of participating gastroenterologists reported no restrictions on the use of albumin (89.8%) in their hospitals. Of the interviewed specialists, 63.6% would use albumin in patients with SBP; however, only 11.4% would use the doses recommended by guidelines. The majority of specialists indicated using albumin at the recommended doses for hepatorenal syndrome (HRS-AKI, 86.4%) and for large volume paracentesis (LVP, 73.3%). The individual responses regarding albumin use for infections/sepsis, hyponatremia, renal impairment, and encephalopathy were heterogeneous. CONCLUSION: The reported management of PH and varices is mostly adherent to guidelines, but endoscopic surveillance in patients without varices is too intense and EBL is overused in the setting of PP. Knowledge on the correct use of early TIPS must be improved among Austrian specialists. Albumin use is widely unrestricted in Austria; however, albumin is often underdosed in established indications.

14.
Gastroenterology ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33307033

RESUMO

BACKGROUND AND AIM: Fibrosis is an independent predictor of death in NASH. We assessed the associations between histologic and non-invasive (NITs) fibrosis tests with clinical and patient-reported outcomes (PROs) in advanced NASH. METHODS: Patients with advanced NASH (NASH CRN stage F3 or F4) were enrolled in four multinational clinical trials of simtuzumab and selonsertib. Liver biopsies, NITs, and PROs (SF-36, CLDQ-NASH, EQ-5D, WPAI) were prospectively collected. RESULTS: 2154 patients with advanced NASH were included: 52.5% F4, 40% male, 72% type 2 diabetes, baseline liver stiffness 24.1±14.2 kPa in F4, 14.6 ± 8.0 kPa in F3, baseline mean ELF score 11.4±1.2 in F4, 10.3±1.0 in F3; median follow-up16 months. Of those with baseline F3, 16.7% experienced disease progression to cirrhosis while those with F4, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NITs (all p<0.0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both F3 and F4 groups (p<0.01 for all NITs in F3; for ELF, NAFLD Fibrosis Score (NFS), FIB-4, liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF ≥10.43, NFS ≥ 1.80, Fibrotest ≥ 0.54, liver stiffness ≥ 23.4 kPa. During treatment, patients with decreases in NITs experienced improvement of their PRO scores while those with increase in NITs had their PRO scores worsened (p<0.05). CONCLUSIONS: Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH.

15.
Wien Klin Wochenschr ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351152

RESUMO

BACKGROUND: Despite the availability of effective and well-tolerated direct acting antivirals (DAAs) against hepatitis C virus (HCV) infection, a substantial number of HCV patients remain untreated. Novel strategies targeting HCV patients with poor adherence are urgently needed to enable HCV elimination. METHODS: We implemented a physician-operated HCV hotline (HCV-Phone) that was promoted within the patient community and referral networks. Previously diagnosed HCV patients were contacted via the HCV-Phone and offered low-barrier access to DAA therapy. Patients/referring physicians could directly call or send messages to the HCV-Phone. The HCV-Phone related and unrelated visits as well as DAA treatment initiations throughout 2019 were documented. Patients were followed until October 2020. This study analyzed treatment initiation, adherence to scheduled visits and outcomes in patients in whom management was assisted by the HCV-Phone. RESULTS: Out of 98 patient contacts via the HCV-Phone 74 attended treatment assessment at our clinic. While 15 (20%) patients were HCV-RNA negative and 1 (1%) patient did not initiate therapy, 58 patients were recruited for DAA therapy via the HCV-Phone. A total of 21 additional patients who started DAAs without HCV-Phone assistance required the use of the HCV-Phone infrastructure later on during treatment, resulting in a total of 79 HCV-Phone related DAA therapies. The poor adherence of patients previously diagnosed with HCV at our clinic is underlined by the long duration from HCV diagnosis to DAA therapy of median 37.0 months (IQR 2.7-181.1 months). A total of 55 (70%) HCV patients achieved a sustained virological response (SVR), 5 (6%) discontinued therapy, 1 (1%) had a reinfection, while 10 (13%) and 8 (10%) patients were lost during DAA therapy or follow-up, respectively. CONCLUSION: The implementation of a physician-operated phone hotline for patients with HCV infection facilitated treatment initiation in an HCV population with poor adherence. Mainly due to losses to follow-up, the SVR rate remained suboptimal with 70%.

16.
Int J Mol Sci ; 21(22)2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33218077

RESUMO

Liver fibrosis represents the wound healing response to sustained hepatic injury with activation of hepatic stellate cells (HSCs). The I148M variant of the PNPLA3 gene represents a risk factor for development of severe liver fibrosis. Activated HSCs carrying the I148M variant display exacerbated pro-inflammatory and pro-fibrogenic features. We aimed to examine whether the I148M variant may impair Hedgehog and Yap signaling, as key pathways implicated in the control of energy expenditure and maintenance of myofibroblastic traits. First, we show that TGF-ß rapidly up-regulated the PNPLA3 transcript and protein and Yap/Hedgehog target gene expression. In addition, HSCs overexpressing PNPLA3 I148M boosted anaerobic glycolysis, as supported by higher lactate release and decreased phosphorylation of the energy sensor AMPK. These cells displayed higher Yap and Hedgehog signaling, due to accumulation of total Yap protein, Yap promoter activity and increased downstream targets expression, compared to WT cells. HSCs exposed to TGF-ß and leptin rapidly increased total Yap, together with a reduction in its inhibited form, phosphorylated Yap. In line, Yap-specific inhibitor Verteporfin strongly abolished Yap-mediated genes expression, at baseline as well as after TGF-ß and leptin treatments in HSCs with I148M PNPLA3. Finally, Yap transcriptional activity was strongly reduced by a combination of Verteporfin and Rosiglitazone, a PPARγ synthetic agonist. In conclusion, HSCs carrying the PNPLA3 variant show activated Yap/Hedgehog pathways, resulting in altered anaerobic glycolysis and enhanced synthesis of Hedgehog markers and sustained Yap signaling. TGF-ß and leptin exacerbate Yap/Hedgehog-related fibrogenic genes expression, while Yap inhibitors and PPARγ agonists abrogate these effects in PNPLA3 I148M carrying HSCs.

17.
RMD Open ; 6(3)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33188136

RESUMO

OBJECTIVES: Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). METHODS: A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation. RESULTS: 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed. CONCLUSION: JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.

18.
Liver Int ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33190346

RESUMO

The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a world-wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID-19. Although liver failure does not seem to occur in the absence of pre-existing liver disease, hepatic involvement in COVID-19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID-19 may range from direct infection by SARS-CoV-2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS-CoV-2 hepatic tropism as well as acute and possibly long-term liver injury in COVID-19.

19.
Gut ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199442

RESUMO

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.

20.
Hepatol Commun ; 4(11): 1637-1650, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33163834

RESUMO

Fatigue and pruritus are common in patients with chronic liver diseases of all etiologies, but clinical awareness is mostly restricted to those with cholestatic liver diseases. We assessed the impact of fatigue and pruritus on patient-reported outcomes (PROs) of patients with advanced nonalcoholic steatohepatitis (NASH). Specifically, PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, Euro-Qol 5 Dimension, and Work Productivity and Activity Impairment instruments) were assessed at baseline in patients with histologically confirmed bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH enrolled in STELLAR 3 and 4. Presence of fatigue and pruritus were indicated by a score of 4 or less on the respective items of the Chronic Liver Disease Questionnaire-NASH (scale range, 1-7). Among the included 1,669 patients with advanced NASH (mean age = 58 ± 9 years, 48% F3, 42% with psychiatric comorbidities), 33% and 27% had fatigue and pruritus, respectively. Patients with NASH with fatigue were younger, more likely to be female, cirrhotic, and diabetic, and had higher body mass index and more comorbidities (all P < 0.05). All PRO scores of patients with fatigue were significantly impaired (mean up to -31% of a PRO range size in comparison to patients without fatigue). In multivariate analysis, predictors of fatigue included diabetes, history of depression or nervous system comorbidities, and lower serum albumin (P < 0.05). Patients with pruritus had demographic characteristics similar to those with fatigue, but a higher prevalence of dermatologic comorbidities. All PROs were impaired (by up to -19% of a range size, all P < 0.01) in patients with NASH with pruritus. Female gender, lower serum albumin, and a history of depression, nervous system, and dermatologic comorbidities were associated with increased risk of pruritus (P < 0.05). Conclusion: Clinically significant fatigue and pruritus are common in patients with advanced NASH, and these symptoms negatively affect PROs.

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