Publications by authors named "Pavel Strnad"

151 Publications

Acceptance of SARS-CoV-2 vaccines by liver transplant recipients and candidates.

Z Gastroenterol 2021 Oct 20. Epub 2021 Oct 20.

Medizinische Klinik III, Universitätsklinikum Aachen (RWTH), Aachen, Germany.

Guidelines recommend vaccination against SARS-CoV-2 in transplant recipients, candidates, and their household contacts. However, little is known about the acceptance of COVID-19 vaccines in these groups.In March 2021, we surveyed 826 liver transplant recipients, candidates, and their household contacts to determine acceptance rates and factors influencing the acceptance of the COVID-19 vaccine; 341 patients (40%) and 237 household contacts (28%) returned the questionnaire. Ninety percent of patients returning the survey reported they were willing to receive the vaccine within the next 6 months or had already started vaccination. Only 2% of patients and 4% of household contacts reported refusing the vaccine, and 8% of patients and 9% of household contacts wanted to postpone vaccination because of concerns about side effects. Having received the influenza vaccine in the last 2 seasons was the strongest indicator of acceptance to receive the SARS-CoV-2 vaccine within 6 months (odds ratio 5.11; 95% confidence interval 2.43-10.74; p < 0.001). Thirty-two percent of responding patients reported fear of side effects as a reason for having refused vaccination before.Although the acceptance of the SARS-CoV-2 vaccine was particularly high among German liver transplant recipients, candidates, and household contacts in this survey, transplant physicians are encouraged to discuss safety concerns with patients who have refused the seasonal influenza vaccine in the past.
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http://dx.doi.org/10.1055/a-1649-8568DOI Listing
October 2021

Hepatobiliary phenotype of individuals with chronic intestinal disorders.

Sci Rep 2021 Oct 7;11(1):19954. Epub 2021 Oct 7.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.

Despite the known functional relationship between the gut and the liver, the clinical consequences of this circuit remain unclear. We assessed the hepatobiliary phenotype of cohorts with celiac disease (CeD), Crohn´s disease (CD) and ulcerative colitis (UC). Baseline liver function tests and the frequency of hepatobiliary diseases were analyzed in 2377 CeD, 1738 CD, 3684 UC subjects and 488,941 controls from the population-based UK Biobank cohort. In this cohort study associations were adjusted for age, sex, BMI, diabetes, and alcohol consumption. Compared to controls, cohorts with CeD, but not CD/UC displayed higher AST/ALT values. Subjects with CD/UC but not CeD had increased GGT levels. Elevated ALP and cholelithiasis were significantly more common in all intestinal disorders. Non-alcoholic steatohepatitis and hepatocellular carcinoma (HCC) were enriched in CeD and CD (NASH: aOR = 4.9 [2.2-11.0] in CeD, aOR = 4.2 [1.7-10.3] in CD, HCC: aOR = 4.8 [1.8-13.0] in CeD, aOR = 5.9 [2.2-16.1] in CD), while cholangitis was more common in the CD/UC cohorts (aOR = 11.7 [9.1-15.0] in UC, aOR = 3.5 [1.8-6.8] in CD). Chronic hepatitis, autoimmune hepatitis (AIH) and cirrhosis were more prevalent in all intestinal disorders. In UC/CD, a history of intestinal surgery was associated with elevated liver enzymes and increased occurrence of gallstones (UC: aOR = 2.9 [2.1-4.1], CD: 1.7 [1.2-2.3]). Our data demonstrate that different intestinal disorders predispose to distinct hepatobiliary phenotypes. An increased occurrence of liver cirrhosis, NASH, AIH and HCC and the impact of surgery warrant further exploration.
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http://dx.doi.org/10.1038/s41598-021-98843-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497585PMC
October 2021

Liver transplantation in malignant disease.

World J Clin Oncol 2021 Aug;12(8):623-645

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany.

Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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http://dx.doi.org/10.5306/wjco.v12.i8.623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394155PMC
August 2021

Hypothermic Oxygenated Machine Perfusion Reduces Early Allograft Injury and Improves Post-transplant Outcomes in Extended Criteria Donation Liver Transplantation From Donation After Brain Death: Results From a Multicenter Randomized Controlled Trial (HOPE ECD-DBD).

Ann Surg 2021 11;274(5):705-712

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Objective: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD).

Background: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT).

Methods: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD).

Results: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314).

Conclusion: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000005110DOI Listing
November 2021

A genome-first approach to mortality and metabolic phenotypes in p.Ala165Thr (rs2642438) heterozygotes and homozygotes.

Med (N Y) 2021 Jul;2(7):851-863.e3

Division of Translational Medicine and Human Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Background: A coding variant in (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive.

Methods: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank.

Findings: p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of rs738409:G. In African-American and Black-British individuals, the allele frequency of p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of rs738409:G.

Conclusions: Together these data highlight as an important liver disease modifier that influences plasma lipids in an allele-dose-dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality calling for future studies exploring its therapeutic potential.

Funding: This study was funded by the German Research Foundation (DFG).
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http://dx.doi.org/10.1016/j.medj.2021.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274545PMC
July 2021

Alpha1-antitrypsin deficiency: New therapies on the horizon.

Curr Opin Pharmacol 2021 08 10;59:149-156. Epub 2021 Jul 10.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Centre for Alpha1-Antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) "Rare Liver" and The European Association for the Study of the Liver (EASL) Registry Group "Alpha1-Liver", Germany. Electronic address:

Alpha1-antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, coding for alpha1-antitrypsin (AAT). AAT is synthesised mainly in the liver and is released into bloodstream to protect tissues (particularly lung) with its antiprotease activity. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is the predominant cause of severe AATD. It interferes with AAT secretion thereby leading to AAT accumulation in the liver and lack of AAT in the circulation and the lung. Accordingly, Pi∗ZZ individuals are strongly predisposed to lung and liver injury. The former is treated by a weekly AAT augmentation therapy, but not medicinal products exist for the liver. Our review summarises the current approaches silencing AAT production, improving protein folding and secretion or promoting AAT degradation.
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http://dx.doi.org/10.1016/j.coph.2021.06.001DOI Listing
August 2021

Various myosteatosis selection criteria and their value in the assessment of short- and long-term outcomes following liver transplantation.

Sci Rep 2021 06 28;11(1):13368. Epub 2021 Jun 28.

Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.

Body composition and myosteatosis affect clinical outcomes in orthotopic liver transplantation (OLT). Here we aimed to compare the value and limitations of various selection criteria to define pre-transplant myosteatosis in the assessment of short- and long-term outcomes following OLT. We retrospectively analyzed the data of 264 consecutive recipients who underwent deceased donor OLT at a German university medical centre. Myosteatosis was evaluated by preoperative computed-tomography-based segmentation. Patients were stratified using muscle radiation attenuation of the whole muscle area (L3Muslce-RA), psoas RA (L3Psoas-RA) and intramuscular adipose tissue content (IMAC) values. L3Muslce-RA, L3Psoas-RA and IMAC performed well without major differences and identified patients at risk for inferior outcomes in the group analysis. Quartile-based analyses, receiver operating characteristic curve and correlation analyses showed a superior association of L3Muslce-RA with perioperative outcomes when compared to L3Psoas-RA and L3IMAC. Long-term outcome did not show any major differences between the used selection criteria. This study confirms the prognostic role of myosteatosis in OLT with a particularly strong value in the perioperative phase. Although, based on our data, L3Muscle-RA might be the most suitable and recommended selection criterion to assess CT-based myosteatosis when compared to L3Psoas-RA and L3IMAC, further studies are warranted to validate these findings.
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http://dx.doi.org/10.1038/s41598-021-92798-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239038PMC
June 2021

Clinical value and limitations of the preoperative C-reactive-protein-to-albumin ratio in predicting post-operative morbidity and mortality after deceased-donor liver transplantation: a retrospective single-centre study.

Transpl Int 2021 Aug 4;34(8):1468-1480. Epub 2021 Jul 4.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Liver transplantation is still associated with a high risk of severe complications and post-operative mortality. This study examines the predictive value of the preoperative C-reactive-protein-to-albumin ratio (CAR) regarding perioperative morbidity and mortality in deceased-donor liver transplantation (DDLT) recipients. In total, 390 DDLT recipients between 05/2010 and 03/2020 were eligible. Predictive abilities of CAR were examined through receiver operating characteristic curve (ROC) analyses. Groups were compared using parametric and non-parametric tests as appropriate. Independent risk factors for morbidity and mortality were identified using uni- and multivariable logistic regression analyses. A good predictive ability for CAR was shown regarding perioperative morbidity (comprehensive complication index ≥75, Clavien-Dindo score ≥4a) and 12-month mortality, with an ideal cut-off of CAR = 26%. Patients with CAR>26% had significantly higher median CCI scores (60 vs. 43, P < 0.001), longer intensive care unit (ICU, 5 vs. 4 days, P < 0.001) and hospital (28 vs. 21 days, P < 0.001) stays and higher 12-month mortality rates (20% vs 6%, P < 0.001). Multivariable analyses identified CAR>26%, pre-OLT inpatient hospitalization (including ICU) and post-operative red blood cell transfusions as independent predictors of severe cumulative morbidity (CCI≥75). Preoperative CAR might be a reliable additional tool to predict perioperative morbidity and mortality in DDLT recipients.
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http://dx.doi.org/10.1111/tri.13957DOI Listing
August 2021

Mortality in Patients With Genetic and Environmental Risk of Liver Disease.

Am J Gastroenterol 2021 08;116(8):1741-1745

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Introduction: The increasing liver-related mortality calls for hepatic surveillance programs. To design them, factors selectively increasing liver-related vs overall mortality need to be identified.

Methods: We analyzed mortality data from 467,558 individuals recruited by the community-based UK Biobank. The mean follow-up was 11.4 years.

Results: While all assessed genetic factors associated with increased liver-specific mortality, only homozygous TM6SF2 mutation and SERPINA1 mutation conferred elevated overall mortality. Among the environmental factors, obesity and metabolic syndrome disproportionately contributed to liver-related deaths.

Discussion: Our data demonstrate an interplay between genetics and environment and provide a basis for hepatic surveillance programs.
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http://dx.doi.org/10.14309/ajg.0000000000001326DOI Listing
August 2021

[Alpha-1 antitrypsin deficiency: cause and cofactor for liver disease].

Dtsch Med Wochenschr 2021 Jun 1;146(11):714-718. Epub 2021 Jun 1.

Medizinische Klinik III, Gastroenterologie, Stoffwechselerkrankungen und Intensivmedizin, Uniklinik Aachen, Aachen, Deutschland.

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder arising due to mutation in alpha1-antitrypsin (AAT). AAT mutations interfere with the AAT production/secretion, cause decreased AAT serum levels and accumulation of AAT in the liver. The excess AAT leads to a proteotoxic liver disease, while the lack of AAT in systemic circulation predisposes to lung injury. While AATD related lung disease is well understood, liver disease needs further awareness. Non-invasive liver stiffness measurement constitutes a useful method to estimate the extent of liver fibrosis. Significant liver fibrosis occurs in 20-35 % of individuals with the classic, severe genotype Pi*ZZ. Genotype Pi*SZ, also known as the compound heterozygous form, confers an increased risk of both liver fibrosis and liver neoplasia. Even the heterozygous genotype Pi*MZ increases the odds of fibrosis in presence of further risk factors such as obesity, male sex, metabolic syndrome and diabetes mellitus. In individuals with non-alcoholic fatty liver disease or alcohol misuse it promotes the development of liver cirrhosis. While no drug treatment exists for AATD-related liver disease, there are several compounds in clinical phase II/III-trials. These either silence the AAT production via siRNA or facilitate the secretion of AAT from the liver due to an improved folding.
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http://dx.doi.org/10.1055/a-1277-9066DOI Listing
June 2021

SARS-CoV-2 infection in alpha1-antitrypsin deficiency.

Respir Med 2021 08 13;184:106466. Epub 2021 May 13.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for Alpha-1 Antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) Registry Group "Alpha-1 Liver", Germany. Electronic address:

Alpha1-antitrypsin deficiency arises due to mutations in alpha1-antitrypsin (AAT) gene and represents the most prominent genetic predisposition to chronic obstructive pulmonary disease and emphysema. Since AAT plays important immunomodulatory and tissue-protective roles and since it was suggested to protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed this association in United Kingdom Biobank, a community-based cohort with >500,000 participants. The most common, mild AATD genotypes were associated neither with increased SARS-CoV-2 infection rates nor with increased SARS-CoV-2 fatalities, while the numbers of severe AATD cases were too low to allow definitive conclusions.
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http://dx.doi.org/10.1016/j.rmed.2021.106466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116136PMC
August 2021

Polymerization of misfolded Z alpha-1 antitrypsin protein lowers CX3CR1 expression in human PBMCs.

Elife 2021 05 18;10. Epub 2021 May 18.

Department of Respiratory Medicine, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.

Expression levels of CX3CR1 (C-X3-C motif chemokine receptor 1) on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host's misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in gene, strongly lower CX3CR1 mRNA expression in human peripheral blood mononuclear cells (PBMCs). This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.
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http://dx.doi.org/10.7554/eLife.64881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205483PMC
May 2021

Shear Wave Elastography and Shear Wave Dispersion Imaging in the Assessment of Liver Disease in Alpha1-Antitrypsin Deficiency.

Diagnostics (Basel) 2021 Mar 31;11(4). Epub 2021 Mar 31.

Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

Liver affection of Alpha1-antitrypsin deficiency (AATD) can lead to cirrhosis and hepatocellular carcinoma (HCC). A noninvasive severity assessment of liver disease in AATD is urgently needed since laboratory parameters may not accurately reflect the extent of liver involvement. Preliminary data exist on two-dimensional shear wave elastography (2D-SWE) being a suitable method for liver fibrosis measurement in AATD. AATD patients without HCC were examined using 2D-SWE, shear wave dispersion imaging (SWD) and transient elastography (TE). Furthermore, liver steatosis was assessed using the controlled attenuation parameter (CAP) and compared to the new method of attenuation imaging (ATI). 29 AATD patients were enrolled, of which 18 had the PiZZ genotype, eight had PiMZ, two had PiSZ and one had a PiZP-Lowell genotype. 2D-SWE (median 1.42 m/S, range 1.14-1.83 m/S) and TE (median 4.8 kPa, range 2.8-24.6 kPa) values displayed a significant correlation (R = 0.475, < 0.05). 2D-SWE, ATI (median 0.56 dB/cm/MHz, range 0.43-0.96 dB/cm/MHz) and CAP (median 249.5 dB/m, range 156-347 dB/m) values were higher in PiZZ when compared to other AATD genotypes. This study provides evidence that 2D-SWE is a suitable method for the assessment of liver disease in AATD. The newer methods of SWD and ATI require further evaluation in the context of AATD.
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http://dx.doi.org/10.3390/diagnostics11040629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066059PMC
March 2021

Expression of Interferons Lambda 3 and 4 Induces Identical Response in Human Liver Cell Lines Depending Exclusively on Canonical Signaling.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Institute for Clinical & Experimental Medicine (IKEM), 14021 Prague, Czech Republic.

Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution.
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http://dx.doi.org/10.3390/ijms22052560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961969PMC
March 2021

PNPLA3 and SERPINA1 Variants Are Associated with Severity of Fatty Liver Disease at First Referral to a Tertiary Center.

J Pers Med 2021 Mar 1;11(3). Epub 2021 Mar 1.

First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

Single nucleotide polymorphisms (SNPs), including and have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435-3.979), < 0.001), and higher odds of ACLD (adjusted odds ratio (aOR): 1.971 (1.448-2.681), < 0.001) and CSPH (aOR: 1.685 (1.180-2.406), = 0.004). While the Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067-4.218), = 0.032). Associations of the G-allele and the Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.
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http://dx.doi.org/10.3390/jpm11030165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999282PMC
March 2021

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

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.
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http://dx.doi.org/10.1136/gutjnl-2020-323729DOI Listing
February 2021

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.

BMC Med 2021 02 17;19(1):39. Epub 2021 Feb 17.

Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.

Background: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity.

Methods: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied.

Results: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease.

Conclusions: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
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http://dx.doi.org/10.1186/s12916-021-01917-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887823PMC
February 2021

Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2.

J Pathol 2021 May 18;254(1):80-91. Epub 2021 Mar 18.

Department of Medicine III, University Hospital Aachen, Aachen, Germany.

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5643DOI Listing
May 2021

Editorial: towards an understanding of increased mortality in coeliac disease-authors' reply.

Aliment Pharmacol Ther 2021 03;53(5):656

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

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http://dx.doi.org/10.1111/apt.16246DOI Listing
March 2021

Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations.

Cells 2021 01 28;10(2). Epub 2021 Jan 28.

Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany.

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic expression was strongly induced, an effect which was absent in mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in and mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.
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http://dx.doi.org/10.3390/cells10020252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918903PMC
January 2021

The role of recipient myosteatosis in graft and patient survival after deceased donor liver transplantation.

J Cachexia Sarcopenia Muscle 2021 04 1;12(2):358-367. Epub 2021 Feb 1.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Background: Myosteatosis is associated with perioperative outcomes in orthotopic liver transplantation (OLT). Here, we investigated the effects of body composition and myosteatosis on long-term graft and patient survival following OLT.

Methods: Clinical data from 225 consecutive OLT recipients from a prospective database were retrospectively analysed (May 2010 to December 2017). Computed tomography-based lumbar skeletal muscle index (SMI) (muscle mass) and mean skeletal muscle radiation attenuation (SM-RA) (myosteatosis) were calculated using a segmentation tool (3D Slicer). Patients with low skeletal muscle mass (low SMI) and myosteatosis (low SM-RA) were identified using predefined and validated cut-off values.

Results: The mean donor and recipient age was 55 ± 16 and 54 ± 12 years, respectively. Some 67% of the recipients were male. The probability of graft and patient survival was significantly lower in patients with myosteatosis compared with patients with higher SM-RA values (P = 0.011 and P = 0.001, respectively). Low skeletal muscle mass alone was not associated with graft and patient survival (P = 0.273 and P = 0.278, respectively). Dividing the cohort into quartiles, based on the values of SMI and SM-RA, resulted in significant differences in patient but not in graft survival (P = 0.011). Even though multivariable analysis identified low SM-RA as an important prognostic marker (hazard ratio: 2.260, 95% confidence interval: 1.177-4.340, P = 0.014), myosteatosis lost its significance when early mortality (90 days) was excluded from the final multivariable model. Patients with myosteatosis showed significantly higher all-cause mortality and in particular higher rates of deaths due to respiratory and septic complication (P = 0.002, P = 0.022, and P = 0.049, respectively).

Conclusions: Preoperative myosteatosis may be an important prognostic marker in patients undergoing deceased donor liver transplantation. The prognostic value of myosteatosis seems to be particularly important in the early post-operative phase. Validation in prospective clinical trials is warranted.
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http://dx.doi.org/10.1002/jcsm.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061365PMC
April 2021

Reply.

Gastroenterology 2021 04 5;160(5):1875-1877. Epub 2021 Jan 5.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for Alpha-1 Antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver".

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http://dx.doi.org/10.1053/j.gastro.2021.01.002DOI Listing
April 2021

Impact of Angiogenesis- and Hypoxia-Associated Polymorphisms on Tumor Recurrence in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

Charité-Universitätsmedizin Berlin, Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, 13353 Berlin, Germany.

Tumor angiogenesis plays a pivotal role in hepatocellular carcinoma (HCC) biology. Identifying molecular prognostic markers is critical to further improve treatment selection in these patients. The present study analyzed a subset of 10 germline polymorphisms involved in tumor angiogenesis pathways and their impact on prognosis in HCC patients undergoing partial hepatectomy in a curative intent. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 127 HCC patients at a German primary care hospital. Genomic DNA was extracted, and genotyping was carried out using polymerase chain reaction (PCR)-restriction fragment length polymorphism-based protocols. Polymorphisms in interleukin-8 (IL-8) (rs4073; = 0.047, log-rank test) and vascular endothelial growth factor (VEGF C + 936T) (rs3025039; = 0.045, log-rank test) were significantly associated with disease-free survival (DFS). After adjusting for covariates in the multivariable model, IL-8 T-251A (rs4073) (adjusted = 0.010) and a combination of "high-expression" variants of rs4073 and rs3025039 (adjusted = 0.034) remained significantly associated with DFS. High-expression variants of IL-8 T-251A may serve as an independent molecular marker of prognosis in patients undergoing surgical resection for HCC. Assessment of the patients' individual genetic risks may help to identify patient subgroups at high risk for recurrence following curative-intent surgery.
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http://dx.doi.org/10.3390/cancers12123826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767259PMC
December 2020

Phenome-wide association study in adult coeliac disease: role of HLA subtype.

Aliment Pharmacol Ther 2021 02 5;53(4):510-518. Epub 2020 Dec 5.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Background: Coeliac disease arises in genetically susceptible individuals, in particular in carriers of HLA-DQ2/DQ8 risk alleles and is associated with various comorbidities. Coeliac disease may confer an increased mortality, but the data are conflicting.

Aims: We aimed to characterize mortality and morbidity in patients with coeliac disease with a special focus on the role of the number of HLA risk alleles.

Methods: We studied coeliac disease-associated morbidity and mortality in ~500 000 participants of the UK Biobank including 2482 individuals with the diagnosis of coeliac disease. We used an unbiased, multivariable Phenome-Wide Association Study (PheWAS) method to uncover the coeliac disease-associated disorders. The tag SNP approach was used to divide the coeliac disease subjects into HLA-DQ2/DQ8-based risk categories.

Results: We found 225 ICD-10 codes significantly associated with coeliac disease. During the median follow-up of 10.7 years, coeliac disease individuals (n = 2482) had higher overall mortality (HR 1.6 [95% CI, 1.4-1.8]) than controls and both an increased occurrence of and an increased mortality from cancer, respiratory and cardiovascular diseases (HR 1.4-1.6). Coeliac disease individuals with 2 HLA-DQ2/8 risk alleles had a similar overall mortality as coeliac disease participants with 0-1 HLA-DQ2/8 alleles, but were more likely to die from lymphoproliferative diseases (HR 7.6 [95% CI, 1.01-57.25]).

Conclusions: Our data suggest that the increased mortality from lymphoproliferative diseases is restricted to those coeliac patients with 2 HLADQ2/8 alleles and that a combination of coeliac disease and HLADQ2/8 alleles is needed to increase the susceptibility. Once confirmed, closer monitoring may be warranted in this high-risk subpopulation.
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http://dx.doi.org/10.1111/apt.16206DOI Listing
February 2021

Serum keratin 19 (CYFRA21-1) links ductular reaction with portal hypertension and outcome of various advanced liver diseases.

BMC Med 2020 11 12;18(1):336. Epub 2020 Nov 12.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.

Background: Keratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies.

Methods: Hepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv).

Results: (i) Hepatic K19 levels were comparable among F0-F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95-11.68]) and mortality (HR = 3.02 [1.78-5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64-4.09]) and of HCC (HR = 1.74 [1.02-2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92-4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores.

Conclusions: Hepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.
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http://dx.doi.org/10.1186/s12916-020-01784-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661160PMC
November 2020

In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers.

Am J Gastroenterol 2020 11;115(11):1857-1868

NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.

Introduction: Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH.

Methods: Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls.

Results: K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%.

Discussion: In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.
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http://dx.doi.org/10.14309/ajg.0000000000000912DOI Listing
November 2020

Decrease of renal resistance during hypothermic oxygenated machine perfusion is associated with early allograft function in extended criteria donation kidney transplantation.

Sci Rep 2020 10 20;10(1):17726. Epub 2020 Oct 20.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Hypothermic oxygenated machine perfusion (HOPE) was recently tested in preclinical trials in kidney transplantation (KT). Here we investigate the effects of HOPE on extended-criteria-donation (ECD) kidney allografts (KA). Fifteen ECD-KA were submitted to 152 ± 92 min of end-ischemic HOPE and were compared to a matched group undergoing conventional-cold-storage (CCS) KT (n = 30). Primary (delayed graft function-DGF) and secondary (e.g. postoperative complications, perfusion parameters) endpoints were analyzed within 6-months follow-up. There was no difference in the development of DGF between the HOPE and CCS groups (53% vs. 33%, respectively; p = 0.197). Serum urea was lower following HOPE compared to CCS (p = 0.003), whereas the CCS group displayed lower serum creatinine and higher eGFR rates on postoperative days (POD) 7 and 14. The relative decrease of renal vascular resistance (RR) following HOPE showed a significant inverse association with serum creatinine on POD1 (r = - 0.682; p = 0.006) as well as with serum urea and eGFR. Besides, the relative RR decrease was more prominent in KA with primary function when compared to KA with DGF (p = 0.013). Here we provide clinical evidence on HOPE in ECD-KT after brain death donation. Relative RR may be a useful predictive marker for KA function. Further validation in randomized controlled trials is warranted.Trial registration: clinicaltrials.gov (NCT03378817, Date of first registration: 20/12/2017).
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http://dx.doi.org/10.1038/s41598-020-74839-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575556PMC
October 2020

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

J Hepatol 2021 01 31;74(1):20-30. Epub 2020 Aug 31.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.

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], p = 4.8×10) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p = 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], p = 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 (p = 0.002) and lower serum triglycerides (p = 1.5×10). 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.
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http://dx.doi.org/10.1016/j.jhep.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755037PMC
January 2021

Non-Invasive Assessment and Management of Liver Involvement in Adults With Alpha-1 Antitrypsin Deficiency.

Chronic Obstr Pulm Dis 2020 Jul;7(3):260-271

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Alpha-1 antitrypsin deficiency (AATD) is a systemic disorder affecting mainly the lung and the liver and is caused by mutations in , the AAT gene. A homozygous "Pi*Z" mutation (Pi*ZZ genotype) may cause liver fibrosis on its own independently of pulmonary AATD manifestation, while heterozygous Pi*Z carriage (Pi*MZ genotype) is considered a strong risk factor for development of liver cirrhosis in patients with concomitant liver disease such as alcoholic and non-alcoholic liver disease. In Pi*ZZ homozygotes, liver disease constitutes the second leading cause of death and is highly heterogeneous. About 35% of Pi*ZZ individuals display significant liver fibrosis on biopsy (i.e., fibrosis stage ≥ 2 on scale 0-4). Among non-invasive methods for liver fibrosis assessment, liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) has been most widely evaluated. Based on these data, Pi*ZZ adults have 20x increased odds of developing advanced liver fibrosis (i.e., fibrosis stage ≥ 3) than adults without AAT mutation. Risk factors for accelerated fibrosis progression are male sex, age ≥ 50 years, alcohol misuse, obesity, diabetes mellitus, or metabolic syndrome. Unlike VCTE, other ultrasound- and magnetic resonance-based elastography methods have been assessed in small cohorts of Pi*ZZ individuals and remain to be comprehensively validated. Among blood-based fibrosis tests, AST-to-platelet ratio index (APRI) correlates moderately with histologic fibrosis stage and LSM. Given APRI's wide availability, it can be used for risk stratification as an adjunct to LSM or when LSM is not at hand. Despite recent efforts, AATD-related liver disease, especially for genotypes other than Pi*ZZ, remains greatly understudied. AATD individuals should be offered liver biochemistry, liver ultrasound, and non-invasive fibrosis assessment at the time of diagnosis to detect potential complications and for proper risk stratification. If signs of AATD-related liver disease occur (i.e., pathologic fibrosis test or repeatedly elevated liver enzymes), patients should be referred to a health care center specialized in AATD-related liver disease and be screened for potentially treatable comorbidities. To exclude the latter, they may need a liver biopsy. Moreover, every health care provider of an AATD individual should be aware of the potential liver manifestation, counsel their patient on modifiable hepatic risk factors, and offer them regular liver check-ups.
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http://dx.doi.org/10.15326/jcopdf.7.3.2019.0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857717PMC
July 2020

Response to Sainath et al.

Am J Gastroenterol 2020 07;115(7):1136-1137

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

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http://dx.doi.org/10.14309/ajg.0000000000000697DOI Listing
July 2020
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