Publications by authors named "Henning Gronbaek"

250 Publications

A novel read methodology to evaluate the optimal dose of Ga-satoreotide trizoxetan as a PET imaging agent in patients with gastroenteropancreatic neuroendocrine tumours: a phase II clinical trial.

EJNMMI Res 2021 Sep 6;11(1):84. Epub 2021 Sep 6.

Ipsen Bioscience, Cambridge, MA, USA.

Background: Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist exhibiting higher tumour-to-background ratios and sensitivity compared to Ga-DOTATOC. This randomised, 2 × 3 factorial, phase II study aimed to confirm the optimal peptide mass and radioactivity ranges for Ga-satoreotide trizoxetan, using binary visual reading. To that end, 24 patients with metastatic gastroenteropancreatic neuroendocrine tumours received 5-20 µg of Ga-satoreotide trizoxetan on day 1 of the study and 30-45 µg on day 16-22, with one of three gallium-68  radioactivity ranges (40-80, 100-140, or 160-200 MBq) per visit. Two Ga-satoreotide trizoxetan PET/CT scans were acquired from each patient post-injection, and were scored by experienced independent blinded readers using a binary system (0 for non-optimal image quality and 1 for optimal image quality). For each patient pair of Ga-satoreotide trizoxetan scans, one or both images could score 1.

Results: Total image quality score for Ga-satoreotide trizoxetan PET scans was lower in the 40-80 MBq radioactivity range (56.3%) compared to 100-140 MBq (90.6%) and 160-200 MBq (81.3%). Both qualitative and semi-quantitative analysis showed that peptide mass (5-20 or 30-45 µg) did not influence Ga-satoreotide trizoxetan imaging. There was only one reading where readers diverged on scoring; one reader preferred one image because of higher lesion conspicuity, and the other reader preferred the alternative image because of the ability to identify more lesions.

Conclusions: Binary visual reading, which was associated with a low inter-reader variability, has further supported that the optimal administered radioactivity of Ga-satoreotide trizoxetan was 100-200 MBq with a peptide mass up to 50 µg. Trial registration ClinicalTrials.gov, NCT03220217. Registered 18 July 2017, https://clinicaltrials.gov/ct2/show/NCT03220217.
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http://dx.doi.org/10.1186/s13550-021-00819-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421477PMC
September 2021

Cognitive impairment in stable Wilson disease across phenotype.

Metab Brain Dis 2021 Oct 3;36(7):2173-2177. Epub 2021 Aug 3.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8200, Aarhus N, Denmark.

In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients with neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes. In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by the PortoSystemic Encephalopathy (PSE) and the Continuous Reaction Time (CRT) tests. Half of the patients were female, and their median age was 35.5 years (IQR 24.5). Their phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 (14%). The duration of treatment was > 2 year in all patients, and their condition was stable as judged by urinary copper excretion, liver enzymes, and clinical assessment. The hepatic patients did not show signs of liver failure. In total, 16 (57%) patients performed worse than normal in the PSE and/or the CRT tests. The two tests were correlated (rho = 0.60, p = 0.0007), but neither correlated with phenotype, MELD-, Child-Pugh score, 24 h-U-Cu, or treatment type. Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.
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http://dx.doi.org/10.1007/s11011-021-00804-6DOI Listing
October 2021

Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single-Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent.

Clin Pharmacol Ther 2021 Jul 31. Epub 2021 Jul 31.

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.

The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1,000 mg metformin. Metformin increased lactate concentrations by 23% (95% confidence interval (CI): 6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (P < 0.05, all) and was lowered at both sampling sites following metformin ingestion (P < 0.01, all). Plasma concentration of GLP-1 was 20% (95% CI: 2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pM, P = 0.05). The median concentration of growth differentiation factor 15 was 10% (95% CI: 1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3,000 ng/mL with a mean portal/arterial ratio of 1.5 (95% CI: 1.2-1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of nonoxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.
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http://dx.doi.org/10.1002/cpt.2382DOI Listing
July 2021

Editorial: metformin for portal hypertension-old dog, new tricks? Authors' reply.

Aliment Pharmacol Ther 2021 08;54(3):347

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, Australia.

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http://dx.doi.org/10.1111/apt.16503DOI Listing
August 2021

A randomised, factorial phase II study to determine the optimal dosing regimen for Ga-satoreotide trizoxetan as an imaging agent in patients with gastroenteropancreatic neuroendocrine tumours.

J Nucl Med 2021 Jul 2. Epub 2021 Jul 2.

Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, United States.

Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumour (NET) detection and localisation. However, the optimal peptide mass and radioactivity ranges for Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomised, 2×3 factorial, multicentre, phase II study. Patients received Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on day 16-22, at one of three gallium-68 radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 minutes after each injection. The primary endpoint was the detection rate of NET lesions imaged by Ga-satoreotide trizoxetan relative to contrast-enhanced CT (CECT) (for each of the six peptide mass/radioactivity range combinations). Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by Ga-satoreotide trizoxetan PET/CT or PET only was at least twice as high as the number of lesions detected by CECT across the six studied peptide mass dose/radioactivity range combinations. There were no differences between the two peptide mass ranges and between the three radioactivity ranges in the number of identified lesions. However, a trend towards a lower relative lesion count was noted in the liver for the 40-80 MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by Ga-satoreotide trizoxetan. Median diagnostic sensitivity of Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. A radioactivity of 100-200 MBq with a peptide mass up to 50 μg were confirmed as the optimal dosing regimen for Ga-satoreotide trizoxetan to be used in future phase III studies.
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http://dx.doi.org/10.2967/jnumed.121.261936DOI Listing
July 2021

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension.

Front Physiol 2021 11;12:649668. Epub 2021 Jun 11.

Department of Hepatology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark.

Introduction: Macrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients and cirrhosis.

Methods: We studied plasma sCD163 and sMR levels in patients with IPH ( = 26), non-cirrhotic PVT ( = 20), patients with cirrhosis PVT ( = 31) and PVT ( = 17), and healthy controls ( = 15).

Results: Median sCD163 concentration was 1.51 (95% CI: 1.24-1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49-2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75-2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls ( < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16-7.73) in cirrhotics PVT and 5.19 (95% CI: 4.18-6.46) PVT ( < 0.01, all). Similar differences were observed for sMR.

Conclusion: Soluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension.
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http://dx.doi.org/10.3389/fphys.2021.649668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231705PMC
June 2021

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.

Aliment Pharmacol Ther 2021 08 24;54(3):320-328. Epub 2021 Jun 24.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia.

Background: Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect.

Aims: To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion.

Methods: In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow.

Results: The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O uptake or inflammation markers between groups.

Conclusions: A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
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http://dx.doi.org/10.1111/apt.16460DOI Listing
August 2021

Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

Acta Oncol 2021 Jul 17;60(7):931-941. Epub 2021 May 17.

Department of Oncology, Haukeland University Hospital, Bergen, Norway.

Background: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic.

Aim: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.
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http://dx.doi.org/10.1080/0284186X.2021.1921262DOI Listing
July 2021

Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner.

Cell Syst 2021 May 5;12(5):432-445.e7. Epub 2021 May 5.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia. Electronic address:

Findings about chronic complex diseases are difficult to extrapolate from animal models to humans. We reason that organs may have core network modules that are preserved between species and are predictably altered when homeostasis is disrupted. To test this idea, we perturbed hepatic homeostasis in mice by dietary challenge and compared the liver transcriptome with that in human fatty liver disease and liver cancer. Co-expression module preservation analysis pointed to alterations in immune responses and metabolism (core modules) in both human and mouse datasets. The extent of derailment in core modules was predictive of survival in the cancer genome atlas (TCGA) liver cancer dataset. We identified module eigengene quantitative trait loci (module-eQTL) for these predictive co-expression modules, targeting of which may resolve homeostatic perturbations and improve patient outcomes. The framework presented can be used to understand homeostasis at systems levels in pre-clinical models and in humans. A record of this paper's transparent peer review process is included in the supplemental information.
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http://dx.doi.org/10.1016/j.cels.2021.04.004DOI Listing
May 2021

Cancer suspicion, referral to cancer patient pathway and primary care interval: a survey and register study exploring 10 different types of abdominal cancer.

Fam Pract 2021 Apr 27. Epub 2021 Apr 27.

Research Centre for Cancer Diagnosis in Primary Care, Research Unit for General Practice, Aarhus, Denmark.

Background: Abdominal cancers represent 30% of all diagnosed cancers. Nevertheless, it is unknown if the general practitioner's (GP's) initial cancer suspicion varies for different abdominal cancer types and how this is associated with referrals to standardized cancer patient pathways (CPPs).

Objectives: To explore initial cancer suspicion in GPs and to investigate how this was associated with GP referrals to CPPs and the duration of the primary care interval (PCI) in 10 different abdominal cancer types.

Methods: We conducted a cohort study on 1104 incident abdominal cancer patients diagnosed in Denmark in 2016 using a combination of survey and register-based data. Poisson regression was used to estimate associations between GP cancer suspicion, CPP referral and PCI duration.

Results: The GPs initially suspected cancer or other serious disease in 46-78% of cases, lowest in kidney cancer, and referred 35-65% to a CPP, lowest in oesophageal cancer. The GP's suspicion at the first presentation was strongly associated with referral to a CPP. The median (0-11 days) and 75th percentile (3-32 days) PCIs varied between the abdominal cancer types. The likelihood of a long PCI was more than 3-fold higher when the GP did not initially suspect cancer.

Conclusion: In up to half of abdominal cancer patients, there is no initial suspicion of cancer or serious disease. CPPs were used in only one-third to two-thirds of patients, depending on cancer type. For kidney cancer, as well as several abdominal cancers, we need better diagnostic strategies to support GPs to enable effective and efficient referral.
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http://dx.doi.org/10.1093/fampra/cmab025DOI Listing
April 2021

Metabolic effects of 1-week binge drinking and fast food intake during Roskilde Festival in young healthy male adults.

Eur J Endocrinol 2021 May 21;185(1):23-32. Epub 2021 May 21.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aims/hypothesis: Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males.

Methods: Fourteen festival participants (FP) were studied before, during and after 1 week's participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline.

Results: The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group.

Conclusions/interpretation: Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.
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http://dx.doi.org/10.1530/EJE-21-0122DOI Listing
May 2021

Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis.

J Hepatol 2021 Aug 12;75(2):342-350. Epub 2021 Jun 12.

Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.

Background & Aims: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis.

Methods: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization.

Results: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9).

Conclusion: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.

Lay Summary: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.
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http://dx.doi.org/10.1016/j.jhep.2021.03.026DOI Listing
August 2021

Combining tissue and circulating tumor DNA increases the detection rate of a CTNNB1 mutation in hepatocellular carcinoma.

BMC Cancer 2021 Apr 8;21(1):376. Epub 2021 Apr 8.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background And Aims: Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC.

Methods: We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up.

Results: In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients.

Conclusion: Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.
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http://dx.doi.org/10.1186/s12885-021-08103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028749PMC
April 2021

Abdominal investigations in the year preceding a diagnosis of abdominal cancer: A register-based cohort study in Denmark.

Cancer Epidemiol 2021 06 6;72:101926. Epub 2021 Mar 6.

Research Center for Cancer Diagnosis in Primary Care, Research Unit for General Practice, Aarhus, Denmark; University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark.

Background: More than 11,500 abdominal cancers are yearly diagnosed in Denmark. Nevertheless, little is known about which investigations the patients undergo before a diagnosis of abdominal cancer. We aimed to investigate the frequency and timing of selected diagnostic investigations during the year preceding an abdominal cancer diagnosis.

Methods: We conducted a nationwide registry-based cohort study of patients aged ≥ 18 years who were diagnosed with a first-time abdominal cancer in 2014-2018. We included the following cancer types: oesophageal, gastric, colon, rectal, liver, gall bladder/biliary tract, pancreatic, endometrial, ovarian, kidney, and bladder cancer. Investigations of interest were transvaginal ultrasound, abdominal ultrasound, colonoscopy, gastroscopy, endoscopic retrograde cholangiopancreatography, cystoscopy, hysteroscopy, abdominal computed tomography and abdominal magnetic resonance imaging. Generalised linear models were used to calculate incidence rate ratios to enable comparison of monthly rates of investigations.

Results: All types of investigations were performed, with varying frequency, across the 11 abdominal cancer types in the year preceding the diagnosis. Increased use of investigations revealed that the timing of the onset differed for the different abdominal cancers, with increases seen 2-6 months before the diagnosis. Abdominal ultrasound, colonoscopy and computed tomography were the investigations with the earliest increase.

Conclusion: In the year before a diagnosis of an abdominal cancer, some patients appear to undergo investigations typically used to detect another cancer type. This indicates that a window of opportunity exists to diagnose some abdominal cancers at an earlier time point. Future studies should explore an alternative clinical pathway to promote earlier diagnosis of abdominal cancers.
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http://dx.doi.org/10.1016/j.canep.2021.101926DOI Listing
June 2021

Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis.

Clin Transl Gastroenterol 2021 03 1;12(3):e00315. Epub 2021 Mar 1.

Department of Hepatology & Gastroenterology, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark.

Introduction: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC.

Methods: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison.

Results: Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients.

Discussion: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516).
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http://dx.doi.org/10.14309/ctg.0000000000000315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925135PMC
March 2021

Interferon lambda 4 genotype and pathway in alcoholic hepatitis.

Scand J Gastroenterol 2021 Mar 19;56(3):304-311. Epub 2021 Feb 19.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Objectives: Single nucleotide polymorphisms within the interferon lambda 4 ( gene influence liver inflammation and fibrosis in chronic liver disease. We investigated whether this is also the case during acute liver disease, alcoholic hepatitis. We, therefore, related variants within the gene to the clinical course of acute alcoholic hepatitis, and characterized the activation state of the IFN lambda system in these patients.

Methods: In this pilot study, 58 patients with alcoholic hepatitis were genotyped for the single nucleotide polymorphism (deltaG, deltaG/TT: IFN lambda 4 positive, TT/TT: IFN lambda 4 negative). The genotypes were related to mortality, infection and inflammation and expression of the IFNL receptor 1 and IFN inducible genes were measured in liver and peripheral leukocytes.

Results: Amongst the alcoholic hepatitis patients who died, the IFN negative patients live longer after diagnosis, and also the IFN negative patients tended to have an overall short-term survival benefit compared to IFN lambda positive patients ( = .058). The IFN lambda 4 negative patients at diagnosis had fewer circulating monocytes and lower plasma soluble CD163. The patients with alcoholic hepatitis had reduced expression of the IFNL receptor 1in both liver and blood compared with healthy controls. In blood, the expression of IFN stimulated genes was lower than in healthy controls and most so in the patients, who died.

Conclusions: The IFN lambda 4 pathway seems involved in the acute disease processes of alcoholic hepatitis and patients without IFN lambda expression seem to have a short-term survival benefit.
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http://dx.doi.org/10.1080/00365521.2021.1874046DOI Listing
March 2021

Efficacy of Dietary Manipulations for Depleting Intrahepatic Triglyceride Content: Implications for the Management of Non-alcoholic Fatty Liver Disease.

Curr Obes Rep 2021 Jun 13;10(2):125-133. Epub 2021 Feb 13.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.

Purpose Of Review: Understanding the effects of dietary manipulations on intrahepatic triglyceride (IHTG) balance will have important implications for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD).

Recent Findings: Reducing calorie intake to induce weight loss is the most potent intervention to decrease IHTG. Carbohydrate restriction during the initial stages of weight loss may be particularly beneficial, but at later stages, the amount of weight loss predominates over diet composition. By contrast, during weight stability, restricting calories from fat seems to be optimal for depleting liver fat. The degree of dietary fat saturation and the glycemic index of the carbohydrate have inconsistent effects on IHTG. Recently, the matrix of some foods (e.g., dairy) has been inversely associated with NAFLD. Dietary macronutrients differ in their effects on liver fat depending on the energy balance and the matrix of the food in which they are consumed. Therefore, investigations into dietary approaches for managing NAFLD should shift their perspective from that of isolated nutrients to that of whole foods and diets and include useful mechanistic insights.
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http://dx.doi.org/10.1007/s13679-021-00430-4DOI Listing
June 2021

No Effect in Alcoholic Hepatitis of Gut-Selective, Broad-Spectrum Antibiotics on Bacterial Translocation or Hepatic and Systemic Inflammation.

Clin Transl Gastroenterol 2021 01 27;12(2):e00306. Epub 2021 Jan 27.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Introduction: In alcoholic hepatitis (AH), translocation of gut bacteria may drive hepatic macrophage activation and systemic inflammation. We investigated the effect of oral non-absorbable, broad-spectrum antibiotic treatment on bacterial translocation and liver and systemic inflammation in AH.

Methods: We consecutively recruited 31 patients with AH. Fourteen were given vancomycin 500 mg, gentamycin 40 mg, and meropenem 500 mg once daily for 7 days. Seventeen patients were a reference group receiving standard-of-care. Circulating markers of bacterial translocation and inflammation were measured at baseline, by day 7 and 90. Gut bacteriome profiling was performed before the intervention and at day 7.

Results: At study entry, blood lipopolysaccharide-binding protein was multifold higher than normal, remained unchanged at day 7, but decreased at day 90 (P < 0.001) with no difference between the study groups. The macrophage activation markers sCD163 and sCD206 showed the same pattern (P < 0.001, day 90), still without group differences. The systemic inflammation markers tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 showed similar dynamics without group differences. There was no difference in 90-day mortality (total of 6 deaths) between the groups. The remnant gut bacteriome was markedly diversified by the intervention with growth of bacterial species rare for human flora.

Discussion: In patients with AH, gut-targeted antibiotic treatment does not change markers of bacterial translocation and liver and systemic inflammation. This suggests that bacterial translocation is less important once the inflammatory process is established or that bacteriome reduction is less important than composition.
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http://dx.doi.org/10.14309/ctg.0000000000000306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846454PMC
January 2021

Increased occurrence of liver and gastrointestinal diseases and anaemia in women with Turner syndrome - a nationwide cohort study.

Aliment Pharmacol Ther 2021 04 7;53(7):821-829. Epub 2021 Feb 7.

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Liver and gastrointestinal diseases are frequent in women with Turner syndrome. However, their association with bleeding disorders, anaemia and the impact of hormone replacement therapy is unknown.

Aims: To investigate the risk of liver and gastrointestinal diseases, haemorrhage and anaemia in women with Turner syndrome compared with the female background population, and the long-term impact of hormone replacement therapy on these conditions.

Methods: One thousand one hundred and fifty-six women with Turner syndrome diagnosed during 1960-2014 were identified using the Danish Cytogenetic Central Registry and linked with personal-level data from the National Patient Registry and the Medication Statistics Registry. Statistics Denmark randomly identified 115 577 age-matched female controls. Negative binomial regression was used to analyse hospital discharge diagnoses. Medical prescriptions, mortality and the effect of hormone replacement therapy were estimated using stratified Cox regression.

Results: Liver disease increased 13-fold (IRR 12.9 (95% CI 5.8-28.8)), due to toxic liver disease (IRR 8.0 (95% CI 1.8-35.4)), liver insufficiency (IRR 6.7 (95% CI 1.7-26.9)), fibrosis/cirrhosis (IRR 16.5 (95% CI 2.2-122.1)) and unspecified liver disease (IRR 10.6 (95% CI 4.4-25.3)). Furthermore, presence of abnormal liver enzymes increased 12-fold (IRR 12.4 (95% CI 4.2-36.6)). The risk of gastrointestinal haemorrhage (IRR 3.4 (95% CI 1.8-6.2)), anaemia (IRR 3.2 (95% CI 2.0-5.0)) and coagulation disorders (IRR 2.9 (95% CI 1.1-7.1)) was increased. However these diagnoses were not associated with inflammatory bowel disease. Gastrointestinal mortality was increased three-fold (HR 3.1 (95% CI 1.5-6.2)), partly due to death by liver disease (HR 3.0 (95% CI 1.1-8.2)), gastrointestinal haemorrhage (HR 29.6 (95% CI 3.1-285.1)) and capillary malformations (HR 18.6 (95% CI 4.1-85.0)). There was no effect of hormone replacement therapy on gastrointestinal risk but a trend towards a beneficial impact on liver diseases.

Conclusions: The risk of being diagnosed with liver disease was higher than previously reported. The occurrence of gastrointestinal haemorrhage and anaemia was increased in Turner syndrome. There was no effect of hormone replacement therapy on gastrointestinal risk but a trend towards a beneficial impact on liver diseases was detected.
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http://dx.doi.org/10.1111/apt.16277DOI Listing
April 2021

Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis.

Front Med (Lausanne) 2020 8;7:615599. Epub 2021 Jan 8.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.
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http://dx.doi.org/10.3389/fmed.2020.615599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820116PMC
January 2021

Administrative Coding in Electronic Health Care Record-Based Research of NAFLD: An Expert Panel Consensus Statement.

Hepatology 2021 Jul 22;74(1):474-482. Epub 2021 Jun 22.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland.

Background And Aims: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach And Results: Researchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions: This expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.
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http://dx.doi.org/10.1002/hep.31726DOI Listing
July 2021

CELL-FREE DNA AND CLINICAL CHARACTERISTICS IN PATIENTS WITH SMALL INTESTINAL OR PANCREATIC NEUROENDOCRINE TUMORS.

Neuroendocrinology 2021 Jan 18. Epub 2021 Jan 18.

Background: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low grade small intestinal (siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA.

Material And Methods: We included 70 NET patients, siNET(n=50) and pNET(n=20). Plasma cfDNA levels were determined by droplet digital PCR for the Beta-2-microglobulin gene every six months during a period of three years, including in a subgroup of 19 patients during Peptide Receptor Radionuclide Therapy (PRRT) therapy.

Results: CfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p<0.0001). cfDNA levels did not predict overall survival (crude HR 0.95 (0.57-1.58), p=0.837, adjusted for smoking status HR 0.77 (0.51-1.17), p=0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p=0.66). CfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p=0.029).

Conclusion: cfDNA levels are higher in NET patients than in healthy controls, however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.
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http://dx.doi.org/10.1159/000514457DOI Listing
January 2021

Macrophage Markers Do Not Add to the Prediction of Liver Fibrosis by Transient Elastography in Patients With Metabolic Associated Fatty Liver Disease.

Front Med (Lausanne) 2020 18;7:616212. Epub 2020 Dec 18.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Non-invasive fibrosis staging is essential in metabolic associated fatty liver disease (MAFLD). Transient elastography (TE) is a well-established method for liver fibrosis assessment. We have previously shown that the macrophage marker sCD163 is an independent predictor for fibrosis in MAFLD. In the present study we tested whether the combination of macrophage markers and TE improves fibrosis prediction. We measured macrophage markers soluble (s)CD163 and mannose receptor (sMR) in two independent cohorts from Italy ( = 141) and Sweden ( = 70) with biopsy-proven MAFLD and available TE. In the Italian cohort, TE and sCD163 showed similar moderate associations with liver fibrosis (rho = 0.56, < 0.001 and rho = 0.42, < 0.001, respectively). TE had an area under the Receiver Operating Characteristics curve (AUROC, with 95% CI) for fibrosis; F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.81 (0.73-0.89), F4 = 0.95 (0.90-1.0). sCD163 also predicted fibrosis well [F ≥ 2 = 0.71 (0.63-0.80), F ≥ 3 = 0.82 (0.74-0.90), F4 = 0.89 (0.76-1.0)]. However, combining sCD163 and TE did not improve the AUROCs significantly [F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.85 (0.78-0.92), F4 = 0.97 (0.93-1.0)]. In the Swedish cohort, TE showed a closer association with fibrosis (rho = 0.73, < 0.001) than sCD163 (rho = 0.43, < 0.001) and sMR (rho = 0.46, < 0.001). TE predicted fibrosis well [F ≥ 2 = 0.88 (0.80-0.97), F ≥ 3 = 0.90 (0.83-0.97), F4 = 0.87 (0.78-0.96)], whereas sCD163 did not (best AUROC 0.75). sMR showed a better prediction [F ≥ 2 = 0.68 (0.56-0.81), F ≥ 3 = 0.82 (0.71-0.92), F4 = 0.79 (0.66-0.93)], but the addition of sMR did not further improve the prediction of fibrosis by TE. In these cohorts of MAFLD patients, TE was superior to macrophage markers for fibrosis prediction and in contrast to our hypothesis the addition of these markers to TE did not improve its predictive capability.
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http://dx.doi.org/10.3389/fmed.2020.616212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775526PMC
December 2020

PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 3.

PLoS One 2020 14;15(12):e0243900. Epub 2020 Dec 14.

Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.

Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243900PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735636PMC
February 2021

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

J Hepatol 2021 05 20;74(5):1097-1108. Epub 2020 Nov 20.

Medical University of Innsbruck, Innsbruck, Austria.

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.

Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.

Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.

Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.

Lay Summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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http://dx.doi.org/10.1016/j.jhep.2020.11.019DOI Listing
May 2021

TERT promoter mutated circulating tumor DNA as a biomarker for prognosis in hepatocellular carcinoma.

Scand J Gastroenterol 2020 Dec 25;55(12):1433-1440. Epub 2020 Oct 25.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.

Background And Aims: Plasma circulating tumor DNA (ctDNA) with tumor-specific mutations is an attractive biomarker. The telomerase reverse transcriptase () C228T promoter mutation is the most prevalent tumor-associated mutation in hepatocellular carcinoma (HCC). We evaluated the presence and prognostic value of the C228T mutation in plasma and tissue in a Danish HCC cohort.

Methods: We analyzed ctDNA from 95 HCC patients and 45 liver cirrhotic patients without HCC for the mutation using droplet digital polymerase chain reaction. We also analyzed DNA from the corresponding primary tumor tissues in 34 HCC patients.

Results: The plasma C228T mutation was detected in 42/95 HCC patients (44%) but in none of the non-HCC patients. The mutation was detected in 23/34 tumor samples (68%). The mutation was associated with increased mortality when detected in plasma (adjusted HR 2.16 (1.20-3.88),  = .010) but not in tumor tissue (adjusted HR 1.11 (0.35-3.56),  = .860). There was a positive correlation between the presence of the mutation in plasma and an advanced TNM stage ( < .0001) and vascular invasion ( = .005). Analysis of the mutation in plasma and tumor DNA from the same patient was concordant in 21/34 samples (62%; kappa value 0.31,  = .014). Non-concordance was associated with an early TNM stage.

Conclusion: The plasma mutation was detected in 44% of HCC patients and in none of non-HCC cirrhotic patients; and was associated with increased mortality. We propose the C228T mutation in ctDNA as a promising HCC biomarker for prognosis.
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http://dx.doi.org/10.1080/00365521.2020.1837928DOI Listing
December 2020

Serological Biomarkers of Tissue Turnover Identify Responders to Anti-TNF Therapy in Crohn's Disease: A Pilot Study.

Clin Transl Gastroenterol 2020 09;11(9):e00217

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Introduction: Anti-tumor necrosis factor (TNF) therapy is effective in inducing remission in Crohn's disease in 60% of patients. No serological biomarkers are available, which can predict response to anti-TNF. We aimed to investigate serological markers of collagen turnover reflecting tissue inflammation as predictors of response to anti-TNF.

Methods: In 2 retrospective observational cohorts, markers for matrix metalloproteinase-degraded type III and IV collagens (C3M and C4M, respectively) and for formation of type III and IV collagens (PRO-C3 and PRO-C4, respectively) were measured in serum and compared with standard C-reactive protein in patients with active Crohn's disease who started infliximab (IFX, n = 21) or adalimumab (ADA, n = 21). Disease activity was classified by the Harvey-Bradshaw index (active disease ≥5); response was defined as clinical remission.

Results: Seventeen patients (81%) treated with IFX were in remission at week 14; 15 patients (71%) treated with ADA were in remission at week 8. Serum C4M at baseline was increased in nonresponders compared with responders (IFX: 35.0 ± 2.4 vs 23.2 ± 2.6, P = 0.04, ADA: 53.0 ± 3.2 vs 34.1 ± 2.8, P = 0.006). C4M levels at baseline predicted response in both cohorts (IFX: odds ratio 39 [95% confidence interval, 2.4-523.9] P = 0.02, cutoff 35.2 nmol/L; ADA: odds ratio 26 [95% confidence interval, 1.8-332.5], P = 0.01, cutoff 46.9 nmol/L). C-reactive protein was not able to predict response to anti-TNF.

Discussion: Response to anti-TNF therapy within the first 14 weeks of treatment can be predicted based on baseline levels of basement membrane marker C4M. This marker could be used as biomarker for response to anti-TNF and could aid in early therapy decision making. Validation in larger well-defined cohorts is needed.
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http://dx.doi.org/10.14309/ctg.0000000000000217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494148PMC
September 2020

Altered balance between collagen formation and degradation after successful direct-acting antiviral therapy of chronic hepatitis C.

J Viral Hepat 2021 02 2;28(2):236-244. Epub 2020 Nov 2.

Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

The effect of direct-acting antiviral (DAA) therapy on extracellular matrix (ECM) turnover, a prominent feature of chronic hepatitis C (CHC), is unknown. ECM protein degradation and formation generate fragments reflecting the tissue turnover balance when quantified in the blood. PRO-C3 and PRO-C4 reflect type III and IV collagen formation; C3M and C4M are degradation markers of type III and IV. We aimed to assess the markers' dynamics with DAA therapy in CHC patients. Plasma PRO-C3, PRO-C4, C3M and C4M were assessed before, during and up till one year after 12-24 weeks of DAA therapy in 77 CHC patients with advanced fibrosis (n = 14) or cirrhosis (n = 63). Liver stiffness was evaluated using transient elastography. PRO-C3, C3M and C4M levels decreased significantly (P < .00001) while PRO-C4 was unchanged (P = .20) during the study period. There was a steep decrease in the PRO-C3/C3M ratio during DAA therapy and follow-up (P < .02). The PRO-C4/C4M ratio was unchanged (P > .27). The dynamics of the collagen markers behaved similarly between patients with advanced fibrosis and cirrhosis. However, the cirrhosis patients had >20% higher levels of C3M, PRO-C4 and C4M at all time points (P < .05). The collagen markers correlated with liver stiffness at baseline and follow-up.Markers of type III and IV collagen formation and degradation decreased during and after successful DAA therapy in CHC patients with advanced liver disease, and associated with disease severity. These results indicate an altered balance between collagen formation and degradation after viral clearance suggesting favourable effects on liver fibrosis.
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http://dx.doi.org/10.1111/jvh.13416DOI Listing
February 2021

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

J Clin Med 2020 Oct 6;9(10). Epub 2020 Oct 6.

Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group ( = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.
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http://dx.doi.org/10.3390/jcm9103213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601647PMC
October 2020

Thrombophilia testing in patients with portal vein thrombosis.

Scand J Clin Lab Invest 2020 Dec 7;80(8):694-698. Epub 2020 Oct 7.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Portal vein thrombosis (PVT) is a rare but severe condition. Several risk factors predispose to PVT. However, it remains unclear to which degree thrombophilia contributes to the risk of PVT and whether PVT patients should be routinely referred for thrombophilia testing. The aim of the present study was to investigate the prevalence of thrombophilia in PVT patients to clarify the relevance of thrombophilia testing in PVT patients. Clinical data and results from thrombophilia investigations were systematically obtained from all PVT patients referred to Centre for Hemophilia and Thrombosis, Aarhus University Hospital, Denmark for thrombophilia testing between 1 of January 2010 and 31 of December 2018 ( = 93). The investigated thrombophilias included factor V Leiden and prothrombin G20210A mutations, deficiency of protein S, protein C and antithrombin, antiphospholipid syndrome, and increased levels of factor VIII. The prevalence of thrombophilia was compared to healthy controls obtained from previously published data on thrombophilia distribution in cohorts of the Western European adult general population. Comparing PVT patients with healthy controls, significantly increased odds of presence of lupus anticoagulant (crude odds ratio (OR) 6.2, 95% confidence interval (CI) 1.8-20.6) were found, whereas no significantly increased odds of inherited thrombophilia were demonstrated. In conclusion, routine testing for inherited thrombophilia in PVT patients does not seem indicated. However, PVT patients should still be tested for antiphospholipid antibodies because patients meeting the criteria for antiphospholipid syndrome preferentially should receive vitamin K antagonists as anticoagulant therapy.
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http://dx.doi.org/10.1080/00365513.2020.1827289DOI Listing
December 2020
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