Publications by authors named "Niels Kristian Aagaard"

34 Publications

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

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

External validation of the Freiburg index of post-TIPS survival.

J Hepatol 2021 09 26;75(3):746-747. Epub 2021 Apr 26.

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

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http://dx.doi.org/10.1016/j.jhep.2021.04.027DOI Listing
September 2021

Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats.

Am J Physiol Gastrointest Liver Physiol 2021 04 6;320(4):G474-G483. Epub 2021 Jan 6.

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

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% ( < 0.01), gene expression of argininosuccinate synthetase 1 () was decreased by 33% ( < 0.05), and plasma ammonia concentrations were eightfold elevated ( < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.
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http://dx.doi.org/10.1152/ajpgi.00136.2020DOI Listing
April 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

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Ugeskr Laeger 2019 Nov;181(45)

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.
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November 2019

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis.

Clin Gastroenterol Hepatol 2020 04 5;18(4):963-973.e14. Epub 2019 Aug 5.

EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain.

Background & Aims: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP).

Methods: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course.

Results: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007).

Conclusions: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.
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http://dx.doi.org/10.1016/j.cgh.2019.07.055DOI Listing
April 2020

Resistance Training Increases Muscle Strength and Muscle Size in Patients With Liver Cirrhosis.

Clin Gastroenterol Hepatol 2020 05 5;18(5):1179-1187.e6. Epub 2019 Aug 5.

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

Background & Aims: Cirrhosis is often complicated by reduced muscle mass and strength, which limits the ability to perform daily activities and affects quality of life. Resistance training can increase muscle strength and mass in elderly and chronically ill patients. We performed a randomized controlled trial to investigate whether resistance training increases muscle strength and size in patients with compensated cirrhosis.

Methods: We performed a prospective study of 39 patients with cirrhosis (Child-Pugh class A or B) seen at an outpatient clinic in Denmark from January 2015 through March 2017. Participants protein intake and activity levels were registered daily. Participants were randomly assigned (1:1) to a group that performed 36 1-hour sessions of physical exercise (supervised progressive resistance training for 1 hour, 3 times weekly for 12 weeks) or a control group (no change in daily activity level). Maximal muscle strength was measured as the peak torque in isokinetic knee extension and muscle size was measured as the cross-sectional area of the quadriceps muscle, assessed by magnetic resonance imaging of the thigh.

Results: The exercise group increased their muscle strength by 13% (from a mean 119 Nm to 134 Nm)-an 11 Nm greater gain in mean strength than that of the control group (P = .05). The exercise group increased their quadriceps cross-sectional area by 10% (from a mean 58.5 cm to 64.6 cm)-a 4.4 cm greater gain than that of the control group (P < .01). The exercise group had significant increases in whole-body lean mass and body cell mass, and significant increases in 6-minute walking distance and the mental component summary of the short form-36 questionnaire. Adverse events were minor and equal between groups.

Conclusions: In a randomized trial of patients with compensated cirrhosis, we found that 12 weeks of supervised progressive resistance training increased muscle strength and size and had beneficial effects on general performance measures, compared with patients who did not change their daily activity routine (control subjects). ClinicalTrials.gov no: NCT02343653.
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http://dx.doi.org/10.1016/j.cgh.2019.07.058DOI Listing
May 2020

Long-term effects and complications of the transjugular intrahepatic portosystemic shunt: a single-centre experience.

Scand J Gastroenterol 2019 Jul 16;54(7):899-904. Epub 2019 Jun 16.

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

Accurate estimates of the long-term risks of adverse outcomes after transjugular intrahepatic portosystemic shunt (TIPS) treatment are needed. The aim of this cohort study was to estimate the risks of stent dysfunction, variceal bleeding, refractory ascites, hepatic encephalopathy (HE), and death after TIPS treatment. We extracted data from electronic medical records of 104 consecutive TIPS patients. Gore® Viatorr® TIPS endoprostheses were used in all patients. We conducted competing risks analysis of the risk of stent dysfunction and variceal bleeding, and Kaplan-Meier estimation of overall survival. The overall 1-year survival after TIPS insertion was 82% (95% confidence interval [CI]: 73-88%), and the 1-year risk of stent dysfunction was 15% (95% CI: 9-22%). In patients who had a TIPS for variceal bleeding, the 1-year risk of rebleeding was 23% (95% CI: 13-35%). In patients who had a TIPS for refractory ascites, the risk of having an unsuccessful ascites outcome 1 year after TIPS for refractory ascites was 35% (95% CI: 21-52%). Overall, the 1-year risk of overt HE was 38% (95% CI: 32-43%). The risk of experiencing any of the defined complications during the first year was 56% (95% CI: 45-66%). TIPS is an effective treatment for variceal bleeding and refractory ascites in most cases, but more than half of the patients experience either death, stent dysfunction, recurrence of symptoms, or overt HE within the first year after the procedure.
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http://dx.doi.org/10.1080/00365521.2019.1630675DOI Listing
July 2019

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

Gastroenterology 2019 07 22;157(1):149-162. Epub 2019 Mar 22.

Department of Gastroenterology, Hospital Ramón y Cajal and CIBERehd, Madrid, Spain.

Background & Aims: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections.

Methods: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study).

Results: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines.

Conclusions: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.
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http://dx.doi.org/10.1053/j.gastro.2019.03.021DOI Listing
July 2019

Progressive resistance training prevents loss of muscle mass and strength in bile duct-ligated rats.

Liver Int 2019 04 25;39(4):676-683. Epub 2018 Nov 25.

Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada.

Background: Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct-ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats.

Methods: A group of BDL-rats underwent a progressive resistance training programme and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed.

Results: BDL + exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups.

Conclusion: Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia; however, a tendency was observed.
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http://dx.doi.org/10.1111/liv.13997DOI Listing
April 2019

Terlipressin for variceal bleeding induces large plasma sodium fluctuations in patients without cirrhosis.

United European Gastroenterol J 2018 Oct 28;6(8):1199-1205. Epub 2018 May 28.

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

Background: Terlipressin is used as pharmacological treatment for variceal bleeding. The drug's physiological effect favours hyponatremia, and rapid changes in plasma sodium (PNa) may cause brain injury. Cirrhosis patients seem to be largely protected against this effect but patients without cirrhosis may not be so.

Objective: The objective of this study was to examine whether terlipressin treatment of patients without cirrhosis leads to more serious fluctuations in PNa than in cirrhosis.

Methods: In a retrospective cohort design, during a 39-month period, 11 patients with prehepatic portal hypertension and no cirrhosis and 134 patients with cirrhosis received a minimum cumulative terlipressin dose of 4 mg during at least 24 hours for variceal bleeding. The groups' PNa changes were compared.

Results: During terlipressin, the non-cirrhotic patients developed a greater reduction in PNa [mean 8.3 (95% confidence interval (CI) 1.9-14.6) vs. 1.8 (1.0-2.7) mmol/l;  = 0.048], a lower nadir PNa [129 (123-135) vs. 133 (132-134) mmol/l;  = 0.06], and within 48 hours after terlipressin a greater increase in PNa [12.6 (3.4-21.7) vs. 2.3 (1.5-3.0) mmol/l;  = 0.03]. Severe (>10 mmol/l change) hyponatriemia or PNa rebound were seen in 27% of these patients but in only 4% of those with cirrhosis ( = 0.02). One non-cirrhotic patient developed permanent brain damage.

Conclusion: Terlipressin treatment of bleeding varices carries a high risk of potentially dangerous PNa fluctuations in patients with non-cirrhotic prehepatic portal hypertension.
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http://dx.doi.org/10.1177/2050640618781205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169052PMC
October 2018

Time course of compromised urea synthesis in patients with alcoholic hepatitis.

Scand J Gastroenterol 2018 05 7;53(5):592-597. Epub 2017 Nov 7.

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

Objectives: Alcoholic hepatitis (AH) markedly decreases the urea synthesis capacity. We aimed to investigate the time course of this compromised essential liver function in patients with AH and its relation to treatment and survival.

Materials And Methods: Thirty patients with AH were included in a prospective cohort study. We measured the substrate-independent urea synthesis capacity, i.e., the functional hepatic nitrogen clearance (FHNC), in the patients at study entry and again at three months (survivors/available: n = 17). Patients with severe disease (Glasgow Alcoholic Hepatitis Score ≥9, n = 17) were randomized to receive either prednisolone or pentoxifylline and were in addition examined after 14 days (n = 9).

Results: FHNC (normal range = 25-45 L/h) was markedly decreased at study entry (median = 5.6 (IQR = 3.0-9.6) L/h) and increased by three-fold in survivors at three months (15.1 (12.0-22.9) L/h; p < .001). In patients with severe AH, FHNC was also increased after 14 days of pharmacologic treatment and showed the greatest increase in the patients taking prednisolone (prednisolone 25.4 (20.6-26.2) L/h vs. pentoxifylline 12.3 (8.0-15.3) L/h; p = .05). FHNC at study entry was lower in 90-day non-survivors than in survivors (p = .04).

Conclusions: The decrease in the urea synthesis capacity in patients with AH was the most marked in short-term non-survivors and partly recovered in survivors at three months. In patients on pharmacologic treatment, recovery was observed already after 14 days, and it was nearly complete in those on prednisolone. Thus, metabolic liver failure in AH seems to be prognostically important, is potentially reversible, and may recover more rapidly following treatment with prednisolone.
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http://dx.doi.org/10.1080/00365521.2017.1399163DOI Listing
May 2018

[Acute-on-chronic liver failure].

Ugeskr Laeger 2017 Sep;179(38)

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute decompensation of liver cirrhosis, organ failure and high short-term mortality (20-80% at one month). The main precipitants are infections and excessive alcohol intake, and the mechanistic features include a high level of systemic inflammation, macrophage activation and liver injury. The severity of ACLF is graded according to the number and extent of organ failures. Prognostic scores help predict mortality and support decisions on intensive treatment or futility.
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September 2017

Branched-chain amino acids for people with hepatic encephalopathy.

Cochrane Database Syst Rev 2017 05 18;5:CD001939. Epub 2017 May 18.

Department of Hepatology and Gastroenterology, Aarhus Kommunehospital, Nørrebrogade 44, Aarhus C, Denmark, DK-8000.

Background: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy.

Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy.

Search Methods: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, and LILACS (May 2017).

Selection Criteria: We included randomised clinical trials, irrespective of the bias control, language, or publication status.

Data Collection And Analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach.

Main Results: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30).

Authors' Conclusions: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.
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http://dx.doi.org/10.1002/14651858.CD001939.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481897PMC
May 2017

Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis.

PLoS One 2016 5;11(7):e0158388. Epub 2016 Jul 5.

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

Background And Aim: Data on quantitative metabolic liver functions in the life-threatening disease alcoholic hepatitis are scarce. Urea synthesis is an essential metabolic liver function that plays a key regulatory role in nitrogen homeostasis. The urea synthesis capacity decreases in patients with compromised liver function, whereas it increases in patients with inflammation. Alcoholic hepatitis involves both mechanisms, but how these opposite effects are balanced remains unclear. Our aim was to investigate how alcoholic hepatitis affects the capacity for urea synthesis. We related these findings to another measure of metabolic liver function, the galactose elimination capacity (GEC), as well as to clinical disease severity.

Methods: We included 20 patients with alcoholic hepatitis and 7 healthy controls. The urea synthesis capacity was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the blood α-amino nitrogen concentration and urea nitrogen synthesis rate during alanine infusion. The GEC was determined using blood concentration decay curves after intravenous bolus injection of galactose. Clinical disease severity was assessed by the Glasgow Alcoholic Hepatitis Score and Model for End-Stage Liver Disease (MELD) score.

Results: The FHNC was markedly decreased in the alcoholic hepatitis patients compared with the healthy controls (7.2±4.9 L/h vs. 37.4±6.8 L/h, P<0.01), and the largest decrease was observed in those with severe alcoholic hepatitis (4.9±3.6 L/h vs. 9.9±4.9 L/h, P<0.05). The GEC was less markedly reduced than the FHNC. A negative correlation was detected between the FHNC and MELD score (rho = -0.49, P<0.05).

Conclusions: Alcoholic hepatitis markedly decreases the urea synthesis capacity. This decrease is associated with an increase in clinical disease severity. Thus, the metabolic failure in alcoholic hepatitis prevails such that the liver cannot adequately perform the metabolic up-regulation observed in other stressful states, including extrahepatic inflammation, which may contribute to the patients' poor prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933397PMC
July 2017

Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF).

J Hepatol 2016 Apr 27;64(4):813-22. Epub 2015 Nov 27.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Background & Aims: Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study.

Methods: Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion.

Results: We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)).

Conclusions: The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.
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http://dx.doi.org/10.1016/j.jhep.2015.11.021DOI Listing
April 2016

Branched-chain amino acids for people with hepatic encephalopathy.

Cochrane Database Syst Rev 2015 Sep 17(9):CD001939. Epub 2015 Sep 17.

Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650.

Background: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy.

Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy.

Search Methods: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index (August 2015).

Selection Criteria: We included randomised clinical trials, irrespective of the bias control, language, or publication status.

Data Collection And Analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach.

Main Results: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30).

Authors' Conclusions: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.
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http://dx.doi.org/10.1002/14651858.CD001939.pub3DOI Listing
September 2015

Branched-chain amino acids for people with hepatic encephalopathy.

Cochrane Database Syst Rev 2015 Feb 25(2):CD001939. Epub 2015 Feb 25.

Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650.

Background: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy.

Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy.

Search Methods: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index on 2 October 2014.

Selection Criteria: We included randomised clinical trials, irrespective of the bias control, language, or publication status.

Data Collection And Analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach.

Main Results: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. Based on the combined Cochrane Hepato-Biliary Group score, we classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30).

Authors' Conclusions: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.
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http://dx.doi.org/10.1002/14651858.CD001939.pub2DOI Listing
February 2015

Propranolol treatment of portal hypertension in cirrhosis patients is better the higher the untreated pressure: a single-centre prospective experience.

Scand J Gastroenterol 2013 Aug 11;48(8):969-73. Epub 2013 Jun 11.

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

Objective: To assess the effect of propranolol treatment on the hepatic venous pressure gradient (HVPG) and the relationship between native HVPG and the effect of propranolol in patients with cirrhosis and portal hypertension in a prospective, observational, single-center study.

Material And Methods: The HVPG was registered prospectively in 124 consecutive cirrhosis patients with and without treatment with propranolol 80 mg daily. Results. 41% of the patients responded to the treatment with the intended reduction of HVPG to <12 mm Hg and/or by >20%. The HVPG reduction was larger for higher native HVPG values (p < 0.001). There was no significant relation between changes in heart rate and changes in HVPG (p = 0.8).

Conclusions: The high fraction of hemodynamic non-responders supports the rationale of measuring the HVPG with and without propranolol treatment to assist the clinical assessment and avoid meaningless and potentially harmful treatment. The positive association between a high native HVPG and propranolol-induced HVPG reduction indicates that pharmacological treatment also benefits patients with advanced portal hypertension.
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http://dx.doi.org/10.3109/00365521.2013.805811DOI Listing
August 2013

Regulation of urea synthesis during the acute-phase response in rats.

Am J Physiol Gastrointest Liver Physiol 2013 Apr 7;304(7):G680-6. Epub 2013 Feb 7.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, DK-8000 Aarhus, Denmark.

The acute-phase response is a catabolic event involving increased waste of amino-nitrogen (N) via hepatic urea synthesis, despite an increased need for amino-N incorporation into acute-phase proteins. This study aimed to clarify the regulation of N elimination via urea during different phases of the tumor necrosis factor-α (TNF-α)-induced acute-phase response in rats. We used four methods to study the regulation of urea synthesis: We examined urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, the in vivo capacity of urea-N synthesis (CUNS), and known humoral regulators of CUNS at 1, 3, 24, and 72 h after TNF-α injection (25 μg/kg iv rrTNF-α) in rats. Serum acute-phase proteins and their liver mRNA levels were also measured. The urea cycle enzyme mRNA levels acutely decreased and then gradually normalized, whereas the urea cycle enzyme proteins remained essentially unchanged over time. The CUNS rose after 3 h and then normalized. The acute-phase response was fully activated at 24 h with markedly increased serum levels of the acute-phase proteins. TNF-α acutely upregulated the CUNS. Later, despite the fully established 24-h acute-phase response and the decreased activity of the urea cycle enzyme genes, there was no change in the urea cycle enzyme proteins or the CUNS. Thus in no phase after the initiation of the acute-phase response was in vivo urea synthesis orchestrated in combination with acute-phase protein synthesis so as to limit N waste.
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http://dx.doi.org/10.1152/ajpgi.00416.2012DOI Listing
April 2013

Branched-chain amino acids and muscle ammonia detoxification in cirrhosis.

Metab Brain Dis 2013 Jun 15;28(2):217-20. Epub 2013 Jan 15.

Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Noerrebrogade, 8000, C Aarhus, Denmark.

Branched-chain amino acids (BCAA) are used as a therapeutic nutritional supplement in patients with cirrhosis and hepatic encephalopathy (HE). During liver disease, the decreased capacity for urea synthesis and porto-systemic shunting reduce the hepatic clearance of ammonia and skeletal muscle may become the main alternative organ for ammonia detoxification. We here summarize current knowledge of muscle BCAA and ammonia metabolism with a focus on liver cirrhosis and HE. Plasma levels of BCAA are lower and muscle uptake of BCAA seems to be higher in patients with cirrhosis and hyperammonemia. BCAA metabolism may improve muscle net ammonia removal by supplying carbon skeletons for formation of alfa-ketoglutarate that combines with two ammonia molecules to become glutamine. An oral dose of BCAA enhances muscle ammonia metabolism but also transiently increases the arterial ammonia concentration, likely due to extramuscular metabolism of glutamine. We, therefore, speculate that the beneficial effect of long term intake of BCAA on HE demonstrated in clinical studies may be related to an improved muscle mass and nutritional status rather than to an ammonia lowering effect of BCAA themselves.
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http://dx.doi.org/10.1007/s11011-013-9377-3DOI Listing
June 2013

Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

Metab Brain Dis 2013 Jun 29;28(2):221-5. Epub 2012 Dec 29.

Department of Medicine, Copenhagen University Hospital Gentofte, Hellerup, Denmark.

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions.
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http://dx.doi.org/10.1007/s11011-012-9372-0DOI Listing
June 2013

Treatment of the hepatorenal syndrome and hyponatremia in cirrhosis - part II.

Dan Med J 2012 Jan;59(1):C4372

Department of Functional Imaging and Research, Section of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Denmark.

National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis.
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January 2012

Treatment of ascites and spontaneous bacterial peritonitis - part I.

Dan Med J 2012 Jan;59(1):C4371

Department of Functional Imaging and Research, Section of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Denmark.

National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis.
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January 2012

Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS.

Gut 2011 Oct 14;60(10):1389-93. Epub 2011 May 14.

Department of Medicine V (Hepato and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark.

Introduction: Hepatic macrophages (Kupffer cells) undergo inflammatory activation during the development of portal hypertension in experimental cirrhosis; this activation may play a pathogenic role or be an epiphenomenon. Our objective was to study serum soluble CD163 (sCD163), a sensitive marker of macrophage activation, before and after reduction of portal venous pressure gradient by insertion of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis.

Methods: sCD163 was measured in 11 controls and 36 patients before and 1, 4 and 26 weeks after TIPS. We used lipopolysaccharide binding protein (LBP) levels as a marker of endotoxinaemia. Liver function and clinical status of the patients were assessed by galactose elimination capacity and Model for End Stage Liver Disease score.

Results: The sCD163 concentration was more than threefold higher in the patients than in the controls (median 5.22 mg/l vs 1.45 mg/l, p<0.001). The sCD163 was linearly related to the portal venous pressure gradient (r(2)=0.24, p<0.001), also after adjustment for cirrhosis status. The sCD163 concentration was 12% higher in the hepatic than in the portal vein (p<0.02). The LBP level was 70% higher in the patients (52.2 vs 30.4 μg/l, p<0.001). During follow-up after TIPS, the sCD163 concentration did not change while LBP almost normalised.

Conclusion: Kupffer cells were activated in patients with liver cirrhosis in parallel with their portal hypertension. The activation was not alleviated by the mechanical reduction of portal hypertension and the decreasing signs of endotoxinaemia. The findings suggest that Kupffer cell activation is a constitutive event that may play a pathogenic role for portal hypertension.
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http://dx.doi.org/10.1136/gut.2010.234542DOI Listing
October 2011

[Picture of the month: portal vein thrombosis].

Ugeskr Laeger 2011 Mar;173(12):902

Medicinsk Afdeling, Haderslev Sygehus, Denmark.

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March 2011

A 15-year-old girl with severe hemolytic Wilson's crisis recovered without transplantation after extracorporeal circulation with the Prometheus system.

Blood Purif 2009 11;28(2):102-7. Epub 2009 May 11.

Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, NBG, Aarhus, Denmark.

Background: Wilson's disease (WD) can present in a fulminant form with hepatocellular dysfunction, hemolysis and multiorgan failure (Wilson's crisis). We present a previously healthy young woman with severe WD whose WD severity score was 13. A score >11 indicates a poor chance of survival and liver transplantation will usually be recommended.

Methods: Penicillamine and acetylcysteine were initially administered, but the patient deteriorated further, and extracorporeal liver support with the Prometheus FPSA (fractionated plasma separation and adsorption) system was initiated. The patient was treated 6 h daily during 3 consecutive days.

Results: Severe hemolysis was reduced to low-grade hemolysis, with no further need for transfusions. The mental state improved and after 4 months practically all biochemical markers were normalized.

Conclusions: This is the first report of FPSA albumin dialysis of a patient with Wilson's crisis and the first report in which a patient with a WD score >11 survived without transplantation.
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http://dx.doi.org/10.1159/000218090DOI Listing
November 2009

Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats.

Growth Horm IGF Res 2009 Oct 23;19(5):426-31. Epub 2009 Feb 23.

Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, DK-8000 Aarhus C, Denmark.

Objectives: Growth hormone (GH) reduces the catabolic side effects of steroid treatment via effects on the amino-nitrogen metabolism. Ipamorelin is a synthetic peptide with GH releasing properties. We wished to study the metabolic effects of Ipamorelin and GH on selected hepatic measures of alpha-amino-nitrogen conversion during steroid-induced catabolism.

Design: Five groups of rats were included: (1) free-fed controls (2) pair-fed controls (3) prednisolone (delcortol, 4 mg x kg(-1) x day(-1)) (4) prednisolone and GH (1 mg x kg(-1) x day(-1)) (5) prednisolone and Ipamorelin (0.5 mg x kg(-1) x day(-1)). After seven days the hepatic capacity of urea-N synthesis (CUNS) was determined in parallel with measurements of liver mRNA levels of urea cycle enzymes, whole-body N-balance, and N-contents of various organs.

Results: Compared to pair-fed controls, prednisolone increased CUNS (p<0.01) as well as the expression of urea cycle genes (p<0.01), and decreased N-balance (p<0.01) as well as organ N-contents (p<0.05). Compared to prednisolone treated animals, co-administration of GH reduced CUNS by 33% (p<0.01), normalized urea cycle gene expression, improved N-balance 2.5-fold, and normalized or improved organ N-contents. In prednisolone treated rats Ipamorelin reduced CUNS by 20% (p<0.05), decreased the expression of urea cycle enzymes, neutralised N-balance, and normalized or improved organ N-contents.

Conclusion: Accelerated nitrogen wasting in the liver and other organs caused by prednisolone treatment was counteracted by treatment with either GH or its secretagogue Ipamorelin, though at the doses given less efficiently by the latter. This functional study of animals confirms that the GH secretagogue exerts GH related metabolic effects and may be useful in the treatment of steroid-induced catabolism.
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http://dx.doi.org/10.1016/j.ghir.2009.01.001DOI Listing
October 2009
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