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The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged >= 18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

Metabolic dysfunction in patients with metabolic fatty liver disease (MAFLD) may increase the risk for diabetes development. The liver is essential for the postprandial control of our metabolism and hormonal response, yet most studies focus on fasting conditions. We therefore studied the fasting and postprandial phase in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD, (n = 9, mean age 50 y, mean BMI 35 kg/m2, no/mild fibrosis) , cirrhosis (n = 10, age 62 y, BMI 32 kg/m2, CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2) , randomized 1:1 to fasting or Nutridrink (Nutricia, 300 kcal) . None of the postprandial patients had type 2 diabetes (T2D) . In the NAFLD/cirrhosis groups, 17/classified as MAFLD. Peripheral blood samples were collected at 0, 15, 45, 60, 90 and 120 minutes. At time point 60, a transjugular liver biopsy and liver vein blood were taken. Levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured in peripheral blood, glucagon and FGF21 also in liver vein blood. Postprandial peak glucose and C-peptide was increased in NAFLD and cirrhosis compared with healthy (mean peak glucose (mM) 7, 10, 6; mean peak C-peptide (pM) 2675, 3340, 1689, respectively) . The postprandial incremental AUC for insulin was significantly increased in patients with NAFLD compared to healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia, a phenotype related to prediabetes. FGF21 was increased in NAFLD and cirrhosis and correlated to age (r= .61, P = .001) and fasting glucose (r = .54, P = .006) . Glucagon levels were higher in liver vein compared to peripheral blood, while FGF21 levels were similar in both compartments. In summary, patients with NAFLD and cirrhosis without T2D showed significant metabolic dysfunction after a standardized meal compared to healthy controls. We found impaired glucose tolerance, hyperinsulinemia and hyperglucagonemia in both NAFLD and cirrhosis, suggesting a condition of prediabetes in patients with MAFLD. Disclosure J. Grandt: None. A.H. Jensen: None. M.P. Werge: None. E.B. Rashu: None. A. Junker: None. L. Hobolth: None. C. Mortensen: None. M. Vyberg: None. R. Serizawa: Consultant; Merck Sharp & Dohme Corp. L. Gluud: Advisory Panel; Novo Nordisk. Consultant; Pfizer Inc. Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. N.J. Wewer Albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc. Speaker's Bureau; Merck & Co., Inc., Mercodia AB. Funding Nicolai J. Wewer Albrechtsen was financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.

Gluco-regulatory disturbances such as hepatic insulin resistance, hyperinsulinemia and prediabetes are commonly present in patients with nonalcoholic fatty liver disease (NAFLD) and those individuals may over time develop full-blown type 2 diabetes. Chronic liver diseases­ such as NAFLD and autoimmune liver diseases (AILDs) are heterogenous but may affect glucose-metabolism similarly. It is, however, unknown if AILDs—such as primary biliary cholangitis (PBC) —display gluco-regulatory impairments. We therefore investigated glucose and hormonal responses during a 75 g oral glucose tolerance test (OGTT) in patients with biopsy-verified, non-cirrhotic PBC (n = 9, age 55 ± y (mean ± sd) , BMI 31 ± 6 kg/m2 (mean ± sd)) , NAFLD (n = 6, age 38 ± 17 y, BMI 31 ± 4 kg/m2) and healthy controls (n = 8, age 23 ± 3 y, BMI 23 ± 2 kg/m2) . None of the participants had diabetes. In the PBC group, 3 had NAFLD. Fasting glucose, c-peptide and insulin levels were significantly increased in PBC and NAFLD compared with healthy controls ([mean (95 % CI) ]; glucose (mM) 5.6 (4.7-6.7) , 5.7 (5.2-6.1) , 4.7 (3.9-5.6) ; c-peptide (pM) 993 (556-1773) , 1334 (1036-1719) , 483 (268-869) ; insulin (pM) 98 (33-298) , 166 (103-267) , 43 (14-136) ; respectively) . Hepatic insulin resistance (reflected by fasting homeostasis model assessment of insulin resistance (HOMA-IR)) was present in PBC (mean 4.0 (95 % CI 1.2-13.9)) and NAFLD (7.0 (4.1-11.9)) but not in healthy controls (1.5 (0.4-5.4)) . There was no significant difference in glucose levels between the groups. Beta-cell secretion (c-peptide) was significantly increased in PBC and NAFLD. Insulin responses were higher in PBC and NAFLD compared with healthy but only reached statistical significance in NAFLD. Our data suggest that patients with PBC have gluco-regulatory disturbances including hepatic insulin resistance and impaired beta-cell function. Metabolic dysfunction of PBC may be underestimated and warrant further investigation. Disclosure A.H. Jensen: None. H. Ytting: Other Relationship; Gilead Sciences, Inc. J. Grandt: None. M.P. Werge: None. E.B. Rashu: None. L.E. Hetland: None. A. Junker: None. L. Hobolth: None. C. Mortensen: None. F. Tofteng: None. M. Vyberg: None. R. Serizawa: Consultant; Merck Sharp & Dohme Corp. L. Gluud: Advisory Panel; Novo Nordisk. Consultant; Pfizer Inc. Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. N.J. Wewer Albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc. Speaker’s Bureau; Merck & Co., Inc., Mercodia AB. Funding Nicolai J. Wewer Albrechtsen were financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude

Frederik Faergemann Lau,1 Signe Bollerup,1 Frederik Engsig,1 Henrik Krarup,2 Lone Hagens Mygind,3 Jesper Bach Hansen,3 Lone Galmstrup Madsen,4,5 Peter Thielsen,6 Ulla Balslev,7 Lars Nørregaard Nielsen,8 Toke S Barfod,9 Mette Rye Clausen,10 Lise Hobolth,11 Alex Lund Laursen,12 Britta Tarp,13 Birgit T Roege,14 Jan Gerstoft,15 Peer Brehm Christensen,16,17 Nina Weis1,5 1Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark; 2Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark; 3Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Medical Gastroenterology, Zealand University Hospital, Koege, Denmark; 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 6Department of Gastroenterology, Copenhagen University Hospital-Herlev, Herlev, Denmark; 7Department of Infectious Diseases, Copenhagen University Hospital-Herlev, Herlev, Denmark; 8Department of Lung- and Infectious Diseases, North Zealand Hospital-Hilleroed, Hilleroed, Denmark; 9Department of Internal Medicine and Infectious Diseases, Zealand University Hospital, Roskilde, Denmark; 10Department of Medical Gastroenterology and Hepatology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 11Department of Gastroenterology, Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark; 12Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; 13Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark; 14Department of Internal Medicine, Kolding Hospital, Kolding, Denmark; 15Department of Infectious Diseases, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 16Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; 17Clinical Institute, University of Southern Denmark, Odense, DenmarkCorrespondence: Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital – Hvidovre, Kettegaard Alle 30, Hvidovre, DK-2650, Denmark, Tel +45 3862 3514, Email nina.weis@regionh.dkObjective: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population.Study Design and Setting: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model.Results: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91– 1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76– 1.21).Conclusion: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population.Keywords: hepatitis B virus, viral infection, atherosclerosis, coronary heart disease, ischemic heart disease, cardiovascular disease, general population

Objective: To evaluate implementation of national guideline recommendations on treatment initiation for chronic hepatitis B (CHB) in Denmark. Methods: Using DANHEP, a nationwide cohort of chronic hepatitis B and C patients attending specialized hospital care in Denmark, we performed a descriptive cohort study from January 2002 through December 2017. We identified patients with CHB in 3 of 5 Danish regions, with at least two hospital/outpatient clinic visits during the study period. Results: We identified 990 CHB patients who remained untreated throughout the study period, and 265 who initiated treatment. At their last visit 952/990 (96%, 95% CI 95–97) untreated patients did not meet current national criteria for treatment initiation while 198/265 (75%, 95% CI 69–80) who initiated treatment met the national criteria. Overall, 198/236 (84%, 95% CI 79–88) who met national treatment criteria, initiated treatment. Conclusion: The majority of CHB patients received care in line with national guideline recommendations for treatment initiation. We found that only few patients eligible for treatment remained untreated. However, a fourth of patients who received treatment were not eligible according to national guidelines.

There are no rehabilitative offers to patients, who are discharged following a hospitalisation with decompensated liver cirrhosis. The development and implementation of a comprehensive rehabilitative offer can lead to early detection and treatment of complications, which could eventually result in hospitalisation. In this review, we argue, that prevention of hospitalisation, self-care, quality of life, patient satisfaction and compliance should form the basis of a rehabilitative offer for patients with liver cirrhosis.

Background & aims Decompensated cirrhosis is characterized by disturbed haemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. In a randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. Methods Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (±8.4), and MELD score 12 (±3.9). Patients received rifaximin 550 mg BD (n=36) or placebo BD (n=18). Blood and faecal (n=15) sampling were conducted at baseline and after four weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in faeces was analysed by 16S rRNA gene sequencing. Results Circulating markers of inflammation, including TNFα, interleukin-6, 10 and 18, Stromal cell-derived factor 1-α, transforming growth factor β-1 and high sensitivity CRP, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In faeces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n=34); or activated LBP (n=37) revealed no effect of rifaximin. Conclusion Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double-blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty-five patients were male, mean age 56 years (±8.4), average Child score 8.3 (±1.3), and Model for End-Stage Liver Disease score 11.7 (±3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 ± 3.8 mm Hg at baseline versus 16.6 ± 5.3 mm Hg at follow-up, compared to the placebo, mean 16.4 ± 4 mm Hg at baseline versus 16.3 ± 4.4 mm Hg at follow-up, P = 0.94. No effect was found on cardiac output, mean 6.9 ± 1.7 L/min at baseline versus 6.9 ± 2.3 L/min at follow-up, compared to placebo, mean 6.6 ± 1.9 L/min at baseline compared to 6.5 ±2.1 L/min at follow-up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes × s/cm 5) revealed no effect of rifaximin. Conclusion: Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017;65:592-603).

BACKGROUND: Non‐selective beta‐blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non‐selective beta‐blocker with additional intrinsic alpha(1)‐blocking effects, which may be superior to traditional, non‐selective beta‐blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non‐selective beta‐blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato‐Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non‐selective beta‐blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I(2) values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato‐Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I(2) = 0%, low‐quality evidence). There appeared to be no differences between carvedilol versus traditional, non‐selective beta‐blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I(2) = 45%, very low‐quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I(2) = 14%, low‐quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long‐term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non‐selective beta‐blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non‐serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I(2) = 88%; very low‐quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non‐selective beta‐blockers both in absolute (MD ‐1.75 mmHg, 95% CI ‐2.60 to ‐0.89; 368 participants; 6 trials; I(2) = 0%; low‐quality evidence) and percentage terms (MD ‐8.02%, 95% CI ‐11.49% to ‐4.55%; 368 participants; 6 trials; I(2) = 0%; low‐quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I(2) = 42%; very low‐quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non‐selective beta‐blockers on mortality, upper gastrointestinal bleeding, serious or non‐serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long‐term, double‐blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

To evaluate the safety of PleurX in cirrhotic patients with refractory ascites.We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period.We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow-up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p = .23 and .96, respectively). Mortality was higher in patients with malignant ascites (p= .01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups.PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings.

Bacterial translocation (BT) may cause infections, in particular, spontaneous bacterial peritonitis (SBP). In the absence of overt infection, BT may further stimulate the immune system and contribute to haemodynamic alterations and complications. Bacterial DNA (bDNA) is claimed to be a promising surrogate marker for BT, although its clinical relevance has been questioned.In 38 cirrhotic patients with and without SBP, bDNA in blood and ascites were assessed by 16S rDNA quantitative PCR. Levels of lipopolysaccharide-binding protein in plasma and highly sensitive C-reactive protein, tumour necrosis factor-α, soluble urokinase plasminogen activating receptor, interleukin-6, interleukin 8, interferon-γ inducible protein-10 and vascular endothelial growth factor in plasma and ascites were measured by multiplex cytokine and ELISA assays.In patients without signs of SBP or positive cultures, we found a high frequency of bDNA but low concordance of bDNA between blood and ascites. Markers of inflammation were not significantly different between blood bDNA-positive (22%), ascites bDNA-positive (52%), and bDNA-negative patients. The 16S rDNA PCR failed to show bDNA in two out of six samples with SBP. Sequencing of positive samples did not determine the source of bDNA.bDNA as assessed by this PCR method was largely unrelated to markers of inflammation and does not seem to be of clinical value in the diagnosis of SBP. According to our results, bDNA is not a reliable marker of BT.

Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis.Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing.Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor β-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin.Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Circulating levels of IGF-I and IGFBP-3 are low in cirrhosis and are related to liver dysfunction. Metabolic disturbances include malnutrition with altered body composition and osteopenia. Since the effects of IGF-I may be associated to changes in body composition and bone mineral content (BMC) in cirrhotic patients, we investigated the relations between changes in the IGF-system and body composition and the effects of long-term alpha- and beta-blockade.The study was designed as a combined cross-sectional and prospective randomised controlled study of 62 patients with cirrhosis. Twenty-three of these patients were randomised to treatment with beta- or combined alpha/beta-blocker for 3 months. Haemodynamics, body composition, and systemic and hepatic IGF-I and IGFBP-3 levels were determined in all patients. In the subgroup changes in body composition and IGF-I/IGFBP-3 levels after 3 months of beta- or combined alpha/beta-blockade were additionally examined.Both the hepatic and the systemic IGF systems were suppressed and correlated with liver dysfunction and anthropometrics (p0.05-0.001). Multivariate analyses revealed that changes in the IGF-system were determined by metabolic liver dysfunction as well as anthropometrics. In the follow-up study, hepatic venous IGF-I (p=0.05) and IGFBP-3 (p=0.02) increased after 3 months only in the group who received beta-blocker. In both groups, fat body mass increased significantly after 3 months (p=0.05-0.001).In cirrhosis, the IGF-system is associated with both anthropometrics and synthetic capacity of the liver. Changes in IGF-I relate to changes in anthropometrics and there seems to be a differential effect depending on the type of adrenoreceptor blockade. Future longitudinal studies are needed to unravel these mechanisms in cirrhosis.

Patients with advanced cirrhosis often develop a hyperdynamic circulation with central hypovolaemia. The events that initiate the systemic haemodynamic abnormalities and the coupling of these factors to splanchnic haemodynamics are still unclear. Objective On the basis of a large population of patients with cirrhosis to identify splanchnic and clinical characteristics associated with the development of the hyperdynamic circulation and survival.We included 410 patients with cirrhosis. In all patients, a full haemodynamic investigation was performed. The data were analysed using regression analyses, principal components analyses, and Cox proportional hazards analyses.Multivariate regression analyses showed that higher cardiac output was independently associated with higher hepatic venous pressure gradient (HVPG) and higher hepatic blood flow (HBF) (p0.00001). Higher heart rate was independently associated with presence of ascites and higher HVPG (p0.0001). Central blood volume and circulation time were independently associated with higher HBF and lower postsinusoidal resistance, respectively (p0.0001). Systemic vascular resistance was independently associated with lower HVPG (p0.0001). The final Cox proportional hazards model showed that decreased survival was independently associated with higher age (p=0.003), lower blood haemoglobin concentration (p=0.0006), higher plasma creatinine (p=0.01), higher plasma alkaline phosphatase (p=0.007), lower right atrial pressure (p=0.004), and higher heart rate (p=0.002).The development of the hyperdynamic circulation and central hypovolaemia are mainly explained by changes in portal pressure and HBF. Together with indicators of liver dysfunction, central hypovolaemia is associated with poorer prognosis.

OBJECTIVES Patients with cirrhosis often exhibit abnormalities in cardiovascular regulation and oxygenation. Many of these patients are treated with β-blockers and aldosterone antagonists that may influence the regulation of systemic haemodynamics, but the specific effects on systemic haemodynamics and oxygenation are less studied. We therefore investigated systemic haemodynamics and oxygenation in patients with cirrhosis before and after 3 weeks of treatment with propranolol or spironolactone. MATERIALS AND METHODS Twenty-two patients with cirrhosis were allocated into three groups as follows: a β-blocker group (n=7), a spironolactone group (n=8) and a control group (n=7). At baseline, and after 3 weeks, we measured the arterial blood pressure (BP), heart rate, Q-T frequency-corrected interval, baroreflex sensitivity, cardiac output, peripheral arterial inflow (ABFin), transcutaneous oxygenation and hormonal status. We also assessed immediate effects of propranolol in the β-blocker group. RESULTS Short-term and long-term β-blockade significantly reduced BP (-7%) and heart rate (-15%) (P

The Finometer measures haemodynamic parameters including cardiac output (CO) using non-invasive volume-clamp techniques. The aim of this study was to determine the accuracy of the Finometer in hyperdynamic cirrhotic patients using an invasive indicator dilution technique as control. CO was measured in twenty-three patients referred for invasive measurements of the hepatic venous pressure gradient on suspicion of cirrhosis. Invasive measurements of CO were performed using indicator dilution technique (CO(I)) and simultaneous measurements of CO were recorded with the Finometer (CO(F)). In six patients, measurements of CO were performed with invasive technique and the Finometer both before and after beta-blockade using 80 mg of propranolol and the changes in CO (DeltaCO(I) and DeltaCO(F) respectively) were calculated to evaluate the Finometers ability to detect relative changes in CO. Mean CO(I) was 6.1 +/- 1.6 [3.9;9.7] l min(-1) (mean +/- SD [range]) compared to mean CO(F) of 7.2 +/- 2.3 [3.1;11.9] l min(-1). There was a mean difference between CO(F) and CO(I) of 1.0 +/- 1.8 [-2.1;4.0] l min(-1) and 95% confidence interval of [0.2;1.8], P

Background: Several new treatments of bleeding oesophageal varices (BOV) have been introduced during the last 25 years; among these are vasoactive drugs, improved endoscopic techniques and prophylactic antibiotics. Aims: The aim was to compare clinical outcomes based on Baveno IV criteria in two patient-cohorts (1983–1987, n=56 and 2000–2007, n=111) with respect to control of bleeding, rebleeding and mortality after a first episode of BOV. Further, we wanted to assess whether an eventual reduction in bleeding-related mortality occurred within the first 5 days or between Days 6 and 42 after the bleeding episode. Methods: Data from medical records were collected, according to the Baveno IV criteria, on key events: type of treatment, failure to control bleeding, failure to prevent rebleeding, 5-day and 6-week mortality. Results: Six-week mortality decreased from 30.4 to 17.1% [odds ratio (OR) 0.44; 0.21–0.95] with a reduction in 5-day mortality from 17.9 to 6.3% (OR 0.31; 0.11–0.86). A non-significant reduction was seen in the 5-day failure rate to control bleeding from 35.7 to 26.1%. Mortality and failure to prevent rebleeding Days 6–42 decreased from 15.2 to 11.5% (NS) and 22.2 to 10.7% (NS) respectively. Mean length of hospital stay decreased from 14.6 ± 12.5 to 9.1 ± 9.0 days (P

A 12-year-old Middle Eastern girl presented with abdominal pain, weight loss, and intermittent pain in both thighs. She was initially suspected of Crohn disease, but this diagnosis was excluded after extensive gastromedical evaluation. Plain x-rays of the femora were normal, whereas the initial Tc-99m methylene diphosphonate (MDP) bone scan showed several foci with increased activity in both femurs. MR scan showed excessive periostal inflammatory and mild intramedullary changes in both femurs. A percutaneous bone biopsy demonstrated changes consistent with chronic recurrent multifocal osteomyelitis (CRMO). The patient's symptoms disappeared spontaneously, but reappeared 1.5 years later, which led to a new MDP bone scan that showed normal findings.

Background and aims Newer studies suggest that carvedilol, a beta-blocker with a moderate anti-alpha-1 activity, is superior to propranolol in reducing the portal pressure and risk of variceal bleeding. The effect on arterial blood pressure is a matter of concern especially in decompensated patients. Aims to assess potential differential effects of beta-blockers and beta-blockers with moderate anti-alpha-1 activity on selected haemodynamic, humoral, and respiratory characteristics in cirrhosis. Methods Patients with cirrhosis and portal hypertension were randomised to receive carvedilol (n = 16) or propranolol (n = 13). Cardiac, systemic and splanchnic parameters along with oxygen saturation and plasma renin were measured at inclusion and after 3 months. Results Arterial blood pressure, heart rate, and cardiac output decreased equally, central circulation time and systemic vascular resistance increased significantly but similarly. Central blood volume, plasma volume and arterial compliance were unaltered. The QTc interval and renin levels decreased in the carvedilol group, however not significantly different from the propranolol group. Arterial oxygen saturation and alveolar arterial oxygen gradient remained constant in both groups. Hepatic venous pressure gradient decreased equally in the carvedilol and propranolol groups (−17% and −20%, non significant). Conclusions Systemic haemodynamics and pulmonary effects of carvedilol and propranolol are modest and this study could not demonstrate any significant difference between the two treatments.

Portal hypertension leads to development of serious complications such as esophageal varices, ascites, renal and cardiovascular dysfunction. The importance of the degree of portal hypertension has been substantiated within recent years. Measurement of the portal pressure is simple and safe and the hepatic venous pressure gradient (HVPG) independently predicts survival and development of complications such as ascites, HCC and bleeding from esophageal varices. Moreover, measurements of HVPG can be used to guide pharmacotherapy for primary and secondary prophylaxis for variceal bleeding. Assessment of HVPG should therefore be considered as a part of the general characterization of patients with portal hypertension in departments assessing and treating this condition.

Carvedilol is a non-selective β-blocker with intrinsic anti-α(1)-adrenergic activity, potentially more effective than propranolol in reducing hepatic venous pressure gradient (HVPG). We compared the long-term effect of carvedilol and propranolol on HVPG and assessed whether the acute response to oral propranolol predicted the long-term HVPG response on either drug.HVPG was measured in 38 patients with cirrhosis and HVPG ≥ 12 mm Hg at baseline and then again 90 min after an oral dose of 80 mg propranolol. Patients were double-blinded randomized to either carvedilol (21 patients) or propranolol (17 patients) and after 90 days of treatment HVPG measurements were repeated.HVPG decreased by 19.3 ± 16.1% (p0.01) and by 12.5 ± 16.7% (p0.01) in the carvedilol and propranolol groups, respectively, with no significant difference between treatment regimens (p = 0.21). Although insignificant, an acute decrease in HVPG of ≥12% was the best cut-off value to predict long-term HVPG response to propranolol when using ROC curve analysis.This randomized study showed that carvedilol is at least as effective as propranolol on HVPG after long-term administration. Furthermore, a predictive value of an acute propranolol test on HVPG could not be confirmed.

Randomized controlled trials have shown beneficial effects of vasoactive drugs, endoscopic treatment and prophylactic antibiotics on the outcome of bleeding oesophageal varices (BOV). However, translating guidelines based on randomized controlled trials into clinical practice is difficult. Our aims were to compare adherence to evidence-based guidelines in BOV between a specialized unit and a community hospital, and to investigate whether differences in adherence affected the outcome.Two cohorts hospitalized during 2000-2007 with a first episode of BOV were retrospectively enrolled, one in a community hospital comprising 66 patients and one in a specialized unit comprising 111 patients. Data on treatment, rebleeding and mortality were collected from medical records according to the Baveno III/IV Criteria.Treatments in the specialized unit versus the community hospital were: vasoactive drugs 79 vs. 66% (P = 0.06), prophylactic antibiotics 55 vs. 27% (P0.01), endoscopic treatment 86 vs. 74% (P= 0.04) and Sengstaken-Blakemore tube was used in 5 vs. 21% (P0.01). Secondary prophylaxis with pharmacological, endoscopic or transjugular intrahepatic portosystemic shunt therapy was initiated in 91 vs. 74% (P0.01) (specialized vs. community). Six-week mortality was 17 vs. 24% (P = 0.25) with 5-day mortality of 6 vs. 3% (P = 0.34) and mortality day 6-42, 12 vs. 22% (P = 0.07) (specialized vs. community). Failure to control bleeding and failure to prevent rebleeding were not statistically different.Our study shows that patients with BOV are more likely to receive therapy according to guidelines when hospitalized in a specialized unit compared with a community hospital. This however did not affect mortality.

We have read with interest the study by Lo et al 1 in a recent issue of Gut . Apart from the findings that short-term therapy with terlipressin in combination with ligation seems to improve outcome in bleeding oesophageal varices (BOVs) compared to longer treatment with terlipressin, a shorter treatment period with terlipressin most likely reduces the risk of severe side effects. Recently, a study observed that during a 5-day terlipressin treatment with 1 mg/4 h, the serum sodium decreased from 138±5 to 130±9 and in …

A 25-year-old woman was hospitalized repeatedly during a 5-year period due to abdominal pain, change in stool pattern, high CRP and leucocytosis. Ultrasound and small bowel examination showed oedema of terminal ileum, and morbus Crohn was initially suspected. A later ileocolonoscopy with biopsy and a pill cam capsule endoscopy were normal. In all cases the condition normalized spontaneously. A thorough interview revealed a recreational use of cocaine, and diary recordings confirmed the association between her abdominal pain and cocaine use. Ischaemic enteritis has previously been described in cocaine users.

It is well known that children and adolescents with type 1 diabetes mellitus (DM) treated in outpatient clinics often have poor metabolic control and thereby a high risk of developing microvascular complications. Our aim was to determine the status of the young type 1 DM patients under 25 years of age attending our adult outpatient diabetes clinic.Retrospectively, we registered HbA1c, screening for complications, success with self-care and non-attendance. We suggest criteria for determining the success of the treatment process and outcome.Thirty-four patients, age 22.2 +/- 2.7 years, attend the clinic. Their latest HbA1c was 9.2 +/- 1.9% (mean SD); 18% had HbA1c pound 7.5%. Intensive insulin therapy was used by 91%. Five patients had either background retinopathy, elevated urinary albumin to creatinine ratio or hypertension ( 130/80) on one occasion within the last two years. Dietary problems were listed in 29% of the records, and insufficient frequency of blood glucose measurements appeared in 29%, while 38% had between three and seven non-attendances. The patients in all three of these groups had significantly higher HbA1c. Screening for complications was successful according to the criteria for blood pressure, HbA1c and retinopathy, but not completely successful for nephropathy and neuropathy.The young type 1 diabetes patients attending our adult outpatient clinic have an unsatisfactorily high HbA1c. Screening for complications is sufficient, and hardly any of the patients have signs of complications, but the rate of non-attendance is high, and there are significant problems with self-care. New individual considerations for these young patients appear to be necessary and standards for the quality of treatment are needed.

An episode of ischemia and reperfusion of the femoral head is thought to be the common pathway in the pathogenesis of femoral head necrosis. The influence of short-term high-dose steroid treatment on femoral head reperfusion after ischemia was investigated in a porcine model. Twenty-two pigs were randomized to receive methylprednisolone 20 mg/day/kg bodyweight intramuscularly for 3 days followed by methylprednisolone 10 mg/day/kg bodyweight for 11 days (n = 11), whereas the control group (n = 11) received no treatment. Femoral head ischemia was achieved by 6 hours of unilateral intraarticular hip pressure increase to 250 mm Hg. Femoral head blood flow was estimated using radiolabeled microspheres (15 microm in diameter) before ischemia, during hip tamponade, and 4 hours after tamponade release. Femoral head blood flow was lower in the corticosteroid treated pigs. Subtotal femoral head ischemia was documented in both groups during joint tamponade. Apart from two femoral head epiphyses in either group, reperfusion after tamponade release on the average occurred to a blood flow level similar to that before ischemia. Short-term high-dose methylprednisolone treatment depressed bone perfusion in general, but had no effect on reperfusion after femoral head ischemia in the porcine model.

The topographic reperfusion pattern of the femoral head after critical ischemia has not yet been investigated. We determined the blood flow of the porcine hip regions with the femoral head epiphysis divided into 24 subregions by the tracer microsphere technique. Blood flow was measured under steady-state conditions, at the end of a 6-hour increase in intracapsular hip joint pressure to 250 mm Hg, and 4 hours after release of the joint tamponade. Total femoral head epiphyseal blood flow decreased with ischemia and regained steady-state perfusion after tamponade. The reperfusion pattern of the femoral head epiphysis appeared identical with that of the steady state before ischemia. However, 2 of the 11 experimental epiphyses remained ischemic in the reperfusion phase. We conclude that hip joint tamponade above the arterial pressure level for 6 hours causes global ischemia in the femoral head epiphysis in the immature pig, without regional differences in reperfusion, and that reperfusion occurs at a level like that of the steady state before ischemia.