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Background & Aims: The function and structure of social relationships influence mortality in individuals within the general population. We compared aspects of social relationships in individuals with cirrhosis and a matched comparison cohort and studied their association with health-related quality of life (HRQoL) and mortality in cirrhosis. Methods: Individuals with cirrhosis and comparators were identified among participants of the Danish National Health Surveys 2010–2017. The surveys included questions on functional (social support and loneliness) and structural (living alone/cohabitating and frequency of contacts with relatives and friends) aspects of social relationships and HRQoL (Short Form-12). We estimated associations of aspects of social relationships with HRQoL and all-cause mortality in individuals with cirrhosis through 2020. Results: Of 541 individuals with cirrhosis and 2,157 comparators, low social support (22% in cirrhosis vs. 13% in comparators), loneliness (35% vs. 20%), and living alone (48% vs. 22%) were more frequent in individuals with cirrhosis than comparators, whereas the frequency of contacts with relatives and friends was similar. Except for living alone, weak functional and structural social relationships were associated with lower mental HRQoL in those with cirrhosis. Physical HRQoL was only marginally associated with social relationships. During 2,795 person-years of follow-up, 269 individuals with cirrhosis died. Functional and not structural aspects of social relationships were associated with risk of mortality in cirrhosis. Specifically, the adjusted hazard ratio was 1.4 (95% CI 1.1–1.9), p = 0.011, for low vs. moderate-to-high social support (functional aspect), and 1.0 (95% CI 0.8–1.3), p = 0.85 for living alone vs. cohabitating (structural aspect). Conclusions: Individuals with cirrhosis have weaker functional and structural social relationships than matched comparators. Weak functional relationships are associated with lower mental HRQoL and increased risk of mortality in individuals with cirrhosis. Impact and implications: This study investigated the prevalence of weak social relationships in individuals with cirrhosis and their influence on health-related quality of life and risk of mortality. Individuals with cirrhosis were nearly twice as likely to report low social support, loneliness, and to live alone than a matched comparison cohort. Low social support and loneliness (functional measures of social relationships) were associated with lower mental health-related quality of life and increased risk of mortality risk in cirrhosis, when adjusting for known confounders. We hope that these results will make healthcare providers aware of the functional aspects of the social relationships of individuals with cirrhosis, in addition to the traditional clinical management, and motivate further research of interventions to strengthen the social support of individuals with cirrhosis.

INTRODUCTION: The study aim was to identify predictors of motivation to reduce alcohol consumption and whether motivation predicts engagement in alcohol misuse treatment in alcohol-related liver disease (ALD). METHODS: Data from health surveys and health-care registries were combined. RESULTS: Of 674 patients with ALD, 65% consumed alcohol. Recent hospital admission and severe alcohol problems were associated with motivation to reduce alcohol consumption. Two-year probability for engagement in misuse treatment was 29% for patients with motivation to reduce alcohol consumption versus 6.5% for patients without motivation. DISCUSSION: ALD patients with recent hospital admission were more motivated to cut down alcohol consumption, and motivation predicted engagement in alcohol misuse treatment. This insight can help us target brief interventions.

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

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.

Sofie Hallager,1 Steen Ladelund,2 Peer Brehm Christensen,3 Mette Kjær,4,5 Birgit Thorup Roege,6 Karin Elmegaard Grønbæk,7 Erika Belard,8 Toke S Barfod,9 Lone Galmstrup Madsen,10 Jan Gerstoft,11 Britta Tarp,12 Henrik Bygum Krarup,13 Nina Weis,1,5 1Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, 2Clinical Research Center, Copenhagen University Hospital, Hvidovre, 3Department of Infectious Diseases and Clinical Institute, Odense University Hospital, University of Southern Denmark, Odense, 4Department of Hepatology, Copenhagen University Hospital, Rigshospitalet, 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 6Department of Internal Medicine, Kolding Hospital, Kolding, 7Department of Gastroenterology, Copenhagen University Hospital, Hvidovre, 8Department of Gastroenterology, Copenhagen University Hospital, Herlev, 9Department of Internal Medicine, Zealand University Hospital, Roskilde, 10Department of Gastroenterology, Zealand University Hospital, Køge, 11Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, 12Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, 13Section of Molecular Diagnostics, Clinical Biochemistry and Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark Background: Chronic hepatitis C (CHC) causes liver cirrhosis in 5%–20% of patients, leading to increased morbidity and mortality. This study aimed to estimate liver-related morbidity and mortality among patients with CHC and cirrhosis in Denmark with and without antiviral treatment and sustained virologic response (SVR). Furthermore we aimed to estimate the rate of hepatocellular carcinoma (HCC) and decompensation associated with certain prognostic factors.Materials and methods: Patients with CHC and cirrhosis registered in the Danish Database for Hepatitis B and C were eligible. Cirrhosis was based on liver biopsy, transient elastography, and clinical cirrhosis. Data were extracted from nationwide registries. The study period was from 2002 until 2013.Results: Of 1,038 patients included, 716 (69%) were male and the median age was 52 years. Median follow-up was 3.8 years, 360 patients died, and 233 of 519 treated patients achieved SVR. Alcohol overuse and hepatitis C virus genotype 3 were associated with an increased incidence rate (IR) of HCC, whereas diabetes and alcohol overuse were associated with increased IRs of decompensation. Achieving SVR reduced all-cause mortality (adjusted mortality rate ratio 0.68 [95% CI 0.43–1.09]) and liver-related mortality (mortality rate ratio 0.6 [95% CI 0.36–1]), as well as liver-related morbidity with adjusted IR ratios of 0.37 (95% CI 0.22–0.62) for HCC and 0.31 (95% CI 0.17–0.57) for decompensation. The IRs of HCC and decompensation remained elevated in patients with alcohol overuse after SVR.Conclusion: Alcohol overuse, hepatitis C genotype 3, and diabetes were associated with liver-related morbidity in patients with CHC and cirrhosis. SVR markedly reduced liver-related morbidity and mortality; however, special attention to patients with alcohol overuse should continue after SVR. Keywords: chronic hepatitis C, cirrhosis, liver-related morbidity, cohort study, sustained virologic response

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) genotype 3 infection with advanced liver disease has emerged as the most challenging to treat. We retrospectively assessed the treatment outcome of sofosbuvir (SOF) based regimes for treatment of HCV genotype 3 infections in a real life setting in Scandinavia.METHODS: Consecutive patients with chronic HCV genotype 3 infection were enrolled at 16 treatment centers in Denmark, Sweden, Norway and Finland. Patients who had received a SOF containing regimen were included. The fibrosis stage was evaluated by liver biopsy or transient liver elastography. The following treatments were given according availability and local guidelines: 1) SOF + ribavirin (RBV) for 24 weeks, 2) SOF + daclatasvir (DCV) +/-RBV for 12-24 weeks, 3) SOF + pegylated interferon alpha (peg-IFN-α) + RBV for 12 weeks or 4) SOF/ledipasvir (LDV) + RBV for 12-16 weeks. The primary endpoint was sustained virological response (SVR) assessed at week 12 (SVR12) after end of treatment.RESULTS: We included 316 patients with a mean age of 55 years (range 24-79), 70% men, 49% treatment experienced, 58% with compensated cirrhosis and 12% with decompensated cirrhosis.In the modified intention to treat (mITT) population SVR12 was achieved in 284/311 (91%) patients. Among 26 treatment failures, five had non-response, 3 breakthrough and 18 relapse. Five patients were not included in the mITT population. Three patients died from reasons unrelated to treatment and two were lost to follow-up. The SVR12 rate was similar for all treatment regimens, but lower in men (p = 0.042), and in patients with decompensated liver disease (p = 0.004).CONCLUSION: We found that sofosbuvir based treatment in a real-life setting could offer SVR rates exceeding 90% in patients with HCV genotype 3 infection and advanced liver disease.

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC) and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C and data from national health registries and patient charts were obtained. Tumor stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stage 0 - 3. We included 1,075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4,988 person years (PY) 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4 - 1.5] in 2002-2003 to 2.9/100 PY [2.4 - 3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL(-1) was 17%. Twenty-three (21%) patients were diagnosed with early stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal and most patients were diagnosed with advanced HCC with a poor prognosis. This article is protected by copyright. All rights reserved.

OBJECTIVE: In Denmark, pregnant women have been screened for hepatitis B virus (HBV) since 2005, and children born to HBV-infected mothers offered hepatitis B immunoglobulin at birth, vaccination against HBV at birth and after 1, 2 and 12 months. The purpose of this study was to determine the risk of vertical HBV transmission in children born to mothers with chronic HBV infection, to investigate the antibody response in the children and to investigate possible maternal predictive risk factors for HBV transmission.MATERIALS AND METHODS: Through the Danish Database for Hepatitis B and C, we identified 589 HBV-infected women who had given birth to 686 children, of whom 370 children were born to 322 women referred to hospital. 132 (36%) children, born to 109 mothers, were included in the study; 128 children had blood samples tested for HBsAg, anti-HBc (total), anti-HBs and HBV-DNA and four children had saliva samples tested for anti-HBc.RESULTS: We found vertical HBV transmission in Denmark to be 2.3% [95% CI: 0.5, 6.5], a high proportion of HBsAg-negative children with low levels of anti-HBs (18.4%) and a high proportion (15.2%) with resolved HBV infection. No maternal risk factor was statistically significantly associated with HBV vertical transmission.CONCLUSION: In a HBV low prevalence setting as Denmark, despite a national vaccination program, vertical HBV transmission occurred in 2.3% of children born to HBV-infected mothers. In addition, a high proportion of the children had insufficient anti-HBs levels and a high proportion had serological signs of resolved HBV infection.

Background. Knowledge about mortality rates (MRS) in patients with chronic hepatitis C (CHC) with cirrhosis is limited. This study aimed to estimate all-cause MRS among patients with CHC with or without cirrhosis in Denmark compared with the general population. Methods. Patients registered in the Danish Database for Hepatitis B and C with CHC and a liver fibrosis assessment were eligible for inclusion. Liver fibrosis was assessed by means of liver biopsy, transient elastography, and clinical cirrhosis. Up to 20 sex-and age-matched individuals per patient were identified in the general population. Data were extracted from nationwide registries. Results. A total of 3410 patients with CHC (1014 with cirrhosis), and 67 315 matched individuals were included. Adjusted MR ratios (MRRs) between patients with or without cirrhosis and their comparison cohorts were 5.64 (95% confidence interval [CI], 4.76-6.67) and 1.94 (1.55-2.42), respectively. Cirrhosis among patients was associated with an MRR of 4.03 (95% CI, 3.43-4.72). A cure for CHC was associated with an MRR of 0.64 (95% CI, 0.40-1.01) among cirrhotic patients and 2.33 (1.47-3.67) compared with the general population. Conclusions. MRS were high among patients with CHC with or without cirrhosis compared with the general population. Curing CHC was associated with a reduction in MR among cirrhotic patients, but the MR remained higher than the general population.

Background: The role of acid in functional dyspepsia is controversial and drug treatment trials indicate that only a subset of patients has acid-related symptoms. A novel single-subject trial design, the Random Starting Day trial (RSD trial), was developed to identify acid-related symptoms. We hypothesized that RSD trial responders and non-responders would react differently to gastric acid stimulation. Development of epigastric pain was expected in RSD trial responders after pentagastrin stimulation during placebo treatment, but not during omeprazole treatment. In non-responders, epigastric pain was expected not to be influenced by gastric acid stimulation or type of treatment. Methods: Nineteen patients were evaluated. Symptomatic response to pentagastrin (6 µg/kg) was assessed twice in each patient following placebo and omeprazole (40 mg bid) treatment in a randomized, double-blind, cross-over design. Epigastric pain was assessed every 15 for 90 min after stimulation using a 5-graded Likert scale and a VAS scale. A positive acid provocation test was defined as an increase of the Likert score of epigastric pain by at least one grade after pentagastrin stimulation during placebo treatment but not during omeprazole treatment. Results: The acid provocation test was positive in 43% (3/7) of responders compared to only 17% (2/12) non-responders. VAS-score changes showed trends towards a more pronounced symptom reduction during omeprazole treatment in responders compared to non-responders. Conclusion: Patients identified as having acid-related dyspepsia more often developed epigastric pain following acid stimulation during placebo and not during omeprazole treatment. Due to the low sample size the difference was not considered significant.

The single subject trial is a randomized controlled trial carried out in the individual patient, and the result obtained is specific to the individual patient and the drug being investigated. This type of trial offers a supplement to traditional parallel group trials, especially in patients with heterogeneous disorders, often characterized by varying treatment responses and/or high placebo response rates. Pooled results from several individual single subject trials could extend the conclusions beyond the individual patient, and help to characterize a subset of responders to a specific treatment or clarify the heterogeneity of the disease. The basic principles of the different single subject trial designs are described. Advantages and limitations are reviewed with a special focus on published trials in functional gastrointestinal disorders. The single subject trial may be a valuable supplement to traditional drug treatment trials, either used as isolated trials in individual patients to determine optimal therapy, or in groups of patients to identify those with a uniform response to treatment. However, the lack of validation and reliability studies limits the value of the single subject trials presented so far.

Immunoglobulin light-chain (AL) amyloidosis is a rare disease that can affect several organs. The aim of this study was to characterize patients with gastrointestinal manifestations of AL amyloidosis, in terms of symptoms, biochemistry, and outcome.Retrospectively, patients with AL amyloidosis admitted for evaluation of malabsorption in a Department of Gastroenterology between January 2000 and December 2006 were identified.A total of 11 patients (4 F, age 60 years, median (range) 50-69) were included in the study. Gastrointestinal amyloidosis was histologically verified in all patients. All patients had gastrointestinal symptoms, 8 of them prior to establishment of diagnosis. Median (range) delay from initial symptoms to diagnosis was 7 (0-24) months. The most prominent symptom was weight loss (n=10) averaging 7 (0-25) kg, followed by diarrhea (n=5). Steatorrhea (2 mild, 1 moderate, 1 severe) was found in 4 of 7 patients examined. At presentation, 9 patients had hypoalbuminemia and 6 patients had anemia. Three patients were treated with home parenteral nutrition. Five patients received conventional chemotherapy (oral melphalan and prednisone) and 5 patients underwent high-dose melphalan and autologous stem-cell transplantation. Five patients died within the observation period, at a median of 10 (3-36) months after the diagnosis was established. Non-survivors tended to have lower albumin levels on admission and more involvement of other organs compared to survivors.Most patients with gastrointestinal AL amyloidosis experience weight loss and all have signs of malabsorption. Despite treatment the prognosis is grave.

The unaided clinical diagnosis of dyspepsia is of limited value in separating functional dyspepsia from clinically relevant organic causes of dyspepsia (gastric and esophageal malignancies, peptic ulcer disease and complicated esophagitis). The identification of one or more alarm features, such as weight loss, dysphagia, signs of gastrointestinal bleeding, an abdominal mass or age over 45 years may help identify patients with a higher risk of organic disease. This review summarizes the frequency of alarm symptoms in dyspeptic patients in different settings (such as the community, primary care and specialist clinics). The prevalence of alarm features in patients diagnosed with upper gastrointestinal malignancy or peptic ulcer disease is described. The probability of diagnosing clinically relevant upper gastrointestinal disease in patients presenting with alarm features and other risk factors is discussed. Alarm features such as age, significant weight loss, use of nonsteroidal anti-inflammatory drugs, signs of bleeding and dysphagia may help stratify dyspeptic patients and help optimize the use of endoscopy resources.