Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study.

Background: The Fibrosis-4 Index (FIB-4) is used as a non-invasive tool for the presence of advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, evidence for an association between FIB-4 and risk of mortality and/or liver-related clinical outcomes is limited. The aim of this study was to investigate the association between FIB-4 and subsequent liver events, cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes examined in routine general practice. Methods: This was a longitudinal cohort study in which eligible adults had obesity and/or type 2 diabetes and ≥1 FIB-4 score calculable from UK Clinical Practice Research Datalink GOLD after 1 January 2001. No alcohol-related disorders and/or chronic liver diseases (except non-alcoholic fatty liver disease) and/or no prescriptions of drugs inducing liver disease were permitted. Individuals were followed until time of first event, 10 years, or 1 January 2020. Analyses were conducted using Aalen-Johansen cumulative incidence functions and Cox proportional hazards models. Findings: Among 44,481 included individuals (mean age 58·8 years; 54% female), there were 979 liver, 6002 cardiovascular, and 8971 mortality events during the 10 years of follow-up. At 10 years, the cumulative incidence of liver events in the high (>2·67), indeterminate (1·30-2·67), and low (<1·30) baseline FIB-4 risk groups were 15%, 3%, and 1%, respectively. Age- and sex-adjusted hazard ratios (HRs) for liver events were elevated in high (16·46; 95% confidence interval [CI] 13·65-19·85) and indeterminate (2·45; 95% CI 2·07-2·90) versus low FIB-4 risk groups. Similar results were found for cardiovascular events and all-cause mortality. Among 20,433 individuals with ≥2 FIB-4 measurements, increase/decrease in FIB-4 12 months after baseline was directly associated with risk of liver events: compared with individuals with low baseline FIB-4 and no change in FIB-4 (reference), the adjusted HR (95% CI) for those with high baseline FIB-4 was 24·27 (16·98-34·68) with a one-unit FIB-4 increase, and 10·90 (7·90-15·05) with a one-unit decrease. Interpretation: In addition to its value as a diagnostic tool, FIB-4 has clinical utility as a prognostic biomarker. Sequential measurement provides a pragmatic, tractable monitoring biomarker that refines risk assessment for liver events, cardiovascular events, and mortality. Funding: Novo Nordisk A/S.

FibroScan-aspartate aminotransferase (FAST) score for monitoring histological improvement in non-alcoholic steatohepatitis activity during semaglutide treatment: post-hoc analysis of a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Currently, assessment of candidate pharmacotherapies in patients with non-alcoholic steatohepatitis (NASH) involves invasive liver biopsy. Non-invasive scores, such as the FibroScan-aspartate aminotransferase (FAST) score, are used to identify candidates for therapy, but their ability to assess disease progression or treatment effect is unknown. We aimed to assess the association between FAST score and histological endpoints. Methods: We conducted a post-hoc analysis using data from a prior randomised, double-blind, placebo-controlled, phase 2b trial at 143 sites across 16 countries. Patients (aged 18-75 years) with biopsy-confirmed NASH, fibrosis stage 1-3, and a Non-alcoholic fatty liver disease Activity Score (NAS) ≥4 were enrolled between January 2017 and September 2018, and randomly assigned to receive once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg or placebo for 72 weeks. A subgroup analysis of patients with FAST score and histological data in the pooled semaglutide treatment and placebo arms at baseline and week 72 was performed. The original trial is registered at ClinicalTrials.gov, NCT02970942. Findings: A total of 122 patients were included in this post-hoc analysis (93 received semaglutide and 29 received placebo). FAST score reduction was associated with achieving the primary endpoint of NASH resolution without worsening of fibrosis in the pooled semaglutide group (area under the receiver operating curve 0.69; 95% confidence interval [CI] 0.58, 0.81). Mean FAST score reduction from baseline to week 72 was greatest in patients who met the primary endpoint vs those who did not in both the semaglutide (-0.40 [95% CI -0.84, 0.04] vs -0.22 [95% CI -0.74, 0.30] points; p = 0.002) and placebo groups (-0.25 [95% CI -0.72, 0.23] vs 0.00 [95% CI -0.50, 0.50] points; p = 0.047). Similarly, mean reductions in FAST score at week 72 were greater in those with NAS improvement vs those without in the semaglutide and placebo groups (≥1 point, -0.36 [95% CI -0.82, 0.11] vs -0.08 [95% CI -0.53, 0.38] points [p < 0.001] and -0.25 [95% CI -0.64, 0.14] vs -0.06 [95% CI -0.40, 0.53] points [p = 0.001]; ≥2 points, -0.40 [95% CI -0.86, 0.06] vs -0.14 [95% CI -0.56, 0.28] points [p < 0.001] and -0.29 [95% CI -0.67, 0.09] vs -0.05 [95% CI -0.40, 0.50] points; [p < 0.001]). A FAST score reduction of more than 0.22 points after semaglutide treatment was associated with meeting the primary endpoint (sensitivity 78%; specificity 60%; positive likelihood ratio 1.26; negative likelihood ratio 0.25; odds ratio 4.93). Interpretation: The potential of the FAST score as a non-invasive monitoring tool to identify histological changes following treatment requires further evaluation and validation. Funding: Novo Nordisk A/S.

Review article: The need for more efficient and patient-oriented drug development pathways in NASH-setting the scene for platform trials.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. METHODS: Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. RESULTS: Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. CONCLUSIONS: PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, 'proof-of-platform' at a smaller scale needs to be provided.

Liver fibrosis in patients with tetralogy of Fallot, an unrecognised complication?

OBJECTIVES: Improved survival has led to a growing population of adults with congenital heart disease (CHD), followed by numerous reports of late complications. Liver disease is a known complication in some patients, with most studies focusing on Fontan associated liver disease. Whether liver disease also exists in other patients with CHD is not fully investigated. Elevated central venous pressure is considered pivotal in the development of liver disease in Fontan associated liver disease, and other patients with alterations in central venous pressure may also be at risk for developing liver fibrosis. We wanted to see if liver fibrosis is present in patients with tetralogy of Fallot. Many patients with tetralogy of Fallot have severe pulmonary regurgitation, which can lead to elevated central venous pressure. Patients with tetralogy of Fallot may be at risk of developing liver fibrosis. MATERIALS AND METHODS: Ten patients (24-56 years) with tetralogy of Fallot and pulmonary regurgitation were investigated for liver fibrosis. All patients were examined with magnetic resonance elastography of liver, hepatobiliary iminodiacetic acid scan, indocyanine green elimination by pulse spectrophotometry, elastography via FibroScan, abdominal ultrasound including liver elastography, and blood samples including liver markers. RESULTS: Three out of ten patients had findings indicating possible liver fibrosis. Two of these had a liver biopsy performed, which revealed fibrosis stage 1 and 2, respectively. The same three patients had an estimated elevated central venous pressure in previous echocardiograms. CONCLUSIONS: Mild liver fibrosis was present in selected patients with tetralogy of Fallot and may be related to elevated central venous pressure.

Paediatric hepatitis B and hepatitis C virus infections: An observational study of a Danish cohort.

AIM: The aim of this study was to describe the epidemiological and clinical characteristics in children with either chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in Denmark. METHODS: In this observational study, children and adolescents with either chronic HBV or HCV infection followed at the largest paediatric departments in Denmark between 2001 and 2013 were included. Data collection included as well epidemiological data as clinical data like virus genotype, viral load, serological markers, liver biochemistry, liver elastography and histology if available. RESULTS: The study included 131 children. None of the patients had decreased liver function or end-stage liver disease during follow-up. Ten of the 18 children who underwent liver biopsy had signs of fibrosis. Thirteen (11%) children with HBV and one (7%) child with HCV received treatment. Different indications and different treatment regimens were used. CONCLUSION: This study confirms that chronic HBV and HCV infections are often mild diseases during childhood. Nevertheless, children are at higher risk of serious liver disease early in life because of the early time of infection and probably also because of the high viral loads.

PET/DW-MRI for evaluating treatment in chronic hepatitis C patients.

This feasibility study set out to investigate the use of FDG-PET/DW-MRI in chronic hepatitis C patients to examine changes in local liver inflammation after treatment with direct-acting antivirals (DAA). Twelve patients with chronic hepatitis C were prospectively enrolled, performing FDG-PET/DW-MRI prior to and after DAA treatment. PET/DW-MRI included PET acquisition 60 and 90 min after FDG-injection, DIXON, for attenuation correction, T2- and DW-MRI with 10 b-values between 0-700 s/mm2. The following parameters were measured from fusion of 3 volumes of interest (VOIs) placed in the liver parenchyma: Mean standard uptake value after 60 and 90 minutes (SUVmean60 and SUVmean90), total Apparent Diffusion Coefficient (ADC), perfusion fraction (PF), pseudo-diffusion (D*) and perfusion-free diffusion (D). We found PET/DW-MRI of chronic hepatitis C patients to be feasible. Patients were cooperative, tolerated the scans well and the image quality was acceptable. A total of 10 patients were available for final analysis. All patients achieved sustained virologic response and normalized alanine-aminotransferase (ALAT) levels after treatment with DAA. Perfusion fraction measured by DW-MRI changed significantly after treatment, from mean 0.21 (± 0.04) to 0.26 (± 0.06), P=0.005 and D* from 0.50 (± 0.13) × 10-3 s/mm2 to 0.62 (± 0.15) × 10-3 s/mm2, P=0.028. All other parameters, including FDG-uptake, was unchanged. These results suggest that liver perfusion is changed shortly after DAA treatment, with no significant change in inflammation. The study concludes that PET/DW-MR is feasible in quantifying perfusion and possibly inflammation in chronic hepatitis C patients and may be used to follow treatment.

Number of hospital contacts with alcohol problems predicts later risk of alcoholic liver cirrhosis.

AIMS: Alcoholic liver cirrhosis is usually preceded by years of heavy drinking. We investigated whether the risk of alcoholic liver cirrhosis increases as the number of hospital contacts with alcohol problems goes up. METHODS: This was a supplementary analysis on a nationwide register-based cohort study. All patients in Denmark with an initial hospital contact with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) 1998-2002, free of liver disease, were followed for diagnosis of alcoholic liver cirrhosis. The number of subsequent hospital contacts with alcohol problems was estimated as a time-dependent variable for each patient. RESULTS: In all, 36,044 hospital patients with an initial hospital contact with alcohol problems were included. These patients had 301,525 subsequent hospital contacts with alcohol problems. Risk of alcoholic liver cirrhosis increased ( p < 0.0001) with number of alcohol hospital contacts in both men and women for up to nine contacts. CONCLUSIONS: The number of prior hospital contacts with alcohol problems might provide clinicians with a helpful metric in deciding whether to offer preventive interventions for alcoholic liver cirrhosis.

Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations: A Systematic Review With Meta-Analysis.

BACKGROUND: Alcoholic liver cirrhosis is preventable and caused by heavy drinking. Few in the general population may be at risk and interventions targeting individuals at high risk may be a more feasible opportunity for prevention than interventions targeting the whole population. METHODS: We conducted a systematic review to identify opportunities to prevent alcoholic liver cirrhosis in high-risk populations. Following MOOSE guidelines, we included observational studies published between 1980 and 2017. Prospective studies of alcohol-problem cohorts were included to investigate whether alcohol-problem cohorts qualify as high-risk populations for alcoholic liver cirrhosis. Studies on the alcohol amount consumed by alcoholic liver cirrhosis patients were included to compare with the amount consumed by the general population. Moreover, studies on alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis were included to identify opportunities to offer prevention interventions. Of 7198 screened references, 38 studies (N = 120,928) were included. RESULTS: Alcohol-problem cohorts qualified as high-risk populations with an incidence of alcoholic liver cirrhosis ranging from 7 to 16% after 8-12 years. The alcohol amount consumed by alcoholic liver cirrhosis patients was high compared to the general population. For example, 45% (95%CI 34, 56) of alcoholic liver cirrhosis patients were drinking >110 g alcohol/day. Finally, there were opportunities to reach alcoholic liver cirrhosis patients prior to diagnosis; 40-61% of alcoholic liver cirrhosis patients had a previous alcohol-related healthcare contact. CONCLUSIONS: We conclude that alcohol-problem cohorts are high-risk populations for alcoholic liver cirrhosis and there seems to be opportunities to reach later alcoholic liver cirrhosis cases with preventive interventions in healthcare settings.

Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study.

OBJECTIVE: New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly. PATIENTS AND METHODS: We randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period. RESULTS: A total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment. CONCLUSIONS: We found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment.

Hospital contacts with alcohol problems prior to liver cirrhosis or pancreatitis diagnosis.

AIM: To evaluate prior hospital contacts with alcohol problems in patients with alcoholic liver cirrhosis and pancreatitis. METHODS: This was a register-based study of all patients diagnosed with alcoholic liver cirrhosis or pancreatitis during 2008-2012 in Denmark. Hospital contacts with alcohol problems (intoxication, harmful use, or dependence) in the 10-year period preceding the diagnosis of alcoholic liver cirrhosis and pancreatitis were identified. RESULTS: In the 10 years prior to diagnosis, 40% of the 7719 alcoholic liver cirrhosis patients and 40% of the 1811 alcoholic pancreatitis patients had at least one prior hospital contact with alcohol problems. Every sixth patient (15%-16%) had more than five contacts. A similar pattern of prior hospital contacts was observed for alcoholic liver cirrhosis and pancreatitis. Around 30% were diagnosed with alcohol dependence and 10% with less severe alcohol diagnoses. For the majority, admission to somatic wards was the most common type of hospital care with alcohol problems. Most had their first contact with alcohol problems more than five years prior to diagnosis. CONCLUSION: There may be opportunities to reach some of the patients who later develop alcoholic liver cirrhosis or pancreatitis with preventive interventions in the hospital setting.

Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study.

Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998-2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry-based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15-year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20-29 years, 5.5% (95% CI, 4.9, 6.2) for 30-39 years, 9.8% (95% CI, 9.0, 11) for 40-49 years, 8.9% (95% CI, 8.1, 9.8) for 50-59 years, 6.2% (95% CI, 5.1, 7.2) for 60-69 years, and 2.5% (95% CI, 1.7, 3.3) for 70-84 years. According to alcohol diagnosis in men, the 15-year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. CONCLUSION: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40-59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2017;65:929-937).

Predictors of heavy drinking after liver transplantation for alcoholic liver disease in Denmark (1990-2013): a nationwide study with competing risks analyses.

OBJECTIVE: Heavy drinking following liver transplantation decreases survival. Little is known of predictors of heavy drinking, which should guide clinicians identifying patients at high risk of return to heavy drinking after transplantation. MATERIAL AND METHODS: We calculated the cumulative incidence of heavy drinking among patients transplanted for alcoholic liver disease in Denmark 1990-2013. We then analyzed pre-transplant demographic and psychiatric characteristics as predictors of post-transplant heavy drinking. Information was obtained from medical records, from nationwide registries and by interview. RESULTS: Among 156 liver-transplanted patients, the cumulative incidence of heavy drinking was 18%, 24% and 27% after 5, 10 and 15 years post-transplant. In univariate analyses of pre-transplant predictors of heavy drinking after transplantation, younger age (p < 0.001), being retired (p = 0.007), anxiety (p = 0.04), personality disorder (p = 0.05) and no lifetime diagnosis of alcohol dependence (p = 0.03) were associated with heavy drinking after transplantation. Smoking (p = 0.06) tended to be associated, whereas depression (p = 0.7) or being married was not (p = 0.7). In the multivariate analysis, only younger age (p = 0.03), being retired (p = 0.007) and no lifetime diagnosis of alcohol dependence (p = 0.003) remained significant predictors. Heavy drinking after transplantation decreased survival beyond 5 years post-transplant (p = 0.004). CONCLUSIONS: There is a high incidence of heavy drinking after liver transplantation for alcoholic cirrhosis in Denmark. Younger age, being retired and no lifetime diagnosis of alcohol dependence were predictors of heavy drinking after transplantation.

Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study.

BACKGROUND & AIMS: Alcohol is the main contributing factor of alcoholic cirrhosis, but less is known about the significance of drinking pattern. METHODS: We investigated the risk of alcoholic cirrhosis among 55,917 participants (aged 50-64 years) in the Danish Cancer, Diet, and Health study (1993-2011). Baseline information on alcohol intake, drinking pattern, and confounders was obtained from a questionnaire. Follow-up information came from national registers. We calculated hazard ratios (HRs) for alcoholic cirrhosis in relation to drinking frequency, lifetime alcohol amount, and beverage type. RESULTS: We observed 257 and 85 incident cases of alcoholic cirrhosis among men and women, respectively, none among lifetime abstainers. In men, HR for alcoholic cirrhosis among daily drinkers was 3.65 (95% CI: 2.39; 5.55) compared to drinking 2-4 days/week. Alcohol amount in recent age periods (40-49 and 50-59 years) was associated with an increased risk, whereas the amount in 20-29 and 30-39 years was not. In men drinking 14-28 drinks/week, HR was 7.47 (95% CI: 1.68; 33.12), 3.12 (95% CI: 1.53; 6.39), and 1.69 (95% CI: 0.79; 3.65) in drinkers of little (<1% of weekly amount), some (1-15%), and mostly wine (50-100%), compared to drinking <14 drinks/week. In general, results were similar for women. CONCLUSIONS: In men, daily drinking was associated with an increased risk of alcoholic cirrhosis. Recent alcohol consumption rather than earlier in life was associated with risk of alcoholic cirrhosis. Compared to beer and liquor, wine might be associated with a lower risk of alcoholic cirrhosis.

Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia.

AIM: To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia. METHODS: Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content. RESULTS: The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 ± 1.7 mmHg, ammonia + vehicle: 6.8 ± 1.0 mmHg, saline + ciclosporin: 3.1 ± 0.5 mmHg, saline + vehicle: 3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression. CONCLUSION: Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.

Liver biopsy performance and histological findings among patients with chronic viral hepatitis: a Danish database study.

We investigated the variance of liver biopsy frequency and histological findings among patients with chronic viral hepatitis attending 10 medical centres in Denmark. Patients who tested positive for HBsAg or HCV- RNA were retrieved from a national clinical database (DANHEP) and demographic data, laboratory analyses and liver biopsy results were collected. A total of 1586 patients were identified of whom 69.7% had hepatitis C, 28.9% hepatitis B, and 1.5% were coinfected. In total, 771 (48.6%) had a biopsy performed (range 33.3-78.7%). According to the Metavir classification, 29.3% had septal fibrosis (> or =F2) and 13.9% had cirrhosis (F4). The frequency of cirrhosis varied from 8.3 to 18.6% among centres, and was independently associated with age, male gender, elevated alanine-aminotransferase (ALT) and non-Danish origin. Among 141 patients with hepatitis C and known duration of infection, cirrhosis had developed in 23% after 20 y of infection. Age above 40 y was a better predictor of cirrhosis than elevated ALT. National database comparison may identify factors of importance for improved management of patients with chronic viral hepatitis.