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Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden., Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression., Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6)., Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Several genotypes associate with a worse histopathological profile in patients with non-alcoholic fatty liver disease (NAFLD). Whether genotypes impact long-term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD., Method: DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non-alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population-based registers. Events of severe liver disease and all-cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression., Results: In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66-8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79-4.14). After up to 40 years of follow-up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15-4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85-11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14-59.47). Overall mortality was not affected by any genetic variant., Conclusion: The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra-hepatic diseases, especially breast and colorectal cancer. Here we investigated long-term outcomes of Swedish patients with HFE mutations., Methods: We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes., Results: Median age at diagnosis was 52 years, 44% were females. During a mean follow-up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver-related outcomes were rare, with a cumulative incidence of <1%., Conclusions: Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma (HCC). In NAFLD, HCC occurs more commonly in the absence of cirrhosis compared with other liver diseases; yet, patients with non-cirrhotic NAFLD-HCC are poorly characterized. Here, we characterized a large cohort of HCC cases and assessed the outcomes of patients with non-cirrhotic NAFLD-HCC., Methods: We identified all cases of HCC treated at the Karolinska University Hospital, Stockholm, Sweden from 2004 to 2017. Patient charts were manually reviewed for variable extraction. Cases were followed passively for all-cause and HCC-related mortality until the end of April 2018. Cox regression was performed to estimate mortality rates and identify mortality risk factors in patients with non-cirrhotic NAFLD-HCC., Results: Totally, 1562 cases with HCC were identified. Of these, 225 (14.4%) had NAFLD-HCC, of which 83 (37%) did not have cirrhosis. Compared with patients with cirrhotic NAFLD-HCC, patients with non-cirrhotic NAFLD-HCC were older (74 vs 70 years, P < 0.001), had a lower prevalence of type 2 diabetes (T2DM) (66% vs 80%, P = 0.02), larger tumours, less frequently underwent liver transplantation (0% vs 11%, P = 0.002), but more frequently underwent resection (35% vs 8%, P < 0.001). Mortality was similar (aHR for non-cirrhotic NAFLD-HCC vs cirrhotic NAFLD-HCC 0.93, 95% CI 0.58-1.51, P = 0.78). Parameters independently associated with increased mortality included the Barcelona Clinic Liver Cancer stage, number of tumours, lower albumin and presence of T2DM., Conclusions: Patients with non-cirrhotic NAFLD-HCC differ from those with cirrhosis in age, tumour size and allocated treatments. Despite these differences, survival is similar., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Patients with non-alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort., Methods: We included 603 biopsy-proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross-linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD., Results: During a mean follow-up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30-1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD., Conclusions: Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation., Method: Population-based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index ≥25 kg/m 2 and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end-stage liver disease., Results: A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994-1995 to 6.2% in 2011-2015 (P = .01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end-stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non--NAFLD patients (aHR 1.03, 95% CI 0.70-1.53 P = .87)., Conclusion: NAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Prognostication in hepatocellular carcinoma (HCC) is demanding. Not only tumour extent and performance status are to be considered, but also liver function, which is often limiting for both survival itself and for treatment possibilities. This study was conducted to assess whether patient-reported questionnaires containing general and liver-specific questions could improve prognostication of survival., Methods: 185 patients with hepatocellular carcinoma in Norway and Sweden were prospectively included. Patients completed the quality-of-life questionnaires EORTC QLQ C30 and HCC18, and clinical, radiological and laboratory parameters were registered. Multivariate Cox regression and Harrell's C-statistics were used to identify the model that best predicted mortality., Results: Quality-of-life data were prognostic for overall survival. Fatigue and nutrition scales were prognostic in the multivariable analyses alone and in combination with clinical parameters. The prognostic value of established scoring systems was increased by the addition of QoL data. The best prognostic power was achieved by combining HCC18 nutrition scale with selected background parameters., Conclusion: Quality-of-life questionnaires can prognosticate mortality in HCC patients. When combined with established scoring systems, both the general cancer questionnaire EORTC QLQ C30, and the additional liver cancer-specific HCC18 increased the prognostic accuracy slightly., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD., Methods: We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into 'high' (n = 89) and 'normal' (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality were obtained from a national, population-based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy., Results: The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (P < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, P < 0.05). There was no difference in mortality between patients with different iron overload patterns., Conclusions: High levels of ferritin are associated with a long-term increased risk of death., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended in clinical guidelines. In real-life management, surveillance rates below 20% have been reported from the United States. We aimed to determine the use of HCC-surveillance in patients diagnosed with HCC in a European setting, and to identify the reasons for surveillance failures., Methods: Age, gender, tumour characteristics, BCLC classification, Child-Pugh stage, pre-existing liver disease, treatment, survival, frequency of HCC surveillance and reasons for surveillance failures were retrospectively determined in 616 patients diagnosed with HCC at Karolinska University Hospital 2005-2012., Results: Hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) were the most common diagnoses. The proportion of HCC patients diagnosed through surveillance was 22%. In 35% of cases, surveillance was missed due to doctor's failure to order surveillance or to diagnose the underlying liver disease. Diagnosis of NAFLD or alcoholic liver disease increased the risk of not receiving surveillance more than two-fold. Undiagnosed liver disease was most common in NAFLD patients. Patients who underwent surveillance had smaller tumours, more frequently received curative treatment, and had better survival compared to those in whom surveillance was indicated but missed., Conclusion: In a European setting, only 22% of HCCs were diagnosed by surveillance, and in more than one-third of cases, surveillance was indicated but missed. NAFLD and alcoholic liver disease were associated with deficient surveillance. Survival was significantly better in patients who underwent surveillance compared with those in whom surveillance was missed although indicated., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Neural cell adhesion molecule (N-CAM) is expressed by activated hepatic stellate cells (HSC), portal fibroblasts, cholangiocytes and hepatic progenitor cells during liver injury. Its functional role in liver disease and fibrogenesis is unknown. The aim of this study was to investigate the role of N-CAM in liver fibrogenesis., Methods: To induce fibrosis, N-CAM knockout mice and wild-type controls were subjected to bile duct ligation (BDL) or repeated carbon tetrachloride (CCl(4) ) injections. Fibrosis was quantified by hydroxyproline, immunhistochemistry staining and image analysis. Protein levels were determined with immunoblotting. HSCs were isolated by ultracentrifugation in a Larcoll gradient and thereafter in vitro stimulated with recombinant transforming growth factor (TGF)-β1., Results: Two weeks after BDL, wild-type mice had developed pronounced liver fibrosis while N-CAM-/- mice had less such alterations. N-CAM-/- mice had less deposition of collagen and fibronectin seen in immunhistochemistry. The protein levels of fibronectin were higher in the liver from the wild type, while laminin were unaltered. CCl(4) -treated N-CAM-/- and wild-type mice showed no significant difference in the extent of liver fibrosis or the expression levels of the above-mentioned genes. HSC isolated from N-CAM-/- mice showed declined levels of smooth muscle actin and desmin after stimulation in vitro with TGF-β1., Conclusions: Loss of N-CAM results in decreased hepatic collagen and fibronectin deposition in mice subjected to BDL, but not in animals exposed to repeated CCl(4) injections. HSC isolated from N-CAM null mice show impaired activation in vitro. This indicates a role of N-CAM in cholestatic liver disease and HSC activation., (© 2011 John Wiley & Sons A/S.)

Background: Hyperbiliverdinaemia is a poorly defined clinical sign that has been infrequently reported in cases of liver cirrhosis or liver carcinoma, usually indicating a poor long-term prognosis., Aims: To clarify the pathogenesis of hyperbiliverdinaemia in an extended case report., Methods: A 64-year-old man with alcoholic cirrhosis was admitted to hospital with severe bleeding from oesophageal varices. Ultrasonography showed ascites, but no dilatation of the biliary tree. The skin, sclerae, plasma, urine and ascites of the patient showed a greenish appearance. Bilirubin levels were normal, and there were no signs of haemolysis. Biliverdin was analysed in plasma and urine with liquid chromatography coupled to mass spectrometry. The seven exonic regions of the biliverdin reductase-A (BVR-A) gene was amplified by polymerase chain reaction and sequenced., Results: Biliverdin was present in plasma and urine. In nucleotide 52 of exon I of the DNA isolated from the hyperbiliverdinaemic patient, we discovered a novel heterozygous C-->T nonsense mutation converting an arginine (CGA) in position 18 into a stop codon (TGA) (R18Stop) predicted to truncate the protein N-terminally to the active site Tyr97. Two children of the proband were heterozygous for the identical mutation in the BVR-A gene, but had no clinical signs of liver disease and had normal levels of biliverdin. The BVR-A gene mutation was not found in 200 healthy volunteers or nine patients with end-stage liver cirrhosis., Conclusion: Hyperbiliverdinaemia (green jaundice) with green plasma and urine may be caused by a genetic defect in the BVR-A gene in conjunction with decompensated liver cirrhosis.

Background/aims: The altered iron metabolism in hepatocellular carcinomas (HCCs), characterized by the iron-deficient phenotype, is suggested to be of importance for tumour growth. However, the underlying molecular mechanisms remain poorly understood. We asked whether these iron perturbations would involve altered expression of genes controlling iron homeostasis., Methods: HCCs were induced in rats by the Solt and Farber protocol of chemical hepatocarcinogenesis, and to evaluate the effects of iron loading, one group of animals were supplemented with dietary iron during tumour progression. Tissue iron contents were determined, labelling indices of S-phase nuclei were calculated, and mRNA levels of iron-regulatory genes were quantitated. Protein levels of ferroportin1 were determined with Western blot., Results: HCCs displayed reduced amount of tissue iron and lack of histologically stainable iron. HCCs expressed significantly higher mRNA levels of genes involved in iron uptake (transferrin receptor-1, divalent metal ion transporter-1), ferroxidase activity (Ferritin-H), and iron extrusion (ferroportin1). The protein levels of ferroportin1 in iron-deficient HCCs were similar as in control livers, and did not increase in HCCs exposed to iron. Hepcidin mRNA levels were decreased in iron-deficient HCCs, rose in response to iron loading and correlated to the tissue iron content., Conclusions: Taken together, the altered expressions of iron-regulatory genes in HCCs possibly reflect an increased demand for bioavailable iron and a high iron turnover in neoplastic cells.