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Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin–antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child–Pugh and MELD score. TAT was increased in all Child–Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only. [ABSTRACT FROM AUTHOR]

Objective: Liver transplantation (LT) is a life-saving procedure for patients with end-stage liver disease, acute liver failure or hepatocellular carcinoma (HCC). Patients with known alcoholic liver cirrhosis (ALC) are usually assessed by an addiction specialist, but patients with other liver diseases may also exhibit harmful drinking. This study aims to assess the drinking habits in LT-recipients with or without a diagnosis of ALC. Patients and methods: Between April 2012 and December 2015, 190 LT-recipients were interviewed using the Lifetime Drinking History (LDH) and the Addiction Severity Index (ASI). Patients were categorized according to their diagnoses: ALC (group A, n = 39), HCC or hepatitis C (group B, n = 56) or other liver diseases (group C, n = 95). Data were analysed using descriptive statistic methods. Results: Fifteen of 95 patients (15.8%) in group C – a cohort without suspected addiction problems – had either alcohol consumption or binge drinking within the upper quartile of the overall cohort. The aetiology of liver disease in this subgroup included mainly cholestatic and cryptogenic liver disease. Illicit drugs had been used by 35% of all patients. Cannabis and amphetamine were the most common drugs and had the longest duration of regular use. Conclusions: LT candidates without known alcohol or drug use may have a clinically significant consumption of alcohol and previous illicit drug use. Efforts should be put on identification of these patients during LT evaluation. The use of structured questionnaires such as the ASI and the LDH could facilitate detection of alcohol and drug problems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2 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. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the diagnostic performance of dynamic perfusion CT (P-CT) for detection of hepatocellular carcinoma (HCC) in the cirrhotic liver.Materials and Methods: Twenty-six cirrhotic patients (19 men, aged 69 ± 10 years) with suspicion of HCC prospectively underwent P-CT of the liver using the 4D spiral-mode (100/80 kV; 150/175mAs/rot) of a dual-source system. Two readers assessed: (1) arterial liver-perfusion (ALP), portal-venous liver-perfusion (PLP) and hepatic perfusion-index (HPI) maps alone; and (2) side-by-side with maximum-intensity-projections of arterial time-points (art-MIP) for detection of HCC using histopathology and imaging follow-up as standard of reference. Another reader quantitatively assessed perfusion maps of detected lesions.Results: A total of 48 HCCs in 21/26 (81%) patients with a mean size of 20 ± 10 mm were detected by histopathology (9/48, 19%) or imaging follow-up (39/48, 81%). Detection rates (Reader1/Reader2) of HPI maps and side-by-side analysis of HPI combined with arterial MIP were 92/88% and 98/96%, respectively. Positive-predictive values were 63/63% and 68/71%, respectively. A cut-off value of ≥85% HPI and ≥99% HPI yielded a sensitivity and specificity of 100%, respectively, for detection of HCC.Conclusion: P-CT shows a high sensitivity for detection of HCC in the cirrhotic liver. Quantitative assessment has the potential to reduce false-positive findings improving the specificity of HCC diagnosis.Key Points: • Visual analysis of perfusion maps shows good sensitivity for detection of HCC. • Additional assessment of anatomical arterial MIPs further improves detection rates of HCC. • Quantitative perfusion analysis has the potential to reduce false-positive findings. • In cirrhotic livers, a hepatic-perfusion-index ≥ 9 9% might be specific for HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The risk for hepatocellular carcinoma (HCC) remained at a low level long-term (up to 8 years) after achievement of sustained virologic response (SVR) in patients with hepatitis C virus–associated liver cirrhosis. Continued surveillance for HCC after SVR is warranted.Background. The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)–infected patients with liver cirrhosis is not fully known.Methods. These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up.Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up.Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed. [ABSTRACT FROM PUBLISHER]

Objective. The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. Patients and methods. 373 patients with hemochromatosis detected through routine health check-ups ( n == 153), family screening ( n == 44), symptoms of arthralgia ( n == 23), investigation of other diseases/symptoms ( n == 108) or signs of liver disease ( n == 45) were monitored for a mean period of 11.9 ±± 5.8 years. The degree of liver fibrosis and survival were analyzed. Results. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Conclusion. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation. [ABSTRACT FROM AUTHOR]

Objectives. Non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis (AIH) and unapparent alcohol abuse may be underlying causes of cryptogenic cirrhosis, but the frequencies of these underlying factors differ between studies. Also, previous studies have shown various outcomes after orthotopic liver transplantation (OLT) for cryptogenic cirrhosis. The aims of this study were (1) to evaluate the presence of NAFLD in patients with cryptogenic cirrhosis evaluated for OLT and (2) to compare the severity of liver disease and patient survival in OLT candidates with cryptogenic cirrhosis and those with cirrhosis of another known origin. Material and methods. Four-hundred and seventy adult patients with end-stage liver cirrhosis evaluated for OLT between 1990 and 2004 were included, of whom 39 had cryptogenic cirrhosis. Clinical, histological and laboratory data that had been prospectively collected were re-evaluated. Results. Seventeen (44%) of the cryptogenic patients had NAFLD in a previous liver biopsy and/or clinical features of the metabolic syndrome. Two patients had occult alcohol over-consumption and one patient had burnt-out AIH. Cryptogenic patients had significantly higher frequencies of diabetes, ascites, and hyponatraemia and weight loss. Patient survival was similar between cryptogenic patients and cirrhotics with a known aetiology. Conclusions. Re-evaluation of patient data discovered probable underlying aetiologies in 51% of patients with cryptogenic cirrhosis evaluated for OLT, of which NAFLD was the most common (44%). Although cryptogenic patients had a more advanced liver disease when evaluated for OLT, patient survival was similar. Recent weight loss was significantly more common in cryptogenic patients, possibly being a sign of liver decompensation and signalling a need for OLT evaluation. [ABSTRACT FROM AUTHOR]

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 ( GA) in position 18 into a stop codon ( GA) (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. [ABSTRACT FROM AUTHOR]

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. Methods We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. Results During a follow-up of mean 20 years (range 0–40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease ( p <0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10 th percentile of time to development of severe liver disease was 22–26 years in F0-1, 9.3 years in F2, 2.3 years in F3, and 0.9 years to liver decompensation in F4. Conclusions In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. Lay summary Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long-term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. [ABSTRACT FROM AUTHOR]