Non-viral Chronic Liver Disease Research Articles

Liver Elastography-based Risk Score for Predicting Hepatocellular Carcinoma Risk.

Liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) accurately assesses fibrosis. We aimed to develop a universal risk score for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. We systematically selected predictors and developed the risk prediction model (HCC-LSM) in the HBV training cohort (n = 2,251, median follow-up of 3.2 years). The HCC-LSM model was validated in an independent HBV validation cohort (n = 1,191, median follow-up of 5.7 years) and a non-viral chronic liver disease (CLD) extrapolation cohort (n = 1,189, median follow-up of 3.3 years). A HCC risk score was then constructed based on a nomogram. An online risk evaluation tool (LEBER) was developed using ChatGPT4.0. Eight routinely available predictors were identified, with LSM levels showing a significant dose-response relationship with HCC incidence (P < .001 by log-rank test). The HCC-LSM model exhibited excellent predictive performance in the HBV training cohort (C-index = 0.866) and the HBV validation cohort (C-index = 0.852), with good performance in the extrapolation CLD cohort (C-index = 0.769). The model demonstrated significantly superior discrimination compared to six previous models across the three cohorts. Cut-off values of 87.2 and 121.1 for the HCC-LSM score categorized participants into low-, medium-, and high-risk groups. An online public risk evaluation tool (LEBER; http://ccra.njmu.edu.cn/LEBER669.html) was developed to facilitate the use of HCC-LSM. The accessible, reliable risk score based on LSM accurately predicted HCC development in patients with chronic hepatitis, providing an effective risk assessment tool for HCC surveillance strategies.

Characteristics of diabetes mellitus patients with nonviral chronic liver disease who developed hepatocellular carcinoma.

Type 2 diabetes mellitus (T2DM) is a well-known risk factor for hepatocellular carcinoma (HCC). However, HCC is often diagnosed at an advanced stage in patients with diabetes because of the lack of the best criteria for surveillance candidates. The aim of this study was to identify risk factors for HCC development in patients with diabetes with nonviral chronic liver disease. Three hundred thirty T2DM patients with nonviral chronic liver disease who underwent surveillance for HCC by imaging techniques between 2009 and 2020 were enrolled in this multicenter cross-sectional retrospective study. Theclinical and laboratory parameters of patients with and without HCC were compared. Age ≥65years, alcohol intake, lack of hepatic steatosis, triglyceride level <111mg/dL, Mac2 binding protein glycosylation isomer (M2BPGi) ≥0.9 cut-off index (COI), α-fetoprotein concentration ≥5ng/mL, and des-γ-carboxy prothrombin concentration ≥26mAU/mL were independently associated with HCC development. When stratified by age, only alcohol intake (odds ratio [OR] 114.19, p<0.001) was associated with HCC development in patients aged <65years, and medication for diabetes mellitus (OR 5.72, p=0.001), lack of hepatic steatosis (OR 4.47, p=0.002), lactate dehydrogenase ≥198IU/L (OR 2.751, p=0.031), M2BPGi ≥1.18 COI (OR 9.05, p<0.001), and FIB-4 index ≥2.59 (OR 3.22, p=0.017) were associated with HCC development in patients aged ≥65years. In addition to age and advanced liver fibrosis, alcohol intake in younger T2DM patients and medication for DM and lack of hepatic steatosis in older T2DM patients should be considered for HCC surveillance by imaging.

Characteristics and Outcomes of Hepatocellular Carcinoma in Patients with C-Viral Chronic Liver Disease and Non-Viral Chronic Liver Disease

Abstract Background Hepatocellular carcinoma (HCC) is the primary liver cancer derived from hepatocytes and accounts for 85–90% of all primary liver cancers, It is the 5th commonest cancer in men and the 7th commonest cancer in women overall in the world. However, it is the third commonest cause of cancer-related death worldwide, exceeded only by cancers of the lung and stomach. Aim The aim of the work is to compare characteristics, behavior and outcomes of Hepatocellular carcinoma (HCC) in patients with viral and non-viral chronic liver disease. Patients and Methods It is a retrospective cohort study In Tropical Medicine department and HCC clinic at Ain Shams University Hospitals. (from 2015 to 2020), divided to 2 groups according to the aetiology of their chronic liver disease : Group 1n = 35: patients with HCC on top of viral chronic liver disease (due to viral C). Group 2n=28: patients with a HCC on top of non-viral chronic liver disease Further stratification of both groups according to BCLC was done. Results This study showed male predominance in both group, viral group is 30 (85.7%) and female 5 (14.3%) with mean age 58.77 ± 7.47 and in non viral group male predominance 18 (64.3%) and female10 (35.7%) with mean age of 48.07 ± 14.42 years' old. There was statistical significance difference between the two groups regarding one year survival 6 patients died in non viral (21.4%) while 16 patients died in viral groups (45.7%). There was statistical significant difference between viral group (n = 35) and non viral groups(n = 28) as regards overall survival, which was higher in non viral groups with mean (11.46) month. Conclusion Non-viral chronic liver disease patients with hepatocellular carcinoma (HCC) have less-severe liver dysfunction at HCC diagnosis and better overall survival compared to counterparts with viral chronic liver disease patients (HCV). Further studies on large number of patients are needed.

Hepatocellular carcinoma risk scores for non-viral liver disease: A systematic review and meta-analysis

BackgroundHepatocellular carcinoma (HCC) risk prediction models may provide a more personalised approach to surveillance for HCC among patients with cirrhosis. This systematic review aims to summarise the performance of HCC prediction models in patients with non-viral chronic liver disease. MethodThe study was prospectively registered with PROSPERO (ID: CRD42022370078) and reported in accordance with PRISMA guidelines. MEDLINE and EMBASE databases were searched using a validated search filter for prediction model studies. Two reviewers independently assessed studies for inclusion and risk of bias. Model performance (discrimination and calibration) were identified to assess the risk of HCC at specified time points. A random effects meta-analysis was done on a subset of studies that reported performance of the same model. Results7,854 studies were identified. After review, 14 studies with a total of 94,014 participants were included. 45% of patients had viral hepatitis, 27% alcohol related liver disease (ArLD) and 19% metabolic associated steatotic liver disease (MASLD). Follow-up ranged from 15.1 - 138 months. Only one model was developed using a competing risk approach. Age (7 models) and sex (6 models) were the most frequently included predictors. Model discrimination (AUROC or c-statistic) ranged from 0.61 - 0.947. Only the ‘aMAP’ score (age, male sex, albumin,bilirubin, and platelets) had sufficient external validation for quantitative analysis, with a pooled c-statistic of 0.81 (95% CI 0.80-0.83). Calibration was reported in only 9 of 14 studies. All studies were rated high risk of bias. ConclusionStudies describing risk prediction of HCC in non-viral chronic liver disease are poorly reported, have a high risk of bias and do not account for competing risk events. Patients with ArLD and MASLD are underrepresented in development and validation cohorts. These factors remain barriers to the clinical utility and uptake of HCC risk models in persons with the commonest liver diseases. Impact and implicationsThe recent EASL policy statement emphasises the potential of risk-based surveillance to reduce both HCC-related deaths and surveillance costs. This study addresses the gap in understanding the performance of current HCC risk models in patients with non-viral liver diseases, reflecting the epidemiological landscape of liver disease in Western countries.In our review of these models, we identified several key concerns regarding reporting standards and risk of bias and confirmed that patients with alcohol-related liver disease (ArLD) and metabolic-associated steatotic liver disease (MASLD) are underrepresented in model development and validation cohorts. Additionally, most models fail to account for the significant risk of competing events, leading to potential overestimation of true HCC risk.This study highlights these critical issues that may hinder the implementation of risk models in clinical practice and offers key recommendations for future model development studies.

Etiological changes of liver cirrhosis and hepatocellular carcinoma-complicated liver cirrhosis in Japan: Updated nationwide survey from 2018 to 2021.

A nationwide survey in 2018 showed decreasing involvement of viral hepatitis and increasing involvement of nonviral liver diseases in the etiology of livercirrhosis (LC) in Japan. An updated nationwide survey was undertaken in 2023. Cases of LC diagnosed between 2018 and 2021 were collected from 75 institutions, and the etiologies of LC were investigated. In addition, the data obtained were compared with the results of previous studies. Among the 15517 cases, alcohol-related liver disease (ALD)-associated LC was the most frequent cause (n=5,487, 35.4%). Hepatitis C virus-associated LC, nonalcoholic steatohepatitis (NASH)-associated LC, and hepatitis B virus-associated LC were ranked as second, third, and fourth, respectively. In comparison to the previous survey, the ratios of viral hepatitis-associated LC decreased (HBV: from 11.5% to 8.1%; HCV: from 48.2% to 23.4%), while the ratios of ALD-associated LC and NASH-associated LC increased (from 19.9% to 35.4% and from 6.3% to 14.6%, respectively). Regarding cases of LC with hepatocellular carcinoma (n=5906), HCV-associated LC (1986 cases, 33.6%) was the most frequent cause. Alcohol-related liver disease-associated LC, NASH-associated LC, and HBV-associated LC were the second-, third-, and fourth-ranked causes, respectively. In comparison to the previous survey, as the cause of hepatocellular carcinoma-complicated LC, HCV-associated LC decreased from 60.3% to 33.6%, while the ratios of ALD-associated LC and NASH-associated LC increased from 14.2% to 28.6% and from 4.2% to 14.0%, respectively. The major causes of LC in Japan are suggested to have been shifting from viral hepatitis to nonviral chronic liver diseases.

Protein kinase C delta enhances the diagnostic performance of hepatocellular carcinoma

Background The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need. Objective This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs. Methods PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC. Results In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels. Conclusions PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.

Nonviral Liver Disease Burden in People Living With HIV and Elevated Transaminases: A Cross-Sectional Study.

Because of improved life expectancy in people living with HIV (PLWH), liver disease is increasingly being recognized. We assessed nonviral chronic liver disease burden in PLWH. The HIV non-virAL liver disease study (2014-2021) prospectively recruited PLWH with elevated serum alanine aminotransferase levels and negative hepatitis serology. Clinically significant hepatic fibrosis (CSHF) was defined as liver stiffness measurement of >7.1 kPa and hazardous alcohol use as Alcohol Use Disorders Identification Test score ≥ 8. Primary outcome was prevalence/predictors of CSHF. Total recruited were n = 274, 92% male, median age 52 (45-59) years, and 96% having undetectable HIV viral load. Overall, n = 97 (35%) had hazardous alcohol use, n = 72 (26%) had metabolic syndrome, and 17%-27% had exposure to hepatotoxic antiretrovirals. Prevalence of CSHF was 20% (n = 54), prevalence of cirrhosis (liver stiffness measurement > 12.5 kPa) being 7% (19/274). Risk factors for CSHF were hazardous alcohol use in 44% (n = 24), metabolic syndrome in 46% (n = 25), and hepatotoxic antiretrovirals in 56% (n = 30), most having more than one risk factor. Independent predictors of CSHF were serum high-density lipoprotein (odds ratio [OR] 0.220; 95% confidence interval [CI]: 0.061 to 0.790, P = 0.020) (inverse relationship); serum aspartate aminotransferase (OR 1.033, 95% CI: 1.001 to 1.067, P = 0.045), and didanosine use (OR 2.878, 95% CI: 1.228 to 6.774, P = 0.015). Moderate-severe hepatic steatosis was identified in 52% (n = 142). FIB-4 and aspartate aminotransferase-to-platelet ratio index performed poorly in predicting CSHF (positive predictive value 27.3% and 30.6%, respectively) and advanced fibrosis (≥F3) (positive predictive value 17.6% and 5.9%, respectively). In this study, 20% of PLWH had CSHF associated with high prevalence of hazardous alcohol use/metabolic syndrome/potentially hepatotoxic antiretrovirals. These potentially modifiable risk factors need addressing.

Clinical features of patients with chronic liver disease in Japan related to alcohol use: Nationwide examination using alcohol use disorders identification test.

Patients often do not respond truthfully to physicians' interviews concerning alcohol. Few reports regarding the level of alcohol dependence in patients with chronic liver disease (CLD) have been presented. This study aimed to elucidate severity distribution in patients with CLD using the alcohol use disorders identification test (AUDIT). From March to June 2022, 2034 Japanese outpatients with CLD, including 415 cases associated with hepatitis C virus, 436 with hepatitis B virus, 173 with alcohol-related liver disease (ARLD), and 1010 with other factors, were interviewed using AUDIT. Clinical features related to alcohol use in these patients were then retrospectively evaluated. In all patients, an AUDIT score 8-14 (harmful use) was noted in 5.8% of hepatitis C virus, 8.9% of hepatitis B virus, 24.3% of ARLD, and 4.4% of other groups, respectively (P<0.001), while a score ≥15 (dependency) was noted in 3.4%, 3.0%, 27.7%, and 1.9%, respectively (P<0.001). When the country was divided into regions, the percentages remained similar. Comparisons between patients with and without an AUDIT score ≥8 (n=1412), performed after exclusion of those without related data (n=622), showed no significant differences for hepatic reserve function, while those with harmful alcohol use were significantly younger (66 vs. 70years, P=0.006) and had a larger percentage of men (80.4% vs. 45.1%, P<0.001). Harmful alcohol and alcohol dependency were observed in approximately 10% of patients with viral or non-viral CLD, after excluding patients with ARLD. Assessment of alcohol intake by use of the AUDIT questionnaire as well as adequate intervention should be considered necessary.

Prevalence of Occult Hepatitis B Infection in Liver Biopsy Sample of Patients with Nonviral Liver Disease

Aim: To determine the prevalence of occult hepatitis B (HBV) infection (OBI) in patients with nonviral liver disease. Materials &amp; methods: This study included 83 HBsAg-negative patients followed up at a gastroenterohepatology clinic. The presence of HBV DNA was investigated by using an in-house nested-PCR method applied to liver parenchymal biopsy samples obtained from patients who underwent due nonviral chronic liver disease. Results: OBI was detected in 19 (22.9%) of the 83 cases, in 11 (44%) of 25 anti-HBc-positive patients, and 15 (31.9%) of 47 anti-HBc and/or anti-HBs antibodies-positive patients. Conclusion: There is a considerable prevalence of OBI among patients with nonviral chronic liver disease. Therefore, it is suggested that closely monitoring HBV can be useful to prevent or more effectively manage possible OBI-related complications among patients with nonviral chronic liver disease, especially those who are HBsAg seronegative or anti-HBV antibody seropositive.

Chronic non-viral liver pathology in military personnel exposed to military-professional factors

Abstract. The prevalence and structure of chronic non-viral liver disease of military personnel whose service is associated with the influence of various military-professional factors are estimated. It is established that the frequency of chronic diffuse liver diseases of viral etiology in a group of servicemen radio-technical troops was 77,3%, from persons engaged in diving and altitude descents 65,9%, pilots of the aerospace defence forces of Russia 62,8%, in persons without exposure to military occupational factors is 69,5%. The largest number of persons suffering from chronic non-viral liver disease in the group of military radio-technical troops, probably related to low levels of physical activity and higher values of body mass index and waist circumference, but also the influence of microwave radiation, can enhance the damaging effects of lipid peroxidation. The lowest prevalence of non-viral chronic diffuse liver diseases among pilots and aquanauts is probably related to the maximum health requirements imposed on military personnel of these categories. It was found that the level of alcohol consumption and the nature of nutrition in the study groups did not significantly differ. The highest values of body mass index and waist circumference in combination with the lowest level of physical activity were observed in the group of military personnel of the radio engineering troops, which is probably due to the nature of daily military service, which is mainly sedentary. Among the metabolic changes of blood serum, increased total cholesterol levels in groups of divers, pilots and military Radio-technical troops compared with a control. In addition, the level of glucose in Aquanauts, as well as triglycerides in soldiers of the radio engineering troops was higher than in the control group. Ultrasound examination in all groups related to the impact of military occupational factors, recorded an increase in the thickness of the left lobe of the liver, and oblique vertical size and thickness of the right lobe in the group of soldiers of the radio-technical troops compared with a control. In addition, the values of the thickness of the intima-media complex as a marker of preclinical atherosclerosis associated with non-alcoholic and alcoholic-metabolic fatty liver diseases in this category of individuals significantly exceed them in the other groups. The maximum level of liver damage in the group of military personnel of radio engineering troops is confirmed by the highest values of the controlled parameter of attenuation of ultrasound, reflecting the degree of liver steatosis.

Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients.

BACKGROUNDReliable biomarkers of cirrhosis, hepatocellular carcinoma (HCC), or progression of chronic liver diseases are missing. In this context, Golgi protein-73 (GP73) also called Golgi phosphoprotein-2, was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells. As a result, GP73 expression was found primarily in biliary epithelial cells, with only slight detection in hepatocytes. However, in patients with acute or chronic liver diseases and especially in HCC, the expression of GP73 is significantly up-regulated in hepatocytes. So far, few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression.AIMTo assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression.METHODSGP73 serum levels were retrospectively determined by a novel GP73 ELISA (QUANTA Lite® GP73, Inova Diagnostics, Inc., Research Use Only) in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa, Greece (n = 366) and Debrecen, Hungary (n = 266). Aspartate aminotransferase (AST)/Platelets (PLT) ratio index (APRI) was also calculated at the relevant time points in all patients. Two hundred and three patients had chronic hepatitis B, 183 chronic hepatitis C, 198 alcoholic liver disease, 28 autoimmune cholestatic liver diseases, 15 autoimmune hepatitis, and 5 with other liver-related disorders. The duration of follow-up was 50 (57) mo [median (interquartile range)]. The development of cirrhosis, liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines. In particular, the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein (AFP) determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients.RESULTSIncreased serum levels of GP73 (> 20 units) were detected at initial evaluation in 277 out of 632 patients (43.8%). GP73-seropositivity correlated at baseline with the presence of cirrhosis (96.4% vs 51.5%, P < 0.001), decompensation of cirrhosis (60.3% vs 35.5%, P < 0.001), presence of HCC (18.4% vs 7.9%, P < 0.001) and advanced HCC stage (52.9% vs 14.8%, P = 0.002). GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score [Area under the curve (AUC) (95%CI): 0.909 (0.885-0.934) vs 0.849 (0.813-0.886), P = 0.003]. Combination of GP73 with APRI improved further the accuracy (AUC: 0.925) compared to GP73 (AUC: 0.909, P = 0.005) or APRI alone (AUC: 0.849, P < 0.001). GP73 levels were significantly higher in HCC patients compared to non-HCC [22.5 (29.2) vs 16 (20.3) units, P < 0.001) and positively associated with BCLC stage [stage 0: 13.9 (10.8); stage A: 17.1 (16.8); stage B: 19.6 (22.3); stage C: 32.2 (30.8); stage D: 45.3 (86.6) units, P < 0.001] and tumor dimensions [very early: 13.9 (10.8); intermediate: 19.6 (18.4); advanced: 29.1 (33.6) units, P = 0.004]. However, the discriminative ability for HCC diagnosis was relatively low [AUC (95%CI): 0.623 (0.570-0.675)]. Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline, was prognostic of higher rates of decompensation (P = 0.036), HCC development (P = 0.08), and liver-related deaths (P < 0.001) during follow-up.CONCLUSIONGP73 alone appears efficient for detecting cirrhosis and superior to APRI determination. In combination with APRI, its diagnostic performance can be further improved. Most importantly, the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and non-viral chronic liver diseases.

Possibilities of transient and two-dimensional shear wave elastography in the diagnosis of fibrosis in nonviral chronic diffuse liver diseases in military personnel

The study examines the possibilities of transient and two-dimensional shear wave elastography in the diagnosis of fibrosis in the most common chronic diffuse liver diseases of non-viral etiology: alcoholic and non-alcoholic fatty liver disease, as well as their combination. It was found that in patients suffering from these diseases, the values of aspartate and alanine aminotransferase, gamma-glutamyl transpeptidase, cholesterol, triglycerides, as well as the oblique vertical size of the right lobe of the liver were significantly (p0,05) higher than in patients of the control group. Moreover, most of these indicators reliably (p0,01) reached the highest values in patients suffering from fatty liver disease of alcohol-metabolic etiology, which confirms a more pronounced damaging effect on the liver with a combination of alcohol and metabolic factors. It has been established that the use of transient and two-dimensional elastography is characterized by high diagnostic significance in determining the stage of fibrosis in chronic diffuse liver diseases of non-viral etiology. The greatest diagnostic significance of elastographic research methods is noted in the third and fourth stages of fibrosis. In the second stage of fibrosis, the quality of diagnostic significance when using transient elastography was higher than when using two-dimensional shear wave. The use of transient and two-dimensional shear wave elastography in most cases avoids liver biopsy in patients suffering from chronic diffuse liver diseases of non-viral etiology. Therefore, in the diagnosis of chronic diffuse liver diseases, the presence and degree of fibrosis is a factor that will largely determine the prognosis, treatment tactics and the likelihood of complications in a particular patient.

Interaction Between Alcohol Use and Metabolic Risk Factors for Liver Disease: A Critical Review of Epidemiological Studies.

Coexistence of alcohol use and metabolic risk-the 2 commonest population risk factors for nonviral chronic liver disease-is a growing concern. Clinical evidence and mechanistic evidence point to considerable supraadditive interaction effects for the development and progression of chronic liver disease between hazardous alcohol use and metabolic abnormalities including obesity, diabetes, and the metabolic syndrome (MetS). Intermittent binge drinking once monthly or more often seems to be associated with progression of liver disease even when average alcohol intake is within the currently allowed limits for a diagnosis of nonalcoholic fatty liver disease (NAFLD), and supraadditive interaction between binge drinking and the MetS has been reported. There are contradictory findings regarding the association between low alcohol use and liver steatosis, but, clearly, the mechanisms of alcoholic hepatotoxicity extend beyond simple fat accumulation. The presence of liver steatosis seems to amplify alcoholic hepatotoxicity. Recent longitudinal studies of NAFLD subjects report low alcohol use associated with both increased fibrosis progression and an elevated risk for liver cancer and severe liver disease. There is no clear safe limit of alcohol intake in the presence of NAFLD or metabolic risk. The interaction effects between alcohol and metabolic dysfunction merit increased attention in public health policy, individual counseling, and risk stratification. Based on current evidence, a strict dichotomization of liver disease into either pure alcoholic or nonalcoholic may be inappropriate.

Impact of etiology of chronic liver disease on hepatocellular carcinoma biomarkers.

The role of serum biomarkers in the surveillance of hepatocellular carcinoma (HCC) is controversial. We assessed the diagnostic performances of alpha-fetoprotein (AFP) and protein-induced by vitamin-K-absence/antagonist-II (PIVKA-II) in 388 cirrhotic patients with chronic liver disease (CLD). Biomarkers were quantified by automated chemiluminescent-enzyme-immunoassays (Fujirebio, Tokyo, Japan) at HCC diagnosis in 258 patients (204 males; median age 66.9 years) and in 130 cirrhotics without HCC (104 males; median-age 60.6 years). CLD etiology in HCC/non-HCC was CHB in 48/35, CHC in 126/56 and Non-Viral in 84/39. Overall AUROC values for AFP and PIVKA-II were 0.698 (95%CI = 0.642-0.753, P< 0.001) and 0.780 (95%CI = 0.730-0.831, P< 0.001). AFP/PIVKA-II AUROC (95%CI) were: 0.822 (0.728-0.915)/0.833 (0.739-0.926) in CHB, 0.648 (0.560-0.736)/0.732 (0.650-0.814) in CHC; 0.640 (0.540-0.740)/0.806 (0.722-0.889) in Non-Viral-CLD. AFP/PIVKA-II diagnostic accuracy was 40.5-59.8%/62.7-73.5% and combining both markers 78.2% for CHB, 77% for Non-Viral-CLD and 75% for CHC. AFP correlated with ALT in HCC patients with CHC (ρ= 0.463/P< 0.001) and Non-Viral CLD (ρ= 0.359/P= 0.047), but not in CHB (treated with antivirals). PIVKA-II correlated with tumour size independently of CLD-etiology (P< 0.001) and AFP in CHB patients only (P= 0.007). The diagnostic performance of AFP and PIVKA-II is significantly influenced by the etiology and activity of CLD; their combination provides a better diagnostic accuracy.

Soluble intercellular adhesion molecule-1 is associated with hepatocellular carcinoma risk: multiplex analysis of serum markers

Individualized assessment of hepatocellular carcinoma (HCC) risk in chronic liver disease remains challenging. Serum biomarkers including cytokines may offer helpful adjuncts to standard parameters for risk prediction. Our aim was to identify markers associated with increased HCC incidence. This was a prospective cohort study of 282 patients with both viral or non-viral chronic liver disease. Baseline serum cytokines and other markers were measured in multiplex with a commercially-available Luminex-based system. Patients were followed until death or HCC diagnosis. We performed Lasso-based survival analysis to determine parameters associated with HCC development. Cytokine mean florescence intensity (MFI) was the primary predictor and HCC development the primary outcome. 25 patients developed HCC with total follow-up of 1,363 person-years. Parameters associated with increased HCC incidence were cirrhosis, hepatic decompensation, and soluble serum intercellular adhesion molecule 1 (sICAM-1) MFI. No other molecules increased predictive power for HCC incidence. On univariate analysis, the parameters associated with HCC incidence in patients with cirrhosis were age, antiviral treatment, and high sICAM-1 MFI; on multivariate analysis, sICAM-1 remained associated with HCC development (adjusted HR = 2.75). On unbiased screening of serum cytokines and other markers in a diverse cohort, baseline sICAM-1 MFI is associated with HCC incidence.

Non-viral liver disease burden in HIV-monoinfected individuals: a longitudinal observational retrospective cohort study

ABSTRACTRecent advances in antiviral therapy have improved outcomes in HIV-positive individuals co-infected with hepatitis B and C virus (HBV/HCV). Our aim was to assess prevalence and predictors of chronic liver disease (CLD) due to the metabolic syndrome (MS), alcohol and antiretrovirals (ARVs) use in HIV-monoinfected individuals. This was a retrospective cohort study (2005–2012). HIV-positive patients with negative HBV/HCV serology and at least two elevated alanine aminotransferase (ALT) levels six months apart were included. Data are presented as mean ± SD or percentage. Despite negative viral serology, 27% (1047/3872) of HIV-positive individuals had persistently elevated ALT. Only 243 (23.2%) were investigated (by imaging in the majority, only 58 undergoing liver biopsy/transient elastography). CLD was identified in 66.2%, this being clinically significant in one in four individuals. Potential CLD risk factors were alcohol (44.2%), hepatotoxic ARVs (74.1%) and MS risk factors (68%) with 68.7% having >1 risk factor. On multivariate logistic regression analysis serum triglyceride (OR 1.482, 95% CI 1.053–2.086, p = .024) was the only independent predictor of CLD. Overall, 4.3% were referred to Hepatology services. In conclusion, less than 6% of HIV-monoinfected individuals with persistently elevated ALT undergo objective assessment of hepatic fibrosis. Despite non-stringent criteria, some degree of non-viral CLD is identified in approximately two-thirds of those investigated, risk factors being synonymous with those for the MS. This increasing yet under-recognised non-viral CLD burden warrants timely recognition to prevent long-term morbidity and mortality.

High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires.

Hepatic T-cell infiltrates and a strong genetic human leukocyte antigen association represent characteristic features of various immune-mediated liver diseases. Conceptually the presence of disease-associated antigens is predicted to be reflected in T-cell receptor (TCR) repertoires. Here, we aimed to determine if disease-associated TCRs could be identified in the nonviral chronic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD). We performed high-throughput sequencing of the TCRβ chain complementarity-determining region 3 of liver-infiltrating T cells from PSC (n = 20), PBC (n = 10), and ALD (n = 10) patients, alongside genomic human leukocyte antigen typing. The frequency of TCRβ nucleotide sequences was significantly higher in PSC samples (2.53 ± 0.80, mean ± standard error of the mean) compared to PBC samples (1.13 ± 0.17, P < 0.0001) and ALD samples (0.62 ± 0.10, P < 0.0001). An average clonotype overlap of 0.85% was detected among PSC samples, significantly higher compared to the average overlap of 0.77% seen within the PBC (P = 0.024) and ALD groups (0.40%, P < 0.0001). From eight to 42 clonotypes were uniquely detected in each of the three disease groups (≥30% of the respective patient samples). Multiple, unique sequences using different variable family genes encoded the same amino acid clonotypes, providing additional support for antigen-driven selection. In PSC and PBC, disease-associated clonotypes were detected among patients with human leukocyte antigen susceptibility alleles. We demonstrate liver-infiltrating disease-associated clonotypes in all three diseases evaluated, and evidence for antigen-driven clonal expansions. Our findings indicate that differential TCR signatures, as determined by high-throughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases; this thereby opens up the prospect of studying disease-relevant T cells in order to better understand and treat liver disease.

Multiple causes of death analysis of chronic diseases: the example of diabetes.

BackgroundIdentifying a single disease as the underlying cause of death (UCOD) is an oversimplification of the clinical-pathological process leading to death. The multiple causes of death (MCOD) approach examines any mention of a disease in death certificates. Taking diabetes as an example, the study investigates: patterns of death certification, differences in mortality figures based on the UCOD and on MCOD, factors associated to the mention of diabetes in death certificates, and potential of MCOD in the analysis of the association between chronic diseases.MethodsThe whole mortality archive of the Veneto Region-Italy was extracted from 2008 to 2010. Mortality rates and proportional mortality were computed for diabetes as the UCOD and as MCOD. The position of the death certificate where diabetes was mentioned was analyzed. Conditional logistic regression was applied with chronic liver diseases (CLD) as the outcome and diabetes as the exposure variable. A subset of 19,605 death certificates of known diabetic patients (identified from the archive of exemptions from medical charges) was analyzed, with mention of diabetes as the outcome and characteristics of subjects as well as other diseases reported in the certificate as predictors.ResultsIn the whole mortality archive, diabetes was mentioned in 12.3 % of death certificates, and selected as the UCOD in 2.9 %. The death rate for diabetes as the UCOD was 26.8 × 105 against 112.6 × 105 for MCOD; the UCOD/MCOD ratio was higher in males. The major inconsistencies of certification were entering multiple diseases per line and reporting diabetes as a consequence of circulatory diseases. At logistic regression the mention of diabetes was associated with the mention of CLD (mainly non-alcohol non-viral CLD). In the subset of known diabetic subjects, diabetes was reported in 52.1 %, and selected as the UCOD in 13.4 %. The probability of reporting diabetes was higher with coexisting circulatory diseases and renal failure and with long duration of diabetes, whereas it was lower in the presence of a neoplasm.ConclusionsThe use of MCOD makes the analysis of mortality data more complex, but conveys more information than usual UCOD analyses.

Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease.

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis.

Hepatocarcinogenesis in non‐alcoholic fatty liver disease in Japan

In Japan, there has been a gradual increase in cases of non-viral chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), occurring with hepatocellular carcinoma (HCC). First, a national survey investigating the etiology of HCC in Japan was performed. Among HCCs based on non-viral disease, alcoholic liver disease with HCC accounted for 7.2% of all HCCs, followed by chronic liver disease of unknown etiology with HCC (5.1%) and NAFLD with HCC (2.0%). The clinical characteristics of these three HCC groups were clearly different. In our second analysis, the HCC development rates among liver cirrhosis with NAFLD, alcoholic cirrhosis, and cirrhosis with hepatitis C virus (HCV) were compared. HCC development rates were 11.3%/5 years in NAFLD cirrhosis, 30.5%/5 years in HCV cirrhosis, and 12.5%/5 years in alcoholic cirrhosis, suggesting that the hepatocarcinogenesis in NAFLD and alcoholic liver disease were similar but were lower than that in HCV. Using Cox hazards analysis, older age, higher serum γ-glutamyl transpeptidase level, and higher Child-Pugh score as risk factors of HCC were identified. Finally, clinical data of NAFLD-HCC with the data for HCC with HCV (HCV-HCC) were compared. The percentage of NAFLD-HCC patients with des-gamma-carboxy prothrombin-positive was higher than that with α-fetoprotein-positive. The 5-year survival and recurrence rates for NAFLD-HCC were almost similar to those for HCV-HCC. In Asian countries, the prevalence of NAFLD is increasing. Therefore, elucidating the pathogenesis and clinical features of HCC in patients with NAFLD is indeed an urgent problem.