ELIMINATE: a PCR record-based macroelimination project for systematic recall of HCV-RNA-positive persons in Austria.

BACKGROUND AND AIMS: Micro-elimination projects targeted to specific hepatitis C virus (HCV) risk populations have been successful. Systematic identification of persons with HCV viremia, regardless of risk group, based on already available laboratory records may represent an effective macroelimination approach to achieve global HCV elimination. METHODS: Persons with a last positive HCV-RNA PCR result between 2008-2020 in the reference virology laboratories in eastern Austria were identified. First, (i) we described their demographic characteristics, (ii) we systematically recalled persons to the respective centers and (iii) started antiviral treatment if HCV-RNA viremia was confirmed, and (iv) recorded sustained virologic response (SVR). This interim report includes the preliminary results from 8 participating centers. RESULTS: During the study period 22,682 persons underwent HCV-RNA PCR testing, 11,216 (49.4%) were positive at any point in time, and 6006 (26.5%) showed detectable HCV-RNA at the last PCR test, suggesting ongoing HCV viremia. At the time of this interim report, 2546/6006 HCV-RNA PCR(+) persons were evaluated: 443/2546 (17.4%) had died, 852/2546 (33.5%) had invalid contact data, and 547/2546 (21.5%) had achieved SVR between data retrieval and recall. Contact could be established in 236/704 (33.5%) of the remaining target population with 97/236 (41.1%) presenting at the clinic for treatment evaluation. Ultimately, 71/236 (30.1%) started antiviral treatment and SVR was documented in 47/71 (66.2%). CONCLUSION: This ELIMINATE project based on systematic assessment of HCV-RNA PCR-records, identified 6006 persons with potential persisting HCV viremia. Invalid contact data and missed visits for treatment evaluation were the main barriers towards HCV elimination within this project. Importantly, many subjects with HCV viremia lost to follow-up were successfully linked to care and started antiviral treatment.

Disease burden of hepatitis C in the Austrian state of Tyrol - Epidemiological data and model analysis to achieve elimination by 2030.

BACKGROUND: In 2016, the World Health Organization (WHO) and 69th World Health Assembly approved the first global health sector strategy (GHSS) on viral hepatitis with the goal to eliminate hepatitis C virus (HCV) infections worldwide. The aim is a 90% reduction of new infections and 65% reduction of HCV-related deaths by 2030. AIM: This study reports on the epidemiology of HCV infections in the Austrian state of Tyrol (total population 750,000) and uses a predictive model to identify how the WHO strategy for elimination of HCV can be achieved. METHODS: We developed a regional disease burden model based on observed local diagnosis data from 2001 to 2016. Scenarios were developed to evaluate the impact of diagnosis and treatment on HCV-related outcomes (viremic prevalence, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths) from 2015 through 2030. RESULTS: In the last 15 years, 1,721 patients living in Tyrol have been diagnosed with chronic HCV infection. When ageing, mortality and treatment were factored in, there were an estimated 2,043 viremic HCV infections in 2016, of which 1,136 cases had been diagnosed. A baseline model predicts a decrease of 588 HCV cases from 2015 to 2030, which would not translate into the significant reduction of infections needed to achieve WHO global health recommendations. A total of 1,843 infected individuals need to be identified and treated to achieve the WHO goals by 2030 (1,254 averted cases as compared to baseline model). Implementation of this strategy would avoid 523 new HCV infections and decreases HCV-related mortality by 73%. CONCLUSION: HCV elimination and >65% reduction of associated mortality are possible for Tyrol, but requires a significant increase in new diagnoses and treatment rate. The model presented in this study could serve as an example for other regions to reliably predict regional disease burden and estimate how WHO goals can be met in the future.

Prognostic significance of hepatic arterial collaterals in liver transplant recipients with biliary strictures.

BACKGROUND: The aim of this study was to determine the prevalence of hepatic artery stenosis (HAS) and the prognostic implications of hepatic arterial collaterals in liver transplant (LT) recipients with biliary strictures. METHODS: The 105 LT recipients transplanted between 2004 and 2015 at our center had documented biliary strictures. HAS and collaterals were assessed in high-quality imaging of the hepatic artery available from 66 recipients. Clinical, demographic, and biochemical recipient and donor data were retrospectively analyzed and tested for their association with biliary or arterial complications after LT. RESULTS: The prevalence of HAS was 68% (45 of 66) in LT recipients with biliary strictures. Seventy-six percent (37 of 49) of patients with nonanastomotic biliary strictures had HAS. This was significantly higher than in patients with anastomotic stricture, where 47% (8 of 17) of patients had a pathological hepatic arteriogram (P=.039). The location of bile duct strictures was not predictive for outcome. In contrast, arterial collaterals were associated with significantly better patient and graft survival. CONCLUSION: Impaired hepatic arterial perfusion is frequently associated with nonanastomotic strictures, but less closely correlated with anastomotic strictures. On survival analysis, hepatic arterial collaterals have a protective effect.

Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.

BACKGROUND & AIMS: Impaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis. METHODS: Patients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand. RESULTS: Both in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort. CONCLUSIONS: Our results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure.

A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection.

BACKGROUND & AIMS: IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment. METHODS: 136 patients (74 male; 35 ± 15 years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p=0.027), (II) age (p=0.031; cut-off: 35 years), (III) peak-bilirubin (p=0.018; cut-off: 6 mg/dl), (IV) HCV-RNA decline within 4 weeks (p<0.001;cut-off: >2.5 log), (V) serum IP-10 (p=0.003; cut-off: 546 pg/ml), (VI) presence of CD4(+) Th1 cells (p=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ≥ 1 log 10 but <2.5 log 10 to 1 point, a decline of ≥ 2.5 log 10 to 2 points. Three scores were evaluated (Score 1: I-IV; Score 2: I-V; Score 3: I-VI). RESULTS: A cut-off of ≥ 3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76-0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53-0.86) and specificity of 87% (95% CI: 0.73-0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86-0.93) at a cut-off of ≥ 4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ≥ 5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%). CONCLUSIONS: The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.

Cystatin C is a strong predictor of survival in patients with cirrhosis: is a cystatin C-based MELD better?

BACKGROUND/AIMS: The model of end stage liver disease (MELD) includes serum creatinine, which is a poor surrogate marker of renal function in patients with cirrhosis. Especially in women and patients with advanced disease creatinine underestimates true renal function. Our objective was to assess whether or not the substitution of creatinine by cystatin C improves the prognostic performance of the model. METHODS: The association between MELD parameters and cystatin C with survival was investigated using a Cox proportional hazards model. A cystatin C-based MELD score was calculated from the results and compared with creatinine-based MELD in terms of discrimination and calibration. RESULTS: Four hundred and twenty-nine patients were included in the study; 19% died and 12% underwent liver transplantation during a median follow-up of 602 days. In multivariate Cox regression, cystatin C was an independent predictor of 90-day mortality with a hazard ratio of 8.0 (95% CI: 2.2-29.6). The median cystatin C-based MELD was 15, the median creatinine-based MELD was 12. Calibration and discrimination for 3 month and 1 year mortality was similar between the scores (AUC > 0.85 for both scores). Gender differences in cystatin C-based MELD were less pronounced than those in the creatinine-based model, because creatinine but not cystatin C was affected by gender. CONCLUSION: Substitution of creatinine by cystatin C does not improve the predictive power of MELD.

Immunoglobulin subclass 4 for the diagnosis of immunoglobulin subclass 4-associated diseases in an unselected liver and pancreas clinic population.

AIMS: The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin subclass 4 (IgG(4) )-associated cholangitis (IAC) is based on imaging studies, serology, histology and a response to steroid therapy. The major serological finding is an elevation of the serum IgG(4) concentration. Previous studies have shown that its sensitivity is about 70% and its specificity exceeds 90% at a cut-off of 140 mg/dl in selected patient populations. The aim of the present study was to assess the performance of serum IgG(4) as a diagnostic parameter in an unselected liver and pancreas clinic population. METHODS AND RESULTS: IgG(4) was prospectively determined in 1412 patients and clinical diagnoses were recorded from a review of patient charts. The prevalence of AIP or IAC in the entire cohort was 1.1% (n= 15). The sensitivity of IgG(4) for the diagnosis of AIP and IAC was 80% and the specificity was 86% at a cut-off value of ≥135 mg/dl. The positive predictive value and the negative predictive value were 6% and 99.7%, respectively. The most common differential diagnosis in patients with elevated IgG(4) was liver cirrhosis. CONCLUSION: IgG(4) has a reasonable sensitivity and specificity in a liver and pancreas clinic population, where liver cirrhosis appears to be the most frequent differential diagnosis for elevated IgG(4) concentrations.

Genetic polymorphisms in dilated cardiomyopathy.

Dilated cardiomypathies (DCM) are characterized by dilatation and pump dysfunction of the heart. DCM has an incidence of 6/100.000 people a year contributing to a considerable number of cases of heart failure. Although etiology and pathogenesis are known to be multifactorial, they remain mostly unidentified. Recent research identified patients affected with DCM with altered gene products. These alterations can roughly be grouped into causative genes, mostly coding for cytoskeletal proteins. Other genes seem to be activated after the disease onset and are able to influence the clinical course. In this study we systematically analyzed the role of genetic polymorphisms, based on peer-reviewed articles, published in scientific journals. A total of 97 original studies and a selected number of 60 genes, that seem to be related to DCM, have been reviewed.

Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas.

The longest open reading frame of PKHD1 (polycystic kidney and hepatic disease 1), the autosomal recessive polycystic kidney disease (ARPKD) gene, encodes a single-pass, integral membrane protein named polyductin or fibrocystin. A fusion protein comprising its intracellular C-terminus, FP2, was previously used to raise a polyclonal antiserum shown to detect polyductin in several human tissues, including liver. In the current study, we aimed to investigate by immunohistochemistry the detailed polyductin localization pattern in normal (ductal plate [DP], remodelling ductal plate [RDP], remodelled bile ducts) and abnormal development of the primitive intrahepatic biliary system, known as ductal plate malformation (DPM). This work also included the characterization of polyductin expression profile in various histological forms of neonatal and infantile cholestasis, and in cholangiocellular carcinoma (CCC) and hepatocellular carcinoma (HCC). We detected polyductin expression in the intrahepatic biliary system during the DP and the RDP stages as well as in DPM. No specific staining was found at the stage of remodelled bile ducts. Polyductin was also detected in liver biopsies with neonatal cholestasis, including mainly biliary atresia and neonatal hepatitis with ductular reaction as well as congenital hepatic fibrosis. In addition, polyductin was present in CCC, whereas it was absent in HCC. Polyductin was also co-localized in some DP cells together with oval stem cell markers. These results represent the first systematic study of polyductin expression in human pathologies associated with abnormal development of intrahepatic biliary tree, and support the following conclusions: (i) polyductin expression mirrors developmental properties of the primitive intrahepatic biliary system; (ii) polyductin is re-expressed in pathological conditions associated with DPM and (iii) polyductin might be a potential marker to distinguish CCC from HCC.