Liver-related Clinical Outcomes Research Articles

Prognostic Value of the Pretransplant Fibrosis-4 Index on Non-Relapse and Overall Mortality following Unrelated Single-Unit Cord Blood Transplantation in Adults

Introduction: The fibrosis-4 (FIB-4) index is a noninvasive marker of liver fibrosis. The FIB-4 index predicts poor outcomes in patients with hepatic and non-hepatic diseases. However, the association of the FIB-4 index with mortality and liver-related clinical outcomes following cord blood transplantation (CBT) is unclear. Methods: We retrospectively evaluated the impact of the pretransplant FIB-4 index on outcomes in 336 adults following single-unit unrelated CBT at our institution. Results: In multivariate analyses, when the FIB-4 index <1.3 group was used as the reference, non-relapse mortality was significantly higher in the FIB-4 index 1.3–2.67 (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.19–5.30) and FIB-4 index >2.67 (HR, 2.34; 95% CI, 1.12–4.90) groups. Overall mortality was significantly higher in the FIB-4 index >2.67 group (HR, 1.66; 95% CI, 1.00–2.73), but with only marginal significance in the FIB-4 index 1.3–2.67 group (HR, 1.59; 95% CI, 0.96–2.64). Hematopoietic recovery, acute and chronic graft-versus-host disease of the liver, and veno-occlusive disease/sinusoidal obstruction syndrome were not associated with the pretransplant FIB-4 index. Conclusion: The pretransplant FIB-4 index is accurate and useful in predicting mortality in adult patients undergoing single-unit unrelated CBT.

Noninferiority Outcomes of Besifovir Compared to Tenofovir Alafenamide in Treatment-Naïve Patients with Chronic Hepatitis B.

: Besifovir dipivoxil maleate (BSV) and tenofovir alafenamide fumarate (TAF) have been recently approved in Korea as the initial antiviral agents for chronic hepatitis B (CHB). However, the real-world outcome data for these drugs remain limited. Therefore, we conducted a noninferiority analysis using real-world data to compare the clinical outcomes of the two nucleotide analogs in treatment-naïve patients with CHB. : We retrospectively investigated a cohort of patients with CHB who received BSV or TAF as first-line antiviral agents. The endpoints were virological response (VR) and liver-related clinical outcomes. : A total of 537 patients, consisting of 202 and 335 patients administered BSV and TAF, respectively, were followed up for 42 months. No significant difference was observed between the VRs of the patients from the two groups. The rates of biochemical response, virologic breakthrough, and incidence rates of hepatocellular carcinoma did not differ between the groups. However, the hepatitis B e antigen seroclearance rate was higher and the renal function declined less in the BSV group. Multivariable analysis indicated older age, alcohol abuse, cirrhosis and ascites, and lower serum HBV DNA level to be independently associated with increased hepatocellular carcinoma risk. The 1:1 propensity score-matched analysis with 400 patients showed VR rates of 85.0% and 88.7% in the BSV and TAF group patients, respectively, at 2 years. The absolute value of the 95% confidence interval for the difference (-0.04 to 0.12) satisfied the a priori limit of a noninferiority of 0.15. : BSV is noninferior to TAF in terms of VR, and their clinical outcomes are comparable to CHB.

The Oral Cholate Challenge Test Quantifies Risk for Liver-Related Clinical Outcomes in Primary Sclerosing Cholangitis

BACKGROUND & AIMSWe quantified hepatic functional impairment using quantitative function tests and linked severity of functional impairment to liver-related complications and outcome in primary sclerosing cholangitis (PSC). METHODSForty-seven patients had baseline testing, and 40 were retested after one year. For each test, cholates labeled with cold, nonradioactive isotopes were administered orally (DuO, SHUNT tests) and intravenously (SHUNT test) and blood was analyzed at 20 and 60 minutes (DuO), or 0, 5, 20, 45, 60, and 90 minutes (SHUNT). Disease severity index (DSI), hepatic reserve (HR%), and portal-systemic shunting (SHUNT%) were calculated. RESULTSThree subgroups with low, moderate, and high disease severity were defined from the age-adjusted results for DSI, HR%, and SHUNT%. Standard laboratory tests, clinical scores, cytokine levels, and clinical outcome correlated with these subgroups. In univariate analysis of baseline tests, SHUNT% was a strong predictor of clinical outcome (n=13 of 47; AUROCs 0.84DuO, 0.90SHUNT). A model combining SHUNT%, DSI (or HR%), platelet count, and changes from baseline was most predictive of outcome (n=10 of 40; AUROCs 0.95DuO, 0.96SHUNT). CONCLUSIONDSI, HR%, and SHUNT% identified subgroups of PSC based on the age-related severity of hepatic impairment that predicted risk for liver-related clinical outcome. Further study is warranted to confirm and validate these intriguing findings both in studies of natural progression of PSC and in clinical trials. DuO enhances the utility of quantitative liver function testing.

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

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

PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease

Background & AimsFibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. MethodsCohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin–bilirubin (ALBI) scores. ResultsIn cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6–4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9–14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8–3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0–13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. ConclusionsPRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and ImplicationsWe tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Liver fibrosis quantification.

Liver fibrosis (LF) is the wound healing response to chronic liver injury. LF is the endpoint of chronic liver disease (CLD) regardless of etiology and the single most important determinant of long-term liver-related clinical outcomes. Quantification of LF is important for staging, to evaluate response to treatment and to predict outcomes. LF is traditionally staged by liver biopsy. However, liver biopsy is invasive and suffers from sampling errors when biopsy size is inadequate; therefore, non-invasive tests (NITs) have found important roles in clinical care. NITs include simple laboratory-based serum tests, panels of serum tests, and imaging biomarkers. NITs are validated against the liver biopsy and will be used in the future for evaluation of nearly all CLDs with invasive liver biopsy reserved for some cases. Both serum tests and some imaging biomarkers such as elastography are currently used clinically as surrogate markers for LF. Several other imaging biomarkers are still considered research and awaiting clinical application in the future. As the evaluation of imaging biomarkers will likely become the norm in the future, understanding pathogenesis of LF is important. Knowledge of properties measured by imaging biomarkers and its correlation with LF is important to understand the application of NITs by abdominal radiologists. In this review, we present a brief overview of pathogenesis of LF, spatiotemporal evolution of LF in different CLD, and severity assessment with liver biopsy. This will be followed by a brief discussion on properties measured by imaging biomarkers and their relationship to the LF.

Impact of PNPLA3 (rs738409-G) Polymorphism on Post-Transplant Outcomes after Liver Transplantation for Alcohol-Related Liver Disease

Background and Aims: We aimed to evaluate the association between PNPLA3 polymorphism and post-liver transplantation (LT) outcomes related to alcohol relapse (AR). Methods: We retrospectively analyzed data from patients receiving LT for alcoholic liver disease (ALD) from 04/2014 to 12/2017. Liver-related clinical outcomes were assessed by the gamma-glutamyltransferase (GGT) level and alcohol-related liver failure (ARLF). Genotyping was performed using prospectively collected DNA samples in both donors and recipients. Results: A total of 83 recipients were enrolled. Post-LT AR occurred in 31 patients (37.3%). Thirty-one patients (14 AR, 9 abstainers) showed elevated GGT levels, and 3 AR patients experienced ARLF. In the multivariate analysis, rs738409 G allele carrier and heavy drinking (HRAR score≥4) were independent risk factors for elevated GGT levels (odds ratio [OR]=8.69, p<0.01; OR=13.07, p=0.01) and ARLF (OR=4.52, p=0.04; OR=19.62, p=0.03). Among 15 heavy AR patients, being an rs738409 G allele carrier was related to GGT elevation (p=0.03) and ARLF (p=0.04), but it was not to GGT elevation in mild drinkers (n=16) or abstainers (n=52). Conclusions: PNPLA3 polymorphism of the recipient genotype can independently affect the post-LT prognosis of LT patients for ALD, especially in heavy AR patients. Therefore, strong abstinence education is recommended in patients with this single nucleotide polymorphism.

Impact of patatin-like phospholipase domain-containing protein 3 (rs738409-G) polymorphism on post-transplant outcomes after liver transplantation for alcohol-related liver disease

We aimed to evaluate the association between patatin-like phospholipase domain-containing protein 3 (PNPLA3) polymorphism and post-liver transplantation (LT) outcomes related to alcohol relapse (AR). We retrospectively analyzed data from patients receiving LT for alcoholic liver disease (ALD) from 04/2014 to 12/2017. Liver-related clinical outcomes were assessed by the gamma-glutamyltransferase (GGT) level and alcohol-related liver failure (ARLF). Genotyping was performed using prospectively collected DNA samples in both donors and recipients. A total of 83 recipients were enrolled. Post-LT AR occurred in 31 patients (37.3%). Thirty-one patients (14 AR, 9 abstainers) showed elevated GGT levels, and 3 AR patients experienced ARLF. In the multivariate analysis, rs738409-G allele carrier and heavy drinking (HRAR score ≥4) were independent risk factors for elevated GGT levels (odds ratio [OR] = 8.69, p < 0.01; OR = 13.07, p = 0.01) and ARLF (OR = 4.52, p = 0.04; OR = 19.62, p = 0.03). Among 15 heavy AR patients, being an rs738409-G allele carrier was related to GGT elevation (p = 0.03) and ARLF (p = 0.04), but it was not to GGT elevation in mild drinkers (n = 16) or abstainers (n = 52). PNPLA3 polymorphism of the recipient genotype can independently affect the post-LT prognosis of LT patients for ALD, especially in heavy AR patients. Therefore, strong abstinence education is recommended in patients with this single nucleotide polymorphism.

Cannabis use history is associated with increased prevalence of ascites among patients with nonalcoholic fatty liver disease: A nationwide analysis.

BACKGROUNDRecent studies have revealed the endocannabinoid system as a potential therapeutic target in the management of nonalcoholic fatty liver disease (NAFLD). Cannabis use is associated with reduced risk for NAFLD, we hypothesized that cannabis use would be associated with less liver-related clinical complications in patients with NAFLD.AIMTo assess the effects of cannabis use on liver-related clinical outcomes in hospitalized patients with NAFLD.METHODSWe performed a retrospective matched cohort study based on querying the 2014 National Inpatient Sample (NIS) for hospitalizations of adults with a diagnosis of NAFLD. The NIS database is publicly available and the largest all-payer inpatient database in the United States. The patients with cannabis use were selected as cases and those without cannabis were selected as controls. Case-control matching at a ratio of one case to two controls was performed based on sex, age, race, and comorbidities. The liver-related outcomes such as portal hypertension, ascites, varices and variceal bleeding, and cirrhosis were compared between the groups. RESULTSA total of 49911 weighed hospitalizations with a diagnosis of NAFLD were identified. Of these, 3820 cases were selected as the cannabis group, and 7625 non-cannabis cases were matched as controls. Patients with cannabis use had a higher prevalence of ascites (4.5% vs 3.6%), with and without cannabis use, P = 0.03. The prevalence of portal hypertension (2.1% vs 2.2%), varices and variceal bleeding (1.3% vs 1.7%), and cirrhosis (3.7% vs 3.6%) was not different between the groups, with and without cannabis use, all P > 0.05. Hyperlipidemia, race/ethnicity other than White, Black, Asian, Pacific Islander or Native American, and higher comorbidity score were independent risk factors for ascites in the cannabis group. Among non-cannabis users, obesity and hyperlipidemia were independent protective factors against ascites while older age, Native American and higher comorbidity index were independent risk factors for ascites. CONCLUSIONCannabis was associated with higher rates of ascites, but there was no statistical difference in the prevalence of portal hypertension, varices and variceal bleeding, and cirrhosis.

Impact of PNPLA3 (rs738409-G) polymorphism on post-transplant outcomes after liver transplantation for alcohol-related liver disease.

We aimed to evaluate the association between PNPLA3 polymorphism and post-liver transplantation (LT) outcomes related to alcohol relapse (AR). We retrospectively analyzed data from patients receiving LT for alcoholic liver disease (ALD) from 04/2014 to 12/2017. Liver-related clinical outcomes were assessed by the gamma-glutamyltransferase (GGT) level and alcohol-related liver failure (ARLF). Genotyping was performed using prospectively collected DNA samples in both donors and recipients. A total of 83 recipients were enrolled. Post-LT AR occurred in 31 patients (37.3%). Thirty-one patients (14 AR, 9 abstainers) showed elevated GGT levels, and 3 AR patients experienced ARLF. In the multivariate analysis, rs738409 G allele carrier and heavy drinking (HRAR score≥4) were independent risk factors for elevated GGT levels (odds ratio [OR]=8.69, P<.01; OR=13.07, P=.01) and ARLF (OR=4.52, P=.04; OR=19.62, P=.03). Among 15 heavy AR patients, being an rs738409 G allele carrier was related to GGT elevation (P=.03) and ARLF (P=.04), but it was not related to GGT elevation in mild drinkers (n=16) or abstainers (n=52). PNPLA3 polymorphism of the recipient genotype can independently affect the post-LT prognosis of LT patients for ALD, especially in heavy AR patients. Therefore, strong abstinence education is recommended in patients with this single nucleotide polymorphism.

Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Biopsy-confirmed liver fibrosis is a prognostic factor for patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with nonalcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint. We searched the MEDLINE, Embase, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all cause and liver related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% confidence interval (CI) values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Metaregression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow-up (in years). Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared with no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); liver transplant RR, 5.42 (95% CI, 1.05-27.89); and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly after adjustment for confounders, including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings. In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.

The Alpha-1 Antitrypsin Polymer Load Correlates With Hepatocyte Senescence, Fibrosis Stage and Liver-Related Mortality.

Alpha-1 antitrypsin deficiency (AATD) is an important, inherited cause of chronic liver disease. Marked variation in fibrosis stages in patients with homozygous deficiency and those factors that determine whether heterozygous carriers develop liver fibrosis, remain unexplained. Murine studies implicate polymerized alpha-1 antitrypsin (AAT) within hepatocytes as pathogenic. The relationship between the quantity of polymerized AAT within hepatocytes (polymer load), stage of hepatic fibrosis and liver-related clinical outcomes (death, evolution to hepatocellular carcinoma, or need for liver transplantation) were investigated using liver tissue from 92 patients at first presentation with either homozygous or heterozygous AATD. Further tissue-based studies were undertaken to determine if polymerized AAT was associated with failure of cell cycle progression, accelerated aging or hepatocyte senescence by immunohistochemical analysis. The AAT polymer load correlated closely with hepatic fibrosis stage and long-term clinical outcome, independent of homozygous or heterozygous status. AAT polymers within hepatocytes correlated closely with failure of cell cycle progression assessed using cell cycle phase markers, accelerated aging manifest as shortened telomeres and other markers consistent with hepatocyte senescence manifest as the presence of nuclear p21 expression and enlarged nuclei. The proportion of p21 positive hepatocytes or hepatocytes with enlarged nuclei correlated with hepatic fibrosis stage and the long-term clinical outcome. These data suggest that accumulation of AAT polymers within hepatocytes drives senescence. Quantitation of both the AAT polymer load or hepatocyte senescence markers correlated with hepatic fibrosis stage and the long-term clinical outcome. Either or both could be considered markers of disease severity and treatment response in clinical trials.

REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis

BackgroundNonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. AimsThe Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. MethodsREGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. ConclusionsREGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. Clinical trial registrationClinicalTrials.gov with the identifier NCT02548351.

Collagen proportionate area is an independent predictor of long-term outcome in patients with non-alcoholic fatty liver disease.

Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies by measuring the amount of collagen deposition as a proportion of the total biopsy area. CPA predicts clinical outcomes in patients with HCV and can sub-classify cirrhosis. To test the ability of CPA to quantify fibrosis and predict clinical outcomes in patients with NAFLD. We assessed consecutive patients with biopsy-proven NAFLD from three European centres. Clinical and laboratory data were collected at baseline and at the time of the last clinical follow-up or death. CPA was performed at two different objective magnifications, whole biopsy macro and ×4 objective magnification, named standard (SM) and high (HM) magnification respectively. The correlation between CPA and liver stiffness was assessed in a sub-group of patients. Of 437 patients, 32 (7.3%) decompensated and/or died from liver-related causes during a median follow-up of 103months. CPA correlated with liver stiffness and liver fibrosis stage across the whole spectrum of fibrosis. HM CPA was significantly higher than SM CPA in stages F0-F3 but similar in cirrhosis, reflecting a higher ability to capture pericellular/perisinusoidal fibrosis at early stages. Age at baseline (HR: 1.04, 95% CI: 1.01-1.08), HM CPA (HR: 1.04 per 1% increase, 95% CI: 1.01-1.08) and presence of advanced fibrosis (HR: 15.4, 95% CI: 5.02-47.84) were independent predictors of liver-related clinical outcomes at standard and competing risk multivariate Cox-regression analysis. CPA accurately measures fibrosis and is an independent predictor of clinical outcomes in NAFLD; hence it merits further evaluation as a surrogate endpoint in clinical trials.

Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease

Background & aimsLong-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features. Methods37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa. ResultsMedian liver stiffness was 4.6 [3–15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis. ConclusionsSignificant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

Multi-organ assessment of compensated cirrhosis patients using quantitative magnetic resonance imaging

Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit vs. harm for therapies. Our aim was to establish the feasibility of magnetic resonance imaging (MRI) to assess changes in Compensated Cirrhosis (CC), and relate this to disease severity and future liver-related outcomes (LROs). A total of 60 patients with CC, 40 healthy volunteers and 7 patients with decompensated cirrhosis were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T1 longitudinal relaxation time, heart rate, cardiac index, and volume assessment of the liver, spleen and kidneys. We explored the association between MRI parameters and disease severity, analysing differences in baseline MRI parameters in the 11 (18%) patients with CC who experienced future LROs. In the liver, compositional changes were reflected by increased T1 in progressive disease (p <0.001) and an increase in liver volume in CC (p = 0.006), with associated progressive reduction in liver (p <0.001) and splenic (p <0.001) perfusion. A significant reduction in renal cortex T1 and increase in cardiac index and superior mesenteric arterial blood flow was seen with increasing disease severity. Baseline liver T1 (p = 0.01), liver perfusion (p <0.01), and renal cortex T1 (p <0.01) were significantly different in patients with CC who subsequently developed negative LROs. MRI enables the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement for a contrast agent. MRI parameters of liver T1, renal T1, hepatic and splenic perfusion, and superior mesenteric arterial blood flow were related to the risk of LROs. This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (Compensated Cirrhosis), using magnetic resonance imaging. The magnetic resonance imaging measures which changed with disease severity and were related to negative liver-related clinical outcomes are described.

A comparison of three proposed methods of newborn screening for early infantile Krabbe disease

Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features.37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa.Median liver stiffness was 4.6 [3–15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis.Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

Assessing risk of fibrosis progression and liver-related clinical outcomes among patients with both early stage and advanced chronic hepatitis C.

ObjectiveAssessing risk of adverse outcomes among patients with chronic liver disease has been challenging due to non-linear disease progression. We previously developed accurate prediction models for fibrosis progression and clinical outcomes among patients with advanced chronic hepatitis C (CHC). The primary aim of this study was to validate fibrosis progression and clinical outcomes models among a heterogeneous patient cohort.DesignAdults with CHC with ≥3 years follow-up and without hepatic decompensation, hepatocellular carcinoma (HCC), liver transplant (LT), HBV or HIV co-infection at presentation were analyzed (N = 1007). Outcomes included: 1) fibrosis progression 2) hepatic decompensation 3) HCC and 4) LT-free survival. Predictors included longitudinal clinical and laboratory data. Machine learning methods were used to predict outcomes in 1 and 3 years.ResultsThe external cohort had a median age of 49.4 years (IQR 44.3–54.3); 61% were male, 80% white, and 79% had genotype 1. At presentation, 73% were treatment naïve and 31% had cirrhosis. Fibrosis progression occurred in 34% over a median of 4.9 years (IQR 3.2–7.6). Clinical outcomes occurred in 22% over a median of 4.4 years (IQR 3.2–7.6). Model performance for fibrosis progression was limited due to small sample size. The area under the receiver operating characteristic curve (AUROC) for 1 and 3-year risk of clinical outcomes was 0.78 (95% CI 0.73–0.83) and 0.76 (95% CI 0.69–0.81).ConclusionAccurate assessments for risk of clinical outcomes can be obtained using routinely collected data across a heterogeneous cohort of patients with CHC. These methods can be applied to predict risk of progression in other chronic liver diseases.

Regenerate: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Multicenter Study of Obeticholic Acid Therapy for Nonalcoholic Steatohepatitis

Introduction: Nonalcoholic Steatohepatitis (NASH) is a slowly progressive chronic liver disease without approved therapies. Patients with NASH and fibrosis are at high risk of increased mortality. Obeticholic Acid (OCA) is a selective and potent farnesoid X receptor (FXR) agonist, that has been shown to improve liver histology, including NAFLD activity score (NAS) and fibrosis, in a Phase 2 clinical trial (FLINT). Furthermore in FLINT, OCA treated patients had significant improvements in select liver biochemistries, markers of inflammation, and select cardiometabolic parameters. The ongoing, randomized, global, Phase 3 study REGENERATE, will further evaluate the effect of OCA on liver histology and clinical outcomes in patients with biopsy-confirmed NASH with stage 2-3 fibrosis. Methods: 2065 patients will be randomized 1:1:1 to 10 mg OCA, 25 mg OCA or placebo (Figure), each added to standard of care. An interim analysis at 18 months will evaluate the effect of OCA on liver histology. Total study duration is driven by time required to accrue a total of 264 outcome events and is estimated to be ˜6 years. Safety assessments will include adverse events (AEs), adjudicated cardiovascular events, and hepatic events as well as laboratory assessments. The effect of OCA on NASH and fibrosis severity will also be assessed by multiple noninvasive methods (FIB-4, APRI, transient elastography, magnetic resonance elastography, etc.).Figure 1Results: The co-primary liver histology endpoints at 18 months include: (I) improvement in fibrosis by ≥1 stage with no worsening of NASH and (II) resolution of NASH with no worsening in fibrosis stage. Further, confirmation of clinical benefit of OCA will be assessed at the end of the study by comparing the time to first occurrence of any of the following adjudicated events: histological progression to cirrhosis; uncontrolled ascites; hospitalization for: variceal bleed, hepatic encephalopathy or spontaneous bacterial peritonitis; hepatocellular carcinoma; liver transplant or eligibility for liver transplant (defined by model for end stage liver disease (MELD) score ≥15); and death. Conclusion: REGENERATE is the first pivotal study in NASH, designed in conjunction with FDA and meant to support approval of OCA for NASH with fibrosis. This robust Phase 3 study is designed to evaluate the effect of OCA on liver histology and effects on progression to cirrhosis, liver-related clinical outcomes and mortality.

Serum models accurately predict liver-related clinical outcomes in chronic hepatitis C.

This study developed liver outcome scores in chronic hepatitis C (CHC) that directly predict liver-related death, hepatocellular carcinoma (HCC), and liver decompensation. Six hundred seventeen CHC patients were followed up for a mean of 6 years and randomized into a training set (n = 411) and a validation set (n = 206). Clinical outcomes were determined using a population-based data linkage system. In the training set, albumin, gamma-glutamyl transpeptidase, hyaluronic acid, age, and sex were in the final model to predict 5-year liver-related death (area under receiver operating characteristic curve [AUROC] 0.95). Two cut points (4.0 and 5.5) defined three risk groups with an incidence rate for liver-related death of 0.1%, 2%, and 13.2%, respectively (P < 0.001). Albumin, gamma-glutamyl transpeptidase, hyaluronic acid, age, and sex were used to predict 5-year liver decompensation (AUROC 0.90). A cut point of 4.5 gave a sensitivity of 94% and a specificity of 84% to predict 5-year decompensation and defined two groups with an incidence rate for decompensation of 0.2% and 5.8%, respectively (P < 0.001). Alkaline phosphatase, α2-macroglobulin, age, and sex were used to predict 5-year HCC occurrence (AUROC 0.95). A cut-point of eight had a sensitivity of 90% and specificity of 88% to predict 5-year HCC occurrence and defined two groups with an incidence rate for HCC of 0.2% and 5.6%, respectively (P < 0.001). Similar results were obtained using the validation set. All three liver outcome scores had excellent predictive accuracy and were able to stratify risk into clinical meaningful categories for CHC patients.