Publications by authors named "John M Vierling"

116 Publications

Prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and biliary injury in liver biopsies from patients with non-alcoholic steatohepatitis.

Pathology 2022 May 5. Epub 2022 May 5.

Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology and Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA.

The significance of portal tract histological changes in non-alcoholic fatty liver disease (NAFLD) remains unclear. In 2019, CymaBay Therapeutics halted clinical trials of seladelpar (a PPARδ agonist) because initial end-of-treatment liver biopsies of patients with non-alcoholic steatohepatitis (NASH) showed concerning features of portal inflammation with plasma cells, interface hepatitis and focal bile duct abnormalities. Adjudication concluded that these findings were present in the initial, as well as the subsequent biopsies. Thus, this study's aim was to determine the prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and features of bile duct damage in liver biopsies of adult patients with NAFLD. The pathology database was searched for cases of NAFLD, including steatosis alone and NASH, from January 2016 to October 2020. Liver biopsies were selected from age and sex matched adult patients with diagnoses of steatosis alone (n=10), NASH fibrosis stage 1 (n=10), stage 2 (n=10), stage 3 (n=10), and stage 4 (n=10). There were 24 males and 26 females with a mean age of 48 years (range 20-79). Exclusion criteria included age <18 years, daily alcohol intake >14 drinks per week, elevation of alkaline phosphatase level, comorbid chronic liver disease, or liver biopsy performed as part of a clinical trial for NASH. Control liver biopsies were selected from age and sex matched persons without significant steatosis and normal liver biochemical tests (n=10). Histological parameters were evaluated in 10 portal tracts or 10 septal areas in each liver biopsy. Portal inflammation and interface hepatitis were graded on a scale of 0-4. Portal plasma cells and bile duct damage were scored from 0-3. Ductular proliferation was assessed by CK7 immunostain and graded from 0-4. NASH biopsies with advanced fibrosis (stage 3 and 4) showed portal inflammatory infiltrates (score 2-3) with readily identifiable plasma cells (score 2), and mild to moderate interface hepatitis (score 2-3). All cases and controls showed focal, mild cholangiocyte changes, characterised by cytoplasmic vacuolation, segmental loss of nuclei, nuclear disarray and apoptosis. NASH patients with advanced fibrosis had frequent and diffuse cholangiocyte changes, along with focal lymphocytic cholangitis and moderate to marked ductular reaction (score 3-4). Histopathological features of advanced NASH frequently include increased portal inflammation with plasma cells, interface hepatitis, cholangiocyte injury and prominent ductular reaction.
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http://dx.doi.org/10.1016/j.pathol.2022.01.009DOI Listing
May 2022

Early Impact of MMaT-3 Policy on Liver Transplant Waitlist Outcomes for Hepatocellular Carcinoma.

Transplant Direct 2022 May 12;8(5):e1313. Epub 2022 Apr 12.

Liver Center, Division of Abdominal Transplantation, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX.

To reduce the disparity in access to liver transplant (LT), United Network for Organ Sharing implemented an exception policy in May 2019, which capped hepatocellular carcinoma (HCC) exception score to the median Model for End-Stage Liver Disease (MELD) at transplant within the donor service area minus 3 points (MMaT-3) after the 6-mo wait period. We aimed to evaluate how this policy affected HCC waitlist outcomes.

Methods: Using United Network for Organ Sharing data, we analyzed waitlist outcomes in HCC patients at the time they received exception points from in the pre-MMaT era (August 15, 2017, to November 15, 2018) and MMaT era (June 1, 2019, to August 30, 2020). Comparisons were made within the HCC group and HCC versus non-HCC (at time of listing) groups in the pre-MMaT and MMaT eras and regions were grouped as low, medium, and high MELD based on MMaT.

Results: HCC group: LT probability within HCC patients decreased by 20% (subhazard ratio [sHR], 0.78; 95% confidence interval [CI], 0.74-0.85) between the eras and decreased by 41% in low MELD regions (sHR, 0.59; 95% CI, 0.52-0.66). Waitlist dropout was unchanged. Matched HCC versus non-HCC groups: HCC patients had 80% higher LT probability (sHR, 1.84; 95% CI, 1.71-1.99) than non-HCC patients in the pre-MMaT era; which decreased to a 14% higher LT probability in MMaT era. In low and medium regions, HCC patients had over twofold higher LT probability in the pre-MMaT era, which decreased to a ~20% higher probability (sHR, 1.14; 95% CI, 1.06-1.23) in the MMaT era. After implementation of the acuity circle policy, HCC patients had lower LT probability (sHR, 0.84; 95% CI, 0.74-0.94) than non-HCC patients.

Conclusions: The geographic disparity between HCC and non-HCC patients has improved with the MMaT-3 policy. Despite lower LT probability for HCC patients, waitlist dropout was not adversely impacted.
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http://dx.doi.org/10.1097/TXD.0000000000001313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005245PMC
May 2022

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.

J Hepatol 2022 Mar 30. Epub 2022 Mar 30.

CymaBay Therapeutics, Inc, Newark, California, United States.

Background & Aims: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid.

Methods: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8.

Results: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events.

Conclusions: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus.

Clinicaltrials:

Gov Number: NCT02955602 CLINICALTRIALSREGISTER.

Eu Number: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.
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http://dx.doi.org/10.1016/j.jhep.2022.02.033DOI Listing
March 2022

Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.

J Hepatol 2022 Apr 20;76(4):841-849. Epub 2022 Jan 20.

Institute of Liver Studies, King's College Hospital, London, United Kingdom; European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Electronic address:

Background & Aims: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment.

Methods: A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis.

Results: The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'.

Conclusions: These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints.

Lay Summary: Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
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http://dx.doi.org/10.1016/j.jhep.2021.12.041DOI Listing
April 2022

Screening for undiagnosed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): A population-based risk factor assessment using vibration controlled transient elastography (VCTE).

PLoS One 2021 30;16(11):e0260320. Epub 2021 Nov 30.

Fatty Liver Foundation, Boise, Idaho, United States of America.

The screening for undiagnosed non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (SUNN) study was a population-based screening study that aimed to provide proof of concept to encourage community-level screening and detection for this non-communicable disease. Current screening guidelines do not recommend the routine screening of nonalcoholic fatty liver disease (NAFLD) for asymptomatic populations, so providers are not encouraged to actively seek disease, even in high-risk patients. This study sought to determine whether a self-selecting cohort of asymptomatic individuals would have scores based on vibration controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) significantly correlated to risk factors to suggest that routine screening for high-risk patients should be recommended. The study recruited 1,070 self-selected participants in Houston and Galveston County, Texas, 940 of which were included in final analysis. A pre-screening survey was used to determine eligibility. VCTE-based scores analyzed steatosis and fibrosis levels. Fifty-seven percent of the study population demonstrated steatosis without fibrosis, suggesting NAFLD, while 16% demonstrated both steatosis and fibrosis, suggesting NASH. Statistically significant risk factors included factors related to metabolic syndrome, race, and age, while statistically significant protective factors included consumption of certain foods and exercise. The findings of this study suggest that high-risk individuals should be screened for NAFLD even in the absence of symptoms and that community-based screenings are an effective tool, particularly in the absence of proactive guidelines for providers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631660PMC
January 2022

Practical Consideration for Drug Monitoring of Tacrolimus in Liver Transplantation Recipients with SARS-CoV-2 Infection.

Liver Transpl 2022 01 16;28(1):127-130. Epub 2021 Sep 16.

Liver Center, Division of Abdominal Transplantation, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX.

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http://dx.doi.org/10.1002/lt.26278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662081PMC
January 2022

Donor Gamma-Glutamyl Transferase Is Associated With Liver Allograft Discard and Failure.

Prog Transplant 2021 06 17;31(2):101-107. Epub 2021 Mar 17.

Division of Abdominal Transplantation, Michael E DeBakey, Department of General Surgery, 3989Baylor College of Medicine, Houston, TX, USA.

Introduction: The disparity between the number of individuals on the wait list and available liver allografts creates the need for a system that maximizes donor liver utilization and predicts graft failure.

Research Question: This study aimed to determine the relationship between donor Gamma-Glutamyl Transferase (GGT), liver discard, and graft failure.

Design: Through multivariate analysis from 53 966 deceased liver donors, we adjusted for donor clinical and demographic characteristics and compared donor GGT with allograft discard. We compared donor GGT ranges with graft failure and analyzed data from 47 269 liver recipients.

Results: After adjusting for other factors, donor GGT was significantly associated with liver discard, with GGT over 200 U/L being most significant (OR 2.74, CI 2.51-2.99). Donor GGT under 20 U/L was also found to be a protective factor for post-transplant graft failure (HR 0.91, CI 0.83 - 1.00).

Conclusion: Going forward, GGT should be included among other characteristics associated with allograft discard considered during the procurement process.
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http://dx.doi.org/10.1177/15269248211002800DOI Listing
June 2021

Trends in Outcomes for Marginal Allografts in Liver Transplant.

JAMA Surg 2020 Aug 5. Epub 2020 Aug 5.

Division of Abdominal Transplantation, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Texas.

Importance: Investigating outcomes after marginal allograft transplant is essential in determining appropriate and more aggressive use of these allografts.

Objective: To determine the time trends in the outcomes of marginal liver allografts as defined by 6 different sets of criteria.

Design, Setting, And Participants: In this cohort, multicenter study, 75 050 patients who received a liver transplant between March 1, 2002, and September 30, 2016, were retrospectively analyzed to last known follow-up (n = 55 395) or death (n = 19 655) using the United Network for Organ Sharing Database. The study period was divided into three 5-year eras: 2002-2006, 2007-2011, and 2012-2016. Kaplan-Meier survival analysis with log-rank test and Cox proportional hazards regression analysis were used to examine the allograft after transplant with marginal allografts, which were defined as 90th percentile Donor Risk Index allografts (calculated over the entire study period), donor after circulatory death allografts, national share allografts, old age (donors >70 years) allografts, fatty liver allografts, and 90th percentile Discard Risk Index allografts. Statistical analysis was performed from August to December 2019.

Main Outcomes And Measures: Allograft failure after transplant as defined by the Organ Procurement and Transplantation Network database.

Results: Among the 75 050 patients (44 394 men; mean [SD] age, 54.3 [9.9] years) in the study, Donor Risk Index, patient Model for End-stage Liver Disease scores, and balance of risk scores significantly increased over time. Multivariate Cox proportional hazards regression analysis indicated that 90th percentile Donor Risk Index allograft survival increased across the study period (2002-2006: hazard ratio, 1.41 [95% CI, 1.34-1.49]; 2007-2011: hazard ratio, 1.25 [95% CI, 1.17-1.34]; 2012-2016: hazard ratio, 1.10 [95% CI, 0.98-1.24]). Secondary definitions of marginal allografts (donor after circulatory death, national share, old age donors, fatty liver, and 90th percentile Discard Risk Index) showed similar improvements in allograft survival.

Conclusions And Relevance: The study's findings encourage the aggressive use of liver allografts and may indicate a need for a redefinition of allograft marginality in liver transplantation.
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http://dx.doi.org/10.1001/jamasurg.2020.2484DOI Listing
August 2020

Presentation and Outcomes of Autoimmune Hepatitis Type 1 and Type 2 in Children: A Single-center Study.

J Pediatr Gastroenterol Nutr 2021 01;72(1):101-107

Baylor College of Medicine, Houston, TX.

Objective: Autoimmune hepatitis (AIH) is designated as type 1 or 2 (AIH-1/2) on the basis of serum autoantibody (Ab) profiles. In children, AIH may present as acute or chronic liver failure or cirrhotic AIH (ALF/CLF/CAIH) with or without overlap sclerosing cholangitis (SC). The aim of this study was to compare demographics, presentation, and outcomes between groups in children.

Methods: A retrospective electronic chart review of children with AIH who met standard diagnostic criteria with histologic confirmation at Texas Children's Hospital was performed, with de novo AIH after liver transplant (LT) excluded. Patients were identified and divided into AIH-1, AIH-2, ALF, CAIH, AIH-SC, and LT and compared using chi-square analysis, Student t-test, and Mood median test.

Results: Among 91 children with AIH, 72 (79.1%) had AIH-1, 19 (20.9%) had AIH-2, 13 (14.3%) had ALF, 25 (27.5%) had CAIH, and 14 (15.4%) had AIH-SC. Both AIH-1/2 had female and Hispanic predominance (72.2/89.5%, 40.3/57.9%). AIH-2 presented at younger mean age in years than AIH-1 (6.8, 12.1, P < 0.05). Both AIH-1/2 had low rates of remission after 1 year of IS (25.4, 35.7%) and most recent (30.6, 54.5%) follow-up. Twenty-two (24.2) patients received LT: 16 had AIH-1 (72.7%), 6 had AIH-2 (27.3%), 9 (40.9%) had ALF, and 13 (59.1%) had CAIH. One-year patient and graft survivals were 100%.

Conclusions: The epidemiology and clinical presentation of AIH-1 and -2 had a few subtle differences. AIH-1 was associated with more complications after LT. More data are needed to better characterize the 2 as separate disease entities.
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http://dx.doi.org/10.1097/MPG.0000000000002892DOI Listing
January 2021

Trends in Outcomes for Marginal Allografts in Liver Transplant.

JAMA Surg 2020 Aug 5. Epub 2020 Aug 5.

Division of Abdominal Transplantation, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Texas.

Importance: Investigating outcomes after marginal allograft transplant is essential in determining appropriate and more aggressive use of these allografts.

Objective: To determine the time trends in the outcomes of marginal liver allografts as defined by 6 different sets of criteria.

Design, Setting, And Participants: In this case-control, multicenter study, 75 050 patients who received a liver transplant between March 1, 2002, and September 30, 2016, were retrospectively analyzed to last known follow-up (n = 55 395) or death (n = 19 655) using the United Network for Organ Sharing Database. The study period was divided into three 5-year eras: 2002-2006, 2007-2011, and 2012-2016. Kaplan-Meier survival analysis with log-rank test and Cox proportional hazards regression analysis were used to examine the allograft after transplant with marginal allografts, which were defined as 90th percentile Donor Risk Index allografts (calculated over the entire study period), donor after circulatory death allografts, national share allografts, old age (donors >70 years) allografts, fatty liver allografts, and 90th percentile Discard Risk Index allografts. Statistical analysis was performed from August to December 2019.

Main Outcomes And Measures: Allograft failure after transplant as defined by the Organ Procurement and Transplantation Network database.

Results: Among the 75 050 patients (44 394 men; mean [SD] age, 54.3 [9.9] years) in the study, Donor Risk Index, patient Model for End-stage Liver Disease scores, and balance of risk scores significantly increased over time. Multivariate Cox proportional hazards regression analysis indicated that 90th percentile Donor Risk Index allograft survival increased across the study period (2002-2006: hazard ratio, 1.41 [95% CI, 1.34-1.49]; 2007-2011: hazard ratio, 1.25 [95% CI, 1.17-1.34]; 2012-2016: hazard ratio, 1.10 [95% CI, 0.98-1.24]). Secondary definitions of marginal allografts (donor after circulatory death, national share, old age donors, fatty liver, and 90th percentile Discard Risk Index) showed similar improvements in allograft survival.

Conclusions And Relevance: The study's findings encourage the aggressive use of liver allografts and may indicate a need for a redefinition of allograft marginality in liver transplantation.
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http://dx.doi.org/10.1001/jamasurg.2020.2484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407315PMC
August 2020

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

J Autoimmun 2020 11 5;114:102514. Epub 2020 Aug 5.

Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.
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http://dx.doi.org/10.1016/j.jaut.2020.102514DOI Listing
November 2020

Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis.

Clin Gastroenterol Hepatol 2021 06 22;19(6):1248-1257. Epub 2020 Jul 22.

Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address:

Background & Aims: Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression.

Methods: We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96.

Results: Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints).

Conclusions: In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.
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http://dx.doi.org/10.1016/j.cgh.2020.07.032DOI Listing
June 2021

Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials.

J Viral Hepat 2020 11 10;27(11):1222-1233. Epub 2020 Aug 10.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16-18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.
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http://dx.doi.org/10.1111/jvh.13357DOI Listing
November 2020

A learning curve in using orphan liver allografts for transplantation.

Clin Transplant 2020 04 9;34(4):e13821. Epub 2020 Mar 9.

Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.

Given the critical shortage of donor livers, marginal liver allografts have potential to increase donor supply. We investigate trends and long-term outcomes of liver transplant using national share allografts transplanted after rejection at the local and regional levels. We studied a cohort of 75 050 candidates listed in the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016. We compared patients receiving national share and regional/local share allografts from 2002-2006, 2007-2011, and 2012-2016, performing multivariate Cox regression for graft survival. Recipient and center-level covariates that were not significant (P < .05) were removed. Graft survival of national share allografts improved over time. National share allografts had a 26% increased risk for graft failure in 2002-2006 but no impact on graft survival in 2007-2011 and 2012-2016. The cold ischemia time (CIT) of national share allografts decreased from 10.4 to 8.0 hours. We demonstrate that CIT had significant impact on graft survival using national share allografts (CIT <6 hours: hazard ratio 0.75 and CIT >12 hours: hazard ratio 1.25). Despite a trend toward sicker recipients and poorer quality allografts, graft survival outcomes using national share allografts have improved to benchmark levels. Reduction in cold ischemia time is a possible explanation.
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http://dx.doi.org/10.1111/ctr.13821DOI Listing
April 2020

Metabolomic biomarkers are associated with mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

Future Sci OA 2019 Dec 17;6(2):FSO441. Epub 2019 Dec 17.

Margaret M & Albert B Alkek Department of Medicine, Section of Gastroenterology & Hepatology, Baylor College of Medicine, Houston, TX, USA.

Aim: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

Materials & Methods: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses.

Results: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392).

Conclusion: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers.
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http://dx.doi.org/10.2144/fsoa-2019-0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997913PMC
December 2019

The challenges of primary biliary cholangitis: What is new and what needs to be done.

J Autoimmun 2019 12 20;105:102328. Epub 2019 Sep 20.

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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http://dx.doi.org/10.1016/j.jaut.2019.102328DOI Listing
December 2019

The Observer Effect in Liver Transplantation Exemplified by Unintended Consequences of Regulation and Selected Outcome Metrics.

Prog Transplant 2019 09 11;29(3):291-292. Epub 2019 Jun 11.

1 Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

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http://dx.doi.org/10.1177/1526924819855378DOI Listing
September 2019

Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature.

J Autoimmun 2019 07 24;101:26-34. Epub 2019 Apr 24.

Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, 451 E. Health Sciences Dr., Davis, CA, 95616, United States.

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (-90.9-96.6) and -0.28% (-21.1-15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4 but not CD8 T cell populations, including decreases in CD4 CCR5+ (p = 0.02) and CD4 PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4 CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes.
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http://dx.doi.org/10.1016/j.jaut.2019.04.005DOI Listing
July 2019

Cost-Effectiveness Analysis of Hepatitis B Virus Screening and Management in Patients With Hematologic or Solid Malignancies Anticipating Immunosuppressive Cancer Therapy.

JCO Clin Cancer Inform 2019 03;3:1-12

University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: National hepatitis B virus (HBV) screening recommendations for patients with cancer anticipating systemic anticancer therapy range from universal screening to screening based on risk of HBV infection, cancer therapy-specific risk of HBV reactivation, or both. We conducted cost-effectiveness analyses to identify optimal HBV screening strategies.

Patients And Methods: We constructed decision-analytic models to analyze three strategies (no screening, universal screening, and selective screening based on use of an HBV infection risk tool) for hypothetic cohorts of patients anticipating anticancer therapy at high or lower risk for HBV reactivation. Model parameters were drawn from previously published studies, the SEER-Medicare database, and other online resources. Outcomes included lifetime expected cost, quality-adjusted life expectancy, and incremental cost-effectiveness ratio, measured in US dollars required to gain an additional quality-adjusted life-year (QALY).

Results: For patients at high reactivation risk, universal screening dominated (ie, was cheaper and more effective than) the other two strategies. Universal screening was associated with a gain in life expectancy of 0.01 QALY compared with no screening and cost $76.06 less than no screening and $4.34 less than selective screening. For those at lower reactivation risk, universal screening still dominated selective screening; however, the incremental cost-effectiveness ratio of the universal screening strategy compared with no screening was $186,917 per QALY gained.

Conclusion: Universal HBV screening is cost effective and cheaper for patients receiving anticancer therapy associated with a high reactivation risk. For patients receiving anticancer therapy associated with a lower reactivation risk, universal screening is not cost effective.
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http://dx.doi.org/10.1200/CCI.18.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874018PMC
March 2019

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors.

Hepatol Commun 2018 Jun 27;2(6):718-731. Epub 2018 Apr 27.

Department of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston TX.

Telomerase reverse transcriptase () mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether mutations can be detected in circulating cell-free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of mutations in The Cancer Genome Atlas HCC specimens was 44.4%. mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with mutations, and vitamin K2 was identified as an upstream regulator. : mutations are detectable in plasma cfDNA. Long-term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. ( 2018;2:718-731).
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http://dx.doi.org/10.1002/hep4.1187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983165PMC
June 2018

Autoantibodies in chronic hepatitis C virus infection: impact on clinical outcomes and extrahepatic manifestations.

BMJ Open Gastroenterol 2018 5;5(1):e000203. Epub 2018 May 5.

Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California, USA.

Goals: To examine the role that autoantibodies (auto-abs) play in chronic hepatitis C virus (HCV) regarding demographics, presence of extrahepatic manifestations and long-term outcomes in a large US cohort.

Background: Auto-abs have been reported to be prevalent in patients with chronic HCV infection, but data on the natural history of these patients are limited.

Study: The study included 1556 consecutive patients with HCV without concurrent HIV and/or HBV who had testing for antinuclear antibody (ANA), antimitochondrial antibody (AMA), antismooth muscle antibody (ASMA) and/or antiliver kidney microsomal antibody (LKM). Primary outcomes included development of cirrhosis, hepatic decompensations, hepatocellular carcinoma (HCC), mortality and/or sustained virological response (SVR) to antiviral therapy.

Results: A total of 388 patients tested positive for any auto-ab (ANA 21.8%, ASMA 13.3%, AMA 2.2% and LKM 1.2%). Patients who tested positive versus negative were more likely to be women (29.3% vs 20.9%, p<0.001) and less likely to achieve SVR with most treated patients receiving interferon-based therapies (37.2% vs 47.1%, p=0.031). There was no difference between groups for baseline laboratory data, disease state or rate of extrahepatic manifestations (42.8% vs 45.0%, p=0.44). Kaplan-Meier analysis revealed no statistically significant difference between groups for the 10-year development of cirrhosis, hepatic decompensations, HCC nor survival. Furthermore, auto-ab positivity was only found to be a predictor for a lower rate of SVR on multivariate analysis (adjusted OR=1.61, 95 %  CI 1.00 to 2.58, p=0.048).

Conclusions: In our cohort, auto-ab positivity was common, especially in women, and predicted a lower rate of SVR but otherwise had no impact on the natural history of chronic HCV or presence of extrahepatic manifestations.
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http://dx.doi.org/10.1136/bmjgast-2018-000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942460PMC
May 2018

Autoimmune hepatitis.

Nat Rev Dis Primers 2018 04 12;4:18017. Epub 2018 Apr 12.

Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.

Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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http://dx.doi.org/10.1038/nrdp.2018.17DOI Listing
April 2018

Unmet needs and new models for future trials in autoimmune hepatitis.

Lancet Gastroenterol Hepatol 2018 05 6;3(5):363-370. Epub 2018 Apr 6.

Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA.

Despite advances in understanding and treatment of autoimmune hepatitis, important unmet clinical needs remain in both adult and paediatric patient populations. The evolving research landscape and assembly of large patient cohorts are creating unique opportunities to translate science into new therapies and care pathways, with the potential to substantially improve the lives of patients with autoimmune hepatitis. However, these areas of unmet need represent real challenges that need to be addressed if this vision is to be realised. In this Viewpoint, we outline the challenges in adult autoimmune hepatitis, particularly in relation to disease-modifying therapy, and trial design and delivery. Paediatric autoimmune hepatitis presents its own set of challenging problems.
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http://dx.doi.org/10.1016/S2468-1253(18)30043-8DOI Listing
May 2018

Predicting Liver Allograft Discard: The Discard Risk Index.

Transplantation 2018 09;102(9):1520-1529

Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX.

Background: An index that predicts liver allograft discard can effectively grade allografts and can be used to preferentially allocate marginal allografts to aggressive centers. The aim of this study is to devise an index to predict liver allograft discard using only risk factors available at the time of initial DonorNet offer.

Methods: Using univariate and multivariate analyses on a training set of 72 297 deceased donors, we identified independent risk factors for liver allograft discard. Multiple imputation was used to account for missing variables.

Results: We identified 15 factors as significant predictors of liver allograft discard; the most significant risk factors were: total bilirubin > 10 mg/dL (odds ratio [OR], 25.23; confidence interval [CI], 17.32-36.77), donation after circulatory death (OR, 14.13; CI, 13.30-15.01), and total bilirubin 5 to 10 mg/dL (OR, 7.57; 95% CI, 6.32-9.05). The resulting Discard Risk Index (DSRI) accurately predicted the risk of liver discard with a C statistic of 0.80. We internally validated the model with a validation set of 37 243 deceased donors and also achieved a 0.80 C statistic. At a DSRI at the 90th percentile, the discard rate was 50% (OR, 32.34; CI, 28.63-36.53), whereas at a DSRI at 10th percentile, only 3% of livers were discarded.

Conclusions: The use of the DSRI can help predict liver allograft discard. The DSRI can be used to effectively grade allografts and preferentially allocate marginal allografts to aggressive centers to maximize the donor yield and expedite allocation.
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http://dx.doi.org/10.1097/TP.0000000000002151DOI Listing
September 2018

Models to Predict Hepatitis B Virus Infection Among Patients With Cancer Undergoing Systemic Anticancer Therapy: A Prospective Cohort Study.

J Clin Oncol 2018 Apr 15;36(10):959-967. Epub 2018 Feb 15.

Jessica P. Hwang, Scott B. Cantor, Andrea Barbo, Heather Y. Lin, Jessica T. Foreman, Harrys A. Torres, Bruno P. Granwehr, Ethan Miller, Cathy Eng, George R. Simon, Sairah Ahmed, Alessandra Ferrajoli, Jorge Romaguera, and Maria E. Suarez-Almazor, The University of Texas MD Anderson Cancer Center; John M. Vierling, Baylor College of Medicine, Houston, TX; Anna S. Lok, University of Michigan, Ann Arbor, MI; and Michael J. Fisch, Aim Specialty Health, Chicago, IL.

Purpose: Most patients with cancer are not screened for hepatitis B virus (HBV) infection before undergoing anticancer therapy, and optimal screening strategies are unknown. We sought to develop selective HBV screening strategies for patients who require systemic anticancer therapy.

Methods: This prospective cohort study included adults age ≥ 18 years with solid or hematologic malignancies who received systemic anticancer therapy at a comprehensive cancer center during 2013 and 2014. Patients underwent hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody testing, and completed a 19-question modified Centers for Disease Control and Prevention (CDC) HBV survey. Multivariable models that predict chronic or past HBV infection were developed and validated using bootstrapping.

Results: A total of 2,124 patients (mean age, 58 ± 13 years) completed the risk survey and HBV testing. Of these, 54% were women; 77% were non-Hispanic white, 11% Hispanic, 8% black, and 4% Asian; and 20% had a hematologic malignancy and 80% a solid tumor. Almost 12% were born outside the United States. The prevalence was 0.3% for chronic HBV infection and 6% for past HBV infection. Significant predictors of positive hepatitis B surface antigen or hepatitis B core antibody tests were as follows: men who had sex with men, black or Asian race, birthplace outside the United States, parent's birthplace outside the United States, household exposure to HBV, age ≥ 50 years, and history of injection drug use. The area under the receiver operating characteristic curve of the model on the basis of these seven predictors was 0.79 (95% CI, 0.73 to 0.82). The modified CDC survey and brief tools with fewer than seven questions yielded similar false-negative rates (0% and 0% to 0.7%, respectively).

Conclusion: An internally validated risk tool performed as well as the modified CDC survey; however, more than 90% of patients who completed the tool would still require HBV testing. Universal HBV testing is more efficient than risk-based screening.
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http://dx.doi.org/10.1200/JCO.2017.75.6387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351320PMC
April 2018

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

Dig Dis Sci 2018 03 1;63(3):665-675. Epub 2018 Feb 1.

Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX, 77030, USA.

Background: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction.

Aim: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates.

Methods: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines.

Results: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism.

Conclusions: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.
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http://dx.doi.org/10.1007/s10620-017-4897-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994910PMC
March 2018

No Gains in Long-term Survival After Liver Transplantation Over the Past Three Decades.

Ann Surg 2019 01;269(1):20-27

Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX.

Objective: The aim of this study was to assess improvements in long-term survival after liver transplant by analyzing outcomes in transplant recipients who survived beyond 1 year.

Summary Of Background Data: Gains in short-term survival following liver transplantation have been gratifying. One-year survival in 1986 was 66% improved to over 92% in 2015. However, little is known about why long-term has not seen similar success.

Methods: We analyzed 111,568 recipients from 1987 to 2016 using the Kaplan-Meier method for time-to-event analysis and multivariable Cox regression.

Results: There were no significant gains in unadjusted long-term outcomes among 1-year survivors over the past 30 years. Only the time periods of 1987 to 1990 [hazard ratio (HR) 1.35, confidence interval CI) 1.28-1.42] and 1991 to 1995 (HR 1.17, CI 1.13-1.21) had a minor increase in risk compared with the period 2011 to 2016. Cause of death analysis suggests malignancy after transplantation is a growing problem and preventing recurrent hepatitis C with direct-acting antivirals (DDAs) may only have a limited impact. Furthermore, rejection leading to graft failure and death had a rare occurrence (1.7% of long-term deaths) especially when compared with the sequelae of long-term immunosuppression: malignancy (16.4%), nonrejection graft failure (9.8%), and infection (10.5%) (P < 0.001).

Conclusion: In stark contrast to short-term survival, there have been no appreciable improvements in long-term survival following liver transplantation among 1-year survivors. Long-term sequelae of immunosuppression, including malignancy and infection, are the most common causes of death. This study highlights the need for better long-term immunosuppression management.
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http://dx.doi.org/10.1097/SLA.0000000000002650DOI Listing
January 2019
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