Publications by authors named "Anna S F Lok"

158 Publications

Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America.

Hepatology 2021 Jun 16. Epub 2021 Jun 16.

Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA.

Background And Aims: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear.

Approach And Results: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg and 58% of HBeAg participants; HBcrAg was quantifiable in 20% of HBeAg (above linear range in the other 80%) and 51% of HBeAg participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg and HBeAg immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg and HBeAg phases (HBV RNA: e ρ = 0.84; e ρ = 0.78; HBcrAg: e ρ = 0.66; e ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg phases only (HBV RNA: e ρ = 0.71; P < 0.001; e ρ = 0.18; P = 0.56; HBcrAg: e ρ = 0.51; P < 0.001; e ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg , but not HBeAg , phases.

Conclusions: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.
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http://dx.doi.org/10.1002/hep.32018DOI Listing
June 2021

Feasibility and early experience of a novel multidisciplinary alcohol-associated liver disease clinic.

J Subst Abuse Treat 2021 Apr 9;130:108396. Epub 2021 Apr 9.

Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, United States of America.

Background: Alcohol cessation improves mortality in alcohol-associated liver disease (ALD), but access to treatment is limited. To address this gap, implementation and early feasibility and outcomes of a multidisciplinary ALD clinic are described.

Methods: The clinic comprised a hepatologist, psychiatrist, psychologist, nurse, and social worker. Patients included those with alcohol-associated cirrhosis or acute alcoholic hepatitis who were not in the transplant evaluation process, who had less than 6 months' sobriety and willingness to engage in alcohol use treatment. Psychosocial metrics in addition to routine hepatic function labs were collected. Treatment plans were tailored based on patient preferences and needs after multidisciplinary discussion.

Results: 89 patients were referred from both inpatient and outpatient settings, with 51 seen during the initial year. 38 remained active in clinic (4 died, 6 discharged, 3 moved to transplant clinic). 55% were women, 88% were white, 61% had private insurance. 49% had alcoholic hepatitis. 71% were decompensated. 80% had severe alcohol use disorder (AUD) and 84% had at least 1 comorbid psychiatric or substance use disorder. 63% chose one-on-one AUD treatment, 57% were prescribed relapse prevention medications. Mean MELD-Na score improved from baseline of 14 (SD 6.6) to 11.3 at 6 months (p=0.01). Hospital utilization significantly declined when comparing 6 months before to 6 months after initial visit (emergency department visits: 0.51 to 0.20 per person-month; inpatient admission: 0.34 to 0.14 per person-month; (β= -0.89, 95% CI -1.18 to -0.60).

Conclusions: A multidisciplinary ALD clinic was feasible with encouraging early outcomes. Further research should explore ways to expand this model and increase clinic capacity.
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http://dx.doi.org/10.1016/j.jsat.2021.108396DOI Listing
April 2021

The 2020 Nobel Prize for Medicine or Physiology for the Discovery of Hepatitis C Virus: A Triumph of Curiosity and Persistence.

Hepatology 2021 Mar 30. Epub 2021 Mar 30.

Gastrointestinal Unit, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston.

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV), a small, enveloped, positive-sense RNA virus belonging to the genus Hepacivirus within the Flaviviridae family. Chronic HCV infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide and an important contributor to global mortality. Dr. Harvey Alter, a hematologist at the Clinical Center of the National Institutes of Health in Bethesda, Maryland, along with his long-term collaborator, Bob Purcell in NIAID, recognized that most cases of posttransfusion hepatitis were unrelated to hepatitis A virus (HAV) or hepatitis B virus (HBV)-hence the term non-A, non-B hepatitis (NANBH)-and showed the NANBH agent was transmissible experimentally.
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http://dx.doi.org/10.1002/hep.31830DOI Listing
March 2021

Bariatric surgery and the risk of alcohol-related cirrhosis and alcohol misuse.

Liver Int 2021 05 20;41(5):1012-1019. Epub 2021 Feb 20.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.

Background & Aims: Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse.

Methods: Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender.

Results: A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P <.001; HR 0.43, P =.02) and alcohol misuse increased for Roux-en-Y and sleeve gastrectomy recipients (HR 1.86 and 1.35, P <.001, respectively). In those who had surgery before 2008, women had increased risk of AC and alcohol misuse compared to women without bariatric surgery (HR 2.1 [95% CI: 1.79-2.41] for AC; HR 1.98 [95% CI 1.93-2.04]).

Conclusions: Bariatric surgery is associated with a short-term decreased risk of AC but potential long-term increased risk of AC in women. Post-operative alcohol surveillance is necessary to reduce this risk.
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http://dx.doi.org/10.1111/liv.14805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204517PMC
May 2021

Appropriate and Potentially Inappropriate Medication Use in Decompensated Cirrhosis.

Hepatology 2021 Jun 19;73(6):2429-2440. Epub 2021 Apr 19.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.

Background And Aims: Patients with decompensated cirrhosis are prescribed numerous medications. Data are limited as to whether patients are receiving medications they need and avoiding those they do not. We examined a large national claims database (2010-2015) to characterize the complete medication profile as well as the factors associated with appropriate and potentially inappropriate medication use in 12,621 patients with decompensated cirrhosis.

Approach And Results: Clinical guidelines and existing literature were used to determine appropriate and potentially inappropriate medications in decompensated cirrhosis. The total medication days' supply was calculated from pharmacy data and divided by the follow-up period for each decompensation. Ascites was the most common (86.5%), followed by hepatic encephalopathy (HE; 37.8%), variceal bleeding (VB; 17.5%), hepatorenal syndrome (6.3%), and spontaneous bacterial peritonitis (SBP; 6.1%). For patients with ascites, 55.8% filled a diuretic. For patients with HE, 32.4% and 63.3% filled rifaximin and lactulose, respectively. After VB, 60.3% of patients filled a nonselective beta blocker, and after an episode of SBP, 48.0% of patients filled an antibiotic for prophylaxis. The minority (4.5%-17.3%) had enough medication to cover >50% follow-up days. Potentially inappropriate medication use was common: 53.2% filled an opiate, 46.0% proton pump inhibitors, 14.2% benzodiazepines, and 10.1% nonsteroidal anti-inflammatory drugs. Disease severity markers were associated with more appropriate mediation use but not consistently associated with less inappropriate medication use.

Conclusions: Patients with decompensated cirrhosis are not filling indicated medications as often or as long as is recommended and are also filling medications that are potentially harmful. Future steps include integrating pharmacy records with medical records to obtain a complete medication list and counseling on medication use with patients at each visit.
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http://dx.doi.org/10.1002/hep.31548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943648PMC
June 2021

Prevalence and clinical features of patients with concurrent HBsAg and anti-HBs: Evaluation of the hepatitis B research network cohort.

J Viral Hepat 2020 09 2;27(9):922-931. Epub 2020 Jul 2.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.

The prevalence of concurrent HBsAg and anti-HBs in plasma of persons with chronic hepatitis B virus (HBV) infection is variable and its clinical significance enigmatic. We examined the prevalence and clinical and virological features of concurrent HBsAg and anti-HBs in children and adults with chronic HBV infection living in North America. A total of 1462 HBsAg positive participants in the Hepatitis B Research Network paediatric and adult cohorts were included (median age 41 (range 4-80) years, 48% female, 11% white, 13% black, 73% Asians). Only 18 (1.2%) were found to be anti-HBs positive (≥10 mIU/mL) at initial study evaluation. Distributions of sex, race, HBV genotype and ALT were similar between participants with and without concurrent anti-HBs. Those who were anti-HBs positive appeared to be older (median age 50 vs 41 years, P = .06), have lower platelet counts (median 197 vs 222 × 103/mm , P = .07) and have higher prevalence of HBeAg (44% vs 26%, P = .10). They also had lower HBsAg levels (median 2.0 vs 3.5 log IU/mL, P = .02). Testing of follow-up samples after a median of 4 years (range 1-6) in 12 of the 18 participants with initial concurrent anti-HBs showed anti-HBs became undetectable in 6, decreased to <10 mIU/mL in 1 and remained positive in 5 participants. Two patients lost HBsAg during follow-up. In conclusion, prevalence of concurrent HBsAg and anti-HBs was low at 1.2%, with anti-HBs disappearing in some during follow-up, in this large cohort of racially diverse children and adults with chronic HBV infection living in North America. Presence of concurrent HBsAg and anti-HBs did not identify a specific phenotype of chronic hepatitis B, nor did it appear to affect clinical outcomes.
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http://dx.doi.org/10.1111/jvh.13312DOI Listing
September 2020

Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad.

Lancet Gastroenterol Hepatol 2020 04 10;5(4):406-417. Epub 2020 Feb 10.

Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, ON, Canada. Electronic address:

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.
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http://dx.doi.org/10.1016/S2468-1253(19)30344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158588PMC
April 2020

Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B.

PLoS Pathog 2019 04 18;15(4):e1007715. Epub 2019 Apr 18.

Department of Internal Medicine, University of Michigan, Ann Arbor MI, United States of America.

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.
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http://dx.doi.org/10.1371/journal.ppat.1007715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490945PMC
April 2019

Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance.

Clin Liver Dis (Hoboken) 2018 Jul 22;12(1):33-34. Epub 2018 Aug 22.

Division of Clinical Decision Making, Tufts Medical Center Tufts University School of Medicine Boston MA.

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http://dx.doi.org/10.1002/cld.728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385899PMC
July 2018

Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.

Alcohol Clin Exp Res 2019 02 22;43(2):334-341. Epub 2019 Jan 22.

Division of Gastroenterology and Hepatology , University of Michigan, Ann Arbor, Michigan.

Background: The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance.

Methods: We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment.

Results: A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either).

Conclusions: AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.
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http://dx.doi.org/10.1111/acer.13944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379081PMC
February 2019

Misconceptions, preferences and barriers to alcohol use disorder treatment in alcohol-related cirrhosis.

J Subst Abuse Treat 2018 08 18;91:20-27. Epub 2018 May 18.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States; Department of Family Medicine, University of Michigan, Ann Arbor, MI, United States; Department of Psychiatry, Ann Arbor, MI, United States; VA Center for Clinical Management Research, Ann Arbor, MI, United States; Transplantation Institute, Loma Linda University Health, Loma Linda, CA, United States.

Background: While alcohol cessation improves mortality in alcoholic liver disease (ALD), many patients struggle to achieve abstinence. Our aim was to characterize ALD patients' preferences, misconceptions, and barriers to alcohol use treatment options.

Methods: This mixed-methods study included outpatients with a history of alcohol-related cirrhosis or alcoholic hepatitis recruited from a hepatology clinic for a survey or an in-depth semi-structured interview. We purposefully sampled men and women, compensated and decompensated patients to ensure adequate representation of gender and severity of liver disease for the qualitative interviews.

Results: 123 patients completed surveys among which 50% reported having at least one drink within the past year while only 20 patients were in any form of current alcohol treatment. Of the 23 patients reporting drinking within 3 months, only 3 were in AUD treatment currently. 17% had at least one misconception about alcohol use or treatment. An additional 22 ALD patients (10 women, 12 men) completed phone interviews of which two-third self-reported alcohol abstinence. All 22 interview participants had awareness of some form of alcohol treatment, but 13 felt that they did not need treatment with several characterizing it as ineffective or a "waste of time." Misconceptions included inaccurate perceptions of relapse medication side effects, beliefs that the presence of advanced liver disease symptoms means it is too late to treat alcohol use, and a lack of understanding about the chronicity of alcohol use disorders. The most common barriers to treatment included unwillingness to be in treatment, financial/insurance and transportation barriers.

Conclusions: Alcohol use treatment was underutilized in many ALD patients, despite active drinking in many. Tailored education and preference sensitive treatment engagement may overcome barriers to alcohol use treatment and promote abstinence.
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http://dx.doi.org/10.1016/j.jsat.2018.05.003DOI Listing
August 2018

Tenofovir to Prevent Perinatal Transmission of Hepatitis B.

N Engl J Med 2018 06;378(24):2348-9

University of Michigan, Ann Arbor, MI

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http://dx.doi.org/10.1056/NEJMc1805396DOI Listing
June 2018

Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists.

Clin Gastroenterol Hepatol 2018 12 24;16(12):1964-1973.e1. Epub 2018 Apr 24.

Department of Internal Medicine and Gastroenterology, University of Michigan, Ann Arbor, Michigan.

Background & Aims: Tumor necrosis factor (TNF) antagonists are the first-line treatment for many autoimmune diseases. However, they have been associated with reactivation of hepatitis B virus (HBV). We determined the rate of HBV reactivation and hepatotoxicity grade 3 or 4 (HT ≥3) in patients treated with an anti-TNF agent for an autoimmune disease.

Methods: We collected data from 8887 adult patients in the Kaiser Permanente Northern California database who began treatment with TNF antagonists for autoimmune diseases (dermatologic, rheumatologic, or gastrointestinal) from 2001 through 2010, followed through December 2012. We obtained data on HBV infection (52% of patients were screened for HBV before treatment), demographic features, comorbidities, and use of immunosuppressive agents. HBV reactivation was defined as 1 of the following: >1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA >2000 IU/mL if no baseline level was available, or reverse seroconversion. HT ≥3 was defined according to the National Cancer Institute Common Toxicity Criteria. We performed multivariable logistic regression to identify factors associated with HT ≥3.

Results: Twenty-three patients tested positive for HB surface antigen (HBsAg) at baseline and 9 of these had HBV reactivation; of the 4267 patients with unknown HBV status at baseline, 2 had HBV reactivation. None of the 178 patients who were HBsAg negative and positive for the hepatitis B core antibody (anti-HBc+) had HBV reactivation. HBV reactivation occurred in 1/5 HBsAg+ patients who received prophylactic antiviral therapy and 8/18 who did not (P = .61). No one with HBV reactivation had liver failure. HT ≥3 occurred in 273 patients (2.7%), but only 3 cases were attributed to HBV. Cirrhosis was significantly associated with HT ≥3 (P < .001).

Conclusion: In a retrospective analysis of patients treated with TNF antagonists for autoimmune diseases, we found HBV reactivation in 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy. Patients should be screened for HBV infection before anti-TNF therapy; HBsAg+ patients should receive prophylactic antiviral therapy, but not HBsAg-negative, anti-HBc+ patients.
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http://dx.doi.org/10.1016/j.cgh.2018.04.033DOI Listing
December 2018

The high burden of alcoholic cirrhosis in privately insured persons in the United States.

Hepatology 2018 09 20;68(3):872-882. Epub 2018 May 20.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.

Alcoholic cirrhosis (AC) is a major cause of liver-related morbidity and mortality in the United States. Rising rates of alcohol use disorders in the United States will likely result in more alcoholic liver disease. Our aim was to determine the prevalence, health care use, and costs of AC among privately insured persons in the United States. We collected data from persons aged 18-64 with AC (identified by codes from the International Classification of Diseases, Ninth and Tenth Revisions) enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009-2015). We determined yearly prevalence, weighted to the national employer-sponsored, privately insured population. Using competing risk analysis, we estimated event rates for portal hypertensive complications and estimated the association between AC and costs as well as admissions and readmissions. In 2015, 294,215 people had cirrhosis and 105,871 (36%) had AC. Mean age at AC diagnosis was 53.5 years, and 32% were women. Over the 7 years queried, estimated national cirrhosis prevalence rose from 0.19% to 0.27% (P < 0.001) and for AC from 0.07% to 0.10% (P < 0.001). Compared to non-AC, AC enrollees were significantly more likely to have portal hypertensive complications at diagnosis and higher yearly cirrhosis and alcohol-related admissions (25 excess cirrhosis admissions and 6.3 excess alcohol-related admissions per 100 enrollees) as well as all-cause readmissions. Per-person costs in the first year after diagnosis nearly doubled for AC versus non-AC persons (US$ 44,835 versus 23,319).

Conclusion: In a nationally representative cohort of privately insured persons, AC enrollees were disproportionately sicker at presentation, were admitted and readmitted more often, and incurred nearly double the per-person health care costs compared to those with non-AC. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29887DOI Listing
September 2018

Diagnosis of Minimal Hepatic Encephalopathy: A Systematic Review of Point-of-Care Diagnostic Tests.

Am J Gastroenterol 2018 04 13;113(4):529-538. Epub 2018 Mar 13.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.

Objectives: Minimal hepatic encephalopathy (HE) is common, characterized by deficits in reaction time and executive function, and strongly associated with disability and mortality. Point-of-care diagnostics performed without specialized skills or equipment are now available, albeit with limited data regarding their generalizability.

Methods: We systematically reviewed MEDLINE, EMBASE, Cochrane Library, and Scopus for diagnostic studies of MHE using broad search terms including HE and minimal, covert, or the names of published diagnostic modalities. We included tests that provide results during clinical visits without requiring neuropsychologists to administer and/or special equipment. These include the Inhibitory Control Test (ICT, n=16), EncephalApp Stroop (n=3), an algorithm based on the Sickness Impact Profile (n=2), and the Animal Naming Test (ANT, n=1).

Results: The populations enrolled in the included study were highly selected, excluding patients with recent (6-months) alcohol or psychoactive medications use. Cutoffs for MHE for each test varied widely. For the ICT, the optimal cutoffs for MHE varied by 300%, whereas healthy control performance varied >400%. The optimal cutoffs for the EncephalApp also varied (by 50%). The gold standards for MHE varied substantially between studies, and clinical outcomes were never used to develop test cutoffs. Data comparing the performance of each modality are lacking. Longitudinal data are limited but suggest that good performance on the ICT, EncephalApp or ANT is associated with reduced risk of developing overt HE.

Conclusion: The point-of-care tests for MHE are promising tools. However, additional longitudinal studies are needed in clinically representative populations of at-risk patients with cutoffs validated based on the development of clinical outcomes.
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http://dx.doi.org/10.1038/ajg.2018.6DOI Listing
April 2018

Dos and Don'ts in the Management of Cirrhosis: A View from the 21st Century.

Am J Gastroenterol 2018 07 9;113(7):927-931. Epub 2018 Mar 9.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA. Veterans Affairs Hospital, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1038/s41395-018-0028-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098714PMC
July 2018

Interview with American Association for the Study of Liver Diseases president Dr. Anna Lok.

Authors:
Anna S F Lok

Hepatol Commun 2017 05 3;1(3):189-192. Epub 2017 May 3.

Department of Internal Medicine University of Michigan Ann Arbor MI.

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http://dx.doi.org/10.1002/hep4.1038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721451PMC
May 2017

Reply.

Hepatology 2018 04 28;67(4):1637-1638. Epub 2018 Feb 28.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1002/hep.29806DOI Listing
April 2018

Reply.

Hepatology 2018 04 27;67(4):1636. Epub 2018 Feb 27.

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1002/hep.29746DOI Listing
April 2018

Use of Liver Imaging and Biopsy in Clinical Practice.

N Engl J Med 2017 12;377(23):2296-2297

University of Michigan, Ann Arbor, MI

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http://dx.doi.org/10.1056/NEJMc1712445DOI Listing
December 2017

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

PLoS One 2017 6;12(11):e0187344. Epub 2017 Nov 6.

University of Michigan Health System, Division of Gastroenterology and Hepatology, Ann Arbor, Michigan, United States of America.

Objective: Assessing 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.

Design: Adults 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.

Results: The 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).

Conclusion: Accurate 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673203PMC
November 2017

A risk score to predict the development of hepatic encephalopathy in a population-based cohort of patients with cirrhosis.

Hepatology 2018 10 14;68(4):1498-1507. Epub 2018 May 14.

Division of Gastroenterology and Hepatology, University of Michigan.

Over 40% of patients with cirrhosis will develop hepatic encephalopathy (HE). HE is associated with decreased survival, falls, motor vehicle accidents, and frequent hospitalization. Accordingly, we aimed to develop a tool to risk-stratify patients for HE development. We studied a population-based cohort of all patients with cirrhosis without baseline HE (n = 1,979) from the Veterans Administration from Michigan, Indiana, and Ohio (January 1, 2005-December 31, 2010) using demographic, clinical, laboratory, and pharmacy data. The primary outcome was the development of HE. Risk scores were constructed with both baseline and longitudinal data (annually updated parameters) and validated using bootstrapping. The cohort had a mean age of 58.0 ± 8.3 years, 36% had hepatitis C, and 17% had ascites. Opiates, benzodiazepines, statins, and nonselective beta-blockers were taken at baseline by 24%, 13%, 17%, and 12%, respectively. Overall, 863 (43.7%) developed HE within 5 years. In multivariable models, risk factors (hazard ratio, 95% confidence interval) for HE included higher bilirubin (1.07, 1.05-1.09) and nonselective beta-blocker use (1.34, 1.09-1.64), while higher albumin (0.54, 0.48-0.59) and statin use (0.80, 0.65-0.98) were protective. Other clinical factors, including opiate and benzodiazepine use, were not predictive. The areas under the receiver operating characteristics curve for HE using the four significant variables in baseline and longitudinal models were 0.68 (0.66-0.70) and 0.73 (0.71-0.75), respectively. Model effects were validated and converted into a risk score. A score ≤0 in our longitudinal model assigns a 6% 1-year probability of HE, while a score >20 assigns a 38% 1-year risk.

Conclusion: Patients with cirrhosis can be stratified by a simple risk score for HE that accounts for changing clinical data; our data also highlight a role for statins in reducing cirrhosis complications including HE. (Hepatology 2017).
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http://dx.doi.org/10.1002/hep.29628DOI Listing
October 2018

Risk Assessment of Hepatocellular Carcinoma in Patients with Hepatitis C in China and the USA.

Dig Dis Sci 2017 11 25;62(11):3243-3253. Epub 2017 Sep 25.

Division of Gastroenterology and Hepatology, University of Michigan Health System, 1500 E Medical Center Dr, Taubman Center SPC 3912, Ann Arbor, MI, USA.

Background: Hepatitis C (HCV) infection is an increasingly common cause of hepatocellular carcinoma (HCC) in China.

Aims: We aimed to determine differences in demographic and behavioral profiles associated with HCC in HCV+ patients in China and the USA.

Methods: Consecutive HCV+ patients were recruited from centers in China and the USA. Clinical data and lifestyle profiles were obtained through standardized questionnaires. Multivariable analysis was conducted to determine factors associated with HCC diagnosis within groups.

Results: We included 41 HCC patients from China and 71 from the USA, and 931 non-HCC patients in China and 859 in China. Chinese patients with HCC were significantly younger, less likely to be male and to be obese than US patients with HCC (all p < 0.001). Chinese patients with HCC had a significantly lower rate of cirrhosis diagnosis (36.6 vs. 78.9%, p < 0.001); however, they also had a higher rate of hepatitis B core antibody positivity (63.4 vs. 36.8%, p = 0.007). In a multivariable analysis of the entire Chinese cohort, age > 55, male sex, the presence of diabetes, and time from maximum weight were associated with HCC, while tea consumption was associated with a decreased HCC risk (OR 0.37, 95% CI 0.16-0.88). In the US cohort, age > 55, male sex, and cirrhosis were associated with HCC on multivariable analysis.

Conclusions: With the aging Chinese population and increasing rates of diabetes, there will likely be continued increase in the incidence of HCV-related HCC in China. The protective effect of tea consumption on HCC development deserves further validation.
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http://dx.doi.org/10.1007/s10620-017-4776-7DOI Listing
November 2017

Use of Liver Imaging and Biopsy in Clinical Practice.

N Engl J Med 2017 08;377(8):756-768

From the Division of Gastroenterology and Hepatology and the Institute for Healthcare Policy and Innovation, University of Michigan (E.B.T., A.S.-F.L.), and the Veterans Affairs Hospital (E.B.T.) - both in Ann Arbor.

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http://dx.doi.org/10.1056/NEJMra1610570DOI Listing
August 2017

NAM 2017 report: A national plan to eliminate hepatitis B and C in the United States by 2030 and the AASLD's response.

Hepatology 2017 10 30;66(4):1020-1022. Epub 2017 Aug 30.

Division of Gastroenterology, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1002/hep.29361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454035PMC
October 2017

Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers.

Hepatology 2017 12 14;66(6):1805-1813. Epub 2017 Sep 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, MI.

Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record-based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record-based "best practice advisory" (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti-HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre-BPA and post-BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post-BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far.

Conclusion: Implementation of an electronic health record-based prompt increased HCV screening rates among baby boomers in primary care by 5-fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017;66:1805-1813).
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http://dx.doi.org/10.1002/hep.29362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696058PMC
December 2017

Characteristics of US-Born Versus Foreign-Born Americans of African Descent With Chronic Hepatitis B.

Am J Epidemiol 2017 Aug;186(3):356-366

Hepatitis B virus (HBV) infection is more common in African Americans than in white Americans. We compared the epidemiologic, clinical, and virological characteristics of US-born African Americans (USAAs) to those of foreign-born African Americans (FBAAs) with chronic hepatitis B. The adult cohort study of the Hepatitis B Research Network enrolls patients with HBV infection from 21 clinical sites in the United States and Canada. A total of 237 (15%) of the adult participants with chronic HBV infection that were enrolled from January 20, 2011, to October 2, 2013, were of African descent, including 57 USAAs and 180 FBAAs (76%). Compared with FBAAs, USAAs were older and more likely to have acquired HBV through sexual exposure, to be HBeAg-positive, to have higher HBV DNA levels, and to be infected with HBV genotype A2. FBAAs from West Africa were more likely to have elevated serum alanine aminotransferase (72% vs. 50%; P < 0.01) and higher HBV DNA levels (median, 3.2 log10 IU/mL vs. 2.8 log10 IU/mL; P = 0.03) compared with East African FBAAs. The predominant HBV genotype among West African FBAAs was E (67%), whereas genotypes A (78%) and D (16%) were common in East African FBAAs. Significant differences were found between USAAs and FBAAs, highlighting the need for tailored strategies for prevention and management of chronic HBV infection for African Americans.
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http://dx.doi.org/10.1093/aje/kwx064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860424PMC
August 2017

A Bayesian screening approach for hepatocellular carcinoma using multiple longitudinal biomarkers.

Biometrics 2018 03 8;74(1):249-259. Epub 2017 May 8.

Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, U.S.A.

Advanced hepatocellular carcinoma (HCC) has limited treatment options and poor survival, therefore early detection is critical to improving the survival of patients with HCC. Current guidelines for high-risk patients include ultrasound screenings every six months, but ultrasounds are operator dependent and not sensitive for early HCC. Serum α-Fetoprotein (AFP) is a widely used diagnostic biomarker, but it has limited sensitivity and is not elevated in all HCC cases so, we incorporate a second blood-based biomarker, des'γ carboxy-prothrombin (DCP), that has shown potential as a screening marker for HCC. The data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a valuable source of data to study biomarker screening for HCC. We assume the trajectories of AFP and DCP follow a joint hierarchical mixture model with random changepoints that allows for distinct changepoint times and subsequent trajectories of each biomarker. The changepoint indicators are jointly modeled with a Markov Random Field distribution to help detect borderline changepoints. Markov chain Monte Carlo methods are used to calculate posterior distributions, which are used in risk calculations among future patients and determine whether a patient has a positive screen. The screening algorithm was compared to alternatives in simulations studies under a range of possible scenarios and in the HALT-C Trial using cross-validation.
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http://dx.doi.org/10.1111/biom.12717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677596PMC
March 2018

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients.

Clin Gastroenterol Hepatol 2017 Apr 25;15(4):584-593.e2. Epub 2016 Aug 25.

Division of Transplant Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

Background & Aims: Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors.

Methods: We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors.

Results: At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.76; and SRTR HR, 0.78; 95% CI, 0.66-0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64-17.45) and 4.41 in SRTR (95% CI, 3.71-5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37-23.04) and 3.94 in SRTR (95% CI, 3.22-4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes.

Conclusions: Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality, and graft failure-related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection.
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http://dx.doi.org/10.1016/j.cgh.2016.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326609PMC
April 2017
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