Hepatology Associates Course
Program Chairs: Amanda J. Chaney, DNP, APRN, FNP-BC, FAANP Jeffrey P. McMahon, MS, PA-C
Sunday, November 10 | 8 am – Noon THE LIVER MEETING® APP EXPLORE • CONNECT • SHARE
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The AASLD EVENTS App is compatible with iPhone, Android, iPad and most tablets. Three Easy Ways to Claim Your CME Credits and MOC Points
The CME/CE/MOC evaluations can be completed in the following ways:
• During the sessions. Use The Liver Meeting® app and evaluate the sessions in real time. Search “Liver Meeting” in the App Store (for your Apple device) or in Google Play (for your Android device). • In your hotel room or at home. Access the evaluation website using your personal device of choice. A link to the CME, CE and MOC evaluation websites will be available at aasld.org/livermeeting. • At the Continuing Education/Certifi cate Stations. Visit this area in Hall A to access evaluations from any available kiosk.
CME and CE credit will be awarded after you have completed your evaluation. You will also have the ability to download and/or print a certifi cate for your records.
MOC points are submitted by AASLD to ABIM and ABP on behalf of its learners. Points are not submitted automatically and will not display immediately on your ABIM or ABP MOC Profi le upon completion of the MOC evaluation.*
Certifi cates of attendance are also available. They may be downloaded and/or printed upon completing the overall evaluation for The Liver Meeting®.
Save your badge! Your email address and badge number will be needed to access The Liver Meeting®/CME evaluation.
*MOC completions are collected on the 15th of each month and submitted to the ABIM and/or ABP by the last day of the month. Table of Contents
2019 Hepatology Associates Course Continuing Education Information ...... 1
Program Agenda ...... 3
Clinical Pearls for Management of Child’s B/C Cirrhotic Angela De Lisle, MHS, PA‐C ...... 4
Controversies in Cirrhosis Renee Pozza, PhD, FNP-BC, FAASLD ...... 31
Long Term Care of the Transplant Patient Carolyn J. Driscoll, PhD, FNP-C ...... 62
Getting the NASH / Obese Patient to Transplant Victoria Gomez, MD ...... 78
Patient Case Studies Amanda Chaney, DNP, APRN, FNP-BS, FAANP ...... 117
Assessment of Abnormal Liver Biochemistries Paul Kwo, MD, FAASLD ...... 136
Management and Outcomes in Local Regional Therapy for HCC Denise Harnois, DO, FAASLD and Kaitlyn Musto, PA-C ...... 198
Hepatitis B Update Anna Lok, MD, FAASLD ...... 234
Faculty, Planner and AASLD Staff Disclosures ...... 266
The Use of AASLD Scientific Program Content Information presented during the Hepatology Associates Course is the property of AASLD and the presenter. Information may not be recorded, photographed, copied, photocopied, transferred to electronic format, reproduced or distributed without the written permission of AASLD and the presenter. Any use of the program content, which includes, but is not limited to, oral presentations, audiovisual materials used by speakers and program handouts without the written consent of AASLD, is prohibited. 2019 Hepatology Associates Course Sunday, November 10 8:00 am – Noon
Program Chairs: Amanda J. Chaney, DNP, APRN, FNP-BC, FAANP and Jeffrey P. McMahon, MS, PA-C
Session Description/Needs Statement This comprehensive program will offer the hepatology provider updated information on managing patients with liver disease and/or in the post-transplant setting. Speakers will review new evidence and the latest tools to help providers deliver high-quality patient care, change practice approaches where needed and help improve patient outcomes.
Learning Objectives Upon completion of this activity, participants will be able to: • State the steps in evaluating a patient with abnormal liver biochemistries, drug-induced liver injury, and viral hepatitis • Discuss several controversies that may occur in the pre- and post-transplant setting • Review the current practice guidelines of NASH management, new treatments on the horizon and care of patients with liver disease and obesity
CONTINUING MEDICAL EDUCATION (CME) Accreditation Statement The American Association for the Study of Liver Diseases (AASLD) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Credit Designation Statement AASLD designates this live activity for a maximum of 3.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
The CME/CE* evaluations are available online and can be completed in the following ways: • During the session: Download The Liver Meeting® app and evaluate the sessions in real time – refer to the CME icon to access the evaluation. • In your hotel room or at home: Access the evaluation website using your personal device of choice. Go directly to the CME evaluation and/or CE* evaluation. • At any Continuing Education/Certificate Stations: Visit the Continuing Education/Certificate Stations in Hall A to access the evaluation from any available kiosk.
Certificates of Attendance Certificates of Attendance are available to attendees completing The Liver Meeting® evaluation and may be printed on-site in Tech Connect or after the meeting at aasld.org/livermeeting by March 15, 2020.
1 CONTINUING EDUCATION (CE) STATEMENT Satisfactory Completion Learners must complete an evaluation form to receive a certificate of completion. Your chosen sessions must be attended in their entirety. Partial credit of individual sessions is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certification board to determine course eligibility for your licensing/certification requirement.
Nurses In support of improving patient care, this activity has been planned and implemented by Amedco LLC and the American Association for the Study of Liver Diseases. Amedco LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Credit Designation Statement— Amedco LLC designates this live activity for a maximum of 3.75 contact hours for nurses. Learners should claim only the credit commensurate with the extent of their participation in the activity.
Nurse Pharmacology Credits Please note onsite agenda for identification of sessions eligible for pharmacotherapeutic hours and self- submit those to your board. Keep the agenda as a reference in case they have questions.
DEADLINE: Be sure to complete the CME and/or CE evaluation for credit at aasld.org/livermeeting before the following dates:
• CME evaluation – March 15, 2020 • CE* evaluation – December 31, 2019
2 2019 Hepatology Associates Course Program Agenda *Presentations indicated with an asterisk are eligible for 1.75 Pharmacology Hours
Session I: Pre/Post Transplant Related Moderators: Amanda J. Chaney and Janet Gripshover
8:00 – 8:05 AM Welcome and Introductions
8:05 – 8:25 AM Clinical Pearls for Management of Child’s B/C Cirrhotic Angela De Lisle, MHS, PA‐C
8:25 – 8:45 AM Controversies in Cirrhosis* Renee Pozza, PhD, FNP-BC, FAASLD
8:45 – 9:00 AM Panel Discussion
9:00 – 9:20 AM Long Term Care of the Transplant Patient* Carolyn J. Driscoll, PhD, FNP-C
9:20 – 9:40 AM Getting the NASH / Obese Patient to Transplant Victoria Gomez, MD
9:40 – 10:10 AM Panel Discussion and Break
Session II: General Hepatology 101 Moderators: Jeffrey P. McMahon and Lisa Hardee
10:10 – 10:15 AM Post Break Remarks Jeffrey McMahon, MS, PA-C
10:15 – 10:35 AM Patient Case Studies Amanda Chaney, DNP, APRN, FNP-BS, FAANP
10:35 – 10:55 AM Assessment of Abnormal Liver Biochemistries* Paul Kwo, MD, FAASLD
10:55 – 11:05 AM Panel Discussion
11:05 – 11:25 AM Management and Outcomes in Local Regional Therapy for HCC* Kaitlyn Musto, PA-C and Denise Harnois, DO, FAASLD
11:25 – 11:45 AM Hepatitis B Update* Anna Lok, MD, FAASLD
11:45 AM – Noon Panel Discussion
3 Clinical Pearls for Management of The Child’s B/C Cirrhotic
Angela M. De Lisle, PA-c, MHS Clinical Instructor of Medicine Department of Digestive Diseases Yale School Of Medicine
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 4 Progression to Cirrhosis
• Natural History
10-20 years 10 + years 1-2 years ______C. Cirrhosis ______D . Cirrhosis_____Further Decompensated__ Death/ Tx 0-5 mm/Hg 6-10 mm/Hg > 10 mm/Hg Non bleeding varices / VH HRS-1, Autonomic dysregulation Ascites / SBP Refractory ascites, Sarco-lipopenia HE Hyponatremia, Portopulmonary HTN HepatioPulmonary Syndrome
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 5 Case Presentation
56 yo M with h/o Alcohol abuse, Alcohol related cirrhosis and obesity (BMI 33) who presents to Post Hospitalization Liver Clinic following a hospitalization for volume overload manifesting as ascites (new) and lower extremity edema.
His ascites was characterized as low protein / high saag, he was seen by RD to review a low Na diet and he was started on diuretics (Lasix 40mg/d and Aldactone 100mg/d)
What Next ?
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 6 Case Presentation
• Knowns : • 56 yo • Longstanding h/o compensated cirrhosis • New ascites • Started on diuretics
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 7 • ? Volume management • ? Variceal status • ? Nutritional Status • ? Bone Density • ? Hepatic Encephalopathy • ? HCC screening • Transplant Candidacy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 8 • ? Volume management • ? Variceal status • ? Nutritional Status • ? Bone Density • ? Hepatic Encephalopathy • ? HCC screening • Transplant Candidacy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 9 • ? Volume management • ? Variceal status • ? Nutritional Status • ? Bone Density • ? Hepatic Encephalopathy • ? HCC screening • Transplant Candidacy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 10 Systematic Approach
• WHY the management needs to be done… • WHAT needs to be done …
• Consider what are the expected outcomes …
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 11 Ascites
• WHY: development of ascites suggests increased portal pressures that often correlate with decline in synthetic function. Presence suggests a mortality in 2-3 years without transplant and suggests a need to refer for consideration of liver transplant eligibility • WHAT : • Characterized in terms of protein / SAAG • Current diuretic dose • “dry” weight (goal) • +/- h/o Spontaneous Bacterial Peritonitis (? Antibiotics)
Garcia-Tsao, G. , Current Management of the Complications of Cirrhosis and Portal Hypertension: Variceal Hemorrhosge, Ascites, and Spontaneous Bacterial Peritonitis. Dig Dis 2016;(34)4:382–386
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 12 Nutritional Status
• WHY : Nutritional status directly correlates with morbidity /mortality outcomes. Consideration to include Sarcopenia in the MELD score • WHAT : • Physical exam • Hand grip, rise from chair, ambulatory speed • MR / CT programs
Montano-Loza, A et al, Sarcopenic Obisity and Myosteatosis are Associated with Higher Mortlity in patients with Cirrhosis. Journal of Cachexia Sarcopenia and Muscle, 2016, 7:126-135 Ad van Vugt, J, et al, A Model including Sarcopenia Surpassses the MELD score in Predicting Waiting List Mortality in cirrhotic Liver Transplant Candidates: A Competing Rish analysis in a National Cohort
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 13 Ascites
Sarcopenia
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 14 Variceal Status
• WHY: To assess risk of variceal bleed • WHAT: • Upper Endoscopy / Capsule endoscopy • Non-selective Beta Blocker initiation vs Band ligation (or both), goal HR • If no varices, screen every 1-2 years
Garcia-Tsao, G, et al. Practice Guidance: Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis and Managent: 2016 Practice Guidance by the American Association for the Study of Liver Disease. Hepatology, 6 (1) 2017. 310 – 335 Jakab, S and Garcia-Tsao, G. Screening and Surveillance of Varices in Patients with Cirrhosis. Clinical Gastroenterology and Hepatology. 2019; 17: 26-29
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 15 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 16 Bone Density
• WHY : Hepatic osteodystrophy (osteoporosis / -malacia) occurs in ~30% of those with chronic liver disease (CLD) • CLD with or without cholestasis • IL-6/ TNF alphpa enhance the activity of osteoclasts • Adipokines such as Leptin inhibit osteoclastogenesis and increase IL-1 and TNF alpha • It is estimated that 40% of those with CLD and osteoporosis/ osteomalacia will experience an osteoportic fracture in their lifetime
Handzlik-Orlik, G, et al. Osteoporosis in Liver Disease: Pathogenesis and Management; Ther Adv Endocrinol Metab. 2016 7(3) 128 - 135
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 17 Bone Density
• Additonal Factors: • Previous Fragility Fracture • Postmenopausal women • Premature Menopause (< 45 yrs) • Secondary amenorrhea (>6 mo) • Male hypogonadism • Low BMI (<19) • Glucocorticoid therapy (>3 mo / 5 mg/d) Handzlik-Orlik, G, et al. Osteoporosis in Liver Disease: Pathogenesis and Management; Ther Adv Endocrinol Metab. 2016 7(3) 128 - 135
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 18 Bone Density
• WHAT : • DEXA scan as a baseline in CLD • Pre tx may consider : risk factors for osteoporosis, thoracolumbar spine x- rays, serum calcium level, phosphate level, 25-OHD level, and free testosterone level (in men) • Repletion with Calcium / Vitamin D • Other treatments such as Estrogens, Raloxifene, testosterone, calcitonin will need to consider weighing risks and benefits
Handzlik-Orlik, G, et al. Osteoporosis in Liver Disease: Pathogenesis and Management; Ther Adv Endocrinol Metab. 2016 7(3) 128 - 135
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 19 DEXA Scan
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 20 Hepatocellular Carcinoma Screening
• WHY : Most common form of primary liver cancer, 6th most common malignant tumor world wide.
• Variable risk based on background disease process : HBV, HCV, Etoh, A1AT, HFE
Thursz, M. et al; EASL Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Journal of Hepatology; 2018; 69(1) 182-236 Morrero, J, et al, Diagnosis, Staging and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology; 2018; 68(2) 723-750
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 21 Hepatocellular Carcinoma Screening
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 22 Hepatocellular Carcinoma Screening
• WHAT: • US / +/- AFP • Triple Phase CT • MRI with and without
Thursz, M. et al; EASL Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Journal of Hepatology; 2018; 69(1) 182-236 Morrero, J, et al, Diagnosis, Staging and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology; 2018; 68(2) 723-750
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 23 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 24 Transplant Candidacy
• WHY : Should be considered for all chronic liver disease carriers who have experienced an index complication
• WHAT: • MELD / CHILD scores • Assess for absolute contraindications • Optimize Eligibility • Hold discussion early …. And often
Martin P et al. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the AASLD and the American Society of Transplantation.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 25 Putting it all together ………………….
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 26 Case Presentation • 56 yo M with Etoh liver disease now complicated by the development of ascites. Plan will be as follows : • Ascites: low protein/high saag, Stable on current regimen. DC wt 180#, today’s wt 176 #. Dry wt 170 # Continue current diuretic doses of Lasix 40 mg/d and Aldactone 100mg/d. Weigh self regularly; report wt up or down by 3# in one week. Low Na diet, Order scan to observe for vascular patency • Variceal Screening: EGD ordered for variceal screening • Nutrition status : mild sarcopenia on exam, recommended increasing protein intake to 1.7g protein/kg/d based on premorbid wt of xx for a total of xx protein grams/d • Bone Denisty: h/o chronic liver disease; DEXA ordered; no steroid use, no h/o Fractures. • HCC screening: no prior dynamic imaging; MRI w/wo ordered
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 27 Case Presentation
• Transplant Candidacy: MELD 18/Child C (12). Good social support, 2 mo sober with last etoh in April 2019. Enrolling in a formal relapse prevention program, good insight. Will continue to follow; consider referral to Transplant for Transplant Evaluation consideration • General • HAV IgG (-) 4-18-19 : plan to vaccinate • HBsAB (+) / HBcAB Totatl (-) 4-18-19 • HCV ab (-) 4-18-19 • HIV ab (-) 4-18-19
• Etiology Specific Treatment : Abstinence, MVI, Folic Acid, Thiamin, proper nutrition, f/u on progress at structured relapse prevention program
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 28 Key Take-Away Points
Management of patients with Chronic Liver Disease is complex and requires a multisystem and (almost) predictive approach in order to manage the common decompensations
Performance of screening / surveillance tools will help identify where your patient is on the spectrum of liver disease
This will allow timely intervention / referral for possible definitive care
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 29 Thank You
Angela M. De Lisle, PA-c, MHS Clinical Instructor of Medicine Department of Digestive Diseases Yale School Of Medicine
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 30 Controversies in Cirrhosis Renee Pozza, PhD, RN, FNP-BC, FAASLD Nurse Practitioner, Southern California Liver Centers
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 31 Objectives:
1. Discuss use of beta blockers in portal hypertension management 2. Evaluate the use of prophylaxis in spontaneous bacterial peritonitis (SBP) 3. Describe herbal medication use in cirrhosis 4. Discuss recent warnings in HCV treatment in the cirrhotic individual
Image: https://www.hepmag.com/blog/difference-fibrosis-cirrhosis Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 32 Staging of Cirrhosis
Reference: Garcia-Tsao, AASLD Practice Guidance Portal Hypertensive Bleeding in Cirrhosis, 2017
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 33 Portal Hypertension Compensated: Childs A
HVPG < 10 mm Hg ≥ 10 mm Hg (CSPH) Varices Absent Absent Present Complications of PH Absent Absent Absent Goals of therapy Prevent CSPH Prevent decompensation Decompensated: Childs B/C HVPG ≥ 12 mm Hg Varices Present Acute VH Previous VH without Previous VH with other Complications of PH other complications complications Prevent further Control Bleeding, Prevent further Goals of Therapy decompensation and prevent rebleeding decompensation death/OLT Adapted from AASLD Practice Guidelines
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 34 Portal Hypertension
Reference: Garcia-Tsao, AASLD Practice Guidance Portal Hypertensive Bleeding in Cirrhosis, 2017
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 35 Management of Portal Hypertension
• Mild portal hypertension is hepatic venous pressure gradient (HVPG) >5 mm Hg but <10 mm Hg. • Treatment Indication: Treat underlying etiology. No indication for beta blockers
Reference: AASLD Practice Guidance 2017; Villanueva, et al. 2016, Hepatology
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 36 Management of Portal Hypertension
• Clinically significant portal hypertension (CSPH) is hepatic venous pressure gradient (HVPG) >10 mm Hg. • Present in 50-60% of compensated patients without varices • Increases risk for development of varices and clinical decompensation (ascites, GI bleed, HE) • Increases risk for development of hepatocellular carcinoma • Treatment Indication: Non-selective beta blockers to prevent bleeding and reduce mortality
Reference: AASLD Practice Guidance 2017; Villanueva, et al. 2016, Hepatology
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 37 Nonselective Beta Blockers
Therapy Recommended Dose Considerations Propranolol • 20-40mg orally twice a day • Resting heart rate (55-60 bpm) • Adjust every 2-3 days until goal is achieved • Hypotension • Maximal daily dose: • 320 mg/day in patients without ascites • 160 mg/day in patients with ascites Nadolol • 20-40 mg orally once daily • Resting heart rate (55-60 bpm) • Adjust every 2-3 days until goal is achieved • Hypotension • Maximal daily dose: • 160 mg/day in patients without ascites • 80 mg/day in patients with ascites Carvedilol • Start with 6.25 mg once a day • Continue indefinitely • After 3 days, increase to 6.5 mg twice-daily • Maximal dose: 12.5 mg/day (except in patients with persistent arterial hypertension Adapted from AASLD Practice Guidelines
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 38 CSPH in Compensated Cirrhosis without Esophageal Varices
• Goal of therapy: Prevent clinical decompensation • Medications aimed at decreasing intrahepatic resistance and splanchnic blood flow may be useful • Timolol trial (2005) showed no difference between placebo and NSBB in prevention of esophageal varices
Reference: Groszmann, et al. 2005 NEJM
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 39 Use of Beta Blockers to prevent decompensation of cirrhosis in patients with CSPH (PREDESCI)
• Study enrolled 201 patients with compensated cirrhosis and CSPH without high-risk varices. • 101 patients received placebo vs. 100 patients received propranolol or carvedilol. • Primary end point was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy)
Reference: Villanueva, et al. 2019, The Lancet
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 40 PREDESCI Results
• Decompensation occurred 27% in the placebo group (N=101). • Decompensation occurred 16% in the beta blocker group (N=100). • The difference was due to decreased incidence of ascites in the beta blocker group. • Overall incidence of adverse events was similar in both groups.
Reference: Villanueva, et al. 2019 The Lancet
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 41 CSPH in Compensated Cirrhosis with Esophageal Varices
• Goal of therapy: Prevent variceal hemorrhage • Reduction to <12 mm Hg or >20% from baseline HVPG is shown to be protective and considered a response to NSBB therapy. • Hemodynamic response to NSBB therapy reduces incidence of decompensation and death.
Reference: Relberger, et al. 2013, Gut.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 42 Prevention of Re-bleed
• High risk of re-bleeding occurs in the first year and is associated with increased mortality. • First line therapy to prevent re-bleeding is NSBB and endoscopic variceal ligation. • Carvedilol is not recommended to prevent re-bleeding. • If individual has a successful TIPS then no indication for NSBB.
Reference: Puente, et al. 2014, Liver Int
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 43 Treatment for Prevention of Recurrent EVH Therapy Recommended Dose Therapy Goals/Follow-Up Propranolol • 20-40 mg orally twice a day • Resting rate of 55-60 beats per • Adjust every 2-3 days until treatment goal is achieved minute • Maximal daily dose: • Systolic blood pressure should • 320 mg/day in patients without ascites not decrease <90 mm Hg • 160 mg/day in patients with ascites • Monitor heart rate at every visit • Continue indefinitely
Nadolol • 20-40 mg orally once a day • Resting rate of 55-60 beats per • Adjust every 2-3 days until treatment goal is achieved minute • Maximal daily dose: • Systolic blood pressure should • 160 mg/day in patients without not decrease <90 mm Hg • 80 mg/day in patients with ascites • Monitor heart rate at every visit Adapted from AASLD Practice Guidelines * Continue indefinitely
Adapted from AASLD Practice Guidelines
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 44 Special Considerations • Decompensated Cirrhotics with Ascites or After SBP • High doses of NSBB’s should be avoided. • NSBB doses should be reduced or discontinued in refractory ascites with signs of severe circulatory dysfunction (hypotension, hyponatremia, or deterioration in renal function)
• Individuals with Bleeding while on NSBB therapy • May be treated with combination NSBB and Endoscopic Variceal ligation or consider TIPS
References: Leithead, et al. 2016 Gut; Bossen, et al. 2016 J Hepatology; Bang, et al. 2016 Liver Int
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 45 First line ascites management Second line ascites management • Stop all alcohol use • Discontinue NSBB, ACE and ARB medications • Sodium restriction • Consider midodrine (esp in • Dual diuretic use (furosemide and hypotensive patients) spironolactone) • Serial therapeutic paracenteses • Discontinue NSAID use • TIPS consideration • Referral for liver transplantation • Referral for liver transplantation
Reference: Runyon, 2012 Practice Guidance Management of Adult Patients with Ascites Due to Cirrhosis Update 2012; EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis, 2018 J Hepatology
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 46 Spontaneous Bacterial Peritonitis
• Risk Factors for development of SBP include: • Cirrhosis • Ascitic fluid total protein <1 g/dL • Total serum bilirubin > 2.5 mg/dL • Variceal hemorrhage • Previous episode of SBP
https:///www.antibioticresearch.org.uk/about-antibiotic-resistance/bacterial-infections https://www.homeeducationalresources.com/products/student-led-microscope
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 47 Meta-Analysis to Evaluate Antibiotic Therapy in SBP
• Aim: Evaluate benefit and harm of different antibiotics used in SBP treatment in decompensated cirrhotics. • Results: 12 intervention trials included. N=1278 patients. Follow-up period 1 week-3months. • Majority given 3rd generation cephalosporins or ciprofloxacin • 75% recovered from SBP 25% mortality within 3 months • No difference in mortality, adverse events, resolution of SBP or decompensation • Conclusion: Significant uncertainty exists about which antibiotic is better
Reference: Prat, et al. 2019 Antibiotic treatment for spontaneous bacterial peritonitis in people with decompensated liver cirrhosis: a network meta-analysis, Cochrane Systematic Review
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 48 Primary Prophylaxis of SBP Secondary Prophylaxis of SBP • Long term use of antibiotics for • Long term use of antibiotics for cirrhotics at high risk of developing cirrhotics with ascites with previous SBP with ascites episode/s of SBP • Drugs used: Ciprofloxacin 500mg PO • Drugs used: Ciprofloxacin 500mg PO daily or Trimethoprim- daily sulfamethoxazole one double-strength • Alternative: Trimethoprim- PO daily sulfamethoxazole one double-strength • Alternative: Levofloxacin 250mg PO PO daily daily • AASLD and EASL guidelines include Norfloxacin but is no longer available in the US
Reference: AASLD Practice Guidance 2012 Management of Adult Patients with Ascites due to Cirrhosis
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 49 Outcomes in Patients with Cirrhosis on Primary Compared to Secondary Prophylaxis for SBP • Study Aim: Compare outcomes in cirrhotic in-patients on primary vs secondary SBP prophylaxis • Methods: Hospitalized patients with cirrhosis from June 2013-Jan 2017 from 14 tertiary hepatology care centers in the US • SBP defined as >250 PMNs in the ascites fluid • Admission and 90 day follow-up period assessed • Enrolled 2731 total patients with 2239 not on SBP prophylaxis
Reference: Bajaj, et al. 2019 Outcomes in Patients with Cirrhosis on Primary Compared to Secondary Prophylaxis for Spontaneous Bacterial Peritonits, American Journal of Gastroenterology.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 50 Results of Outcomes between Primary and Secondary SBP Prophylaxis • After propensity-matching for MELD and albumin N= 154 per group • 75% were on fluoroquinolones in each group • Patients on Primary prophylaxis had a higher rate of ICU admissions, acute kidney injury, and mortality compared to the Secondary prophylaxis group despite similar length of stay and development of acute-on-chronic liver failure. • Liver transplantation rates were similar between groups. • Despite primary or secondary prophylaxis 10-25% of cirrhotics still develop SBP.
Reference: Bajaj, et al. 2019 Outcomes in Patients with Cirrhosis on Primary Compared to Secondary Prophylaxis for Spontaneous Bacterial Peritonits, American Journal of Gastroenterology.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 51 Case Study
• 58 year old Hispanic female referred to your office for HCV evaluation • History of DM Type 2 on Metformin 500mg BID and Vit D with Calcium • Was screened for HCV by PCP and found to have HCV Ab+
Retrieved from: https://www.keithrn.com/product/etoh-pneumonia-clinical-reasoning-case-study-copy/ Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 52 Evaluation results:
• Wt =210 lbs, Ht 5’6” BMI=33.9 • Physical Exam: Palmar erythema, no ascites • Labs: Genotype 3, HCV PCR 1,200,000 copies/ml, Plts 110, Alb 3.5, T.B. 0.8, AST/ALT=56/65, AFP=6.1 • EGD shows No Varices | Abd CT shows no liver lesions, no ascites • Elastography shows CAP of 290 and kPA 12.4
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 53 Diagnosis
• Chronic Hepatitis C infection/questionable NASH • Compensated Cirrhosis
You discuss HCV therapy with her and she asks: • Can she take herbal products or a Liver Cleanse to help her liver?
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 54 Retrieved from: Costco.com
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 55 Livertox.nlm.nih.gov Herbal and Dietary supplements
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 56 Milk Thistle Tumeric
• Herb: silymarin marianum • Plant root: Curcuma longa • Animal models show prevention or • Anti-inflammatory amelioration of acute liver injury • Anti-oxidant effects • Human studies are inconclusive • Generally considered safe • Recent meta-analysis showed • Reported cases of idiosyncratic reduction in AST/ALT but without liver injury/transient serum clinical significance enzyme elevations
References: https:livertox.nlm.nih.gov; Navarro, et al. 2014 Hepatology; Bunchorntavakul et al. 2013 Aliment Pharmacol https:livertox.nlm.nih.gov; Soleimani, et al. 2019 Phytotherapy Research; Ribeiro de Avelar, et al. 2017 World J Gastroenterol https://www.znaturalfoods.com/milk-thistle-seed-powder-organic
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 57 FDA Safety Communication on the Use of PI-Containing DAA Regimens for HCV Recently the FDA issued a safety announcement about the rare occurrence of serious liver injury with the use of protease-inhibitor (PI)-containing regimens for hepatitis C (HCV), including Glecaprair/pibrentasvir (Mavyret), Elbasvir / Grazoprevir (Zepatier) and sofosbuvir/velpatasvir/voxilaprevir (Vosevi).
States that the use of these drugs to treat chronic hepatitis C in patients with moderate to severe liver impairment has resulted in rare cases of worsening liver function or liver failure. These medicines are not indicated for use in patients with moderate to severe liver impairment. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence-serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and Accessed on August 28, 2019
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 58 FDA Safety Communication: Serious Liver Injury with PI- Containing DAA Regimens
Serious liver injury per PI-containing regimen (n) FDA received reports of 63 46 cases of worsening liver function, including liver failure and 8 deaths, in HCV patients
14 treated with PI-Containing DAA Regimens 3 13 18 21 11 63 63 63 63 GLE/PIB EBR/GZR SOF/VEL/VOX
https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence-serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and Accessed on August 28, 2019
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 59 FDA Safety Communication: Serious Liver Injury with PI- Containing DAA Regimens Baseline Liver Function (%) More than half of the cases with no 33 29 cirrhosis or compensated cirrhosis (CC) were misclassified and had evidence of 21 advanced liver disease or risk factors for 17 decompensation (low platelets, portal hypertension, alcohol abuse, other liver comorbidities).
No Cirrhosis CC DC Unknown
https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence-serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and Accessed on August 28, 2019
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 60 In closing:
• Non-selective beta blockers are an important intervention for cirrhotic patients with portal hypertension. • SBP is a significant factor in mortality of cirrhotic individuals and treatment with broad-spectrum antibiotics as prevention may need reconsideration. • Herbal and Dietary Supplements (HDS) are commonly used by patients with liver disease, however there is a need for more human studies to show benefit vs. risk. • Monitoring of HCV cirrhotic patients while on HCV therapy remains critical.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 61 LONG TERM CARE OF THE LIVER TRANSPLANT PATIENT Carolyn Driscoll PhD FNP-C Nurse Practitioner Charlottesville Gastroenterology Associates
62 Liver Transplant Outcomes
• Liver transplant survival and outcomes continue to improve
• 8250 liver transplants in 2018
• Treatment of choice for chronic liver failure, acute liver failure, and hepatocellular carcinoma
• Survival: • 1 yr: 89.6% • 3 yr: 80.8% • 5 yr: 72.85%
63 Long Term Post Transplant Care
• Management of complex chronic • Primary Care Provider illness • Transplant Hepatology Providers • Cancer screening • Transplant Surgeons • Chronic immunosuppression
64 Common Post Transplant Complications
• Cardiovascular disease
• HTN
• Diabetes
• Dyslipidemia
• Chronic kidney disease
• Malignancies
65 Cardiovascular Disease
• Up to 30% of post transplant deaths related to cardiovascular or CVD post liver txp cerebrovascular complications (Pelaez-Jaramillo, Diab Ther 2018 35 PE 9(2)) 30 • CVD developed in 10.6%, 20.7%, and 30.3% of recipients within 1, 5, and 8 years, respectively (Fussner, L, 2015, Liv Transplant) 25 • Contributing factors: 20 • Underlying liver disease: NAFLD and ETOH 15 • Obesity, age, male sex, DM, metabolic syndrome, renal dysfunction, immunosuppression 10
• Post transplant NAFLD 5
• Management: 0 • Control of Metabolic syndrome and associated factors, lifestyle 1 yr 5 yr 8 yr modification, immunosuppression, screening for vascular and cardiac issues (Pisano, G. World J Gastro. 2016 22(40):8869
66 Hypertension
• 40-85% of patients develop HTN post transplant • Goal BP 130/80 or less • Management • Monitor BP at least every 6 months • Calcium channel blockers: amlodipine, nifedipine • Diltiazem, verapamil, nicardipine may increase IS levels • Diuretics: Furosemide, chlorthalidone, HCTZ • ACE/ARBs • Avoid in early post transplant period • Can be used in select pts • Alpha blockers and beta blockers
• Carvedilol may increase IS Issa, D and Alkhouri, N.2015, Cleveland Clinic Journal of Medicine 82(6) McGuire et. al. 2009, AJT. 9:1988 AASLD Pracice Guideline: Adult LT Management (2013) 67 Diabetes • Wide variation in reported incidence of DM after liver transplant • 10.8 - 33% in first year post transplant
• Contributing factors: Classic risks, virus (HCV, CMV), pretransplant dx (NAFLD), immunosuppression, donor factors
• Contributes to higher mortality at 5 yr post transplant (36.5 vs 13.9%)
• Higher incidence renal insufficiency
• Management: • Early strict glucose control reduces long term risks • Good long term control beneficial; follow ADA guidelines • Target HgbA1C <7.0% • Lifestyle modifications, medications
Pelaez-Jaramillo. 2018, Diab Ther 9(2): 521 AASLD Practice Guideline: Adult LT Management (2013) 68 Dyslipidemia
• Incidence 45-69%
• Risk factors: obesity, diabetes mellitus, cholestatic liver disease, and immunosuppressant medications (esp. sirolimus)
• Management • Lipid panel screening annually after first year • LDL>100 requires treatment • Lifestyle modifications: exercise, weight loss
Issa, D and Alkhouri, N.2015, Cleveland Clinic Journal of Medicine 82(6) McGuire et. al. 2009, AJT. 9:1988 AASLD Practice Guideline: Adult LT Management (2013) 69 Dyslipidemia: Medications
• Statins • Pravastatin and fluvastatin (moderate intensity) not metabolized by CYP 3A4 • Atorvastatin and rosuvastatin (high intensity) are metabolized by CYP 3A4
• Ezetimibe can be added if control suboptimal
• Isolated hypertriglyceridemia • Fish oil up to 4 gm/day if tolerated • Gemfibrozil or fenofibrate can be added but require close monitoring for side effects (i.e rhabdomyolosis and myopathy)
Husing, H, (2016) World J Gastro. Mar 28; 22(12 AASLD Practice Guideline: Adult LT Management (2013) 70 Chronic Kidney Disease • 2nd highest rate of CKD (GFR < 29 ml/min/1.73 m2 BSA) • 1 yr: 8%; 3 yr: 14%; 5 yr: 18%, 10yr: 26%
• As much as 25% of decline occurs in first year • Associated with: • Anemia, renal osteodystrophy, electrolyte abnormalities
• Contributing factors: • Pretransplant renal function, immunosuppression, HTN, DM
• Management • Monitor creatinine clearance using an estimating equation (ie GFR calculator) • Minimize immunosuppression as tolerated • Annual spot urine protein:creatinine ratio • Control/reduce other contributing factors
• AVOID NSAIDs and nephrotoxic meds Issa, D and Alkhouri, N.2015, Cleveland Clinic Journal of Medicine 82(6) McGuire et. al. 2009, AJT. 9:1988 AASLD Practice Guideline: Adult LT Management (2013) 71 Malignancy Type of Cancer Relative Risk
• Higher risk of de novo Skin Cancer malignancy after LT Basal or Squamous cell 20-70% • 3-5% at 1-3 yrs post transplant Melanoma 3-5% • 11-20% at 10 yrs post Colorectal cancer 10-30% if UC present transplant Similar to general population if non ID/PSC Lymphoma 10-30% Oropharyngeal 3-14% Kidney 5-30% Lung 1.7-2.5% Breast Similar to general population Acuna, SA, et al. (2017) JT 17:103 McGuire et. al. 2009, AJT. 9:1988 AASLD Practice Guideline: Adult LT Management (2013) Wong, G et. al. (2017) AJD 17:2243 72 Malignancy: Screening Recommendations
• Skin • Annual skin check w/dermatologist 5 yrs or more after transplant • More frequent w/h/o skin cancer or for suspicious lesion
• Colorectal cancer • Annual screening colonoscopies w/biopsies for pts w/IBD/PSC • Follow American Cancer Society (ACS) guidelines for other screening
• Breast • Follow ACS guidelines for general population
• HCC • If graft cirrhosis develops, abdominal imaging every 6-12 months
73 Obesity
• Weight gain is common after liver transplant
• Approximately 20% of non-obese pts become obese
• All patients require ongoing dietary counselling
• Recommend regular exercise
• Refer for behavioral weight loss programs
• Bariatric surgery may be considered if other programs fail
Issa, D and Alkhouri, N.2015, Cleveland Clinic Journal of Medicine 82(6) McGuire et. al. 2009, AJT. 9:1988 AASLD Practice Guideline: Adult LT Management (2013)
74 Preventive Care: Bone Health
• BMD testing • annually for first 5 yrs if osteopenic • every 2-3 yrs if normal bone density at time of transplant • After 5 yrs, screen based on results
• Calcium/Vit D supplementation
• Weight bearing exercise
• Bisphosphonates if indicated
AASLD Practice Guideline: Adult LT Management (2013)
75 Preventive Care • Vaccines • No live vaccines • Annual flu shot • Pneumovax 23 and Prevnar 13 • Tetanus • HAV and HBV
• Smoking cessation • Decrease contribution to higher risk for lung, head and neck cancers, CAD, stroke, COPD, vascular events and graft loss
• ETOH • ABSTAIN if ETOH etiology of liver disease • Enter therapy or counselling if return to drinking
• Sun exposure • Avoid excess exposure • Wear sunscreen (at least SPF 15) and protective clothing
AASLD Practice Guideline: Adult LT Management (2013) 76 Health Promotion • Frequency of monitoring labs and liver tests can be individualized based on time from transplant, complications, and stability of labs • Review immunosuppression regimen every 6 months • Minimize risk of tick, mosquito, and sun exposure: • Long sleeves, long pants, shoes, socks • Avoid high risk times: dawn/dusk
• Frequent hand washing • Avoid consumption of water from rivers/lakes • Avoid unpasteurized food products, raw/undercooked eggs, seafood, meat, chicken, and pork • Weight management • Regular counselling to minimize obesity • Refer for behavioral management first, surgical management if not successful
77 Getting the Patient with NASH/Obesity to Transplant
Victoria Gómez, M.D.| Assistant Professor of Medicine | Mayo Clinic, Florida
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 78 Introduction: Obesity Pandemic
• 700 million adults with obesity (BMI* ≥ 30)
• In the U.S. for adults > 20 years of age: • 68.8% overweight or obesity • 35.7% obesity
• Obesity is a major risk factor for: • Cardiovascular disease • Diabetes Mellitus • Chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC) https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Body Mass Index (BMI)- defined as kg/m2 https://ourworldindata.org/obesity
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 79 Introduction: Obesity and Liver Disease
• Risk of developing nonalcoholic fatty liver disease (NAFLD) is 5 times greater for persons with obesity versus without obesity
• In patients with biopsy-proven nonalcoholic steatohepatitis (NASH), obesity is independently associated with fibrosis progression
• Fibrosis progression + weight gain to cirrhosis • Increased risk of decompensation over 2 to 5 years, and higher risk of HCC
Bellentani S et al. Ann Intern Med. 2000;132:112-117 Fassio E et al. Hepatology. 2004;40:820-826
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 80 NASH and Liver Transplantation
• NASH has become second most common indication for listing for liver transplantation (LT)in the USA in 2013 after HCV • In parallel to rising rates of obesity
• Patients with NASH are: • Less likely to undergo LT • Slower progression of disease (MELD) • Less likely to receive MELD exception points • Comorbidities (cardiovascular) • Less likely to survive for 90 days on the waitlist compared compared to patients with HCV, ALD, HCV and ALD
HCV- Hepatitis C virus infection ALD- alcoholic liver disease Segev et al. Ann Surg. 2008;248(5): 863-70 Data derived from UNOS/OPTN data Wong RJ et al. Gastroenterology. 2015;148:547-555
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 81 BMI, Obesity and LT Outcomes
• Strict BMI cutoff does not exist
• BMI is an imperfect measure of surgical risk in patients with cirrhosis • Volume overload • Variable distribution of visceral and subcutaneous adiposity
• Comparable patient and graft survival between liver transplant recipients with or without obesity • US liver transplant experience
Spengler EK et al. Transplantation. 2017;101(10):2288-2296
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 82 Why Address Weight Loss/Obesity Management pre-LT?
• Less access to available grafts particularly living donor grafts, due to graft-to-body weight restrictions
• Increased technical difficulties during surgery, including mean operative time
• Perioperative issues: wound infections, dehiscence, longer hospital stay, incisional hernias
• Recurrence of NAFLD/NASH in donor liver- Pretransplant overweight status strong predictor
Spengler EK et al. Transplantation. 2017;101(10):2288-2296 Bonner K, Heimbach JK. Curr Opin Organ Transplant. 2018;23:244-249 Malik SM et al. Liver Transpl 2009;15(12):1843-51 Kappus M, Abdelmalek M. Clin Liver Dis 2017;21:321-335
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 83 Management of NASH/Obesity Before LT
• Complex and challenging
• Goals of evaluation and management: • Thorough evaluation with intense workup for CV disease due to presence of metabolic syndrome • Weight reduction with strict supervision • Reduction/improvement in metabolic comorbidities • Reduction of liver fibrosis
• Improvement in survival while waiting for LT, and access to available grafts
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 84 Treatments for Obesity
E F F I C A FDA Medications C Y Risk
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 85 Adapted from B. Abu Dayyeh Multidisciplinary Approach to Weight Loss
Transplant Hepatology
Transplant Dietician
Bariatric Behavioral Clinic Psychologist
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 86 Treatment of NAFLD/NASH: How do we achieve this?
Romero-Gómez M et al. J Hepatology. 2017;67:829-846 Vilar-Gómez E et al. Gastroenterology. 2015;149:367-378
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 87 The Reality….
Specific challenges: • Sarcopenia • Protein calorie malnutrition • Poor functional status/exercise intolerance • Decompensation
Lower chance of achieving weight loss goal
Romero-Gómez M et al. J Hepatology. 2017;67:829-846
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 88 Treatments for Obesity BMI 40+ kg/m2
E F F I C A FDA Medications C Y Risk
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 89 Adapted from B. Abu Dayyeh Role of Bariatric Surgery
• Pre-liver transplant
• Simultaneous bariatric surgery and liver transplantation
• Post-liver transplant
• Optimal timing not well determined and varies on the patient
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 90 Pre-transplant Bariatric Surgery
• Very small and selective pool of candidates
• Risk of 30-day mortality in patients with decompensated cirrhosis is high • Comparison study of patients with compensated vs decompensated cirrhosis who underwent bariatric surgery • 3,888 compensated vs 62 decompensated patients with cirrhosis • 16.3% for decompensated cirrhosis vs 0.9% for compensated vs 0.3% for patients without cirrhosis
Moski JD et al. Clin Gastroenterol Hepatol. 2011;9:897-901
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 91 Types of Bariatric Surgery
Adjustable gastric band Vertical sleeve gastrectomy (VSG) Roux-en-Y gastric bypass (RYGB)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 92 VSG versus RYGB: Which to choose in LT patients?
RYGB: - Longer operation - Restrictive + malabsorptive - Weight loss is quite rapid - Difficult access to stomach and duodenum VSG: - Remnant stomach - Less operative time - Altered anatomy ERCP - Restrictive - Weight loss more gradual - Endoscopic access to stomach and duodenum - Gastric varices/PHG - Access to biliary tree Bonner K, Heimbach JK. Curr Opin Organ Transplant. 2018;23:244-249 Zhang Y et al. Obes Surg. 2015;25:19-26
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 93 Pre-transplant Bariatric Surgery: SG
• Advantages: • Target patients with low MELD scores and well controlled complications of liver disease • Sustained weight loss after SG may reduce risk for further hepatic decompensation • Improve liver function to point where LT may not be needed for some time • Lower risk of intolerance to oral intake (compared to simultaneous SG+ LT)
Sharpton SR et al. Liver Transplantation. 2019;25:538-544
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 94 Pre-transplant Bariatric Surgery: SG
• Retrospective cohort of 32 patients who underwent laparoscopic SG • Median age 55 ys, 72% female (N=23), 50% Child-Pugh B, hx of prior decompensation • Median BMI 45 kg/m2 • Complications • Renal insufficiency requiring albumin administration (N=1) • Transient encephalopathy secondary to medication effect (N=1) • Gastric staple line leak due to retention of orogastric tube (N=1) • No reoperations or 30-day postoperative mortality • No liver-related morbidity in the perioperative period
Sharpton SR et al. Liver Transplantation. 2019;25:538-544
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 95 • Mostly stable or improved MELD score at 6 months • Median BMI at 12 months 32.9 kg/m2 • 5/32 had increase in MELD score at 6 months (range 2-6) • Reduction of 11.3 kg/m2 in BMI
Sharpton SR et al. Liver Transplantation. 2019;25:538-544
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 96 Eligibility for LT After SG
• 28 (88%) patients deemed eligible to be actively listed for LT within 6 months following SG • Of the 4 not eligible: • 3 patients transferred care to another center or did not return for follow up • 1 patient experienced postoperative gastric leak with additional complications, precluding LT
• Among the 28 eligible patients: • Listing deferred in 7 patients because of low MELD score (“being too well”) • Remaining 21 actively listed for LT • 14 underwent LT (including all 5 patients with HCC)
• Median time between SG and LT was 22 months (14-88 months) Sharpton SR et al. Liver Transplantation. 2019;25:538-544
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 97 SG Before LT: Summary
• SG before LT is technically feasible in select patients
• Acceptable complication rates
• Significant and sustained weight loss with: • Resolution or improvement in obesity-related comorbidities • High rates in eligibility for active listing to LT • Postpone/delay the need for LT
Sharpton SR et al. Liver Transplantation. 2019;25:538-544
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 98 Simultaneous Bariatric Surgery- Liver Transplantation • Advantages: • Both liver disease and obesity are addressed with one operation and hospital recovery • Reduce issues with adhesions found at a re-operative surgery • Potentially eliminate barrier such as insurance approval for a second (i.e bariatric) surgery • Patient preference to avoid a second operation
Zamora-Valdes et al. Hepatology. 2018;68 (2):485-495 Bonner K, Heimbach JK. Curr Opin Organ Transplant. 2018;23:244-249
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 99 Simultaneous LT + SG: The Mayo Clinic Experience
• Protocol adopted in 2006 at Mayo Clinic in Rochester, Minnesota
• Lifestyle modification intervention for all patients with BMI ≥ 35 kg/m2at listing
• If successful with weight loss and achieved BMI < 35 kg/m2 and MELD score high enough to access transplantation patients underwent LT
• Those unable to achieve BMI < 35 kg/m2 but had MELD score high enough to access transplantation patients offered simultaneous LT and SG
Zamora-Valdes et al. Hepatology. 2018;68 (2):485-495
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 100 Simultaneous LT + SG: The Mayo Clinic Experience
• LT = 36, LT + SG = 13 included in analysis*
• Overall: LT = 45, LT + SG = 29
• Mean BMI at LT 47 k/m2 • All LT performed using deceased donor livers
• Significantly higher %TBW at all time points for LT + SG after LT • 100% of LT + SG patients maintained > 10% loss in TBW compared to 30% of LT group
* Only patients with > 3 years follow up included in analysis %TBW- percent total body weight loss Zamora-Valdes et al. Hepatology. 2018;68(2):485-495
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 101 Simultaneous LT + SG: The Mayo Clinic Experience
• LT+SG patients had lower prevalence of hypertension, insulin resistance and hepatic steatosis
• LT+SG patients required fewer antihypertensive medications and lipid agents at last follow up
• Survival not statistically different between cohorts
Zamora-Valdes et al. Hepatology. 2018;68 (2):485-495
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 102 Simultaneous LT + SG: Summary
• Intense lifestyle intervention is feasible and can help patients achieve weight loss before LT
• LT+SG results in more profound and sustainable weight loss compared to LT alone and results in greater probability of sustaining > 10% TBW after LT
• LT+SG resulted in greater improvement in metabolic parameters
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 103 Treatments for Obesity BMI 40+ kg/m2
BMI 30-40+ kg/m2
E
F BMI 25-30 kg/m2 F I C A ? C Y
Risk Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 104 Adapted from B. Abu Dayyeh Treatments for Obesity BMI 40+ kg/m2
BMI 30-40+ kg/m2
E
F BMI 25-30 kg/m2 F Endoscopic I Bariatric C Therapies A C Y
Risk Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Adapted from B. Abu Dayyeh 105 Endoscopic Bariatric Therapies (EBTs)
• Provide an effective and minimally invasive treatment approach to obesity
• Increase treatment options beyond surgery, medications and lifestyle measures
• May be a suitable option for selected patients • Primary therapy • Bridge to surgery (bariatric and non-bariatric)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 106 Intragastric Balloon (IGB) Therapy
• Eight IGBs in the world market, 3 approved by FDA:
• Mechanisms of action: • Delays gastric emptying • Early satiety due to space occupying device
Orbera Reshape Duo Obalon
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 107 108 % TBWL with Orbera: US Pivotal Trial (ITT) N= 255
IGB+ LIP patient can achieve 3 x weight loss at 6 months compared to LIP alone
Majority of weight loss occurs in the first 3 months
Courcoulas A et al. Int J Obes. 2017;41(3):427-433
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 109 IGB Therapy in NASH/Obesity Treatment +/- Pre-LT?
• Limited Data
• Special considerations (in addition to standard evaluation): • Size of esophageal varices • Presence of gastric varices • Severity of portal hypertensive gastropathy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 110 IGB Improves NAFLD Activity Score
• Single center pilot study from Singapore • Patients randomized to IGB + AHA Diet or sham IGB placement + AHA Diet x 6 months • N= 8 IGB therapy, N= 10 control group • Liver biopsy obtained pre and post IGB placement • Significant decrease in mean BMI, NAFLD activity scores (NAS), and trend toward improvement in steatosis scores
AHA- American Heart Association Lee Y et al. Gastrointest Endosc. 2012;76:756-60
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 111 IGB Improves NASH
• Open label study from Mayo Clinic (N=21 subjects) • EUS-guided core liver biopsy at time of IGB placement and removal • MR Elastography (MRE) used to diagnose early NASH, and was repeated after balloon removal • Liver stiffness and fat fraction improved significantly on repeat MRE • NAS improved in 87% subjects: • 73% achieved ≥ 2 points improvement in NAS • Fibrosis regression in 20% of subjects • All subjects with early fibrosis regressed
EUS- endoscopic ultrasound Bazerbachi F et al. Gastrointest Endosc. 2018;87(6S):AB118-119
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 112 IGB as a Bridge to Liver Transplantation
• Single center in India of patients with BMI > 40 or BMI 35-40 with low GRWR (N=8 enrolled with IGB therapy) • Five underwent LT (0.6% of total LTs [n=828]) • Nausea, vomiting • No deaths
GRWR- graft to recipient weight ratio Choudhary et al. Indian J Gastroenterol. 2016;35(2):113-116
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 113 IGB as a Bridge to Liver Transplantation: The Future?
• Larger prospective studies needed
• Protocols need to be tailored to high risk patients
• Cost- mostly out of pocket
• Post LT- weight gain, especially after IGB removal
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 114 Takeaway Points • Obesity/NASH cirrhosis are on the rise, and management of this patient population must take into account both liver and cardiovascular related comorbidities
Hepatology Team • Effective weight loss is effective in improving and possibly halting NASH progression, with a target goal of at least >10% TBW Bariatric Bariatric Surgery Clinic
• A multidisciplinary approach is required to help provide the best option(s) for achieving and sustaining weight loss Endoscopic Lifestyle • Lifestyle intervention Bariatric Intervention • Bariatric Surgery Therapies • Endoscopic Bariatric Therapies (?)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 115 Thank you!
Check out my YouTube Channel for information on EBTs!
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 116 Case Studies: General Hepatology 101
Amanda Chaney, DNP, APRN, FAANP Nurse Practitioner Assistant Professor of Medicine & Associate in Transplant Medicine, Mayo Clinic
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 117 Case Study #1 – Abnormal LFTs
Patient Profile Gender/Age Female/45 Ethnicity Hispanic Height 5’ 5” Weight 195 lbs BMI 32.4 Occupation Insurance agent PMH Obesity, type 2 DM, hypothyroidism Meds Metformin, levothyroxine Allergies NKDA Family Hx DM, CAD, MI (Father)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 118 History of Present Illness
• Arrives to ER for 1 week history of itching and yellowing of skin • Recent dx of acute bronchitis; prescribed 14 day course of sulfamethoxazole-trimethoprim DS BID (completed 7 days) • ROS: fatigue, nausea, RUQ abd pain • Denies alcohol consumption
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• VS: BP 120/75, HR 90, RR 24, Temp 38.2 • General: jaundiced; scleral icterus, severe itching/areas of excoriations on arms • Skin: mild maculopapular rash to chest and back • Heart: S1/S2 present; RRR • Lungs: CTAB • GI: no hepatomegaly or splenomegaly; + bowel sounds; obese abdomen • Neuro: follows command appropriately; no asterixis
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Lab Result
CBC Normal • Ultrasound: liver shows fatty INR 1.2 infiltrate consistent with fatty Alk Phos 250 liver disease; patent vasculature; presence of gallstones ALT/AST 75/42
Total bilirubin 12
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• What do you ask the patient next? • What is your differential diagnosis? • What medications should be started or stopped? • Other considerations?
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Patient Profile Gender/Age Male/59 Ethnicity AA Height 6’ 2” Weight/BMI 198 lbs Occupation Financial Analyst PMH Type 2 DM, hypercholesterolemia, HTN Meds Lisinopril, pravastatin Allergies NKDA Family Hx MI, DM, CAD– Father, Breast cancer – Mother
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• Presents to emergency room with a 3 week history of abdominal swelling and worsening fatigue. Symptoms have worsened over the past 2 days. • Wife reports that sometimes he says things that are “off” or do not make sense. Happening off and on for the past 2 months • ROS: fatigue, worsening SOB with activities of daily living (walking dog or going up stairs); no chest pain, or dizziness. No change in bowel habits • Denies current alcohol consumption; social/occasional glass of wine
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• VS: BP 145/90, HR 89, RR 18, Temp 37.0 • General: appears dyspneic with conversation; oriented to person, place; states year is 2001 • Heart: S1/S2 present; RRR • Lungs: CTAB • GI: distended; non-tender to palpation; no hepatomegaly or splenomegaly; + bowel sounds • Neuro: follows command appropriately; mild asterixis
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Lab Result
CBC Hgb 8.7, Plt count 45 WBC normal INR 1.3 • Ultrasound: liver shows cirrhotic liver with sequela of portal Glucose 320 hypertension; patent vasculature; no portal vein thrombosis; ALT/AST/Alk Phos normal moderate ascites; 2.5 cm Total/Direct bilirubin 2.0/1.2 hypoechoic mass in right lobe, with recommendation for further Renal profile Na 130, K 3.4, Creatinine studies. 1.1, BUN 20
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 126 What’s next? . . . . • Paracentesis performed • 5.5 liters removed – clear, yellow fluid • Cell count: WBC 150, 5% neutrophils • Sent for gram stain, cultures, TP • MR abd w/wo contrast • Cirrhosis with sequela of portal hypertension including varices, splenomegaly, and small ascites; 2.5 cm x 1.8 cm mass seen in segment 5 with arterial phase hyperenhancement with washout and enhancing capsule
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• Decompensated cirrhosis • Hepatic encephalopathy • Ascites • Uncontrolled DM • ?Hepatocellular carcinoma
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• Refer to a liver transplant center for full LT evaluation • Plans for: • TxHepatology consultation • Interventional Radiology consultation • ?candidate for local regional HCC treatment?
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Patient Profile Gender/Age Female/42 Ethnicity Caucasian Height 5’7” Weight/BMI 135 lbs Occupation Grocery cashier PMH IVDU, Hep C (treated 2018), asthma, depression, anxiety Meds None Allergies PCN Family Hx Father – cirrhosis, Mother – ovarian cancer (deceased 45)
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• Arrives to your clinic for a new diagnosis of hepatitis B. • Seen by PCP 2 weeks ago after her new boyfriend told her that he has hepatitis B. Lab work done by PCP (next slide) • ROS: fatigue, nausea, anxiety • Denies current alcohol or any IVDU consumption • Social history: prior IVDU history (5 years off and on); completed drug rehab program and has been clean for 2 years;
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Lab Result
CBC Normal
INR 1.0 • Ultrasound: hepatomegaly, no Alk Phos/ALT/AST 220 / 1,520 / 1,230 splenomegaly, no ascites, thickened gallbladder wall, Total bilirubin 3.2 normal bile ducts. Viral hepatitis serologies HBsAg +, Anti-HBs -, Anti-HBc IgM +, HBeAg + HBV DNA 365,000 IU/mL HCV RNA - undetectble
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• VS: BP 112/69, HR 68, RR 16, Temp 37.0 • General: appears thin, malnourished; older than stated age • Heart: S1/S2 present; RRR • Lungs: CTAB • GI: hepatomegaly, no splenomegaly; + bowel sounds; flat abdomen • Neuro: follows command appropriately; no asterixis
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• As the liver specialist seeing this patient, what do you do next? • Would you order any additional testing? • What education would you provide the patient? • What considerations should you think about given the patient has received treatment for hepatitis C? • What is your treatment of choice?
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• Case #1: Abnormal LFTs • Case #2: Decompensated cirrhosis and HCC • Case #3: Hepatitis B
Think about these cases as we have our experts bring insight into these scenarios
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Paul Y Kwo, MD Professor of Medicine Stanford University
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 136 Assessment of Abnormal Liver Biochemistries • Liver chemistries including ALT, AST, alkaline phosphatase and bilirubin are markers of liver injury, not liver function, and should be referred to as liver chemistries, or liver tests. • Albumin, bilirubin, and prothrombin time are markers of hepatocellular function that can be influenced by extrahepatic factors. • The laboratory measurements of ALT, AST, and alkaline phosphatase are highly reproducible
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 137 Aminotransferases • ALT and AST are the most widely ordered liver chemistries that reflect injury to the liver. • ALT is mainly localized in the liver, more specific than AST for hepatic origin. • AST is more widely distributed in the liver as well as cardiac, skeletal, kidney and brain tissue • ALT predominantly localizes to the cytosol, AST localizes to the mitochondria. • These levels increase in the serum with the death of hepatocytes, either by necrosis or apoptosis.
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Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 139 What are truly normal liver chemistry tests? • A true healthy normal ALT level in prospectively-studied populations without identifiable risk factors for liver disease ranges from 29-33 IU/L for males and 19-25 IU/L for females, and levels above this should be assessed • Elevated ALT or AST above the ULN in a population without identifiable risk factors is associated with increased liver-related mortality • There is a linear relationship between ALT level and BMI that should be assessed by physicians • Important with the contribution of NAFLD • A normal ALT level may not exclude significant liver disease.. • AST and ALT ULN ranges can vary between different labs.
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Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. AJG. 1402017 Jan;112(1):18. Our ALT levels are evolving upward
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Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. https://www.cdc.gov/obesity/data/prevalence-maps.html 158 ALT and AST levels and liver related mortality Author /Year Proposed ALT/AST cutoff ALT/AST level for Comments level increased mortality
3X increase in all cause Arndt 1998 AST 18 AST> 18 mortality
RR of liver mortality 2.9 (2.4 to 3.5) and 9.5 (7.9 to 11.5) in Kim 2004 ALT <20 ALT 30-39 men , 3.8 (1.9 to 7.7) and 6.6 (1.5 to 25.6) in women ALT (ULN 45 IU/L for Men, 29 ALT 45-90 M SMR risk 1.32 for 1-2X ULN, Lee 2008 for females 29-58 for F and 1.78 for >2X ULN
ALT > 30 for M Increased liver related Ruhl 2009 ALT 30 IU/L M, 19 IUL for F ALT >19 for F mortality
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Arndt V , Brenner H , Rothenbacher D et al. . Int Arch Occup Environ Health 1998 ; 71 : 405 – 12 . Kim HC , Nam CM , Jee SH et al. Br Med J 2004 ; 328 : 983 . . Lee TH , Kim WR , Benson JT et al.. Hepatology 2008 ; 47 : 880 – 7 . Ruhl CE , Everhart JE. Gastroenterology 2009 ; 136 ( 477-85 ): e11 159 How do you diagnose NASH?
• Liver biopsy is the GOLD standard for now Do we have to do a biopsy on EVERYONE with fatty liver disease??
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Category Blood Tests Assessing Fibrosis Stage in NAFLD
. NAFLD fibrosis score . AST/ALT ratio “Simple” lab/clinical indices . FIB-4 score . APRI
. FibroTest† “Expanded” lab indices . FibroMeter . ELF test* Direct fibrosis markers . PIIINP
• *Assays HA, PIIINP, and TIMP-1; F3/4 fibrosis, AUC: 0.90 (95% CI: 0.84-0.96) not avaialble in US. † • Includes total bilirubin, GGT, α2-macroglobulin, ApoA1, and haptoglobin, corrected for age and sex; F3/4 fibrosis, AUC: 0.88 (95% CI: 0.82-0.92). Routine liver tests do not differentiate NAFL vs NASH or accurately stage fibrosis
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Technique Visualize Liver
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• Defined as an impairment in bile flow • Cholestatic liver profile is characterized by an elevation in alkaline phosphatase with or without an elevation in bilirubin. • 2 other enzymes also elevate in cholestasis: gamma glutamyl transferase (GGT) and 5´ nucleotidase (rarely ordered) • Alkaline phosphatase elevation seen in those who are less than 18 years old, or in women who are pregnant • In children, the alkaline phosphatase level is increased up to three times the upper limit of normal, and in pregnant patients it can be increased up to two times that of normal (placenta) • Normal Alk phos level ~ 125 IU/l • GGT may be ordered to confirm alk phos is hepatic in origin
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 164 ALKALINE PHOSPHATASE SITES OF PRODUCTION hepatocyte hepatocyte Site
Liver Hepatocyte cannalicular membrane NOT bile duct cell
Bone Intestine Kidney Placenta Tumors Lung Ovary Bile duct cells Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Hepatology. 2015 Jun;61(6):2080-90. doi: 10.1002/hep.27715. Epub 2015 Feb 24. 165 Clinical assessment of the patient with elevated liver tests should begin wit a thorough history and physical examination • ALT elevation may be confirmed with an AST elevation • Alkaline phosphatase elevation may be confirmed with a GGT elevation • History should include risk factors for underlying liver disease, associated medical conditions, use of alcohol, and use of medications including over-the- counter products and herbal supplements • Physical examination should assess for stigmata of chronic liver disease (frequent) , as well as signs or symptoms pointing to a specific liver disease etiology (uncommon)
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• Herbal therapies and other natural treatments have no adverse effects
• “But doctor, they are natural”
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• Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels as compared to the alkaline phosphatase level. • Cholestatic injury is defined as disproportionate elevation in alkaline phosphatase level as compared to AST and ALT levels. • Mixed pattern of injury is defined as elevation of both alkaline phosphatase and AST/ALT levels. • Isolated hyperbilirubinemia is defined as elevation of bilirubin with normal alkaline phosphatase and AST/ALT levels.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 169 R ratio is a useful tool to recognize patterns of injury
• Calculated by the formula R = (ALT value ÷ ALT ULN) ÷ (alkaline phosphatase value ÷ alkaline phosphatase ULN) • R ratio of > 5 defined as hepatocellular injury • < 2 cholestatic injury • 2-5 mixed pattern.
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• Borderline AST and/or ALT elevation is defined as < 2X ULN • Mild AST and/or ALT elevation as 2-5X ULN • Moderate AST and/or ALT elevation 5-15X ULN • Severe AST and/or ALT elevation >15X ULN • Massive AST and/or ALT > 10,000 IU/L
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• Fulminant hepatic failure (FHF) or acute liver failure (ALF), defined as the rapid development of acute liver injury with severe impairment of the synthetic function as manifested by prolonged prothrombin time and hepatic encephalopathy in a patient without obvious, previous liver disease requires immediate evaluation regardless of ALT level
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 172 Borderline ALT elevation < 2x ULN
History and physical exam CBC/platelet count, AST/ALT, Alk Phos, TB, albumin, PT/INR If negative, consider Discontinue hepatotoxic meds HBsAg, HBcAb, HBsAb, HCV observation for 3-6 months Discontinue alcohol consumption Ab with PCR confirmation if +, with repeat AST/ALT, Alk Phos, Assess for risk factors for fatty liver iron panel, Abdominal TB or and viral hepatitis ultrasound
If persistently elevated, continue investigation: ANA, ASMA, gamma- If normal, further testing at globulin ,ceruloplasmin, Alpha-1 discretion of clinician or refer to antitrypsin phenotype and may hepatologist for consderation of consider additional tests based on liver biopsy history (e.g. celiac sprue, tick-borne disease, thyroid disease, muscle disorders)
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Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. AJG. 1732017 Jan;112(1):18. Abnormal laboratory tests seen with excess alcohol consumption
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Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 174 The changing epidemiology of Hepatitis C increase in hepatitis C cases in ages 20-39 years of age due to opiate epidemic
Bimodal distribution of hepatitis C
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. https://www.health.ny.gov175/statistics/diseases/communicable/index.htm Clinical Significance of Serological Markers for HBV Infection
HBsAg Acute/Chronic infection Anti-HBc IgM Acute infection HBeAg Higher infectivity Anti-HBe Lower infectivity Anti-HBs Immunity Anti-HBc IgG and HBsAg Chronic infection Anti-HBc IgG and anti-HBs Resolved infection (previous exposure)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 176 Mild Elevation of ALT:2-5x ULN CBC/platelet count, History and physical exam AST/ALT, Alk Phos, TB, If negative, consider Discontinue hepatotoxic meds albumin, PT/INR observation for 3 months Discontinue alcohol HBsAg, HBcAb, HBsAb, with repeat AST/ALT, Alk consumption HCV Ab with PCR Phos, TB or continue confirmation if +, iron Assess for risk factors for fatty investigation liver and viral hepatitis panel, Abdominal ultrasound
If persistently elevated, continue investigation: ANA, ASMA, gamma-globulin ceruloplasmin, Alpha-1 antitrypsin phenotype and may consider additional tests based on history (e.g. celiac sprue, tick-borne disease, thyroid disease, muscle disorders) If no diagnosis, consider diagnostic liver biopsy
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Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. AJG. 1772017 Jan;112(1):18. Indications for testing Alpha 1-antitrypsin deficiency • Neonatal hepatitis syndrome • Chronic hepatitis/elevated liver tests • Cryptogenic cirrhosis (unknown etiology)
• Hepatocellular cancer Pi phenotype Risk of Liver Disease
• Precocious emphysema MM 0 • ?first degree relatives ZZ 10-20%
MZ ↑
SZ ↑
MS 0
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• Biochemistry: typically marked elevation of AST/ALT (300-500 IU/mL) compared to alkaline phosphatase • Type 1(80% in US): anti-nuclear (ANA), anti-smooth muscle (SMA) • Serum gamma-globulin greater than 1.5 x upper limit of normal with autoimmune markers • Liver histology chronic hepatitis ± lobular necrosis/bridging: May see abundance of plasma cells • Other etiologies of liver disease absent
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• Transferrin saturation >45%) and/or elevated ferritin • HFE locus testing •1 mutation (C282Y) accounts for 85% of cases •H63D and S65C are minor mutation • If C282Y/C282Y confirmed and ferritin > 1000 mcg/l or elevated aminotransferase levels, then •Liver biopsy Hepatic iron index >1.9 (mmoles/pg dry weight/age in years), requires liver biopsy: still gold standard •If C282Y/H63D or other genotype
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. AASLD practice guideline 2011 180 Wilsons disease: Cannot transport copper out of the liver Indications for testing Diagnostic algorithm
Genetic testing available , not widely used due to large number of mutations
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 181 Moderate Elevation of ALT:5-15x ULN
CBC/platelet count, AST/ALT, Alk Phos, History and physical exam TB, albumin, PT/INR, HAV Ig M, HAV Discontinue hepatotoxic meds IgG, HBsAg, HBcAb IgM, HBcAb IgG, If signs of acute liver failure and alcohol HBsAb, HCV Ab with PCR confirmation --> urgent liver if +, , iron panel, ceruloplasmin, ANA, consultation with Evaluate for signs of acute SMA, gamma-globulin consideration of referral to liver failure a liver transplant center Abdominal ultrasound
If diagnostic evaluation negative --> consideration for diagnostic liver biopsy if medically stable
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 182 Evaluation of Severe Elevation of AST and/or ALT levels:>15x ULN
CBC/platelet count, AST/ALT, Alk Phos, TB, albumin, PT/INR History and physical exam HAV IgM, HBsAg, HBcAb IgM, HBsAb, HCV Ab,HSV, EBV, If signs of acute liver failure --> urgent liver Discontinue hepatotoxic CMV, ceruloplasmin ANA, ASMA, Anti-LKM, IgG, serum drug consultation with meds and alcohol panel, urine toxicology panel consideration of referral Doppler abdominal ultrasound Evaluate for signs of acute to a liver transplant liver failure Consider n-acetyl cysteine if any evidence of acetaminophen center ingestion
If diagnostic evaluation negative --> consideration for diagnostic liver biopsy if medically stable
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 183 Evaluation of Severe Elevation of AST and/or ALT levels:>10,000 IU/ml
CBC/platelet count, AST/ALT, Alk Phos, TB, albumin, PT/INR History and physical exam HAV IgM, HBsAg, HBcAb IgM, HBsAb, HCV Ab,HSV, EBV, CMV, Discontinue hepatotoxic meds and alcohol ceruloplasmin ANA, ASMA, Anti-LKM, IgG, serum drug panel, urine Assess for toxic ingestions, ischemia, and rhabdomyolysis toxicology panel Doppler abdominal ultrasound Consider n-acetyl cysteine if any evidence of acetaminophen Evaluate for signs of acute liver failure ingestion
If signs of acute liver failure If diagnostic evaluation negative --> consideration for diagnostic liver biopsy if --> urgent liver consultation with consideration of medically stable referral to a liver transplant center
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 184 Acetaminophen toxicity is the most common form of acute liver failure in the US • Previously, acute viral hepatitis thought to be most common cause of acute liver failure
• Acetaminophen now accounts for over half of all cases of acute liver failure in US • Use with caution combination acetaminophen/narcotic medications • 2 grams of acetaminophen is always safe (3 grams is maximal dose)
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*
*Some data suggests higher rate of idiosyncratic reactions with minimum doses of > 50 mg than with exposure < 10 mg drug
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Immuno-oncologic agents also produce idiosyncratic injury to the liver Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Hoofnagle JH, Björnsson ES. Drug-Induced Liver Injury—Types and Phenotypes. New England Journal of Medicine.187 2019 Jul 18;381(3):264-73. Algorithm for evaluation of elevated serum alkaline phosphatase: Normal total bilirubin and serum transaminases
If GGT normal --> evaluate for non-hepatobiliary etiologies History and physical exam If GGT abnormal --> Obtain right upper quadrant ultrasound, confirm with serum GGT evaluate for potential hepatotoxic medications, check AMA, ANA, SMA
If evaluation negative and alkaline phosphatase > 2x ULN --> consider liver biopsy If persistent elevation of serum alkaline If evaluation negative and alkaline phosphatase 1-2x ULN -> consider observation phosphatase after 6 months observation If ductal dilatation identified --> ERCP or MRCP --> consider liver biopsy If AMA positive --> evaluate for primary biliary cirrhosis/cholangitis
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 188 Primary biliary cholangitis (PBC) •Cholestatic liver disease characterized by inflammatory destruction of intralobular and septal bile ducts (recently changed name from primary biliary cirrhosis) • Progressive disease that leads to cirrhosis and portal hypertension • Female predilection (9:1) • Anti-mitochondrial antibody (AMA) present in 90 – 95% of cases •Pathophysiology is not known; immunologic mechanisms appear to be important
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• Chronic cholestatic liver disease that progresses to cirrhosis • Characterized by obliterative fibrosis of intra- and extra-hepatic bile ducts • Frequently found in association with chronic ulcerative colitis, less commonly Crohn’s colitis • Pathogenesis is unknown though likely autoimmune • should be considered in patients with chronic cholestasis in the setting of inflammatory bowel disease
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 190 Algorithm for evaluation of elevated serum alkaline phosphatase: Elevated serum transaminases ±elevated bilirubin
History and physical exam If ductal dilatation --> ERCP, MRCP Check right upper quadrant ultrasound If no ductal dilatation --> check AMA, ANA, SMA
If persistent elevation of serum If AMA positive --> evaluate for primary biliary cirrhosis/cholangitis alkaline phosphatase after 6 months observation If AMA negative and alkaline phosphatase > 2x ULN --> consider liver biopsy or MRCP --> consider liver biopsy or MRCP If AMA negative and alkaline phosphatase 1-2x ULN --> consider observation
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 191 Algorithm for evaluation of elevated serum alkaline phosphatase: Elevated serum transaminases ±elevated bilirubin
History and physical exam If ductal dilatation --> ERCP, MRCP Check right upper quadrant ultrasound If no ductal dilatation --> check AMA, ANA, SMA
If persistent elevation of serum If AMA positive --> evaluate for primary biliary cirrhosis/cholangitis alkaline phosphatase after 6 months If AMA negative and alkaline phosphatase > 2x ULN --> consider liver biopsy or observation MRCP --> consider liver biopsy or MRCP If AMA negative and alkaline phosphatase 1-2x ULN --> consider observation
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 192 Algorithm for evaluation of elevated serum total bilirubin (unconjugated)
History and physical exam Review medications Assess liver transaminases and serum alkaline Evaluate for hemolysis phosphatase Evaluate for Gilbert's syndrome
If persistent elevation is otherwise unexplained, is symptomatic, is worsening over time, and/or If persistent elevation is otherwise unexplained, may consider diagnostic testing for associated with abnormal Gilbert's syndrome (UGT1A1 genotype) and evaluate for uncommon etiologies transaminases --> consider liver biopsy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 193 Unconjugated hyperbilirubinemia • Gilbert’s syndrome is present in 2% of the US population. • Defect in UDP-glucuronyl transferase, autosomal recessive • unconjugated hyperbilirubinemia with normal conjugated bilirubin, and is of no clinical consequence. • Diagnosis by finding normal alk phos, GGT, no biliary dilatation • Fasting raises bilirubin level • phenobarbital partially induces UDP-GT and reduces bilirubin • Hemolysis
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 194 Algorithm for evaluation of elevated serum total bilirubin (conjugated)
History and physical exam Review medications Evaluate for clinically overt etiologies: sepsis, TPN, cirrhosis, Assess liver transaminases and serum alkaline biliary obstruction phosphatase Perform right upper quadrant ultrasound
If persistent elevation is otherwise unexplained, is symptomatic, is worsening If ductal dilatation --> ERCP or MRCP over time, and/or associated with abnormal transaminases If no ductal dilatation --> check AMA, ANA, SMA --> consider liver biopsy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 195 MRCP with large distal common bile duct stone
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 196 Key Take-Away Slide
• You will often encounter elevated liver chemistries in practice with NAFLD, alcoholic liver disease and viral hepatitis being most common • Normal ALT should be less than 29-33 IU/L in males and 19-25 IU/L in females based on liver-related mortality • The degree of elevation of ALT should guide your evaluation • Use your non-invasive tests to assess the severity of NAFLD • Always consider medicines and supplements when considering abnormal liver tests
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 197 Management and Outcomes of Local Regional Therapy for HCC Denise M. Harnois| D.O., FAASLD, FAGA | Mayo Clinic Kaitlyn R. Musto| PA-C | Mayo Clinic
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 198 Learning Objectives: - Importance of multidisciplinary approach to care for patients with hepatocellular carcinoma (HCC) - Focus on the management of local regional therapies for HCC - Non-surgical treatment options - Local ablative therapy - Radiofrequency (RFA), Microwave (MWA), Irreversible Electroporation (IRE), and Stereotactic body radiotherapy (SBRT) - Transarterial therapy - Transarterial chemoembolization (TACE) and Transarterial radioembolization (TARE)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 199 Hepatocellular Carcinoma (HCC): An Overview - HCC is the most common primary liver tumor - 80% have known underlying cirrhosis at the time of HCC diagnosis - Personal experience and specialty of treating provider can result in variability of management and effect long term outcomes
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Marrero, J. et al. HEPATOLOGY 2018, Vol. 68, No 2 ; Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465;200 Denys, A. , HCC standard of care treatment guidelines and algorithms [video webinar] Interventional Radiology
Hepatobiliary Palliative Care Surgery Multidisciplinary
Patient Care of HCC with Radiation HCC Transplant Oncology
Oncology
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 201 Barcelona Clinic Liver Cancer (BCLC) classification is the most widely used staging system and should be utilized in the evaluation of patients with HCC.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Llovet, J. M. et al. (2016) Hepatocellular carcinoma, Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.18202 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 Assessment of Disease Severity Child-Turcott-Pugh Score
Points 1 2 3 Encephalopathy None Grade 1-2 Grade 3-4
Ascites None Mild Moderate Grade A: Score 5-6 Grade B: Score 7-9 INR <1.7 1.7-2.1 >2.1 Grade C: Score 10-15 Albumin (mg/dL) >3.5 2.8-3.5 <2.8
Bilirubin (mg/dL) <2 2.1-3.0 >3.0
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Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 204 Role of Local Regional Therapy
HCC presentation is not uniform and treatment therapies depend on tumor size, number, location, etc.
Patients have varying treatment goals and assessment of tumor burden in addition to liver function, patient physical status, and cancer-related symptoms effect treatment modality and goal of curative vs non-curative therapy.
More than 70% of all HCC will see treatment by an Interventional Radiologist.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Geschwind, J et al., Radiology 2016 May , 279 (2):630-40 Marrero et al., Hepatology, Vol.205 68, No. 2, 2018 Heimbach, J et al. HEPATOLOGY 2018 HCC BCLC Stage: 0, A
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 206 Ablative Therapy
The concept behind ablative therapy: Destruction of tumor cells can be completed by the injection of chemical substances or modifying the local tumor temperature - Percutaneously or during laparoscopy
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 207 Radiofrequency Ablation (RFA)
How it works: ‐ Hyperthermic ‐ Electrical current agitates ions generating a local rise in temperature that results in cell death Indications/Advantages: ‐ BCLC 0, A ‐ Centrally located lesions < 3 cm ‐ Tissue Sparing ‐ Lower rate of adverse events than liver resection Disadvantages/Limitations: ‐ Location limitations (subcapsular/gallbladder/diaphragm/heart) due to risk of thermal injury of adjacent structure ‐ Heat sink effect (cooling effect of blood flow near large vessels) ‐ Increasing tumor size > 3 cm ‐ Increased cancer related mortality than liver resection
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 Heimbach, J et al. HEPATOLOGY208 2018 Microwave ablation (MWA) * How it works: ‐ Hyperthermic ‐ Electromagnetic microwaves cause frequency dependent flipping of water molecules generating intra-tumoral heat Indications/Advantages: ‐ BCLC 0, A, B ‐ Tumors < 5 cm ‐ Less sensitive to heat sink effect ‐ Higher temperatures can be reached in a shorter time than RFA Limitations: ‐ Not as effective in tumors > 5 cm ‐ Treatment effect varies between different devices. ‐ No reliable end point to set the amount of energy deposition
*more frequently used than RFA
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 Marrero et al., Hepatology, Vol. 68, No. 2, 2018209 Irreversible Electroporation (IRE) How it Works: ‐ Non-thermic ‐ High frequency electron pulses to create irreparable transmembrane pores leading to cell death and sparing of the extracellular matrix Indications/Advantages: ‐ High cell density tissue (tumors) ‐ Local control of ablation zone ‐ Limited risk of thermal injury to neighboring critical structures ‐ Insensitive to heat sink effect ‐ Advantage of multibipolar mode (predictability of margins) Limitations: ‐ Risk of recurrence due to needle tract seeing ‐ Preliminary clinical data ‐ General anesthesia and major analgesic drugs is mandatory
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 210 Stereotactic Body Radiation Therapy (SBRT)
How it Works: ‐ High radiation doses delivered externally to focal lesions in few fractions ‐ Developing form of liver directed therapy Indications/Advantages: ‐ BCLC A ‐ Small (< 4 cm) tumors in a location not amendable to ablation or resection ‐ Recurrence after ablation ‐ Local control with manageable side effect profile
Limitations: ‐ Risk of radiation induced liver disease
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 211 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 212 Local Ablation Tumor ablation techniques have improved along with the imaging-guidance tools required to ensure their successful application.
AASLD/EASL Recommendations Ablation is the standard of care for patients with BCLC stage A tumors not suitable for surgery
The use of ablation should be dependent on the local expertise
Adults with Child’s A cirrhosis and resectable T1 or T2 HCC should undergo resection over RFA
The use of adjuvant therapy is not recommended for patients with HCC following successful resection or ablation Risk of recurrence after resection or ablation is related to tumor characteristics at the time of procedure including , size, degree of differentiation, and the presence of lymphovascular invasion. Surveillance with contrast enhanced CT or MRI should be performed every 3-6 months. External beam radiotherapy is under investigation and there is no robust evidence to support this therapeutic approach in the management of HCC
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Heimbach, J et al. HEPATOLOGY 2018 EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019213 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 HCC BCLC Stage: A, B
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 214 Trans-arterial therapy
The concept behind trans-arterial treatment:
HCC is supplied by hepatic artery while surrounding tissues can be sustained by portal venous system
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Viveiros, P et al. Cancers 2019, 11: 1085 215 TACE (Transarterial Chemoembolization)
How it Works: ‐ Macroembolic therapy is administered targeting the arterial hypervascularization of HCC and blocks tumor blood supply to cause tumor necrosis ‐ Bland particles (TAE) ‐ Emulsion of chemotherapeutic agent (doxorubicin/cisplatin) in lopiodol (cTACE) ‐ Drug-eluding beads loaded with doxorubicin (DEBTACE)
Indications/Advantages: ‐ Careful patient selection- BCLC B (C), CP A (CP B) ‐ Extensively studied, safety proven ‐ Improved survival over best supportive care in BCLC B/C
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Viveiros, P et al. Cancers 2019, 11: 1085 Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 216 TACE Limitations: ‐ Contraindicated in the setting of portal vein thrombosis (PVT) ‐ Inferior overall survival compared to liver resection in resectable lesions ‐ Elevated risk of acute liver failure (CP B, CP C, and portal vein thrombosis)
Post-Embolization Syndrome: ‐ Self limited toxicity with full recovery in 1-2 weeks ‐ Fever, local pain, nausea ‐ Transient elevation of bilirubin, AST, ALT ‐ Rare: liver rupture, abscess, biloma, femoral artery pseudoaneurysm, pulmonary embolism.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Viveiros, P et al. Cancers 2019, 11: 1085 Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 217 TACE Benefits of TACE in appropriately selected patients have been robustly demonstrated
AASLD/EASL Recommendations TACE is recommended for patients with BCLC stage B HCC and should be carried out selectively
Local regional therapy is recommended over no treatment for patients with BCLC stage B HCC
The use of drug-eluting beads has shown similar benefit to conventional TACE and either can be utilized
TACE should not be used in patients with: ‐ Decompensated liver disease ‐ Advanced liver and/or kidney dysfunction ‐ Macroscopic vascular invasion ‐ Extrahepatic spread Appropriate timing for discontinuation of TACE and initiation of systemic therapy remains a challenge
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Heimbach, J et al., HEPATOLOGY 2018 EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019218 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 Combination Therapy: TACE + Ablation
189 patients: 4 year overall survival 59% vs 45% in favor of TACE+RFA (p=0.002)
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 219 HCC BCLC Stage: B, C
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 220 Transarterial Radioembolization (TARE)/ Selective Internal Radiotherapy (SIRT) 90Yttrium Radiotherapy for HCC Glass spheres (TheraSphere®, BTG) - FDA (HDE) approval for use in patients with unresectable hepatocellular carcinoma (HCC).
Resin spheres (SIR-Spheres®, Sirtex) - FDA approval for the treatment of unresectable metastatic liver tumors from primary colorectal cancer with adjuvant intrahepatic artery FUDR.
Melting the plastic- tea colored
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 221 TARE/SIRT
How it works: Two part procedure to prevent extrahepatic microsphere administration: ‐ Planning angiogram for mapping hepatic arterial anatomy ‐ Any branches supplying extrahepatic structures are occluded ‐ Technetium-99m macroaggregated albumin (MAA) perfusion scan confirms the perfusion is limited to the liver and measures the lung shunt fraction (< 5%) ‐ Y-90 coated microspheres are delivered via microcatheter through the tumor arterial blood supply. ‐ Microembolic treatment allows the hepatic artery to remain patent ‐ Hypervascularity of HCC allows for penetration and dispersion of high doses of radiation into the tumor while allowing sufficient residual blood flow to the vessel without causing ischemia
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Viveiros, P et al. Cancers 2019, 11: 1085 Lurje I, et al. Int. J. Mol. Sci. 2019, 20, 1465 222 TARE/SIRT Indications/Advantages: • BCLC A, B, C • Portal vein thrombosis is not a contraindication • Evidence of prolonged time to progression vs TACE • Lower incidence in tumor progression and favorable toxicity profile vs systemic therapy in BCLC A, B
Limitations: • Risk of recurrence due to needle tract seeing • Preliminary clinical data • General anesthesia and major analgesic drugs is mandatory
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Salem, R et al. Gastro 2016 Viveiros, P et al. Cancers 2019, 11: 1085 Lurje I, et al. Int. J. Mol.223 Sci. 2019, 20, 1465 TARE/SIRT AASLD/EASL Recommendations Patients who are ineligible for or progress after TARE/TACE should be considered for systemic therapy TARE using yttrium-90 microspheres has been investigated in: ‐ Patients with BCLC-A for bridging to transplantation ‐ Patients with BCLC-B to compare with TACE ‐ Patients with BCLC-C to compare with sorafenib Current data: ‐ Show good safety profile and local tumor control ‐ Fail to show overall survival benefit compared to sorafenib in BCLC-B and -C patients The subgroup of patients benefiting from TARE needs to be defined Systemic therapy is the standard of care in patients with advanced HCC with vascular invasion and/or extrahepatic metastasis with significantly improved overall survival compared to supportive care Patients at BCLC D stage, who are not LT candidates, should receive palliative support, including management of pain, nutrition and psychological support The AASLD does not recommend one form of local regional therapy over another
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Heimbach, J et al. HEPATOLOGY 2018 EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019224 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 Y-90/TACE
SPACE Trial PREMIER Trial (Kudo) 2011 (Lencioni 2016) Vouche (2015) RCT RCT RCT Retrospective # of patients 24 21 229 229 153 154 102 Child Pugh A/B A A 98% A/B BCLC A/B N/A B A IA Therapy Y90 cTACE cTACE+ cTACE+ DEBs+ DEBs+ Y90 placebo sorafenib placebo sorafenib CR+PR 87% 74% N/A N/A 35% 43% 88% Criteria EASL/WHO N/A mRECIST mRECIST TTP (median mo) >26 6.8 3.7 5.4 5.5 5.6 33.1
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 225 TARE vs TACE
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Salem R, et al. GASTRO 2016 226 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Toskich, B et al. Hepatology 2018 227 Phase 3 Trial Results With Level I Evidence Two phase 3 trials compared TARE/SIRT with sorafenib in patients with advanced BCLC B and BCLC C disease. - SARAH (SorAfenib versus Radioembolization in Advanced HCC) - SIRveNIB (SIRT Versus Sorafenib in Asia‐Pacific Patients with HCC) Both were negative trials, failing at primary endpoint of superiority to sorafenib. - Y90 group had fewer treatment adverse events. - Y90 should not be recommended as a substitute for patients who are appropriate candidates for systemic therapy.
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Bejjani, A et al. CLD 2019 Marrero et al., Hepatology, Vol. 68, No. 2, 2018 228 Phase 3 Trial Results With Level I Evidence
SORAMIC (SORAfenib in combination with local Micro-therapy guided by gadolinium-EOB-DTPA-enhanced MRI) evaluated the combination of Y90 and sorafenib versus sorafenib alone for patients with BCLC C HCC.
- No improvement of OS in the palliative cohort for the combination treatment group (12.1 months) compared with sorafenib alone (11.5 months).
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Bejjani, A et al. CLD 2019 229 Assessment of response to treatment
Different methods of response assessment are appropriate for different treatments
AASLD/EASL Recommendations Assessment of response in HCC treated by local regional therapy should be based on mRECIST (modified Response Evaluation Criteria in Solid Tumors) Multiphasic contrast-enhanced CT or MRI are recommended for assessment of response after resection, local regional or systemic therapies
Complete pathologic response
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EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019 Marrero et al., Hepatology,230 Vol. 68, No. 2, 2018 BCLC Stage: HCC
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Marrero et al., Hepatology, Vol. 68, No. 2, 2018 231 Interventional Radiology
Hepatobiliary Palliative Care Surgery Multidisciplinary
Patient Care of HCC with Radiation HCC Transplant Oncology
Oncology
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 232 Key Take-Away Slide [this slide is required]
Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. 233 Hepatitis B Update
Anna S. Lok, MD, DSc Alice Lohrman Andrews Professor in Hepatology Director of Clinical Hepatology Assistant Dean for Clinical Research University of Michigan, Ann Arbor, MI, USA
234 Outline
• ABCs of Hepatitis B – Interpretation of HBV tests – Indications for treatment and choice of therapy • HBV reactivation – Definition – Clinical settings and risk factors – Efficacy of prophylactic antiviral – Prevention
235 Initial Evaluation of Patients with Hepatitis B
• Clinical evaluation • Lab tests – Viral replication: HBeAg, anti-HBe, HBV DNA – Rule out HCV, HDV, HIV, other causes of liver disease if indicated – Assess liver disease severity – liver chemistry, CBC+P, prothrombin time • +/- Abdominal ultrasound – assess cirrhosis, surveillance for liver cancer • +/- Liver biopsy / non-invasive assessment of fibrosis • Vaccination against hepatitis A • Counseling on precautions to prevent transmission of infection, alcohol use, and healthy lifestyle
236 Serological Markers of HBV Infection
HBsAg (surface antigen) Acute/Chronic infection
Anti-HBc IgM (IgM core antibody) Recent infection
HBeAg (e antigen) High infectivity
Anti-HBe (e antibody) Low infectivity
Anti-HBs (surface antibody) Immunity
Anti-HBc IgG + HBsAg Chronic infection
Anti-HBc IgG + anti-HBs Resolved infection
Screening for HBV infection: HBsAg and anti-HBs +/- anti-HBc IgG
237 Interpretation of HBV Serology
HBsAg Total IgM anti- Anti-HBs Interpretation anti-HBc HBc – – – – Not been exposed
+ + – – Chronic infection
+ + + – Acute Infection
– + – + Immunity from past infection
– – – + Immunity after vaccination
– + – – Occult / past HBV infection
238 Isolated Anti-HBc+ (HBsAg-, anti-HBs-)
• Most common scenario: past HBV with spontaneous loss of HBsAg, particularly in – Persons living in or from endemic areas – Persons with risk factors for HBV • Risk behaviors • HCV or HIV infection • HBV DNA – Usually not detected in serum except for those who are HIV+ – Often detected in liver
239 Approved HBV Treatments • Interferons (IFN) – Standard IFN alfa - 1992 – Pegylated IFN alfa - 2005 • Nucleos(t)ide analogues – Lamivudine (Epivir) - 1998 – Adefovir (Hepsera) - 2002 – Entecavir (Baraclude) - 2005 – Telbivudine (Tyzeka) - 2006 – Tenofovir disoproxil fumarate (Viread) – 2008 – Tenofovir alafenamide (Vemlidy) - 2016
240 HBV Treatment: When to Start?
MONITOR TREAT TREAT NOW & DEFER NOW OR MONITOR? TREATMENT UNTIL INDICATED
Activity and stage of liver disease at presentation Predicted risk of cirrhosis, liver failure and HCC
241 AASLD Guideline Recommendations Regarding When to Start Treatment AASLD 2015 HBeAg+, no cirrhosis Immune tolerant No treatment except age >40, 3rd trimester pregnancy Immune active Treat, HBV DNA >20,000 IU/mL, ALT elevated, moderate- severe inflammation / fibrosis
HBeAg-, no cirrhosis Inactive No treatment if truly inactive Immune active Treat, HBV DNA >2,000 IU/mL, ALT elevated, moderate- severe inflammation / fibrosis
Cirrhosis Compensated Treat regardless of ALT, especially if HBV DNA >2000 IU/mL Decompensated Treat regardless of ALT and HBV DNA
242 Terrault N, Hepatology 2016; 63: 261 When to Initiate Treatment in Non-Cirrhotics?
243 Choice of Treatment
Nucleos/tide Treatment Interferon Analogues Route Parenteral Oral Duration of treatment Finite duration 12 mos Long duration, years to life Antiviral activity Modest, additional Stronger antiviral activity immunomodulatory effects HBsAg loss 1-3% after 1 yr Rare, 0-1% after 1 year
Resistant mutants None ETV, TDF, TAF <1% after 5 years Side effects Frequent Rare, Adefovir / tenofovir DF nephrotoxicity 244 Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF) Impact on Bones and Kidneys TAF – improved drug delivery to hepatocytes, less systemic exposure
Bone mineral density Glomerular filtration rate
Agarwal K, J Hepatol 2018; 68: 672 245 Efficacy of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF) at 96 Weeks
Randomized trial – 2:1 TAF vs. TDF HBeAg+ and HBeAg- chronic hepatitis B
TAF 25 mg TDF 300 mg TAF 25 mg TDF 300 mg n=581 n=292 n=285 n=140
HBV DNA <29 IU/mL 73% 75% 90% 91%
HBeAg loss 22% 18% na na
HBsAg loss 1% 1% <1% 0
ALT normalization 75% 68% 81% 71%
246 Agarwal K, J Hepatol 2018; 68: 672 Reactivation of Hepatitis B Increase in HBV replication • HBsAg+ persons with serum HBV DNA
– ≥2 log10 increase from baseline, or
– ≥3 log10 IU/mL if undetectable at baseline, or
– ≥4 log10 IU/mL if baseline not available • HBsAg-, anti-HBc+, anti-HBs+/- – Reverse seroconversion (reappearance of HBsAg), or – Detection of serum HBV DNA
AASLD Guidance, Terrault N, Hepatology 2018; 67: 1560 247 Liver Outcomes Associated with HBV Reactivation Hepatitis flare • ALT increase to ≥3x baseline and >100 U/L Liver failure – any of the following • Clinical decompensation: ascites, encephalopathy • Impaired hepatic synthetic function – total bilirubin >3 mg/dL or – INR >1.5 (in the absence of anticoagulation) Death following liver failure
+ Evidence of HBV reactivation
AASLD Guidance, Terrault N, Hepatology 2018; 67: 1560 248 Reactivation of Hepatitis B during Cancer Chemotherapy
Liver failure
8 HBV DNA log
6
Liver injury
Resolution, 4 10
ALT U/L ALT Increase HBV
spontaneous or IU/mL replication with antiviral 2
Pre 0 1 2 3 4 5 6 Months after starting chemotherapy 249 Clinical Settings in Which HBV Reactivation May Occur • Cancer patients (including solid tumors) receiving systemic chemotherapy including kinase inhibitors • Recipients of hematopoietic stem cell or solid organ transplant • Patients with hepatocellular carcinoma receiving transarterial chemotherapy • Patients with oncologic, GI, rheumatologic, dermatologic or other conditions receiving anti-CD20, anti-TNF, long-term steroid or other immunosuppressive agents • Patients with chronic HCV receiving IFN or DAA therapy • Patients with HIV/HBV coinfection being taken off antiretroviral with HBV activity
250 Immunosuppressive Therapies Associated with HBV Reactivation • Cancer chemotherapy • Antibodies that block function of B cells (notably anti-CD20) or other immune cells • Corticosteroids • Biologics: anti-TNF, IL-17, CTLA-4…. • Others: methotrexate, molecular target agents (tyrosine kinase inhibitors ..), anti-rejection treatment
251 Immunosuppressive Therapies Associated with HBV Reactivation • Cancer chemotherapy • Antibodies that block function of B cells (notably anti-CD20) or other immune cells • Corticosteroids • Biologics: anti-TNF, IL-17, CTLA-4…. • Others: methotrexate, molecular target agents (tyrosine kinase inhibitors ..), anti-rejection treatment • Many patients receive combination of immunosuppressive drugs or are switched from one regimen to another during the course of the disease. Potential for new cancer drugs, molecular agents, or biologics to cause HBV reactivation often unknown because HBsAg+ patients usually excluded from trials. 252 Incidence and Outcomes of HBV Reactivation
• Systematic review of 14 studies of lamivudine to prevent HBV reactivation during chemotherapy • Data from HBsAg+ patients who did not receive prophylactic antiviral
Event Overall, n/N (%) Range HBV reactivation 164/424 (38.7%) 24% - 88%
HBV-related hepatitis 159/476 (33%) 24% - 88%
HBV-related liver 21/162 (13.0%) 5% - 33% failure HBV-related death 27/494 (5.5%) 0% - 63%
253 Loomba R, Ann Intern Med 2008; 148: 519 Efficacy of Prophylactic Lamivudine on HBV Reactivation during Chemotherapy
• Systematic review of 14 studies – 275 prophylactic lamivudine and 475 controls • Prophylactic lamivudine decreased – HBV reactivation and HBV-related hepatitis by 79- 100% – HBV-related ALF by 100% – HBV-related death by 80-100% – Cancer-related death by 26%
Loomba R, Ann Intern Med 2008; 148: 519 254 Prophylactic Antiviral is More Effective than On-demand Therapy
Prophylactic Therapeutic Antiviral Antiviral* No. of patients1 15 (LAM) 15 Hepatitis flare 3 10 HBV-related hepatitis 0 7 HBV-related ALF 0 1 No. of patients2 26 (LAM) 25 Hepatitis flare 4 15 HBV-related hepatitis 2 12 HBV-related severe hepatitis 0 5 No. of patients3 41 (ETV) 39 HBV reactivation 1 7 HBsAg reverse seroconversion 0 4 *Antiviral started at first sign of HBV reactivation 1Lau G, Gastroenterol 2003; 125: 1742; 2Hsu255 C, Hepatology 2008; 47: 844; 3 Huang YH, J Clin Oncol 2013; 31: 2765 Risk Factors for HBV Reactivation • Host Factors – Male, older age • Disease Factors – Hematologic malignancies especially lymphomas • Treatment Factors – Intensity of immunosuppression – Conditioning therapy for bone marrow / hematopoietic stem cell transplantation – Use of rituximab, high dose steroids, anthracyclines • Viral Factors – HBsAg+ > anti-HBc+ > HBV seronegative – High pretreatment HBV DNA
256 Pooled Rates of HBV Reactivation in HBsAg-, Anti-HBc+ Patients in Relation to Detection of Serum HBV DNA Systematic review, 55 studies with 3640 HBsAg-, anti-HBc+ patients
Reactivation can occur in patients with undetectable serum HBV DNA
257 Cholongitas E, Ann Gastroenterol 2018; 31: 480 Pooled Rates of HBV Reactivation in HBsAg-, Anti-HBc+ Patients in Relation to Anti-HBs Status Systematic review, 55 studies with 3640 HBsAg-, anti-HBc+ patients Presence of anti-HBs decreases but does not eliminate risk of HBV reactivation
Presence of anti-HBs decreases but does not eliminate risk of HBV reactivation 258 Cholongitas E, Ann Gastroenterol 2018; 31: 480 Risk Stratification for HBV Reactivation
HBsAg-, Therapy HBsAg+ anti-HBc+ Anti-CD20 Very high Moderate Hematologic stem cell transplantation High dose corticosteroids High Low Other cytokine inhibitors, e.g. anti-CD52 Combination cytotoxic chemotherapy Moderate Rare (without corticosteroids) Anti-TNF Anti-rejection therapy for solid organ transplant recipients
Azathioprine, methotrexate Low Rare
259 Di Bisceglie AM, Hepatology 2015; 61: 703 AASLD Recommendations • All patients should be screened for HBsAg and anti-HBc prior to immunosuppressive or cytotoxic therapies. • HBsAg+ patients should initiate anti-HBV prophylaxis. • HBsAg-, anti-HBc+ patients could be carefully monitored with ALT, HBV DNA, and HBsAg q1-3 months with the intent of on-demand antiviral therapy except for patients receiving anti-CD20 therapy or undergoing stem-cell transplantation, for whom anti-HBV prophylaxis is recommended. • When indicated, anti-HBV prophylaxis should be initiated as soon as possible before or simultaneous with onset of immunosuppressive therapy. • Anti-HBV prophylaxis should continue for ≥6 months (or ≥12 months for patients receiving anti-CD20) after completion of immunosuppressive therapy. HBV DNA and ALT levels should be monitored for 12 months after cessation of anti-HBV therapy. • Anti-HBV drugs with high resistance barrier (ETV, TDF, TAF) are preferred.
AASLD Guidance,Terrault N, Hepatology 2018; 67: 1560 260 FDA Warning in HCV DAA Package Insert
• HBV reactivation has been reported in HBV/HCV coinfected patients who were undergoing or recently completed treatment with HCV DAA, and who were not receiving HBV antiviral. Some cases have resulted in liver failure and death.
261 Incidence of HBV Reactivation during HCV DAA Therapy • Systematic review and meta-analysis of 17 observational studies up to 9/30/17 • 242 HBsAg+ – HBV reactivation: 24% (95% CI 19-30) – HBV-reactivation hepatitis: 9% (95% CI 5-16) • HBV DNA Mucke M, Lancet Gastroenterol Hepatol 2018; 3: 172 262 Prevention of HBV Reactivation in HBV/HCV Coinfected Patients Receiving HCV DAA Therapy • HBV reactivation during HCV DAA treatment is common in HBsAg+ patients but rare in HBsAg-/anti-HBc+ patients – Hepatitis flare is rare in absence of confounders AASLD Guidance recommendations • Test all patients for HBsAg and anti-HBc before initiation of HCV treatment • HBsAg+, test HBV DNA at baseline – Meet criteria for HBV treatment, initiate HBV antiviral – HBV DNA low or undetectable, monitor HBV DNA and ALT • HBsAg-/anti-HBc+, monitor ALT – Check HBV DNA if ALT increase and initiate HBV antiviral if HBV DNA+ www.hcvguidance.org 263 Case • F/32, IDU until 2 months ago • Completed HCV treatment 1 year ago with SVR • Presented with acute hepatitis, ALT 1230, t bil 3.2 • Diagnosis – which tests to order – HAV – acute HBV: IgM anti-HAV – HBV – acute HBV: HBsAg, IgM anti-HBc (can be positive in severe flares of chronic hepatitis B), HBV DNA or reactivation of HBV by HCV DAA – HCV – reinfection or late relapse: HCV RNA (anti-HCV will remain positive for many years in patients with prior chronic HCV infection despite resolution of infection) 264 Case • F/32, IDU until 2 months ago • Completed HCV treatment 1 year ago with SVR • Presented with acute hepatitis, ALT 1230, t bil 3.2 • Diagnosis – which tests to order – HAV – acute HBV: IgM anti-HAV – HBV – acute HBV: HBsAg, IgM anti-HBc (can be positive in severe flares of chronic hepatitis B), HBV DNA or reactivation of HBV by HCV DAA – HCV – reinfection or late relapse: HCV RNA (anti-HCV will remain positive for many years in patients with prior chronic HCV infection despite resolution of infection) • This patient: HBsAg+, IgM anti-HBc+, HBeAg+, HBV DNA 365,000 IU/mL, HCV RNA undetectable Not HCV, more likely acute HBV than exacerbation of chronic HBV (new boyfriend with HBV) Should have been vaccinated against HBV and HAV 265 Faculty, Planner and AASLD Staff Disclosures This live educational activity has been planned in accordance with AASLD and ACCME Standards of Commercial Support by members of the Hepatology Associates Course faculty and the following planning committees: Hepatology Associates Committee, Education Committee, Scientific Program Committee, and the Governing Board. As an accredited provider, AASLD requires individuals involved in the planning of continuing medical education (CME) activities to disclose all financial relationships, including those of their spouse or partner, with a commercial interest within the past 12 months. A commercial interest is defined as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. All conflicts of interest are resolved prior to participation. Statement on off-label and investigational use: Speakers are asked to make a reasonable effort to identify during their presentation any discussion of off-label or investigative use or application of a product or device. Financial disclosures will appear at the beginning of each session and are provided below: Hepatology Associates Course Faculty Disclosures Wen-Xing Ding, PhD Nothing to Disclose Ariel E. Feldstein, PhD, MD Consulting: Mylan Pharmaceutical Grant/Research Support: SV Mpre/Daewoong Management Position: Fatima University Medical Center Speaking and Teaching: Takeda, Menarini/Gilead Amanda Chaney Nothing to Disclose Angela DeLisle Nothing to Disclose Carolyn Driscoll Nothing to Disclose Victoria Gomez Consulting: Olympus Janet Gripshover Speaking and Teaching: Gilead Sciences, Abbvie Pharmaceuticals Lisa Hardee Nothing to Disclose 266 Denise Harnois Nothing to Disclose Paul Kwo Advisory Committee or Review Panel: Ribavirin Pregnany Registery, Edigene, Ferring, Eisai, Aligos, Abbvie, Conatus, Gilead, Mallinckrodt Consulting: Janssen, Surrozen, Durect Grant/Research Support: Assembly, Janssen, Eiger, Abbvie, BMS, Allergan Stock Shareholder: Durect Anna Lok Advisory Committee or Review Panel: Gilead, Spring Bank, TARGET, CLEAR B, Epigenomics Consulting: Roche, Diasorin, Huahui Grant/Research Support: Assembly, BMS, Gilead, TARGET Jeffrey McMahon Nothing to Disclose Kaitlyn Musto Nothing to Disclose Renee Pozza Nothing to Disclose Planner Disclosures Veeral Ajmera (Annual Meeting Education Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Luminist Incorporated Gyorgy Baffy (Annual Meeting Education Committee) Nothing to Disclose Meena Bansal (Governing Board and Scientific Program Committee) Data Safety Monitoring Board for Industry or Commercial Enterprise: TREAT Consortium (NIH; not commercial entity) Research Grants: Paid to institution: NIH R01 Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Kinetix Group; Boehringer-Ingelheim Ramon Bataller (Annual Meeting Education Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Echosens Alex Befeler (Scientific Program Committee) Stock/Stock Options with Relevant Pharmaceutical or Biotechnology Companies: Amgen 267 long term stockholder (independently managed by CPA), Gilead long term stockholder (independently managed by CPA) Research Grants: mallinckrodt, Salix, Sillajen Jorge Bezerra (Governing Board and Scientific Program Committee) Research Grants: Gilead; Shyer Andres Cardenas (Annual Meeting Education Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Boston Scientific Corp Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Mallinckrodt Pharmaceuticals - Consultant Andres Carrion (Hepatology Associates Committee) Commercial Speaker's Bureau: Intercept pharmaceuticals, Merck, Alexion pharmaceuticals, BMS Lisa Catalli (Hepatology Associates Committee) Advisory Committee or Review Panel: Gilead Lisa Cervantes (Hepatology Associates Committee) Disclosures were not provided Amanda Chaney (Hepatology Associates Committee) Nothing to Disclose Raymond Chung (Governing Board and Scientific Program Committee) Data Safety Monitoring Board for Industry or Commercial Enterprise: DSMB Alnylam Research Grants: Gilead Sciences. Abbvie, Boehringer Ingelheim, BMS, Roche, Janssen, Merck, Kaleido, Synlogic Virginia Clark (Annual Meeting Education Committee) Research Grants: Genfit James Daniel (Annual Meeting Education Committee) Research Grants: Gilead and Hoffmann- La Roche Laurie DeLeve (Annual Meeting Education Committee and Governing Board) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Abbvie, Pfizer, Daiichi Sankyo, Boehringer-Ingelheim Intellectual Property Rights (Patents, Royalties, Licensing fees): 2017-230-01 US no. 62/544,589 End- organ selective MMP inhibition enhances bone marrow progenitor cell recruitment, COMPOSITIONS AND METHODS FOR AMELIORATING TISSUE INJURY, ENHANCING LIVER REGENERATION AND STEM CELL THERAPIES -(sole inventor) - Applicant: University of Southern California, GBC ref.: 6177.132445PCT Michael Fried (Governing Board and Scientific Program Committee) Research Grants: AbbVie, BMS, Gilead, Merck, National Institutes of Health Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: AbbVie, BMS, Merck, TARGET PharmaSolutions (All uncompensated) 268 Stock/Stock Options with Relevant Pharmaceutical or Biotechnology Companies: TARGET PharmaSolutions (Maintained in independent blind trust) Elizabeth Goacher (Hepatology Associates Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Gilead Pharmaceuticals, AbbVie Pharmaceuticals, Dova Pharmaceuticals, Intercept Pharmaceuticals Commercial Speaker's Bureau: Intercept Pharmaceuticals, Gilead Pharmaceuticals, bbVie Pharmaceticals Janet Gripshover (Hepatology Associates Committee) Speaking and Teaching: Gilead Sciences, Abbvie Pharmaceuticals Lisa Hardee (Hepatology Associates Committee) Nothing to Disclose Dawn Harrison (Hepatology Associates Committee) Advisory Committee or Review Panel: Gilead Advisory Board Meeting Patrick Horne (Hepatology Associates Committee, Annual Meeting Education Committee, and Scientific Program Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Abbvie, Gilead, Intercept Sofia Jakab (Annual Meeting Education Committee) Nothing to Disclose Michael Kriss (Annual Meeting Education Committee) Nothing to Disclose Laura Kulik (Annual Meeting Education Committee) Nothing to Disclose John Lake (Governing Board) Research Grants: CymbaBay, Data Safety Monitoring Board for Industry or Commercial Enterprise: Intercept DSMB Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: SRTR Bruce Luxon (Governing Board) Data Safety Monitoring Board for Industry or Commercial Enterprise: DSMB for Baxalta; DSMB for Sparks (for treatment of Hemophilia) Leadership in related society: Board, Committee, Journal: Research Committee member for the ACG John Magee (Scientific Program Committee) Nothing to Disclose 269 Mitchell Mah'moud (Annual Meeting Education Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Chronic Liver a Disease Foundation Harmeet Malhi (Scientific Program Committee) Research Grants: NIH R01 NIH U01 Jeffrey McMahon (Hepatology Associates Committee) Advisory Board: Intercept Pharmaceuticals NP/PA Advisory Board Dec 2015 Lopa Mishra (Governing Board) Research Grants: NIH Czarina Morley (Hepatology Associates Committee) Disclosures were not provided David Mulligan (Governing Board) Nothing to Disclose Mary Panther (Annual Meeting Education Committee) Nothing to Disclose Mary Jeanne Perino Phillips (Hepatology Associates Committee) Nothing to Disclose K. Gautham Reddy (Scientific Program Committee) Research Grants: CymaBay; Genfit; Intercept; Target PharmaSolutions; Arrowhead; Gilead; Durect; Commercial Speaker's Bureau: Intercept, Dova Leadership in related society: Board, Committee, Journal: Member, Training Committee: American College of Gastoneterology Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Intercept Suzanne Robertazzi (Hepatology Associates Committee) Disclosures were not provided David Sass (Hepatology Associates Committee) Advisory Board: Intercept Pharmaceuticals Vicki Shah (Hepatology Associates Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Abbvie Advisory Board, Gilead Advisory Board, Intercept Advisory Board Hemant Shah (Annual Meeting Education Committee) Advisory Board: Abbvie, Gilead, Intercept, Lupin, Merck, Pendopharm 270 Ronald Sokol (Governing Board) Research Grants: Paid to institution: Lumena/Shire; Albireo Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Alexion; Albireo; Retrophin; Shire; Mirum Richard Sterling (Annual Meeting Education Committee) Scientific Consultant/Advisor to Industry or Commercial Enterprise, including Development of Educational Presentations: Gilead, Roche, AbbVie, Baxter, Pfizer, Merck within the last 12 months. I have had no activity with Gilead, AbbVie, and Merck in the last 6 months in anticipation of the Non- Invasive Guidelines paper that is expected to start 2018. Research Grants: Gilead, Roche, True Health, AbbVie, Abbott Grace Su (Annual Meeting Education Committee and Scientific Program Committee) Intellectual Property Rights (Patents, Royalties, Licensing fees): Patent on Image analysis and Morphomics Leadership in related society: Board, Committee Journal: Member, Clinical Guidelines Committee, AGA; Company Employee, Officer, Director : My husband and son have equity interest in Applied Morphomics and Prenovo. Norah Terrault (Hepatology Associates Committee and Governing Board) Advisory Committees or Review Panels: Dova Pharmaceuticals Grant/Research Support: AbbVie, Gilead, BMS, Merck Jason Vanatta (Annual Meeting Education Committee) Nothing to Disclose Kymberly Watt (Scientific Program Committee) Expert testimony: Intercept - site- PI Gilead - site PI, co-I Conatus - site co-I Novartis - previous site PI, co author study subanalysis Pfizer- site co-I (all multicenter study related) Stock/Stock Options with Relevant Pharmaceutical or Biotechnology Companies: BMS; Arbutus; Madrigal; Viking Steven Weinman (Annual Meeting Education Committee) Nothing to Disclose Maureen Whitsett (Annual Meeting Education Committee) Nothing to Disclose 271 AASLD Staff Disclosures Amy D'Amato Nothing to Disclose Greg Bologna Nothing to Disclose Katie Duggan Nothing to Disclose Julie Deal Nothing to Disclose Stephanie Graham Nothing to Disclose Stephanie Grimsby Nothing to Disclose Jessica Jessop Nothing to Disclose Janeil C. Klett Nothing to Disclose John Lingerfelt Nothing to Disclose Julia Merrill Nothing to Disclose Bette Anne Preston Nothing to Disclose Denise Seise Nothing to Disclose 272 Webinars Accredited Activities Resources Recorded Conferences Access the most up-to-date hepatology content anytime, anywhere. View and download The Best of The Liver Meeting® slides, recorded presentations from other AASLD meetings, webinars and the Fundamentals of Liver Disease Curriculum. LiverLearning® is your premier source for hepatology educational content. Visit liverlearning.aasld.org today. Become an AASLD Member The American Association for the Study of Liver Diseases (AASLD) is the professional home to over 6,300 scientists, researchers, educators, physicians and health care professionals committed to preventing and curing liver diseases. AASLD connects members all over the world to the best science, educational resources and innovation in the fi eld with: Access to AASLD’s journals, practice guidelines and our online education portal, LiverLearning® Registration discounts for AASLD events, including The Liver Meeting®, Emerging Trends Conferences, Digestive Disease Week® and more The chance to collaborate with colleagues who share your specifi c areas of interest in Special Interest Groups (SIGs) Networking and professional development opportunities Join today and be part of the leading organization dedicated to advancing the fi eld of hepatology. www•aasld•org/membership Making the Impossible Possible: A World Without Liver Disease To achieve this goal, we need a consistent, stable source of funding. As the largest private supporter of liver disease research and training in the United States, AASLD Foundation will continue to be that stable source of funding with your help. Your Support is Critical YOUR GIFTS We still have a significant gap every year between what can be funded HAVE FUNDED: and the resources available to sustain and grow awards and initiatives. With your generosity, we will be able to continue: Over ■■ Building stable funding resources ■■ Raising more unrestricted funds to address new research needs $50 million in Research and Career ■■ Enhancing training and education Development Awards* ■■ Increasing public awareness of liver disease The Liver Meeting® is the perfect time to make a donation to AASLD Foundation. Donors enjoy additional benefits during the meeting, 5 including invitations to events and access to a VIP and Donor Lounge free online (based on level of donation). modules ■■ Visit the AASLD Foundation Booth in the Main Lobby to make a gift as part of our and learn more about our efforts and award recipients Fundamentals ■■ Give online at aasldfoundation.org/donate or via The Liver Meeting® app of Liver Diseases ■■ Federal employee? You can pledge a gift to CFC #75219 program. ■■ Contribute when you renew your membership dues *AASLD and AASLD Foundation funding since 2000. A gift of any amount will help accomplish so much for liver disease research and training. Thank you for your support. aasldfoundation.org/donate The AASLD Foundation is tax-exempt under §501(c)(3) of the Internal Revenue Code. Contributions made to the AASLD Foundation are deductible charitable contributions to the extent permitted by §170 of the Internal Revenue Code. We recommend you consult your tax advisor for details. @AASLDFoundation CALL FOR APPLICATIONS 2020 Research & Career Development Awards AASLD Foundation is investing even more in innovative hepatology research and in the people who study and treat liver disease. Funding available for: Application Deadlines ■■ Early to mid-career investigators Research Awards: pursuing liver‑related research. DECEMBER 4, 2019 (for funding beginning July 1, 2020) ■■ Front-line providers seeking Bridge Award: CYCLE 2: JANUARY 15, 2020 hepatology-focused training to (for funding beginning May 1, 2020) adequately treat and care for liver Advanced/Transplant Hepatology disease patients. Award and NP/PA Clinical Hepatology Fellowship: ■■ Travel to educational meetings, JANUARY 15, 2020 (for funding beginning July 1, 2020) including the Abstract Travel Awards Questions? Contact [email protected] and the Emerging Liver Scholar SPECIAL FUNDING ANNOUNCEMENT Resident Travel Awards.* Additional funding is available for research in * These awards have different deadlines. To find out more and to apply, refer to the “Travel Awards” section Autoimmune Liver Diseases at aasldfoundation.org/awards See aasldfoundation.org/autoimmunefunding for eligible categories and restrictions. LEARN MORE AND APPLY AT aasldfoundation.org/awards @AASLDFoundation 2020 AASLD MEETINGS AASLD/AGA Digestive Disease Week® Academic Skills Workshop May 2-5 February 8-9 Chicago, IL Charlotte, NC Transplant Hepatology Emerging Topic Conference Board Review Course Nuclear Receptors as Common Clinical August 15-16 Targets for the Treatment of Cholestatic Dallas, TX and Nonalcoholic Fatty Liver Diseases March 20-21 Emerging Topic Conference Washington, D.C. metro area Intrahepatic Cholangiocarcinoma: The Next Horizon AASLD/EASL NAFLD September 2020 and NASH Clinical Endpoints Conference The Liver Meeting® March 21-22 November 13-17 Washington, D.C. metro area Boston, MA AASLD/EASL Masterclass November/December 2020 Visit aasld.org/calendar for up-to-date meeting information.