Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study

Adrian Reuben; Holly Tillman; Robert J. Fontana; Timothy Davern; Brendan McGuire; R. Todd Stravitz; Valerie Durkalski; Anne M. Larson; Iris Liou; Oren Fix; Michael Schilsky; Timothy McCashland; J. Eileen Hay; Natalie Murray; Obaid S. Shaikh; Daniel Ganger; Atif Zaman; Steven B. Han; Raymond T. Chung; Alastair Smith; Robert Brown; Jeffrey Crippin; M. Edwyn Harrison; David Koch; Santiago Munoz; K. Rajender Reddy; Lorenzo Rossaro; Raj Satyanarayana; Tarek Hassanein; A. James Hanje; Jody Olson; Ram Subramanian; Constantine Karvellas; Bilal Hameed; Averell H. Sherker; Patricia Robuck; William M. Lee

doi:10.7326/M15-2211

Original Research |7 June 2016

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study

Adrian Reuben, MBBS; Holly Tillman, MS; Robert J. Fontana, MD; Timothy Davern, MD; Brendan McGuire, MD; R. Todd Stravitz, MD; Valerie Durkalski, PhD; Anne M. Larson, MD; Iris Liou, MD; Oren Fix, MD; Michael Schilsky, MD; Timothy McCashland, MD; J. Eileen Hay, MBBS; Natalie Murray, MD; Obaid S. Shaikh, MD; Daniel Ganger, MD; Atif Zaman, MD; Steven B. Han, MD; Raymond T. Chung, MD; Alastair Smith, MB, ChB; Robert Brown, MD; Jeffrey Crippin, MD; M. Edwyn Harrison, MD; David Koch, MD; Santiago Munoz, MD; K. Rajender Reddy, MD; Lorenzo Rossaro, MD; Raj Satyanarayana, MD; Tarek Hassanein, MD; A. James Hanje, MD; Jody Olson, MD; Ram Subramanian, MD; Constantine Karvellas, MD; Bilal Hameed, MD; Averell H. Sherker, MD; Patricia Robuck, PhD; William M. Lee, MD

Adrian Reuben, MBBS

From University of Texas Southwestern Medical Center and Baylor University Medical Center, Dallas, Texas; Medical University of South Carolina, Charleston, South Carolina; University of Washington, Seattle, Washington; Washington University, St. Louis, Missouri; University of California, San Francisco, and California Pacific Medical Center, San Francisco, California; University of Nebraska, Omaha, Nebraska; Mount Sinai Medical Center and Columbia University Medical Center, New York, New York; Mayo Clinic, Rochester, Minnesota; University of Pittsburgh, Pittsburgh, Pennsylvania; Northwestern University, Chicago, Illinois; Oregon Health Sciences Center, Portland, Oregon; University of California, Los Angeles, Los Angeles, California; University of Michigan, Ann Arbor, Michigan; Yale University, New Haven, Connecticut; University of Alabama, Birmingham, Alabama; Massachusetts General Hospital, Boston, Massachusetts; Duke University, Durham, North Carolina; Mayo Clinic, Scottsdale, Arizona; Albert Einstein Medical Center and University of Pennsylvania, Philadelphia, Pennsylvania; Virginia Commonwealth University, Richmond, Virginia; University of California, Davis, Davis, California; Mayo Clinic, Jacksonville, Florida; University of California, San Diego, San Diego, California; Ohio State University, Columbus, Ohio; University of Kansas Medical Center, Kansas City, Kansas; Emory University, Atlanta, Georgia; University of Alberta, Edmonton, Alberta, Canada; and National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Holly Tillman, MS

Robert J. Fontana, MD

Timothy Davern, MD

Brendan McGuire, MD

R. Todd Stravitz, MD

Valerie Durkalski, PhD

Anne M. Larson, MD

Iris Liou, MD

Oren Fix, MD

Michael Schilsky, MD

Timothy McCashland, MD

J. Eileen Hay, MBBS

Natalie Murray, MD

Obaid S. Shaikh, MD

Daniel Ganger, MD

Atif Zaman, MD

Steven B. Han, MD

Raymond T. Chung, MD

Alastair Smith, MB, ChB

Robert Brown, MD

Jeffrey Crippin, MD

M. Edwyn Harrison, MD

David Koch, MD

Santiago Munoz, MD

K. Rajender Reddy, MD

Lorenzo Rossaro, MD

Raj Satyanarayana, MD

Tarek Hassanein, MD

A. James Hanje, MD

Jody Olson, MD

Ram Subramanian, MD

Constantine Karvellas, MD

Bilal Hameed, MD

Averell H. Sherker, MD

Patricia Robuck, PhD

William M. Lee, MD

Article, Author, and Disclosure Information

This article was published at www.annals.org on 5 April 2016.

From University of Texas Southwestern Medical Center and Baylor University Medical Center, Dallas, Texas; Medical University of South Carolina, Charleston, South Carolina; University of Washington, Seattle, Washington; Washington University, St. Louis, Missouri; University of California, San Francisco, and California Pacific Medical Center, San Francisco, California; University of Nebraska, Omaha, Nebraska; Mount Sinai Medical Center and Columbia University Medical Center, New York, New York; Mayo Clinic, Rochester, Minnesota; University of Pittsburgh, Pittsburgh, Pennsylvania; Northwestern University, Chicago, Illinois; Oregon Health Sciences Center, Portland, Oregon; University of California, Los Angeles, Los Angeles, California; University of Michigan, Ann Arbor, Michigan; Yale University, New Haven, Connecticut; University of Alabama, Birmingham, Alabama; Massachusetts General Hospital, Boston, Massachusetts; Duke University, Durham, North Carolina; Mayo Clinic, Scottsdale, Arizona; Albert Einstein Medical Center and University of Pennsylvania, Philadelphia, Pennsylvania; Virginia Commonwealth University, Richmond, Virginia; University of California, Davis, Davis, California; Mayo Clinic, Jacksonville, Florida; University of California, San Diego, San Diego, California; Ohio State University, Columbus, Ohio; University of Kansas Medical Center, Kansas City, Kansas; Emory University, Atlanta, Georgia; University of Alberta, Edmonton, Alberta, Canada; and National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
Previously published in abstract form in Reuben A, Battenhouse H, Fontana RJ, Davern TJ, Durkalski V, Lee WM. Improved outcomes of acute liver failure (ALF) in the United States (US): updated overview of results in a prospective study of ALF 1998-2011. Hepatology. 2012;56(suppl):965A. Abstract no. 1658.
Acknowledgment: Participating site investigators are listed as authors. The authors gratefully acknowledge the contributions of the many site coordinators and the patients and their families who made the study possible, as well as the ongoing support of the staff of the National Institute of Diabetes and Digestive and Kidney Diseases, including Sherry Brown and Rebecca Torrance. The University of Texas Southwestern Administrative Group included Ezmina Lalani, Carla Pezzia, Corron Sanders, Nahid Attar, Linda S. Hynan, and Angela Bowling. Members of the Data Coordination Unit of the Medical University of South Carolina included Wenle Zhao, Catherine Riley, Jaime Speiser, Michelle Gottfried, Sarah Williams, and Caitlyn Ellerbe.
Grant Support: By the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK-U-01-58369).
Disclosures: Dr. Reuben reports grants from the National Institutes of Health during the conduct of the study. Ms. Tillman reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr. Fontana reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr. Durkalski reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr. Larson reports grants from the National Institutes of Health during the conduct of the study. Dr. Schilsky reports grants from Wilson Therapeutics and personal fees from Gilead Sciences and Kadmon outside the submitted work. Dr. Shaikh reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr. Han reports grants from UT Southwestern during the conduct of the study. Dr. Brown reports grants and personal fees from Gilead Sciences, AbbVie, Bristol-Myers Squibb, Janssen, and Merck outside the submitted work. Dr. Crippin reports personal fees from Vertex Pharmaceuticals, Gilead Sciences, Genentech, AbbVie, and Merck outside the submitted work. Dr. Harrison reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr. Hanje reports personal fees from Salix Pharmaceuticals outside the submitted work. Dr. Olson reports other support from the National Institutes of Health during the conduct of the study and personal fees from Baxter Healthcare outside the submitted work. Dr. Lee reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study and grants from Bristol-Myers Squibb, Gilead Sciences, Merck, and Ocera outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2211.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Lee (e-mail, william.lee@utsouthwestern.edu).
Requests for Single Reprints: William M. Lee, MD, Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, Suite 420, Dallas, TX 75390-8887; e-mail, william.lee@utsouthwestern.edu.
Current Author Addresses: Dr. Reuben: Division of Gastroenterology & Hepatology, Medical University of South Carolina, 114 Doughty Street, Suite 249, MSC 702, Charleston, SC 29425-2900.
Ms. Tillman and Dr. Durkalski: Medical University of South Carolina, Data Coordination Unit, 135 Cannon Street, Charleston, SC 29425.
Dr. Fontana: University of Michigan, Taubman Center, Floor 3, Reception D, 1500 East Medical Center Drive, Ann Arbor, MI 48109.
Dr. Davern: California Pacific Medical Center, 2340 Clay Street, Floor 3, San Francisco, CA 94115.
Dr. McGuire: University of Alabama, 1808 7th Avenue South, Boshell Diabetes Building 815, Birmingham, AL 35294.
Dr. Stravitz: Virginia Commonwealth University, 1200 East Broad Street, 14th Floor, PO Box 980341, Richmond, VA 23298-0341.
Drs. Larson and Fix: University of Washington, Swedish Liver Center, 1124 Columbia Street, Suite 600, Seattle, WA 98104.
Dr. Liou: University of Washington, 1959 NE Pacific Street, Box #356175, Seattle, WA 98195-6175.
Dr. Schilsky: Yale University, 310 Cedar Street, FMB 121, New Haven, CT 06510-3218.
Dr. McCashland: University of Nebraska, 98200 Nebraska Medical Center, Omaha, NE 68198.
Dr. Hay: Mayo Clinic, 200 1st Street SW, Rochester, MN 55905.
Dr. Murray: Baylor University Medical Center, 1400 8th Avenue, Fort Worth, TX 76104.
Dr. Shaikh: University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA 15213.
Dr. Ganger: Northwestern University, 676 North Saint Clair, Suite 1900, Chicago, IL 60611.
Dr. Zaman: Oregon Health Sciences Center, 3303 SW Bond Avenue, Portland, OR 97239.
Dr. Han: Pfleger Liver Institute, University of California, Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095-7302.
Dr. Chung: Massachusetts General Hospital, Warren 1007C, Boston, MA 02114.
Dr. Smith: INC Research, 3201 Beechleaf Court, Raleigh, NC 27604.
Dr. Brown: Columbia University Medical Center, 622 West 168th Street, #14, New York, NY 10032.
Dr. Crippin: Washington University, 4921 Parkview Place, #8, St. Louis, MO 63110.
Dr. Harrison: Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259.
Dr. Koch: Medical University of South Carolina, 25 Courtenay Drive, ART, 7100A, Charleston, SC 29425-8908.
Dr. Munoz: Albert Einstein Medical Center, 245 North 15th Street, New College Building, 12th Floor, Room 12318, Philadelphia, PA 19102.
Dr. Reddy: University of Pennsylvania, Division of Gastroenterology, 2 Dulles, HUP, Philadelphia, PA 19104.
Dr. Rossaro: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404.
Dr. Satyanarayana: Mayo Clinic, 4500 Pablo Professional Court, #378, Jacksonville, FL 32224.
Dr. Hassanein: University of California, San Diego, 230 Prospect Place, Coronado, CA 92118.
Dr. Hanje: The Ohio State University, 395 West 12th Avenue, Suite 200, Doan Office Tower, Columbus, OH 43210.
Dr. Olson: University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160.
Dr. Subramanian: Emory University, 1365 Clifton Road NE, Clinic B, 6th Floor, Atlanta, GA 30322.
Dr. Karvellas: University of Alberta, 1-40 Zeidler Ledcor Centre, 8540 112th Street, Edmonton, Alberta T6G 2X8, Canada.
Dr. Hameed: University of California, San Francisco, 350 Parnassus Avenue, San Francisco, CA 94117.
Drs. Sherker and Robuck: National Institute of Diabetes and Digestive and Kidney Diseases, 6707 Democracy Boulevard, Room 659, Bethesda, MD 20892-5450.
Dr. Lee: Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, Suite 420, Dallas, TX 75390-8887.
Author Contributions: Conception and design: A. Reuben, H. Tillman, R.J. Fontana, B. McGuire, O.S. Shaikh, R. Brown, L. Rossaro, P. Robuck, W.M. Lee.
Analysis and interpretation of the data: A. Reuben, H. Tillman, R.J. Fontana, B. McGuire, R.T. Stravitz, V. Durkalski, M. Schilsky, D. Ganger, S.B. Han, S. Munoz, L. Rossaro, R. Satyanarayana, A.H. Sherker, P. Robuck, W.M. Lee.
Drafting of the article: A. Reuben, R.J. Fontana, R.T. Stravitz, D. Ganger, C. Karvellas, P. Robuck, W.M. Lee.
Critical revision of the article for important intellectual content: A. Reuben, H. Tillman, R.J. Fontana, B. McGuire, R.T. Stravitz, V. Durkalski, M. Schilsky, S.B. Han, R.T. Chung, A. Smith, R. Brown, D. Koch, S. Munoz, K.R. Reddy, R. Subramanian, A.H. Sherker, P. Robuck, W.M. Lee.
Final approval of the article: A. Reuben, H. Tillman, R.J. Fontana, T. Davern, B. McGuire, R.T. Stravitz, V. Durkalski, A.M. Larson, I. Liou, O. Fix, M. Schilsky, T. McCashland, J.E. Hay, N. Murray, O.S. Shaikh, D. Ganger, A. Zaman, S.B. Han, R.T. Chung, A. Smith, R. Brown, J. Crippin, M.E. Harrison, D. Koch, S. Munoz, K.R. Reddy, L. Rossaro, R. Satyanarayana, T. Hassanein, A.J. Hanje, J. Olson, R. Subramanian, C. Karvellas, B. Hameed, A.H. Sherker, P. Robuck, W.M. Lee.
Provision of study materials or patients: R.J. Fontana, T. Davern, B. McGuire, R.T. Stravitz, A.M. Larson, I. Liou, O. Fix, M. Schilsky, O.S. Shaikh, D. Ganger, A. Zaman, R.T. Chung, R. Brown, M.E. Harrison, D. Koch, S. Munoz, K.R. Reddy, L. Rossaro, J. Olson, R. Subramanian, B. Hameed.
Statistical expertise: H. Tillman, V. Durkalski.
Obtaining of funding: O.S. Shaikh, W.M. Lee.
Administrative, technical, or logistic support: A.M. Larson, A.H. Sherker, P. Robuck, W.M. Lee.
Collection and assembly of data: A. Reuben, H. Tillman, R.J. Fontana, T. Davern, B. McGuire, R.T. Stravitz, A.M. Larson, O. Fix, M. Schilsky, T. McCashland, O.S. Shaikh, A. Zaman, S.B. Han, R. Brown, J. Crippin, M.E. Harrison, S. Munoz, K.R. Reddy, L. Rossaro, R. Satyanarayana, J. Olson, R. Subramanian, W.M. Lee.

Abstract

Background:

Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction—without prior advanced liver disease—that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively.

Objective:

To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers.

Design:

Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440)

Setting:

31 liver disease and transplant centers in the United States.

Patients:

Consecutively enrolled patients—without prior advanced liver disease—with ALF (n = 2070).

Measurements:

Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013).

Results:

Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period.

Limitations:

The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers.

Conclusion:

Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study.

Primary Funding Source:

National Institutes of Health.

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2016 American College of Physicians

Original Research |7 June 2016

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study

Abstract

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Original Research |7 June 2016

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study

Abstract

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