Association Between Plasma Level of Galectin-9 and Survival of Patients With Drug- Induced Acute Liver Failure  Hugo R. Rosen, Scott W. Biggins, Toshiro Niki, Jane Gralla, Holly Hillman, Mitsuomi Hirashima, Michael Schilsky, William M. Lee W.M. Lee, MD, Anne M. Larson, MD, Iris Liou, MD, Timothy Davern, MD, Oren Fix, MD, Michael Schilsky, MD, Timothy McCashland, MD, J. Eileen Hay, MBBS, Natalie Murray, MD, A. Obaid S. Shaikh, MD, Andres Blei, MD, Daniel Ganger, MD, Atif Zaman, MD, Steven H.B. Han, MD, Robert Fontana, MD, Brendan McGuire, MD, Raymond T. Chung, MD, Alastair Smith, MB, ChB, Robert Brown, MD, Jeffrey Crippin, MD, Edwin Harrison, Adrian Reuben, MBBS, Santiago Munoz, MD, Rajender Reddy, MD, R. Todd Stravitz, MD, Lorenzo Rossaro, MD, Raj Satyanarayana, MD, Tarek Hassanein, MD, Grace Samuel, Ezmina Lalani, Carla Pezzia, Corron Sanders, PhD, Nahid Attar, Linda S. Hynan, PhD, Valerie Durkalski, PhD, Wenle Zhao, PhD, Catherine Dillon, Holly Battenhouse, Tomoko Goddard Hugo R. Rosen, Scott W. Biggins, Toshiro Niki, Jane Gralla, Holly Hillman, Mitsuomi Hirashima, Michael Schilsky, William M. Lee W.M. Lee, MD, Anne M. Larson, MD, Iris Liou, MD, Timothy Davern, MD, Oren Fix, MD, Michael Schilsky, MD, Timothy McCashland, MD, J. Eileen Hay, MBBS, Natalie Murray, MD, A. Obaid S. Shaikh, MD, Andres Blei, MD, Daniel Ganger, MD, Atif Zaman, MD, Steven H.B. Han, MD, Robert Fontana, MD, Brendan McGuire, MD, Raymond T. Chung, MD, Alastair Smith, MB, ChB, Robert Brown, MD, Jeffrey Crippin, MD, Edwin Harrison, Adrian Reuben, MBBS, Santiago Munoz, MD, Rajender Reddy, MD, R. Todd Stravitz, MD, Lorenzo Rossaro, MD, Raj Satyanarayana, MD, Tarek Hassanein, MD, Grace Samuel, Ezmina Lalani, Carla Pezzia, Corron Sanders, PhD, Nahid Attar, Linda S. Hynan, PhD, Valerie Durkalski, PhD, Wenle Zhao, PhD, Catherine Dillon, Holly Battenhouse, Tomoko Goddard  Clinical Gastroenterology and Hepatology  Volume 14, Issue 4, Pages 606-612.e3 (April 2016) DOI: 10.1016/j.cgh.2015.09.040 Copyright © 2016 AGA Institute Terms and Conditions

Figure 1 (A) Immunohistochemistry of paraffin-embedded liver biopsy in patient with isoniazid-induced liver failure. (B) Gal-9 is up-regulated as compared with normal biopsy, which is negative for Gal-9 (original magnification ×200; Courtesy of Maxwell Smith, MD, Mayo Clinic, Scottsdale, AZ). Clinical Gastroenterology and Hepatology 2016 14, 606-612.e3DOI: (10.1016/j.cgh.2015.09.040) Copyright © 2016 AGA Institute Terms and Conditions

Figure 2 Mean values and box plots of admission Gal-9 levels (pg/mL) in patients with DILI or APAP. Wilcoxon rank sum used for analyses. Clinical Gastroenterology and Hepatology 2016 14, 606-612.e3DOI: (10.1016/j.cgh.2015.09.040) Copyright © 2016 AGA Institute Terms and Conditions

Figure 3 Kaplan-Meier analyses for survival according to admission plasma Gal-9 levels and MELD. (A) Plasma Gal-9 (above or below 690 pg/mL) identifies patients with higher risk of mortality from ALF related to idiosyncratic DILI or APAP. (B) MELD ≥30 identifies patients with decreased transplant-free survival. (C) Lack of correlation between Gal-9 and MELD performed on same day. (D) Assignment of ALF patients into low-, intermediate-, or high-risk for 21-day mortality or transplant according to combination of Gal-9 and MELD values. Clinical Gastroenterology and Hepatology 2016 14, 606-612.e3DOI: (10.1016/j.cgh.2015.09.040) Copyright © 2016 AGA Institute Terms and Conditions

Figure 4 Competing risk estimates of cumulative incidence function for death (allowing for transplant) using Fine and Gray method for Gal-9 and MELD groups, with proportional hazards for the effect of MELD and the effect of Gal-9 separately. The plot is based on the first model shown in Table 1, assuming a constant HR for MELD (8.68; P < .001) and a constant HR for Gal-9 (2.92; P = .001). The HR for MELD ≥30, Gal-9 ≥690 vs MELD <30, Gal-9 <690 is 25.33 (6.88–93.31; P < .001) See text for details. Clinical Gastroenterology and Hepatology 2016 14, 606-612.e3DOI: (10.1016/j.cgh.2015.09.040) Copyright © 2016 AGA Institute Terms and Conditions

Supplementary Figure 1 Transplant or death as event according to (A) Gal-9, (B) MELD, or (C) combination in APAP population. Clinical Gastroenterology and Hepatology 2016 14, 606-612.e3DOI: (10.1016/j.cgh.2015.09.040) Copyright © 2016 AGA Institute Terms and Conditions