Monocyte Count in Alcoholic Hepatitis Implications for severity

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Monocyte Count in Alcoholic Hepatitis Implications for severity and prognosis JORDAN VOSS THIS WORK

Monocyte Count in Alcoholic Hepatitis Implications for severity and prognosis JORDAN VOSS THIS WORK WAS SUPPORTED BY A CTSA GRANT FROM NCATS AWARDED TO THE UNIVERSITY OF KANSAS FOR FRONTIERS: UNIVERSITY OF KANSAS CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (# TL 1 TR 002368 AND # TL 1 TR 002368). THE CONTENTS ARE SOLELY THE RESPONSIBILITY OF THE AUTHORS AND DO NOT NECESSARILY REPRESENT THE OFFICIAL VIEWS OF THE NIH OR NCATS.

Background: Alcoholic Liver Diseases §Alcoholic Hepatitis Normal § Acute, severe liver inflammation § Acute

Background: Alcoholic Liver Diseases §Alcoholic Hepatitis Normal § Acute, severe liver inflammation § Acute rise in bilirubin (Jaundice) § Modest rise in AST, AST>ALT § ~20% of those with alcoholic liver disease will experience § High 30 day mortality 20 -30%, especially with continued drinking Abstinence Most Steatosis regular drinkers 20% of Heavy drinkers Fibrosis/ Cirrhosis Alcoholic Hepatitis 20% of those with ALD

Background: AH Pathogenesis §Alcohol causes release of lipopolysaccharide (LPS) from Gram negative bacteria in

Background: AH Pathogenesis §Alcohol causes release of lipopolysaccharide (LPS) from Gram negative bacteria in the gut §LPS enters liver via portal venous circulation and induces inflammation through interaction with Kupffer cells § Kupffer cells release a variety of inflammatory cytokines (TNFa, monocyte chemotactic protein-1) which cause systemic inflammation and recruitment of additional white blood cells § Circulating monocytes are known to enter the liver and contribute to continued inflammation This Photo by Unknown Author is licensed under CC BY-SA

Monocytosis in AH § 2 previous studies suggest monocytosis in alcoholic hepatitis: § Mckeever,

Monocytosis in AH § 2 previous studies suggest monocytosis in alcoholic hepatitis: § Mckeever, U. et al. MONOCYTOSIS: A FEATURE OF ALCOHOLIC LIVER DISEASE. The Lancet 322, 1492 (1983). § N=12 § Diagnostic uncertainty § Thomas, L. Monocytosis Correlated With Acute Alcoholic Hepatitis: A Case Report and Literature Review. Blood 122, 4725– 4725 (2013). § N=1 §No previous study of role of monocytosis on disease severity, prognosis

Objectives § To determine the absolute monocyte count (AMC) in patients with alcoholic hepatitis

Objectives § To determine the absolute monocyte count (AMC) in patients with alcoholic hepatitis § To determine the relationship between AMC and disease severity § To determine the relationship between AMC and mortality § To determine the relationship between AMC and response to treatment with glucocorticoids

Methods: §Retrospective analysis of all patients admitted to the University of Kansas Hospital with

Methods: §Retrospective analysis of all patients admitted to the University of Kansas Hospital with an ICD 9 (571. 1) or ICD 10 (K 70. 1) diagnosis of alcoholic hepatitis. § Modifiers: Hospital diagnosis, Encounter diagnosis, Hospital problem, primary diagnosis, principal problem §Patients identified through query of the Healthcare Enterprise Repository for Ontological Narration (HERON), an i 2 b 2 based research data repository §Conversion of raw datafiles into a final analytic dataset was achieved using SQLite Studio §Statistical analysis in SAS version 9. 4, SAS Institute Inc. , Cary, NC, USA § One sample Student’s T test to compare absolute blood counts to laboratory reference ranges § Pearson’s correlation coefficient to evaluate relationship between AMC, MELD, and MDF § Logistic regression to evaluate the effect of AMC on mortality

Methods Inclusion criteria: ◦ 18 -70 years old ◦ Admitted to Hospital ◦ Billing

Methods Inclusion criteria: ◦ 18 -70 years old ◦ Admitted to Hospital ◦ Billing or Clinical diagnosis of AH ◦ AST > 50 ◦ AST/ALT >1. 5 ◦ Serum bilirubin >3 mg/d. L Exclusion Criteria ◦ Bacterial Infections: spontaneous bacterial peritonitis, sepsis, pneumonia, urinary tract infection ◦ Immune compromising conditions: HIV, congenital ◦ Hematologic malignancies

725 Patients 18 -70 year old admitted to hospital with diagnosis of AH 428

725 Patients 18 -70 year old admitted to hospital with diagnosis of AH 428 Patients Exclude infection, malignancy, immunodeficiency (via HERON) 189 Patients Apply research criteria for AH (SAS) • 50 < AST <400 • AST/ALT >1. 5 • Bilirubin > 3 162 Patients 1 or more AMC during admission

Results: Demographics § 66% Male § 77% White, 8. 5% Black, 13% other §

Results: Demographics § 66% Male § 77% White, 8. 5% Black, 13% other § 11% Hispanic, Latino, or Spanish origin §Average 46. 6 years, range 22 -68 §Median length of stay 5 days §Comorbidities: § Hepatitis C (HCV): 17. 5% § Hepatitis B: 2. 1% §Medication Use § 9% of patients received glucocorticoids § 20. 6% received pentoxifylline

Results §Mean AMC: 0. 96 K/u. L (95% CI 0. 88 - 1. 03)

Results §Mean AMC: 0. 96 K/u. L (95% CI 0. 88 - 1. 03) § Significantly higher than upper limit of normal (0. 80) P<0. 0001 §Mean WBC: 11. 38 K/u. L (95% CI 10. 4 - 12. 3) § Not significantly higher than upper limit of normal (11. 0) P=0. 433 §Mean ALC: 1. 33 K/u. L (95% CI 1. 20 - 1. 46) § Within normal reference range (1. 0 -4. 8) §Mean ANC: 8. 20 K/u. L (95% CI 7. 41 -9. 00) § significantly higher than the upper limit of normal (7. 0) P=0. 003 §All 1 sample, two-sided T tests

Results: AMC is correlated with severity MELD Score: Model for End Stage Liver Disease

Results: AMC is correlated with severity MELD Score: Model for End Stage Liver Disease • Predicts 90 day Mortality • Bilirubin, INR, Creatinine, Sodium MDF Score: Maddrey Discriminant Function • Predicts prognosis and guides treatment • Bilirubin, Prothrombin time

Results: AMC is correlated with severity mean 0. 76, n=43 P=0. 0002 mean 1.

Results: AMC is correlated with severity mean 0. 76, n=43 P=0. 0002 mean 1. 03, n=119 MDF Score: Maddrey Discriminant Function • Mild: < 32 • Severe: >32 – consider treatment with glucocoritcoids (ACG guidelines)

Results: AMC & Mortality §Simple Logistic Regression Mortality Admission AMC Odds Ratio P value

Results: AMC & Mortality §Simple Logistic Regression Mortality Admission AMC Odds Ratio P value Day 10 AMC Odds Ratio P value 30 Day 1. 68 0. 337 6. 52 0. 028 90 Day 2. 15 0. 085 2. 94 0. 099 180 Day 1. 76 0. 172 4. 34 0. 031 365 Day 1. 15 0. 723 5. 85 0. 013 §Multiple Logistic Regression § 90 Day Mortality: AMC (OR 2. 68, P=0. 032) and HCV infection (OR 2. 93, P=0. 048) § No increased odds of mortality: § Age, sex, steroid use, pentoxifylline Mortality 30% 25% 20% 15% 10% 5% 0% 30 Day Mortality 90 Day Mortality 180 Day Mortality 1 Year Mortality

Conclusions §Patients with AH have elevated absolute monocyte and neutrophil counts in comparison to

Conclusions §Patients with AH have elevated absolute monocyte and neutrophil counts in comparison to normal reference ranges. §Absolute monocyte count is positively correlated with disease severity as determined by MELD and MDF scores. §Patients with severe AH (MDF>32) have significantly higher monocyte counts compared to those with mild AH. §Increased monocyte count at 10 days is associated with increased odds of mortality § May represent a more severely ill cohort

Limitations §Retrospective design §Does not establish causation § Although previous research has implicated the

Limitations §Retrospective design §Does not establish causation § Although previous research has implicated the monocyte in the pathogenesis of AH §Small sample representing the group with 10 day follow up AMC §Unexpectedly small number of cases receiving glucocorticoids and Lille score labs prevented assessment of the effect of AMC on response to glucocorticoids

Future Directions §Relevance to response to steroids § STOPAH trial (2015) favored steroids over

Future Directions §Relevance to response to steroids § STOPAH trial (2015) favored steroids over pentoxifylline §Diagnostic significance of monocyte count? § By itself AMC is nonspecific but it may increase the utility of existing models such as the MDF § Correlation with biopsy results §These findings favor continued emphasis on the monocyte in mechanistic and therapeutic studies at the basic and translational level § Currently working on a study that involves measurement of monocyte gene expression in response to LPS in an attempt to understand the role of monocytes in the pathogenesis of and susceptibility to AH

Acknowledgements §Steven Weinman, MD Ph. D §Russ Waitman, Ph. D §Maren Lowrance

Acknowledgements §Steven Weinman, MD Ph. D §Russ Waitman, Ph. D §Maren Lowrance

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