Hepatic Encephalopathy Exploring the neuropsychiatric consequences of cirrhosis

Hepatic Encephalopathy: Exploring the neuropsychiatric consequences of cirrhosis Module 1 Introduction to cirrhosis and its complications This material was prepared under the guidance of Dr. Christopher Rose, Dr. Hemant Shah, Dr. Puneeta Tandon and Dr. Philip Wong Use for education purposes only This educational program has been endorsed by the Canadian Association for the Study of the Liver (CASL)

Meet the Steering Committee Dr. Christopher Rose, Ph. D. Dr. Hemant Shah, MD. Associate Professor in the Department of Medicine at the Université de Montréal and his laboratory, Hepato-Neuro, has been established at the CRCHUM since 2006. His research interests lie within the area of hepatic encephalopathy. Assistant Professor, Staff Hepatologist and Clinic Director at the Francis Family Liver Clinic, Toronto Western Hospital, University of Toronto. His clinical focus is viral liver disease and he maintains a busy teaching practice. Dr. Rose is currently Secretary of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism, and Chair of the Research Committee of the Canadian Association for the Study of the Liver. Disclosures: Calithera Biosciences, Lupin Pharmaceuticals, Ocera Therapeutics, Relypsa. In addition to clinical care, Dr. Shah is actively engaged in projects to develop innovative models of care for viral hepatitis, progress interprofessional collaboration and improve knowledge levels amongst primary care and specialty providers. Dr. Shah has graduate training in Health Practitioner Education. Disclosures: Abbvie, Gilead Sciences, Intercept Pharmaceuticals, Lupin Pharmaceuticals, Merck. Dr. Puneeta Tandon, MD. Dr. Philip Wong, MD. Director of the Cirrhosis Care Clinic at the University of Alberta in Edmonton. Associate Professor, Royal Victoria Hospital, Division of Gastroenterology and Hepatology at Mc. Gill University, Montreal, QC. Research interests include the complications associated with decompensated cirrhosis as well as the impact of Nutrition and Exercise therapy in cirrhosis. Disclosures: Lupin Pharmaceuticals. He is a co-author of the joint AASLD-EASL guidelines on hepatic encephalopathy and his clinical and research interests include outcomes in liver transplantation, viral hepatitis and complications of cirrhosis. Disclosures: Abbvie, Astellas Pharma, Bristol-Myers Squibb, Gilead Sciences, Lupin Pharmaceuticals, Merck, Roche.

Chronic Liver Disease & Cirrhosis An Introduction

Chronic Liver Disease 5, 049 deaths a year in Canada due to chronic liver disease, an increase of 27. 9% in mortality occurring over a period of eight years. About 400 liver transplants/year in Canada; one third of patients on waiting list die due to a shortage of organs. 1 in 10 Canadians experience some degree of liver malfunction Liver disease in Canada: a crisis in the making an assessment of liver disease in Canada. March 2013. Canadian Liver Foundation.

HVPG: hepatic venous pressure gradient. Adapted from Garcia-Tsao, G. , Friedman, S. , Iredale, J. and Pinzani, M. (2010), Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology, 51: 1445– 1449. doi: 10. 1002/hep. 23478

Complications of Cirrhosis

Assessing Liver Disease http: //www. mdcalc. com/meldna-meld-na-score-forliver-cirrhosis/ http: //www. mdcalc. com/child-pughscore-for-cirrhosis-mortality/

The socioeconomic burden of cirrhosis on family and caregivers "The specific limitations in the activities of the family were for the last 3 years due to cirrhosis-related medical expenses compared with what they were 3 years previous. " Bajaj JS, Wade JB, Gibson DP, et al. The Multi-Dimensional Burden of Cirrhosis and Hepatic Encephalopathy on Patients and Caregivers. The American journal of gastroenterology. 2011; 106(9): 1646 -1653. doi: 10. 1038/ajg. 2011. 157.

Hepatic Encephalopathy Overview

Hepatic Encephalopathy • Is a major complication of liver disease/failure • Is a serious metabolic syndrome • Is characterized by cognitive, psychiatric and motor disturbances • Hepatic encephalopathy can be subdivided into Covert and Overt • Covert HE: difficult to diagnose without psychometric testing. • Overt HE: can be easily diagnosed without the use of psychometric tests.

Epidemiology • The cumulative numbers indicate that overt HE will occur in up to 40% of those with cirrhosis. 1 • At the time of diagnosis of cirrhosis the prevalence of Overt HE is 10%-14%. 2, 3 • 20%-80% of patients with cirrhosis suffer from Minimal /Covert HE. 4, 5 • Develops in 10%-50% in patients with transjugular intrahepatic portosystemic shunt (TIPS). 6, 7 1. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. Amodio, Piero et al. Journal of Hepatology , Volume 35 , Issue 1 , 37 - 45 2. Saunders JB, Walters JR, Davies AP, Paton A. A 20 -year prospective study of cirrhosis. British Medical Journal (Clinical research ed). 1981; 282(6260): 263 -266. 3. Romero-Gomez M, et al. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. The American Journal of Gastroenterology (2001) 96, 2718– 2723; doi: 10. 1111/j. 1572 -0241. 2001. 04130. x 4. Screening of subclinical hepatic encephalopathy. Groeneweg, Michael et al. Journal of Hepatology , Volume 32 , Issue 5 , 748 – 753. 5. Bajaj JS. Management options for minimal hepatic encephalopathy. Expert Rev Gastroenterol Hepatol. 2008; 2: 785 -790. 6. Papatheodoridis, G. V. , Goulis, J. , Leandro, G. , Patch, D. and Burroughs, A. K. (1999), Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: A meta-analysis. Hepatology, 30: 612– 622. doi: 10. 1002/hep. 510300316 7. Nolte, W. , Wiltfang, J. , Schindler, C. , Münke, H. , Unterberg, K. , Zumhasch, U. , Figulla, H. R. , Werner, G. , Hartmann, H. and Ramadori, G. (1998), Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: Clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology, 28: 1215– 1225. doi: 10. 1002/hep. 510280508

Hospitalizations secondary to HE are on the rise In-Hospital Mortality and Economic Burden Associated With Hepatic Encephalopathy in the United States From 2005 to 2009 Stepanova, Maria et al. Clinical Gastroenterology and Hepatology , Volume 10 , Issue 9 , 1034 - 1041. e 1 The nationwide estimates for hospital discharges with HE are calculated using the NIS sampling weights.

HE carries a higher mortality than other cirrhosis complications Danish Cohort: Alcoholic Cirrhosis. 12 -year study (1993 -2005) 45% death rate in first month Jepsen, P. , Ott, P. , Andersen, P. K. , Sørensen, H. T. and Vilstrup, H. (2010), Clinical course of alcoholic liver cirrhosis: A Danish populationbased cohort study. Hepatology, 51: 1675– 1682. doi: 10. 1002/hep. 23500.

HE is a poor predictor of survival (Even Covert HE) Stewart, C. A. , Malinchoc, M. , Kim, W. R. and Kamath, P. S. (2007), Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl, 13: 1366– 1371. doi: 10. 1002/lt. 21129

HE impacts all aspects of quality of life

Burden to patient and caregiver higher if encephalopathy present Reprinted by permission from Macmillan Publishers Ltd: Am J Gastroenterol Bajaj JS, Wade JB, Gibson DP, et al. The Multi-Dimensional Burden of Cirrhosis and Hepatic Encephalopathy on Patients and Caregivers. The American journal of gastroenterology. 2011; 106(9): 1646 -1653. doi: 10. 1038/ajg. 2011. 157. , copyright 2011.

Hepatic Encephalopathy Pathophysiology

Astrocyte swelling (brain edema) = neuronal dysfunction HE Normal M. D. Norenberg, “The role of astrocytes in hepatic encephalopathy, ” Neurochemical Pathology. Vol. 6, no. 1 -2, pp. 13– 33, 1987. R. F. Butterworth, “Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy, ” Neurochemistry International. Vol. 57, no. 4, pp. 383– 388, 2010.

Multifactorial

HE Precipitating Factors Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 71 – 735. doi: 10. 1002/hep. 27210

Brain Volume affected as a result of HE Garcia-Martinez, R. , Rovira, A. , Alonso, J. , Jacas, C. , Simón-Talero, M. , Chavarria, L. , Vargas, V. and Córdoba, J. (2011), Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume. Liver Transpl, 17: 38– 46. doi: 10. 1002/lt. 22197

Hepatic Encephalopathy Clinical Classification

Spectrum of cognitive impairment in HE

Clinical Classification of HE (West Haven/Conn Score) Level of Consciousness Neuropsychiatric Symptoms Neurological Symptoms Normal Impairments only measurable with psychometric tests None "Minimal HE" Slight mental slowing Euphoria/dysphoria irritability and anxiety, shortened attention span Fine motor skills affected Increased fatigue, apathy or lethargy Slight personality disorder, slight disorientation to time and place. Flapping tremor, ataxia, slurred speech Somnolence Aggression, marked disorientation to time and place. Rigour, clonus, asterixis Coma -

Covert Hepatic Encephalopathy West Haven/Conn Score (0 -1)

Covert HE • Defined as the presence of test-dependent brain dysfunction in patients with CLD who are not disoriented or display asterixis. • Affects 20 -80% of patients with cirrhosis. • Poor patient QOL, more driving accidents, falls, cognitive impairment. • Signs of impairment typically first noticed by family members or caregivers. Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 71 – 735. doi: 10. 1002/hep. 27210. D’Amico G, et al. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci. 1986; 31: 468 -475. POORDAD, F. F. (2007), Review article: the burden of hepatic encephalopathy. Alimentary Pharmacology & Therapeutics, 25: 3– 9. doi: 10. 1111/j. 17466342. 2006. 03215. x

Covert HE leads to and increases chance of developing OHE Reprinted by permission from Macmillan Publishers Ltd: Am J Gastroentero , Patidar KR, Thacker LR, Wade JB, et al. Covert Hepatic Encephalopathy Is Independently Associated With Poor Survival and Increased Risk of Hospitalization. The American journal of gastroenterology. 2014; 109(11): 1757 -1763. doi: 10. 1038/ajg. 2014. 264. , copyright 2014.

Covert HE affects employment Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis. 2001; 16: 37 -41.

Impaired Driving Performance with Covert HE 15 Controls (n = 67) No Covert HE (n = 27) Median Number 12 13. 1*† 11. 9*† Covert HE (n = 51) Overt HE (n = 22) 9 8. 2*† 7. 9 6. 7 5. 8*† 6 4. 7 3 2. 0*† 1. 0 0 0. 7 1. 4*† Vehicular Collisions 4. 3 3. 4 1. 8 0. 9 1. 5 Speeding Citations Road-Edge Excursions Center Crossings *P<. 01 vs controls. †P<. 01 vs patients with no Covert HE. Reprinted by permission from Macmillan Publishers Ltd: Am J Gastroentero , Bajaj J, et al. The Effect of Fatigue on Driving Skills in Patients With Hepatic Encephalopathy. The American journal of gastroenterology. 2009; 104: 898 -905. doi: 10. 1038/aj. 2009. 7 copyright 2009.

MHE = Poor Quality of Life Screening of subclinical hepatic encephalopathy. Groeneweg, Michael et al. Journal of Hepatology , Volume 32 , Issue 5 , 748 – 753.

Covert Hepatic Encephalopathy Testing

Assessing CHE via the Psychometric Hepatic Encephalopathy Score (PHES) • • • Time to perform test is measured for NCT A&B, and serial dotting. DST is measured as a number of correct responses in 90 sec. The line drawing task measures the number of errors and the time to completion. DHIMAN, R. K. , SARASWAT, V. A. , VERMA, M. and NAIK, S. R. (1995), Figure connection test: A universal test for assessment of mental state. Journal of Gastroenterology and Hepatology, 10: 14– 23. doi: 10. 1111/j. 1440 -1746. 1995. tb 01041. x Hepatic Encephalopathy in Patients with Cirrhosis. Marsha Y Morgan, and Matthew Stubbs, Int J Clin Rev 2011; 02: 04 doi: 10. 5275/ijcr. 2011. 02. 04

Stroop test (Encephal. App) • Time to perform test is measured and compared to normal. • Faster than PHES to administer. Bajaj JS, Thacker LR, Heumann DM, Fuchs M, Sterling RK, Sanyal AJ, et al. The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology. 2013; 58: 1122 -1132. www. encephalapp. com

Conclusion Module 1

HE in Canada • HE is a spectrum of cognitive impairment. • HE results in poor patient and caregiver QOL. • HE, both Overt and Covert, is a poor predictor of survival. • It is important to diagnose early. • Currently there is no consensus in Canada when to report a patient with Covert HE to pull his driving licence.