Hepatic Encephalopathy . A 2016 perspective

Hepatic Encephalopathy A 2016 perspective Rajiv Jalan UCL Institute for Liver and Digestive Health Royal Free Hospital Malaga 2016 Disclosures (Rajiv Jalan): •Inventor: Ornithine phenyl acetate for the treatment of hepatic encephalopathy (licensed to Ocera Therapeutics) •Consultancy and Speaker Fees: Ocera Therapeutics, Grifols, Norgine •Research Collaboration: Ocera Therapeutics, Grifols, Gambro •Chief Investigator: Sequana medical sponsored study of alfapump •Founder: UCL spin-out company, Yaqrit Ltd Questions •Classification of Hepatic Encephalopathy –Covert vs Minimal –The brain in ACLF •Pathogenesis of HE –Ammonia and Inflammation •New concepts of underlying mechanisms –Involvement of different inflammatory cell types in HE •Why may HE increase the risk of death of cirrhotic patients? •Is HE truly reversible? •Interorgan ammonia metabolism: The basis of novel therapies of HE Questions •Classification of Hepatic Encephalopathy –Covert vs Minimal –The brain in ACLF •Pathogenesis of HE –Ammonia and Inflammation •New concepts of underlying mechanisms –Involvement of different inflammatory cell types in HE •Why may HE increase the risk of death of cirrhotic patients? •Is HE truly reversible? •Interorgan ammonia metabolism: The basis of novel therapies of HE Classification of HE: Clarification or Confusion? Vilstrup et al. J Hepatol 2014 One disease or two? Patients Unimpaired n=23 mHE n=39 Grade 1 HE n=44 Age (year) 59 ± 6 58 ± 10 58 ± 12 MELD 15 ± 6 14 ± 6 16 ± 6 Albumin (g/dL) 2.8 ± 0.7 2.9 ± 0.5 2.9 ± 0.5 Ammonia (mol/L) 48 ± 11 61 ± 14* 62 ± 12* Sodium (mmol/L) 136 ± 5 136 ± 6 135 ± 5 Creatinine (mol/L) 91 ± 60 69 ± 39 81 ± 43 WBC count (x 109/L) 5.0 ± 2.2 6.5 ± 3.1 7.4 ± 4.8 *p<0.05 compared with unimpaired Thomsen et al. Plosone 2016 Mortality Thomsen et al. Plosone 2016 Complications requiring hospitalisations Unimpaired n=23 mHE n=39 Grade 1 HE n=44 Infections n (%) 2 (9) 7 (18) 15 (34) HE n (%) 1 (4) 3 (8) 8 (18) Thomsen et al. Plosone 2016 Grade 1 HE patients have more immune dysfunction Unimpaired n=23 mHE n=39 Grade 1 HE n=44 P-value Bacterial DNA n (%) 5 (22) 14 (36) 25 (57) P=0.01 Neut. resp. burst (%) 13 ± 11 13 ± 14 22 ± 22 P=0.03 Phagocytosis (GMFI) 84 ± 15 81 ± 13 78 ± 10 P=0.16 Cause or Effect? Thomsen et al. Plosone 2016 Prospective Study in ICU admitted patients with ACLF with an without HE •N=101 •HE graded using West Haven cirteria •Overt HE: Defined as Grade 2 or more •Patients monitored –Sequential arterial ammonia –Inflammatory markers –Reverse jugular catheter to monitor oxygen saturation •Standard of care defined Sawhney et al. Liver Transplantation 2016 The presence of HE determines the risk of death in ACLF patients studied prospectively (n=101) Sawhney et al. Liver Transplantation 2016 Ammonia levels in overt HE (likely no ACLF) Ong et al. Am J Med 2003 Ammonia levels were an independent predictor of severity of HE What about patients with ACLF? Sawhney et al. Liver Transplantation 2016 Inflammation (WCC) Sawhney et al. Liver Transplantation 2016 In ACLF and Brain oxygenation Sawhney et al. Liver Transplantation 2016 The severity of hyperammonemia and jugular venous oxygen saturation determines risk of HE Sawhney and Holland-Fischer et al. AASLD 2014 Pathophysiology of HE in ACLF HE severity in ACLF Ammonia Inflammation Cerebral Oxygenation Sawhney et al. Liver Transplantation 2016 Liver Injury Acute Chronic Acute Liver Failure Cirrhosis Portosystemic shunt (+/-) Type A Type B Type C ACLF Inflammation + Organ Failure ?Type D Where would the Type D fit in? Questions •Classification of Hepatic Encephalopathy –Covert vs Minimal –The brain in ACLF •Pathogenesis of HE –Ammonia and Inflammation •New concepts of underlying mechanisms •Why may HE increase the risk of death of cirrhotic patients? •Is HE truly reversible? •Interorgan ammonia metabolism: The basis of novel therapies of HE CIRRHOSIS and PORTAL HYPERTENSION AMMONIA DYSBIOSIS BACTERIAL TRANSLOCATION ENDOTOXEMIA Unifying Hypothesis BACTERIAL PRODUCTS PRIMING OF ORGANS + BRAIN Increased TLR4 receptor Cytokine Storm HE INSULT Questions •Classification of Hepatic Encephalopathy –Covert vs Minimal –The brain in ACLF •Pathogenesis of HE –Ammonia and Inflammation •New concepts of underlying mechanisms •Why may HE increase the risk of death of cirrhotic patients? •Is HE truly reversible? •Interorgan ammonia metabolism: The basis of novel therapies of HE NH3 Liver Disease HE SEPSIS Hypothesis Ammonia induces spontaneous respiratory burst through effects on p38 MAP kinase pathway p38 antagonist: 10 µM SB203580 Shawcross and Jalan et al. Hepatology 2007 NH3 Liver Disease HE SEPSIS Hypothesis Can Hepatic Encephalopathy produce Immune Failure? Prass et al. J Exp Med. 2009 Sep 1;198(5):725-36. Due to apoptotic loss of Lymphocytes Shift from Th-1 to Th-2 Phenotype Reversed by inhibition of Sympathetic System García-Martinez R. et al 2011 Episodes of HE lead to neurodegeneration What is the mechanism? Expression of Serpin-1, a marker of senescence is increased in HE Cortex Cerebellum Hippocampus Oria et al. EASL 2014 Therapeutic Approaches CIRRHOSIS and PORTAL HYPERTENSION AMMONIA DYSBIOSIS BACTERIAL TRANSLOCATION ENDOTOXEMIA Unifying Hypothesis BACTERIAL PRODUCTS PRIMING OF ORGANS + BRAIN Increased TLR4 receptor Cytokine Storm HE INSULT 0 0.2 0.8 1.0 0.4 0.6 Follow-up, mo 0 12 24 36 48 Patients Free of Hepatic Encephalopathy, % Estimation Cohort 75 34 66 26 46 17 22 6 19 6 Patients at risk, n Short-short or short-long Long-long 0 0.2 0.8 1.0 0.4 0.6 Follow-up, mo 0 12 24 36 48 Patients Free of Overt Hepatic Encephalopathy, % Validation Cohort 121 56 78 34 29 18 9 4 7 2 Patients at risk, n Short-short or short-long Long-long Romero-Gomez M et al. Ann Intern Med 2010;153:281–88 Secondary Prophylaxis Lactulose for Secondary Prophylaxis Gastroenterology, 2009;137:885–91. Follow-up (months) 1.0 0.8 0.6 0.4 0.2 0.0 2 4 6 8 10 12 14 16 18 20 p=0.001 Probability of breakthrough hepatic encephalopathy Patients at risk Lactulose Placebo 61 64 60 62 59 59 58 50 51 37 45 33 38 28 28 19 10 13 7 8 1 4 Placebo (n=64) Lactulose (n=61) Rifaximin for Secondary Prophylaxis of HE: Recurrence 58% risk reduction (NNT = 4 over 6 months) Bass et al, N Engl J Med, 2010;362:1071–81. 22 46 0 50 Recurrent HE (patients - %) p<0.001, HR 0.42 (95% CI, 0.28–0.64) Patients (%) Days since randomization Hazard ratio with rifaximin, 0.42 (95% CI, 0.28–0.64) p<0.001 100 80 60 40 20 0 0 28 56 84 112 140 168 Rifaximin 550 mg bid Placebo (n=140) (n=159) Rifaximin 550 mg bid Placeb (n=140) (n=159) Time to first recurrent HE episode Recurrent HE Licensed by NICE and FDA All patients Non-rifaximin patients 0 0.2 0.4 0.6 0.8 1.0 Proportion of patients without an HE event Hazard Ratio: 0.56 95% CI: (0.32, 0.99) p value:0.047 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 GPB Placebo 119 126 0 0.2 0.4 0.6 0.8 1.0 Proportion of patients without an HE event Hazard Ratio: 0.29 95% CI: (0.12, 0.73) p value:0.0086 GPB Placebo Time to HE event. The time to the first HE event over time is depicted for all patients (top panel; n=178), in patients not on rifaximin at baseline (middle panel; n=119), and in patients on rifaximin at baseline (bottom panel; n=59) Rockey D et al. Hepatology 2014;59:1073–83 AMMONIA Baseline Treatment* Placebo 54 (34) umol/L 58 umol/L/wk GPB 48 (35) umol/L 46 umol/L/wk Glycerol phenylbutyrate reduces ammonia and prevents HE Treatment of the Acute Episode Treat precipitating event Nutrition Clean Bowel Treat precipitating factors Reduce ammonia: GPB; OP In patients in whom there is no response? Albumin Dialysis Low protein diet? Normal protein diet for episodic HE: results of a randomised study Cordoba et al. J of Hepatol •Outcome of HE was no different. •Protein synthesis was similar. •Those on the lowprotein diet group showed higher protein breakdown. Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy: The HELP Randomized Clinical Trial Rahimi et al. JAMA Intern Med. 2014;174(11):1727-1733. Hepatic Encephalopathy Minimal Overt Current Lactulose Future Rifaximin GPB OP Primary Prophylaxis Secondary Prophylaxis Acute Episode Probiotics Future Rifaximin GPB OP Lactulose Rifaximin Future GPB OP Lactulose Rifaximin Future PEG GPB OP Albumin MARS Summary Summary •Classification of HE –Covert HE is a heterogenous entity –HE in ACLF should be classified separately •The mechanisms of the deleterious effects of ammonia are being redefined –Ammonia and inflammation are synergistic in causing HE –Both are targets of therapy •HE is not reversible and efforts to prevent 1st and recurrent episodes is urgently needed •New therapeutic strategies for HE are emerging –More clinical trial data are needed Acknowledgements Nathan Davies Raj Mookerjee Stephen Hodges Naina Shah Lorette Noirette Pamela Leckie Yalda Sharifi Debbie Shawcross Gavin Wright Sambit Sen Lisa Cheshire Vanessa Stadlbauer Christian Steiner Dharmesh Kapoor Kevin Moore V Balasubranium Fatma Saleh Maria Jover Andrew Proven Yalda Sharifi Vikram Sharma Department of Health funding to UCL/UCLH for the Comprehensive Biomedical Research Centre Giovanni Tritto Montse De Oca Maria Jover Fausto Andreola Luisa Baker Karla Lee Jane Macnaughtan Gautam Mehta Danielle Adebayo Karla Lee Isidora Ranchal Helen Jones Graziella Privitera Peter Holland Fischer Rohit Sawhney Rita Garcia Martinez Marc Oria Francesco Di Chiara Anna Hadjihambii Abe Habtesion Krista Rombouts Stewart Macdonald Karen Louise Thomsen