Acute Liver Failure Neil Shah, MD UNC School of Medicine High-Impact Hepatology Saturday, Dec 8 th, 2018
Disclosures None
Outline Overview of ALF Management of ALF Diagnosis of ALF Treatments and Support Acute on Chronic Liver Failure (ACLF)
Acute Liver Failure (ALF) Definition: Onset of coagulopathy (INR > 1.5) and encephalopathy within 8 (to 26) weeks in a patient without prior liver disease* *Exceptions: Wilson s Disease, HBV or AIH Clinical decompensation can be rapid Cerebral edema and infection are leading causes of death 30-40% spontaneous survival with ICU care Relatively rare: ~2000 cases annually Liver Transplantation leads to good survival 1-Year à 80% 5-Year à 75%
Etiology and Outcomes in the US Etiology % Affected Acetaminophen 39% DILI 13% Hepatitis A 4% Hepatitis B 7% Ischemic Hepatitis 6% Autoimmune 4% Wilson Disease 3% Budd-Chiari 2% Indeterminate 17% Ostapowicz, MD et al. Ann Intern Med. 2002
Look for Etiology Early and Treat Treatable Acetaminophen Amanita Mushroom Autoimmune Hepatitis Budd-Chiari Hepatitis B Herpes Simplex Acute Fatty Liver of Pregnancy Wilson s Disease Transplant Contraindicated Infiltrating Cancer N-Acetylcysteine, Lavage, Charcoal PenG IV steroids Anticoagulation, TIPS TDF/TAF, Entecavir IV Acyclovir Delivery TRANSPLANT Test Sensitivity Specificity Likelihood ratio ALP : Bilirubin < 4 94% 96% 23 AST : ALT > 2.2 94% 86% 7 Both tests 100% 100% Korman JD Hepatology. 2008
Initial and General Management Early Recognition! INR not often checked with labs Grade I-II Encephalopathy: Transfer Grade III-IV Encephalopathy: Intubate and Transfer Monitor blood tests every 8-12 hours Liver enzymes, INR, electrolytes Renal Function à CVVHD? ABG Ammonia à > 200 with poor prognosis Blood glucose à D10 gtt? Liver Biopsy not necessary May lead to fluid overload in attempts to correct coagulopathy
Specific Management Circulatory Colloid preferred, MAP > 75 mmhg Vasopressin controversial à ICP CVVHD > ihd Infection No data for prophylaxis Surveillance cultures recommended Coagulopathy IV Vitamin K FFP or PLT only for active bleeding H 2 Blocker for GI ppx Encephalopathy HOB Elevation Propofol preferred for sedation Lactulose Pros/Cons Seizures? à Phenytoin Cerebral Edema Hyperventilate: PaCO2 goal 25 mmhg IV mannitol Hypertonic saline Phenobarbital infusion ICP Monitoring: Center dependent Lee WM et al. Hepatology Sept 2011
Benefit of NAC in Non-Tylenol ALF Lee WM, Gastroenterology. 2009 Sep
High-Volume Plasma Exchange in ALF Randomized: SMT (n=17) vs HVPE (n=16) More vasopressor use in SMT; more renal failure in HVPE Higher transplant-free survival in HVPE group (75% vs 38%) Improved NH 3 clearance in HVPE group à unclear significance Maiwall et al, Abstract 288, Liver Meeting 2018
We Are Getting Better at Treating ALF 67.1% 45.1% 75.3% 56.2% Overall Transplant-Free Survival 19.2% 35.7% Transplant-Free Survival; Listed Patients Slide Adapted from Dr. Paul Hayashi Reuben et al. Ann Intern Med. 2016
Reuben et al. Ann Intern Med. 2016 Why Are We Better? Gastro paper published End of study period for NAC in non-apap failure
Acute on Chronic Liver Failure (ACLF) Largest prospective database by CANIONIC investigators à EASL Described as acute decompensation of cirrhosis associated with organ failure (OF) and high short-term mortality (28-day mortality 15%) Affects ~30% of hospitalized patients with cirrhosis 28-Day Mortality: 33% 90-Day Mortality: 51% Can develop in outpatients, risk factors include: High MELD, anemia, presence of ascites and low MAP Hernaez R, et al. Gut 2017 Moreau R, et al. Gastroenterology. 2013
Prognostic Models for ACLF CLIF-SOFA Grayed out à Defines organ failure Jalan et al. J Hepatol. 2014 Hernaez R, et al. Gut 2017
CLIF-C ACLF Score Calculator https://www.clifresearch.com/toolscalculators.aspx
ACLF Grades and Mortality Grades of ACLF No ACLF ACLF Ia ACLF Ib ACLF II ACLF III Clinical characteristics No organ failure, or single non-kidney organ failure, creatinine <1.5 mg/dl, no HE Single renal failure Single non-kidney organ failure, creatinine 1.5 1.9 mg/dl and/or HE grade 1 2 Two organ failures Three or more organ failures Hernaez R, et al. Gut 2017
ACLF is Dynamic Initial Grade ACLF-1 (%) Prevalence (n = 202) ACLF-2 (%) Prevalence (n = 136) ACLF-3 (%) Prevalence (n = 50) No ACLF (n = 165) ACLF-1 (n = 70) Final Grade ACLF-2 (n = 59) ACLF-3 (n = 94) 110 (54.5) 49 (24.3) 18 (8.9) 25 (12.4) 47 (34.6) 19 (14.0) 35 (25.7) 35 (25.7) 8 (16.0) 2 (4.0) 6 (12) 34 (68) ACLF Grade at Days 3-7 after diagnosis predicted 28-day and 90-day mortality more accurately than ACLF at diagnosis Gustot et al Hepatology. 2015
Early Change in Score Predicts Survival 48 patients with ACLF admitted to ICU with CLIF-SOFA scores calculated at D0, D2, D5 and D7 Change in CLIF-SOFA between D2 and D5 or D7 best indicator of survival Kotha et al. Abstract 291, Liver Meeting 2018
Precipitants of ACLF Bacterial Infection 32% GI Bleeding 13% Active Alcoholism (within 3 months) 25% Other* 9% None Identifiable 44% More Than One 14% *TIPS, Surgery, LVP without Albumin, HBV/AIH Flare Moreau R, et al. Gastroenterology. 2013
Rising Burden of EtOH in ACLF EtOH abuse disproportionately affects youth Reviewed 112,174 admissions over 8 years (2006-2014) and analyzed in two age groups (< 35 and > 35) Alcoholic Hepatitis: 40.6% vs 16.5% ACLF-2: 26.8% vs 21.8% ACLF-3: 7.2% vs 3.4% Axley PD et al, Abstract 282, Liver Meeting 2018
Arroyo et al, Nature Reviews Disease Primers June 2016 Management of ACLF Supportive care, similar to that of ALF Infectious workup and low threshold for Abx Circulatory support with albumin +/- vasopressors HRS treatment +/- CVVHD Avoid unnecessary transfusions of FFP and PLT Adrenal insufficiency commonly seen Specific Management G-CSF à improves short-term survival, but only studied in ACLF-1 patients Extracorporeal liver support systems (ECAD) à MARS Liver Transplantation
Stange et al, Abstract 293, The Liver Meeting 2018 Saliba et al, Abstract 286, The Liver Meeting 2018 ECAD for ACLF? Open Albumin Dialysis (OPAL) previously described to be better than MARS (Charcoal-based) Cross-over study of 30 patients with ACLF OPAL better at removing bile acids and toxin load OPAL better at improving encephalopathy too No report of clinical outcomes 62 patients with ACLF Majority were alcohol (62%) Survival à 1 mo: 56%, 3 mo 47% Overall transplant-free survival 28% Those with ACLF-3 had lowest survival à deemed futile
Arroyo et al, Nature Reviews Disease Primers June 2016 Liver Transplantation for ACLF 5-year post-olt Survival > 80% But only feasible in < 25% of patients Can aid with prognosis/goals of care discussion
Good Post-OLT Survival for ACLF-3 UNOS database: 6,010 patients identified with ACLF-3 1-year post-olt survival ACLF-3 81.1% vs 88.4% and 91.7% in ACLF-2 and ACLF-1 Risk factors for mortality: Respiratory failure High Donor Risk Index Sundaram et al, Abstract 2349, The Liver Meeting 2018
Summary Early detection and treatment of ALF is key Let the kidneys go and initiate CVVHD if needed Minimize unnecessary transfusions for coaguloapathy Acute on chronic liver failure is a distinct entity from simple decompensation CLIF-SOFA score and subsequent ACLF grade correlates better than MELD for prognosis and can help with prognosis Alcohol decompensations are on the rise Liver transplant works, but window is small, so transfer early