Acute Liver Failure Devina Bhasin MD Clinical Asst

Acute Liver Failure Devina Bhasin, MD Clinical Asst Professor of Medicine Mercer University School of Medicine Transplant Hepatologist Piedmont Transplant Institute

Acute Liver Failure Definition • Rapid onset of synthetic dysfunction – jaundice, coagulopathy, encephalopathy • No prior liver disease – Exceptions: • HBV reactivation, autoimmune, Wilson’s • Interval between jaundice and encephalopathy determines course of disease – < 2 -6 weeks: Fulminant hepatic failure with rapid course to recovery or death/transplant – 2 weeks-3 months: Subfulminant hepatic failure slow course proceeding inevitably to death/transplant

Acute Liver Failure – Difference between rapid decompensation of known liver disease and Acute Liver Failure

Acute Liver Failure Normal liver Acute liver failure Cirrhosis

Acute Liver Failure Grade of Encephalopathy • Grade 0 None • Grade 1 Day/night reversal, abnl psychometrics, asterixis • Grade 2 Slurred speech, + asterixis • Grade 3 Lethargic but arousable, +/- asterixis • Grade 4 Coma, -asterixis

Acute Liver Failure Call the Transplant Center!

Acute Liver Failure Etiology • Acetaminophen (Tylenol), > 10 g/day – Can be less with chronic ETOH & malnutrition • Idiosyncratic drug reactions (DILI) • Viruses (hepatitis A, B, D, and E) • Metabolic diseases (Wilson’s Disease) • Ischemia (Budd-Chiari Syndrome) • Autoimmune hepatitis • Idiopathic • Others (AFLP, HELLP syndrome, heat stroke, infiltrative malignancy, mushroom poisoning)

Acute Liver Failure Etiology in Adults All other 20% Acetaminophen 39% HAV/HBV 11% Unknown 17% N=308 Idiosyncratic drugs 13% Ann Intern Med 2002; 137: 947 -954.

Acute Liver Failure Things That Don’t Do It • • • Hemochromatosis Alpha-1 -Antitrypsin deficiency Cystic fibrosis Hepatitis C (questionable case reports) Nonalcoholic fatty liver disease (NAFLD) Cholestatic liver diseases (PBC, PSC)

Acute Liver Failure Outcome in U. S. Survey (1998 -2001) N=308 (17 centers) Spontaneous Survivors 132 (43%) Transplanted 89 (29%) Alive 75 Died Before Transplant 87 (28%) Died 14 Ann Intern Med 2002; 137: 947 -954.

Acute Liver Failure Demographics APAP Drug (n=120) (n=40) IND (n=53) Other (n=95) P value Gender (%F) 79 73 60 72 NS Age 36 41 38 43 0. 02 Coma 50 43 47 47 NS ALT 4310 574 947 1060 <0. 001 Bili 4. 3 20 25 13 <0. 001 OLT 6 53 51 36 <0. 001 Spontaneous survival 73 25 17 33 NS Ann Intern Med 2002; 137: 947 -954.

Goals of First 24 Hours • Two things to determine at initial presentation: – Etiology • Immediately treatable cause? – Acetaminophen – Autoimmune hepatitis – Acute fatty liver of pregnancy/HELLP • Immediately reversible cause? – Budd-Chiari • Futile cause? – Wilson’s disease and FHF (mortality 100%) – Prognosis • Likelihood of death • Likelihood of needing transplant – (Transplant candidacy? )

Acute Liver Failure-Acetaminophen Outcome

Acute Liver Failure Prognosis: King’s College Criteria l Acetaminophen induced acute liver failure – Systemic p. H < 7. 30 or – PT > 100 seconds – Creatinine > 3. 5 mg/dl – Stage III or IV coma

Acute Liver Failure-Acetaminophen Therapy • Intravenous dosing of N-acetylcysteine (Acetadose ®) – Loading dose 150 mg/kg in 200 ml of 5% dextrose infused over 15 minutes followed by a maintenance dose of 50 mg/kg of 500 ml of 5% dextrose infused over 4 hours followed by 100 mg/kg in 1000 ml of 5% dextrose infused over 16 hours. • Oral – Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours to complete 17 doses.

Acute Liver Failure Prognosis: King’s College Criteria • Non-acetaminophen – PT > 100 seconds – OR any three of the following: – PT > 50 seconds – Age < 10 or > 40 years – Etiology other than Hepatitis A or B – Jaundice > 7 days before onset of encephalopathy – Bilirubin > 17 mg/dl

Acute Liver Failure Goals of First 24 Hours • First Do No Harm – Avoid sedatives or sleepers • Interferes with prognosticators • Will take time to metabolize – Judicious use of factor replacement • Interferes with prognosticators – Avoid nephrotoxins • aminoglycosides, CT contrast, NSAIDs

Acute Liver Failure Initial Work-up Key labs for prognosis – – – – CBC Electrolytes with Cr Liver enzymes PT/INR Factor VII activity Factor VIII activity (control) – Arterial p. H at presentation – Urine/serum toxicology screen – Acetamenophen – Serum alcohol screen – Ammonia – Lactate – Pregnancy test – Viral serologies – Autoimmune markers (include Ig. G) – Ceruloplasmin

Acute Liver Failure Initial Work-up • Key studies for etiology – Acetaminophen level – HAV/HBV serologies (HAV Ig. M, HBc. Ig. M) – Ceruloplasmin (younger ages) – ANA, SMA, Quantitative Ig. G – DOPPLER ultrasound liver – HSV (young, pregnant female) • Additional info – Family history – Medications – OTC/Herbs

Acute Liver Failure Herbal Medications § § § § • • • Jin Bu Huan Sho-saiko-to Ma Huang He Shon Wu Comfrey Germander Chaparral Leaf Kava kava Greater celandine Hydroxycut Lipo. Kinetix Comfrey Senecio

Acute Liver Failure Initial Work-up • Key info for transplant candidacy – – – – Social history (Alcohol/drugs) Psychiatric history (Depression/suicide attempt) Family support Urine tox screen Serum alcohol HIV test Medical co-morbidities (morbid obesity)

Acute Liver Failure Complications • Renal failure • Infectious complications • Cerebral edema

Acute Liver Failure Other Management Issues • • • Monitor for hypoglycemia Meticulous care of central lines Avoid volume overload Nutrition Coagulopathy

Acute Liver Failure Renal Failure • Occurs in up to 33% of patients • Often multifactorial: – volume depletion, ATN, hepatorenal • Octreotide/midodrine combination? • Urine sodium • Avoid CT contrast, avoid NSAIDS, empiric aminoglycosides • Patients tolerate volume overload poorly – central pressure monitoring/central line – pulmonary artery catheter

Acute Liver Failure Infectious Complications • 80% of patients with ALF – Bacteremia in 20 -25% • Gut translocation & instrumentation • Usually respiratory and urinary tract • Gram negatives, Staph and Strep • Fungal infection in up to 33% • All patients should be cultured broadly with low threshold for empiric antibiotics • Sepsis may preclude transplant

Acute Liver Failure Cerebral Edema • • • Found in up to 80% of patients dying with FHF Possibly due to gut derived neurotoxins leading to vasogenic and cytotoxic edema Arterial ammonia does correlates with degree of cerebral edema (ammonia >150) Difficult to diagnose with CT, thus high index of suspicion and early monitoring essential – Frequent neurological examination If untreated leads to herniation and death, transplantation the only “cure”

Acute Liver Failure Cerebral Edema • Classic signs of ICP elevation: – Cushings Triad • systemic hypertension • Bradycardia • irregular respirations • Neurologic manifestations – increased muscle tone – hyperreflexia – altered pupillary responses • However, early in the course of acute liver failure, these signs and symptoms may be absent or difficult to detect

Acute Liver Failure Cerebral Edema • Treatment (may buy some time) • Mannitol • 0. 5 -1. 0 gm/kg • Hyperventilation • Elevation of head to 30 degrees • Over-hydration can elevate ICP • Minimizing patient agitation/stimulation • Hypertonic Saline • Decrease water influx into the brain and thereby reduce cerebral edema and IC • Na 145 -155

Acute Liver Failure • Acute, life-threatening liver injury in previously healthy individual • True ALF has component of hepatic encephalopathy • Multiple etiologies: – APAP, other drugs, viral – up to 1/3 are unknown cause • Prognosis partially dependent upon etiology • Clinical/lab criteria are imperfect for determining outcome

Acute Liver Failure • First 24 hours: – Focus on immediately treatable or reversible causes – N-acetylcysteine for everyone – Begin evaluation for etiology – First do no harm: sedatives, clotting factors, nephrotoxins, infection – Help determine transplant candidacy

Transplant Evaluation • Transplant Team – Hepatologist – Surgeon – Physician Assistant – Nurse coordinator – Psychologist/Psychiatrist – Social worker – Dietician – Financial Coordinator • Affiliated consultants – Psychiatry – Nephrology – Cardiology – Pulmonology – Anesthesiology – Others

ELAD Liver Support System • Extracorporeal support of liver function • Continuous treatment of plasma ultrafiltrate for up to 5 days • Ultrafiltration Circuit + ELAD Cartridges

ELAD Liver Support System 34

Efficacy and Safety of ELAD® in Subjects with Acute on Chronic Hepatic Failure (AOCH) • Phase 2 b multi-center, open-label, randomized, concurrently-controlled subjects with AOCH • Conducted in US and EU • Subjects were prospectively stratified into two groups before randomization: • Stratum 1: Acute Alcoholic Hepatitis (AAH) • Stratum 2: Patients with chronic liver disease, decompensated by a precipitating event • Randomization into Standard of Care (SOC) or ELAD plus SOC

VTI-206 Clinical Data: AILD cohort (n=29) • • VTI-206: Phase 2 b AILD Study – U. S. /EU – 37 AILD subjects in predefined cohort, 26 sites – Randomized, controlled, open-label – 90 -day overall survival endpoint Overall survival Per Protocol Outcome – 69% overall survival on ELAD vs. 44% on control at day 90 (p=0. 27); n=29 – Median Survival: >100 days ELAD vs. 65 days control – • No ELAD patient died after day 12 No unexpected ELAD related safety issues From data presented at Plenary Session of 18 th Congress of the ILTS (2012), by L. Teperman, MD, Chief of Transplant Surgery at NYU.

case • 18 y/o WF admitted with abd discomfort, malaise, fatigue for 1 week • She was found to have abn LFTs with AST 113, ALT 85, AP 32 GGT 80 TB 7. 9 INR 1. 8 • Transferred to PH, TB continue to rise to 14 (> 50% indirect) with development of HE • Additional lab data revealed ceruloplasmin level of 10 and other tests for ALF were negative

Case Acute Decompensated Wilson’s Disease Fulminant Wilson’s Disease Mortality without Transplant = 100%

Case • She underwent comprehensive evaluation for transplant and was approved • She was listed as Status 1 • Underwent successful OLT in day 3 • She was discharged in 6 days after the surgery • She is now more than one year posttransplant with stable graft function

Case • Her 24 hour urine copper 27, 106 ug/24 • Hepatic quantitative copper 2241 mcg/gm dry weight • Explant histology revealed micronodular cirrhosis, steatosis, cholestasis, hepatocyte necrosis (c/w acute decompensated wilson disease)

Case • 28 y/o WF gravida 1 with no significant PMH presented to her OB for her routine visit at 37 weeks gestation • Stable VS except BP 158/98 • 1+ pedal edema, 1+ proteinuria • She was sent to ER for further evaluation: Hgb 10, Plt 106, AST 290, ALT 317, LDH 371 • Working dx of HELLP (Hemolysis, Elevated Liver enzymes Low Platelets) syndrome was made and underwent emergent uneventful C-section

Case • Post-op she developed back pain and profound hypotension, she was transferred to ICU for resuscitation • Lab: AST 1696, ALT 1253, LDH 1262, Plt 10 K, Cr 0. 8 • CT Abdomen: sub-capsular, perihepatic hemmorage and hepatic rupture

Case • Her platelet count dropped to 6 k (nadir) • She was treated with Plasmapheresis and high dose corticosteroid • She became oliguric/anuric, CRRT was initiated • Serologies for hepatitis A, B, C and HIV were negative, ANA, ASMA, AMA, ceruloplasmin were negative • Her ABO blood type was O

Case • Her transaminases continue to rise and peaked >7000 • Despite aggressive therapy with steroid, plasmapheresis, FFP, PRBC and platelets she bacame encephalopathic and was intubated for airway protection and transferred to transplant center

Case • On arrival she was unresponsive, intubated and on pressors • Head MRI was negative • AST 1319, ALT 763, TB 7. 6, WBC 23 K, Hgb 8. 4, Hct 26. 6, Plt 39 K, BUN 20, Cr 4. 1, INR 1. 5, LDH 2215, ammonia 148, lactic acid 5. 1

Case • Next few days she continued to remain comatose with elevated transaminases, bilirubin, INR and low factors (V and VII) • She underwent comprehensive evaluation for OLT and placed on the UNOS waiting list as status 1

Case • Transplant surgery was performed with standard fashion using piggyback technique • Native liver revealed impressive hepatic rupture with surrounding hematoma

Case • Histology demonstrated massive hepatic necrosis, steatosis, cholestasis and necrotic vessels

Native Liver Explant Pathology (H&E X 40)

Native Liver Explant Pathology (H&E X 100)