Brian Kim USC Transplant Hepatology October 16, 2018 Acute Liver Failure Brian Kim USC Transplant Hepatology October 16, 2018

Definition Acute liver failure (ALF) or fulminant liver failure is most commonly defined as the onset of encephalopathy within 26 weeks (or whatever threshold used) of development of jaundice Liver injury with encephalopathy and impaired synthetic dysfunction (INR ≥ 1.5) in a patient without known cirrhosis or pre-exisiting liver disease Exceptions can include patient with HBV, AIH, Wilson Disease, but not alcoholic liver disease

Acute Liver Failure Onset of jaundice to encephalopathy Hyper-acute < 7 days Acute 7-28 days Sub-acute 5-26 weeks

Acute Liver Failure is not… Acute on chronic liver failure or decompensated cirrhosis Preexisting liver disease (cirrhosis) Bleeding Infection Cancer Acute alcoholic hepatitis Acute liver injury Jaundice +/- coagulopathy Normal mental status May deteriorate into ALF

Acute Liver Failure vs. Decompensated Cirrhosis ALF patients generally present with severe hepatic dysfunction Hepatic encephalopathy as a result of hepatic necrosis/cytokine release High INR as a result of hepatic necrosis Decompensated cirrhotic patients generally present with portal hypertension complications Variceal hemorrhage Ascites Hepatic encepahlopathy as a result of portosystemic shunting (macro vs. micro) Can have considerable overlap ALF can potentially have considerably higher mortality than patients with decompensated cirrhosis (more on this later)

Acute liver failure Approximately 2000 cases annually in the US 3/4 white 3/4 female Median age 38 years ALFSG

Causes Acetaminophen Other drugs (>400 associated with ALF) Augmentin INH Valproic acid Toxins – mushrooom (Amanita phalloides) Viral hepatitis HAV HBV +/- HDV HEV HSV Autoimmune hepatitis Wilson disease Budd-Chiari Shock liver Hyperthermia Acute fatty liver of pregnancy Malignant infiltration Hemophagocytic lymphohistiocytosis (HLH) Reye’s syndrome Indeterminate (15-20%) Not causes of ALF Alcohol Hemochromatosis NASH HCV?

Etiologies of ALF in the US (N=324) ALFSG

Clinical Presentation Symptoms can be nonspecific Fatigue Nausea/vomiting Abdominal pain Confusion Physical Exam Alteration in mental status Asterixis, clonus Evidence of liver injury on labs Elevated AST/ALT, TB, INR Renal failure Pancytopenia

Diagnostic Work-Up Thorough history to obtain potential etiologies (pmh, family history, medication hx, ingestions, etc) Physical exam Find subtle mental status changes Signs of underlying chronic liver disease

Diagnostic Work-up Labs Imaging Transjugular liver biopsy LFTs, INR Viral serologies Acetaminophen level Arterial ammonia AFP, phos pH Imaging Ultrasound with dopplers Transjugular liver biopsy

Some Etiology Specific Therapies Acetaminophen Wilson disease activated charcoal if recent ingestion plasmaphresis - temporizing Autoimmune hepatitis N-acetyl-cysteine steroids? HBV Pregnancy related lamivudine, entecavir or tenofovir delivery HSV acyclovir Mushroom poisoning silibinin (milk thistle), penicillin G

How do people die from ALF? Cerebral edema Infection/sepsis

Hepatic encephalopathy Part of the diagnosis of acute liver failure Decreased ammonia and false neurotransmitter metabolism Increased cytokine release from hepatic necrosis

Grades of Encephalopathy Changes in behavior with minimal change in level of consciousness Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior Marked confusion; incoherent speech, sleeping most of the time but arousable to vocal stimuli Comatose, unresponsive to pain, decorticate or decerebrate posturing

Cerebral Edema Most serious complication of acute liver failure Combination of cytotoxic and vasogenic edema Osmotic disturbances from cytokine/toxin release Increased blood flow from impaired cerebrovascular autoregulation Lead to intracranial hypertension (ICH) with uncal herniation Cerebral edema and ICH seen in 35% of patient with grade III and 75% in grade IV encephalopathy CT imaging is rarely helpful early

Cerebral Edema Grade I/II Grade III/IV Close monitoring Avoid all sedation Questionable role of lactulose – may make liver transplant difficult Grade III/IV Intubation with sedation Efforts to reduce intracranial pressure (ICP) Elevated head of bed Hyperventilation Mannitol infusion Hypertonic saline CRRT Hypothermia ICP monitoring Cerebral perfusion pressure = MAP – ICP; goal ICP<20mmHg and keep CPP >60mHg controversial

Infection Patients at risk for bacterial and fungal infection Empiric antibiotics do appear to reduce incidence of infection Start empiric, broad spectrum antibiotics in all patients with hypotension and SIRS Consider empiric antifungal coverage in patients renal failure

Bleeding Risk for DIC/hyperfibrinolysis Elevated INR may not reflect bleeding risk Spontaneous bleeding risk is rare Routine FFP transfusion not recommended INR followed for prognosis Vitamin K is fine

Management of Other Complications Continuous renal replacement therapy (CRRT) for volume overload and renal failure – especially in patients with advanced encephalopathy and hypotension Vasopressor support Glucose drip for hypoglycemia

Prognosis Overall mortality 30-40% Multiple factors influence mortality Cause of liver failure acetaminophen has best outcome, >50% survival idiopathic drug reaction has poorest outcome, <25% survival Degree of encephalopathy Important to determine prognosis to determine who needs a liver transplant

Encephalopathy and Prognosis Grade of Encephalopathy Short-term transplant-free Survival Short-term survival after liver transplant I-II 52% 77% III-IV 33% 56%

King’s College Criteria Prognostic system developed from King’s College Hospital in London Predict transplant-free mortality Meta-analysis shows 68-69% sensitivity, 82%-92% specificity Two separate criteria Acetaminophen Non-acetaminophen

King’s College Criteria - Acetaminophen pH <7.3 or arterial lactate >3.0mmol/L after early fluid resuscitation Or All three: Grade III/IV encephalopathy INR > 6.5 Cr >3.4 mg/dL

King’s College Criteria – Non-acetaminophen INR > 6.5 Or Three of five Age < 10 or > 40 years INR ≥ 3.5 TB ≥ 17mg/dL Unfavorable etiology – Wilson, idiopathic drug reaction, non A, B hepatitis Development of encephalopathy > 7 days after jaundice

Management Supportive care Follow mental status, transaminases, and INR closely Early involvement and transfer to transplant center Liver transplantation Rapid work-up with thorough psycho-social evaluation Listed as ”Status 1” 1 year survival is lower than for other Tx After 1 year, survival improved

Future Directions Better prognostic score Better monitoring of ICP Liver dialysis

Key Points ALF is marked by rapid deterioration in liver function resulting in encephalopathy and coagulopathy Early recognition and involvement of transplant hepatology is essential Determining etiology may help to target early therapy to prevent deterioration – especially in acetaminophen Supportive care is hallmark of ALF treatment Determining prognosis can help determine who will best benefit from liver transplantation