Acute Liver Failure

1. Sara Karjoo, MD Kathleen Loomes, MD Children’s Hospital of Philadelphia Reviewed by John Stutts, MD of the Professional Education Committee Acute Liver Failure

2. What you need to know for the boards • 2011 AAP Pediatric Gastroenterology Content Guideline: • Formulate a management plan for a patient with acute hepatic failure • Know the prognostic features of acute hepatic failure in children • Know the differential diagnosis of acute hepatic failure • Understand and manage the various complications associated with acute hepatic failure

3. Introduction • Adult definition: • Rapid deterioration of liver function AND • Evidence of coagulation abnormality (INR ≥ 1.5) AND • Results in any degree of mental alteration/encephalopathy • No pre-existing liver disease • Illness < 26 weeks duration • Pediatric definition: • No evidence of chronic liver disease • Biochemical evidence of acute liver injury • Hepatic coagulopathy defined as INR ≥ 1.5 not corrected by Vitamin K in the setting of hepatic encephalopathy OR INR ≥ 2.0 regardless of presence or absence of hepatic encephalopathy

4. May or may not include all of the following: Signs and symptoms • Prodrome of malaise and lethargy • Jaundice (often but not always seen) • Excess bleeding or bruising • Right upper quadrant tenderness (variably seen) • Inability to palpate or percuss the liver (decreased liver volume) • Hepatomegaly (viruses, malignancy, Budd-Chiari syndrome, etc) • Altered mental status, or progression to encephalopathy…

5. Hepatic encephalopathy(Adult definition) Clinical Manifestation Slowness of mentation. Disturbed sleep-wake Drowsiness, confusion, disorientation Sleepy but arousable, stupor, unresponsive to commands, hyperreflexia, + Babinski Unconscious, absent reflexes, decerebrate and decorticate to pain Asterixis Slight Present Present Absent EEG Findings Minimal Generalized slowing Grossly abnormal Delta waves HARD TO ASSESS IN CHILDREN Stage I II III IV

6. Epidemiology • 2000 cases yearly • Very rare • Acute liver failure accounts for 10% of pediatric liver transplantation

7. Causes Majority of ALF in children is an indeterminate cause -PALF Study, Journal of Pediatric 2006

8. Pathophysiology • Depends on the etiology • Common features: • Acute loss of hepatocellular function • Hypoglycemia • Lactic acidosis • Coagulopathy • GI bleeding • Systemic inflammatory response • Seizures • Multi-organ system failure and myocardial dysfunction • Increased infection rates due to impaired macrophage function and deficit of acute phase reactants

9. Diagnosis • Laboratory and key physical exam finding: • Altered mental status • Elevated INR ≥ 1.5 or PT ≥ 4-6 seconds above normal range • A thorough history: • Onset of symptoms • Family history of liver disease • Exposure to medications, drugs, sick contacts, travel history • Work up is guided by age of presentation • Infancy • Childhood/ Adolescent

10. Infancy • Most likely diagnoses include: • neonatal hemochromatosis/ GALD/ congenital alloimmune hepatitis • Virus/ infections • Cardiovascular causes • Metabolic disease • Mitochondrial disease • Medications/ toxins/ drugs • Less likely to find autoimmune hepatitis in this age group

11. Work up during infancy • Drug testing • Acetaminophen level, drug screening • Viral serologies and PCRs • Metabolic work up: • Plasma ammonia (arterial draw) • Lactate/ pyruvate • Acylcarnitine profile • Urine succinylacetone • Urine organic acids (UOA) • Serum amnino acids (SAA) • Liver biopsy • Cardiac etiologies • Echo • BNP

12. Childhood/ Adolescence • More likely to be caused by: • HELLP syndrome • Toxins/Drugs • Wilson’s Disease • Autoimmune • Malignancy • Budd-Chiari syndrome • Infections

13. Work up during childhood/ adolescence • General labs/workup: • Chemistries • Arterial blood gas measurement • CBC and type and screen • Pregnancy test (HELLP Syndrome) • Jaundice, coagulopathy, low platelets associated with hypoglycemia, hypertention, protienuria, with steatosis on imaging and liver biopsy • Liver biopsy • Drug screening • Acetaminophen level, drug screening • Infectious work up • Viral serologies and PCRs

14. Work up during childhood/ adolescence • Autoimmune Hepatitis work up • Auto-antibodies (ANA, ASMA, anti-LKM, anti-SLA, IgG) • Wilson’s Disease • Slit lamp examination • Urine copper and serum ceruloplasmin • Total bilirubin and alkaline phospatase ratio • Plasma ammonia • Vascular etiology/ Budd-Chiari • US abdomen with doppler • Malignancy • LDH, AFP, Uric acid, blood smear

15. Management • Admission to ICU and transfer to center that specializes in liver transplantation • Supportive care vs. monitoring for progression needing liver transplantation • Surveillance of co-morbitities and complications: • Sepsis • Neurological changes (encephalopathy, seizures) • Circulatory failure • Renal failure • Monitor and treat reduced serum glucose

16. Management:Coagulopathy • Patients with coagulopathy should be treated with vitamin K subcutaneously (age dependent doses) • Transfusion of platelet and FFP prior to invasive procedures, and in the setting of hemorrhage

17. Management:Neurological Symptoms • Cerebral edema, uncal herniation, and intracranial hypertension are the most serious complications • May contribute to hypoxic brain injury • AVOID CEREBRAL DEPRESSANTS • More beneficial to control seizures because they increase ICP with very short acting benzodiazepine then phenytoin

18. Management:Neurological Symptoms • Grade 1-2 encephalophathy • Can be managed on ward in quiet environment with frequent neurologic checks • ICU transfer and CT head if consciousness declines • Avoid sedation if possible • Can consider treatment with lactulose to decrease ammonia levels

19. Management:Neurological Symptoms • Grade 3-4 encephalopathy • Intubation and mechanical ventilation are mandatory • Cisatracurium is preferred because it does not increase ICP • Propofol decreases cerebral blood flow • ICU frequent blood and neurologic monitoring

20. Management:Infections • Treat acquired infections aggressively because they can progress to encephalopathy and cerebral edema • Infection is a major cause of mortality in acute liver failure • Role for prophylactic antibiotics

21. Management:GI Bleeding and Nutrition • Patients with ALF in ICU should receive prophylaxis with H2 blocker or PPI for acid related gastrointestinal bleeding associated with stress • Enteral and parental nutrition decrease the risk of GI bleeding due to stress ulceration • Enteral nutrition is best, and do not need severe restriction of protein • Use higher dextrose fluid to combat hypoglycemia • Monitor and replace deficiency in phosphate, potassium, magnesium

22. Management: Renal and Cardiovascular • Renal dysfunction seen in severe disease • Hemodynamic alterations lead to renal failure • May need dialysis • May see both azotemia or oliguria • May need to treat hypotension with pressors • Search for etiology of cardiomyopathy or myocarditis • Treat causes of alkylosis

23. Management:Other Concepts • Low level of aminotransferases may not reflect recovery, actually may be a sign of severe liver destruction • Steroids are helpful in setting of autoimmune disease, but not universally recommended in all causes of ALF • Limit sodium in fluids • Start diuretics to treat ascites

24. Indications forLiver transplant in ALF • Difficult decision because of inadequate predictors of prognosis, and depends on etiology • Liver failure from APAP ingestion more likely to recover vs. liver failure from Wilson’s disease • MELD scores, KCH criteria, and others are not good predictors of prognosis • Liver transplantation is considered if there is progression of liver disease with expected hepatic failure

25. Prognosis • Carries a high morbidity and mortality • However many patients recover • Short-term survival (1 year) including those undergoing transplantation is greater than 65% • The children who had an indeterminate cause have a poorer outcome

26. References • Lee, W. M.; Larson, A. M.; Straviz, R. T. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. Hepatology: 2011, 1-22. • http://www.palfstudy.org/information.asp • Acute Liver Failure Lecture by Kathy Loomes August 31, 2012. • Dhawan, A.; Cheeseman, P.; Mieli-Vergani, G. Approches to acute liver failure in children. Pediatric Transplantation, 2004: 8, 584-588. • Squires, R. H. Acute liver failure in children. Seminars in liver disease, 2008: 28, 153-166. • SQUIRES, R.H.; et al. ACUTE LIVER FAILURE IN CHILDREN: THE FIRST 348 PATIENTS IN THE PEDIATRIC ACUTE LIVER FAILURE STUDY GROUP. The Journal of Pediatrics, 2006;148:652-8.