Acute Liver Failure (ALF) in Children Dan W Acute Liver Failure (ALF) in Children Dan W. Thomas, MD Medical Director Hepatology & Liver Transplantation Children’s Hospital Los Angeles Professor of Clinical Pediatrics Keck/USC School of Medicine

Acute Liver Failure (ALF) in Children Dan W. Thomas, M.D. I have no relevant financial relationships with the manufactured (s) or any commercial product (s) and/or provider of commercial products or services discussed in this CME activity. I do not intend to discuss unapproved/investigative use of commercial product (s) / device (s) in my presentation.

AASLD Practice Guidelines: The Management of Acute Liver Failure- Update 2011. Lee WL, Larson AM, Stravitz RT @ www.aasld.org

Objectives Definition Causes Prognostic factors Management Encephalopathy (HE) Outcome

Definition No evidence of pre-existing liver disease Biochemical evidence of acute hepatic injury Elevated bilirubin, abnormal LFT’s Coagulopathy INR > 2.0 not correctable by vitamin K +/-HE INR > 1.5 in the presence of encephalopathy Encephalopathy May occur up to 2 months after onset of jaundice < 4 year old: coma grade scale (GCS) > 4 year old: stages 1-4

Objectives Definition Causes Prognostic factors Management Encephalopathy Outcome

Causes of Acute Liver Failure in Children Developed countries Indeterminate 49% Acetaminophen 14% Non-APAP drug 5% Metabolic 10% Autoimmune 6% Infectious 6% Circulatory 5% Other 5% J. Pediatr 2006; 148:652-8 JPGN 2005;40:575-581 J Hepatol 2006; 44:134-141 Undeveloped Countries Infection (viral) 90% Other 10% DDS 1998; 43:1311-1316

Non-typable viral hepatitis Aplastic Anemia - 30% NK cell dysfunction

Acetaminophen toxicity (APAP)

Wilson’s Disease Excessive copper accumulation, low ceruloplasmin Characteristic low alkaline phosphatase level Kayser- Fleischer rings may NOT be present Associated with hemolytic anemia & elevated unconjugated bilirubin level

Wilson’s – Clinical Diagnosis KF rings Low ceruloplasmin Ur Cu ≥ 250 ug/24 hr All 3 must be + Q Cu with liver biopsy or genetic test if not (AASLD recommendations)

Autoimmune hepatitis Elevated total serum protein Usually have abn AIH antibody tests (ANA, smooth muscle, anti LKM, liver soluble antigen) Response to medical therapy is variable

Objectives Definition Causes Prognostic factors Management Encephalopathy Outcome

Outcome - Children Overall transplant-free survival ≤ 40% Etiology specific transplant-free survival Acetaminophen 100% Sepsis 65% Autoimmune 50% Viral 43% Hematological 40% Unknown 38% Metabolic 35% J Hepatol 2006;44:134-141

Outcome - Adults Overall transplant-free survival ≥ 75% 20% increased use of I.V. N-acetylcysteine regardless of etiology Reuben A. et al, Ann Int Med;2016 154:724-733

Use of N-acetylcysteine in Children with Non-APAP ALF No benefit/worse TSF Currently not recommended Squires R et al, Hepatology 2013:57:1542-1549

Prognosis Coagulation Factors Factor V < 20% Factor VII < 5% % necrosis on liver biopsy Liver biopsy is controversial > 70% necrosis = non recovery

King’s College Criteria Prognostic Factors King’s College Criteria K King’s College Criteria (listed in 2011 AASLD update on ALF)

Objectives Definition Causes Prognostic factors Management Encephalopathy Outcome

Management of Acute Liver Failure EARLY Transfer to Transplant Center Coagulopathy No correction unless active bleeding Risk of bleeding increases if INR >4 or with interventional procedure Encephalopathy Risk of cerebral edema Avoid benzodiazepines/opiates Avoid electrolyte fluxes ?ICP monitoring Normalize blood sugar Broad spectrum antibiotics High risk of serious infection If child becomes unstable, has high WBC, or fever

Coagulopathy Anticoagulant Procoagulant

Objectives Definition Causes Prognostic factors Management Encephalopathy of ALF Outcome hepatic encephalopathy

General Classification of Hepatic Encephalopathy Class A Associated with acute liver failure Risk of cerebral edema Class B Associated with porto-systemic bypass Class C Associated with cirrhosis

Hepatic Encephalopathy Stage II Drowsiness/confusion Inappropriate behavior *asterixis (older children) EEG: generalized slowing Stage I Slowness of mentation Sleep-wake cycle disturbance No EEG changes

Hepatic encephalopathy Stage III Sleepy but arousable Delerious Hyperreflexia/+ Babinsky EEG: grossly abnormal Stage IV Unconscious Decerebrate or decorticate posture EEG: Delta wave

Pediatric GCS

Hepatic Encephalopathy of ALF Vaquero J et al, Sem Liver Dis 2003 (23): 259Vaquero

Brain Edema is a preterminal event in Acute Liver Failure Vaquero J et al, Sem Liver Dis 2003 (23): 259Vaquero

Stages of ALF Hepatic Encephalopathy in Children

Hepatic Encephalopathy Frequent clinical assessment NO definite correlation between NH3 levels with Clinical assessment Electrophysiological measurements Hypoglycemia Electrolyte abnormalities Uremia Infection Administered sedatives/opiates Underperfusion of the brain

Hepatic Encephalopathy- Pathogenesis Normal hepatic metabolic & detoxification functions fail. Mileau of neurotransmitters (e.g. GABA, serotonin, dopamine, glutamate, glutamine) becomes perturbed. Benzodiazepine receptors are upregulated. Disruption of the blood-brain barrier(BBB). Desjardins P et al, J Clin Exp. Hepatol, 2012 (60): 690.

Broken Dam Theory Cirrhotic liver leak of molecules and toxins into the systemic circulation ALF/Necrotic liver flood of AA’s (tyrosine, phenylalanine, tryptophan), SCFA, phenols, thiols, mercaptans, NH3 into the systemic circulation

Benzodiazepine-receptors Synergestic effects of neurotransmitters Neurotransmitters Glutamine + Glutamate GABA increased GABA-Cl current/ brain water porosity Benzodiazepine-receptors Increased receptor number Increased affinity Serotonin & Dopamine Increased glutamine results in increased tryptophan and tyrosine cross the BBB and are precursor neurotransmitters

Ammonia (NH3 crosses BBB)

Effect of NH3 in Hepatic Encephalopathy NH3 on PET scan Increased cerebral extraction Increased brain permeability Increased metabolic rate Increased glutamine NH3 metabolism is astrocyte-dependent (Urea cycle is only in the liver) NO LINEAR CORRELATION TO BLOOD AMMONIA

Pivotol role of astrocytes in NH3 metabolism and glutamine in HE

Altered Glial-Neuronal Crosstalk in HE Crosstalk in HE astrocyte neuron Scott TR et al, World J Gastroenterol 2013 (19):9240

Why does cerebral edema occur in ALF ? Butterworth RF, J Clin Exp Hepatol 2015 (5): S96

“Trojan Horse Effect” Scott TR et al, World J Gastroenterol 2013 (19): 9240

Added negative effects in ALF HE: Increased water channel uptake - Astrocytes

Aquaporin 4 in Astrocytes in HE Rao KVR et al, J Neuropath Exp Neurol 2010 (69): 869

ALF Other pathophysiologic considerations… Other factors contributing to brain damage and multi-organ failure

Role of SIRS – Activated by Liver Necrosis

Treatment of Hepatic Encephalopathy Supportive - Treat infection, electrolyte abnormalities, correct blood glucose, avoid sedatives/opiates, normalize circulation ? Neomycin, ? Rifaximin, ? Lactulose Future???

CVVH in ALF Hepatic encephalopathy Multi organ failure - Hepatorenal syndrome Excessive fluid accumulation e.g. administration of blood products, clotting factors, FFP IV drip Bridge to LVT MARS

Hemofiltration

Objectives Definition Causes Prognostic factors Management Encephalopathy Outcome Critical role of early referral to Pediatric Liver Transplant Center

Post transplant Outcome - ALF Accounts for only 12% of all transplants High mortality on waiting list (? LRD) Six months survival: 74.5% Compared to 89% High risk patients Grade 4 encephalopathy Age less than 1 Renal failure Liver transplantation 2004; 10:1364-71

Summary- ALF All patients with acute liver failure require urgent referral to a pediatric liver transplant center Hemofiltration plays a potential role in treatment and prevention of neurological complications Sudden clinical decompensation due to acute hepatic encephalopathy (brain swelling), bleeding, and/or infection are common and lethal. LVT is presently the only curative treatment for irreversible ALF. N – acetylcysteine RX for non-APAP ALF in children currently is not recommended.

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