PEDIATRIC ACUTE LIVER FAILURE: PEARLS AND PRIORITIES
Ryan Himes, M.D. Section Head, Pediatric Gastroenterology, Hepatology, & Nutrition Medical Director, Pediatric Liver Transplant Program Ochsner Medical Center, New Orleans
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION DISCLOSURES
• No relevant conflicts-of-interest
• Discussion of off-label use: • Molecular Adsorbent Recirculating System
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION OBJECTIVES • List common causes of acute liver failure in children of different ages
• Explain the concept “balanced coagulopathy”
• Utilize N-acetyl cysteine for appropriate cases of acute liver failure
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION CASE STUDY: 2-MONTH-OLD MALE
• Unremarkable term delivery • Growing well on Similac • Developed blood-streaked stools • Assessed by his pediatrician milk protein allergy suspected • Alimentum started, but he vomited every feed
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION CASE STUDY: 2-MONTH-OLD MALE
• Seen in the emergency center • Pyloric US normal • Passed a “PO challenge” and sent home • Grandmother introduces a concoction of boiled rice and sugar • Vomiting worsens, prompting return EC visit • Abdominal US and UGI studies normal
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION CASE STUDY: 2-MONTH-OLD MALE
SODIUM [H] 143 AST 444 (H) COLOR URINE YELLOW CARBON DIOXIDE [LL] 12 ALT 206 (H) APPEARANCE URINE [A] CLOUDY GLUCOSE [LL] 47 Alkaline Phos 573 (H) GLUCOSE URINE [A] 3+ BUN [L] 5 GGT 57 BILIRUBIN URINE NEGATIVE CREATININE [H] 1.16 Albumin 3.2 KETONE URINE [A] 1+ Bili Unconjugated 0.0 SPEC GRAV URINE 1.022 WBC 13.52 Bili Conjugated 2.1 (H) BLOOD URINE [A] TRACE HGB 11.1 PH URINE 5.5 HCT 34.3 Ammonia 179 (HH) PROTEIN URINE [A] 4+ PLATELET [H] 626 INR (HH) 8.3 UROBILINOGEN URINE <2.0 NITRITE URINE NEGATIVE PH BLOOD 7.12 LEUKO URINE NEGATIVE BICARBONATE 10 LACTATE [H] 10.2 RED SUB URINE [A] 3+
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION DDX FOR ALF IN A 2-MONTH-OLD
• Infection/sepsis (vomiting, 100.7 in EC) • FAO defect (1+ ketone with hypoglycemia) • Galactosemia • Tyrosinemia • Hereditary Fructose Intolerance • Storage disorders
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION Galactosemia Tyrosinemia HFI Incidence 1:63,000 1:100,000 1:20,000 Age Neonate Infant, child Infant, child V/D/lethargy X X X Hypoglycemia X X X Acidosis X X X Anemia Hemolytic Non-hemolytic Phos/Mg/Rickets X X Renal Fanconi Fanconi Fanconi
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION Common Infant Formulas Carbohydrate Source
Enfamil, Gerber, Similac Lactose, rice starch, maltodextrin
Nutramigen Corn syrup solids, cornstarch Corn syrup solids, dextrose, Pregestimil cornstarch Alimentum Sucrose, tapioca starch
Elecare, Neocate, Nutramigen AA Corn syrup solids
ALDOB sequence: p.R60X & p.A150P
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION AST
ALT
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION INR
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION PALF: Background, Natural History, & Etiology
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION DEFINITION OF PEDIATRIC ACUTE LIVER FAILURE
Sudden onset of… 1. Biochemical evidence of liver injury 2. Vitamin K-resistant coagulopathy . INR > 2 . INR 1.5-1.9, if encephalopathy is present 3. In an individual with no underlying liver disease
Pediatric Acute Liver Failure Study Group GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION PALF EPIDEMIOLOGY
• Uncommon; ? 100-200 cases/year • No age, sex, racial, ethnic predilection • Weak signal for seasonality (Dec-Feb > Jun-Aug) • Accounts for 10-15% of pediatric LTs performed in the US annually (~50-75) • 15-20% of patients with PALF die awaiting LT
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION NATURAL HISTORY
Alive Liver Function Liver
Prodrome Dead Time GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Adapted from Liver Disease in Children, Suchy, Sokol, & Ballistreri ETIOLOGY • PALF represents the final common pathway for a diverse set of conditions • Direct injury • Host response • 33%-67% of PALF is indeterminate in etiology • Age of the patient is the most important factor in developing an initial differential diagnosis
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION INFANT/NEONATAL ALF <4 weeks 4-8 weeks 9 weeks-1 year Indeterminate 38% 41% 45% Acetaminophen 0 5% 5% Metabolic 16% 27% 20% Autoimmune 0 0 6% Viral 22% 0 4% Shock 4% 9% 6% GALD 14% 14% 1% HLH 1% 0 6%
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Pediatric Acute Liver Failure Study Group CHILD/ADOLESCENT ALF 1-5 years 6-10 years >10 years Indeterminate 67% 62% 32% Acetaminophen 4% 3% 29% Metabolic 5% 8% 9% Autoimmune 7% 5% 10% Viral 5% 3% 5% Shock 2% 7% 3% GALD 0 0 0 HLH 2% 0 0
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Pediatric Acute Liver Failure Study Group PALF: Practical Issues in Evaluation and Management
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION Initial Stabilization Discussion with LT center
Diagnostic Advanced ICU care Evaluation
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION DIAGNOSTIC EVALUATION A critically important initial priority is rapidly identifying a cause for PALF
Survival with native liver 94% acetaminophen 1. Identify treatable conditions 41% non-APAP drug 2. Informs prognosis 45% indeterminate 3. Aids in decision making vis-à-vis transplantation
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION EXCLUDE TREATABLE CONDITIONS
Entity Treatment Initial Test Galactosemia Exclude dietary lactose GALT activity Tyrosinemia Tyr & Phe exclusion, NTBC Urine succinylacetone Hereditary Fructose Intolerance Exclude dietary fructose & sucrose History Herpes Simplex Virus Acyclovir PCR Gestational Alloimmune Liver IVIG and exchange transfusion History, ferritin Disease Acetaminophen N-acetylcysteine Acetaminophen level Autoimmune Hepatitis Steroids Antibodies, total IgG
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION SPECIAL CONSIDERATIONS FOR POTENTIAL TRANSPLANT CANDIDATES • Advanced cardiopulmonary disease • Uncontrolled malignancy not confined to the liver • Mitochondrial disorders • Untreatable infection outside the liver • Cerebral edema
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION DIAGNOSTIC EVALUATION
• Blood is precious-someone must be its steward 1. Labs needed for life support 2. High priority diagnostic tests 3. Routine priority diagnostic tests
• Liver biopsy?
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION LIVER BIOPSY: PRIMUM NON NOCERE
• Prognosis • Diagnosis • Often a short window to obtain • Balance risks of transport, sedation, bleeding
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION 12-YEAR-OLD FEMALE
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Courtesy Mihail Firan, MD EXPLANT - 8 DAYS LATER
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Courtesy Mihail Firan, MD ADVANCED ICU CARE
1. Coagulopathy
2. Hepatic Encephalopathy
3. N-acetylcysteine for non- acetaminophen PALF
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Bernal & Wendon, NEJM, 2013 (1) COAGULOPATHY
Goal: avoid bleeding complications & unnecessary administration of blood products • INR widely used to gauge liver synthetic function • May overestimate the degree of coagulopathy • Balanced reduction in hepatic synthesis of both procoagulant and anticoagulant proteins
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION Balanced coagulopathy of liver failure
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION
Trppodi & Mannucci, NEJM, 2011 5-year-old male with ALF INR 3.1, platelets 422,000
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION COAGULOPATHY – TREATMENT
• Administer parenteral vitamin K • Avoid efforts to “correct” the INR or platelet count with blood products except where there is bleeding, or an invasive procedure is required • Obtain thromboelastography/ROTEM to evaluate the entire kinetics of hemostasis (pro-, anticoagulant factors, fibrinogen, platelets, red cells) • Plasmapheresis for unbalanced coagulopathy with bleeding
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION HEPATIC ENCEPHALOPATHY - MOLECULAR ADSORBENT RECIRCULATING SYSTEM • FDA cleared for acute poisoning and HE due to chronic liver disease in adults • Add-on to conventional CRRT circuit • Efficient removal of protein-bound molecules in addition to the clearance of water-soluble molecules in CRRT
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION Does not remove Removes • Albumin • Bilirubin • IgG • Bile acids • Clotting • Copper factors • Ammonia • Binding • Cytokines proteins • Nitric oxide
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION (3) N-ACETYLCYSTEINE FOR NON-APAP ALF
• Adult patients with non-APAP ALF • 81 = NAC, 92 = Placebo • Transplant-free survival 52% vs. 30% (p<0.05) • Benefit appears limited to early stage HE
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION • Children with non-APAP PALF • 92 = NAC, 92 = Placebo • 70% of both groups had HE grade 1-2
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION OBJECTIVES • List common causes of acute liver failure in children of different ages
• Explain the concept “balanced coagulopathy”
• Utilize N-acetyl cysteine for appropriate cases of acute liver failure
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION THANK YOU
Ryan Himes, MD [email protected] cell 713-882-0032
GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION