pediatric acute liver failure: pearls and priorities...1. biochemical evidence of liver injury 2....

GASTROENTEROLOGY, HEPATOLOGY, & NUTRITION

Ryan Himes, M.D.

Section Head, Pediatric Gastroenterology, Hepatology, & Nutrition

Medical Director, Pediatric Liver Transplant Program

Ochsner Medical Center, New Orleans

PEDIATRIC ACUTE LIVER FAILURE:PEARLS AND PRIORITIES


• No relevant conflicts-of-interest

• Discussion of off-label use:

• Molecular Adsorbent Recirculating System

DISCLOSURES


• 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

OBJECTIVES


• Unremarkable term delivery

• Growing well on Similac

• Developed blood-streaked stools

• Assessed by his pediatricianmilk protein allergy suspected

• Alimentum started, but he vomited every feed

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




SODIUM [H] 143CARBON DIOXIDE [LL] 12GLUCOSE [LL] 47BUN [L] 5 CREATININE [H] 1.16

WBC 13.52HGB 11.1 HCT 34.3PLATELET [H] 626

AST 444 (H) ALT 206 (H) Alkaline Phos 573 (H)GGT 57Albumin 3.2Bili Unconjugated 0.0 Bili Conjugated 2.1 (H)

Ammonia 179 (HH)INR (HH) 8.3

PH BLOOD 7.12BICARBONATE 10LACTATE [H] 10.2

COLOR URINE YELLOWAPPEARANCE URINE [A] CLOUDY GLUCOSE URINE [A] 3+ BILIRUBIN URINE NEGATIVE KETONE URINE [A] 1+ SPEC GRAV URINE 1.022 BLOOD URINE [A] TRACE PH URINE 5.5 PROTEIN URINE [A] 4+ UROBILINOGEN URINE <2.0NITRITE URINE NEGATIVE LEUKO URINE NEGATIVE

RED SUB URINE [A] 3+


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


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


Common Infant Formulas Carbohydrate Source

Enfamil, Gerber, Similac Lactose, rice starch, maltodextrin

Nutramigen Corn syrup solids, cornstarch

PregestimilCorn syrup solids, dextrose, cornstarch

Alimentum Sucrose, tapioca starch

Elecare, Neocate, Nutramigen AA Corn syrup solids

ALDOB sequence: p.R60X & p.A150P


AST

ALT


INR


PALF: Background, Natural History, & Etiology


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

DEFINITION OF PEDIATRIC ACUTE LIVER FAILURE

Pediatric Acute Liver Failure Study Group


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


NATURAL HISTORYLi

ver

Fun

ctio

n

Time

Pro

dro

me

Alive

Dead

Adapted from Liver Disease in Children, Suchy, Sokol, & Ballistreri


• 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

ETIOLOGY


<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%

INFANT/NEONATAL ALF



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



PALF: Practical Issues in Evaluation and Management


Initial Stabilization

Discussion with LT center

Diagnostic Evaluation

Advanced ICU care


DIAGNOSTIC EVALUATION

A critically important initial priority is

rapidly identifying a cause for PALF

1. Identify treatable conditions

2. Informs prognosis

3. Aids in decision making vis-à-vis transplantation

Survival with native liver94% acetaminophen41% non-APAP drug45% indeterminate


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 Disease

IVIG and exchange transfusion History, ferritin

Acetaminophen N-acetylcysteine Acetaminophen level

Autoimmune Hepatitis Steroids Antibodies, total IgG

EXCLUDE TREATABLE CONDITIONS


• Advanced cardiopulmonary disease

• Uncontrolled malignancy not confined to the liver

• Mitochondrial disorders

• Untreatable infection outside the liver

• Cerebral edema

SPECIAL CONSIDERATIONS FOR POTENTIAL TRANSPLANT CANDIDATES


• 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?

DIAGNOSTIC EVALUATION


LIVER BIOPSY: PRIMUM NON NOCERE

• Prognosis

• Diagnosis

• Often a short window to obtain

• Balance risks of transport, sedation, bleeding


12-YEAR-OLD FEMALE

Courtesy Mihail Firan, MD


Courtesy Mihail Firan, MD

EXPLANT - 8 DAYS LATER


ADVANCED ICU CARE

1. Coagulopathy

2. Hepatic Encephalopathy

3. N-acetylcysteine for non-acetaminophen PALF

Bernal & Wendon, NEJM, 2013


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

(1) COAGULOPATHY


Balanced coagulopathy of liver failure

Trppodi & Mannucci, NEJM, 2011


5-year-old male with ALFINR 3.1, platelets 422,000


• 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

COAGULOPATHY – TREATMENT


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


Removes

• Bilirubin

• Bile acids

• Copper

• Ammonia

• Cytokines

• Nitric oxide

Does not remove

• Albumin

• IgG

• Clotting factors

• Binding proteins


(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


• Children with non-APAP PALF• 92 = NAC, 92 = Placebo• 70% of both groups had HE grade 1-2


• 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

OBJECTIVES


THANK YOU

Ryan Himes, [email protected]

cell 713-882-0032

mailto:[email protected]

pediatric acute liver failure: pearls and priorities...1. biochemical evidence of liver injury 2....

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