neonatal liver failure fallo hepático neonatal - sap.org.ar hepato nutri/pdfs... · idiopathic...

5° Congreso Argentino de Gastroenterología, Hepatología y Nutrición Pediátricas

Neonatal liver failureFallo hepático neonatal

Eve A. Roberts, M.D., M.A., FRCPCDivision of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick ChildrenAdjunct Professor of Paediatrics, Medicine and Pharmacology, University of Toronto

Adjunct Scientist, Genetics and Genome Biology, Hospital for Sick Children Research InstitutePhD candidate, Department of Philosophy, Dalhousie University


• Conflict of interest: I have no conflicts of interest to declare.

• Acknowledgements:• Andrew James, M.B.B.S., FRCPC, Hospital for Sick

Children, Toronto• Coady Family Fund for Hepatic Research

Key points—neonatal liver failure• Neonatal liver failure (NLF) is special because it

does not fit with definitions of acute liver failure formulated for children and adults.

• Liver disease can span from fetal life into the newborn period.

• Infants may present with features of acute liver damage (acute-pattern NLF) or decompensated cirrhosis (chronic-pattern NLF).

• Mitochondrial disorders are important causes of NLF.

• Prompt accurate diagnosis is important for best medical or surgical intervention.

Acute liver failure (“ALF”):definition from adult hepatology

• Hepatic damage resulting in loss of critical synthetic and detoxifying functions

• Coagulopathy• Encephalopathy

• Time frame: within 4-8 weeks of onset of apparent liver disease

• Assumption: liver was entirely normal before the disease process began.

Acute liver failure in children:current consensus definition

• Paediatric age-bracket requires a non-restrictive definition.

• Extensive and precipitous loss of hepatic function in a child not previously known to have liver disease

• Time-frame not specified but ≈ ‘acute’• Encephalopathy omitted• Easy-to-use clinically (based on history + INR ± bilirubin)

What about liver failurein babies?

• Both the general (adult) and the paediatric definition do not work well.

• The major conceptual problem: many babies have not lived long enough to fit the definitional time frame

• Second problem: some babies present with biochemical features of chronic liver disease--difficult to call it “acute” liver failure

PALF ‘take’ on this problem• Pediatric Acute Liver Failure (PALF) definition of

acute liver failure in children (2006):• Biochemical evidence of acute liver injury +• No evidence of chronic liver disease +• INR>1.5 unresponsive to vitamin K and accompanied

by hepatic encephalopathy, or• INR>2.0 regardless of hepatic encephalopathy

• PALF definition of neonatal liver failure (2011)• Same criteria as above• Occurring in the first 4 weeks of life

• This definition addresses the first issue but not the second since emphasis is explicitly on acute disease.

Neonatal liver failure (NLF)• Our claim: Prenatal→postnatal time-line

imposes need for special definition• Our definition: severe hepatic dysfunction with

- intractable coagulopathy- metabolic instability- signs of liver damage

presenting in the neonatal period (first 3 months of life) (first 60 days?) (first 100 days?) (first 4 weeks?)

• Somewhat more structured than “failure of the synthetic function within 4 weeks of birth” (Shammugam et al. Eur J Pediatr 2011;170:573)

Neonatal liver failure—critical refinement

• Neonatal liver failure has two patterns:• Acute• Chronic

• Difference has to do with the character of the liver damage.

• NLF—acute pattern = marked elevation of serum aminotransferases (normal at/near time of delivery—suffers severe acute insult)

• NLF—chronic pattern = severely compromised synthetic function but normal or only mildly elevated serum aminotransferases for age (extensive damage during fetal period)

Acute pattern Chronic patternInfection Hepatitis B virus

Hepatitis C (rare)Parvovirus B19

Herpes simplex virus (HSV 1, HSV2)Human herpesvirus 6 (rare)Echovirus, Coxsackie A and B, adenovirusBacterial septicemia

Metabolic diseases Hereditary tyrosinemia, type 1 Hereditary tyrosinemia, type 1

Galactosemia Galactosemia

[TRMU] TRMU (mito-specific tRNA-midifying enzyme)

Hereditary fructosemia, alpha-1-antirtrypsin defic

Citrin deficiency

Mevalonate kinase deficiencyAdenosine deaminase deficiency

Mitochondrial disorders

“Reye-like syndromes”Pearson syndromeMitochondrial translation elongation factor Deoxyguanosine deficiency

“Reye-like syndromes”Pearson syndromeMitochondrial translation elongation factorDeoxyguanosine deficiencyCitrullinemia type 1Non-alloimmune perinatal hemochromatosis (1° PH)

Neoplasia Neuroblastoma Erythrophagocytosis syndromes

Congenital leukemia Wolcott-Rallison syndrome

1° Hemophagocytic lymphohistiocytosis (perforin and other mutations)

1° Hemophagocytic lymphohistiocytosis (perforinand other mutations)

Immune Gestational alloimmune liver disease (GALD)GALD without Fe overloadTransplacental anti-Kp(a)

Vascular Hepatic vein thrombosisHepatic vein outflow block (physiological)

Segmental hepatic vein thrombosis

Idiopathic Fetal asphyxia (?) ‘Le foie vide’ (hepatic non-regeneration syndrome)

Idiopathic neonatal hepatitis, of extreme severity








Citrin deficiency





















Citrin deficiency







Hemophagocytic lymphohistiocytosis (perforin and other mutations)

1° Hemophagocytic lymphohistiocytosis (perforinand other mutations)






Our Canadian study of NLF • Prospective 2-year highly inclusive national study• Respondents were mainly general pediatricians

and neonatologists• Limited to infants in the first 60 days of life

• Nearly all patients presented within 2 weeks of birth• Incidence approximately 1:70,000 live births

• Acute-pattern versus chronic-pattern strategy worked well

• Chronic-pattern NLF more common than acute-pattern• No survivors among acute-pattern NLF infants; among

chronic-pattern NLF infants, only the GALD patient died

Outcomes in a large retrospective sstudy

Shammugam et al. Eur J Pediatr 2011;170:573

Notion of ‘chronic pattern NLF’ highlights importance of liver injury in fetus

• Comparatively limited knowledge of hepatic function in the fetus

• No albumin: α-fetoprotein performs its role• Different spectrum of cytochromes P450• Delayed maturation of bilirubin glucuronosyl

transferase• Different bile acids produced• ‘Partially by-passing’ vascular supply

• Left lobe versus right lobe

• Congenital cirrhosis:• Concept from the 1950s• No single pathogenesis—vascular disorders prominent

Figure from: http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2020/2020%20Exam%20Reviews/Exam%201/CH19%20Blood%20Flow.htm

Mitochondrial disorders causing NLF• Why so difficult to diagnose? Numerous clinical

pictures—highly variable mechanisms1. Complex I: fatal infantile lactic acidosis, …, Leigh2. Complex III: GRACILE (BCS1L mutations)3. Coenzyme Q10 deficiency: myopathy ±

myoglobinuria; ataxia; Leigh-like + renal4. Mitochondrial DNA depletion: hypotonia, lactic

acidosis, ↑CPK, liver failure• Deoxyguanosine kinase (DGUOK) mutations• Deoxythymidine kinase (TK2) mutations• MPV17 mutations (see Navajo neuropathy), TSFM mutations• POLG1 mutations (Alpers syndrome)• TWINKLE (PEO1) mutations

• The first step is to have a high index of suspicion. The next step is to measure serum lactate/pyruvate ratio!

Figure from http://www.bbc.com/news/health-18393682

Gestational alloimmune liver disease (GALD)—main cause of PH

• Rationale for alloimmune mechanism:• Resembles Rh incompatibility: 2nd and later infants;

recurrence rate after first affected too high for genetic mechanism

• Maternal half-siblings affected but not paternal half-siblings• No genetic defects found in HFE spectrum (in affected infants

or in parents)• Supportive data: IV-Ig strategy works well to prevent• Target antigen has not been found• Complement-mediated injury (C′5b-9)• Similarity to NLE where mechanism

involves anti-Ro and/or anti-La• PH literature annotates numerous cases with maternal

positivity for anti-Ro or anti-La or ANA (see Pediatr Devel Pathol2012;15:450 for review)

J Pediatr 1990;116:238

NLE with Fe (no NLF)

What is perinatal (= neonatal) hemochromatosis?

It is a syndrome or phenotype.

Primary=geneticMito regulators?

Fe metabolismpathway?

∆4-3-oxosteroid-5β-reductase deficiencyalmost always secondary

InfectionParvo B19CMVHepatitis X

Mitochondrial disorderPearson syndromeGRACILE syndromeCitrullinemia type 2DGUOK mutation[2 HSC patients]

Immune-mediatedUndetermined AbNeonatal lupus

Fe results from process Fe causes damage ?

Not HFE

My tentative revised classification:

(Note association with Down syndrome.)

e.g. iron regulatory proteins?

‘le foie vide’• We described an infant who was normal at birth

but seems to have had an acute illness and then presented in NLF—chronic pattern.

• Biochemistry looked as if there were no hepatocytes.• Liver histology showed complete absence of

hepatocytes.• We called this ‘le foie vide’—empty liver

• One case has recently been published.• Three other cases have been shown/described to

me.• These infants look as if they have PH/NH but they

do not. Possible non-regeneration syndrome.

Summary—neonatal liver failure• Neonatal liver failure (NLF) is special because it does

not fit definitions of acute liver failure formulated for children and adults.

• Liver disease can span from fetal life into the newborn period. Our understanding of fetal physiology is deficient—area for future research.

• Infants may present with features of acute liver damage (acute-pattern NLF) or decompensated cirrhosis (chronic-pattern NLF).

• Mitochondrial disorders are important causes of NLF and generally overlooked!

• Prompt accurate diagnosis is important for best/most appropriate medical or surgical intervention. Outcome is not necessarily dismal.


Thank you!Muchas gracias!

neonatal liver failure fallo hepático neonatal - sap.org.ar hepato nutri/pdfs... · idiopathic...

Documents