This document discusses the approach to a case of neonatal liver failure. It begins by describing the case presentation and initial workup. Key points include that metabolic diseases are a common cause of neonatal liver failure. The document then discusses priorities in management, which include stabilizing life-threatening issues and starting investigations. Common causes like galactosemia, tyrosinemia, and HSV hepatitis are discussed. Newer concepts in management like N-acetylcysteine are also covered. Finally, the case is summarized as mitochondrial DNA depletion syndrome caused by a novel mutation in the DGUOK gene.

1. Approach to a case of
neonatal liver failure
Dr Meet Leuva
2nd year resident, V S hospital
Dr Manoj K Ghoda
Consultant Gastroenterologist
Ahmedabad

2. This is the story of Tanya....
..........And what she taught us
There is always more to learn
Lessons learnt

4. Neonatal Liver Failure
At another hospital
• 1st child of 2degree consanguineous
parents
• IUGR
• NVD
• Hypoglycemia (sugar 35mg) onD1
Hypoglycemia soon after birth: Perinatal events, Galactosemia, GSDs, Organic
acidemia, PHHI
Hypoglycemia starting late in infancy or early childhood: FAOD, PHHI, HFI, Insulinoma,
GSDs

5. Readmitted* (at the same hospital) NNU D5
•Vomiting
•Dehydration
•“Rapid” breathing
* Lesson: Repeated admission should raise the suspicion of metabolic
disease

6. •Metabolic acidosis with pH of 7.1 and high
anion gap
•Jaundice: SBR 25 mg., mainly conjugated
•Transaminitis; ALT 600, AST 500, GGT 500
•Coagulopathy, INR 4, PT 40 sec (10.3), not
corrected by IV Vit K
•S. Albumin 2.1 , Glob 1.8
•Ammonia 375 µmol/L ( up to 180 at this age)
Anion gap = AG = [Na+] + [K+] - [Cl-] - [HCO3-].
Normal range: 8 to 16 mmol/L
Anion gap metabolic acidosis: Consider organic acidopathy, lactic acidosis, and
ketoacidosis. These are not measured in above equation and hence they produce a
“gap”

7. •Hypoglycemia, blood sugar 35 mg%
•RFTs were normal, Urea 23, creat 1.0
•CBC: Mild normochromic, normocytic anemia, Hb 11.2,
WCC 14,000, Plt 2,30,000, reticulocytes 2%
•Urine reducing substances ( non glucose) negative;
•USG: Normal size and echo texture, collapsed GB, CBD
could not be visualized, IHBR normal, portal vein and
splenic vein normal

8. Sepsis work up:
WCC 14,000 with 70% polys
CRP: 5 ( up to 1 mg/L)
Blood culture obtained for aerobic, anerobic; and fungal
culture
Urine microscopy normal, culture awaited.
CXR: NAD

9. What is your working diagnosis here?
What would be your priorities here?

10. Diagnosed as Acute Liver Failure.
Neonatal liver failure can be defined as "failure* of
the synthetic function of liver within 4 weeks
of birth".
Encephalopathy is not essential for the diagnosis.
*Uncorrectable coagulopathy with INR >1.5 in
patients with hepatic encephalopathy, or INR> 2.0 in
patients without encephalopathy.

11. Why Acute Liver Failure in neonates assume
significance?
Acute liver failure (ALF) is potentially devastating process[1–3]
It progresses fast resulting in death or transplant if not
arrested with appropriate treatment
Lesson
Once ALF it is diagnosed there is no time to loose.

12. What are your priorities here?

13. Priorities in such cases are as follows
Simultaneously...
•Correct any immediate life threatening
complication/ events
•Start investigations to arrive at a diagnosis and
treat accordingly; or
•Arrange for a speedy and safe transport if your
centre is not geared for such emergencies

14. What are the likely causes of neonatal
liver failure?
Etiology of neonatal liver failure
In neonates and infants, metabolic diseases are the
main cause of ALF.[1,9] Amongst non-metabolic causes,
HSV is common and it is an emergency.
In older children, viruses, drug-induced hepatotoxicity
and autoimmune hepatitis are the most common
identified causes of ALF.

15. Do all causes of neonatal liver failure
have same intensity or timeframe of
presentation?

16. •Neonatal Hemochromatosis
•Zellweger syndrome
•Mitochondrial liver diseases
May be present at birth
•Tyrosinemia
•Galactosemia
•Hemophagocytic Lymphocytic syndrome
•HSV hepatitis
May take few days to weeks to manifest
Lesson: Time of presentation may provide clue as
to the underlying etiology

17. Overall what features should make you
suspect metabolic disease?

18. Metabolic Diseases: When should the
alarm bell ring?
if you see a child with…..
• Intermittent illness
• Recurrent unexplained vomiting.
• Failure to thrive.
• Aversion to certain food or the illness starting with
particular food.

19. When to suspect IEM ?
Or a child with….
• Rapid deterioration for no obvious reasons.
• Rapidly progressive encephalopathy of obscure
origin.
• Hypotonia, seizures, especially if hard to control.

20. When to suspect IEM ?
Or if the child has….
• Apnea or respiratory distress.
• Sepsis, particularly with E. coli
• Unusual odor.
• Jaundice.
• Dysmorphic features.
• Organomegaly.

21. •Sugar
•Urinary reducing
substances, urinary
ketones,
•Ammonia
•Urea
•Total Galactose, Galactose
phosphate/ Gal-1-T,
Metabolic tests which may be required and are
now available....
•Lactate
•Ferritin and transferrin
saturation
•Triglycerides
•Alpha- fetoprotein
•Acyl carnitine profile
•Plasma aminoacids
•Urinary organic acids
•Urinary GAG estimation

22. What basic treatment a pediatrician needs
to start irrespective of the cause if
metabolic cause is suspected?

23. The basic principles for treatment of suspected
metabolic disorders are*:
•Prevent catabolism –
•Use IV dextrose.
•Limit the intake of the offending substance - if possible, through
manipulation of the diet. Limit protein in urea cycle disorders, fatty
food in FAOD
Lesson:
Stabilize the patient without bothering to find out the cause of
illness if the patient is acutely ill.
*Hoffman and Zschocke

24. Important non-metabolic causes of
neonatal liver failure ?
•HSV hepatitis
•Hemophagocytic syndrome

25. How and when to suspect HSV hepatitis?
•Could be confused with bacterial sepsis.[30,34]
•Vesicular skin lesions are the most predominant symptom
consistent with neonatal herpes.
•Later on....DIC, hepatitis, pneumonitis, and seizures.[11,29,35]
Lesson: HSV hepatitis is an emergency and
once suspected treatment is mandatory

26. Hemophagocytic lymphohistiocytosis (HLH)
•Rare but potentially fatal.
• Fever, hepatosplenomegaly, pancytopenia, lymphadenopathy
•Cutaneous involvement occurs in as many as 65% of patients.
•An inherited more prevalent with parental consanguinity

27. Non metabolic investigations of neonatal liver
failure:
Infectious :
culture from cutaneous lesions or oropharynx for HSV
Viral markers
cytomegalovirus PCR, IgM varicella zoster virus, IgM Epstein-
barr virus, HIV 1 and 2,
Hemophagocytosis
Serum triglyceride, cholesterol, ferritin and bone marrow biopsy

28. What are the new concepts in management of
Liver failure ?

29. Newer concepts in management of Liver
failure...
To prevent hepatocyte damage
•N-acetyl cysteine (NAC) infusion in non-acetaminophen
causes of ALF [20] @ 100 mg/kg/d in all cases of ALF
irrespective of the etiology.

30. •To prevent cerebral edema
•Prophylactic infusion of 3% saline to maintain sodium at 145-
155 mmol/L ....is preferred over mannitol.
•If neurological signs .. or ICP is above 25 mm Hg, a bolus of IV
mannitol (0.25-1 g/kg, 20%). Repeated if serum osmolality is
less than 320 mosmol/L.
•Hyperventilation with reduction of pCO2 to <35 mmHg.....in
patients with impending herniation where mannitol therapy
fails [23].
•No ....hypothermia, prophylactic phenytoin or corticosteroids in
the management of raised ICP in ALF

31. Sedation:
•Should be avoided (unless there is a back-up plan for
ventilation) to prevent worsening or assessment of
encephalopathy.
•If sedation is mandatory, 1-2 mg/kg of propofol can be
given.

32. Managing Hyperammonemia:
•Sodium Benzoate/ Butyrate: 250 mg/Kg in 5-10% D, loading
over 90 mins followed by 250-500mg/Kg over 24 hours.
•Arginine:
•Carnitine: Do not give Carnitine if Cardiomyopathy is suspected.
•Single oral dose of N-Carbamyl glutamate if NAGS deficiency is
suspected or in organic acidemia
•If these doesn’t work hemofiltration (CRRT) not simple dialysis

33. Coagulopathy
•No routine correction
•FFP if significant bleeding, or while performing invasive
procedure or in situations of extreme coagulopathy with INR>7.
•Cryoprecipitate ... For hypofibrinogenemia (<100 mg/dL).
•Recombinant factor VIIa is beneficial in patients with prolonged
INR despite FFP, who are volume overloaded [26].
•No Platelet transfusion unless platelet count of 10-20,000 or
significant bleeding with platelet count <50,000/mm3 [5,27].

34. Empirical antibiotics ... where infection or the likelihood of
impending sepsis is high e.g.
 cultures positive,
 progression of, or advanced stage (III/IV) HE,
 refractory hypotension,
 renal failure,
 presence of SIRS (temperature >38°C or <36°C, WCC
>12,000 or <4,000/mm3, tachycardia).
•...for patients listed for liver transplantation (LT),
•A third-generation cephalosporin, vancomycin/teicoplanin, and
fluconazole are recommended.
•Fungal infections, particularly Candida albicans, in one third of
patients with ALF.

35. Lesson learnt..
No.... No..... No
•Hepamerz
•Lactulose
•Mannitol..except surge in
ICP
•Routine FFP
•Routine antibiotics

36. Coming back to our case...
Transferred to our unit
• Appeared very sick
• Conservative Rx for ALF
• Rx for NNH (IVIG) (Intrauterine growth
restriction (IUGR) occurs in 25% of infants
with neonatal hemochromatosis)
• Glucose @ 7mg/kg/min
What is
going on
here

37. Coming back to our case....
• Plasma Amino Acids
– Normal
• Organic Acids
– Lactate moderately increased (16
mMol).
– Increased TCA cycle metabolites
• Acylcarnitines – within normal
limits for neonate

38. Neonatal Liver Failure
• Further investigation for
mitochondrial disease
• MRI / MRS of Brain
– Reported structurally
normal
– Normal appearance of
basal ganglia
– Lactate peak in BG
• Muscle & Liver Bx
– Intrafibre lipid / steatosis

39. Neonatal Liver Failure
• Muscle & Liver mtDNA
– 37% mean in liver
– 45% mean in muscle
• Nuclear DNA tests
– POLG1 common
mutations negative
– Homozygous for a novel
mutation in DGUOK
• Diagnosis =
MITOCHONDRIAL DNA
DEPLETION SYNDROME
secondary to mutation
in DGUOK gene

40. Suspecting Mitochondrial Diseases
• Look for multisystem
disease
– Cardiomyopathy
– Renal tubulopathy
– CNS disease – MRI/MRS
– Muscle disease
• Hypotonia
• Muscle biopsy
•Persistent lactic acidosis
•Increase in TCA cycle
metabolites
•Hypoglycemia

41. Summary:
•Neonatal liver failure is an emergency
•Most of the causes are metabolic
•Galactosemia, Tyrosinemia, Neonatal
hemochromatosis, HSV hepatitis and
Hemophagocytosis are treatable and must be
actively looked for
•Familiarize your self with newer therapies

42. Thank you;difficult questions will be answered in
Sanskrit

45. Pediatric ALF
(a) evidence of liver dysfunction within 8 weeks of onset of
symptoms (with or without overt symptoms)
(b) uncorrectable coagulopathy with INR >1.5 in patients with
hepatic encephalopathy, or INR> 2.0 in patients without
encephalopathy; and
(c) no evidence of chronic liver disease either at presentation or
in the past.
Vidyut Bhatia, Ashish Bavdekar and Surender Kumar Yachha for the Pediatric Gastroenterology
Chapter of Indian Academy of Pediatrics.
Management of Acute Liver Failure in Infants and Children: Consensus Statement of the Pediatric
Gastroenterology Chapter, Indian Academy of Pediatrics. Indian Pediatr 2013;50: 477-482

46. Management in the Intensive Care Unit
•A central venous line preferred.
•The fluids titrated as per requirement.
Vasoactive drugs if required.

47. Monitoring in ICU
(a) vital signs, including blood pressure every 4 hours, more frequently in an
unstable child
(b) continuous oxygen saturation monitoring
(c) neurological observations/coma grading, electrolyte, arterial blood
gases, blood sugar every 12 hourly (more frequently in an unstable
child); prothrombin time should be monitored 12 hourly till patient
stabilizes or decision to perform a transplant is taken
(d) daily measurements of liver span and prescription review
(e) liver function tests, blood urea, serum creatinine, calcium and phosphate
at least twice weekly. Surveillance of blood and urine cultures should be
done during the course of illness.

48. Electrolyte disturbances and glucose
homeostasis:
•Hyponatremia, hypokalemia, hypocalcemia, hypophosphatemia and
hypomagnesemia are commonly observed.
•Persistent hyponatremia and hypoglycemia are poor prognostic parameters.
•Patients with ALF are at an increased risk for hypoglycemia secondary to
failure of hepatic gluconeogenesis, hyperinsulinemia and secondary bacterial
infections. But remember, hyperglycemia could be equally dangerous as it
increases osmotic pressure and may be damaging to brain
•Intravenous fluids should be tailored in accordance to electrolyte, sugar and
renal status of the patient.