Tanya was admitted at another hospital and one day 1 she had hypoglycemia. Nothing much was made of her hypoglycemia and was discharged next day.
While at home Tanya was mot well at all with excessive crying and persistent vomiting and hence was readmitted.
She had high anion gap acidosis and deep conjugated hyperbilirubinemia, with transaminitis and gross synthetic function derangement; as shown here.
She had hypoglycemia but otherwise CBC and Renal functions were normal. USG was unremarkable, although CBD could not be visualized.
Sepsis work up was done. A large number of admissions with neonatal jaundice, up to 1/3 in some studies, are due to cholestasis of inflammation, i.e. Secondary to infections; which when adequately treated results in resolution of jaundice. Therefore sepsis work up is an integral part of investigations for neonatal jaundice.
Even in a short span of life, neonates behave differently to various insults and therefore presentations for various etiologies could be distinctly different.
Some metabolic diseases affect crucial liver functions and mother can’t protect the child and hence they manifest in utero with IUGR or something like that. Other diseases are such that mother provides protection till birth and hence these metaboic derangements take time to manifest.
If you see a neonatal failure or for that matter any other disease in this age group, what makes you suspect metabolic diseases?
Now that you have hopefully stabilized the patient and have some clue as to the broad category of underlying etiology; so how will you proceed further from here? First panel shows routine tests which have metabolic significance and except tests for Galactosemia all are universally available.
Some steps are needed immediately without proof of metabolic etiology or precise nature of the metabolic etiology to prevent damage or death
IV dextrose switches off almost all metabolism and the treatment of choice. Dextrose may worsen condition only in pyruvate carboxylase deficiency which it self appears to be very uncommon
normal but overactive histiocytes and lymphocytes that commonly appears in infancy, although it has been seen in all age groups.
Lactulose, once the main stay of treatment for hyperammonemia is out of favor now.
Management of intracranial hypertension. Cerebral edema is one of the most important cause of death; nearly 80% develop cerebral edema and one has to treat it proactively.
Usually hyperammonemia is not life threatening on its own in liver failure and sodium benzoate which is available as oral powder, will take care of it. Sod butyrate is not availble easily. Both provide alternative pathwa for ammonia detoxification. Arginine, carnitine and N-Carbamyl glutamate are mainly required in life threatening hyperammonemia of Urea Cycle Disorders
Avoid correcting coagulopathy unless mandatory because you will loose a good marker for prognostication
No routine antibiotics unless as specified above
Because of high lactate and increased TCA/ Krebb’s cycle metabolite our focus was now on mitochondrial liver diseases. Normalacyl carnitine profile makes Faaty Acid Oxidation Disorders unlikely
These are intermediate mitochondrial DNA levels
2 neonatal liver failure
Approach to a case of
neonatal liver failure
Dr Meet Leuva
2nd year resident, V S hospital
Dr Manoj K Ghoda
This is the story of Tanya....
..........And what she taught us
There is always more to learn
Neonatal Liver Failure
At another hospital
• 1st child of 2degree consanguineous
• Hypoglycemia (sugar 35mg) onD1
Hypoglycemia soon after birth: Perinatal events, Galactosemia, GSDs, Organic
Hypoglycemia starting late in infancy or early childhood: FAOD, PHHI, HFI, Insulinoma,
Readmitted* (at the same hospital) NNU D5
* Lesson: Repeated admission should raise the suspicion of metabolic
•Metabolic acidosis with pH of 7.1 and high
•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
•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
Sepsis work up:
WCC 14,000 with 70% polys
CRP: 5 ( up to 1 mg/L)
Blood culture obtained for aerobic, anerobic; and fungal
Urine microscopy normal, culture awaited.
What is your working diagnosis here?
What would be your priorities here?
Diagnosed as Acute Liver Failure.
Neonatal liver failure can be defined as "failure* of
the synthetic function of liver within 4 weeks
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.
Why Acute Liver Failure in neonates assume
Acute liver failure (ALF) is potentially devastating process[1–3]
It progresses fast resulting in death or transplant if not
arrested with appropriate treatment
Once ALF it is diagnosed there is no time to loose.
Priorities in such cases are as follows
•Correct any immediate life threatening
•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
What are the likely causes of neonatal
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.
Do all causes of neonatal liver failure
have same intensity or timeframe of
•Mitochondrial liver diseases
May be present at birth
•Hemophagocytic Lymphocytic syndrome
May take few days to weeks to manifest
Lesson: Time of presentation may provide clue as
to the underlying etiology
Overall what features should make you
suspect metabolic disease?
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
When to suspect IEM ?
Or a child with….
• Rapid deterioration for no obvious reasons.
• Rapidly progressive encephalopathy of obscure
• Hypotonia, seizures, especially if hard to control.
When to suspect IEM ?
Or if the child has….
• Apnea or respiratory distress.
• Sepsis, particularly with E. coli
• Unusual odor.
• Dysmorphic features.
•Total Galactose, Galactose
Metabolic tests which may be required and are
•Ferritin and transferrin
•Acyl carnitine profile
•Urinary organic acids
•Urinary GAG estimation
What basic treatment a pediatrician needs
to start irrespective of the cause if
metabolic cause is suspected?
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
Stabilize the patient without bothering to find out the cause of
illness if the patient is acutely ill.
*Hoffman and Zschocke
Important non-metabolic causes of
neonatal liver failure ?
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
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
Non metabolic investigations of neonatal liver
culture from cutaneous lesions or oropharynx for HSV
cytomegalovirus PCR, IgM varicella zoster virus, IgM Epstein-
barr virus, HIV 1 and 2,
Serum triglyceride, cholesterol, ferritin and bone marrow biopsy
What are the new concepts in management of
Liver failure ?
Newer concepts in management of Liver
To prevent hepatocyte damage
•N-acetyl cysteine (NAC) infusion in non-acetaminophen
causes of ALF  @ 100 mg/kg/d in all cases of ALF
irrespective of the etiology.
•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
•No ....hypothermia, prophylactic phenytoin or corticosteroids in
the management of raised ICP in ALF
•Should be avoided (unless there is a back-up plan for
ventilation) to prevent worsening or assessment of
•If sedation is mandatory, 1-2 mg/kg of propofol can be
•Sodium Benzoate/ Butyrate: 250 mg/Kg in 5-10% D, loading
over 90 mins followed by 250-500mg/Kg over 24 hours.
•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
•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 .
•No Platelet transfusion unless platelet count of 10-20,000 or
significant bleeding with platelet count <50,000/mm3 [5,27].
Empirical antibiotics ... where infection or the likelihood of
impending sepsis is high e.g.
progression of, or advanced stage (III/IV) HE,
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.
No.... No..... No
•Mannitol..except surge in
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
Coming back to our case....
• Plasma Amino Acids
• Organic Acids
– Lactate moderately increased (16
– Increased TCA cycle metabolites
• Acylcarnitines – within normal
limits for neonate
Neonatal Liver Failure
• Further investigation for
• MRI / MRS of Brain
– Reported structurally
– Normal appearance of
– Lactate peak in BG
• Muscle & Liver Bx
– Intrafibre lipid / steatosis
Neonatal Liver Failure
• Muscle & Liver mtDNA
– 37% mean in liver
– 45% mean in muscle
• Nuclear DNA tests
– POLG1 common
– Homozygous for a novel
mutation in DGUOK
• Diagnosis =
secondary to mutation
in DGUOK gene
•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
Thank you;difficult questions will be answered in
(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
(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
Management in the Intensive Care Unit
•A central venous line preferred.
•The fluids titrated as per requirement.
Vasoactive drugs if required.
Monitoring in ICU
(a) vital signs, including blood pressure every 4 hours, more frequently in an
(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.
Electrolyte disturbances and glucose
•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.