Approach to a case of

neonatal liver failureDr Meet Leuva

2nd year resident, V S hospitalDr Manoj K Ghoda

Consultant GastroenterologistAhmedabad

This is the story of Tanya.... ..........And what she taught us

There is always more to learn

Lessons learnt

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, PHHIHypoglycemia starting late in infancy or early childhood: FAOD, PHHI, HFI, Insulinoma, GSDs

Readmitted* (at the same hospital) NNU D5

• Vomiting•Dehydration• “Rapid” breathing

* Lesson: Repeated admission should raise the suspicion of metabolic disease

• 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”

• 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% polysCRP: 5 ( up to 1 mg/L)

Blood culture obtained for aerobic, anerobic; and fungal culture

Urine microscopy normal, culture awaited.

CXR: NAD

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 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.

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

LessonOnce ALF it is diagnosed there is no time to loose.

What are your priorities here?

Priorities in such cases are as followsSimultaneously...

•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

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.

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

• 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

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

particular food.

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.

When to suspect IEM ?

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

•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

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

Lesson: 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 ?

•HSV hepatitis•Hemophagocytic syndrome

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 failure:

Infectious :culture from cutaneous lesions or oropharynx for HSVViral markerscytomegalovirus PCR, IgM varicella zoster virus, IgM Epstein-barr virus, HIV 1 and 2,

Hemophagocytosis

Serum triglyceride, cholesterol, ferritin and bone marrow biopsy

What are the new concepts in management of Liver failure ?

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.

•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

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.

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

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].

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.

Lesson learnt..

No.... No..... No

•Hepamerz•Lactulose•Mannitol..except surge in ICP•Routine FFP•Routine antibiotics

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

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

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

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

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

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

Thank you; difficult questions will be answered in

Sanskrit

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

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 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.

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.