ACUTE LIVER FAILURE IN CHILDREN

DR.VIDEESH GUIDED BY

DNB TRAINEE DR.ANITA

M.D (PAEDS)

INTRODUCTION

Acute liver failure (ALF) is a clinical syndrome resultingfrom massive necrosis or from severe functionalimpairment of hepatocytes.

Functions including:

Synthetic

Excretory

Detoxification

all are severely impaired.

DEFINITIONThe original definition of fulminant hepatic failure as coined by Trey and Davidson in 1970 stipulated an onset of hepatic encephalopathy within 8 weeks of the first symptoms of illness, in patients without pre-existing liver disease.

The recognition that different clinical patterns of acute liver failure related to aetiology and prognosis, has led to revision of this definition and the development of differerent classifications.

O`GRADY et al proposed three subcategories of ALF

TYPE INTERVAL CEREBRAL

EDEMA

PROGNOSIS CAUSES

HYPERACUTE <7 days common moderate Hep A,B

Acetaminoph

en

ACUTE 8-28 days common poor Non-A/B/C,

drugs

SUBACUTE 29days-24

wks

rare poor Non-A/B/C,

drugs

• Biochemical evidence of acute liver injury of <8wksduration

• No evidenvce of chronic liver disease

• PT>15sec or INR>1.5 not corrected by Vit K in thepresence of clinical hepatic encephalopathy

• PT>20sec or INR>2 regardless of encephalopathy.

The currently accepted definition includes:

EPIDEMIOLOGY

The true incidence of ALF in children is not known

It is estimated that 0.2%-1% of all acute hepatitis can progress to liver failure.

ETIOLOGY :In about half to two-third of patients with ALF

etiology is unknown.

INFECTIVE

• Hepatitis virus A, B, C, D, E

• Herpes simplex

• Epstein Barr virus

• Parvovirus B19

• Varicella zoster

• CMV

• Adenovirus

• Echovirus

• Coxsackie virus

ADRUG REACTIONS AND TOXINS

• Acetaminophen (paracetamol) overdose

• Halothane

• Isoniazid

• Sodium Valproate

• Phenytoin

• Herbal remedies

• Ecstasy(Methylene Dioxymetamphetamine)

AMETABOLIC

• Wilson’s diseaseA

• Neonatal hemochromatosis

• Tyrosinemia type 1

• Mitochondrial disorders

• Hereditary fructose intolerance

• Alpha-1 antitrypsin deficiency

• Niemann-pick disease

• Indian childhood cirrhosis

• Glycogen storage disease type 4

• Urea cycle defect

ISCHAEMIC

• Budd–Chiari syndrome

• Venoocclusive disease

• Right sided congestive heart failure

• Cardiogenic shock

MISCELLANEOUS

• Massive malignant infiltration

• Severe bacterial sepsis

• Heat stroke

• Autoimmune hepatitis

• Viral infection on underlying chronic liver disease.

In India, the etiological proportions are seen as HAV infection(35%),HEV(15%), Mixed HAV,HEV (15%) and HBV(10%),non A to E(15%) and Drug induced (5%).

If appropriate testing is not done hepatitis B may not be diagnosed since one-third to one-half of acute liver failure become seronegative for hepatitis B surface antigen (HBsAg) after a few days.

Superinfection of hepatitis B with delta virus causes ALF in 50% of cases.

Reactivation of hepatitis B or C virus may lead to ALF following antitumour chemotherapy or cessation of immunosuppressive therapy.

Massive infiltration of the liver as in a lymphoma can lead to ALF

Wilson’s disease must always be excluded in any patient who is less than 35 years old, particularly if haemolysis is associated.ALF can be due to superimposed acute viral infection.

PATHOLOGY

Patchy or confluent massive necrosis of hepatocytes is

seen on liver biopsy.

Multilobular or bridging necrosis with collapse of the

reticulin framework of the liver occurs.

There may be little or no regeneration of hepatocytes

Centrilobular pattern of necrosis :

• Acetaminophen hepatotoxicity

• Circulatory shock

Microvesicular fatty infiltrate of

hepatocytes :

• Reye’s syndrome,

• β-oxidation defects,

• Tetracycline toxicity

NECROSIS OF HEPATOCYTES

PATHOGENESIS

About 1-2% of patients with viral hepatitis experience ALF.

Massive destruction of hepatocytes is due to:

• Cytotoxic effect of the virus,

• Immune response to the viral antigen.

Hepatotoxic metabolites bonding covalently to macromolecular cell constituents occurs in:

• Acetaminophen,

• Isoniazid.

Fulminant hepatic failure may follow depletion of intracellular substrates involved in detoxification, particularly glutathione.

Factors contributing to the pathogenesis include :

• Impaired hepatocyte regeneration,

• Altered parenchymal perfusion,

• Endotoxemia,

• Decreased hepatic reticuloendothelial function.

The pathogenesis of hepatic encephalopathy relates to:

• Increased serum levels of ammonia

• False neurotransmitters, amines

• Increased γ-aminobutyric acid receptor activity

• Increased circulating levels of endogenous benzodiazepine-like compounds

CLINICAL FEATURESInitially prodromal symptoms include:

• Low grade fever

• Abdominal pain

• Anorexia

• Vomiting

These symptoms are followed by

• Progressive jaundice

• Fetor hepaticus

A rapid decrease in liver size without clinical improvement is an ominous sign.

A hemorrhagic diathesis and ascites can also develop

Patients with hepatic encephalopathy initially have minor disturbances of consciousness or motor function.

Irritability, poor feeding, and a change in sleep rhythm may be the only findings in infants.

Asterixis may be demonstrable in older children.

Patients are often somnolent or confused or combative on arousal and eventually may become responsive only to painful stimuli.

Patients may rapidly progress to deeper stages of coma that include:

• Extensor responses

• Decerebrate

• Decorticate posturing

Respirations are usually increased early, but respiratory failure may occur in stage IV coma

STAGES I II III IV

Symptoms Periods of lethargy,

euphoria, reversal

of day-night

sleeping, may be

alert

Drowsiness,

inappropriate

behaviour,

agitation, wide

mood

swings,

disorientation

Stupor but

arousable,

confused,

incoherent

speech

Coma

IVa responds to

noxious stimuli

IVb no

response

Signs Trouble drawing

figures, performing

mental tasks

Asterixis, fetor

hepaticus,

Incontinence

Asterixis,

hyperreflexia,

extensor

reflexes,

rigidity

Areflexia, no

asterixis,

flaccidity

Electroencep

halogramNormal Generalized

slowing, q

waves

Markedly

abnormal,

triphasic

waves

Markedly

abnormal

bilateral

slowing,

d waves,

electric-cortical

silence

STAGES OF HEPATIC ENCEPHALOPATHY

ACUTE LIVER FAILURE :

MANAGEMENT

Acute liver failure is a medical emergency , often associated with unpredictable and sometimes fatal outcome.

Recovery occurs if liver gets adequate time to regenerate with supportive therapy.

Every child with ALF must be treated in ICU setting preferably with liver transplant facility.

AIMS OF THE THERAPY

To prevent & manage complications,

To access the etiology & treat accordingly,

Preparing the patient for liver transplantation if lack of spontaneous recovery by intensive supportive care.

INITIAL WORKUP &

INVESTIGATIONS

GENERAL :• Complete blood count• Liver function tests• Ammonia levels• PT , INR• Blood sugar level• Electrolytes• RFT• Urine analysis• Blood culture• Blood gas and acid-base parameters• Blood grouping-cross match• X-ray chest

VIRAL HEPATITIS MARKERS :

• HAV IgM Antibody

• HEV IgM Antibody

• HBsAg

• Anti HBc IgM Antibody

• HBV DNA

Store sera prior to administration of any blood products for further investigations if needed

IN PRESENCE OF SEVERE

HEMOLYSIS OR SEVERE ANEMIA

• Malaria parasite, malaria antigen

• G6PD level estimation

• Ceruloplasmin, urine copper

• Leptospira antibody

Liver biopsy has no role in ALF

IN SELECTED PATIENTS :

• Autoimmune markers (Coombs test, antinuclear

antibody, liver kidney microsomal antibody (LKM), smooth muscle antibody)

• Ceruloplasmin, urinary copper

• Paracetamol level, Sodium valproate level

• Urine succinylacetone

GENERAL PRINCIPLES OF CARE AND

MONITORING PROTOCOL

• Ensure complete asepsis

• Establish adequate IV access (CVP line)

• Continous monitoring of vital signs

• Pulse oximetry

• Neurological/ coma grading every two hrly

• Blood sugar estimation 2-6 hrly as needed

• Electrolytes, ABG, PT, LFT, RFT 12-24 hrly

• CBC, Blood culture, ESR, urine culture,

CRP, x-ray chest 24-72 hrly

• Nasogastric tube for feeding/ drainage

• Urinary cathetre

• Care of bowel, bladder, back, skin, eyes

STANDARD PROTOCOL FOR

MANAGEMENT OF ALF

• Raise head end (30°-45°) and maintain head in neutral position

• Inj. Cefotaxim and Cloxacillin

• IV Fluids N/5 saline in 10% dextrose at 2/3rd of maintenance after initial fluid resuscitation

• KCl to be added as per serum potassium level.

• Lactulose through NG Tube.

• Mannitol 20% 3-5ml/kg/dose IV slow bolus 4-6 hrly for 6-8 doses (In grade 3-4 coma).

• Ranitidine IV 12 hrly.

• Inj. Vit K.

• Hepatic coma feeds.

CONDITIONS WITH SPECIFIC

THERAPYNo. Condition Therapy

01. Acetaminophen toxicity N-acetyl cysteine

02. Amanita poisoning Penicillin & silibinin

03. Herpes simplex Acyclovir

04. Malaria Antimalarials

05. Enteric encephalopathy Cefotaxim/ceftriaxone

06. Wilsons disease d-penicillamine

07. Tyrosinemia Nitisinone

08. Leptospirosis Penicillin, doxycycline,

tetracyclines

There is increasing evidence for use of N-acetyl cysteine(NAC) infusion in all cases of ALF irrespective of the etiology

Dose : 100 mg/kg/day.

NUTRITION • Catabolic stage characterised by increased negative

nitrogen balance & increased resting energy expenditure.

• Enteral nutrition with higher caloric density feeds to avoid excessive free water and hypo-osmolality.

• Normal protein intake in stage ii & iii encephalopathy.

• Afterwards restriction of proteins.

FLUID AND ELECTROLYTE

DISTURBANCES

HYPOTENSION :

• Volume replacement with NS, RL, plasma or blood.• Give 2/3rd maintenance fluid - N/5 saline in 10% dextrose.• Avoid overloading.• If MAP (DBP+1/3PP) is <60mmHg – Start Inotropes.

METABOLIC ACIDOSIS :

• Suspect fluid deficit.• Look for sepsis (if no fluid deficit).

HYPOKALAEMIA :

• Can precipitate & worsen the severity of hepatic encephalopathy.

• Associated with metabolic alkalosis.• Give KCL infusion.

METABOLIC ALKALOSIS :

• Increase IV KCL to next step.

HYPONATREMIA :

• Restrict fluids to 2/3-3/4 maitenance.• Restrict sodium infusion to <2mEq/kg/day.

HYPERNATREMIA :

• May be precipitated with lactulose administration :reduce/stop lactulose.

• Give N/5 fluids including correction fluid.

HYPOGLYCEMIA :

• Infuse 50 % Dextrose @ 1ml/kg.• Maintain blood sugar between 100-200mg/dl.

ANTIBIOTICS

Empirical administration of antibiotics is recommended whereInfection or impending risk of sepsis is high

• Surveillance cultures reveal significant isolates

• Progression of or advanced stage hepatic encephalopathy

• Refractory hypotension

• Presence of SIRS components

• Patients listed for OLT ( immunosupression )

PREVENTION OF GI HEMORRHAGE

• Secondary to gastritis, stress ulcers, coagulopathy

• Inj. Vit K <1 yr -2.5mg/day >1 yr -5mg/day>5 yr -10mg/day

• IV ranitidine

• IV proton pump inhibitor

HEPATIC ENCEPHALOPATHY

• Reduce or stop protein in grade iii /iv

• Prefer vegetable proteins-BCAA

• Lactulose-0.5ml/kg/dose every 6 hrs orally

• Nonabsorbable oral antibiotics- Rifaximin

• Analgesia and judicious sedation- Propofol, benzodiazepines

COMPLICATIONS OF MANAGEMENT

01.RAISED INTRACRANIAL PRESSURE

Sustained rise of ICP >20 mmHg

C/F - Abnormally reacting pupils- Increased muscular tone- Decerebrate posturing- Abnormal reflexes- Focal seizures- Loss of brainstem reflexes- Bradycardia- Increased B.P.

CEREBRAL EDEMA(B/W STAGE II&III ) HAS VERY POOR PROGNOSIS

& ALL EFFORTS SHOULD BE TAKEN TO PREVENT IT.

STRATEGIES TO PREVENT CEREBRAL

EDEMA

• Avoid excessive handling, suctioning, stimulation

• Prevent coughing, vomiting, frequent movements, neck veins compression, fever, hypertension, hypoxia

• Raise head end 30°. Avoid neck flexion

• Fluid restriction to 60-75% of maintenence with good cerebral perfusion pressure

• Mannitol 20% 0.5gm/kg over 10-15min repeated 4-6hrly for max 72hr in mild to moderate ICP(<60mmHg).

• In anuric or ARF patient dialysis with mannitol

• Elective ventilation- hyperventilate to maintain pCO2 bw 30-35mmHg

• Mannitol resistant CE- Sodium Thiopental ( bolus dose 24mg/kg over 15min f/b slow iv infusion bw 1-2mg/kg/hr )

• Refractory ICP- Indomethacin 25mg infused iv over 1min

02.CONVULSIONS

• Phenytoin 10mg/kg iv slowly. Wait for 20 min. if no response then repeat.

• Maintainence 5-8 mg/kg/day.

• If convulsions persist, Phenobarbitone 10-15mg.kg slowly & wait for 20 min.

• Maintainence 5mg/kg/day in two doses

• If no response Thiopentone iv may be used but watch for Hypotension.

03.HEMORRHAGE

• If PT <30sec – FFP only for invasive procedures

• If PT >30sec – FFP 10ml/kg.

• Severe bleeding – FFP & Platelet transfusion.

• Significant hypofibrinogenemia (<100mg/dl) - Cryoprecipitate

• Recombinant factor VIIa – when FFP has failed to correct INR , volume overload, before invasive procedures with high risk of bleeding.

04.RENAL FAILURE

• Due to hepatorenal syndrome, dehydration, acute tubular necrosis.

• Maintain urine o/p >1ml/kg/hr.

• Try colloid challenge 10ml/kg. repeat if no response.

• Diuretics.

• Renal replacement therapy- in fluid overload,

unresponsive renal failure, hyperkalemia.

05.SEPSIS• Signs- tachycardia, raised core-toe temp. gradient,

fall in BP or urine output, hypoglycaemia, hypothermia, deterioration in mental state, fits, acidosis.

• Common organisms- Staphylococci, Gram negative bacteria,Fungal infections.

• Broad spectrum antibiotics - IV Cloxacillin/Ampicillin + IV Cefotaxim/Ceftazidime.

• Antifungals/Metronidazole may be added if no response in 48-72hrs.

• Avoid Aminoglycosides.

LIVER TRANSPLANTATION

LT is the only definitive treatment for ALF.

Several prognostic scoring systems have been devised to predict mortality and to identify those requiring early LT.

These include King’s College Hospital (KCH) criteria, pediatric end-stage liver disease (PELD) score, APACHE II, and Clichy criteria.

The KCH criteria have been shown to have a better performance than the Clichy criteria and is widely

used.

Liver transplantation could be :

CADAVERIC1)Whole graft – When the whole liver is used.2)Spilt graft – When the donor liver is used for two recipients.3)Reduced graft – When the donor liver is reduced to suit the size for recipient.

LIVING RELATEDWhen a live donor gives part of his/her liver to

recipient.

Contraindications for pediatric LT

Active uncontrollable and untreatable sepsis,

Severe cardiopulmonary disease, Multi-organ failure, Extrahepatic malignancy, Mitochondrial disease, Active substance abuse, HE grade IV with severe neurological

impairment

Outcome : In more than 50% of children with ALF there is poorsurvival unless LT is offered at the appropriate time.

Poor Prognostic factors - Liver necrosis- Multi organ failure- INR >4 - Young age of the child (<1 yr)- Need for dialysis before LT

The prognosis is better with hepatitis A,acetaminophen overdose and ischemia (approximately60% spontaneous survival), and

poor with drug-inducedALF (non-acetaminophen), hepatitis B, and indeterminate

cases.

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