DIRECT HYPERBILIRUBINEMIA IN NEONATES

(NEONATAL CHOLESTASIS)

By: Dr Naved Akhter

JUNE 6, 2014

DIRECT HYPERBILIRUBINEMIA

• Conjugated hyperbilirubinemia in a neonate is defined as a serum direct/conjugated bilirubin concentrationt greater than 1.0 mg/dl,if the TSB is <5.0mg/dl. or

Greater than 20 % of TSB if the TSB is >5.0mg/dl. (ref. IAP,INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 & CLOHARTY)

• Conjugated hyperbilirubinemia is defined biochemically as a conjugated bilirubin level of >2mg/dL and >20% of the total bilirubin.

(REF DOI: 10.1542/pir.33-7-29Pediatrics in Review 2012;33;29 1,AAP)

NEONATAL CHOLESTASIS • Neonatal cholestasis is defined as conjugated hyperbilirubinemia occuring in

the newborn as a consequence of diminished bile flow, with the passage of high coloured urine with or without acholic stools.

( REF.INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 )

Incidence

• In India it constitutes 19%-33% of all chronic liver disease in children reporting to tertiary care hospitals.

• Affects 1 in 2500 live births.

( REF.INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 )

ETIOLOGIES

• Intrahepatic causes

• Extrahepatic causes

Biliary drainage

INTRAHEPATIC ETIOLOGIES

Hepatocellular causes Bile duct injury (Neonatal hepatitis)• Idiopathic: INH• Toxic Intrahepatic bile duct hypoplasia or paucity.• Genetic/Chromosomal • Infectious• Metabolic• Miscellaneous

Intrahepatic disorders• Idiopathic Idiopathic Neonatal Hepatitis.• Intrahepatic cholestasis,persistent

Severe intrahepatic cholestasis with progressive hepatocellular disease.

Alagille syndrome(syndromic paucity of the intrahepatic bile ducts,arteriohepatic dysplasia)

Nonsyndromic paucity of the intrahepatic bile ducts.• Intrahepatic cholestasis,recurrent

BRIC Benign recurrent intrahepatic cholestasis. Hereditary cholestasis with lymhedema(Aagenaes syndrome) • Anatomic Congenital hepatic fibrosis or infantile polycystic disease(liver &

kidney) Caroli disease

• Toxic– TPN-associated cholestasis(>2 weeks) generally in LBW infants.

It occurs due to parenteral use of lipids.Sepsis & ischemic necrosis may also cause cholestasis.

– Drug-induced cholestasis• Genetic/Chromosomal– Trisomy 18,Trisomy 21

• Infectious– Bacterial sepsis (E. coli,Staph. Aureus,listeria,tuberculosis,group B beta

hemolytic streptococcus,syphillis,HIV)– Hepatitis B and C,rubella,herpes,EBV,coxsackie

virus,adenovirus,echoviruses 14 & 19• Parasitic : toxoplasma

• Metabolic– Disorders of Carbohydrate Metabolism• Galactosemia• Fructosemia• Glycogen Storage Disease Type IV

– Disorders of Amino Acid Metabolism• Tyrosinemia• Hypermethioninemia

– Disorders of Lipid Metabolism• Niemann-Pick disease• Gaucher disease

– Disorders of Bile Acid Metabolism• 3B-hydroxysteroid dehydrogenase/isomerase• Trihydroxycoprostanic acidemia

Peroxisomal Disorders• Zellweger syndrom

Disorders of bile acid transport.• Rotor syndrome• Dubin johnson syndrome• Mitochondrial hepatopathie

Endocrine Disorders• Hypothyroidism• Idiopathic Hypopituitarism.

Systemic disorders• Shock• Heart failure• Neonatal lupus erythematosus.

Miscellaneous

• Haemophagocytic lymphohistiocytosis• Neonatal leukemia• Erythroblastosis foetalis.• Intestinal obstruction.• ARC syndrome(arthrogryposis,renal tubular dysfunction and

cholestasis)

• GENETIC : PFIC (Progressive familial intrahepatic cholestasis)• PFIC type1(Byler’s disease),type 2 and type 3.

EXTRAHEPATIC CAUSES

• Biliary atresia: accounting for 40% to 50% of all cases.

(ref. DOI: 10.1542/pir.33-7-291Pediatrics in Review 2012;33;291AAP)

• Choledochal cyst• Bile duct stenosis• Spontaneous perforation of the bile duct• Cholelithiasis• Inspissated bile/mucus plug• Extrinsic compression of the bile duct.• Neonatal sclerosing cholangitis.

Events that leads to cholestasis

• The pathophysiology of acquired BA is that of a brisk inflammatory response involving both the intra and extrahepatic bile ducts.

• The ducts are destroyed gradually and replaced with fibrous scar tissue.• The lumen of the bile duct is eventually obliterated and normal bile flow is

impaired,leading to cholestasis

CONSEQUENCES OF PROLONGED CHOLESTASIS

CLINICAL PRESENTATION

Jaundice• Scleral icterus• Hepatomegaly• Acholic stools• Dark urine• Other signs and symptoms depend on specific disease process

History

Physical examination

InvestigationsUrgent investigations:– CBC with PS.– LFT ( to know the hepatic dysfunction)

Total Bilirubin(0.2 -1mg%) and direct bilirubin(0.0-0.4mg%),ALT(5-35U/L),

AST(5-40U/L), alkaline phosphatase(25-250U/L).– GGT (elevated level demonstrate bile duct damage and BA)(8-78U/L)– PT/PTT/INR(demonstrate the hepatic biosynthesis capacity)– Electrolytes.– Blood culutre.– Urine culture, routine microscopy.– RBS (pre-feed).– Ascitic tap (if ascitis).

Further test

• Ophthalmologic examination.• Serum/ urine bile acid levels• DCT and coomb’s test.• Cord blood IgM.• Sweat chloride.(cystic fibrosis)• HBsAG in mother and infant.• Liver biopsy:• light microscopy.

• specific enzyme assay.

• TORCH, VDRL, Hepatitis B/C, HIV,FTA-ABS, CFT for rubella, CMV, herpes.(t/r/o infection)

• T4, TSH

• Serum cortisol

• Alfa -1 AT levels and phenotype

• Galactose -1 Phosphate Uridyl transferase

(to r/o galactosemia) & urine reducing substance(elevated in galactocemia).

• Urinary succinyl acetone (to r/o tyrosinemia)

• Cholesterol, triglycerides(elevated in alagille syndrome)

• S. iron and ferritin levels (to r/o neonatal hemachromatosis)

Algorithmic approach to differentiate EHBA from NH (<60 days)

Approach to late presentation of EHBA (>60 days of life)

GOALS OF TIMELY EVALUATION

Diagnostic algorithm for Mx of Neonatal Cholestasis

Dx algorithm to help in the Mx of Neonatal Cholestasis

Approach to diagnosis: NASPGHAN

Radiological evaluation

Ultrasonography

Excludes choledochal cyst, dilated CBD. Findings s/o BA:1. GB length (<1.5cm long/small lumen)2. GB contraction .3. Triangular cord sign: a triangular- or tubular-shaped echogenic

density that was located immediately cranial to the portal vein bifurcation and is 3mm or more thick.

Sonogram illustrates method of measuring gallbladder length (long arrow) and width (short arrow). These measurements were obtained using maximal longitudinal image.

15-day-old female neonate with unknown cause of infantile cholestasis. Sonogram reveals tubular echogenic cord (arrows). "Triangular cord" was 0.3–0.4 cm wide and 1.3–1.6 cm long.

Hepatobiliary Scintigraphy

• Technetium ,99Tc –disopropylliminodiacetic acid(DISIDA)dyes used.• If Tc not available,I -131 rose bengal fecal excretion test may be used.• A nasoduodenal tube can be passed and fluid collected in 2-hrs aliquots for 24

hrs.• If there is no bile treat with phenobarbital,5mg/kg/day for 7 days( to enhance

the isotope excretion)and repeat the duodenal fluid collection.• Depends on hepatocellular function & patency of biliary tract.• Neonatal Hepatitis: delayed uptake, normal excretion.• Biliary Atresia: normal uptake, absent excretion.• Sensitive (97%) not specific (80%) for EHBA.

• If no extrahepatic obstruction,the child may be observed with careful follow up.

• If extrahepatic obstruction,the baby will need an exploratory laparotomy,cholangiogram and liver biopsy.

Invasive studies

– Duodenal intubation– Percutaneous liver biopsy– Percutaneous transhepatic cholangiography or intraoperative

cholangiogram: GOLD standard in the dx of Biliary atresia,a KASAI procedure is indicated if contrast is unable to fill the biliary tract or reach the intestine.

– ERCP: Endoscopic Retrograde Cholangiopancreatography.– MRCP:Magnetic Resonance Cholangiopancreatography.

Indications for laparotomy-IAP

1) Acholic stools & liver bopsy-BA

2) Biopsy equivocal but acholic stools, intrahepatic causes r/o, non excreting HIDA.

3) Biopsy equivocal,acholic stools, baby 7 wks & lap and peroperative cholangiogram.

4) Biopsy equivocal, acholic stools, ERCP atresia.

ERCP image

LIVER BIOPSYMost imp. Inv in differentiating NH and BA.Accuracy of 83% to 97%.Prerequisites: Normal PT & platelet count.Complications:

Bleeding

Bile peritonitis

Pneumothorax

• EHBA is characterized by presence of proliferation of interlobular ducts, plugged with bile casts and portal tracts show fibrosis.

• The liver parenchyma may be normal, or may show intrahepatocytic or canalicular cholestasis.

• But in advanced cases after 2 months of life there may be full-fledged changes of secondary biliary cirrhosis.

• In neonatal hepatitis there is marked parenchymal injury suggesting focal necrosis, ballooning degeneration,giant cell transformation , inflammatory infiltrate, pseudoacinar formation and portal tract may show mild portal triaditis.

There is no fibrosis until the disease is chronic• Diagnosis of PIBD can be made on histology if the ratio of presence of

bile ducts to portal tracts is less than 0.4 to 0.6. But liver biopsy should contain minimum

• 5 portal tracts to make the diagnosis of PIBD in a biopsy specimen.

F/O Neonatal hepatitis

• Marked irregularities in size of hepatocytes.• Bile canaliculi reduced.• Kupffer cells swollen.• Extramedullary hematopoiesis.

• Relative absence of bile duct proliferation.

F/O Biliary atresia

• Proliferation of proximal ductules.• Bile plugs.• Portal tract lymphatics and arterioles dilated.• Secondary paucity of portal bile ducts.• Intracellular and canalicular cholestasis.

EXTRAHEPATIC BILIARY ATRESIA

• Generally acholic stools with onset at about 2 weeks-old• Average birth weight• Hepatomegaly with firm to hard consistency• Female predominance• No well-documented familial cases.• Increased incidence of polysplenia syndrome and intra-abdominal

vascular anomalies• Normal uptake on radionucleotide scan with absent excretion• Biopsy shows bile duct proliferation, bile plugs, portal or perilobular

fibrosis and edema, and intact lobular structure

IDIOPATHIC NEONATAL HEPATITIS

• Generally normal stools or acholic stools with onset at one month-old• Low birth weight• Normal liver on exam or hepatomegaly with normal to firm

consistency• Male predominance• Familial cases (15-20%).• FINDINGS• Impaired uptake on radionucleotide scan with normal excretion• Biopsy shows intralobular inflammation with focal hepatocellular

necrosis and disruption of the hepatic architecture. No alteration of the bile ducts.

• Giant cell transformation occurs but is non-specific.

ALPHA-1-ANTITRYPSIN DEFICIENCY

• Alpha-1-antitrypsin makes up 90% of alpha-1-globulin fraction• Associated with PiZZ (about 10-20% will have liver disease) and rarely

with PiSZ and PiZ-null phenotypes• Biopsy shows hepatocellular edema, giant cell transformation,

necrosis, and pseudoacinar transformation.• Biopsy also shows accumulation of PAS-positive, diastase-resistant

globules in the cytoplasm of periportal hepatocytes.• Varying degrees of fibrosis correlate with disease prognosis.

INTRAHEPATIC CHOLESTASIS SYNDROMES

• Includes several diagnostic entities.• Biopsies show cholestasis. • May show paucity of intrahepatic bile ducts, giant cell

transformation, and/or fibrosis.

MANAGEMENT OF NEONATAL CHOLESTASIS

• Medical management.• Surgical management.

• First goal in managing children with cholestasis is the recognition of diseases amenable to specific medical therapy (eg.galactosemia,tyrosenemia,hypothyroidism) or early surgical intervention(biliary atresia,choledochal cyst).

TREATMENT

• Medical management– Nutritional support.– Treatment of pruritus.– Choleretics and bile acid-binders.– Management of portal hypertension and its consequences.

IMPAIRMENT MANAGEMENT(NASPGHAN)

MANAGEMENTIAP

Malabsorption Medium chain TGs given Medium chain TGs given,breast feeding cont, 200 Kcal/kg/d,1-2 gm protein/kg/d

Fat soluble vit malabsorption

Vit A deficiency 10,000-15,000 IU 50,000 IU i.m or10,000 IU monthly

Vit E deficiency

50-400 IU/d; oral alfa tocopherol 50-200 mg/d orally

Vit D deficiency 5000 -8000IU/d of D23-5 mcg/kg/d of 25 HCC

30,000 IU i.m –diagnosisOr 400-1200 IU/day

Vit K deficiency 2.5 -5.0 mg alternate day. 5 mg/d im x3 days,5 mg wkly.Perform PT monthly.

Microutrient deficiency Ca, P, Zn supplementation Ca, P, Zn supplementation

Water soluble Vit def. 2 times RDA supplementation 2-5 times RDA supplementation

OTHER VITAMIN AND MINERAL

REQUIREMENTS IN INFANTS WITH CHOLESTASIS• Water soluble vitamins Oral 1-2 times the RDA

• Calcium** Oral 20-100 mg/kg/d

• Phosphorus Oral 25-50 mg/kg/d

• Zinc Oral 1 mg/kg/d

• Magnesium Oral 1-2 mEq/kg/d

Intravenous 0.3-0.5 mEq/ kg over3 hours of 50% solution

• Elemental iron Oral 5-6 mg/kg/d

TREATMENT

• Treatment of pruritus– Bile acid-binders: cholestyramine (4-8 g/day)– Ursodeoxycholic acid (15-20 mg/kg/day)– Phenobarbital (5mg/kg/day)– Rifampicin (10 mg/day)– Terfenadine (1-3 mg/kg/day)– Photothearpy with UV/ Infrared rays x 3-10 min/day

TREATMENT• Management of portal hypertension and its consequences– Variceal bleeding• Fluid rescuscitation• Blood products• Sclerotherapy• Balloon tamponade• Portovenous shunting

– Ascites• Sodium restriction• Diuretics: spironolactone, furosemide• Albumin• Paracentesis

– Thrombocytopenia managed with platelet infusions when clinically indicated

TREATMENT

• Surgical– Kasai procedure for biliary atresia– Limited bile duct resection and re-anastomosis– Choledochal cyst excision– Cholecystectomy– Liver transplantation

KASAI PROCEDURE

• Performed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.

• Roux-en-Y portoenterostomy• Bile flow re-established in 80-90% if performed prior to 8 weeks-old.• Bile flow re-established in less than 20% if performed after 12 weeks-

old.

• Success of the operation is dependent on the presence and size of ductal remnants, the extent of the intrahepatic disease, and the experience of the surgeon.

• Complications are ascending cholangitis and re obstruction as well as failure to re-establish bile flow.

LIVER TRANSPLANTATION

• Biliary atresia is the most common indication for transplant and may be the initial treatment when detected late or may be used as a salvage procedure for a failed Kasai.

• Used early in cases of tyrosinemia.• Cost: In excess of Rs 15,00,000 to Rs 20,00,000• Only few centres in india.

Indications:• Decompensated liver disease(ascites and/or encephelopathy) .• Failed portoenterostomy. • 1-year survival rate- 85-90%• 5-8 year survival rate- 75-80%

• 1/3 to 1/2patients are of Biliary Atresia.(Whitington et al SEMIN LIVER DIS1994;14:303-317)

Prognosis Biliary Atresia:• Age(< 8 wks): the single most important determinant in successful

management of BA. • Of pts. Undergoing Kasai’s procedure, 80% jaundice free if done

before 60 days, as against 25-35% of infants operated later on.(Mieli –Vergani et al.

LANCET 1989;1:421-423)

Neonatal Hepatitis:

• No indicators to predict prognosis.

Long term outcome

Biliary Atresia:

• Mean survival in untreated pts. :19 mths (Hays et al. SURGERY 1963;54:373-375)

• 3-year survival : <10% (Karrer et al J PEDIATR SURG 1990;25:1076-1080)

Neonatal Hepatitis:• Upto 60% of pts.with idiopathis NH recover completely without any

specific therapy.• Upto 10% die acutely of bleeding manifetstations or fulminant hepatic

failure.

• 30 % progress to liver cirrhosis and death due to CLD.

Key messages• Refer early to specialised centres.• Congenital infection is the commonest cause of cholestatic jaundice in

infants.• Percutaneous liver biopsy is safe and most useful for diagnosis.

• Surgery for BA and choledochal cyst should be done before 2 months of

age.

Thank You