Neonatal cholestasis

NEONATAL NEONATAL CHOLESTASISCHOLESTASIS

Dr Surya Kumar

OBJECTIVESOBJECTIVES To know when cholestatic liver disease

should be excluded in the diagnosis of an infant who has jaundice.

How to evaluate a neonate with conjugated hyperbilirubinemia.

Know the therapeutic management of neonates with cholestasis.

Understand the differential diagnosis for neonatal cholestasis.

DEFINITIONSDEFINITIONS

NASPGHAN Definition : Prolonged conjugated

hyperbilirubinemia that occurs in the newborn period with conjugated bilirubin concentration >1 mg% if the total bilirubin <5.0mg% or >20% of the total bilirubin if the total bilirubin >5.0mg%.

(Moyer et al J PEDIATR GASTROENTEROL NUTR 2004;39:115)

IAP Definition: Neonatal cholestasis is defined as

conjugated hyperbilirubinemia > 1.5-2 mg% in a newborn/ infant with passage of high coloured urine with or without acholic stools.

(Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-

851)

Incidence:Incidence:

Constitutes 30% of hepatobiliary disorders in india. ( Consensus report on neonatal cholestasis syndrome,INDIAN

PEDIATRICS 2000;37:845-851)

Affects one in 2500 live births.

ETIOLOGIESETIOLOGIES

Intrahepatic causes

Extrahepatic causes

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES

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


Idiopathic Neonatal HepatitisToxic

◦TPN-associated cholestasis◦Drug-induced cholestasis

Genetic/Chromosomal◦Trisomy 18◦Trisomy 21


Infectious◦Bacterial sepsis (E. coli, Listeriosis,

Staph. aureus)◦TORCHES◦Hepatitis B and C◦Echo virus

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIESMetabolic

◦Disorders of Carbohydrate Metabolism Galactosemia Fructosemia Glycogen Storage Disease Type IV

◦Disorders of Amino Acid Metabolism Tyrosinemia Hypermethioninemia

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIESMetabolic (cont.)

◦Disorders of Lipid Metabolism Niemann-Pick disease Gaucher disease

◦Disorders of Bile Acid Metabolism 3B-hydroxysteroid

dehydrogenase/isomerase Trihydroxycoprostanic acidemia

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIESMetabolic (cont.)

◦Peroxisomal Disorders Zellweger syndrome

◦Endocrine Disorders Hypothyroidism Idiopathic hypopituitarism


Metabolic (cont.)◦Miscellaneous Metabolic Disorders Alpha-1-antitrypsin deficiency Cystic fibrosis Neonatal iron storage disease


Miscellaneous◦Arteriohepatic dysplasia (Alagille syndrome)

◦Nonsyndromic paucity of intrahepatic bile ducts

◦Caroli’s disease◦Byler’s disease◦Congenital hepatic fibrosis

EXTRAHEPATIC ETIOLOGIESEXTRAHEPATIC ETIOLOGIES Extrahepatic biliary atresia Choledochal cyst Bile duct stenosis Spontaneous perforation of the bile

duct Cholelithiasis Inspissated bile/mucus plug Extrinsic compression of the bile duct

(Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)

CLINICAL PRESENTATIONCLINICAL PRESENTATIONJaundiceScleral icterusHepatomegalyAcholic stoolsDark urineOther signs and symptoms depend on

specific disease process

GOALS OF TIMELY GOALS OF TIMELY EVALUATIONEVALUATIONDiagnose and treat known medical

and/or life-threatening conditions.

Identify disorders amenable to surgical therapy within an appropriate time-frame.

Avoid surgical intervention in intrahepatic diseases.

APPRACH TO DIAGNOSIS- IAPAPPRACH TO DIAGNOSIS- IAP

Approach to diagnosis: Approach to diagnosis: NASPGHANNASPGHAN

History:History:

History (contd.)History (contd.)

Physical examination:Physical examination:

Physical exam (contd)Physical exam (contd)

Investigations:Investigations:Urgent investigations:◦CBC with PS, ◦LFT: Total and direct bilirubin, SGOT,

SGPT, alkaline phosphatase, GGT,PT/PTTK.◦Electrolytes.◦Blood culutre.◦Urine culture, routine microscopy.◦RBS (pre-feed).◦Ascitic tap (if ascitis).

Further tests:Further tests:Ophthalmologic examination.Serum/ urine bile acid levels.DCT and coomb’s test.Cord blood IGM.FTA-ABS, CFT for rubella, CMV, herpes.

Sweat chloride.HBsAG in mother and infant.Liver biopsy:

light microscopy. specific enzyme assay.

• TORCH, VDRL, Hepatitis B/C, HIV• T4, TSH• Serum cortisol• Alfa -1 AT levels and phenotype• Galactose -1 Phosphate Uridyl transferase(to r/o galactosemia)• Urinary succinyl acetone (to r/otyrosinemia)• Cholesterol, triglycerides• S. iron and ferritin levels (to r/o neonatalhemachromatosis)

Radiological evaluationRadiological evaluation

Ultrasonography

Excludes choledochal cyst, dilated CBD. Findings s/o BA:1. GB length (<1.5cm long/small lumen)2. GB contraction [CI<86% ± 18% (mean ± SD)

in 6-week-old infants and 67% ± 42% in 4-month-old infants]

3. Triangular cord sign: a triangular- or tubular-shaped echogenic density that was located immediately cranial to the portal vein bifurcation and was 3 mm or more thick (Kanegawa et al. AJR 2003;181:1387)

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:Hepatobiliary Scintigraphy:

Tc labelled IDA dyes used.Depends on hepatocellular function &

patency of biliary tract.Neonatal Hepatitis: delayed uptake, n.

excretion.Biliary Atresia: normal uptake, absent

excretion.Sensitive (97%) not specific (80%) for

EHBA.Phenobarbitol priming (5mg/kg x 5d)

Gayatri devi 2.5 m/F(2000) CHOLEDOCHAL CYST

Invasive studiesInvasive studies◦Duodenal intubation◦Percutaneous liver biopsy◦Percutaneous transhepatic

cholangiography◦ERCP◦MRCP◦Exploratory laparotomy with

intraoperative cholangiogram

ERCP imageERCP image

intra- and extrahepatic (c) biliary dilatation, as well as focal intrahepatic biliary cystic dilatations (arrows). g = gallbladder.

Percutaneous transhepatic Percutaneous transhepatic cholangiographycholangiography

LIVER BIOPSY:LIVER BIOPSY:Most imp. Inv in differentiating NH

and BA.Accuracy of 83% to 97%.Prerequisites: Normal PT & platelet

count.Complications: Bleeding Bile peritonitis Pneumothorax

F/o neonatal hepatitis: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: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.

Indications for laparotomy-IAPIndications for laparotomy-IAP

1) Acholic stools & liver bopsy-BA2) 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.

EXTRAHEPATIC BILIARY EXTRAHEPATIC BILIARY ATRESIAATRESIA

Generally acholic stools with onset at about 2 weeks-old

Average birth weightHepatomegaly with firm to hard

consistencyFemale predominanceNo well-documented familial cases

EXTRAHEPATIC BILIARY EXTRAHEPATIC BILIARY ATRESIAATRESIA

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 IDIOPATHIC NEONATAL HEPATITISHEPATITIS

Generally normal stools or acholic stools with onset at one month-old

Low birth weightNormal liver on exam or

hepatomegaly with normal to firm consistency

Male predominanceFamilial cases (15-20%)

IDIOPATHIC NEONATAL IDIOPATHIC NEONATAL HEPATITISHEPATITIS

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 ALPHA-1-ANTITRYPSIN DEFICIENCYDEFICIENCY

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.

ALPHA-1-ANTITRYPSIN ALPHA-1-ANTITRYPSIN DEFICIENCYDEFICIENCY

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 INTRAHEPATIC CHOLESTASIS SYNDROMESSYNDROMES

Includes several diagnostic entities.Biopsies show cholestasis. May show

paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis.

TREATMENTTREATMENT

Surgical◦Kasai procedure for biliary atresia◦Limited bile duct resection and re-

anastomosis◦Choledochal cyst excision◦Cholecystectomy◦Liver transplantation

KASAI PROCEDUREKASAI PROCEDUREPerformed for biliary atresia that is

not surgically correctable with excision of a distal atretic segment.

Roux-en-Y portoenterostomyBile 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

KASAI PROCEDUREKASAI PROCEDURESuccess 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 reobstruction as well as failure to re-establish bile flow.

TREATMENTTREATMENT

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/d AQUASOL-A

50,000 IU i.m –diagnosis10,000 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 –diagnosis& monthly

Vit K deficiency 2.5 -5.0 mg alternate day as water soluble derivative of menadione.

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

TREATMENTTREATMENT

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

TREATMENTTREATMENTManagement of portal hypertension

and its consequences◦Variceal bleeding

Fluid rescuscitation Blood products Sclerotherapy Balloon tamponade Portovenous shunting Propanolol

TREATMENTTREATMENTManagement of portal hypertension

and its consequences (cont.)◦Ascites

Sodium restriction Diuretics: spironolactone, furosemide Albumin Paracentesis

◦Thrombocytopenia managed with platelet infusions when clinically indicated

LIVER TRANSPLANTATIONLIVER TRANSPLANTATIONBiliary 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 100,000 $Only few centres in india

Liver transplantationLiver transplantationIndications:1)Decompensated liver disease(ascites

and/or encephelopathy) .2)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)

PrognosisPrognosis 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 outcomeLong term outcomeBiliary 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 messagesKey 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

Neonatal cholestasis

Health & Medicine