WELCOME

Presenters:Dr. Maimuna SayeedDr. Zahid HasanDr. Raihanur Rahman

Case scenarioRizwan, a 3 month old boy presented with jaundice since 1st day of life & intermittent pale stool for same duration. He was delivered at term with average birth weight by LUCS. His perinatal period was uneventful and there was no H/O delayed passage of meconium, constipation, lethargy, vomiting, convulsion or any rash.

On examination, he was icteric & there was no facial dysmorphism. His weight & height were within normal range & hepatomegaly was present. Lab investigation showed direct hyperbilirubinemia.

Neonatal Cholestasis

Objectives

• To know when cholestatic liver disease should be suspected in infant who has jaundice.

• How to evaluate a neonate with conjugated hyperbilirubinemia.

• To understand the differential diagnosis for neonatal cholestasis.

• To know the therapeutic management of neonates with cholestasis.

Definition

Neonatal cholestasis is defined biochemically as prolonged elevation of the serum level of conjugated bilirubin beyond the 1st 14 days of life.

(Nelson textbook of pediatrics, 20th ed.)

Cholestasis is defined as diminished bile formation or flow, and is manifested by abnormal conjugated hyperbilirubinemia:•a conjugated bilirubin ˃1 mg/dL, if the total

bilirubin is ˂5 mg/dL•a conjugated bilirubin level ˃20% of the total

bilirubin, if the total bilirubin is ˃5 mg/dl

(Paediatric Practice Gastroenterology by Warren P. Bishop)

Pathogenesis

Etiologies

Neonatal cholestasisExtra hepatic disease

Biliary atresia

Choledochal cyst

Spontaneous perforation of bile duct

Inspissated bile syndrome

Bile duct stenosis

Extrinsic compression of the bile duct

Intra hepatic diseaseIdiopathic

Idiopathic Neonatal Hepatitis

InfectiousTORCH infection

Bacterial sepsis

Enterovirus

Echovirus

Intra hepaticMetabolic

Disorder of CHO metabolismGalactosemia

Fructosemia

Glycogen storage disease

Disorder of amino acid metabolismTyrosinemia

Disorder of Lipid MetabolismNiemann-Pick disease

Gaucher disease

Peroxisomal disordersZellweger syndrome

Endocrine disordersHypothyroidism

Hypopituitarism

Miscellaneous metabolic disordersAlpha-1-antitrypsin deficiency

Cystic fibrosis

Neonatal iron storage disease

Intra hepaticToxic

TPN–associated cholestasis

Drug induced cholestasis

Genetic/chromosomalDown’s Syndrome

Intrahepatic bile duct paucitySyndromic

Alagille syndrome

Non-syndromic

Cholestatic syndromePFIC- type 1,2,3

Benign recurrent cholestasis

IschemicPerinatal asphyxia

Prevalence

•Neonatal cholestasis: 1 in 2500 live birth.•Biliary atresia: 1 in 10000 to 15000 infants.• Idiopathic neonatal hepatitis: 1 in 5000 to 10000

live birth.

(McKiernan PJ et al. Lancet 2000)

Neonatal Hepatitis

36%

Biliary Atresia26%

INH24%

Others14%

(Bazlul Karim AS, Kamal M, Cholestatic jaundice during infancy: experience at a tertiary-care center in Bangladesh, Indian J Gastroenterology, 2005 Mar-Apr;24(2):52-4.)

Biliary Atresia

• It is a progressive obliterative inflammatory process involving the bile ducts, resulting in obstruction of bile flow leading to cholestasis, hepatic fibrosis, and eventually cirrhosis. •Average birth weight•Hepatomegaly with firm to hard consistency•Female predominance•No well-documented familial cases

Perinatal85%

Embryonic15%

•Associated congenital anomalies:1. Spleen- asplenia, polysplenia, double

spleen2. Portal vein- absent, cavernomatous

transformation3. Situs inversus4. Malrotation of gut5. Cardiac anomalies6. Annular pancrease7. Duodenal, esophageal, jejunal atresia8. Polycystic kidney9. Cleft palate

Idiopathic Neonatal Hepatitis

• It is an ever-shrinking percentage of cases of intrahepatic cholestasis (10-20%) in which the characteristic “giant cell hepatitis” lesion is present on liver biopsy & for which no infectious, genetic, metabolic or anatomic cause is identified.•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%)

Difference Between BA & INH

Characteristics Biliary Atresia Idiopathic Neonatal Hepatitis

Sex Female Male

Incidence Sporadic Familial (20%)

Relation with gestational age

Term, AGA Preterm, LBW, SGA

Associated anomaly Present Absent

Pale stool Persistently Intermittently

Jaundice Mild to moderate Moderate to severe jaundice

Hepatomegaly Abnormal size & consistency

Common

Thriving Thriving well Not thriving well

Biliary Atresia INHGGT Highly raised Mildly raised

USG No contraction after meal Contraction of GB before and after meal

Hepatobiliary Scintigraphy

Dye uptake good but no excretion

Less uptake but complete excretion

Biopsy Architecture preserved Bile plug Bile ductular

proliferation Periportal fibrosis

Architecture lost Giant cell

transformation

Choledochal Cyst

• Localized cystic dilatation of common bile duct is called choledocal cyst.•25% patient present in neonates with prolonged

jaundice & cholestasis.•75% present later in childhood with the triad of

• Intermittent jaundice•Recurrent abdominal pain•Abdominal mass

Galactosemia

•Manifested after ingestion of galactose containing milk.•Here galactose-1-phosphate accumulation occur

due to galactose-1-phosphate Uridyl transferase enzyme deficiency.• Present with vomiting, loose motion, persistent

jaundice, FTT, hepato-splenomegaly, septicemia, cataract, repeated hypoglycemia and convulsion.

Inspissated Bile Syndrome

•Conjugated hyperbilirubinemia resulting from severe jaundice associated hemolysis due to Rh or ABO incompatibility is termed as inspissated bile syndrome.

Alpha-1-antitrypsin Deficiency

•Alpha-1-antitrypsin makes up 90% of alpha-1-globulin fraction•Biopsy also shows accumulation of PAS-positive,

diastase-resistant eosinophilic granule.•Varying degrees of fibrosis correlate with disease

prognosis.

TPN Related Cholestasis

• It develops in >50% of infants with birth weight <1000 gram & in <10% of term infants after giving prolonged parenteral feeding.•This may be due to lack of enteral feeding

→reduction of gut hormone secretion → reduce bile flow → biliary stasis.

How to Evaluate a Neonate with Cholestatic Jaundice?

Cardinal Feature

Appears within first 3 months of life• Jaundice•Dark urine•Pale stools•Hepatomegaly

Goals of Timely Evaluation

•Diagnose 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.

From History

History Taking

Age at presentation Within first 3months of life

Sex INH is common in male &BA is common in female

Prolonged jaundice Persisting >2weeks after birth

Pale stool

• Persistent BA• Intermittent NHS

Dark urine Cholestasis

Abdominal distension OrganomegalyLethargy Galactosemia

Vomiting GalactosemiaPruritus Cholestasis

Antenatal

• Fever & Rash TORCH

• Abortion• Miscarriage

Metabolic

Natal

• Term BA

• Pre-term INH

Birth weight

• SGA/LBW INH

• AGA BA

Postnatal

• Onset of jaundice• Poor feeding• Lethargy • Hoarse cry• Constipation• Delayed passage of meconium

Hypothyroidism

• Convulsion Congenital infection

Developmental milestone

• Normal BA• Delayed Congenital infection

HypothyroidismMetabolic diseases

Family history• Consanguinity Metabolic disease• Sib affected INH

Physical Examination

General ExaminationAppearance

• Irritable, lethargic Congenital infectionMetabolic diseases

• Dysmorphic Alagille syndromeDown syndromeHypothyroidism

Head

• Wide anterior fontanelle HypothyroidismDown’s syndrome

• Seborrheic Dermatitis Histiocytosis X

Pallor

Jaundice

Vital signs

• Heart rate

• Respiratory rate Increase in infection

Alimentary System

Oral cavity

• Cleft lip• Cleft palate

BA

Abdomen

• Pott belly• Umbilical hernia

Hypothyroidism

• Hepatomegaly (firm)• Splenomegaly BA

Congenital infection• Right hypochondriac mass Choledochal cyst

• Ascites Late stage (3-4 months later)

Cardio-pulmonary System

Lungs• RTI Down’s syndrome

Cystic fibrosis• Tachypnea Infection

Heart• Murmur Congenital rubella syndrome

Down’s syndromeAlagille syndrome

• Endocardial cushion defect Down’s syndrome• TOF Alagille syndrome

• Pulmonic stenosis/atresia Alagille syndrome

Upper limb

• Simian crease• Clinodactyly

Down’s syndrome

Lower limb

• Frog leg position• Saber shin• Osteochondritis

Congenital syphilis

• Sandal gap Down’s syndrome Anthropometry

• OFC Microcephaly in congenital infection• Weight and height FTT in INH

Congenital infection

Other Examination

Skin survey

• Rash Sepsis, TORCH

• Dry skin• Dermatitis

Hypothyroidism

Eye examination

• Cataract Galactosemia

• Choreo-retinitis CMVRubellaToxoplasma

• Cherry red spots Niemen-Pick disease• Posterior embryotoxon Alagille syndrome• Optic nerve Hypoplasia Pan-hypopituitarism

Investigations

A. Initial investigations:To establish cholestasis and determine severity of liver disease

1. Fractionated S. Bilirubin2. Liver function test

•ALT•AST•PT•GGT•ALP•Serum albumin

B. To detect conditions that require immediate treatment-

1. CBC2. Urine R/E3. Cultures of blood & urine4. Serum T4, TSH5. To detect metabolic conditions- Urinalysis,

urine for non glucose reducing substance6. TORCHS IgM screening

C. To differentiate extrahepatic from intrahepatic causes of cholestasis

1. Imaging studies•Ultrasonography •Hepatobiliary scintigraphy

2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography

Ultrasonography

USG of whole abdomen, with special attention to HBS, to see:

•Absent/Small/non visualized gall bladder• Lack of post prandial contraction of GB.•Triangular cord sign•Choledochal cyst•Choledocholithiasis, biliary sludging•Perforation of bile duct

Triangular Cord sign: a cone shaped fibrotic mass cranial to the bifurcation of portal vein.

Hepatobiliary Scintigraphy

Premedication•Phenobarbitone: 5 mg/kg/day for 5 days.Dye used•HIDA: 99m Tc labelled imino-diacetic acid•DISIDA: 99m Tc di-isopropyl IDA•MBRIDA: Mebrophenine IDA

Normal

In Biliary Atresia

•Depends on hepatocellular function & patency of biliary tract•Sensitive (70%) but not so specific for EHBA

•Neonatal Hepatitis: delayed uptake, normal excretion•Biliary Atresia: normal uptake, absent excretion

Percutaneous Liver Biopsy

• Most important investigation in differentiating INH and BA.

• Accuracy of 83% to 97%.• Prerequisites: Normal CBC, PT, APTT & USG• Complications:

o Bleedingo Bile peritonitiso Pneumothorax

Findings: Biliary Atresia• Bile ductular

proliferation• Bile plugs• Portal/peri-lobular

edema and fibrosis• Intact basic lobular

architecture

Findings: Idiopathic Neonatal Hepatitis•Distortion of lobular

architecture•Giant cell

transformation

Per-operative Cholangiography

To establish Other Diagnosis

•Alpha Feto-protein level (Tyrosinaemia)•S. Alpha-1-antitrypsin level•Sweat chloride (Cystic fibrosis)•Urine/serum amino acids (Metabolic conditions)•X-ray chest (Congenital infection)•X-ray skull and long bones (Congenital infection)•Echo (Congenital infection, Alagille syndrome)•Bone marrow study (Storage disease)

Management of Neonatal Cholestasis

A. Supportive Management

•Parental counseling•Nutritional support•Treatment of pruritus•Choleretics and bile acid-binder

Nutritional Support

•Adequate calories (125% of RDA) and protein•Supplement calories with medium chain

triglycerides (Pregestimil, Portagen )•Treatment and/or prophylaxis for fat-soluble vitamin

deficiencies (vitamins A, D, E, and K)•Water soluble vitamins – Twice the RDA•Supplemental calcium and phosphate when bone

disease is present

Dosage Schedule for Lipid Soluble Vitamins

•Vitamin A: 25,000-50,000 IU I/M EAM•Vitamin D: 30,000-60,000 IU I/M EAM•Vitamin E: 25 IU/kg oral – Daily•Vitamin K: 1mg/kg I/M – 14 days

Treatment of Pruritus•As a choleretic•Ursodeoxycholic acid (20-25mg/kg/day)•Phenobarbital (5mg/kg/day)

•Naltrexone•Diphenhydramine•Bile acid-binders• cholestyramine (4-8g/day)

•Rifampicin (10mg/day)•Terfenadine (1-3mg/kg/day)•Photothearpy with UV/ Infrared rays x 3-10 min/day

B. Specific management

• INH- no specific treatment•BA- Kasai procedure followed by Liver Transplantation•Hypothyroidism- life long thyroxine•Galactosemia- avoid galactose containing diet•Choledochal cyst- excision of the cyst•Congenital infection- according to causative organism• Liver transplantation

Kasai Procedure

•Roux-en-Y porto-enterostomy•Bile flow re-established in 90% if performed prior to 8 weeks of life.•Bile flow re-established in less than 20% if performed after 12 weeks of life.•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.Others are•When initial treatment was given lately/

Portoenterostomy not done•Failed portoenterostomy•Decompensated cirrhosis and end stage liver

disease despite initial successful Kasai.

Prognosis and OutcomeBiliary Atresia:• Age(< 8 wks): the single most important

determinant in successful management of BA.

• Patients 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)

• 50-80% will die without LT by 1 yr, if Kasai not done.

• 90-100% will die by age 2 yrs• 70-80% require LT after Kasai during 1st 2

decade.• 80-90% long term survival after LT.

Neonatal Hepatitis:• No indicators to predict prognosis.• In sporadic case, 60-70% disease free survival,

<5% severe liver disease or cirrhosis.• In familial case, 20-30% recover.