NEONATAL CHOLESTASIS

PRIYANKA VISHWAKARMA

INTRODUCTION
Accounts for 30% of pediatric hepatobiliary diseases. Neonatal cholestasis is a pathological condition in

which bile flow is affected resulting in accumulation of biliary substances (bilirubin, bile acids and cholesterol) in blood and extrahepatic tissues and clinically manifested as conjugated hyperbilirubinemia.
Incidence: 1 in 2500 live births

DEFINITION
Prolonged elevation of serum levels of conjugated

bilirubin beyond the 1st 14 days of life.

Elevated conjugated bilirubin is defined as direct bil.

>1 mg/dl if total bil. is less than 5 mg/dl or more than 20% of the total bil level if total bil is more than 5mg/dl.

NEONATAL CHOLESTASIS SYNDROME

Heterogenous group of hepatobiliary disorders

responsible for cholestasis in infancy.

Extrahepatic obstruction 2. Hepatocellular causes 3. Paucity of intrahepatic ducts
1.

CAUSES:
A. EXTRAHEPATIC OBSTRUCTION:
1. 2.

3.
4. 5.

6.
7.

Biliary atresia Choledochal cyst Neonatal sclerosing cholangitis Bile duct stricture/stenosis Inspissated bile Spontaneous perforation of bile duct Mass

B. HEPATOCELLULAR CAUSES
1. 2.

Idiopathic neonatal hepatitis

Infection: Generalised bacterial sepsis Viral: CMV, Rubella, herpes, HIV, varicella Others: toxoplasmosis, malaria, syphilis, t.b., listeriosis, urinary tract infection.

Genetic or chromosomal: Trisomy 17, 18, 21 Donahue syndrome

3.

4.

Metabolic : Galactosemia Tyrosinemia Hypothyroidism Panhypopituitarism Cystic fibrosis Alpha 1 antitrypsin deficiency Disorder of lipid metabolism Disorder of bile acid biosynthesis Neonatal iron storage disease Zellweger (cerebrohepatorenal syndrome)

others: Parentral nutrition related Intrahepatic cholestasis (PFIC): FIC 1 def, BSEP def, MDR 3 deficiency Familial benign recurrent cholestasis associated with lymphedema (aagenaes) Congenital hepatic fibrosis Carolis disease
5. C. PAUCITY OF INTRAHEPATIC BILE DUCTS: 1. Sndromic: alagilles syndrome 2. Non syndromic

ETIOLOGY: EXPERIENCE IN INDIA

Total cases analysed 1008

Hepatocellular causes- 53% (Neonatal hepatitis -47%, Metabolic- 4%, Others-2%) Among neonatal hepatitis (n=468),idiopathic giant cell hepatitis64%, TORCH-22%, Sepsis-8% and in 6% cases other causes like malaria, UTI etc. Obstructive causes - 38% (Biliary atresia 34%, Choledochal cyst 4%) Ductal paucity - 3% Idiopathic - 6%

WHAT IS THE NEED FOR EARLY DIAGNOSIS?

1.

For early surgical intervention e.g. Extra hepatic biliary atresia (EHBA). The success of surgical correction of biliary atresia (Kasai's operation) is significantly reduced if it is performed after 8 weeks of age.

2. To recognise disorders amenable to specific

medical therapy e.g. sepsis/galactosemia etc.

3. To institute early conservative/empiric management.

APPROACH TO NEONATAL CHOLESTASIS

WHOM TO INVESTIGATE? any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin.
However, breast-fed infants who can be reliably

monitored and who have an otherwise normal history (no dark urine or light stools) and physical examination may be asked to return at 3 weeks of age and, if jaundice persists, have measurement of total and direct serum bilirubin at that time.

STEPS
1.

Detect conditions that require immediate treatment and determine severity of liver disease.

2. Differentiate extrahepatic disorders from

intrahepatic causes of cholestasis.

3. Establish other specific diagnoses.

HISTORY :
Similar problems with sibs or parents?

Consanguinity?
Maternal infection that can affect baby? Past ABO or Rh disease or Rh negative?

Birth weight: SGA may imply intrauterine infection

Feeding history and history of weight gain? FTT: Neonatal hepatitis

Anorexia and FTT: galactosemia, hereditary fructose

intolerance

HISTORY:
Bowel history Vomiting: metabolic disease, pyloric stenosis, bowel

obstruction(atresia, annular pancreas) Delayed stools: hypothyroidism, cystic fibrosis Diarrhoea: infection, metabolic disease Clay colour stools: biliary atresia
Urine colour: dark urine s/o conjugated

hyperbilirubinemia

Excessive bleeding: coagulopathy vit k deficiency Exposure to toxins or drugs

PHYSICAL EXAMINATION
Vitals, height, weight, OFC, nutritional status. Scleral icterus. Skin color. Evidence of sepsis : sick baby sepsis, uti, congenital

infection, metabolic disorder. Dysmorphic facies: alagilles syndrome- broad forehead, deep set widely spaced eyes, long straight nose, underdeveloped mandible. Down syndrome Hypothyroidism Zellweger syndrome

PHYSICAL EXAMINATION
Examination of eye and fundus:

cataract galactosemia, rubella

Chorioretinitis- TORCH Posterior embryotoxins- alagilles syndrome

Cherry red spot- lipid storage disorders.

Skin: bruises, petechie, rashes s/o coagulopathy Systemic examination: evidence of liver failure, heart

failure, other CHDs, liver and spleen. Stool and urine color

DIFFERENCE BETWEEN OBSTRUCTIVE AND NON OBSTRUCTIVE CAUSES

INVESTIGATIONS
Aim : 1. To identify treatable condition 2. Recognize complication 3. Early referral

Urgent invesigations: Blood counts PT, LFT Blood culture Urine microscopy & culture, for reducing substance Routine blood sugar Ascitic tap( if ascites)

VALUE OF SPECIFIC TESTS:

Serum bil fractionation (conjugated bil assessment) 2. Urine and serum bile acids measurement 3. Hepatic synthetic function( albumin, coagulation profile) including GGTP & ALP
1. Indicates cholestasis

Confirms cholestasis Severity of hepatic

dysfunction High GGTP & ALP: obstructive cause Low GGTP & high ALP: PFIC Low GGTP & ALP: hepatocellular cause

 Alpha 1 antitrypsin phenotype Thyroxine and TSH Sweat chloride and mutation

Suggests ( or excludes) PiZZ

phenotype Endocrinopathy
cystic fibrosis

analysis

Urine and serum amino acids

and urine reducing substance

metabolic liver disease

TORCH, VDRL, hpatitis B,C, HIV

transferase

Viral infections

Galactose 1 phosphate uridyl

Galactosemia

Serum iron and ferritin

Neonatal hemochromatosis

 USG abdomen

Identifies choledochal cyst,

choledocholithiasis, perforation of bile duct.

TRIANGULAR CORD SIGN:

s/o EHBA ( high sensitivity & specificity )

Small or absent gall bladder:

EHBA( low sensitivity & specificity )

 Hepatobiliary scintigraphy

Dye seen in duodenum:

( HIDA scan): injected radioactive material normally excreted into intestine in a predictable time period. Priming with phenobarbitone 5mg/kg/d. for 5 to 7 days. Follow up scan after 24 hours.

rules out obstructive cause. ( high specificity) Dye not seen in duodenum: EHBA or severe intrahepatic cholestasis. ( low sensitivity)

 PERCUTANEOUS

LIVER BIOPSY:

Biliary atresia :bile

most valuable procedure

ductular proliferation, presence of bile plugs, and portal or perilobular edema and fibrosis, with the basic hepatic lobular architecture intact. diffuse hepatocellular disease, with distortion of lobular architecture, marked infiltration with inflammatory cells, and focal hepatocellular necrosis; the bile ductules show little alteration.

Neonatal hepatitis: severe,

 PERCUTANEOUS

Giant cell transformation

LIVER BIOPSY:

is found in infants with either condition and has no diagnostic specificity. PAS positive granules: alpha 1 AT deficiency Ductal paucity : alagille syndrome Necroinflammatory duct lesion: sclerosing cholangitis Specific findings for metabolic and storage diseases

 MRCP ERCP Duodenal aspirate

Not used

analysis Intraoperative cholangiography / peroperative cholangiography

Gold standard to confirm

EHBA.

TREATMENT
Specific Supportive TREATBLE CAUSES: Medical: 1. Sepsis 2. UTI 3. Congenital infections 4. Galactosemia 5. Hypothyroidism 6. Tyrosinemia

Treatment of complications Liver transplantation

Surgical : 1. Biliary atresia ( KASAI PORTOENTEROSTOMY)

2. Choledochal cyst 3. Spontaneous perforation of bile duct

MEDICAL MANAGEMENT OF PERSISTENT CHOLESTASIS

CLINICAL IMPAIRMENT
Malnutrition resulting

MANAGEMENT
Replace with dietary

from malabsorption of dietary long-chain triglycerides Fat-soluble vitamin malabsorption: 1. Vitamin A deficiency (night blindness, thick skin) 2. Vitamin E deficiency (neuromuscular degeneration)

formula or supplements containing medium-chain triglycerides. Cal- 125% RDA 15,000 IU/day as Aquasol A as oral -tocopherol or TPGS

Replace with 10,000-

Replace with 50-400 IU/day

3. Vitamin D deficiency (metabolic bone disease)

Replace with 5,000-

4.

Vitamin K deficiency (hypoprothrombinemia) Micronutrient deficiency Deficiency of water-soluble vitamins

8,000 IU/day of D2 or 35 g/kg/day of 25hydroxycholecalciferol Replace with 2.5-5.0 mg every other day as watersoluble derivative of menadione Calcium, phosphate, or zinc supplementation Supplement with twice the recommended daily allowance

 Retention of biliary

constituents such as cholesterol (itch or xanthomas) Pruritus

Administer choleretic

Progressive liver disease;

portal hypertension (variceal bleeding, ascites, hypersplenism) End-stage liver disease (liver failure)

bile acids (ursodeoxycholic acid, 15-30 mg/kg/day) Phenobarbitone, rifampicin, UDCA, cholestyramine Interim management (control bleeding; salt restriction; spironolactone) Transplantation

PROGNOSIS
Prognosis of neonatal hepatitis is very good if diagnosed early

and appropriate treatment is instituted.

For patients with idiopathic neonatal hepatitis, the variable

prognosis might reflect the heterogeneity of the disease.

In sporadic cases, 60-70% recover , 5-10% have persistent

fibrosis or inflammation, and a smaller percentage have more severe liver disease, such as cirrhosis.

Infants usually die early in the course of the illness, owing to

hemorrhage or sepsis

PROGNOSIS
In familial variety, only 20-30% recover; 10-15% acquire

chronic liver disease with cirrhosis. Liver transplantation may be required.

In EHBA even after successful portoenterostomy, one

third die during first year of operation, one third die by 10 year of age, one third survive with some compromised liver function.

With liver transplantation survival of EHBA has

improved to 90% in best centres.

CONCLUSION
Ensure early referral to appropriate health facilities for

further investigations and treatment.

The investigations need to be carried out on an

emergency basis to identify treatable causes.

The mainstay for supportive management is to improve

nutritional status.

For those progressing to end stage liver disease, liver

transplantation is the answer.

REFERENCES
NELSON TEXTBOOK OF PEDIATRICS 19th ed. 2. IAP TEXTBOOK OF PEDIATRICS 4th edition 3 Consensus Report on Neonatal Cholestasis Syndrome- Pediatric Gastroenterology Subspecialty Chapter of Indian Academy of Pediatrics
1.

THANK YOU