Date post: | 12-Apr-2017 |
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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.