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Seminar on neonatal cholestasis

This document provides information about evaluating a neonate presenting with cholestatic jaundice. It discusses performing a history and physical exam to identify potential etiologies. Key lab investigations are outlined to establish cholestasis and severity of liver injury. Imaging studies like ultrasound and hepatobiliary scintigraphy can help differentiate between extrahepatic and intrahepatic causes. The document reviews various etiologies of neonatal cholestasis including biliary atresia, idiopathic neonatal hepatitis, choledochal cyst, galactosemia, and TPN-related cholestasis. Timely evaluation is important to diagnose treatable conditions and identify those requiring surgical intervention.

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Introduction to the seminar topic and a case scenario of a 2-month-old infant presenting with jaundice.

Defines neonatal cholestasis and objectives for identifying and managing the condition.

Definition of cholestasis, including criteria for elevated conjugated bilirubin, and pathogenesis.

Detailed causes of neonatal cholestasis, including extrahepatic and intrahepatic origins.

Prevalence statistics for neonatal cholestasis and its various forms like biliary atresia and idiopathic hepatitis.

Description and characteristics of biliary atresia, including embryonic and perinatal factors.

Description of idiopathic neonatal hepatitis, differences from biliary atresia, and clinical characteristics.

Diagnostic procedures for identifying conditions like choledochal cyst and discussing TPN-related cholestasis.

Causes including inspissated bile syndrome and cardinal features of cholestasis in newborns.

Goals and methods of evaluating cholestatic jaundice in neonates, including history and physical examination.

Various clinical features to look for during examinations of patients suspected of cholestasis.Laboratory tests and imaging studies used in diagnosing cholestasis and differentiating intra vs extrahepatic causes.

Management strategies, including nutritional support, specific treatments for underlying conditions, and pruritus.

Prognosis outcomes for biliary atresia and neonatal hepatitis, emphasizing the importance of timely treatment.

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Welcome to Seminar Presenters: Dr. Rumana Islam Dr.Bikush Chandra Paul Resident year-1 Paediatric Neurology & Neurodevelopment
Case scenario Maisha, a 2 months old girl presented with- • Jaundice since 3rd day of life & • Persistant pale stool for same duration. • She was delivered at term with average birth weight • No H/O delayed passage of meconium,constipation, lethargy, vomiting, convulsion or any rash.
Case scenario • On examination, she was icteric & there was no facial dysmorphism. • Anthropometrically well thriving. • Hepatomegaly present. • Lab investigation- Shows direct hyerbillirubinemia.
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 neonatal 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
Extrahepatic causes- Billiary atresia Bile duct stenosis Choledocal cyst Spon.perforation of bile duct CBD stenosis Primary sclerosing cholangitis Inspissated bile syndrome CBD ligation CBD stricture Mass (neoplasia)
Intra hepatic Idiopathic Idiopathic Neonatal Hepatitis TORCH infection Bacterial sepsis Infectious Enterovirus Echovirus Intrahepatic causes
Intra hepatic Metabolic Disorder of CHO metabolism Galactosemia Fructosemia Glycogen storage disease Disorder of amino acid metabolism Tyrosinemia Disorder of Lipid Metabolism Niemann-Pick disease Gaucher disease Peroxisomal disorders Zellweger syndrome Miscellaneous metabolic disorders Hypothyroidism Endocrine disorders Hypopituitarism Alpha-1- antitrypsin deficiency Cystic fibrosis Neonatal iron storage
Intra hepatic Toxic TPN– associated cholestasis Drug induced cholestasis Genetic/chromosom al Down’s Syndrome Intrahepatic b.duct paucity Syndromic Alagille syndrome Non-syndromic PFIC- type 1,2,3 Cholestatic syndrome BRIC Ischemic Perinatal 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 35% Biliary Atresia 26% INH 24% Others 15% (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
Biliary Atresia cont..
•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 Biliary Atresia cont..
Embryonic 20% Perinat al 80% Biliary Atresia cont..
•Associated congenital anomalies: 1. Spleen- asplenia, polysplenia, double spleen 2. Portal vein- absent, cavernomatous transformation 3. Situs inversus 4. Malrotation of gut 5. Cardiac anomalies 6. Annular pancrease 7. Duodenal, esophageal, jejunal atresia 8. Polycystic kidney 9. Cleft palate
Idiopathic Neonatal Hepatitis
intrahepatic cholestasis (10-20%) in whic It is an ever-shrinking percentage of cases of 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 He patitis Sex Female Male Incidence Sporadic Familial (20%) Relation with gestat ional 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 & co nsistency Common Thriving Thriving well Not thriving well
Biliary Atresia INH USG No contraction after meal Contraction of GB before and after meal Hepatobiliary Sci ntigraphy Dye uptake good but no exc retion Less uptake but complete exc retion Biopsy  Architecture preserved  Bile plug  Bile ductular pro liferation  Periportal fibrosis  Architecture lost  Giant cell transfor mation Difference Between BA & INH cont..
Choledochal Cyst
•Localized cystic dilatation of common bile ductis 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 Choledochal Cyst cont..
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. Galactosemia cont..
TPN Related Cholestasis
• It develops in >50% of infants with birth weight <1000 gram & in <10% of term infants after giving prolonged parenteral feeding(>2 wk) • Risk factors-Prematurity Short bowel syndrome Functional liver immaturity Sepsis Lack of enteral feeding Toxicity from component of parenteral nutrition • This may be due to lack of enteral feeding →reduction of gut hormone secretion → reduce bile flow → biliary stasis. TPN Related Cholestasis cont..
• Biopsy-Hepatocellular & canalicular cholestasis occour, steatosis & periportal fibrosis seen on liver biopsy,billiar y chirrosis can develop with continued parenteral nutrit ion • Management-Trophic enteral feeding,UDCA,alternative to soy based lipid emulsion • Liver transplantation or combined liver intestinal transpl antation may be needed in end stage liver disease & w xtreme short bowel syndrome. TPN Related Cholestasis cont..
Inspissated Bile Syndrome
• Inspissated bile within the distal CBD may cause obstructive jaundice in newborn. • Causes-Haemolysis ,diuretic therapy, parenteral nutrition, prematurity, cystic fibrosis. • Difficult to distinguish from biliary atresia. • In both condition-jaundice ,acholic stool ,conjugated hyperbillirubinemia, no biliary excretion on a radionuclide scan. • USG reveals –dialated proximal bile ducts & i nspissated bile. Inspissated Bile Syndrome cont..
Cardinal Feature Appears within first 3 months of life •Jaundice •Dark urine •Pale stools •Hepatomegaly
Dark urine & pale stool
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.
How to Evaluate a Neonate with Cholestatic Jaundice?
From History
History Taking Age at presentation Within first 3months of life Sex INH is common in male & BA i s common in female Prolonged jaundice Persisting >2weeks after birth Pale stool • Persistent BA • Intermittent INH Dark urine Cholestasis Abdominal distension Organomegaly Lethargy Galactosemia
Vomiting Galactosemia Pruritus 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 Hy pothyroidism Metabolic diseases Family history • Consanguinity Metabolic disease • Sib affected INH
Physical Examination
General Examination Appearance • Irritable, lethargic Congenital infection Me tabolic diseases • Dysmorphic Alagille syndrome Do wn syndrome Hypoth yroidism Head • Wide anterior fontanelle Hypothyroidism Down ’s syndrome • Seborrheic Dermatitis Histiocytosis X Vital signs • Heart rate ,temp • Respiratory rate Increase in infection
Alimentary System Oral cavity • Cleft lip • Cleft palate BA Abdomen • Pott belly • Umbilical hernia Hypothyroidism • Hepatomegaly (firm) • Splenomegaly Storage disease Congenital infection • Right hypochondriac mass Choledochal cyst • Ascites Late stage (3-4 months later)
Cardio-pulmonary System Lungs • RTI ( Tachypnea,crackles, wheeze) Down’s syndrome Cysti c fibrosis Heart • Feature ASD,VSD,PDA TOF Congenital rubella syndrome Dow n’s syndrome • Endocardial cushion defect Down’s syndrome • Dextrocardia Alagille syndrome • Peripheral Pulmonary stenosis. Alagille syndrome
Upper limb • Simian crease • Clinodactyly Down’s syndrome Lower limb • Frog leg position • Excessive crying during handling 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 • Patechie, purpura , Seborrheic Dermatitis Sepsis, TORCH, histocytosis x • Dry skin • Dermatitis Hypothyroidism Eye examination • Jaundice • Cataract Galactosemia ,Rubella • Choreo-retinitis CMV Rubella Toxopla sma • Cherry red spots Niemann-Pick disease • Posterior embryotoxon Alagille syndrome • Optic nerve Hypoplasia Pan-hypopituitarism
EYE FINDING….
Chorioretinitis
Cherry red spot
Posterior embryotoxon
Hypoplasia of optic nerve
Investigations
A. To establish cholestasis: • 1. Fractionated S. Bilirubin: • A conjugated (direct) bilirubin concentration of >1 mg /dl with a total bilirubin of <5 mg/dl, or >20% of the tot al bilirubin concentration if the total is >5 mg/dl. • Ref:
B. To determine severity of liver injury: • ALT- ↑ • (ALT is a cytosolic enzyme that is present in highest concentrations in the liver. Elevation of enzyme activiti es in serum results from damage to the tissues rich in t he aminotransferases, or to a change in cell membra ne permeability allowing ALT to leak from damaged cells into serum.) • PT -↑, INR- > 1.4.
• GGT ↑ : (It is a canalicular enzyme. GGT is most elevate d in all children with biliary atresia, sclerosing cholangitis, paucity of intrahepatic bile ducts (Alagille syndrome), and cholestatic patients with α1-antitrypsin deficiency. • The presence of ↑ed GGT in both intrahepatic and extrahepatic cholestasis is variable and cannot be used to differentiate between them.
• AST (AST is present as both cytosolic and mitochondrial isoenzymes and is found in high concentrations in many tissues other than the liver, including heart muscle, skeletal muscle, kidne y, brain, pancreas, lung, leukocytes, and red cells) . • S Albumin (unless features of CLD is there).
• ALP (It is also a canalicular enzyme; but also found in several tissues, including the bone osteoblasts, the brush border of enterocytes in the small intestine, PCT of the kidney, placenta, and WBC. A normal growing child has elevated of serum AP of bon e origin, therefore, is not indicative of hepatic or biliary disease).
C.Todetect conditions that require immediate treatment (& also to identify etiology)- 1. CBC with PBF, C/S 2. Urine R/E & C/S 3. Urine for Benedict’s test followed by glucose strip test to exclude galactosemia. 4. Serum FT4, TSH 5. TORSCH IgM screening
D.Todifferentiate extrahepatic from intrahepatic causes of cholestasis: 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
• From Ultrasonography we get information about: - liver structure, size and echotexture. - GB size, gallstones and sludge in the GB & bile ducts, - To define cystic or obstructive dilatation of the biliary tree. - Ascites.
 CBD dilatation >4mm is associated with congenita l choledochal malformations and inspissated bile.
choledochal malformations: choledochal cyst-
- The sensitivity and specificity of USG in detectin g biliary atresia varies from 73%-100% and 67% to 100%, respectively. Ref:
• Triangular Cord sign: a cone shaped fibrotic mass cranial to the bifurcation of portal vein is found in biliary atresia.
• Triangular Cord sign has a sensitivity of 62– 93%, and a specificity of 96–100%.
C. To differentiate extrahepatic from intrahepatic causes of cholestasis 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
 Hepatobiliary Scintigraphy Premedication •Phenobarbitone: 5 mg/kg/day for 5 days. Dye used •HIDA: 99m Tclabelled imino-diacetic acid •DISIDA: 99m Tcdi-isopropyl IDA •MBRIDA: Mebrophenine IDA
Normal
In Biliary Atresia
Hepatobiliary scintigraphy • In Biliary Atresia, there is usually a rapid hepatic extraction of tracer, but no subsequent excretion of tracer into the gut. •Neonatal Hepatitis: uptake is delayed, but with normal excretion.
• 50% of patients with interlobular bile duct paucity, and 25% of patients with INH also demonstrated no biliary excretion of tracer in HIDA scan. • This significantly lowers its specificity. Sensitive of scintigraphy is 70% but not so specific for EHBA. (Ref: Gilmour SM , et al. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. Journal of Nuclear Medicine : 01 Aug 1997, 38(8):1279-1282.)
Why PHB priming: • Bile flow into the bile canaliculi can be both bile acid-dependent & bile acid-independent. Bile acid -dependent flow is the result of active transport by ATP-ase. • Bile acid-independent flow is mainly the result of the secretion of glutathione (an antioxidant) into bile. PHB acceletates glutathione excretion. • PHB increases the bile acid independant fraction of bile flow.
C. To differentiate extrahepatic from intrahepatic causes of cholestasis 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
Percutaneous Liver Biopsy • Most important investigation in differentiating INH and BA. • Prerequisites: Normal CBC, PT, APTT & USG. • Complications: o Bleeding o Bile peritonitis o Pneumothorax
Findings: Biliary Atresia • Bile duct proliferation • Bile plug in small bile ducts • Portal or perilobular edema and fibrosis, with • Intact basic lobular architecture.
Findings: Idiopathic Neonatal Hepatitis •Distortion of basic lobular architecture •Marked infiltration with inflammatory cells •Focal hepatocellular necrosis, with •Giant cell transformation of the hepatocytes.
• Liver biopsy is 100% sensitive and 76% spec ific in detecting biliary atresia.
Per-operative Cholangiography
• Percutaneous transhepatic cholangiography an visualize the biliary tract. • However, laparoscopic cholecystocholangiography can be used to evaluate the biliary tract in case of small infants.
Toestablish Other Diagnosis • X-ray chest (Congenital infection, Sepsis) • X-ray skull: Intracranial calcification- periventricular calcification in CMV & parenchymal calcification in Toxoplasma infection.
X-ray long bones (Congenital Syphilis infection): 'Radiograph showing bilaterally symmetrical multiple areas of erosion and destruction of the metaphysis of proximal and distal humerus, femur and tibia suggestive of bilaterally symmetrical osteochondritis
• Echo (Congenital infection: PDA, VSD in rubella, Alagille syndrome: PS. Down syndrome: VSD, ASD, PDA) • Bone marrow study (Storage disease: GSD; Lipid st orage disease- Gaucher, Niemann-Pick disease; M PS).
•Alpha Feto-protein level (Tyrosinaemia) •S. Alpha-1-antitrypsin level ↓ed, distinctive histo logic feature of PAS +ve, diastase-resistant glob ules in the ER of hepatocytes (α1-antitrypsin defi ciency). •Sweat chloride: > 60mEq/L (Cystic fibrosis). •Urine/serum amino acids (Metabolic conditions) :
Management of Ne onatal Cholestasis
A. Supportive Management •Parental counseling •Nutritional support •Treatment of pruritus •Choleretics and bile acid-binder
Nutritional Support •Adequate calories (125% of RDA), •Protein: 2-3 gm/kg/day (if encep. then 0.5-1 gm/kg/day). •MCT (C8-12)oil supplements: 1–2 mL/kg daily in 2–4 doses.
•Essential fatty acids (Linolenic acid, linoleic acid, arachidonic acid): Corn oil, oral or IV lipid emulsions. •Water soluble vitamins – Twice the RDA. •Supplemental Ca+2, P, Zn, Se, Iron.
Fat soluble vitamin supplementation (vitamins A, D, E, and K) •Vitamin A: 25,000-50,000 IU I/M every alternate month. •Vitamin D: 30,000-60,000 IU I/M every alternate month. •Vitamin K: 0.2mg/kg I/M – every alternate week. •Vitamin E: 25 IU/kg oral – every alternate week.
Pruritus in cholestasis: • Pruritus is a distressing manifestation of both intrahepatic and extrahepatic cholestasis. Its severit y can vary from mild to severe and sometimes becomes intractable.
Pruritus in cholestasis... .. • Children with: - paucity of interlobular bile duct disorders (Alagille syndrome), - PFIC, PSC, - unsuccessful portoenterostomy and - benign recurrent intrahepatic cholestasis appear to be most severely affected with pruritus. Bunchorntavakul C, et al. 2012
Why priritus? • Elevated serum and skin concentration of bile acid was previously thought to be responsible for the pruritus, but a direct causal relationship between itching and bile acid levels in skin an d/or serum has not been confirmed. (Ref: Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic l iver disease. Clin Liver Dis 2012;16:331–346).
• Bergasa et al. Suggested that pruritus here is CNS origin & is mediated by opiate receptor system. (Ref- Bergasa NV. The itch of liver disease. S emin Cutaneous Med Surg. 2011;30:93–98).
Treatment of Pruritus •As a choleretic agent: •Ursodeoxycholic acid (20-25mg/kg/day). •Phenobarbital (5mg/kg/day). •Naloxone- an opioid antagonist. •Antihistamin- Diphenhydramine. •Bile acid binders: they bind bile acids within the gut lumen, ↑ing their fecal excretion: cholestyramine (4- 8g/day).
• Rifampicin (10mg/day): mechanisms of rifampicin on pruritus include: activation of enzymes (UDGT- 1A and cytochrome P450) and stimulation of 6α- hydroxylation of bile acids, thereby promoting uri nary excretion of dihydroxy and monohydroxy bil e acids.
• Partial biliary diversion and ileal exclusion for intractable pruritus uncontrolled by medical therapy. • Here the GB is anastomosed end to side to the blind proximal portion of a jejunal conduit with the distal end of the conduit brought out to the skin as a permanent cutaneous stoma.
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 has been re-established in >80% of infants who were referred for surgery within 60 days after birth. • The success rate drops dramatically, to <20%, when it is done after 90 days of age.
• In most patients, variable degrees of intrahepatic cholangiopathy persists. Thus the long-term prognosis is related directly to the: • establishment of successful bile flow and
- the disappearance of jaundice (with S biliru bin <1mg/dl), with the native liver in childre n within 3 months of hepatoportoenterosto my.
• In these children 10-year survival ranges from 73% to 92% . • In those patients in whom jaundice remains and bile flow is inadequate, the 3-year survival rate decreases to <20%.
• 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/Portoen. Not done •Failed portoenterostomy •Decompensated cirrhosis and end stage liver disease despite initial successful Kasai.
Prognosis and Outcome Biliary Atresia: •Bile flow has been re-established in >80% of infants who were referred for surgery within 60 days after birth. •The success rate drops dramatically, to <20%, when it is done after 90 days of age.
• 50-80% will die without liver transplantation by 1 yr, if Kasai not done. • 90-100% will die by age 2 yrs • 70-80% require liver transplantation after Kasai during 1st 2 decade. • 80-90% long term survival after liver transplantation
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.
Thank you all

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Seminar on neonatal cholestasis

  • 1.
    Welcome to Seminar Presenters: Dr. Rumana Islam Dr.BikushChandra Paul Resident year-1 Paediatric Neurology & Neurodevelopment
  • 2.
    Case scenario Maisha, a2 months old girl presented with- • Jaundice since 3rd day of life & • Persistant pale stool for same duration. • She was delivered at term with average birth weight • No H/O delayed passage of meconium,constipation, lethargy, vomiting, convulsion or any rash.
  • 3.
    Case scenario • Onexamination, she was icteric & there was no facial dysmorphism. • Anthropometrically well thriving. • Hepatomegaly present. • Lab investigation- Shows direct hyerbillirubinemia.
  • 5.
  • 6.
    Objectives • To knowwhen 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 neonatal cholestasis.
  • 7.
  • 8.
    Neonatal cholestasis isdefined biochemically as prolonged elevation of the serum level of conjugated bilirubin beyond the 1st 14 days of life. (Nelson textbook of pediatrics, 20th ed.)
  • 9.
    • Cholestasis isdefined 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)
  • 10.
  • 14.
  • 16.
    Extrahepatic causes- Billiary atresia Bileduct stenosis Choledocal cyst Spon.perforation of bile duct CBD stenosis Primary sclerosing cholangitis Inspissated bile syndrome CBD ligation CBD stricture Mass (neoplasia)
  • 17.
    Intra hepatic Idiopathic Idiopathic Neonatal Hepatitis TORCH infection Bacterialsepsis Infectious Enterovirus Echovirus Intrahepatic causes
  • 18.
    Intra hepatic Metabolic Disorderof CHO metabolism Galactosemia Fructosemia Glycogen storage disease Disorder of amino acid metabolism Tyrosinemia Disorder of Lipid Metabolism Niemann-Pick disease Gaucher disease Peroxisomal disorders Zellweger syndrome Miscellaneous metabolic disorders Hypothyroidism Endocrine disorders Hypopituitarism Alpha-1- antitrypsin deficiency Cystic fibrosis Neonatal iron storage
  • 19.
    Intra hepatic Toxic TPN– associated cholestasis Drug induced cholestasis Genetic/chromosom al Down’s Syndrome Intrahepaticb.duct paucity Syndromic Alagille syndrome Non-syndromic PFIC- type 1,2,3 Cholestatic syndrome BRIC Ischemic Perinatal asphyxia
  • 20.
  • 21.
    •Neonatal cholestasis: 1in 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)
  • 22.
    Neonatal Hepatitis 35% Biliary Atresia 26% INH 24% Others 15% (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.)
  • 23.
  • 24.
  • 25.
    •It is aprogressive 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 Biliary Atresia cont..
  • 26.
  • 28.
    •Associated congenital anomalies: 1.Spleen- asplenia, polysplenia, double spleen 2. Portal vein- absent, cavernomatous transformation 3. Situs inversus 4. Malrotation of gut 5. Cardiac anomalies 6. Annular pancrease 7. Duodenal, esophageal, jejunal atresia 8. Polycystic kidney 9. Cleft palate
  • 29.
  • 30.
    intrahepatic cholestasis (10-20%)in whic It is an ever-shrinking percentage of cases of 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%).
  • 31.
    Difference Between BA& INH Characteristics Biliary Atresia Idiopathic Neonatal He patitis Sex Female Male Incidence Sporadic Familial (20%) Relation with gestat ional 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 & co nsistency Common Thriving Thriving well Not thriving well
  • 32.
    Biliary Atresia INH USGNo contraction after meal Contraction of GB before and after meal Hepatobiliary Sci ntigraphy Dye uptake good but no exc retion Less uptake but complete exc retion Biopsy  Architecture preserved  Bile plug  Bile ductular pro liferation  Periportal fibrosis  Architecture lost  Giant cell transfor mation Difference Between BA & INH cont..
  • 33.
  • 34.
    •Localized cystic dilatationof common bile ductis 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 Choledochal Cyst cont..
  • 36.
  • 38.
    •Manifested after ingestionof 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. Galactosemia cont..
  • 39.
  • 40.
    • It developsin >50% of infants with birth weight <1000 gram & in <10% of term infants after giving prolonged parenteral feeding(>2 wk) • Risk factors-Prematurity Short bowel syndrome Functional liver immaturity Sepsis Lack of enteral feeding Toxicity from component of parenteral nutrition • This may be due to lack of enteral feeding →reduction of gut hormone secretion → reduce bile flow → biliary stasis. TPN Related Cholestasis cont..
  • 41.
    • Biopsy-Hepatocellular &canalicular cholestasis occour, steatosis & periportal fibrosis seen on liver biopsy,billiar y chirrosis can develop with continued parenteral nutrit ion • Management-Trophic enteral feeding,UDCA,alternative to soy based lipid emulsion • Liver transplantation or combined liver intestinal transpl antation may be needed in end stage liver disease & w xtreme short bowel syndrome. TPN Related Cholestasis cont..
  • 42.
  • 43.
    • Inspissated bilewithin the distal CBD may cause obstructive jaundice in newborn. • Causes-Haemolysis ,diuretic therapy, parenteral nutrition, prematurity, cystic fibrosis. • Difficult to distinguish from biliary atresia. • In both condition-jaundice ,acholic stool ,conjugated hyperbillirubinemia, no biliary excretion on a radionuclide scan. • USG reveals –dialated proximal bile ducts & i nspissated bile. Inspissated Bile Syndrome cont..
  • 46.
    Cardinal Feature Appears withinfirst 3 months of life •Jaundice •Dark urine •Pale stools •Hepatomegaly
  • 47.
    Dark urine &pale stool
  • 49.
    Goals of TimelyEvaluation •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.
  • 50.
    How to Evaluatea Neonate with Cholestatic Jaundice?
  • 51.
  • 52.
    History Taking Age atpresentation Within first 3months of life Sex INH is common in male & BA i s common in female Prolonged jaundice Persisting >2weeks after birth Pale stool • Persistent BA • Intermittent INH Dark urine Cholestasis Abdominal distension Organomegaly Lethargy Galactosemia
  • 53.
    Vomiting Galactosemia Pruritus Cholestasis Antenatal •Fever & Rash TORCH • Abortion • Miscarriage Metabolic Natal • Term BA • Pre-term INH Birth weight • SGA/LBW INH • AGA BA
  • 54.
    Postnatal • Onset ofjaundice • Poor feeding • Lethargy • Hoarse cry • Constipation • Delayed passage of meconium Hypothyroidism • Convulsion Congenital infection Developmental milestone • Normal BA • Delayed Congenital infection Hy pothyroidism Metabolic diseases Family history • Consanguinity Metabolic disease • Sib affected INH
  • 55.
  • 56.
    General Examination Appearance • Irritable,lethargic Congenital infection Me tabolic diseases • Dysmorphic Alagille syndrome Do wn syndrome Hypoth yroidism Head • Wide anterior fontanelle Hypothyroidism Down ’s syndrome • Seborrheic Dermatitis Histiocytosis X Vital signs • Heart rate ,temp • Respiratory rate Increase in infection
  • 57.
    Alimentary System Oral cavity •Cleft lip • Cleft palate BA Abdomen • Pott belly • Umbilical hernia Hypothyroidism • Hepatomegaly (firm) • Splenomegaly Storage disease Congenital infection • Right hypochondriac mass Choledochal cyst • Ascites Late stage (3-4 months later)
  • 58.
    Cardio-pulmonary System Lungs • RTI (Tachypnea,crackles, wheeze) Down’s syndrome Cysti c fibrosis Heart • Feature ASD,VSD,PDA TOF Congenital rubella syndrome Dow n’s syndrome • Endocardial cushion defect Down’s syndrome • Dextrocardia Alagille syndrome • Peripheral Pulmonary stenosis. Alagille syndrome
  • 59.
    Upper limb • Simiancrease • Clinodactyly Down’s syndrome Lower limb • Frog leg position • Excessive crying during handling Congenital syphilis • Sandal gap Down’s syndrome Anthropometry • OFC Microcephaly in congenital infection • Weight and height FTT in INH Congenital infection
  • 60.
    Other Examination Skin survey •Patechie, purpura , Seborrheic Dermatitis Sepsis, TORCH, histocytosis x • Dry skin • Dermatitis Hypothyroidism Eye examination • Jaundice • Cataract Galactosemia ,Rubella • Choreo-retinitis CMV Rubella Toxopla sma • Cherry red spots Niemann-Pick disease • Posterior embryotoxon Alagille syndrome • Optic nerve Hypoplasia Pan-hypopituitarism
  • 61.
  • 62.
  • 63.
  • 64.
  • 65.
  • 66.
  • 67.
    A. To establishcholestasis: • 1. Fractionated S. Bilirubin: • A conjugated (direct) bilirubin concentration of >1 mg /dl with a total bilirubin of <5 mg/dl, or >20% of the tot al bilirubin concentration if the total is >5 mg/dl. • Ref:
  • 68.
    B. To determineseverity of liver injury: • ALT- ↑ • (ALT is a cytosolic enzyme that is present in highest concentrations in the liver. Elevation of enzyme activiti es in serum results from damage to the tissues rich in t he aminotransferases, or to a change in cell membra ne permeability allowing ALT to leak from damaged cells into serum.) • PT -↑, INR- > 1.4.
  • 69.
    • GGT ↑: (It is a canalicular enzyme. GGT is most elevate d in all children with biliary atresia, sclerosing cholangitis, paucity of intrahepatic bile ducts (Alagille syndrome), and cholestatic patients with α1-antitrypsin deficiency. • The presence of ↑ed GGT in both intrahepatic and extrahepatic cholestasis is variable and cannot be used to differentiate between them.
  • 70.
    • AST (ASTis present as both cytosolic and mitochondrial isoenzymes and is found in high concentrations in many tissues other than the liver, including heart muscle, skeletal muscle, kidne y, brain, pancreas, lung, leukocytes, and red cells) . • S Albumin (unless features of CLD is there).
  • 71.
    • ALP (Itis also a canalicular enzyme; but also found in several tissues, including the bone osteoblasts, the brush border of enterocytes in the small intestine, PCT of the kidney, placenta, and WBC. A normal growing child has elevated of serum AP of bon e origin, therefore, is not indicative of hepatic or biliary disease).
  • 72.
    C.Todetect conditions thatrequire immediate treatment (& also to identify etiology)- 1. CBC with PBF, C/S 2. Urine R/E & C/S 3. Urine for Benedict’s test followed by glucose strip test to exclude galactosemia. 4. Serum FT4, TSH 5. TORSCH IgM screening
  • 73.
    D.Todifferentiate extrahepatic fromintrahepatic causes of cholestasis: 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
  • 74.
    • From Ultrasonographywe get information about: - liver structure, size and echotexture. - GB size, gallstones and sludge in the GB & bile ducts, - To define cystic or obstructive dilatation of the biliary tree. - Ascites.
  • 75.
     CBD dilatation>4mm is associated with congenita l choledochal malformations and inspissated bile.
  • 76.
  • 77.
    - The sensitivityand specificity of USG in detectin g biliary atresia varies from 73%-100% and 67% to 100%, respectively. Ref:
  • 78.
    • Triangular Cordsign: a cone shaped fibrotic mass cranial to the bifurcation of portal vein is found in biliary atresia.
  • 80.
    • Triangular Cordsign has a sensitivity of 62– 93%, and a specificity of 96–100%.
  • 81.
    C. To differentiateextrahepatic from intrahepatic causes of cholestasis 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
  • 82.
     Hepatobiliary Scintigraphy Premedication •Phenobarbitone:5 mg/kg/day for 5 days. Dye used •HIDA: 99m Tclabelled imino-diacetic acid •DISIDA: 99m Tcdi-isopropyl IDA •MBRIDA: Mebrophenine IDA
  • 83.
  • 84.
  • 85.
    Hepatobiliary scintigraphy • InBiliary Atresia, there is usually a rapid hepatic extraction of tracer, but no subsequent excretion of tracer into the gut. •Neonatal Hepatitis: uptake is delayed, but with normal excretion.
  • 86.
    • 50% ofpatients with interlobular bile duct paucity, and 25% of patients with INH also demonstrated no biliary excretion of tracer in HIDA scan. • This significantly lowers its specificity. Sensitive of scintigraphy is 70% but not so specific for EHBA. (Ref: Gilmour SM , et al. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. Journal of Nuclear Medicine : 01 Aug 1997, 38(8):1279-1282.)
  • 88.
    Why PHB priming: •Bile flow into the bile canaliculi can be both bile acid-dependent & bile acid-independent. Bile acid -dependent flow is the result of active transport by ATP-ase. • Bile acid-independent flow is mainly the result of the secretion of glutathione (an antioxidant) into bile. PHB acceletates glutathione excretion. • PHB increases the bile acid independant fraction of bile flow.
  • 89.
    C. To differentiateextrahepatic from intrahepatic causes of cholestasis 1. Imaging studies •Ultrasonography •Hepatobiliary scintigraphy 2. Percutaneous liver biopsy 3. Percutaneous trans-hepatic cholangiography
  • 90.
    Percutaneous Liver Biopsy •Most important investigation in differentiating INH and BA. • Prerequisites: Normal CBC, PT, APTT & USG. • Complications: o Bleeding o Bile peritonitis o Pneumothorax
  • 91.
    Findings: Biliary Atresia •Bile duct proliferation • Bile plug in small bile ducts • Portal or perilobular edema and fibrosis, with • Intact basic lobular architecture.
  • 92.
    Findings: Idiopathic NeonatalHepatitis •Distortion of basic lobular architecture •Marked infiltration with inflammatory cells •Focal hepatocellular necrosis, with •Giant cell transformation of the hepatocytes.
  • 93.
    • Liver biopsyis 100% sensitive and 76% spec ific in detecting biliary atresia.
  • 95.
  • 96.
    • Percutaneous transhepaticcholangiography an visualize the biliary tract. • However, laparoscopic cholecystocholangiography can be used to evaluate the biliary tract in case of small infants.
  • 97.
    Toestablish Other Diagnosis •X-ray chest (Congenital infection, Sepsis) • X-ray skull: Intracranial calcification- periventricular calcification in CMV & parenchymal calcification in Toxoplasma infection.
  • 98.
    X-ray long bones(Congenital Syphilis infection): 'Radiograph showing bilaterally symmetrical multiple areas of erosion and destruction of the metaphysis of proximal and distal humerus, femur and tibia suggestive of bilaterally symmetrical osteochondritis
  • 100.
    • Echo (Congenitalinfection: PDA, VSD in rubella, Alagille syndrome: PS. Down syndrome: VSD, ASD, PDA) • Bone marrow study (Storage disease: GSD; Lipid st orage disease- Gaucher, Niemann-Pick disease; M PS).
  • 101.
    •Alpha Feto-protein level(Tyrosinaemia) •S. Alpha-1-antitrypsin level ↓ed, distinctive histo logic feature of PAS +ve, diastase-resistant glob ules in the ER of hepatocytes (α1-antitrypsin defi ciency). •Sweat chloride: > 60mEq/L (Cystic fibrosis). •Urine/serum amino acids (Metabolic conditions) :
  • 102.
  • 103.
    A. Supportive Management •Parentalcounseling •Nutritional support •Treatment of pruritus •Choleretics and bile acid-binder
  • 104.
    Nutritional Support •Adequate calories(125% of RDA), •Protein: 2-3 gm/kg/day (if encep. then 0.5-1 gm/kg/day). •MCT (C8-12)oil supplements: 1–2 mL/kg daily in 2–4 doses.
  • 105.
    •Essential fatty acids(Linolenic acid, linoleic acid, arachidonic acid): Corn oil, oral or IV lipid emulsions. •Water soluble vitamins – Twice the RDA. •Supplemental Ca+2, P, Zn, Se, Iron.
  • 106.
    Fat soluble vitaminsupplementation (vitamins A, D, E, and K) •Vitamin A: 25,000-50,000 IU I/M every alternate month. •Vitamin D: 30,000-60,000 IU I/M every alternate month. •Vitamin K: 0.2mg/kg I/M – every alternate week. •Vitamin E: 25 IU/kg oral – every alternate week.
  • 108.
    Pruritus in cholestasis: •Pruritus is a distressing manifestation of both intrahepatic and extrahepatic cholestasis. Its severit y can vary from mild to severe and sometimes becomes intractable.
  • 109.
    Pruritus in cholestasis..... • Children with: - paucity of interlobular bile duct disorders (Alagille syndrome), - PFIC, PSC, - unsuccessful portoenterostomy and - benign recurrent intrahepatic cholestasis appear to be most severely affected with pruritus. Bunchorntavakul C, et al. 2012
  • 110.
    Why priritus? • Elevatedserum and skin concentration of bile acid was previously thought to be responsible for the pruritus, but a direct causal relationship between itching and bile acid levels in skin an d/or serum has not been confirmed. (Ref: Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic l iver disease. Clin Liver Dis 2012;16:331–346).
  • 111.
    • Bergasa etal. Suggested that pruritus here is CNS origin & is mediated by opiate receptor system. (Ref- Bergasa NV. The itch of liver disease. S emin Cutaneous Med Surg. 2011;30:93–98).
  • 112.
    Treatment of Pruritus •Asa choleretic agent: •Ursodeoxycholic acid (20-25mg/kg/day). •Phenobarbital (5mg/kg/day). •Naloxone- an opioid antagonist. •Antihistamin- Diphenhydramine. •Bile acid binders: they bind bile acids within the gut lumen, ↑ing their fecal excretion: cholestyramine (4- 8g/day).
  • 113.
    • Rifampicin (10mg/day):mechanisms of rifampicin on pruritus include: activation of enzymes (UDGT- 1A and cytochrome P450) and stimulation of 6α- hydroxylation of bile acids, thereby promoting uri nary excretion of dihydroxy and monohydroxy bil e acids.
  • 114.
    • Partial biliarydiversion and ileal exclusion for intractable pruritus uncontrolled by medical therapy. • Here the GB is anastomosed end to side to the blind proximal portion of a jejunal conduit with the distal end of the conduit brought out to the skin as a permanent cutaneous stoma.
  • 115.
    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
  • 116.
  • 118.
    • Bile flowhas been re-established in >80% of infants who were referred for surgery within 60 days after birth. • The success rate drops dramatically, to <20%, when it is done after 90 days of age.
  • 119.
    • In mostpatients, variable degrees of intrahepatic cholangiopathy persists. Thus the long-term prognosis is related directly to the: • establishment of successful bile flow and
  • 120.
    - the disappearanceof jaundice (with S biliru bin <1mg/dl), with the native liver in childre n within 3 months of hepatoportoenterosto my.
  • 121.
    • In thesechildren 10-year survival ranges from 73% to 92% . • In those patients in whom jaundice remains and bile flow is inadequate, the 3-year survival rate decreases to <20%.
  • 122.
    • Complications are: -ascending cholangitis and - re-obstruction, as well as - failure to re-establish bile flow.
  • 123.
    Liver Transplantation  Biliaryatresia is the most common indication for transplant.  Others are: • When initial treatment was given lately/Portoen. Not done •Failed portoenterostomy •Decompensated cirrhosis and end stage liver disease despite initial successful Kasai.
  • 125.
    Prognosis and Outcome BiliaryAtresia: •Bile flow has been re-established in >80% of infants who were referred for surgery within 60 days after birth. •The success rate drops dramatically, to <20%, when it is done after 90 days of age.
  • 126.
    • 50-80% willdie without liver transplantation by 1 yr, if Kasai not done. • 90-100% will die by age 2 yrs • 70-80% require liver transplantation after Kasai during 1st 2 decade. • 80-90% long term survival after liver transplantation
  • 127.
    Neonatal Hepatitis: • Noindicators to predict prognosis. • In sporadic case, 60-70% disease free survival, <5% severe liver disease or cirrhosis. • In familial case, 20-30% recover.
  • 128.