PEDIA 2 • PEDIATRICS II • DIDACTIC PEDIATRICS • MODULE •

SHIFT
NEONATAL CHOLESTASIS
#
August 22, 2022
Portia Menelia D. Monreal, MD LEC #3
January 26, 2023
Figure 1. Bilirubin Metabolism
LECTURE OUTLINE
I. Cholestasis VI. Other things to Consider MUST KNOW INFORMATION
A. Causes of Cholestasis A. Physiologic Jaundice ● Any disorder that increases unconjugated bilirubin (and hence, enterohepatic
B. Neonatal Cholestasis B. Breastfeeding Jaundice vs circulation) will lead to UNCONJUGATED hyperbilirubinemia.
C. Hyperbilirubinemia Breast Milk Jaundice ● On the other hand, any disorder that blocks bile excretion or prevents excretory
II. Approach to Diagnosis C. Cholestatic Jaundice Beyond function of the liver will lead to CONJUGATED hyperbilirubinemia which is the
A. History six months of life marker for cholestasis.
B. Physical Examination VII. Summary
C. Laboratory Evaluation VIII. Hepatitis A
A. CAUSES OF CHOLESTASIS
D. Ultrasound of the Liver A. Clinical Manifestations
E. Fasting Abdominal Ultrasound B. Diagnosis ● Intrahepatic Obstruction
F. Hepating Imaging Procedures C. Serologic Course ○ An injury to hepatocytes or an alteration in hepatic physiology leads to a
1. CT Scan and Ultrasound D. Complications reduction in the rate of secretion of solutes and water
2. Scintigraphy E. Treatment ○ Severe hepatocellular dysfunction
3. Percutaneous liver biopsy F. Prevention ● Extrahepatic Obstruction
4. Cholangiography IX. Hepatitis B ○ Bile pigment is visible in the intralobular bile ducts or throughout the
5. Endoscopic retrograde A. Pathogenesis parenchyma as bile lakes or infarcts
cholangiography B. Clinical Manifestations ○ Biliary tree obstruction
G. Extrahepatic Biliary Atresia C. Serologic Markers ○ Obstruction in the flow of bile
H. Idiopathic Neonatal Hepatitis D. Complications
III. Intrahepatic Biliary Hypoplasia E. Treatment
IV. Infectious Hepatitis F. Prevention
V. Metabolic diseases of the liver X. Summary
XI. Q&A
XII. References
XIII. Review Questions

important/must know book previous trans updated lecturer’s key points

I. CHOLESTASIS Figure 2. Cause of Cholestasis.

● Chole-: bile, -stasis: static flow
● Accumulation in serum of substances normally excreted in bile B. NEONATAL CHOLESTASIS
○ Conjugated bilirubin, cholesterol, and bile acids ● Prolonged elevation of serum levels of conjugated bilirubin beyond the first
● Conjugated bilirubin is the marker for cholestasis 14 days of life
● Caused by extrahepatic or intrahepatic obstruction to bile flow ● Jaundice that appears after 2 weeks of age
● Bilirubin Metabolism ○ Progresses after this time or does not resolve at this time
○ Hemoglobin breaks down to heme and globin ● Abnormal direct/conjugated bilirubin
○ Heme is converted to biliverdin by heme oxygenase ○ >1 mg/dL (>17 mmol/L)
○ Biliverdin is converted to unconjugated bilirubin by biliverdin reductase
○ Unconjugated bilirubin (hydrophobic) will bind to albumin and go to the
1. CLINICAL PRESENTATION
liver where it gets conjugated by glucuronyl transferase
○ Conjugated bilirubin is excreted in the bile and into the gastrointestinal ● Jaundice
tract ○ Can be the very first or the only sign of hepatic dysfunction in neonates
■ It is acted upon by intestinal bacteria and excreted in the stool as ○ Icteric sclera & jaundiced skin
stercobilin (gives color to stool) from stercobilinogen ○ >50% of patients
■ Some percentage of conjugated bilirubin is excreted in urine as ○ Develops in the first week of life
urobilin (gives color to the urine) from urobilinogen ● Acholic stools
■ Small percentage is converted back to unconjugated bilirubin by ○ Pale-colored stools
enzyme beta-glucuronidase ○ Most commonly seen in biliary atresia
○ Unconjugated bilirubin returns to enterohepatic circulation ■ Can also be seen in neonate hepatitis when there is severe
hepatocellular dysfunction
○ Transient in neonatal hepatitis due to severe hepatocellular dysfunction
● Urine
○ Highly colored or dark
● Liver/Spleen
○ Hepatomegaly with a firm consistency
○ Splenomegaly

C. HYPERBILIRUBINEMIA
● Condition in which there is too much bilirubin in the blood
● Causes a yellowing of the baby's skin, eyes, and other tissues (jaundice)

1. UNCONJUGATED BILIRUBINEMIA
● Tightly bound to albumin
● Unconjugated bilirubin is carried by albumin to the liver (not water soluble;
lipophilic)
○ Where it is conjugated by enzyme glucuronyl transferase before it is
excreted into the bile and intestines
● May be due to increased production & hemolysis, decreased hepatic
removal and altered metabolism of bilirubin

2. CONJUGATED BILIRUBINEMIA
● Only fraction to appear in the urine (water soluble; hydrophilic)

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 ● Reflects decreased excretion by damaged hepatic parenchymal cells or ○ Vitamin E Deficiency
disease of the biliary tract (e.g. obstruction, sepsis, toxins, inflammation, & ○ Hepatic Encephalopathy
genetic/metabolic causes) ● Inspect urine and stool color
II. APPROACH TO DIAGNOSIS ○ Dark-colored urine or pale-looking stool may indicate cholestasis
○ Newborn - normally colorless urine

A. HISTORY
● Onset of jaundice
○ Does it occur during the first 24 hours of life or after the first
○ 24 hours of life or 1st week of life?
■ Jaundice in the first 24 hours of life = PATHOLOGIC
■ Jaundice AFTER the first 24hrs of life = PHYSIOLOGIC
○ Different onset = different conditions
● Birth History
○ Term or preterm?
○ Were there problems during the birth of the infant? Was it a stormy
course? Is the infant preterm? Low birthweight?
Figure 3. (Left) Acholic stools. Almost white, creamy and like the color of
■ There is increased incidence of neonatal cholestasis or neonatal
chalk. (Right) Normal color of stools
hepatitis
● Change in the color of stool or urine
● History of breastfeeding and source of nutrition
○ Is the infant exclusively breastfed or drinks infant formula?
○ Breast Milk jaundice
■ Lasts for 12 weeks
■ Fractionation of the bilirubin: mainly unconjugated
hyperbilirubinemia
● Feeding Pattern
○ Does the infant have feeding intolerances? Do you have problems with
latching or breastfeeding? Irregularity?
○ Adequate feeding during the first 24 hours of life?
○ Can lead to dehydration
● Weight Loss
○ Accompanying manifestation of possible infections
● Pruritus
● Bleeding
○ Was Vitamin K given at birth?
○ If vitamin K was given, bleeding could be due to hypothrombinemia Figure 4. Stool color chart. Only numbers 7, 8, and 9 are normal stool colors. This is a
● Maternal conditions that may predispose to jaundice chart given to parents to assess their child's stool.
○ Maternal diabetes mellitus
○ Maternal infections or exposure to infections such as rubella
● Fetal ultrasound
○ Shows congenital malformations
● Past ABO/Rh disease
○ Ask for maternal blood type and fetus blood type to determine
incompatibility
● Family history of jaundice
○ Might be due to causes that are familial
● Newborn Screening
○ Conditions can be easily ruled out when we have the results at hand

B. PHYSICAL EXAMINATION
● General health status
○ Is the infant ill-looking or well-looking?
○ Preterm or term? Figure 5. Bilirubinuria. Normal urine color (Right) varies according to the hydration status
■ Pre-term and had a stormy course, most likely dealing with of the patient. Bilirubinuria (Left) is dark colored/highly colored urine containing bilirubin or
neonatal hepa caused by the deposition of bile pigments.
● Fever
○ Infection causes cytokine release that can lead to the development of C. LABORATORY EVALUATION
cholestasis
● Anthropometric Data ● Done when encountered patients presented with jaundice
○ Get infant’s weight and length ● Bilirubin Fractionation
○ Plot against growth chart to know if infant is thriving well ○ Direct bilirubin on >1 mg/dL
● Jaundice, bruising, or petechiae ● Serum Transaminases
● Abdomen ○ AST & ALT
○ Distention ○ Elevated levels are indicative of acute liver/parenchymal injury
○ Liver size and consistency ● Synthetic Function of the Liver
■ Normal: neonatal liver palpated 2cm below the right costal margins ○ PT (INR), albumin
■ If liver edge is palpable beyond 3.5 cm, then there is hepatomegaly ○ Reflects severity of liver disease
■ In biliary atresia: liver is firm ■ Detect early prolongation = Give Vitamin K
○ Spleen size and consistency ○ We should include PT and PTT in initial workups to assess for bleeding
■ Present in cases of biliary atresia after the newborn period ○ TPAG (Total Protein, Albumin, Globulin)
■ If there is splenomegaly after 2-4 weeks, think of hematologic or ● Test Indicative of Obstruction
storage disorder ○ Bile acids, Alkaline phosphatase, 5-nucleotidase, Gamma glutamyl
○ Presence of ascites transpeptidase
○ Abdominal wall vasculature ■ Elevated when obstruction is present
● Other signs of liver disease ○ Gamma glutamyl transpeptidase: More specific than ALP in detecting
○ Check for the following: cholestasis because the latter can increase in liver, bone, or muscle
■ Spider angiomas: chest; altered estrogen metabolism problems
■ Xanthomas: cholesterol deposits ● Other parameters that may reflect severity of liver disease
■ Palmar erythema: increased BF to fingers due to vasodilation ○ Glucose, Ammonia, Electrolytes, Cholesterol
● Check other organ systems
○ Conditions seen in the heart or eyes can be associated with liver D. ULTRASOUND OF THE LIVER
diseases
● Provides information about the size, composition, and blood flow of the liver
■ Eyes: Presence of cataracts & Fleischer rings in Wilson’s Disease
● Assess gallbladder size, detect dilatation of biliary tract and choledochal cyst
■ Ears: Sensorineural hearing loss
● Biliary Atresia
■ Heart: Levocardia? Cardiac murmur?
○ Small or absent gallbladder
● 30% will present with congenital anomalies such as the
○ Nonvisualization of the common duct
problems in the heart
○ Presence of triangular cord sign
● Neurologic status
● Portal Hypertension
○ Tone and asymmetry of muscles
○ Evaluate patency of portal vein
○ Infant’s movements
○ Collateral circulation
● Pathologic causes |

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 ○ Size of spleen
○ Amount of ascites

Figure 9. Scintigraphy of extra- and intrahepatic obstruction. Left: Extrahepatic

obstruction. The uptake in the liver is good but no excretion into the duodenum. Right:
Figure 6. Anatomic relationship between the fibrous ductal remnant and the blood Neonatal Hepatitis. There is poor uptake in the liver but excretion of the dye to the
vessels in the porta hepatis. Short black arrows: Triangular cord signs Green: intestines is good
common bile duct (located anterior and superior); Red: hepatic artery; Blue: portal
vein. The portal triad will enter into the opening of the liver. 3. PERCUTANEOUS LIVER BIOPSY
● Uses:
○ Histologic diagnosis
○ Enzyme analysis
○ Analysis of stored material
○ Monitor response to therapy, detect complications of treatment or
progression of liver disease
● Contraindications:
○ Prolonged PT or INR
○ Thrombocytopenia
○ Suspicion of vascular or cystic lesion
○ Severe ascites

Figure 7. Triangular cord sign ultrasound. There is a focal area of echogenicity 4. CHOLANGIOGRAPHY
>4mm thickness anterior to the bifurcation of the main portal vein. ● Done intraoperatively for direct visualization of intrahepatic and extrahepatic
biliary tree after injection of opaque material
● Evaluates cause, location, and extent of obstruction

5. ENDOSCOPIC RETROGRADE CHOLANGIOGRAPHY (ERCP)

● Alternative for examining bile ducts in older children
● Papilla of Vater is cannulated to outline the anatomy of bile and pancreatic
ducts
● Rarely done in infants

Table 1. Value of Specific Tests in the Evaluation of Patients Suspected with Neonatal
Cholestasis.
TEST RATIONALE
Serum Bilirubin Fractionation ● Documents cholestasis (Direct bilirubin on >1
mg/dL)
Figure 8. Triangular cord sign. Surgical findings of a triangular fibrous ductal
remnant, atretic gallbladder, and fibrous common bile duct seen in biliary atresia. Assessment of Stool Color ● Indicates bile flow into intestine (pale yellow
stools)
IMPORTANT: Absence of triangular cord sign does not exclude biliary atresia Urine Bile Acids Measurement ● Confirms cholestasis; may indicate inborn error
of bile acid biosynthesis
E. FASTING ABDOMINAL ULTRASOUND Hepatic Synthetic Function ● Indicates severity of hepatic dysfunction
● Findings suggestive of Biliary Atresia: (Albumin, Coagulation Profile)
○ Triangular cord sign 𝛼-1 antitrypsin ● Suggests or excludes PiZZ (Homozygous Z)
■ 73-92% sensitive, 98-100% specific, 95% negative predictive value Thyroxine or TSH ● Suggests or exclude endocrinopathy
for intrahepatic cholestasis
○ Absence of Common Bile Duct Sweat chloride ● Suggests or excludes cystic fibrosis
■ 93% sensitive, 92% specific Urine/Serum Amino Acids & Urine ● Suggests or excludes metabolic disorders
○ Small or undetectable gallbladder Reducing Substance
■ 20-70%of BA Ultrasonography ● Suggests or excludes choledochal cyst
○ Polysplenia
● May detect Triangular cord (TC) sign suggesting
■ 10% sensitive, 100% specific
biliary atresia
Hepatobiliary scintigraphy ● Documents bile duct patency or obstruction
F. HEPATIC IMAGING PROCEDURES
Liver Biopsy ● Distinguishes biliary atresia from neonatal
hepatitis; suggests alternative diagnosis
1. CT SCAN & ULTRASOUND
● Both can be used to guide percutaneous needle biopsy of the liver
● CT scan is less suitable for children <2 years old due to:
○ Smallness of structures
○ Paucity or minimal fat content of their abdominal structures
○ Heavy sedation is needed

2. SCINTIGRAPHY
● Injected radioactive material that is normally excreted into the intestine within a
predictable time
● Differentiates intrahepatic from extrahepatic obstruction in neonates
○ Extrahepatic: uptake occurs but excretion of isotope is delayed or
absent
○ Intrahepatic: uptake is poor but excretion into the bile and intestines
eventually ensues Figure 10. Algorithmic Approach. Prototype for intrahepatic bile duct injury is the
● Best when scanning is preceded by a 5–7-day treatment of phenobarbital
Alagille syndrome. Metabolic diseases includes 𝛼-1-antitrypsin deficiency and
○ To prime the biliary tree before the procedure is done (Phenobarbital is
Wilson disease. Viral disease includes TORCH infections.
able to convert unconjugated bilirubin to conjugated bilirubin)

G. EXTRAHEPATIC BILIARY ATRESIA

● Prototype for extrahepatic disease
● 1:10,000-15,000 live births
● More common in East Asian countries (1:5000)

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 ● 3 TYPES: specific)
■ Perinatal (70%)
● Most common
● No congenital anomalies
■ Biliary Atresia Splenic Malformation (15%)
● Manifests with heterotaxia malformation
○ Situs inversus, Malrotation, Polysplenia, Interrupted inferior
vena cava, CHD
■ Biliary Atresia with other congenital malformations (15%)
● Choledochal cyst
● Kidney anomalies
● Clinical features
○ Females > Males
○ Generally acholic stools with onset of about 2 weeks old
○ Average birth weight
○ Hepatomegaly; Upon palpation, liver is firm to hard consistency
○ Unlikely to recur within the family
○ On ultrasound: Gallbladder is not visualized or it is a micro gallbladder and
there is presence of triangular cord sign
○ On scintigraphy: Normal uptake on radionucleotide scan with no excretion
or no flow to the intestines

H. IDIOPATHIC NEONATAL HEPATITIS Figure 11. Left: Normal hepatic cell Right: Biopsy slide of a normal liver. Portal Triad at
● 1:5000-1000 births periphery.
● Familial incidence of 20%
● Generally normal stools or acholic stools (in severe cases) with onset at one
month old
○ Acholic stools transiently seen in severe hepatocellular dysfunction
● Low birthweight
● Normal liver on exam or hepatomegaly with normal to firm consistency
● On scintigraphy: Impaired uptake on radionucleotide scan with normal
excretion

Table 2. Extrahepatic Biliary Atresia VS Idiopathic Neonatal Hepatitis

EXTRAHEPATIC IDIOPATHIC NEONATAL
BILIARY ATRESIA HEPATITIS
Family History (-) 20% familial
incidence
Associated Anomalies Polysplenia, (-)
abdominal
heterotaxia,
malrotation Figure 12. Schematic Diagram. When there is proliferation in the bile duct, you will see the
Prematurity (-) Yes proliferation of the ducts in the sinusoids, it will appear as a train of bile ducts.
Duodenal aspirate (-) (+ for bile acids)
Acholic stools Usually persistent Stools usually
pigmented,
occasional transient
acholic
Hepatomegaly Increase size with (+/-)
abnormal
consistency
Splenomegaly Sometimes More common
Jaundice at birth Never Rarely
Jaundice at 2-4 weeks 2-4 weeks
presentation
Dark yellow urine Yes Yes Figure n. Liver biopsy. Left: Biliary atresia Right: Idiopathic neonatal hepatitis
Serum transaminases May be normal Frequently abnormal
Table 3. Biliary Atresia VS Idiopathic Neonatal Hepatitis Biiopsy
BILIARY ATRESIA IDIOPATHIC NEONATAL HEPATITIS
ALP / GGT/ 5NT Increased Usually normal
● Bile duct proliferation ● Giant cell transformation
Ultrasound GB usually not GB +/- ● Bile plugs ● Lobular disarray
visualized; ● Portal or perilobar fibrosis, with ● Inflammatory cells in portal
(+) triangular cord* edema areas
*Triangular cord represents fibrotic mass cranial to bifurcation of portal vein ● Preservation of hepatic lobules ● Bile ductules show little or
no alteration
● Ballooning of hepatocytes
Hepatobiliary Scintigraphy
with multiple nuclei
EXTRAHEPATIC IDIOPATHIC NEONATAL
BILIARY ATRESIA HEPATITIS
III. INTRAHEPATIC BILIARY HYPOPLASIA / PAUCITY
Uptake Normal Impaired
Excretion into bowel ● Alagille syndrome – prototype
No Eventually occurs
○ Disorder of embryogenesis: Absence or marked reduction in the
Biopsy Differences number of interlobular bile ducts in the portal triads with normal sized
EXTRAHEPATIC IDIOPATHIC NEONATAL branches of portal vein and hepatic arteriole
BILIARY ATRESIA HEPATITIS ○ “Disappearing bile duct syndrome” in adults
Diffuse hepatocellular ● Clinical presentation
disease ✓ (w/ focal necrosis) ○ Unusual facial characteristics (deep set eyes, straight nose,
underdeveloped mandible)
Bile ductular ○ CVS anomalies (Tetralogy of Fallot, pulmonary stenosis, pulmonary
proliferation ✓ atresia, VSD, ASD, & aortic coarctation)
○ Vertebral arch defects (butterfly vertebra, fused vertebrae, spina bifida
occulta, & rib anomalies)
Bile plug/ Bile lakes
✓ ○ Growth retardation, pancreatic insufficiency, vasculopathy, & defective
spermatogenesis
Lobular architecture
Intact Distorted IV. INFECTIOUS HEPATITIS
Portal & perilobular ● A small percentage of cases of neonatal hepatitis syndrome
edema & fibrosis ✓ ● HSV, enterovirus, CMV, Hepatitis B, TORCH
○ CMV (most common), Hepatitis B (rare)
Giant cells ✓ ✓✓ (more common; not
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 V. METABOLIC DISEASES OF THE LIVER Vitamin K deficiency Replace with 2.5-5.0 mg every other
(Hypoprothrombinemia) day as water soluble derivative of
Table 4. Metabolic Diseases of the liver and Clinical Presentation
menadione
Metabolic - Ceiling: 10 mg
Description Clinical Presentation
Disease Micronutrient deficiency Calcium, zinc or phosphate
𝛼-1-antitrypsin Most common Deficient Emphysematous lung supplementation
deficiency allele z - Calcium included in multivitamins, Zinc
If this is suspected, is given separately
request for stains Deficiency of water-soluble Supplement with twice the
accompanying the liver vitamins recommended daily allowance
biopsy
Retention of biliary Administer choleretic bile acids,
Galactosemia Deficient galactose Very sick newborn with
constituents ursodeoxycholic acid 15-20 mg/kg/day
enzyme seizure, jaundice,
(e.g. cholesterol) to enhance bile flow
lethargy, cataract
and minimize pruritus
Tyrosinemia Disorder of AA Renal tubulopathy
metabolism, deficiency of Progressive liver disease Control bleeding, salt restriction,
tyrosinase enzyme (Variceal bleeding, ascites, spironolactone
hypersplenism)
Zellweger Disorder in kidney and liver Peroxisomal disorder,
syndrome Very rare cerebral, hepatic, and renal End stage liver disease Transplantation
dysfunction (Liver failure)

Endocrinopathy Hypothyroidism
VI. OTHER THINGS TO CONSIDER
Galactosemia, Tyrosinemia, Endocrine problems can be ruled out by newborn screening

A. PHYSIOLOGIC JAUNDICE
● Increased bilirubin production from breakdown of fetal red cells combined
with transient limitation in the conjugation of bilirubin by the immature
neonatal liver
● Visible on the 2nd-3rd day of life
● Decreases between the 5th-7th day of life
● Indirect/unconjugated bilirubin rises at a rate of < 5mg/dL/24hrs

B. BREASTFEEDING JAUNDICE vs BREASTMILK JAUNDICE

Table 7. Comparison of breastfeeding and breast milk jaundice

Breastfeeding Breastmilk
Jaundice Jaundice
Type of Indirect Indirect
Jaundice
Onset 1st week of life After 7 days of life; max
conc. in 2nd- 3rd week
as high as 20-30 mg/dL
Incidence in 13% 2%
Figure 13. Different causes of cholestasis breastfed (more in breastfed than
infants bottle fed)
Mechanism Due to decreased May be due to
Table 5. Complications of Cholestasis intake leading to glucuronidase in some
Complications Mechanisms dehydration & breastmilk
Growth failure Malabsorption of fat-soluble decreased caloric
vitamins & malnutrition intake
Treatment and Increase frequency of Temporary cessation of
Degenerative neuromuscular Vit E deficiency
Prevention breastfeeding; breastfeeding may lead to
syndrome
discourage use of rapid drop in bilirubin
Pruritus, xanthomas Accumulation of bile acids & glucose water
cholesterol in serum & tissues
Spider angioma Altered estrogen metabolism
Portal hypertension, ascites, Progressive fibrosis & cirrhosis C. CHOLESTATIC JAUNDICE BEYOND SIX MONTHS OF LIFE
esophageal varices ● Infections
○ Viral Hepatitis
V. HEPATITIS B ○ Liver abscess
A. MANAGEMENT OF BILIARY ATRESIA ● Extrahepatic obstruction
○ Pancreatic pathology
● Exploratory laparotomy and direct cholangiography to determine the ○ Gallstones
presence and site of obstruction ○ Choledochal cysts
● Direct drainage – for patients with correctable lesions ● Inherited Conjugated Hyperbilirubinemia
● Kasai procedure – surgical ○ Dubin-Johnson syndrome - jaundiced but asymptomatic
○ Hepatoportoenterostomy ■ Elevated direct bilirubin
○ Indicated for those with non-correctable lesions ○ Rotor Syndrome – jaundiced but asymptomatic
○ Goal: Establish bile flow ■ Both direct and indirect hyperbilirubinemia
○ Success rate >90% if performed before 8 weeks of life ● Wilson disease – associated with eye problems and disorder of copper
○ Short term benefit: decompression and drainage sufficient to forestall the metabolism
onset of cirrhosis and sustain growth until liver transplantation can be
done
VII. SUMMARY
Table 6. Medical management of persistent cholestasis | 
● What will you ask?
Clinical Impairment Management ○ Onset of jaundice
Malnutrition from malabsorption MCT formula (medium chain ○ Maternal history of infections
of long chain fats triglycerides; around 6-12 carbons) – ○ Maternal Intake of drugs
preferred because it does not need bile ○ Blood type (ABO incompatibility)
acids ● What will you look for?
Vitamin A deficiency Replace with 10-15,000 IU/day ○ Color of urine & stool (direct/actual visualization)
(Night blindness, thick skin) ● What laboratory exams will you request for?
○ Bilirubin fractionation (direct, indirect, and total bilirubin)
Vitamin E deficiency Replace with 50-400 IU/day ○ Albumin
(Neuromuscular degeneration) ○ PT and PTT; if abnormal, urgent administration of vitamin K
Vitamin D deficiency Replace with 5-8,000 IU/ day of ○ Differentiate conjugated or unconjugated hyperbilirubinemia
(Metabolic bone disease) D2 or 3-5 ug/kg/day of ● What will make you suspect of neonatal cholestasis?
25-hydroxycholecalciferol ○ Jaundice

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 ○ Pale/acholic stools and antipruritic agents for prolonged cholestasis
○ Hepatomegaly ● Serial monitoring for signs of ALF
○ Direct bilirubin >1 mg/dL ■ If ALF is diagnosed, refer for transplantation
● What ancillary procedures should you do to confirm diagnosis?
○ Liver biopsy F. PREVENTION
● What complications may arise?
○ Malnutrition, growth failure, bleeding, portal hypertension, etc. ● Contagious from 2 weeks before to 1 week after onset of jaundice so should
● How will you manage the baby? be excluded from school, childcare or work
○ Biliary atresia → Kasai procedure to establish bile flow ● Careful handwashing
○ Neonatal hepatitis → Manage patient medically ○ Particularly after changing diapers and before preparing/serving food
○ Liver cocktails - Vitamin ADEK ● Hospital setting
● What complications may arise? ○ Contact and standard precautions are recommended for 1 week after
○ Malnutrition, growth failure, bleeding, portal hypertension, etc. onset of symptoms
○ Important to monitor patient ● Vaccination with Hepatitis A vaccine
○ Inactivated virus, approved for children >1 y/o
○ 2 doses; 2nd dose given 6-12 months after the first dos, IM
VIII. HEPATITIS A
○ Immunoglobulins for pre-and post-exposure prophylaxis
● Most prevalent of the 5 viruses
● An RNA virus from picornavirus family accounting for 50% of all clinically ● Prognosis: Excellent with no long-term sequelae
apparent acute viral hepatitis A in the US
● Highly contagious
IX. HEPATITIS B
● Transmission: Person to person contact through fecal-oral route
● Common source: Foodborne and waterborne outbreaks ● Hepadnaviridae family: DNA Virus
● Incubation period: 3 weeks ● Detectable antigens/Markers:
○ Fecal excretion starts late in the incubation period, peaks before the ○ Hepatitis B surface antigen (HBsAg)
onset of symptoms, resolves by 2 weeks after the onset of jaundice ○ Hepatitis B core antigen (HBcAg)
■ In infants: prolonged fecal viral excretion ■ Encodes viral DNA
■ Patient is contagious before clinical symptoms are apparent and ○ Hepatitis B envelope antigen (HBeAg)
remains so until viral shedding ceases ■ Marker for active viral replication
■ Correlates with HBV DNA levels
● Suggest viral load
A. CLINICAL FEATURES ● Worldwide spread with 1.25M chronic carriers in the US
● In young children: often anicteric like other forms of viral gastroenteritis ● More common in adults 20-39 y/o
● Symptomatic in older adolescents and adults, immunocompromised, and those ○ ¼ will develop serious sequelae in their lifetime
with underlying liver disease ● Efficient transmission through blood transfusion and sexual contact
● Acute febrile illness with abrupt onset of anorexia, nausea, malaise, ○ Most common transmission is perinatal
vomiting, and jaundice ■ From mothers to their infant
● Typical duration of illness: 7-14 days ● Risk Factors:
● Other organ systems involved ○ Intravenous acquisition by drugs or blood products
○ Enlarged LN and spleen, BM may be hypoplastic/aplastic, GIT ○ Acupuncture or tattoos
ulceration, pancreatitis, myocarditis ○ Sexual contact
○ Rare: nephritis, arthritis, leukocytoclastic vasculitis, and ○ Institutional care
cryoglobulinemia due to circulating immune complexes ○ Intimate contact with carriers
○ 40% with no identifiable risk factors
B. DIAGNOSIS ● In children, the most important risk factor is perinatal exposure to HBsAg+ and
especially HBeAg+ mother
● Detection of antibodies to HAV, specifically anti-HAV IgM ● >90% of infants if untreated become chronically infected
○ By radioimmunoassay, viral particles in stool, or PCR ● Hepatitis B is inconsistently recovered from human milk
○ Detectable when symptoms are clinically apparent and remains positive ○ Therefore, breastfeeding is still encouraged especially in remote
for 4-6 months after acute infection areas with no substitutes
● Neutralizing IgG anti-HAV ● Risk of developing chronic HBV infection (HBsAg+ >6 months) is inversely
■ Detected within 8 weeks of symptom onset related to age of acquisition
■ Confers long term protection ○ The risk of developing chronic HBV is higher in younger infants
● Virus excreted in stools ● Associated with chronic liver disease and hepatocellular CA
○ 2 weeks before to 1 week after onset of symptoms
● Rises in AST, ALT, bilirubin, ALP, 5NT, GGT
A. PATHOGENESIS
C. SEROLOGIC COURSE ● Non-cytopathogenic virus causing injury by immune mediated process
● Nucleocapsid antigens HBcAg and HBeAg together with class 1 MHC make
● 2-3 weeks of incubation the cell a target for cytotoxic T cell lysis
● Onset of symptoms → Rise in anti-HAV IgM ● Tolerance phenomenon: High incidence of chronic carrier state in children
● Viremia at 2 weeks before onset and 1 week after with no or little inflammation in the liver
● Decrease IgM → Rise in Anti-HAV IgG → Immunity → Anti-HAV IgG persists ● In the absence of tolerance, the liver is massively attacked by T cells and will
for 4-8 weeks present with acute liver failure
● Circulating immune complexes can occur in patients who develop polyarteritis
nodosa, vasculitis, Guillain-Barré Syndrome, and glomerulonephritis

B. CLINICAL MANIFESTATIONS
● Many acute cases are asymptomatic
● Usual acute symptoms are similar to HAV and HCV infections
○ But may be more severe
○ Can involve the skin and joints
● Elevated ALT is the first biochemical evidence
● Manifestations:
○ Lethargy
○ Anorexia
○ Malaise
○ Can be preceded by a sickness like prodrome of arthralgia, urticarial or
macular skin rashes
Figure 14. Hepatitis A Time vs Course of infection. ● Jaundice (present in 25%) begins 8 weeks after exposure and lasts for 4
weeks
D. COMPLICATIONS ● Symptoms are present for 6-8 weeks
● Physical Examination Findings:
● Acute liver failure – rare ○ Icteresia
● Prolonged Cholestatic Syndrome ○ Enlarged liver tender to palpation signs of
○ Waxing and waning of jaundice ■ Hepatic Encephalopathy
○ Pruritus ■ Acute liver failure
○ Fat malabsorption

E. TREATMENT
● No specific treatment
● Adequate hydration, supplementation with fat-soluble vitamins (Vit. A, D, E, K),

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 C. SEROLOGIC MARKERS ○ Lamivudine - oral synthetic nucleoside that inhibits viral enzyme reverse
transcriptase
● HBsAg first to appear and coincides with symptoms ● HBe clearance (34%)
● IgM anti-HBc Ag identifies acute infection as it rises after infection and ● For older children
remains positive for months before being replaced by anti-HBc IgG which ■ Given for a long period of time (beyond 6 months) because the
persists for years YMDD variant has mutated
○ Chronic carriers: ○ Others:
■ (+) Anti-HBc (IgG) ■ Adefovir - purine analog (23%); for >12 y/o
■ (+) HBsAg ■ Entecavir - nucleoside analog (21%); for >2 y/o
○ Recovered: ■ Tenofovir - nucleotide analog (21%); for >12 y/o
■ (+) Anti-HBs ■ Peginterferon alpha
■ (+) Anti-HBc (IgG)
● Anti-HBs marks recovery and protection
● HBeAg marks infectivity F. PREVENTION
● Anti-HBe marks improvement and is a goal of therapy in chronically infected ● Universal vaccination with Hepatitis B vaccine beginning at birth
patients ○ 3 doses at 0, 1, and 6 months
○ Infants born to HBsAg mother should be given their first dose of Hep B
Table 7. Serologic markers in resolved, vaccinated, and chronic Hepatitis B. vaccine as well as 0.5 mL of HBIG within 12 hours after birth
HBsAg Anti-HBc Anti-HBs ● Hepatitis B immunoglobulin
Resolved Hepatitis B (-) (+) (+) ○ Post exposure prophylaxis (contact with HBsAg+ source, intimate or
Vaccinated (-) (-) (+) identifiable blood exposure, immunocompromised)
Chronic Hepatitis B (+) for 6 months (+) (-) ■ Serologic markers of a vaccinated infant:
● (+) Anti-HBs
● (-) Anti-HBc IgG

X. SUMMARY
● Cholestatic jaundice is always pathologic
● Recognize and confirm presence of cholestasis
● Identify correctible lesions or conditions where specific therapy is available to
prevent further damage and long-term complications
● Know the many conditions that lead to cholestatic jaundice
● Differentiate extrahepatic from the intrahepatic causes of cholestatic jaundice
● Know the treatment of cholestatic jaundice
○ To know surgical and medical management
● Know the presentation and serologic course of Hepatitis A and B

XI. Q&A
● Would ABO incompatibility present with jaundice in infants more than 2
years old?
○ If ABO incompatibility, jaundice will present within the first 24 hours of life.
If your patient has jaundice after 2 weeks of age, investigate for other
causes because it may not be physiologic jaundice anymore.
○ If patient is exclusively breastfeeding → think of breast milk as the cause
○ Have to know if dealing with direct hyperbilirubinemia or indirect
Figure 15. Typical Serologic course in Patients with Acute Hepatitis B infection with hyperbilirubinemia so we must do bilirubin fractionation
recovery. ● Why is treatment of phenobarbital a week prior to scintigraphy
warranted? Why that drug specifically?
○ Phenobarbital is known to enhance conversion of indirect bilirubin to
direct bilirubin
○ We want that when we deal with scintigraphy, we are dealing with the
conjugated form of bilirubin
○ Safe to give with this age
● Phenobarbital won’t cause any side effects with the infant knowing
it’s a barbiturate?
○ No, we only give them for 3-5 days.
● Can the infant get Hep B through breastfeeding?
○ Negligible provided when infant is given vaccine and immunoglobulin at
birth
○ We don't usually find Hep B virus in breast milk
● What drugs induce release of bilirubin or impair the metabolism?
○ We ask mother for history of intake of drugs
○ If mother is diabetic, may have intake of diabetic drugs which
predispose the infant to jaundice
○ If mother is taking anticonvulsant drugs, also predisposes infant to
jaundice
○ If mother has infection like toxoplasmosis, rubella, CMV, herpes, syphilis
→ predispose to jaundice

XII. REFERENCES
Figure 16. Typical Serological course in patients progressing to Chronic Hepatitis B
● Monreal, P.M., (2022), Neonatal Cholestasis. [Powerpoint Presentation].
infection.
Manila, Philippines: Faculty of Medicine and Surgery, University of Santo
Tomas, PEDIA 2
D. COMPLICATIONS ● Batch 2023 (2021). Cholestasis.
● Acute liver failure with coagulopathy, encephalopathy, and cerebral
edema occurs more frequently XIII. REVIEW QUESTIONS
○ Risk is increased when there is co-infection or superinfection with HDV CTBA/TF
○ Treatment: liver transplantation 1. Biliary atresia is different from idiopathic neonatal hepatitis by this feature in
● Chronic hepatitis the history/PE
○ Can lead to cirrhosis, end stage liver disease, and primary hepatocellular a. Persistently alcoholic stools
CA b. Consistently pigmented stools
● Membranous glomerulonephritis c. Normal Liver span
d. Family history of similar condition
E. TREATMENT 2. Histologic assessment is relevant in the diagnosis and management of
● No current therapy is reliably successful Cholestatic Jaundice. Liver biopsy findings that point to Neonatal Hepatitis
● Treatment of acute HBV is largely supportive include/s:
● Goal: a. Steatosis
○ Reduce viral replication (undetectable HBV DNA) b. Ballooning and lobular distortion
○ Seroconversion to Anti-Hbe c. Bile duct proliferation
● Antiviral drugs: d. Bile plugs and stasis
○ Interferon - long term viral response (25%), subcutaneous, for 24 weeks 3. In a child with jaundice, which among the following choices are more specific
for obstructive cholestasis?
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 a. GGT and 5’ nucleotidase
b. Serum aminotransferase and INR
c. Aspartate aminotransferase and blood glucose
d. Alkaline phosphatase and alanine aminotransferase

ABA

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 IX. FREEDOM WALL

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