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NEONATAL JAUNDICE ▫ Primary complication is neurotoxicity of UCB across

 Yellow discoloration of the skin and sclerae due to the BBB (mostly in the basal ganglia, pons, &
elevated serum bilirubin (2-2.5 mg/dL); physical evidence cerebellum), known as kernicterus
of jaundice usually seen in levels of 5-10mg/dL
 Severity of jaundice:
o Sclera icterus (3mg/dL) ▫ Can be caused by:
o Face (5mg/dL) a. Hepatocellular dysfunction
o Mid-abdomen (15mg/dL) b. Biliary obstruction
o Soles (20mg/dL) c. Abnormal excretion of bile acids / bilirubin


▫ Formed from the degradation of heme-containing
compounds (eg. Hgb)
 Total serum bilirubin should be fractionated to
1 Microsomal heme oxygenase catabolizes heme differentiate between conjugated and unconjugated
to biliverdin hyperbilirubinemia
2 Reduction of biliverdin to bilirubin by biliverdin  Hemolysis can interfere with assays, resulting in a falsely
reductase producing unconjugated bilirubin elevated conjugated fraction
3 Binding of UCB to albumin  Aspartate aminotransferase (AST) and Alanine
4 Bilirubin uptake by hepatocytes aminotransferase (ALT) used as arkers for hepatocelular
5 Conjugation of bilirubin (CB) w/ glucuronic acid by injury
bilirubin uridine diphosphate glucoronosyltransferase  Increased ALT level is more suggestive of liver disease
(UDPGT)  Markedly elevated levels (>5 to 10-fold) of both AST and
ALT can be due to:
6 Excretion of CB from the hepatocyte through
▫ Hepatitis, hepatotoxicity, ischemia, or
cannaliculi (biliary tree) to the duodenum
genetic/metabolic liver disorders
7 Bacterial hydrolysis converts CB to urobilinogen  Elevation of AST in excess of ALT suggests extrahepatic
8 Reabsorption via: Excretion via: source of injury
▫ enterohepatic ▫ Renal excretion of
circulation urobilinogen ALKALINE PHOSPHATASE
▫  - glucoronidase ▫ Conversion of  Enzyme found in bile ducts, bone, intestine, placenta, &
hydrolizes CB to urobilinogen to tumors
UCB and stercobilin and  Elevations occur with hepatobiliary disease but also in
reabsorbed via excreted in feces normal growth, healing fractures, vit. D deficiency, bone
enterohepatic disease, pregnancy and malignancy
circulation (in  Fractionation of alkaline phosphatise isoenzymes can
neonates) help determine its site of origin
 In evalusation of hyperbilirubinemia:
▫ UCB is lipophilic, cannot be excreted by the kidneys, ▫ Alp > 3x normal indicates cholestasis
and can easily cross cell membranes and the blood ▫ Milder elevation suggestive of hepatocellular disease
▫ CB is a polar, water soluble compound  More specific for biliary tract disease compared
HYPERBILIRUBINEMIA aminotransferases
 Can result from alteration of any step in the process of  GGT elevations are inducible by alcohol & certain drugs
bilirubin formation (phenytoin & Phenobarbital)
 Classified either as Conjugated (direct) or Unconjugated  Can be elevated in chronic pulmonary disease, liver
(indirect) depending on CB concentration in serum failure, or DM
 Conjugated hyperbilirubinemia exists when more than  Helpful in confirming that an elevated Alp is a result of
20% of the total bilirubin or >2mg/dL is conjugated liver disease and in differentiating familial cholestatic
▫ Can be caused by: BILE ACIDS
a. Increased production of bilirubin  Sensitive measure of cholestatic disease
b. Decreased delivery to the liver  Levels are generally very high in primary cholestasis &
c. Decreased hepatic uptake biliary obstruction
d. Decreased conjugation  Mildly increased (>2x normal) in hepatocelLular disease
e. Increased enterohepatic circulation of bilirubin
 Produced in the liver; reflecting hepatic synthetic  In which specific pattern of injury (eg. Paucity of bile
function ducts / bile duct proliferation)
 Used in monitoring progression of chronic liver disease  Specific markers of disease may be identified (inclusions
nad in discriminating acute illness vs. Chronic disorder in 1-antitrypsin deficiency) or measured (metabolic
 Hypoalbuminemia may be secondary to nephritic enzyme activity)
syndrome or protein-losing enteropathy
 Note age at onset and duration of jaundice
 Best marker of hepatic synthetic function (since clotting
▫ Onset after 24 hr of age
factors are produced in the liver)
▫ Not persisting beyond 14 days of age (1 mo if breast-
 If PT is prolonged, document response to parenteral
administration of vit K (Vit K deficiency)
 Acholic stools
 Consider disseminated intravascular coagulation &
▫ Indicate obstruction of the biliary tree; can also be
thrombosis of a major blood vessel as alternative causes
seen in severe hepatocellular injury
for prolonged PT
 Delayed passage of meconium (within 24-48 hrs) may be
IMAGING 2° to cystic fibrosis or Hirschsprung disease
ULTRASONOGRAPHY  Assess prenatal and perinatal history
 Useful, non-invasive, rel. Inexpensive for evaluation of ▫ Maternal infections (Syphilis, Toxoplasmosis, CMV,
liver disease Hep B, Enterovirus, HSV, HIV) that can cause
 Provides info on size & consistency of liver, spleen, and cholestatic liver disease in neonate
anatomic abnormalities of the biliary tree, gallstone & ▫ Premature infants are more prone to higher level of
hepatic masses bilirubinemia and prolonged hyperbilirubinemia
 Dilated intrahepatic ducts – indicate extrahepatic ▫ Symptoms of constipation, hypotonia & hypothermia
obstruction could indicate Hypothyroidism
 Doppler UTZ – demonstrate dynamic flow in hepatic ▫ Hx of repeated affected neonates could indicate
blood vessels & portal vein (Portal HTN) Alloimune hepatitis
 Delayed feeding
 Breast-feeding associated w/ inc levels og UCB and
 Aid in diagnosis of biliary atresia
longer duration of jaundice
 Administration of Phenobarbital (5mg/kg/day) for 5 days
 Vomiting
before the study may inc bile flow, increasing diagnostic
▫ (+) lethargy and poor feeding is suggestive of
metabolic disorder
COMPUTED TOMOGRAPHY ▫ Can also be a symptom of intestinal obstruction
 Useful in identifying mass lesions within the liver (malrotation / volvulus)
 CT + contrast used to define nature of liver tumors
 CT angiography to define anatomy of portal and hepatic
 Jaundice spreads in a cephalopedal direction
 Pallor may indicate hemolytic disease
MAGNETIC RESONANCE  Petechiae suggestive of thrombocytopenia, possible
 Can demonstrate storage of heavy metals such as iron sepsis, congenital infection, or severe haemolytic disease
(Neonatal iron storage disease)  Dysmorphic features:
 MR cholangiopancreatography (MRCP) is rel non-invasive ▫ Microcephaly + jaundice is associated with
that helps visualize abnormalities of the intrahepatic & congenital viral infections
extrahepatic biliary tree and the pancreatic duct system ▫ Zellweger syndrome
o Narrow cranium, prominent forehead,
hypertelorism, epicanthal folds, large
 Performed for evaluation of biliary anatomy
▫ Alagille syndrome
 Both diagnostic and therapeutic for common duct stones
o Triangular face w/ broad forehead,
and strictures
hypertelorism, deep-set eyes, long nose,
 Both diagnostic & therapeutic; alternative to ERCP  Ophthalmologic findings
 Done under UTZ guidance, where needle passes through ▫ (+) cataracts – galactosemia and rubella
liver to biliary tree where contrast is injected ▫ Chorioretinitis – congenital infections
 Contraindicated in marked ascites or irreversible ▫ Nystagmus w/ hypoplasia of optic nerve –
coagulopathy hypopituitarism w/ septo-optic dysplasia
 Complications include bleeding, pneumothorax,  Presence of heart murmurs caused by underlying
infection, and bile leakage congenital heart diseases associated with:
▫ Trisomies  Hematologic evaluation must be performed to identify
▫ Syndromic forms of Biliary atresia (Polysplenia cause of hyperbilirubinemia
syndrome) ▫ CBC with examination of smear
Note: can also be a result of hepatic ischemia/congestion ▫ Reticulocyte count
due to hyperbilirubinemia ▫ Direct Coombs test
 Microphallus can be associated with septo-optic ▫ Blood typing
dysplasia and hypopituitaism
DIFFERENTIAL DIAGNOSIS  Hct >65% by venipuncture
 Important to differentiate between physiologic and  Results from increased bilirubin production due to
pathologic jaundice increased RBC mass
 Total and fractionated bilirubin measurement should be  Associated with maternal DM, maternal-fetal / twin-twin
performed if assessment of physiologic jaundice is transfusion, intrauterine hypoxemia, endocrine
questionable disorders, and delayed cord clamping
PATHOYSIOLOGY  In patients w/ reticulocytosis, unconjugated
 Increased bilirubin production due to normal increased hyperbilirubinemia and inc nucleated RBC count w/ low-
neonatal red blood cell mass and decreased lifespan of normal Hct
RBC (80 days)
 Lower albumin concentration and binding capacity (dec
 Maternal IgG to infant’s erythrocytes cross the placenta
albumin binding) resulting in lowerUCB transport to the
resulting in RBC destruction
 Bilirubin uptake in the 1st week of life is defective (dec Rh INCOMPATIBILITY
Glutathione S-transferase B)  presents with pallor, hepatosplenomegaly and rapidly
 Impaired conjugation due to dec activity of UDPGT developing jaundice
 Inc enterohepatic circulation of UCB due to:  occurs when and Rh-negative mother gives birth to a Rh-
▫ Inc concentration of -glucoronidase positive infant
▫ Dec intestinal bacterial flora → diminished  diagnosis is confirmed by:
urobilinogen formation ▫ Rh-positive infant
▫ (+) direct Coombs test result
MANIFESTATION ▫ Maternal antibody coating infant’s RBC
 Peak bilirubin level < 13 mg/dL on 3rd -5th day of life  Administration of anti-D gamma globulin (RhoGAM) after
 Decrease to normal by 2 weeks of age delivery to Rh-negative women reduce incidence of Rh
 Conjugated fraction of < 20% sensitization and erythroblastosis fetalis
BREAST MILK JAUNDICE  Management depending on degree of hemolysis may be
 Unconjugated hyperbilirubinemia of > 13 mg/dL postnatal phototherapy and/or exchange transfusion

Early / Breast-feeding Late / Breast-milk ABO INCOMPATIBILITY

Jaundice Jaundice  Common in infants with blood type A or B born to a type
o Occurs within the first o Occurs after the 1st O mother
5 days of life week of life  Hemolysis develops in 50% of sensitized infants with a
o In infants not feeding o Peaks between 2nd & bilirubin level > 10mg/dL
adequately; may be 3rd week of life (10-20  Diagnosis:
dehydrated / mg/dL) ▫ Blood smear: (+) anemia, reticulocytosis, &
malnourished o May be due to spherocytosis
▫ Inhibition of ▫ Weakly-positive direct Coombs
UDPGT activity ▫ (+) indirect Coombs test
▫ Inc enterohepatic ERYTHROCYTE DEFECTS
 Kernicterus as a rare complication  associated w/ a family Hx of hemolysis, transfusions,
cholecystectomy, or splenectomy
MANAGEMENT  Hemolysis results from fragility of RBC
 Rooming-in and frequent feeding dec risk of breast-  Presents with:
feeding jaundice ▫ Anemia, jaundice, and splenomegaly
 If bilirubin exceeds 20mg/dL in breast-fed infant ▫ Blood smear: spherocytosis . elliptocytosis
 Discontinue breast-feeding for 24hrs ▫ (-) Coombs test
 Phototherapy
 Exchange transfusion ENZYME DEFECTS
A. G6PD deficiency ▫ Oxytocin, excess vit K in preterm infants,
 Most common antibiotics, phenol disinfectants and herbal
 Manifests as neonatal jaundice on day 2 or 3 after remedies
birth; or in later childhood (jaundice associated with
acute haemolytic crisis)
 Depends on degree of elevation of bilirubin (> 20-30
B. Pyruvate kinase deficiency
mg/dL in healthy, term infants w/o evidenc of hemolysis)
 Enzymatic deficiency in the glycolytic pathway
 Mostly autosomal recessive mode of transmission PHOTOTHERAPY
 Produces reduction of bilirubin by 1-2mg/dL in 4-6 hours
 Photoisomerization and photodegradation of
unconjugated bilirubin to more water-soluble forms; to
 Heterogenous group of disorders
be excreted in bile & urine
 50% dec in UDPGT activity from defect in gene
 Possible complications: retinal damage, diarrhea, &
responsible for this enzyme
 Dec in hepatocyte bilirubin uptake
 Begun at levels below exchange transfusion (~5mg/dL) or
 Generally asymptomatic until 2nd or 3rd decade of life
during prep for exchange transfusion
 All lab tests are normal except for inc indirect bilirubin
 Diagnosis is clinical;confirmed by 2 to 3-fold rise in UCB  Indicated for severe hyperbilirubinemia
during 24hr fast  Indications:
▫ Term infants with evidence of hemolysis and
bilirubin >25-30mg/dL
 Rare autosomal recessive condition caused by mutation
▫ Non-responsive to phototherapy
of gene coding for UDPGT
▫ (+) signs of kernicterus:
 High-pitched cry, gaze paralysis, fever,
▫ Marked hyperbilirubinemia (20-40mg/dL) in
lethargy,& opisthotonic posture
neonatal period of a healthy infant
▫ Untreated individuals develop kernicterus CONJUGATED HYPERBILIRUBINEMIA
▫ Lab results show  Important to evaluate infant for potentially treatable
o (-) CB in bile or serum problems
o (-) dec in serum UCB during Phenobarbital ▫ Characterized by prolonged PT
administration ▫ Initial administration of IV vit K to avoid spontaneous
▫ Treatment via exchange transfusion, intensive hemorrhage
phototherapy, and liver transplant ▫ Managed with oral fat-soluble vitamin
B. TYPE II supplementation until cholestasis resolves
▫ Onset at birth with <5% normal UDPGT activity  HYPOGLYCEMIA
▫ Bile contains bilirubin monogluronides ▫ Associated with severe hepatic dysfunction,
▫ Bilirubin level of 8-25mg/dL metabolic disorders, and hypopituitarism
▫ Responds to Phenobarbital administration ▫ Serum glucose level is measured before feeding
LUCEY-DRISCOLL SYNDROME ▫ Managed with frequent feeding, continuous feeding,
 Transient familial neonatal hyperbilirubinemia or IV dextrose infusions
 Appears in the first few days of life and resolves by 2-  HYPERAMMONEMIA
3weeks of age ▫ Present in sever liver dysfunction and metabolic liver
 Results from inhibition of UDPGT by substance found in disorders
both infant & maternal serum ▫ Checked in infants presenting with lethargy or
 Bilirubin level can rise until 60mg/dL (resulting in change in mental status
kernicterus)  Other labs included in evaluation:
 Treated with exchange transfusion ▫ Aminotransferases, GGT, and Alkaline phosphatise
 When Hct is normal, no evidence of hemolysis / OBSTRUCTIVE/ANATMOIC ABNORMALITIES
consumptive process BILIARY ATRESIA
o GI Obstruction  Result of a progressive inflammatory process leading to
▫ vomiting, abdominal distention, delayed obliteration of the lumen of the extraheptic duct
passage of meconium  Leading indication for liver transplant in pediatric
▫ investigate via imaging population
o Hypothyroidism / Hypopituitarism  Manifestation:
▫ Look at thyroxine and TSH levels ▫ Icteric at birth and develops jaundice at 2-6 weeks of
o Drug administration age
▫ Jaundice, dark urine, and acholic stools  Triangular face w/ broad forehead,
 Types: hypertelorism, deep-set eyes, long nose,
A. Embryonic / Fetal Form pointed mandible
▫ There is no jaundice-free period ▫ Vertebral arch defects
▫ Associated with cardiac defects, polysplenia,  butterfly vertebrae, hemivertebrae, decreased
malrotation and situs inversus interpedicular distance
B. Perinatal Form ▫ Posterior embryotoxon (ocular)
▫ There may be jaundice-free interval after ▫ Cardiac defects
resolution of normal physiologi jaundice  peripheral pulmonic stenosis to complex CHDs
▫ No associated anomalies ▫ renal anomalies, pancreatic insufficiency, and growth
 Diagnostics: retardation may be present
▫ Conjugated hyperbilirubinemia, acholic stools and ▫ pruritus develops by 4-6 mos of age
elevated GGT suggests prompt evaluation ▫ Xanthomas appear in association with markedly
▫ Ultrasound: elevated cholesterol
 to exclude other treatable anatomic  Autosomal dominant transmission
abnormalities (eg. Choledocal cyst)  Diagnosis is confirmed by liver biopsy
 Gallbladder is absent or collapsed
▫ Liver biopsy
 Periportal edema & fibrosis, bile duct
 Blood and urine cultures should be obtained
proliferations, and bile duct plugs
 May present with poor feeding, lethargy, vomiting, temp
▫ Hepatobiliary scintigraphy
instability, apnea, bradycardia, or shock
 Demonstrates uptake of tracer but no
 E. Coli most common etiologic agent –
excretion into the duodenum
hyperbilirubinemia caused by endotoxin-mediated
 Requires pretreatment with Phenobarbital
canalicular dysfunction
(due to delay in diagnosis)
 Other gram-negative causes: Listeria, Staphylococcus,
 Inconclusive in hepatic dysfunction
and Streptococcus
 Management: Surgery
▫ Should be performed before 2 mos. of age  Manifests at 7-14 days of age with lethargy, por feeding,
▫ Kasai Procedure a vesicular rash, jaundice, hepatomegaly, temp
 portoenterostomy procedure in which porta instability, encephalitis, and coagulopathy
hepatis is transacted, and a loop of intestine  Diagnosis by identification of virus in skin lesions through
is brought up to drain the bile ducts ▫ Direct fluorescent antibody staining
 complication: Bacterial ascending ▫ Polymerase chain rxn of HSV in blood & CSF
cholangitis  Treatment with IV Acyclovir
▫ Liver Transplant
o Supplementation with MCT oil and fat-soluble
 Manifests within 1-7 days after birth with similar
presentation w/ HSV except for macular rash
 Portal HTN w/ splenomegaly, esophageal varices, and
 Diagnosis by polymerase chain reaction or viral culture
ascitis can develop overtime
 Treatment by IV immunoglobulin and Pleconaril
 Presentation:
 90% are asymptomatic at birth
▫ In neonates: conjugated hyperbilirubinemia w/
 Can manifest within the first 24 hrs after birth w/ IUGR,
jaundice, vomiting, acholic stools and hepatomegaly
conjugated hyperbilirubinemia, haemolytic anemia,
▫ In older children: jaundice, abdominal pain, and RUQ
thrombocytopenic purpura, and hepatosplenomegaly
 Diagnosis by urine culture
 Diagnosis by UTZ and confirmed by MR cholangiography
 Treatment via Ganiciclovir and CMV immunoglobulin
or intraoperatice cholangiography
 Treatment by surgical excision HEPATITIS B
 Seen in mothers who are seropositive for hep B e antigen
or have acquired acute infection in the last trimester
 Abnormal development of multiple organs related to
 Perinatal infection can be prevented with hep B immune
defective JAG-1/NOTCH-2 signaling
globulin and vaccination
 Clinical features:
▫ Marked reduction in number of interlobar bile ducts SYPHILIS
(most important)  Presents with jaundice, fever, diffuse macular-papular
▫ Unusual facies rash, hepatosplenomegaly, edema, anemia, and
periostitis in severely infected infants
 Diagnosis via
o Nontreponemal serologic tests on cord blood  Most common inherited cause of neonatal cholestasis
o Confirmation from infant serum showing  Manifests in early infancy with prolonged conjugated
▫ (+) IgM for syphilis hyperbilirubinemia, failure to thrive, acholic stools,
▫ (+) Immunoglobulin G fluorescent treponemal hepatoegaly, and possible ascitis
antibody  Diagnosis is by serum phenotyping (ZZ)
 Treated with IV Penicillin for 10-14 days  Treatment is supportive
 IgM titers should be obtained or histologic examination  Incidence is increased among infants w/ meconium ileus
of placenta should be done  Diagnosis is confirmed with:
 Mostly asymptomatic; in severe infection may present o Sweat chloride test
with hydrocephaly/microcephaly, intracranial o Detecting abnormal gene
calcifications, chorioretinitis, aseptic meningitis, jaundice,
purpura, and hepatomegaly
 May manifest with hypoglycaemia, microphallus,
 Postnatal treatment:
jaundice, and signs of hypothyroidism
▫ Pyrimethamine and Sulfadiazine
 Wandering nystagmus seen in Hypopituitarism
▫ Folinic acid (to prevent folate deficiency)
associated w/ septo-optic dysplasia
TREATABLE METABOLC DISORDERS  Resolution by treatment of underlying endocrine
 Life-threatening disorder
 Autosomal recessive disorder with deficiency of
 Related to defective transport of bile acids
galactose-1-phosphate uridyltransferase
 Finding suggestive by:
▫ needed for conversion of galactose to glucose
▫ presence of cholestasis in absence of physical
▫ accumulation is hepatotoxic
damage to bile ducts
 once lactose is introduced in diet, infant presents with
▫ normal GGT except for PFIC type 3 variant
vomiting, diarrhea, jaundice, hepatomegaly, & cataracts
 autosomal recesive disorder with 3 types (refer to
 often presents with E.coli sepsis at 1st wk of life
 Laboratory evaluation:
▫ Prolonged PT  Diagnosis of exclusion; common in premature / SGA
▫ Hemolytic anemia infants
▫ Aminoaciduria  Hepatobiliary scintigraphy demonstrates delayed uptake,
▫ (+) galactose in urine but there is usually excretion into the duodenum unless
 Diagnosis by confirmed deficiency of enzyme in the hepatitis is severe
erythrocytes and leukocytes  Treatment is supportive
 Transfusion may cause false-negative results
 Treatment by eliminating galactose in diet
Malabsorption of fats and fat-soluble vitamins occur as a
HEREDITARY FRUCTOSE INTOLERANCE (Fructosemia) result of dec concentration of bile salts in intestinal lumen
 Uncommon  Affected infants should be given formulas containing
 Manifests w/ hepatic failure when exposed to medium-chain triglycerides (MCTs)
fructose/sucrose in formula, juice, fruit, or medication  Caloric intake excess of 150 kcal/kg/day to maintain
 Treatment by removal of fructose, sucrose, and sorbitol growth
from diet  Proper monitoring of growth
▫ Anthropometric evaluation of skinfold and mid-arm
 Diagnosed by serum amino acid levels and urine organic
 Supplemental vit A, D, E, K to prevent visual problems,
rickets, neuropathy, and coagulopathy
 Elevated urinary succinylacetone (pathognomonic)
 Ascitis can be managed w/ Na restriction and diuretics
 Treatment by dietary restriction of phenylalanine,
methionine, & tyrosine and use of 2-(2-nitro-4-
 Suggested by conjugated hyperbilirubinemia w/ low-
normal GGT, and low-normal total bile acid levels
 Detected by bile acid FAB-MS urinalysis
 Treatment with oral cholic acid supplementation


Figure 1: Diagnostic Approach to Neonates/Infants with Hyperbilirubinemia