Charles Ferdinand

405120215
www.studyblue.com
 Jaundice & hyperbilirubinemia in
•
newborn
Hyperbilirubinemia is a common and, in most cases, benign
problem in neonates
– severe indirect hyperbilirubinemia is potentially neurotoxic
– conjugated-direct hyperbilirubinemia often signifies a serious
hepatic or systemic illness

• Jaundice  1st wk of life in approximately 60% of term

infants and 80% of preterm infants
– results from the accumulation in skin of unconjugated, nonpolar,
lipid-soluble bilirubin pigment
– deposition of the pigment after it has been converted in the
liver cell

• Unconjugated form  neurotoxic in infants at certain

concentration & under various conditions
 Etiology of unconjugated
hyperbilirubinemia
• Transition of bilirubin metabolism from the fetal stage

• Etiology of unconjugated hyperbilirubinemia

– increases the load of bilirubin to be metabolized by the liver
– damages or reduces the activity of the transferase enzyme
– competes for or blocks the transferase enzyme
– leads to an absence or decreased amounts of the enzyme or to
reduction of bilirubin uptake by liver cells

• Early feeding decreases whereas breast-feeding and dehydration

increase serum levels of bilirubin
• Meconium has 1 mg bilirubin/dL and may contribute to jaundice
• Drugs (oxytocin and chemicals used in the nursery such as phenolic
detergents)  unconjugated hyperbilirubinemia
 Risk factor of unconjugated
hyperbilirubinemia
• Jaundice visible on the 1st day of life
• A sibling with neonatal jaundice or anemia
• Unrecognized hemolysis (ABO, Rh, other blood group,
incompatibility); UDP-glucuronyl transferase deficiency
(Crigler-Najjar, Gilbert disease)
• Nonoptimal feeding (formula or breast-feeding)
• Deficiency of glucose-6-phosphate dehydrogenase
• Infection (viral, bacterial). Infant of diabetic mother;
Immaturity (prematurity)
• Cephalohematoma or bruising. Central hematocrit >65%
(polycythemia)
• East Asian, Mediterranean, Native American heritage
 Clinical manifestations
• Jaundice
– may appear at any time during the neonatal period, depending on the cause
– begins on the face and, as serum levels increase, progresses to the abdomen
and then the feet
– Jaundice to the mid-abdomen, signs or symptoms, high-risk factors 
nonphysiologic jaundice  hemolysis must be evaluated

• Jaundice from deposition of indirect bilirubin  bright yellow or orange

• Jaundice of the obstructive type (direct bilirubin)  greenish or muddy
yellow cast

• lethargic and may feed poorly

• Signs of kernicterus rarely appear on the 1st day of jaundice
 Differential diagnosis
• Jaundice within 1st 24 hr of life  immediate attention
(erythroblastosis fetalis, concealed hemorrhage, sepsis, or
intrauterine infections)

• Hemolysis (rapid rise in serum bilirubin (>0.5 mg/dL/hr);

anemia, pallor, reticulocytosis, hepatosplenomegaly, and a
positive family history)

• Jaundice that first appears on the 2nd or 3rd day  usually

physiologic but may represent a more severe form

• Familial nonhemolytic icterus (Crigler-Najjar syndrome);

early-onset breast-feeding jaundice  2nd or 3rd day
• Jaundice appearing after 3rd day – 1 week 
bacterial sepsis & urinary tract infections
(syphilis, toxoplasmosis, cytomegalovirus, or
enterovirus)

• Jaundice secondary to extensive ecchymosis or

hematoma may occur during the 1st day or later

• Polycythemia may  early jaundice

• Jaundice noticed initially > 1 week of life 
– breast milk jaundice,
– septicemia,
– congenital atresia or paucity of the bile ducts,
– hepatitis,
– galactosemia,
– hypothyroidism,
– CF,
– congenital hemolytic anemia (spherocytosis); other
hemolytic anemias; hemolytic anemia related to drugs
• Persistent jaundice during 1st mo 
– inspissated bile syndrome (which may follow
hemolytic disease of the newborn),
– hyperalimentation-associated cholestasis,
– hepatitis,
– cytomegalic inclusion disease, syphilis, toxoplasmosis,
– familial nonhemolytic icterus,
– congenital atresia of the bile ducts,
– galactosemia
Approach to the patient
Physiological jaundice (icterus
neonatorum)
LO 4
Physiologic jaundice (icterus neonatorum)
• Under normal circumstances 
– level of indirect-reacting bilirubin in umbilical cord
serum is 1-3 mg/dL;
– rises at a rate of less than 5 mg/dL/24 hr  visible
jaundice on the 2nd – 3rd day
– Peaking between the 2nd and 4th days at 5-6 mg/dL
and decreasing to below 2 mg/dL between the 5th
and 7th days of life
• Result of increased bilirubin production after the
breakdown of fetal red blood cells & transient
limitation in the conjugation of bilirubin by the
liver
• 6-7% of full-term infants have indirect bilirubin
levels greater than 12.9 mg/dL and less than 3%
have levels greater than 15 mg/dL

• Premature infants  rise in serum bilirubin tends

to be the same or a little slower than that in term
infants, but it is of longer duration
– peak being reached between the 4th and 7th days (8-
12 mg/dL)
• Risk factors for indirect hyperbilirubinemia
– maternal diabetes,
– race (Chinese, Japanese, Korean, and Native American),
– prematurity,
– drugs (vitamin K3, novobiocin),
– altitude,
– polycythemia,
– male sex,
– trisomy 21,
– cutaneous bruising,
– cephalohematoma,
– oxytocin induction,
– breast-feeding,
– weight loss (dehydration or caloric deprivation),
– delayed bowel movement, and
– a sibling who had physiologic jaundice
 Diagnosis of physiologic jaundice
Jaundice Peak bilirubin concentration Bilirubin rate of Remarks
accumulation
Appears Disappears mg/dL Age in days

Full term Indirect 2-3 days 4-5 days 10-12 2-3 <5 Usually
relates to
premature Indirect 3-4 days 7-9 days 15 6-8 <5 degree of
maturity

< -- Risk for

exaggerated
physiologic
jaundice
Pathological jaundice

LO 4
 Pathologic hyperbilirubinemia
• if their time of appearance, duration, or pattern
of serially determined serum bilirubin
concentrations varies significantly from that of
physiologic jaundice
• if the course is compatible with physiologic
jaundice but other reasons exist  neurotoxicity
of unconjugated bilirubin

• Associated risk factors: Asian race, prematurity,

breast-feeding, or weight loss
 Etiology
• Probably a deficiency or inactivity of bilirubin
glucuronyl transferase (e.g., Gilbert syndrome)
> an excessive load of bilirubin for excretion
• Combination of G6PD deficiency and a
mutation of the promoter region of UDP-
glucuronyl transferase 1  indirect
hyperbilirubinemia, in the abscence of
hemolysis’ signs
 Complication
• High indirect serum bilirubin levels 
Kernicterus (bilirubin encephalopathy)
• << bilirubin levels with asphyxia,
intraventricular hemorrhage, hemolysis, or
drugs that displace bilirubin from albumin 
Kernicterus
Kernicterus

LO 4
 Kernicterus
• ~bilirubin encephalopathy  neurologic syndrome
resulting from the deposition of unconjugated bilirubin
in the basal ganglia and brainstem nuclei

• Pathogenesis
– interaction between unconjugated bilirubin levels,
– albumin binding and unbound bilirubin levels,
– passage across the blood-brain barrier, and
– neuronal susceptibility to injury

• Risk factors
– Disruption of the blood-brain barrier by disease, asphyxia,
or other factors and maturational changes in blood-brain
barrier permeability
• Rare  healthy term infants and in the
absence of hemolysis if the serum level is
under 25 mg/dL
• previously healthy, predominantly breast-fed
term infants  bilirubin levels exceed 30
mg/dL (21-50 mg/dL)  Kernicterus
• Onset is usually in the 1st wk of life, but it may
be delayed to the 2nd-3rd wk
 Clinical manifestations
• Appear 2-5 days after birth in term infants and as
late as the 7th day in premature ones

• Lethargy, poor feeding, and loss of the Moro

reflex are common initial signs
• Gravely ill and prostrated, with diminished
tendon reflexes and respiratory distress
• Opisthotonos with a bulging fontanel, twitching
of the face or limbs, and a shrill high-pitched cry
may follow
• mildly affected infants  mild to moderate
neuromuscular incoordination, partial deafness, or
"minimal brain dysfunction," occurring singly or in
combination; may inapparent until child enters school

• Advanced cases 
– convulsions and spasm occur
– stiffly extending their arms in inward rotation with the fists
clenched
• Many infants  progress to these severe neurologic
signs die
• Survive
– may appear to recover and for 2-3 mo show few
abnormalities
– 1st year  opisthotonos, muscle rigidity, irregular
movements, and convulsions tend to recur
– 2nd year  opisthotonos and seizures abate, but irregular,
involuntary movements, muscle rigidity, or in some infants,
hypotonia increase steadily
– 3rd year  complete neurologic syndrome is often
apparent and consists of bilateral choreoathetosis with
involuntary muscle spasms, extrapyramidal signs, seizures,
mental deficiency, dysarthric speech, high-frequency
hearing loss, squinting, and defective upward movement
of the eyes
 Clinical features for Kernicterus
• Acute form
– Phase 1 (1st 1-2 days): poor sucking, stupor, hypotonia,
seizures
– Phase 2 (middle of 1st wk): hypertonia of extensor
muscles, opisthotonos, retrocollis, fever
– Phase 3 (after the 1st wk): hypertonia

• Chronic form
– First year: hypotonia, active deep tendon reflexes,
obligatory tonic neck reflexes, delayed motor skills
– After 1st yr: movement disorders (choreoathetosis,
ballismus, tremor), upward gaze, sensorineural hearing
loss
 Preventable causes of kernicterus
(AAP)
• early discharge (<48 hr) with no early follow-up (within 48 hr of
discharge); this problem is particularly important in near-term
infants (35-37 wk gestation)
• failure to check the bilirubin level in an infant noted to be jaundiced
in the 1st 24 hr
• failure to recognize the presence of risk factors for
hyperbilirubinemia
• underestimating the severity of jaundice by clinical (i.e., visual)
assessment
• lack of concern regarding the presence of jaundice delay in
measuring the serum bilirubin level despite marked jaundice or
delay in initiating phototherapy in the presence of elevated bilirubin
levels
• failure to respond to parental concern regarding jaundice, poor
feeding, or lethargy
 Recomendations (AAP)
• any infant who is jaundiced before 24 hr
requires measurement of the serum bilirubin
level, and if it is elevated, the infant should be
evaluated for possible hemolytic disease
• follow-up should be provided within 2-3 days
of discharge to all neonates discharged earlier
than 48 hr after birth
– Early follow-up is particularly important for infants
younger than 38 wk gestation
Jaundice associated with breast
feeding
LO 4
 Jaundice associated with breast
feeding
• Significant elevations in unconjugated bilirubin (breast milk
jaundice)  2% of breast-fed term infants after 7th day of
life (max 10-30 mg/dL during 2nd – 3rd week)
• If breast-feeding is continued  hyperbilirubinemia
gradually decreased & persist for 3-10 wk at lower levels
• If nursing is discontinued  serum bilirubin falls rapidly,
usually reaching normal levels within a few days

• e/ some the milk contains a glucuronidase that may be

responsible for jaundice
• Cessation of breast-feeding for 1-2 days and
substitution of formula for breast milk  rapid
decline in serum bilirubin  nursing can be
resumed without a return of the
hyperbilirubinemia to its previously high levels

• Frequent breast-feeding (>10/24 hr), rooming-in

with night feeding, and discouraging 5% dextrose
or water supplementation  reduce the
incidence of early breast-feeding jaundice
Treatments for jaundice in
neonatus
LO 4
 Treatment
• Phototherapy
– indirect hyperbilirubinemia are reduced on exposure
to a high intensity of light in the visible spectrum
– broad-spectrum white, blue, special narrow-spectrum
(super) blue, and less often, green lights have been
effective in reducing bilirubin levels

– Complications
• loose stools, erythematous macular rash, a purpuric rash
associated with transient porphyrinemia, overheating and
dehydration (increased insensible water loss, diarrhea),
chilling from exposure of the infant, and bronze baby
syndrome
• Exchange transfusion
– performed if intensive phototherapy has failed to
reduce bilirubin levels to a safe range and if the
risk of kernicterus exceeds the risk of the
procedure or the infant has signs of kernicterus

– Complications
• acidosis, electrolyte abnormalities, hypoglycemia,
thrombocytopenia, volume overload, arrhythmias, NEC,
infection, graft vs host disease, and death
 Suggested Maximal Indirect Serum
Bilirubin Concentrations (mg/dL) in
Birth weight (g)
Preterm
Uncomplicated
Infants
Complicated
< 1000 12-13 10-12
1000 – 1250 12-14 10-12
1251 – 1499 14-16 12-14
1500 – 1999 16-20 15-17
2000 – 2500 20-22 18-20

•Complications include perinatal asphyxia, acidosis, hypoxia, hypothermia,

hypoalbuminemia, meningitis, intraventricular hemorrhage, hemolysis, hypoglycemia,
or signs of kernicterus.

Phototherapy is usually started at 50-70% of the maximal indirect level. If values

greatly exceed this level, if phototherapy is unsuccessful in reducing the maximal
bilirubin level, or if signs of kernicterus are evident, exchange transfusion is indicated
 Approach to Indirect
Hyperbilirubinemia in Healthy Term
Infants Without Hemolysis
Bilirubin (mg/dL)
Age (hr) Observation Fototherapy Exchange Photo + ex.
transf transf
<24 +++
24-48 >= 12 15-18 20 >= 25
48-72 >= 15 18-20 25 >= 30
>72 >= 18 20 25 >= 30
 Other therapies
• Tin (Sn)-protoporphyrin
– reduction of bilirubin levels
– inhibit the conversion of biliverdin to bilirubin by heme
oxygenase
– A single intramuscular dose on the 1st day of life may reduce
the need for phototherapy
– but the effect is no greater than that achieved with
phototherapy

• Intravenous immunoglobulin
– (500 mg/kg/dose over a 4 hr period), given q12 hr for 3 doses
 reducing bilirubin levels in patients with Coombs-positive
hemolytic anemia, presumably by reducing hemolysis
Neonatal cholestasis

LO 4
 Neonatal cholestasis
• prolonged elevation of serum levels of
conjugated bilirubin beyond the first 14 days of
life

• Etiology
– infectious, genetic, metabolic, or undefined
abnormalities giving rise either to mechanical
obstruction of bile flow or to functional impairment of
hepatic excretory function and bile secretion
– stricture or obstruction of the common bile duct;
biliary atresia is the prototypic obstructive
abnormality
Classification
 Mechanisms
• inborn errors of bile acid metabolism associated with
accumulation of toxic primitive bile acids + failure to
produce normal choleretic and trophic bile acids 
metabolic liver disease
• autoimmune mechanisms  neonatal liver injury
• Cholangitis  progressive sclerosis and narrowing of the
biliary tree  complete obliteration (biliary atresia)
• Functional abnormalities in the generation of bile flow may
also have a role in neonatal cholestasis
• inefficient liver cell transport and metabolism of bile acids
in early life  decrease bile flow  production of
abnormal toxic bile acids
 Evaluation
• Clinical manifestations
– hepatocyte injury or bile duct obstruction 
decreased bile flow  icterus, dark urine, light or
acholic stools, and hepatomegaly
– Hepatic synthetic dysfunction 
hypoprothrombinemia and a bleeding disorder
• Laboratory findings
– Conjugated hyperbilirubinemia > 20%
Long term complication & treatments
• specific metabolic illness (galactosemia), or
other metabolic diseases (tyrosinemia) 
– sepsis,
– an endocrinopathy (hypothyroidism or
panhypopituitarism),
– nutritional hepatotoxicity

• Administration of vitamin K  prevent

hemorrhage
Neonatal hepatitis syndrome

LO 4
 Neonatal hepatitis
• neonatal hepatitis  intrahepatic cholestasis,
forms
– Idiopathic neonatal hepatitis
• occur in either a sporadic or a familial form, is a disease
of unknown cause
• In the past, patients with α1-antitrypsin deficiency were
included in this category
– Infectious hepatitis in a neonate
• due to a specific virus, such as herpes simplex,
enteroviruses, CMV, or, rarely, hepatitis B
Intrahepatic bile duct paucity

LO 4
 Intrahepatic bile duct paucity
• absence or marked reduction in the number
of interlobular bile ducts in the portal triads

• Histologic features
– congenital bile duct absence
– partial failure of bile duct development
– progressive bile duct atrophy
– disappearance of the bile ducts due to segmental
destructive processes
 Alagille syndrome
• ~arteriohepatic dysplasia
• e/ mutations in human Jagged 1 gene (JAG1)
• most common syndrome incorporating
intrahepatic bile duct paucity
• progressive destruction of bile ducts
• Clinical manifestations
– facial characteristics (broad forehead; deep-set,
widely spaced eyes; long, straight nose; and an
underdeveloped mandible)
– ocular abnormalities (posterior embryotoxon)
– cardiovascular abnormalities (usually peripheral
pulmonic stenosis, sometimes tetralogy of Fallot)
– vertebral arch defects and failure of anterior vertebral
arch fusion (butterfly vertebrae)
– tubulointerstitial nephropathy
– growth retardation and defective spermatogenesis
may reflect nutritional deficiency
• Prognosis
– Prolonged survival
– pruritus, xanthomas with markedly elevated
serum cholesterol levels
– neurologic complications of vitamin E deficiency if
untreated
 Byler disease
• severe form of progressive intrahepatic cholestasis
(PFIC type 1)
• characterized by unique structural abnormalities in the
bile canalicular membrane
• clinical differentiation from Alagille syndrome 
absence of bile duct paucity & extrahepatic features

• Clinical manifestations
– failure to thrive, steatorrhea, pruritus, rickets, and low γ-
glutamyl transpeptidase levels
– Cirrhosis gradually develops
 Aagenaes syndrome
• form of idiopathic familial intrahepatic cholestasis
associated with lymphedema of the lower
extremities
• e/ decreased hepatic lymph flow or hepatic
lymphatic hypoplasia

• Clinical manifestations
– episodic cholestasis with elevation of serum
aminotransferases, alkaline phosphatase, and bile
acids
– Between the episodes  asymptomatic
 Zellweger (cerebrohepatorenal)
syndrome
• autosomal recessive genetic disorder marked by
progressive degeneration of the liver and kidneys
• 1/100,000 births
• 6-12 mo  fatal
• Hepatic cells on ultrastructural exam  no peroxisomes

• Clinical manifestations
– severe, generalized hypotonia and markedly impaired
neurologic function with psychomotor retardation
– abnormal head shape and unusual facies, hepatomegaly, renal
cortical cysts, stippled calcifications of the patellas and greater
trochanter, and ocular abnormalities
• Neonatal iron storage disease (NISD)
– rapidly progressive disease characterized by increased iron
deposition in the liver, heart, and endocrine organs
without increased iron stores in the reticuloendothelial
system
– multiorgan failure and shortened survival
• Deficiency of Δ4-3-oxosteroid-5β reductase
– Th/ cholic acid and ursodeoxycholic acid
• Deficiency of 3β-hydroxy C27-steroid dehydrogenase (3-
HSD) isomerase
–  progressive familial intrahepatic cholestasis
– Th/ administered orally to downregulate cholesterol 7α-
hydroxylase activity, limit the production of 3β-hydroxy-Δ5
bile acids, and facilitate hepatic clearance, has been
effective in reversing hepatic injury
Biliary atresia

LO 4
 Biliary atresia
• ~progressive obliterative cholangiopathy
• distal segmental bile duct obliteration with patent
extrahepatic ducts up to the porta hepatis
• 85% of the cases  obliteration of the entire
extrahepatic biliary tree at or above the porta
hepatis

• Incidence
– 1/10,000-15,000 live births
• Clinical manifestations
– acholic stools
– Palpation of the liver  abnormal size or consistency in patients
with extrahepatic biliary atresia

• Other examination
– Abdominal USG  identify choledocholithiasis, perforation of
the bile duct, or other structural abnormalities of the biliary tree
such as a choledochal cyst
– Hepatobiliary scintigraphy
– Percutaneous liver biopsy  bile ductular proliferation, the
presence of bile plugs, and portal or perilobular edema and
fibrosis, with the basic hepatic lobular architecture intact
• Management
– undergo exploratory laparotomy and direct
cholangiography  presence and site of
obstruction
– Direct drainage in patients with correctable lesion
– No correctable lesion is found 
hepatoportoenterostomy procedure of Kasai can
be carried out (success rate: 90% if performed < 8
wk of life)
 Ikterus (umum)
• Perubahan warna kulit, sklera mata, jar.lain
karena bilirubin yang meningkat.
• Ikterus ringan (2-2,5 mg/dl)
• Ikterus berat /jelas (7 mg/dl)
 Patofisiologi
• Prahepatik
• Intrahepatik
• Pascahepatik
 Penyakit gangguan bilirubin
• Tak terkonjugasi
• Terkonjugasi
- kolestasis
- non kolestasis
 References
• Dalley, Arthur F. Keith L Moore. Clinically Oriented
Anatomy. 5th edition. Lippincott Williams &
Wilcins; 2006
• L. Mescher, Anthony. Junquera’s Basic Histology
Text and Atlas. 20th edition. United State: The
McGraw-Hills; 2010
• Nelson Textbook of Pediatric, 19th edition
• Sherwood,Lauralee. Fisiologi Manusia dari Sel ke
Sistem. Cetakan pertama edisi 2. Jakarta: EGC;
2001