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Hyperbilirubinemia: Causes, Types, Prevention and Treatment
1.
2. INTRODUCTION
Definition: Hyperbilirubinemia refers to an excessive level
of bilirubin in the blood and is characterized by a yellowish
discoloration of the skin, sclerae, mucous membranes and
nails.
Occurs in 60% of term and 80% of preterm neonates
Bilirubin is the end product of heme degradation
Most of the daily production comes from the breakdown of
RBCs in the RES
Heme biliverdin bilirubin
Bilirubin is released & bound to serum albumin
Bilirubin is uptake & conjugated with glucuronic acid
Finally conjugated bilirubin is excreted in bile
3. Bilirubin
Non – heme source
25% of bilirubin
Hb → globin + haem
1g Hb = 34mg bilirubin
Represent about 75%
4. Normally s. bilirubin level vary between 0.3 - 1.2mg/dl.
A bilirubin level of more than 2 mg/dl manifest
biochemically where as level of >5 mg/dL manifests
clinically in neonates
UNCONJUGATED B.
1- Insoluble in water can
not be excreted in urine
2-Tightly compounded to
s. albumin
3- Toxic
CONJUGATED B.
1-Water soluble& can be
excreted in urine
2- Loosely bound to
albumin.
3-Non toxic
5. RISK FACTORS FOR DEVELOPMENT OF SEVERE HYPERBILIRUBINEMIA
IN INFANTS ≥35 WEEKS OF GESTATION
MAJOR RISK FACTORS
1-Predischarge TSB or TcB level in the high-risk zone
2-Jaundice observed in the frst 24 hr
3-Blood group incompatibility with positive direct coombs test,
other known hemolytic disease (glucose-6-phosphate
dehydrogenase defciency).
4-Gestational age 35-36 wk
5-Previous sibling received phototherapy
6-Cephalohematoma or signifcant bruising
7-Exclusive breast-feeding, particularly if nursing is not going well
and weight loss is excessive
8-East Asian race*
6. MINOR RISK FACTORS
1-Predischarge TSB or TcB level in the high intermediate-risk zone
2-Gestational age 37-38 wk
3-Jaundice observed before discharge
4-Previous sibling with jaundice
5-Macrosomic infant of a diabetic mother
6-Maternal age ≥25 yr
7-Male gender
DECREASED RISK (these factors are associated with decreased risk of
signifcant jaundice)
1-TSB or TcB level in the low-risk zone
2-Gestational age ≥41 wk
3-Exclusive bottle-feeding
4-Black race
5-Discharge from hospital after 72 hr
7.
8. Etiology:
1- increases the load of bilirubin to be metabolized by the liver
(hemolytic anemias, polycythemia, bruising or internal
hemorrhage, shortened red blood cell life as a result of
immaturity or transfusion of cells, increased enterohepatic
circulation, infection)
2-damages or reduces the activity of the transferase
enzyme or other related enzymes (genetic defciency,
hypoxia, infection thyroid defciency)
3- competition for blockage of the transferase enzyme
(drugs and other substances requiring glucuronic acid
Conjugation)
9. 4- absence or decreased amounts of the enzyme or reduction
of bilirubin uptake by liver cells (genetic defect, and
prematurity).
5-hypoproteinemia
6- displacement of bilirubin from its binding sites on
albumin by competitive binding of drugs such as
Sulfafurazole and moxalactam, acidosis, and increased free
fatty acid concentration secondary to hypoglycemia,
starvation, or hypothermia.
10. Types of jaundice
In new born babies bilirubin metabolism is immature
which results in the occurrence of hyperbilirubinemia in
the first few days of life.
Many factors are implicated:
1-increased destruction of RBC
2-increase enterohepatic circulation
3-decreased ability of the liver to conjugate bilirubin
4-decreased uptake by the liver due to low level of ligandin
11. Characteristics of Physiological
Jaundice
1-First appears between hours of age
2-Maximum intensity seen on 4-5th day in term and 7th
day in preterm neonates
3-Does not exceed 15 mg/dl
4-Clinically undetectable after 14 days.
5-No treatment is required but baby should be observed
closely for signs of worsening jaundice.
6- does not rise more than 5mg/dl/day
12. 1-Appears within 24 hours of age
2-Increase of bilirubin > 5 mg / dl / day
3-Serum bilirubin > 15 mg / dl
4-Jaundice persisting after 14 days
5-Stool clay / white colored and urine staining clothes
yellow
6-Direct bilirubin> 2 mg / dl
13. Causes of jaundice:
Appearing within 24 hours of age
1-Hemolytic disease of NB : Rh, ABO
2-Infections: TORCH, malaria, bacterial
3-G6PD deficiency
4-thalassemia
5-spherocytosis
Appearing between 24-72 hours of life
1-Physiological
2-Sepsis
3-Polycythemia
4-Intraventricular hemorrhage
5-Increased entero-hepatic circulation
14. After 72 hours of age
1-Sepsis
2-Cephalhaematoma
3-Neonatal hepatitis
4-Extra-hepatic biliary atresia
5-Breast milk jaundice
15. Causes of prolonged jaundice:
A-unconjugated hyperbilirubinemia
1-Breast feeding jaundice
In exclusively breast feed infants
Appears at 24-48 hrs of age
Occur during first wk of life
Disappears by 3rd week
Its related to inadequate B.F
T/t:Proper & adequate B.F
16. 2-Breast milk jaundice
In 2-4 % EBF babies after the 7th day of life
SBr>10mg/dl beyond 3rd-4th week
Should be differentiated from Hemolytic jaundice,
hypothyroidism, G6PD def
T/t: Some babies may require PT
Continue breast feeding
Usually declines over a period of time
3-congenital hypothyroidism
4-spsis
5-intestinal stasis, hirschsprung dz, meconium ileus
6-criggler najjar syndrome
17. B-conjugated hyperbilirubinemia: fraction >10% of total
SBR
1-infection
2-galactosemia, fructosemia, tyrosinemia
3-cystic fibrosis
4-dubin johnson syndrome
5-rotors syndrome
6-ideopathic neonatal hepatitis
7-alpha 1 anti-trypsin def.
8-hypothyroidism, hypopitutarism
9-biliary atresia
18. Kernicterus
Kernicterus is a neurologic syndrome resulting from the
deposition of unconjugated (indirect) bilirubin in the
basal ganglia and brainstem nuclei. There is neuronal loss
,necrosis & giliosis .The pathogenesis of kernicterus is
multifactorial and involves an interaction between
unconjugated bilirubin levels, albumin binding and
unbound bilirubin levels, passage across the blood-brain
barrier, and neuronal susceptibility to injury
Brain damage caused by bilirubin depends on:
1-level of s.bilirubin & albumin
2-bilirubin binding by albumin
3-status of BBB
4-susceptibility of the CNS
19. Risk factor for kernicterus:
1-asphyxia
2-acidosis
3-hypoglycemia
4-prematurity
5-severe hyperbilirubinemia
6-G6PD def.
7-Crigler-Najjar syndrome type I
8-Gilbert's syndrome
20. CLINICAL FEATURES OF KERNICTERUS
ACUTE FORM
Phase 1 (1st 1-2 days): poor suck, stupor, seizures
Phase 2 (middle of 1st wk): hypertonia of extensor
muscles, opisthotonus, fever, high pitched cry,
retracted neck
Phase 3 (after the 1st wk): hypotonia
CHRONIC FORM
1st year: hypertonia, active deep tendon refexes,
delayed motor skills
After 1st yr: movement disorders (choreoathetosis,
ballismus, tremor), upward gaze, sensorineural
hearing loss, dental dysplasia , MR
21. preventable causes of kernicterus:
(1) 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 of gestation);
(2) failure to check the bilirubin level in an infant noted to
be jaundiced in the first 24 hr;
(3) failure to recognize the presence of risk factors for
hyperbilirubinemia;
(4) underestimation of the severity of jaundice by clinical
(visual) assessment;
(5) lack of concern regarding the presence of jaundice;
(6) delay in measuring the serum bilirubin level despite
marked jaundice or delay in initiating phototherapy in the
presence of elevated bilirubin levels;
(7) failure to respond to parental concern regarding jaundice,
poor feeding, or lethargy
25. Clinical assessment of
jaundice
(Kramer’s staging)
Area of body bilirubin level mg/dl
1-Face 4-6mg/dl
2-upper trunk 6-8mg/dl
3-lower trunk &thigh 8-14mg/dl
4-arms&lower legs 14-19mg/dl
5-palms &soles ≥20mg/dl
26. Investigation: it depend on the suspected cause and
include
1- s. bilirubin (total, direct ,indirect)
2-ABO & Rh of baby and mother
3-Hb ,retic. , blood film
4-coombs test, G6PD assay
5-blood culture
6-TORCH screen
7-LFT
8-blood sugar
27. Clinical
Jaundice
> 12 mg/dl and
infant < 24 hr old
Coomb’s test
Positive
Identify antibody
Rh, ABO etc
Negative
Direct
bilirubin
< 12 mg/dl and infant
> 24 hr old
Follow bilirubin
level
Measure
Billirubin
28. Direct bilirubin
> 2 mg/dl
Consider
Hepatitis
Intrauterine,viral,or
Toxoplasmatic inf.
Biliary obstr.
Sepsis
Galactosemia
Cholestasis
Hemochromatosis
< 2 mg/dl
Hematocrit
Normal or low
High (Polycythemia)
29. Normal or Low
RBC morphology
Reticulocyte Count
NORMAL
Enclosed hemorrhage
Increased enterohep. circ.
Breast milk, Hypothyroidism,
Crigler-Najjar syndrome
Infant of diabetic mother
RDS, Asphyxia
Infections, Drugs(eg
novobiocin), galactosemia
ABNORMAL
Spherocytosis
Elliptocytosis etc.
ABO Incompatibility
Red cell enzyme def
Alpha thallasemia
Drugs(eg penicillin
30. Prevention:
1-promote&support breastfeeding
2-perform a thorough risk assessment for all infant
3-provide parents with written & verbal inform. About
newborn jaundice
4-provide appropriate follow-up
5-identify preterm infant and provide close monitoring
6-interpret all bilirubin levels according to infant age in
hours
31. 7-establish nursery protocols for identifying & evaluating
hyperbilirubinemia
8-recognize that visual assessment of bilirubin levels is
inaccurate
9-measure bilirubin levels in all infants with jaundice in the
first 24 hours after delivery
10-treat newborns as indicated with physiotherapy or
exchange transfusion
32. Treatment
Purposes:
1- reduce level of serum bilirubin and prevent bilirubin
toxicity
2-Prevention of hyperbilirubinemia: early feeds, adequate
hydration
Reduction of bilirubin levels either by phototherapy or
exchange transfusion
33. Phototherapy: refers to the use of light to convert bilirubin
molecules in the body into water soluble isomers that can
be excreted by the body. Bilirubin absorb light in the blue
range wavelength(420-470nm)
Phototherapy reduce bilirubin level about 2-3mg/dl per day
.But intensive phototherapy can reduce level of bilirubin
by 10mg/dl per day
The therapeutic effect of phototherapy depends on:
1- the light energy emitted in the effective range of
wavelengths
2-the distance between the lights and the infant
3-and the surface area of exposed skin
4-the rate of hemolysis
5- the intensity of light
6-hydration
34.
35. Serum bilirubin levels and hematocrit should be monitored
every 4-8 hr in infants with hemolytic disease and
those with bilirubin levels near toxic range for the
individual infant. Serum bilirubin monitoring should
continue for at least 24 hr after cessation of phototherapy.
Complication:
1-loose stools, erythematous macular rash, purpuric rash
2-overheating, dehydration (increased insensible water
loss, diarrhea)
3-hypothermia from exposure
.
36. 4-bronze baby syndrome occurs in the presence of direct
hyperbilirubinemia ,
The term bronze baby syndrome refers dark, grayish
brown skin discoloration in infants undergoing
phototherapy. Almost all infants observed with this
syndrome have had signifcant elevation of direct-
reacting bilirubin and other evidence of obstructive
liver disease. The discoloration may be due to photo-
induced modifcation of porphyrins
37. 5-skin damage
6- skin rash
7-damage to immature retina
8-blocked nose
9- hypocalcemia
10- decrease LV output which lead to decrease renal
perfusion
11- agitation & distress
38. B-exchange transfusion:
Double-volume exchange transfusion is 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. ET replace 85% of infant blood
& reduce bilirubin level by 50%. It should be used for any
newborn with a total serum bilirubin of greater than 428
μmol/l ( 25 mg/dL )
Complication:
A-early complication:
1-metabolic acidosis
2-electrolyte abnormalities
3-hypoglycemia
4-hypocalcemia
40. Other therapy:
1-intravenous immunoglobulin: 500mg/kg especially in
coombs +ve test
2-Metalloporphyrins: The mechanism of action is
competitive enzymatic inhibition of conversion of heme
protein to biliverdin.
A single intramuscular dose on the 1st day of life may
reduce the need for subsequent phototherapy.
particularly in patients with ABO incompatibility or
G6PD defciency.
41. Complications from metalloporphyrins include transient
erythema if the infant is receiving phototherapy
C-phenobarbital: promote liver enzymes and protein
synthesis to induce hepatic bilirubin metabolism
D-protoporphyrin: inhibit conversion of biliverdin to
bilirubin by heme oxygenase
42. Prognosis
Early recognition and treatment of
hyperbilirubinemia prevents severe brain
damage. But brain damage due to kernicterus
remain a devastating event