Bilirubin metabolism

1
Bilirubin metabolism

• RBCs in newborn has the life span of 70-90 days
  compared with 120 days in adult. Hemoglobin is
  degraded to heme and globin after breakdown of
  RBCs in reticuloendothelial system. Heme is
  converted to biliverdin by heme oxygenase.
  biliverdin is converted to bilirubin by
  biliverdin reductase. Bilirubin is attached to
  albumin and is transferred to hepatic cells from
  sinusoids. Bilirubin is then conjugated to
  monoglucuronide and diglucuronide which are water
  soluble and can be excreted via renal and biliary
  systems. Approximately 25 of excreted bilirubin
  is deconjugated and reabsorbed by enterohepatic
  circulation, 10 is excreted in stool and the
  remaining part is converted to urobilinogen.

2
Four stages of bilirubin metabolism

• 1-transport
• 2-hepatic uptake
• 3-conjugation
• 4-excretion.
• in neonates uptake and conjugation are the more
  restrictive steps.

3
Different forms of bilirubin in serum

• Bilirubin exists in four different forms in
  serum
• 1-unconjugated bilirubin
• 2-free bilirubin
• 3-conjugated bilirubin
• 4-d bilirubin

4
Physiologic hyperbilirubinemia

• 1-never begins in the first 24 h
• 2-maximum bilirubin level of 12mg/dl in terms and
  10-14 in preterms
• 3-returns to normal after 10 days in terms and
  10-14 days in preterms
• 4- maximum rising rate is 5mg/dl/day
• 5-direct level is not more than 1mg/dl

5
Neonatal hyperbilirubinemia

• Term neonates
• peak level of 5-6mg/dl in white and African
  American babies and 10-14mg/dl in Asian American
  babies between 72 and 120hr of age.
• Preterm neonates
• peak level of 10-12mg/dl by the fifth day of
  life.
• Postterm neonates
• nearly all post mature neonates and
  approximately half of SGA term neonates may be
  expected to have little or no physiologic
  jaundice, with peak total serum bilirubin
  concentrations of less than 2.5mg/dl.

6
Nonphysiologic jaundice

• STB concentrations have been defined as
  nonphysiologic
• if the concentration exceeds
• 5 mg/ dL on the first day of life in a term
  neonate,
• 10 mg/ dL on the second day,
• or 12 to 13 mg/ dL thereafter,
• based on data from
• the national Collaborative Perinatal Project
• (Hardy et ai,1979).

7
Causes of unconjugated hyperbilirubinemia

• Isoimmune hemolytic disease (ABO- Rh
  incompatibility between mother and fetus).
• Erythrocyte enzymatic defects (G6PD PK
  deficiency).
• Erythrocyte structural defects (spherocytosis,
  elliptocytosis, pyknocytosis).
• Infection
• Concealed hemorrhage
• Gillbert syndrome
• Crigler-Najjar syndrome type12
• Transient familial neonatal hyperbilirubinemia
  (Lucey- Driscoll syndrome).
• Pyloric stenosis
• Hypothyroidism
• Breast feeding jaundice
• Breast milk jaundice

8
ABO Rh incompatibility

• Mother O
• Infant A B AB
• Mother Rh negative
• Infant Rh positive

9
Lucey - Driscoll syndrome

• A rare disorder in which every neonate of certain
  mothers may be expected to develop severe
  unconjugated hyperbilirubinemia during the first
  48 hrs of life with TSB concentration of usually
  20 mg/dl or greater.
• Cause
• high concentration of UGT inhibitor in maternal
  and neonatal serum

10
Pyloric stenosis

• three causes of hyperbilirubinemia are
• 1- decrease UGT activity
• 2-decreased caloric supplement
• 3-enhanced enterohepatic circulation

11
Hypothyroidism

• UGT activity in congenital hypothyroidism is
  deficient and may remain suboptimal for weeks or
  months.
• Treatment with thyroid hormone promptly
  alleviates the hyperbilirubinemia.

12
Breast milk jaundice

• Significant elevation in unconjugated bilirubin
  develops in an estimated 2 of breast-fed term
  infants after the 7th day of life, with maximal
  concentrations as high as 10-30 mg/dL reached
  during the 2nd-3rd week. If breast-feeding is
  continued, the bilirubin gradually decreases but
  may persist for 3-10 wk at lower levels. If
  nursing is discontinued, the serum bilirubin
  level falls rapidly, reaching normal levels
  within a few days. With resumption of
  breast-feeding, bilirubin levels seldom return to
  previously high levels. Phototherapy may be of
  benefit. Although uncommon, kernicterus can occur
  in patients with breast-milk jaundice. The
  etiology of breast-milk jaundice is not entirely
  clear, but may be attributed to the presence of
  glucuronidase in some breast milk.

13
Breast feeding jaundice

• occurs in the 1st week of life, in breast-fed
  infants who normally have higher bilirubin levels
  than formula-fed infants.
• Hyperbilirubinemia (gt12 mg/dL) develops in 13 of
  breast-fed infants in the 1st wk of life and may
  be due to decreased milk intake with dehydration
  and/or reduced caloric intake.
• Giving supplements of glucose water to
  breast-fed infants is associated with higher
  bilirubin levels, in part because of reduced
  intake of the higher caloric density of breast
  milk.
• Frequent breast-feeding (gt10/24 hr), rooming-in
  with night feeding, discouraging 5 dextrose or
  water supplementation, and ongoing lactation
  support may reduce the incidence of early
  breast-feeding jaundice.

14
First day jaundice

• Neonatal jaundice in first 24hr of life is due to
• ABO or Rh incompatibility until proved
  otherwise.

15
Diagnostic work up

• Regardless of gestation or time of appearance of
  jaundice, patients with significant
  hyperbilirubinemia require a complete diagnostic
  evaluation, which includes
• 1-CBC reticulocyte count peripheral blood smear
• 2- blood group of mother and neonate
• 3- direct coombs test
• 4- G6PD

16
Hemolytic jaundice

• 1-reticulocytosis
• 2-smear with evidence of RBC destruction
• 3-drop in hemoglobin
• 4- direct coombs positive
• 5- mother/neonate blood group incompatibility
• 6-G6PD deficiency
• 7- daily increment gt 5mg/dl

17
Visual estimation of jaundice

• Bilirubin is at least 5 mg/dl if the sclera and
  face is yellow.
• Chest yellow about 10mg/dl
• Umbilicus about 15mg/dl
• Knee about 20mg/dl
• Ankle about 25mg/dl
• Sole more than 25mg/dl

18
Phototherapy exchange level

• Exchange level may be estimated according to the
  premature infant chart or chart for premature
  infants more than 35wk.
• Phototherapy is started at 75 of the exchange
  level.
• Phototherapy is discontinued at 50 of the
  exchange level.

19
phototherapy guidline GAgt 35wk

• Phototherapy guideline

20

• Exchange transfusion guideline GAgt35wk

21
Suggested Maximal Indirect Serum
BilirubinConcentrations (mg/ dL) in Preterm
Infants
Birth weight Uncomplicated Complicated
lt 1000g 12 - 13 10 - 12
1000 1250g 12 - 14 10 - 12
1250 1500g 14 - 16 12 - 14
1500 2000g 16 - 20 15 - 17
2000 2500g 20 - 22 18 - 20
22

23
Sequelae of unconjugated hyperbilirubinemia

• Transient encephalopathy
• early bilirubin toxicity is transient and
  reversible. this is suggested by clinical
  observations of increasing lethargy with rising
  TSB concentrations, which reverses after exchange
  transfusion.
• Kernicterus
• in term neonates several phases have been
  classically described.
• Phase1 is marked by poor sucking, hypotonia and
  depressed sensorium.
• Phase 2 fever, retrocollis and hypertonia that
  may progress to frank opisthotonus. Phase 3
  hypertonia becomes less pronounced, but high
  pitched cry, hearing and visual abnormalities,
  poor feeding and athetosis are manifest.
  Seizures may also occur. The usual time course
  for progression of disease is approximately 24
  hours. Long term survivors often demonstrate
  choreoathetoid cerebral palsy, upward gaze palsy,
  sensorineural hearing loss, and less often mental
  retardation and dental dysplasia during later
  infancy and childhood.

24
KERNICTERUS

• Kernicterus, or bilirubin encephalopathy, is a
  neurologic syndrome
• resulting from the deposition of unconjugated
  (indirect)bilirubin
• in the
• basal ganglia
• and
• brainstem nuclei.

25
KERNICTERUS

• 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.

26
KERNICTERUS

• level of indirect bilirubin,
• duration of exposure to elevated levels,
• the cause of jaundice, and
• the infant's well-being.

27
KERNICTERUS

• The precise blood level above which
  indirect-reacting bilirubin or free bilirubin
  will be toxic for an individual infant is
  unpredictable, but kernicterus is rare in healthy
  term infants and in the absence of hemolysis if
  the serum level is lt25 mg/dL.

28
KERNICTERUS

• The risk in infants with hemolytic disease is
• directly related to serum bilirubin levels.
• The duration of exposure needed to produce toxic
  effects is unknown.

29
NCIDENCE AND PROGNOSIS

• By pathologic criteria,
• Kernicterus will develop in 1/3 of infants (all
  gestational ages)
• with untreated hemolytic disease and bilirubin
  levels gt25-30 mg/dL.
• Reliable estimates of the frequency of the
  clinical syndrome
• are not available because of the wide spectrum of
  manifestations.

30
NCIDENCE AND PROGNOSIS

• Overt neurologic signs have a grave prognosis
• More than 75 of such infants die,
• and 80 of affected survivors have bilateral
  choreoathetosis with involuntary muscle spasms.
• Mental retardation, deafness, and spastic
  quadriplegia are common.

31
Factors affecting the risk of kernicterus

• Hypoproteinemia
• Drugs competing for binding to albumin
• Acidosis
• Increased free fatty acid levels
• Hypoglycemia
• Hypothermia
• Asphyxia
• Infection
• Prematurity
• Hyperosmolality
• IVH

32
Factors affecting the risk of kernicterus

• Delay in passage of meconium, which contains 1 mg
  bilirubin/dL, may contribute to jaundice by
  enterohepatic circulation after deconjugation by
  intestinal glucuronidase.
• Oxytocin
• Phenolic detergents
• Polycythemia
• IDM

33
Risk factors for development of severe
hyperbilirubinemia
34
Phototherapy

• three independent mechanisms have been proposed
  to explain the action of phototherapy in reducing
  serum bilirubin concentrations in neonates.
• Geometric photoisomerization
• Intramolecular cyclization
• Oxidation

35

36
Standard phototherapy -intensive phototherapy

• lamps are normally positioned within 40cm or in
  cases of
• intensive phototherapy
• within 15-20cm of the patient.
• The patient should be on an open warmer or in a
  crib as opposed to an incubator.
• A prolonged on-off schedule may not be as
  effective as continuous therapy , but an on-off
  cycle of less than 1hour is apparently as
  effective as continuous treatment.
• Complications
• 1- retinal degeneration 2-increase in body and
  environmental temperature 3-loose stool 4-bronze
  baby syndrome 5-hypocalcemia 6-DNA damage 7-risk
  of PDA in VLBW.

37
Efficacy

• The use of phototherapy has decreased the need
  for exchange transfusion in term and preterm
  infants with hemolytic and nonhemolytic jaundice.
• When indications for exchange transfusion are
  present, phototherapy should not be used as a
  substitute
• however, phototherapy may reduce the need for
  repeated exchange transfusions in infants with
  hemolysis.

38
The therapeutic effect of phototherapy depends on
the

1. Light energy emitted in the effective range of
   wavelengths,
2. the distance between the lights and the infant,
3. the surface area of exposed skin,
4. the rate of hemolysis and
5. in vivo metabolism and excretion of bilirubin.

39
Frequency of bilirubin check

• Depends on the bilirubin level.
• In hemolytic disease and bilirubin level near
  exchange, sampling should be done q4-8h to ensure
  bilirubin has fallen to a nontoxic level, then
  the frequency of check may be decreased to q12h.
• Checking bilirubin level with a phototherapy
  duration less than 4hr is not useful, because
  there is no decrement with such a short duration.

40
When to subtract direct bilirubin from total?

• In making decision about exchange transfusion
  direct bilirubin should not be subtracted from
  total, unless the direct level is more than 50
  of total. (f)

41
Complications

• Complications associated with phototherapy
  include
• loose stools,
• erythematous macular rash,
• purpuric rash associated with transient
  porphyrinemia,
• dehydration (increased insensible water loss,
  diarrhea),
• hypothermia from exposure,
• overheating,
• bronze baby syndrome.
• The term bronze baby syndrome refers to a
  sometimes-noted dark, grayish-brown skin
  discoloration in infants undergoing phototherapy.
  Almost all infants observed with this syndrome
  have had significant elevation of direct-reacting
  bilirubin and other evidence of obstructive liver
  disease. The discoloration may be due to
  photo-induced modification of porphyrins, which
  are often present during cholestatic jaundice and
  may last for many months. Despite the bronze baby
  syndrome, phototherapy can continue if needed.

42
Preparations- cautions

• Before initiating phototherapy, the infant's eyes
  should be closed and adequately covered to
  prevent light exposure and corneal damage. Eye
  shields should be fitted properly to avoid
  pressure injury to the closed eyes, corneal
  excoriation if the eyes can be opened under the
  binding, and nasal occlusion. Body temperature
  should be monitored, and the infant should be
  shielded from bulb breakage. Irradiance should be
  measured directly and details of the exposure
  recorded (type and age of the bulbs, duration of
  exposure, distance from the light source to the
  infant).
• In infants with hemolytic disease, care must be
  taken to monitor for the development of anemia,
  which may require transfusion.
• Anemia may develop despite lowering of bilirubin
  levels.
• Clinical experience suggests that long-term
  adverse biologic effects of phototherapy are
  absent, minimal, or unrecognized.

43
Prophylactic phototherapy

• In premature infants less than 1500g phototherapy
  is usually started on admission to prevent
  bilirubin rising which may approach exchange
  levels during the hospital course.

44
Exchange transfusion

• it is the standard mode of therapy for immediate
  treatment of hyperbilirubinemia to prevent
  kernicterus. in this technique, the equivalent of
  two neonatal blood volumes (170cc/kg)is replaced
  in aliquots not more than 10 of total blood
  volume. The procedure usually takes 1-2hours. By
  the end of double volume exchange transfusion
  only about 15 of circulating erythrocytes
  remain, but the serum bilirubin is still 45-60
  of the pre exchange level. Immediately after the
  exchange further equilibration takes place which
  is completed within 30 minutes and produces the
  early rebound of plasma bilirubin to 60 to 80
  of the pre exchange level. Blood sugar, calcium,
  sodium, potassium, bilirubin, HCT, platelet count
  should be measured 4hr after exchange .

45

• Exchange set

46

47
Potential complications of exchange transfusion

• Thrombocytopenia
• Portal vein thrombosis or other thromboembolic
  complications
• Umbilical or portal vein perforation
• Acute necrotizing enterocolitis (NEC)
• Arrhythmia, cardiac arrest
• Hypocalcemia, hypomagnesemia, hypoglycemia
• Metabolic acidosis, rebound metabolic alkalosis
• Graft versus host disease
• HIV, HBV, HCV infections
• All other potential complications of blood
  transfusion

48
LED
49
LED
50

51
Halogen lamps
52
Fiberoptic phototherapy
53
photoblanket
54
Rebound

• Serum bilirubin may rise after discontinuation of
  phototherapy, especially in the case of hemolytic
  jaundice and in preterm infants.
• Bilirubin measurement is recommended 24 hr after
  phototherapy discontinuation if the cause of
  jaundice is considered to be hemolytic or if the
  infant is premature.

55
Follow up

• All infants with hyperbilirubinemia at exchange
  level should be referred for hearing screening
  after discharge.
• Infants suffering hemolytic jaundice due to ABO
  Rh incompatibility should be controlled for
  anemia after discharge, and may be candidate for
  human recombinant erythropoietin.

56
Home phototherapy

• Because most of the devices commonly used for
  home phototherapy do not provide the same degree
  of irradiance or surface area exposure as those
  available in the hospital, home phototherapy, of
  necessity, is used in the prophylactic rather
  than in the therapeutic mode.

57
Hyperbilirubinemia

• 1- CBC Retic PBS Coombs G6PD Blood
  group/ Rh Bilirubin total direct
• 2- phototherapy conventional double
  intensive ( better in bassinet than incubator)
• 3- check bilirubin q4-6-8-12-24h
• 4- work up for sepsis if suspected
• 5- IVIG in ABO Rh incompatibility
• 6- Albumin transfusion (not common practice)
• 7- Exchange transfusion preparation with NPO 4h
  
• duration 45 60 min. followed with post
  exchange lab tests? CBC PLT BS Ca Na K
  Bilirubin total direct and PO feeding
  started after 2 4 h.
• 8- D/C breast feeding for 48 h.
• 9- white sheet or foil coverage around incubator
  or bassinet
• 10- decrease distance between baby and lamps