Hyperbilirubinemia

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Hyperbilirubinemia
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Objectives

• Present an interesting case
• Review the new guidelines from the AAP on
  hyperbilirubinemia
• Review pathologic hyperbilirubinemia and
  hemolytic disease of the newborn

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The Case Of A.A.

• A.A is a full term, African American male infant
  born to a 33 y/o type O, Rh neg, Antibody neg,
  PNL neg, GBS pos mother by vaginal delivery. Mom
  received PCN x 1 dose PTD.
• Apgars 8/9/9
• Pt admitted to NBN for routine care
• Mother planned to breast feed
• Pt noted to be jaundiced, and bilirubin was
  checked at 36 hrs of life.
• On physical exam, he was well appearing with no
  hepatosplenomegaly.

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What is Hyperbilirubinemia?

• Definition
• If lt 24 hrs old 5 mg/dl or greater
• If 24-48 hrs old 10 mg/dl or greater
• In FT infants 15 mg/dl or greater
• In preterm infants 12mg/dl or greater
• In any neonate Inc. of 5 mg/dl in 24 hrs
• OR 0.2 mg/dl per hour

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Where does Bilirubin Come From?
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How do we get rid of bilirubin?

• Unconjugated Bilirubin
• Not water soluble
• Not excretable
• Associated with toxic effects of bilirubin
• Bilirubin conjugation
• Occurs in liver
• Makes bilirubin water soluble and excretable
• Achieved by adding glucuronic acid to bilirubin
• Enzyme is UDP-Glucuronyl transferase

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Physiologic Jaundice

• Affects nearly all newborns
• Causes
• Increased bilirubin production
• Due to breakdown of fetal RBCs
• Limited ability for conjugation in newborn liver
• Jaundice may be seen by 72-96 hrs
• Peak level typically 5-6 mg/dl, does not exceed
  17-18 mg/dl
• 6-7 of newborns have bili gt12.9
• lt3 of newborns have bili gt15

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Physiologic Jaundice

• Risk Factors
• Bruising, Cephalohematoma Breast Feeding
• Family Hx jaundice Weight Loss
• Race Delayed BM
• Chinese, Japanese Prematurity
• Korean High Altitude
• Native American Oxytocin
• Maternal Age gt25

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The Case Of A.A.

• Total bilirubin was 18.7 with direct fraction of
  0.4.
• Assuming bili was 2 at birth, rate of rise 0.4
  mg/dl per hour
• What should we do with this pt?
• Watch? Regular vs. Intensive PTX? Exchange
  Transfusion?

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Treatment of Hyperbilirubinemia in the Healthy
Term Newborn
Healthy not ill appearing, otherwise healthy,
no evidence of hemolysis In all situations, use
intensive PTX if bili fails to decline with
conventional PTX
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Definition of Pathologic Hyperbilirubinemia

• Jaundice in the 1st 24 hrs of life
• Bilirubin gt 95th ile for age in hours
• Rate of rise gt0.2 mg/dl per hour

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Differential Dx for Pathologic Indirect
Hyperbilirubinemia

• Hemolytic disease
• Blood group incompatibility
• Red cell membrane defects (spherocytosis etc)
• Enzyme defects (G6PD)
• Infection
• Sepsis
• Cephalohematoma/Bruising

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Differential Dx for Pathologic Indirect
Hyperbilirubinemia

• Polycythemia
• Infant of diabetic mother
• Fetal transfusion
• Delayed cord clamping
• Miscellaneous
• Hypothyroidism
• Hypoxia
• Acidosis

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Differential Dx for Pathologic Indirect
Hyperbilirubinemia

• Decreased Conjugation
• Criggler Najjar, Gilbert Disease
• Deficiency of UGT (UDP Glucuoronyltransferase)
• Breast Milk Jaundice

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The Case Of A.A.

• The pt was started on double phototherapy
• He continued to breast feed and PC formula. He
  was voiding and stooling well.
• Additional labs were sent.

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Recommended work up for Hyperbilirubinemia

• Total and Direct Bilirubin
• Blood type and Coombs
• to determine risk of incompatibility
• Serum albumin (optional)
• Low level may lower threshold for intervention
• CBC with diff
• Anemia/polycythemia, signs of infection
• Smear for red cell morphology
• membrane defects
• Reticulocyte count
• Evidence of red cell destruction
• G6PD
• if suggested by ethnic background or poor
  response to PTX
• Mediterranean, Middle East, Arabian Peninsula,
  Southeast Asia, Africa
• 11-13 of African Americans have G6PD!

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Indications for Work up of Jaundice

• Jaundice in 1st 24 hrs
• Jaundice excessive for pts age
• Infant receiving PTX or bili rising rapidly and
  unexplained by history
• Jaundice present at or beyond 3 wks, or sick
  infant
• Bili approaching exchange levels or not
  responding to PTX

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The Case Of A.A.

• CBC and CRP were labs were reassuring
• A.A was not anemic or polycythemic
• Smear was unremarkable
• Reticulocyte count was sent but specimen was
  clotted
• The pt was found to be B positive, Coombs
  Positive.
• Albumin and G6PD were not sent.
• (Remember that Mom was O negative)

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The Case Of A.A.

• A diagnosis of presumed ABO incompatibility was
  made.
• Should this information change our management
  plan?

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Initiation of Intensive Phototherapy
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Recommendations for Intensive PTX

• Risk Factors
• Isoimmune Hemolytic Disease
• G6PD
• Asphyxia
• Significant Lethargy
• Temperature Instability
• Sepsis
• Acidosis
• Albumin lt 3 mg/Dl

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Recommendations for Intensive PTX

• Guidelines are based on limited evidence
• An AAP clinical practice guideline
• Conventional phototherapy is an option at bili
  2-3 mg/Dl below the Intensive PTX level
• Expect a decline of 1-2 mg/dl within 4-6 hrs
• Failure of intensive PTX suggests hemolytic
  disease or some other pathologic process

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Alloimmune Hemolytic Disease

• Maternal IgG to fetal red cells
• Fetal cells cross placenta (fetal-maternal
  hemorrhage)
• Can occur any time during pregnancy
• Occurs in 64-100 of pregnancies after delivery
• Antibodies may be made to ABO blood group, Rh
  (D), C, Kell (K1), Fy, and others.
• IgG crosses from mother to infant during
  gestation, causing hemolysis

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Alloimmune Hemolytic Disease

• Alloimunization to clinically significant blood
  group Ag occurs 0.04 - 0.3 of pregnancies.
• Variation (risk) based on
• Frequency of blood group antigen in different
  populations
• Birth rates/abortion rates

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ABO Incompatibility

• Occurs Statistically in 1/5 pregnancies
• Why dont we see more ABO hemolytic disease?
• A and B IgM exist where antigens not present on
  red cells (ie type B has anti A IgM), even
  without sensitization
• IgM does not cross placenta
• Hemolytic disease occurs in type O moms
• May have anti A,B IgG even before sensitization
• More likely to develop high titers of IgG after
  sensitization

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ABO Incompatibility

• Hemolytic Disease Usually Mild
• ABO antigens not fully developed on red cells at
  birth
• Antigens similar to A and B are present on other
  tissues that neutralize the anti A,B Abs.

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Rh Disease

• Only 1/6 multiparous D neg women develop ABS with
  D pos pregnancies, even without RhoGAM
• In infants with detectable anti D Abs
• 50 unaffected or mildly affected
• 30 moderate neonatal disease
• 20 severely affected in utero
• RH disease less severe in ABO incompatible
  fetuses
• ABO Antibodies in maternal serum destroy fetal
  cells before maternal immune system reacts to D
  antigen
• Set up for Rh Disease is ABO compatible, Rh
  incompatible mother-infant pair

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RHIG (RhoGAM)

• Rate of Hemolytic Disease of the Newborn declined
  from 40.5 to 10.6 cases/ 10,000 births after
  introduction in 1980
• Only helps protect against development of
  antibodies to Rh
• Works by
• Destroying fetal cells in maternal circulation
• Coating antigens on fetal cells
• Activating inhibitory intracellular signally
  pathways to decrease antibody production

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Hemolytic Anemia

• Treatment
• Usual Tx of hyperbilirubinemia
• Gamma Globulin
• Failure to respond to intensive phototherapy
• Bilirubin within 2-3 mg/Dl of exchange level

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The Case Of A.A.

• Bilirubin was rechecked after 15 hours on double
  phototherapy (at 51 hours of life) and it was
  22.2 with direct fraction of 0.5.
• The patient was transferred to the NICU for
  intensive phototherapy and IV fluids.
• Bilirubin in the NICU, 3 hours later (at 54
  hours of life) was up to 25.1 with a direct
  fraction of 0.6.
• What are we worried about? Does he need an
  exchange transfusion now?

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Toxic effects of bilirubin

• Kernicterus
• Originally a pathologic diagnosis
• Bilirubin staining of Cerebellum and Brainstem
  Nuclei
• Term may be used interchangeably with chronic
  bilirubin encephalopathy

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Acute Bilirubin Encephalopathy

• Early Phase first few days
• Reversible (?)
• Lethargy, Hypotonia, Poor Suck
• Intermediate Phase later in the first week
• Nervous system damage may be reversible with
  exchange transfusion
• Moderate Stupor, irritability
• Hypertonia
• Opisthosotonos, Retrocollis
• Fever and high pitched cry alternating with
  drowsiness and hypotonia

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Acute Bilirubin Encephalopathy

• Advanced Phase after the first week
• Nervous system damage probably irreversible
• Shrill cry
• No feeding
• Apnea, deep stupor
• Seizure, coma, death

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Chronic Bilirubin Encephalopathy

• Occurs during the first year
• Athetoid Cerebral Palsy
• Auditory Dysfunction
• Dental enamel dysplasia
• Paralysis of Upward gaze
• Intellectual and other handicaps (less common)

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Exchange Transfusions

• Double exchange transfusion
• Infants blood replaced by donor blood
• Performed by removing and replacing small amounts
  over 2 3 hours
• Removes 85 of red cells
• Removes 45 of plasma bilirubin
• Because bilirubin reequilibrates between intra
  and extra vascular spaces

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Exchange Transfusions
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Exchange Transfusions

• Risk Factors for Requiring Exchange Transfusion
• Isoimmune hemolytic disease
• G6PD
• Asphyxia
• Significant lethargy
• Temperature instability
• Acidosis
• Sepsis

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Exchange Transfusions

• Guidelines
• Level at which exchange transfusion is
  recommended despite intensive PTX
• If bili over exchange level upon admission,
  exchange if bili remains above that level after 6
  hrs of treatment.
• Immediate exchange for evidence of acute
  bilirubin encephalopathy
• Guidelines are based on limited evidence
• An AAP clinical practice guideline

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Exchange Transfusions

• Bili (mg/dl) / Alb (g/dL) Ratio
• Level at which exchange should be considered
• May use with T bili to determine need for
  exchange transfusion

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Exchange Transfusions

• Risks
• Death 3/1000
• Significant Morbidity 50/1000 (5)
• Apnea
• Bradycardia/arrhythmia
• Cyanosis
• Vasospasm
• Thrombosis
• Necrotizing Enterocolitis
• Thrombocytopenia/coagulopathy
• Hypocalcemia
• All Risks of Blood transfusion (infection, GVHD
  etc)
• Hypoxic Ischemic encephalopathy

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The Case Of A.A.

• The bilirubin remained persistently in the low
  twenties over the next twelve hours.
• No signs of acute bilirubin encephalopathy were
  noted.
• A double exchange transfusion was performed.

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Exchange Transfusions
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1st exhange
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The Case Of A.A.

• The post exchange transfusion bilirubin was 19.2.
  
• Over the following 2 days, the pt underwent 3
  more exchange transfusions.
• Pre exchange bilis were 20.8, 24.1, and 22
  respectively.
• Post exchange bilis were 18, 19.3, 21
  respectively.

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2nd exchange
3rd exchange
1st exhange
4th exchange
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The Case Of A.A.

• Something was fishy.

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The Case Of A.A.

• Prior to the 4th exchange transfusion, further
  testing was performed
• Infants blood
• B positive - Liver enzymes normal
• Coombs neg - LDH normal
• G6PD negative - Haptoglobin low
• Cord blood
• No Anti-B antibodies were found
• Positive anti-D antibodies

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The Case Of A.A.

• Back to the drawing board.

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The Case Of A.A.

• Questions
• Why were there no anti-B antibodies found in the
  cord blood?
• Why were there anti-D antibodies found the in the
  cord blood?
• Why was repeat coombs test negative while the
  bilirubin continued to rise?
• What else can we do?

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• Why were there no anti-B antibodies found in the
  cord blood?
• Perhaps the jaundice was caused by antibodies to
  one of the other antigens (c, K1 etc)

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• Why were there anti-D antibodies found the in the
  cord blood?
• Probably due to the RhoGAM (anti D antibodies)
  given to mom prior to delivery.

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• Why was repeat coombs test negative while the
  bilirubin continued to rise?
• Other causes contributing to hyperbilirubinemia
  such as criggler najjar and red cell membrane
  defects were considered, although none were
  proven.

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• What else can we do?

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The Case Of A.A.

• On the day of the fourth (and final) exchange
  transfusion, an experimental medication, tin
  mesoporphyrin, was given

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2nd exchange
3rd exchange
SNMP given
1st exhange
4th exchange
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Tin Mesoporphyrin

• Decreases bilirubin production
• A heme analog that competitively inhibits heme
  oxygenase
• Heme oxygenase is the rate limiting step in
  conversion of heme to bilirubin

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The Case Of A.A.

• The pts bilirubin dropped precipitously
• No further exchange transfusions were needed
• The pt was off phototherapy 3 days later (DOL
  7).

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2nd exchange
3rd exchange
SNMP given
1st exhange
4th exchange
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The Case Of A.A.

• Follow up
• A.A was follow by hematology and gastroenterology
• No firm diagnosis was made, but his illness was
  thought to be due to hemolytic disease caused by
  a minor blood group antigen
• At his six month well child check, he was growing
  and developing normally
• No hyperbilirubinemia recurred

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Key points

• Be vigilant about newborn jaundice
• Review the new AAP hyperbilirubinemia guidelines
• Check for risk factors for increased
  hyperbilirubinemia/kernicterus
• Use nomograms (along with your clinical
  judgment!!)

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References

• American Academy of Pediatrics. Practice
  Guideline Management of Hyperbilirubinemia in
  the Healthy Term Newborn. Pediatrics. 1994 94
• American Academy of Pediatrics. Clinical
  Practice Guideline Management of
  Hyperbilirubinemia in the Newborn Infant 35 or
  More Weeks of Gestation. Pediatrics. 1994 144

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The Coombs Test(Direct Antiglobulin Test)

• Detects IgG or complement bound to the red cell
  membrane
• Patients red cells isolated from plasma,
  antiglobulin reagent added.
• Agglutination of red cells is a positive result.

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The Antibody Screen(indirect Coombs test)

• Detects red cell antibodies that exist in the
  patients serum.
• Test serum is incubated with normal RBCs
• Antiglobulin added to these RBCs.
• Agglutination is the positive result