Hyperbilirubinemia Final

8/10/2019 Hyperbilirubinemia Final

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Neonatal hyperbilirubinemiaJFK pediatric core curriculum

MGH Center for Global Health

Pediatric Global Health Leadership Fellowship

Credits:

Brett Nelson, MD, MPHRachel Siegel, MD

Susan OBrien, MD


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Discussion outline

Bilirubin pathophysiology

Physiologic and non-physiologic jaundice

Causes of non-physiologic jaundice Unconjugated hyperbilirubinemia

Conjugated hyperbilirubinemia

Workup Treatment


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Bilirubin is breakdown product of heme,

from circulating RBCs

Carried by albumin to hepatocytes, where

processed for excretion

In hepatocytes, uridine

diphosphogluconurate

glucuronosyltransferase (UGT) catalyzes

conjugation of bilirubin with glucuronic acid

Conjugated bilirubin is now more water

soluble and can be excreted in bile (and

urine)


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Epidemiology: neonatal jaundice

Neonatal jaundice is quite common

>50% of normal newborns and

80% of preterm infants have some degree of

jaundice

Two types of neonatal jaundice:

Normal / physiological

Abnormal / non-physiological


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Reasons for physiologic jaundice

In term newborns, bilirubin production is 2-3

times higher than in adults

Hematocrit of 50-60%, shorter RBC life span (90

days), and increased turnover of RBCs Bilirubin clearance decreased in newborns,

mainly due to deficiency of enzyme UGT

UGT activity in term infants at 7 days is ~1% of adult

liver and doesnt reach adult levels until 14 weeks

Increase enterohepatic circulation of bilirubin,

further increasing bilirubin load


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Greater concerns in preterm infants

Even more RBC turnover and destruction

Physiologically impaired conjugation and

elimination of bilirubin

An even less mature liver

Reduced bowel motility due to inadequate

oral intake

Delayed elimination of meconium

Increased enterohepatic circulation


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Physiologic jaundice

Jaundice appears around 72 hrs of life

Bilirubin peaks


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Two forms of hyperbilirubinemia

Unconjugated / indirect hyperbilirubinemia: Pre-hepatic cause, or impairment in conjugation

VS.

Conjugated / direct hyperbilirubinemia: Injury at the level of the hepatocytes, or post-hepatic

obstruction

Consider diagnosis of conjugated hyperbilirubinemiaif direct bilirubin is >3mg/dL, or is >10% of totalbilirubin


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Non-physiologic jaundice

Early jaundice

Starts on first day of life

Jaundice of long duration

>14 days in term or >21 days in preterminfants

Deep jaundice

Palms and soles deep yellow Objectively, high bilirubin lab levels

Jaundice with fever


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Differential diagnosis:

Unconjugated hyperbilirubinemia Breastfeeding jaundice

Occurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasingfeeding frequency)

Breast milk jaundice Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by

temporary switch to formula)

Hemolysis

ABO/Rh incompatibility RBC membrane defects

Alpha thalassemia

G6PD deficiency

Cephalohematoma

Polycythemia

Infection

Hypothyroidism Gilberts impaired conjugation, associated with stress, no overt hemolysis

Crigler-Najjars absent (type 1) or diminished (type 2) UDP-glucoronyl transferase


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Differential diagnosis:

Conjugated hyperbilirubinemia Biliary atresia

~60% of cases; an obliterative process of bile ducts; diagnosed by U/Sor biopsy

Infection Hepatitis B, TORCH

Metabolic Galactosemia Alpha-1-antitrypsin deficiency: most common genetic cause

Dubin Johnson or Rotors syndrome: defective liver secretion of bilirubin

Iatrogenic Drug-mediated

TPN-related: occurs in ~2/3 of infants given TPN over 2 weeks ofduration; unknown mechanism, possibly mediated by bacterialendotoxins, oxidative stress, glutathione depletion

Idiopathic neonatal non-infectious hepatitis (diagnosis of exclusion)


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The concern: Kernicterus

Bilirubin exceeds albumin-

binding capacity, crosses BBB,

and deposits on basal ganglia

and brainstem nuclei

Risks increase with levels >20

mg/dl

Or lower levels in setting of sepsis,

meningitis, hemolysis, hypothermia,hypoglycemia, or prematurity


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Signs of kernicterus

Acute sequelae:

Poor suck, lethargy, hypotonia, seizure

Then hypertonia (opisthotonus, retrocollis),

fever, high-pitched cry

Chronic sequelae:

Choreoathetoid CP, gaze paresis,

sensorineural hearing loss, mental retardation


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Cause analysis of kernicterus

Early discharge


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Work up: assess risk factors

Maternal: Race or ethnic group

(Asian, Mediterranean)

ABO, Rh incompatibility

Previous jaundiced infant

Advanced maternal age Diabetes

Infant: Gestation


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Work up: laboratory studies

Where possible, confirm clinical jaundice withbilirubin levels

Possible additional investigations, depending on

likely diagnoses and lab availability: Hemoglobin/hematocrit (PCV) to look for hemolysis Blood smear

Reticulocyte count

WBC to look for signs of infection (WBC 20, or I:T ratio

>20%) Blood type of baby and mother, and Coombs test

Syphilis serology (e.g. VDRL)

G6PD screen, thyroid function tests, liver ultrasound


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Treatment options:

Unconjugated hyperbilirubinemia

Hydration / feeding

Consider formula supplementation with temporary

interruption of breastfeeding

Phototherapy (see next slide) Antibiotics if suspected infection

Antimalarials if fever and positive smear

(Exchange transfusion)

(IVIG in immune-mediated red cell destruction)


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Diagnosis of jaundice can be

very difficult in dark-skinnedbabies

Scleral icterus may be more

sensitive marker but is a later

sign

High level of suspicion is

required!


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Phototherapy

Clinical indications1:

Jaundice on day 1

Jaundice in premature infant

Deep jaundice involving palms and soles

of the feet

Laboratory indications:

In full-term infants, bilirubin levels per

Bhutani curves In premature infants, when bilirubin level

5xweight (e.g. threshold for 3kg

newborn = 3kg x 5 = 15mg/dl)

1. Pocket Book of Hospital Care for Children. WHO. 2005.


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Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age withbirth weight of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or morebased on the hour-specific serum bilirubin values. (Subcommittee on Hyperbilirubinemia, Pediatrics

2004;114:297-316)

Bhutani curve: identifying risk


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Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation.(Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)

Bhutani curve: phototherapy


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WHO guidelines: phototherapy

Pocket Book of Hospital Care for Children. WHO. 2005.


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Key points regarding treatment:

Bilirubin levels above 20 are an emergency that

need to be treated emergently

Multiple unit phototherapy, up to 6-8 lights, ifthey are available, can and should be used

If bilirubin is high, need to provide multi-unittherapy, encouragement of frequent feeding and

possibly IV fluids as well


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Treatment:

Conjugated hyperbilirubinemia

Phototherapy is contraindicated

Treat underlying cause

Phenobarbital increases conjugation and excretion of bilirubin;

however, could affect cognitive development,therefore used cautiously

Ursodiol increases biliary flow and improves cholestatic

jaundice


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Conclusion

Neonatal jaundice is a very common condition

Important to prevent kernicterus

Pathologic jaundice is early, deep, quickly

progressing, or of long duration Assess jaundice through identifying risk factors

and laboratory analysis

Bhutani curves guide phototherapy treatment for

unconjugated hyperbilirubinemia Treat underlying cause of conjugated

hyperbilirubinemia

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