INTRODUCTIONDefinition: 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

Bilirubin

Non – heme source

25% of bilirubin

Hb → globin + haem

1g Hb = 34mg bilirubin

Represent about 75%

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

RISK FACTORS FOR DEVELOPMENT OF SEVERE HYPERBILIRUBINEMIAIN 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-phosphatedehydrogenase 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 welland weight loss is excessive

8-East Asian race*

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

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 enterohepaticcirculation, infection)

2-damages or reduces the activity of the transferaseenzyme 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)

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.

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

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

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

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

After 72 hours of age

1-Sepsis

2-Cephalhaematoma

3-Neonatal hepatitis

4-Extra-hepatic biliary atresia

5-Breast milk jaundice

Causes of prolonged jaundice:

A-unconjugated hyperbilirubinemia1-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

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

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

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

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

CLINICAL FEATURES OF KERNICTERUS

ACUTE FORM

Phase 1 (1st 1-2 days): poor suck, stupor, seizures

Phase 2 (middle of 1st wk): hypertonia of extensormuscles, 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, sensorineuralhearing loss, dental dysplasia , MR

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

historyonset / duration

pain

nausea & vomiting

loss of weight

itching

color of stool

color of urine

past history

family history

examinationcolor of skin

severity of jaundice

anemia

liver

spleen

gall bladder

Ascites

Rash or petechiae

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

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

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 bilirubinlevel

Measure Billirubin

Direct bilirubin

> 2 mg/dl

Consider

Hepatitis

Intrauterine,viral,orToxoplasmatic inf.

Biliary obstr.

Sepsis

Galactosemia

Cholestasis

Hemochromatosis

< 2 mg/dl

Hematocrit

Normal or low

High (Polycythemia)

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(egnovobiocin), galactosemia

ABNORMAL

Spherocytosis

Elliptocytosis etc.

ABO Incompatibility

Red cell enzyme def

Alpha thallasemia

Drugs(eg penicillin

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

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

TreatmentPurposes:

1- reduce level of serum bilirubin and prevent bilirubintoxicity

2-Prevention of hyperbilirubinemia: early feeds, adequate hydration

Reduction of bilirubin levels either by phototherapy or exchange transfusion

Phototherapy: refers to the use of light to convert bilirubinmolecules 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 bilirubinby 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

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

.

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

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

B-exchange transfusion:

Double-volume exchange transfusion is performed if intensive phototherapy has failed to reduce bilirubinlevels 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

5-thrombocytopenia 6-volume overload

7-arrhythmias 8-NEC, infection

B-late complication:

1-late onset anemia

2-GVH disease

3- portal hypertension & portal vein thrombosis

4- inspissated bile syndrome

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 hemeprotein 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.

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

PrognosisEarly recognition and treatment of hyperbilirubinemia prevents severe brain damage. But brain damage due to kernicterusremain a devastating event

THANKS FOR LISTENING

Presented by:

Haider Faroon