Jaundice Flashcards
Definition
Jaundice is the visible manifestation of increased levels of
bilirubin in the body.
– It is not a disease, but only a symptom
Values
*Normal BR =0,1 - 1mg/dl (2-17μmol/l)
(max 1,3-1,5mg/dl)
*Conjugated BRD =0-0,3mg/dl (0-5 μmol/l)
*In adults sclera appears jaundiced when serum bilirubin exceeds
BR>2mg/dl (5-7mg/dl in neonates)
Bilirubin
End product of hemoglobin metabolism that is excreted in
bile.
1g Hb ⇒ 34mg BR
In neonates -75% : from catabolism of circulating RBCs
-25% :*from ineffective erythropoiesis
BR has no known physiologic function
The non-conjugated form has the potential CNS
toxicity due to fat soluble properties and
hematoencephalic barrier permeability during the
neonatal period
- Unconjugated BR (indirect)
– Non-polar, toxic, water insoluble compound, MW 584
– Permeates easily through lipid-containing barriers (blood-brain
barrier – important risk of neurotoxicity – kernicterus)
– Requires conjugation with glucuronic acid to form a water soluble
product that can be excreted
- It will circulate to the liver reversibly bound to albumin (MW 70,000)
- Conjugated (direct) bilirubin - polar, high MW, water-soluble
compound
Conjugation
- Conjugated bilirubin crosses the placenta very little and conjugation
is not active in the fetus (low levels of UDPGT - about 1% of the
adult levels at 30 - 40 weeks gestation) - After birth, the levels of UDPGT rise rapidly but do not reach the
adult levels until 4-6 weeks of age. - Ligandins, which are necessary for intracellular transport of bilirubin,
are also low at birth and reach adult levels by 3-5 days.
Enterohepatic circulation
- Conjugated bilirubin is unstable and easily hydrolyzed to
unconjugated bilirubin. - This process occurs non-enzymatically in the duodenum and
jejunum
!!! It occurs also in the presence of beta-glucuronidase, an enteric
mucosal enzyme having high levels:
- in newborn infants
- in human milk.
Hyperbilirubinemia
Hyperbilirubinemia
-Direct (Conjugated)
-Indirect (Un-conjugated)
Conjugated Hyperbilirubinemia is present,
* >10 -25% of total bilirubin is conjugated
* >2mg/dl is conjugated
If neither criteria is met, hyperbilirubinemia is classified
as un-conjugated.
Kernicterus
- “nuclear jaundice“, german term, with kern = grain,
core, indicating the most commonly afflicted region
of the brain (ie, the nuclear region).
Kernicterus or bilirubin encephalopathy
neurologic syndrome resulting from deposition of unconjugated (
indirect) bilirubin in the basal ganglia and brainstem nuclei
Pathogenesis is multifactorial Unconjugated bilirubin levels
- Albumin binding and unbound bilirubin levels
- Passage across the blood brain barrier
- Neuronal susceptibility to injury
- Disruption of the blood – brain barrier by : disease, asphyxia, acidoza…
Kernicterus factors favoring
– increased BR production,
– acidosis (sepsis), hypoproteinemia,
– the presence of substances that compete with the binding of
albumin BR (metabolites, drugs),
– altered hepatic metabolism of BR,
– increasing BR enterohepatic recirculation
- Important factors in the appearance of kernicterus :
– the BR (unconjugated, free) level,
– the day of exposure (day3)
Uncojugated BR induced CNS damage (basal ganglia)
- Clinical signs - days 2-10
– Severe depression: lethargy, decreased / disappearance of archaic
reflexes (sucking, Moro)
– Excitation: opistotonus, seizures, screaming, bulging AF
– Death/neurological sequelae: impaired hearing, vision, cerebral
palsy, seizures, memory loss, behavioral disorders
Causes of Kernicterus
1.Massive haemolysis
2.Criegler Najjar disease ( tip I Arias),
3.Prematurity
Clinical Findings
Acute
Lethargy
Poor feeding
Tone abnormalities
Opisthotonus
High pitched cry
Seizures
Apnea
Abnormal auditory brainstem response
Chronic
Mild neurodevelopmental delays
Choreoathetoid cerebral palsy
Paralysis of upward gaze
Sensorineural hearing loss
Dental dysplasia
KERNICTERUS – PREVENTION
Universal screening for hyperbilirubinemia in the first 24 -48 hr of life
to detect infants at high risk for severe jaundice and bilirubin –
induced neurologic dysfunction
Any infant who is jaundiced before 24 hr requires measurement of
the serum bilirubin level and if it is elevated - infant should be
evaluated for possible hemolytic disease
Follow –up should be provided within 2 – 3 days of discharge to all
neonates discharged earlier than 48 hr after birth
Early follow –up is particularly important for infants younger than 38
weeks gestation
Increased bilirubin production
– Daily 6-10mg/kg/day BR (3-4mg/kg/day adult)
– Larger circulating red blood cell volume
– Shortened RBC lifespan (70-90 days vs 120 days in adult)
– Substantial production from other sources
Lower plasmatic transport
In newborn the albumin affinity for bilirubin is low
Limited hepatic capacity of bilirubin metabolism
– Defective uptake from plasma into liver cell (deficiency of
LIGANDIN)
– Defective conjugation (UDP-glucuronosyl transferase: <1% of adult
activity during the first 10 days of life)
– Decreased excretion
Increased entero-hepatic circulation
– 6 times higher than in the adult
– Higher in intestinal obstructions, decreased intestinal motility,
fasting
INCREASED PRODUCTION OF BILIRUBINE
Increased erythrocyte turnover
- NORMAL - Shortened RBC lifespan
- PATOLOGIC - HEMOLYSIS - blood group incompatibilities
(ABO/Rh), enzyme deficiencies (G6PD, piruvatkinaza),
structural anomalies(sferocytosis…)
Blood sequestered (hemoragies)
- Hematoma /cephalhematoma, hemangiomas
Encreased enterohepatic circulation of BR
- NORMAL: newborn in the first week
- PATOLOGICAL : mechanical obstructions (intestinal atresia,
meconium plug), neurologic cause, ileus paralytic
Neonatal jaundice (BRI) mechanism
- Low hepatic ligandins
- Decreased GLUCURONONYL TRANSFERASE ACTIVITY
– Temporary in every newborn
– Far low in CrieglerNajjar sdr, LuceyDriscoll sdr
– Moderately low in Gilbert sdr,
– Low in hypopituitarism, hypotiroidism - MULTIFACTORIAL
– Sepsis
– Prematurity
– Breast milk jaundice - Intra and extrahepatic CHOLESTASIS
An abnormal reduction in bile
formation/excretion
– Neonatal hepatitis
– Biliary atresia - CONGENITAL CAUSES
– Sdr. Dubin-Johnson
– Sdr. Rotor
Neonatal jaundice generalities
HISTORY
– Incompatibility ABO/Rh with the mother
– Maternofetal infection, fetal distress
Neonatal jaundice
CLINICAL EXAM
– JAUNDICE :difficult to appreciate the intensity
!!! more important the onset (definitely pathological if <36 hours);
– Appearance of stool and urine
– Signs of abnormal hemolysis: pallor, edema, serous effusion (ascites,
hepatosplenomegaly), extramedullary hematopoiesis, hemoglobinuria
(cherry red urine)
– Signs of infection (especially neurological signs)
NEONATAL JAUNDICE
LABORATORY
– CBC (peripheral blood smear - red blood cell
morphology, reticulocyte count
– ABO group, Rh
– Coombs tests
– BRT/BRD/ BRI
– Albumin level (index of saturation with bilirubine)
NEONATAL JAUNDICE
CLASSIFICATION
ONSET
- Onset :
– Early (in the first 24-36hours),
– “Normal ” – at 48-72 hours after birth,
– At any other time (generally > 72 hours after birth) - BR Type : with predominance of BRI or BRD
- Congenital / acquired
- NB abnormal if: the onset is < 36 hours, the BR level
rises rapidly (>0,5mg/dl/day), the duration is
extended or there are other changes associated
NEONATAL JAUNDICE
CLASSIFICATION
- Physiological Jaundice (premature newborns)
- Hemolytic Jaundice (early onset, risk of kernicterus,
rapid raise in BR>0,5mg/kg/hour) - Infectious Jaundice (possible onset from birth, sepsis)
- Prolonged Jaundice
– With IBR
– With DBR
PHYSIOLOGICAL JAUNDICE
First appears - day 2-3
Maximum intensity seen on 4-5th day in term and 7th day
in preterm neonates
Does not exceed 15 mg/dl
Clinically undetectable after 14 days (21 in prematures).
Normal urine and stools
No hepatosplenomegaly, no signs of infection
No treatment is required but baby should be observed
closely for signs of worsening jaundice.
PHYSIOLOGICAL JAUNDICE IS EXLUDED IF
- The onset is in the first 24 hours of life
- TBR rises with > 5mg/dl/day
- TBR >12,9mg/dl (15mg/dl in a premature newborn)
- DBR >1,5-2mg/dl
- It lasts >1-2 weeks in the newborn at term /// 2-3
weeks in a premature newborn
PHYSIOLOGICAL JAUNDICE
TREATMENT
– Fototherapy (at term >13-14mg/dl, premature >10mg/dl)
– Exchange transfusion
– Fluid therapy, iv albumin
Phototherapy
has been the mainstay of treating
hyperbilirubinemia since the 1960s.
- Phototherapy causes structural isomerization, forming
lumirubin, which is then excreted in the bile and urine. - Since photoisomers are water soluble, they should not
be able to cross the blood-brain barrier, so starting
phototherapy should decrease the risk of kernicterus - To be effective, bilirubin must be present in skin, hence
no role for prophylactic phototherapy
HEMOLYTIC JAUNDICE
- The onset is < 36 hours of life
- Risk of kernicterus
- Causes
– Blood Group Incompatibilities (ABO, Rh)
– Structurally Abnormal Red cells
– Non-immune Hemolytic Anemias (G6PD deficiency)
– Severe sepsis - Clinic
– Jaundice (variable as intensity)
– Normal Urine and stool
– Hepatosplenomegaly
HEMOLYTIC JAUNDICE DIAGNOSIS
- Diagnosis
– History, Clinical exam
– TBR/ IBR/ DBR
– CBC with peripheral blood smear
– Blood group (ABO, Rh) – mother and child
– Coombs Test
– Evaluation for sepsis /TORCH/associated pathology
HEMOLYTIC JAUNDICE TREATMENT
– In severe forms - exchange transfusion
– Supportive treatment, parenteral nutrition
– Sepsis treatment - antibiotherapy
BREAST MILK/FEEDING JAUNDICE
- BRI jaundice
- Healthy newborn, no signs of infection, no signs of
hemolysis - Normal urine and stool
- Onset from the first week; can last until 8 weeks of age
- 50-70% of newborns have jaundice
- Moderate (>12 mg/dL) develops in 4% of bottlefed compared to 14%
of breastfed - Severe jaundice (>15 mg/dL) occurs in 0.3% bottlefed vs
2% of breastfed
Breastfeeding Jaundice vs Breastmilk Jaundice
Lecture
JAUNDICE IN NEWBORNS AND INFANTS
- PHYSICAL EXAMINATION
– Jaundice
– Dark urine, acholic stools
– Pruritus/itch (after 4-5 months)
– Hepatomegaly - BIOLOGIC
– DBR > 10-25% TBR (sometimes it reaches 50-90%)
– Hyperlipemia (total colesterol)
– Elevated alkaline phosphatase, 5 nucleotidaza
– Steatorrhea
PATHOLOGICAL JAUNDICE
- Clinical jaundice detected before 24 hours of age
- Rise in serum total bilirubin by more than 5 mg/dl/ day (>5mg/dl on first
day , 10 mg/dl on second day and 12- 13 mg/dl thereafter in term
babies) - Serum bilirubin more than 15 mg/dl
- Clinical jaundice persisting beyond 14 days of life
- Clay/white colored stool and/or dark urine staining the nappy yellow
- Direct bilirubin >2 mg/dl at any time.
- Treatment is required in the form of phototherapy or exchange blood
transfusion.
– ! You should investigate to find the cause of a pathological jaundice.
INTRAHEPATIC CHOLESTASIS: normal extrahepatic
biliary tract, no obstruction
– Infectious diseases (sdr TORCH, HVB, sifilis, lysteria)
– Genetic causes (Down’s)
– Metabolic causes (galactosaemia, glycogenosis, CF, α1-
antitrypsin deficiency)
– Toxic causes (sepsis with endotoxinemia, TPN
associated cholestasis)
EXTRAHEPATIC CHOLESTASIS : extrahepatic biliary
obstruction (anatomical or mechanical)
– Extrahepatic biliary atresia
– Choledochal Cyst
– Tumors (rhabdomiosarcomas)
NEONATAL CHOLESTASIS
- History, Clinical exam
- TBR, DBR, IBR + lipids (cholesterol, TG) + AP
- TGO, TGP
- Albumine, protrombine level (hepatic synthesis)
- Cultures (blood, urine)
- Serology (TORCH, agHBs, HIV, VDRL)
- α1-antitrypsine //T4, TSH
- Sweat test
- Metabolic screening
- Ultrasound (liver, biliary tract)
- liver scintigraphy
- Liver biopsy
Neonatal Hepatitis
- PHYSICAL SIGNS
– Kepatic dysfunction present from the beginning
– Clotting disorders
– Stools : normal and acholic (alternating)
– Variable intensity of jaundice (spontaneous
improvements) - TREATMENT
– Supportive and symptomatic
– Diet (hypercaloric, MCT and vegetable fats)
– Vitamin K
– Pruritus: colistiramine, phenobarbital
– ?? Corticosteroids ?? (improvement of bile flow)
Extrahepatic biliary atresia
- PHYSICAL SIGNS
– Symptom-free interval (2-3 weeks)
– Progressive jaundice (cholestasis)
– Verdinic jaundice the skin colour turns to green
– Progressive atrepsia (severe malnutrition)
– Later: biliary cirrhosis (ascites, portal hypertension) - TREATMENT
– Surgical treatment – the only option
– Kasai portoenterostomy – restoration of bile flow to the intestine
– Best results if < 60 days
– Liver transplantation
CHILD’S JAUNDICE
HISTORY:
Age at onset of symptoms. E.g.: Wilson’s disease
commonly manifests in pre-adolescents & adolescents.
Past/present use of any drugs
History of blood transfusion/ dialysis
Exposure to viral hepatitis
Any history of chronic illness; hemoglobinopathies.
Family history of inheritable disorders: Wilson’s.
CHILD’S JAUNDICE
Indirect hyperbilirubinemia
Hemolytic
Gilbert syndrome – nonhemolytic jaundice
Hemolytic
Auto-immune hemolytic anemias
Drug induced hemolytic anemias
Erythrocyte membrane defects
Erythrocyte enzyme defects
Hemoglobinopathies
Congestive cardiac failure
Sepsis
Gilbert syndrome – nonhemolytic jaundice
(an autosomal dominant inherited liver disorder characterized by jaundice
due to unconjugated hyperbilirubinemia, resulting from a partial
deficiency in hepatic bilirubin glucurononyl-transferase activity).
CHILD’S JAUNDICE
Direct hyperbilirubinemia
- **Infectious jaundice **– most frequent
– HAV, HBV, EBV, leptospirosis - Chronic Hepatopathies
-
Toxic jaundice (drugs)
– Overdose /side effect of a cytotoxic substance
– Analgesics, antipyretics, antibiotics, chemotherapy,
anticonvulsants, cytotoxic and immunosuppressive drugs
– Mushrooms, industrial toxics….
CHILD’S JAUNDICE
DIRECT HYPERBILIRUBINEMIA
Obstructive
Gall stones
Primary sclerosing cholangitis
Choledochal cyst
Tumors
Infections
Hepatitis A, B, C, D, E
EBV,CMV
Varicella zoster
HIV
Leptospirosis
Congenital (noncholestatic) Jaundice
Dubin Johnson Syndrome
Sdr. Rotor Syndrome
Dubin Johnson Syndrome
a benign, inherited liver disorder (autosomal recessive) characterized clinically by chronic, predominantly conjugated, hyperbilirubinemia (without elevation of liver enzymes - ALT, AST and histopathologically by black-brown
pigment deposition in parenchymal liver cells.
Sdr. Rotor Syndrome
is a benign, inherited liver disorder characterized by chronic, predominantly conjugated, nonhemolytic hyperbilirubinemia with normal liver histology.
