case conference - pediatrics - jaundice

PediatricCase Conference

Bernardo and BesaBlock 1 UPCM Class 2017

GENERAL DATA andCHIEF COMPLAINT

2 month oldFemale with

HISTORY OFPRESENTILLNESS

BORN FT, NSD TO A 28 Y.O. PRIMIGRAVID, AT HOME,

ASSISTED BY A MIDWIFE

UNEVENTFUL PERINATAL COURSE

BREASTFED WITH GOOD

SUCK, ASLEEP MOST OF THE TIME, FEEDS

ONLY EVERY 4 TO 6 HRS

REPORTED TO BE A GOOD

BABY BECAUSE SHE RARELY

CRIES

JAUNDICE NOTED ON THE 4TH DAY OF

LIFE, PERSISTED TO TIME OF CONSULT

STOOLS NOT ACHOLIC

Other questions to ask! Family history

Other family members with jaundice or known family history of Gilbert syndrome

Anemia, splenectomy, or bile stones in family members or known heredity for hemolytic disorders

Liver disease History of pregnancy and delivery

Maternal illness suggestive of viral or other infection Maternal drug intake Delayed cord clamping Birth trauma with bruising and/or fractures. Was newborn screening done

Postnatal history Stools: Frequency Breastfeeding Greater than average weight loss Symptoms or signs of hypothyroidism Symptoms or signs of metabolic disease Exposure to total parental nutrition

Differential DiagnosesDDx Rule in/supportive Rule out/not supportive

physiologic jaundice *must exclude other known causes of jaundice

persistent jaundice noted on 4th day of life

breastfeeding jaundice breastfed persistent jaundice

congenital hypothyroidism jaundice asleep most of the time feeds only every 4 to 6 hrs good baby

with good suck


erythroblastosis fetalis jaundice no history of ABO or Rh incompatibility

course of illness

hemorrhage (e.g. caput succedaneum) jaundice no history of prolonged delivery, assisted delivery or birth trauma

congenital infection (e.g. neonatal hepatitis)

jaundice within first week of life

no history of apparent signs and symptoms of infection

biliary atresia persistent jaundice stools not acholic

PhysicalExamination

And labs

hypotonic with hoarse cry

CR = 70 (bradycardia) RR = 34 (bradypnea)T = 37C (afebrile)

weight = 3.5 kg(below -2, underweight)

length = 48cm head(below -3, severely stunted)

circumference = 38 cm(below 0, normocephalic)

coarse facies, large open

fontanelles, macroglossia

globular abdomen with umbilical hernia

essentially normal heart and

lung findings

normal female external genitalia

Other questions to ask! Thyroid PE Liver and Spleen

Liver Span Spleen Size

Gross examination of the Head

Skin For bruises, hematomas, etc.

DDx Rule in/supportive Rule out/not supportive

physiologic jaundice *must exclude other known causes of jaundice persistent jaundice noted on 4th day of life

breastfeeding jaundice breastfed persistent jaundice

congenital hypothyroidism jaundice asleep most of the time feeds only every 4 to 6 hrs good baby hypotonic hoarse cry bradycardia and bradypnea underweight severely stunted increased head circumference coarse facies large open fontanelles macroglossia globular abdomen umbilical hernia

with good suck

Differential Diagnoses

DDx Rule in/supportive Rule out/not supportive

erythroblastosis fetalis jaundice no history of ABO or Rh incompatibility

course of illness

hemorrhage (e.g. caput succedaneum, cephalhematoma)

jaundice no history of prolonged delivery, assisted delivery or birth trauma

congenital infection jaundice within first week of life

bradycardia bradypnea


afebrile

biliary atresia persistent jaundice stools not acholic

Differential Diagnoses

LABORATORY RESULTSFT4 1.4 (nv = 11-24 pmol/L)TSH - 200 (nv = 0.3-3.8mIU/L)

Total bilirubin = 20 (nv < 5mg/dL)B1 (unconjugated) = 19

B2 (conjugated) = 1

ADDITIONAL LABSTHYROID SCAN

CBCBLOODTYPING


physiologic jaundice *must exclude other known causes of jaundice persistent jaundice noted on 4th day of life

breastfeeding jaundice breastfed hyperbilirubinemia

persistent jaundice

congenital hypothyroidism jaundice asleep most of the time feeds only every 4 to 6 hrs good baby hypotonic hoarse cry bradycardia bradypnea underweight severely stunted coarse facies large open fontanelles macroglossia globular abdomen umbilical hernia increased TSH, decreased FT4 hyperbilirubinemia

with good suck


erythroblastosis fetalis jaundice hyperbilirubinemia

no history of ABO or Rh incompatibility

course of illness

hemorrhage (e.g. caput succedaneum) jaundice hyperbilirubinemia

no history of prolonged delivery, assisted delivery or birth trauma

congenital infection jaundice within first week of life

bradycardia bradypnea


afebrile

biliary atresia persistent jaundice hyperbilirubinemia

stools not acholic

hyperbilirubinemiaaccumulation of bilirubin in tissues

observed during the 1st week of life in approximately 60% of term infants and 80% of preterm infants

Clinically apparent: Neonates: >5mg/dL (>85 umol/L)

Children & adults: >2-3mg/dL (>34-51 umol/L)

end product from indirect, unconjugated bilirubin that has undergone conjugation in the liver cell microsome by the enzyme uridine

diphosphoglucuronic acid (UDP)glucuronyl transferase

yellow color usually results from the accumulation of unconjugated,nonpolar, lipid-soluble bilirubin pigment in the skin

an end product of heme- protein catabolism from a series of enzymatic reactions by heme- oxygenase and biliverdin reductase and nonenzymatic reducing agents in the reticuloendothelial cells

heme oxygenase, biliverdin reductase

UDP-glucuronyl transferase

UNCONJUGATED CONJUGATED

Lipophilic (non-polar) Van den Bergh: indirect-acting

Hydrophilic Van den Bergh: direct-acting

Neurotoxic Indicator of potentially serious hepatic disorders/systemic illnesses

Bright yellow/orange appearance Greenish/muddy yellow

Caus

es of

incr

ease

in

unco

njug

ated

biir

ubin Increased bilirubin

hemolytic anemia polycythemia bruising or internal hemorrhage

transfusion reaction increased enterohepaticcirculation

infection

Reduced activity of transferase enzyme Gilbert syndrome hypoxia infection thyroid deficiency

Competition or blocking of transferase enzyme drug-induced

Absence or reduction of amount of transferase enzyme or reduction of bilirubin uptake Gilbert syndrome prematurity

PHYSIOLOGIC(Icterus neonatorum)

PATHOLOGIC

Onset 2-3 days (term)3-4 days (pre-term)

Timing, pattern, duration varies from physiologic (e.g, 14 days)

Disappears 10-14 days Variable

Type of Hyperbilirubinemia

Indirect Indirect/direct

Rate of bilirubinincrease

Appearance in the first 24-36 hours of

life

Serum bilirubin elevation

>5mg/dL/24 hours

Serum bilirubin >12 mg/dL

(term) or >10-14 mg/dL (pre-

term)

Persistence >14 days

Direct bilirubin fraction

>2mg/dL (any time)

HISTORY AND PE

Family history (hemolytic) Lethargy

Pallor (hemolytic) Poor feeding

Hepatosplenomegaly Anorexia

Acholic stool Apnea

Dark colored urine (bilirubin) Bradycardia

Vomiting Abnormal VS (hypothermia)

ETIOLOGIES OF PATHOLOGIC JAUNDICE

Hemolytic anemia, polycythemia, erythroblastosis fetalis, bruising, hemorrhages, infections, enterohepatic circulation Increased production

Transferase enzyme deficiency, hypoxia, drug competition, infection, thyroid deficiency, prematurity, genetic defect

Intrahepatic pathology leading to decreased conjugation

Infection, biliary atresia, choledochal cystImpaired/decreased excretion

BASED ON ONSETEARLY

(within 24 hours)INTERMEDIATE

(within first 2 weeks)LATE

(> 2 weeks)

HEMOLYTIC CAUSES Physiologic jaundice CONJUGATED

Rh isoimmunisation Breastfeeding jaundice Bile duct obstruction

ABO incompatibility Sepsis Biliary atresia

G6PD deficiency Crigler-Najjar syndrome Neonatal hepatitis

Polycythemia, bruising

CONGENITAL INFECTION UNCONJUGATED

TORCH, syphillis Breastmilk jaundice

Infection

Hypothyroidism

BASED ON ONSETOnset of Jaundice Differentials

0-1st day of lifeHEMOLYTIC: Erythroblastosis fetalis (hemolytic disease of the newborn),

concealed hemorrhage, sepsis, congenital infections (TORCH)

2nd -3rd day of lifePhysiologic jaundice

Familial non-hemolytic icterus(Crigler-Najjar syndrome), early onset breast feeding jaundice

3rd day- 1st week of life Bacterial sepsis, urinary tract infection, TORCH infections, polycythemia

After the 1st week of lifeLate onset breast milk jaundice, sepsis, biliary atresia, congenital paucity

of the bile ducts, hypothyroidism, cystic fibrosis, congenital hemolytic anemia

After the 1st month of lifeHyperalimentation associated cholestasis, hepatitis, TORCH infections, Crigler-Najjar syndrome, biliary atresia, galactosemia, inspissated bile

syndrome, hypothyroidism

BASED ON TYPE OF HYPERBILIRUBINEMIA

UNCONJUGATED (indirect)

CONJUGATED(direct)

Increase in total bilirubin 20% as direct bilirubin Increase in total bilirubin 20% as direct bilirubin

Jaundice, yellow stools, colorless urine Jaundice, pale/acholic stool, dark urine

Frequently due to a hematologic cause Always consider liver disease

Rarely a primary liver disease Also known as cholestatic jaundice

Breast milk jaundice Bile duct obstruction

Infection Biliary atresia

Hypothyroidism Neonatal hepatitis

JAUNDICE

Unconjugated

Increased bilirubinproduction

Hemolytic Non-hemolytic

Decreased Conjugation

Conjugated

Decreased excretion Impaired excretion

ABO and RH incompatibility Spherocytosis G6PD deficiencyHemoglobinopathy

Physiologic jaundice Birth trauma Polycythemia Sepsis

Prematurity Breast milk jaundice Crigler-Najjar Syndrome Gilberts SyndromeHypothyroidism

Infective Metabolic

-TPN-induced- Galactosemia- Maternal DM- Hypopituitar.- Hypothyroid.

Genetic-Turners- Trisomy 18/21- Alpha one antitrypsin def.

Drug-induced

Biliary atresia Choledochal cyst Neonatal sclerosing cholangitis PILBD

Comm

on Ca

uses

of Ja

undi

ce Hepatitis Physiologic Jaundice Biliary atresia Hypothyroidism

ONSET Late Intermediate Late Late

TYPE Conjugated Unconjugated Conjugated Either

SYMPTOMS JaundiceDark urine JaundiceJaundiceAbdominal distension

Jaundice

SIGNS Hepatomegaly - Decreased bowel sounds

HypotoniaCoarse faciesMacroglossia

~20 mg/dLHIGH BILIRUBIN LEVELS

TOXIC TO DEVELOPING CNS

Acute manifestations of toxicity in the first few weeks of birth

Signs: Lethargy Hypotonia and poor such progressing

hypertonia (opisthotonos and retrocollis) high pitched cry and eventually to seizures and coma

Pathologic diagnosis characterized by bilirubin staining of the brain stem nuclei

Chronic bilirubin encephalopathy Clinical findings:

Athetoid cerebral palsy, (+/-) seizures Developmental delay Hearing deficit Oculomotor: Parinauds sign Dental dysplasia Intellectual impairment

Standard Diagnostics

for Jaundice

Total serum bilirubin: direct and indirect fractions

Blood work-upo CBCo Blood typingo Hemoglobin levelso Reticulocyte countso RBC morphology by PBS

Coombs Test Abdominal UTZ Other tests:

o Liver function test: AST, ALT, ALP, GGTo X-ray, urinalysis, blood gas

A

VALUESOF SPECIFICTESTS IN THEEVALUATIONOF PATIENTSWITHSUSPECTEDNEONATALCHOLESTASIS

LABORATORYEVALUATION

OF THEJAUNDICED

INFANT>35 WEEKS

OFGESTATION

Hyperbilirubinemia

Phototherapy and if unsuccessful, exchange transfusion remain the primary treatment modalities used to keep the maximum

total serum bilirubin below pathologic levels

MANAGEMENT GOALPrevent neurotoxicity related to indirect-reacting

bilirubin while not causing undue harm

TREATMENT MODALITIES

Phototherapy Intravenous immunoglobulin Metalloporphyrins

Barbiturates Exchange transfusion

Phototherapy Clinical jaundice and indirect hyperbilirubinemia are reduced by

exposure to a high intensity o light in the visible spectrum Bilirubin in the skin absorbs light energy, causing several

photochemical reactions. There are two major products formed: 4Z,15E-bilirubin and Lumirubin

Decreased the need for exchange transfusion in term and preterm infants with hemolytic and nonhemolytic jaundice

Complications: loose stooles, erythematous macular rash, purpuric rash (porphyrinemia), overheating, dehidration, hypothermia, bronze baby syndrome

Phototherapy Intravenous immunoglobulin Metalloporphyrins BarbituratesExchange

transfusion

Intravenous immunoglobulin Adjunctive treatment for hyperbilirubinemia due to isoimmune

hemolytic disease Recommended when serum bilirubin is approaching

exchange levels despite maximal interventions including phototherapy


transfusion

Metalloporphyrins Competitive enzymatic inhibition of the rate-limiting

conversion of heme-protein to biliverdin by heme-oxygenase


transfusion

Barbiturates Increases production of UDP-glucoronyl transferase in the

liver with minimal side effects


transfusion

Exchange transfusion Double volume exchange transfusion is performed if

intensive phototherapy has failed to reduce bilirubin levels to a safe range and if the risk of kernicterus exceeds the risk of the procedure


transfusion

Overview deficient production of thyroid hormones in newborns majority are NOT hereditary but results from thyroid dysgenesis: aplasia,

hypoplasia, ectopia one of the most common preventable causes of mental retardation in

children detected by newborn screening

o 1/3495 screened newborns (December 2009)

Sources: Kliegman, R.M., Stanton, B.F., Schor, N.F., St. Geme, J.W. & Berhman, R.E. (2011). Nelson Textbook of Pediatrics 19th ed. USA: Elsevier Saunders.Chiong, M.A., Fagela-Domingo, C., Capistrano-Estrada, S.C., & Gepte, M.B. (2010) Basic Information for Physicians. October 2010. Manila: National Institutes of Health.

PathophysiologyWhen T4 and T3 production is

insufficient, there is a compensatory increase in TSH.

A biochemical profile of low T4 level and high TSH is consistent with

primary congenital hypothyroidism.

Source: Chiong, M.A., Fagela-Domingo, C., Capistrano-Estrada, S.C., & Gepte, M.B. (2010) Basic Information for Physicians. October 2010. Manila: National Institutes of Health.

EtiologyPrimary hypothyroidism Central (hypopituitary) hypothyroidism

Dysgenesis

Dyshormonogenesis

TSH unresponsiveness

Thyroid hormone transport defect

Iodine deficiencies

Maternal antibodies

Maternal medications

PIT-1 mutations

PROP-1 mutations

TSH deficiency

multiple pituitary deficiencies

TRH deficiency

TRH unresponsiveness

Mutations in the TRH receptor

Sources: Kliegman, R.M., Stanton, B.F., Schor, N.F., St. Geme, J.W. & Berhman, R.E. (2011). Nelson Textbook of Pediatrics 19th ed. USA: Elsevier Saunders.

Thyroid dysgenesis

most common cause of congenital hypothyroidism (80 - 85%)o aplasia - 33%o ectopia and hypoplasia - 66%

cause unknown in most cases occurs sporadically maternal antithyroid, thyroid growth-blocking and cytotoxic

antibodies are suggested factors

Primary hypothyroidism


Thyroid dyshormonogenesis

account for 15% of cases detected by newbornscreening

autosomal recessive goiter is almost always present



Thyroid dyshormonogenesis May be a mutation in:

o sodium - iodide transporter - iodide transporter defecto thyroid peroxidase gene - thyroid organification or coupling

defect most common of the T4 synthetic defects

o DUOXA2 maturation factor or DUOX2 gene - defects in H2O2 generation

o thyroglobulin gene - thyroglobulin synthesis defecto DEHAL1 gene - deiodination defect




mutation in monocarboxylate transporter 8 (MCT8) impaired passage of T3 into neurons elevated serum T3 levels, low T4 levels, normal or

mildly elevated TSH levels, psychomotor retardation



Maternal antibodies aka maternal thyrotropin receptor-blocking antibody (TRBAb) or

thyrotropin-binding inhibitor immunoglobulin inhibition of binding of TSH to its receptor in the neonate suspected if:

o mother has history of autoimmune thyroid disease (e.g. Graves disease, Hashimotos thyroiditis) or hypothyroidism on replacement therapy

o subsequent siblings have recurrent congenital hypothyroidism of a transient nature

half-life of antibody - 21 days remission of hypothyroidism - 3 - 6 mos.




mutation in TSH-receptor gene autosomal recessive associated with Type 1a pseudohypoparathyroidism -

due to dysfunctional Gs protein



Iodine deficiency

aka endemic goiter most common cause of congenital hypothyroidism

worldwide more likely in preterm infants because of their

dependence on maternal iodine



Maternal medication

radioiodine given for treatment of Graves disease or thyroid cancer

fetal thyroid is capable of trapping iodide by 70 - 75 days AOG

radioiodine contraindicated in lactating women - readily excreted in milk



TSH and TRH deficiency

associated with developmental defects of the pituitary or hypothalamus

most are not detected by newborn screening majority have associated multiple pituitary deficiencies

o present with hypoglycemia, persistent jaundice, micropenis, septo-optic dysplasia, midline cleft lip, midface hypoplasia

Central hypothyroidism


TSH and TRH deficiency

PIT - 1 mutations - TSH, GH, prolactin PROP - 1 mutations - TSH, GH, prolacitn, LH, FSH,

ACTH HESX1 mutations - TSH, GH, prolactin, ACTH deficiency defects in TSH subunit gene

Central hypothyroidism


EtiologyPrimary hypothyroidism

Central (hypopituitary) hypothyroidism

Dysgenesis

Dyshormonogenesis



Iodine deficiencies

Maternal antibodies

Maternal medications

PIT-1 mutations

PROP-1 mutations

TSH deficiency

multiple pituitary deficiencies

TRH deficiency

TRH unresponsiveness

Mutations in the TRH receptor


Clinical PresentationSSx decreased activity large anterior fontanelle poor feeding poor weight gain poor growth jaundice constipation hypotonia hoarse cry

PE findings coarse facial features macroglossia large fontanelles umbilical hernia mottled, cool and dry skin developmental delay pallor myxedema goiter


Diagnostics decreased serum T4, elevated TSH if low or low-normal serum total T4, normal TSH TBG deficiency no

pathologic consequence newborn screening - heel prick between 2 and 5 days of life

o if positive for CH, needs confirmatory thyroid function testo moderately elevated TSH levels repeat screeningo 90% of CH are detectedo if with family history thyroid function test regardless of newborn

screening resultso if same birth siblings diagnosed with CH re-screening


Diagnostics thyroid imaging (using technetium-99m or iodine-123) to document etiology

o ectopic thyroid tissue - thyroid dysgenesiso thyroid aplasia - TRBab, iodide trapping defecto normally situated thyroid gland - thyroid dyshormonogenesis

radiographso absence of distal femoral epiphysis retardation of osseous developmento deformity (beaking) of T12, L1 or L2o large fontanelso wide sutureso intersutural (wormian) boneso enlarged and round sella turcica


Fig. 1: Anterior projection of a thyroid gland scintigraphy performed on a 20-day-old boy, showing non-visualization of the thyroid gland (a). Whole body imaging is performed in order to reveal ectopic gland

localization (b).

Source: Salanci, B.V., Kirath, P.O, & Gunay, E.C. (2005). Role of scintigraphy in congenital thyroid anomalies. The Turkish Journal of Pediatrics, 47: 364 - 369. Retrieved from http://www.turkishjournalpediatrics.org/pediatrics/pdf/pdf_TJP_284.pdf

Fig. 2a: Thyroid scintigraphy with 99m-Tc pertechnetate of 15-day-old boy revealed

uptake of radioactivity in the midline, superior to the thyroid gland lodge.

Fig. 2b: On the lateral view, the markers (X: chin, Y: mandible angle) defined the exact localization of the gland.


Fig. 3a: The thyroid gland was not visualized in the thyroid lodge (arrow) in a six- month-

old boy using Tc-99m pertechnetate.

Fig. 3b: Repeated thyroid scintigraphy two months later showed faint radioactivity uptake in the thyroid gland (arrow).


Fig. 4: An 18-month-old boy presented with enlarged goiter and increased uptake of 99m-Tc pertechnetate, secondary to TSH stimulation. The gland was enlarged [markers (M) on the lateral side of

the gland measure 5 cm] and just above the sternal notch (J).


Management oral levothyroxine - mainstay of treatment

o optimal dose still controversialo higher doses can normalize T4 quickly and

improve cognitive scores but children more prone to develop behavioraldifficulties later

o recommended dose - 10 - 15 mcg/kg/day, dose gradually decreasing with age

o overtreatment craniosynostosis and temperament problems


tablet is crushed and mixed with few ml of watero mixing with soy formula or formula containing iron is NOT

recommended due to interference with absorption of medication


monitoringo observe clinical parameters: linear growth, weight gain, head

circumference, developmental progression and overall well-being

o at more frequent intervals when compliance is in question or abnormal values obtained

o if still hypothyroid at 3 y.o., hormone replacement and medical monitoring usually required for life

after initiation of treatment at 2 and 4 weeks

first 6 months of life every 1 to 2 months

between 6 mo. and 3 y.o. every 3 to 4 months

thereafter until growth is completed every 6 to 12 months


COmplications


Prog

nosis early diagnosis and adequate treatment normal linear growth and intelligence

if severely affected reduced IQ and other neuropsychological sequelaesuch as incoordination, hypotonia or hypertonia, short attention span, speech problems, problems in vocabulary, reading comprehension, arithmetic and memory


case conference - pediatrics - jaundice

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