Jaundice in children

Jaundice in children Microchapters
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differential Diagnosis
Epidemiology and Demographics
Risk factors
Natural History, Complications and Prognosis
Diagnosis
Treatment
Prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Anaya, M.D.[2]

Synonyms and keywords: Jaundice in kids; hyperbilirubinemia

Overview

The word 'Jaundice' was derived from the french word for yellow which is jaune. Jaundice may be classified into two broad categories based on its time of onset and cause; physiologic and pathologic jaundice. Jaundice is caused by high concentrations of bilirubin in the bloodstream. A condition known as Hyperbilirubinemia. Hyperbilirubinemia can result from abnormalities in the metabolism of bilirubin which could occur at any stage from its production which is a result of the excessive breakdown of red blood cells, defects in its hepatic metabolism, and its post hepatic transport. Pathologic causes of jaundice can be classified into causes of conjugated and unconjugated hyperbilirubinemia. Differentials for jaundice are very limited however some skin discolorations in healthy individuals can look like jaundice in certain circumstances. The prevalence of jaundice varies among patient populations. In infants born at term, 60% will develop jaundice in their first-week of life. This rises to 80% in preterms. Common risk factors in the development of Jaundice in children are a family history of jaundice, family history of a child born with jaundice, hyperthyroidism in mother, medication use by mother, etc. It is essential for every clinician to note that jaundice is not always a benign condition therefore, extensive investigation of a child with jaundice is necessary to prevent severe complications. Symptoms of Jaundice in children may include the following: yellowish discoloration of the skin, sclera, and mucous membrane, time of onset, duration, and progression. Patients with jaundice usually appear yellow on the skin, mucous membranes, and/or sclera. A useful technique in assessing the severity of jaundice is by using the principle of skin discoloration progressing in a cephalo-caudal direction in newborns. Laboratory findings include measuring the serum bilirubin from a blood sample. The total and conjugated portions are measured and the unconjugated fraction is measured by subtracting the conjugated fraction from the total. Echocardiography can detect cardiac abnormalities in patients with Alagille syndrome and biliary atresia. Ultrasonography of the abdomen is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia. Treatment options include phototherapy, intravenous immunoglobulin(IVIG), and exchange transfusion. Pharmacological options do exist. Surgery is the mainstay of therapy or the definitive treatment for most obstructive causes of conjugated hyperbilirubinemia. Several etiologies may be generally difficult to prevent however the prevention of complications from jaundice is equally crucial. Parents should be educated on how to recognize jaundice very early in a neonate so as to present promptly for management.

Historical Perspective

• The word 'Jaundice' was derived from the french word for yellow which is jaune.
• Earliest known texts of Icterus neonatorum dates back to the medical records of the Providence Lying-in Hospital in the late 19th century. A phenomenon observed amongst several neonates in their first week of stay and attributed to breastfeeding which was the predominant way neonates were fed.
• A severe form termed Icterus gravis was better understood in the 1940s when advances in immunology and genetics led to the discovery of the Rh group of red cell antigens explaining its frequent recurrences in families after a first child becomes affected. These advances in hemolytic diseases birthed effective treatment modalities and screening methods that included maternal serology and amniocentesis in the perinatal period.
• The Baby Boom Years of the 1960s which was flanked by an increase in birth rates led to the development of the Rh-immune antiglobulin. This was as a result of a corresponding rise in the rate of neonatal jaundice. Thus, Rh erythroblastosis became very rare with screening and immunoglobulin prophylaxis during the antenatal period.
• The principles behind Phototherapy were first discovered at Rochford General Hospital, Essex in the 1950s. Babies taken outside to the warm sunshine with the aim of taking a break from the confines of an incubator literarily became less yellow than before. Subsequently, lab results further confirmed this discovery.

Classification

• Jaundice may be classified into two broad categories based on its time of onset and cause.
  • Physiologic jaundice:
    • Seen after the first 24 hours of life.
    • Serum bilirubin levels never rise >5mg/dl daily and maximum concentration is about 12mg/dl and 14mg/dl in full terms and preterms respectively.
    • Reaches the highest levels in the 4th-5th days and resolves within 2 weeks in both full-term and preterm infants.
    • Infants usually appear well.
  • Pathological jaundice:
    • Appears anytime from the first few hours of life.
    • Serum bilirubin levels rise at a rate of >5mg/dl per day or 0.5mg/dl per hour and maximum concentration is usually >12mg/dl and >14mg/dl in full terms and preterms respectively.
    • Infants appear ill and pale with abnormal discoloration of urine and stool.

Pathophysiology

• Jaundice is caused by high concentrations of bilirubin in the bloodstream. A condition known as Hyperbilirubinemia.
• Hyperbilirubinemia can result from abnormalities in the metabolism of bilirubin which could occur at any stage from its production which is as a result of the excessive breakdown of red blood cells, defects in its hepatic metabolism, and its post hepatic transport.
• Hemoglobin released from the breakdown of old or defective red blood cells is composed of heme and globin. Globin is broken down into its component amino acids and recycled while heme is split into iron and biliverdin by the enzyme, heme oxygenase in the reticuloendothelial system. Iron is transferred to ferritin and used again to make hemoglobin while biliverdin is converted to bilirubin by biliverdin reductase.
• Bilirubin, which is water-insoluble becomes coupled to albumin and transported into hepatic cells for conjugation.
• This albumin-bilirubin compound is broken down and the unconjugated bilirubin enters the cytosol of hepatocytesto be conjugated to glucuronic acid in the endoplasmic reticulum by the enzyme, Uridine diphosphate glucuronosyltransferase (UDPGT).
• Conjugated bilirubin is secreted into bile and then into the small intestine after being stored in the gall bladder. It eventually gets to the colon where it is acted upon by bacterial flora and deconjugated to urobilinogen. Most of these are excreted into feces as the brown pigment, stercobilin, and the rest is reabsorbed into the blood, converted to yellow urobilin which is eventually excreted into the urine.
• Conjugated or unconjugated hyperbilirubinemia gives a clue as to the defective mechanism/point in the system responsible for the metabolism of bilirubin.

Causes

• Causes of jaundice in children can be classified as follows:

Causes of jaundice in children

Physiologic

Pathologic

Unconjugated hyperbilirubinemia

Conjugated hyperbilirubinemia

Hemolytic

Non-hemolytic

•Rh incompatibility •ABO incompatibility •Hemoglobinopathies (Thalassemia) •Hematomas •Polycythemia •Sepsis

•Crigler-Najjar syndrome I and II •Gilbert syndrome •Breast milk jaundice

Infectious

Obstructive

Drugs

Genetic/Metabolic

Storage disorders

Endocirnopathies

•Viral •Bacterial •Parasitic

•Biliary atresia •Choledochal cyst •Inspissated bile syndrome •Neonatal sclerosing cholangitis •Congenital hepatic fibrosis •Intrinsic/extrinsic mass

•Ceftriaxone •Isoniazid •Erythromycin •Rifampin •Sulfa drugs •Parenteral nutrition •Methotrexate

•Alpha 1 antitrypsin deficiency •Alagille syndrome •Cystic fibrosis •Tyrosinemia •Galactosemia •Rotor syndrome •Trisomies 18 and 21

•Gaucher's disease •Niemann-pick disease •Glycogen storage diseases •Mucolipidoses

•Hypopituitarism •Hypothyroidism •McCune Albright syndrome

Differentiating Jaundice in children from other Diseases

• Differentials for jaundice are very limited however some skin discolorations in healthy individuals can look like jaundice in certain circumstances.
• Use of the antimalarial and antihelminthic drug, Quinacrine can cause yellowish discoloration of the skin of individuals who take it.
• Excessive consumption of fruits and vegetables high in carotenes such as carrots and sweet potatoes can cause a skin discoloration termed as Carotenoderma.
• The above differentials spare the mucous membranes and sclera.

Epidemiology and Demographics

• The prevalence of jaundice varies among patient populations.
• In infants born at term, 60% will develop jaundice in their first-week life. This rises to 80% in preterms.
• 5-10% of neonates will require being admitted for the treatment of pathological jaundice.
• Causes of jaundice also vary with age groups. In newborns, immature hepatic conjugation, hemolysis, and certain congenital disorders are top causes while Hepatitis A infection is a cause seen more in older children.
• Death rate is 0.28 per 1 million live births.

Age

• Patients of all age groups may develop jaundice.
• It is more commonly observed in newborns and the elderly populations.

Gender

• Gender predilection can be observed in the etiology of jaundice.
• An example is the documented male preponderance of Glucose-6-Phosphate dehydrogenase (G6PD) deficiency with an incidence of 4.5% males to 0.5% in females.

Race

• Racial predilection for jaundice is observed in a cause of unconjugated hyperbilirubinemia, Gilbert syndrome.
• This is caused by a genetic mutation in the gene responsible for the production of the enzyme, UDPGT. It is a diagnosis of exclusion and symptoms are triggered by stressful situations like dehydration, illness.
• It has a prevalence of 5-10% in Caucasian and Asian populations.

Risk Factors

• Common risk factors in the development of jaundice in children are:
  • Family history of jaundice
  • Family history of a child born with jaundice
  • Hyperthyroidism in mother
  • Medication use by mother
  • Gestational Diabetes Mellitus (GDM)
  • Race (Asian)
  • Age >25 years
  • ABO incompatibility
  • Rh incompatibility
  • Exclusive breastfeeding
  • Inability to breastfeed adequately
  • Primiparity
  • Oxytocin use during labor
  • Prematurity
  • Weight loss(child)
  • Male gender
  • Polycythemia
  • Cephalhematoma, hematoma in spleen or liver, resulting in excessive hemolysis with red blood cell breakdown
  • Trisomy 21
  • G6PD deficiency
  • Congenital infection (TORCHES)

Natural History, Complications and Prognosis

• It is essential for every clinician to note that jaundice is not always a benign condition therefore, extensive investigation of a child with jaundice is necessary to prevent severe complications.
• Bilirubin-induced neurological dysfunction (BIND) seen in the setting of extremely high unconjugated bilirubin levels is a rare complication.
• It is a condition in which high levels of unconjugated bilirubin crosses the immature blood-brain-barrier of neonates and binds to glial tissue and brainstem nuclei.
• Lack of colonic bacteria in neonates also predisposes them to this outcome due to increased enterohepatic reabsorption of deconjugated bilirubin.
• Bilirubin encephalopathy, a catastrophic neurologic outcome known as Kernicterus or death are likely complications if treatment is either delayed or not promptly instituted.
• Early symptoms of kernicterus are:
  • Poor feeding
  • Irritability
  • High-pitched cry
  • Apnea
  • Floppy muscles
• As the illness progresses, more severe symptoms are:
  • Seizures
  • Muscular spasms
  • Cerebral palsy
  • Learning problems
  • Loss of hearing
• Complications from the causes of conjugated hyperbilirubinemia include:
  • Liver failure
  • Malabsorption of fat and fat-soluble vitamins from cholestasis
  • Portal hypertension
  • Cirrhosis
  • Progression to hepatocellular carcinoma (HCC)
  • Cholangiocarcinoma in patients with choledochal cyst
  • Post Kasai procedure ascending cholangitis
• Prognosis of jaundice in children especially is very good with prompt diagnosis and treatment. However, conjugated hyperbilirubinemia from obstructions of the hepatic and biliary tree have poorer outcomes.

Diagnosis

Symptoms

• Symptoms of Jaundice in children may include the following:
  • Yellowish discoloration of the skin, sclera, and mucous membrane
  • Time of onset and duration
  • Progression. Involvement up to what body part?
  • Poor feeding
  • Irritability
  • Fever
  • Pruritus
  • Rash
  • Pains in the joints
  • Recent travel history
  • Diarrhea
  • Urine and stool color change
  • Anorexia
  • Weight loss
  • Body pains like abdominal discomfort/pains?

Physical Examination

• Patients with jaundice usually appear yellow on the skin, mucous membranes, and/or sclera. A useful technique in assessing the severity of jaundice is by using the principle of skin discoloration progressing in a cephalo-caudal direction in newborns.
• If discoloration has progressed to the thigh level, samples for urgent serum bilirubin should be taken.
• A limitation to this method is in infants who are already receiving phototherapy and those with darker colored skin.
• Examination may be remarkable for other findings such as:
  • Irritable infant
  • Fever
  • Rash
  • Examine urine and stool
  • Small or large for age
  • Lymph node enlargement
  • Muscle spasms
  • Unconsolable cry
  • Cardiac murmurs
  • Hepatomegaly
  • Splenomegaly
  • Ascites

Laboratory Findings

• Measuring the level of bilirubin.
  • Serum bilirubin from a blood sample. The total and conjugated portions are measured and the unconjugated fraction is measured by subtracting the conjugated fraction from the total.
  • Knowing the type of hyperbilirubinemia will guide further workup in identifying the cause of jaundice. Predominantly conjugated or mixed hyperbilirubinemia gives a clue of hepatic or post-hepatic etiology.
  • Transcutaneous bilirubinometer. The accuracy of this can be altered by skin thickness and color.
  • Bilimeter
• Complete blood count with differentials and smear
• Blood and Rh group
• G6PD levels
• Newborn screening for:
  • Cystic fibrosis
  • Tyrosinemia
  • Galactosemia
  • Hypothyroidism
• To assess liver synthetic function:
  • Prothrombin time (PT)
  • Serum albumin
• Liver function tests
  • AST
  • ALT
  • ALP
  • GGT
• Alpha 1 antitrypsin levels and phenotype
• Viral serologies
  • Hepatitis A Virus (HAV)
  • HBV
  • HCV
  • HDV
  • HEV
  • HIV
  • CMV
  • EBV
  • Parvovirus B19
• Serum ammonia
• Blood cultures
• Urinalysis
• Urine microscopy, culture, and sensitivity
• Stool microscopy, culture, and sensitivity
• TORCH screening
• Serum ferritin
• Serum ceruloplasmin
• Autoimmune antibodies

Electrocardiogram

• There are no ECG findings associated with Jaundice in children.
• It may be used to monitor cardiac rhythms during treatment.

X-ray

• Chest radiograph can reveal cardiomegaly in individuals with Alagille syndrome.

Echocardiography and Ultrasound

• Echocardiography can detect cardiac abnormalities in patients with Alagille syndrome and biliary atresia.
• Ultrasonography of the abdomen is used to screen for biliary atresia, choledochal cysts or cholestatic workup in the setting of conjugated hyperbilirubinemia.

CT scan

• CT scan of the abdomen is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia.

MRI

• MRI is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia.

Other Imaging Findings

• Other imaging modalities used for screening for cholestatic workup include the following:
  • Magnetic resonance cholangiopancreatography (MRCP)
  • Endoscopic retrograde cholangiopancreatography (ERCP)
  • Hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid analog (HIIDA)
  • Percutaneous transhepatic cholangiography (PTC)

Other Diagnostic Studies

• Diagnostic laparoscopy with/without treatment
• Liver biopsy

Treatment

Medical Therapy

• Treatment of Jaundice is usually tailored towards the underlying etiology whether it a hematologic disease or a hepatobiliary pathology.
• Treatment options include the following:
  • Phototherapy: Usually first line in neonates with severe hyperbilirubinemia to prevent neurologic sequelae.
  • Intravenous immunoglobulin(IVIG): helpful in hemolytic diseases and can be used in place of phototherapy and/or exchange transfusion.
  • Exchange transfusion: When the above options become inadequate to reduce levels of rising bilirubin or at the slightest clue of bilirubin encephalopathy, an exchange transfusion is done usually in the NICU/PICU and should be closely followed up for complications like:
    • Cardiac arrhythmias
    • Sepsis
    • Hyperkalemia
    • Hypocalcemia
    • Necrotising enterocolitis
    • Exchange transfusion also removes hemolytic antibodies from Rh isoimmunization and ABO incompatibility.
  • Pharmacologic remedies such as:
    • Phenobarbitone
    • Metalloporphyrins
• Patients with pruritus especially older kids can be treated with warm baths or given antihistamines. Cholestyramine can be used in severe cases of pruritus.
• Appropriate antiviral therapy for jaundice of viral etiology.

Surgery

• Surgery is the mainstay of therapy or the definitive treatment for most obstructive causes of conjugated hyperbilirubinemia.
• Examples of procedures for common disorders are:
  • Choledochoentersotomy for choledochal cyst
  • Hepatoportoenterostomy or the Kasai procedure for biliary atresia
  • Irrigation of the biliary tract for inspissated bile
  • Surgical drainage for common bile duct perforation
• Timing of procedure with regards to the age of the child, nutritional support in the form of vitamins, and caloric replacements are extremely essential for the success of the procedure.

Prevention

• Several etiologies may be generally difficult to prevent however the prevention of complications from jaundice is equally crucial.
• Parents should be educated on how to recognize jaundice very early in a neonate so as to present promptly for management. Some phone apps and an icterometer are novel means of accurately detecting jaundice.
• Appropriate vaccinations should be received prior to international travels.
• Prescribed medications should be taken in recommended dosages.
• Herbal medications should be avoided unless a physician clears it as safe.
• Smoking, use of illicit drugs, and excess alcohol intake should be avoided in children.
• Proper hand washing for pregnant mothers