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' is 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 such as 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, which 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 the mother, medication use by the 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 yellowish discoloration of skin, sclera, and mucous membrane. 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 are also there. 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 the management.

Historical Perspective

• The word 'Jaundice' is derived from the French word for yellow which is jaune.
• Very early records of Icterus neonatorum date back to the medical records of the Providence Lying-in Hospital in the late 19th century. A feature observed amongst several neonates in the first week of life and attributed to breastfeeding.
• Icterus gravis, a more dire presentation was better understood in the 1940s when advances in immunology and genetics led to the discovery of the Rh group of red cell antigens. It explained its recurrent nature in families after a first child becomes affected. These advances also led to the development of effective treatment modalities along with screening methods such as maternal serology and amniocentesis in the perinatal period.
• An increase in birth rates during the Baby Boom period of the 1960s enabled the completion of clinical trials that led to the development of the Rh-immune antiglobulin, following a corresponding rise in the rate of neonatal jaundice. With screening and immunoglobulin prophylaxis, Rh erythroblastosis subsequently became very rare.
• The idea behind the development of phototherapy was first discovered at Rochford General Hospital, Essex in the 1950s. Babies carried out to the warm sunshine with the aim of having a timeout from the incubator literally 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 as shown in the table below:

Classification of Jaundice

Type of Jaundice	Details
Physiologic jaundice	Seen after the first 24 hours of life. Serum bilirubin never exceeds >5mg/dl daily and the maximum concentration is about 12mg/dl and 14mg/dl in full terms and preterms respectively. The highest levels are attained in the first 4-5 days of life and resolve within 2 weeks in both full-term and preterm infants. Infants usually appear well.
Pathological jaundice	Seen anytime from the first few hours of life. Serum bilirubin increases 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 from the breakdown of effete red blood cells is composed of heme and globin. Globin is further dismantled 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.
• Water-insoluble bilirubin 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 hepatocytes to be conjugated to glucuronic acid in the endoplasmic reticulum by the enzyme, uridine diphosphate glucuronyltransferase (UDPGT).
• This conjugated form of bilirubin is secreted into bile and then into the small intestine after being stored in the gall bladder. It subsequently reaches the colon where it is acted upon by bacterial flora and deconjugated to urobilinogen. Most 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.
• Hyperbilirubinemia whether conjugated or unconjugated gives a clue as to the defective point in the metabolism of bilirubin.

Causes

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

Differentiating jaundice in children from other diseases

• Alternative diagnoses for jaundice are limited however, some skin discolorations in healthy individuals can resemble jaundice in certain circumstances.
• Use of the antimalarial and anti-helminthic 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 of life which 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 the top causes, whereas 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 population.

Gender

• Gender preference 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 predisposition for jaundice is observed in a cause of unconjugated hyperbilirubinemia such as Gilbert syndrome.
• A genetic mutation in the gene responsible for the production of the enzyme, UDPGT is its cause. Diagnosis is made only when alternative explanations have been ruled out. Symptoms are triggered by stressful situations such as dehydration, and illness.
• It has a prevalence of 5-10% in Caucasian and Asian populations.

Risk Factors

• Common risk factors for the development of jaundice in children are:
  • Family history of jaundice
  • Family history of a child born with jaundice
  • Hyperthyroidism in the mother
  • Medication used by the 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
  • Hematoma in spleen or liver, cephalhematoma, causing 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.
• In the setting of very high unconjugated bilirubin levels, a rare complication known as bilirubin-induced neurological dysfunction (BIND) is observed.
• Elevated levels of unconjugated bilirubin crosses the immature blood-brain-barrier of neonates binding 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 is promising with prompt diagnosis and treatment. However, conjugated hyperbilirubinemia from the obstructions of hepatic and biliary tree have poorer outcomes.

Diagnosis

Symptoms

• Symptoms of jaundice in children may include the following:
  • Skin, sclera and mucous membrane discoloration
  • Time of onset and duration
  • Progression (involvement up to which body part)
  • Poor feeding
  • Irritability
  • Fever
  • Pruritus
  • Rash
  • Pain in joints
  • Recent travel history
  • Diarrhea
  • Urine and stool color change
  • Anorexia
  • Weight loss
  • Body pains such as abdominal discomfort/pains

Physical Examination

• Patients 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.
• This method is not necessary for infants who are already receiving phototherapy and those with darker colored skin.
• Other findings on examination are:
  • Irritable infant
  • Fever
  • Rash
  • Examine urine and stool
  • Small or large for age
  • Lymph node enlargement
  • Muscle spasms
  • Inconsolable 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 first 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. Conjugated or mixed hyperbilirubinemia gives a speculation 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

• A 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

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

MRI

• A 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 (HIDA)
  • 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 the 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 such as:
    • 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, antibacterial, and antiparasitic therapy for jaundice of viral, bacterial and parasitic etiology respectively.

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 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 the management. Some phone apps and an icterometer are novel means of accurately detecting jaundice.
• Appropriate vaccinations should be received prior to international travel.
• Prescribed medications should be taken in recommended dosages.
• Herbal medications should be avoided unless a physician clears it.
• Smoking, use of illicit drugs, and excess alcohol intake should be avoided in children and pregnant women.
• Proper hand washing for pregnant mothers.