83  Prolonged Jaundice

83.1 Introduction

Jaundice is one of the most common clinical findings in the neonatal period, affecting approximately 60% of term and 80% of preterm newborns. In most cases, neonatal jaundice is physiological and resolves within the first week of life. However, when jaundice persists beyond the expected period, it is termed prolonged jaundice, and warrants thorough evaluation to exclude underlying pathology such as biliary atresia, hypothyroidism, or hemolytic disease.

Early recognition and appropriate management of prolonged jaundice are essential to prevent complications such as cholestasis, kernicterus, and long-term hepatic injury.

83.2 Definition

Prolonged (or persistent) neonatal jaundice is defined as jaundice persisting beyond: - 14 days in term infants, or - 21 days in preterm infants.

The key to evaluating prolonged jaundice lies in distinguishing between conjugated (direct) and unconjugated (indirect) hyperbilirubinaemia.

• Unconjugated hyperbilirubinaemia: often benign (e.g., breast milk jaundice, haemolysis), but may occasionally indicate pathological processes.
• Conjugated hyperbilirubinaemia: always pathological and indicative of hepatobiliary disease or systemic disorder.

83.3 Bilirubin Metabolism: Brief Review

Bilirubin is a breakdown product of haem derived from senescent red blood cells.

1. Production: Haem is converted to biliverdin, then to unconjugated bilirubin in the reticuloendothelial system.
2. Transport: Unconjugated bilirubin binds to albumin for transport to the liver.
3. Hepatic uptake and conjugation: Hepatocytes conjugate bilirubin with glucuronic acid via the enzyme UDP-glucuronyl transferase, forming conjugated (water-soluble) bilirubin.
4. Excretion: Conjugated bilirubin is excreted in bile into the intestines, converted to urobilinogen and stercobilin, and eliminated in faeces. A portion is reabsorbed via the enterohepatic circulation.

Disruption at any step can result in elevated serum bilirubin and jaundice.

83.4 Classification

Prolonged jaundice can be broadly divided into:

1. Predominantly unconjugated (indirect) hyperbilirubinaemia
2. Predominantly conjugated (direct) hyperbilirubinaemia (cholestatic jaundice)

The distinction is made using serum bilirubin fractionation: - Conjugated bilirubin > 20% of total, or > 34 µmol/L (2 mg/dL) is pathological.

83.5 Causes of Prolonged Jaundice

83.5.1 A. Predominantly Unconjugated Hyperbilirubinaemia

83.5.1.1 1. Breast Milk Jaundice

• Occurs in healthy, exclusively breastfed infants.
• Typically appears after the first week and may persist for up to 6 weeks.
• Mechanism: presence of β-glucuronidase and other substances in breast milk that increase enterohepatic circulation of bilirubin.
• Infant is otherwise healthy with normal weight gain and stool/urine colour.

83.5.1.2 2. Breastfeeding (Lactation Failure) Jaundice

• Seen in the first week due to inadequate milk intake and dehydration.
• Leads to increased enterohepatic circulation and elevated unconjugated bilirubin.

83.5.1.3 3. Haemolytic Disorders

• ABO or Rh incompatibility
• G6PD deficiency (common in Ghana and other African settings)
• Hereditary spherocytosis, pyruvate kinase deficiency
• These conditions cause increased haemolysis and bilirubin production.

83.5.1.4 4. Hypothyroidism

• Reduced hepatic conjugation and decreased gut motility leading to prolonged unconjugated jaundice.

83.5.1.5 5. Crigler–Najjar and Gilbert Syndromes

• Rare genetic disorders of bilirubin conjugation.
  • Crigler–Najjar Type I: complete absence of glucuronyl transferase (severe).
  • Crigler–Najjar Type II and Gilbert syndrome: partial deficiency.

83.5.1.6 6. Prematurity

• Immature hepatic conjugation enzyme systems.

83.5.2 B. Predominantly Conjugated Hyperbilirubinaemia (Cholestatic Jaundice)

Conjugated bilirubin is water-soluble; its presence in serum is always abnormal and indicates hepatocellular or obstructive disease.

83.5.2.1 1. Biliary Atresia

• Progressive, idiopathic obliteration of extrahepatic bile ducts.
• Presents with jaundice after 2 weeks, pale (acholic) stools, dark urine, and hepatomegaly.
• Requires urgent surgical intervention (Kasai portoenterostomy).

83.5.2.2 2. Neonatal Hepatitis (Idiopathic or Infectious)

• Inflammation and dysfunction of hepatocytes.
• Causes include viral infections (CMV, rubella, hepatitis B, enteroviruses) and bacterial sepsis.

83.5.2.3 3. Metabolic Disorders

• Galactosaemia: deficiency of galactose-1-phosphate uridyl transferase leading to liver dysfunction, vomiting, and hypoglycaemia.
• Tyrosinaemia type I, α1-antitrypsin deficiency: cause hepatocellular damage and cholestasis.

83.5.2.4 4. Endocrine Disorders

• Hypopituitarism, hypothyroidism may present with prolonged conjugated jaundice.

83.5.2.5 5. Parenteral Nutrition–Associated Cholestasis

• Seen in preterm infants on prolonged parenteral nutrition.

83.5.2.6 6. Genetic or Structural Disorders

• Alagille syndrome: paucity of intrahepatic bile ducts, associated with cardiac and facial anomalies.
• Choledochal cysts: congenital dilatation of the bile ducts causing obstruction.

83.6 Clinical Features

83.6.1 A. History

• Onset and duration of jaundice
• Feeding history: breast or formula, adequacy of feeds
• Colour of stool (pale/acholic vs normal yellow)
• Colour of urine (dark vs normal)
• Growth pattern and weight gain
• Family history of haemolytic disorders or liver disease
• Maternal infections during pregnancy (e.g., hepatitis, TORCH)
• Perinatal history (asphyxia, sepsis, prematurity)

83.6.2 B. Physical Examination

• General appearance: activity level, growth, nutritional status
• Colour: extent of jaundice (blanching under natural light)
• Stool and urine: observe directly if possible
• Hepatomegaly: common in biliary atresia and hepatitis
• Splenomegaly: may indicate haemolysis or portal hypertension
• Dysmorphic features: suggest syndromic or metabolic disorders
• Signs of hypothyroidism: macroglossia, umbilical hernia, hypotonia
• Other: ascites, petechiae (suggests liver failure)

83.7 Investigations

The goal is to differentiate between conjugated and unconjugated hyperbilirubinaemia and identify underlying causes.

83.7.1 Initial Screening

1. Total and direct (conjugated) serum bilirubin: essential first step.
   • Conjugated > 34 µmol/L or >20% of total = cholestasis.
2. Full blood count, reticulocyte count: anaemia and reticulocytosis suggest haemolysis.
3. Blood group and Coombs test: for ABO/Rh incompatibility.
4. Peripheral smear: to detect spherocytes or other RBC abnormalities.
5. Thyroid function tests (TFTs): rule out hypothyroidism.
6. G6PD screening: especially in African and Asian infants.
7. Liver function tests (ALT, AST, ALP, GGT, albumin, PT/INR): assess hepatocellular or cholestatic pattern.

83.7.2 Additional/Targeted Tests

• Urine analysis: bilirubin (present in conjugated jaundice), reducing substances (galactosaemia).
• Viral studies: TORCH, hepatitis panel, CMV PCR.
• Metabolic screening: galactose-1-phosphate, amino acid profile.
• Ultrasound abdomen: evaluate biliary tree and liver architecture.
• Hepatobiliary scintigraphy (HIDA scan): assess bile excretion; non-visualization of intestines after tracer administration suggests biliary atresia.
• Liver biopsy: gold standard for differentiating biliary atresia from neonatal hepatitis.

83.8 Differential Diagnosis

• Physiological jaundice (if prolonged due to mild immaturity)
• Breast milk jaundice
• Biliary atresia
• Neonatal hepatitis
• Hypothyroidism
• G6PD deficiency
• Sepsis
• Galactosaemia or other metabolic disorders

83.9 Management

Management depends on the underlying cause and the type of hyperbilirubinaemia.

83.10 A. General Principles

1. Identify the cause early.
2. Differentiate conjugated from unconjugated jaundice.
3. Prevent bilirubin encephalopathy in unconjugated hyperbilirubinaemia.
4. Provide nutritional and supportive care.

83.10.1 B. Management of Unconjugated Prolonged Jaundice

83.10.1.1 1. Breast Milk Jaundice

• Continue breastfeeding; it is benign.
• If bilirubin is significantly elevated (>250 µmol/L), a temporary 24-hour interruption with formula may cause rapid decline.
• No need for phototherapy unless bilirubin levels approach treatment thresholds.

83.10.1.2 2. Breastfeeding/Lactation Failure Jaundice

• Encourage frequent and effective breastfeeding (8–12 times/day).
• Manage dehydration if present.

83.10.1.3 3. Haemolytic Causes

• Manage underlying haemolysis:
  • Exchange transfusion if bilirubin at neurotoxic levels.
  • Avoid oxidative drugs in G6PD deficiency.

83.10.1.4 4. Hypothyroidism

• Treat with levothyroxine once confirmed.

83.10.1.5 5. Crigler–Najjar Syndrome

• Type I: lifelong phototherapy, liver transplantation may be curative.
• Type II: responds to phenobarbital.

83.10.2 C. Management of Conjugated (Cholestatic) Jaundice

83.10.2.1 1. Biliary Atresia

• Early diagnosis is critical (surgery before 8 weeks improves prognosis).
• Kasai portoenterostomy is the initial procedure.
• Postoperative management includes antibiotics, fat-soluble vitamins (A, D, E, K), and nutritional support.

83.10.2.2 2. Neonatal Hepatitis

• Supportive therapy with adequate nutrition, vitamin supplementation, and management of complications.
• Antiviral therapy if specific infection identified.

83.10.2.3 3. Metabolic Disorders

• Galactosaemia: eliminate galactose from the diet immediately.
• Tyrosinaemia: low tyrosine and phenylalanine diet, nitisinone therapy.
• α1-Antitrypsin deficiency: supportive care; avoid hepatotoxic drugs.

83.10.2.4 4. Endocrine Disorders

• Replacement therapy for hypothyroidism or hypopituitarism.

83.10.3 5. Parenteral Nutrition–Associated Cholestasis

• Reduce or discontinue parenteral nutrition; promote enteral feeding.
• Use ursodeoxycholic acid to improve bile flow.

83.10.3.1 6. Symptomatic Management

• Fat-soluble vitamins: due to malabsorption in cholestasis.
• Medium-chain triglyceride (MCT)-based feeds: improve calorie intake.
• Pruritus relief: cholestyramine, ursodeoxycholic acid.

83.11 Complications

• Kernicterus (bilirubin encephalopathy): from severe unconjugated hyperbilirubinaemia.
• Malnutrition: from fat malabsorption in cholestasis.
• Coagulopathy: due to vitamin K deficiency.
• Liver failure: in progressive hepatobiliary disease.
• Portal hypertension and cirrhosis: in biliary atresia and chronic hepatitis.

83.12 Prognosis

• Unconjugated causes (breast milk jaundice, mild haemolysis) have excellent prognosis with supportive care.
• Biliary atresia: prognosis depends on early detection and successful surgery. Delayed intervention leads to cirrhosis and need for liver transplantation.
• Metabolic and genetic disorders: outcome depends on prompt diagnosis and disease-specific therapy.

83.13 Prevention

• Promote exclusive breastfeeding and early postnatal follow-up.
• Routine newborn screening for G6PD deficiency and congenital hypothyroidism.
• Early recognition of pale stools and dark urine by caregivers.
• Prompt referral of any infant jaundiced beyond 2 weeks for evaluation.

83.14 Approach Summary for Prolonged Jaundice

1. Assess duration and severity.
2. Fractionate bilirubin.
3. Conjugated > 20% or >34 µmol/L → evaluate for cholestasis.
4. Check stool colour and urine colour.
5. Investigate systematically (haemolysis, thyroid, infection, metabolic, anatomical).
6. Manage cause-specific and provide supportive care.
7. Refer early for suspected biliary atresia.

83.15 Key Takeaways

• Any infant jaundiced beyond 2 weeks must be evaluated for pathological causes.
• Always determine if the bilirubin is conjugated or unconjugated.
• Conjugated hyperbilirubinaemia is never physiological.
• Early diagnosis of biliary atresia (<8 weeks) markedly improves outcomes.
• Supportive care (nutrition, vitamins, prevention of complications) is crucial.

83.16 Suggested References

1. World Health Organization. Pocket Book of Hospital Care for Children, 3rd Edition, 2023.
2. Ghana Health Service. Standard Treatment Guidelines, 2022.
3. Balistreri WF, Bezerra JA. Neonatal cholestasis. J Pediatr. 2021;229:8–17.
4. Fawaz R et al. Guideline for the evaluation of cholestatic jaundice in infants. J Pediatr Gastroenterol Nutr. 2017;64(1):154–168.
5. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants. J Pediatr Gastroenterol Nutr. 2004;39(2):115–128.