What are the causes of hepatomegaly in neonates?

Causes of Hepatomegaly in Neonates

Neonatal hepatomegaly has a broad differential diagnosis that includes metabolic disorders, infections, cardiac causes, hematologic conditions, storage diseases, and structural abnormalities, with the most critical being those requiring immediate intervention to prevent mortality such as sepsis, congenital heart failure, and biliary atresia. 1

Life-Threatening Causes Requiring Immediate Recognition

Cardiac Causes

• Congestive heart failure from structural heart disease (particularly ductal-dependent lesions) presents with hepatomegaly, and any neonate with shock and hepatomegaly should be started on prostaglandin infusion until complex congenital heart disease is ruled out by echocardiography 2
• Hepatic arteriovenous malformations can present with isolated massive hepatomegaly and lead to high-output cardiac failure if undiagnosed 3
• Diffuse hepatic infantile hemangiomas cause severe hepatomegaly before 4 months of age and can lead to abdominal compartment syndrome, compromised ventilation, renal failure, or high-output cardiac failure 2

Infectious Causes

• Neonatal sepsis presents with hepatomegaly alongside tachycardia, respiratory distress, poor feeding, poor tone, and reduced perfusion, particularly with maternal chorioamnionitis or prolonged rupture of membranes 2
• Perinatal infections including hepatitis B virus, hepatitis C virus, and HIV cause hepatocellular cholestasis in the first weeks of life 4

Metabolic Emergencies

• Inborn errors of metabolism resulting in hyperammonemia or hypoglycemia can simulate septic shock and present with hepatomegaly 2
• Galactosemia should be identified through newborn screening as it requires immediate dietary intervention 2

Metabolic and Storage Disorders

Glycogen Storage Diseases

• GSD Type III presents with hypoglycemia and hepatomegaly in children, with elevated transaminases (often >500 IU/L) and elevated CK levels 2
• Pompe disease (GSD Type II) can rarely cause severe infantile cardiomyopathy with hepatomegaly from cardiac failure, distinguished by absence of hypoglycemia 2
• Phosphorylase kinase deficiency (PRKAG2 gene mutations) presents with severe infantile hypertrophic cardiomyopathy 2

Other Storage Diseases

• Gaucher disease and Niemann-Pick disease present with hepatomegaly but are distinguished by massive splenomegaly and absence of hypoglycemia 2
• Lysosomal storage diseases account for 5.2% of all nonimmune hydrops fetalis cases and 29.6% of idiopathic cases, often presenting with hepatomegaly 2

Cholestatic Disorders

• Neonatal cholestasis (incidence 1 in 2,500 live births) is genetic/metabolic in 25-30% of cases and includes conditions like progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, and alpha-1 antitrypsin deficiency 2
• Biliary atresia requires differentiation from metabolic cholestasis through hepatobiliary scintigraphy and must be identified early for Kasai portoenterostomy 4
• Citrin deficiency (SLC25A13 mutations) causes neonatal intrahepatic cholestasis 2

Nutritional Causes

Protein-Energy Malnutrition

• Kwashiorkor causes hepatomegaly due to fatty infiltration of the liver, presenting with edema, growth failure, and poor feeding 5, 6
• Infants typically show weight significantly below expected for age with inadequate protein and calorie intake 5

Hematologic and Oncologic Causes

Tumors and Vascular Lesions

• Hepatic hemangiomas in infants with ≥5 cutaneous hemangiomas require screening ultrasonography, as multifocal or diffuse hepatic lesions can cause macrovascular shunting and high-output failure 2
• Hepatoblastoma risk is increased in overgrowth syndromes including Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, and Perlman syndrome 2

Hydrops Fetalis

• Nonimmune hydrops fetalis associated with hepatomegaly can result from cardiac failure, hepatic cirrhosis, hepatic necrosis, cholestasis, polycystic liver disease, or hepatic hemangiomas causing arteriovenous shunting 2

Syndromic Associations

• Mulibrey nanism includes hepatomegaly as part of the constellation with growth retardation, constrictive pericarditis, and metabolic deficiencies 2
• Perlman syndrome presents with macrosomia, renal dysplasia, nephroblastomatosis, and hepatomegaly 2
• Simpson-Golabi-Behmel syndrome (GPC3/GPC4 mutations) includes hepatomegaly with macrosomia, distinctive craniofacial features, and increased tumor risk 2

Diagnostic Approach

Initial Evaluation for Hepatomegaly with Hypoglycemia

When hepatomegaly coexists with hypoglycemia, obtain: 2

• Blood glucose, lactate, uric acid
• Hepatic profile including liver function studies
• CK, plasma total and free carnitine, acylcarnitine profile
• Urinalysis and urine organic acids
• Review newborn screening results for fatty acid oxidation disorders and galactosemia

Key Distinguishing Features

• Beta-hydroxybutyrate elevation at time of hypoglycemia distinguishes GSD from fatty acid oxidation disorders (which show hypoketosis) and hyperinsulinism 2
• Massive splenomegaly with hepatomegaly suggests Gaucher or Niemann-Pick disease rather than GSD 2
• Cyanosis, cardiac murmur, or differential upper/lower extremity blood pressures mandate echocardiography and prostaglandin infusion to rule out ductal-dependent congenital heart disease 2

Imaging

• Abdominal ultrasound assesses liver size, texture, and focal lesions 7
• Hepatobiliary scintigraphy differentiates biliary atresia from intrahepatic cholestasis 2
• Echocardiography is mandatory to exclude structural heart disease and assess for cardiomyopathy 2

Common Pitfalls

• Failure to distinguish cardiac from metabolic causes can delay life-saving prostaglandin therapy in ductal-dependent lesions 2
• Missing biliary atresia by not recognizing acholic stools and conjugated hyperbilirubinemia delays surgical intervention 2, 4
• Overlooking hepatic hemangiomas in infants with multiple cutaneous hemangiomas misses opportunity for early treatment before cardiac decompensation 2
• Assuming all hepatomegaly with hypoglycemia is GSD without checking beta-hydroxybutyrate can miss fatty acid oxidation disorders requiring completely different management 2