What are the differential diagnoses for a 1-year-old child presenting with fever and significantly elevated liver enzymes (aspartate aminotransferase (AST) of 1700 and alanine aminotransferase (ALT) of 1178)?

Differential Diagnoses for a 1-Year-Old Child with Fever and Markedly Elevated Transaminases

In a 1-year-old child presenting with fever, AST 1700 IU/L, and ALT 1178 IU/L, the primary differential diagnoses include acute viral hepatitis (particularly hepatitis A, B, or E), acute necrotizing encephalopathy associated with influenza, autoimmune hepatitis, neonatal hemochromatosis, alpha-1 antitrypsin deficiency, and medication/toxin-induced liver injury.

Severity Classification and Clinical Significance

These transaminase elevations represent severe hepatocellular injury (>10× upper limit of normal), indicating massive hepatocyte necrosis that requires urgent evaluation and potential hepatology referral. 1

• Using pediatric reference ranges, ALT >125 IU/L (5× ULN for females) or >165 IU/L (5× ULN for males) represents moderate elevation, while >250 IU/L represents severe elevation 1
• This child's values exceed 40-50× the upper limit of normal, indicating acute and severe hepatocellular damage 1
• The AST:ALT ratio of 1.44 suggests hepatocellular injury rather than alcoholic liver disease (which would show AST:ALT >2) 2

Primary Infectious Differential Diagnoses

Acute Viral Hepatitis

Viral hepatitis (hepatitis A, B, C, D, or E) commonly presents with ALT elevations >400 IU/L and fever in children, making this the most likely diagnosis. 1

• Hepatitis B surface antigen (HBsAg), hepatitis B core IgM antibody (anti-HBc IgM), and hepatitis C antibody (anti-HCV) should be tested immediately 1
• Hepatitis A IgM and hepatitis E IgM should be included in the initial workup 1
• Acute viral hepatitis typically shows higher ALT than AST elevations, consistent with this presentation 1

Influenza-Associated Acute Necrotizing Encephalopathy

Acute necrotizing encephalopathy occurs mainly in children aged 1-5 years with influenza, characterized by high fever, convulsions, and raised liver transaminases in some patients. 3

• The onset is typically 2-4 days after respiratory symptoms, with fewer than 10% of patients surviving 3
• Symmetrical multifocal brain lesions with bilateral thalamic involvement are characteristic on MRI 3
• Neurological symptoms including lethargy, extreme irritability, seizures, or altered consciousness should prompt consideration of this diagnosis 3

Reye's Syndrome

Reye's syndrome presents with protracted vomiting, encephalopathy, and hepatic dysfunction with more than threefold increase in ALT and AST, typically 24-48 hours after viral illness onset. 3

• This diagnosis requires acute non-inflammatory encephalopathy with altered consciousness, elevation of ammonia levels, and hepatomegaly in 50% of patients 3
• Minimal or absent jaundice is characteristic, distinguishing it from other causes of acute liver failure 3
• Aspirin exposure history is critical, as there is a clear association with aspirin therapy during viral illness 3
• Mortality has fallen from 50% to less than 20% with earlier diagnosis and aggressive therapy 3

Metabolic and Genetic Causes

Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency accounts for 7-18% of neonatal cholestasis cases (excluding biliary atresia) and can present with elevated transaminases and fever in infancy. 3

• Liver dysfunction is often first noted at 1-2 months of life with prolonged jaundice or hepatomegaly, though presentation can occur throughout the first year 3
• Laboratory analysis reveals moderately elevated conjugated bilirubin levels and elevated serum transaminase activity 3
• Alpha-1 antitrypsin phenotyping by isoelectric focusing should be performed in all infants with conjugated hyperbilirubinemia and elevated transaminases 4
• Fulminant hepatic failure in infancy is rare but has been described 3

Neonatal Hemochromatosis

Neonatal hemochromatosis is the leading cause of acute liver failure requiring transplantation in neonates, with infants typically presenting within the first few days to months of life with severe hepatic injury. 4

• This diagnosis should be considered in any infant with acute liver failure and markedly elevated transaminases 4
• Iron studies and assessment for extrahepatic siderosis are diagnostic 4

Autoimmune and Inflammatory Causes

Autoimmune Hepatitis

Autoimmune hepatitis can present with acute liver failure in children, characterized by markedly elevated transaminases (typically >5× ULN), fever, and acute submassive hepatocyte necrosis with brisk T lymphocyte infiltration. 5

• Type 2 autoimmune hepatitis has been reported in children as young as 3 years old presenting with acute liver failure 5
• Autoimmune markers including antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin G levels should be evaluated 1
• Liver biopsy may show acute submassive hepatocyte necrosis with CD3+ T lymphocyte infiltration 5
• Treatment with high-dose methylprednisolone can result in rapid normalization of transaminases and avoid liver transplantation 5

Medication and Toxin-Induced Liver Injury

Medication-induced liver injury should be considered in any child with markedly elevated transaminases, requiring thorough review of all medications, over-the-counter drugs, and herbal supplements. 1, 2

• All medications should be checked against the LiverTox® database for hepatotoxic potential 1
• Acetaminophen toxicity is a common cause of acute liver failure in children and requires immediate assessment of acetaminophen levels 6
• Discontinuation of suspected hepatotoxic medications is essential, with expected normalization within 2-8 weeks if medication-induced 1

Critical Immediate Evaluation Required

Laboratory Assessment

Immediate laboratory evaluation must include fractionated bilirubin, complete blood count, comprehensive metabolic panel, prothrombin time/INR, and ammonia level to assess synthetic function and risk of acute liver failure. 4

• Normal albumin, bilirubin, and INR indicate preserved liver synthetic function, suggesting no immediate acute liver failure 1
• Elevated bilirubin >2× ULN or INR elevation indicates hepatic synthetic dysfunction requiring urgent hepatology referral 1
• Ammonia elevation suggests risk of hepatic encephalopathy and requires urgent intervention 3

Urgent Hepatology Referral Criteria

Urgent referral to a pediatric hepatologist or liver transplant center is mandatory if ALT >5× ULN with bilirubin >2× ULN, evidence of synthetic dysfunction (elevated INR, low albumin), or any signs of hepatic encephalopathy. 1, 4

• Children with acute liver failure or acute decompensation require immediate evaluation at a pediatric liver transplant center 4
• Timely referral is paramount to avoid missing progressive but treatable liver disease 7

Additional Diagnostic Considerations

Extrahepatic Causes

Creatine kinase should be measured to exclude muscle injury as a source of transaminase elevation, particularly if the child has engaged in unusual physical activity or has muscle symptoms. 1, 2

• AST is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it less specific for liver injury 1
• Muscle disorders including rhabdomyolysis can elevate AST more than ALT 2

Imaging Evaluation

Abdominal ultrasound should be performed urgently to assess for biliary obstruction, focal liver lesions, hepatomegaly, and structural abnormalities. 1, 2

• Ultrasound has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 1, 2
• Biliary dilation or focal lesions require more urgent intervention 1

Common Pitfalls to Avoid

• Do not assume elevated transaminases are benign in a febrile child—this level of elevation indicates severe hepatocellular injury requiring urgent evaluation 1
• Do not overlook neurological symptoms—lethargy, irritability, seizures, or altered consciousness may indicate acute necrotizing encephalopathy or Reye's syndrome requiring immediate intervention 3
• Do not delay hepatology referral—children with ALT >1000 IU/L and fever require urgent specialist evaluation to avoid missing treatable causes of acute liver failure 4, 7
• Do not forget to assess synthetic function—bilirubin, INR, albumin, and ammonia levels are critical for determining severity and need for urgent transplant evaluation 4