Pediatric Hepatitis: Comprehensive Differential Diagnosis Guide
1. Infectious Causes
Viral Hepatitis A
- Key diagnostic points:
- Positive IgM Anti-HAV
- History of contaminated food/water exposure
- Acute onset with prodromal symptoms
- Peak ALT > AST typically
- Self-limiting course
Viral Hepatitis B
- Key diagnostic points:
- HBsAg positive
- IgM Anti-HBc for acute infection
- HBV DNA levels
- Consider perinatal transmission
- Risk of chronicity age-dependent (90% in neonates, 5-10% in older children)
Viral Hepatitis C
- Key diagnostic points:
- Anti-HCV positive
- HCV RNA for confirmation
- Often asymptomatic in children
- Consider maternal transmission
- Genotype testing guides treatment
Viral Hepatitis E
- Key diagnostic points:
- IgM Anti-HEV
- Travel history to endemic areas
- More severe in pregnant adolescents
- Usually self-limiting
- PCR for confirmation
Epstein-Barr Virus (EBV)
- Key diagnostic points:
- Positive Monospot test
- EBV VCA IgM
- Lymphocytosis with atypical lymphocytes
- Splenomegaly common
- Associated lymphadenopathy
Cytomegalovirus (CMV)
- Key diagnostic points:
- CMV IgM and PCR
- Consider in immunocompromised
- Congenital infection pattern
- Associated thrombocytopenia
- May see chorioretinitis
Adenovirus
- Key diagnostic points:
- PCR detection
- Associated respiratory/GI symptoms
- More severe in immunocompromised
- Often self-limiting in immunocompetent
- May see conjunctivitis
Herpes Simplex Virus (HSV)
- Key diagnostic points:
- PCR for HSV DNA
- High mortality in neonates
- Often associated with skin lesions
- Marked coagulopathy
- Very high aminotransferases (>1000)
- Consider in first 30 days of life
Varicella Zoster Virus (VZV)
- Key diagnostic points:
- VZV PCR positive
- Characteristic skin lesions
- More severe in immunocompromised
- Elevated transaminases usually mild
- Consider in post-transplant patients
- May see concurrent pneumonitis
Parvovirus B19
- Key diagnostic points:
- PCR for B19 DNA
- IgM antibodies
- Associated aplastic crisis in hemolytic anemias
- Characteristic "slapped cheek" rash
- Arthritis may be present
- Severe in immunocompromised
Enterovirus
- Key diagnostic points:
- PCR from stool/CSF
- Summer/fall seasonality
- Often associated myocarditis
- Hand-foot-mouth disease association
- Severe in neonates
- CSF pleocytosis common
Human Immunodeficiency Virus (HIV)
- Key diagnostic points:
- HIV PCR in infants
- HIV antibodies in older children
- CD4 count decrease
- Consider opportunistic infections
- May have IRIS after HAART
- Check maternal status
Toxoplasma gondii
- Key diagnostic points:
- IgM and IgG antibodies
- PCR in congenital cases
- Consider in immunocompromised
- Associated chorioretinitis
- Brain calcifications in congenital
- May see hydrocephalus
Listeria monocytogenes
- Key diagnostic points:
- Blood culture positive
- Consider in neonates
- Associated meningitis
- Maternal fever history
- Gram-positive rods in CSF
- May have granulomas on biopsy
Leptospirosis
- Key diagnostic points:
- MAT test positive
- IgM antibodies
- Exposure history key
- Conjunctival suffusion
- Associated renal failure
- Biphasic illness pattern
Dengue Virus
- Key diagnostic points:
- NS1 antigen early
- IgM/IgG antibodies
- Travel history to endemic areas
- Thrombocytopenia marked
- Warning signs for severe dengue
- Hepatomegaly common
Yellow Fever Virus
- Key diagnostic points:
- PCR in early phase
- IgM antibodies
- Travel to endemic areas
- Vaccination status
- Jaundice with fever
- Marked coagulopathy
Crimean-Congo Hemorrhagic Fever
- Key diagnostic points:
- PCR detection
- IgM antibodies
- Tick exposure history
- Severe thrombocytopenia
- DIC common
- Geographic distribution key
Echovirus
- Key diagnostic points:
- PCR from stool/CSF
- More common in summer
- Neonates at high risk
- Associated meningitis
- May see rash
- Outbreak history important
2. Autoimmune Causes
Autoimmune Hepatitis Type 1
- Key diagnostic points:
- ANA and/or SMA positive
- Elevated IgG levels
- Female predominance
- Associated autoimmune conditions
- Liver biopsy: interface hepatitis
Autoimmune Hepatitis Type 2
- Key diagnostic points:
- Anti-LKM1 and/or Anti-LC1 positive
- Often younger presentation
- More severe course than Type 1
- May have associated autoimmune polyendocrinopathy
- Higher risk of fulminant presentation
IgG4-Related Hepatobiliary Disease
- Key diagnostic points:
- Elevated serum IgG4 (>135 mg/dL)
- IgG4+ plasma cells on biopsy
- Storiform fibrosis pattern
- Often multi-organ involvement
- Associated autoimmune pancreatitis
- Biliary strictures common
- Excellent steroid response
- Risk of relapse high
Primary Sclerosing Cholangitis-AIH Overlap
- Key diagnostic points:
- Elevated transaminases and GGT
- Positive ANA/ASMA
- Cholangiographic changes
- IgG typically elevated
- Interface hepatitis on biopsy
- Often IBD association
- Poor prognosis overall
- Paris criteria diagnostic
APECED Syndrome
- Key diagnostic points:
- AIRE gene mutation
- Addison's disease
- Hypoparathyroidism
- Chronic mucocutaneous candidiasis
- Anti-liver kidney microsomal type-1
- Multiple autoimmune manifestations
- Ectodermal dystrophy
- Interferon-ω autoantibodies
IPEX Syndrome
- Key diagnostic points:
- FOXP3 gene mutation
- Early-onset diabetes
- Enteropathy severe
- Eczematous dermatitis
- Multiple autoantibodies
- Reduced T-regulatory cells
- Male predominance
- Often fatal without HSCT
3. Metabolic/Genetic Causes
Wilson Disease
- Key diagnostic points:
- Low ceruloplasmin
- Elevated 24-hour urinary copper
- Kayser-Fleischer rings
- ATP7B gene mutation
- AST:ALT ratio > 2.2 suggestive
Alpha-1 Antitrypsin Deficiency
- Key diagnostic points:
- Low serum A1AT levels
- Pi typing (ZZ most severe)
- Associated lung disease
- Genetic testing confirms
- Liver biopsy: PAS-positive globules
Galactosemia
- Key diagnostic points:
- Positive newborn screen
- GALT enzyme activity
- Elevated galactose-1-phosphate
- Presents in newborn period
- E. coli sepsis common
Tyrosinemia Type 1
- Key diagnostic points:
- Elevated succinylacetone in urine
- Elevated alpha-fetoprotein
- Elevated methionine
- Rickets may be present
- Characteristic cabbage-like odor
- Renal tubular dysfunction
- High risk of hepatocellular carcinoma
Hereditary Fructose Intolerance
- Key diagnostic points:
- Symptoms after fructose exposure
- Hypoglycemia after fructose
- ALDOB gene mutation
- Food aversion characteristic
- Improvement with fructose elimination
- Associated proximal tubular dysfunction
- Liver biopsy: steatosis + fibrosis
Glycogen Storage Disease Type 1
- Key diagnostic points:
- Fasting hypoglycemia
- Lactic acidosis
- Hepatomegaly from birth
- "Doll-like" facies
- Growth failure characteristic
- Elevated uric acid
- No ketones during hypoglycemia
Mitochondrial Hepatopathies
- Key diagnostic points:
- Elevated lactate/pyruvate ratio
- Multi-organ involvement
- Muscle weakness common
- Developmental delay
- Respiratory chain enzyme defects
- MRI brain changes
- Muscle biopsy: ragged red fibers
Niemann-Pick Disease Type C
- Key diagnostic points:
- Vertical supranuclear gaze palsy
- Filipin staining positive
- NPC1/NPC2 gene mutation
- Neonatal cholestasis
- Progressive neurological deterioration
- Foam cells in bone marrow
- Splenomegaly prominent
Alagille Syndrome
- Key diagnostic points:
- JAG1/NOTCH2 mutation
- Bile duct paucity
- Characteristic facies
- Butterfly vertebrae
- Pulmonary stenosis
- Posterior embryotoxon
- Growth failure common
- Variable expressivity
ALGS2 (NOTCH2-related)
- Key diagnostic points:
- NOTCH2 mutations
- Milder phenotype than JAG1
- Renal involvement common
- Cardiac defects variable
- Less typical facies
- Better prognosis
- Later onset possible
- Variable penetrance
MDR3 Deficiency
- Key diagnostic points:
- ABCB4 gene mutation
- High GGT cholestasis
- Early gallstone disease
- Maternal history of ICP
- Progressive liver disease
- Low phospholipids in bile
- Variable age of onset
- Response to UDCA variable
ARC Syndrome
- Key diagnostic points:
- VPS33B/VIPAR mutation
- Arthrogryposis
- Renal tubular dysfunction
- Cholestasis
- Ichthyosis common
- Platelet alpha-granule defect
- Severe failure to thrive
- Poor prognosis
Citrin Deficiency
- Key diagnostic points:
- SLC25A13 mutation
- Citrullinemia type 2
- Neonatal cholestasis
- High protein preference
- Growth failure
- Fatty liver common
- Variable presentation
- Diet modification helps
MEGDEL Syndrome
- Key diagnostic points:
- SERAC1 mutation
- 3-Methylglutaconic aciduria
- Deafness
- Encephalopathy
- Leigh-like syndrome
- Elevated lactate
- Progressive course
- MRI shows basal ganglia changes
Zellweger Syndrome
- Key diagnostic points:
- PEX gene mutations
- Very long chain fatty acids elevated
- Characteristic facies
- Hypotonia severe
- Absent peroxisomes
- Brain migration defects
- Retinal abnormalities
- Early death common
Mevalonate Kinase Deficiency
- Key diagnostic points:
- MVK gene mutation
- Periodic fever syndrome
- Elevated IgD levels
- Lymphadenopathy
- Abdominal pain attacks
- Elevated urinary mevalonate
- Rash during attacks
- Response to IL-1 blockade
DGUOK Deficiency
- Key diagnostic points:
- DGUOK gene mutation
- mtDNA depletion
- Nystagmus common
- Hypotonia
- Progressive liver failure
- Elevated tyrosine
- Neurological progression
- Poor prognosis overall
Citrin Deficiency
- Key diagnostic points:
- Elevated citrulline
- Characteristic food preference
- Growth failure
- SLC25A13 gene mutations
- Higher prevalence in East Asians
- Fatty liver on imaging
- Protein aversion typical
- May present as NICCD in infants
Wolman Disease
- Key diagnostic points:
- LIPA enzyme deficiency
- Adrenal calcifications
- Severe malabsorption
- Presentation <6 months
- Massive hepatosplenomegaly
- Foam cells in biopsy
- Failure to thrive marked
- Very poor prognosis without treatment
Congenital Disorders of Glycosylation
- Key diagnostic points:
- Abnormal transferrin isoforms
- Inverted nipples common
- Cerebellar involvement
- Multisystem involvement
- Failure to thrive
- Characteristic fat pads
- Coagulopathy common
- Genetic testing confirms type
NBAS Deficiency
- Key diagnostic points:
- Recurrent acute liver failure
- Fever triggers episodes
- Short stature common
- Ophthalmoplegia may occur
- Skeletal abnormalities
- NBAS gene mutation
- Better prognosis than LARS
- Prevention of fever important
Gaucher Disease
- Key diagnostic points:
- Low glucocerebrosidase
- Hepatosplenomegaly marked
- Bone involvement common
- Chitotriosidase elevated
- CCL18 elevated
- Gaucher cells in marrow
- Type 1 most common
- Neurological in type 2/3
4. Toxic Causes
Drug-Induced Liver Injury
- Key diagnostic points:
- Detailed medication history
- Temporal relationship to drug
- R-factor calculation
- Exclusion of other causes
- Consider genetic susceptibility
Acetaminophen Toxicity
- Key diagnostic points:
- History of ingestion
- Elevated acetaminophen levels
- AST > ALT typically
- Rumack-Matthew nomogram
- Associated coagulopathy
Isoniazid Hepatotoxicity
- Key diagnostic points:
- Usually within 3 months
- Slow acetylator risk
- May be asymptomatic
- ALT >3x ULN significant
- Risk with other hepatotoxins
- Requires prompt discontinuation
- Consider NAC in severe cases
Valproic Acid Hepatotoxicity
- Key diagnostic points:
- Higher risk in <2 years
- Hyperammonemia common
- Microvesicular steatosis
- Risk with polytherapy
- Mitochondrial toxicity
- Carnitine deficiency may occur
- Screen for POLG mutations
Mushroom Poisoning (Amanita)
- Key diagnostic points:
- Delayed onset >6 hours
- Early GI symptoms
- Amatoxin in urine
- Rapid ALT elevation
- Three-phase illness
- Coagulopathy late
- History of foraging key
- Family cluster common
Chinese Herb Nephropathy
- Key diagnostic points:
- History of herb use
- Aristolochic acid exposure
- Progressive renal failure
- Urothelial atypia
- DNA adducts present
- Interstitial fibrosis
- Cancer risk increased
- Slow progression typical
Methotrexate Toxicity
- Key diagnostic points:
- Cumulative dose effect
- Risk with renal dysfunction
- Mucositis common
- Pancytopenia may occur
- Folate deficiency risk
- Elevated methotrexate level
- Fibrosis on long-term
- Monitor PDGFR-β levels
Systemic Diseases
Hemophagocytic Lymphohistiocytosis (HLH)
- Key diagnostic points:
- Fever >7 days
- Ferritin >10,000 ng/mL
- Cytopenias in ≥2 lines
- Low NK cell activity
- High soluble CD25
- Triglycerides >265 mg/dL
- Hemophagocytes in tissue
Langerhans Cell Histiocytosis
- Key diagnostic points:
- CD1a positive cells
- Sclerosing cholangitis pattern
- Skin/bone involvement common
- Diabetes insipidus may occur
- Characteristic skull lesions
- S100 protein positive
- Risk of biliary cirrhosis
Systemic Juvenile Idiopathic Arthritis
- Key diagnostic points:
- Quotidian fever pattern
- Evanescent rash
- Arthritis
- Very high ferritin
- Risk of macrophage activation
- Elevated IL-18 levels
- Neutrophilic leukocytosis
Chronic Granulomatous Disease
- Key diagnostic points:
- DHR test abnormal
- Recurrent infections
- Liver abscesses common
- Granulomas on biopsy
- Inflammatory bowel disease-like
- X-linked or AR inheritance
- Poor neutrophil oxidative burst
Cystic Fibrosis-Associated Liver Disease
- Key diagnostic points:
- CFTR mutation
- Elevated sweat chloride
- Focal biliary cirrhosis
- Multilobular cirrhosis late
- Portal hypertension common
- Associated steatosis
- Usually presents by age 10
DRESS Syndrome
- Key diagnostic points:
- Drug reaction with eosinophilia
- Systemic symptoms
- Delayed onset 2-6 weeks
- HHV-6 reactivation common
- Characteristic rash
- Lymphadenopathy
- Multiple organ involvement
- RegiSCAR criteria diagnostic
GALD (Gestational Alloimmune Liver Disease)
- Key diagnostic points:
- Presents in newborn period
- Very high ferritin
- C4d positive hepatocytes
- Extrahepatic siderosis
- High alpha-fetoprotein
- Maternal history key
- MRI shows iron deposition
- Previous pregnancy losses
PFIC Type 4 (TJP2 Deficiency)
- Key diagnostic points:
- Normal GGT cholestasis
- TJP2 gene mutation
- Early-onset gallstones
- Progressive liver failure
- Severe pruritus
- High serum bile acids
- Protein-losing enteropathy
- HCC risk increased
MARS Deficiency
- Key diagnostic points:
- Recurrent ALF episodes
- Intercrisis recovery
- MARS gene mutation
- Growth failure common
- Developmental delay
- Hypermethioninemia
- Brain white matter changes
- Triggers include infections
Vascular Causes
Budd-Chiari Syndrome
- Key diagnostic points:
- Hepatic vein thrombosis on imaging
- Ascites common
- Consider underlying thrombophilia
- Doppler ultrasound diagnostic
- May see caudate lobe hypertrophy
Veno-Occlusive Disease
- Key diagnostic points:
- History of HSCT/chemotherapy
- Weight gain/ascites
- Right upper quadrant pain
- Elevated bilirubin
- Doppler shows reduced portal flow
Mitochondrial Disorders
POLG-Related Disorders
- Key diagnostic points:
- POLG gene mutation
- Alpers-Huttenlocher syndrome
- Valproate sensitivity
- Seizures common
- Progressive liver failure
- Developmental regression
- mtDNA depletion
- Poor prognosis
MPV17-Related Disease
- Key diagnostic points:
- MPV17 gene mutation
- Hepatocerebral mtDNA depletion
- Early-onset liver failure
- Hypoglycemia
- Growth failure
- Neurological deterioration
- Lactic acidosis
- Variable presentation age
NBAS Deficiency
- Key diagnostic points:
- NBAS gene mutation
- Fever-triggered hepatitis
- Short stature
- Skeletal abnormalities
- Recurrent liver crises
- Optic atrophy possible
- Better prognosis than other MDs
- Fever prevention critical
Other Causes
Neonatal Hemochromatosis
- Key diagnostic points:
- Elevated ferritin and transferrin saturation
- MRI shows iron deposition
- Presents in newborn period
- Extrahepatic siderosis
- Consider gestational alloimmune mechanism
Progressive Familial Intrahepatic Cholestasis
- Key diagnostic points:
- Genetic testing (PFIC 1-3)
- Low/normal GGT in PFIC 1/2
- High GGT in PFIC 3
- Severe pruritus
- Specific bile acid patterns
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