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