Persistent hypertransaminasemia in asymptomatic children: A stepwise approach

Table 1 Main causes of asymptomatic hypertransaminasemia in children

Hepatic origin	Extrahepatic origin
Obesity (non-alcoholic fatty liver disease)	Duchenne/Becker muscular dystrophy (prevalence: 1:4700)
Viral infections (major and minor hepatotropic viruses)	Other myopathies (e.g., caveolinopathies; prevalence: 1:14000 to 1:120000)
Autoimmune liver disease	Myocardiopathies
(prevalence: 1:200000)
Celiac disease and inflammatory bowel disease	Nephropathies
Wilson’s disease (prevalence: 1:30000)	Hemolytic disorders
Cystic fibrosis (prevalence: 1:2500) and Shwachman-Diamond syndrome (prevalence: 1:50000)	Macro - AST (prevalence: 30% of children with isolated aspartate aminotransferasemia)
Alpha1 antitrypsin deficiency (prevalence: 1:7000)
Other genetic and metabolic diseases1
Toxic: Drugs and alcohol
Cryptogenic hypertransaminasemia

¹Refer to Table 3. AST: Aspartate aminotransferase.

Table 2 Retesting panel; first, second, and third line investigations in children with asymptomatic mild hypertransaminasemia

Retesting panel1	First line panel		Second and third line panels
	Liver function tests	Etiology tests
ALT AST CPK GGT	Conjugated and unconjugated bilirubin Protein electrophoresis Serum albumin Prothrombin time and partial thromboplastin time Blood cell count Hepatic ultrasonography If only AST elevation is confirmed: PEG test and electrophoresis for macro-AST	Viral markers (HAV, HBV, HCV) Minor hepatotropic viruses serology (e.g., EBV, CMV) Ceruloplasmin, serum copper ANA, SMA, LKM, LC1, anti-SLA, total IgG Serum α1 antitrypsin EMA, tTgasi IgA, deamidated AGA IgA (< 2 yr), total IgA	Urinary copper, molecular ATP B7 analysis HCV RNA, HBV DNA Genetic and metabolic enlarged screening2 (“non-alcoholic fatty liver disease bin”) Sweat test Fecal elastase, steatocrit Other hepatic imaging techniques (MRI, ERCP, CT, etc.) Liver biopsy3 Jejunal biopsy (after celiac disease serology)

¹After at least one week off from exercise;

²Genetic and metabolic enlarged screening: blood gases, lactic acid, serum ammonium concentrations, blood and urinary amino acids, urinary reducing substances, urinary organic acids, transferrin isoforms, screening test for congenital disorders of glycosylation, α1 anti-trypsin phenotype;

³Modified from the reference of 28. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; PEG: Polyethylene glycol; CPK: Creatine kinase; GGT: Gamma-glutamyl transferase; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; EBV: Epstein-Barr virus; CMV: Cytomegalovirus; ANA: Antinuclear antibodies; SMA: Smooth muscle antibodies; LKM: Anti-microsomal antibodies; LC1: Anti-liver cytosol antibodies type 1; SLA: Soluble liver antigen; IgG: Immunoglobulin G; EMA: Anti-endomysial antibodies; tTgasi: Anti-tissue transglutaminase antibodies; AGA: Anti-gliadin antibodies; IgA: Immunoglobulin A; ATP B7: ATP binding protein 7; MRI: Magnetic resonance imaging; ERCP: Endoscopic retrograde cholangiopancreatography; CT: Computed tomography.

Table 3 Fatty liver disease; possible causes in likely asymptomatic children and adolescents

General or systemic	Genetic-metabolic causes	Drugs/chemicals
Obesity	Cystic fibrosis	Ethanol
Metabolic syndrome	Shwachman syndrome	Ecstasy, cocaine, solvents
Obstructive sleep apnea	Wilson’s disease	Nifedipine
Polycystic ovary syndrome	Alpha 1-antitrypsin deficiency	Diltiazem
Diabetes mellitus type 1	Fructosemia	Estrogens
Thyroid disorders	Cholesterol ester storage disease	Corticosteroids
Hypothalamic-pituitary disorders	Glycogen storage disease (type I, VI and IX)	Methotrexate
Inflammatory bowel disease	Mitochondrial and peroxisomal defects	Prednisolone
Celiac disease	α- and β-oxidation defects	Valproate
Protein calorie malnutrition	Organic acidosis	Vitamin
Rapid weight loss	Abeta or hypobetalipoproteinemia	Zidovudine and HIV treatments
Anorexia nervosa	Porphyria cutanea tarda	Solvents
Small intestinal bacterial overgrowth	Homocystinuria	Pesticides
Hepatitis C	Familial hyperlipoproteinemias
	Bile acids synthesis defects
	Congenital disorders of glycosylation
	Citrin deficiency
	Turner syndrome

Modified from the references of 30 and 38. HIV: Human immunodeficiency virus.

Table 4 Clinical and laboratory findings for orienting diagnosis of some genetic metabolic liver diseases

Clinical/laboratory findings	Possible genetic-metabolic cause	Prevalence	Liver involvement
Pancreatic failure, hematological disorders	Shwachman syndrome	1:50000	+++1
Asymptomatic, hemolysis	Wilson’s disease	1:30000	+++
Previous neonatal cholestasis, hepatomegaly	Alpha 1 antitrypsin deficiency	1:7000	+++
Hypoglycemia, hepatomegaly	Glycogen storage disease (type I, VI and IX)	From 1:100000 to 1:1000000	+++
Fructose refusal, hepatomegaly	Hereditary fructose intolerance	1:20000	+++
Lethargy, increased serum ammonia levels	Urea cycle defects	1:30000 (all disorders)	++
Lethargy, increased serum ammonia levels	Urea cycle defects	1:30000 (all disorders)	++
Chubby face, fatty liver, specific serum amino acids pattern	Citrin deficiency	1:20000 in East Asia	++
Failure to thrive, lactic acidosis	Mitochondrial diseases	1:8500 (all disorders)	+
Failure to thrive, ketoacidosis, hypoglycemia	Organic acidosis	1:1000 (all disorders)	+
Mild coagulopathy, clinical phenotype	Congenital disorders of glycosylation	From 1:10000 to 1:100000	+
Short stature, female gender, karyotype	Turner syndrome	1:2000	+
Failure to thrive, positive sweat test	Cystic fibrosis	1:2500	+

¹First 1-2 yr of life; +: Possible; ++: Frequent; +++: Almost always.