Overall Bottom Line

The term LFTs is often misused to refer to serum chemistry tests.
Liver disease is evaluated by tests that detect liver injury, impaired bile flow or cholestasis, synthetic capacity, excretory function and metabolic function.
Interpretation of abnormalities of the specific tests in the context of pediatric liver disease is described.
Screening tests that need to be performed when abnormal aminotransferases are noted are described.
An algorithm suggesting an approach when a child presents with abnormal aminotransferases is presented.

Section 1: Tests that Evaluate Liver Injury (Algorithm 35.1)

Serum aminotransferases include ALT and AST.
LDH is a cytoplasmic enzyme present in many tissues including liver and therefore has limited specificity.
ALT (formerly SGPT) is primarily localized to liver and in the cytosol.
AST (formerly SGOT) is present in liver (mitochondria and cytosol), heart, skeletal muscle, kidney and brain.
The aminotransferases lack some sensitivity as values may be normal despite presence of inflammation on liver biopsy and also lack specificity as they may be elevated in non-hepatic conditions like myopathy and hypothyroidism.
The ULN for ALT varies widely and many use a value around 50 IU/L. More recently, a study using National Health and Nutrition Examination Survey data showed that the 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free, pediatric participants were 25.8 IU/L (boys) and 22.1 IU/L (girls), much lower than is used in clinical practice.
The most common cause of elevated aminotransferases in pediatric practice is NAFLD; BMI >85th percentile overweight, BMI >95th percentile obese.

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Algorithm 35.1 Diagnosis of abnormal transaminases in children

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Elevated ALT and AST commonly seen in children

AST and ALT >15 times normal

AST > ALT

ALT > AST

Screening laboratory tests for abnormal aminotransferases

CBC, INR.
BUN, creatinine, electrolytes, albumin, GGT, total and direct bilirubin.
Toxicology screen, glucose, ammonia (when ALT, AST >10 times normal).
Viral hepatitis: hepatitis A IgG and IgM, hepatitis B surface antigen and antibody, hepatitis C antibody.
Autoimmune hepatitis screen: immunoglobulin G, antinuclear antibody, smooth muscle antibody, liver kidney microsomal (LKM) antibody.
Wilson disease screen: ceruloplasmin, 24 hour urinary copper.
Alpha-1 antitrypsin deficiency: alpha-1 phenotype.
Creatinine phosphokinase, aldolase, LDH (AST > ALT, concern for extra-hepatic cause of elevated aminotransferases).

Section 2: Tests that Evaluate Impaired Bile Flow or Cholestasis

Serum GGT varies by age: normal value up to 400 IU/L in neonates and reducing to 50 IU/L by a year of age.
GGT is elevated typically in biliary obstruction.
Cholestasis with low/normal GGT is characteristically seen in progressive familial intrahepatic cholestasis (PFIC 1 and 2) and inborn errors of bile acid synthesis.

Increased GGT

The most likely source of ALP are liver and bone.
Normal growing children and adolescents have elevation of ALP of bone origin.
Increased ALP associated with elevated GGT or 5’nucleotidase is considered of hepatic origin.
Increased ALP in the absence of liver disease may be:
- Secondary to chronic renal failure.
- Familial inheritance, blood type B or O.
- Pregnancy.
- Transient hyperphosphatemia of infancy.
Decreased ALP is seen in:
- Zinc deficiency (zinc is a co-factor for ALP).
- Wilson disease.

PFIC

Is a rare but important familial cause of cholestasis in the newborn.
Is divided into three types based on mutations in genes encoding transport proteins responsible for the production of bile.
Mothers of children with PFIC, who are heterozygous for the mutation especially ABCB4 have intrahepatic cholestasis of pregnancy, pruritus during pregnancy, post-natal resolution.

PFIC1 (Byler disease)

Mutation in ATP8B1, a P-type ATPase that is an aminophospholipid flippase that is responsible for maintaining canalicular lipid asymmetry.
Presents by 1 year of age with low GGT cholestasis, elevated transaminases, pruritus, hepatosplenomegaly, malabsorption, failure to thrive and rickets.
Given the protein is present in other epithelia – there is also extrahepatic involvement with diarrhea, deafness, pancreatitis, renal tubular acidosis and/or lung disease.
Histology reveals a bland hepatocellular, canalicular cholestasis with coarse granular bile on electron microscopy.
Biliary diversion may help the pruritus. Liver transplantation is not the preferred option in view of extra-hepatic involvement.

PFIC2

Mutation in ABCB11 which codes for bile salt export pump that is responsible for bile acid transport across the canalicular membrane.
Similar to PFIC1 there is low GGT cholestasis in infancy, with transaminases elevated >5 ULN, but there is no extra-hepatic involvement.
Rapid progress to cirrhosis and possibility of development of HCC and cholangiocarcinoma in the first year of life.
Histology shows giant-cell hepatitis and lobular cholestasis with finely granular/filamentous bile in dilated bile canaliculi on electron microscopy.
Monitoring of AFP and regular US scans important.
Biliary diversion and liver transplantation are required in many.

PFIC3

Mutation in ABCB4, which codes for MDR3 (multidrug resistance protein 3), causing malfunction of a transporter required for biliary phosphatidylcholine secretion → reduced biliary phospholipid → renders the biliary epithelium susceptible to damage by the biliary bile acids.
Age of onset is variable but usually after infancy and GGT is high.
Histology shows bile ductular proliferation and mixed inflammatory infiltrates. Periductal sclerosis affecting the interlobular bile ducts and biliary cirrhosis eventually occurs.
Oral ursodeoxycholic acid is useful.
Liver transplantation is required once cirrhosis develops.

Benign recurrent intrahepatic cholestasis (BRIC)

Milder form of low GGT cholestasis.
BRIC1 and BRIC2 are thought to be secondary to missense mutations of ATP8B1 and ABCB11 respectively.
Intermittent episodes of cholestasis and severe pruritus.
Chronic liver damage does not occur.

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