Pediatric liver function test: smarter interpretation

Navigating through Liver Function Tests (LFTs) has been a perpetual puzzle for me! This post serves as my endeavor to unravel the complexities surrounding LFTs, aiming not only to clear my own confusion but also to offer clarity to anyone who stumbles upon it. Join me on this journey of understanding liver function, and let's demystify these intricate tests together. Your insights and feedback are not only welcome but crucial in making this exploration beneficial for all.

Part One: Tests that detect injury to hepatocytes (serum enzyme tests)

1. ALT/SGPT

ALT or SGPT (always confuses me so I prefer to call ALT always) is a primary marker of liver cell injury (I remember L for Liver) and is more sensitive and specific than AST. When liver cells die, they leak into the blood, but there is no correlation with the extent of the damage.

A) High ALT (>15-20 times)

  1. Ischaemia (Much Higher) (Shock, hypotension, CCF, comes down rapidly)
  2. Viral hepatitis, Autoimmune
  3. Drug toxicity (PCM), Severe toxic hepatitis
  4. Acute Budd Chiari syndrome

B) Moderate ALT (5-15 times)

  1. Liver – Chronic Liver disease (eg Chronic hepatitis)
  2. Cholestasis (with ALP, GGT)
  3. Cardiac –Severe hepatic congestion in cardiac failure
  4. Other: Muscle injury, Kidney injury

C) Slight increase in ALT (<5 times)

  1. Liver: Neonatal hepatitis
  2. Hemochromatosis
  3. Autoimmune hepatitis
  4. NASH, EHBA
  5. Alpha1-antitrypsin deficiency, Wilson’s disease
  6. Infection: Infectious mononucleosis
  7. Drugs: Almost any drug. (ATT, AED, Antibiotics, NASAIDS), PCM therapeutic doses.

False low ALT

Patient on dialysis, Pyridoxine deficiency can show relatively lower values of ALT. Also, drugs are more likely to cause an asymptomatic abnormality in liver function.

2) AST/SGOT

AST is less sensitive marker for liver injury and can be elevated in other organ dysfunction as well.

OriginLiver, cardiac, skeletal muscle, kidney, brain, pancreas.
Reflects Reflects damage to the hepatic cell, but less specific for liver disease than ALT (l for liver).
Normal Value

A) High rise in AST (>20 times)

  1. Ischaemic liver injury(Shock, hypoperfusion)
  2. Acute viral hepatitis
  3. Drug-induced hepatic injury

B) Moderate rise in AST (15-20 times)

  1. Cardiovascular system: Congestive cardiac failure
  2. Infection: Infectious mononucleosis
  3. Liver: Alcoholic cirrhosis

C) Mild rise in AST (5-10 times)

  1. Liver: Chronic hepatitis Especially alcoholic
  2. Skeletal muscle: DMD, Dermatomyositis, Infl. B calf muscle myositis

D) Even milder rise in AST (<5 times)

  1. Blood: Haemolytic anemia, hemolysis
  2. Liver: Fatty liver, Metastatic hepatic tumor
  3. Drugs: Almost any drug

Asymptomatic Transaminitis

Slight elevations of AST or ALT levels, within 1.5 times the normal range, should not immediately be interpreted as signs of liver disease. It's important to consider other factors and further examinations before jumping to conclusions about the presence of liver-related injury.

Often, in the early course of the disease, only a slight elevation may be observed in the patient. It is not until a follow-up test that a significant rise becomes apparent.

WHY?
Unlike the values in many other biochemical tests, AST and ALT levels do not follow a normal bellshaped distribution in the population.

They have a skewed distribution characterized by a long tail at the high end of the scale.

Ratios between AST and ALT

AST/ALT ratio can be a very useful tool to in differentiating primary pathologies.

AST: ALT =1 (Equal rise)

Similar and simultaneous rise in AST and ALT can be seen in

  1. Ischaemia
  2. Shock and hypo-perfusion
  3. Hypoxic injury

AST: ALT <1

When comparing ALT and AST levels, a notable increase in ALT in comparison to AST is commonly observed in pathologies primarily associated with Hepatocellular damage, particularly in acute conditions.

  1. PCM poisoning with hepatocellular necrosis.
  2. Viral hepatitis
  3. Toxic hepatitis
  4. Cholestatic hepatitis
  5. Chronic active hepatitis, NASH, etc

AST: ALT >2.5

The AST levels increase more significantly compared to ALT in the following pathologies.

  1. CLD, cirrhosis
  2. Wilsons disease, cirrhosis
  3. Bile duct obstruction, Tumours
  4. Alcoholic liver disease

WHY?

Depletion of vitamin B6 in chronic alcoholics. ALT and AST both use B6 as a coenzyme, but the synthesis of ALT is more strongly inhibited by pyridoxine deficiency than is the synthesis of AST. Alcohol also causes mitochondrial injury, which releases the mitochondrial isoenzyme of AST.

3. ALKALINE PHOSPHATASE (ALP)

Source Liver, bone, placenta and intestine
Reason for riseResult of increased synthesis of the enzymes by cells lining the bile canaliculi, in response to cholestasis that may be intra or extra-hepatic.
Primary valueTo identify cholestatic disorders, can rise even before the rise in bilirubin.

Increased ALP

The normal value of alkaline phosphatase is between 30 and 120 IU/L, this may vary a bit from lab to lab.

  1. Liver
    • Sensitive for biliary obstruction,
    • Intrahepatic/Extrahepatic cholestasis. (Highest levels)
    • EHBA (Marked rise)
    • Viral hepatitis
  2. Renal
    • Renal failure
  3. Infiltration
    • Hepatic metastasis,
    • amyloidosis,
    • granulomatous diseases
  4. Cardiovascular
    • Heart failure (Milder)
  5. Infections
    • Inf mononucleosis,
    • Fungal infection (Marked rise)
  6. Bone
    • Usually non-pathological in growing children
    • Osteomalacia, Bone metastasis, Paget's disease (very very high)
    • Deficiency-induced rise in rickets, Rapid bone growth
    • Hyperparathyroidism
  7. Physiological
    • Released in excess from the placenta in late pregnancy.
    • Blood type O and B: Released from the small intestine after a fatty meal.

    Isolated rise in ALP

    The significance of ALP elevation with otherwise normal transaminase and bilirubin values remains unclear, however, isolated elevation of ALP can be seen in

    1. Use of drugs such as Cimetidine, furosemide, phenobarb (Enzyme induction)
    2. CCF but Often associated with AST and ALT rise.
    3. Diabetes
    4. Hyperthyroidism

    Low ALP

    Lower levels of alkaline phosphatase can give clues toward following pathologies.

    1. Malnutrition
    2. Zn deficiency
    3. Vit c Deficiency
    4. Hypothyroidism
    5. Pernicious anemia
    6. Congenital Hypophosphatasia

    How to confirm the Liver Origin of alkaline phosphatase?

    There are two ways to differentiate whether or not the origin of rise in ALP if from liver or non-liver origin.

    Isoenzyme assays

    There are 60 types of Isoenzymes of ALP, that can be separated by electrophoresis to identify the liver and other organ-specific isoenzymes. This is expensive and mostly for research purposes. (Expensive)

    Raised GGT and 5′-nucleotidase

    GGT and 5′-nucleotidase are often raised in primary liver pathologies. An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should always warrant prompt evaluation for bone diseases.

    Normal agewise Variation in ALP

    ALP levels vary with age. ALP levels are generally higher in children and adolescents because of physiological osteoblastic activity.

    Levels may be up to 3 times higher than in healthy adults, coinciding with periods of maximum bone growth velocity


    TestCholestaticInfiltrativeHepatocellular
    AST, ALT > ALP Typical
    ALP > AST, ALTTypical
    Elevation ALP but
    normal AST, ALT levels 
    TypicalTypical

    Low ALP/ bilirubin ratio: Role in prognosis

    A low ALP/ bilirubin ratio can be seen in fulminant Wilson disease.
    Regardless of the cause of acute hepatic failure, a low ALP/bilirubin ratio is associated with a poor prognosis.

    4. GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT)

    SourceLiver (Biliary tract), Renal tubules, Brain, pancreas, intestinal cells and prostrate glands
    Normal levels10 - 30 IU/L
    UseTo detect hepatobiliary damage

    Note: Normal agewise Variation in GGT

    In normal full-term neonates, serum GGT activity is six to seven times the upper limit of the adult reference range; levels decline and reach adult levels by 5 to 7 months of age

    GGT is the most sensitive (More than ALT) investigation for detecting hepatobiliary disease, but its use is limited by lack of specificity. It is particularly sensitive to alcoholic liver disease.

    Increased levels of serum GGT

    High levels of GGT are seen in

    1.  Liver diseases with Hepatobilliary insult
      • EHBA - Marked elevation,
      • Any obstructive jaundice
      • Acute viral hepatitis, peaks in 2nd or 3rd week, and may remain elevated for 6 weeks.
    2. Other
      • GBS,
      • Dystrophica myotonia,
      • Pancreatitis,
      • Brain tumours,
      • Renal failure,
      • Diabetes Mellitus,
      • Prostatic disease,
      • Cardiac disease.

    Isolated elevation of GGT level 

    Isolated levels of GGT can be seen in the following, without any evidence of liver injury.

    1. Drugs such as Phenobarbitone, phenytoin, paracetamol, tricyclics
    2. Alcohol-induced liver disease

    Uses of GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT)

    1. It confers liver specificity to an elevated alkaline phosphatase level.
    2. It is more specific for cholestatic liver disease except in some PFIC.  
    3. In cases of transaminitis with AST/ALT >2, the elevation of GGTP further supports the diagnosis of alcoholic liver disease.

    Note:

    1. An isolated elevation of the GGTP level does not need to be further evaluated unless there are additional clinical risk factors for liver disease.
    2. Common bile duct stone Condition can simulate acute hepatitis, although AST and ALT elevation can be seen immediately, the elevation of ALP and GGT can take some time.

    ALP and γ-glutamyltransferase (GGT) in the diagnosis of cholestasis

    1. ALP and γ-glutamyltransferase (GGT) levels typically rise to several times after several days of bile duct obstruction or intrahepatic cholestasis.
    2. Diagnostic confusion can occur when a patient presents within a few hours after acute bile duct obstruction from a gallstone. In this situation, AST and ALT levels often reach 500 u/L or more in the first hours and then decline, whereas ALP and GGT levels can take several days to rise.

    5. Lactate Dehydrogenase (LDH)

    SourceHeart, red blood cells (e.g., hemolysis)
    How it is produced?Non-specific rise in liver diseases needs to be interpreted with other tests.
    UseNon-specific rise in liver diseases, needs to be interpreted with other tests.

    Organ-specific Isoenzymes

    There are 5 isoenzymes of LDH, the identification of isoenzymes for specific organ involvement is not possible in routine clinical practice.

    LD1 and LD2 Heart, RBC, kidneys
    LD3Lungs
    LD4 and LD5Liver and skeletal muscle

    Raised LDH

    1. CVS
      • Hepatic congestion (ccf),
      • Rheumatic HD,
      • Myocarditis,
      • Shock
    2. RS
      • Pulmonary embolus
      • Infarction
    3. Haematological
      • Pernicious anaemia
      • Haemolytic anaemia
      • Sickle cell anaemia
    4. Hepatobiliary
      • Hepatitis,
      • Active cirrhosis
      • Hepatic congestion due to any cause

    Part 2: Shortly
    Tests of the Liver’s biosynthetic capacity.
    Tests of the liver’s capacity to transport organic anions and to metabolize drugs.

    Author

    about authors

    Ajay Agade | DNB(Pediatrics), FNB(Pediatric Intensive Care), Fellowship in Pediatric pulmonology and LTV

    Ajay is a Paediatric Intensivist, currently working in Pediatric Pulmonology & LTV at Great Ormond Street Hospital NHS, London

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