PEDIATRIC LIVER FUNCTION TEST : SMARTER INTERPRETATION

For me LFT 's are always confusing! The post is basically an attempt to get rid of my own confusions and should anybody, comes across this and find it useful then all the better!

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

1. ALT/SGPT

Primarily marker of hepatocellular injury (most sensitive, more specific than AST),
Liver cell death —> leaks in blood.
No correlation with extent of 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 chiary 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.

D) False low ALT: Dialysis, Pyridoxine deficiency

Note: Drugs more likely to cause an asymptomatic abnormality in liver function.

2) AST/SGOT

Origin: Liver, cardiac, skeletal muscle, kidney, brain, pancreas.
Reflects damage to the hepatic cell , but less specific for liver disease.

A) High AST (>20 times)

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

B) Moderate AST (15-20 times)

1. CVS: (CCF)
2. Infection: (Infectious mononucleosis)
3. Liver: (Alcoholic cirrhosis)

C) Mild AST (5-10 times)

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

D) Even milder AST (<5 times)

1. Blood: Haemolytic anaemia, haemolysis
2. Liver; Fatty liver, Metastatic hepatic tumour
3. Drugs: Almost any drug

Ratios between AST and ALT are useful in differentials

AST: ALT =1 (Equal rise)

      1.  Ischaemia ( Shock, hypoxia, hypoperfsion injury)

AST: ALT <1 ( More ALT, specific for Hepatocellular damage )

      1, PCM poisoning with hepatocellular necrosis
      2. Viral hepatitis, toxic hepatitis, Cholestatic hepatitis
      3. Chronic active hepatitis, NASH

AST: ALT >2.5 (More AST)

       1. CLD, cirrhosis
       2. Wilsons disease, cirrhosis
       3. Bile duct obstruction, Tumours
        (Adults: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.

 Asymptomatic Transaminitis

 Slight AST or ALT elevations (within 1.5 × normal) do not necessarily indicate liver disease.

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.

3. ALKALINE PHOSPATASE (ALP)

Source: liver, bone, placenta and intestine
Result of increased synthesis of the enzymes by cells lining the bile canaliculli, in response to cholestasis (intra or extra-hepatic)

Primary value: cholestatic disorders (Even before a rise in bilirubin.)

# Increased ALP : (n: 30 – 120 IU/L)

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

# Isolated rise in ALP

     1. Drugs: Cimetidine, furosemide, phenobarb (Enzyme induction )
     2. CCF (Often associated with AST and ALT rise)
     3. Diabetes
     4. Hyperthyroidism

(The significance of ALP elevation with otherwise normal transaminase and bilirubin values remains unclear)

# Low ALP

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

How to confirm Liver Origin of alkaline phosphatase

1. Isoenzymes (60 types) of ALP can be separated by electrophoresis (Expensive)
2. Raised GGT and 5′-nucleotidase , deranged LFT (Easy)

(An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt an evaluation for bone diseases)

Note:

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

Test                        Cholestatic         Infiltrative       Hepatocellular
AST, ALT > ALP              Typical              -                     -

ALP > AST, ALT               -                  Typical                -

Elevation ALP ,
normal AST, ALT levels       -                  Typical           Typical

# Low ALP/ bilirubin ratio: 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) (> 10 - 30 IU/L)

Source: liver (Biliary tract), Renal tubules, Brain, pancreas, intestinal cells and prostrate glands

Note: 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 most sensitive (More than ALT) for detecting hepatobiliary damage, but use limited by lack of specificity. Particularly sensitive in alcoholic liver disease.

1. Increased levels of serum GGT (Liver : Response to any Hepatobilliary injury)

1. EHBA (Marked elevation), Obstructive jaundice
2. Acute viral hepatitis (peak 2nd or 3rd week, may remain for 6 weeks)
3. Other: GBS, Dystrophica myotonia, Pancreatitis, Brain tumours, Renal failure, DM, Prostatic disease, Cardiac dis.

2. Isolated elevation of GGT level (no actual liver disease)
      Drugs: Phenobarbitone, phenytoin, paracetamol, tricyclics
      (Adults:Alcohol)

GGTP USES:

1. It confers liver specificity to an elevated alkaline phosphatase level; thus cholestasis (except in some PFIC).  

2. In aminotransferase level elevations with AST/ALT >2, elevation of GGTP further supports 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, AST and ALT become elevated immediately, but elevation of ALP and GGT is delayed.

MARKERS 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 per 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)

Source: Heart, red blood cells (e.g., hemolysis)
Lactate Dehydrogenase (LDH) catalyses the reversible conversion of lactic acid to pyruvic acid. The final step in Embden-Meyerhoff pathway, providing bridge to Krebs cycle and thus cellular energy.

5 main isoenzymes:

1. LD1 and LD2 – Heart, RBC, kidneys
2. LD3 – Lungs
3. LD4 and LD5 – Liver and skeletal muscle

Raised LDH

1. CVS: Hepatic congestion (ccf), Rheumatic HD, Myocarditis, Shock
2. RS: Pulmonary embolus and infarction
3. Haematological: Pernicious anaemia, Haemolytic anaemia, Sickle cell anaemia
4. Hepatobiliary: Hepatitis, Active cirrhosis, Hepatic congestion.

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

Image source:  Erin M, Flickr

References:

1. Liver Function Tests and their Interpretation B.R. Thapa and Anuj Walia Indian Journal of Pediatrics, Volume 74—July, 2007.
2. AGA Technical Review on the Evaluation of Liver Chemistry Tests. Gastroenterology 2002;123:1367–1384.
3. David e. Johnston, MD. Special Considerations in Interpreting Liver Function Tests. Am Fam Physician. 1999 Apr 15;59(8):22232230.
4. Jose C Cabrera-Abreu and Anne Green. Gamma-Glutamyltransferase: value of its measurement in paediatrics. Ann Clin Biochem 2002; 39: 22- 25.
5. "Isolated" elevation of alkaline phosphatase: significance in hospitalized patients. J Clin Gastroenterol. 1990 Aug;12(4):415-9.
6. Approach to the Patient with Liver Disease: A Guide to Commonly Used Liver Tests http://www.clevelandclinicmeded.com/.
7. http://www.aafp.org/afp/2005/0315/p1105.html.