1. INVESTIGATION OF HEPATOBILIARY DISEASE

2. 1) DETECTION OF HEPATIC ABNORMALITY
LIVER FUNCTION TESTS USED TO ASSESS LIVER DISEASE
Bilirubin
Aminotransferases
Alkaline phosphatase
Gamma-glutamyl transferase
Albumin

3. The clinical suspicion of liver disease usually leads to the measurement of the liver function tests which are not truly function tests, (provide little prognostic information and do not indicate a specific diagnosis), although they may point to an underlying pathological process and direct further investigation.

4. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are located in the cytoplasm of the hepatocyte.
Although both transaminase enzymes are widely distributed in other tissues of the body, the activities of ALT outside the liver are low and therefore this enzyme is considered more specific for hepatocellular damage.
The alkaline phosphatase enzymes in the liver are localised in the sinusoidal and biliary canalicular membrane.

5. The transaminases, GGT and alkaline phosphatase concentrations should be considered together.
Large increases of aminotransferase activity associated with small increases of alkaline phosphatase activity favour hepatocellular damage;
small increases of aminotransferase activity and large increases of alkaline phosphatase and GGT activity favour biliary obstruction.

7. DRUGS INCREASING PLASMA GAMMA-GLUTAMYL TRANSFERASE
Isolated elevation of the serum GGT is relatively common and may occur during ingestion of microsomal enzyme-inducing drugs
DRUGS INCREASING PLASMA GAMMA-GLUTAMYL TRANSFERASE
Barbiturates
Carbamazepine
Ethanol
Glucocorticoids
Phenytoin
Rifampicin

8. Other biochemical tests may become altered in patients with liver disease.
Hyponatraemia occurs in severe liver disease.
Serum urea may be reduced due to impaired hepatic synthesis.
Increased urea may occur following gastrointestinal haemorrhage or (when associated with a high serum creatinine) is indicative of hepatorenal failure, which carries a bad prognosis.

9. Haematological investigations are also commonly abnormal in patients with liver disease
A normochromic normocytic anaemia may reflect recent gastrointestinal haemorrhage
Chronic blood loss may cause a hypochromic microcytic anaemia secondary to iron deficiency.
macrocytosis is associated with alcohol misuse.
Leucopenia and thrombocytopenia may complicate portal hypertension and hypersplenism.
Leucocytosis may occur with cholangitis, alcoholic hepatitis and hepatic abscesses.

10. 2) TESTS TO DETERMINE THE SEVERITY AND ACTIVITY OF LIVER DISEASE
A- Biochemical tests
measurement of the serum bilirubin and albumin concentrations are truly tests of liver function.
Serum albumin is a marker of synthetic function and is a valuable guide to the severity of chronic liver disease.
A falling serum albumin in liver disease is a bad prognostic sign.
In acute liver disease initial albumin levels may be normal (has prolonged half life).

11. B- Coagulation tests
The liver synthesises most coagulation factors, and requires vitamin K to activate factors II, VII, IX and X.
Prothrombin time (PT) (which depends on factors I, II, V, VII and X) is also a marker of synthetic function.
Because of its short half-life (5-72 hours), it is a sensitive indicator of both acute and chronic liver disease.
Vitamin K deficiency should be excluded as the cause of a prolonged PT by giving an intravenous bolus (10 mg) of vitamin K
Prothrombin times vary in different laboratories, therefore; The International Normalized Ratio (INR) may be used.

12. TOTAL BILIRUBIN (N = 0.3-1.0 mg/dL or 5-17 mol)
Liver Function Tests
TOTAL BILIRUBIN (N = mg/dL or 5-17 mol)
Causes of elevated levels:
Prehepatic – increased bilirubin production (e.g. hemolytic anemias, internal hemorrhage)
Hepatic – deficiencies in bilirubin metabolism (e.g. dec. uptake, impaired conjugation, dec. secretion of bilirubin)
Posthepatic – obstruction of bile ducts, either within the liver or outside the liver
Diagnosis narrowed down by looking at levels of direct bilirubin

13. Liver Function Tests
DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5 mol)
If direct bilirubin is normal  problem is excess unconjugated bilirubin  location of problem is upstream of bilirubin excretion  suspect hemolysis,
If direct bilirubin is elevated  liver conjugating normally but unable to excrete  suspect hepatocellular cause or bile duct obstruction by gallstones or cancer

14. Liver Function Tests
DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5 mol)
If indirect fraction > 85% of the total  hemolysis or another cause of unconjugated hyper-bilirubinemia
Elevated B2 in the absence of other liver chemistry test abnormalities  hereditary disorder of hepatic secretion of bilirubin into the canaliculus (e.g. Dubin Johnson or Rotor’s)

15. Liver Function Tests
ALBUMIN
Main constituent of total protein
Normal: 3.5 – 5.0 g/dL
Decreased in:
Chronic liver disease (e.g., cirrhosis)
Nephrotic syndrome
Poor nutritional state or states of protein catabolism
Not a useful marker of synthetic liver function

16. Other Tests Commonly Requested
Coagulation Tests (e.g. INR)
International Normalized Ratio
Measures the speed of a particular pathway of coagulation, comparing it to the normal
If increased  blood is taking longer to clot
Will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired

17. ALANINE TRANSAMINASE (ALT)
Liver Function Tests
ALANINE TRANSAMINASE (ALT)
Serum Glutamic Pyruvate Transaminase (SGPT) or alanine aminotransaminase
Present in hepatocytes; cytosolic enzyme
Normal: 5 – 35 IU/L
Dramatic increase in: acute liver damage such as viral hepatitis or paracetamol overdose
Elevations measured in multiples of the upper limit of normal (ULN)

18. ASPARTATE TRANSAMINASE (AST)
Liver Function Tests
ASPARTATE TRANSAMINASE (AST)
Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransaminase
Mitochondrial
Also associated with liver parenchymal cells
Normal: 5 – 40 IU/L
Dramatic increase in: acute liver damage
Also present in rbc, cardiac & skeletal muscles

19. Liver Function Tests
Aminotransferases are most helpful in differentiating hepatocellular injury from cholestasis --
Persistent high serum levels > 400 U/L favor generalized hepatocellular injury (e.g. acute hepatitis)
Values < 400 U/L favor cholestasis and may also be seen in mild hepatocellular injuries from viruses, drugs, alcohol, cirrhosis and primary or metastatic neoplasms

20. Liver Function Tests ALKALINE PHOSPHATASE
Enzyme in the cells lining the biliary ducts of the liver
Normal: 40 – 200 IU/L (15-20 y/o); 35 – 125 IU/L ( y/o)
Elevation > 4x the normal  cholestasis of either intrahepatic or extrahepatic cause
Dramatic increase in: large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver
Also present in bone and placental tissue  higher in growing children

21. Liver Function Tests
GAMMA GLUTAMYL TRANSPEPTIDASE (GGT)
Normal: 10 – 48 IU/L
Like ALP, can be found in canalicular membranes
More sensitive marker for cholestatic damage than ALP
May be elevated with even minor, sub-clinical levels of liver dysfunction
Elevated in alcohol toxicity (acute and chronic)

22. Other Tests Commonly Requested
5’ Nucleotidase (5’ NTD)
Specific for cholestasis or damage to the intra- or extrahepatic biliary system
Used as substitute for GGT for ascertaining whether an elevated ALP is of biliary or extra-biliary origin

23. Other Tests Commonly Requested
Serum Glucose (BG, Glu)
Liver’s ability to produce glucose is usually the last function to be lost in the setting of fulminant liver damage
Lactate Dehydrogenase (LDH)
Found in many body tissues, including the liver
Elevated levels may indicate liver damage

25. Patterns of Liver Chemistry Test Abnormalities
Bilirubin
Alkaline phosphatase
Amino- transferase
Albumin
Prothrombin time
Hemolysis
Inc. (usu. B1)
Normal
Acute hepatocellular
+/- inc. (B1 and B2)
Normal or < 3x normal
Usu. >400 (ALT>AST)
Chronic hepatocellular
Usu. <300 U/L
May be dec.
Often prolonged; doesn’t correct with vit. K
Cholestasis
Usually inc. (B1 and B2)
> 4x normal
Usually < 300 U/L
Usually normal
Normal; corrects with vit. K if prolonged
Infiltrative
> 4x normal; inc. GGT
< 300 U/L