liver function test

1. Liver Function Tests (LFTs)
Lecture - 4

2. Major Metabolic Functions of the Liver
• Synthetic Function
• Plasma proteins (albumin, globulins), cholesterol,
triglycerides and lipoproteins
• Detoxification and excretion
• Ammonia to urea (urea cycle), bilirubin, cholesterol, drug
metabolites
• Storage Function
• Vitamins A, D, E, K and B12
• Production of bile salts
• Helps in digestion

3. Some example of liver dysfunction
• Hepatocellular disease
• Cholestasis (obstruction of bile flow)
• Cirrhosis
• Hepatitis
• Jaundice
• Liver cancer
• Steatosis (fatty liver)
• Genetic Disorders
• Hemochromatosis (iron storage)

4. Liver Function Tests (LFTs)
• Noninvasive methods for screening of liver dysfunction
• Help in identifying general types of disorder
• Assess severity and allow prediction of outcome
• Disease and treatment follow up

5. Classification of LFTs
Group I: Markers of liver dysfunction
▫ Serum bilirubin: total and conjugated
▫ Urine: bile salts and urobilinogen
▫ Total protein, serum albumin and albumin/globulin ratio
▫ Prothrombin Time

6. Classification of LFTs
Group II: Markers of hepatocellular injury
▫ Alanine aminotransferase (ALT)
▫ Aspartate aminotransferase (AST)

7. Classification of LFTs
Group III: Markers of cholestasis
▫ Alkaline phosphatase (ALP)
▫ g-glutamyltransferase (GGT)

8. Limitations of LFTs
• Normal LFT values do not always indicate absence of liver disease
• Liver a has very large reserve capacity
• Asymptomatic people may have abnormal LFT results
• Diagnosis should be based on clinical examination

9. Bilirubin
Bilirubin is derived from haem, an iron containing protoporphyrin
mainly found in haemoglobin. An adult normally produces about
450 μmol of bilirubin daily. It is insoluble in water and is
transported in plasma almost totally bound to albumin. It is taken
up by liver cells and conjugated to form mono- and
diglucuronides, which are much more soluble in water than
unconjugated bilirubin. The conjugated bilirubin is excreted into
the bile. The main functional constituents of the bile are the bile
salts, which are involved in fat digestion and absorption from the
small intestine.

10. In the terminal ileum and colon the bilirubin conjugates are
attacked by bacteria to form a group of compounds that are
known collectively as stercobilinogen, most of which are excreted
in faeces. Some are absorbed and eventually re-excreted from the
body by way of bile (the enterohepatic circulation). Small
amounts of these tetrapyrroles are found in urine in which they
are known as urobilinogen.
When the biliary tract becomes blocked, bilirubin is not excreted
and serum concentrations rise. The patient becomes jaundiced.

13. The aminotransferases (AST and ALT)
The activities of two aminotransferases, AST and ALT, are widely
used in clinical practice as a sensitive, albeit non-specific, index of
acute damage to hepatocytes irrespective of its aetiology.
Causes of liver damage include hepatitis, no matter the causative
agent, and toxic injury, which may accompany any one of a large
number of insults to the liver, including drug overdose. Acute
liver damage due to shock, severe hypoxia and acute cardiac
failure is also seen.

14. Alkaline phosphatase (ALP)
Increases in alkaline phosphatase activity in liver disease are the result of increased
synthesis of the enzyme by cells lining the bile canaliculi, usually in response to
cholestasis, which may be either intra- or extrahepatic. Cholestasis, even of short
duration, results in an increased enzyme activity to at least twice the upper end of the
reference interval. High alkaline phosphatase activity may also occur when space-
occupying lesions (e.g. tumors) are present. It also occurs in cirrhosis.
Liver is not the sole source of alkaline phosphatase activity. Substantial amounts are
present in bone, small intestine, placenta and kidney. Placental alkaline phosphatase
appears in the maternal blood in the third trimester of pregnancy. Occasionally, the
cause of a raised alkaline phosphatase will not be immediately apparent. The liver and
bone isoenzymes can be separated by electrophoresis. However, an elevated γGT would
suggest that the liver is the source of the increased alkaline phosphatase.

15. Gamma-glutamyl transpeptidase (γGT)
γGT is a microsomal enzyme that is widely distributed in tissues including
liver and renal tubules. The activity of γGT in plasma is raised whenever
there is cholestasis, and it is a very sensitive index of liver pathology. It is
also affected by ingestion of alcohol, even in the absence of recognizable
liver disease. Alcohol and drugs such as phenytoin induce enzyme activity.

16. Plasma proteins
Albumin is the major protein product of the liver. It has a long biological
half-life in plasma (about 20 days), and therefore significant falls in albumin
concentration are slow to occur if synthesis is suddenly reduced.
Hypoalbuminemia is a feature of advanced chronic liver disease. It can also
occur in severe acute liver damage.
Alpha-fetoprotein (AFP) is synthesized by the fetal liver. In normal adults it
is present in plasma at low concentrations (<3 kU/L). Measurement of AFP
is of value in the investigation of hepatocellular carcinoma in which serum
concentrations are increased in 80–90% of cases. AFP is also used as a
marker for germ cell tumors.

17. Prothrombin time
The prothrombin time, which is a measure of the activities of certain
coagulation factors made by the liver, is sometimes used as an indicator of
hepatic synthetic function. Prothrombin has a very short half-life, and an
increased prothrombin time may be the earliest indicator of reduced
hepatic synthesis.

18. Jaundice
Jaundice is a yellow discoloration of the skin or sclera. This is due to the
presence of bilirubin in the plasma and is not usually detectable until the
concentration is greater than about 50 μmol/L. Normally the bilirubin
concentration in plasma is less than 21 μmol/L. It is normally conjugated
with glucuronic acid to make it more soluble, and excreted in the bile.
There are three main reasons why bilirubin levels in the blood may rise:
Haemolysis. The increased haemoglobin breakdown produces bilirubin,
which overloads the conjugating mechanism.
Failure of the conjugating mechanism within the hepatocyte.
Obstruction in the biliary sytem.

19. Both conjugated bilirubin and unconjugated bilirubin may be present in
plasma. Conjugated bilirubin is water-soluble. Unconjugated bilirubin is not
water-soluble and binds to albumin from which it may be transferred to
other proteins such as those in cell membranes. It is neurotoxic, and if
levels rise too high in neonates, permanent brain damage can occur.
Jaundice may be a consequence of haemolysis, cholestasis or
hepatocellular damage. In addition there are inherited disorders of
bilirubin metabolism. Gilbert’s disease is the most common and causes a
mild unconjugated hyperbilirubinemia because of defective hepatic uptake
of bilirubin. In this condition bilirubin levels rise on fasting.

20. Haemolysis
Increased bilirubin production caused by haemolysis gives a predominantly
unconjugated hyperbilirubinemia. This, in combination with immature liver
function, is commonly encountered in babies. A rapidly rising bilirubin in a
neonate should be carefully monitored as it may give rise to brain damage
(kernicterus).
Extrahepatic biliary obstruction
Gallstones can partially or fully block the bile duct. Such a blockage is
known as extrahepatic obstruction. If the blockage is complete, both
bilirubin and alkaline phosphatase are raised. There is little or no
urobilinogen in urine. Stools will be pale in color.

21. Hepatocellular damage
Obstruction may be secondary to damage to the hepatocytes by infection
or toxins, rather than damage to the biliary tract. The most common
causes of acute jaundice seen in adults are viral hepatitis and paracetamol
poisoning. In these cases, not only are the bilirubin and alkaline
phosphatase levels raised, but AST and ALT are elevated indicating
hepatocellular damage.

24. Serum bilirubin levels
• Normal
• 0.2 – 0.8 mg/dL
• Unconjugated (indirect):
• 0.2 – 0.7 mg/dL
• Conjugated (direct):
• 0.1 – 0.4 mg/dL
• Latent jaundice:
• Above 1 mg/dL
• Jaundice:
• Above 2 mg/dL