obstruction to the biliary tract

 acute hepatocellular damage

 chronic liver disease.

Bilirubin

Bilirubin is derived from haem, an iron-containing protoporphyrin mainly found in haemoglobin (Fig 28.2). 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. Normal bile contains bilirubin monoglucuronide as 25% and the diglucuronide as 75% of the total, accompanied by traces of unconjugated bilirubin. The main functional constituents of the bile are the bile salts, which are involved in fat digestion and absorption from the small intestine. Serum bile acid concentrations are more sensitive indices of hepatic transport function than are total bilirubin measurements.

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. The jaundiced patient is described further on pages 58–59.

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 (see pp. 60–61).

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 in infiltrative diseases of the liver, when space-occupying lesions (e.g. tumours) 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. In normal blood, the alkaline phosphatase activity is derived mainly from bone and liver, with small amounts from intestine. 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 (see below) would suggest that the liver is the source of the increased alkaline phosphatase.

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. In acute hepatic damage, changes in γGT activity parallel those of the aminotransferases.

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. Hypoalbuminaemia is a feature of advanced chronic liver disease. It can also occur in severe acute liver damage.

The total serum globulin concentrations is sometimes used as a crude measure of the severity of liver disease.

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 tumours (pp. 140–141).

Other proteins, such as α₁-antitrypsin and caeruloplasmin, are measured in the diagnosis of specific diseases affecting the liver (p. 61).

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.