When the glucose concentration is high in the portal vein, it is converted to glycogen and the carbon skeletons of fatty acids, which are transported to adipose tissue as very low-density lipoprotein (VLDL). During fasting, the systemic plasma glucose concentration is maintained by the breakdown of glycogen (glycogenolysis) or by the synthesis of glucose from substrates such as glycerol, lactate and amino acids (gluconeogenesis). Fatty acids reaching the liver from fat stores may be metabolized in the tricarboxylic acid cycle, converted to ketones or incorporated into triglycerides (see Chapter 13).

Hepatocytes synthesize:

The liver has a very large functional reserve. Deficiencies in synthetic function can be detected only if liver disease is extensive. Before a fall in plasma albumin concentration is attributed to advanced liver disease, extrahepatic causes must be excluded, such as the loss of protein through the kidney, gut or skin, or across capillary membranes into the interstitial space, as in even mild inflammation or infection (see Chapter 19).

Prothrombin levels, assessed by measuring the prothrombin time, may be reduced because of impaired hepatic synthesis, whether due to failure to absorb vitamin K or to hepatocellular damage. If hepatocellular function is adequate, parenteral administration of vitamin K may reverse the abnormality.

The excretion of bilirubin is considered in more detail below. Other substances that are inactivated and excreted by the liver include the following:

Efficient excretion of the end products of metabolism and of bilirubin depends on:

At the end of their lifespan, red blood cells are broken down by the reticuloendothelial system, mainly in the spleen. The released haemoglobin is split into globin, which enters the general protein pool, and haem, which is converted to bilirubin after the removal of iron, which is reused (see Chapter 21).

About 80 per cent of bilirubin is derived from haem within the reticuloendothelial system. Other sources include the breakdown of immature red cells in the bone marrow and of compounds chemically related to haemoglobin, such as myoglobin and the cytochromes. Less than 300 µmol of bilirubin is produced daily from the breakdown of erythrocytes, while the normal liver is able to conjugate up to about 1 mmol/day, and
therefore hyperbilirubinaemia is an insensitive index of parenchymal hepatic disease.

Bilirubin is normally transported to the liver bound to albumin. In this form it is called unconjugated bilirubin, which is lipid soluble and therefore, if not protein bound, can cross cell membranes, including those forming the blood-brain barrier. In this form it is potentially toxic; however, at physiological concentrations it is all protein bound.

In the adult, about 300 µmol per day of bilirubin reaches the liver, where it is transferred from plasma albumin, through the permeable vascular sinusoidal membrane. The hepatocytes can process a much greater load than this. Bilirubin is bound to ligandin (Y protein). From there it is actively transported to the smooth endoplasmic reticulum, where it is conjugated with glucuronate by a process catalysed by uridine diphosphate glucuronyl transferase.

Bilirubin monoglucuronide passes to the canalicular surfaces of the hepatocytes, where, after the addition of a second glucuronate molecule, it is secreted by active processes into the bile canaliculi. This process is largely dependent on the active secretion of bile acids from hepatocytes. These energy-dependent steps are the ones most likely to be impaired by liver damage (hypoxia and septicaemia) and by increased pressure in the biliary tract. Other anions, including drugs, may compete for binding to ligandin, thus impairing bilirubin conjugation and excretion. Novobiocin inhibits glucuronyl transferase, thus exacerbating unconjugated hyperbilirubinaemia. Bilirubin is often assayed by the Van den Bergh reaction, which allows conjugated (direct-reacting) and unconjugated (indirect-reacting) bilirubin to be distinguished.

Strictly speaking, changes in plasma enzyme activity generally indicate liver cell membrane damage rather than hepatic function capacity. Because these enzymes are also present in other tissues, changes in plasma activities may reflect damage to those tissues rather than to the liver (see Chapter 18).

The measurement of plasma albumin and prothrombin time may be used to assess function. The hepatic synthetic and secretory capacities are large; only severe and usually prolonged liver disease, for example cirrhosis, demonstrably impairs albumin and prothrombin synthesis.

A high plasma conjugated bilirubin concentration indicates impaired hepatic excretory function but as this is also raised in hepatocellular disease it is not specific for cholestasis. This may be accompanied by a high plasma alkaline phosphatase (ALP) activity, as we will now see. Jaundice has been described above.

Fresh urine analysis may confirm the presence of bilirubin (conjugated hyperbilirubinaemia) and urobilinogen

Urine Multistix include stabilized, diazotized 2,4-dichloraniline, which reacts with bilirubin to form azobilirubin. The test will detect about 3 µmol/L of bilirubin. Drugs, such as large doses of chlorpromazine, may give false-positive results.

Urine Multistix also include paradimethylaminobenzaldehyde, which reacts with urobilinogen. Urine Multistix do not react with porphobilinogen. This test will detect urobilinogen in urine from some normal individuals. False-positive results may occur after taking drugs such as para–aminosalicylic acid and some sulphonamides.

Raised total plasma bile acid concentrations in the third trimester of pregnancy associated with pruritus are suggestive of obstetric cholestasis, which can lead to both maternal and fetal morbidity and mortality. Elevation of plasma ALT concentration may follow the increase in the concentration of plasma bile salts (see Chapter 10).

Owing to the very large hepatic reserve, tests for impairment of metabolic (including synthetic and
secretory) function are relatively insensitive indicators of liver disease. There are a number of new tests that are being devised to improve the accuracy of the diagnosis of hepatic disorders. Tests of hepatocellular activity have been proposed, such as galactose elimination capacity, the aminopyrine breath test, indocyanine green clearance, and monoethylglycinexylidide (MEGX) production. All these tests are indirect measures of hepatic activity that rely on measuring compounds or their metabolites after they have been acted on by the liver. As yet, they do not have a place in routine clinical diagnosis.

Cholestasis may be either:

It is essential to distinguish between intrahepatic and extrahepatic causes of cholestasis, as surgery may be indicated for the latter but is usually contraindicated for intrahepatic lesions. The biochemical findings may be similar:

Patients with prolonged and more widespread cholestasis may present with severe jaundice and pruritus due to the deposition of retained bile salts in the skin; the plasma bilirubin concentration may be more than 800 µmol/L. More rarely, there is bleeding due to malabsorption of vitamin K, with consequent prothrombin deficiency. Cholesterol retention may cause hypercholesterolaemia. Dark urine and pale stools suggest biliary retention of conjugated bilirubin.

The jaundice caused by extrahepatic obstruction due to malignant tissue is typically painless and progressive, but there may be a history of vague persistent back pain and weight loss. By contrast, intraluminal obstruction by a gallstone may cause severe pain, which, like the jaundice, is often intermittent. Gallstones may not always cause such symptoms. If a large stone lodges in the lower end of the common bile duct, the picture may be indistinguishable from that of malignant obstruction.

Although most of the findings are directly attributable to cholestasis, biliary back pressure may damage hepatocytes, and plasma aminotransferase activities may increase. Unless the cause is clinically obvious, evidence of dilated ducts due to extrahepatic obstruction should be sought using tests such as ultrasound, computerized tomography (CT) scanning or cholangiography.

This is a rare autoimmune disorder that occurs most commonly in middle-aged women. Destruction and proliferation of the bile ducts produce a predominantly cholestatic picture, with pruritus and a plasma ALP activity that may be very high. Jaundice develops late in most patients. Mitochondrial antibodies are detectable in the plasma of more than 90 per cent of cases; the plasma immmunoglobulin M (IgM) concentration is usually raised. Patients may also manifest hypercholesterolaemia, xanthelasma (see Chapter 13), other autoimmune disorders and osteoporosis.

Prolonged parenteral nutrition may be associated with a progressive increase in plasma ALP activity and a subsequent rise in the plasma aminotransferase concentrations. The cause is not known, although biliary sludging may occur and the biochemical changes may return to normal when the parenteral feeding is discontinued. Cyclical parenteral nutrition may help the situation when patients are fed intermittently (see Chapter 14).