Introduction

The liver is of vital importance in intermediary metabolism and in the detoxification and elimination of toxic substances (Fig. 5.1). Damage to the organ may not obviously affect its activity, as the liver has considerable functional reserve and, as a consequence, simple tests of liver function (e.g. plasma bilirubin and albumin concentrations) are insensitive indicators of liver disease. Tests reflecting liver cell damage (particularly the measurement of the activities of hepatic enzymes in plasma) are often superior in this respect. The categorization of such tests as ‘liver function tests’ is clearly a misnomer, but seems likely to endure. Various tests have been devised to provide a quantitative assessment of functional hepatic cell activity (see p. 90), but they are not suitable for use in routine clinical practice.

Figure 5.1 Major functions of the liver.

The results of the standard biochemical liver function tests rarely provide a precise diagnosis on their own, as they reflect the basic pathological processes common to many conditions. However, biochemical tests are cheap, non-invasive and widely available, and are of value in directing the use of other diagnostic tests, notably imaging and liver biopsy. They are also useful in detecting the presence of liver disease and in following its progress. Serological tests (e.g. for autoantibodies and evidence of viral infection) are also important in the investigation of liver disease.

The liver has a dual blood supply: approximately two-thirds from the portal vein, which drains much of the gut and through which most of the nutrients absorbed from the gut reach the liver; and the remainder from the hepatic artery, which supplies most of the liver’s oxygen. Blood leaves the liver through hepatic veins, which drain into the inferior vena cava.

The metabolic activity of the liver takes place within the parenchymal cells, which constitute 80% of the organ mass; the liver also contains Kupffer (reticuloendothelial) cells and stellate cells (the major cell type responsible for fibrosis). Parenchymal cells are contiguous with the venous sinusoids, which carry blood from the portal vein and hepatic artery, and with the biliary canaliculi, the smallest ramifications of the biliary system (Fig. 5.2). Substances destined for excretion in the bile are secreted from hepatocytes into the canaliculi, pass through the intrahepatic ducts and reach the duodenum via the common bile duct.

Figure 5.2 Microstructure of the liver. The liver consists of acini in which sheets of hepatocytes, one cell thick, are permeated by sinusoids carrying blood (black arrow) from the portal venules and hepatic arterioles to the central vein. Bile (red arrow) is secreted from the hepatocytes into canaliculi, which drain into the bile ducts.

The most common disease processes affecting the liver are:

Patients with liver disease often present with characteristic symptoms and signs, particularly jaundice, the yellow-orange discoloration of the skin caused by a high plasma concentration of bilirubin, but the clinical features may be non-specific and, in some patients, liver disease is discovered incidentally. Because of the intimate relationship between the liver and biliary system, extrahepatic biliary disease may present with clinical features suggestive of liver disease or may have secondary effects on the liver. For instance, obstruction to the common bile duct may cause jaundice and, if prolonged, a form of cirrhosis.

Bilirubin metabolism

Bilirubin is derived mainly from the haem moiety of haemoglobin molecules and is liberated when senescent red cells are removed from the circulation by the reticuloendothelial system (Fig. 5.3); the iron in haem is reutilized but the tetrapyrrole ring is degraded to bilirubin. Other sources of bilirubin include myoglobin and the cytochromes.

Figure 5.3 Excretion of bilirubin by the liver. Bilirubin, which is bound to albumin in the plasma, is taken up into hepatocytes, conjugated in the smooth endoplasmic reticulum and excreted via the bile ducts into the gut, where it is converted to urobilinogen. Most of the urobilinogen is oxidized to stercobilin in the colon and excreted in the stool. Some urobilinogen is absorbed from the small intestine and enters the enterohepatic circulation. While most is excreted in the bile, some reaches the systemic circulation and is excreted in the urine.

Unconjugated bilirubin is not water soluble: it is transported in the bloodstream bound to albumin. In the liver, it is taken up by hepatocytes in a process involving specific carrier proteins. It is then transported to the smooth endoplasmic reticulum, where it undergoes conjugation, principally with glucuronic acid, to form mono- and diglucuronides; this process is catalysed by the enzyme bilirubin-uridyl diphosphate (UDP) glucuronosyl transferase. The resulting conjugated bilirubin is water soluble and is secreted into the biliary canaliculi, eventually reaching the small intestine via the ducts of the biliary system. Secretion into the biliary canaliculi is the rate-limiting step in bilirubin metabolism. In the gut, bilirubin is converted by bacterial action into urobilinogen, a colourless compound. Some urobilinogen is absorbed from the gut into the portal blood. Hepatic uptake of this is incomplete: a small quantity reaches the systemic circulation and is excreted in the urine. Most of the urobilinogen in the gut is oxidized in the colon to a brown pigment, stercobilin, which is excreted in the stool.

Some 300 mg of bilirubin is produced daily but the healthy liver can metabolize and excrete ten times this amount. The measurement of plasma bilirubin concentration is thus an insensitive test of liver function: it is frequently normal in early or mild liver disease

The bilirubin normally present in the plasma is mainly (approximately 95%) unconjugated; because it is protein bound, it is not filtered by the renal glomeruli and, in health, bilirubin is not detectable in the urine. Bilirubinuria reflects an increase in the plasma concentration of conjugated bilirubin, and is always pathological.

Although jaundice is a frequent feature of liver disease, it may not be obvious clinically unless the plasma bilirubin concentration is more than two and half times the upper limit of normal; that is, more than 50 µmol/L. Hyperbilirubinaemia can be caused by increased production of bilirubin, impaired metabolism, decreased excretion or a combination of these. The causes of jaundice are listed in Figure 5.4.

Figure 5.4 Classification and major causes of jaundice. In hepatitis, bilirubin metabolism may be affected at various steps. The jaundice is usually due mainly to conjugated bilirubin.

The biochemical assessment of liver function

Plasma bilirubin concentration

Hyperbilirubinaemia is not always present in patients with liver disease, nor is it exclusively associated with liver disease. For example, it is not usually present in patients with well-compensated cirrhosis but it is a common feature of advanced pancreatic carcinoma.

Unconjugated hyperbilirubinaemia

When an excess of bilirubin is unconjugated, the concentration in adults rarely exceeds 100 µmol/L. In the absence of liver disease, unconjugated hyperbilirubinaemia is most often due either to haemolysis or to Gilbert’s syndrome, an inherited abnormality of bilirubin metabolism (see p. 98).

In haemolysis, hyperbilirubinaemia is due to increased production of bilirubin, which exceeds the capacity of the liver to remove and conjugate the pigment. Nevertheless, more bilirubin is excreted in the bile, the amount of urobilinogen entering the enterohepatic circulation is increased and urinary urobilinogen is increased. Laboratory findings in haemolytic (prehepatic) jaundice are summarized in Figure 5.5.

Figure 5.5 Laboratory findings that may be present in haemolytic jaundice.

Activity of the hepatic conjugating enzymes is usually low at birth but increases rapidly thereafter; the transient ‘physiological’ jaundice of the newborn reflects this. With excessive haemolysis, as in Rhesus incompatibility, or a lack of enzyme activity, as occurs in prematurity and in the Crigler–Najjar syndrome, there may be a massive rise in the plasma concentration of unconjugated bilirubin. If bilirubin concentration exceeds approximately 340 µmol/L in infants, its uptake into the brain may cause severe, irreversible brain damage (kernicterus).

Conjugated hyperbilirubinaemia

This condition is due to leakage of bilirubin from either hepatocytes or the biliary system into the bloodstream when its normal route of excretion is blocked. The water-soluble conjugated bilirubin entering the systemic circulation is excreted by the kidneys, as a result of which the urine develops a deep orange-brown colour. In complete biliary obstruction, no bilirubin reaches the gut, no stercobilin is formed and the stools are pale in colour. The differential diagnosis of jaundice due to conjugated bilirubin is considered on p. 97.

Hyperbilirubinaemia can be due to an excess of either or both conjugated and unconjugated bilirubin. The separate measurement of these entities is useful in the diagnosis of neonatal jaundice, where there may be some doubt as to the relative contribution of defective conjugation and other causes; it is less often required in adults and the chemical methods are anyway not wholly reliable at detecting small increases in either fraction. If the plasma bilirubin concentration is <100 µmol/L and other tests of liver function are normal, it can be inferred that the raised levels are due to the unconjugated form of the pigment. The urine can be tested to confirm this because with unconjugated hyperbilirubinaemia there is no bilirubin in the urine. In adults, severe jaundice is almost always a result of conjugated hyperbilirubinaemia.

A third fraction of bilirubin, consisting of conjugated bilirubin bound covalently to albumin, is found in the plasma of patients with longstanding conjugated hyperbilirubinaemia. This substance has a half-life similar to that of albumin. Its persistence in the plasma during the resolution of liver disease or after the relief of obstruction explains the persistence of jaundice in the absence of bilirubinuria that can occur in these circumstances.

Plasma proteins

Albumin is synthesized in the liver and its concentration in the plasma is in part a reflection of the functional capacity of the organ. Plasma albumin concentration tends to decrease in chronic liver disease, but is usually normal in the early stages of acute hepatitis owing to its long half-life (approximately 20 days). There are many other causes of hypoalbuminaemia, as discussed on p. 226, but a normal plasma albumin concentration in a patient with chronic liver disease implies adequate synthetic function; a fall implies a significant deterioration.

The prothrombin time, usually expressed as a ratio (the international normalized ratio, INR) to a control value, is a test of plasma clotting activity and reflects the activity of vitamin-K-dependent clotting factors synthesized by the liver, of which factor VII has the shortest half-life (4–6 h). An increase in the prothrombin time is often an early feature of acute liver disease, but a prolonged prothrombin time may also reflect vitamin K deficiency (in which case, a single parenteral dose of vitamin K should normalize the prothrombin time within 18 h).

A polyclonal increase in immunoglobulins is a frequent finding in patients with chronic liver disease (particularly of autoimmune origin) and may cause an increase in plasma total protein concentration even when albumin concentration is decreased. Plasma immunoglobulin A (IgA) is often increased in alcoholic liver disease, IgG in autoimmune hepatitis and IgM in primary biliary cirrhosis, but these changes are non-specific. More useful diagnostic information may be obtained from measuring individual autoantibodies: anti-mitochondrial antibody is increased in almost all patients with primary biliary cirrhosis, and anti-smooth muscle and anti-nuclear antibodies in many patients with autoimmune hepatitis (Fig. 5.6). Viral infection, an important cause of both acute and chronic liver disease, can be detected by measurement of viral antigens and antibodies to them.

Figure 5.6 Typical frequencies (%) of occurrence of autoantibodies in autoimmune liver diseases.

Diagnostically useful changes in the concentrations of other plasma proteins are shown in Figure 5.7.

Figure 5.7 Plasma proteins of diagnostic value in liver disease.

Liver disease

Acute hepatitis

Acute hepatitis is usually caused by viral infection (particularly with hepatitis viruses A, B, C, D and E but also Epstein–Barr virus and cytomegalovirus) or toxins (e.g. alcohol, carbon tetrachloride, various fungal toxins and a host of drugs, of which the most frequently implicated is probably paracetamol (acetaminophen)). There is considerable variation in the severity and time course of the disease, but the pattern of changes in the standard liver function tests reflects the common underlying pathological process and is similar whatever the cause.

Patients may present with jaundice but there is often a pre-icteric stage with relatively non-specific symptoms such as anorexia and malaise. Infection with hepatitis A usually occurs in children and is often asymptomatic (it is less likely to be so in adults); hepatitis E is endemic in many areas of the world but is infrequently acquired in the UK.

Early in the course of acute hepatitis, bilirubin and urobilinogen are usually readily detectable in the urine by a simple dip-stick technique. For as long as the plasma bilirubin is raised, bilirubin continues to be excreted in the urine. Urobilinogen may disappear from the urine at the height of the jaundice, when, because of cholestasis, no bilirubin reaches the gut, but it reappears as the hepatitis resolves and biliary excretion returns to normal. These changes (Fig. 5.8) are of no practical value in the management of hepatitis, but the detection of bilirubin in the urine is a simple and valuable diagnostic pointer to hepatitis in the pre-icteric stage of the illness.

Figure 5.8 Typical biochemical changes during acute hepatitis. N, normal.

Many cases of viral hepatitis resolve completely. In severe cases, hepatic failure may develop (fulminant hepatitis), but most patients who survive the acute illness eventually recover completely, aminotransferase activities falling to normal in 10–12 weeks. In some cases of infection with hepatitis B and C viruses, aminotransferase activities remain elevated; antigenaemia persists and chronic liver disease ensues. Infection with hepatitis A or E never leads to chronic disease, although some patients experience prolonged cholestasis with hepatitis E. Infection with hepatitis E carries a particular risk (to the mother and the fetus) during pregnancy.

 Case history 5.1

A 20-year-old student developed a flu-like illness with loss of appetite, nausea and pain in the right hypochondrium. On examination, the liver was just palpable and was tender. Two days later, he developed jaundice, his urine became darker in colour and his stools became pale.

Investigations

	On presentation	1 week later
Serum: bilirubin	38 µmol/L	230 µmol/L
albumin	40 g/L	38 g/L
AST	450 U/L	365 U/L
ALP	70 U/L	150 U/L
GGT	60 U/L	135 U/L
Urine: bilirubin	positive	positive
urobilinogen	positive	negative

Comment

The first set of results is characteristic of early hepatitis, with a raised aminotransferase (AST) activity reflecting cell damage. This usually precedes the rise in bilirubin and the development of jaundice. Impairment of the hepatic secretion of conjugated bilirubin and of urobilinogen uptake from the portal blood causes both these substances to be excreted in the urine.

The second set of results shows the expected high serum bilirubin but with a fall in AST as the phase of maximum cellular damage has passed. An increase in ALP, usually of not more than three times the ULN, is common at this stage. In hepatitis, the bilirubin in plasma is both conjugated and unconjugated, with the former predominating. Conjugated bilirubin is excreted in the urine and the pale stool reflects the decreased biliary excretion. The albumin concentration has remained normal in this acute illness.

Acute liver failure

This term encompasses a range of clinical syndromes of severe liver dysfunction and encephalopathy (neuropsychiatric dysfunction) developing within six months of the first clinical evidence of disease. It is also referred to as fulminant hepatic failure.

Acute liver failure can be hyperacute (encephalopathy developing within seven days of the onset of jaundice), acute (7–28 days) or sub-acute (jaundice preceding encephalopathy by 5–12 weeks). It is a rare condition: toxins and drugs (e.g. paracetamol) and viral hepatitis are the most frequent causes. The underlying hepatic lesion is usually potentially reversible, as the liver has a considerable capacity for regeneration, but the metabolic disturbance is profound and the prognosis poor: acute hepatic failure is often accompanied by renal failure.

Metabolic features of acute hepatic failure include severe hyponatraemia, hypocalcaemia and hypoglycaemia. Hydrogen ion homoeostasis is frequently disturbed. Lactic acidosis may develop as a result of the failure of hepatic gluconeogenesis from lactate, but may be masked by a respiratory alkalosis caused by toxic stimulation of the respiratory centre. Generalized depression of the brainstem may lead to respiratory arrest. In some cases (although not usually with paracetamol poisoning), a metabolic alkalosis predominates: this is in part related to excessive urinary potassium loss, due to intracellular potassium depletion and secondary aldosteronism, and in part to the accumulation of basic substances, such as ammonia, in the blood.

Despite the fact that renal failure may also be present, the plasma urea concentration is often relatively low, reflecting decreased hepatic synthesis. The plasma creatinine concentration is theoretically a more reliable guide both to renal function and to whether the patient should be haemodialysed, but some methods of measuring creatinine are subject to interference by bilirubin and produce invalid results in patients with jaundice. The prothrombin time is greatly prolonged as a result of impaired hepatic synthesis of clotting factors, and bleeding is an almost universal clinical problem.

Hepatic encephalopathy is the term used to describe the reversible neuropsychiatric syndrome that can occur in both acute and chronic liver failure: it is discussed on p. 94. Patients with acute liver failure are at particular risk of developing raised intracranial pressure, for which the first-line treatment is intravenous mannitol. This acts by increasing plasma hyperosmolality and necessitates its monitoring.

Management

Management involves support of vital functions and correction of the metabolic imbalances. Respiratory failure may necessitate artificial ventilation and renal replacement treatment may be required if renal failure occurs. Close cooperation between the laboratory and clinical staff is vital in the management of acute hepatic failure. Techniques for artificial hepatic support include systems based on dialysis using a high flux membrane impregnated with albumin, and bioartificial devices based on cultured hepatocytes. Both techniques have shown some success, but can only provide temporary support while the patient’s own liver undergoes regeneration. In severe disease, the liver may be damaged to an extent that prevents regeneration, and only hepatic transplantation offers a prospect of long-term survival.

The use of liver transplantation as treatment for acute hepatic failure has highlighted a need for good prognostic information. Factors that are considered include the aetiology of the liver failure, rapidity of onset, severity of acidosis, presence of renal failure, severity of encephalopathy and any relative or absolute contraindications. The most useful laboratory test is the prothrombin time, a value of >50 s (INR > 4) indicating a very poor prognosis.

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