Bilirubin

Bilirubin pigment is a breakdown product of the haem moiety of haemoglobin (Fig. 16.2). It is produced at sites of red cell destruction (e.g. spleen) and circulates in the blood in an unconjugated water-insoluble form bound to albumin. In the liver it is conjugated to glucuronic acid by the enzyme glucuronyl transferase. Conjugated bilirubin is water-soluble and can therefore appear in the urine if the outflow of bile from the liver is interrupted; the patient’s urine then becomes stained with conjugated bilirubin. Bilirubin is converted by bacteria in the intestine to faecal urobilinogen (stercobilinogen), some of which is absorbed and then excreted, mostly in the bile to complete its enterohepatic circulation or, in only trace amounts normally, by the kidneys to appear in the urine as urobilinogen. Stercobilinogen is oxidised to stercobilin (faecal urobilin), the principal faecal pigment.

Fig. 16.2 Simplified pathways of bilirubin metabolism. Excessive breakdown of haemoglobin, as in haemolytic anaemias, will lead to increased biliary excretion of bilirubin. Biliary obstruction will cause regurgitation of conjugated water-soluble bilirubin into the blood which is then excreted in the urine, causing it to darken. Liver cell damage in hepatitis will cause impaired biliary excretion of urobilinogen and conjugated bilirubin; these are excreted in the urine, causing it to darken. The enterohepatic circulation, which involves urobilinogen, also returns cholic acid and chenodeoxycholic acid to the liver; this enhances bile secretion.

In early or recovering viral hepatitis, impaired biliary excretion results in preformed stercobilinogen appearing in the urine in excess as urobilinogen; this is one sensitive marker of early liver injury. In well-established biliary obstruction, the urinary urobilinogen concentration falls, because the cessation of biliary excretion into the gut results in sustained absence of synthesis of faecal urobilinogen.

Enzymes

In liver cell injury, damage to the membranes of cells and their organelles allows intracellular enzymes to leak into the blood, where the elevated concentrations can be measured. Examples include ALT, AST and GGT. Their diagnostic usefulness is summarised in Table 16.1.

The enzyme alkaline phosphatase is normally present in bile. Obstruction to the flow of bile, by gallstones for example, causes regurgitation of alkaline phosphatase into the blood, resulting in increased serum concentrations.

Many of these enzymes are not exclusively specific to the liver; therefore the results of diagnostic serum assays need careful interpretation.

Albumin

Albumin is a major serum protein synthesised by the liver cells. It has a relatively long half-life, compared to that of clotting factors (see below), so liver damage has to persist before decreased serum levels are found. In chronic liver disease, such as cirrhosis, a low serum albumin concentration is an important manifestation of liver failure, which results in peripheral oedema and contributes to the presence of ascites due to a reduction in plasma oncotic pressure.

Clotting factors

Liver cells synthesise the vitamin K-dependent clotting factors, deficiency of which results in a bleeding tendency. This can be detected in the laboratory by measuring the prothrombin time. A prolonged bleeding and prothrombin time is a further manifestation of liver failure and, because these clotting factors have a relatively short half-life, deficiency may be found quite early in the course of the illness. The prothrombin time should be measured before performing a liver biopsy or undertaking surgery on a patient with liver disease to avoid the risk of unexpected haemorrhage. These clotting factor deficiencies can be corrected by administration of high doses of vitamin K or of the clotting factors themselves.

Pre-hepatic jaundice

The main cause of pre-hepatic jaundice is haemolysis, due for example to hereditary spherocytosis or autoimmune red cell destruction (see Ch. 23). In these conditions there is excessive production of bilirubin from the haemoglobin released from lysed red cells. Because the excess bilirubin is unconjugated, it is not excretable in the urine; the urine colour is normal (hence the synonym ‘acholuric jaundice’). The bile, however, may contain so much bilirubin that there is a risk of pigment gallstone formation.

Intrahepatic jaundice

Hepatic disorders in which jaundice may be a feature include:

In these conditions there is accumulation of bilirubin within the liver (intrahepatic cholestasis), often histologically evident in biopsies as plugs of bile pigment distending canaliculi. The excess bilirubin is predominantly conjugated, is therefore water soluble and is excreted in the urine, causing darkening; this is a simple but diagnostically useful observation.

Post-hepatic jaundice

Obstruction of the extrahepatic bile ducts is an important cause of jaundice necessitating urgent investigation and alleviation in order to prevent serious damage to the liver. Important causes are:

As with intrahepatic causes, some of which also directly interfere with biliary drainage (e.g. primary biliary cirrhosis, sclerosing cholangitis), the excess bilirubin is conjugated and darkens the urine. Conversely, the patient’s faeces are pale. Pruritus is a common and troublesome symptom, probably due to bile salt accumulation.

Aetiology

The major causes of acute liver injury are:

Direct physical injury to the liver, such as laceration in a road traffic accident, is another important form of acute liver injury, but the focal nature of the injury contrasts with the diffuse injury produced by the agents listed above. Recovery from acute liver injury, focal or diffuse, is attributable to the capacity of the organ for cellular regeneration.

Clinicopathological features

The clinical and laboratory manifestations of acute liver injury are:

Most of the signs and symptoms of acute liver damage are predictable from the known functions of the liver. The best known is jaundice (or icterus) due to failure of the liver to secrete bile at the rate at which it is formed in the body from the destruction of red cells. Severe acute liver damage can lead to bruising and haemorrhage, due to clotting factor deficiency, and coma due to the accumulation of toxic metabolites that mimic neurotransmitters (‘false neurotransmitters’).

Laboratory investigations

Laboratory investigations will reveal evidence of liver cell damage, in that there will be elevated levels of serum enzymes, particularly the transaminases, and bilirubin. Liver cell damage results in some impairment of bilirubin conjugation, but also failure to excrete conjugated bilirubin and any stercobilinogen absorbed from the gut. Consequently, the urine is darkened by the presence of excess conjugated bilirubin and urobilin (derived by oxidation from urobilinogen) that cannot be excreted by the liver (Fig. 16.2). Eventually, as the liver damage persists, urobilinogen disappears from the urine because little or no bilirubin is being excreted by the liver. Jaundice due to bile duct obstruction—commonly by gallstones—also results in dark urine due to excess conjugated bilirubin that cannot be excreted by the liver; urobilinogen is usually absent, unless the obstruction is of very recent onset or intermittent, because no bilirubin reaches the intestine. Examination of urine and faeces (for colour) can therefore assist in the differential diagnosis of jaundice (Table 16.2).

Histology

In almost all cases of acute liver injury there will be liver cell degeneration or death and an inflammatory reaction. Superimposed on this uniform reaction to acute injury are, in many cases, diagnostic changes specific to the causative agent.

Also evident in liver biopsies will be the pattern of cell damage, from which the prognosis can be deduced (Fig. 16.3):

Fig. 16.3 Patterns of liver cell death and their clinicopathological significance. Death of the liver cells immediately surrounding central veins denotes cardiac failure, some other impediment to venous drainage, or some toxic cause (e.g. paracetamol overdose). Bridging necrosis (in acinar zone 3) is a feature of severe hepatitis. Interface hepatitis is death of liver cells at the margin of the portal tracts; this is a feature of chronic hepatitis due to a variety of causes. Apoptotic death of single cells is typical of acute viral hepatitis.

Hepatitis viruses

The main hepatitis viruses (Table 16.3) are:

These hepatitis viruses are immunologically distinct. Infection usually confers life-long immunity to the infecting virus but not to the others.

The clinical features range from a trivial illness without jaundice (anicteric hepatitis) which may escape detection (this is a common result of HAV infection) to a more significant illness with jaundice and other clinical evidence of disturbed liver function. Sometimes the illness is dominated by jaundice, with little elevation of serum transaminases (cholestatic hepatitis). Severe infection leads to overt liver failure.

Yellow fever, caused by a group B arbovirus, shares many clinical and histological features with the illness usually designated viral hepatitis, but it is not normally included within this group for the purposes of description, mainly because its geographical distribution is very restricted.

The liver may also become infected by many other viruses, but these are not regarded as ‘hepatitis viruses’ because the infection is not confined to the liver. Examples include:

Hepatitis B virus

The main characteristics of hepatitis B are:

• spread by blood, blood-contaminated instruments, blood products and venereally

• relatively long incubation period

• liver damage by antiviral immune reaction

• carrier state exists

• relatively serious infection.

Infection by HBV used to be called ‘serum hepatitis’ because it was known to be transmitted by blood and blood products. This is because infected, but apparently healthy, individuals can carry the virus in their blood and pass it on to others by the transfusion of blood or its products. This mode of transmission is much less common now that blood donors are screened by testing for the presence of the virus. However, the term ‘serum hepatitis’ has been abandoned because it misleadingly excludes transmission of the virus by other methods, notably venereally; the disease is often transmitted between homosexual males. HBV can also be transmitted by contaminated needles, such as may be used for tattooing or by drug addicts. There is a relatively high incidence of the carrier state in underdeveloped countries and the virus can be transmitted vertically from mother to child—in utero, during delivery or through intimate post-natal contact.

Specific diagnosis is made by seeking the hepatitis B surface antigen (HBsAg, formerly known as ‘Australia antigen’ because it was first detected in the serum of an Australian aborigine). The presence of the ‘e’ antigen (HBeAg) in the patient’s serum indicates active viral replication.

HBV produces liver cell damage not by a direct cytopathic effect but by causing viral antigens to appear on the cell surface (HBsAg); these are then recognised by the body’s immune system and the infected liver cells are destroyed (Fig. 16.4). Thus, if immunity is generally impaired or there is specific tolerance to the antigen, the virus can survive in the liver cells without causing damage; such patients become asymptomatic carriers of the virus and their body fluids are a hazard to other individuals. Liver biopsies of HBV-infected carriers show that the liver cells have a ground-glass texture to their cytoplasm due to the abundance of virus particles.

Fig. 16.4 Comparison of the pathogenesis of HAV and HBV hepatitis. The A virus, in contrast to the B virus, appears to be directly cytopathic. The B virus evokes liver cell injury by causing viral antigens to be expressed on the liver cell surface (HBsAg, hepatitis B surface antigen). The infected cells are eliminated immunologically, but an asymptomatic carrier state can ensue in the absence of specific immunity. The pathogenesis of other hepatitis viral infections is less certain.

HBV infection is much more serious than HAV. Infection is more likely to produce a clinical illness and jaundice, and it is more likely to result in long-term sequelae such as chronic hepatitis and cirrhosis, or even death due to fulminating acute infection causing extensive hepatic necrosis. HBV is also involved in the pathogenesis of liver cell carcinoma.

Histology

Histological features of acute viral hepatitis are:

Although the pathogenesis of the liver cell damage resulting from HAV and HBV infection is different, the changes in the liver in a typical case are very similar (Fig. 16.5). The principal features are:

Fig. 16.5 Liver histology in acute viral hepatitis. There is disarray of the liver cell plates, accompanied by an inflammatory infiltrate and liver cell apoptosis (arrowed).

The swelling of liver cells, portal oedema and the infiltration by inflammatory cells are responsible for hepatomegaly in viral hepatitis.

In severe viral hepatitis there may be confluent liver cell death, resulting in liver failure. At autopsy the liver will be small, have a wrinkled instead of a smooth capsule, and show extensive necrosis on the cut surfaces.

HCV infection often results in numerous lymphocytes within the vascular sinusoids and fatty change in the hepatocytes, sometimes with relatively little evidence of active liver cell death. This combination of features is unusual in HAV or HBV infection.

Histology

The fatty change (steatosis) is evident as fat globules within the cytoplasm of the liver cells; those in the centrilobular or acinar zone 3 areas are usually most severely affected. Fatty change by itself is a relatively non-specific event because it is seen in many disorders. More specific, but not exclusive, to alcoholic liver injury is Mallory’s hyalin; this is an intracytoplasmic aggregate of ubiquinated intermediate filaments in the liver cells (Fig. 16.6). This is usually accompanied by acute inflammation and, in contrast to pure fatty change, denotes an appreciable risk of progression to irreversible architectural disturbance and possibly cirrhosis.

Fig. 16.6 Histology of alcoholic liver disease. Fatty change is conspicuous, and there is Mallory’s hyalin (arrowed) in the cytoplasm of an injured hepatocyte.

Pathogenesis

Alcohol produces liver injury by a variety of mechanisms (Fig. 16.7):

Fig. 16.7 Pathogenesis of alcoholic liver disease. There is increased peripheral release of fatty acids, and increased synthesis of fatty acids and triglycerides within the liver cells. Acetaldehyde, a product of alcohol metabolism, is probably responsible for liver cell injury, manifested by the formation of Mallory’s hyalin. There is increased collagen synthesis by fibroblasts and by the perisinusoidal cells of Ito.

Sustained alcoholic liver injury results in irreversible architectural disturbance, initially the linking of portal tracts and/or terminal hepatic venules by fibrous tissue, and ultimately nodular regeneration of the liver cells; this is alcoholic cirrhosis.

Recommended safe limits for alcohol continue to be debated. However, the current consensus is that, in men, up to 21 units of alcohol per week is unlikely to be harmful. In women, the safe limit is usually regarded as 14 units of alcohol per week. (One unit of alcohol is 10 ml by volume, equivalent to: half a pint, or c. 300 ml, of beer; or 25 ml of spirits. A small glass of wine contains 1.5 units.)

Aetiology

Chronic hepatitis is due to a variety of causes. Important causes include:

Classification

Classification of chronic hepatitis involves assessment of:

Clues to the aetiological type of chronic hepatitis can be discovered from examination of the liver biopsy (Table 16.4), but in most cases the cause of the liver disease is already known from previous investigations (e.g. markers of HBV or HCV infection). The main purpose of the biopsy is to assess the severity of the liver damage and thereby to guide decisions about the patient’s clinical management.

The grade of severity of the liver cell damage and inflammation is based on assessment of:

Fig. 16.9 Histology of interface hepatitis. Degenerate liver cells adjacent to the edge of a portal tract are associated with dense inflammatory cell infiltration. This leads to progressive erosion of liver architecture, frequently culminating in cirrhosis.

Each of these features is scored using published protocols, such as those devised by Ishak and others, to derive a total histological activity index. This numerical score can then be translated into a named grade of severity, which may be minimal, mild, moderate or severe chronic hepatitis (Fig. 16.10). The greater the severity, the greater the risk of progression to significant architectural disturbance or, eventually, cirrhosis.

Fig. 16.10 Histology of mild chronic hepatitis. The dense lymphocytic infiltrate is confined to the portal tract (arrowed) and there is no erosion of hepatic architecture. This grade of activity progresses only rarely to cirrhosis.

The stage of the architectural disturbance is also assessed histologically and ranges from normal architecture, fibrous enlargement of portal tracts, bridging fibrosis, to cirrhosis. The greater the disturbance, the less likely it is to be reversible when the inflammatory activity has subsided.

Haemosiderosis

Haemosiderosis usually results from parenteral iron overload, as in the case of a patient with aplastic anaemia treated with blood transfusions. In this instance, the iron liberated from eventual lysis of the transfused blood cells cannot be reutilised in the patient for haemoglobin synthesis because of absence of haemopoiesis, so it accumulates in various organs, notably in the liver where it is stored as haemosiderin, mainly in Kupffer cells. Haemosiderosis is not commonly associated with significant liver damage or progression to cirrhosis; however, if cirrhosis does develop as a result of massive iron overload by this mechanism, the condition is referred to as secondary haemochromatosis.

Haemosiderosis can also occur in alcoholic liver disease because alcohol enhances iron absorption from the gut. Any hepatic architectural disturbance is more likely to be due to the alcohol than the iron in these cases.

Primary (genetic) haemochromatosis

Primary haemochromatosis is the most common form of iron overload. It is an inherited autosomal recessive (except for a rare autosomal dominant type) disease usually due to HFE gene defects (most commonly a C282Y mutation) on chromosome 6 near the HLA-A locus. Heterozygotes have increased absorption of iron, but only in homozygotes does this reach dangerous levels. The defect causes excessive absorption of iron in the small intestine even when transferrin, the iron-binding protein in the blood, is fully saturated. By adult life the total body iron stores may reach as high as 40–60 g (normal about 4 g). The disease is clinically manifested more commonly in men than women; pre-menopausal women compensate for the excessive iron absorption through natural iron loss due to menstrual bleeding.

For many years the iron is deposited, as haemosiderin, in the hepatocytes without any clinical effects. Eventually, however, the iron deposition becomes more extensive, involving Kupffer cells, bile duct epithelium and portal tract connective tissue (Fig. 16.11). Hepatic fibrosis ensues, followed by cirrhosis. In advanced cases the haemosiderin is deposited in other tissues, notably in endocrine organs; the clinical syndrome of ‘bronze diabetes’ is due to concomitant iron-induced damage to the pancreatic islets (resulting in diabetes) and the effect of raised melanotrophin levels on the skin (resulting in bronze coloration). Cardiac failure and impotence may also result.

Fig. 16.11 Histology of haemochromatosis. The portal tract and the liver cells contain brown granules of haemosiderin. This has caused portal fibrosis and, if untreated, will eventually lead to cirrhosis.

If the condition is diagnosed in the pre-cirrhotic phase, the process may be arrested by depleting the body’s iron stores by regular venesection or by the administration of desferrioxamine, a chelating agent. The genetic aetiology of primary haemochromatosis means that it is important to screen first-degree relatives to identify those at risk from this potentially treatable liver disease.

Secondary haemochromatosis

Unlike primary haemochromatosis, secondary haemochromatosis is not a single discrete disease entity. It may be due to increased iron in the diet (e.g. excessive medicinal iron tablets) or to parenteral iron loading. For example, secondary haemochromatosis may be seen in patients with aplastic anaemia and haemoglobinopathies who have received multiple transfusions. It is possible, however, that the liver damage in some cases is due to co-existent post-transfusion viral hepatitis rather than iron overload.

Autoimmune hepatitis

Females > males

Liver biopsy shows chronic hepatitis, often with plasma cells and liver cell rosettes

Anti-smooth muscle, antinuclear or anti-LKM antibodies, raised IgG and transaminases

Autoimmune hepatitis occurs more commonly in females and is characterised histologically by the appearance of chronic hepatitis, often dominated by numerous plasma cells and rosette-like arrangements of swollen liver cells. Formerly called ‘lupoid’ hepatitis, it is not related to systemic lupus erythematosus, although it shares the presence of antinuclear antibodies in the serum with that condition. Auto-antibodies to smooth muscle antigens or to nuclear DNA or to liver–kidney microsomal (LKM) antigens are also often present. Associated biochemical factors include raised serum IgG and transaminases. Patients often benefit from treatment with steroids.

Primary biliary cirrhosis

Females > males

Liver biopsy shows bile duct destruction, granulomas, ductular proliferation, fibrosis, and eventual cirrhosis

Raised IgM and alkaline phosphatase, anti-mitochondrial antibody, pruritus, jaundice, xanthelasmas

Primary biliary cirrhosis is misleadingly named because cirrhosis is a late manifestation of the disease and many patients have the condition diagnosed before this stage is reached.

The stages in the development of the disease are:

Fig. 16.12 Histology of primary biliary cirrhosis. Lymphocytes surround a bile duct, the epithelium of which is damaged as a result of the autoimmune process.

Copper accumulates in the liver cells because it can no longer be adequately excreted in the bile.

In addition to the biopsy appearances, which may not be absolutely diagnostic in the later stages, other important features of primary biliary cirrhosis include:

Morphological classification

Classified by the average size of the regeneration nodules, cirrhosis may be:

A cirrhotic liver intermediate between these two categories is described as ‘mixed’.

One of the commonest causes of micronodular cirrhosis is alcoholic liver disease. The significance of macronodular cirrhosis, irrespective of cause, is that it is believed to carry a greater risk of complication by liver cell carcinoma. Macronodular cirrhosis may also be difficult to diagnose with certainty in needle biopsies because the abnormal architecture is not often revealed fully in such small tissue samples.

Aetiological classification

The aetiological classification of a cirrhotic liver can often be deduced from clinical, biochemical, immunological or biopsy features (Fig. 16.14). Important causes include:

Fig. 16.14 Common causes of cirrhosis.

In countries such as the UK, alcohol is one of the commonest causes. If the cause is unknown, then the cirrhosis is labelled cryptogenic (hidden cause) or idiopathic, although with modern investigations the proportion of cases thus designated is falling.

Liver failure

Liver failure results in:

Cirrhosis may be functionally compensated or decompensated. Indeed, if the disease process that led to the cirrhosis is now inactive, then there may be no detectable abnormalities of liver function. Liver failure is a manifestation of decompensation (Table 16.5) and is characterised clinically by:

Table 16.5 Pathophysiological basis of clinical features of chronic liver disease

Hepatic encephalopathy is due to the failure of the liver to eliminate toxic nitrogenous products of gut bacteria; some of these mimic the effect of neurotransmitters (i.e. they are ‘false neurotransmitters’). Renal failure may also occur with hepatic failure (hepato-renal syndrome). The patient’s breath has a characteristic odour (fetor hepaticus).

Failure to eliminate endogenous steroid hormones results in secondary hyperaldosteronism, causing sodium and water retention and, in the male, loss of secondary sexual characteristics and gynaecomastia due to hyperoestrogenism. ‘Spider naevi’ are small vascular lesions on the skin, commonly seen in pregnancy, associated with hyperoestrogenism in cirrhosis.

Defective Kupffer cell function may be responsible for the increased incidence of bacteraemia in patients with cirrhosis, sometimes in the absence of other manifestations of liver failure.

Portal hypertension

Cirrhosis is the commonest cause of portal hypertension (Fig. 16.15). In cirrhosis, the increased blood pressure (>7 mmHg) in the hepatic portal vein is due to a combination of:

Fig. 16.15 Causes and pathogenesis of portal hypertension. Portal hypertension may be due to haemodynamic abnormalities proximal or distal to the sinusoids or at the sinusoidal level. Increased portal vascular resistance and intrahepatic shunting between high-pressure hepatic arterial and low-pressure portal venous channels are postulated explanations for portal hypertension in cirrhosis.

Portal hypertension leads to oesophageal varices (Fig. 16.16) and haemorrhoids (because normal anastomoses between the portal and systemic venous systems at these sites are enlarged) and also contributes to the development of ascites. Oesophageal varices are a particularly serious complication because these thin-walled dilated veins are prone to rupture, causing massive haematemesis which can be fatal. Other manifestations of portal hypertension include the less common ‘caput medusae’ around the umbilicus. Portal hypertension may be further complicated by portal vein thrombosis; this complication can lead to sudden clinical deterioration.

Fig. 16.16 Oesophageal varices. The gastro-oesophageal junction has been sliced to reveal numerous dilated, thin-walled veins in a cirrhotic patient who died from a massive haematemesis.

Liver cell carcinoma

Cirrhosis is a premalignant condition; it is associated with liver cell dysplasia and an increased risk of liver cell carcinoma. The tumour often appears to be multifocal, arising at multiple sites within the liver. The risk is greatest in macronodular cirrhosis and applies to all aetiological types. Liver cell carcinoma is considered in more detail below.

Liver cell adenoma

Liver cell adenoma is a benign, well-differentiated neoplasm of liver cells. It forms a well-circumscribed nodule, with a texture and colour resembling that of the normal liver. Adenomas may arise spontaneously, but an increased incidence occurs in patients taking anabolic, androgenic or oestrogenic steroids. They may be clinically silent or cause hepatomegaly. Occasionally haemoperitoneum due to spontaneous rupture may be the first manifestation.

Angioma

Angioma, a benign vascular neoplasm, is sometimes multiple, rarely exceeding a few centimetres in diameter. Angiomas are rarely of clinical significance, but they may be mistaken for something more sinister when found unexpectedly during a laparotomy.

Bile duct hamartoma

Bile duct hamartomas are not strictly tumours but are tumour-like congenital malformations. They are usually small and often multiple, sometimes referred to as von Meyenberg complexes. They are often seen in association with congenital hepatic fibrosis.

Focal nodular hyperplasia

Focal nodular hyperplasia is neither a true neoplasm nor, despite its name, a hyperplastic disorder; it is thought to be hamartomatous. It is usually solitary and up to 50 mm in diameter. At its centre is a stellate mass of fibrous connective tissue in which there are numerous small bile ducts. The rest of the lesion comprises liver cells and vascular sinusoids. These lesions are usually clinically silent, but they can become abnormally vascular, enlarge and rupture in patients receiving oestrogenic steroids such as oral contraceptives.

Metastases

The commonest malignant neoplasms in the liver are metastases from primary lesions in another organ. These metastases usually form multiple deposits with central necrosis, causing an umbilicated appearance when they are visible on the liver surface. They are usually white unless they are derived from a malignant melanoma, in which case they may be dark brown or black. Common primary origins for hepatic metastases include the entire gastrointestinal tract, including pancreas and bowel, the lung and the breast.

Metastases receive their vascular supply from the hepatic arterial system. This is sometimes selectively perfused with cytotoxic drugs or artificially embolised to induce infarction.

Liver cell carcinoma

Liver cell carcinoma (hepatocellular carcinoma) is one of the commonest tumours in some parts of the world (Fig. 16.17). Known or suspected aetiological factors include:

Fig. 16.17 Geographic areas of high incidence of liver cell carcinoma. The tumour occurs in all countries, particularly in patients with cirrhosis. Regions with a well-documented, very high incidence are shaded.

Fig. 16.18 Liver cell carcinoma arising in a cirrhotic liver. Cirrhosis is a pre-neoplastic condition. Several tumour nodules are present, perhaps reflecting the multifocal origin in cirrhotic livers.

Various growth patterns are recognised, resembling to a variable extent the normal trabecular arrangement of liver cells. If the tumour is sufficiently well differentiated it retains the capacity to secrete bile, so that the tumour and any metastases from it appear bile-stained. In cirrhotic livers, liver cell carcinomas are often multifocal.

A type of liver cell carcinoma with specific features is the fibrolamellar variant in which the neoplastic liver cells are arranged in broad bands or lamellae separated by dense fibrous tissue. This variant occurs most often in young women, without cirrhosis as a predisposing cause.

Liver cell carcinomas often produce alpha-fetoprotein. This is a normal serum protein of the fetus, synthesis of which declines towards the end of gestation when it is replaced by albumin. Alpha-fetoprotein is secreted by the tumour cells into the patient’s blood, where it is a useful diagnostic marker.

Cholangiocarcinoma

Cholangiocarcinoma is an adenocarcinoma of bile duct epithelium. In liver biopsies this gland-forming neoplasm can be extremely difficult to distinguish from metastatic adenocarcinoma from some other organ. Known aetiological factors include infestation with the Chinese liver fluke Clonorchis sinensis and with Opisthorchis viverrini, both of which induce recurrent pyogenic cholangitis (‘oriental cholangitis’). There is also an increased incidence of cholangiocarcinoma in patients with ulcerative colitis, particularly in those who have developed sclerosing cholangitis.

Angiosarcoma

This highly malignant neoplasm originates from the endothelium of the vascular sinusoids and infiltrates the liver by spreading along the vascular sinusoids. Known aetiological factors include vinyl chloride, used in the manufacture of polyvinyl chloride (PVC), and administration of the now-obsolete alpha-emitting radiological contrast medium Thorotrast (Ch. 11).

Hepatoblastoma

Hepatoblastoma is a rare malignant neoplasm of the liver occurring almost exclusively in children below the age of 5 years. In a significant proportion of cases it is associated with various developmental abnormalities. Histologically, its growth pattern resembles some features of the embryonic liver, but it is not uncommon to find unexpected tissues such as muscle. The prognosis is poor.

Simple cysts

Simple cysts are common, relatively small (10–20 mm in diameter), and often multiple. Sometimes they are associated with lesions elsewhere, as in the rare von Hippel–Lindau syndrome. They have little or no intrinsic clinical importance.

Hydatid cysts

Hydatid cysts are due to the parasite Echinococcus granulosus. They are usually many centimetres in diameter, have a fibrous laminated wall and contain numerous daughter cysts (Fig. 16.19). Great care must be taken during surgical removal, because spillage of the cyst fluid into the peritoneum may precipitate anaphylactic shock due to the presence of hydatid antigens in a patient already sensitised to them.

Fig. 16.19 Hydatid cyst of the liver. The surgically resected cyst has been opened to reveal the enclosed daughter cysts.

Choledochal cysts

Choledochal cysts are uncommon congenital cysts of the bile ducts which may be intra- or extrahepatic. Their presence predisposes to cholangitis.

Pathogenesis

Cholesterol stones may form if there is an imbalance between the ratio of cholesterol and bile salts; normally, the latter form micelles which have a hydrophilic exterior enclosing the hydrophobic cholesterol. Thus, gallstones can result from:

Pathological effects

The pathological effects of gallstones include (Fig. 16.21):

Fig. 16.21 Pathological effects of gallstones.

Acute cholecystitis

Usually associated with gallstones

Initially sterile, then infected

Complications include empyema and/or rupture

Acute cholecystitis is usually due to obstruction of the outflow from the gallbladder by a gallstone. The initial inflammatory reaction is due to the irritant effects of bile and is therefore usually sterile at this stage. However, stasis of bile predisposes to infection, which then stimulates a more vigorous and often pyogenic acute inflammatory response. The gallbladder wall becomes oedematous, due to increased vascular permeability, and infiltrated with acute inflammatory cells. The lumen distends with pus, and stretching of the wall already weakened by inflammation leads to a risk of perforation and peritonitis. Alternatively, a fistula may form with the second part of the duodenum and allow stones to enter the bowel lumen. Large stones may occasionally lodge at the ileocaecal valve and cause intestinal obstruction (gallstone ileus).

An inflamed gallbladder grossly distended with pus is called an empyema.

Chronic cholecystitis

Invariably associated with gallstones

Fibrosis and Aschoff–Rokitansky sinuses

Chronic cholecystitis may develop insidiously or after repeated episodes of acute cholecystitis.

The gallbladder wall is thickened by fibrosis and is relatively rigid. Thus obstructive jaundice due to gallstones is not usually associated with a palpable gallbladder because the stones will be associated with chronic cholecystitis and therefore a rigid gallbladder. Conversely, obstructive jaundice due to carcinoma of the head of the pancreas often results in a palpable distended gallbladder; this is the pathological basis of Courvoisier’s law.

The thick gallbladder wall has within it Aschoff–Rokitansky sinuses, mucosal herniations (diverticula) often containing inspissated bile or even small stones. The wall bears an infiltrate of chronic inflammatory cells and the blood vessels often show endarteritis obliterans (Fig. 16.22). A stone is often found in Hartmann’s pouch, a pathological dilatation in the neck of the gallbladder formed by increased intraluminal pressure or impaction of the stone.

Fig. 16.22 Histology of chronic cholecystitis. A thickened gallbladder with diffuse chronic inflammatory infiltration and Aschoff–Rokitansky sinuses (arrowed).

A rare variant is xanthogranulomatous cholecystitis in which lipid-laden macrophages and giant cells accumulate in large numbers; this mimics a neoplasm grossly and, specifically, a clear-cell carcinoma histologically. The lesion, like its more common renal counterpart, xanthogranulomatous pyelonephritis, is prone to cause fistulae.

Diseases of intrahepatic bile ducts

A clinical picture similar to that of biliary obstruction can result from diseases of intrahepatic bile ducts such as:

These conditions can usually be distinguished by careful clinical assessment, liver biopsy and imaging techniques.

Acute pancreatitis

Aetiological factors include duct obstruction, shock, alcohol, etc.

Amylase is released into blood (diagnostically useful)

Often haemorrhagic

Fat necrosis in surrounding tissue binds calcium

Aetiology

Acute pancreatitis (Fig. 16.23) may be due to:

• obstruction of the pancreatic duct

• bile reflux

• alcohol, particularly acute intoxication

• vascular insufficiency (e.g. shock)

• mumps virus infection

• hyperparathyroidism

• hypothermia

• trauma

• iatrogenic factors (e.g. after ERCP).

Fig. 16.23 Common causes of pancreatitis.

Although many cases are mild, acute pancreatitis is often a serious disorder with a high mortality. It is more common in adults than in children. The condition is serious because the gland, once injured, releases its lytic enzymes into the blood, contributing to the severe shock, and into the surrounding tissue, causing tissue digestion.

Chronic pancreatitis

Commonest cause is alcohol (long-term excess)

Pancreas shows fibrosis and exocrine atrophy

May result in intestinal malabsorption due to loss of pancreatic secretions

Clinicopathological features

Chronic pancreatitis is more common in adults than in children, and presents with intermittent upper abdominal and back pain and weight loss. A plain X-ray of the upper abdomen often reveals flecks of calcification due to previous fat necrosis. ERCP or MRCP often shows that the pancreatic ducts are distorted by scar tissue resulting from the chronic inflammatory process.

The exocrine tissue is eventually replaced by fibrosis (Fig. 16.24) and, if localised, its hard texture mimics that of a carcinoma when the gland is palpated during laparotomy. The endocrine component of the gland is relatively unaffected except at an advanced stage.

Fig. 16.24 Histology of chronic pancreatitis. There is considerable loss of acini and replacement by fibrosis. Inflammatory cells are relatively inconspicuous at this late stage. Islets of Langerhans (one is arrowed) sometimes escape destruction, but their loss can result in diabetes mellitus.