Chapter 7 Liver, biliary tract and pancreatic disease
GALL BLADDER AND BILIARY SYSTEM
Tumours of the billary tract
In many countries, alcohol is the major cause of liver disease, followed by hepatitis C virus infection. Hepatitis B virus is still a significant factor but widespread vaccination will reduce its prevalence. Non-alcoholic fatty liver disease is associated with the metabolic syndrome and is increasing in affluent countries. Health education and the improvement in public health should help to stop the spread of viral infections and reduce risk factors for metabolic syndrome.
Imaging techniques enable the liver, biliary tree and pancreas to be visualized with precision, resulting in earlier diagnosis. Therapeutic endoscopy, laparoscopic and minimally invasive surgery are now widely available for biliary tract and pancreatic disease. Finally, liver transplantation is established therapy for both acute and chronic liver disease.
Structure of the liver and biliary system
The liver is the body’s largest internal organ (1.2–1.5 kg) and is situated in the right hypochondrium. A functional division into the larger right lobe (containing caudate and quadrate lobes) and the left lobe is made by the middle hepatic vein. The liver is further subdivided into eight segments (Fig. 7.1) by divisions of the right, middle and left hepatic veins. Each segment has its own portal pedicle, permitting individual segment resection at surgery.
Figure 7.1 Segmental anatomy of the liver, showing the eight hepatic segments. I, caudate lobe; II–IV the left hemiliver; V–VIII the right hemiliver.
The hepatic blood supply constitutes 25% of the resting cardiac output and is delivered via two main vessels, entering via the liver hilum (porta hepatis):
The hepatic artery, a branch of the coeliac axis, supplies 25% of the hepatic blood flow. The hepatic artery autoregulates flow ensuring a constant total blood flow.
The portal vein drains most of the gastrointestinal tract and the spleen. It supplies 75% of hepatic blood flow. The normal portal pressure is 5–8 mmHg; flow increases after meals.
The blood from these vessels is distributed to the segments and flows into the sinusoids via the portal tracts.
Blood leaves the sinusoids, entering branches of the hepatic vein which join into three main branches before entering the inferior vena cava.
The caudate lobe is an autonomous segment as it receives an independent blood supply from the portal vein and hepatic artery, and its hepatic vein drains directly into the inferior vena cava.
Lymph, formed mainly in the perisinusoidal space, is collected in lymphatics which are present in the portal tracts. These small lymphatics enter larger vessels which eventually drain into the hepatic ducts.
The acinus is the functional hepatic unit. This consists of parenchyma supplied by the smallest portal tracts containing portal vein radicles, hepatic arterioles and bile ductules (Fig. 7.2). The hepatocytes near this triad (zone 1) are well supplied with oxygenated blood and are more resistant to damage than the cells nearer the terminal hepatic (central) veins (zone 3).
Figure 7.2 Diagram of an acinus. Zones 1, 2 and 3 represent areas supplied by blood, with zone 1 being best oxygenated. Zone 3 is supplied by blood remote from afferent vessels and is in the microcirculatory periphery of the acinus. The perivascular area (star-shaped green area around THV) is formed by the most peripheral parts of zone 3 of several adjacent acini and is the least well oxygenated. THV, terminal hepatic venule; PT, portal triad.
The sinusoids lack a basement membrane and are loosely surrounded by specialist fenestrated endothelial cells and Kupffer cells (phagocytic cells). Sinusoids are separated by plates of liver cells (hepatocytes). The subendothelial space between the sinusoids and hepatocytes is the space of Disse, which contains a matrix of basement membrane constituents and stellate cells (see Fig. 7.23).
Stellate cells store retinoids in their resting state and contain the intermediate filament, desmin. When activated (to myofibroblasts) they are contractile and probably regulate sinusoidal blood flow. Endothelin and nitric oxide play a major role in modulating stellate cell contractility. Activated stellate cells produce signal proteins for synthesis or inhibition of degradation of extracellular matrix components, including collagen, as well as cytokines and chemotactic signals (see p. 328).
The biliary system
Bile canaliculi form a network between the hepatocytes. These join to form thin bile ductules near the portal tract, which in turn enter the bile ducts in the portal tracts. These then combine to form the right and left hepatic ducts that leave each liver lobe. The hepatic ducts join at the porta hepatis to form the common hepatic duct. The cystic duct connects the gall bladder to the lower end of the common hepatic duct. The gall bladder lies under the right lobe of the liver and stores and concentrates hepatic bile; its capacity is approximately 50 mL. The common bile duct is formed at the junction of the cystic and common hepatic duct and is 8 mm in diameter or less, passing through the head of the pancreas, narrowing at its lower end to pass into the duodenum. The common bile duct and pancreatic duct open into the second part of the duodenum most often through a common channel at the ampulla of Vater, which contains the muscular sphincter of Oddi. This contracts rhythmically and prevents all of the bile from entering the duodenum, by maintaining a higher pressure than the gall bladder in the fasting state.
Functions of the liver
Protein metabolism (see also p. 197)
Synthesis and storage
The liver is the principal site of synthesis of all circulating proteins apart from γ-globulins (produced in the reticuloendothelial system). The liver receives amino acids from the intestine and muscles and, by controlling the rate of gluconeogenesis and transamination, regulates plasma levels. Plasma contains 60–80 g/L of protein, mainly albumin, globulin and fibrinogen.
Albumin has a half-life of 16–24 days, and 10–12 g are synthesized daily. Its main functions are to maintain the intravascular oncotic (colloid osmotic) pressure, and to transport water-insoluble substances such as bilirubin, hormones, fatty acids and drugs. Reduced synthesis of albumin over prolonged periods produces hypoalbuminaemia and is seen in chronic liver disease and malnutrition. Hypoalbuminaemia is also found in hypercatabolic states (e.g. trauma with sepsis) and in diseases associated with an excessive loss (e.g. nephrotic syndrome, protein-losing enteropathy).
Transport or carrier proteins such as transferrin and caeruloplasmin, acute-phase and other proteins (e.g. α1-antitrypsin and α-fetoprotein) are also produced in the liver.
The liver also synthesizes all factors involved in coagulation (apart from one-third of factor VIII) – that is, fibrinogen, prothrombin, factors V, VII, IX, X and XIII, proteins C and S and antithrombin (see Ch. 8) as well as components of the complement system. The liver stores large amounts of vitamins, particularly A, D and B12, and lesser amounts of others (vitamin K and folate), and also minerals – iron in ferritin and haemosiderin and copper.
Degradation (nitrogen excretion)
Amino acids are degraded by transamination and oxidative deamination to produce ammonia, which is then converted to urea and excreted by the kidneys. This is a major pathway for the elimination of nitrogenous waste. Failure of this process occurs in severe liver disease.
Glucose homeostasis and the maintenance of the blood sugar is a major function of the liver. It stores approximately 80 g of glycogen. In the immediate fasting state, blood glucose is maintained either by glucose release from breaking down glycogen (glycogenolysis) or by synthesizing new glucose (gluconeogenesis). Sources for gluconeogenesis are lactate, pyruvate, amino acids from muscles (mainly alanine and glutamine) and glycerol from lipolysis of fat stores. In prolonged starvation, ketone bodies and fatty acids are used as alternative sources of fuel as the body tissues adapt to a lower glucose requirement (see Ch. 5).
Fats are insoluble in water and are transported in plasma as protein-lipid complexes (lipoproteins). These are discussed in detail on page 1005.
The liver has a major role in metabolizing of lipoproteins. It synthesizes very-low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs). HDLs are the substrate for lecithin-cholesterol acyltransferase (LCAT), which catalyses the conversion of free cholesterol to cholesterol ester (see below). Hepatic lipase removes triglyceride from intermediate-density lipoproteins (IDLs) to produce low-density lipoproteins (LDLs) which are degraded by the liver after uptake by specific cell-surface receptors (see Fig. 20.19).
Triglycerides are mainly of dietary origin but are also formed in the liver from circulating free fatty acids (FFAs) and glycerol and incorporated into VLDLs. Oxidation or de novo synthesis of FFA occurs in the liver, depending on the availability of dietary fat.
Cholesterol may be of dietary origin but most is synthesized from acetyl-CoA mainly in the liver, intestine, adrenal cortex and skin. It occurs either as free cholesterol or is esterified with fatty acids; this reaction is catalysed by LCAT. This enzyme is reduced in severe liver disease, increasing the ratio of free cholesterol to ester, which alters membrane structures. One result of this is the red cell abnormalities (e.g. target cells) seen in chronic liver disease. Phospholipids (e.g. lecithin) are synthesized in the liver. The complex interrelationships between protein, carbohydrate and fat metabolism are shown in Figure 7.3.
Formation of bile
Bile secretion and bile acid metabolism
Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin. Two processes are involved in bile secretion across the canalicular membrane of the hepatocyte – bile salt-dependent and bile salt-independent processes – each contributing about 230 mL/day. Another 150 mL daily is produced by epithelial cells of the bile ductules.
Bile formation requires uptake of bile acids and other organic and inorganic ions across the basolateral (sinusoidal) membranes by multiple transport proteins (sodium taurocholate co-transporting polypeptide (NTCP) and sodium independent organic anion transporting polypeptide 2 (OATP2), Fig. 7.4). This process is driven by Na+/K+-ATPase in the basolateral membranes. Intracellular transport across hepatocytes is partly through microtubules and partly by cytosol transport proteins.
Figure 7.4 Cholesterol synthesis and its conversion to primary and secondary bile acids. All bile acids are normally conjugated with glycine or taurine. BSEP, bile salt export pump; MRP2, multidrug-resistant protein 2; MDR3, multidrug-resistant 3; OATP2, Na+ independent organic anion-transporting polypeptide 2; NTCP, Na+ taurocholate co-transporting polypeptide.
Bile acids are also synthesized in hepatocytes from cholesterol, the rate-limiting step being those catalysed mainly by cholesterol-7α-hydroxylase and the P450 enzymes (CYP7A1 and CYP8B1).
The bile acid receptor, farnesoid X, blocks bile acid formation from cholesterol and also regulates the transport proteins (NTCP, OATP2) that increase bile acid uptake by the liver. It is target for a new class of therapeutic drugs, farnesoid X receptor (FXR) agonists.
The canalicular membrane contains multispecific organic anion transporters, mainly ATPase dependent (ATP binding cassette), the multidrug-resistance protein 2 (MRP2), multidrug resistance protein (MDR3) and the bile salt excretory pump (BSEP), which carry a broad range of compounds including bilirubin diglucuronide, glucuronidated and sulphated bile acids and other organic anions against a concentration gradient into the biliary canaliculus. Na+ and water follow the passage of bile salts by diffusion across the tight junction between hepatocytes (a bile salt-dependent process). In the bile salt-independent process, water flow is due to other osmotically active solutes such as glutathione and bicarbonate.
Secretion of a bicarbonate-rich solution is stimulated mainly by secretin and is inhibited by somatostatin. This involves several membrane proteins, including the Cl−/HCO3− exchanger and the cystic fibrosis transmembrane conductance regulator which controls Cl− secretion, and water channels (aquaporins) in cholangiocyte membranes.
The bile acids are excreted into bile and then pass via the common bile duct into the duodenum. The two primary bile acids – cholic acid and chenodeoxycholic acid (Fig. 7.4) – are conjugated with glycine or taurine, which increases their solubility. Intestinal bacteria convert these acids into secondary bile acids, deoxycholic and lithocholic acid. Figure 7.5 shows the enterohepatic circulation of bile acids.
Figure 7.5 Recirculation of bile acids. The bile salt pool is relatively small and the entire pool recycles six to eight times via the enterohepatic circulation. Synthesis of new bile acids compensates for faecal loss.
The average total bile flow is 600 mL/day. When fasting half flows into the duodenum and half is diverted into the gall bladder. The gall bladder mucosa absorbs 80–90% of the water and electrolytes, but is impermeable to bile acids and cholesterol. Following a meal, the I cells of the duodenal mucosa secrete cholecystokinin, which, stimulates contraction of the gall bladder and relaxation of the sphincter of Oddi, allowing bile to enter the duodenum. An adequate bile flow is dependent on bile salts being returned to the liver by the enterohepatic circulation.
Bile acids act as detergents; their main function is lipid solubilization. Bile acid molecules have both a hydrophilic and a hydrophobic end. In aqueous solutions they form micelles, with their hydrophobic (lipid-soluble) ends in the centre. Micelles are expanded by cholesterol and phospholipids (mainly lecithin), forming mixed micelles.
Bilirubin is produced mainly from the breakdown of mature red cells by Kupffer cells in the liver and reticuloendothelial system; 15% of bilirubin is formed from catabolism of other haem-containing proteins, such as myoglobin, cytochromes and catalases.
Normally, 250–300 mg (425–510 mmol) of bilirubin are produced daily. The iron and globin are removed from haem and are reused. Biliverdin is formed from haem and then reduced to form bilirubin. The bilirubin produced is unconjugated and water-insoluble, due to internal hydrogen bonding, and is transported to the liver attached to albumin. Bilirubin dissociates from albumin and is taken up by hepatic cell membranes and transported to the endoplasmic reticulum by cytoplasmic proteins, where it is conjugated with glucuronic acid and excreted into bile. The microsomal enzyme, uridine diphosphoglucuronosyl transferase, catalyses the formation of bilirubin monoglucuronide and then diglucuronide. This conjugated bilirubin is water-soluble and is actively secreted into biliary canaliculi and excreted into the intestine within bile (Fig. 8.5). It is not absorbed from the small intestine because of its large molecular size. In the terminal ileum, bacterial enzymes hydrolyse the molecule, releasing free bilirubin which is then reduced to urobilinogen, some of which is excreted in the stools as stercobilinogen. The remainder is absorbed by the terminal ileum, passes to the liver via the enterohepatic circulation, and is re-excreted into bile. Urobilinogen bound to albumin enters the circulation and is excreted in urine via the kidneys. When hepatic excretion of conjugated bilirubin is impaired, a small amount is strongly bound to serum albumin and is not excreted by the kidneys; it accounts for the persistent hyperbilirubinaemia for a time after cholestasis has resolved.
Hormone and drug inactivation
The liver catabolizes hormones such as insulin, glucagon, oestrogens, growth hormone, glucocorticoids and parathyroid hormone. It is also the prime target organ for many hormones (e.g. insulin). It is the major site for the metabolism of drugs (see p. 348) and alcohol (see p. 225). Fat-soluble drugs are converted to water-soluble substances that facilitate their excretion in the bile or urine. Cholecalciferol is converted to 25-hydroxycholecalciferol.
The hepatic reticuloendothelial system contains many immunologically active cells. The liver acts as a ‘sieve’ for bacterial and other antigens carried to it by the portal vein from the gastrointestinal tract. These antigens are phagocytosed and degraded by the Kupffer cells, which have specific membrane receptors for ligands and are activated by several factors, such as infection. They are part of the innate immune system and secrete interleukins, tumour necrosis factor (TNF), collagenase and lysosomal hydrolases. Antigens are degraded without the production of antibody, as there is very little lymphoid tissue and thus, they are prevented from reaching antibody-producing sites and thereby prevent generalized adverse immunological reactions. The reticuloendothelial system also plays a role in tissue repair, T and B lymphocyte interaction, and cytotoxic activity in disease processes. Following stimulation by, for example, endotoxin, the Kupffer cells release IL-6, IL-8 and TNF-α. These cytokines stimulate sinusoidal, stellate, and natural killer, cells to release pro-inflammatory cytokines. The stimulated hepatocytes themselves express adhesion molecules and release IL-8, which is a potent neutrophil chemoattractant. Homing of mucosal lymphocytes (enterohepatic circulation) has been proposed. These exogenous leucocytes again release more cytokines – all damaging the function of the hepatocyte, including bile formation which leads to cholestasis. Cytokines also stimulate hepatic apoptosis.
Investigative tests can be divided into:
Urine tests – for bilirubin and urobilinogen
Imaging techniques – to define gross anatomy
Blood tests ordered for ‘liver function’ are usually processed by an automated multichannel analyser to produce serum levels of bilirubin, aminotransferases, alkaline phosphatase, γ-glutamyl transpeptidase (γ-GT) and total proteins. These routine tests are markers of liver damage, but not actual tests of ‘function’ per se. Subsequent investigations are often based on these tests.
Useful blood tests for certain liver diseases are shown in Table 7.1.
Primary biliary cirrhosis
Anti-nuclear, smooth muscle (actin), liver/kidney microsomal antibody
Raised serum immunoglobulins:
Primary biliary cirrhosis
Hepatitis A, B, C, D, E and others
Serum iron, transferrin saturation, serum ferritin
Serum and urinary copper, serum caeruloplasmin
Cirrhosis (± emphysema)
Anti-nuclear cytoplasmic antibodies
Primary sclerosing cholangitis
Markers of liver fibrosis
Non-alcoholic fatty liver disease
e.g. HFE gene (hereditary haemochromatosis)
Liver function tests
This is a marker of synthetic function and is useful to gauge the severity of chronic liver disease: a falling serum albumin is a bad prognostic sign. In acute liver disease initial albumin levels may be normal.
This is also a marker of synthetic function. Because of its short half-life, it is a sensitive indicator of both acute and chronic liver disease. Vitamin K deficiency should be excluded as the cause of a prolonged PT by giving an intravenous bolus (10 mg) of vitamin K. Vitamin K deficiency commonly occurs in biliary obstruction, as the low intestinal concentration of bile salts results in poor absorption of vitamin K.
Prothrombin times vary in different laboratories depending upon the thromboplastin used in the assay. The International normalized ratio (INR) was developed to standardize anticoagulation with coumarin derivatives, but is very variable in liver disease, and causes large differences when included in prognostic scores for cirrhosis across different centres.
Serum bilirubin is normally almost all unconjugated. In liver disease, increased serum bilirubin is usually accompanied by other abnormalities in liver biochemistry. Differentiation between conjugated or unconjugated bilirubin is only necessary in congenital disorders of bilirubin metabolism (see below) or to exclude haemolysis.
These enzymes (often referred to as transaminases) are contained in hepatocytes and leak into the blood with liver cell damage. Two enzymes are measured:
Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme (80%; 20% in cytoplasm) and is also present in heart, muscle, kidney and brain. High levels are seen in hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure.
Alanine aminotransferase (ALT) is a cytosol enzyme, more specific to the liver so that a rise only occurs with liver disease.
This is present in hepatic canalicular and sinusoidal membranes, but also in bone, intestine and placenta. If necessary, its origin can be determined by electrophoretic separation of isoenzymes or bone-specific monoclonal antibodies. In clinical practice, if the γ-GT is also abnormal the ALP is presumed to come from the liver.
Serum ALP is raised in both intrahepatic and extrahepatic cholestatic disease of any cause, due to increased synthesis. In cholestatic jaundice, levels may be four to six times the normal limit. Raised levels also occur with hepatic infiltrations (e.g. metastases), and in cirrhosis, frequently in the absence of jaundice. The highest serum levels due to liver disease (>1000 IU/L) are seen with hepatic metastases and primary biliary cirrhosis.
This is a microsomal enzyme present in liver, but also in many tissues. Its activity can be induced by drugs such as phenytoin and by alcohol. If the ALP is normal, a raised serum γ-GT can be a useful guide to alcohol intake (see p. 1182). However, mild elevations of γ-GT are common, even with a small alcohol consumption and is also raised with fatty liver disease. It does not necessarily indicate liver disease if the other liver biochemical tests are normal. In cholestasis the γ-GT rises in parallel with the ALP as it has a similar pathway of excretion. This is also true of 5-nucleotidase, another microsomal enzyme that can be measured in blood.
Additional blood investigations
A full blood count may show anaemia. The red cells are often macrocytic and can have abnormal shapes – target cells and spur cells – owing to membrane abnormalities. Vitamin B12 levels are normal or high, while folate levels are often low owing to poor dietary intake. Other changes are caused by the following:
Bleeding produces a hypochromic, microcytic picture.
Alcohol causes macrocytosis, sometimes with leucopenia and thrombocytopenia.
Hypersplenism results in pancytopenia.
Cholestasis can often produce abnormal-shaped cells, and also deficiency of vitamin K.
Haemolysis may accompany acute liver failure and jaundice.
Aplastic anaemia occurs in up to 2% of patients with acute viral hepatitis.
A raised serum ferritin with transferrin saturation (>60%) is seen in hereditary haemochromatosis.
a1-Antitrypsin. A deficiency of this enzyme can produce cirrhosis.
α-Fetoprotein. This is normally produced by the fetal liver. Its reappearance in increasing and high concentrations in adults indicates hepatocellular carcinoma. Increased concentrations in pregnancy in blood and amniotic fluid suggest fetal neural tube defects. Blood levels are also slightly raised with regenerative liver tissue in patients with hepatitis, chronic liver disease and also in teratomas.
Raised urinary copper, and low serum cooper and caeruloplasmin in Wilson’s disease (see p. 341).
Increased γ-globulins are thought to result from reduced phagocytosis by sinusoidal and Kupffer cells of the gut absorbed antigens. These antigens then stimulate antibody production in the spleen, lymph nodes and portal tract lymphoid and plasma cell infiltrates. In primary biliary cirrhosis, the predominant raised serum immunoglobulin is IgM, while in autoimmune hepatitis it is IgG. IgG4 is helpful in autoimmune pancreatitis.
Anti-mitochondrial antibody (AMA) in serum is found in over 95% of patients with primary biliary cirrhosis (PBC) (p. 338). Several different AMA subtypes are described, depending on their antigen specificity, and are also found in autoimmune hepatitis and other autoimmune diseases. AMA is demonstrated by an immunofluorescent technique and is neither organ- nor species-specific. M2 subtype is specific for PBC.
Nucleic, smooth muscle (actin), liver/kidney microsomal antibodies can be found in serum, often in high titre, in patients with autoimmune hepatitis. These serum antibodies can also be found in other autoimmune conditions and other liver diseases.
Anti-nuclear cytoplasmic antibodies (ANCA) can be found in serum of patients with primary sclerosing cholangitis.
Fibrosis plays a key role in the outcome of many chronic liver diseases. Blood tests are being used to detect and quantify fibrosis and thereby decrease the need of liver biopsy. To date, these have been developed mainly for chronic hepatitis C, and less so for non-alcoholic fatty liver disease.
Commercial tests are available which measure α2-macroglobulin, α2-haptoglobulin, γ-globulin, apoprotein A1, γ-GT and total bilirubin. Some are based on age, blood ferritin, glucose, AST, ALT, platelet count and bodyweight. These results are formulated to determine a fibrosis index. The indices are sensitive and specific (>90%) for the absence of fibrosis, and have 80% sensitivity and specificity for severe fibrosis, but cannot reliably assess the severity of fibrosis.
Markers of matrix deposition include procollagen I and III peptide and type IV collagen. Markers of matrix degradation, e.g. matrix metalloproteinase (MMP) 2 and 9, and tissue inhibitors of metalloproteinases (TIMPS), e.g. TIMP1 and 2, all are being used as markers of fibrosis.
AST to platelet ratio index (APRI) is less accurate than the tests mentioned above.
These tests are performed routinely for haemochromatosis (HFE gene) and for α1-antitrypsin deficiency. Markers are also available for the most frequent abnormal genes in Wilson’s disease (see p. 341).
Dipstick tests are available for bilirubin and urobilinogen. Bilirubinuria is due to the presence of conjugated (soluble) bilirubin, is found in patients with jaundice due to hepatobiliary disease, but is absent if unconjugated bilirubin is the major cause of jaundice. The presence of urobilinogen in urine in practice is of little value but suggests haemolysis or hepatic dysfunction.
This is a non-invasive, safe and relatively cheap technique. It involves the analysis of the reflected ultrasound beam detected by a probe moved across the abdomen. The normal liver appears as a relatively homogeneous structure. The gall bladder, common bile duct, pancreas, portal vein and other structures in the abdomen can be visualized. Abdominal ultrasound is useful in:
the detection of gallstones (Fig. 7.6)
focal liver disease – lesions >1 cm
general parenchymal liver disease
assessing portal and hepatic vein patency
Figure 7.6 Gall bladder ultrasound with multiple echogenic gallstones causing well-defined acoustic shadowing. (1) gall bladder; (2) gallstones; (3) echogenic shadow.
Other abdominal masses can be delineated and biopsies obtained under ultrasonic guidance.
Colour Doppler ultrasound will demonstrate vascularity within a lesion and the direction of portal and hepatic vein blood flow (Fig. 7.7).
Figure 7.7 Doppler signal of the portal vein is shown as a trace and the visual counterpart in red showing patency and forward flow into the liver.
Ultrasound contrast agents, mostly based on production of microbubbles within flowing blood, enhance the detection of vascularity, allowing the detection of abnormal circulation within liver nodules, giving a more specific diagnosis of hepatocellular carcinoma.
Hepatic stiffness (transient elastography). Using an ultrasound transducer, a vibration of low frequency and amplitude is passed through the liver, the velocity of which correlates with hepatic stiffness. Stiffness (measured in kPa) increases with worsening liver fibrosis (sensitivity and specificity 80–95% compared to liver biopsy). It is not accurate enough to diagnose cirrhosis, and less accurate for less severe fibrosis. It cannot be used in the presence of ascites and morbid obesity, and it is affected by inflammatory tissue and congestion. Acoustic radiation force impulse is incorporated into standard B mode ultrasonography and has similar physical principles to transient elastography.
A small high-frequency ultrasound probe is incorporated into the tip of an endoscope and placed by direct vision into the lumen of the gut. The close proximity of the probe to the pancreas and biliary tree permits high-resolution ultrasound imaging. It allows accurate staging of small, potentially operable, pancreatic tumours and offers a less invasive method for bile duct imaging. It has a high accuracy in detection of small neuroendocrine tumours of the pancreas. EUS-guided fine-needle aspiration of tumours provides cytological/histological tissue for confirmation of malignancy. EUS is also used to place transmural tubes to drain pancreatic and peripancreatic fluid collections.
Computed tomography (CT) examination
CT during or immediately after i.v. contrast shows both arterial and portal venous phases of enhancement, enabling more precise characterization of a lesion and its vascular supply (Fig. 7.8). Retrospective analysis of data allows multiple overlapping slices to be obtained with no increase in the radiation dose, providing excellent visualization of the size, shape and density of the liver, pancreas, spleen, lymph nodes and lesions in the porta hepatis. Multi-planar and three-dimensional reconstruction in the arterial phase can create a CT angiogram, often making formal invasive angiography unnecessary. CT also provides guidance for biopsy. It has advantages over US in detecting calcification and is useful in obese subjects, although US is usually the imaging modality used first to investigate liver disease.
Magnetic resonance imaging (MRI)
MRI produces cross-sectional images in any plane within the body and does not involve radiation. MRI is the most sensitive investigation of focal liver disease. Diffuse liver disease alters the T1 and T2 characteristics. Other fat-suppression modes such as STIR allow good differentiation between haemangiomas and other lesions. Contrast agents such as intravenous gadolinium, which allow further characterization of lesions, are suitable for those with iodine allergy, and provide angiography and venography of the splanchnic circulation. This has superseded direct arteriography.
Magnetic resonance cholangiopancreatography (MRCP)
This technique involves the manipulation of data acquired by MRI. A heavily T2-weighted sequence enhances visualization of the ‘water-filled’ bile ducts and pancreatic ducts to produce high-quality images of ductal anatomy. This non-invasive technique is replacing diagnostic (but not therapeutic) ERCP (see below), and is usually the next test if a biliary abnormality is present on US examination.
Plain X-rays of the abdomen
These are rarely requested but may show:
Radionuclide imaging – scintiscanning
In a 99mTc-IODIDA scan, technetium-labelled iododiethyl IDA is taken up by the hepatocytes and excreted rapidly into the biliary system. Its main uses are in the diagnosis of:
Upper GI endoscopy is used for diagnosis and treatment of varices, detection of portal hypertensive gastropathy, and for associated lesions such as peptic ulcers. Colonoscopy may show portal hypertensive colopathy. Capsule endoscopy can identify small intestinal varices.
Endoscopic retrograde cholangiopancreatography (ERCP)
This technique outlines the biliary and pancreatic ducts. It involves the passage of an endoscope into the second part of the duodenum and cannulation of the ampulla. Contrast is injected into both systems and the patient is screened radiologically. Contrast medium with a low iodine content of 1.5 mg/mL is used for the common bile duct so that gallstones are not obscured; a higher iodine content of 2.8 mg/mL is used for the pancreatic duct. Diagnostic ERCP has been replaced by MRCP in nearly all clinical settings. Therapeutic ERCP involves the following:
Common bile duct stones can be removed after performing a diathermy cut of the sphincter to facilitate their withdrawal. Sphincterotomy has a morbidity rate of 3–5%: acute pancreatitis is the commonest, severe haemorrhage is rare. There is an overall mortality of 0.4%.
The biliary system can be drained by passing a tube (stent) through an obstruction, or placement of a nasobiliary drain.
Brachytherapy can be administered after placement at ERCP for therapy of cholangiocarcinoma.
A raised serum amylase is often seen following ERCP and pancreatitis is the most common complication. Cholangitis with or without septicaemia is also seen, and broad-spectrum antibiotics (e.g. 500 mg ciprofloxacin × 2) should be given prophylactically to all patients with suspected biliary obstruction, or a history of cholangitis.
Percutaneous transhepatic cholangiography (PTC)
Under a local anaesthetic, a fine flexible needle is passed into the liver. Contrast is injected slowly until a biliary radicle is identified and then further contrast is injected to outline the whole of the biliary tree. In patients with dilated ducts, the success rate is near 100%. PTC is performed if ERCP fails or is likely to be technically difficult.
In difficult cases ERCP and PTC are sometimes combined, PTC showing the biliary anatomy above the obstruction, with ERCP showing the more distal anatomy. If an obstruction in the bile ducts is seen, a bypass stent can usually be inserted with or without temporary external biliary drainage. Contraindications of PTC are as for liver biopsy (see below). The main complications are bleeding and cholangitis with septicaemia, and prophylactic antibiotics should be given as for ERCP.
This is performed by selective catheterization of the coeliac axis and hepatic artery. It outlines the hepatic vasculature and the abnormal vasculature of hepatic tumours, but spiral CT and magnetic resonance scanning have replaced diagnostic angiography. The portal vein can be demonstrated with increased definition using subtraction techniques replacing splenoportography (by direct splenic puncture).
In digital vascular imaging (DVI), contrast given intravenously or intra-arterially can be detected in the portal system using computerized subtraction analysis.
Hepatic venous cannulation allows abnormal hepatic veins to be diagnosed in patients with Budd–Chiari syndrome and is also used to measure portal pressure indirectly. There is a 1:1 relationship of occluded (by balloon) hepatic venous pressure, with portal pressure in patients with alcoholic or viral-related cirrhosis. The height of portal pressure has prognostic value for survival in cirrhosis, and a difference of the occluded minus the free hepatic venous pressure (hepatic venous pressure gradient HVPG) of 20% or more from baseline values or <12 mmHg, has been associated with protection from rebleeding, and prevention of other complications of cirrhosis.
Retrograde CO2 portography is used when there is doubt about portal vein patency and can be combined with transjugular biopsy and hepatic venous pressure measurement.