Liver, biliary tract and pancreatic disease

Chapter 7 Liver, biliary tract and pancreatic disease

The liver

Structure of the liver and biliary system

The liver

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.

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 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).

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).

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.

Lipid metabolism

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.

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.

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 metabolism

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.

Immunological function

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:

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.

Blood tests

Useful blood tests for certain liver diseases are shown in Table 7.1.

Table 7.1 Useful blood and urine tests for certain liver diseases

Test Disease

Anti-mitochondrial antibody

Primary biliary cirrhosis

Anti-nuclear, smooth muscle (actin), liver/kidney microsomal antibody

Autoimmune hepatitis

Raised serum immunoglobulins:



Autoimmune hepatitis


Primary biliary cirrhosis

Viral markers

Hepatitis A, B, C, D, E and others


Hepatocellular carcinoma

Serum iron, transferrin saturation, serum ferritin

Hereditary haemochromatosis

Serum and urinary copper, serum caeruloplasmin

Wilson’s disease


Cirrhosis (± emphysema)

Anti-nuclear cytoplasmic antibodies

Primary sclerosing cholangitis

Markers of liver fibrosis

Non-alcoholic fatty liver disease


Hepatitis C

Genetic analyses

e.g. HFE gene (hereditary haemochromatosis)

Liver biochemistry

γ-Glutamyl transpeptidase

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

Immunological tests

Imaging techniques

Ultrasound examination

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:

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).

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.

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.

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Mar 31, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Liver, biliary tract and pancreatic disease

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