Causes	Associated clinical findings
Exudative (high protein)
Carcinoma	Weight loss ± hepatomegaly
Tuberculosis	Weight loss + fever
Transudative (low protein)
Cirrhosis	Hepatomegaly
	Splenomegaly
	Spider naevi
Renal failure (including nephrotic syndrome)	Generalised oedema Peripheral oedema Elevated jugular venous pressure (JVP)
Congestive heart failure

1 Assessment of encephalopathy

Functional anatomy and physiology

Applied anatomy

Normal liver structure and blood supply

The liver weighs 1.2–1.5 kg and has multiple functions, including key roles in metabolism, control of infection, elimination of toxins and by-products of metabolism. It is classically divided into left and right lobes by the falciform ligament, but a more useful functional division is into the right and left hemilivers, based on blood supply (Fig. 23.1). These are further divided into eight segments according to subdivisions of the hepatic and portal veins. Each segment has its own branch of the hepatic artery and biliary tree. The segmental anatomy of the liver has an important influence on imaging and treatment of liver tumours, given the increasing use of surgical resection. A liver segment is made up of multiple smaller units known as lobules, comprised of a central vein, radiating sinusoids separated from each other by single liver cell (hepatocyte) plates, and peripheral portal tracts. The functional unit of the liver is the hepatic acinus (Fig. 23.2).

Blood flows into the acinus via a single branch of the portal vein and hepatic artery situated centrally in the portal tracts. Blood flows outwards along the hepatic sinusoids into one of several tributaries of the hepatic vein at the periphery of the acinus. Bile, formed by active and passive excretion by hepatocytes into channels called cholangioles which lie between them, flows in the opposite direction from the periphery of the acinus. The cholangioles converge in interlobular bile ducts in the portal tracts. The hepatocytes in each acinus lie in three zones, depending on their position relative to the portal tract. Those in zone 1 are closest to the terminal branches of the portal vein and hepatic artery, and are richly supplied with oxygenated blood, and blood containing the highest concentration of nutrients and toxins. Conversely, hepatocytes in zone 3 are furthest from the portal tracts and closest to the hepatic veins, and are therefore relatively hypoxic and exposed to lower concentrations of nutrients and toxins compared to zone 1. The different perfusion and toxin exposure patterns, and thus vulnerability, of hepatocytes in the different zones contribute to the often-patchy nature of liver injury.

Liver cells

Hepatocytes comprise 80% of liver cells. The remaining 20% are the endothelial cells lining the sinusoids, epithelial cells lining the intrahepatic bile ducts, cells of the immune system (including macrophages (Kupffer cells) and unique populations of atypical lymphocytes), and a key population of non-parenchymal cells called stellate or Ito cells.

Endothelial cells line the sinusoids (Fig. 23.3), a network of capillary vessels that differ from other capillary beds in the body in that there is no basement membrane. The endothelial cells have gaps between them (fenestrae) of about 0.1 micron in diameter, allowing free flow of fluid and particulate matter to the hepatocytes. Individual hepatocytes are separated from the leaky sinusoids by the space of Disse, which contains stellate cells that store vitamin A and play an important part in regulating liver blood flow. They may also be immunologically active and play a role in the liver’s contribution to defence against pathogens. The key role of stellate cells in terms of pathology is in the development of hepatic fibrosis, the precursor of cirrhosis. They undergo activation in response to cytokines produced following liver injury, differentiating into myofibroblasts, which are the major producers of the collagen-rich matrix that forms fibrous tissue (Fig. 23.4).

Fig. 23.3 Non-parenchymal liver cells.
(B = B lymphocytes; NK = natural killer cells; PMN = polymorphonuclear leucocytes; T = T lymphocytes).

Blood supply

The liver is unique as an organ as it has dual perfusion, receiving a majority of its supply via the portal vein, which drains blood from the gut via the splanchnic circulation and is the principal route for nutrient trafficking to the liver, and a minority from the hepatic artery. The portal venous contribution is 50–90%. The dual perfusion system, and the variable contribution from portal vein and hepatic artery, can have important effects on the clinical expression of liver ischaemia (which typically exhibits a less dramatic pattern than ischaemia in other organs, a fact that can sometimes lead to it being missed clinically), and can raise practical challenges in liver transplant surgery.

Biliary system and gallbladder

Hepatocytes provide the driving force for bile flow by creating osmotic gradients of bile acids, which form micelles in bile (bile acid-dependent bile flow), and of sodium (bile acid-independent bile flow). Bile is secreted by hepatocytes and flows from cholangioles to the biliary canaliculi. The canaliculi join to form larger intrahepatic bile ducts, which in turn merge to form the right and left hepatic ducts. These ducts join as they emerge from the liver to form the common hepatic duct, which becomes the common bile duct after joining the cystic duct (see Fig. 23.2). The common bile duct is approximately 5 cm long and 4–6 mm wide. The distal portion of the duct passes through the head of the pancreas and usually joins the pancreatic duct before entering the duodenum through the ampullary sphincter (sphincter of Oddi). It should be noted, though, that the anatomy of the lower common bile duct can vary widely. Common bile duct pressure is maintained by rhythmic contraction and relaxation of the sphincter of Oddi; this pressure exceeds gallbladder pressure in the fasting state, so that bile normally flows into the gallbladder, where it is concentrated tenfold by resorption of water and electrolytes.

The gallbladder is a pear-shaped sac typically lying under the right hemiliver, with its fundus located anteriorly behind the tip of the 9th costal cartilage. Anatomical variation is common and should be considered when assessing patients clinically and radiologically. The function of the gallbladder is to concentrate, and provide a reservoir for, bile. Gallbladder tone is maintained by vagal activity, and cholecystokinin released from the duodenal mucosa during feeding causes gallbladder contraction and reduces sphincter pressure, so that bile flows into the duodenum. The body and neck of the gallbladder pass postero-medially towards the porta hepatis, and the cystic duct then joins it to the common hepatic duct. The cystic duct mucosa has prominent crescentic folds (valves of Heister), giving it a beaded appearance on cholangiography.

Hepatic function

Carbohydrate, amino acid and lipid metabolism

The liver plays a central role in carbohydrate, lipid and amino acid metabolism, and is also involved in metabolising drugs and environmental toxins (Fig. 23.5). An important and increasingly recognised role for the liver is in the integration of metabolic pathways, regulating the response of the body to feeding and starvation. Abnormality in metabolic pathways and their regulation can play an important role both in liver disease (e.g. non-alcoholic fatty liver disease (NAFLD)) and in diseases that are not conventionally regarded as diseases of the liver (such as type II diabetes mellitus and inborn errors of metabolism). Hepatocytes have specific pathways to handle each of the nutrients absorbed from the gut and carried to the liver via the portal vein.

• Amino acids from dietary proteins are used for synthesis of plasma proteins, including albumin. The liver produces 8–14 g of albumin per day, and this plays a critical role in maintaining oncotic pressure in the vascular space and in the transport of small molecules like bilirubin, hormones and drugs throughout the body. Amino acids that are not required for the production of new proteins are broken down, with the amino group being converted ultimately to urea.

• Following a meal, more than half of the glucose absorbed is taken up by the liver and stored as glycogen or converted to glycerol and fatty acids, thus preventing hyperglycaemia. During fasting, glycogen is broken down to release glucose (gluconeogenesis), thereby preventing hypoglycaemia (p. 800).

• The liver plays a central role in lipid metabolism, producing very low-density lipoproteins and further metabolising low- and high-density lipoproteins (see Fig. 16.14, p. 452). Dysregulation of lipid metabolism is thought to have a critical role in the pathogenesis of NAFLD. Lipids are now recognised to play a key part in the pathogenesis of hepatitis C, facilitating viral entry into hepatocytes.

Clotting factors

The liver produces key proteins that are involved in the coagulation cascade. Many of these coagulation factors (II, VII, IX and X) are post-translationally modified by vitamin K-dependent enzymes, and their synthesis is impaired in vitamin K deficiency (p. 997). Reduced clotting factor synthesis is an important and easily accessible biomarker of liver function in the setting of liver injury. Prothrombin time (PT; or the International Normalised Ratio, INR) is therefore one of the most important clinical tools available for the assessment of hepatocyte function. Note that the deranged PT or INR seen in liver disease may not directly equate to increased bleeding risk, as these tests do not capture the concurrent reduced synthesis of anticoagulant factors, including protein C and protein S. In general, therefore, correction of PT using blood products before minor invasive procedures should be guided by clinical risk rather than the absolute value of the PT.

Bilirubin metabolism and bile

The liver plays a central role in the metabolism of bilirubin and is responsible for the production of bile (Fig. 23.6). Between 425 and 510 mmol (250–300 mg) of unconjugated bilirubin is produced from the catabolism of haem daily. Bilirubin in the blood is normally almost all unconjugated and, because it is not water-soluble, is bound to albumin and does not pass into the urine. Unconjugated bilirubin is taken up by hepatocytes at the sinusoidal membrane, where it is conjugated in the endoplasmic reticulum by UDP-glucuronyl transferase, producing bilirubin mono- and diglucuronide. Impaired conjugation by this enzyme is a cause of inherited hyperbilirubinaemias (see Box 23.17, p. 937). These bilirubin conjugates are water-soluble and are exported into the bile canaliculi by specific carriers on the hepatocyte membranes. The conjugated bilirubin is excreted in the bile and passes into the duodenal lumen.

Fig. 23.6 Pathway of bilirubin excretion.

Once in the intestine, conjugated bilirubin is metabolised by colonic bacteria to form stercobilinogen, which may be further oxidised to stercobilin. Both stercobilinogen and stercobilin are then excreted in the stool, contributing to its brown colour. Biliary obstruction results in reduced stercobilinogen in the stool, and the stools become pale. A small amount of stercobilinogen (4 mg/day) is absorbed from the bowel, passes through the liver, and is excreted in the urine, where it is known as urobilinogen or, following further oxidisation, urobilin. The liver secretes 1–2 L of bile daily. Bile contains bile acids (formed from cholesterol), phospholipids, bilirubin and cholesterol. Several biliary transporter proteins have been identified (Fig. 23.7). Mutations in genes encoding these proteins have been identified in inherited intrahepatic biliary diseases presenting in childhood, and in adult-onset disease such as intrahepatic cholestasis of pregnancy and gallstone formation.

Fig. 23.7 Biliary transporter proteins.
On the hepatocyte basolateral membrane, NTCP (sodium taurocholate co-transporting polypeptide) mediates uptake of conjugated bile acids from portal blood. At the canalicular membrane, these bile acids are secreted via BSEP (bile salt export pump) into bile. MDR3 (multidrug resistance protein 3), also situated on the canalicular membrane, transports phospholipid to the outer side of the membrane. This solubilises bile acids, forming micelles and protecting bile duct membranes from bile salt damage. FIC1 (familial intrahepatic cholestasis 1) moves phosphatidylserine from the inside to the outside of the canalicular membrane; mutations result in familial cholestasis syndrome in childhood. MDR2 (multidrug resistance 2) regulates transport of glutathione. MRP2 (multidrug resistance protein 2) transports bilirubin and is induced by rifampicin. OATP (organic anion transporter protein) transports bilirubin and organic anions.

Storage of vitamins and minerals

Vitamins A, D and B₁₂ are stored by the liver in large amounts, while others, such as vitamin K and folate, are stored in smaller amounts and disappear rapidly if dietary intake is reduced. The liver is also able to metabolise vitamins to more active compounds, e.g. 7-dehydrocholesterol to 25(OH) vitamin D. Vitamin K is a fat-soluble vitamin and so the inability to absorb fat-soluble vitamins, as occurs in biliary obstruction, results in a coagulopathy. The liver also stores minerals such as iron, in ferritin and haemosiderin, and copper, which is excreted in bile.

Immune regulation

Approximately 9% of the normal liver is composed of immune cells (see Fig. 23.3). Cells of the innate immune system include Kupffer cells derived from blood monocytes, the liver macrophages and natural killer (NK) cells, as well as ‘classical’ B and T cells of the adaptive immune response (p. 76). An additional type of atypical lymphocyte, with phenotypic features of both T cells and NK cells is thought to play an important role in host defence, through linking of innate and adaptive immunity. The enrichment of such cells in the liver reflects the unique importance of the liver in preventing microorganisms from the gut entering the systemic circulation.

Kupffer cells constitute the largest single mass of tissue-resident macrophages in the body and account for 80% of the phagocytic capacity of this system. They remove aged and damaged red blood cells, bacteria, viruses, antigen–antibody complexes and endotoxin. They also produce a wide variety of inflammatory mediators that can act locally or may be released into the systemic circulation.

The immunological environment of the liver is unique in that antigens presented within it tend to induce immunological tolerance. This is of importance in liver transplantation, where classical major histocompatibility (MHC) barriers may be crossed, and also in chronic viral infections, when immune responses may be attenuated. The mechanisms that underlie this phenomenon have not been fully defined.

Investigation of liver and hepatobiliary disease

Investigations play an important role in the management of liver disease in three settings:

• identification of the presence of liver disease

• establishing the aetiology

• understanding disease severity (in particular, identification of cirrhosis with its complications).

When planning investigations it is important to be clear as to which of these goals is being addressed.

Suspicion of the presence of liver disease is normally based on blood biochemistry abnormality (‘liver function tests’, or ‘LFTs’), undertaken either as a result of clinical suspicion or, increasingly, in the setting of health screening. Less commonly, suspicion arises after a structural abnormality is identified on imaging.

Aetiology is typically established through a combination of history, specific blood tests and, where appropriate, imaging and liver biopsy.

Staging of disease (in essence, the identification of cirrhosis) is largely histological, although there is increasing interest in non-invasive approaches, including novel imaging modalities, serum markers of fibrosis and the use of predictive scoring systems.

The aims of investigation in patients with suspected liver disease are shown in Box 23.1.

23.1 Aims of investigations in patients with suspected liver disease

• Detect hepatic abnormality

• Measure the severity of liver damage

• Detect the pattern of liver function test abnormality: hepatitic or obstructive/cholestatic

• Identify the specific cause

• Investigate possible complications

23.2 ‘Hepatitic’ and ‘cholestatic’/‘obstructive’ liver function tests

Pattern	AST/ALT	GGT	ALP
Biliary obstruction	↑	↑↑	↑↑↑
Hepatitis	↑↑↑	↑	↑
Alcohol/enzyme-inducing drugs	N/↑	↑↑	N

N = normal; ↑ mild elevation (< twice normal); ↑↑ moderate elevation (2–5 times normal); ↑↑↑ marked elevation (> 5 times normal).

(ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase)

23.3 Drugs that increase levels of gamma-glutamyltransferase

Other biochemical tests

Other widely available biochemical tests may become altered in patients with liver disease:

• Hyponatraemia occurs in severe liver disease due to increased production of antidiuretic hormone (ADH; Fig. 16.5, p. 435).

• Serum urea may be reduced in hepatic failure, whereas levels of urea may be increased following gastrointestinal haemorrhage.

• When high levels of urea are accompanied by raised bilirubin, high serum creatinine and low urinary sodium, this suggests hepatorenal failure, which carries a grave prognosis.

• Significantly elevated ferritin suggests haemochromatosis. Modest elevations can be seen in inflammatory disease and alcohol excess.

Haematological tests

Blood count

The peripheral blood count is often abnormal and can give a clue to the underlying diagnosis:

• A normochromic normocytic anaemia may reflect recent gastrointestinal haemorrhage, whereas chronic blood loss is characterised by a hypochromic microcytic anaemia secondary to iron deficiency. A high erythrocyte mean cell volume (macrocytosis) is associated with alcohol misuse, but target cells in any jaundiced patient also result in a macrocytosis. Macrocytosis can persist for a long period of time after alcohol cessation, making it a poor marker of ongoing consumption.

• Leucopenia may complicate portal hypertension and hypersplenism, whereas leucocytosis may occur with cholangitis, alcoholic hepatitis and hepatic abscesses. Atypical lymphocytes are seen in infectious mononucleosis, which may be complicated by an acute hepatitis.

• Thrombocytopenia is common in cirrhosis and is due to reduced platelet production, and increased breakdown because of hypersplenism. Thrombopoietin, required for platelet production, is produced in the liver and levels fall with worsening liver function. Thus platelet levels are usually more depressed than white cells and haemoglobin in the presence of hypersplenism in patients with cirrhosis. A low platelet count is often an indicator of chronic liver disease, particularly in the context of hepatomegaly. Thrombocytosis is unusual in patients with liver disease but may occur in those with active gastrointestinal haemorrhage and, rarely, in hepatocellular carcinoma.

Coagulation tests

These are often abnormal in patients with liver disease. The normal half-lives of the vitamin K-dependent coagulation factors in the blood are short (5–72 hours) and so changes in the prothrombin time occur relatively quickly following liver damage; these changes provide valuable prognostic information in patients with both acute and chronic liver failure. An increased PT is evidence of severe liver damage in chronic liver disease. Vitamin K does not reverse this deficiency if it is due to liver disease, but will correct the PT if the cause is vitamin K deficiency, as may occur with biliary obstruction due to non-absorption of fat-soluble vitamins.

Immunological tests

A variety of tests are available to evaluate the aetiology of hepatic disease (Boxes 23.4 and 23.5). The presence of liver-related autoantibodies can be suggestive of the presence of autoimmune liver disease (although false-positive results can occur in non-autoimmune inflammatory disease such as NAFLD). Elevation in overall serum immunoglobulin levels can also be suggestive of autoimmunity (immunoglobulin (Ig)G and IgM). Elevated serum IgA can be seen, often in more advanced alcoholic liver disease and NAFLD, although the association is not specific.

23.5 How to identify the cause of LFT abnormality

Diagnosis	Clinical clue	Initial test	Additional tests
Alcoholic liver disease	History	LFTs AST > ALT; high MCV	Random blood alcohol
Non-alcoholic fatty liver disease (NAFLD)	Metabolic syndrome (central obesity, diabetes, hypertension)	LFTs	Liver biopsy
Chronic hepatitis B	Injection drug use; blood transfusion	HBsAg	HBeAg, HBeAb HBV-DNA
Chronic hepatitis C		HCV antibody	HCV-RNA
Primary biliary cirrhosis	Itching; raised ALP	AMA	Liver biopsy
Primary sclerosing cholangitis	Inflammatory bowel disease	MRCP	ANCA
Autoimmune hepatitis	Other autoimmune diseases	ASMA, ANA, LKM, immunoglobulin	Liver biopsy
Haemochromatosis	Diabetes/joint pain	Transferrin saturation, ferritin	HFE gene test
Wilson’s disease	Neurological signs; haemolysis	Caeruloplasmin	24-hr urinary copper
α₁-antitrypsin	Lung disease	α₁-antitrypsin level	α₁-antitrypsin genotype
Drug-induced liver disease	Drug/herbal remedy history	LFTs	Liver biopsy
Coeliac disease	Malabsorption	Endomysial antibody	Small bowel biopsy

(ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; HBeAb = antibody to hepatitis B e antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HFE = haemochromatosis (high iron/Fe); LKM = liver-kidney microsomal antibody; MCV = mean cell volume; MRCP = magnetic resonance cholangiopancreatography)

Imaging

Several imaging techniques can be used to determine the site and general nature of structural lesions in the liver and biliary tree. In general, however, imaging techniques are unable to identify hepatic inflammation and have poor sensitivity for liver fibrosis unless advanced cirrhosis with portal hypertension is present.

Ultrasound

Ultrasound is non-invasive and most commonly used as a ‘first-line’ test to identify gallstones, biliary obstruction (Fig. 23.8) or thrombosis in the hepatic vasculature. Ultrasound is good for the identification of splenomegaly and abnormalities in liver texture, but is less effective at identifying diffuse parenchymal disease. Focal lesions, such as tumours, may not be detected if they are below 2 cm in diameter and have echogenic characteristics similar to normal liver tissue. Bubble-based contrast media are now routinely used and can enhance discriminant capability. Doppler ultrasound allows blood flow in the hepatic artery, portal vein and hepatic veins to be investigated. Endoscopic ultrasound provides high-resolution images of the pancreas, biliary tree and liver (see Fig. 23.45, p. 985).

Computed tomography and magnetic resonance imaging

Computed tomography (CT) detects smaller focal lesions in the liver, especially when combined with contrast injection (Fig. 23.9). Magnetic resonance imaging (MRI) can also be used to localise and confirm the aetiology of focal liver lesions, particularly primary and secondary tumours.

Fig. 23.9 CT scan in a patient with cirrhosis.
The liver is small and has an irregular outline (black arrow), the spleen is enlarged (long white arrow), fluid (ascites) is seen around the liver, and collateral vessels are present around the proximal stomach (short white arrow).

Hepatic angiography is seldom used nowadays as a diagnostic tool, since CT and MRI are both able to provide images of hepatic vasculature, but it still has a therapeutic role in the embolisation of vascular tumours such as hepatocellular carcinoma. Hepatic venography is now rarely performed.

Cholangiography

Cholangiography can be undertaken by magnetic resonance cholangiopancreatography (MRCP, Fig. 23.10), endoscopy (endoscopic retrograde cholangiopancreatography, ERCP, Fig. 23.11) or the percutaneous approach (percutaneous transhepatic cholangiography, PTC). The latter does not allow the ampulla of Vater or pancreatic duct to be visualised. MRCP is as good as ERCP at providing images of the biliary tree but has fewer complications and is the diagnostic test of choice. Both endoscopic and percutaneous approaches allow therapeutic interventions, such as the insertion of biliary stents across malignant bile duct strictures. The percutaneous approach is only used if it is not possible to access the bile duct endoscopically.

Fig. 23.10 MRCP showing a biliary stricture due to cholangiocarcinoma in the distal common bile duct (C).
The proximal common bile duct (B) is dilated but the pancreatic duct (P) is normal.

Histological examination

An ultrasound-guided liver biopsy can confirm the severity of liver damage and provide aetiological information. It is performed percutaneously with a Trucut or Menghini needle, usually through an intercostal space under local anaesthesia, or radiologically using a transjugular approach.

Percutaneous liver biopsy is a relatively safe procedure if the conditions detailed in Box 23.6 are met, but carries a mortality of about 0.01%. The main complications are abdominal and/or shoulder pain, bleeding and biliary peritonitis. Biliary peritonitis is rare and usually occurs when a biopsy is performed in a patient with obstruction of a large bile duct. Liver biopsies can be carried out in patients with defective haemostasis if:

23.6 Conditions required for safe percutaneous liver biopsy