Dr.Muslim Alkafaji
FUNCTIONAL ANATOMY AND PHYSIOLOGYNormal 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. 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. The functional unit of the liver is the hepatic acinus. 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.
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:
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. 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.
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 metabolizing drugs and environmental toxins. 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).
• 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.
• The liver plays a central role in lipid metabolism, producing very low-density lipoproteins and further metabolising low- and high-density lipoproteins. 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. 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.Bilirubin metabolism and bile:
The liver plays a central role in the metabolism of bilirubin and is responsible for the production of bile. Between 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. 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. Once in the intestine, conjugated bilirubin is metabolized 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.
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 fatsoluble 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.
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.
Liver blood biochemistry
Liver blood biochemistry (LFTs) includes the measurement of serum bilirubin, aminotransferases, alkaline phosphatase, gamma-glutamyl transferase and albumin. Most analytes measured by LFTs are not truly ‘function’ tests but, given that they are released by injured hepatocytes, instead provide biochemical evidence of liver cell damage. Liver function per se is best assessed by the serum albumin, PT and bilirubin because of the role played by the liver in synthesis of albumin and clotting factors and in clearance of bilirubin. Although LFT abnormalities are often non-specific, the patterns are frequently helpful in directing further investigations. Also, levels of bilirubin and albumin and the PT are related to clinical outcome in patients with severe liver disease, reflected by their use in several prognostic scores: the Child–Pugh and MELD scores in cirrhosis, the Glasgow score in alcoholic hepatitis and the King’s College Hospital criteria for liver transplantation in acute liver failure.
Bilirubin and albumin
The degree of elevation of bilirubin can reflect the degree of liver damage. A raised bilirubin often occurs earlier in the natural history of biliary disease (e.g. primary biliary cirrhosis) than in disease of the liver parenchyma (e.g. cirrhosis) where the hepatocytes are primarily involved. Swelling of the liver within its capsule in inflammation can, however, sometimes impair bile flow and cause an elevation of bilirubin level that is disproportionate to the degree of liver injury. Caution is therefore needed in interpreting the level of liver injury purely on the basis of bilirubin elevation. Serum albumin levels are often low in patients with liver disease. This is due to a change in the volume of distribution of albumin, and reduced synthesis. Since the plasma half-life of albumin is about 2 weeks, albumin levels may be normal in acute liver failure but are almost always reduced in chronic liver failure.
Alanine aminotransferase and aspartate aminotransferase
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are located in the cytoplasm of the hepatocyte; AST is also located in the hepatocyte mitochondria. Although both transaminase enzymes are widely distributed, expression of ALT outside the liver is relatively low and this enzyme is therefore considered more specific for hepatocellular damage. Large increases of aminotransferase activity favour hepatocellular damage, and this pattern of LFT abnormality is known as ‘hepatitic’. Alkaline phosphatase and gamma-glutamyl transferase Alkaline phosphatase (ALP) is the collective name given to several different enzymes that hydrolyse phosphate esters at alkaline pH. These enzymes are widely distributed in the body, but the main sites of production are the liver, gastrointestinal tract, bone, placenta and kidney. It levels rise with intrahepatic and extrahepatic biliary obstruction and with sinusoidal obstruction, as occurs in infiltrative liver disease.
Gamma-glutamyl transferase (GGT) is a microsomal enzyme found in many cells and tissues of the body. The highest concentrations are located in the liver, where it is produced by hepatocytes and by the epithelium lining small bile ducts. The function of GGT is to transfer glutamyl groups from gamma-glutamyl peptides to other peptides and amino acids. The pattern of a modest increase in aminotransferase activity and large increases in ALP and GGT activity favours biliary obstruction and is commonly described as ‘cholestatic’ or ‘obstructive’. Isolated elevation of the serum GGT is relatively common, and may occur during ingestion of microsomal enzyme-inducing drugs, including alcohol, but also in NAFLD.
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)
• 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, where as 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 falsepositive 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.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 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. 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.
Computed tomography and magnetic resonance imaging
Computed tomography (CT) detects smaller focal lesions in the liver, especially when combined with contrast injection. Magnetic resonance imaging (MRI) can also be used to localise and confirm the aetiology of focal liver lesions, particularly primary and secondary tumours.
Cholangiography
Cholangiography can be undertaken by magnetic resonance cholangiopancreatography (MRCP), endoscopy (endoscopic retrograde cholangiopancreatography, ERCP) 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.