Liver Anatomy and Physiology Lecture Notes

4PY019 – PCC1: Liver Anatomy and Physiology Lecture Notes Gross anatomy Situated below the diaphragm in the right hypochondrium, the liver is contained within the protective Glisson’s capsule. It is divided in to right and left lobes by the two main branches of the hepatic portal vein (HPV) along the line of the mid hepatic vein and the falciform ligament. This ligament attaches the liver to the diaphragm and anterior abdominal wall. The two lobes are further sub-divided in to 8 hepatic segments which are supplied by branches of the hepatic portal vein. The HPV drains the GI tract and spleen, supplying the liver with ¾ of its blood flow; the remaining ¼ being from the hepatic artery. Fine anatomy Lobules, sinusoids and bile canaliculi Microscopically, the liver is viewed as a collection of polyhedral lobules, each possessing a central vein into which efferent blood drains. Triads of blood vessels are found at the angles of the lobule: the portal venule, the hepatic arteriole and the biliary ductule. At the lobule angles afferent blood drains from the branches of the HPV and hepatic artery into sinusoidal cords which run in to the central vein. It is these cords of hepatic cells which carry out the metabolic functions of the liver. The sinusoids are surrounded by phagocytic Kupffer cells and are separated from each other by plates of hepatocytes. The space between the sinusoidal endothelium and the hepatocytes is known as the Space of Disse which comprises basement membrane constituents and stellate cells which regulate sinusoidal blood flow. Dendritic cells act as antigen presenting cells to lymphocytes. Microvilli help to increase the hepatocyte surface area available for transferring substances. Triads and zones Functionally, liver tissue is better viewed as hepatic triads from which sinusoids radiate outwards from the venules into the surrounding lobules. Each functional unit is called the hepatic acinus. The hepatocytes which are served by each acinus fall in to one of three acinar zones according to their proximity to the portal venule. Zone 1 cells, being in closest proximity, receive blood which is rich in oxygen and nutrients rendering them more resistant to injury. Conversely, zone 3 cells are closer to the central venule and therefore receive less oxygen and nutrients rendering them the most susceptible to injury. Zone 1 hepatocytes respond readily to changes in glucose or insulin levels and are predominantly responsible for glycolysis and gluconeogenesis. They also carry out protein synthesis, beta-oxidation of fatty acids, cholesterol synthesis and bile acid secretion. Zone 3 hepatocytes are predominantly responsible for cytochrome P450 activity and NADPH and NADH reductase metabolism, making them more susceptible to drug-induced damage. Biliary system - gross anatomy and bile canaliculi Bile acids emulsify dietary lipids in order to improve digestion by pancreatic lipases and enhance absorption of fat-soluble vitamins. Hepatocytes manufacture bile from water, bile acids, cholesterol, phospholipids and bilirubin, most of which are obtained from the distal ileum via the portal circulation. Within the lobules, bile flows in the opposite direction to that of efferent blood along tightly sealed, protective canaliculi and in to biliary ductules which are situated at the lobule angles. Canaliculi also provide a join between neighbouring hepatocytes. Cholangiocytes also manufacture bile- they line the intrahepatic and extrahepatic biliary tree and are differentiated into various shapes depending upon their site. Along with the other vessels in the triad, the ductule can be considered as the central part of the acinus. The ductules eventually drain in to the right or left hepatic ducts and then on to the common hepatic duct. This then joins with the cystic duct from the gallbladder to form the common bile duct. The gall bladder’s function is to store and concentrate hepatic bile, absorbing 80-90% of the water and electrolytes but retaining the bile acids and cholesterol. From the CBD, bile is secreted at the ampulla of Vater into the duodenum under the control of the sphincter of Oddi. This sphincter is responsible for preventing bile from being released during fasting. The ampulla can also be cannulated during endoscopic retrograde cholangiopancretography (ERCP) for the purposes of imaging or treating obstructive jaundice caused by conditions such as pancreatic cancer or gallstones. Functions of the liver Proteins Protein synthesis The liver synthesises virtually all circulating proteins from essential (must be obtained in the diet) and non-essential amino acids, also regulating AA levels in the plasma through gluconeogenesis and transamination: • Albumin: maintains plasma oncotic pressure; transports fat soluble drugs and bilirubin. The liver produces up to 12g/day of albumin. It has a half-life of 16-24 days. Hypoalbuminaemia is seen in chronic liver disease (a useful indicator) and malnutrition. • Coagulation factors [fibrinogen (I), prothrombin (II), V, VII, IX, X, XIII, proteins C and S, and antithrombin]: production is reduced in acute liver failure or cirrhosis this causing a raised PT and INR. These parameters are therefore indicative of the synthetic function of the liver. • α-fetoprotein: present in foetal plasma (lower levels in Down’s syndrome) and in liver carcinoma. • Caeruloplasmin: involved in copper metabolism • Transferrin: transports iron • α1-antitrypsin: limits plasma circulation of important proteases; deficient in emphysema • Complement components: involved in defence against infection and the inflammatory process • Haptoglobin: removes aged haemoglobin particles Protein catabolsim Ninety percent of excess nitrogen is converted to urea: Amino acids are degraded by transamination and oxidative deamination to ammonia which is converted to urea by the Krebs-Henseleit urea cycle (the Urea cycle). The urea produced is then excreted renally. Additionally Amino acids can also be degraded to ketoacids for metabolism via the Krebs-citric acid cycle (the Krebs cycle). Fatty acids are also metabolised by the Krebs cycle, through which energy-rich ATP is eventually produced. Glucose homeostasis The liver is able to store approximately 80g of glycogen. Postprandially, ingested glucose and fructose is taken up through the portal circulation and stored as glycogen thus preventing excessive hyperglycaemia. The glucose-6-phosphate intermediary can also be used to synthesise fatty acids and then triglyceride. In the fasting state, essential basal glucose levels can be maintained by glycogenolysis or gluconeogenesis. The latter involves production of glucose from lactate, pyruvate and amino acids from muscle tissue, and glycerol following stored fat lipolysis. Lipid metabolism Fats, including cholesterol and triglycerides, being insoluble in water are transported from the gut and liver to the tissues as lipoproteins. The liver synthesises VLDLs and HDLs, with IDL and LDL being derived from VLDL. Cholesterol ensures that cell membranes are fluid, acts as a precursor for the production of steroid hormones e.g. progesterone, testosterone, oestradiol and cortisol, and is also a constituent of bile acids. Cholesterol is also absorbed from the diet as well as being synthesised in the adrenal cortex, the intestines and the skin. Cholesterol is esterified by lecithin-cholesterolacyltransferase and transported by HDL. In liver disease (e.g. cholestasis such as in PBC) this enzyme is reduced leading to a greater relative proportion of free to esterified cholesterol. This can lead to altered membrane structure resulting e.g. in red cell abnormalities. Triglycerides are formed in the liver and are also absorbed from the GIT. They are used as a transportable energy source. The liver synthesises the phospholipid lecithin which is contained within cell membranes. Bile synthesis and recirculation Bile acids are lost in the faeces but most is continuously re-circulated in the enterohepatic circulation and absorbed across sinusoidal membranes by transport proteins. Some bile salts are absorbed freely across the intestinal wall in deconjugated form (re-conjugation then occurs within the hepatocytes) whereas conjugated bile salts must be reabsorbed actively. Transport proteins are also used to move primary bile salts (as well as bilirubin diglucuronide) into canaliculi. New bile acids must also be synthesised by the liver to maintain the bile salt pool at 2.5 5g. In the intestine the primary bile acids (cholic acid and chenodeoxycholic acid) that are secreted in the bile are conjugated with glycine and taurine to increase their solubility. Intestinal bacteria then convert the primary bile acids to secondary bile acids (deoxycholic acid and lithocholic acid) Bilirubin metabolism The end-product, bilirubin is produced following the breakdown of red blood cells and other haemcontaining proteins in the Kupffer cells of the liver and also elsewhere in the reticuloendothelial system, (mainly in the spleen). The porphyrin ring of haem is cleaved to yield biliverdin which is then converted to bilirubin whilst the iron and globin is reused. Unconjugated bilirubin is water-insoluble. Consequently, circulating unconjugated bilirubin is bound to albumin in the plasma and transported* to the liver where it is taken up into hepatocytes and conjugated to water soluble forms (monoglucuronides and diglucuronides) and then normally excreted in bile. Conjugated bilirubin is converted in the gut by bacteria to urobilinogen which is then either: excreted in the stools as stercobilinogen (providing stool colour); reabsorbed, recirculated through and then re-excreted by the liver; or bound to albumin and excreted renally. Raised urinary bilirubin levels are indicative of a higher conjugated bilirubin levels and therefore point to an underlying pathology. *NB. Rifampicin inhibits this carrier mediated process, which can precipitate hyperbilirubinaemia. Detoxification Key points: • Major site for drug metabolism • Phase 1 involves cytochrome P450 metabolism and phase 2 involves biotransformation with conjugation • Metabolites can be inactive, active or they can be reactive/toxic intermediates • Lipid soluble drugs are subject to extensive first pass metabolism and their metabolism is therefore affected by hepatic blood flow. Lipid soluble drugs tend to be metabolised into more soluble forms for excretion • Polar drugs (or conjugated metabolites) are soluble and tend to be excreted in bile • Higher molecular weight drugs tend to be excreted in the biliary system whereas lower molecular weight drugs tend to be excreted renally • The liver is involved in the activation of Vitamin D3 by 25-Hydroxylation Other Immunological function: Repeated from earlier - Sinusoidal endothelial cells are devoid of basement membrane which, coupled with the presence or pores, permits exchange of macromolecules with the space of Disse. These cells contain adhesion molecules which are able to capture inflammatory cells from the afferent blood. The liver therefore also acts as a protective sieve for bacterial and other antigens entering via the portal circulation. Kupffer cells are phagocytic liver macrophages which act upon foreign antigens such as bacteria arriving via the portal circulation. They are activated by bacterial cell wall components and cytokines. Storage: Energy (glycogen, fat – see above); Vitamins A, B12, D, E, K: Minerals: iron, copper; Toxins e.g. DDT Signs and symptoms of liver disease • • • • General/nonspecific symptoms include malaise, anorexia, weight loss, N&V, steatorrhoea (pale fatty stools), arthropathies, fevers, Dupuytren’s contracture [tendon contraction with permanent flexure of the finger(s)]. In acute disease symptomatic patients may present with anorexia, malaise, N&V, fever and progressive jaundice, pale stools, dark urine, abdominal pain and hepatomegaly. In chronic disease, general signs include jaundice and fever. Patients may experience pain in the right hypochondrium due to liver distension; GI bleeds; pruritis due to cholestasis (impaired bile flow); and endocrine induced changes such as breast swelling, testicular atrophy, amenorrhoea and loss of libido. Patients can also show parotid gland enlargement; Dermatological manifestations include spider naevi - vascular ‘spiders’ which form in the skin around the drainage areas of the superior vena cava (above the nipple line - face, neck, hands, arms); contractures; palmar erythema (due to hyperdynamic circulation); finger clubbing (due to hypoxaemia associated with hepatopulmonary syndrome); xanthomas (cholesterol deposits). Other dermatological changes include purpura, leuconychia (white nails), pigmented ulcers and scratch marks secondary to pruritis. Jaundice in chronic disease normally only appears in the later stages. In decompensated liver failure portosystemic encephalopathy causes neurological reactions: disorientation and drowsiness and patients can eventually go into a coma. Other features of decompensated disease include ascites, dilated abdominal veins and oedema. Portal vascular disease (including portal hypertension and oesophageal varices) is particularly associated with cirrhosis and is caused by impaired hepatic blood flow. This causes portal –systemic shunting to collateral vessels leading to oesophageal and upper GI varices. These can haemorrhage torrentially - a life-threatening emergency. Portal hypertension itself can cause splenomegaly and may show on examination as dilated abdominal veins (umbilical and paraumbilical). Portal hypertension is the main cause of ascites and encephalopathy due to the shunting of blood from the portal to the systemic circulation.