Liver Anatomy and Function

• Session 1 focuses on the liver's structure and function and was authored by Sarah James.
• A diagram shows the liver, gallbladder, stomach, bile duct, small intestine, and pancreas.

Learning Objectives

• Functional anatomy of the liver should be described
• Classical and acinar lobule concepts of liver anatomy and function should be distinguished
• Bile formation and its function should be explained
• Central role of the liver in fat and cholesterol metabolism should be explained
• Central role of the liver in carbohydrate metabolism is described

Liver Characteristics

• The adult liver typically weighs 1.2 - 1.6 kg
• The adult liver accounts for 2-5% of body weight and 4-5% of neonates
• The liver has four lobes: right, left, caudate, and quadrate
• Hepatocytes make up around 80% of the liver's volume
• The remainder of the liver comprises sinusoidal cells (33%), bile ducts (2%), connective tissue (2.2%), and blood vessels (1.8%).

The Liver

• The anterior view of the liver shows the falciform ligament, inferior vena cava, right and left triangular ligaments, right and left lobes, fissure for teres ligament, porta hepatis, proper hepatic artery, portal vein, teres ligament, and gallbladder.
• The posterior view of the liver illustrates the caudate lobe, coronary ligament, hepatic veins, caudate process, and quadrate lobe, with the common bile duct visible.

Functions of the Liver

• Clears the blood of drugs and other poisonous substances.
• Regulates blood levels of amino acids, which form the building blocks of proteins.
• Produces certain proteins for blood plasma.
• Produces bile, which helps carry away waste and break down fats in the small intestine during digestion.
• Processes hemoglobin for its iron content, storing iron.
• Produces cholesterol and special proteins to help carry fats through the body.
• Regulates blood clotting.
• Clears bilirubin, also from red blood cells; accumulation causes yellow skin and eyes.
• Converts excess glucose into glycogen for storage and balances glucose levels.
• Resists infections by producing immune factors and removing bacteria from the bloodstream.
• Converts poisonous ammonia to urea, which is excreted in the urine.

Blood Supply

• The liver receives a dual blood supply.
• The hepatic artery provides oxygenated blood, accounting for 30% of resting cardiac output.
• The hepatic portal vein comes from the GI tract.
• The liver has a dynamic vascular system and serves as a blood reservoir
• Single venous drainage is present where central veins in each lobule coalesce into the hepatic vein.

Circulatory Route of Materials Absorbed in the Small Intestine and Colon

• The small intestine delivers materials to the liver via hepatic veins and the hepatic portal vein and then into general circulation via the hepatic vein

Functional Anatomy

• The 3D anatomy of the liver is crucial to its functions.
• The relationship of the circulatory and biliary systems is fundamental to the liver's overall function.
• Diseases that alter the liver's structure can seriously compromise its function, such as cirrhosis

Hepatic Lobules

• Blood enters the lobules through branches of the portal vein and hepatic artery, then flows out through sinusoids.
• The bile system operates with countercurrent flow

The Hepatocyte

• Hepatocyte plasma membrane has 3 surfaces: sinusoidal, canalicular, and intercellular

Formation of Lymph

• About half of the body's lymph is formed in the liver.
• A large amount of fluid and proteins in sinusoidal endothelial cells is collected in small lymphatic capillaries
• Liver disease causing high portal pressure can lead to excessive lymph production and ascitic fluid accumulation

Kupffer Cells

• Kupffer cells are large numbers of immune cells in sinusoids
• They remove particulates and microbes from the intestinal tract before they enter systemic circulation
• Kupffer cells are involved in recycling old red blood cells and in blood cleansing

Structure of the Hepatic Lobule

• The classical liver lobule has a hexagonal shape and is related to anatomical structure.
• The acinus has a diamond shape and relates to blood flow and metabolic function

Metabolism and Blood Flow

• The hepatic acinus is centered on a line connecting two portal triads and extending to adjacent central veins
• Zone I has the most oxygenated blood
• Zone III has the poorest oxygenation and is the most susceptible to ischaemic injury

The Acinus

• Zone I hepatocytes conduct gluconeogenesis, β-oxidation of fatty acids, and cholesterol synthesis.
• Zone III hepatocytes primarily perform glycolysis, lipogenesis, and drug detoxification via cytochrome-P450.
• Zonal patterns of injury exist; for example, paracetamol toxicity affects zone III

Bile Production

• The liver produces 600-1000 ml of bile per day, the gallbladder can store 40-70 ml
• Bile is a yellowish-green liquid constantly secreted by hepatocytes.
• Bile contains bile pigments (bilirubin, biliverdin), bile salts (digestive function), cholesterol and electrolytes

Biliverdin and Bilirubin

• The breakdown products of heme are biliverdin and bilirubin.
• Produced in the spleen and Kupffer cells
• Bilirubin is toxic at moderately elevated levels, causing jaundice
• Bilirubin is conjugated with glucuronic acid in hepatocytes, making it water-soluble.
• It is excreted in bile into the small intestine as bilirubin diglucuronide (BDG).
• Intestinal flora converts BDG to urobilinogen, then to stercobilinogen, which gives feces its brown color

Bilirubin Elimination

• The transformation of bilirubin results in its subsequent excretion in urine and feces

Accumulation of Bile Pigments

• Jaundice, liver disease and blockage of bile ducts can cause accumulation of bile pigments
• Symptoms inclue: yellowish skin, sclerae, mucous membranes.

Bile Acids and Bile Salts

• Bile acids are steroid acids derived from cholesterol, such as cholic acids
• Bile salts are conjugates of glycine and taurine (amines) with cholic acids and a cation (sodium) like glycocholate and taurocholate
• Increase water solubility, preventing passive reabsorption in the small intestine
• Powerful detergents break down fat globules, which are absorbed in the smallintestine
• Some cholesterol released into bile has no function in bile.

Bile Canaliculus

• Active bile acid secretion, uses ATP
• Aided by countercurrent flow of blood and bile

Bile Secretion

• Bile is secreted by the liver, stored in the gallbladder and ejected into the small intestine

Gallstones

• Bile acids, phospholipids, and cholesterol can form mixed micelles and vesicles.
• Vesicles keep water-insoluble cholesterol molecules in solution.
• Excess cholesterol relative to bile salts exceeds solubilizing capacity, leading to supersaturated bile containing cholesterol crystals.

Composition of Hepatic Duct Bile

• Water: 97.0%
• Bile salts: 0.7%
• Bile pigments: 0.2%
• Cholesterol: 0.06%
• Inorganic salts: 0.7%
• Fatty acids: 0.15%
• Phosphatidyl choline: 0.2%
• Fat: 0.1%

Human Bile Acids (% in Bile):

• Cholic acid: 50
• Chenodeoxycholic acid: 30
• Deoxycholic acid: 15
• Lithocholic acid: 5

Role of Bile in Fat Metabolism

• Bile acids and lecithin emulsify fats in the small intestine
• Lipase breaks down fat into fatty acids and monoglycerides.
• MG's and FA's are absorbed through villi.

Metabolism of Triglycerides

• Triglycerides cannot be absorbed in the duodenum.
• The first step is Lipolysis to create glycerol plus three free fatty acids using lipases and bile acids/salts.
• Enterocytes rebuild and package cholesterol and proteins into chylomicrons
• Excreted into lymph and then to the liver

Blood Lipoproteins

• Lipoproteins are classified based on density, from low to high (protein:cholesterol)
• Chylomicrons transport exogenous products (dietary)
• Very low-density lipoprotein carries newly synthesized triglycerides from the liver to adipose tissue.
• Low-density lipoprotein carries cholesterol from the liver to cells.
• High-density lipoprotein collects cholesterol from tissues back to the liver

Biosynthesis of Glucose

• The liver contributes to the biosynthesis of lipids

Triglycerides and Fatty Acids

• Are digested in the gut
• Triglycerides are eventually stored around the body

Cholesterol

• 20-25% of total cholesterol is produced in the liver.
• Synthesized in intestines, adrenal glands, and reproductive organs.
• Derived from dietary sources - cheese, egg yolks, and meat.
• Cholesterol synthesis is balanced with the amount in the GI tract.
• It is required for membrane permeability, fluidity, production of steroid hormones, vitamin D, and bile acids.
• 50% of cholesterol in bile is reabsorbed.

Cholesterol Synthesis

• Cholesterol synthesis can be limited using statins to inhibit the enzyme HMG-CoA reductase

Amino Acid Metabolism

• Amino acids are absorbed in the gut and then carried to the liver
• The liver acts as the primary site of nitrogen metabolism through synthesis, catabolism, and gluconeogenesis
• Transamination (glutamine synthesis) oxidatively removes nitrogen to produce NH2
• Excess nitrogen is converted to urea for elimination in the urea cycle

Liver Carbohydrate Metabolism

• Glucose acts as a 'sink', regulating blood glucose levels
• Glycogen serves as a storage form of glucose
• Glycogenolysis involves the breakdown of glycogen to glucose
• Gluconeogenesis involves glucose synthesis from amino acids and lactate

Glycogen and Glycogenolysis

• Central storage facility for glucose is in the liver
• Overnight fasting and exercise
• Reduces osmotic potential of blood
• Prevents excess glycation of proteins and phospholipids
• Normal fasting blood glucose = 4-7 mM
• Indicates there isnt diabetes if equal to that range

The Structure of Glycogen

• Glycogen is a polymer of glucose.
• Glucose molecules are joined by linear structures α(1→4) linkage & branch points α(1→6) linkage.
• Branch length ~10 glucoses
• One end is joined to glycogenin

Gluconeogenesis

• Generation of additional glucose and energy and removal of carbon substrates
• Anaerobic glycolysis for energy
• Lactate has two fates
• oxidation in Krebs Cycle
• conversion back to glucose – gluconeogenesis (liver)
• Liver and Muscles

Summary of Metabolism

• Glucose 'sink' – regulates blood glucose
• Glycogen – storage form
• glycogenolysis – breakdown to glucose
• Gluconeogenesis – glucose synthesis from amino acids, lactate

Some Common Diseases of the Liver

• Jaundice (abnormal bilirubin metabolism & excretion)
• Viral hepatitis (A, B, C, D, E, G)
• Chronic inflammatory liver disease (hepatitis)
• Toxic liver diseases (alcohol, drugs, hepatotoxins)
• Metabolic liver disease (haemochromatosis, Wilson's)
• Parasitic infections like: Entamoeba histolytica, Malaria, Leishmaniasis, Bacteria
• Cirrhosis (irreversible end-stage of many diseases)
• Liver tumors
• Gallstones

Liver Function Tests

• The liver performs various functions, makes chemicals that pass into the bloodstream and bile
• Can be measured in a blood sample
• Liver disorders alter their levels and can indicate risk.