Liver Anatomy and Function

• Liver physiology covers the storage, synthetic, metabolic and excretory functions of the liver, and identifies the physiological consequences of hepatic disease
• Liver physiology includes the clinical laboratory assessment of liver function and hepatic failure and describes how the body handles bilirubin
• Liver physiology also includes the anatomical and physiological considerations in hepatic blood flow, and the changes that occur with anesthesia
• Liver physiology outlines the reticulo-endothelial functions of the liver
• Liver physiology explains the protective function of the liver between the gut and the body
• Liver physiology describes the portal circulation and its significance

Functional Anatomy of the Liver

• The liver is the largest visceral organ, weighing between 1.2-1.5 kg

Microanatomy: Hepatic Lobule

• Liver has two basic units
• Hepatic lobule is the basic histological unit
• Consists of a central hepatic efferent venule (central vein) with cords of a single layer of hepatocytes and sinusoids converging into it
• Acinus is the basic functional unit
• Parenchymal mass formed between the two central veins and portal triads
• Blood enters Acinus from terminal branches of hepatic arteriole and portal venule (from portal triad) and drains into sinusoids then into central vein
• Acinus is divided into 3 functional zones:
• Periportal (zone 1) receives sinusoidal blood first, highest O2 content, highest metabolic rate
• Mediolobular (zone 2) receives blood next, low O₂ content, moderate metabolic activity
• Centrilobular (zone 3) receives sinusoidal blood last, lowest O2 content, vital for metabolism and drug biotransformation
• Zone 1 is most affected by toxins/poisons as it receives sinusoidal blood first
• Zone 3 is most affected by low hepatic blood flow and hypoxemia as it receives poorly oxygenated sinusoidal blood last
• Portal Triad consists of the Hepatic arteriole and Portal venule
• Portal Triad runs parallel with a Bile canaliculi
• Hepatic Sinusoid is a low-pressure microcirculatory system of the acinus formed by anastomosis of a hepatic arteriole with a portal venule
• Hepatic Sinusoid contains sphincters at hepatic arterioles, hepatic venous sinusoid and arteriolar-portal shunts
• Hepatic Sinusoid role is to facilitate the exchange of nutrients/waste between blood and hepatocytes, and act as a reservoir for blood, depending on sphincter tone

Cells of the Liver: Hepatocytes

• Hepatocytes form the bulk of the liver: 60% cell mass and 80% volume
• Cords of hepatocytes, in single layer, are arranged in laminae through which sinusoids interconnect
• Hepatocytes are polygonal with 3 key surfaces: Space of Disse (sinusoidal), Bile canaliculi, and adjacent hepatocyte
• Microvilli exists on the sinusoidal and bile canaliculi sides to allow secretion/absorption functions
• Organelles carry out most of the liver's function
  • rER is for protein synthesis
  • sER drug biotransformation, bilirubin metabolism, and urea synthesis
  • Peroxisome is for FA ẞ-oxidation
  • Golgi apparatus is for glycoprotein synthesis, storage of albumin, bile, and lipoproteins
  • Lysosome deposits bile, ferritin, and copper
  • Mitochondria provides ATP

Cells of the Liver: Kupffer cells

• Kupffer cells are the second most common cell in liver, at 40% cell mass and 20% volume
• Macrophages line the sinusoids within “space of Disse"
• Kupffer cell role is the Reticulo-endothelial functions of the liver, phagocytosis of bacteria, destruction of endotoxins, protein denaturation, accumulate ferritin/haemosiderin, haemopoetic function (in utero only)
• Fenestrated endothelial cells line the sinusoids and allow molecular exchange of substrates/waste between hepatocyte and sinusoids (via Space of Disse)
• Pitt cells are mobile lymphocytes (Active NK cells) attached to sinusoidal endothelium for a defensive role against infection and tumor cells
• Ito cells store fat and retinoid, can transform to contractile cells with cytokine stimulation, and deposit collagen causing fibrosis

Functions of the Liver: Metabolic functions

• The liver's Glucostat role maintains blood glucose level within strict limits
  • Low blood glucose increases glucagon (and counter-regulatory hormones) and decreases insulin, stimulates hepatic glycogenolysis and gluconeogenesis and inhibits glycogen synthesis and glycolysis
  • High blood glucose increases insulin and decreases glucagon (and counter-regulatory hormones), stimulates hepatic glycogen synthesis and glycolysis, and inhibits gluconeogenesis and glycogenolysis
• Uptake of dietary monosaccharides from portal vein converts complex sugars to glucose and dietary monosaccharides are taken up passively via an insulin-independent GLUT 2 transporter
• Liver glucokinase converts glucose to G6P
• This facilitates continuous uptake of glucose (and other monosaccharides) into hepatocyte by passive diffusion along their [ ] gradients
• 10% of dietary glucose is stored as glycogen, 40% converted to TAGs as fat stores, and 50% used in glycolysis, forms ATP for other liver functions
• Glycolysis of glucose does energy production, 38 ATP made from aerobic glycolysis and [O] phosphorylation (via TCA and ETC), and lipogenesis using pyruvate to form acetyl-coA for LCFAs, later stored as TAGs
• Glycogen metabolism does Glycogenolysis, hepatic glycogen is degraded to G6P (via Glycogen phosphatase), then to glucose via Glucose 6-Phosphatase (an enzyme specific to the liver only)
• Glycogen synthesis converts Glucose to G6P (via liver glucokinase) to G1P then to UDP-glucose, Glycogen synthetase then builds up glycogen using UDP-glucose substrates
• Glucose stored in glycogen is produced l°ly from gluconeogenesis, only 10% dietary glucose is used for storage in glycogen
• Gluconeogenesis derives glucose primarily from lactate, but also from pyruvate, glycerol, and glucogenic a.a's.
• Metabolism of lactate, derived peripherally from anaerobic metabolism, is converted to pyruvate via Cori cycle, which is then used for:
  • Conversion to glucose via gluconeogenesis, 70% of lactate
  • Conversion to acetyl-CoA (30% of lactate)
• Pentose phosphate shunt converts glucose to NADPH and ribose-5-phosphate, NADPH is vital for biotransformation of steroid hormones and drugs

Functions of the Liver: Lipid metabolism

• Fatty acid oxidation for energy production does LCFAs degrades into Acetyl-CoA then produces ATP
• Ketone production does acetyl-CoA converts to HMG-CoA in liver then to ketone bodies, used as an alternate fuel source
• Metabolism of TAGs and fat stores does lipogenesis using acetyl-CoA to synthesise LCFAs then combined with glycerol-phosphate for TAGs
• Lipolysis is the hydrolysis of liver fat stores where TAGs break down to FAs and glycerol
• Synthesis of cholesterol occurs when Acetyl-CoA converts to HMG-CoA in the liver then to mevalonic acid by rate-limiting HMG CoA reductase
• Hepatic cholesterol is derived from diet, peripheral sources, and de novo synthesis
• Fate of hepatic cholesterol includes exported as lipoproteins, secreted directly into bile, Converted bile salts, Incorporated into steroid hormones, Incorporated into cell membranes
• Synthesis of phospholipids forms from Acetyl CoA then incorporates into in cell membranes and lipoproteins
• Lipoprotein handling for peripheral distribution of lipids is where Intestinal TAGs are absorbed as digested components then transported to the liver
  • Short-chain FAs transferred directly to liver via portal vein without re-esterification
  • Long-chain FAs are re-esterified to form TAGs and packaged with cholesterol esters within Chylomicrons then system to adipocytes then Chylomicron remnants are taken up by liver
• In the liver, TAGs either reconstituted from FAs/glycerol from chylomicron remnants or synthesised via lipogenesis
• They are then packaged with cholesterol esters, phospholipids, non- esterified FAs and proteins in VLDL then to LDL to distribute lipids to peripherally

Functions of the Liver: Protein metabolism

• Liver produces all plasma proteins EXCEPT immunoglobulins: albumin, globulins and fibrinogen
  • Transport proteins (Eg. lipoproteins, transferrin, ceruloplasmin
  • Haematological proteins (Eg. CFs, fibrinolytics, haptoglobin, coagulation inhibitors
  • Immune proteins (Eg. complement, acute phase proteins
  • Enzymes (Eg. A1AT, PC
  • Hormones (Eg. IGF-1, TPO, EPO, angiotensinogen)
• Creatine is synthesised by liver used in muscle as an energy store then metabolised to creatinine and excreted
• Protein catabolism involves protein is broken down into a.a.
• Amino acid metabolism metabolises to other a.a., glucose, acetyl-CoA, substrates, and NH3

Functions of the Liver: Metabolism

• Liver synthesizes purine and pyrimidine bases
• Liver metabolises purines , or by recycling them via “salvage pathway”, and pyrimidines
• Endogenous compounds and drugs/xenobiotics are lipophilic and difficult to excrete
• Liver metabolises compounds via reactions so they increase hydrophilic , and decrease active/toxic:
  • Phase I reactions ↑ reactivity of compound and ↑ H₂O solubility of compound
  • Oxidation (major) via CYP450, Reduction via reductase, Hydrolysis via hydrolyase
  • Metabolites of phase 1 reactions may be pharmacologically active and/or toxic
  • Phase II reactions are conjugation reactions add polar groups to phase I metabolites
  • Glucuronidation (major) via Glucuronosyl transferases

Functions of the Liver: Other

• Glycogen store, adult has 100 g of glycogen, permits Glucostat function
• Fat store, Vitamin Store fat-soluble vitamins, Metals store, Blood reservoir
• Hepatic sinusoids and portal venous system are compliant, can store 500 mL of blood
• Production of urea where Ammonia is an end-product of amino acid metabolism
• The Urea Cycle is an ATP converts toxic NH3 to Urea via less-toxic excreted

Functions of the Liver: Production of bile

• Liver produces 1 L bile daily, passes into gallbladder for concentration to 20% volume
• Bile includes Bile salts, and Bilirubin water
• Uunconjugated bilirubin is formed by the breakdown of haem proteins by macrophages
• Haemproteins broken down into haem and other moieties
• Haem is then processed by two enzymes where Haem oxygenase Converts O + Haem to Biliverdin + Fe + CO, CO excreted
• BIlverdin reductase reduces biliverdin to unconjugated bilirubin
• Unconjugated bilirubin is bound to albumin then transported to liver via OATP transporter
• Converted in sER by UDP-Glucuronyltransferase into conjugated bilirubin:
• UDP-Glucuronic acid + Bilirubin converts Bilirubin Monoglucuronide + UDP then 2x Bilirubin Monoglucuronide converts Bilirubin Diglucuronide + Bilirubin
• Conjugated bilirubin is actively secreted and added as one of the components of bile, passed into intestines
• Intestinal flora converts to Urobilinogen where reabsorbed into portal circulation then excreted by kidney
• Bile salts are absorbed into portal circulation, converted to stercobilinogen excreted
• Functions of bile salts facilitate intestinal digestion of lipids , enhances absorption of cholesterol
• Keeps cholesterol solubilised and induces motility
• 1º bile acids are produced in hepatocytes from cholesterol conjugated with glycine and taurine to increase H2O solubility , then excreted
• Metabolised by intestinal bacteria to form 2º bile acids
• Biliary fistula causes: Loss of H2O , Loss of bile salts , Loss of electrolytes , and Loss of HCO3-

Functions of the Liver: Reticulo-endothelial system

• Liver contains Kupffer cells that line the hepatic sinusoids with functions
  • Immunological, Filter portal blood
    • Iron accumulation regulates recycling BM for Hb production, Haematopoietic, Coagulation, Bilirubin
• Reticulo-endothelial system functions includes:
  • Antigen-presenting
  • Phagocytosis
  • Production
• Haematological functions consist of erythropoiesis, platelet synthesis, coagulation and endocrine functions
• Endocrine functions:
  • Activation of hormones
  • Production of hormones
  • Inactivation of hormones
• Acid-base Balance, contributes 20% of bodies CO, and Amino acid metabolism

Hepatic Blood Flow

• Total hepatic blood flow is liver receives blood supply, oxygenation from Hepatic artery: 30 % total hepatic and Hepatic portal vein: Drains 70% Hepatic O2 efficiency helps with low blood flow and consumption
• Hepatic microvasculature are sinuses that create low pressure.
• Role of Liver vessels help with:
  • Exchange nutrients
  • Acts as reservoir for blood.

Hepatic regulation

• Veins receive sinusoidal blood and leave for IVG
• arterial blood= MAP – Hepatic venous pressure/vascular hepatic resistance
• Intricnsic help to keep blood flow regulated , -autoregulation and autoregulation helps keep steady state and increase with blood loss .

Extrinsic control of Blood Flow

• Neuroendocrine uses
  • Neural and adr
    • Hepatic artery releases and has high and low receptors.
• External factors
• Physiological and pathophysillogical
• HFB changes blood flow
• Anesthesia can change and alter pressure

Measuring Hepatic Blood Flow

• Ways to find blood
• Electromagnetic uses to find how much is blood in the systems
• Indrect uses Ficks Law
• The amunt of sustance entering much equal outflow of blood.
• Cleanse tequniques
• ICG and ICG tequnuicqies
• Liver extracts substances and cleans up.

Liver Functon Test

• These can tell if liver is hurt
• Test and give clues to diseases

Synthetic Function

• Help test proteins, albumim globim etc.

Platelet/Hemaglobin

• Show what liver and platelets can do.

Metabolic

• Shows how fast and metabloic the functions are.

Bilirubin levels

• Direct or indict what it can be.

Hepatocellular Injury:

• Can see cells and see liver damage, due to disease and injury
• Cholestasis can see infection of liver, or alcohol Physiological consequences of Hepatic Disease include:
• Due to heart problems HTN, ascites.
• Cns effects, Due to toxins building.
• Circulatory, increase blood rate.
• Respiratory has heart cant function Renal renal failure and function Haematological, clotting anemic, infection Metabolic:
• due to all problems from disease
• Lack function cant do vitamin and mineral fat is a problem.