13. Hepatic Physiology

• Functional liver anatomy is important in nutrient metabolism, detoxification, and bile production.

Blood Supply

• 80% of the liver's blood supply comes from the portal vein, rich in nutrients, amino acids, and peptides from the GI tract.
• 20% of the blood supply is from the hepatic artery which provides oxygen-rich blood and chylomicra.
• Blood drains through sinusoids over hepatocytes into the central vein.
• Centrilobular hepatocytes are more susceptible to ischemia and toxins causing centrilobular necrosis.

Bile Drainage

• Hepatocytes are in plates radiating from a central vein.
• Bile canaliculi form between basolateral membranes of hepatocytes, connecting to bile ductules.
• Bile flows in the opposite direction of blood flow.

Nutrient Metabolism

• The liver is important for maintaining constant blood nutrient levels.

Carbohydrate Metabolism

• A primary liver function is to maintain euglycemia (80-120 mg/dL in dogs and cats).
• This is achieved by maintaining a constant glucose input into the blood via three mechanisms.

Glycogenolysis

• Glycogenolysis (glycogen is a glucose polymer) helps main glucose input.
• The liver stores a large amount of glycogen
• Glycogen lysis releases glucose, increasing blood glucose.
• Intense exercise can deplete glycogen stores, decreasing blood glucose.

Gluconeogenesis

• Gluconeogenesis is a slower process than glycogenolysis.
• Glucose is synthesized from non-carbohydrate sources.
• Deaminated amino acids (from dietary or muscle breakdown).
• Glycerol (from triglyceride backbone).
• Propionic acid (VFA)
• Gluconeogenesis is regulated by endocrine hormones like glucagon, glucocorticoids, epinephrine, and thyroxine.

Interconversion of Monosaccharides

• The liver converts other monosaccharides such as galactose or fructose into glucose.
• This process is slower than glycogenolysis or glycoproteins.

Nitrogen Metabolism

• The liver is the main site for amino acid, uric acid, and ammonia metabolism.
• Uric acid results from purine breakdown, forming nucleic acids.
• Ammonia results from protein processing or breakdown.
• Protein metabolism generates heat.
• The liver consumes 20-40% of daily oxygen intake.

Amino Acid Metabolism

• Four fates of amino acids absorbed from the intestine.
• Synthesis into Hepatic and plasma proteins
• Hepatic proteins are metabolic and structural, maintaining liver structure and function.
• Plasma proteins are primarily synthesized by the liver (90%).
• 10% of plasma proteins are circulating antibodies from WBCs.

Major Plasma Proteins

• Albumin is the main plasma protein, carrying hydrophobic substances and contributing to COP.
• Clotting factors like fibronogen and prothrombin are produced; liver disease can cause abnormal clotting.
• α and β Globulins are specialized proteins, carrying steroid hormones, cholesterol, copper, and substrates like angiotensinogen.

Transamination

• Used in synthesizing non-essential amino acids.
• Essential amino acids cannot be synthesized by the body and must be acquired via diet.

Deamination

• Occurs when amino acids are in excess, used for gluconeogenesis.
• Ammonia (NH3) released enters the urea cycle, while the carbon skeleton is used for glucose synthesis.

Liver Bypass

• Allows amino acids to enter general circulation to make other tissue proteins.
• Increased blood NH3 is toxic to the CNS, detoxified by conversion to urea.

Ammonia Metabolism

• Ammonia in the blood comes from hepatic deamination and absorption from the large intestine or rumen.
• Ammonia enters the urea cycle in hepatocytes, then urea enters circulation.
• The fate of urea: 75% is excreted in urine; 25% enters the GI tract.
• Urea is lipid-soluble and diffuses from blood across the epithelium, found in saliva (ruminants).
• Bacterial ureases in the LI or rumen break down urea to NH3, where microbes use NH3 and CHO skeletons to synthesize microbial proteins

Clinical Relevance: Ammonia Intoxication

• NH3 is toxic to the CNS, causing lethargy, head pressing, and coma.
• Causes include:
• Liver Disease: Hepatic insufficiency leads to hepatic encephalopathy, as the damaged liver cannot synthesize NH3 into urea.
• Urea poisoning: primarily in cattle, from feeding non-protein nitrogen without enough dietary carbohydrates, leading to overwhelming urea cycle.
• Ornithine deficiency: in cats, due to an essential amino acid deficiency in the feline diet.

Uric Acid Metabolism

• Most species metabolize purines into uric acid.
• At the liver, uric acid is transported into hepatocytes by the uric acid transporter (SLC2A9)
• Hepatic uricase converts uric acid to allantoin, which is excreted in urine.
• At the kidney, the uric acid transporter also removes some uric acid from the urine.
• Dalmatian dogs have inherited mutations in the urate transporter (SLC2A9), uric acid cannot enter the hepatocyte for metabolism to allantoin
• Uric acid is filtered into the kidney's urine, but cannot resorb, then high levels of urate in urine means high potential for urate stones in urinary bladder

Lipid Metabolism

• The liver maintains the equilibrium of lipid input and output.
• A healthy liver is ~3% fat. Increased fat interferes with liver function, which causes inflammation.

Sources of Uric Acid

• Diet, red meat, organ meats, seafood, bacterial flora
• Endogenously sloughed intestinal cells

Lipid Input to the Liver

• Dietary: Chylomicra from intestinal fat absorption.
• Circulating chylomicra carry triglycerides (TGs).
• Lipoprotein lipase, synthesized in adipose, cardiac, and skeletal muscle, hydrolyzes triglycerides in chylomicrons.
• Apolipoproteins bind to lipoprotein lipase
• After digestion, smaller chylomicron remnants pass through liver sinusoids into the space of Disse, then cleared for metabolism or bile excretion.

Hepatic Lipid Synthesis

• Hepatic cells convert excess de-aminated amino acids and sugars to free fatty acids for metabolism and lipoprotein formation.

Lipid Mobilization from Adipose Tissue

• Mobilizing lipase is located in body fat stores.
• In a calorie deficit, mobilizing lipase liberates FFA from stored TG to the liver for which enter circulation for metabolism.
• Mobilizing lipase activity is regulated by endocrine hormones (glucocorticoids, glucagon).

Lipid Output from the Liver

• Three fates of fat.
• Hepatic lipoprotein formation.
• Hepatic cells synthesize FFA into triglycerides, phospholipids, and cholesterol.
• Lipoprotein formation requires lipotrophic substances like phospholipids, choline, and methyl group donors.

Types of Lipoproteins

• VLDL: Very low-density lipoprotein.
• LDL: Low-density lipoprotein.
• IDL: Intermediate density lipoprotein.
• HDL: High-density lipoprotein.
• HDL ('good' cholesterol) and LDL ('bad' cholesterol, associated with atherosclerosis).
• Most cholesterol is synthesized in the liver (80%).
• Hepatic synthesis is inversely related to dietary cholesterol input.
• Cholesterol esters are important in hepatic synthesis of bile acids.

Hepatic Catabolism of Lipid for Energy

• β-oxidation of FFA in the liver yields acetyl coenzyme A (acetyl CoA).
• Acetyl CoA then enters Kreb's citric acid cycle for oxidation. OAA is also needed for the Kreb cycle

Ketone Body Formation in the Liver

• When insufficient OAA is available, acetyl CoA is synthesized into ketone bodies.
• Acetone (3C).
• Acetoacetate (4C).
• β-hydroxybutyrate (4C).
• Ketone bodies enter circulation and is used as an energy source by muscle and neurons.

Clinical Relevance: Negative Energy Balance

• The liver increases circulating ketones
• Decreased OAA and FFA mobilized turns to AcCoA then Ketone bodies
• Severe situations will look like: Very low OAA, ↑↑ FFA mobilized then ↑↑↑AcCoA creating lots of Ketone bodies leading to Ketoacidosis
• Elevated circulating ketone bodies cause ketosis and acetone odor on breath.
• Excessive ketones decrease blood pH, leading to CNS signs, seen in untreated diabetes.

Clinical Relevance: Fatty Liver

• The Increased percentage of fat in the liver impairs liver function.
• Causes include:
• Choline deficiency decreases apolipoprotein synthesis.
• Excessive fat input to the liver.
• Starvation and mobilization of body stores.
• Excessive dietary protein and CHO. rare

Vitamin and Mineral Metabolism

• The liver synthesizes, activates, and stores vitamins.

Fat-Soluble Vitamins

• Bile promotes absorption efficiency, Liver stores A and D.
• Vitamin A is stored for 1-2 years in hepatic stellate cells.
• Vitamin D is stored and undergoes the 1st activation step.
• Vitamin E is an antioxidant with little storage.
• Vitamin K is used to synthesize prothrombin.

Water-Soluble Vitamins

• B vitamins are required in the diet of mammals (except adult foregut fermenters/coprophagous animals).
• Some water-soluble vitamins are activated in the liver.
• Vitamin C is synthesized in the liver by most species except Primates and Guinea pigs (Scurvy)

Iron

• Stored as ferritin in the liver and other tissues, retained very efficiently, lost mainly via hemorrhage.
• Soil high in Iron content for grazing animals, can increase radical produced in gut leading to tissue damage/inflammation.

Detoxification Function

• The liver detoxifies or metabolizes a number of compounds.
• Exogenous: drugs and toxins
• Endogenous: cause disease if uncleared.
• many are conjugated with glucuronic acid for excretion via bile.
• Coffee increases hepatic glucuronyl transferase expression, increasing detox and decreasing liver cancer risk.

Degradation of Heme Pigments and Excretion as Bilirubin

• Heme is complexed with iron, found in RBCs (hemoglobin) and muscle (myoglobin).
• Oxygen binds reversibly with heme.
• RBCs turnover, the RBC lyse, releasing heme.

Bilirubin

• Porphyrin is toxic and must be detoxified by conversion to bilirubin.
• Bilirubin = breakdown product (found in bile, but not bile)
• Bile = mostly water with bile salts, bilirubin, fats, and inorganic salts.
• RBCs lyse and then release hemoglobin
• Hemoglobin (Hb) binds to haptoglobin in plasma, then cleared by the reticuloendothelial system.
• Within RES: -Heme oxygenase causes release of Fe and converts porphyrin to biliverdin. -Biliverdin reductase turns biliverdin into unconjugated bilirubin (yellow-red pigment). -Unconjugated bilirubin is released to albumin (poorly water-soluble). -At the liver, unconjugated bilirubin is cleared by hepatocytes Conjugated with glucuronic acid.

Excretion - Bacteria

• Bacteria converts conjugated bilirubin to urobilinogen.
• Urobilinogen converts to stercobilin to brown feces.
• Obstructed bile flow prevents bilirubin in gut and stercobilin creating gray feces.
• Some urobilinogen is absorbed from blood into kidney as urobilin resulting in yellow colored urine.

Clinical Relevance: Jaundice

• Yellow skin from excess bilirubin.
• Caused by excessive hemolysis, biliary obstruction, liver parenchymal disease.
• Certain causes of jaundice can be differentiated by van den Bergh test
• Indirect: unconjugated bilirubin.
• Direct: conjugated bilirubin.

Hemolytic Jaundice (Dx)

• Increase in indirect bilirubin (overwhelms liver conjugation).
• Obstructive Jaundice (Dx): increase direct and bilirubin leaks into blood.
• Neonatal jaundice (preterm infants): any increase in bilirubin formation overwhelms conjugation capacity
• Treated with phototherapy.

Bile secretion and Reabsorption

• Bile is a main liver function.
• Bile functions include:
• Emulsification of dietary lipids (micelle formation).
• Excretion of toxic products
• Bile constituents include:
• Bile acids (75% of total solids).
• Cholesterol
• Pigments
• Electrolytes and water

Bile Acid Synthesis

• Bile acids synthesized from cholesterol in the liver.
• Primary bile acids: Cholate, Chenodeoxycholate.
• Primary bile acids are conjugated with taurine or glycine to make secondary bile acids
• Example: Tauracholic acid
• Lowers pKa of bile acid - Ionized at intestinal pH
• Conjugation makes bile salts more water-soluble

Enterohepatic Recycling

• After entering the intestinal lumen, bile salts form micelles with dietary fat.
• Released bile salts travel to the terminal ileum where absorbed by Na-coupled transport.
• Most are reabsorbed to complete cycle
• Control of Hepatic Biliary Secretion Modes of secretion: tonic and augmented secretion. Choleresis is increased bile secretion. Bile salts help mild choleretic by recycling Secretion stimulates and water secretion from bile ducts.

Gallbladder Function

• Bile is stored in the gallbladder until the meal intake.
• Concentrates bile salts and lowers bile pH which can prevent Ca2+ precipitation.
• Control of Gallbladder Contraction/Emptying
• CCK main cholegogue
• Acetylcholine - mild cholegogue.