1. DUAL FUNCTIONS OF LIVER

2. FUNCTIONAL ANATOMY OF LIVER AND BILIARY SYSTEM

Liver

• Liver is the largest gland in the body.
• It weighs about 1.5 kg in man.
• It is situated in the upper and right side of the abdominal cavity immediately beneath the diaphragm.

Hepatic Lobes and Lobules

• Liver is made up of many lobes called hepatic lobes.
• Each lobe consists of many lobules called hepatic lobules.
• Hepatic lobule is the structural and functional unit of liver.
• It is a honeycomb-like structure.
• It is made up of liver cells called hepatocytes.

Hepatocytes and Hepatic Plates

• Hepatocytes are arranged in hepatic plates.
• Each plate is made up of two columns of cells.
• In between the two columns of each plate lies a bile canaliculus.
• In between neighboring plates, a space called sinusoid is present.
• Sinusoid is lined by endothelial cells.
• Macrophages called Kupffer cells are present in between the endothelial cells.

Portal Triads

Each portal triad consists of three vessels:

1. A branch of hepatic artery.
2. A branch of portal vein.
3. A tributary of bile duct.

• Portal triads are the canals surrounding each hepatic lobule.
• Lobules are lined by perivascular fibrous capsule.
• Each hepatic lobule is surrounded by many portal triads.

Bile Flow Through Liver

• Branches of hepatic artery and portal vein open into the sinusoid.
• Sinusoid opens into central vein.
• Central vein empties into hepatic vein.
• Bile secreted by hepatic cells is emptied into bile canaliculus.
• From canaliculus, bile enters tributaries of bile duct.
• Tributaries of bile duct from the neighboring lobules unite to form small bile ducts.
• The small bile ducts unite and finally form right and left hepatic ducts.
• Right and left hepatic ducts emerge out of liver.

Biliary System

• Biliary system or extrahepatic biliary apparatus is formed by gallbladder and extrahepatic bile ducts.
• Right and left hepatic bile ducts join to form common hepatic duct.
• Common hepatic duct unites with cystic duct from gallbladder to form common bile duct.
• Common bile duct unites with pancreatic duct to form common hepatopancreatic duct or ampulla of Vater.
• Ampulla opens into duodenum.

Sphincter of Oddi

• There is a sphincter called sphincter of Oddi at the lower part of common bile duct before it joins pancreatic duct.
• It is formed by smooth muscle fibers of bile duct.
• Sphincter of Oddi is normally kept closed, so that bile secreted from liver enters gallbladder where it is stored.
• Upon appropriate stimulation, the sphincter opens and allows flow of bile from gallbladder into intestine.

3. BLOOD SUPPLY TO LIVER

Liver receives the maximum blood supply of about 1,500 mL/min. It receives blood from two sources:

• Hepatic artery
• Portal vein

Hepatic Artery

• Hepatic artery arises directly from aorta and supplies oxygenated blood to liver.
• After entering the liver, hepatic artery divides into many branches.
• Each branch enters a portal triad.

Hepatic Portal Vein

• Hepatic portal vein is formed by superior mesenteric vein and splenic vein.
• It brings deoxygenated blood from stomach, intestine and spleen.
• Blood from hepatic artery mixes with portal blood in the hepatic sinusoids.
• Hepatic cells obtain oxygen and nutrients from the sinusoids.

Hepatic Vein

• Substances synthesized by hepatic cells, waste products and carbon dioxide are discharged into sinusoids.
• Sinusoids drain into central vein of hepatic lobule.
• Central veins from many lobules unite to form bigger veins.
• These finally form right and left hepatic veins.
• Hepatic veins open into inferior vena cava.

Blood Flow Through Liver

1. Hepatic artery / portal vein
2. Interlobular vein
3. Sinusoid
4. Central vein
5. Hepatic vein
6. Inferior vena cava
7. Right atrium

4. ENTEROHEPATIC CIRCULATION

Enterohepatic circulation is the circulation of many substances including bile salts and bilirubin that are absorbed from intestine and transported to liver through hepatic portal vein.

Significance

• It is responsible for recycling both metabolized and nonmetabolized substances.
• Many important substances that are secreted or excreted by liver into small intestine through bile are brought back to liver via enterohepatic circulation.

Substances Passing Through Enterohepatic Circulation

1. Monosaccharides
2. Amino acids
3. Bile salts
4. Conjugated bilirubin
5. Urobilinogen
6. Gastrointestinal hormones
7. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs)

5. NERVE SUPPLY TO LIVER

• Parenchyma of liver is supplied by sympathetic fibers from celiac plexus.
• It is also supplied by parasympathetic fibers from anterior and posterior trunks of vagus.
• All the nerve fibers reach the hepatic tissues by passing through hepatic artery and hepatic portal vein.

6. PROPERTIES AND COMPOSITION OF BILE

Bile is a golden yellow or greenish fluid.

It enters the digestive tract along with pancreatic juice through ampulla of Vater.

Properties of Bile

Composition of Bile

• Bile contains 97.6% of water.
• Bile contains 2.4% of solids.

7. SECRETION OF BILE

• Bile is secreted by hepatocytes.
• Initial bile secreted by hepatocytes contains large quantity of bile acids, bile pigments, cholesterol, lecithin, fatty acids and electrolytes.
• From hepatocytes, bile passes through canaliculi and hepatic ducts to reach common hepatic duct.
• From here, bile may enter the intestine or gallbladder.
• Sodium, bicarbonate and water are added to bile when it passes through the ducts.
• These substances are secreted by epithelial cells of the ducts.
• Addition of sodium bicarbonate and water increases the total quantity of bile.

8. STORAGE OF BILE

• Most of the bile from liver enters the gallbladder where it is stored.
• It is released from gallbladder into intestine whenever it is required.

Changes Taking Place in Bile During Storage in Gallbladder

1. Volume is reduced because of absorption of large amount of water and electrolytes except calcium and potassium.
2. Concentration of bile salts, bile pigments, cholesterol, fatty acids and lecithin is increased because of absorption of water.
3. The pH is slightly decreased.
4. Specific gravity is increased.
5. Mucin is added.

Differences Between Liver Bile and Gallbladder Bile

9. BILE SALTS

Bile salts are the sodium and potassium salts of bile acids, which are conjugated with glycine or taurine.

Bile salts are formed in liver.

Formation of Bile Salts

• Bile salts are formed from the primary bile acids:
  • Cholic acid
  • Chenodeoxycholic acid
• These are formed in liver and enter the intestine through bile.
• Due to bacterial action in intestine, primary bile acids are converted into secondary bile acids.

Enterohepatic Circulation of Bile Salts

• About 90 to 95% of bile salts from intestine are transported to liver through enterohepatic circulation.
• Remaining 5 to 10% of bile salts enter large intestine.
• Here, bile salts are converted into deoxycholate.

Functions of Bile Salts

1. Emulsification of Fats

• Emulsification is a process during which fat globules are broken down into minute droplets and made in the form of a milky fluid called emulsion.
• Emulsification occurs in small intestine by the action of bile salts.
• Fats cannot be digested directly by lipolytic enzymes of GI tract because fats are insoluble in water.
• Bile salts reduce surface tension of fats by their detergent action.
• Thus fat globules are broken into minute particles which can be easily digested by lipolytic enzymes.
• Emulsification by bile salts needs the presence of lecithin from bile.

2. Absorption of Fats

• Bile salts help in absorption of digested fats from intestine into blood.
• Bile salts combine with fats and make complexes of fatty acids called micelles.
• Fats in the form of micelles can be absorbed easily.

3. Choleretic Action

• Bile salts stimulate secretion of bile from liver.
• This action is called choleretic action.

4. Cholagogue Action

• Cholagogue is an agent which causes contraction of gallbladder and release of bile into intestine.
• Bile salts act as cholagogues indirectly by stimulating secretion of hormone cholecystokinin.
• This hormone causes contraction of gallbladder resulting in release of bile.

5. Laxative Action

• Laxative is an agent which induces defecation.
• Bile salts act as laxatives by stimulating peristaltic movements in intestine.

6. Prevention of Gallstone Formation

• Bile salts prevent formation of gallstone by keeping cholesterol and lecithin in solution.
• In the absence of bile salts, cholesterol precipitates along with lecithin and forms gallstone.

10. BILE PIGMENTS

• Bile pigments are the excretory products in bile.
• The bile pigments are bilirubin and biliverdin.
• Bilirubin is the major bile pigment in human beings.

Formation and Excretion of Bile Pigments

1. Senile erythrocytes are destroyed in reticuloendothelial system and hemoglobin is released from them.
2. Hemoglobin is broken into globin and heme.
3. Heme is split into iron and pigment biliverdin.
4. Iron goes to iron pool and is reused.
5. First formed pigment biliverdin is reduced to bilirubin.
6. Bilirubin is released into blood from reticuloendothelial cells.
7. In blood, bilirubin is transported by plasma protein albumin.
8. Bilirubin circulating in blood is called free bilirubin or unconjugated bilirubin.
9. It is insoluble in water and soluble in fat.
10. Within few hours after entering circulation, free bilirubin is taken up by liver cells.
11. In liver, free bilirubin is conjugated with glucuronic acid to form conjugated bilirubin by enzyme glucuronyl transferase.
12. Conjugated bilirubin is soluble in water and is also called direct bilirubin.
13. Conjugated bilirubin is then excreted into intestine through bile.

Fate of Conjugated Bilirubin

1. In intestine, 50% of conjugated bilirubin is converted into urobilinogen by intestinal bacteria.
2. First formed bilirubin is deconjugated to free bilirubin which is later reduced into urobilinogen.
3. Remaining 50% of conjugated bilirubin from intestine enters liver through enterohepatic circulation and is re-excreted in bile.
4. Most of the urobilinogen from intestine enters liver via enterohepatic circulation and later is re-excreted through bile.
5. About 5% of urobilinogen is excreted by kidney through urine.
6. In urine, urobilinogen is converted into urobilin by oxidation due to exposure to air.
7. Some of urobilinogen is excreted in feces as stercobilinogen.
8. In feces, stercobilinogen is oxidized to stercobilin.

Normal Plasma Levels of Bilirubin

• Normal bilirubin (total bilirubin) content in plasma is 0.5 to 1.5 mg/dL.
• When it exceeds 1 mg/dL, the condition is called hyperbilirubinemia.
• When it exceeds 2 mg/dL, jaundice occurs.

11. FUNCTIONS OF BILE

Most of the functions of bile are due to bile salts.

Functions of Bile Salts

• Digestive function — responsible for digestion of fats by lipolytic enzymes of GI tract.
• Absorptive function — responsible for absorption of digested fats from intestine into blood.
• Excretory function — bile pigments are major excretory products of bile.
• Laxative action.
• Antiseptic action.
• Choleretic action.
• Maintenance of pH in gastrointestinal tract.
• Prevention of gallstone formation.
• Lubrication function — mucin in bile acts as lubricant for chyme in intestine.
• Cholagogue action.

Other Substances Excreted in Bile

• Heavy metals such as copper and iron.
• Some bacteria such as typhoid bacteria.
• Some toxins.
• Cholesterol.
• Lecithin.
• Alkaline phosphatase.

12. FUNCTIONS OF LIVER

1. Metabolic Function

Liver is the organ where maximum metabolic reactions are carried out such as metabolism of carbohydrates, proteins, fats, vitamins and many hormones.

2. Storage Function

Many substances such as glycogen, amino acids, iron, folic acid and vitamins A, B12 and D are stored in liver.

3. Synthetic Function

• Liver produces glucose by gluconeogenesis.
• It synthesizes all the plasma proteins and other proteins except immunoglobulins, such as clotting factors, complement factors and hormone-binding proteins.
• It synthesizes steroids, somatomedins and heparin.

4. Secretion of Bile

• Liver secretes bile, which contains bile salts, bile pigments, cholesterol, fatty acids and lecithin.
• Bile salts are mainly due to bile salts.
• Bile salts are required for digestion and absorption of fats in intestine.
• Bile helps to carry waste products and excess of fats which are excreted through feces or urine.

5. Excretory Function

• Liver excretes cholesterol.
• Liver excretes bile pigments.
• Liver excretes heavy metals like lead, arsenic and bismuth.
• Liver excretes toxins.
• Liver excretes bacteria and virus.

6. Heat Production

Liver is an organ where maximum heat is produced because of metabolic reactions.

7. Hemopoietic Function

• In fetus, liver produces blood cells during hepatic stage.
• It stores vitamin B12 necessary for erythropoiesis and iron necessary for synthesis of hemoglobin.
• Liver produces thrombopoietin that promotes production of thrombocytes.

8. Hemolytic Function

Senile RBCs after the lifespan of 120 days are destroyed by reticuloendothelial cells (Kupffer cells) of liver.

9. Inactivation of Hormones and Drugs

• Liver catabolizes hormones such as growth hormone, parathormone, cortisol, insulin, glucagon and estrogen.
• It also inactivates drugs particularly fat-soluble drugs.
• Fat-soluble drugs are converted into water-soluble substances, which are excreted through bile or urine.

10. Defensive and Detoxification Functions

• Kupffer cells of liver play an important role in defense of the body.
• Liver is also involved in detoxification of foreign bodies.
• Foreign bodies such as bacteria or antigens are swallowed and digested by Kupffer cells of liver by phagocytosis.
• Reticuloendothelial cells of liver also produce substances like interleukins and tumor necrosis factor, which activate the immune system of the body.
• Liver cells are involved in removal of toxic property of various harmful substances.
• Removal of toxic property of a harmful agent is known as detoxification.

Detoxification in Liver Occurs by Two Ways

1. Destruction of substances by means of metabolic degradation.
2. Conversion of toxic substances into non-toxic substances by means of conjugation with glucuronic acid, sulfates.

13. GALLBLADDER

Gallbladder or cholecyst is a small and pear-shaped organ situated just beneath liver.

• Gallbladder stores bile.
• Capacity of gallbladder is approximately 50 mL.
• Gallbladder is not essential for life.
• It is removed by cholecystectomy in patients suffering from gallbladder dysfunction.
• After cholecystectomy, patients do not suffer from any major disadvantage.
• In some species, gallbladder is absent.

Functions of Gallbladder

1. Storage of Bile

Bile is continuously secreted from liver. It is released into intestine only intermittently and most of the bile is stored in gallbladder till it is required.

2. Concentration of Bile

• Bile is concentrated while it is stored in gallbladder.
• Mucosa of gallbladder rapidly reabsorbs water and electrolytes except calcium and potassium.
• Bile salts, bile pigments, cholesterol and lecithin are also reabsorbed.
• The concentration of these substances in bile increases 5 to 10 times.

3. Alteration of pH of Bile

The pH of bile decreases from 8–8.6 to 7–7.6 and becomes less alkaline when it is stored in gallbladder.

4. Secretion of Mucin

Gallbladder secretes mucin into bile. Mucin acts as lubricant for movement of chyme in intestine.

5. Maintenance of Pressure in Biliary System

Due to concentrating capacity, gallbladder maintains pressure of about 7 cm H₂O in biliary system. This pressure is essential for release of bile into intestine.

Filling and Emptying of Gallbladder

• Usually, sphincter of Oddi is closed during fasting.
• Pressure in biliary system is only 7 cm H₂O.
• Because of this pressure, bile from liver enters the gallbladder.
• While taking food or when chyme enters intestine, gallbladder contracts along with relaxation of sphincter of Oddi.
• Pressure increases to about 20 cm H₂O.
• Because of increased pressure, bile from gallbladder enters intestine.

14. REGULATION OF BILE SECRETION

Bile secretion is a continuous process although the amount secreted may be less during fasting.

Secretion starts increasing 3 hours after meal.

Secretion of bile from liver and release of bile from gallbladder are influenced by some chemical factors.

Chemical Factors Regulating Secretion and Release of Bile

1. Choleretics
2. Cholagogues
3. Hydrocholeretic agents

1. Choleretics

Choleretic is the substance which increases secretion of bile from liver.

Effective choleretic agents:

• Acetylcholine
• Secretin
• Cholecystokinin
• Acid chyme in intestine
• Bile salts

2. Cholagogues

Cholagogue is an agent which increases the release of bile from gallbladder into intestine by contracting gallbladder.

Common cholagogues:

• Bile salts
• Calcium
• Fatty acids
• Amino acids
• Inorganic acids

All the above substances stimulate secretion of cholecystokinin, which in turn causes contraction of gallbladder and flow of bile into intestine.

3. Hydrocholeretic Agents

Hydrocholeretic agent is a substance which causes secretion of bile from liver with large amount of water and less quantity of solids.

Neural Factor

Stimulation of parasympathetic nerve (vagus) causes contraction of gallbladder by releasing acetylcholine.

Vagal stimulation occurs during cephalic phase and gastric phase of gastric secretion.

Hormonal Factor

When a fatty chyme enters the intestine from stomach, intestinal secretion releases cholecystokinin. This hormone causes contraction of gallbladder.

15. LIVER FUNCTION TESTS

Liver function tests or hepatic function tests are a group of blood tests used to assess the health and normal functioning of liver.

Following are liver function tests:

1. Total bilirubin
2. Total protein
3. Total albumin
4. Albumin/Globulin ratio
5. Alkaline phosphatase (ALP)
6. Alanine transaminase (ALT)
7. Aspartate aminotransferase (ALT)
8. Gamma glutamyl transferase (GGT)

16. APPLIED PHYSIOLOGY: DISORDERS OF LIVER AND GALLBLADDER

1. Jaundice or Icterus

Jaundice or icterus is the condition characterized by yellow coloration of the skin, mucous membrane and deeper tissues due to increased bilirubin level in blood.

• Normal serum bilirubin level is 0.5 to 1.5 mg/dL.
• Jaundice occurs when bilirubin level exceeds 2 mg/dL.

Types of Jaundice

1. Prehepatic or hemolytic jaundice.
2. Hepatic or hepatocellular or cholestatic jaundice.
3. Posthepatic or obstructive or extrahepatic jaundice.

Prehepatic or Hemolytic Jaundice

• Occurs because of excess destruction of RBCs resulting in increased blood level of free (unconjugated) bilirubin.
• Function of liver is normal, but the quantity of bilirubin increases enormously.
• Liver cells cannot excrete that much bilirubin.
• Bilirubin accumulates in blood resulting in jaundice.

Common causes:

• Renal disorder
• Hypersplenism
• Burns
• Infections such as malaria
• Hemoglobin abnormalities such as sickle cell anemia or thalassemia
• Drugs or chemical substances causing red cell damage
• Autoimmune diseases

Hepatic or Hepatocellular or Cholestatic Jaundice

This is a type of jaundice that occurs due to damage of hepatic cells. Because of the damage, conjugated bilirubin from liver cannot be excreted and it returns to blood.

Causes:

• Viral hepatitis
• Alcoholic hepatitis
• Cirrhosis of liver
• Exposure to toxic materials

Posthepatic or Obstructive or Extrahepatic Jaundice

This type of jaundice occurs because of obstruction of bile flow at any level of biliary system. Bile cannot be excreted into small intestine. Bile salts and bile pigments enter the circulation.

Causes:

• Gallstones
• Cancer of biliary system or pancreas

Jaundice in Newborn Babies

In newborn babies, because of high count, RBCs are destroyed in large numbers. This increases blood level of bilirubin. Babies develop jaundice because their liver is not fully developed to excrete that much bilirubin.

Hepatitis

Hepatitis is liver damage characterized by swelling and inadequate functioning of liver. Hepatitis may be acute or chronic. In severe conditions, it may lead to liver failure and death.

Causes of Hepatitis

• Viral infection
• Bacterial infection
• Excess alcohol

Viral Hepatitis

Viral hepatitis is the type of hepatitis caused by viruses which include A, B, C, D and E.

• Hepatitis A and E cause acute infections.
• Hepatitis B, C and D cause acute and chronic infections.
• Hepatitis caused by hepatitis B virus is more common and considered more serious because it may lead to cirrhosis and cancer of liver.

Features of Hepatitis

• Fever
• Nausea
• Vomiting
• Diarrhea
• Loss of appetite
• Jaundice
• Liver failure and death in severe conditions

Cirrhosis of Liver

Cirrhosis of liver refers to inflammation and damage of parenchyma of liver resulting in degeneration of hepatic cells and dysfunction of liver.

It is caused by infection, obstruction of biliary system and liver enlargement due to intoxication.

Features of Cirrhosis of Liver

• Fever
• Nausea and vomiting
• Jaundice
• Portal hypertension
• Muscular weakness
• Wasting of muscles
• Coma in advanced stages

Gallstones

Definition

Gallstone is a solid crystal deposit that is formed by cholesterol, calcium ions and bile pigments in gallbladder or bile duct. Cholelithiasis means presence of gallstones in gallbladder.

Formation of Gallstones

Normally, cholesterol is water soluble. Under some abnormal conditions, it precipitates resulting in formation of crystals in mucosa of gallbladder. Bile pigments and calcium are attached to the crystals resulting in formation of gallstones.

Causes of Gallstone Formation

1. Reduction in bile salts.
2. Excess of cholesterol or disturbed cholesterol metabolism.
3. Excess of calcium ions due to increased concentration of bile.
4. Damage or infection of gallbladder epithelium.
5. Obstruction of bile flow from the gallbladder.

Features of Gallstone

• Pain in stomach area or upper right part of belly under the ribs.
• Nausea
• Vomiting
• Abdominal bloating
• Indigestion