Histology of Digestive System

Liver: Histology

• Is the primary metabolic organ in the body and the largest gland
• Has both endocrine (directly into blood stream) and exocrine (into ducts) secretions
• The liver is the organ where nutrients form the GI are processed and stored for use by other organs.
  • Liver has the first shot at the nutrients
  • Liver is inserted between 2 parts of the vascular system; hepatic portal veins from GI and inferior vena cava (distribution center).
• It serves as an interface between the GI (extracts nutrients) and the blood (which distributes nutrients)
• The liver is in the optimal position in the circulatory chain for accumulating and metabolizing nutrients and elminating / neutralizing toxins
• The liver performs a variety of crucial physiological functions which can be divided into 3 classes
  • Vascular functions: the storage and filtration of blood.  The liver is made up of 50% vascular channels.
  • Secretory / excretory functions

1. 1. • vitamin storage / excretion: A, B12, C, D, E, K
      • synthesis and secretion of bile

1. • Metabolic functions:

1. 1. • Protein synthesis (albumin regulates plasma osmotic pressure, prothrombin, fibrinogen for clotting cascade).
      • Lipoprotein and cholesterol synthesis.

• • • Carbohydrate metabolism (gluconeogenesis, glycogenolysis, glycogenesis). Make glucose / glycogen (can interconvert) and release it into plasma.

• • • Metabolism of lipid-soluble drugs and steroids- Is a detox center.
    • Urea formation (from ammonium ions). When break apart proteins, ammonia is byproduct.

Liver gross Anatomy:

• Located in the upper right quadrant of the abdominal cavity, below the diaphragm
• Appears reddish-brown in the living state
• Consists of 4 lobes of parenchymal tissue: right, left, quadrate, caudate.
• Enveloped by dense irregular CT capsule – Glisson’s capsule, which is covered by the mesothelium of the peritoneum.
• Weighs about 3 lbs
• A short transverse fissue (portal hepatis) partially separates the L and R lobes posteriorly and is the site of entry / exit of blood vessels, lymphatics, nerves, and ducts.
• The R and L lobes of the liver are separated anteriorly by a fibrous CT plate called the falciform ligament.

Blood supply:

• The liver is highly vascular and blood flow is estimated at 1500-200 ml / min nearly 1/3 total cardiac output.
• Gets large venous supply of blood and drains into the venous system.
• The liver has a dual blood supply, receiving blood from both arterial and venous sources.
• 75% of the blood supply of the liver comes from the hepatic portal vein from capillaries of the GI, spleen, pancreas.
• The portal veins give rise to smaller diameter distributing veins and inlet venules which radiate outward toward the sinusoids. In the sinusoids is where blood is dumped and all important functions occur.
• The liver lays directly in the path of blood vessels which convey nutrient-rich blood laden (with the products of digestion) for metabolism by hepatocytes.
• Portal vein enters into portal hepatisà eventually empty into sinusoids.
• Exit point for blood is the central vein of each lobule→ dump into sublobular veins→ collecting veins→ hepatic vein→ IVC.
• 25% of the blood is derived from the L and R hepatic arteries, branches of the celiac trunk of the abdominal aorta.
  • The hepaic arteries give rise to smaller distributing arterioles and inlet arterioles
  • These carry oxygen rich blood to the hepatocytes.
• The inlet arterioles and venules empty into endothelial lined sinusoids which separate the plates of hepatocytes in he parenchyma.
• The sinusoids empty into terminal hepatic venules at the center of each liver lobule and are termed Central Veins.
• The central veins empty into a series of progressively larger veins:
  • Sublobular veins and collecting veins
  • Eventually form the right and left hepatic veins that exit the liver

Internal structure of the Liver:

• The parenchyma of the liver is composed of hepatocytes arranged in hexagonal shaped lobules surrounded by CT.
• In pigs and other animals, the CT elements are quite prominent, but in the human liver, the CT is incomplete and difficult to discern.
• Between the lobules are regions of denser CT comprosing an area known as the oprtan tract.
  • This contains the major vessels of the liver: hepatic artery, hepatic portal vein, bile duct, lymph vessels.
  • The Triad: incoming hepatic arteriole, incoming hepatic portal venule, bile duct (can see very well due to large cuboidal cells in wall)
• Little holes at corners of hexagon represent vascular input to the lobule  (portal tract).  Central vein is the draining vessel in the center of each lobule.

Portal tract is Separated from the Parenchyma by:

1. A narrow space – space of Moll (thought to be the origin of hepatic lymph)
2. A sleeve of modified hepatocytes – limiting plate (thought to be important in liver regeneration). Not different from other hepatocytes in appareance.  But damage to these cells will inhibit liver regeneration.

Hepatocytes of the lobule are arranged in plates or cords separated by sinusoids.

• The center of each lobule is pierced by central vein which drains blood form the sinusoids.
• Sinusoids radiate toward the central vein.
• The liver is essentially a giant molecular sieve.  It has such a large blood supply and is organized in such a way to expose the hepatocytes to components of the blood.

3 concepts of Liver Organization:

• Classic lobule: described on the basis of CT arrangement (lobulation is distinct in humans due to sparse perilobular CT)
  • Defined by hexagonal shaped parenchymal region and bounded by portal tracts at each corner of the hexagon, with a central vein in its center.
  • Blood flows from perimeter of lobule, run through sinusoids, drain into central veins.  The excretory product of the liver (bile) flows in opposite direction- it flows outward toward the bile duct portion of triad.  Blood goes from periphery to center, bile goes from center to periphery.
• Portal lobule: Thinking of liver as a gland
  • In most exocrine glands, a “lobule” consists of secretory units whose outflow drains into a common interlobular duct. In the liver this would be the bile duct of the portal tract.
  • The portal lobule is

1. 1. • Described in terms of bile flow
      • A triangular region of hepatocytes with a central vein at the apices of the triangle and the portal triad (with accompanying bile duct) at the center

• • • Bile flows from the periphery to the center of portal lobule into the interlobular bile duct.

1. Hepatic Portal Acinus: Most useful view:
   • Is the most recently proposed concept of liver organization.
   • Smallest functional unit of the liver – Acinus
   • Diamond shaped mass of hepatocytes lying between two central veins at the apices of its long axis and two portal tracts at apices its short axis.
   • The meridian of the diamond is traversed by pre-terminal branches of a distributing arteriole which supplies blood to the sinusoids.
   • Can divide the hepatocytes into 3 zones:

• • • Those closest to arteriole / venous input = Zone 1
    • Those intermediately close = Zone 2

• • • Those farthest away from input, but close to central vein. (zone 1,2,3).

Zone 1: Cells closet to the Arteriole

• Receive excellent supply of oxygenated blood and nutrients
• Minimally exposed to metabolic waste

Zone 2: cells further from vessels than zone 1

• Receive only moderately oxygenated  blood
• Intermediate exposure to metabolic waste

Zone 3: Cells closet to the central vein

• Receives poorly oxygenated blood
• High exposure to metabolic waste
• Constitutes the primary site of alcohol and drug detoxification and its hepatocytes are much more vulnerable to toxic damage than those of zone 1. liver disease often shows degeneration of zone 3 cells first. All toxins upstream have drifted downstream toward zone 3.  these are the most metabolically fragile cells in the liver.  Taxing the liver will cause these cells to die off first.

Hepatic Plates and Sinusoids:

• Within each lobule, hepatocytes are arranged in thin cords / plates 1-2 cells thick, separated by thin endothelial lined sinusoids.
• The hepatic plates form a continuously anastomosing labyrinth of cells.
• The sinusoids form a continuous vascular channel within the lobule which ultimately empties in the central vein at the center of the lobule.
• Hepatocytes are not in direct contact with the sinusoids but are separated from them by a thin perisinusoidal space = space of Disse:
  • This is the holding area for nutrients / toxins which can flow back and forth.
  • Membranes of endothelial cells have many holes- are discontinuous capillaries.  These sieve plates allow the straining of plasma: thus, plasma can leave, cells cannot.
  • This space contains blood plasma, but not blood cells or platelets
  • Numerous microvilli protruding from the surface of hepatocytes
  • Perisinusoidal cells of Ito
    • Irregular cells with long cytoplasmic processes
    • Concentrate vitamin A → converted into precursor of retinal→ dumped back into plasma in perisinusoidal space→ goes into vasculature toward the eye→ becomes chemical for sight transduction.
    • Function not well understood, may play role in fibrosis / cirrhosis.

1. • Hepatocytes have microvilli that go into the space of Disse to increase surface area to aid in nutrient uptake.

The wall of the hepatic sinusoids are formed from simple squamous endothelial cells:

• The endothelial cells are discontinuous and without a continuous basal lamina.
• The membrane of the endothelial cells is riddled with clusters of small holes = sieve plates.
  • These specializations of the endothelium allow for the passage of substances under .5 microns to pass through the endothelial wall and into the cell membrane.
  • The sinusoid epithelium is supported by a delicate network of reticular fibers

Spanning the width of the sinusoids = family of phagocytes called Kupffer cells.

• The lumen of the sinusoid often contains large branched phagocytic cells = kupffer cells.
• Derived form mononuclear phagocytic line.
• These cells phagocytose damaged red blood cells and plasma debris.

Structure of hepatocyte:

• Hepatocytes perform a wide variety of functions directed primarily at:
  • Metabolizing the end-products of absorption from the alimentary canal.
  • Storing these as cellular inclusions and releasing them into the sinusoids in response to hormonal/ neural signals.
  • The cells are large polygonal shaped cells which are packed together to form thin plates / cords of the liver parenchyma.
  • They exhibit variation in structure depending on their position within the liver lobule.  Smooth ER would be greater in zone 3 for detox etc.
• Organelles / inclusions:
  • Nucleus of variable size, occasional binucleated
  • Numerous mitochondria
  • Abundant RER and free ribozomes (protein synthesis)
  • Prominent golgi (for molecular packing)
  • Numerous peroxisomes, lysosomes, endosomes.
  • Lipid droplets – VLDL (increased after fatty meal)
  • Hepatocytes have abundant SER responsible for drug metabolism and detoxification

1. 1. • Number increases with lipid soluble toxin levels (metabolism of lipid soluble compounds)
      • Lumen of the SER contains an elaborate enzyme system = microsomal mixed function oxidase system. Responsible for metabolism of barbiturates, antibiotics, toxins.

• • • Methylation, conjugation, and oxidation are the most common methods for drug inactivation and detoxification performed by the hepatocyte SER.

• • • The cytochrome P-450 system is the major enzyme system in the liver involved in drug metabolism.
    • Many of these liver enzymes are inducible and up-regulated by continuous exposure to a compound.
      1. This can effect the long term delivery and efficacy.
      2. If drug is metabolized more efficiently, will develop tolerance for the drug.
  • The liver is also a major site of “first pass” metabolism of commonly used therapeutic drugs.
    • When give drug orally, it gets into vasculature by GI absorption.
    • That blood which carries the drug will first go to the liver. This is unfortunate since the liver is most capable organ for destroying the drug.
    • Before it goes to the systemic circulation it is deactivated by the liver. Thus, some drugs are best administered intravenously.

Hepatocyte Domains:

• Polygon shaped hepatocytes within the hepatic plates have two types of surfaces.
  • Those which border other hepatocytes = lateral domain
  • Those that border the sinusoids = sinusoidal domain
• Lateral domain:
  • The membranes of adjoining hepatocytes delimit a tubular space 1-2 micrometers between them = bile canaliculus.

1. 1. • Initial portion of the bile duct system.
      • This is a joining between two liver cells formed by infolding of membrane.

• • • Is a spherical channel, with each cell forming hemisphere.

• • • This goes throughout entire liver cord to form a fluid filled channel into which bile can be excreted.
    • The walls of the liver cell membrane at this point have microvili which pariticpate in exocytosis.
    • Formed solely from the hepatocyte membranes.

• • • Important point is that this channel does not have its own lining, it is made only by the hepatocyte membranes.
    • The points of fusion of these cells (membrane) have tight junctions to exclude bile from going into intercellular spaces outside the channel. This indentation is ½ across lateral extent of cell.

• • • Membranes adjancent to the canaliculi are surrounded by tight junctions:
    • Short microvilli protturde from the lumenal surface of the canaliculi.

1. • Bile canaliculi form a ring around hepatocytes and connect with those of adjacent hepatocytes to form a complex branched network which converges on the portal region of the lobule.
   • Bile canaliculi empty into the bile ductules, called the canals of Herring, in the portal region which leads to the portal bile ducts.

1. 1. • Both the bile ductules and the bile ducts are lined by cuboidal epithelium.
      • Portal bile ducts empty into successively larger ducts which fuse with the left and right hepatic ducts.

Sinusoidal domain:

• Surface of the hepatocyte that is adjacent to the sinusoid (and space of Disse).
• Hepatocytes are not in direct contact with the sinusoid epithelia but are separated from it by the space of Disse.
• This compartment serves as a molecular holding tank for substances entering or leaving the hepatocyte.
• Hepatocytes membranes bording the sinusoids.
  • Elaborate numerous microvilli into the space of Disse which increase the surface area and promote absorption.
  • Display high levels of Na+ / K+, ATPase and adenylate cyclase activity which facilitate membrane transport.

Gall bladder

Histology of the gall bladder:

• Gall bladder is a hollow pear shaped organ attached to the posterior – inferior surface of the liver
• The primary function of the gall bladder is to store, concentrate (through water extraction), and release bile.
• Bile is synthesized in the liver, stored and concentrated in the gall bladder and released in the duodenum.
• Since it does not synthesize its own secretory product, the gall bladder is not considered a gland.
• The gallbladder is a blind pouch which leads via a neck to the cystic duct, where it joints the common hepatic duct to form the common bile duct which empties into the duodenum.
• The wall of the gallbladder has 5 layers.
  • Lumenal surface: a simple columnar epithelium composed of

1. 1. • Clear cells
      • Brush cells with microvilli

1. • Lamina propria: composed of vascularized CT.
   • Muscularis externa: composed of smooth muscle of mixed orientation. Only have one layer of muscle unlike GI tract. Contraction of this muscle causes the release of bile out through the duct.
   • A layer of perimuscular CT
   • A thin outer simple squamous epithelium (serosa).

The gallbladder receives bile from the liver via common hepatic duct and can store up to 70 ml of bile.

• Bile plays a role in
  • Emuslfication of fat to aid fat digestions
  • Excretion of waste products form the degradation of worn out red blood cells.
  • Excretion of excess cholesterol synthesized in the liver
  • Elimination of heme breakdown products also removed with bile
• Once in the gallbladder, bile is concentrated 5-10 times by the removal of water and ions by the gallbladder epithelium.
• The gallbladder releases up to 1200 ml of bile / day into the duodenum through cystic and common bile ducts following contraction of the smooth muscle layer.
• The signal for the gallbladder contraction is the hormone cholecystokinin- pancreozymogen produced by the enteroendocrine cells of the intestinal epithelium.
• The flow of bile is controlled by the sphincter choledochus, at the junction of the common bile duct and the duodenum which are relaxed in response to CCK release. This sphincter opens the common bile duct.
• Bile empties into the duodenum at an expanded junction with the common bile duct = ampulla of vater. (location of sphincter ampullae)

Gallstones:

• Choleserol secreted by the liver often precipitates in the gallbladder forming solid masses = gallstones.
• Gallstones can reach 1-3 cm in diamter and obstruct the normal flow of bile by lodging in the cystic or common hepatic ducts resulting in a painful condition.

Pancrease:

Histology of the pancreas:

• The pancreas is another accessory GI organ that promotes digestion in the GI tract by supplying enzymes that assist in the digestion of proteins, fats, carbohydrates.
• Is an oblong tubuloacinar gland nestled within the curvature of the duodenum.
• 4 regions: uncinate process, head, body, tail. Secretions are drained by the pancreatic duct.
• It is enveloped by a thin capsule of CT which forms delicate septae that divide the organ into lobules.  Loose CT arising from the septae also surround each glandular unit.

Pancreas has both an endocrine an exocrine function:

• Exocrine function: derived from pancreatic acinar cells. (pancreatic acini)
  • Synthesize / secrete pancreatic enzymes.
  • They empty into specific duct system which empties into the duodeneum.
• Endocrine function: the endocrine function of the pancreas is performed by a separate populaton of cells that are aggregated into clusters with different apperance than acinar cells, they are multihormonal organ called Islets of langerhans.  Focus is on exocrine function for now.
• Functional units of the exocrine pancreas are formed by tubuloacinar glands composed of secretory acinar cells and their accompanying ducts.
• Acini are around to oval shaped secretory units composed of
• • 40-50 pyramidal shaped acinar cells which form the secretory component
  • 3-4 centrally located low cuboidal centroacinar cells, which form the beginnings of the duct system.
• The centroacinar cells lead to the initial duct of the duct system leaving a secretory unit = intercalated ducts.

Pancreatic ducts:

• Intercalated ducts from neighboring acini join together to form larger intralobular ducts composed of simple cuboidal columnar cells.
• Intralobular ducts from several lobules converge to form larger interlobular ducts  composed of low columnar epithelium.
• The interlobular ducts empty into the main pancreatic duct which merges with the duodenum.

Pancreatic acinar cells: Pyramidal shaped cells with an ultrastructure typical of a cell polarized for protein synthesis and secretion. These cells are somewhat polarized.

• Basal region:
  • Basal surface rests on basement membrane which surrounds each acinus
  • Round nucleus
  • Extremely well developed RER in basal aspect of cell and numerous polysomes (basophilic)
  • Numerous mitochondria
• Apical region:
  • Numerous secretory zymogen granules whose number fluctuates with the state of fasting (are acidophilic)
  • Well developed golgi apparatus
  • Nurmous microvilli on the luminal surface
  • Tight junctions (adhering junctions) and desmosomes (gap junctions) connect adjacent cells and isolate the lumen from intercellular space.

Acinar cells synthesize and secrete a variety of enzymes which aid in the digestion of proteins:

• Enzymes are secreted as inactive proenzymes which are activated by trypsin in the duodenum.
• Pancreas is protected from autodigestion from premature activation of proteolytic enzymes in the acinus or ducts by a trypsin inhibitor secreted by the acinar cells.
• Iinflammatory diseases of the pancreas (pancreatitis), can result in the lysis of the acinar cells and the subsequent release of active digestive enzymes into the abdominal cavity causing serious organ damage.  This is by autodigestion.

Centroacinar cells:

• The lumen of each acinus is occupied by 3-4 light staining centroacinar cells which represent the initial portion of the intercalated ducts.
• These cells are small stellate in shape with relatively clear cytoplasm.
• The nuclei of these cells can be observed in the central lumen of the acini and are diagnostic for pancreatic tissue.
• these cells along with other duct cells secrete bicarbonate ions which maintain the duodenal pH within limits appropriate for pancreatic enzyme function.
• thus, 2 separate cells: acinar cells make enzyme, and centroacinar cells make the buffer.  Both go through ducts and to duodenum.

Regulation of pancreatic secretions:

Acinar cells

• Acinar cell enzyme secretion is regulated by the hormone cholecystokinin (CCK) produced in the epithelium of the duodenum and is triggered by GI motility.
• Basal surface of acinar cell contain CCK receptors.
• Centroacinar cells: the secretion of centroacinar cells is regulated by levels of the hormone secretin (also by GI motility) produced by duodenal epithelium.

Pancreatic islets of langerhans:

• Multihormonal micro-organs in the form of ovoid groups of clear endocrine cells scattered throuought the exocrine pancreas.
• Most numerous in the tail region of the pancreas.

Clinical:

Liver disease:

• Hepatitis:
  • Most common blood borne infection, 3.9 million cases in US and 170 million worldwide. Has 6 genotypes.
  • Infection and inflammation resulting in destruction of hepatocytes. Dead cells are replaced by fibrous tissue.
  • Leading cause of liver transplant.
  • Results in: fatigue, decreased appetite, weakness, nausea, joint and muscle pain, fibrosis of the liver.
  • Treatment: Anti viral drugs (interferon and ribaviron).
  • Most common is type C. types include: A,B,C,D,E
  • Causes restructuring of hepatic cords into nonfunctional components
• Cirrhosis:
  • Chronic disease of liver
  • Fibrosis of liver following hepatocyte damage.
  • Associated with alcoholism, chronic hepatitis, bile obstruction
  • Drainage of blood and bile disrupted resulting in:

1. 1. • Jaundice
      • Portal hypertension

• • • Esophageal varices, GI bleeding

• • • Anemia, hepatic coma due to accumulation of ammonia (no longer removed)

• • Is the most common liver disease.
• Inherited diseases of the liver:
  • Wilson’s disease:
  • Autosomal recessive causing copper to accumulate in the liver, brain, cornea, kidneys
  • Affects 1/30K people worldwide
  • Treatment: low Cu diet.

• Hemochromatosis:

1. • Inherited disease of iron overload
   • Symptoms: joint pain, fatigue, abdominal pain

• • Treatment: phlebotomy: 1 pint every 2-4 months.

Common laboratory liver function tests:

• Liver enzymes: particularly aminotransferases, which increase with hepatocyte damage.
  • Aspartate aminotransferase: AST
  • Alanine aminotransferase: ALT
• Increased bilirubin
• decreased plasma protein
• increased blood clotting times.

Liver failure: significant damage to liver hepatocytes generally affects all of the functions of the liver.

• Reduced protein synthesis
  • Decreased albumin synthesis leads to decreased osmotic pressure in the blood, resulting in edema
  • Reduced synthesis of clotting factors resulting in spontaneous internal bleeding
• Reduced metabolic detoxification
  • Increased plasma levels of biological toxins (esp. ammonia)
  • May lead to hepatic coma due to ammonia accumulation (esp. in brain).
• Decreased bile secretion
  • The array of hepatic cords have been disturbed.
  • Bile accumulation in the liver and plasma manifested as a yellowish discoloration of the skin = jaundice.