Accessory glands of GIT

Liver, Gall bladder, Pancreas

Water and Ions

• Water– Can move in either

direction across wall of small intestine depending on osmotic gradients

• Ions– Sodium, potassium,

calcium, magnesium, phosphate are actively transported

Digestive glands

Salivary glandsPancreas

Liver

Saliva • Lubricant – mucous and water

moistens oral cavity and chewed food (1000 ml every 24 hours)

• Sensory – dissolves substances responsible of taste

• Digestive – salivary amylase and maltase

• Defense – mechanical disposal of debris; lysozyme, lactoferrin, IgA

Salivary corpuscles are desquamated squamous epithelial cells from the mouth plus some white blood cells

Saliva Secretions from saliva Function

MucinsLubricate food; Protect teeth against acid; Help protect against bacteria, viruses, fungi

Digestive Enzymesa-Amylase – digests starches, Lipase – digests fats, Protease – digests proteins

Lysozyme, Peroxidases, Lactoferrin, Histatins, Cystatins Anti-bacterial agents

Secretory Immunoglobulin A, Histatins, Cystatins Anti-fungal, anti-viral agents

Bicarbonate ions, Phosphate ions, Proteins

Help protect teeth and soft tissues against acidic conditions

Calcium ions, Phosphate ions, Proline-rich proteins

Help maintain mineral content of tooth enamel

Salivary glands

• Exocrine glands

• Composed of – mucous, – serous and – mixed acini

Salivary gland secretions

• Hormonal influences (e.g. aldosterone, ADH) may alter the composition but NOT the rate of secretion. E.g., – hypoaldosteronism, the Na+/K+ ratio in saliva is high, – hyperaldosteronism, it is low. .

The acini secrete a fluid plasma-like in osmolarity and electrolyte composition

Ducts, hypotonicity of saliva by the - absorption of Na+ and Cl- - Secretion of of K+ and HCO3

- - No water absorption- (The ducts are relatively impermeable to water).

Gland Type Saliva Type

Parotid, and Von Ebner’s (on the tongue) Serous

Sublingual Mostly mucous

Submandibular Mixed, more serous than mucous

Most minor Mucous

Parotid – serous

Sublingual – mucous +

serous demilunes

Submandibular – mixed

Parotid – serous Sublingual – mucous + serous demilunes

Submandibular - mixed

Nervous control of salivary secretions

Parasympathetic stimulation - Ach

Myoepithelial cells

Acinar cell

13

Oral epitheliumOral epithelium

Minor salivary glandsMinor salivary glands

Pancreas

PancreasExocrine and endocrine organ

–Exocrine• serous acini

(tubuloacinar gland)

–Endocrine• islets of Langerhans

16

Lack of myoepithelial cells

Pancreatic acini

Pancreatic acini

• Cells present basal basophilia (RER) and numerous basal mitochondria

• Apical cytoplasm with secretory granules (eosinophilic zymogen granules)

• Tubular or pear-shaped structures• Several cells around an irregular central lumen• Centroacinar cells• Intercalated and intralobular ducts secrete large

volumes of fluid rich in sodium and bicarbonate

60 percent of the membrane system of acinar cells corresponds to RER

Centroacinar cells are the intercalated ducts - are responsible for the initiation of the alkalinization of pancreatic juice

Salivary gland

Myopepithelial cell

Pancreas

• Centro acinar cells• No myoepithelial

cells• Hormonal

regulation of secretion

• No striated ducts

20

Intra lobular

Interlobular

Simple columnar epithelium

Part of intercalated duct

Pancreatic ducts

Pancreas is unique among compound acinous glands because it has intercalated ducts extended into the acini (centroacinar cells)

Gradual transition from simple squamous (centroacinar cells)

to

cuboidal (outside acini – intralobular ducts) and then

columnar epithelium (interlobular ducts)

There are NO STRIATED DUCTS in the pancreas

22© University of Duke

PancreasPancreas

23

Intercalated ductsIntercalated ducts

Interlobular ductInterlobular duct

24© University of DukePancreasPancreas

Islet of LangerhansIslet of Langerhans

Serous aciniSerous acini

25

PancreasPancreas

Islet of LangerhansIslet of Langerhans

Serous aciniSerous acini

26© University of DukePancreasPancreas

Islet of LangerhansIslet of Langerhans

Pancreatic enzymes are usually released in an inactive form.

Pancreatic juiceCCK

(humoral)Secretin

(humoral)

Na+, Cl-, HCO3-Isotonic secretion

HCO3- contributes to neutralisation of the acidic gastric chyme that enters the duodenum and provides optimal alkaline pH for pancreatic enzymes.

Pancreatic Juice

• Lipases (triacylglycerol lipase, cholesterol esterase, colipase, phospholipase A2)

• Ribonucleases and deoxyribonucleases• Carboxypeptidases and aminopeptidases• Proteolytic enzymes (i.e. trypsinogen, trypsin,

chymotrypsinogen, chymotrypsin)• Pancreatic amylase*• Elastase• Cholesterol esterase• Sodium bicarbonate

These enzymes are released in an inactive form, as proenzymes

An alkaline pH is necessary for all these enzymes to function

30

In the glycocalyx (brush border enzyme)

Pancreatic secretion

Pancreatic acinar cell • The pancreatic acinar cell is the functional unit of the exocrine pancreas. It

synthesizes, stores, and secretes digestive enzymes.

• Under normal physiological conditions, digestive enzymes are activated only once they have reached the duodenum.

• Premature activation of these enzymes within pancreatic acinar cells leads to the onset of acute pancreatitis; it is the major clinical disorder associated with pancreatic acinar cells.

31

Trypsin not only digests the pancreatic tissue, but activates the other enzymes (elastase, phospholipase)

Pancreatic Control• Secretin – promotes abundant watery

and bicarbonate-rich secretion (secretion of duct cells)

• Cholecystokinin – promotes the scanty enzyme-rich secretion (pancreatic acini)

• Vasoactive intestinal peptide – stimulates bicarbonate secretion

• Pancreatic polypeptide – inhibit both type of secretions

Gastric acid stimulate the secretion of secretin

Long-chain fatty acids, few amino acids and gastric acid stimulate the secretion of CCK

Cystic Fibrosis (CF) and the pancreas

• Pancreatic enzyme secretion uses the CFTR chloride channel.

• This channel is defective in people with CF, and causes them to have problems with the digestion of food and absorption of nutrients.

Pancreatitis

• Inflammation of the pancreas, which may be detected with blood tests that reveal several abnormalities. These include elevated levels of the – pancreatic enzymes amylase and lipase, – elevated white blood cell count, – elevated liver enzymes and bilirubin, – high blood sugar (hyperglycemia) and – low calcium levels

Endocrine Pancreas

…will be studied with the other endocrine glands

Insulin may be needed locally for secretin and CCK in order to promote the exocrine secretion

Gall bladder &

Liver

Right and Left hepatic ducts

Liver

Mixed gland

Heaviest in the body (1400 - 1600 gm)

Complex circulation

Diverse secretion

Function of liver

39

Fetal liver

• Is a sight of extra-medullary (outside of bone marrow [medulla of bone])

• Nucleated red blood cells are pictured

40

Liver structure

• Hepatocytes perform main hepatic functions

• Three-dimensional pattern of 1 to 2 cells thick plates

• Sinusoidal spaces between the plates

• The portal areas and the central vein are easily discerned

42

Portal areas have branches of the structures at the porta hepatis

Portal areas then have:An arteryA veinA bile ductA lymphatic

The confluence of the central veins creates the suprahepatic vein

Blood supply of liver

• Dual blood supply:– Portal vein - Venous from the intestines

• 65 – 85 % of the total

– Aorta – arterial from hepatic artery • 15 – 35 % of the total

• The blood leaves the liver through the hepatic vein

• The bile is created in the hepatocytes, and leaves the liver through the bile duct in the porta hepatis

45

Oxygen needed in hepatic metabolism comes from

the aorta

Nutrients, toxins and pathogens come from

the intestines

The bile flow backwards respect to the blood flow

Lymph flows in the same direction as the bile

Blood and bile flow in the liver

Lymph and plasma flow - liver

• Plasma that does not return to the sinusoid from the perisinusoidal space drains to the space of Mall and then to the periportal connective tissue, becoming lymph

• It enters the lymphatic vessel of the portal area, merges with other vessels and leaves the liver at the porta hepatis to join the thoracic duct– 80 % of the liver lymph follows this pathway, and constitutes the vast

majority of lymph in the thoracic duct

– The remaining 20 % drains into the lymphatic vessels that accompany the hepatic veins

48

Central veinCentral vein

Portal spacePortal space

49

Portal spacePortal space

50

Lymph vesselsLymph vessels

Hepatic arteryHepatic artery

Portal veinPortal veinBile duct

Lobules of the liver

• Classic lobule – one central vein and three to six portal areas in the vertices of an hexagon

• Portal lobule – central portal area and three central veins in the vertices of a triangle

• Hepatic acinus – two central veins and two portal areas in the vertices of a rhombus

55

Lobules of liverClassic lobule is still used to describe the morphologic pathology of several hepatic diseases

The portal lobule was focused in bile flow in the liver physiology

Best model to explain both liver diseases and functions - Rappaport, 1976

Functional Division of Zones• Acinar zone 1

– Oxidative energy metabolism– Gluco(neo)genesis (glucose output)– Lipolysis– Urea synthesis from amino acids– Conjugation with glutathione, sulfate, – glucuronic acid– Regeneration

• Acinar zone 3– NAD(P)H generation– Glycolysis (glucose uptake)– Liponeogenesis– Bile acid synthesis– Urea synthesis from ammonia– Cytochrome P450-dependent biotransformation

Oxygen supply and consumption are higher in zone 1 than in zone 3

Acinar zone 2 shares the functions of the other zones

Intralobular Organization

• Around portal areas, small hepatocytes are arranged as a one cell thick sheet (limiting plate)– Space of Mall – Between the limiting plate and the

connective tissue

Blood vessels and branches of bile ducts perforate the limiting plate

Intralobular Organization

• The sinusoidal lumen is lined by endothelial and Kupffer cells

• These cells and the hepatocytes are separated by the perisinusoidal space (Disse space)

In the perisinusoidal space we can find pericytes, few fibroblast and some collagen and reticular fibres, among other components

Sinusoids

• Receive blood from the portal areas (artery and vein) and release it into the central vein

• Low pressure systems• Greater diameter than capillaries (9 – 12 µm)• Two cells in the lining

– Endothelial cells– Kupffer cells

61

Portal spacePortal space

Central veinCentral vein

Liver cells

HepatocytesEndothelial cells

Kupffer cellsStellate cells / Ito cells

Pit cells Biliary epithelial cells (BECs)

Stem cells

Hepatocytes • Polygonal cells• Nuclei are round or oval, may indicate polyploidy (up to 25%

of the hepatocytes may be binucleated)– 800 – 2000 mitochondria, – 200 – 300 peroxisomes, – large SER and RER, – 50 Golgi apparatuses

• There is no basal lamina supporting the hepatocytes• Rare mitosis (1 per 15000 cells) in a healthy normal adult liver• Cytoplasm varies in appearance depending on the metabolic

activity of the cell and the amount of food storages on a given moment

• Cell appearance is also related with its position in the zones of the hepatic acinus

Hepatocytes

• Three surfaces:– Basal – face the

perisinusoidal spaces or the connective tissue of portal area

– Lateral – in contact with the adjacent hepatocytes

– Apical – form one margin of the bile canaliculus

Endothelial cells• Sieve between sinusoidal lumen and space of Disse

• Endocytosis, both specific (transferrin, caeruloplasmin transcobalamine II, glucosaminoglucans, HDL, LDL, procollagen) and nonspecific

• Very vulnerable to ischemia

These endothelial cells are of the fenestrated type, with fenestrae larger than those found in type II endothelial capillaries (~ 100 nm in diameter)

Kupffer cells

• Highly mobile macrophages attached to the endothelium– Also known as stellate sinusoidal macrophages– Largest population of macrophages in the body

• Phagocyte and antigen-presenting cell– Secretes plenty of substances important in phagocytosis

and chemical mediation of the immune response

• Make 5 percent of the protein exported by the organ

67

Kupffer cellsKupffer cells

Stellate / Ito cells

• Lie in the perisinusoidal space• They have long cytoplasmic processes that extend

below the endothelial cells• Fat storing cell , Vit A• Contain actin and myosin and contract in response to

endothelin and substance P– Contribute to regulate the diameter of sinusoids and

hence the blood flow– Called as modified pericytes

Stellate cells

• Liver injury leads to loss of lipid droplets, proliferation, and change of the normal appearance of these cells to a myofibroblast-like phenotype

• In this stage they secrete of type I and III collagen and laminin (fibrogenesis)

• They are very important for understanding hepatic diseases characterized by fibrosis

70

Kupffer cellKupffer cell

Ito’s cellsIto’s cells

Pit cells• Highly mobile natural killer cells (hepatic NK cells) at

the sinusoidal surface of the endothelial cells– They are the most active and cytotoxic cells of the

naturally occurring NK cells

• Short-lived cells that are renewed from circulating lymphocytes that differentiate in the sinusoids– Pit cells can also proliferate locally

• Spontaneous cytotoxicity against tumor cells and virus infected hepatocytes

Stroma

• Glisson’s capsule surrounds the organ and enters it in the porta hepatis

• Connective tissue prominent in the portal space, surrounding the structures of the triad

• Connective tissue in the perisinusoidal space is scant, and just proliferate in diseases (hepatic fibrosis)

• The reticular fibres in the perisinusoidal space create a network that supports the liver parenchyma and keeps the sinusoids open

Biliary epithelial cells

• Form the bile ducts• Secrete bicarbonate-rich solution• Include the ductular cells and those ones that line

the bigger biliary ducts

• Secretion of bile is ATP dependent……. Thus we have Secretion of bile is ATP dependent……. Thus we have ATPase on hepatocytes.ATPase on hepatocytes.

Bile canaliculi• 0.5 – 1.5 µm in diameter

channel-type structures created between adjacent hepatocytes (apical surfaces)– Equivalent to the lumen of

the acinus– Tight junctions isolate the

canaliculus from other portions of the intercellular space

• Connected with the bile duct on the portal space through the ductule (canal of Hering)– Ductular cells – cuboidal

75

76

77

Bile canaliculiBile canaliculi

Endothelial cellEndothelial cell

78

Bile canaliculi (Silver stain)Bile canaliculi (Silver stain)

Bile ducts

• Interlobular bile ducts of the portal areas (15 – 40 µm) are lined with simple cuboidal epithelium that becomes columnar where the structures get bigger

• Cells with well-developed microvilli

• As they become bigger, their wall becomes fibrous and smooth muscle cells appear in the duct wall

80

Gall Bladder• Blind, pear-shaped 8 x 4 cm (3 x 1.5 in), very elastic

diverticulum of the common hepatic duct, connected to it through the cystic duct

• STORAGE OF BILE– 20-60 ml capacity

• CONCENTRATION OF BILE (upto 20 times)– By reabsorption of Na+ ions

• EJECTION OF BILE– CCK stimulation causing GB contraction & dilation of sphincter of

Oddi.

• Chloride and bicarbonate are actively absorbed by the gallbladder epithelium

• CCK is the most potent stimulator of the gall bladder

Gall bladderMucous membrane – many deep folds,

lined by simple columnar epithelium with microvilli and basal infoldings.

– NO SUBMUCOSA– NO Muscularis mucosa– NO Goblet cells– Spiral valve of Heister is a spiral fold

of the mucosa inside the neck of the gallbladder

Muscularis – irregular in thickness and orientation

Adventitia and serosa – part of the gallbladder is attached to Glisson’s capsule and the rest is covered by peritoneum

84

GallbladderGallbladder

Na Cl

Na Cl pumps

Flow of NaCl & H2O

H2O

85

• G is obviously pleased with herself, smiling widely as she looks at her record from the local swimming class. After losing nearly two stones in weight in the last 5 months,

• “I feel really optimistic and well now but 18 months ago, it was a very different story,” says G, who is proud mother to 6 children aged between 16 and 3. I have always felt fabulous when I have been pregnant. I put on a bit of weight over the years, but who doesn’t?” she laughs.

• At the age of 38, with youngest daughter just a few months old, G began to feel unwell. “I put it down to having a lot on with the family but I felt really tired and quite sick a lot of the time. I was also waking up absolutely drenched in sweat at night,” recalls G.

Pain Attacks • The symptoms carried on but were so mild and non-specific that G didn’t even

bother going to see her doctor. One night, however, she ended up in casualty after developing severe pains suddenly that affected her left arm and shoulder. “I was convinced I was having a heart attack – I had never felt pain like it.

• An ECG showed nothing abnormal and the pain went as quickly as it had come. She still continued to feel vaguely under the weather but with no more pain she carried on as normal for another 8 months. “It was my older daughter’s 15th birthday we went out for a Chinese buffet. When we got home I was doubled up in pain and was violently sick. My fears of a heart attack came back but the pain disappeared again and I then thought it was just indigestion.

Case 1

86

Ultrasound

87

Gall stone Pancreatitis

• Endoscopic retrograde cholangiopancreatography (ERCP).

• An ERCP is a way of looking at your pancreas through a slim flexible tube, called an endoscope, that is inserted into your mouth and down to the pancreas.

• An endoscope is fitted with a tiny fiber optic camera that gives the physician a detailed view of the pancreas.

Cholecystitis

• Condition in which the wall of the gallbladder becomes inflamed. A blood test that detects elevated levels of white blood cells may indicate the presence of cholecystitis.

Extrahepatic Biliary Passages

• Extrahepatic ducts are lined by simple columnar epithelium that secretes mucus

• Smooth muscle appears as isolated bundles in the common bile duct, but become more organized as it approaches the ampulla of Vater

91

Q 2Q 2

In cirrhosis we expect this cell to actively secrete collagen:

a) Ito cellb) Pit cellc) Hepatocyted) Endothelial celle) Ductular cell

In cirrhosis we expect this cell to actively secrete collagen:

a) Ito cellb) Pit cellc) Hepatocyted) Endothelial celle) Ductular cell

92

A 45 year old mother of 4 has a sharp pain in her RUQ that A 45 year old mother of 4 has a sharp pain in her RUQ that radiates to her right shoulder. She is taken to her radiates to her right shoulder. She is taken to her gasteroenterologist who does a HIDA (hepatobiliary gasteroenterologist who does a HIDA (hepatobiliary iminodiacetic acid) scan and diagnoses her problem. What is iminodiacetic acid) scan and diagnoses her problem. What is the most likely diagnosis?the most likely diagnosis?

A. cirrhosisA. cirrhosisB. choleithaisisB. choleithaisisC. hepatocelluar carcinomaC. hepatocelluar carcinomaD. pancreatitisD. pancreatitisE. hepatitisE. hepatitis

Q 3Q 3Q 3Q 3

93

Hepatocyte • Protein synthesis• Protein storage

• Transformation of carbohydrates

• Synthesis of cholesterol, bile salts and phospholipids

• Detoxification, modification, and excretion of exogenous and endogenous substances

• Glycogen storage

Glycogen accumulation

94

Hepatocytes function• Serum albumin, fibrinogen, and the prothrombin group of clotting factors

(except for Factor3,4).

• It is the main site for the synthesis of lipoproteins, ceruloplasmin, transferrin, complement, and glycoproteins.

• Hepatocytes manufacture their own structural proteins and intracellular enzymes.

• Synthesis of proteins is by the rough endoplasmic reticulum (RER), and both the rough and smooth endoplasmic reticulum (SER) are involved in secretion of the proteins formed.

• The endoplasmic reticulum (ER) is involved in conjugation of proteins to lipid and carbohydrate moieties synthesized by, or modified within, the hepatocytes.

95

http://www.bu.edu/histology/m/i_main00.htm (for EM pictures)

• Highly geometric hepatocytes in a sample liver.

• Liver reveals tiny microvilli lining the interior of a bile canaliculus.