Histology Ch 18 628-647
Liver to Gallbladder
-liver is largest mass of tissue in the body: 2.5% of body weight
-enclosed in a capsule of fibrous connective tissue (Glisson’s capsule), and a visceral peritoneum
-anatomically divided into two large (left and right) lobes and two smaller (quadrate and
caudate) lobes
-liver develops as endodermal evagination from wall of foregut that forms hepatic diverticulum
-the diverticulum proliferates to form the hepatocytes which are arrange in liver cords to form
the parenchyma of liver
-original stalk of diverticulum  common bile duct, and an outgrowth from common
bile duct forms the cystic diverticulum  gallbladder/cystic duct
Liver Physiology – plasma proteins are produced and secreted by the liver; liver stores and
distributes nutrients and vitamins from bloodstream
-maintains glucose and regulates VLDLs
-degrades toxic substances and drugs
-it is an exocrine organ, producing bile, bile salts, phospholipids, and cholesterol
Liver produces Plasma Proteins:
1. Albumin – regulates plasma volume and tissue fluid balance by maintaining osmotic pressure
2. Lipoproteins – synthesizes VLDL- transport of triglycerides from liver to organs, also produces
LDLs and HDLs. LDL – transport cholesterol to tissues, HDL – transport away from tissues
3. Glycoproteins – iron transport proteins like haptoglobin, transferrin, and hemopexin
4. Prothrombin and Fibrinogen – important components in blood clotting
5. nonimmume a-globulins and B-globulins – help maintain plasma colloid osmotic pressure
Liver stores and converts several vitamins and iron
1. Vitamin A – important in vision; precursor to retinal which is required for synthesis of
rhodopsin in the eye. When Vit. A levels in blood fall, liver mobilizes storage sites and released
into circulation as retinol bound to retinol binding protein
2. Vitamin D (cholecalciferol) – important in calcium and phosphate metabolism for bones and
teeth, and is acquired from diet and sun, and is distributed to skeletal muscles and adipose
-liver converts vitamin D to 25-hydroxycholecalciferol, the predominant form in circulation, and
then converted in kidney to 1,25-hydroxycholecalciferol, 10x more potent than active vitamin D
3. Vitamin K – hepatic synthesis of thrombin and other clotting factors, derived from diet and
synthesis by small intestine bacteria, where it is transported to liver on chylomicrons
-vitamin K deficiency is associated with hypoprothrombinemia and bleeding
4. Iron storage, metabolism, homeostasis – synthesizes transferrin (plasma transport),
Haptoglobin (binds to free hemoglobin in plasma), Hemopexin (transport of free heme in
blood), Ferritin (iron stored within hepatocyte cytoplasm) or may be converted to hemosiderin
Clinical Correlation: Lipoproteins - complexes of proteins and lipids involved in cholesterol and
triglyceride transport in the blood. Hormones like estrogen and thyroid hormones regulate this
-four classes of lipoproteins: chylomicrons, VLDL, LDL, HDL; differing by increasing density
chylomicrons – made in small intestine and function to transport fat to bloodstream
VLDLs – synthesized in liver and transport most triglycerides from liver to other organs. VLDL is
associated with apolipoprotein B-100 (apoB-100), aiding in VLDL secretion
-in congenital liver disease such as abetalipoproteinemia, liver unable to produce apoB-100
leading to blockage of secretion of VLDLs
LDLs and HDLs are produced in plasma and a smaller amount in liver. LDLs transport cholesterol
from liver to peripheral organs, and HDLs are the opposite (LDL levels associated with disease)
Liver degrades drugs and toxins – degrades drugs, toxins, and other xenobiotics because
kidneys cannot excrete hydrophobic substances, and liver converts them to more soluble form
in 2 phases:
1. Phase 1 (Oxidation) – hydroxylation and carboxylation to the foreign compound, and is
performed in the hepatocyte sER and mitochondria, and involves cytochrome P450
2. Phase 2 (conjucation) – conjucates with glucuronic acid, glycine, or taurine and makes
the product of phase 1 even more water soluble to be easily removed by kidneys
Liver is involved in many other important metabolic pathways – liver is important in
carbohydrate metabolism as it maintains an adequate supply of nutrients for cell processes. In
glucose, liver creates glucose-6-phosphate which is stored as glycogen or used in glycogenolysis
-liver functions in fat metabolism and B-oxidation of fatty acids
-liver produces ketone bodies that are used as fuel
-cholesterol is used in the formation of bile salts, synthesis of VLDLs and biosynthesis of
organelles
-urea in the body from ammonium is derived from a liver protein
-liver involved in synthesizing nonessential amino acids
Bile production is an exocrine function of the liver – liver involved in metabolic conversions
involving substrates delivered by blood from digestive system involved in bile production
-contains conjugated and degraded waste products as well as metabolite-binding substances
-bild is carried from liver parenchyma to hepatic duct  cystic duct  gallbladder where it is
concentrated, then  common bile duct  duodenum
Endocrine-like functions of liver are represented by ability to modify structure and function of
hormones – Liver’s endocrine functions include:
1. Vitamin D – converted to 25-hydroxycholecalciferol, the active form of vitamin D
2. Thyroxine – hormone secreted by thyroid (T4), converted to T3 by liver (active)
3. Growth Hormone – hormone secreted by pituitary and modified by liver produced
growth hormone-releasing hormone (GHRH), inhibited by somatostatin
4. Insulin/glucagon – secreted by pancreas, degraded by the liver
The hepatic portal vein and the hepatic artery, both of which enter at a hilum called the porta
hepatis, is also where the bile duct leaves the liver, supply Blood Supply to the Liver
-the liver receives blood initially supplied by intestines, pancreas, spleen, and it is mostly
deoxygenated in the hepatic portal vein
-portal blood contains nutrients/toxic materials, blood cell breakdown, endocrine secretions
-liver is first organ exposed to toxic substances
-hepatic artery is a branch off of the celiac trunk, carries oxygenated blood to the liver (25% of
supply)
-blood from portal vein and artery mix, therefore liver never gets fully oxygenated blood
Portal Triad- hepatic portal vein, hepatic artery, bile duct system
-sinusoids – make contact with hepatocytes and provide for exchange of substances between
blood and liver cells
-sinusoids lead to terminal hepatic venule (central vein) that empties into sublobular
veins, which leaves liver through hepatic veins and enters IVC
Structural Organization of the Liver –
1. Parenchyma – plates of hepatocytes one cell thick, separated by sinusoidal capillaries
2. Connective Tissue Stroma – continuous with Glisson Capsule; vessels, nerves, lymph
and bile ducts travel within connective tissue stroma
3. Sinusoidal Capillaries (sinusoids) – vascular channels between hepatocyte plates
4. Perisinusoidal Spaces (spaces of Disse) –lie between sinusoidal endothelium and
hepatocytes
-There are 3 ways to describe function of liver
1. Classic Lobule – hexagonal mass of tissue one cell thick separated by anastomosing system of
sinusoids that perfuse cells with mixed portal and arterial blood
-at the center is a terminal hepatic venule (central vein) into which sinusoids drain
-at the edges of the portal canal, between connective tissue stroma and hepatocytes, is
a small space called the periportal space (space of Mall) thought to be lymph origin
2. Portal Lobule – emphasizes exocrine function of the liver (bile), and the morphological acis is
the interlobular bile duct of the portal triad of the classic lobule
-outer margins are imaginary lines drawn between 3 central veins closest to portal triad
3. Liver Acinus – structural unit that provides best correlation between blood perfusion,
metabolic activity, and liver pathology
-smallest functional unit of hepatic parenchyma
-The short axis is defined by terminal branches of portal triad that lie along the border
between two classic lobules
-The Long Axis is a line drawn between the two central veins closest to the short axis
Zone 1 – closest to the short axis and the blood supply from penetrating branches of
portal vein and hepatic artery; corresponds to the periphery of classic lobules
Zone 2 – lies between zones 1 and 3 and has no sharp boundaries
Zone 3 – farthest from short axis and closest to terminal hepatic vein.
-zone 1 receives O2, nutrients, and toxins first, and are the last to die if circulation is impaired
and the first to regenerate
-zone 3 cells are first to show ischemic necrosis during reduced perfusion and the first to show
fat accumulation
-last to respond to toxic substances and bile stasis
Clinical Correlation – Congestive heart Failure and liver necrosis
-liver injury may be triggered by hemodynamic changes in circulatory system
-in congestive heart failure, heart is unable to provide oxygenated blood to meet metabolic
requirements of liver, and zone 3 is the first to be affected as they lie furthest, and they receive
blood already depleted of oxygen, and they undergo liver necrosis
-no noticeable changes are seen in zones 1 and 2, representing periphery of classic lobule
-necrosis is referred to as central trilobular necrosis
-if as a result of hypoxia, it is referred to as cardiac cirrhosis, and regeneration of
hepatocytes is minimal
Blood Vessels of the Parenchyma – blood vessels that occupy portal canals are called
interlobular vessels, which form the smallest portal triads send blood into sinusoids
-sinusoid blood flows toward the central vein, becomes larger, and empties into IVC
-lumen of the portal vein is larger than the hepatic artery, and hepatic artery supplies sinusoids,
connective tissue, and other structures
-central vein is thin-walled vessel that receives blood from hepatic sinusoids
-endothelial lining is surrounded by small amounts of spirally arranged connective tissue
fibers
-central vein is also called the terminal hepatic venule
-the sublobular vein receives blood from terminal hepatic venules has a distinct layer of
connective tissue fibers, bot hcollagenous and elastic, external to the endothelium.
-there are no valves in hepatic veins
Hepatic sinusoids are lined with a thin discontinuous endothelium – the endothelium has a
discontinuous basal lamina that is absent over large areas apparent due to large fenestrae and
large gaps between neighboring endothelial cells
-hepatic sinusoids differ from other sinusoids in that a cell type called stellate sinusoidal
macrophage, or Kupffer cell is a regular liner
Kupffer cells belong to mononuclear phagocytic system – Kupffer cells are derived from
monocytes and line sinusoids
-processes of these cells span lumen and can occlude sinusoid
-possible assistance in breakdown of damaged RBC getting there from spleen
-ferritin from iron is converted to hemosiderin granules and stored in kupffer cells
Perisinusoidal Space (Space of Disse) – site of exchange of materials between blood and liver
-lies between basal surface of hepatocytes and endothelial cells and kupffer cells
-microvilli project from hepatocytes that increase surface area for material exchange
-no significant barrier exists between plasma in sinusoid and hepatocyte membrane
-proteins and lipoproteins are transferred into blood through this space
-in fetal liver, space between blood vessels and hepatocytes contains islands of blood-forming
cells; and also occurs in adult chronic anemia
Hepatic stellate cells (Ito cells) store vitamin A; but differentiate into myofibroblasts and
synthesize collagen – hepatic stellate cells store Vit A in the form of retinyl esters within
cytoplasmic lipid droplets
-vitamin A is released from Ito cells as retinol bound to retinol binding protein (RBP), which is
then transported from liver to retina, converting opsin to rhodopsin
-fish liver oils are sources of vitamin A
-in chronic inflammation or liver cirrhosis, stellate cells lose lipid and vitamin A storage capability
and differentiate into myofibroblasts which play a role in hepatic fibrogenesis (Type I, III
collagen) inside perisinusoidal space, causing liver fibrosis
-increased amount of perisinusoidal fibrous stroma is an early sign of liver toxic response
-stellate cells remodel ECM during recovery from liver injury
Lymphatic Pathway – hepatic lymph originates in the perisinusoidal space, where it drains into
the periportal space (space of Mall) between stroma of portal canal and outermost hepatocytes
-lymph travels in same direction as bile, and drains into the thoracic duct
Hepatocytes – make up anastomosing cell plates of liver lobule, many are binucleate
-long-lived cells (5 months), and are capable of regeneration when liver substance is lost
-hepatocyte cytoplasm is acidophilic , and many components are recognizable:
-basophilic rER and ribosomes, 800-1000 mitochondria/cell, multiple Golgi complexes in
eac hcell, large numbers of peroxisomes, glycogen deposits, lipid droplets of various
sizes, lipofuscin pigment in lysosomes
-2 surfaces of hepatocyte face perisinusoidal space, and 2 face neighboring hepatocytes, and
face bile canaliculi
Perixisomes are numerous in hepatocytes – may have 200-300 of them per cell. Peroxisomes
are a major site of oxygen use and perform functions similar to mitochondria
-generate large amounts of hydrogen peroxide, and peroxisomes have catalase which degrades
H2O2
-one half of ethanol ingested is converted to acetaldehyde by enzymes in liver
-Catalase, d-amino acid oxidase, and alcohol dehydrogenase are found in peroxisomes
-peroxisomes involved in B-oxidation, gluconeogenesis, and metabolism of purines
sER can be extensive in hepatocytes – contains enzymes for degradation and conjugation of
toxins and drugs as well as enzymes for synthesizing cholesterol and lipid portion of lipoproteins
-sER undergoes hypertrophy after alcohol, drugs, and certain chemotherapeutic agents (cancer)
-stimulation of sER by ethanol enhances its ability to detoxify other drugs, carcinogens, and
pesticides
Golgi in hepatocytes consists of up to 50 units – each consist of 3-5 cisternae with many large
vesicles, believed to all be involved in exocrine secretion of bile, but other granules shown may
be VLDL and lipoprotein precursors
Lysosomes concentrated near bile canaliculus corresponds to peribiliary dense bodies –
hepatocyte lysosomes are heterogeneous and components can be identified: lipofuscin pigment
granules, digested organelles, and myelin figures
-hepatic lysosomes may be normal storage site for iron as ferritin
Biliary Tree – 3D system of channels of increasing diameter that bile flows through from
hepatocytes to gallbladder and then to intestine, capable of modifying bile flow and changing its
composition in response to hormonal and neural stimulation
-Biliary tree is lined by cholangiocytes which monitor bile flow and regulate its content
-cholangiocytes are epithelial cells lining biliary tree, have tight junctions between cells, and
have a basal lamina; each contains primary cilium that senses luminal flow
Bile canaliculus is a small canal formed by apposed grooves in surface of adjacent hepatocytes
– smallest branches of biliary tree are the bile canaliculi where hepatocytes secrete bile,
completely surround 4 sides of the 6-sided hepatocytes and have tight junctions, zonula
adherens and desmosomes
-ATPases and alkaline phosphatases can be found in these canaliculi
-bile flow is CENTRIFUGAL, from region of terminal hepatic venule (central vein) to portal canal
opposite to blod flow
-bile canaliculi transition to form short Canals of Hering
Canals of Hering are lined by hepatocytes AND cuboidal cholangiocytes – the canal exhibits
contractile activity that assists with unidirectional flow of bile toward portal canal
-functional disturbance in contractile activity may contribute to intrahepatic cholestasis
(obstruction of bile flow)
-Canals of Hering serve as reservoir of liver progenitor cells, where the stem cell niche is.
-these cells can differentiate into hepatocytes or bile duct cells
-Canals of hering harbors specific hepatic stem cells
Bile ductule represents part of biliary tree that is lined entirely by cholangiocytes – canals of
hering flow into intrahepatic bile ductule lined ONLY by cholangiocytes
-ductules carry bile to the interlobular bile ducts that form part of portal triad that are cuboidal
near the lobules and become COLUMNAR as they reach porta hepatis
-as bile ducts get larger, they acquire a dense connective tissue containing elastic fibers
-smooth muscle cells appear in this connective tissue as it approaches hilum
-Interlobular ducts converge to form right and left hepatic ducts which join to form the
common hepatic duct
-In some people, the ducts of Luschka are located in CT between liver and gallbladder near the
neck of gallbladder, and connect with the cystic duct, not lumen of gallpladder
Extrahepatic bile ducts carry the bile to the gallbladder and duodenum – common hepatic duct
is lined with columnar epithelium that resembles that of the gallbladder, and resembles layers
of alimentary tract, EXCEPT for the muscularis mucosa
-Cystic duct connects common hepatic duct to gallbladder and carries bile both into and out of
the gallbladder
-distal to cystic duct we find the common bile duct that connects to duodenum at the
ampulla of Vater
-thickening of muscularis externa of duodenum at ampulla constitutes sphincter of Oddi
that surrounds both common bile duct and pancreatic duct
Human Liver secretes 1L of bile a day – bile fulfills 2 functions: (1) absorption of fat and (2)
excretion of cholesterol, bilirubin, Fe, and Cu
-90% of bile salts, a component of bile, is reabsorbed by the gut and transported back to liver
-Cholesterol and phospholipid lecithin is delivered to the gut with bile, are reabsorbed
-Bilirubin glucuronide, the detoxified product of hemoglobin breakdown, is not recycled and is
excreted with feces to give them their color
-failure to absorb bilirubin can produce jaundice
-bile flow from liver is controlled by hormones and neural
-increased bile flow with cholecystokinin (CCK), gastrin, and motilin
-steroid hormones decrease bile secretion from liver
-parasympathetic stimulation increases bile flow by contracting gallbladder and relaxing
sphincter of Oddi
Liver has both sympathetic and parasympathetic innervation – nerves enter liver at porta
hepatis
-sympathetic fibers innervate blood vessels, and increased stimulation causes vascular
resistance, decreased hepatic blood volume, and increased serum glucose
-parasympathetic fibers innervate large ducts and maybe blood vessels, stimulation of which
promotes glucose uptake and utilization
Gallbladder – pear-shaped, distensible sac attached to visceral surface of liver, and is a blind
pouch that connects, via a neck, to the cystic duct that receives dilute bile from hepatic duct
-Gallbladder concentrates and stores bile (removing 90% of H2O from incoming bile), resulting
in increased bile salts, cholesterol, and bilirubin concentrations
-hormonal stimulation by enteroendocrine cells of small intestine cause contraction and release
of bile from gallbladder
Mucosa of gallbladder has several characteristic features – possess numerous muscosal folds
consisting of SIMPLE COLUMNAR EPITHELIUM which has:
-apical microvilli
-apical junctional complexes joining adjacent cells and forms a barrier between lumen
and intercellular compartment
-localized concentrations of mitochondria in apical and basal cytoplasm
-complex lateral plications
-cells resemble absorptive cells of intestine, and localize Na/K ATPase on lateral membrane and
secretory vesicles in apical cytoplasm
-Lamina propria of mucosa is rich in fenestrated capillaries with no lymphatic vessels
-lamina propria is very cellular, containing lymphocytes and plasma cells
-Mucin-secreting glands present in lamina propria in normal gallbladder near neck of organ, but
more commonly found in inflamed gallbladders
Wall of gallbladder lacks muscularis mucosa and submucosa – external to lamina propria is a
muscularis EXTERNA that has collagen and elastic fibers, but does not have muscularis mucosa
or submucosa
-external to muscularis externa is layer of dense CT containing blood vessels, lymph and
autonomic nerves
-Layer of tissue where gallbladder attaches to liver is called the adventitia, and the unattached
surface is covered by a serosa or visceral peritoneum consisting of a layer of mesothelium + CT
-deep diverticula of mucosa called Rokitansky-Aschoff Sinuses extend through muscularis
externa, and are thought to presage pathologic changes and develop as a result of hyperplasia
and herniation of epithelial cells through muscularis externa
-bacteria may accumulate in these sinuses causing chronic inflammation
Concentration of bile requires coupled transport of Salt and Water – epithelial cells of
gallbladder actively tansport Na, Cl, and HCO3 from cytoplasm into intercellular compartment of
epithelium.
-ATPase is on lateral plasma membrane, and this transport mechanism is similar to cells in colon
-gallbladder epithelium expresses aquaporins water channels (AQP1 and AQP9), which
facilitate rapid, passive movement of H2O
-active transport of Na, Cl, and HCO3 across lateral membrane into intercellular compartment
causes concentration of electrolytes in intercellular space to increase, causing an osmotic
gradient between the space and cytoplasm
-H2O moves from cytoplasm and from lumen into intercellular space because of
gradient, and the intercellular space will distend
-hydrostatic pressure created forces isotonic fluid out of intercellular compartment into
subepithelial connective tissue, and the fluid that enters lamina propria passes into fenestrated
capillaries that underlie epithelium
-final modification of bile is as a result of active transport of Na, Cl, and HCO3, and passive
aquaporin-mediated transport of H2O across plasma membrane of epithelial cells of gallbladder