22. The anatomy, histology and development of the liver and biliary ducts and gallbladder.

*Liver is intraperitoneal, except for bare area, and has FOREGUT origin

Anatomy of Liver

• General Info
  • largest gland in the body and largest organ(after skin)
  • weighs app. 1500 g; 2.5 % of adult body weight
  • in late fetus: twice as large( 5% of body weight)
• Location
  • lies mainly in the right upper quadrant of the abdomen
    
  • hidden and protected by the thoracic cage and diaphragm
  • normal liver lies deep to ribs 7-11 on the right side and crosses the midline towards the left nipple.
    
  • L. occupies most of the right hypochondrium, the upper epigastrium and extends into the left hypochondrium
  • inf to the diaphragm, which separate it from the pleura, lungs, pericardium and heart
• Function
  • all nutrition absorbed from the gastrointestinal tract are initially conveyed first to the liver by the portal venous system(except for fat)
  • metabolic activities, glycogen storage and secretion of bile,
  • degrade or conjugate toxic substances to render them harmless
  • Protein synthesis
  • Heparin production
  • Breakdown of Hemoglobin
  • Hematopoiesis = RBC production
  • Storage of vitamins, Fe, and Cu
  • Bile function:
    • bile passes from the liver via the biliary ducts
    • R & L Hepatic ducts, join to form the common bile duct, which unite to form the cystic duct to form the bile duct
    • the liver produces bile continuously,
      
    • between meals it accumulates and is stored in the gallbladder, which also concentrates the bile by absorbing water and salts.
    • when food arrives in the duodenum, the gallbladder sends concentrated bile through the bile ducts to the duodenum

• Surface Projection
  • Upper border = 5th rib @ mid inguinal line
  • Lower border = @ ant axillary line –> midinguinal line, follows the R costal arch, then @ end of 10th, asc obliquely into epigastrium, crosses midline @ transpyloric line, @ 8th L rib, enters hypochondrium
  • Lower and upper border meet jsut medial to L midinguinal line
• Topography
  • 2 surfaces = diaphragmatic, and visceral.
  • the diaphragmatic surface of the liver is smooth and dome shaped, where it is related to the concavity of the inf surface of the diaphragm

  • Impressions on the visceral surface:

    1) gastric + pyloric areas: right side of the ant. aspect of the stomach

    2) duodenal area: sup. part of the duodenum

    3) lesser omentum: extends into the fissure for the ligamentum venosum

    4) fossa for gallbladder

    5) colic area: right colic flexure + right transverse colon

    6) renal+ suprarenal areas: right kidney + suprarenal gland

• Parts
  • separated into R & L lobe ant by falciform ligament (a fold of peritoneum that attaches the liver to ant ab wall)
  • (post) – split into 4 lobes by a number of structures that make a “H” pattern on the visceral surface
    • 4 lobes are : R, L, caudate, and quadrate. (quadrate functionally part of L lobe, and caudate functionally part of both)
    • H made up of R and L sagittal fissures & transverse limb:
      • R-ant = fossa of gallbladder (sits on quadrate)
      • R-post = IVC fossa
      • L ant = falciform and round ligament
      • L post = ligamentum venosum, and hepatogastric lig.
      • Transverse limb = Porta Hepatis = ( portal vein, hapatic artery + lymphatic vessels+ hepatic nerve plexus+ hepatic ducts that supply + drain the liver enter and leave it.
    • Round ligament = remnant of umbilical v., @ inf free edge of falciform ligament
    • Ligamentum venosum = remnant of Ductus venosus, which shunts a significant majority (80%) of the blood flow of the umbilical vein directly to the inferior vena cava. Thus, it allows oxygenated blood from the placenta to bypass the liver.
• Peritoneal Relations of Liver
• • subphrenic recesses: sup. extensions of the peritoneal cavity(greater sac) exists between diaphragm + ant. + sup. aspects of the diaphragmatic surface of the liver
    • seperated into right and left recesses by the falciform ligament
  • suphepatic space= portion of the supracolic compartment of the peritoneal cavity immediately inf. to the liver
  • hepatorenal recess= posterosuperior extension of the suphepatis space, lying between the right part of the visceral surface of the liver and kidney/ suprarenal gland
    • cavity- deepest part(deepest next to rectovesical pouch) in supine position, fluid draining from the omental bursa flows into this recess.
    • communicates ant. with the right subphrenic recess
    

    Recesses of Liver

    

    Ligaments of Liver

  • bare area of liver: diaphragmatic surface is covered with visceral peritoneum, except there.
    • It lies in direct contact with the diaphragm.
    • is demarcated by the reflection of peritoneum from the diaphragm to it as the ant(upper) + post(lower) layers of the coronary ligament.
  • Right triangular ligament: end  of coronary lig on R side
  • Left triangular ligament: end of coronary lig of L side
  • Hepatogastric ligament
  • Hepatorenal ligament
  • Hepatoduodenal ligament = remnant of ventral mesoduodenum, connect portal v. and duodenal cap
  • Hepatogastric and hepatoduodenal ligament together make up the borders of epilploic (omental) foramen, that leads from greater sac to lesser sac (behind the stomach), some say it also makes up the lesser omentum
  • ventral mesogastrium – liver develops in this, and the liver divides it into two ligaments: the lesser omentum & falciform ligament.
    
  • Bare area – no peritoneal coverage. Borders on both sides is falciform ligament, anterior and posterior leaf of coronary ligament, triangular ligament where ant/post leaves of coronary ligament unite. *Location of where hepatic v enter IVC
• Blood Supply
  • receives O2  blood from hepatic a
  • have many many many variations
    
  • de-O2, nutrient rich, poss toxic blood –> portal v (portal v discussion another topic, please look at that one)
    
  • Hepatic a proper –>ascends in hepatoduodenal lig (R edge of lesser omentum) splits into R and L Hepatic a, R hepatic gives cystic a, Hepatic a immediately split into segmental branches
    • R Hepatic = R lobe, R 1/2 of caudate lobe
    • L Hepatic = L lobe, quadrate lobe, L 1/2 of caudate lobe
  • Hepatic v – drains blood of liver, usually 3 of them, Sinusoids of liver –> bigger br –> hepatic v –> IVC (@ bare area)
• Lymph supply
  • Liver is major lymph producing organ
  • Superficial lymph nodes
    • in fibrous capsule of liver, just below the peritoneum
      
  • Deep lymph nodes
    • in CT with portal triads and hepatic v.
  • Superficial  l.n.  from ant diaphragmatic and visceral surface, and deep lymph vessels from around portal triads –> hepatic nodes, along hepatic vessels and ducts in lesser omentum–> celiac nodes –> cisterna chili
  • Superficial l.n. from post diaphragmatic and visceral surface –> bare area of liver –> phrenic nodes, a or to lymph nodes with hepatic v to IVC, thru diaphragm –>  post mediastinal nodes –> R lymph/thoracic duct
  • lymph can also go –>  L gastric, parasternal, and from round ligament area, umbilical nodes.
• Innervation
  • hepatic n plexus @ porta hepatis, these branches come from the celiac plexus which sits around the celiac trunk
  • SNS = from celiac plexus
  • PNS = ant/post vagal trunks
  • N fibers run with arteries

Biliary Ducts & Gall Bladder

*Intraperitoneal, part of foregut

Gallbladder

• Location
  • Jxn of R 9th CC and lat border of rectus abdominus  where midinguinal line crosses 10th rib (fundus of it)
• General Info/Topography
  • Pear shaped sac on inf surface of liver in fossa b/wR lobe and quadrate lobe.
  • lies right next to the 1st/2nd part of  diaphragm
  • touches transverse part of colon
• SP = above, can only be palpated if gallstone present * made of calcifications of cholesterol and/or bilirubin. Gallstones more common in women than men, especially those with multiple pregnancies and/or overweight, and older.
• Function
  • receives and stores bile and concentrated by absorbing H20 and salts and stores it
  • contracts to expel bile via (+) by CCK, which is produced by duodenal mucosa when food arrives there
  • Bile used to breakdown fat and fat soluble vitamins
• Parts
  • Fundus – wide end, projects from the inf border of liver, located at tip of right 9th CC
  • Body – on visceral surface of liver, in GB fossa
  • Neck – narrow, tapered and runs towards porta hepatic, location of cystic duct
• Blood Supply
  • primarily cystic a, from R Hepatic a
  • cystic v
    
    • from the biliary ducts and neck of gallbladder –> portal v, joins v from hepatic ducts and upper bile duct
    • from fundus and body –> visceral surface of liver –> hepatic sinusoids
• Lymph Drainage
  • cystic lymph nodes –> hepatic lymph nodes –> celiac lymph nodes
• Innervation
  • SS = R phrenic n
  • SNS = celiac plexus
  • PNS = CN X
  • fibers run with cystic a.

Biliary System:

• Bile is made in Liver and stored in gallbladder. Bile is released into the duodenum when food arrives, and therefore fat needs to be broken down. Hepatocytes  secrete bile into bile canaliculi in b/w them.
• Bile canaliculi unite to from intrahepatic bile ducts, that lie in portal triads with the hepatic portal v and hepatic arteries.
• Bile ductules combine to form R and L Hepatic ducts
• R & L Hepat ducts combine to form  Common Hepatic Duct
• Cystic duct to gall bladder is from common hepatic duct
  • have spiral valves (Heister’s valves) which keep duct open si if common bile duct closed, bile –> cystic duct –> GB
• Common Hepatic + Cystic duct = Common bile duct
  • 10 cm long and 1 cm in diameter
  • lies in b.w hepatic a and portal v
  • ususally embedded into post. surface of the head of the pancreas.
  • Left side of the desending part of the duodenum, the bile duct comes into contact with the main pancreatic duct.
  • These ducts run oblique through the wall of this part of the duodenum, where they unite to form the hepatopancreatic ampulla, the dilation within the major duodenal papilla.
  • distal end of ampulla opens into great duodenal papilla (about 1/3 way down descending part of duodenum, also called papilla of Vater, or Greater Duodenal papilla)
• Sphincter of Oddi holds the opening of the papilla closed  – there are three parts to it, forming a sphincter for the bile duct, pancreatic duct, and for the papilla itself. PNS activity opens it.

Histology of Liver and Gallbladder

#57 Pig Liver * H&E

Structures to Identify:

• Fxn’l lobule
• central v
• Bile duct
• hepatic a
• portal v
• CT septa
• lymph nodule
• sinusoids
• bile canaliculi
• Kupffer cells
• Glisson’s capsule
• Hepatocytes (parenchyme)

Low power magnification: you see the lobular patternof the human liver, but less CT than for pic liver. Pig liver shows hepatic lobules the best b/c of prominent CT septa invaginating from surrounding Glisson’s capsule.

Medium power magnification:  hepatic lobules containing the central vein are dermacated by narrow stripes of interlobular CT made of reticular fibers.

Organization of Hepatic Lobules:

• Functional units of the liver, described as lobules or acini, are made up of irregular interconnecting sheets of hepatocytes seperated from one another by the blood sinusoids.
• parenchyme of liver is hepatocyte – normally 2 layers with sinusoids in b/w
• Sinusoids convery mixed blood of Liver –> drain into central v.
  
• radiating from central v –> periphery of lobule = plates of hepatic cells, with hepatic sinusoids in b/w, where venous and arterial blood mix
  
• Space of Disse = b/w hepatocytes basal surface (sinusoids),
  
  • Perisinisoidal space b/w endoth of sinusoids and parenchyme
  • have microville that go into space and absorb protein from sinusoids
  • contain Ito cells and hepatocytes

3 ways of describing Hepatic lobules:

• Classical lobule model – has at its center the v surrounded by  Space of Mall, (b/w CT stroma and outermost hepatocytes), sinusoids, and hepatic triad
• Portal lobule model – emphasizes exocrine fxn of liver and has bile duct in center (part of portal triad)
• Liver acinus model – best correlation among blood perfusion and metabolic activity and liver pathology
  • eliptical region between 2 central v and interlobular septum, divided into 3 zones
  • hepatic a, portal v, and bile duct from portal triad at periphery of lobules

Portal tracts contain the portal triad: with in the interlobular CT septa, each lobule has several portal triads surrounding it.

1. interlobular vein: branch of portal vein

2. interlobular artery: a branch of the proper hepatic artery, a thick- walled vessel with smaller diameter and the typical structure of arterioles or arteries

3. interlobular bile duct: ducts of variable size, lined by simple cuboidal or columnar epithelium

Cells of Liver

• Kupffer cells – belong to MPS, derived from monocytes, lie in sinusoid walls with endothelium, have pacytoic capabilites to help degrade RBCs and Fe/ferritin. In case of splenectomy, # inc to make up the difference in Hgb and RBC breakdown = see them best in RAT slide #57C, special staining required to see properly.
• Ito cells – in space of Disse, stores vit A (precursor of retinol) that is needed for proper vision.
  • Note = In pathological cases, differentiate into myofibroblasts and secrete collagen, causing  fibrosis.
    
• Hepatocytes – main parenchymal cells of liver, last 5 months, need lots of mitochondria for energy
  • polyhedral in shape
  • tight junction in b.w w/ bile canaliculi
  • peroxisomes (H2O2 –> H2O +O2)
  • Smooth ER to detox drugs
  • Endocrin fxn = secret apolipoproteins
  • lysosomes for degradation

More General Info

• Liver cells are large, polygoneal cells with round, centrally located nucleus and prominent nucleus
• Binucleate cells are seen in this section. The hepatocytes form flat, anastomosing cords;
• Sinusoids are found between the hepatic cords, the sinusoids are lined by a discontinous layer of endothelium with flattend and condensed nuclei.
• Kupffer cells are also present there, they are larger+ darker then the other cells of the sinusoids; sinusoids contain all the cellular elements of blood
• The space as a fine slit between the sinusoid lining cells + the hepatocytes(the space of disse)is at the limit of the resulution of the LM.
• Sometimes the hepatic capsule(Glisson’s capsule) is visible as a thin layer of CT, covered by simple squamous epithelium(visceral peritoneum) on the surface.
• It also contains substances that bind to metabolites in the intestine to aid absorption.
• A series of ducts of increasing diameter diameter + complexity, beginning with canaliculi between individual hepatocytes + ending with the common bile duct, deliver bile from the liver + gallbladder to the duodenum.

Endocrine v Exocrine Function

• each liver has both exocrine + endocrine functions;
  
• exocrine secretion of the liver:
  • secretes bilirubin (byproduct of  RBC breakdown produced by Kupffer cells)
  • Antibodies – produced in LP of SI/LI taken from blood by hepatocytes –> bile –> lumen of SI = control bacteria level there.
    
  • produce bile which contains conjugated+ degrated waste products that are delivered back to the intestine for disposal.
  • release up to 1L of bile to canaliculi daily
  • Bile flow:  Bile canaliculi –> bile duct –> hepatic duct –> cystic duct –> gallbladder –>cystic duct –> common bile duct –> duodenum
    
• The endocrine secretion of the liver
  • are released directly into the blood that supplies the liver cells
  • these secretions include albumin, nonimmune alpha + beta globulins, prothrombin + glycoprotins including fibronectin
  • activation of vitamin D, thyroxin, and growth hormone
    
  • Glucose (released from stored glycogen) + T3  (the more active deiodination product of thyroxine), are also released directly into the blood.

Blood Supply/Lymph Drainage w/in liver

• from portal v (spleen, stomach, pancreas, SL, LI) + hepatic a proper
• portal blood contains:
  • absorbed degrade materials from GI tract
  • blood cells from spleen
  • pancreatic endocrine secretions
• venous blood from portal v mixes with arterial blood from hepatic a proper in a 75%/25% ratio in portal capillaries
• flows within perilobular a/v
• as said perviously, blood drains into sinusoids, lined with discontinous endothelium– which allows the communication of hepatic blood with hepatocytes
• remember that blood and bile never mix, they have seperate flow channels
• Lymph –> Space of Mall, located in endothelial lining –>drain into v. –> thoracic duct

# 57A Pig Liver *AZAN

• blue = collagen
• stains CT capsule, loose CT (collagen type I and II)
• stains reticular fibers in space of Disse
• AZAN = azocarmine red, and aniline blue

#57C Rat Liver * Toluidin Blue & Nuclear fast red

• Structures to Identify: sinusoids, Kupffer cells, Endothelium cells, Hepatocytes, Bile canaliculi
• To demonstrate structures of parenchyme of liver
• Kupffer cells are clearly visible, b/c they phagocytose the dye – present in sinusoids
• Hepatocytes clearly defined
• NFR stains nuclei red
• Sometimes, bile canaliculi will be visible b/w hepatocytes

#58 Human Liver *H&E

• Structures to Identify:  portal v, bile duct, hepatic a/v, central v, parenchyme, lymph nodules
• same features as rat, but CT stroma not as prominent
• if hepatic v, present, it will be alone and not in hepatic triad

Histology of Gallbladder #56 *H&E

Structures to Identify:

• Mucosa – deep folds when GB empty
• smooth m
• glands ( only in neck region)
• Rokitansky-Aschoff sinuses
• a/v
• adventia/serosa

General Info

• concentrates and stores bile for delivery into duodenum – done by salt active transport from bile and passive movement of H2O in response to salt transport
• Bile flow = R/L Hepatic ducts –> common hepatic duct –> cystic duct –> GB–> cystic duct –> common bile dcut –> duodenal papilla of Vater

Mucosa

• characterized by tall columnar epithelium with so called  diverticuli or crypts, where the mucosa makes deep folds. LOOK FOR THESE – v. characteristic of GB = Rokitansky – Aschoff sinuses
  
  • advential invaginations of mucosal membrane
  • common site of bile stones inflammation, as these can close themselves off into closed sacs, where bacteria can collect
  • can extend into musc. layer
  • from as a result of inc pressure in GB and damage to wall of GB
• has absorption function like in SI/LI
• concentration of mitchondria found on basal/apical surfaces
• Na/K ATPases on lat cell surfaces (not seen, theory only)
• cells also have microvilli to increase surface area = absorption of H2O andminerals = concentrate bile
• LP = rich in fenestrated capillaries for absorption and lymphocytes as usual

No Submucosa or Musc Mucosa!!

Musc ext

• below LP, contains unordered smooth m layers

• • contract when activated by hormones from SI enteroendocrine cells
  • contract dec volume of GB –> bile expelled into cystic duct
• lots of elastic fibers interwoven with it
• have CT covering smooth m bundles with a/v/lymphatics/nevers

Outer Layers:

• On Liver side = adventia – (CT layer rich in elastic fibers, n fibers, adipose tissue – no peritoneal coverage)
  • if is adventia, will have intercalated ducts to absorb bile and aberrant bile ducts = Ducts of Luschka
    • these ducts are non-functional
    • located on post wall of GB
    • may be present, are remnants of bile duct system
    • look like small lumen surrounded by cuboidal epithelium
    • none are connected to lumen of GB, some may be connected to liver
• On unattached side = serosa – (visceral peritoneum, layer of mesothelium and loose CT
  • subserosa with it = thin squamous like layer

Embryology of Liver/Gallbladder

• Liver primordium appears in the middle of 3. week, as outgrowth of the endodermal epithelium at the distal end of the foregut
• This outgrowth, the hepatic diverticulum, or liver bud, consits of rapidly proliferating cells that penetrate the septum transversum= the mesodermal plate between the pericardial cavity and the stalk of the yolk sac.
• While hepatic cells continue to penetrate the septum, the connection between the hepatic diverticulum+ the forgut (duodeneum) narrows, forming the bile duct.
  
• A small  ventral outgrowth is formed by the bile duct, + and this outgrowth gives rise to the gallbladder+ the cystic duct.
• During furhter development, epithelial liver cords intermingle with the vitelline + umbilical veins, which form hepatic sinusoids.
• Liver cords differentiate into the parenchyme(liver cells) + form the lining of the biliary ducts.
• Hematopoietic cells, Kupfer cells + CT cells are derived from mesoderm of the septum transversum
• When liver cells have invaded the entire septum transversum, so that the organ bulges caudally into the abdominal cavity–> mesoderm of the septum transversum lying between the liver and the foregut+ the liver+ ventral abdominal wall become membranous –> forming the lesser omentum+ falciform ligament.
• Together, having formed the peritoneal connection between the forgut+ the ventral abdominal wall, they are known as the ventral mesogarstrium.

The surface of the liver differentiate into visceral peritoneum, exept on its cranial surface.

• In this region, the liver remains in contact with the rest of the original septum transversum.
• this portion of the septum, which consits of densey packed mesoderm, will form the central tendon of the diaphragm
• the surface of the liver that is in contact with the tendon of the diaphragm = bare area of the liver (never covered by peritoneum)
  

@ 10 th week: weight of liver app. 10 % of the total body weight

• this may be attributed partly to the large numbers of sinusoids,also imp. Factor: is its hematopoietic function.
• large nests of proliferating cells, which produce red + white blood cells, lie between hepatic cells+ and wall of the vessels.
• this activity gradually subsides, during the last 2 month of intrauterine life + only small hematopoietic islands remain at birth.the weight of the liver is then only 5% of the total body weight.

@ 12th week: bile is formed by hepatic cells

• since the gallbladder + cystic duct have developed + the cystic duct has joined the hepatic duct to form the bile duct, bile can enter the gastrointestinal tract, consequence= contents take on a dark green colour.
• due to positional changes of the duodenum, the entrance of the bile ducts gradually shifts from the initial ant. position to a posterior one, and consequently the bile duct passes behind the duodenum.