Liver and Gallbladder Physiology and Pathology (Week 12) Flashcards
approximate weight of the liver
1.2-1.5kg
(~ 2-5% of adult body weight)
What role does the liver play in the circulatory system?
receives portal blood that drains the stomach, small intestine, large intestine, pancreas, and spleen
What role does the liver play in the immune system?
Kupffer cells of the liver represent up to 80% of the mononuclear phagocyte system
How many lobes does the liver have?
4
(right, left, quadrate, caudate)
The quadrate lobe is located ___________ (inferiorly/superiorly)
inferiorly
The caudate lobe is located _____________ (anteriorly/posteriorly)
posteriorly
Note: this lobe is non-palpable
___________ ligaments anchors the liver to the diaphragm
Coronary
_____________ ligament separates right and left lobe
Falciform
___________ ligament (aka “ligamentum teres”) separates quadrate and left lobe, connects the liver to the umbilicus, and is a remnant of the left umbilical vein
Round
Note: found on the free border of the falciform ligament
____________ separates the caudate lobe and left lobe, and is a remnant of the ductus venosus
Ligamentum venosum
The __________ separates the quadrate lobe and right lobe
Hint: not a ligament
gallbladder
The liver receives OXYGENATED blood from the __________
hepatic artery
The liver receives DEOXYGENATED, [extra] nutrient-rich blood from the ___________
hepatic portal vein
The porta hepatis is an opening that allows for what three things to enter the liver?
1) hepatic artery
2) portal vein
3) common hepatic duct (bile passage)
__________ are also known as liver cells
hepatocytes
Note: these are the major functional cells of the liver; they are specialized epithelial cells and make up 80% of the volume of the liver
Hepatocytes are arranged into ____________ (plates of hepatocytes bordered by hepatic sinusoids), which are highly branched structures
hepatic laminae
Hepatocytes are arranged into lobules, whereby the lobules surround a __________ that drains hepatic sinusoids and empties into the hepatic vein, and whereby the lobules are cornered by portal triads
central vein
What is a portal triad composed of?
1) bile duct
2) portal arteriole (branch of hepatic artery)
3) portal venule (branch of portal vein)
What is found between hepatocytes?
- bile canaliculi
- cholangiocytes
small ducts found between hepatic laminae that collect bile
bile canaliculi
___________ line bile ductules and ducts
Cholangiocytes
capillary system specific to the liver
hepatic sinusoids
Hepatocytes are separated from sinusoids by the ___________
space of Disse
True or False: Hepatic sinusoids are an area where blood from the portal vein and hepatic artery mix
True
They converge and drain into the central vein
What type of cell is found in the space of Disse?
hepatic stellate cell (aka “Ito” cell)
major cell type involved in liver fibrosis, becomes active when there is damage, secretes collagen and extracellular matrix in response to damage leading to scar tissue formation
hepatic stellate cell (“Ito” cell)
Why are hepatic stellate cells also categorized as lipocytes (fat cells)?
they can store lipid droplets in their cell body containing vitamin A retinol esters
resident macrophage of the liver
Kupffer cell
Note: These are derived from circulating monocytes
What is the function of Kupffer cells?
phagocytose old RBCs, hemoglobin, particulate matter, cellular debris, and microorganisms
Hepatocytes, the bile duct system, and hepatic sinusoids can be organized into functional units called ___________
hepatic acinus
approximately oval shaped mass that includes portions of 2 neighbouring hepatic lobules (the overlapping space between the two lobules = oval); has a short axis and long axis
hepatic acinus
There are 3 zones around the short axis of a hepatic acinus. What are they? Which is the most oxygenated? Which is the least oxygenated?
Zone 1 (MOST oxygenated; closer to short axis)
Zone 2
Zone 3 (LEAST oxygenated; furthest from short axis
True or False: Hepatocyte function differs based on zone within hepatic acinus
True
Periportal hepatocytes in zone 1 specialize in _____________
oxidative metabolism
Pericentral hepatocytes in zone 3 specialize in ________________
biotransformation of drugs
What are the functions of the liver?
- biotransformation & degradation
- bile production
- storage and synthesis of nutrients
- bilirubin conjugation
Describe the liver’s role in biotransformation and degradation
the liver metabolizes, detoxifies, and inactivates both endogenous and exogenous compounds
processes lipophilic chemicals into polar, water-soluble metabolites… excretes them into bile or returns them to circulation
converts important hormones and vitamins into their more active forms (e.g., hydroxylation of vitamin D, deiodination of T4 to T3)
Hepatocytes import compounds from the blood via its _________ membrane
basolateral
True or False: Hepatocytes may chemically modify or degrade products intracellularly
True
Hepatocytes excrete molecules into bile via its __________ membrane
apical
Note: the apical membrane = canalicular, aka it contains canals (this is how we can tell the difference between the apical and basolateral membrane)
What structure at the basolateral membrane provides energy for transporting solutes into the hepatocyte
Na+/K+ pump
(maintains low intracellular Na+… diffusion of Na+ down its concentration gradient fuels various active transporters)
There are also several Na-independent transporters in the liver. What are some examples?
organic anion-transporting polypeptides (OATPs)
organic cation transporter (OCT)
responsible for uptake of a variety of endogenous and exogenous amphipathic compounds (e.g., bile acids, bilirubin, ecosanoids, prostaglandins, statin drugs, methotrexate)
organic anion-transporting polypeptides (OATPs)
responsible for uptake of a variety of lipophilic organic cations (e.g., acyclovir, lidocain, epinephrine, norepinephrine, histamine)
organic cation transporter (OCT)
The third step of biotransformation and degradation in the liver is divided into two phases.
Describe the first phase
oxidation or reduction reactions typically catalyzed by P-450 cytochrome enzymes (aka CYP450)
(may include hydroxylation, dealkylation, dehalogenation,etc.)
ultimately 1 atom of oxygen is inserted into the substrate, making it more polar
RH –> ROH
True or False: Some drugs and herbs can alter the function of P-450 cytochrome enzymes (e.g., Hypericum perforatum)
True
The third step of biotransformation and degradation in the liver is divided into two phases.
Describe the second phase
conjugation, whereby a highly hydrophilic compound is added
ROH –> RO-conjugate
(typically involves addition of glucuronate, sulfate, or glutathione)
Describe step 4 (aka “phase III”) of biotransformation and degradation in the liver
conjugated compound is transported OUT of the hepatocyte
secreted into bile across canalicular membrane OR into the blood via sinusoidal membrane
Note: this requires transporters on either membrane (e.g., ATP-binding Casette aka “ABC”, which can be found on both membranes to help transport a wide variety of conjugated drugs and bilirubin into bile or blood)
Describe the liver’s function of bilirubin conjugation
senescent erythrocytes (aka old RBCs) are phagocytosed by macrophages (recall: there are resident macrophages in the liver) and heme will be degraded into bilirubin and released into the blood
Unconjugated bilirubin is carried to the liver bound to _________
albumin
Note: “unconjugated” = nothing added onto it
Once in the liver, bilirubin will be __________
conjugated
(into bilirubin glucuronide)
Note: This occurs via addition of 1-2 residues of glucuronic acid, which is catalyzed by uridine diphosphate gluconosyntransferase
The liver excretes bilirubin glucuronide into ________
bile
Bacteria in the _____________ converts some of the conjugated bilirubin back into bilirubin
ileum and colon
Note: this bilirubin will be converted to urobilinogen, of which some will be converted into stercobilin (the main pigment of feces) and the rest will be reabsorbed into the blood and filtered by the kidneys (gives urine its yellow colour)
After absorption, how are nutrients brought to the liver?
hepatic portal vein
What types of substrates can the liver synthesize?
- bile
- albumin
- coagulation factors
- plasma proteins/lipoproteins
What are the two functions of bile production by the liver?
1) elimination of exogenous and endogenous waste products (e.g., bilirubin and cholesterol)
2) promotes digestion and absorption of lipids from the intestines
Bile is synthesized from __________ in the liver
cholesterol
Note: this yields primary bile acids
Conjugation of bile acids (prior to being secreted into bile) yields ____________
bile salts
the process by which bile in the ileum and colon is dehydroxylated by bacteria and reabsorbed, yielding secondary bile salts
enterohepatic circulation
Note: the secondary bile salts must also be conjugated before being re-secreted into bile
What else is bile composed of other than bile salts?
- phospholipids
- IgA (inhibit bacterial growth in bile)
- excretory wastes (cholesterol, bile pigments/bilirubin, lipophilic drugs & metabolites, oxidized glutathione, trace minerals)
outline the bile flow pathway
hepatocyte (formation of bile) –> bile canaliculi –> bile ductules –> hepatic/bile ducts (right & left) –> common hepatic duct –> cystic duct –> common bile duct –> duodenum
Where is bile the most concentrated?
gallbladder
Recall: liver produces bile, gallbladder stores it
small, pear-shaped organ on inferior aspect of liver, ~10 cm in length and 4cm in cross section
gallbladder
How much liquid can the adult gallbladder hold?
30-50 mL
The gallbladder is continuous with the _______ duct
cystic
What type of cells are in the epithelium of the gallbladder’s mucosa layer?
simple columnar
Note: this makes sense because there is lots of absorption happening
When does the gallbladder begin to empty?
when food digestion begins in the upper GI tract (not esophagus but stomach)
True or False: Gallbladder emptying occurs with rhythmical contractions of gallbladder wall and requires simultaneous relaxation of the sphincter of Oddi
True
What regulates gallbladder emptying?
- CCK (mostly)
- acetylcholine-secreting nerve fibers from vagus and ENS
a condition characterized by diffuse remodelling of the liver into parenchymal nodules, surrounded by fibrous bands and variable degree of vascular shunting
cirrhosis
What are the leading causes of cirrhosis?
- chronic hep B
- chronic hep C
- nonalcoholic fatty liver disease
- alcoholic liver disease
Describe the pathophysiology of cirrhosis
stellate cells become activated (e.g., by inflammatory cytokines, toxins, etc.) and differentiate into highly fibrogenic myofibroblasts (essentially creating scar tissue)
True or False: Many patients with cirrhosis are asymptomatic until most advanced stages of disease.
True
Note: However, when symptoms are present, they are often non-specific (e.g., anorexia, weight loss, weakness)
True or False: Reversal of cirrhosis is not possible
False
Reversal is possible. However, the condition often progresses until liver failure
What are some complications of cirrhosis?
- liver failure –> can lead to jaundice, nausea/vomiting, encephalopathy, and coagulation defects
True or False: Cholelithiasis (aka gallstones) is the most common biliary tract disease
True
(affects 10-20% of adults in high income countries)
What are the two main types of choleithiasis (gallstones)?
1) cholesterol stones (crystalline cholesterol monohydrate)
2) pigment stones (bilirubin calcium salts)
What are the major risk factors for gallstones?
- age (middle to older age)
- sex (female > male)
- estrogen exposure/environment
- obesity
- rapid weight loss
In the pathogenesis of cholesterol gallstones, ___________ concentrations exceed the solubilizing capacity of bile (supersaturation)
cholesterol
Note: due to this supersaturation of bile with cholesterol, this leads to the cholesterol nucleating into solid cholesterol monohydrate crystals
The pathogenesis of pigment gallstones can be associated with an excessive production of ____________ (e.g., in chronic hemolytic anemia), Ileal disease (reduction of bile acids), or infection of the gallbladder (bacteria deconjugates bile)
bilirubin
What are the clinical features of cholelithiasis?
- biliary pain (can be excruciating/constant or colicky/spasmodic)
Note: pain is due to inflammation of gallbladder (cholecystitis) and/or biliary obstruction; usually in RUQ or epigastric area, which may radiate into right scapula; may last 1-5 hours, ebb then repeat
What are some complications of cholelithiasis?
- acute cholecystitis (inflammation of gallbladder); common indication for abdominal surgery/emergency cholecystectomy
- large stone may erode through the wall of the duct or gallbladder and get into the small intestine –> leading to intestinal obstruction
- increased risk for carcinoma of the gallbladder
What are some signs/symptoms associated with acute cholecystitis other than RUQ/epigastric pain?
- mild fever
- anorexia
- tachycardia
- sweating
- nausea/vomiting
yellow discolouration of the skin
jaundice
yellow discolouration of the sclera
icterus
excessive extrahepatic production of bilirubin (e.g., hemolytic anemias, resorption of blood from internal hemorrhage, ineffective erythropoeisis)
Does this describe pre-/intra-/or post-hepatic causes of jaundice?
pre-hepatic causes
impaired bile flow (e.g., due to duct obstruction)
Does this describe pre-/intra-/or post-hepatic causes of jaundice?
post-hepatic causes
reduced hepatocyte uptake, impaired conjugation (genetic deficiency of UGTIAE activity aka Gilbert syndrome), decreased hepatocellular excretion (e.g., deficiency of canalicular membrane transporters, cirrhosis)
Does this describe pre-/intra-/or post-hepatic causes of jaundice?
intra-hepatic causes
