Download Hepatology: Anatomy, Physiology and Dev

-The liver has diaphragmatic and visceral surfaces which contact the diaphragm and abdominal viscera,
respectively. Note the right triangular, left triangular, and coronary ligaments that attach to the diaphragm.
Note also the bare area not covered by peritoneum. Anteriorly, there is a fold of peritoneum connecting the liver
to the umbilicus called the falciform ligament, which contains the round ligament or ligamentum teres. It is the
remnant of the umbilical vein that brought oxygenated blood from the placenta to the fetus heart. The
ligamentum venosum is the remnant of the fetal ductus venosus that shunted blood from the umbilical vein to
the inferior vena cava to bypass the liver. In the adult liver, the porta hepatis includes the hepatic arteries from
the hepatic artery proper, the hepatic portal vein, and the hepatic and cystic ducts joining to form the common
bile duct.
- The portal vein brings nutrients and other compounds absorbed by the GI tract to be stored and/or processed.
- Anatomical lobes: Note how the inferior vena cava, gallbladder, ligamentum teres, ligamentum venosum, and
porta hepatis form an “H” shape on the visceral surface. It divides the liver into 4 anatomical lobes based on outer
appearance – the right, left, caudate, and quadrate lobes.
- Functional lobes: These are based on the distribution of the hepatic arteries, portal vein, and hepatic bile duct.
-The liver and gallbladder play important roles in
digestion via the production and storage of bile. The
liver is also the major organ for metabolism and
detoxification. The pancreas also produces digestive
enzymes to break down proteins, sugars, and fats.
- The processes described above are the exocrine
functions of the liver and gallbladder. But they also
have endocrine roles, secreting compounds into the
bloodstream. The hepatocytes produce albumin,
fibrinogen, and thrombin, for example. The pancreatic
islets produce insulin, glucagon, and somatostatin.
- The liver, gallbladder, and pancreas receive blood
supply from the celiac trunk. One main branch is the
common hepatic artery, leading to the hepatic artery
proper that branches into left and right hepatic arteries
to supply the liver. The right hepatic artery gives off
the cystic artery to supply the gallbladder.
- The pancreas is supplied by multiple vessels. The
body and tail are supplied by the dorsal, inferior, and
great pancreatic arteries, which all branch off the
splenic artery (another main branch of the celiac
trunk). The head, neck, and uncinate process are
supplied by anastomoses of arteries branching off the
celiac trunk and superior mesenteric artery. The
gastroduodenal artery, from the common hepatic
artery, divides into the anterior and posterior superior
pancreaticoduodenal arteries. They anastomose with
inferior branches of the inferior pancreatico-duodenal
artery from the superior mesenteric artery. The same
arteries supply the duodenum.



Sole blood supply to the bile duct is through the
hepatic artery via the cystic artery
Reduced blood flow through the hepatic artery
causes ischemic injury to the extrahepatic bile
ducts
Ischemia or damage to the bile duct often leads to
injury, fibrosis, stricture
- The liver is divided into many hepatic lobules. Inflow to the liver
involves hepatic arteries, which bring oxygenated blood to hepatic
tissue, and portal veins, which bring nutrients and other
compounds absorbed by the GI tract to be processed and/or stored
in the liver. Outflow also involves two routes – hepatic veins which
drain into the inferior vena cava and the common hepatic duct
which joins the cystic duct and empties bile into the duodenum.
- Major characteristics of the liver are portal triads (labeled
“portal” in bottom left and shown in the middle) and central veins
(labeled in bottom left and shown in the right). Red arrows indicate
direction of blood flow within blood sinusoids flanking cords of
liver cells.
- Note the portal triad contains 1) the portal vein, 2) the hepatic
artery, and 3) the bile duct. Each has its typical appearance. The
central vein is lined with endothelial cells, with perforations into
which the sinusoids empty.
- Once again, inflow to the liver involves
oxygenated blood via hepatic arteries and
absorbed nutrients and compounds from
the GI tract via the hepatic portal veins.
- All venous drainage from the GI tract and
abdominal visceral organs enters the portal
system back to the liver. The overall order
is as following: arteries → capillaries →
veins → portal vein → hepatic sinusoids →
veins → vena cava → heart.
- In contrast, the caval system is as
following: arteries → capillaries → veins →
vena cava → heart. Obviously, this is the
circulatory system within the rest of the
body.
- The portal and caval system are not
exclusive from each other. There are 4 sites
of portocaval anastomoses:
- 1) esophageal veins
- 2) paraumbilical veins
- 3) rectal veins
- 4) retroperitoneal veins
- If there is liver damage or cirrhosis –
accumulation of fibrous tissue that
constricts the sinusoids – there may be
portal hypertension. This may lead to
varicose veins at the 4 sites of anastomoses.
Anatomy of Liver Acinus
bile duct
hepatic artery
portal vein
blood flow
bile
portal triad
sinusoids
Michigan Histology Collection
central vein
HV
PV
American Gastroenterological Association
Space of Disse
Other serum
proteins
Albumin
Kupffer Cell
Tissue macrophage
Filtration device
bacteria, endotoxin
Releases inflammatory mediators
that influence hepatocytes
positively or negatively
Looking Down a Sinusoid at a Kupffer Cell
Poised to Grab Passing Bacteria
Ito Cell/Fat-storing Cell
Rare cell, located in sinusoids under
endothelium
Stores lipophilic materials such as
Vitamin A
Stimulated by chronic inflammation/alcohol
converts to myofibroblast
produces collagen and extracellular matrix
Responsible for much of the excess fibrotic
material in cirrhosis
Ito Cell (Fat-storing Cell) on a Sinusoid (S)
Defects in Glucose Metabolism
in Liver Disease
Acute liver failure:
Hypoglycemia
(rapid neuronal death)
Chronic liver disease:
Insulin resistance
and diabetes
(unknown mechanism)
UREA
Fatty acid metabolism within hepatocytes
albumin
FABP
hepatocyte
free fatty acid pool
to mitochondria
for energy
cholin
e
esterification to
TAG
excess
glucose,
amino acids
Apo
B100
VLDL
cholesterol
esters
Regents of the University of Michigan
Greater Role of the Liver in Production
and
Metabolism of Lipoproteins and Lipids
HDL Chol.
LDL
Cholesterol
Gut
Liver
Chylomycrons
TG
CM remnants
TG
VLDL-TG
BILE
Cholesterol
Bile acids
Phospholipids
Fatty Liver with Inflammation
Liver as Protein Synthetic Machine
Vena cava
systemic outflow
Liver synthesizes and secretes:
Lipoproteins
Albumin
Clotting factors
Anti-proteases (α1-anti-trypsin)
Fibrinogen
Complement factors
Ceruloplasmin
Transferrin and other binding
proteins
Hepatic artery
carries arterial
blood with blood
proteins
Portal vein carries
venous blood from
intestine, spleen and
pancreas
Protein Secretion Defects in Liver Disease
Example
Clinical Consequence
Albumin
Decreased plasma oncotic pressure/
edema
Decreased binding of hydrophobic
compounds
Clotting factors :
Decreased factors II, VII, IX and X
Increased bleeding
Fibrinogen
Decreased fibrin formation in clotting
Defects in Protein Synthesis/release also cause liver disease:
Alpha1-Anti-trypsin Deficiency
Image of pathophysiology of alpha-1anti-trypsin deficiency removed
PAS Stain Showing Retained Globs of Mutant
Alpha1 Anti-trypsin Protein in Hepatocyte ER
Lipoprotein release: another liver
synthetic function
VLDL: a combination of fat and
protein
Bile Formation

Transports material to the intestine for
excretion





Drugs, toxins, xenobiotics
Cholesterol
Bilirubin
Copper
Transports bile acids to the intestine to aid
in fat absorption




Organic acid synthesized in liver from
cholesterol
Conjugated to amino acids
Secreted in bile - essential for fat
digestion/absorption
Reabsorbed in distal ileum and returned to
liver via portal vein
Cholesterol: Flat (planar) hydrophobic compound
OH
Metamorphosis to a bile acid
you now have a tri-hydroxy bile acid: cholic acid
OH
COOH
OH
OH
One more change conjugation of an amino acid to the side chain yields
Taurocholate (taurine conjugated cholic acid)
OH
CO NH
OH
COOH
OH
Bile acids cycle between
the liver and the small
intestine.
Bile acid
synthesis
Total bile acid pool is
about 3 grams.
Liver
About 90% of bile acids
are reabsorbed in the
terminal ileum.
However about 5-10% of
bile acids are lost daily
into the colon. Effect?
Small bowel
Colon
Liver synthesizes about
5-10% of the total bile acid
pool each day.
Resection of 40 cm of
the terminal ileum will
result in what problem?
Bile acid
synthesis
Bile acid loss into the cecum
will increase. What will
this cause?
Liver
Liver upregulates bile
acid synthesis and bile
acid pool remains normal.
Fat absorption remains
the same.
Colon
40 cm resection
of terminal ileum
Bile acid
synthesis
Resection of >100 cm of
the terminal ileum will
result in what problem?
Liver
Initially, bile acid loss into
the colon will be massive.
What will be the initial
effect of this loss of bile
acids into the colon?
Colon
>100 cm resection
of terminal ileum
Resection of > 100 cm of
the terminal ileum will
result in what problem
over time?
Bile acid
synthesis
Liver upregulates bile
acid synthesis but cannot
keep up with loss rate. Bile
acid pool is reduced
Fat is malabsorbed.
Liver
Colon
> 100 cm resection
of terminal ileum
As the bile acid pool falls,
loss into the colon is less
per day and secretory
diarrhea due to bile acids
converts to steatorrhea
(+ secretory diarrhea
from fatty acids).
Cholestyramine:
bile acid binding resin
that removes bile acids
from the enterohepatic
circulation
Bile acid
synthesis
Liver
Liver upregulates bile acid
synthesis (using up
what compound in the
process?)
If liver cannot keep up,
what happens?
Small bowel
Colon
Less free bile acid in
the colon causes what?
Liver takes up and excretes many other organic compounds:
bilirubin is the classic and historic example
Hepatic Bilirubin Transport
SER
RBC
breakdown
in RES
UDP-glucuronide
+
Unconj BR
Conj
BR
Unconj
Bilirubin
Unconj BR
Bile
Canaliculus
Conj
BR
MRP-2:
Multispecific organic
anion transporter
Conj
BR
AT P
Blood
Hepatocyte
Conjugated bilirubin
Glutathione S-conjugates
other organic anions
Hepatic Bilirubin Transport and Mechanisms
of Hyperbilirubinemia
Gilbert's syndrome (mild)
Crigler-Najjar syndrome (severe)
SER
Hemolysis
Unconj
Bilirubin
Bile
Canaliculus
Unconj BR
Conj
BR
Multispecific organic
anion transporter
Conj
BR
AT P
Conjugated bilirubin
Glutathione S-conjugates
other organic anions
Blood
Hepatocyte
Dubin-Johnson syndrome
Rotor's syndrome
?estrogen/cyclosporin



Bilirubin conjugation is an example
Many other organic compounds undergo two-step
biotransformation
 Example: cholesterol to bile acids
After biotransformation, metabolites excreted
 Larger, lipophilic molecules excreted in bile
 Smaller (<400 Da) transported to blood and
excreted by kidneys
Prometheus
Bound
P.P.Reubens
An early case of
of hepatic regeneration
P. P. Rubens






Hypoglycemia
Poor blood clotting
Cholestasis and jaundice
Increased blood ammonia - affects
cognitive function
Decreased drug disposition
Abnormal lipid metabolism




Liver exhibits a wide range of functions
Liver diseases may cause malfunction of one
or more normal function
Functions regulated separately so any one
liver disease can affect each to a different
extent
Liver diseases cause:


Altered liver functions
Altered tests of liver injury















At the end of this presentation students should be able to:
1. Describe the basic organization of the liver cell plate and its functional
consequences:
a.
Blood supply
b.
Configuration of hepatocytes
c.
Configuration of other liver cells
d.
Concentration gradients in sinusoidal blood.
2. Describe the basic physiological processes the liver utilizes to accomplish function:
a.
transport
b.
metabolism
c.
biotransformation
d.
synthesis
e.
secretion
3. Be able to give examples of the consequences of liver damage on above processes.
4. Be able to give examples of possible consequences of liver disease/injury on liver barrier
function and hepatic regeneration.
Cystic artery
sole supply to bile duct
Dual Blood Supply of Liver
liver
Hepatic artery: 20%
Portal vein: 80%
spleen
pancreas
Regents of the University of Michigan
Liver has dual blood
supply:
80% portal vein
20% hepatic artery



Increased vena caval pressure/hepatic vein
obstruction?
Decreased hepatic artery blood flow?
and/or
Decreased
portal vein blood flow?
Effects on the bile duct?
Normal
Budd-Chiari
Hemorrhage in
pericentral area;
hepatic vein
obscured
Dilated upstream
sinusoids;
atrophic/ischemic
hepatocytes
Decreased inflow: ischemic infarction
Liver Cell
Anatomy:
Consider
functional
consequences
Image showing relationship between sinusoid,
sinusoid lining cells, and hepatocyte removed.
Scanning Electron micrograph of Liver
The Liver:
The Body’s Refinery
Defects in Glucose Metabolism
in Liver Disease
Acute liver failure:
Hypoglycemia
(rapid neuronal death)
Chronic liver disease:
Insulin resistance
and diabetes
(unknown mechanism)
UREA
Fatty acid metabolism within hepatocytes
albumin
FABP
hepatocyte
free fatty acid pool
to mitochondria
for energy
cholin
e
esterification to
TAG
excess
glucose,
amino acids
Apo
B100
VLDL
cholesterol
esters
Regents of the University of Michigan
Greater Role of the Liver in Production
and
Metabolism of Lipoproteins and Lipids
HDL Chol.
LDL
Cholesterol
Gut
Liver
Chylomycrons
TG
CM remnants
TG
VLDL-TG
BILE
Cholesterol
Bile acids
Phospholipids
Fatty Liver with Inflammation
Liver as Protein Synthetic Machine
Vena cava
systemic outflow
Liver synthesizes and secretes:
Lipoproteins
Albumin
Clotting factors
Anti-proteases (α1-anti-trypsin)
Fibrinogen
Complement factors
Ceruloplasmin
Transferrin and other binding
proteins
Hepatic artery
carries arterial
blood with blood
proteins
Portal vein carries
venous blood from
intestine, spleen and
pancreas
Protein Secretion Defects in Liver Disease
Example
Clinical Consequence
Albumin
Decreased plasma oncotic pressure/
edema
Decreased binding of hydrophobic
compounds
Clotting factors :
Decreased factors II, VII, IX and X
Increased bleeding
Fibrinogen
Decreased fibrin formation in clotting
Defects in Protein Synthesis/release also cause liver disease:
Alpha1-Anti-trypsin Deficiency
Image of pathophysiology of alpha-1anti-trypsin deficiency removed
PAS Stain Showing Retained Globs of Mutant
Alpha1 Anti-trypsin Protein in Hepatocyte ER
Lipoprotein release: another liver
synthetic function
VLDL: a combination of fat and
protein
The unique position and
blood supply of the liver
also affect liver physiology
Anatomy of Liver Acinus
bile duct
hepatic artery
portal vein
blood flow
bile
portal triad
sinusoids
Michigan Histology Collection
central vein
Peri-central vein (hepatic vein) clotted off with
ischemic damage to hepatocytes
Peri-central
ischemia
HV clot
Peri-portal
normal tissue
Not all liver cells are alike.
Substances found in higher concentrations in the portal vein
•Albumin
•CPS
•FABP
•HMG CoA
Substances found in higher concentrations in the hepatic vein
•P450s
•ADH
•C7αH
•Cysteine
•GR
•Gluatamate
α2µG
•GS
•GLUT-1
α-KG
Normal cells
PV
HV
Necrosis
Bile Formation

Transports material to the intestine for
excretion





Drugs, toxins, xenobiotics
Cholesterol
Bilirubin
Copper
Transports bile acids to the intestine to aid
in fat absorption




Organic acid synthesized in liver from
cholesterol
Conjugated to amino acids
Secreted in bile - essential for fat
digestion/absorption
Reabsorbed in distal ileum and returned to
liver via portal vein
Bile Acid
Cholesterol
Cholesterol: Flat (planar) hydrophobic compound
OH
Metamorphosis to a bile acid
OH
Lose the double bond
Metamorphosis to a bile acid
OH
Shorten the side chain
Metamorphosis to a bile acid
COOH
OH
Add a carboxylic acid group
and bend this below the
plane of the rings
Metamorphosis to a bile acid
COOH
OH
Add a hydroxyl group
that is bent down
OH
Metamorphosis to a bile acid
Add another
hydroxyl group
OH
COOH
OH
OH
Metamorphosis to a bile acid
you now have a tri-hydroxy bile acid: cholic acid
OH
COOH
OH
OH
One more change conjugation of an amino acid to the side chain yields
Taurocholate (taurine conjugated cholic acid)
OH
CO NH
OH
COOH
OH
Conjugated tri-OH Bile Acid
Hydrophobic side
OH- OH-
OH-
COOHydrophilic side
Bile acids
from
intestine
To intestine for
fat digestion
Bile acids cycle between
the liver and the small
intestine.
Bile acid
synthesis
Total bile acid pool is
about 3 grams.
Liver
About 90% of bile acids
are reabsorbed in the
terminal ileum.
However about 5-10% of
bile acids are lost daily
into the colon. Effect?
Small bowel
Colon
Liver synthesizes about
5-10% of the total bile acid
pool each day.
Resection of 40 cm of
the terminal ileum will
result in what problem?
Bile acid
synthesis
Bile acid loss into the cecum
will increase. What will
this cause?
Liver
Liver upregulates bile
acid synthesis and bile
acid pool remains normal.
Fat absorption remains
the same.
Colon
40 cm resection
of terminal ileum
Bile acid
synthesis
Resection of >100 cm of
the terminal ileum will
result in what problem?
Liver
Initially, bile acid loss into
the colon will be massive.
What will be the initial
effect of this loss of bile
acids into the colon?
Colon
>100 cm resection
of terminal ileum
Resection of > 100 cm of
the terminal ileum will
result in what problem
over time?
Bile acid
synthesis
Liver upregulates bile
acid synthesis but cannot
keep up with loss rate. Bile
acid pool is reduced
Fat is malabsorbed.
Liver
Colon
> 100 cm resection
of terminal ileum
As the bile acid pool falls,
loss into the colon is less
per day and secretory
diarrhea due to bile acids
converts to steatorrhea
(+ secretory diarrhea
from fatty acids).
Cholestyramine:
bile acid binding resin
that removes bile acids
from the enterohepatic
circulation
Bile acid
synthesis
Liver
Liver upregulates bile acid
synthesis (using up
what compound in the
process?)
If liver cannot keep up,
what happens?
Small bowel
Colon
Less free bile acid in
the colon causes what?
Liver takes up and excretes many other organic compounds:
bilirubin is the classic and historic example
Hepatic Bilirubin Transport
SER
RBC
breakdown
in RES
UDP-glucuronide
+
Unconj BR
Conj
BR
Unconj
Bilirubin
Unconj BR
Bile
Canaliculus
Conj
BR
MRP-2:
Multispecific organic
anion transporter
Conj
BR
AT P
Blood
Hepatocyte
Conjugated bilirubin
Glutathione S-conjugates
other organic anions




Newborn infants have poorly
developed bilirubin
conjugation enzymes and
jaundice is common.
Premature infants are even
more affected
Unconjugated bilirubin in the
brain causes permanent
damage (kernicterus)
How to prevent brain damage
in neonates?
Regents of the University of Michigan
Martybugs, Wikimedia Commons.
Hepatic Bilirubin Transport and Mechanisms
of Hyperbilirubinemia
Gilbert's syndrome (mild)
Crigler-Najjar syndrome (severe)
SER
Hemolysis
Unconj
Bilirubin
Bile
Canaliculus
Unconj BR
Conj
BR
Multispecific organic
anion transporter
Conj
BR
AT P
Conjugated bilirubin
Glutathione S-conjugates
other organic anions
Blood
Hepatocyte
Dubin-Johnson syndrome
Rotor's syndrome
?estrogen/cyclosporin
Bilirubin:
Jaundice
The first liver
disease test
CDC



Bilirubin conjugation is an example
Many other organic compounds undergo two-step
biotransformation
 Example: cholesterol to bile acids
After biotransformation, metabolites excreted
 Larger, lipophilic molecules excreted in bile
 Smaller (<400 Da) transported to blood and
excreted by kidneys
Step-wise Synthesis of
Bile Acids from Cholesterol
Steps are analogous to Phase I and Phase II
steps of drug/xenobiotic metabolism
Cholesterol
P450- mediated
hydroxylations
OH group
amino acid
Conjugation
of side chain
to glycine or
taurine
Liver and Gut
Barrier Functions
Liver RES/filter
Metabolism
Biliary excretion
Liver helps to remove/eliminate:
Insoluble,
nonabsorbable
compounds
Xenobiotics: metabolism, excretion
Xenobiotics
Drugs
Drugs
Bacteria
(acid,:physical metabolism, excretion
barrier,
gut immune
Bacteria
:
Kupfer cells
system, liver RES)
Intestine
mucosal barrier
Pancreas
Liver’s Magic Trick: Regeneration
Image of liver regeneration process removed
Prometheus
Bound
P.P.Reubens
An early case of
of hepatic regeneration
P. P. Rubens






Hypoglycemia
Poor blood clotting
Cholestasis and jaundice
Increased blood ammonia - affects
cognitive function
Decreased drug disposition
Abnormal lipid metabolism




Liver exhibits a wide range of functions
Liver diseases may cause malfunction of one
or more normal function
Functions regulated separately so any one
liver disease can affect each to a different
extent
Liver diseases cause:


Altered liver functions
Altered tests of liver injury
Additional Source Information
for more information see: http://open.umich.edu/wiki/AttributionPolicy
Slide 73, Image 1 (top): Martybugs, "Jaundice phototherapy," Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Jaundice_phototherapy.jpg,
CC; BY-SA 3.0, http://creativecommons.org/licenses/by-sa/3.0/.