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02.01.12(a): Liver Physiology
1. Author(s): Rebecca W. Van Dyke, M.D., 2012
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3. M2 GI Sequence
Liver Physiology
Rebecca W. Van Dyke, MD
Winter 2012
4. Learning Objectives
• 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.
7. V ena cava
s y s te m ic o u tflo w U n iq u e P o s itio n a n d
B lo o d S u p p ly o f th e L iv e r
H e p a tic a rte ry
s y s te m ic in p u t
Cystic artery
sole supply to bile duct
P o rta l v e n o u s
in flo w fro m g u t,
s p le e n a n d
p a n c re a s
In te s tin e
P a n c re a s
8. Anatomy of Liver Acinus
bile duct
hepatic artery
portal vein
blood flow
portal triad bile
sinusoids
Michigan Histology Collection central vein
9. Dual Blood Supply of Liver
liver
Hepatic artery: 20%
Portal vein: 80%
spleen
pancreas
Liver has dual blood
Regents of the University of Michigan supply:
80% portal vein
20% hepatic artery
10. What are the Functional
Consequences of….?
• Increased vena caval pressure/hepatic
vein obstruction?
• Decreased hepatic artery blood flow?
and/or
Decreased portal vein blood flow?
• Effects on the bile duct?
11. Budd-Chiari Syndrome: Obstruction
of the Hepatic Vein(s)
Normal Budd-Chiari
Hemorrhage in Dilated upstream
pericentral area; sinusoids;
hepatic vein atrophic/ischemic
obscured hepatocytes
13. Bile Duct
• 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
23. 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
26. U n iq u e P o s itio n a n d D iv e r s e
F u n c tio n s o f th e L iv e r :
Vena cava M e ta b o lic C e n te r a n d
s y s te m ic o u tflo w B io c h e m ic a l F a c to r y
L iv e r r e g u la te s n u tr ie n t
flo w to s y s te m ic c ir c u la tio n
d u r in g fe e d in g a n d fa s tin g
L iv e r s y n th e s iz e s a n d
r e le a s e s b lo o d p r o te in s
L iv e r ta k e s u p a n d H e p a tic a r te r y
d is p o s e s o f a w id e v a r ie ty c a r r ie s c ir c u la tin g
of com pounds n u tr ie n ts ,
h o rm o n e s
In te s tin e
P o r ta l v e n o u s
in flo w fr o m g u t G lu c o s e
c a r r ie s p r o d u c ts A m in o A c id s
o f d ig e s tio n a n d L ip id s
p a n c r e a tic
h o rm o n e s
G lu c o s e
A m in o a c id s
L ip id s P a n c re a s
28. Liver and Glucose Metabolism
Fasted state
Fed state Amino acids from
muscle/cell protein
Glucose
GLUT-2
Gluconeo-
genesis
Other
Sugars Glucose
Acetyl-CoA
TCA cycle
Fatty acid Glycogen
and
Triglyceride
synthesis
Glucose
29. Defects in Glucose Metabolism
in Liver Disease
Acute liver failure: Hypoglycemia
(rapid neuronal death)
Chronic liver disease: Insulin resistance
and diabetes
(unknown mechanism)
30. Liver and Amino Acid Metabolism
Fed state Fasted state
Dietary protein Release from
muscle/cell protein
Amino Acids
TCA cycle
Amino Acids
Urea synthesis
Hepatic
proteins
Gluconeogenesis UREA
Secreted
proteins Ketones
Glycogen
Glucose
Albumin Glucose Ketones
Clotting factors
Lipoproteins
31. Liver and Lipid Metabolism
Fed state Fasted state
Dietary Triglyceride Fatty acids
CM remnants (adipose tissue)
Prostaglandin
synthesis
FATTY ACIDS
Phospholipids
Triglycerides β-oxidation
Acetyl-CoA
Apolipo-
VLDL proteins
Glucose
Ketones
Amino acids
VLDL Ketones
32. Fatty acid metabolism within hepatocytes
albumin
hepatocyte
FABP
free fatty acid pool
excess
esterification to TAG glucose,
to mitochondria
amino acids
for energy
Apo
choline B100
VLDL
cholesterol
esters
Regents of the University of Michigan
33. Greater Role of the Liver in Production
and
Metabolism of Lipoproteins and Lipids
LDL HDL Chol.
Cholesterol
Gut
Liver
Chylomycrons CM remnants
TG TG VLDL-TG
BILE
Cholesterol
Bile acids
Phospholipids
36. 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
37. 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
38. Defects in Protein Synthesis/release also cause liver disease:
Alpha1-Anti-trypsin Deficiency
Image of pathophysiology of alpha-1-
anti-trypsin deficiency removed
39. PAS Stain Showing Retained Globs of Mutant
Alpha1 Anti-trypsin Protein in Hepatocyte ER
41. V ena cava U n iq u e P o s itio n a n d
B lo o d S u p p lyThe e L iv e r
o f th unique position and
s y s te m ic o u tflo w
blood supply of the liver
also affect liver physiology
H e p a tic a rte ry
s y s te m ic in p u t
P o rta l v e n o u s
in flo w fro m g u t,
s p le e n a n d
p a n c re a s
In te s tin e
P a n c re a s
42. Anatomy of Liver Acinus
bile duct
hepatic artery
portal vein
blood flow
portal triad bile
sinusoids
Michigan Histology Collection central vein
43. E c o E ie t E tra tio b H p to y s inS rie
ffe t f ffic n x c n y e a c te e s
P rta
o l H p tic
ea
V in
e V in
e
In u
pt O tp t
u u
10
0% 5%
44. E ie t E tra tio o O y e b H p to y sinS rie
ffic n x c n f x g n y e a c te e s
P rta
o l
v in=8 %o
e 0 f
flow
p 2= 4 m
0 4 m
H g H p tic
ea
V in
e
p 2= 3
0 2
m H
m g
H p tic
ea
a ry=2 %o
rte 0 f
flow
p 2= 1 6
0 4
m H
m g
46. Peri-central vein (hepatic vein) clotted off with
ischemic damage to hepatocytes
Peri-central
ischemia
HV clot
Peri-portal
normal tissue
47. 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
50. L iv e r C o n n e c ts to In te s tin e
S y s te m ic o u tflo w th ro u g h P o rta l V e in a n d
B ile D u c ts
L iv e r e x c re te s flu id (b ile ) a n d
d e liv e rs m a n y o rg a n ic s o lu te s
to th e in te s tin e
B iliru b in
B ile a c id s
C h o le s te ro l
L ip o p h ilic d ru g s
S y s te m ic in flo w
B ile a s a
g a rb a g e
dum p
P o rta l v e n o u s
in flo w fro m g u t
In te s tin e
P a n c re a s
52. Functions of Bile
• Transports material to the intestine for
excretion
– Drugs, toxins, xenobiotics
– Cholesterol
– Bilirubin
– Copper
• Transports bile acids to the intestine to
aid in fat absorption
53. Bile Acids
• 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
65. Hepatic Bile Acid Transport
Blood
Diffusion
Bile acid Hepatocyte
+
Na
Potential-dependent
Bile acid bile acid transporter
Sodium-coupled Bile
transport Canaliculus
ADP
Bile acids
ATP
ATP-dependent
bile acid transporter
Bile acids
from
Bile acid
intestine To intestine for
Facilitated diffusion
fat digestion
66. Enterohepatic Circulation of Bile Acids: recycling
is efficient Bile acids cycle between
the liver and the small
Bile acid
synthesis intestine.
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 Liver synthesizes about
Colon 5-10% of the total bile acid
pool each day.
67. Enterohepatic Circulation of Bile Acids: Ilial loss
Bile acid Resection of 40 cm of
synthesis the terminal ileum will
result in what problem?
Bile acid loss into the cecum
Liver will increase. What will
this cause?
Liver upregulates bile
acid synthesis and bile
acid pool remains normal.
Fat absorption remains
the same.
Colon 40 cm resection
of terminal ileum
68. Enterohepatic Circulation of Bile Acids:
Loss of most of the 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
69. Enterohepatic Circulation of Bile Acids: Lost of
Ileum
Resection of > 100 cm of
the terminal ileum will
Bile acid
synthesis result in what problem
over time?
Liver upregulates bile
Liver acid synthesis but cannot
keep up with loss rate. Bile
acid pool is reduced
Fat is malabsorbed.
As the bile acid pool falls,
loss into the colon is less
per day and secretory
diarrhea due to bile acids
converts to steatorrhea
Colon (+ secretory diarrhea
> 100 cm resection from fatty acids).
of terminal ileum
70. Enterohepatic Circulation of Bile Acid:
Cholestyramine
Bile acid Cholestyramine:
synthesis bile acid binding resin
that removes bile acids
from the enterohepatic
circulation
Liver
Liver upregulates bile acid
synthesis (using up
what compound in the
process?)
If liver cannot keep up,
what happens?
Small bowel Less free bile acid in
Colon the colon causes what?
71. Liver takes up and excretes many other organic compounds:
bilirubin is the classic and historic example
Hepatic Bilirubin Transport
SER
UDP-glucuronide
RBC +
breakdown Unconj BR
in RES
Conj
BR
Unconj BR Bile
Unconj Canaliculus
Bilirubin
Conj
BR
MRP-2:
Multispecific organic
anion transporter
Conj Conjugated bilirubin
BR Glutathione S-conjugates
other organic anions
ATP
Blood
Hepatocyte
72. Jaundice of the Neonate
• 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
73. Phototherapy for
Unconjugated
Hyperbilirubinemia of the
Neonate
Martybugs, Wikimedia Commons.
74. Hepatic Bilirubin Transport and Mechanisms
of Hyperbilirubinemia
Gilbert's syndrome (mild)
Crigler-Najjar syndrome (severe)
SER
Hemolysis
Unconj BR Bile
Unconj Canaliculus
Bilirubin
Conj
BR
Multispecific organic
anion transporter
Conj Conjugated bilirubin
BR Glutathione S-conjugates
other organic anions
AT P
Blood
Hepatocyte
Dubin-Johnson syndrome
Rotor's syndrome
?estrogen/cyclosporin
78. Liver Biotransformation/Excretion of
Endogenous/Exogenous Compounds
• 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
79. Phase 1 and Phase 2 Biotransformation in Liver
O Sugar
OH OH
Glucuronyl
CYP (P450) transferase
ER ER
Phase 1 Phase 2
Oxidative reactions Conjugation to polar ligands:
(OH-groups added) glucuronide and other sugars
CYP (P45)-mediated amino acids
sulfate
glutathione
80. 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
Conjugation
of side chain
OH group
to glycine or
amino acid taurine
81. L iv e r a n d G u t
B a rrie r F u n c tio n s
In s o lu b lehelps to remove/eliminate:
Liver ,
n o n a b s o rb a b le
com pounds
L iv e r R E S /filte r X e n o Xenobiotics: metabolism, excretion
b io tic s
D ru g s
M e ta b o lis m
B ilia ry e x c re tio n B a c teDrugs ,:p h y s ic a l metabolism, excretion
ria (a c id
b aBacteria m u n e Kupfer cells
rrie r, g u t im :
s y s te m , liv e r R E S )
In te s tin e
m u c o s a l b a rrie r
P a n c re a s
84. Functional Consequences of
Losing a Large Amount of Liver
Due to Resection/Necrosis?
• Hypoglycemia
• Poor blood clotting
• Cholestasis and jaundice
• Increased blood ammonia - affects
cognitive function
• Decreased drug disposition
• Abnormal lipid metabolism
85. Summary
• 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
86. 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/.
