Download Chap 70 - The Liver As An Organ

The Liver As An Organ
Physiology III, Tri 4
Guyton & Hall, Chapt. 70
I. The Liver
A. largest visceral organ = 2.5% of body wt.
B. receives 25% of cardiac output
1. 70-80% is from portal vein
a. from gut
b. poorly oxygenated
2. hepatic artery
C. contains lobes
D. functional unit = lobule
1. cylinder structure
2. several millimeters in length
3. 0.8 to 2 millimeters in diameter
4. 50,000 to 100,000 lobules/liver
E. lobules are constructed around a central vein
1. central vein empties into hepatic vein
2. hepatic vein empties into inferior vena cava
F. hepatic cellular plates
1. radiate centrifugally from the central vein like spokes of a wheel
2. two cells thick
G. sinusoids
1. lie between hepatic cellular plates
2. allows for the "collecting of blood" from the hepatic artery and
portal vein
3. has continuous flow of portal venous blood
4. endothelial in nature - extremely large pours
5. do not have basement membrane
6. are lined with specialized cells:
a. Kupffer cells (a.k.a. reticuloendothelial cells)
1. from macrophages
2. part of the fixed reticuloendothelial system
3. degrades:
a. bacteria
b. RBC's
c. debris
b. Ito cells
1. located near
a. Kupffer cells
b. sinusoid cells
2. contain fat droplets
3. stores vit. A
H. bile canaliculi
1. lie between the hepatic plates
2. empty into the bile ducts
I. hepatocytes are connected by tight junctions
J. arrangement of hepatocytes along liver sinusoids allow for rapid exchange of
molecules
K. hepatic arterioles
1. in the interlobular septa
2. supply arterial blood to the septal tissues between the adjacent lobules
3. empty into sinusoids
L. space of Disse
1. lies between the endothelial cells and hepatic cells
2. connect with lymphatic vessels in the interlobular septa
3. removes excess fluid via the lymphatic vessels
II. Functions of the Liver
A. vascular function
1. storage of blood - absorbs 0.5 -1.0 liter of blood
2. filtration of blood
B. metabolic functions
C. secretory and excretory functions - bile formation and distribution
III. Vascular Function
A. blood flow/min:
1. 1100 ml from portal vein
2. 350 ml from hepatic artery
3. 1450 ml/min total hepatic blood flow
4. 29% of resting cardiac output
B. Fick principle - measurement of blood flow
Hepatic blood flow (ml/min) = rate of dye excretion (mg/min)
A-V difference in dye (mg/ml)
C. pressure and resistance
1. portal vein = 9 mmHg
2. hepatic vein = 0 mm Hg
3. small pressure difference = low resistance
4. flow = 1.45 liters/min
D. cirrhosis
1. fibrous tissue
a. destroys parenchymal cells
b. restriction of blood vessels
c. impedence of flow
2. causes:
a. alcoholism
b. poisons - ex. carbon tetrachloride
c. viruses - ex. hepatitis
d. infections
E. blood reservoir:
1. normally: 450 ml ~ 10% of total blood volume
2. in congestive heart failure: can increase by and extra 0.5 to 1 liter
F. lymph flow
1. under resting conditions, ½ of lymph formed is from the liver
2. contains high protein concentration - 6 gm/dl
G. Ascites
1. increase in hepatic venous pressure (only 3 - 7 mm Hg above normal)
2. transude leaks through liver capsule
3. fluid collects in the abdomen
4. plasma like fluid (contains 80 - 90% as much protein as plasma)
H. hepatic macrophage system
1. blood flow to liver contains intestinal bacteria
2. Kupffer cells endocytosis bacteria within 0.01 seconds of exposure
3. < 1% of bacteria from portal blood leaves the liver
IV. Metabolic Function
A. detoxification
1. metabolism of drugs and xenobiotics often involves conjugation
2. conjugation is for the production of a less toxic water-soluble form
B. ethanol detoxification to acetate
1. requires the use of 2NAD+
2. males make more dehydrogenase enzyme than females and can detox
alcohol faster
(1st enzyme) alcohol
dehydrogenase
Ethanol
NAD+
acetaldehyde
dehydrogenase
(toxic)
Acetaldehyde
NADH + H+
NAD+
cytosol of hepatocyte
CoA
Acetate
citric acid cycle
NADH + H+
in mitochondrion
3. excess ethanol metabolism will tie up the NAD+ required for the
conversion of malate to oxaloacetate step of gluconeogenesis (inhibit
gluconeogenesis).
Malate
Oxaloacetate
NAD+
NADH + H+
4. excess ethanol metabolism after exercise will cause dehydration
5. enhancement of process of pyruvate reduction to lactic acid
Pyruvate
Lactate
NADH + H+
NAD+
(regenerated)
C. R-H degradation by the cytochrome P450 system
1. Phase I
a. for increasing water solubility, the body oxidizes the R-H to the
alcohol R-OH
b. enzymes are not well developed in newborn or the aged
c. excess production of enzymes (ex. smokers) will cause faster
degradation of drugs = less effect of medication
d. protein dependent -  protein   monooxygenases
e. monooxygenases:
1. uses 1 oxygen
2. not specific in nature
3. located in microsomal and intramitochondrial
membranes
NADPH + H+
Reducing equivalent
NADP+
OX
cyt P450
reductase
Fe-S
reduction
OX
RH
O2
cyt P450
reduction
H2O
RHO
2. phase II
a. the liver can still make R-OH more soluble by conjugation of
the newly made alcohol
b. (R-OH) most often conjugated with glucuronic acid
c. others:
1. glycine
2. taurine
3. sulfates
D. carbohydrate metabolism
1. functions:
a. storage of glycogen
1. maintains blood glucose levels
2. glucose buffer function
b. conversion of galactose and fructose to glucose
c. gluconeogenesis
1. occurs when blood glucose falls below normal
2. AA and glycerol are converted into glucose
d. formation of chemical compounds of carbohydrate metabolism
2. glucose
a. blood glucose following a meal
b. glucose is taken to liver via portal system
c. facilitated transport moves glucose into liver; co-transported
with sodium in the small intestine
d. glucose is phosphorylated by hexokinase to produce Glucose-6phosphate (G-6-P)
e. G-6-P used in the formation of glycogen
3. fructose
a. moved via facilitated transport - uptake from small intestine
b. phosphorylated to produce fructose 1-phosphate
c. fructose 1-phosphate is converted to G-6-P or used in the
glycolytic pathway
4. galactose
a. moved via facilitated transport - from gut Na co-transport
b. phosphorylated to produce galactose 1-phosphate
c. uridine diphosphate is then added to get UDP-galactose
d. UDP-galactose is used in glycolipid/glycoprotein structure in
the lipid membrane - glycocalyx
e. OR - converted to UDP-glucose and recycled
E. gluconeogenesis
1. formation of glucose
a. during starvation
b. during decreased CHO intake
2. oxaloacetate is used for the formation of glucose (reverse glycolysis not an exact reversal)
3. glucose is the preferred fuel of the brain
4. AA are used for fuel
a. alanine is most commonly used
b. found in abundance in muscle tissue
c. Alanine cycle
F. formation of glycogen
1. storage form of glucose
2. 7 - 10% of liver weight is glycogen
3. from lactate
a. 1/3 of lactate is used to produce glucose
b. 2/3 of lactate is used to produce pyruvate
G. glycogen degradation
1. -1-4 and -1-6 ; highly branched
2. 1st enzyme:
a. glycogen phosphorylase breaks down glycogen to
glucose-1-phosphate
b. glycogen is the major storage form of fuel - ATP and creatinephosphate stores are small
c. McArdle's disease - missing glycogen phosphorylase
3. 2nd enzyme:
a. release of glucose for the cell
b. G-6-Phosphatase
1. dephosphorylation is required
2. phosphorylated glucose can not leave the cell
c. skeletal muscle does not have G-6-Phosphatase
d. skeletal muscle does not release glucose into the blood
e. hormones which affect these processes:
1. insulin - liver is very sensitive to insulin
2. glucagon
3. epinephrine
H. fat metabolism
1. high rate of oxidation of fatty acids to supply energy for other
bodily functions
a. to derive energy from neutral fats:
1. fat is first split by beta-oxidation into two-carbon acetyl
radicals to form acetyl-CoA
2. acetyl-CoA can enter the citric acid cycle
3. excess acetyl-CoA is converted to acetoacetic acid
4. acetoacetic acid is transported throughout the body and
absorbed by other tissues
5. acetoacetic acid can be reconverted to acetyl-CoA and
oxidized
6. palmitic acid - base fatty acid synthesis in cytosol
7. liver lacks ketone acid transferase and can not use
ketone bodies for fuel
8. RBC and adrenal medulla can only use glucose
Fatty Acids
Acetyl-CoA
TCA cycle (in the presence of CHO)
Ketone bodies (in the absence of CHO)
9. brain prefers glucose but can use ketone bodies
10. ketone bodies
keto acidosis
a.  fluid loss to get rid of ketones
b.  mineral loss (especially Na+)
c. dehydration
d. emesis = vomiting
HDL
Gut
Chylomicrons
Remnant
Liver
Cholesterol
VLDL
IDL
LDL
Tissue
triacylglycerols
2. formation of most of the lipoproteins
a. lipoproteins produced in the liver:
1. VLDL - transport of fat products from liver
2. LDL
3. HDL
a. moves cholesterol (small amount) to liver
b. also produced by plasma
b. chylomicrons and VLDL (very little ir any) are lipoproteins
produced in the gut
c. chylomicrons are larger than VLDL
d. chylomicrons transport products of fat digestion from the gut to
various tissues
e. lipoprotein lipase:
1. required for lipid removal from chylomicron
2. elevated levels in the obese
f. the liver has LDL, HDL, and IDL receptors
g. liver is the main organ for getting rid of cholesterol
h. triacylglycerol is largest component in chylomicrons
i. VLDL gives rise to LDL as it gives up triacylglycerol
3. synthesis of large quantities of cholesterol and phospholipids
a. 80% of cholesterol synthesized in the liver (from Acetyl-CoA)
is converted into bile salts
b. phospholipids are synthesized in the liver and transported in the
lipoproteins
c. cholesterol and phospholipids are used by the cell for:
1. membrane formation
2. intracellular structures
3. chemical substances for cellular function
4. hormone production (steroids)
4. conversion of large quantities of carbohydrates and proteins into fat
a. almost all fat synthesis form CHO and proteins occurs
in the liver
b. transported in lipoproteins to the adipose tissue
I. protein metabolism - necessary for life
1. deamination of AA
a. primarily occurs in the liver
b. required for:
1. AA to be used as energy
2. AA conversion into CHO or fats
2. formation of urea for removal of ammonia from the body fluids
a. removes ammonia from plasma
b. without this function, hepatic coma and death can occur
c. is a result of ammonia released by deamination from
AA degradation
3. formation of plasma proteins
a. all are formed in the liver except gamma globulins
b. rate of formation 15 - 50 gm/day
c. plasma proteins produced by the liver
1. fibrinogen
2. prothrombin
3. transferrin
4. transferrin
5. haptoglobin
6. hemopexin
7. albumin:
a. main protein produced by the liver
b. about 3 g/day is produced
c. required for maintaining osmotic pressure
d. acts as a buffer
4. interconversions among AA and other substances
a. liver can synthesize all non-essential AA
b. AA are required for the synthesis of non-essential AA (11) form
essential ones (9)
c. essential AA:
1. histidine
2. threonine
3. phenylalanine
4. isoleucine
5. leucine
6. valine
7. lysine
8. methionine
9. arginine (sometimes)
Examples:
Phenylalanine
Methionine
Tyrosine (difference is OH group)
Cysteine (used for producing disulfide
bonds)
V. Excretion of Bilirubin in the Bile
A. bilirubin
1. greenish yellow pigment
2. major end product of hemoglobin degradation
3. bilirubin excretion is diagnostic tool for hemolytic blood diseases and
some liver diseases
B. RBC
1. 120 day lifespan
2. tissue macrophages = reticuloendothelial system
a. split hemoglobin into globin and heme
b. heme ring is opened to give:
1. free iron that is transported in the blood by transferrin
2. straight chain of four pyrrole nuclei that eventually
forms bilirubin
c. free (unconjugated) bilirubin is transported by albumin
d. bilirubin is transported to the liver and conjugated with:
1. glucuronic acid to form bilirubin glucuronide (80%)
2. sulfate to form bilirubin sulfate (10%)
e. bilirubin is excreted from the hepatocytes by an active transport
process into the bile canaliculi and into the intestines
f. bacteria in the gut convert bilirubin to urobilinogen
g. most urobilinogen is reabsorbed and re-excreted by the liver
h. 5% of urobilinogen is excreted by the kidneys in urine and
oxidized with exposure to air to form urobilin
i. in the feces urobilinogen is altered and oxidized to form
stercobilin
SEE Figure 70-2, Page 887 in Guyton and Hall
C. jaundice
1. yellowish tint to body tissues
2. due to large quantities of bilirubin in the extracellular fluids
3. causes of jaundice:
a.  destruction of RBCs with rapid release of bilirubin
into the blood
b. obstruction of the bile ducts
c. damage tot he liver cells so that even the usual amounts
of bilirubin cannot be excreted in the GI tract
D. types of jaundice:
1. hemolytic jaundice:
a. excretory function of the liver is not impaired
b. RBC hemolyzed rapidly
c. hepatic cells cannot excrete bilirubin as fast as it is formed
d.  rate of formation of urobilinogen
e.  rate of urobilinogen absorption
f. most plasma bilirubin is in the "free" form
(van den Bergh reaction)
2. obstructive jaundice:
a. obstruction of bile ducts
1. gall stones
2. cancer
b. damage to the hepatic cells (hepatitis)
c. bilirubin cannot pass from the blood into the intestines
d. blood levels of conjugated bilirubin increase
e. urobilinogen in the urine is negative
f. stools are clay-colored - lack of stercobilin and bile pigments
g. significant quantities of conjugated bilirubin appear in the urine
(shaking the urine produces intense yellow foam)
VI. Storage Capabilities of the Liver
A. fat-soluble vitamins
1. vit A:
a. precursor of -carotene
b. -carotene is 2 vit A's combined
c. forms:
1. retinal (aldehyde)
2. retinoic acid
3. retinol
d. retinol is the form that is transported by chylomicrons
e. -carotene overdose causes skin color to be yellow/orange
f. -carotene overdose in pregnancy can harm unborn child
2. vit. D:
a. transported by chylomicron in non-esterified form to liver
b. is activated 1st by hydroxylation in the liver to form 25cholecalciferol (not the most active form)
c. 2nd hydroxylation occurs in the kidneys (1, 25dihydroxycholecalciferol = most active form)
3. vit. K
a. prothrombin production requires vit. K and CO2
b. active form produced in the liver
c. stored in liver and muscle
4. vit B12
a. 5 - 12 mg of vit B12 stored in the liver (50 - 90%)
b. enough to last 3-5 years
B. the liver is important in the storage and homeostasis of iron
1. presented in both heme and non-heme forms
a. heme - meats
b. non-heme forms - phytate in vegetables
2. transferrin - protein carrier of iron
3. ferritin
a. short-term storage of iron
b. easily released
c. stored in epithelial tissue
4. hemosiderin
a. long term storage of iron
b. not easily released
VII. Endocrine functions of the Liver
A. modification and amplification of hormone activity
1. vit. D
a. cholecalciferol (1st hydroxylation, 2nd occurs in kidney)
b. acts as a hormone
2. growth hormone = somatotropin
a. modified by insulin-like growth factors
b. somatomedins
3. thyroxine - modified by the liver
B. hormone degradation
1. insulin - liver is very sensitive to insulin
2. glucagon
3. growth hormone - half life of 20 minutes
4. gastrin