physiology of liver as an inddispensible organ stating its many vital functions.

1. LIVER
Seat & Mirror Of The Soul
Dr. Misbah-ul-Qamar

2. Summarized Functions Of Liver
(1) Filtration and storage of blood
(2) Metabolism of carbohydrates, proteins,
fats, hormones, and foreign chemicals
(3) Formation of bile
(4) Storage of vitamins and iron
(5) Formation of coagulation factors.
Dr. Misbah-ul-Qamar

3. Physiologic anatomy of liver
• Largest organ in the body (1.5 kg= 3.3 pounds)
• It contributes 2% of total body weight in average
adult human
• Functional unit = liver lobule
• The human liver contains 50,000 to100,000
lobules.
Dr. Misbah-ul-Qamar

4. STRUCTURE OF LIVER LOBULE
• It is a cylindrical structure with
– Length= several millimeters
– Diameter= 0.8-2 millimeters
• It is constructed around a central vein
Dr. Misbah-ul-Qamar

5. Main components of a lobule
• Central vein
• Cellular plates
• Portal venules
• Hepatic sinusoids
• Hepatic arterioles
Dr. Misbah-ul-Qamar

6. Structure Of The Liver Lobule
1. Central Vein:
In the centre of lobule ( central vein  hepatic veins  vena cava )
2. Lobule is composed of Cellular Plates:
 Radiate from the central vein like spokes in a wheel.
 each plate is Usually two cells thick
 Between adjacent cells lie bile canaliculi that empty
into bile ducts
There are fibrous septa which separate adjacent liver lobules.
In the septa lie bile ducts, portal venules, hepatic arterioles &
lymphatic vessels
3. Portal Venules :
Receive their blood from portal vein (venous outflow of GIT)
From venules, blood flow into hepatic sinusoids
Dr. Misbah-ul-Qamar

7. Dr. Misbah-ul-Qamar

8. Lobule structure (cont’d)
5. Hepatic Sinusoids
 Lie between the hepatic plates
 Blood flows from portal venules and arterioles
to sinusoids then into the central vein
 That’s how hepatic cells are exposed
continuously to portal venous blood
Hepatic arterioles:
 Supply arterial blood to the septal tissues
between the adjacent lobules
 Many of arterioles drain directly into sinusoids
Dr. Misbah-ul-Qamar

9. Dr. Misbah-ul-Qamar

10. Venous sinusoids are lined by:
(1) Endothelial cells
(2) Kupffer cells (liver macrophages)
Significance of Kupffer cells
They are capable of phagocytizing bacteria & other foreign
matter in hepatic sinus blood
Dr. Misbah-ul-Qamar

11. Spaces of Disse
Also called peri-sinusoidal spaces
Narrow tissue spaces between endothelial
cells and the hepatic cells
Endothelial lining has extremely large pores
These spaces connect with lymph vessels in septum
Significance
Excess fluid in spaces is removed through lymphatics
Large substances (portions of plasma proteins) can
move freely into spaces through large pores of
endothelium
Dr. Misbah-ul-Qamar

12. Blood Flow Design Of Liver
Dr. Misbah-ul-Qamar

13. Dr. Misbah-ul-Qamar

14. Unique features of circulation
through liver
Dr. Misbah-ul-Qamar

15. Hepatic Vascular and Lymph Systems
Blood flows through liver from
portal vein and hepatic artery
• High blood flow
• Sinusoids receive 1350ml/min
(27% of CO)
• From portal vein=1050ml/min
• From hepatic artery=
300ml/min
The liver has high blood flow and
low vascular resistance
• Low vascular resistance
• Pressure in portal vein= 9mmHg
• Pressure in hepatic vein=0mmHg
• This small pressure difference
shows very low resistance to
blood flow through sinusoids
Dr. Misbah-ul-Qamar

16. Cirrhosis of the liver greatly increases
resistance to blood flow
• Cirrhosis :
• Destruction of parenchyma of liver and its
replacement with fibrous tissue
• Fibrous tissue contracts around the blood vessels,
and impedes blood flow thus increasing
resistance
• Cause : Alcoholism
Ingestion of poisons like carbon
tetrachloride
Viral diseases like hepatitis
Dr. Misbah-ul-Qamar

17. The Liver Has Very High Lymph Flow
• Half of the lymph formed in the body arises in the liver.
• Hepatic sinusoids are very permeable  passage of fluid and
proteins into the spaces of disse
• Protein concentration of lymph from liver= 6g/dl(slightly less
than that of plasma)
• Extreme permeability of the liver sinusoid epithelium allows
large quantities of lymph to form.
Dr. Misbah-ul-Qamar

18. In case of High hepatic vascular
pressure
• When pressure in hepatic vein rises (3-7mmHg
above normal:
– Excessive amount of fluid begin to transude into
lymph
– Fluid also leak into abdominal cavity through
outer surface of liver capsule
• Similarly blockage of portal flow causes portal
hypertension
Dr. Misbah-ul-Qamar

19. Portal hypertension
• Prolonged elevation of portal venous pressure
above normal
• Increased capillary pressure in intestinal wall-
loss of fluid from capillaries into wall and
lumen of the intestines
Dr. Misbah-ul-Qamar

20. Causes of portal hypertension:
1. Formation of clot (portal vein thrombosis)
2. Cirrhosis of liver
3. Veno-occulusive disease
4. Cystic liver disease
5. Sarcoidosis
6. drugs
Dr. Misbah-ul-Qamar

21. Ascites:
• Collection of free fluid in the peritoneal cavity
• Transudation of fluid into lymph and leakage
from surface of liver into abdominal cavity due
to high pressure in hepatic veins
Dr. Misbah-ul-Qamar

22. Liver regeneration & transplant
Dr. Misbah-ul-Qamar

23. Regulation of liver mass- Regeneration
Liver possesses a remarkable ability to restore itself
after significant hepatic tissue loss from either
partial hepatectomy or acute liver injury as long as
injury is uncomplicated by infection or
inflammation.
• During this process, hepatocytes replicate until
original size and volume has been restored
• Hepatocyte growth factor, produced by
mesenchymal cells, cause liver cell division
• Blood levels increase 20 fold after partial
hepatectomy
Dr. Misbah-ul-Qamar

24. • Other growth factors are also involved like;
1. Epidermal growth factor
2. Tumor necrosis factor
3. Interleukin-6
Dr. Misbah-ul-Qamar

25. Termination of regeneration:
Transforming growth factor -𝛽, a cytokine
released by hepatocytes-potent inhibitor of liver
cell proliferation.
Dr. Misbah-ul-Qamar

26. Role of Hepatic stellate cells in liver
regeneration
• These are liver specific resident mesenchymal
stem cells.
• they secrete growth factors promoting the
regeneration of hepatic epithelial cells.
Dr. Misbah-ul-Qamar

27. Transplant
• Only a small portion of donor’s liver is
transplanted which attains normal mass
through regeneration
Dr. Misbah-ul-Qamar

28. Functions of liver
Love your liver!
Dr. Misbah-ul-Qamar

29. Major 4 functions of liver
①Reservoir function
②Blood cleansing function
③Metabolic functions
④Bile formation & excretion
Dr. Misbah-ul-Qamar

30. RESERVOIR FUNCTION
Dr. Misbah-ul-Qamar

31. The Liver Functions as a Blood Reservoir
 Liver is a large expandable, venous organ capable of
acting as a blood reservoir blood is stored in its blood
vessels.
Supplies extra blood in times of diminished blood volume.
 Normal blood volume in liver = 450 milliliters( including
that in both hepatic veins & hepatic sinuses)
 Maximum blood volume which can be stored in liver =
0.5 to 1liter
Dr. Misbah-ul-Qamar

32. In which conditions blood storage
occurs in liver?
 Congestive cardiac failure
 When high pressure in rt. Atrium causes back pressure in
liver
 In times of excess blood/plasma volume
Dr. Misbah-ul-Qamar

33. BLOOD CLEANSING FUNCTION
Through hepatic macrophage system
Dr. Misbah-ul-Qamar

34. Why portal blood needs cleansing
• Blood flowing through intestinal capillaries
picks up many bacteria from intestines
• As indicated by the growth of colon bacilli in:
– Blood sample from portal vein before it enters
liver: occurs almost always when cultured
– Blood sample from systemic circulation:
extremely rare
Dr. Misbah-ul-Qamar

35. Hepatic Macrophage System consisting of
Kupffer cells
What are Kupffer cells:
• Large phagocytic macrophages that line the
hepatic venous sinuses
• Main Function: Cleanse blood of bacteria & endotoxins
from portal circulation as it passes through the sinuses
• Cellular debris, viruses, proteins & particulate matter in
blood are also phagocytosed
• Other functions performed by Kupffer cells:
– processing of antigens,
– release of various proteins, enzymes, cytokines and other
chemical mediators Dr. Misbah-ul-Qamar

36. Cleansing effectiveness of liver
• Kupffer cells perform their action at a high
speed only a momentary contact of 0.01
second with a bacterium transports it inward
through the wall of kupffer cell bacterium is
permanently lodged inside macrophage until
digested
• Less than 1% of the bacteria entering the
portal blood succeeds in passing through the
liver
Dr. Misbah-ul-Qamar

37. Endocrine function
Secretion of hormones
• Erythropoietin – 10% is secreted from liver
• Thrombopoietin- stimulates platelet
production
• Insulin like growth factor-I- stimulates growth
• Hepcidin- inhibits iron uptake from the
intestines
Dr. Misbah-ul-Qamar

38. Activating vitamin D in conjunction with kidneys
Dr. Misbah-ul-Qamar

39. Formation of blood cells:
• During intrauterine life.
• This function is lost at birth but liver retain the
potentiality of forming red blood cells
Dr. Misbah-ul-Qamar

40. Removal of worn out red blood cells by
reticuloendothelial cells in conjunction with
spleen and bone marrow
Dr. Misbah-ul-Qamar

41. Metabolic functions of liver
• Liver is a large, chemically reactant pool of
cells that have a high rate of metabolism
• Involved in metabolism of
1. Carbohydrate
2. Protein
3. Fats
Dr. Misbah-ul-Qamar

42. Protein
Metabolism
• 1. Deamination of amino acids
• 2. Formation of urea for removal of
ammonia.
• 3. Formation of all plasma proteins
except gama globulins
• 4. Inter-conversions of the various
amino acids and synthesis of other
compounds from amino acids
Most important
function of liver
Body cannot dispense
with liver for protein
metabolism for more
than a few days
without death ensuing
Dr. Misbah-ul-Qamar

43. De-amination
• It is required before protein is used for energy or
converted into carb or fat
– E.g,: deamination of alanine plays an important role in
hepatic gluconeogenesis
• Enzymatic processes convert amino acids to their
respective keto acids.
– Some deamination can occur in other tissues of body
(kidney) but mainly in liver
– Branched chain amino acids are primarily metabolized by
skeletal muscle
• Large amount of ammonia is also formed in
deamination
Dr. Misbah-ul-Qamar

44. Formation of urea
• Ammonia formed from deamination is highly
toxic to tissues
– (↑ ammonia due to liver disease = hepatic coma)
– Decreased blood flow through liver (shunting of
portal vein into vena cava) excessive ammonia
(extremely toxic condition)
• 2 molecules of ammonia+ CO2 = Urea
• Urea thus formed readily diffuses out of liver
& can be excreted by kidneys
Dr. Misbah-ul-Qamar

45. Formation of plasma proteins
• 90% of plasma proteins formed by liver:
– Albumin
– Alpha1-antitrypsin
– Proteases/elastases
– All coagulation factors (exception: factor VIII & Von Willebrand factor)
• Max. rate of plasma protein production by liver: 15-50g/day
– Even if half plasma proteins lost somehow, liver can replenish in 1-2
weeks
• Plasma protein depletion causes liver enlargement by rapid mitosis
of hepatic cells rapid output of PPs.
– Chronic liver disease (e.g., cirrhosis edema & ascites due to very low
albumin)
Dr. Misbah-ul-Qamar

46. Inter-conversion between AAs
This transamination allows formation of non-
essential AAs & compensate for any dietary
deficiency
Mechanism: transamination from available
amino acid to keto acid
• A keto acid is formed by liver (with required
chemical composition) an amino radical is
transferred to take place of keto oxygen
Dr. Misbah-ul-Qamar

47. Dr. Misbah-ul-Qamar

48. Role of liver in Carbohydrate
metabolism
1. Glycogen storage
2. Inter-conversion of carbs
3. Gluconeogenesis
4. Fomation of chemical compounds
Dr. Misbah-ul-Qamar

49. Glycogen storage
• 1. Storage of large amounts of glycogen: most
of glucose absorbed from meal is stored as
glycogen in liver
• When glycogen storage is exceeded, glucose is
stored as fat in liver or adipose tissue
• Only liver & muscle can store significant
amount of glycogen
Dr. Misbah-ul-Qamar

50. Glucose buffer action
• Glycogen storage function allows liver to
perform its glucose buffer action
– remove excess glucose from blood & thus
maintain normal blood glucose concentration
– Returns it when blood levels fall
Importance of liver’s buffer action:
• of In a person with poor liver function:
glucose level after carb rich meal may rise 2-3
times
Dr. Misbah-ul-Qamar

51. Inter-conversion of carbs
• 2. Conversion of galactose and fructose to
glucose
• Final products of carbohydrate metabolism
are glucose, fructose & galactose all cells
utilize glucose to produce energy in form of
ATP via glycolysis or citric acid cycle
Dr. Misbah-ul-Qamar

52. Gluconeogenesis
– amino acids & glycerol (from triglycerides) are
converted into glucose
– again to maintain blood glucose concentration
when glucose level falls below normal
– Glucocorticoids, catecholamines, glucagon &
thyroid hormone greatly enhance gluconeogenesis
by liver– whereas insulin inhibits it
Dr. Misbah-ul-Qamar

53. Carb metabolism (cont’d)
• 4. Formation of many chemical compounds
from intermediate products of carbohydrate
metabolism–liver & kidney are unique in their
capacity to form lactate, pyruvate, amino
acids & glycerol.
• Note: liver can also utilize the phospho-
gluconate pathway which not only provides
energy but also produces an important
cofactor in synthesis of fatty acids.
Dr. Misbah-ul-Qamar

54. Dr. Misbah-ul-Qamar

55. Fat Metabolism
• Although most cells of the body metabolize fat, certain
aspects of fat metabolism occur mainly in liver
• 1. Oxidation of fatty acids to supply energy for body functions
• 2. Synthesis of large quantities of cholesterol, phospholipids,
and most lipoproteins
• 3. Synthesis of fat from proteins and carbohydrates
Dr. Misbah-ul-Qamar

56. How energy is extracted from fats
• Neutral fat is first split into glycerol & fatty
acids
• Then fatty acids are split by beta oxidation
into two-carbon acetyl radicals that form
acetyl coenzyme A
• acetyl-CoA can enter the citric acid cycle & be
oxidized to liberate energy
Note: Beta-oxidation can take place in all cells of
body but it occurs especially rapidly in hepatic cells
Dr. Misbah-ul-Qamar

57. Liver’s role in energy provision to
other tissues
• Liver itself cannot use all all the acetyl-CoA
that is formed it is transported throughout
body in a highly soluble form( acetoacetic
acid)
– Acetoacetic acid condensation of 2 molecules of
acetyl CoA
• In tissues it is reconverted to acetyl CoA & is
oxidized for energy
Dr. Misbah-ul-Qamar

58. Anabolic role of liver in fat metabolism
• 80% of cholesterol synthesized in liver is
converted into bile salts
• Remainder of cholesterol & phospholipids are
transported in lipoproteins to tissue cells
where they form:
– Cell membranes
– Intracellular structures
– Multiple chemical substances for cellular function
Dr. Misbah-ul-Qamar

59. Anabolic role of liver in fat metabolism
• When carb stores are saturated, liver converts
excess ingested carb into fat
• Almost all the fat synthesis in body from carb
& proteins occur in liver
• Fatty acids thus formed can be used
immediately or are transported in lipoprotein
to adipose tissue
Dr. Misbah-ul-Qamar

60. RBCs & renal medulla can utilize
only glucose
Neurons normally utilize only
glucose but after a few days of
starvation, they can switch to
breakdown products of fatty acids
made by liver
Dr. Misbah-ul-Qamar

61. Dr. Misbah-ul-Qamar

62. Other Metabolic Functions
of the Liver
1.The liver is a storage site for vitamins.
2.The liver stores iron as ferritin.
3.The liver forms a large proportion of the blood substances used in
coagulation.
eg: fibrinogen, prothrombin, Factor VII,
• Vit K dependant : prothrombin ,Factors VII, IX, and X
4.The liver removes or excretes drugs, hormones, and other
substances.
Dr. Misbah-ul-Qamar

63. Storage of vitamins
• Vitamins stored in greatest quantity in liver is
vitamin A
• Large quantities of vitamin D and B12 also
stored in liver
Dr. Misbah-ul-Qamar

64. Storage of iron as ferritin
• Greatest proportion of body’s extra iron is
stored in hepatic cells
• Apoferritin protein in hepatocytes can
combine reversibly with iron
• Liver is also important blood iron buffer as
ferritin releases the iron when body fluids’
iron levels are low
Dr. Misbah-ul-Qamar

65. Formation of blood substances used in
coagulation
Makes most of the pro-coagulants with exception of
factor III, IV, VIII
Fibrinogen, prothrombin, accelerator globulin, factor VII
For the formation of these substances, liver requires
vitamin K
In its absence coagulation may be prevented by
decreased concentration of these substances
Liver also makes protein regulators of coagulation &
fibrinolytic pathways.
Such regulators include: protein C, Plasminogen
activator inhibitor, antithrombin III.
Dr. Misbah-ul-Qamar

66. Coagulopathy in liver disease
• Most common coagulation disturbances
occurring in liver disease include
thrombocytopenia & impaired humoral
coagulation.
• The INR is used to measure blood clotting
time. A high INR usually means that liver is not
working optimally.
Dr. Misbah-ul-Qamar

67. Removal and excretion of drugs,
hormones and minerals
Liver provides an active chemical medium to detoxify drugs
into bile such as
Sulfonamides
Penicillin
Ampicillin
Erythromycin
Thyroxine & steroid hormones (estrogen, cortisol,
aldosterone) are either altered or excreted by liver
Normal thyroid function is dependent on hepatic formation of
more active T3 from T4
Also a major site of degradation for insulin, glucagon & ADH
Excretion of body calcium also depend on liver through bile.
Dr. Misbah-ul-Qamar

68. other important proteins produced by
liver
• Transport proteins: transferrin, haptoglobin,
ceruloplasmin
• Complement proteins: C-reactive protein,
serum amyloid-A, alpha1-acid glycoprotein
Dr. Misbah-ul-Qamar

69. Excretion of bilirubin
• It is a greenish yellow pigment which is an end
product of Hb degradation
• Measurement of bilirubin provides valuable
tool for diagnosing blood & liver diseases
Dr. Misbah-ul-Qamar

70. Dr. Misbah-ul-Qamar

71. 600-1000ml/day
BILE
Dr. Misbah-ul-Qamar

72. Composition Of Bile
• Water
• Inorganic salts : Na+ , K+, Ca++, Cl-, HCO3
• Bile salts: Sodium tauro-cholate , Sodium glyco-
cholate
• Pigments: Bilirubin and Biliverdin
• Lipids: Cholesterol, Lecithin and traces of fatty acid
Dr. Misbah-ul-Qamar

73. 4 major functions of bile
• Fatty acid metabolism
• Excretion of waste products
• Kill off bad microbes
• Blood sugar metabolism (through role of BAs
as signalling molecules in glucose metabolism)
Dr. Misbah-ul-Qamar

74. Basic functions of bile
1. Plays main role in fat digestion & absorption
because of bile salts
2. It serves as a mean for excretion of waste products
(bilirubin & excess cholesterol) from blood
Dr. Misbah-ul-Qamar

75. Other functions
• Alkalinity of bile help in neutralizing acidity of
chyme
• Excretion of bile pigments, heavy metals,
toxins, cholesterol, and lecithin.
Dr. Misbah-ul-Qamar

76. Functions of bile due to bile salts
• Bile salts emulsify fat globules-help in digestion
• Absorption of fats
• Bile salts stimulate secretion of bile from liver-
choleretic action
• Cholagogue action-increase release of bile from gall
bladder by stimulating the secretion of cholecystokinin
• Bile salts act as laxatives by causing CCK release
(enhancing motility)
Dr. Misbah-ul-Qamar

77. Overview of biliary transport
Dr. Misbah-ul-Qamar

78. Secretion of bile
• Secreted by hepatocytes
• Contains large quantities of bile acids, bile
pigments, cholesterol, lecithin and fatty acids
• Bile from the hepatocytes is secreted into
biliary canaliculi
Dr. Misbah-ul-Qamar

79. Formation And Conduction Of Bile
Formed by hepatic cells
Bile canaliculi
Terminal bile duct
Hepatic duct
Common bile duct(CBD)
Duodenum Gall Bladder through
cystic duct
Dr. Misbah-ul-Qamar

80. Dr. Misbah-ul-Qamar

81. Dr. Misbah-ul-Qamar

82. Physiologic anatomy of biliary
secretion
• Bile is secreted in 2 stages
• Secretion of initial bileparenchymal
secretion
• Addition of 2nd secretion (ductal secretion)
Dr. Misbah-ul-Qamar

83. Stages of bile secretion
• Initial bile is secreted from hepatocytes into
bile canaliculi which flows toward bile ducts,
finally reaching into duodenum or gallbladder
• In its course through bile ducts, 2nd portion of
liver secretion is added to initial.
Dr. Misbah-ul-Qamar

84. Stages of bile secretion
• Initial bile:
– It contains large amounts of bile acids, cholesterol
& other organic constituents
• Additional secretion:
– This additional secretion is watery solution of
sodium & bicarbonate, stimulated by secretin
– It can increase total quantity of bile as much as
100%
Dr. Misbah-ul-Qamar

85. Role of secretin in controlling bile
secretion
• Secretin may increase bile secretion,
sometimes doubling it after a meal
• This increase consists of rich watery solution
of sodium bicarbonate by epithelial cells of
bile ductules
• This bicarbonate helps in neutralizing the HCl
from stomach
Dr. Misbah-ul-Qamar

86. Storage of bile
• Bile is secreted continually by liver cells
• It is stored in gallbladder until needed in
duodenum
• Gallbladder can hold 30-60ml,
• bile is concentrated 5-fold (upto 20-fold)
• GB is not a passive reservoir of bile, it absorbs,
secretes & alters constituents of bile.
Dr. Misbah-ul-Qamar

87. How the bile is concentrated in
GB?
Dr. Misbah-ul-Qamar

88. Concentration of bile in gallbladder
• water, sodium, chloride & other electrolytes
(HCO3) are absorbed from gallbladder mucosa
• Absorption is caused by active transport of
sodium through epithelium
• This transport is followed by secondary
absorption of chloride, water & others
• bile is concentrated which contains bile salts,
cholesterol, lecithin & bilirubin
Dr. Misbah-ul-Qamar

89. Dr. Misbah-ul-Qamar

90. Liver secretion of cholesterol
• Bile salts are formed in hepatic cells from
cholesterol in blood plasma
• In the process of secreting bile salts
– 1-2 grams of cholesterol are removed from blood
plasma
– It is secreted into the bile each day
• Amount of cholesterol in bile is determined by
quantity of fat that the person eats
Dr. Misbah-ul-Qamar

91. Dr. Misbah-ul-Qamar

92. Formation of gallstones
• Cholesterol is insoluble in pure water
• Bile salts & lecithin in bile combine with cholesterol &
form a colloidal solution in gallbladder
• Under abnormal conditions
– when there is excessive absorption of water (active sodium
transport & passive water absorption from chronically
inflammed GB mucosa) & bile salts from gallbladder
epithelium,
– cholesterol is left behind which begins to precipitate
– First small crystals of cholesterol are formed which
progress to gallstones
Dr. Misbah-ul-Qamar

93. Gallstones
• These could have calcium nature also which
normally is prevented by acidifying GB bile
through secretion of hydrogen ion from GB
mucosa.
Dr. Misbah-ul-Qamar

94. Dr. Misbah-ul-Qamar

95. Functions of Gallbladder
1. Storage of bile
2. Mucosal absorption
3. Concentration of bile constituents
4. Maintenance of pressure in biliary system
5. Secretion of mucin
6. Alteration of bile pH
Dr. Misbah-ul-Qamar

96. Functions of Gallbladder
• Storage of bile: because bile is continuously formed &
released by hepatocytes but not continuously utilized.
• Released from GB intermittently when required
• Mucosal absorption: Absorbs H2O, Na+, Cl- and other
electrolytes from bile
• Bile concentration: Concentrates bile salts, cholesterol,
lecithin and bilirubin in bile
Dr. Misbah-ul-Qamar

97. Functions of gallbladder (cont’d)
• Maintenance of pressure in biliary system:
due to the concentrating capacity, gallbladder
maintains pressure (7cmH2O) in biliary system.
• This pressure is essential for release of bile
into intestine
Dr. Misbah-ul-Qamar

98. Functions of gallbladder (cont’d)
• Secretion of mucin: mucin is added to bile
when bile is released into intestine.
• Mucin acts as lubricant for movement of
chyme in intestine
Dr. Misbah-ul-Qamar

99. Functions of gallbladder (cont’d)
• Alteration of bile pH: pH of bile is decreased
from 8-8.6 to 7-7.6. it becomes less alkaline
when it is stored in gallbladder
Dr. Misbah-ul-Qamar

100. Dr. Misbah-ul-Qamar

101. Emptying of gallbladder requires
• Contraction of GB
• Relaxation of sphincter of Oddi
Dr. Misbah-ul-Qamar

102. Emptying of Gallbladder
1. Contraction of GB
Causes:
 Cholecystokinin
 Vagal stimulation (weak effect)
2. Relaxation of sphincter of Oddi
Causes:
 Cholecystokinin
 Neurogenic (vagus)
 Receptive relaxation during peristalsis
Dr. Misbah-ul-Qamar

103. Dr. Misbah-ul-Qamar

104. Dr. Misbah-ul-Qamar

105. Bile salts
Dr. Misbah-ul-Qamar

106. Bile salts
• Liver cells synthesize about 6gm of bile salts
daily
• Precursor of bile salts: cholesterol
• Sources of cholesterol
– Diet
– Synthesized in liver cells during course of fat
metabolism
Dr. Misbah-ul-Qamar

107. Formation of bile salts
Cholesterol formation of bile acids ( end
products of cholesterol catabolism)
conjugation of bile acidsformation of bile salts
Dr. Misbah-ul-Qamar

108. Formation of bile salts
Cholesterol is first converted into Bile acids:
• Cholic acid in about equal quantities
• Chenodeoxycholic acid
• These acids combine with glycine & taurine to
form conjugated bile acids
• Salts of these acids are then secreted in bile
Sodium glycholate
Sodium taurocholate
Dr. Misbah-ul-Qamar

109. FUNCTIONS Of Bile Salts
1. Emulsification of fats:
2. Micelles formation:
Dr. Misbah-ul-Qamar

110. Emulsification of fats
Bile salts and agitation by GIT breaks fat globules
to smaller size
This emulsification is also called detergent
function of bile salts
– Detergent action decreases the surface tension of
particles
– It allows agitation in intestinal tract to break fat
globules into minute sizes
Dr. Misbah-ul-Qamar

111. Micelles formation
Micelles are small physical complexes of lipid
molecules that arrange themselves in a
spherical form in aquous solutions.
Micelles have amphipathic nature (contain both
hydrophilic & hydrophobic regions)
Bile salts form micelles of fatty acids,
monoglycerides, cholesterols & other lipids
Dr. Misbah-ul-Qamar

112. Micelle formation (cont’d)
It is even more important function of bile salts than
emulsification
The micelles are semi-soluble in chyme due to
electrical charges of bile salts
This is how bile salts carry micelles to intestinal
mucosa for absorption
Without bile salts, 40% of ingested fats are lost in
feces
Dr. Misbah-ul-Qamar

113. Applied physiology: use of orlistat
• The drug binds to lipases in gut & blocks their
action
• Reduced micelle formation due to orlistat
induced blockage of triglycerides digestion
Dr. Misbah-ul-Qamar

114. Recycling of bile salts
Role of enterohepatic circulation
Dr. Misbah-ul-Qamar

115. Dr. Misbah-ul-Qamar

116. ENTEROHEPATIC CIRCULATION
94% of bile salts are absorbed from gut into portal blood
Passed to liver, absorbed by hepatocytes through sinusoids
Again excreted into bile
Again reabsorbed
Dr. Misbah-ul-Qamar

117. Reabsorption Of Bile Salts From Gut
• On average bile salts make an entire circuit 17
times before being excreted in feces
Sites for reabsorption:
• The bile salts which are reabsorbed from gut
– One half are absorbed by diffusion through
mucosa in early portion of small intestine
– Remainder is absorbed by active transport process
through mucosa of distal ileum
Dr. Misbah-ul-Qamar

118. Importance of enterohepatic
circulation
• Quantity of bile secreted each day is highly
dependent on availability of bile salts
• Greater the quantity of bile salts in
enterohepatic circulation greater the rate of
bile secretion
Dr. Misbah-ul-Qamar

119. Amount of bile salts
• Usually total amount of bile salts in circulation
is 2.5 grams
• 1.1g/dl bile salts secretion from liver.
Dr. Misbah-ul-Qamar

120. Dr. Misbah-ul-Qamar

121. • Many waste substances are excreted in the
bile and eliminated in the feces. One of these
is the greenish yellow pigment Bilirubin.
• BILIRUBIN:
• Major end product of hemoglobin
degradation
• Helps in diagnosing hemolytic blood diseases
and various types of liver diseases
Dr. Misbah-ul-Qamar

122. Origin & fate of bilirubin
RBCs rupture after 120 days
Released hemoglobin is phagocytized by tissue
macrophages
Split into globin and heme
Heme ring is opened to give
(1) Free iron (2) Protoporphyrin IX
(Stored as ferritin) (Converted to bilirubin)
Dr. Misbah-ul-Qamar

123. Dr. Misbah-ul-Qamar

124. • Initially biliverdin, is formed but immediately reduced to bilirubin
• Released from the macrophages into the plasma.
• Binds to Albumin in plasma
• Absorbed through hepatic cells
• Conjugated with glucuronic acid to form bilirubin glucuronide,
• Excreted from the hepatocytes into intestine through bile canaliculi and
then into the intestines.
• Converted to urobilinogen by action of bacteria
• Urobilin in urine Stercobilin in fecesDr. Misbah-ul-Qamar

125. Dr. Misbah-ul-Qamar

126. Dr. Misbah-ul-Qamar

127. Don’t wait for jaundice to appear!
Beware of bilirubinuria.
Dr. Misbah-ul-Qamar

128. Bilirubin & its relation to jaundice
Dr. Misbah-ul-Qamar

129. It is jaundice, nigga!
• Yellowish tint to the
body tissues
Dr. Misbah-ul-Qamar

130. Jaundice—Excess Bilirubin in the
ECF
• Large quantities of bilirubin in the extracellular fluids,
• Free Bilirubin Or Conjugated Bilirubin.
• Normal plasma concentration = 0.5 mg/dl
• Detectable clinically when plasma bilirubin exceeds 1.5mg/dl
• Can rise to = 40 mg/dl
Dr. Misbah-ul-Qamar

131. What Could Be The Causes Of
Jaundice
• Excessive hemolysis
• Obstruction to bile outflow from liver
Dr. Misbah-ul-Qamar

132. • Causes of jaundice
(1) Hemolytic Jaundice
• Increased destruction of red blood cells, with rapid
release of bilirubin into the blood.
• Excess bilirubin is beyond the conjugating ability of
liver so the excess bilirubin is in UNCONJUGATED form
(2) Obstructive Jaundice
• Obstruction of the bile ducts due to stones or damage
to the liver cells due to cancer
• The bilurubin is normally conjugated but can not be
excreted into the intestine due to obstruction.
• The bilirubin formed is CONJUGATED
Dr. Misbah-ul-Qamar

133. Mechanisms producing jaundice:
• Increased production of bilirubin
• Impaired excretion of bilirubin
Dr. Misbah-ul-Qamar

134. Types of jaundice:
1. Hemolytic jaundice prehepatic
2. Hepatocellular jaundice hepatic
3. Cholestatic jaundice post hepatic
Dr. Misbah-ul-Qamar

135. Dr. Misbah-ul-Qamar

136. Hemolytic jaundice
• Also known as prehepatic jaundice
• Increased destruction of red blood cells or
their precursors in bone marrow
• Anemia, malaria, neonatal jaundice,
transfusion reactions and autoimmune
diseases
• Previously known as achluric jaundice (no bile
pigments in urine & excessive unconjugated
bilirubin in circulating blood)
Dr. Misbah-ul-Qamar

137. Hemolytic jaundice (cont’d)
Clinical features:
• Pallor of skin
• Splenomegaly
• Normal or dark colored stools
• Urine is dark colored-increased urobilin
Dr. Misbah-ul-Qamar

138. Hemolytic jaundice (cont’d)
Investigations:
• Plasma bilirubin level
high (< 6mg/dl)
– Hyperbilirubinaemia is of
unconjugated type
• Urobilinogen is
increased in urine
• No bilirubinurea
• Liver function tests are
otherwise normal
Dr. Misbah-ul-Qamar

139. Hepatocellular jaundice
• Results from inability of liver to transport
bilirubin into bile as a consequence of
parenchymal liver disease
– Congenital diseases like gilbert’s syndrome,
crigler- najjar, dubin- johnson syndrome and rotor
syndrome
– Acquired: Acute or chronic liver parenchymal
disease
Dr. Misbah-ul-Qamar

140. Hepatocellular jaundice
• Both conjugated and unconjugated bilirubin is
increased in plasma
• Other clinical features and investigations vary
with the underlying disease
Dr. Misbah-ul-Qamar

141. Cholestatic jaundice
• Occurs as a result of obstruction of bile flow
• Stones in bile ducts, carcinoma of head of
pancreas, ampullary carcinoma,
cholangiocarcinoma, biliary strictures, drugs,
alcohol, sclerosing cholangitis
Dr. Misbah-ul-Qamar

142. Cholestatic jaundice
• Jaundice
• dark urine
• pale stools (clay colored stools due to
deficiency of bile salts)
• Steatorrhea and weight loss
• Hyperbilirubinaemia of conjugated type
• Liver function tests are abnormal
Dr. Misbah-ul-Qamar

143. Dr. Misbah-ul-Qamar
Purple intensified on
alcohol addition

144. Van den Bergh reaction
It is a specific test for identification of increased
serum bilirubin levels.
Normal serum gives a negative Van Den Bergh
reaction.
Dr. Misbah-ul-Qamar

145. Van den Bergh reaction (cont’d)
Principle: diazotitised sulfanilic acid reacts with
bilirubin to form a purple coloured azobilirubin.
Reagent used: Diazo reagent (mixture of sulphanilic
acid, hydrochloric acid & sodium nitrite)
Test- 2 types
Direct (measures conjugated bilirubin) produce purple
color immediately
Indirect (measures total bilirubin) gives purple color
only on addition of alcohol
Dr. Misbah-ul-Qamar

146. Let’s get wasted?
• What does binge
drinking do to your liver
(ALD)?
• Causes acute or chronic
inflammation of liver
Dr. Misbah-ul-Qamar

147. Liver cirrhosis
• It is a late stage of scarring (fibrosis) of the
liver caused by many forms of liver diseases &
conditions, such as hepatitis & chronic
alcoholism.
• 1st sign of cirrhosis: Jaundice
• Survival rate of cirrhosis: at 5 years, it vary
from 0-80%
Dr. Misbah-ul-Qamar

148. LFTs
Dr. Misbah-ul-Qamar

149. At a glance
• Bilirubin
• AST (10-40units/L) & ALT (7-56units/L),
AST/ALT ratio is increased in disease.
• Total proteins (60-80g/L) & A/G ratio (normal:
slightly higher than one)
Dr. Misbah-ul-Qamar

150. Summary of LFTs
Dr. Misbah-ul-Qamar

151. LFTs: Bilirubin
1.Determination of total, unconjugated and
conjugated bilirubin in serum
Total serum bilirubin: 0.3-1.0mg/dL
Conjugated bilirubin: 0.1-0.3mg/dL
Unconjugated bilirubin: 0.2-0.7mg/dL
Dr. Misbah-ul-Qamar

152. 2.Urine bilirubin:
• presence of bilirubin in urine always indicates
a disease
• Seen in hepatic and post hepatic jaundice
Dr. Misbah-ul-Qamar

153. Estimation of urobilinogen
– Urobilin in urine
– Urobilinogen in feces
• Urobilinogen is colorless, urobilin has yellow
pigment.
Dr. Misbah-ul-Qamar

154. 3.Fecal urobilinogen:
• 100-250mg of urobilinogen is excreted in feces
• Increased in hemolytic jaundice
• Decreased in hepatic and post hepatic
jaundice
Dr. Misbah-ul-Qamar

155. 4.Urinary urobilin:
• Normally 0.5-4mg/day is excreted in urine
• Increased excretion in hemolytic conditions
• Decreased excretion in biliary obstruction
Dr. Misbah-ul-Qamar

156. • Serum transaminases:
1. AST-SGOT
2. ALT-SGPT
• Increased in hepatitis
Dr. Misbah-ul-Qamar

157. Serum alkaline phosphatase:
• Level is increased in extrahepatic and
intrahepatic biliary obstruction
• It is an early sign of cholestatic liver damage
caused by drugs
• High values also occur in osteoblastic diseases
of bones e.g. rickets
Dr. Misbah-ul-Qamar

158. Plasma proteins level
• Serum albumin level decreases in liver disease
• Decreased albumin/globulin ratio
Tests of coagulation
• Prothrombin time is prolonged
Dr. Misbah-ul-Qamar

159. Cholesterol (free and esterified) levels of serum
help in assessing liver function
• Increased in complete obstruction of bile duct
Dr. Misbah-ul-Qamar

160. Indicator of glycogenic function of liver
Intravenous galactose tolerance test:
• It determines the rate of utilization of
galactose by liver.
• In liver damage, galactose is metabolized at a
slower rate.
• 0.5 gram of galactose is given by intravenous
injection. Normally it disappears in 75minutes.
Dr. Misbah-ul-Qamar

161. Epinephrine tolerance test
• Response of liver glycogen to adrenaline for
assessment of metabolic function of liver
• Epinephrine markedly stimulates glycogen
breakdown to glucose in liver increase in
blood glucose levels
Dr. Misbah-ul-Qamar

162. Tumor
• Plasma alpha fetoprotein:
increased in primary hepatoma
Dr. Misbah-ul-Qamar

163. Other investigations
• Viral markers(HbSAg, anti HCV)
• Ultrsonography, CT scan and MRI,
• Liver biopsy
Dr. Misbah-ul-Qamar

164. Clinical manifestations of severe liver
disease
• Asthenia (loss of strength)
• Jaundice
• Fetor hepaticus
• Hamorrhages
• Portal hypertension
• Ascites
• Hepatic encephalopathy
Dr. Misbah-ul-Qamar

165. Symptoms of end-stage liver disease
• Easy bleeding or bruising
• Persistent or recurring yellowing of skin &
eyes
• Intense itching
• Loss of appetite & nausea
• Swelling due to fluid buildup in abdomen &
legs
Dr. Misbah-ul-Qamar

166. Wilson’s disease/ hepatolenticular
degeneration
Rare genetic disorder
• Excess copper is stored in
various body tissues,
particularly the liver, brain
& corneas of eyes
• Symptoms don’t appear
until copper builds up in
heavy amountJaundice,
personality changes
(anxiety, psychosis, speech
& coordination problems)
Kayser-Fleischer ring
Dr. Misbah-ul-Qamar

167. ALF
Dr. Misbah-ul-Qamar

168. Acute liver failure (ALF)
• It ia a rare syndrome defined by rapid decline
in hepatic function.
Dr. Misbah-ul-Qamar

169. ALF
• Cause: ALF might be
caused by toxicity of
drugs, viral infection,
vascular problem
(shock) etc.
• Features: Characterized
by jaundice,
coagulopathy (INR>1.5),
& hepatic
encephalopathy in
patients with no
evidence of prior liver
disease.
Dr. Misbah-ul-Qamar

170. Dr. Misbah-ul-Qamar

171. Liver repair
• Liver has a unique & extraordinary capacity for
repair through regeneration, even in adult
organisms, though not overnight nor for
eternity.
• It can restore upto 70% of lost mass &
function after just a few weeks.
Dr. Misbah-ul-Qamar

172. Mechanism for Liver repair (cont’d)
• In a healthy adult liver, cells are dormant &
rarely undergo cell division.
• However if liver is damaged, the liver cells re-
enter the cell cycle to divide & produce more
of themselves.
• Damaged liver cells undergo reprogramming
to repair & restore themselves through a
signal to return to an early stage of postnatal
organ development.
Dr. Misbah-ul-Qamar