Transcript PANKREAS - Univerzita Karlova v Praze

Structure and function
of liver and gallbladder
Romana Šlamberová, M.D. Ph.D.
Department of Physiology, 3rd
Faculty of Medicine
Liver
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Largest organ in the body
Contributing about 1/50 of the total body weight (about 1.5 kg in
adults)
Basic functional unit of the liver is the liver lobule (0.8 -2 mm in
diameter; 50-100 thousands in the liver)
High blood flow - 1350 ml/min to liver sinusoids (1050 ml from
the portal vein, 300 ml from hepatic artery) = functional and
nutritive blood circulation
Physiologically – low vascular resistance (small difference
between pressures in the portal vein and hepatic vein) - in case
of pathological changes (steatosis or cirrhosis), the vascular
resistance increases, blood flow decreases (portal
hypertension, ascites)
Department of Physiology, 3rd
Faculty of Medicine
Function of the liver
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Liver is the largest gland in the body
1. Formation and secretion of bile
2. Detoxication of various substances
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Metabolic products of intestine microbes
Exogenous toxins (medicaments, alcohol, poisons)
Hormones (thyroxine, estrogen, cortisol, aldosterone)
3. Synthesis of plasma proteins
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Acute-phase proteins
Albumin
Clotting factors
Steroid-binding and other hormone-binding proteins
Department of Physiology, 3rd
Faculty of Medicine
Function of the liver (2)
4. Coagulation (synthesis of most of the coagulating factors).
Vitamin K is required for the formation of Factors II (prothrombin),
VII (proconvertin), IX (Christmas factor), X (Stuart factor).
5. Blood reservoir – filtration and storage of blood (450 ml =
almost 10 % of the body’s total blood volume). In cardiac failure it
can be stored there up to 1 l of blood.
6. Immunity (Kupffer cells = macrophages)
7. Vitamins - metabolism and storage of vitamins A, D and B12
8. Relation to blood formation
 storage of vitamin B12
 metabolism of iron and its storage as ferritin (hepatic cell
contains apoferritin and when excess of iron in the blood it forms
ferritin) = blood iron buffer
 participation on production of erythropoietin Department of Physiology, 3rd
Faculty of Medicine
Function
protein metabolism
 Deamination of amino acids
 Formation of urea for removal of ammonia from the
body fluids
 Formation of plasma proteins (90% of all plasma
proteins, up to 50 g of plasma proteins daily) – not
gamma globulins (cirrhosis = very low albumins =
ascites and edema)
 Interconversions of the various amino acids and
synthesis of other compound from amino acids
Department of Physiology, 3rd
Faculty of Medicine
Function
protein metabolism (2)
Protein metabolism disorder in hepatic diseases
 Ammonia detoxication disorder and failure of urea formation (ammonia
comes from bacterial degradation of nitrogen substances in intestines, from
intestine mucosa during glutamin degradation, from degradation of
aminoacids in kidneys and muscles )
 Hyperamonemia = increase of ammonia blood concentration (>50 μmol/l)
 Hepatic encephalopathy = toxic effect of ammonia in the brain (? Binding
of ammonia to glutamate = glutamine)
 Mental changes (capriciousness, disorientation, sleeping disorders,
chaotic speech, personality changes)
 Motoric changes (increased in muscle reactivity, hyperreflexion, tremor)
 Hepatic coma to death
 Endogenous = viral hepatitis and poisoning (hepatic cells desintegration)
 Exogenous = final status of chronic cirrhosis (ammonia and other toxic
substances bypass the liver through the extrahepatic anastomoses)
Department of Physiology, 3rd
Faculty of Medicine
Function
carbohydrate metabolism
Maintaining a normal blood glucose concentration
 Storage of glycogen (1-4 %) – removing excess of
glucose from blood, storage, fast return when the blood
concentration decreases = Glucose buffer function
 Conversion of galactose and fructose to glucose
 Gluconeogenesis
 Formation of many chemical compounds from
intermediate products of carbohydrate metabolism
 Pentose phosphate pathway is source of the NADPH
(reduction synthesis) and ribose (synthesis of
nucleotides)
Department of Physiology, 3rd
Faculty of Medicine
Function
carbohydrate metabolism (2)
Carbohydrate metabolism disorder in hepatic diseases
 Hyperglycemia in patients with cirrhosis after carbohydrate
rich meal (50% has glucose tolerance, 10% has hepatic
diabetes mellitus)
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Combination of pathological glucose tolerance test, hyperinsulinemia,
and increased insulin tolerance (liver insuficience  decrease of
glucose utilization  hyperglycemia  hyperinsulinemia  downregulation of insulin receptors  insulin rezistence)
Hypoglycemia in alcohol abusers – alcohol suppresses citrate
cycle and thereby impairs gluconeogenesis from aminoacids.
After depletion of glycogen storages comes hypoglycemia that
threatens the patient’s life.
Department of Physiology, 3rd
Faculty of Medicine
Function
fat metabolism
 Oxidation of fatty acids to supply energy for other body
function
 Synthesis of large quantities of cholesterol (80% of
cholesterol synthesized in the liver is converted
into bile salts), phospholipids, and most lipoproteins
 Inactivation of steroids and their excretion of the body
 Synthesis of fat from proteins and carbohydrates
Department of Physiology, 3rd
Faculty of Medicine
Function
fat metabolism (2)
Fat metabolism disorder in hepatic diseases
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Dyslipoproteinemia
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Hypertriacylglycerolemia - ↑ LDL – from decreased activity of hepatic lipase
↑ IDL (intermediate density lipoprotein) and ↓ HDL – from decreased production
of LCAT (lecitincholesterolacyltransferase) = transformation of VLDL to LDL =
cirrhosis
↓ cholesterol – decreased esterification of cholesterol when decreased activity of
LCAT
↑ cholesterol – decreased excretion of cholesterol in bile due to cholestasis or
increased synthesis due to decreased intestinal resorption of lipids = causes
steatosis of the liver
Hepatic steatosis – accumulation of TAG minimaly in ½ of the hepatocytes
(if less = steatosis of hepatic cells)
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Toxic substances including alcohol and medicaments
Nutrition (obesity, malnutrition, kwashiorkor)
Metabolic disorder (DM, hyperlipoproteinemia, pregnancyí)
Department of Physiology, 3rd
Inflammation of intestines
Faculty of Medicine
Amount of abused alcohol and its
level in the blood
Alcohol level in the
blood (‰)
Signs of
drunkenness
(%)
5 - 10
Driving a car
0.1 – 0.5
Amount of abused
alcohol in 80 kg person
(g)
5 – 25
0.6 – 1.5
30 – 75
30 – 70
potentially dangerous
1.6 – 3.0
80 – 150
70 – 95
dangerous
3.1 – 5.0
150 – 300
100 (heavy poisoning)
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5.1 – 7.0
300 - 450
Drunk up at once on an empty
stomach = 0,4 ‰ in blood
100 (mortal
poisoning)
usually safe
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Department of Physiology, 3rd
Faculty of Medicine
Acute intoxication with alcohol
Stage 1: Signs of drunkenness are not necessary evident
Basic symptom is euphoria.
Patient is talkative or in contrast silent more than usually
and has subjective feeling of increased mental activity.
Objectively = decreased reflex reactions and working performance
Stage 2: Selfcontrol disorders
Inattention and talking problems
Unsteady walking
Increased self-confident
Loss of emotions control
– increased aggressiveness
or tearfulness
Increased libido, decreased capability.
Decreased reflex reaction
Dangerous for car driving!
Department of Physiology, 3rd
Faculty of Medicine
Acute intoxication with alcohol (2)
Stage 3: High muzziness
 Unsteady walking or unable to walk
 Unclear talking
 Often nausea and vomiting
 Falling a sleep
Stage 4: Deep sleep followed by coma
 Cold skin
 Bradypnoa a tachycardia
 Coma
 Death due to failure of breeding and vasomotor centers.
Department of Physiology, 3rd
Faculty of Medicine
Bile
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secreted by cells of the liver into the bile duct, which drains into
the duodenum.
Between meals the duodenal orifice (m. sfincter Oddi) is closed
and bile flows into the gallbladder, where it is stored (50 – 80 ml).
The bile is concentrated in the gallbladder from 97% to 89% of
the water (osmotic gradient)
m. sfincter Oddi opens by food intake within 30 minutes, the
presence of aminoacids and fatty acids in duodenum activates
the cholecystokinin, which causes gallbladder contractions and
excretion of bile
production of 500-1000 ml of bile daily
pH = 7,1-7,3
Department of Physiology, 3rd
Faculty of Medicine
Composition of bile
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Water = 97 %
Bile salts (0.7%) = primary bile acids are transported to the bile
as sodium and potassium salts
 Cholic acid (converted by colon bacteria to Deoxycholic acid)
 Chenodeoxycholic acid (converted by colon bacteria to
Lithocholic acid)
Function:
 reduction of surface tension
 responsible for the emulsification of fat preparatory to its
digestion and absorption in small intestine
 tend to form micelles, because of their amphipathic character
(have both hydrophilic and hydrophobic domains)
Department of Physiology, 3rd
Faculty of Medicine
Composition of bile (2)
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Bile pigment (0,2%) = glucuronides bilirubin and
biliverdin (golden-yellow color of bile)
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Cholesterol (0,06%) – raises in patients with obstructive
icterus
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Inorganic salts (0,7%)
Fatty acids (0,15%)
Lecithin (0,1%) = the main phospholipide of bile
Fat (0,01%)
Alcaline phosphatase
Department of Physiology, 3rd
Faculty of Medicine
Enterohepatic circulation of bile
salts
Daily synthesis of bile salt to replaced the lost = 0.2 – 0.4 g/day
The total bile salt pool = 3.5 g
Recycling: the entire pool recycles 6-8 times / day (2 times / meal)
Micelles = cylindrical discs
formed by bile salt
Function: Keeping fat in
solution and transporting fat
to the brush boarder of the
intestinal epithelial cells,
where they are absorbed.
Hydrophilic surface and
hydrophobic interior with fat
inside (fat acids and
cholesterol).
Department of Physiology, 3rd
Faculty of Medicine
Enterohepatic circulation of bile
salts (2)
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90-95 % of the bile salt are
absorbed from the small intestine
some by nonionic diffusion, most
by Na+ - salt cotransport in the
terminal ileum).
5-10% of the bile salt enter the
colon and are converted to
deoxycholic acid (from Cholic
acid) or lithocholic acid (from
Chenodeoxycholic acid).
Deoxycholic acid is absorbed
back and transported back to
portal vein of the liver.
Lithocholic acid is insoluble and
is mostly excreted.
Department of Physiology, 3rd
Faculty of Medicine
Bilirubin – Metabolism & Excretion
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Formed in the tissues by the
breakdown of hemoglobin.
In the circulation bound to albumin.
In the liver bilirubin dissociates and
free bilirubin enters liver cells, where it
is bound to cytoplasmic proteins.
Bilirubin diglucuronide is more
water-soluble and is mostly transported
to the bile canaliculi and to the
intestines and changes to
Stercobilinogen and after oxidation to
Stercobilin. Only small amount
escapes into the blood and is excreted
by the urine as Urobilin (oxidized form
of Urobilinogen).
Department of Physiology, 3rd
Faculty of Medicine
Icterus (Jaundice)
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Detectable when the total plasma bilirubin > 2mg/dl (34
mol/l)
Reasons:
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excess production of bilirubin (hameolytic anemia)
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decreased uptake of bilirubin into hepatic cells
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disturbed intracellular protein binding or conjugation
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disturbed secretion of conjugated bilirubin into the bile
canaliculi
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intrahepatic or extrahepatic bile duct obstruction
Department of Physiology, 3rd
Faculty of Medicine
Icterus (2)
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Non-conjugated icterus (hemolytic) due to reasons
1-3 = the free bilirubin rises
Conjugated icterus (obstructive) due to reasons 4
or 5 = bilirubin glucuronide regurgitase into the blood
Differentiation
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van den Bergh reaction (rate conjugated/non-conjugated
bilirubin in the blood)
From urine (non-conjugated bilirubin is not present in urine,
conjugated bilirubin turns urine foam when shaking to
intense yellow)
Department of Physiology, 3rd
Faculty of Medicine