PATHOPHYSIOLOGY OF HEPATIC FAILURE

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PATHOPHYSIOLOGY OF HEPATIC FAILURE

• Assoc. Prof. J. Plevkova MD, PhD,

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Anatomy and physiology
Basal anatomical unit lobulus
hepatal cells organized into the hexagonal
structure around the v. centralis

Basal functional unit acinus
field of hepatal cells organized around the
portobilial space
3 different fields (according the distance from
the portal space
1. central field
2. middle positioned field
3. most peripheral field
different functions, different oxygen supply,
substrate supply, heterogeneous sensitivity to
noxas
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Hepatal cell

• Vascular surface orientation to sinusoidal
  vessel, surface is willows forming microvili,
  active processes of reabsorbtion, up take of
  oxygen and nutrients from the GUT leaving blood
• Bile surface two cells are forming bile
  canaliculus, specific properties of the cell
  membrane, increased activity of excretion
  processes, increased energy demands

vascular surface
mitochondria SER GER, lyzosomes
bile canaliculus
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Main hepatal functions
Metabolic functions - carbohydrates
- glycogen storage - glycogenolysis release of
glucose - gluconeogenesis - glucose up take -
lactic acid up take - metabolizing of other sugar
molecules - pentózový cyklus ? NADPH
- regulation of blood glucose level
(glucostatic function)
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Main hepatic functions
Metabolism of fat
- production of TAG - production of VLDL -
cholesterol synthesis - FFA synthesis and
degradation - ketogenesis
Metabolism of proteins
- degradation of AA - production of urea -
synthesis of plasmatic proteins
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Metabolism of steroids synthesis of bile acids
from cholesterol, their conjugation and
elimination into the bile, their action is
detergent, bile acid have enterohepatal
circulation
Metabolism of hormones effect on hepatic
function, or degradation - insulin,
glucagon, growth hormone, glucocorticoids,
catecholamine, thyroxin, other steroid hormones
Metabolism of vitamins - A,D, B12
Metabolism of purins uric acid
Metabolism of water and minerals
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Hepatic functions

• Hemopoesis restricted to in utero fetal
  development,
• in pathological situations extramedullar
  haemopoesis could be activated
• hematological malignant tumors affecting bone
  medulla, in normal conditions liver plays
  indirect role in this process storage of vit
  B12 and iron

• Detoxication both endogenous and exogenous
  substances are bio -transformed in the liver
  cells
• Biotransformation involves several phases
• inactivation of the former active molecule by
  chemical reactions
• conjugation with glycin, taurin, glucuronic acid
  conversion into soluble molecules
• final elimination by urine or bile excretion

Thermoregulatory function
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Hepatic insufficiency

• Process characterized by restriction, suppression
  or failure of hepatic function which is
  manifested by homeostatic imbalance in the
  functions provided by the liver cells.
• Manifestation of the failure is present when the
  hepatic cells are required to provide more
  metabolic work. In basal conditions The failure
  could not be necessarily manifested.
• Acute failure - per acute / fulminant course of
  hepatitis, toxic injury
• Chronic failure cirrhosis
• Exogenous failure - induced or provoked by
  external noxas, like alcohol, GUT bleeding,
  drugs, increased protein in take
• Endogenous failure as a natural consequence of
  internal hepatic disease /consequence of
  hepatitis, biliar cirrhosis... /

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Hepatic failure
Symptoms and signs resulting from the liver
functions lack are present and manifested in
basal conditions
Partial hepatic insufficiency
Only one function, or some of the functions are
impaired, but definitely not all of the
functions secured by the liver cells
Total hepatic insufficiency
All hepatic functions are impaired, the cells are
not able enough to provide liver provided
homeostasis
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Noxas affecting hepatic cells
1. infectious viruses, bacteria, parasites
2. toxic - direct hepatotoxic effect
- in direct hepatotoxic effect -
amanita phaloides toxin phaloidin -
tetrachlormetan, org. solutions - aflatoxin -
paracetamol /high dose/, antibiotics,
chemoterapeutics, cytostatic drugs,
contraceptive pills, anesthetics etc.
3. immune processes anaphylactic shock, PBC,
lupoid hepatitis
4. hypoxia obstruction of a. hepatica, right
heart failure
5. chronic inflammations, tumors, cirrhosis
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1. Impairment of metabolic functions
A., Carbohydrates metabolism

• damage of enzymes ( severe, mostly acute insuf.)
  ? hypoglycaemia
• -in severe hepatic insuf.
• impairment of gluconeogenesis ?
• ?
  blood glucose and lack of glucose in CNS
• - chronic hepatic insuf. - hyperglycaemia and
  insuline resistance

advanced hepatic insuf.
? pyruvate blood level, lactic acid blood level,
? - ketoglutaric acid ?anoxidative metabolism of
pyruvate ? ?acetoin, ?
2,3 butylenglykol
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? blood level of insulin and glucagon
a., ? relese of these hormones from the pancreas
possible mechanisms involved - activation of
Kupfer cells by systemic toxemia - Kupfer cells
produce endogenous mediators stimulating both
insulin and glucagon release
b., ? up take of insulin and glucagon by insuf.
liver cells
possible mechanism involved - inability of
damaged cells to increase expression of receptor
molecule - by passing of the blood between the
portal and systemic circulation
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B., Fat metabolism

• - ? FFA blood level
• ? metabolic pathways of FFA in liver ? ?
  synthesis of composed
• lipid molecules
• - ? synthesis of short chain FFA
• - ? synthesis of prebeta- and alfa- lipoproteins

C., Protein metabolism
In acute phase ? synthesis of proteins
enzymes, inflammatory factors, markers
In severe or long lasting course of insuf. ?
synthesis - ? concentration of plasma proteins
(except immunoglobulins)
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Changes of the plasma protein spectrum
? concentration of albumins ? concentration of
fibrinogen (leter) ? concentration of alfa1,
alfa2, beta-globulins ? concentration of
cerulopasmin, specific transport proteins ?
concentration of immunoglobulin ? activity of
specific enzymes (UDP -GT? ? concentration of
pro coagulative factors II.,V.,VII.,IX.,X. ?
concentration hepatic enzymes indicators
Foetor hepaticus
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4. Homeostasis disturbances, water and minerals
imbalance

• Mechanisms hypoalbuminemia, changes in the
  circulation,
• activation of RAA system
• - opsiuria
• retention of fluids and Na in the body volume
  overload for CVS
• increase of ADH secretion hyponatraemia due
  to dilution of ECC
• hypokalaemia (muscles weakness, hypo motility
  of the GUT, dysrhythmias)
• metabolic alkalosis in ECC, but acidosis in ICC
• worse ionization of ammonium to NH4 , more
  molecules persist in neutral form - better
  penetration through the membranes (CNS?

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5. Cirkulatory changes
- hyperkinetic circulation ? CO ( ? rate, ?
stroke volume) ? peripheral vascular resistance
in splanchnic circulation, other regional
circulations may suffer from vasoconstriction
/muscles, kidneys/ ? plasma volume /RAA
Mechanisms involved
-? level of vasodilating substances in systemic
circulation, mosly NO -? level of
vasoconstrictive mediators (ANF,endothelin,seroto
nin)
tachycardia, low systolic and diastolic pressure,
skin vasodilatation, murmors
Manifestation
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Hepatopulmonary syndrome
- arterial hypoxemia , ? saturation of Hb with
oxygen - cyanosis, dyspnoe - digital clubbing
intrapulmonal vasodilatation ?
intrapulmonal right to left shunts
Mechanisms involved
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Hepatorenal syndrome

• - functional acute renal failure which is
  present in patients suffering from severe hepatic
  diseases followed by ascites and by changes in
  systemic circulation
• increased stimulation of RAA - impairment of
  renal regional circulation
• decrease of glomerular filtration
• extreme retention of Na and fluids in the body
• decreased water elimination
• Clinical course of renal failure copy the
  clinical course of hepatic failure, if liver is
  being better the kidneys are better too, a vice
  versa

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Hormonal system
? breakdown of cortisol in the liver cells ?
concentration of aldosteron, cause it's break
down is decreased Frequently manifested
disorder ? concentration of estrogens (in men)
gynecomastia, body hair loss, testicular
atrophy, inpotention, spider naevi ?
concentration of androgens (in women)
virilisation, menstruation
irregularity Hormones primarily breaking down in
liver
insulin
estrogens glucagon progesterone growth
hormone parathormon glucocorticosteroids
some of GUT hormones
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Mechanisms of hormonal inbalance

• - impairment of hormone metabolism in insuf.
  liver
• - ?? secretion of hormone in endocrine organs
• - abnormal regulation of hormonal pathways
• ? release of the hormone or it's inactivation in
  liver or other tissues
• - production of abnormal molecules with hormone
  like properties
• - impaired answer of target tissue
• abnormalities induced by changes in the type of
  diet, or nutrients,
• or induced by drugs

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Other symptoms and signs of hepatic failure
psychic or mental changes hypovitaminosis -
A,D,E,K, folic acid,B1,B6 anemia intermittent
fever /FUO/ icterus pruritus
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Portal hypertension
Long lasting increase of blood pressure in v.
portae , more than 5-15 mmHg Pre hepatic
portal hypertension
- obliteration of v. porte, v. lienalis
(infection, trauma, thrombosis, tumor invasion)
Causes
- development of collateral circulation
Consequences
- enlargement of the spleen
- esophageal varixes
- ascites, but it is rare
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Hepatic portal hypertension
- cirrhosis of the liver (alcohol, biliar
cirrhosis, hemo- chromatosis, Wilson's
disease) - myeloproliferat. diseases (liver and
spleen) - m. Hodgkin, leukemia (infiltration of
peri portal fields) - sarcoidosis pathogenesis
unknown - alcohol induced hepatopathy without
cirrhosis - metastasis of tumors - cystic
diseased of the liver
Causes
Post hepatic portal hypertension
- block of hepatic veins or VCI (Budd - Chiari
sy.)
- extra hepatic causes (constrictive
pericarditis, severe heart failure)
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Consequences of portal hypertension
1. Collateral circulation
- esophageal submucosal veins (esofag. varixes)
- rectal submucosal veins (haemorrhoids)
- veins of parietal peritoneum - caput medusae
- anastomosis between hepatic capsulla and
diaphragm
- anastomosis between v. renalis sin. and v.
lienalis
- decrease of hypertension in portal
circulation - diagnostic tool
Význam
2. Increase of lymphatic flow in the liver
- lymph contains small admixture of blood
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3. Ascites

• portal hypertension
• circulatory changes vasodilatation and
  hyperkinetic circulation
• hypoalbuminaemia
• neuro humoral changes
• decrease of renal perfusion
• retention of Na and water
• overproduction of hepatic lymph

Pathogenetic factors
Consequences
pressure inside the abdominal cavity spontaneous
bacterial peritonitis increased position of
diaphragm decrease of vital capacity of lungs
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portal hypertension
splanchnic arteriolar
VD
hypotension and underfiling of systemic
circulation sympathetic system ADH RAA retention
of Na a water
? splanchnic capillary pressure and permeability
? lymph production
inadequate volume compensation
adequate volume compensation
ASCITES
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vasodilatation
hypoalbuminaemia
? ef. arterial volume
volumoreceptors/ baroreceptors
? symp. syst. ?ADH ?RAA ?
sensitivity to ANF
retention of Na and water changes of renal
perfusion
portal hypertension
edemas
ascites
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4. Increase of plasmatic volume - volume overload
for CVS
5. Hypersplenism
- enlargement of red pulpa in the spleen
- enlargement of the spleen with peripheral
cytopenia
- decrease of total Le and Plt count
The most common cause of death
esophageal varixes bleeding
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Hepatic - portosystemic encephalopathy
impairment of CNS functions caused by advanced
hepatic failure and opening of porto-systemic
shunts

• Causes and mechanisms of encephalopathy
• increased ammonium level
• toxic substances of intestinal origin /
  mercaptan, fenol, FA/
• increased permeability of hematoencephalic
  barrier
• impairment of neurotransmission including false
  neurotransmitters
• changes of metabolic energy producing pathways
  in the brain
• endotoxins, cytokines, nitric oxide
• Factors enhancing encephalopathy
• GUT bleeding, increased protein in take,
  alcalosis, renal failure, some drugs effects.....

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NH3
systemic circulation
brain
mercaptan, fenol, FA, endotoxin
liver NH3 glutamine urea
NH3
metabolism
kidneys
portal hypertension - shunts
GUT bleeding food endogenous sources
merkaptan fenol, FA endotoxin
NH3
proteins
bacteria
GUT
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Manifestation of porto-systemic encephalopathy

• Neuro- psychiatric signs and symptoms
• in adequate moods euphoria or aggression
• disorders of sleep inversion
• motoric changes gentle movements dysgraphia,
  dysartria
• abnormal coordination tremor during movements
• flapping tremor
• uunconsciousness, coma

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Icterus metabolism of bilirubin

• yellow color of skin, eyes, mucosa due to
  increased level of bilirubin
• typical in situations characterized by
  imbalance between production, metabolism and
  elimination of bilirubin
• normal value Bi lt 17 ?mol/l
• three times increased blood Bi level Bi is
  transported from the blood into the tissues,
  predominantly into the tissues with high amount
  of elastic fibers,
• classification according the pathogenetic
  mechanism

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Increased production pre hepatic type
metabolic changes inside the liver cells intra
hepatic type - up - take - conjugation -
transport onto the bile surface of cells
disorders of excretion into the GUT post
hepatic type
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Classification
a., pre hepatic b., intra hepatic -
problems with up take of Bi from plasma

(Gilberts sy.)
? un conjugated Bi plasma level
- defect in conjugation of Bi (neonatal icterus,
Crigler Najjars sy.)
- defect in excretion of Bi ( Dubin Johnsons
sy. Rotors sy.)

• hepatic injury caused by (virus, alcohol, drugs,
  congestion,
• sepsis, toxins) all three steps in the Bi
  pathway could be damaged

c., post hepatic extrahepatal bile tubular
system is blocked by
bile stone, tumor, cholangitis, pancreatitis
? mostly conjugated Bi
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Pre hepatic type - haemolytic

• amount of plasma Bi exceed capabilities of liver
  cells to up take and conjugate Bi
• Causes of Increased Bi plasma level
• enhanced hemolysis congenital or acquired HA,
  post transfusion reaction
• reabsorption of large hematomas, after trauma or
  major surgery, vessel catheterization, aneurysm
  disrupture
• Un effective hemopoesis shunt Bi -
  magaloblastic anemia due to lack of intrinsic
  factor, folic acid or B12
• Laboratory
• ? unconjugated Bi plasma level
• liver is metabolizing increased amount of Bi
  changes of the stools and bile color
  pleiochromic bile and hypercholic stools
• urobilinogen arising from the GUT penetrates
  into the blood enterohepatic circulation
  overloaded hepatocytes are not able to pick up
  this molecule therefore urobilinogen is present
  in the urine

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Hepatic type hepatocellular injury

• There are at least three important processes of
  bilirubin metabolism
• up take from the blood on the blood surface and
  transport into the ER and microsomes (protein Y
  - ligandin)
• conjugation with glucuronic acid (UDP
  glucuronyl transferase in microsomes)
• Excretion of conjugated bilirubin through the
  membrane on the bile surface into the bile
  capillary
• Therefore the classification sometimes involved
  pre microsomal, microsomal and postmicrosomal
  forms of icterus

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Hepatic type

• Abnormalities of the up take
• Gilberts syndrome functional impairment of the
  transport of inorganic ions in hepatocyte, a
  number of metabolic consequences, but
  hyperbilirubinemia is the most obvious sign
• AD disease, hepatic laboratory screening is
  normal, also histological structure of liver is
  normal
• Bi is slightly elevated, the patient is not
  always yellow, but definitely at specific
  situations intercurrent infections, processes
  linked with increased metabolic work requirement
  a lot of physical exercise, infection, drugs,
  alcohol, starvation
• categorized into the group of benign
  hyperbilirubinemias

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Hepatic type

• Abnormalities of conjugation process absolute
  or relative insuf. of UDP GT,
• Icterus of the newborns - elimination of fetal
  Hb, conjugative system is completely ready just
  in the end of the 10. L.M. , hematoencephalic
  barrier is immature
• Physiologic icterus - about 50 of term kids
  rapid onset in the 2. 3. day, rapidly
  disappears due to accelerate development of the
  conjugative system
• Icterus of pre term kids immaturity of
  conjugative system at the premature birth, rapid
  onset, but is more persistent than previous one
  type, risk of penetration of Bi free fraction
  into the CNS /critical level is 300 ?mol/l -
  bilirubin encephalopathy
• transient block of UDP GT breastfeed kids,
  block of UDP GT by 3, 20 pregnandiol from the
  maternal milk
• Crigler Najars syndrome two forms AD, AR,
  abnormalities of the structure of UDP GT caused
  by genetic mutation fo the UDP GT gene severe
  metabolic changes

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Hepatic type

• Abnormalities of Bi excretion into the bile
  capillary
• Dubin Johnsons sy. genetic disorder of Bi
  excretion, excretion of other substances into the
  bile capillary is not affected, pigment is
  therefore accumulated inside the hepatocytes
• Rotors sy. similar disorder but without
  pigment accumulation
• Both these syndromes are categorized as the
  benign hyperbilirubinemias, usually are
  accidental findings in lab blood tests, there is
  only hyperbilirubinemia, patient is not yellow,
  other hepatocyte functions are not affected,
  prognosis is OK,
• Intrahepatic cholestasis failure of bile
  secretion
• Lab depends on whether Bi is conjugated or not
• increased level of conjugated Bi by pass from
  the bile surface by reflux into the blood
  capillary surface
• If the underlying condition of icterus is
  abnormal conjugation, therefore unconjugated Bi
  is increased
• conjugated Bi is present in urine
• UBG in urine
• hepatocyte damage is linked with ALT, AST
  elevation
• damage of the bile surface is linked with GMT,
  ALP elevation

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Posthepatic type

• Partial or total block of extra hepatic bile
  ducts dct. hepaticus communis, dct. choledochus
• Intraluminal obstruction the most common type
  of intraluminal obstruction are bile stones
  transported from the gallbladder during the bile
  colic into the extra hepatic ducts, where it is
  trapped
• Extra luminal obstruction pancreatic tumors,
  compressions, post inflammatory of after surgery
  strictures /fibrosis/
• Total obstruction is characterized by generalized
  jaundice, skin scratching or prorates and shift
  of coagulation/bleeding balance into the bleeding
  side due to K vat. lack
• Laboratory
• increased level of conjugated Bi, bile acids,
  cholesterol, ALP, GMT,
• urobilinogen is not present in urine
• stolica without pigment acholic, increased
  amount of lipid particles in the excrements -
  steatorrhea

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• Patophysiology of bile secretion
• 600 800 ml of bile per day
• water, bile acids, cholesterol, phospholipids,
  bilirubin, minerals, other steroid molecules
• the ratio of each composition is responsible fro
  the fluidity of the bile
• Bile is essential for fat digestion, therefore
  absorption of fatty particles and molecules
  soluble in fat (vitamins, D,E K,A?
• ? production of bile salts, secreting, vague
  nerve
• ? emptying of gallbladder CCK, fat in food

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Cholelithiasis bile stones

• bile stones are crystalic structures originated
  from the bile due to condensation or vrstvy of
  bile components
• Composition of bile stones
• 75 cholesterol stones ( F?,
  M? )
• 25 pigment stones
  (unconjugated bilirubin)
• Cholesterol in bile
• is present in micelle form cholesterol bile
  salts phosphatidylcholin (lecithin)
• maintenance of micelle form
• due to balance in cholesterol/bile salts
  lecithin ratio
• Increased concentration of cholesterol in the
  bile leads to super saturation of the micelle
  solution ? micelle vesicles

These micelle vesicles are precursors for
crystallization of the cholesterol stones
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Shifting of the CH/ (BS L)

1. Increased secretion of cholesterol into the
bile a., ?synthesis of
CH (? activity of HMG CoA reductasis)
b., ? (inhibition) of
esterification process of CH
(in ex. progesteron in
pregnancy inhibits
acetyl CoA - cholesterol
transferasis)
c., obesity, ? intake in nutrients, sudden weight
loss
2. Decreased secretion of bile salts into the
bile
a., decrease of total amount of BS stores
(Crohn disease, resection of the intestine ?? BA
loss, decreased EH circulation of BA and
BS) b., long time stasis - sequestration of BS in
gallbladder (no food intake for longer
time, no food period for one night is not enough
dangerous, it does not lead to
sequestration? parenteral feeding - ?
enterohepatal circulation of BS)
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• 2. - secretion of cholesterolu is higher than
  secretion of bile salts
• ? ? ratio CH/ BS L
• This ratio is increaseing also due to increased
  estrogene concentration, estrogenes activate 12 ?
  - hydrogenasis ?? production of cholesterol ??
  ratio of cholic acid/ chenodeoxycholic acid
• more cholesterol than bile salts is present in
  the bile

3. Decreased concentration of lecithin
vegetable only diet
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Pigment bilirubin stones Composition
calcium salt of bilirubin molecule
? black stones calcium bilirubinate
calcium
carbonate calcium phosphate
? brown stones
calcium bilirubinate stearate
palmitate
cholesterol
Mechanism involved ?
concentration of unconjugated bilirubin
gallblader dysfunction a., ?
release of Hb from RBC - haemolytic anemias
b., ? conjugation
process in liver hepatic cirrhosis

• c., nonenzymatic deconjugation of Bi in bile
• d., enzymatic deconjugation of Bi in bile (? -
  glucosidasis)
• due to bacteria (in brown stones causes)
• bacteria ? enzymatic deconjugation of BS
  ??micelle form ?
• precipitation and crystallization of
  cholesterol)
• black stones causes - a,b,c i
• decrease capability of gallbladder
  for acidification of bile

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Contribution of gallblader dysfunction
a., disorders of gallbladder emptying
- deficiency of (CCK) -
nonselective increased tonus of the vagus nerve
- pregnancy

• consequence
• bile is stored in the gallbladder for longer
  time? precipitation of
• crystals forming up of concrements big
  stones
• if bile is stored for a longer time there ?
  stimulation of PGL
• ?? mucus production ? formation of the
  nuclei for
• 
  crystallization

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Consequences and symptoms of bile stones
1. Colic - /spasmodic pain, contractions of
smooth muscles/specific type of visceral pain due
to block of extra hepatic bile ducts / dct.
cysticus, dct. choledochus/ with bile stone
? pressure in the duct in front
of obstruction ?? peristaltic
contractions to restore normal bile flow Pain is
localized in the epigastrium, near the RRA,
irradiation into the back, symptoms of vagus
nerve stimulation, nausea, vomiting, Murphy
2. Fever bile stones acute cholecystitis
3. Bacterial cholangoitis stagnation of the
bile inside the intrahepatic ducts
- ? pressure in intrahepatic ducts ?
dilatation of the ducts
4. Icterus of post hepatic type occlusion of
dct. choledochus or papilla Vateri
5. Biliar pancreatitis occlusion of papilla
Vateri increased pressure in
pancreatic ductus retrograde
auto digestion
6. Gallbladder cancer
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Cholelestasis block of bile flow
Causes a., intrahepatic - cystic fibrosis,
granulomatosis,
drug side effects (allopurinol,

sulfonamids), increased concentration of
estrogens
(pregnacy, contrac. pills? b.,
extrahepatic due to occlusion of extrahepatic
bile ducts

• Consequences
• ? fluidity of cell membrane in bile ducts
• (?content of cholesterol, effect of bile
  salts)
• villous surface of the cells is reduced or
  damaged
• impairment of structure ? impairment of duct
  mobility

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Manifestation of cholestasis
due to retention of bile components

• bilirubin ? icterus
• cholesterol ? deposition of cholesterol into the
  skin, tendons, membranes of liver and kidney
  cells, or RBC
• bile salts ? pruritus, skin scratching,
  bradycardia bile acids have digitalis like
  effect onto the sinus node
• malabsorbtion, def. of vit D, E K, A , fatty
  stools due to bile absence in the GUT

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