Download Pathophysiology of hepatic failure

PATHOPHYSIOLOGY OF
HEPATIC FAILURE
Assoc. Prof. J. Plevkova MD, PhD,
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
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
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)
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
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
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
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... /
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
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
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
 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
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)
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
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
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,serotonin)
Manifestation
tachycardia, low systolic and diastolic pressure,
skin vasodilatation, murmors
Hepatopulmonary syndrome
- arterial hypoxemia ,  saturation of Hb with oxygen
- cyanosis, dyspnoe
- digital clubbing
Mechanisms involved : intrapulmonal vasodilatation

intrapulmonal right to left shunts
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
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
glucagon
growth hormone
glucocorticosteroids
estrogens
progesterone
parathormon
some of GUT hormones
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
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
Portal hypertension
Long lasting increase of blood pressure in v. portae , more than 5-15 mmHg
Pre hepatic portal hypertension
Causes:
- obliteration of v. porte, v. lienalis (infection, trauma,
thrombosis, tumor invasion)
Consequences: - development of collateral circulation
-
enlargement of the spleen
- esophageal varixes
- ascites, but it is rare
Hepatic portal hypertension
Causes: - 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
Post hepatic portal hypertension
- block of hepatic veins or VCI (Budd - Chiari sy.)
- extra hepatic causes (constrictive pericarditis, severe heart failure)
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
Význam:
-
decrease of hypertension in portal circulation
- diagnostic tool
2. Increase of lymphatic flow in the liver
- lymph contains small admixture of blood
3. Ascites
Pathogenetic factors:
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
Consequences
pressure inside the abdominal cavity
spontaneous bacterial peritonitis
increased position of diaphragm
decrease of vital capacity of lungs
portal hypertension
splanchnic
arteriolar VD
↑ splanchnic capillary
pressure and
permeability
hypotension and
underfiling of systemic
circulation
sympathetic system
ADH
RAA
↑ lymph production
ASCITES
retention of Na a water
inadequate volume
compensation
adequate volume
compensation
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
ascites
edemas
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
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.....
NH3
systemic circulation
brain
mercaptan, fenol, FA, endotoxin
liver
NH3
metabolism
NH3
glutamine
urea
kidneys
portal hypertension
- shunts
GUT bleeding
merkaptan
fenol, FA
NH3
proteins
bacteria
endotoxin
GUT
food
endogenous sources
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




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 < 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
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
Classification
a., pre hepatic
 un conjugated Bi plasma level
b., intra hepatic -
problems with up take of Bi from plasma
(Gilbert´s sy.)
- defect in conjugation of Bi (neonatal icterus,
Crigler – Najjar´s sy.)
- defect in excretion of Bi ( Dubin – Johnson´s sy.
Rotor´s 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
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
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
Hepatic type
Abnormalities of the up take
Gilbert´s 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
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 – Najar´s syndrome – two forms AD, AR, abnormalities of the structure of
UDP – GT caused by genetic mutation fo the UDP GT gene – severe
metabolic changes
Hepatic type
Abnormalities of Bi excretion into the bile capillary
Dubin – Johnson´s sy. – genetic disorder of Bi excretion, excretion of other
substances into the bile capillary is not affected, pigment is therefore accumulated
inside the hepatocytes

Rotor´s 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
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
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
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
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)
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
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
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
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
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
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