Upload
belinda-jenkins
View
236
Download
0
Tags:
Embed Size (px)
Citation preview
PATHOPHYSIOLOGY OF HEPATIC FAILURE
Assoc. Prof. J. Plevkova MD, PhD,
Anatomy and physiology
Basal anatomical unit: lobulushepatal cells organized into the hexagonal structure around the v. centralis
3 different fields (according the distance from the portal space
1. central field
2. middle positioned field
3. most peripheral field
Basal functional unit: acinusfield of hepatal cells organized around the portobilial space
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
bile canaliculus
mitochondria
SER
GER, lyzosomes
Main hepatal functions
Metabolic functions - carbohydrates- - glycogen storageglycogen storage
- glycogenolysis – release of glucose
- gluconeogenesis
- glucose up take
- lactic acid up take
- metabolizing of other sugar molecules
- pentózový cyklus NADPH
- r- regulation of blood glucose level (glucostatic function)
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
Main hepatic functions
Metabolism of hormones – effect on hepatic function, or degradation - insulin, glucagon, growth hormone, glucocorticoids, catecholamine, thyroxin, other steroid hormones
Metabolism of purins – uric acid
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 vitamins - - A,D, B12
Metabolism of water and minerals
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 functions
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 injuryChronic 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 insufficiency
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, cirrhosis5. 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 acidanoxidative metabolism of pyruvate acetoin, 2,3 butylenglykol
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
blood level of insulin and glucagon
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
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
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
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 liverinsulin estrogensglucagon progesteronegrowth hormone parathormonglucocorticosteroids 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 changeshypovitaminosis - A,D,E,K, folic acid,B1,B6anemiaintermittent fever /FUO/icterus
pruritus
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
Long lasting increase of blood pressure in v. portae , more than 5-15 mmHg
Pre hepatic portal hypertension
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- - aalcohol induced hepatopathy without cirrhosis- m- metastasis of tumors- - ccystic 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. AscitesPathogenetic 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 lymphConsequences
pressure inside the abdominal cavity
spontaneous bacterial peritonitis
increased position of diaphragm
decrease of vital capacity of lungs
ASCITES
↑ lymph production
↑ splanchnic capillary pressure and permeability
portal hypertension
splanchnic arteriolar VD
hypotension and underfiling of systemic circulation
sympathetic system
ADH
RAA
retention of Na a water
inadequate volume
compensation adequate volume compensation
portal hypertension
vasodilatation hypoalbuminaemia
ef. arterial volume
volumoreceptors/ baroreceptors
↑ symp. syst. ↑ADH ↑RAA sensitivity to ANF
retention of Na and water changes of renal
perfusion
edemasascites
5. Hypersplenism
- - enlargement of the spleen with peripheral cytopenia
- enlargement of red pulpa in the spleen
- - decrease of total Le and Plt count
The most common cause of death:
esophageal varixes bleeding
4. Increase of plasmatic volume
- volume overload for CVS
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.....
liver
NH3
glutamine urea
metabolism
GUT
GUT bleeding
food
endogenous sources
proteinsNH3bacteria
portal hypertension
- shunts
NH3
systemic circulation brainNH3
kidneys
merkaptan
fenol, FA
endotoxin
mercaptan, fenol, FA, endotoxin
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
a., pre hepatic
b., intra hepatic - problems with up take of Bi from plasma (Gilbert´s sy.)
un conjugated Bi plasma level
- 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
Classification
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
Abnormalities of the up takeAbnormalities 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 accumulationBoth 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
Hepatic type
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 daywater, 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 ratioIncreased 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 biled., 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 flowPain 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
6. Gallbladder cancer
5. Biliar pancreatitis – occlusion of papilla Vateri – increased pressure in pancreatic ductus – retrograde auto digestion
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 componentsdue 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