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