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 toin 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 - peracute / fulminant course of hepatitis, toxic injury Chronicfailure– 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“ providedhomeostasis

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 procoagulative 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) tachycardia, low systolic and diastolic pressure, skin vasodilatation, murmors Manifestation

Hepatopulmonary syndrome - arterial hypoxemia ,  saturation of Hb with oxygen - cyanosis, dyspnoe - digital clubbing intrapulmonal vasodilatation  intrapulmonal right to left shunts Mechanisms involved :

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 estrogens glucagon progesterone growth hormone parathormon glucocorticosteroids 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 - 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

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 periportal 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)

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

3. Ascites • portal hypertension • circulatory changes – vasodilatation and hyperkinetic circulation • hypoalbuminaemia • neurohumoral 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

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

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

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 brain systemic circulation 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

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 b., intra hepatic - problems with up take of Bi from plasma (Gilbert´s sy.) un conjugatedBi 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 bilestone, 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

PATHOPHYSIOLOGY OF HEPATIC FAILURE