肝性脑病英文课件

1、Hepatic FailureTao Wang, PH.D., Associated professorPathophysiology departmentAnhui Medical University2 Introduction and Conception Etiology Hepatic insufficiency Hepatic failure Hepatic encephalopathy (focal point) Hepatorenal syndromeHepatic Failure3PART I Introduction and ConceptionLiverThe large

2、st and most metabolically complex organ1. The liver42. The liver anatomyThe liver is divided into 2 main lobes, each consisting of many lobules.These lobules are surrounded by branches of the hepatic artery, which supplies the liver with oxygenated blood.The portal vein supplies nutrient-rich blood.

3、 Deoxygenated blood from the liver drains into the hepatic veins. A network of ducts carries bile from the liver to the gallbladder and the small intestine53. The functions of the liver Substance metabolism immune function Hemostasis regulation production and secretion of bile Bio-transformation (de

4、toxification) 64. Hepatic insufficiencySevere damage in liver cells will result in serious condition, manifesting as jaundice, bleeding, infection, renal dysfunction or encephalopathy, termed all together these syndromes of hepatic insufficiency.Acute Hepatic insufficiency Chronic Hepatic insufficie

5、ncy 75. Hepatic failureTerminal stage of hepatic insufficiencyHepatic encephalopathy (focal point)Hepatorenal syndromePrimary clinical manifestations8PART II Etiology1. Biological2. Physical and chemical 3. Inherited conditions 4. Immune 5. Nutritional causesHepatitis virus (such as HBV), bacteria,

6、parasites, etc.Industrial toxins, some drugs, alcohol, etc.Idiopathic hemochromatosis, Wilsons disease, etc.Extent of inflammation and necrosis 9PART III Hepatic insufficiencyLiverVarious etiology causeshepatocytesNon-parenchymalcellsdamagedamage Kupffer cells, hepatic satellite cells, lipocytes, li

7、ver associated lymphocytes, hepatic sinusoid endothelial cellsHepatic insufficiency10Syndromes of Hepatic insufficiency1. Metabolic disorders2. Water and electrolytes imbalance3. Disorders in production of bile salts and elimination of bilirubin4. Impaired kupffer cells functionCarbohydrate Metaboli

8、c DisordersLipid Metabolic DisordersProtein Metabolic DisordersHepatic AscitesElectrolytic Metabolic Disorders111. Metabolic disorders1) Carbohydrate Metabolic DisordersCarbohydrate Metabolism of liverTo maintain concentrations of glucose in blood within a narrow, normal range. insulinA hormone prod

9、uced by the pancreas that regulates glucose levels in the blood. It is normally produced in response to raised glucose levels following a meal and promotes glucose absorption into the liver and muscle cells (where it is converted into energy).Excess glucose entering the blood after a meal is rapidly

10、 taken up by the liver and sequestered as the large polymer, glycogenglycogenesis12glyconeogenesisglycogenolysiswhen blood concentrations of glucose begin to decline, the liver activates other pathways which lead to depolymerization of glycogenWhen hepatic glycogen reserves become exhaused, as occur

11、s when an animal has not eaten for several hours, the hepatocytes , recognize the problem and activate additional groups of enzymes that begin synthesizing glucose out of such things as amino acids and non-hexose carbohydrates. 13Severe liver diseaseHypoglycemiaHyperglycemiaCaused by a decrease in f

12、unctional hepatocyte mass.When glucogen reserves are depleted:gluconeogenensis impared; inactivation of insulin weakenCaused by portal-to-systemic shuntingDecrease the postprandial extraction of glucose from protal bloodSome patients may suffer abnormal glucose tolerance141. Metabolic disorders2) Li

13、pid Metabolic DisordersLiver is the center of lipid metabolismManufacturing 80% of the cholesterolSynthesizing, storing and exporting triglyceridesAssembling, secreting and taking up lipoprotein particle, such as VLDL, LDL, and HDL.Severe liver diseaseDisturbance of lipid metabolismSyndromes of fat

14、accumulation(fatty liver)In certain chronic liver diseasePrimary biliary cirrhosisDestruction of bile ductsBile flow decreaseDecrease lipid clearance via bilehyperlipidemiaThese patients often develop xanthomas accumulation of cholesterol 161. Metabolic disorders3) Protein Metabolic DisordersThe liv

15、er manufactures and secretes many of the protein found in plasmaalbuminSome clotting factorsSome binding proteinsSome hormone precursorsTo maintain plasma oncotic pressureTo regulate hemostasisSteroid and thyroid hormone-binding protein to regulate metabolismangiotensinogen to regulate blood pressur

16、eInsulin like growth factor-1 to regulate growth17Other roles of the liver in protein metabolismProcesses of oxidative deamination and transaminationThe urea cycle allows nitrogen to be excreted in the form of ureaSevere liver diseaseDisturbance of protein metabolismDecreased conversion of ammonia t

17、o ureaPlasma proteins decreaseElevated ammonia levelalbuminClotting factorsHepatic encephalopathyEdema and ascitesBleeding tendancy192. Water and electrolytes imbalance1) Hepatic AscitesAscties is the presence of the excess fluid in the peritoneal cavityIt is a late-staged manifestation of the liver

18、 disease.20Mechanisms of Hepatic Ascites1) An increase in capillary pressureCauses: portal hypertension; obstruction of venous and lymph flow 2) Decrease in colloidal osmotic pressureCause: impaired synthesis of albumin3) Salt and water retention by the kidneyCause: effective blood volume is reduced

19、 because of fluid shift and vasodilation glomerular filtration rate (GFR) rennin-angiotension-aldosterone system (+) metabolism of aldosterone portal-to-systemic shunting vasodilatory products are dilvered to the systemic circulation 212. Water and electrolytes imbalance2) Electrolytic Metabolic Dis

20、orders1) Hypokalemia2) Hyponatremia223. Disorders in production of bile salts and Elimination of bilirubinSevere liver diseaseA failure to secrete bileA Failure to solubilize substancesMalabsorption and deficiency statesDecreased elimination of bilirubinElevation of serum bilirubin and jaundiceJaund

21、ice: Yellowing of the skin and the whites of the eyes, caused by an accumulation of bilirubin in the blood.234. Impaired kupffer cells functionKupffer cells function1) Removing and phagocytizing old and defective blood cells, bacteria, etc.2) Producing a variety of bioactive substances and cytokines

22、, such as IL-1, IL-6 etc.24dysfunction of Kupffer cellsLoss of clearance function to bacteriaPortal-systemic shuntingEnteric toxins enter the systemic circulationEnteric endotoxemia25BriefSymptoms of hepatic failureWater and electrolytesimbalanceHypo or hyper-glycemiaHyperlipidemia and xanthomasPlas

23、ma proteins decrease edema, bleedingMetabolic disordersHepatic AscitesHypokalemia and HyponatremiaDisorders in production of bile saltsand Elimination of bilirubinMalabsorption and deficiency statesElevation of serum bilirubin and jaundiceImpaired kupffer cells functionEnteric endotoxemia26Hepatic e

24、ncephalopathy (HE) is a primary clinical manifestation of hepatic failure.PART IV Hepatic encephalopathynIntroduction and ConceptionnEtiology and classification nPathogenesis nPrecipitating factors of HEnPrinciples of treatment271. Introduction and ConceptionConception of hepatic encephalopathyHE is

25、 a complex, potentially reversible disturbance in central nervous system that occurs as a consequence of severe liver diseases.Four stages of hepatic encephalopathy1. Slightly altered mood or behaviour2. Somnipathy and inappropriate behaviors 3. Drowsy and psychopathy4. Deep coma282. Etiology and cl

26、assification Etiology Chronic liver diseasesFulminant hepatic failure (FHF)Viral infectionDrug reaction Poisoning with carbon tetrachloride or phosphorusCirrhosis of any origin29Classification Endogenous HE Have no apparent precipitating factors Often caused by extensive liver cell destruction Exoge

27、nous HE Precipitated by some known agents or abnormalities such as: gastrointestinal bleeding ingestion many proteins Often caused by portal-systemic shuntsAccording to origin30According to clinical characteristicnAcute or subacute encephalopathynAcute or subacute recurrent encephalopathynChronic re

28、current encephalopathynChronic permanent encephalopathy313. Pathogenesis Ammonia Intoxication False Neurotransmitters Amino Acid imbalance The Gamma-Aminobutyric Acid hypothesisSeveral hypotheses32 Ammonia IntoxicationBasis1.Healthy dogCreating a portal-systemic shuntingFed by meatcomatose2. 80% pat

29、ients with HEBlood ammonia levels3. Cirrhosis patients ingestion of a large amounts of proteinHepatic coma4. HE patients with cirrhosisTherapies to reduceammonia absorptionAmeliorations of HE33Cause for elevated ammoniaIn normal conditionsUreaAmmoniaKidneyAmmoniaProteins, aminesUrea, purinesAmmonia

30、is mainly produced in gastrointestinal tractAmmonia is detoxified in liver by conversion to urea through Krebs-Henseleit urea cycle.34In Hepatic failureKrebs-Henseleit urea cycle function is impairedBlood ammonia level increased (endogenous)OrnithineCitrullineargininearginase NH3NH3Urea In hepatic f

31、ailure： substrates enzyme ATPPortal-systemic shunting also reduces the urea production (exogenous)35Ammonia production increased Blood ammonia level increased1) Production of ammonia in intestine lumen increased2) Production of ammonia in kidney increasedProtein, urea, purinedegradedEnzyme of bacter

32、iaammoniaglutamineglutaminaseammonia3) Production of ammonia in skeletal muscle increasedEndogenous HEKidneyBlood NH3NH3UreaNH3NH3proteinureaAmmonia production Urea Cycle function impaired Liver cell mass damaged Hyperammonemia Intoxication of ammonia on brain 37Exogenous HEAmmonia production Portal

33、-systemic shunting Hepatic cirrhosisHyperammonemia Intoxication of ammonia on brain 38Intoxication of ammonia on brainAmmonia production Portal-systemic shunting (exogenous)Urea Cycle function impaired (endogenous)Hyper-ammonemia HEIntoxication of ammonia on brain1) Impairment of energy metabolism i

34、n brain2) Alternation of the neurotransmitters3) Inhibiting action on nerve cells membrane4) Mitochondrial permeability transition induced by Oxidative stress 391) Impairment of energy metabolism in brainGlucose is the most important fuel for cerebral energy.Hyperammonemia Depression in cerebral glu

35、cose metabolismATP output reductiontricarboxylic acid cycle 402) Alternation of the neurotransmittersHyperammonemia Dominant neurochemical lesions413) Inhibiting action on nerve cells membraneHyperammonemia Inhibiting brain Na+-K+ ATPaseIncrease of intracellular sodiumImpairment of Neurotransmission

36、424)Mitochondrial permeability transition (MPT) induced by Oxidative stress Hyperammonemia Dysfunction of astrocytes1) In cultured astrocytes, ammonia induces MPT, frequently caused by oxidative stress2) Increased free radical production in cultured astrocytes exposed to ammonia3) Antioxidants can i

37、nhibit the MPT in ammonia-treated cultured astrocytesThere are some argument against Ammonia intoxication hypothesis 10% of HE patients have normal serum ammonia levels some patients with hyperammonemia have no HE signsSo there are synergistic action of multiple toxins on the CNS.44 False Neurotrans

38、mittersBasisHE patients with fulminant hepatitis L-dopa treatmentRecover quickly L-dopa is a precursor of normal neurotransmittersnormal neurotransmitters, such as dopamine and norepinephrine, are endogenous singnaling molecules secreted by neurons that can alter the behavior of neurons or effector

39、cells. 45Conception False Neurotransmitters (FNT) is a kind of chemical substance, which have similar structures of true neurotransmitters (NNT), but much weaker activity than true neurotransmitters.HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2phenolethanolamineoctopamineNor

40、mal Neurotransmitters False Neurotransmitters 47 Amino Acid imbalanceSynthesis of neurotransmitter is dependent on the rate of precursor amino acidsBranch chain amino acids (BCAA)Aromatic amino acids (AAA)Valine, leucine and isoleucinePrecursors of NNTTyrosine, phenylalanine and tryptophanPrecursors

41、 of FNTNormally, plasma BCAA to AAA rate is 3-3.5In HE patients, plasma BCAA to AAA rate is 0.6-1.248Decreased plasma BCAA levelsMechanisms 1) Ammonia In HE patients, BCAA might be utilized for detoxification of ammonia.2) hyperinsulinismmetabolism of insulinhyperinsulinismPortal-systemic shuntingUp

42、take of BCAA into muscle3) Inflammation cytokineTumor necrosis factor-Decreased plasma BCAA levels49Increased plasma AAA levelsMechanisms 1) Dysfunction of hepatic deamination 2) Release of AAA from the necrotic hepatocytesphenethylaminephenolethanolaminetyrosameinoctopamineAAABCAABlood-brain barrie

43、r5-hydroxytryptophanserotoninDopaphenylalaninetyrosinetryptophanvector多巴胺NEdopamineNEInhibitoryFNTFNTNNTDysfunction of synthesis of neurotransmitters in brain51Decreased plasma BCAA levelsIncreased plasma AAA levelsIn HE patients, plasma BCAA to AAA rate decreasedNeuronal contents of NNT FNT Reduced

44、 neural exitation Increased neural inhibitonBRIEFFNT and amino acid imbalance52 The Gamma-Aminobutyric Acid hypothesisBasis1) The Gamma-Aminobutyric Acid (GABA) is a inhibitory neurotransmitter in CNS, as a cause of HE.2) Increased GABA-ergic tone is observed in patients with cirrhosis3) Flumazenil,

45、 a benzodiazepine antagonist, can transiently reverse HE in patients with cirrhosis53Increased plasma GABA levels Hepatic failureDecreased hepatic metabolism of GABAGut absorption (intestinal bacteria and the intestinal wall)Blood GABA levelsThe permeability of the blood-brain barrier to GABASome GA

46、BA reaches GABA receptors and augment GABA-ergic neurotransmission54Mechanism 1. Increased density and/or affinity of receptors for GABA on the supramolecular complex.GABA/BZ receptor/chloride ionophore complexA GABA receptor a BZ receptor a chlorideionophore (that contains receptor for barbiturates

47、)Notes: Administration of benzodiazepines and barbiturates to patients with cirrhosis increases GABA-ergic tone and predisposes depression552. Mechanism of GABA-ergic inhibitory neurotransmissionGABA receptor (+)Neuronal membrane permeability to Cl-Cl- resting potential of the neurons is more negati

48、ve than normal.Cl- ionophore openingNeural Membrane hyperpolarizationLeading to consciousness and motor control impaired564. Precipitating factors of HE1) Gastrointestinal BleedingThe most important is Nitrogenous overloadHypovolemia, shock, hypoxiaAmmonia production2) Abuse of sedatives and narcoti

49、c3) Massive paracentesis and excessive diuresisbenzodiazepines and barbituratesFluid or electrolyte abnormalities and acid base disturbance4) Infections tissue breakdown4) Infections Protein breakdown575. Treatment of HEPrinciples 1) Eliminating or correcting precipitating factors2) Reducing plasma

50、ammonia and other toxin3) Correcting plasma amino acid imbalance and supplying normal neurotransmitters4) Improving hepatocyte functions5) Liver transplantation58ConceptionThe definition of hepatorenal syndrome (HRS) is refered to the development of a reversible and functional renal failure in patie

51、nts with sever liver diseases (acute or chronic in absence of any other identified cause of renal pathology. PART IV hepatorenal syndrome59MechanismRenal blood supplyGlomerular filtration rate (GFR) Acute functional renal failureHepatic failureRenal vasoconstriction？60Factors involved in renal vasoc

52、onstriction1) Stimulated sympathetic nervous system2) Renin-Angiotension-Aldosterone system (+)3) Increase vasopressin release4) Other humoral factorsSuch as endothelin, NO, PGs, ets.61Thanks62 Introduction and Conception Etiology Hepatic insufficiency Hepatic failure Hepatic encephalopathy (focal point) Hepatorenal syndromeHepatic Failure632. Water and electrolytes imbalance1) Hepatic AscitesAscties is the presence of the excess fluid in the peritoneal cavityIt is a late-staged manifestation of the liver disease.641. Introduction and ConceptionConception of hepatic encephalo