肝性脑病英文

1、1肝性脑病英文肝性脑病英文第第1页页/共共68页页2nIntroduction and ConceptionnEtiologynHepatic insufficiencynHepatic failure Hepatic encephalopathy (focal point) Hepatorenal syndromeHepatic Failure第第2页页/共共68页页3PART I Introduction and ConceptionLiverThe largest and most metabolically complex organ1. The liver第第3页页/共共68页页42

2、. 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. Deoxygenated blood from the liver drains into the he

3、patic veins. A network of ducts carries bile from the liver to the gallbladder and the small intestine第第4页页/共共68页页53. The functions of the liver Substance metabolism immune function Hemostasis regulation production and secretion of bile Bio-transformation (detoxification) 第第5页页/共共68页页64. Hepatic ins

4、ufficiencySevere 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 insufficiency 第第6页页/共共68页页75. Hepatic f

5、ailureTerminal stage of hepatic insufficiencyHepatic encephalopathy (focal point)Hepatorenal syndromePrimary clinical manifestations第第7页页/共共68页页8PART II Etiology1. Biological2. Physical and chemical 3. Inherited conditions 4. Immune 5. Nutritional causesHepatitis virus (such as HBV), bacteria, paras

6、ites, etc.Industrial toxins, some drugs, alcohol, etc.Idiopathic hemochromatosis, Wilsons disease, etc.Extent of inflammation and necrosis 第第8页页/共共68页页9PART III Hepatic insufficiencyLiverVarious etiology causeshepatocytesNon-parenchymalcellsdamagedamage Kupffer cells, hepatic satellite cells, lipocy

7、tes, liver associated lymphocytes, hepatic sinusoid endothelial cellsHepatic insufficiency第第9页页/共共68页页10Syndromes of Hepatic insufficiency1. Metabolic disorders2. Water and electrolytes imbalance3. Disorders in production of bile salts and elimination of bilirubin4. Impaired kupffer cells functionCa

8、rbohydrate Metabolic DisordersLipid Metabolic DisordersProtein Metabolic DisordersHepatic AscitesElectrolytic Metabolic Disorders第第10页页/共共68页页111. Metabolic disorders1) Carbohydrate Metabolic DisordersCarbohydrate Metabolism of liverTo maintain concentrations of glucose in blood within a narrow, nor

9、mal range. insulinA hormone produced 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 t

10、he blood after a meal is rapidly taken up by the liver and sequestered as the large polymer, glycogenglycogenesis第第11页页/共共68页页12glyconeogenesisglycogenolysiswhen blood concentrations of glucose begin to decline, the liver activates other pathways which lead to depolymerization of glycogenWhen hepati

11、c glycogen reserves become exhaused, as occurs 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. 第第12页页/共共68页页13Severe liver

12、 diseaseHypoglycemiaHyperglycemiaCaused by a decrease in functional 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 suff

13、er abnormal glucose tolerance第第13页页/共共68页页141. Metabolic disorders2) Lipid 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 H

14、DL.第第14页页/共共68页页Severe liver diseaseDisturbance of lipid metabolismSyndromes of fat accumulation(fatty liver)In certain chronic liver diseasePrimary biliary cirrhosisDestruction of bile ductsBile flow decreaseDecrease lipid clearance via bilehyperlipidemiaThese patients often develop xanthomas accum

15、ulation of cholesterol 第第15页页/共共68页页161. Metabolic disorders3) Protein Metabolic DisordersThe liver manufactures and secretes many of the protein found in plasmaalbuminSome clotting factorsSome binding proteinsSome hormone precursorsTo maintain plasma oncotic pressureTo regulate hemostasisSteroid an

16、d thyroid hormone-binding protein to regulate metabolismangiotensinogen to regulate blood pressureInsulin like growth factor-1 to regulate growth第第16页页/共共68页页17Other roles of the liver in protein metabolismProcesses of oxidative deamination and transaminationThe urea cycle allows nitrogen to be excr

17、eted in the form of urea第第17页页/共共68页页Severe liver diseaseDisturbance of protein metabolismDecreased conversion of ammonia to ureaPlasma proteins decreaseElevated ammonia levelalbuminClotting factorsHepatic encephalopathyEdema and ascitesBleeding tendancy第第18页页/共共68页页192. Water and electrolytes imbal

18、ance1) Hepatic AscitesAscties is the presence of the excess fluid in the peritoneal cavityIt is a late-staged manifestation of the liver disease.第第19页页/共共68页页20Mechanisms of Hepatic Ascites1) An increase in capillary pressureCauses: portal hypertension; obstruction of venous and lymph flow 2) Decrea

19、se in colloidal osmotic pressureCause: impaired synthesis of albumin3) Salt and water retention by the kidneyCause: effective blood volume is reduced because of fluid shift and vasodilation glomerular filtration rate (GFR) rennin-angiotension-aldosterone system (+) metabolism of aldosterone portal-t

20、o-systemic shunting vasodilatory products are dilvered to the systemic circulation 第第20页页/共共68页页212. Water and electrolytes imbalance2) Electrolytic Metabolic Disorders1) Hypokalemia2) Hyponatremia第第21页页/共共68页页223. Disorders in production of bile salts and Elimination of bilirubinSevere liver diseas

21、eA failure to secrete bileA Failure to solubilize substancesMalabsorption and deficiency statesDecreased elimination of bilirubinElevation of serum bilirubin and jaundiceJaundice: Yellowing of the skin and the whites of the eyes, caused by an accumulation of bilirubin in the blood.第第22页页/共共68页页234.

22、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, such as IL-1, IL-6 etc.第第23页页/共共68页页24dysfunction of Kupffer cellsLoss of clearance function to bacteriaPortal

23、-systemic shuntingEnteric toxins enter the systemic circulationEnteric endotoxemia第第24页页/共共68页页25BriefSymptoms of hepatic failureWater and electrolytesimbalanceHypo or hyper-glycemiaHyperlipidemia and xanthomasPlasma proteins decrease edema, bleedingMetabolic disordersHepatic AscitesHypokalemia and

24、HyponatremiaDisorders in production of bile saltsand Elimination of bilirubinMalabsorption and deficiency statesElevation of serum bilirubin and jaundiceImpaired kupffer cells functionEnteric endotoxemia第第25页页/共共68页页26Hepatic encephalopathy (HE) is a primary clinical manifestation of hepatic failure

25、.PART IV Hepatic encephalopathynIntroduction and ConceptionnEtiology and classification nPathogenesis nPrecipitating factors of HEnPrinciples of treatment第第26页页/共共68页页271. Introduction and ConceptionConception of hepatic encephalopathyHE is a complex, potentially reversible disturbance in central ne

26、rvous 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 coma第第27页页/共共68页页282. Etiology and classification Etiology Chronic liver diseasesFul

27、minant hepatic failure (FHF)Viral infectionDrug reaction Poisoning with carbon tetrachloride or phosphorusCirrhosis of any origin第第28页页/共共68页页29ClassificationnEndogenous HEnHave no apparent precipitating factorsnOften caused by extensive liver cell destructionnExogenous HE nPrecipitated by some know

28、n agents or abnormalities such as: gastrointestinal bleeding ingestion many proteinsnOften caused by portal-systemic shuntsAccording to origin第第29页页/共共68页页30According to clinical characteristicnAcute or subacute encephalopathynAcute or subacute recurrent encephalopathynChronic recurrent encephalopat

29、hynChronic permanent encephalopathy第第30页页/共共68页页313. Pathogenesis Ammonia Intoxication False Neurotransmitters Amino Acid imbalance The Gamma-Aminobutyric Acid hypothesisSeveral hypotheses第第31页页/共共68页页32 Ammonia IntoxicationBasis1.Healthy dogCreating a portal-systemic shuntingFed by meatcomatose2. 8

30、0% patients with HEBlood ammonia levels3. Cirrhosis patients ingestion of a large amounts of proteinHepatic coma4. HE patients with cirrhosisTherapies to reduceammonia absorptionAmeliorations of HE第第32页页/共共68页页33Cause for elevated ammoniaIn normal conditionsUreaAmmoniaKidneyAmmoniaProteins, aminesUr

31、ea, purinesAmmonia is mainly produced in gastrointestinal tractAmmonia is detoxified in liver by conversion to urea through Krebs-Henseleit urea cycle.第第33页页/共共68页页34In Hepatic failureKrebs-Henseleit urea cycle function is impairedBlood ammonia level increased (endogenous)OrnithineCitrullinearginine

32、arginase NH3NH3Urea In hepatic failure： substrates enzyme ATP Portal-systemic shunting also reduces the urea production (exogenous)第第34页页/共共68页页35Ammonia production increased Blood ammonia level increased1) Production of ammonia in intestine lumen increased2) Production of ammonia in kidney increase

33、dProtein, urea, purinedegradedEnzyme of bacteriaammoniaglutamineglutaminaseammonia3) Production of ammonia in skeletal muscle increased第第35页页/共共68页页Endogenous HEKidneyBlood NH3 NH3UreaNH3 NH3proteinureaAmmonia production Urea Cycle function impaired Liver cell mass damaged Hyperammonemia Intoxicatio

34、n of ammonia on brain 第第36页页/共共68页页37Exogenous HEAmmonia production Portal-systemic shunting Hepatic cirrhosisHyperammonemia Intoxication of ammonia on brain 第第37页页/共共68页页38Intoxication of ammonia on brainAmmonia production Portal-systemic shunting (exogenous)Urea Cycle function impaired (endogenous

35、)Hyper-ammonemia HEIntoxication of ammonia on brain1) Impairment of energy metabolism in brain2) Alternation of the neurotransmitters3) Inhibiting action on nerve cells membrane4) Mitochondrial permeability transition induced by Oxidative stress 第第38页页/共共68页页391) Impairment of energy metabolism in b

36、rainGlucose is the most important fuel for cerebral energy.Hyperammonemia Depression in cerebral glucose metabolismATP output reductiontricarboxylic acid cycle 第第39页页/共共68页页402) Alternation of the neurotransmittersHyperammonemia Dominant neurochemical lesions第第40页页/共共68页页413) Inhibiting action on ne

37、rve cells membraneHyperammonemia Inhibiting brain Na+-K+ ATPaseIncrease of intracellular sodiumImpairment of Neurotransmission第第41页页/共共68页页424)Mitochondrial permeability transition (MPT) induced by Oxidative stress Hyperammonemia Dysfunction of astrocytes1) In cultured astrocytes, ammonia induces MP

38、T, frequently caused by oxidative stress2) Increased free radical production in cultured astrocytes exposed to ammonia3) Antioxidants can inhibit the MPT in ammonia-treated cultured astrocytes第第42页页/共共68页页There are some argument against Ammonia intoxication hypothesis 10% of HE patients have normal

39、serum ammonia levels some patients with hyperammonemia have no HE signsSo there are synergistic action of multiple toxins on the CNS.第第43页页/共共68页页44 False NeurotransmittersBasisHE patients with fulminant hepatitis L-dopa treatmentRecover quickly L-dopa is a precursor of normal neurotransmittersnorma

40、l neurotransmitters, such as dopamine and norepinephrine, are endogenous singnaling molecules secreted by neurons that can alter the behavior of neurons or effector cells. 第第44页页/共共68页页45Conception False Neurotransmitters (FNT) is a kind of chemical substance, which have similar structures of true n

41、eurotransmitters (NNT), but much weaker activity than true neurotransmitters.第第45页页/共共68页页HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2phenolethanolamineoctopamineNormal Neurotransmitters False Neurotransmitters 第第46页页/共共68页页47 Amino Acid imbalanceSynthesis of neurotransmitt

42、er 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 of FNTNormally, plasma BCAA to AAA rate is 3-3.5In HE patients, plasma BCAA to AAA rate is 0.6-

43、1.2第第47页页/共共68页页48Decreased plasma BCAA levelsMechanisms 1) Ammonia In HE patients, BCAA might be utilized for detoxification of ammonia.2) hyperinsulinismmetabolism of insulinhyperinsulinismPortal-systemic shuntingUptake of BCAA into muscle3) Inflammation cytokineTumor necrosis factor-Decreased pla

44、sma BCAA levels第第48页页/共共68页页49Increased plasma AAA levelsMechanisms 1) Dysfunction of hepatic deamination 2) Release of AAA from the necrotic hepatocytes第第49页页/共共68页页phenethylaminephenolethanolaminetyrosameinoctopamineAAABCAABlood-brain barrier5-hydroxytryptophanserotoninDopaphenylalaninetyrosinetry

45、ptophanvector多巴胺多巴胺NEdopamineNEInhibitoryFNTFNTNNTDysfunction of synthesis of neurotransmitters in brain第第50页页/共共68页页51Decreased plasma BCAA levelsIncreased plasma AAA levelsIn HE patients, plasma BCAA to AAA rate decreasedNeuronal contents of NNT FNT Reduced neural exitation Increased neural inhibi

46、tonBRIEFFNT and amino acid imbalance第第51页页/共共68页页52 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, a benzodiazepine antagonist

47、, can transiently reverse HE in patients with cirrhosis第第52页页/共共68页页53Increased 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 GABA reaches GABA

48、 receptors and augment GABA-ergic neurotransmission第第53页页/共共68页页54Mechanism 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)N

49、otes: Administration of benzodiazepines and barbiturates to patients with cirrhosis increases GABA-ergic tone and predisposes depression第第54页页/共共68页页552. Mechanism of GABA-ergic inhibitory neurotransmissionGABA receptor (+)Neuronal membrane permeability to Cl-Cl- resting potential of the neurons is

50、more negative than normal.Cl- ionophore openingNeural Membrane hyperpolarizationLeading to consciousness and motor control impaired第第55页页/共共68页页564. Precipitating factors of HE1) Gastrointestinal BleedingThe most important is Nitrogenous overloadHypovolemia, shock, hypoxiaAmmonia production2) Abuse

51、of sedatives and narcotic3) Massive paracentesis and excessive diuresisbenzodiazepines and barbituratesFluid or electrolyte abnormalities and acid base disturbance4) Infections tissue breakdown4) Infections Protein breakdown第第56页页/共共68页页575. Treatment of HEPrinciples 1) Eliminating or correcting pre

52、cipitating factors2) Reducing plasma ammonia and other toxin3) Correcting plasma amino acid imbalance and supplying normal neurotransmitters4) Improving hepatocyte functions5) Liver transplantation第第57页页/共共68页页58ConceptionThe definition of hepatorenal syndrome (HRS) is refered to the development of

53、a reversible and functional renal failure in patients with sever liver diseases (acute or chronic in absence of any other identified cause of renal pathology. PART IV hepatorenal syndrome第第58页页/共共68页页59MechanismRenal blood supply Glomerular filtration rate (GFR) Acute functional renal failureHepatic

54、 failureRenal vasoconstriction？第第59页页/共共68页页60Factors involved in renal vasoconstriction1) Stimulated sympathetic nervous system2) Renin-Angiotension-Aldosterone system (+)3) Increase vasopressin release4) Other humoral factorsSuch as endothelin, NO, PGs, ets.第第60页页/共共68页页61ThanksThanks第第61页页/共共68页页62nIntroduction and ConceptionnEtiologynHepatic insufficiencynHepatic failure Hepatic encephalopathy (focal point) Hepatorenal syndromeHepatic Failu