1、肝性脑病英文课件PART I Introduction and ConceptionLiverThe largest and most metabolically complex organ1.The liver2.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
2、blood.The portal vein supplies nutrient-rich blood.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 intestine3.The functions of the liver Substance metabolism immune function Hemostasis regulation producti
3、on and secretion of bile Bio-transformation(detoxification)4.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 in
4、sufficiency Chronic Hepatic insufficiency 5.Hepatic failureTerminal stage of hepatic insufficiencyHepatic encephalopathy(focal point)Hepatorenal syndromePrimary clinical manifestationsPART II Etiology1.Biological2.Physical and chemical 3.Inherited conditions 4.Immune 5.Nutritional causesHepatitis vi
5、rus(such as HBV),bacteria,parasites,etc.Industrial toxins,some drugs,alcohol,etc.Idiopathic hemochromatosis,Wilsons disease,etc.Extent of inflammation and necrosis PART III Hepatic insufficiencyLiverVarious etiology causeshepatocytesNon-parenchymalcellsdamagedamage Kupffer cells,hepatic satellite ce
6、lls,lipocytes,liver associated lymphocytes,hepatic sinusoid endothelial cellsHepatic insufficiencySyndromes of Hepatic insufficiency1.Metabolic disorders2.Water and electrolytes imbalance3.Disorders in production of bile salts and elimination of bilirubin4.Impaired kupffer cells functionCarbohydrate
7、 Metabolic DisordersLipid Metabolic DisordersProtein Metabolic DisordersHepatic AscitesElectrolytic Metabolic Disorders1.Metabolic disorders1)Carbohydrate Metabolic DisordersCarbohydrate Metabolism of liverTo maintain concentrations of glucose in blood within a narrow,normal range.insulinA hormone p
8、roduced 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 rapidl
9、y taken up by the liver and sequestered as the large polymer,glycogenglycogenesisglyconeogenesisglycogenolysiswhen blood concentrations of glucose begin to decline,the liver activates other pathways which lead to depolymerization of glycogenWhen hepatic glycogen reserves become exhaused,as occurs wh
10、en 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.Severe liver diseaseHypoglycemiaHyperglycemiaCaused by a decrease in functional
11、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 tolerance1.Metabolic disorders2)Lipid Metabolic D
12、isordersLiver 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 accumulation(fatty li
13、ver)In certain chronic liver diseasePrimary biliary cirrhosisDestruction of bile ductsBile flow decreaseDecrease lipid clearance via bilehyperlipidemiaThese patients often develop xanthomas accumulation of cholesterol 1.Metabolic disorders3)Protein Metabolic DisordersThe liver manufactures and secre
14、tes 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 pressureInsulin like growth fact
15、or-1 to regulate growthOther 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 to ureaPlasma proteins decre
16、aseElevated ammonia levelalbuminClotting factorsHepatic encephalopathyEdema and ascitesBleeding tendancy2.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.Mechanisms of Hepatic
17、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 because of fluid shift and vasodilation
18、 glomerular filtration rate(GFR)rennin-angiotension-aldosterone system(+)metabolism of aldosterone portal-to-systemic shunting vasodilatory products are dilvered to the systemic circulation 2.Water and electrolytes imbalance2)Electrolytic Metabolic Disorders1)Hypokalemia2)Hyponatremia3.Disorders in
19、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 jaundiceJaundice:Yellowing of the skin and the whites of the eyes,
20、caused by an accumulation of bilirubin in the blood.4.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.dysfunction of Kupffer cellsLoss of cle
21、arance function to bacteriaPortal-systemic shuntingEnteric toxins enter the systemic circulationEnteric endotoxemiaBriefSymptoms of hepatic failureWater and electrolytesimbalanceHypo or hyper-glycemiaHyperlipidemia and xanthomasPlasma proteins decrease edema,bleedingMetabolic disordersHepatic Ascite
22、sHypokalemia and HyponatremiaDisorders in production of bile saltsand Elimination of bilirubinMalabsorption and deficiency statesElevation of serum bilirubin and jaundiceImpaired kupffer cells functionEnteric endotoxemiaHepatic encephalopathy(HE)is a primary clinical manifestation of hepatic failure
23、.PART IV Hepatic encephalopathynIntroduction and ConceptionnEtiology and classification nPathogenesis nPrecipitating factors of HEnPrinciples of treatment1.Introduction and ConceptionConception of hepatic encephalopathyHE is a complex,potentially reversible disturbance in central nervous system that
24、 occurs as a consequence of severe liver diseases.Four stages of hepatic encephalopathySlightly altered mood or behaviourSomnipathy and inappropriate behaviors Drowsy and psychopathyDeep coma2.Etiology and classification Etiology Chronic liver diseasesFulminant hepatic failure(FHF)Viral infectionDru
25、g reaction Poisoning with carbon tetrachloride or phosphorusCirrhosis of any originClassificationnEndogenous HEnHave no apparent precipitating factorsnOften caused by extensive liver cell destructionnExogenous HE nPrecipitated by some known agents or abnormalities such as:gastrointestinal bleeding i
26、ngestion many proteinsnOften caused by portal-systemic shuntsAccording to originAccording to clinical characteristicnAcute or subacute encephalopathynAcute or subacute recurrent encephalopathynChronic recurrent encephalopathynChronic permanent encephalopathy3.Pathogenesis Ammonia Intoxication False
27、Neurotransmitters Amino Acid imbalance The Gamma-Aminobutyric Acid hypothesisSeveral hypotheses Ammonia IntoxicationBasis1.Healthy dogCreating a portal-systemic shuntingFed by meatcomatose2.80%patients with HEBlood ammonia levels3.Cirrhosis patients ingestion of a large amounts of proteinHepatic com
28、a4.HE patients with cirrhosisTherapies to reduceammonia absorptionAmeliorations of HECause for elevated ammoniaIn normal conditionsUreaAmmoniaKidneyAmmoniaProteins,aminesUrea,purinesAmmonia is mainly produced in gastrointestinal tractAmmonia is detoxified in liver by conversion to urea through Krebs
29、-Henseleit urea cycle.In Hepatic failureKrebs-Henseleit urea cycle function is impairedBlood ammonia level increased(endogenous)OrnithineCitrullineargininearginase NH3NH3Urea In hepatic failure：substrates enzyme ATP Portal-systemic shunting also reduces the urea production(exogenous)Ammonia producti
30、on increased Blood ammonia level increased1)Production of ammonia in intestine lumen increased2)Production of ammonia in kidney increasedProtein,urea,purinedegradedEnzyme of bacteriaammoniaglutamineglutaminaseammonia3)Production of ammonia in skeletal muscle increasedEndogenous HEKidneyBlood NH3 NH3
31、UreaNH3 NH3proteinureaAmmonia production Urea Cycle function impaired Liver cell mass damaged Hyperammonemia Intoxication of ammonia on brain Exogenous HEAmmonia production Portal-systemic shunting Hepatic cirrhosisHyperammonemia Intoxication of ammonia on brain Intoxication of ammonia on brainAmmon
32、ia production Portal-systemic shunting(exogenous)Urea Cycle function impaired(endogenous)Hyper-ammonemia HEIntoxication of ammonia on brain1)Impairment of energy metabolism in brain2)Alternation of the neurotransmitters3)Inhibiting action on nerve cells membraneMitochondrial permeability transition
33、induced by Oxidative stress 1)Impairment of energy metabolism in brainGlucose is the most important fuel for cerebral energy.Hyperammonemia Depression in cerebral glucose metabolismATP output reductiontricarboxylic acid cycle 2)Alternation of the neurotransmittersHyperammonemia Dominant neurochemica
34、l lesions3)Inhibiting action on nerve cells membraneHyperammonemia Inhibiting brain Na+-K+ATPaseIncrease of intracellular sodiumImpairment of NeurotransmissionMitochondrial permeability transition(MPT)induced by Oxidative stress Hyperammonemia Dysfunction of astrocytes1)In cultured astrocytes,ammoni
35、a induces MPT,frequently caused by oxidative stressIncreased free radical production in cultured astrocytes exposed to ammonia3)Antioxidants can inhibit the MPT in ammonia-treated cultured astrocytesThere are some argument against Ammonia intoxication hypothesis 10%of HE patients have normal serum a
36、mmonia levels some patients with hyperammonemia have no HE signsSo there are synergistic action of multiple toxins on the CNS.False NeurotransmittersBasisHE patients with fulminant hepatitis L-dopa treatmentRecover quickly L-dopa is a precursor of normal neurotransmittersnormal neurotransmitters,suc
37、h as dopamine and norepinephrine,are endogenous singnaling molecules secreted by neurons that can alter the behavior of neurons or effector cells.Conception False Neurotransmitters(FNT)is a kind of chemical substance,which have similar structures of true neurotransmitters(NNT),but much weaker activi
38、ty than true neurotransmitters.HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2phenolethanolamineoctopamineNormal Neurotransmitters False Neurotransmitters Amino Acid imbalanceSynthesis of neurotransmitter is dependent on the rate of precursor amino acidsBranch chain amino acid
39、s(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 0.6-1.2Decreased plasma BCAA levelsMechanisms 1)Ammonia In HE patients,BCAA might be
40、utilized for detoxification of ammonia.2)hyperinsulinismmetabolism of insulinhyperinsulinismPortal-systemic shuntingUptake of BCAA into muscle3)Inflammation cytokineTumor necrosis factor-Decreased plasma BCAA levelsIncreased plasma AAA levelsMechanisms 1)Dysfunction of hepatic deamination 2)Release
41、of AAA from the necrotic hepatocytesphenethylaminephenolethanolaminetyrosameinoctopamineAAABCAABlood-brain barrier5-hydroxytryptophanserotoninDopaphenylalaninetyrosinetryptophanvector多巴胺多巴胺NEdopamineNEInhibitoryFNTFNTNNTDysfunction of synthesis of neurotransmitters in brainDecreased plasma BCAA leve
42、lsIncreased plasma AAA levelsIn HE patients,plasma BCAA to AAA rate decreasedNeuronal contents of NNT FNT Reduced neural exitation Increased neural inhibitonBRIEFFNT and amino acid imbalance The Gamma-Aminobutyric Acid hypothesisBasisThe Gamma-Aminobutyric Acid(GABA)is a inhibitory neurotransmitter
43、in CNS,as a cause of HE.2)Increased GABA-ergic tone is observed in patients with cirrhosis3)Flumazenil,a benzodiazepine antagonist,can transiently reverse HE in patients with cirrhosisIncreased plasma GABA levels Hepatic failureDecreased hepatic metabolism of GABAGut absorption (intestinal bacteria
44、and the intestinal wall)Blood GABA levelsThe permeability of the blood-brain barrier to GABASome GABA reaches GABA receptors and augment GABA-ergic neurotransmissionMechanism 1.Increased density and/or affinity of receptors for GABA on the supramolecular complex.GABA/BZ receptor/chloride ionophore c
45、omplexA GABA receptor a BZ receptor a chlorideionophore(that contains receptor for barbiturates)Notes:Administration of benzodiazepines and barbiturates to patients with cirrhosis increases GABA-ergic tone and predisposes depression2.Mechanism of GABA-ergic inhibitory neurotransmissionGABA receptor(
46、+)Neuronal membrane permeability to Cl-Cl-resting potential of the neurons is more negative than normal.Cl-ionophore openingNeural Membrane hyperpolarizationLeading to consciousness and motor control impaired4.Precipitating factors of HE1)Gastrointestinal BleedingThe most important is Nitrogenous ov
47、erloadHypovolemia,shock,hypoxiaAmmonia production2)Abuse of sedatives and narcotic3)Massive paracentesis and excessive diuresisbenzodiazepines and barbituratesFluid or electrolyte abnormalities and acid base disturbance4)Infections tissue breakdown4)Infections Protein breakdown5.Treatment of HEPrinc
48、iples 1)Eliminating or correcting precipitating factors2)Reducing plasma ammonia and other toxin3)Correcting plasma amino acid imbalance and supplying normal neurotransmitters4)Improving hepatocyte functions5)Liver transplantationConceptionThe definition of hepatorenal syndrome(HRS)is refered to the
49、 development of 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 syndromeMechanismRenal blood supply Glomerular filtration rate(GFR)Acute functional renal failureHepatic fa
50、ilureRenal vasoconstriction？Factors involved in renal vasoconstriction1)Stimulated sympathetic nervous system2)Renin-Angiotension-Aldosterone system(+)3)Increase vasopressin release4)Other humoral factorsSuch as endothelin,NO,PGs,ets.ThanksThanks此课件下载可自行编辑修改，仅供参考！此课件下载可自行编辑修改，仅供参考！感谢您的支持，我们努力做得更好！谢谢
