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.Th
2、e 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 hepatic v
3、eins.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 insufficiencySe
4、vere 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 failureTerminal sta
5、ge 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,parasites,etc.Industrial toxins,
6、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,lipocytes,liver associated lymphocytes,he
7、patic 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 functionCarbohydrate Metabolic DisordersLipid Metab
8、olic 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,normal range.insulinA hormone produced by the p
9、ancreas 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 taken up by th
10、e 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 hepatic glycogen reserves become exhaused,as occurs whe
11、n 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 diseaseHypoglycemiaHyperglycemiaCaused by a decrease
12、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 suffer abnormal glucose tolerance第第13页页/共共68页页141.Metabolic
13、 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 HDL.第第14页页/共共68页页Severe liver diseaseDisturbance of lipid metabo
14、lismSyndromes 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 accumulation of cholesterol 第第15页页/共共68页页161.Metabolic disorders3)Pr
15、otein 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 and thyroid hormone-binding protein to regulate metabolismangiotens
16、inogen 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 excreted in the form of urea第第17页页/共共68页页Severe liver diseaseDisturba
17、nce 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 imbalance1)Hepatic AscitesAscties is the presence of the excess fluid i
18、n 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)Decrease in colloidal osmotic pressureCause:impaired synthesis of albumin3)Sa
19、lt 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-to-systemic shunting vasodilatory products are dilvered to the systemic circula
20、tion 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 diseaseA failure to secrete bileA Failure to solubilize substancesMalabsorption and defic
21、iency 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.Impaired kupffer cells functionKupffer cells function1)Removing and phagocytizing old
22、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-systemic shuntingEnteric toxins enter the systemic circulationEnteric endotoxemia第第24页页/共共6
23、8页页25BriefSymptoms of hepatic failureWater and electrolytesimbalanceHypo or hyper-glycemiaHyperlipidemia and xanthomasPlasma proteins decrease edema,bleedingMetabolic disordersHepatic AscitesHypokalemia and HyponatremiaDisorders in production of bile saltsand Elimination of bilirubinMalabsorption an
24、d 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.PART IV Hepatic encephalopathynIntroduction and ConceptionnEtiology and classification nPathog
25、enesis 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 nervous system that occurs as a consequence of severe liver diseases.Four stages of hepatic encepha
26、lopathy1.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 diseasesFulminant hepatic failure(FHF)Viral infectionDrug reaction Poisoning with carbon tetrachloride or phospho
27、rusCirrhosis 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 known agents or abnormalities such as:gastrointestinal bleeding ingestion many proteinsnOften caused by por
28、tal-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 encephalopathynChronic permanent encephalopathy第第30页页/共共68页页313.Pathogenesis Ammonia Intoxication False Neurotransmi
29、tters 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 meatcomatose2.80%patients with HEBlood ammonia levels3.Cirrhosis patients ingestion of a large amounts of proteinHepatic
30、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,aminesUrea,purinesAmmonia is mainly produced in gastrointestinal tractAmmonia is detoxified in liver by conversion to
31、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)OrnithineCitrullineargininearginase NH3NH3Urea In hepatic failure：substrates enzyme ATP Portal-systemic shunting also reduces the urea prod
32、uction(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 increasedProtein,urea,purinedegradedEnzyme of bacteriaammoniaglutamineglutaminaseammonia3)Production of ammonia in skeletal
33、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 Intoxication of ammonia on brain 第第36页页/共共68页页37Exogenous HEAmmonia production Portal-systemic shunting Hepatic cirrhosisHyperammo
34、nemia 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)Hyper-ammonemia HEIntoxication of ammonia on brain1)Impairment of energy metabolism in brain2)Alternation of the neurotr
35、ansmitters3)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 brainGlucose is the most important fuel for cerebral energy.Hyperammonemia Depression in cerebral glucose metabolismATP output
36、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 nerve cells membraneHyperammonemia Inhibiting brain Na+-K+ATPaseIncrease of intracellular sodiumImpairment of Neurotransmission第第4
37、1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 MPT,frequently caused by oxidative stress2)Increased free radical production in cultured astrocytes exposed to ammonia3)Antioxidants ca
38、n 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 serum ammonia levels some patients with hyperammonemia have no HE signsSo there are synergistic action of multiple toxins on the CNS.第第43
39、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 neurotransmittersnormal neurotransmitters,such as dopamine and norepinephrine,are endogenous singnaling molecules secreted by neurons that can alter the behavi
40、or 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 neurotransmitters(NNT),but much weaker activity than true neurotransmitters.第第45页页/共共68页页HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2Norepinephinedop
41、amineCHOHCH2NH2phenolethanolamineoctopamineNormal Neurotransmitters False Neurotransmitters 第第46页页/共共68页页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 isoleucinePrecursor
42、s of NNTTyrosine,phenylalanine and tryptophanPrecursors of FNTNormally,plasma BCAA to AAA rate is 3-3.5In HE patients,plasma BCAA to AAA rate is 0.6-1.2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)hyperinsulinis
43、mmetabolism of insulinhyperinsulinismPortal-systemic shuntingUptake of BCAA into muscle3)Inflammation cytokineTumor necrosis factor-Decreased plasma 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
44、页页/共共68页页phenethylaminephenolethanolaminetyrosameinoctopamineAAABCAABlood-brain barrier5-hydroxytryptophanserotoninDopaphenylalaninetyrosinetryptophanvector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
45、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第第51页页/共共68页页52 The Gamma-Aminobutyric Acid hypothesisBasis1)The Gamma-Aminobutyric Acid(GABA)is a inhibitory neurotransmi
46、tter 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 cirrhosis第第52页页/共共68页页53Increased plasma GABA levels Hepatic failureDecreased hepatic metabolism of GABAGut absorption (
47、intestinal bacteria and the intestinal wall)Blood GABA levelsThe permeability of the blood-brain barrier to GABASome GABA reaches GABA 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.GA
48、BA/BZ receptor/chloride ionophore complexA 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 depression第第54页页/共共68页页552.Mechanism of GAB
49、A-ergic inhibitory neurotransmissionGABA receptor(+)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 impaired第第55页页/共共68页页564.Precipitating factors of
50、HE1)Gastrointestinal BleedingThe most important is Nitrogenous overloadHypovolemia,shock,hypoxiaAmmonia production2)Abuse of sedatives and narcotic3)Massive paracentesis and excessive diuresisbenzodiazepines and barbituratesFluid or electrolyte abnormalities and acid base disturbance4)Infections tis
