消化系统内科学课件：Hepatic-Encephalopathy.ppt

1、ZHOU QiDepartment of Gastroenterology and HepatologyTongji HospitalnName : SongnAge : 56nGender : malenAdmission date : 2002/11/20nPast History : HBV carrier no history of diabetes mellitus, epilepsy, stroke, or brain trauma Case presentBrief History He was admitted to our hospital because of genera

2、lized seizures for several hours and loss of consciousness (status epilepticus) after having some meat soup. Brief History During the course of admission, jaundice was noted by jaundice skin. GOT: 254, GPT: 290, Bil 7.4/4.3 And Sugar poor control was also noted.Course and Management nNH3 : 173 nALB

3、: 25nPT : 33.4/11.3nAPTT : 84.1/36.2Diagnosis?nChest and abdominal roentgenograms, brain computed tomography (CT) and magnetic resonance imaging (MRI) were normal, nAbdominal echosonography and CT revealed atrophic cirrhotic liver and splenomegaly. After antiepileptic therapy (phenytoin sodium) and

4、treatment for hepatic encephalopathy (branched chain amino acids; BCAA),status epilepticus and loss of consciousness were resolved. The plasma NH3 level returned to a normal level concurrently with his clinical improvement. Definition HE (Hepatic Encephalopathy) is a wide spectrum of neuro-psychiatr

5、ic abnormalities occurring in patients with significant liver dysfunction due to an as yet uncertain mechanism or a reversible decrease in neurologic function caused by liver disease. Significant liver dysfunction implies one of following:n acute liver failure n cirrhosis with or without major porto

6、systemic shuntingn major portosystemic shunting without cirrhosisbasic theories of pathophysiologyn Reduced hepatic production of compounds which maintain normal central nervous system (CNS) function.nFailure of hepatic detoxification of neuroactive compounds arising from the gut. Despite the freque

7、ncy and characteristic clinical features of HE, the precise mechanisms involved are not fully defined. PathophysiologynDirect ammonia neurotoxicitynMultiple synergistic neurotoxins: ammonia, mercaptans, octanoic acidnSynthesis of false neurotransmitters and plasma amino acid imbalancen Alterations i

8、n central nervous system (CNS) tryptophan metabolites, such as serotoninnExcess gamma aminobutyria acid (GABA)nPresence of “endogenous” or “natural” benzodiazepines. specific hypothesis of hepatic encephalopathyTable 1. Pathogenesis of Hepatic Encephalopathy Toxins (ammonia and mercaptants)Ammonia a

9、nd mercaptants produced by action of intestinal bacteria on urea and protein are elevated in blood and brain as a result of defective hepatic clearance and lead to impaired neural function through cytotoxicity, cell swelling, and depletion of glutamineGABAergic neurotransmission Defective hepatic cl

10、earance of GABA produced by intestinal bacteria, increased neuronal GABA synthesis, and increased production of benzodiazepine receptor agonists leads to neuronal inhibition through stimulation of GABA receptor complex in postsynaptic membranes. False neurotransmitters Increased in the ratio of plas

11、ma aromatic amino acids to branched-chains acids increases brain levels of aromatic amino acid precursors for false neurotransmitters Ammonia HypothesisnAmmonia is a key intermediate in nitrogen and protein metabolism. The gastrointestinal tract is the primary site of ammonia production. Nitrogenous

12、 compounds in the colon, which include ingested proteins and secreted urea, are degraded by bacteria and liberate ammonia that is than absorbed into the portal circulation, where concentrations are five-to ten-fold greater than in mixed venous blood. The liver has a very high first-pass extraction o

13、f ammonia, resulting in clearance from portal system and prevention of ammonia entry into the systemic circulation. Within hepatocytes, ammonia is rapidly converted by a series of enzymatic reactions to non-toxic glutamine and, in separate reactions, is synthesized into urea for secretion by the kid

14、neys. In addition to the urea transport, the kidneys represent a site for ammonia generation and actively secrete ammonia into the urine. Indeed , there is a net increase in the concentration of ammonia in renal veins as compared with renal arteries; and the concentrations of ammonia in the renal ve

15、ins is increased by hypokalemia and use of diuretics. Clinical studies support a role for hypokalemia in of hepatic encephalopathy through effects on renal genesis of ammonia. nAfter bolus injection of radiolabed ammonia, the liver, bladder and brain show appreciable uptake. In encephalopathy, arter

16、ial ammonia levels increase and the rate of brain ammonia accumulation also increases. Because muscle is an important site for ammonia clearance, the muscle atrophy seen in advanced cirrhosis may contribute to the increase in brain uptake.Ammonia Hypothesis Patients with cirrhosis are subject to cha

17、nge in systemic fluid and electrolyte balance by virtue of the sodium and water retention that accompanies cirrhosis and by the frequent use of potent diuretics. Hypokalemia frequently develops in cirrhotic patients as a consequence of diuretic-induced urinary losses, diarrhea, vomitting, and nutrit

18、ional deficiencies. Hypokalemia can cause alkalosis in cirrhosis.Ammonia HypothesisFirst hypokalemia increases ammonia production by the kidney. Second, hypokalemia and alkalosis favor cellular uptake of ammonia. Because most of the bodys potassium stores are found in the intracellular space, loweri

19、ng of potassium concentrations in the extracellular fluid stimulates efflux of intracellular potassium out of cells to restore extracelluar concentrations. Cells compensate for the loss of potassium by a net uptake of sodium and hydrogen irons to maintain electroneutrality, leading to relative alkal

20、inization of the extracellualr space and acidification of the intracellular space. Because ammonia and the ammonium radical exist in equilibrium, the extracellular alkalosis increases the portion of membrane-permeable ammonia, whereas the intracellular acidosis serve to trap ammonium within the cell

21、. Thus, the net effect of hypokalemia is a shift of ammonia into neurons or other cells where it exerts its toxic effects.Table 2. Effects of Ammonia on Brain Function Electrophysiological effects of the ammonium ion Effects on the inhibitory postsynaptic potential (IPSP) Effects on glutamatergic ne

22、urotransmission (postsynaptic)Effects on brain energy metabolism Inhibition of -ketoglutarate dehydrogenase Effects on astrocytic function Decreased expression of the glutamate transporter GLT-1 Increased expression of peripheral-type benzodiazepine receptors Alzheimer type II astrocytosisEffects on

23、 the glutamate neurotransmitter system Direct postsynaptic effects Impaired neuron-astrocytic trafficking of glutamate Inhibition of glutamate uptake Altered glutamate receptorsEffects medicated by formation of glutamine in brain Cytotoxic brain edema Increased uptake of aromatic amino acidsOther ef

24、fects Stimulation of L-arginine uptake, nNOS expressionAmmonia hypothesisSummary of ammonia intoxication -aminobutyric acid (GABA) hypothesisnStudies in humans and animal models have implicated the GABA-receptor complex as a key contributor to neuronal inhibition in hepatic encephalopathy. nThe GABA

25、-receptor complex is located to postsynaptic membranes and constitutes the principal inhibitory network in the central nervous. It consists of 1、a GABA-binding site facing the extracellular surface, 2、a chloride-selective pore that opens in response to GABA binding to permit influx of chloride and p

26、roduce membrane hyperpolarization3、close associated barbiturate and benzodiazepine receptor sites that potentiate the effects of GABA. Theoretically, increases in GABAergic transmission could result from increased availability of extracellular GABA or benzodiazepine receptor ligands. The liver conta

27、ins high concentrations of GABA and GABA transaminase. Consequently, liver injury disrupts GABA homeostatic mechanisms and may contribute to the pathogenesis of hepatic encephalopathy. False Neurotransmitters It has been postulated that altered concentrations of various other neurotransmitter substa

28、nces occur in the brain in the patients of cirrhosis. Noradrenaline and dopamine are important, false neurotransmitters include GABA,octopamin, histamine, serotonin etc. They compete with normal neurotransmitters. Displacing them and thereby impairing dopaminernergic neurotransmission in brain of pa

29、tients of HE. Patients with cirrhosis have an important imbalance in the brain and plasma between levels of methionine and the aromatic amino acid (AAA) compared with the branched amino acid (BCAA). The normal plasma ratio of BCAAs to AAAs of 3.5 falls to 1.0 in patients with cirrhosis. Because AAAs

30、 and BCAAs compete for the same blood- brain carrier transport site ,cerebral uptake o f AAAs increases, in turn promoting synthesis of the false neurotransmitters . Aromatic/branched-chain amino acid imbalance theorycomprehensive viewCause of hepatic encephalopathyNitrogenous encephalopathyNon-nitr

31、ogeneous encephalopathyUremia/azotemia Gastrointestinal bleedingDehydrationMetabolic alkalosisConstipationExcessive dietary proteinInfectionSedatives, benzodiazepinesBarbituratesHypoxia, hypoglycemiaHypothyroidismAnemia Common clinical factors that may precipate hepatic encephalopathy in cirrhosisnH

32、epatic encephalopathy presents as a spectrum of neurologic abnormalities, but the principal clinical features alone are each nonspecific.nSubtle impairments of memory, consciousness, and personality are easily overlooked if the underlying liver disease is not recognized. Clinical PresentationsnAlter

33、natively, even if there have been well-defined periods of encephalopathy, it may be difficult to assess whether recovery has been complete.nIn contrast, the clinical features of advanced encephalopathy and asterixis in a patient with known cirrhosis and portal hypertension are characteristic, and th

34、e combination of asterixis, hyperammonemia, and other clinical features permits confident recognition of portosystemic encephalopathy.nIt occurs most notably in patients with portal hypertension and shunting of blood away from the liver. In the setting of chronic liver disease, the onset is often in

35、sidious and is characterized by subtle and sometimes intermittent changes in memory, personality, concentration, and reaction times.nTypically, early changes are subclinical, and are recognized only in retrospect, but latent encephalopathy can be clinically significant.Clinical PresentationsnStudies

36、 of compensated cirrhotic patients without clinical evidence of encephalopathy indicated that more than half were unfit to drive, as assessed by a battery of psychometric tests. Although these results cannot be extended to all patients with cirrhosis, the implications for patients and for society ar

37、e important in view of the prevalence of cirrhosis.nWith progression of encephalopathy, the neurologic abnormalities become more apparent and are commonly grade on a numerical reflecting increasing degrees of neurologic dysfunction.Table 4. Clinical stages of Hepatic EncephalopathyClinical StageInte

38、llectual Function Neuromuscular FunctionSubclinicalNormal examination, but work or driving may be impairedSubtle changes on psychometric or number connection testsStage IImpaired attention, irritability, depression, or personality changeTremor, incoordination apraxiaStage IIDrowsiness, behavioral ch

39、anges, poor memory and computation, sleep disordersAsterixis, slowed or slurred speech, ataxiaStage IIIConfusion and disorientation, somnolence, amnesiaHypoactive reflexes, nystagmus, clonus and muscular rigidityStage IVStupor and comaDilated pupils, and decerebrate posturing; oculocephalic reflex,

40、absence of response to stimuli in advanced stagesnumber connection testsnThe manifestations of stage I HE reflect involvement of higher cortical functions, with decreases in attention span, changes in personality, irritability, and impaired computational and construction skills. A changes in sleep p

41、attern with wakefulness at night and drowsiness during the day is notable. The EEG, if measured, is usually normal but may show subtle slowing of the dominant frequency.Clinical PresentationsnProgression to stages II is characterized by an exaggeration of these cortical manifestations, with more dro

42、wsiness and lethargy, and by appearance of movement disorders reflecting increasing involvement of the descending reticular system or other neurologic structures. nThese include tremors, incoordination, and the onset of asterixis. nIn cooperative patients, asterixis is commonly evaluated by asking t

43、he patient to hold the arms extended with the wrists dorsiflexed. Alternatively, the examiner can grip the patients hand and lightly hold the wrist in a dorsiflexed position, and the periodic relaxations are also apparent. In the setting of mental confusion, drowsiness, and personality changes, the

44、presence of asterixis is very suggestive of underlying HE. nAn EEG performed in stage II usually shows slower rhythms and appearance of triphasic waves in the frontal regions.nProgression to stage III, defined as increasing obtundation in a still arousable patients, or to stages IV, in which the pat

45、ients is comatose, reflects either severe bilateral cortical dysfunction or involvement of the brainstem and reticular activating system. Asterixis may be lost, and hyperreflexia and muscle rigidity become apparent.n The EEG shows severe slowing with frequencies in the theta and delta ranges. Even t

46、hough the clinical features may be fully reversible with treatment, encephalopathy of this degree is generally a manifestation of advanced liver disease and is associated with a very poor long-term prognosis.nThese clinical features of hepatic encephalopathy are non-specific, and there is considerab

47、le overlap in the presence and severity of the finding. nSimilar manifestations can accompany hypoxia, acidosis, drugs, or other metabolic and toxic insults. Consequently, it is important to consider and exclude these possibilities by appropriate drug screens and testing. It is worth emphasizing tha

48、t the neurologic manifestations of hepatic encephalopathy are generally symmetric.clinical classification nAcute liver failure-associated hepatic encephalopathy (ALFA-HE) nAssociated with chronic liver disease and/or portosystemic shunting Diagnosis A historical points suggesting occult liver diseas

49、e and/or portosystemic shunting n Past history of i. v. drug use (hepatic B or C)n Family history of cirrhosis (hemochromatosis)n Residence in areas endemic for schistosomiasisn Umbilical sepsis (splanchnic vein thrombosis)n History of Pancreatitis (splenic vein thrombosis)n Past history of hepatiti

50、s(hepatic B or C, alcoholic hepatitis)n Past history of use of hepatotoxic drugs, e.g., methotrexate, nitrofurantoinB Physical signs suggesting underlying significant liver disease n Fetor hepaticusn Spider telangiectases (especially in men)n Gynecomastian Loss of body hair (in men)n Testicular atro