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Hepatic insufficiency

Hepatic insufficiency. Zhang Xiao-ming Dept. pathophysiology. Clinical Example. 患者 ， 男 ， 62 岁 ， 20 年前患过肝炎 ， 后治愈 。 10 年前因上腹部不适伴隐痛及食欲不振入院 ， 检查肝大肋下 1cm ， 肝功能异常 ， 经治疗后症状好转出院 。 5 年前上述症状加重 ， 进食时上腹部不适感加重 ， 有时伴恶心 、 呕吐 ， 症状反复持续至今 。 1d 前在饭店进食大量肉类后出现恶心 、 呕吐 ， 进而出现神志恍惚 、 烦躁不安 。 遂急诊入院 。. Clinical Example.

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Hepatic insufficiency

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  1. Hepatic insufficiency Zhang Xiao-ming Dept. pathophysiology

  2. Clinical Example 患者，男，62岁，20年前患过肝炎，后治愈。10年前因上腹部不适伴隐痛及食欲不振入院，检查肝大肋下1cm，肝功能异常，经治疗后症状好转出院。5年前上述症状加重，进食时上腹部不适感加重，有时伴恶心、呕吐，症状反复持续至今。1d前在饭店进食大量肉类后出现恶心、呕吐，进而出现神志恍惚、烦躁不安。遂急诊入院。

  3. Clinical Example 查体：神志恍惚，步履失衡，烦躁不安，皮肤、巩膜黄染，颈静脉怒张，面部及前胸有蜘蛛痣。腹稍隆，肝可触及，质硬，边缘较钝。脾大在肋下3横指，质硬。叩诊移动性浊音（+）。心肺无异常。食道钡餐显示食道下段静脉曲张。 化验：胆红素34.2mol/L，SGPT120u，血氨120 g/dl。

  4. Function of the liver • Digestion • excretion • synthesizing • detoxification • metabolic • immune

  5. Causes of Liver Disease • Biological Factors: • Physical and Chemical Factors: • Genetic Factors: • Immunity Factors: • Nutritional Factors:

  6. Hepatic insufficiency Jaundice Bleeding infection renal dysfunction encephalopathy Severe damage in liver cells Causes hepatic failure

  7. hepatic encephalopathy Neuropsychiatric symptoms occuring in patients with severe liver diseases are usually summarized as hepatic encephalopathy (HE)

  8. Classification Endogenous HE 25% Fulminant hepatic failure Exogenous HE 75% Portal-systemic encephalopathy Plasma level of ammonia↑

  9. Stages • Stage 1： slight altered mood or behavior including sleeping rhythm, light flapping tremor ； • Stage 2：drowsy, inappropriate behavior • Stage 3： Coma but arousable, speech incomprehensible • Stage 4：Coma , no response to painful stimuli, no flapping tremor。

  10. Clinical presentation Coma Drowsiness Confusion Sleeping disorder Apathy Childishness

  11. Pathogenesis Multifarious toxins → Dysfunction of CNS (No obvious morphological change) Several hypotheses to uncover the mystery

  12. Ammonia intoxication hypothesis • Supporting evidence • 80% of HE show increased plasmaammonia level • patients with hepatocirrhosis have elevated level of ammonia • symptom of HE and alteration in electroencephalogram(EEG) after high protein diet

  13. NH3 clearance （urea cycle） NH3 production Under normal condition, the production and the clearance of NH3isin balance Plasma ammonia: <59μmol/L

  14. NH3 clearance NH3 production Severe hepatic dysfunction Hyperammonemia HE

  15. Causes (1) urea synthesis ↓,ammonmia clearance ↓ • ATP ↓ • enzyme ↓ • substance ↓ urea ↓; NH3↑

  16. Production of urea:2NH3+4ATP→1 urea

  17. bacterium mucosa edema Intes. amino acid Renal dys -function Intestinal urea NH3 Activity of muscle Acetylic acid decompose Urine intestinal pH (2) production of ammonia↑ hemorrhage

  18. 管腔 血液 肾小管上皮细胞 H+ NH3 NH4+ 酸中毒时

  19. 血液 管腔 肾小管上皮细胞 OH- NH3 碱中毒时

  20. 肠道 血液 pH NH3 H+ ＋ NH3 NH4+ 经肠道排出

  21. The reasons of NH3↑ Production↑ clearance↓ GI tract urea syntheses liver renal NH3 Portal-systmic shunts muscles

  22. Effect of ammonia on CNS (1) Decreasing energy production (2) Changing neurotransmitters increasing glutamine and GABA decreasing glutamic acid and acetyl choline (3) Disturb membrane function

  23. (1) Ammonia interferes with brain energy metabolism: ATP production ↓, expending↑ α酮戊二酸↓ NH3+NADH ↓+H+ 谷氨酸 H2O+NAD+ ATP ↓ glutamine Glutamic acid+NH3 Pyruvate decarboxylase (丙酮酸脱羧酶) － Acetyl CoA ↓ pyruvate

  24. (2) Ammonia alters brain neurotransmitter • Glutamic acid(Glu) ↓ glutamine(Gln)↑ • Acetylcholine(Ach) ↓ GABA↑ Acetyl CoA+choline Ach

  25. 高血氨的毒性作用 葡萄糖 6-磷酸葡萄糖 磷酸果糖激酶 NADH NAD 乙酰辅酶A 丙酮酸 乳酸 + 草酰乙酸 胆碱 乙酰胆碱 琥珀酸 柠檬酸 ATP NAD NADH α-酮戊二酸 γ-氨基丁酸 NADH +NH3 NAD +NH3 谷氨酰胺 谷氨酸 ATP

  26. NH3 K+ Na+-K+-ATPase Na+ (3) Ammonia inhibits nerve cell excitability

  27. Summary of ammonia intoxication Urea synthesis production of ammonia↑ Severe hepatic dysfunction hyperammonemia Brain dysfunction Elevated level of brain ammonia

  28. 2.False neurotransmitter hypothesis Positive evidence: • No correlation in ammonia lever and clinical symptom in 20% HE patients • Treatment of coma patients with L-dopa recover the consciousness

  29. (1) Reticular formation of brain stem and the maintenance of waking state • the maintenance of waking state is depending on the ascending activiating system of Reticular formation • eg: electrically stimulate Reticular formation→arouse animal destroy headend of Reticular formation → permanent stupor • NA and dopamine are important neurotransmitters

  30. 脑干网状结构与觉醒

  31. Brain stem reticular structure maintains consciousness through NT Cerebral cortex Secondary Neuron Interbrain NT Brain stem reticular structure Ascending nerve impulse

  32. Excitation of secondary neuron Excitation of secondary neuron synapse FNT compete receptor True NT Normal Hepatic failure Mode shown replacement of true NTs FNT in HF

  33. (2) False neurotransmitters and liver coma (Intest.) (blood) N：苯丙氨酸↑ 肠菌 苯乙胺 酪氨酸↑ (decarboxylase) 酪胺 (portal vein) liver ( monoamine oxidase) clearance Liver： 苯乙胺↑、 酪胺↑→ brain failure β-hydroxylase  苯乙醇胺 羟苯乙醇胺 replace NE、DA，but its physiological effect is weak coma

  34. Norepinephrine Phenylethanolamine CH2CH2NH2 CHOHCH2NH2 HO HO CHOHCH2NH2 CHOHCH2NH2 HO HO HO Dopamine Octopamine True neurotransmitters False neurotransmitters

  35. 3. Plasma amino acid imbalance hypothesis Healthy: branched chain aa/aromatic aa＝ 3.0～3.5/1 (BCAA) (AAA) Liver failure: BCAA↓/AAA↑＝0.6～1.2 often <1 BCAA: valine(缬氨酸), leucine（亮氨酸）, isoleucine（异亮氨酸） AAA: phenylalanine（苯丙氨酸），tyrosine（酪氨酸），tryptophan（色氨酸）

  36. Hormone regulation of AA imbalance and NT production Insulin BCAA Hepatic dysfunction BCAA/AAA Portal systemic circulation Insulin / glucagon AAA Dysfunction in excitation NT FNT AAA enter to brain Coma

  37. 丙 乙 ① ③ ④ ②

  38. Central dogma for AA imbalance & FNT hypothesis AAA FNT Phenylalanine Phenylethanolanine Tyrosine → Octopamine Tryptophan Serotonin Ascending reticular activating system (-) Coma

  39. 4. GABA hypothesis Supporting evidence Blood GABA level significantly increased in experimental rabbits with hepartic encephalopathy Over-expressed GABA receptor was seen in brain of hepatic encephalopathy

  40. Dysfunction of liver Blood GABA Collateral circulation Hemorrhage of digestive tract GABA in brain Blood-brain barrier permeability GABA hypothesis

  41. Post-synapse inhibition

  42. Pre-synapse inhibition

  43. Comprehensive view Blood Brain Intestine GABA ↑ → GABA↑ ATP↓ NH3 ↑ → GA↓, Ach↓ ↓ Glutamine↑ Glucagon→ AAA↑ → AAA↑→FNT Insulin → BCAA↓

  44. Precipitating factors 1. Toxins produced in intestine↑ 2. Permeability of blood – brain barrier↑ 3. Increased sensitivity of brain to toxins by hypoxia, fluid and electrolytes abnormalities, infection, hypnotics etc

  45. Treatment Principle of HE • Prevent precipitating factors • To decrease blood ammonia • BCAA、L-dopa

  46. 肝肾综合征 (Hepatorenal syndrome)

  47. 肝肾综合征(hepatorenal syndrome) 是指肝硬化患者在失代偿期所发生的功能性肾功能衰竭及重症肝炎所伴随的急性肾小管坏死。

  48. 一、肝肾综合征的类型 (Classification of hepatorenal syndrome)

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