Download 12.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
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。
Function of the liver

Digestion

excretion

synthesizing

detoxification

metabolic

immune
Causes of Liver Disease
– Biological Factors:
– Physical and Chemical Factors:
– Genetic Factors:
– Immunity Factors:
– Nutritional Factors:
Hepatic insufficiency
Jaundice
Bleeding
infection
renal dysfunction
Severe
damage in
liver cells
encephalopathy
hepatic failure
Causes
hepatic encephalopathy
Neuropsychiatric symptoms occuring
in patients with severe liver diseases
are usually summarized as
hepatic encephalopathy (HE)
Classification
Endogenous HE
25%
Fulminant hepatic failure
Exogenous HE
75%
Portal-systemic encephalopathy
Plasma level of ammonia↑
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。
Clinical presentation
Coma
Drowsiness
Confusion
Sleeping disorder
Apathy
Childishness
Pathogenesis
Multifarious toxins → Dysfunction of CNS
(No obvious morphological change)
Several hypotheses to
uncover the mystery
1. Ammonia intoxication hypothesis
Supporting evidence

80% of HE show increased plasma
ammonia level
 patients with hepatocirrhosis have
elevated level of ammonia
 symptom of HE and alteration in
electroencephalogram(EEG) after high
protein diet
Plasma ammonia: <59μmol/L
NH3 production
NH3 clearance
（ urea
cycle ）
Under normal condition, the production
and the clearance of NH3 is in balance
NH3 clearance
NH3 production
Severe hepatic dysfunction
Hyperammonemia
HE
Causes
(1) urea synthesis ↓,ammonmia
clearance ↓
• ATP ↓
• enzyme ↓
• substance ↓
urea ↓; NH3↑
Production of urea:
2NH3+4ATP→1 urea
(2) production of ammonia↑
mucosa edema
hemorrhage
Renal dys
-function
Intes. amino acid
Intestinal urea
Activity of
muscle
Urine
intestinal
bacterium
Acetylic acid
decompose
pH
NH3
血液 肾小管上皮细胞 管腔
H+
NH3
酸中毒时
NH4+
血液
肾小管上皮细胞 管腔
NH3
碱中毒时
OH-
肠道
血液
pH
H+ ＋ NH3
NH4+
经肠道排出
NH3
The reasons of NH3↑
Production↑
clearance↓
GI tract
renal
muscles
urea syntheses
NH3
Portalsystmic
shunts
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
(1) Ammonia interferes with brain
energy metabolism: ATP production ↓,
expending↑
α酮戊二酸↓
NH3+NADH ↓+H+
谷氨酸
H2O+NAD+
ATP ↓
Glutamic acid+NH3
glutamine
Pyruvate decarboxylase－
pyruvate
(丙酮酸脱羧酶)
Acetyl CoA ↓
(2) Ammonia alters brain
neurotransmitter
• Glutamic acid(Glu) ↓
• Acetylcholine(Ach) ↓
Acetyl CoA+choline
glutamine(Gln)↑
GABA↑
Ach
高血氨的毒性作用
葡萄糖
6-磷酸葡萄糖
磷酸果糖激酶
NADH
乳酸
NAD
乙酰辅酶A
+
丙酮酸
胆碱
草酰乙酸
NAD
NADH
γ-氨基丁酸
琥珀酸
柠檬酸
ATP
α-酮戊二酸
NADH
NAD
+NH3
+NH3
谷氨酸
ATP
谷氨酰胺
乙酰胆碱
(3) Ammonia inhibits nerve cell
excitability
NH3
K+
Na+-K+-ATPase
Na+
Summary of ammonia intoxication
Severe hepatic
dysfunction
Urea synthesis
production of ammonia↑
hyperammonemia
Brain
dysfunction
Elevated level of
brain ammonia
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
(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
脑
干
网
状
结
构
与
觉
醒
Brain stem reticular structure
maintains consciousness through NT
Cerebral cortex
Secondary
Neuron
Interbrain
NT
Brain stem reticular
structure
Ascending nerve impulse
Excitation of
secondary
neuron
Excitation of
secondary
neuron
synapse
True NT
Normal
FNT compete
receptor
Hepatic failure
Mode shown replacement of true
NTs FNT in HF
(2) False neurotransmitters and liver coma
N：苯丙氨酸↑
肠菌
苯乙胺
(Intest.)
(blood)
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
True neurotransmitters
HO
CHOHCH2NH2
HO
HO
CH2CH2NH2
HO
Norepinephrine
Dopamine
False neurotransmitters
CHOHCH2NH2
CHOHCH2NH2
HO
Phenylethanolamine
Octopamine
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）
Hormone regulation of AA imbalance and
NT production
Hepatic
dysfunction
Portal systemic
circulation
Dysfunction
in excitation
Coma
Insulin
BCAA
BCAA/AAA
Insulin /
glucagon
NT
FNT
AAA
AAA enter
to brain
丙
乙
②
④
①
③
Central dogma for AA imbalance & FNT
hypothesis
AAA
FNT
Phenylalanine
Tyrosine
→
Tryptophan
Phenylethanolanine
Octopamine
Serotonin
-
( )
Ascending reticular activating system
Coma
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
GABA hypothesis
Dysfunction of liver
Collateral circulation
Blood GABA
Hemorrhage of
digestive tract
Blood-brain barrier permeability
GABA in
brain
Post-synapse inhibition
Pre-synapse inhibition
Comprehensive view
Blood
Intestine GABA ↑
NH3 ↑
↓
Glucagon→ AAA↑
Insulin → BCAA↓
Brain
→
GABA↑
ATP↓
→ GA↓, Ach↓
Glutamine↑
→ AAA↑→FNT
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
Treatment Principle of HE



Prevent precipitating factors
To decrease blood ammonia
BCAA、L-dopa
肝肾综合征
(Hepatorenal syndrome)
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。
一、肝肾综合征的类型
(Classification of
hepatorenal syndrome)
(一) 肝性功能性肾衰竭
(Hepatic functional renal failure)
患者肾脏无器质性病变，
但肾血流量明显减少，肾小
球滤过率降低，而肾小管功
能正常。
(二)肝性器质性肾衰竭
(Hepatic parenchymal renal failure)
器质性肾衰竭的主要病理
变化是肾小管坏死。主要与肠
源性内毒素血症和大出血有关。
二、肝性功能性肾衰竭的发病机制
(Mechanisms of hepatic
functional renal failure)
肝硬变患者在失代偿期
发生的少尿是功能性的
(一)
肾素-血管紧张素系统兴奋
(Excitement of reninangiotension system)
肾血流量减少
激活肾素-血管
紧张素系统
肾血管收缩
(二)交感-肾上腺髓质系统兴奋
(Excitement of sympathetic
nervous-adrenal medulla system)
有效循环血量
血容量
交感-肾上腺髓质
系统兴奋
(三) 前列腺素合成不足
(Diminished synthesis
of prostaglandin)
前列腺素合
成酶抑制剂
肾血流量和肾
小球滤过率
(四)内毒素血症
(Endotoxemia)
(五) 假性神经递质蓄积
(Accumulation of false
neurotransmitter)
假性神经递质
肾皮质血流量