patholophysiology of Hepatic Failure Pathophysiology（病理生理学） Pathology uploaded by prabesh 杰诗

1. Dept. of PathologyDept. of Pathology
Medical CollegeMedical College
Hunan Normal UniversityHunan Normal University
(( 湖南 范大学医学院病理学教研室师湖南 范大学医学院病理学教研室师 )) 1
Chapter 13Chapter 13
Hepatic FailureHepatic Failure
（肝 衰竭）脏（肝 衰竭）脏

2. 22
Hepatic FailureHepatic Failure
a.a. IntroductionIntroduction
b.b. EtiologyEtiology
c.c. Functional & Metabolic ChangesFunctional & Metabolic Changes
d.d. Hepatic EncephalopathyHepatic Encephalopathy
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

3. Functions of the Liver
11 、、 MetabolismMetabolism ：： Materials and energyMaterials and energy
22 、、 SecretionSecretion ：： BileBile
33 、、 SynthesisSynthesis ：： Albumin, coagulation factorsAlbumin, coagulation factors
44 、、 Immune functionImmune function
55 、、 DetoxificationDetoxification ：： Drugs, toxins andDrugs, toxins and
metabolic wastesmetabolic wastes

4. 4
Definition
Various harmful factors
↓
Hepatocytes and non-parenchymal cells damaged
↓
Severe disturbance of liver function
↓
Degeneration, necrosis and fibrosis of liver tissue
↓
“Hepatic insufficiency”
↓
“Hepatic failure”
Hepatic encephalopathy
Hepatorenal syndrome

5. 55
Hepatic FailureHepatic Failure
a.a. IntroductionIntroduction
b.b. EtiologyEtiology
c.c. Functional & Metabolic ChangesFunctional & Metabolic Changes
d.d. Hepatic EncephalopathyHepatic Encephalopathy
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

6. Etiology
Environmental Factors (– 85%)
Infection
Alcoholism
Poison
Genetic Factors (– 15%)

7. Global Distribution of CHB Carriers
Low < 2% Intermediate 2-8% High > 8%
HBsAg Prevalence
Source: World Health Organization / Centers for Disease Control and Prevention.

8. Alcoholism
#2 Killer of the Liver
45 g/d ， 5
y ， 29.8 ％

9. 1010
Hepatic FailureHepatic Failure
a.a. IntroductionIntroduction
b.b. EtiologyEtiology
c.c. Functional & Metabolic ChangesFunctional & Metabolic Changes
d.d. Hepatic EncephalopathyHepatic Encephalopathy
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

10. 11
(1)(1) metabolismmetabolism::
(2)(2)
(3)(3)
(4)(4)
(5)(5)
(6)(6)
(7)(7) OrganOrgan dysfunctiondysfunction
hepatorenal syndrome, hepatic encephalopathyhepatorenal syndrome, hepatic encephalopathy
Disturbance ofDisturbance of metabolismmetabolism::
carbohydrate, lipids, protein, vitaminscarbohydrate, lipids, protein, vitamins
Dysfunction ofDysfunction of bile metaboilsmbile metaboilsm::
hyperbilirubinemia, intrahepatic cholestasishyperbilirubinemia, intrahepatic cholestasis
Disorder ofDisorder of coagulationcoagulation::
generation↓ or consumption↑generation↓ or consumption↑
→→ clotting factor↓→ bleedingclotting factor↓→ bleeding
tendencytendency
Dysfunction ofDysfunction of detoxication (bioconversion)detoxication (bioconversion)
drug metabolism; detoxication of toxins;drug metabolism; detoxication of toxins;
inactivation of hormonesinactivation of hormones
Dysfunction ofDysfunction of immuneimmune ((Kuppfer cells)Kuppfer cells)
bacterial infection, bacteremia, intestinal endotoxemiabacterial infection, bacteremia, intestinal endotoxemia
Effects of Hepatic Failure on the Body
Acid-baseAcid-base andand electrolyteelectrolyte disturbancedisturbance
hyperkalemia, alkalosishyperkalemia, alkalosis

11. 1. Metabolic Dysfunction
1) Glucose metabolism dysfunction
Decreased blood sugar
Glycogen synthesis, storage↓
Inactivation of insulin↓ → hyperinsulinemia

12. 2) Lipid metabolism dysfunction
 Dysfunction of lipid absorption
↓ bile secretion
 Fat accumulation → fatty liver
↓ secretion of lipids (cholesterol and triglycerides)

13. EdemaEdema
Hemorrhagic tendencyHemorrhagic tendency
Decrease in defense functionDecrease in defense function
AnemiaAnemia
3) Protein metabolism dysfunction

14. 4) Vitamin metabolism dysfunction
Vit K—hemorrhagic tendency （出血倾
向）
Vit D (25-OH)—osteoporosis （骨 疏质
松）
Vit A —Night blindness （夜盲症）

15. Hyperbilirubinemia → Jaundice
2. Bile metabolism dysfunction

16. 3. Dysfunction of Coagulation
Subcutaneous hemorrhage

17. 4. Dysfunction of Detoxication
Estrogen inactivation ↓ → dilation of arterioles

18. 5) Immune Dysfunction
Kupffer cell dysfunction
Decreased complements
Intestinal endotoxemia

19. 6. Water and Electrolyte Imbalance
Edema - hepatic ascites

20. Hypokalemia ADS Excretion of K↑→ +
↑
Intake of K+
↓
Respiratory
Metabolic
Alkalosis

21. 7. Organ Dysfunction
Hepatorenal syndrome
Hepatic encephalopathy

22. 2323
Hepatic FailureHepatic Failure
a.a. IntroductionIntroduction
b.b. EtiologyEtiology
c.c. Functional & Metabolic ChangesFunctional & Metabolic Changes
d.d. Hepatic Encephalopathy (HE)Hepatic Encephalopathy (HE)
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

23. Apoptosis Oxygen Society Education Program Tome & Briehl 24
Hepatic Encephalopathy
Concept
Staging
Pathogenesis

24. 25
A serial of
Neuropsychical symptoms
Hepatic encephalopathy
Concept
Acute or chronic liver disease
Hepatic coma
ultimate clinical manifestation of HE

25. Apoptosis Oxygen Society Education Program Tome & Briehl 26
Hepatic Encephalopathy
Concept
Staging
Pathogenesis

26. Stage I: Apathy (unemotional) Period
 Slight personality and behavioral disorders
 Memory loss
 Learning disability, disorientation

27. Stage II: Confusion Period
 Mental confusion
 Increased muscle tone, asterixis

28. Stage III: Drowsiness Period
 Irritability
 Temper

29. Stage IV: Coma period
 Loss of consciousness

30. Staging of Hepatic Failure
Apathy
Confusion
Drowsiness
Coma

31. Apoptosis Oxygen Society Education Program Tome & Briehl 32
Hepatic Encephalopathy
Concept
Staging
Pathogenesis

32. 33
a. Theory of ammonia intoxication
b. Theory of false neurotransmitters
c. Theory of amino acid imbalance
d. Theory of GABA (gamma-aminobutyric acid)
Pathogenesis of Hepatic
Encephalopathy

33. 34
①① The ammonia level in blood of 80% HE patients wasThe ammonia level in blood of 80% HE patients was
increased by 1~3 fold.increased by 1~3 fold.
②② HE may be induced by eating nitrogen-containing foodHE may be induced by eating nitrogen-containing food
in patients with liver cirrhosis, and restricting intakein patients with liver cirrhosis, and restricting intake
may alleviate HE.may alleviate HE.
③③ Ammonia-lowering treatment was effective in part ofAmmonia-lowering treatment was effective in part of
patients with HE.patients with HE.
④④ Animal model of HE may be created with ammoniumAnimal model of HE may be created with ammonium
chloride.chloride.
Evidence Supporting Ammonia Intoxication

34. Normal
Urea NH3
Excretion
NH3
AAs
Urea
Metabolism of
NH3 in liver:
Urea Cycle

35. NH3 production NH3 clearance
Balanced Production and Clearance
of Ammonia

36. 39
Causes of Increased Plasma Level of
Ammonia
1) Excessive generation of ammonia
2) Decreased removal of ammonia

37. 40
Bleeding of GI tract
→ Proteins entering GI tract
Portal vein hypertension
→ Blood stagnancy and edema of enteric wall
Increased muscle activity
→ Adenylate breakdown, releasing more NH3
Alkalosis
NHNH44
++
NHNH33
OHOH++
HH++
1) Excessive Generation
of Ammonia

38. ----Disturbance of Urea (Ornithine) CycleDisturbance of Urea (Ornithine) Cycle
----Formation of Collateral CirculationFormation of Collateral Circulation
2) Decreased Removal of NH3

39. Disturbance of Urea Cycle
Damage of liver
↓
Disturbance of Urea Cycle
(Ornithine Cycle)
↓
Decreased removal of ammonia
↓
More ammonia entering blood Ornithine
Citralline
Arginine
NH3
NH3
Urea

40. NH3↑
NH3Urea ×
NH3↑
NH3
AAs
Urea
Disturbance of Urea Cycle
Ornithine
Citralline
Arginine
NH3
NH3
Urea

41. NH3
血 NH3↑ NH3↑
NH3↑
NH3↑
Collateral
Circulation
↑
NH3
AAs
Urea
Formation of Collateral Circulation

42. 45
Toxic Effects of Ammonia on Brain
1) Interfering cerebral energy metabolism
2) Changes of neurotransmitters in the brain
3) Direct inhibitory effect on neural cell membrane

43. Glutamine↑
GABA
Acetyl CoA ↓
NH3
↓
Glutamate ↓
Glucose
PyruvateLactate
Oxaloacetate
Citrate
Succinate
α-Ketoglu-
tarate
ATP
Choline Acetylcholine ↓
ATP ↓
↓
46
1) Interfering Cerebral Energy Metabolism
GABA: γ-aminobutyric acid

44. Excitatory
neurotransmitters （ Glutamate 、 acetylch
oline ）↓
Inhibitory neurotransmitters
（ Glutamine 、 GABA ）↑
2) Changes of Neurotransmitters in the Brain

45. Glutamine↑
GABA
Acetyl CoA ↓
NH3
↓
Glutamate ↓↓
Glucose
PyruvateLactate
Oxaloacetate
Citrate
Succinate
α-Ketoglu-
tarate
Choline Acetylcholine ↓
ATP
48
2) Changes of Neurotransmitters in the Brain
① Excitatory neurotransmitters↓
② Inhibitory neurotransmitters ↑

46. 49
.
3) Direct Inhibitory Effect on Neural Cell Membrane
NH3 ↑
Inhibit nerve impulse transmission
K+
inflow ↓
Interfere Na+
-K+
pump Compete w/ K+

48. 51
a. Theory of ammonia intoxication
b. Theory of false neurotransmitters
c. Theory of amino acid imbalance
d. Theory of GABA (gamma-aminobutyric acid)
Pathogenesis of Hepatic
Encephalopathy

49. HO
HO
CHOHCH2NH2
HO
CHOHCH2NH2HO
HO
CH2CH2NH2
Norepinephrine
Dopamine
CHOHCH2NH2
Phenylethanolamine
Octopamine
Normal Neurotransmitters (NNT)
vs. False Neurotransmitters (FNT)
NNT FNT

50. Phenylalanine Phenylethanolamine (PE)
Tyrosine Octopamine (OP)
PE
OP
Breakdown ×
PE
OP

51. Mode shown replacement of
NNT w/ FNT in HE
NNT Synapse FNT
Normal Hepatic failure
×

52. 56
a. Theory of ammonia intoxication
b. Theory of false neurotransmitters
c. Theory of amino acid imbalance
d. Theory of GABA (gamma-aminobutyric acid)
Pathogenesis of Hepatic
Encephalopathy

53. 57
3. Theory of Amino Acid Imbalance
 Branched chain amino acid (BCAA):
Valine, leucine, isoleucine
 Aromatic amino acid (AAA):
Phenylalanine, tyrosine, tryptophan
 BCAA/AAA ratio:
BCAA
AAA
Normal
3~3.5
HE
0.6~1.2

54. Effects of Amino Acid Imbalance
BCAA↓, AAA↑
Excessive AAA entering brain
False neurotransmitters
(Phenylethanolamine, Octopamine)
Brain function disturbed

55. 60
a. Theory of ammonia intoxication
b. Theory of false neurotransmitters
c. Theory of amino acid imbalance
d. Theory of GABA (gamma-aminobutyric acid)
Pathogenesis of Hepatic
Encephalopathy

56. 6161
Hepatic FailureHepatic Failure
a.a. IntroductionIntroduction
b.b. EtiologyEtiology
c.c. Functional & Metabolic ChangesFunctional & Metabolic Changes
d.d. Hepatic EncephalopathyHepatic Encephalopathy
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

57. 62
Pathophysiological Basis of
Prevention and Treatment
a.a. Eliminate causative or inducing factorsEliminate causative or inducing factors
b.b. Lower blood ammoniaLower blood ammonia
c.c. Modulate neurotransmittersModulate neurotransmitters
d.d. Liver transplantationLiver transplantation

58. 63
Eliminate causative or inducing factors
 Limit protein intake from the diet
 Prevent upper GI hemorrhage
 Keep stool unobstructed

59. 64
Lower blood ammonia level
 Oral administration of lactulose
to preventing ammonia absorption
 Oral administration of neomycin
to inhibit bacteria
 Supplement Glutamate and Arginine
 Prevent alkalosis

60. 65
Modulate neurotransmitters
 Administration of true neurotransmitters (L-dopa)
L-dopa: precursor of dopamine
 BCAA-rich amino acid mixture to correct amino
acid imbalance

61. Lactulose Lactate and Acetate
Intestinal pHAbsorption of NH3
NHNH44
++
NHNH33
OHOH++
HH++
Use of Lactulose Prevent Ammonia
Absorption
Lactulose