Physiology and Pathophysiology of Liver and Pathophysiology of Liver . ... Focal biliary cirrhosis...
Transcript of Physiology and Pathophysiology of Liver and Pathophysiology of Liver . ... Focal biliary cirrhosis...
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Prof. Anil Dhawan MD FRCPCH
Director , King’s Cell Therapy Unit
Director Paediatric Liver GI and Nutrition
Centre
King’s College Hospital
London
Physiology and Pathophysiology of Liver
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Remit of the talk
• Applied anatomy
• Synthetic functions
• Detoxification functions
• Common pathophysiology states in liver disease – Hepatorenal syndrome
– Hepatopulmonary syndrome
– Ascites
– Encephalopathy
– Portal hypertension
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Hepatic Blood Flow
Dual blood supply
Hepatic Artery (40%)
Portal vein (60%)
Outflow
Three Hepatic Veins
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Formation of bile
Central function of liver
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PC
OCT
NTCP OATP
OC
BA OA
MDR3
OA
MRP2
BSEP
BA
FIC1
MDR1
PS
Cholangiocyte
Cl-
AQPBA
ASBT
AECl-
HCO3-
H2O
CFTR
Cl-
PL
Ch
ABCG5/8
MRPsOSTα/β
Hepatocyte
Focal biliary cirrhosis
cAMP
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glycogen
G6P
pyruvate lactate
glucose
organic acids
NH4+
Urea
Urea cycle
PDH
ATP
TCA cycle
respiratory chain
reducing equivalents
protein
amino acids
triglycerides
free fatty acids
fatty acyl-CoA
ß-oxidation
acylcarnitines
ketones
galactose
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organic acids
NH4+
Urea
Urea cycle
protein
amino acids
• aminoacidopathies
• organic acidemia
• urea cycle disorders
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2-oxo-isocaproate 2-oxo-3-methyl-n-valerate
isovaleryl-CoA 2-methylbutyryl-CoA
3-methylcrotonyl-CoA tiglyl-CoA
3-methylglutaconyl-CoA 2-methyl-3-(OH)butyryl-CoA
3-(OH)-3-methylglutaryl-CoA 2-methylacetoacetyl-CoA
acetacetic acid acetyl-CoA
propionyl-CoA
methylmalonyl-CoA
succinyl-CoA
l-leucine isoleucine valine
2-oxoisovalerate
isobutyryl-CoA
methylacrylyl-CoA
3-(OH)isobutyryl-CoA
3-(OH)isobutyrate
methylmalonyl semialdehyde
propionic acidaemia
isovaleric acidaemia
3-methylglutaconic
acidaemia
HMG CoA lyase def b- ketothiolase def
3-methylcrotonyl
CoA carbox def.
methylmalonic acidaemia
MSUD
pathway: branched chain amino acids
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Detoxification Functions of Liver
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2. Toxin-concentration
3. SecondaryOrgandysfunctions
1. Initial Event
•Infection (bact./viral)•Bleeding•Intoxication•Ischemia•other
Toxin Hypothesis of Liver failure:
•Brain (HE, Edema)•Kidneys (HRS)•Cardiovascular system(SVRI, MAP , CI)•Bone marrow (Depression)•Immune system (Activation/Paralysis)•Liver (Inflammation, Necrosis, Apoptosis)
Hydrophobic substances•Hydrophobic bile acids
•Bilirubin•plasmatic NO•Prostacycline•Indol/Phenol-
Metabolits•Toxic fatty acids
•Thiols•Digoxin/Diazepam-
like subst....
Hydrophilic substances•Ammonia•Lactate
•AAA
Vicious cycle of autointoxication
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NAFLD In Children
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Pathogenesis of NAFLD
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Fatty acids
Esterification
Synthesis of
Fatty acidsTriglycerides
VLDL
Export
Oxidation
Mitochondria
Peroxisomes
Microsomes
HEPATOCYTE
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HEPATOCYTE
Insulin
TNF-
Rad
PC-1
Leptin
Fatty acids
Lipid peroxidation
Fatty acids
Increase in cytochrome P-450 4A
Increase in cytochrome P-450 2E1
Mitochondrial
ß-oxidation overload
Accumulation
of fatty acids
Hyperinsulinemia
Increase in glycoloysis
Decrease in
apolipoprotein
B-100
Synthesis of fatty acids
VLDL
X
Adipocytes
X
Insulin
TNF-
Rad
PC-1
Leptin
Fatty acids
XIncreased uptake
of fatty acids
Accumulation of triglycerides
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HEPATOCYTE
Fatty acids
Insulin
XTNF-
Rad
PC-1
Leptin
Fatty acids
PPAR-
Insulin
XTNF-
Rad
PC-1
Leptin
Fatty acids
Increased uptake
of fatty acids
Adipocytes
Expression of
uncoupling protein-2
Peroxisomal
ß-oxidation
Mitochondrial
ß-oxidation
Chain-shortened
acyl-coenzyme A
H2O2
Diacarboxylic
fatty acid
Microsomal
-oxidation
H2O2
Acyl-coenzyme A
Acyl-coenzyme A
synthetase
Increase in
lipolysis
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Pathogenesis of NAFLD
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Pathogenesis of NAFLD
ROS to Steatohepatitis
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Vascular Pathologies
• Portal inflow – EHPVO
– Portal Vein Sclerosis
• Hepatic artery pathologies– Rare , hepatic artery problems more seen after LTx
• Hepatic venous outflow – Budd Chiari Syndrome
– Sinusoidal obstruction syndrome
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Medussa Head venous pattern
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Spider Naevi
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Renal Involvement In Liver Disease
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Pathogenesis of Acute Kidney Injury
Arterial vasodilatation (‘’VASOPLEGIA’’)
Decreased SVR High Cardiac Output
Renal Auto-regulation becomes Pressure Dependent - Intra-renal Vasoconstriction
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Aetiology of renal involvement in LD
• Multifactorial
• Hypovolaemia induced pre-renal AKI
• Acute tubular necrosis due to profound
hypovolemia and hypotension.
• Direct drug nephrotoxicity (paracetamol,
NSAIDs) OR Drugs affecting both liver/kidney
• Hepatorenal syndrome
• Intra-abdominal hypertension (IAH) and
development of ICS 44
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HEPATO-RENAL SYNDROME
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HRS - Diagnosis of exclusion
• Hepatorenal syndrome (HRS) is defined as the
occurrence of renal failure in a patient with
advanced liver disease in the absence of an
identifiable cause of renal failure
• The diagnosis of HRS is one of exclusion,
so investigations should be performed to
rule out other common causes of AKI.
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Characteristics of Type 1 and Type 2 Hepatorenal Syndrome
Course Precipitating Event
History of Diuretic-Resistant Ascites
Prognosis
Type -1 HRS Precipitous doubling ofserum creatinine in < 2 weeks
Present in > 50% of cases
May or may not bepresent
Without therapy-90-daysurvival of 10%
Type -2 HRS Gradually progressive
Absent Always Present
Median survival-6 months
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Ascites
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Intra-abdominal pressureSugrue et al Arch Surg 1999 134:1082 Malbrain CCM 2005;33:315
263 patients 40.7% increased IAP
Renal dysfunction:
32% with IAP elevated
14% with normal IAP
32% IAP > 12
40% IAP > 20
CVP
PcwP
Compliance
IAP
IVCP
403020100
IAP
40
30
20
10
0
SVCP
403020100
IAP
40
30
20
10
0
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HEPATOPULMONARY SYNDROME
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HPS and clubbing in CLD
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Arterial Oxygenation Defect induced by intrapulmonary vascular dilatation(IPVD) associated with hepatic disease
Definition – HEPATOPULMONARY
SYNDROME
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Hepatopulmonary syndrome (HPS)
Liver disease
Shunting & Intrapulmonary
Arterial hypoxemia Vascular dilatation
In absence of intrinsic cardiopulmonary disease
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• Enhanced pulmonary production of nitric oxide
• Exhaled nitric oxide increased in HPS , normalise after
transplant
• Nitric oxide synthesized by nitric oxide synthase – eNO
and iNO
• eNO – pulmonary endothelial cells
• iNO – alveolar macrophages
• Endothelin 1 acts through ET-A (vascular smooth
muscle)or ET-B receptors (pulmonary endothelium)
• ET-A causes vasoconstriction, ET-B causes vasodilatation
Pathogenesis
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Mechanism of hypoxaemia in HPS
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• Non-specific
• Dyspnoea at rest/exertion
• Platypnoea/orthodeoxea – Arterial PaO2 decreases by
5% or more when the patient moves from a supine to an
upright position -further ventilation-perfusion mismatch
• Spider nevi, digital clubbing, cyanosis
• Differential Diagnosis :
Several pulmonary complications or pleural
complications
Porto-pulmonary hypertension (PPHTN)
Clinical Features of HPS
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CARDIOVASCULAR INVOLVEMENT IN ALF
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Cardiovascular changes in ALF -
Pathogenesis
• Multi-factorial
• Lesser intake, ongoing losses - hypovolaemia
• Severe SIRS and sepsis play a paramount role.
• Vasodilatation - due to loss of vascular tone leads to systemic hypotension, low effective arterial blood volume and high cardiac output
• Cytokine release from the failing liver appears to be partly responsible for the observed haemodynamic disturbances
• Subclinical myocardial injury
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Implication
The associated cardiovascular collapse and
organ hypo-perfusion may be central to the
progression of multiple organ failure
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Strategy
• Target hypovolaemia - fluids
• Target SIRS, infection - antibiotics
• Target vasodilatation – vasopressors-
noradrenaline , vasopressin
• If myocardial depression - Inotropes
• Target Adrenal insufficiency
• Optimise oxygen delivery
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Neurological Involvement In Liver Disease
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Neurologic Support; Brain Swelling
Neurotoxins; ↑ Ammonia Systemic Inflammatory Response
Increased intra-cellular osmotic load
Astrocytic metabolism to glutamine
Mitochondrial toxicity
Failure of energy metabolism
Neurotransmitter alterations
Alterations in BBB ?
Mitochondrial toxicity
Failure of energy metabolism
Water/neurotoxin permeability
Vascular function
Vasomotor dysfunctionEndothelial dysfunction
Acute Hepatic Dysfunction
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Neurological involvement in ALF
• Highly contentious in ALF
• Concept of Hyperaemia vs Ischaemia
• Risk factors for ICP ??
• Neuro-critical care monitoring –To Bolt or Not
to bolt ???
• Role of non/minimally invasive monitoring ??
• Management uncertainties ??????
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Who is at risk of raised ICP?
• 25-75% of ALF with Grade iii/iv
encephalopathy
• Rapid onset
• High ammonia
• Younger age
• Inotropic support
• RRT
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Neurologic Support; Arterial Ammonia and Risk of Cerebral Oedema
ALF Cases, n=165
BERNAL W, ET AL. HEPATOLOGY 2007; 46:1844-52
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Why does raised ICP matter
• Compromises CPP
• Transtentorial herniation
• 2nd commonest cause of death in ALF
• Does measuring it help?
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Summary
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Conclusions
Understanding of applied anatomy and physiology is essential to understand the complications and natural history of liver disease