novel technologies for organ assessment · detoxification immune control metabolism . 5 some...
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Novel Technologies for Organ Assessment
• Assessment of liver function
Vanessa Banz, MD, PhD
Daniel Candinas, MD
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Relevance of assessing liver function
•Prognostic context in acute and end
stage liver disease
•Adjusting pharmakodynamics
•Prevention of liver failure after partial
liver resection
•Assessing donor liver function (life and
cadaveric)
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Synthesis
Vasoregulation
Detoxification
Immune control
Metabolism
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Some Metabolic functions
• Glucose and Fatty Acids
• Lipoprotein
• Plasma Protein
• Vitamin Metabolism (A & D)
• Xenobiotics
• Bilirubin
• Receptor Mediatied Endocytosis and Metabolism
• Iron & Copper Metabolism
• Amino Acid Metabolism
• Etc..
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The liver as a vasoregulatory organ
Casting of the mouse liver vasculature by D. Sidler, D. Inderbitzin & V. Djonov, D. Candinas
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Full liver function depends on the integrity of all
cellular compartments (e.g. biliary microcirculation)
Haratake et al; Hepatology
1991;14(6):1196-200.
Hepatic artery
thrombosis after
OLT
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The liver as an immune organ
• Infection and Sepsis are dominant causes of death in liver
failure
– Chronic liver failure
– Acute liver failure
– Small for size syndrome
– Post transplant
How to measure immune function?
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Breaching Barriers.
Franz J. Zemp et al., Sci Transl Med 2014;6:237fs22
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Liver firewall function is compromised in liver disease independently of alterations in innate
immunity.
Maria L. Balmer et al., Sci Transl Med 2014;6:237ra66
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Fig. 4. Disturbance of host-microbial mutualism in human patients with liver dysfunction.
Maria L. Balmer et al., Sci Transl Med 2014;6:237ra66
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Immune functions (numerous interactions)
Hepatology. 2014 Dec;60(6):2109-17. doi:
10.1002/hep.27254.
Immune tolerance in liver disease
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And the hepatocyte as the agent
J Immunol. 2016 Jan 1;196(1):17-21. doi:
10.4049/jimmunol.1501668.
Hepatocytes as Immunological Agents.
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there is no liver function test available that
measures all components of liver function
Restricted information on functionality
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Functions tests – a choice
• Passive Liver function tests
– Bilirubin
– Albumin and Coagulation factor synthesis
• Clinical grading systems
– Child Pugh Score
– MELD Score
• Dynamik Quantitaty tests
– Indocyanine Greeen Clearance Test
– Galaktose Capacity Test
• Mulecular nuclear imaging techniques
– 99mTc-Galactosyl Serum Albumin Scintigraphy
– 99mTc-Mebrofenin Hepatobiliary Scintigraphy
• From morphology to function
– Imaging assessment
– Stiffness
– Histology
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Passive tests: Bilirubin
• plasma concentration -> indirect information on uptake, conjugation,
excretion of the liver
• any liver pathology that affects organic anion transporting polypeptide
expression automatically alters bilirubin kinetics
e.g. cytokines released by Kupffer cells
skew bilirubin-related test outcomes
• influenced by nonhepatic factors
plasma bilirubin concentration is not a parameter of
liver function per se in these instances
Hoekstra, Annals of Surgery 2013
Tanaka, Transplantation 2006
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Passive tests: Albumin & Clotting Factors
• Factor V, XIII, fibrinogen, antithrombin, α2-plasmin inhibitor,
and plasminogenare exclusively synthesized by the liver
• Plasma concentrations are indirect indicators of liver
synthesis function Hoekstra, Annals of Surgery 2013
Clichy-Villejuif (CV) criteria in France (Factor V & Encephalopathy) J. Bernuau et al: Hepatology 1991
“The performance of current criteria for SU transplantation could be improved if
paracetamol-induced ALF and non–paracetamol-induced ALF were split and 2
other items were included in this model: the bilirubin level and creatinine
clearance. “ Cherqui et al: Liver Transpl 21:512-523, 2015
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Arterial pH < 7.3 or
Prothrombin time > 100 s
Grad III Encephalopathy
Creatinin > 300 µmol/L
Age < 30 yrs & Factor V < 20%
Age >30 yr & Factor V < 30%
Scoring Systems in Acute liver failure
Time to recovery ?
Underlying disease
Preserved function
Cerebral oedema
Metabolic failure
Multiorgan failure
Complications Regeneration
Kings criteria
Clichy-Villejuif criteria
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Scoring Systems in Chronic liver failure
• Bleeding
• Jaundice
• Malnutrition
• Ascites
• Oedema
• Pruritus
• Encephalopathy
• Malignoma
Synthetic failure and
portal hypertension
Child Pugh
MELD
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Dynamic tests: Indocyanine Green Clearance Test
• Tricarbocyanine dye that binds to albumin & lipoproteins
• Distributes uniformely after injection within 3 min
• Exclusively cleared by hepatocytes and excreted into bile
• Elimination depends on: blood flow, cellular uptake, biliary
extrection
–Plasma disappearance rate
(PDR) normal ranges:16% and 25% per minute
– Indocyanine green elimination
rate constant (indocyanine green-k)
– Indocyanine green-R15
(% clearance at 15 min)
Paumgartner G. Schweiz Med Wochenschr. 1975
Faybik P. Transplant Proc. 2006
Sakka SG. Assessing liver function. Curr Opin Crit Care. 2007
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IGC Validation
• Several studies report moderate-high correlation with
outcome after surgery, liver resection, transplantation
• Conversly ICG may be misrepresentativ:
– strongly dependent on hepatic blood flow alterations,
inhomogenous structural changes
– reduced transport capacity
Caveat in:
–cholostatic patients
– Hemodynamically instable patients
Limited value Hoekstra, Annals of Surgery 2013
Inderbitzin D: J Gastrointest Surg. 2005
Lam CM: Br J Surg. 1999
Watanabe Y: J Cardiothorac Vasc Anesth 1999
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Dynamic tests: Galactose Elimination Capacity Test
• Determines the metabolic capacity
• Galactose is phosphorylated intracellularly to galactose-1-
phosphate by galactokinase. Galactose-1-phosphate is
then converted to glucose-1-phosphate by the action of 4
enzymes
• GEC is calculated from serial serum samples 20 - 50 min
postinjection
Goresky CA: J Clin Invest. 1973
Holden HM: J Biol Chem. 2003
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GEC Validation
• prognostic significance in
–chronic liver disease
– fulminant hepatic failure
• Abnormal clearance in patients with liver metastasis
• Alterations in liver metabolims affect predictive value
–Environmental changes
–Hypoxia (HRE Sites in key enzyme) D. Stroka, personal communiction
– Increased membrane synthesis during liver regeneration
–Altered galactose kinetics during regeneration and fasting
–Only global function measured (no anatomical correlate)
Herold C: Liver. 2001
Redaelli CA: Ann Surg. 2002
Reichen J: Hepatology. 1991
Hoekstra, Annals of Surgery 2013
+/- robust test, time consuming
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Molecular imaging techniques: 99mTc-Galactosyl
Serum Albumin Scintigraphy
• 99mTc-diethylenetriamine-pentaacetic acid-galactosyl human serum
albumin = analogue ligand of asialoglycoprotein binding to
asialoglycoprotein receptors on
the hepatocyte cell membrane
• Receptors are expressed only
on the hepatocyte sinusoidal
surface facing the space of
• Uptake via receptor-mediated
endocytosis.
• The liver is the only uptake site
Hoekstra L: Annals of Surgery. 257(1):27-36, January 2013. Digital Object Identifier: 10.1097/SLA.0b013e31825d5d47
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Validation: 99mTc-Galactosyl Serum Albumin Scintigraphy
• Test has proven valuable in cirrhotic patients
• Demonstrated a good relationship with conventional liver
function tests and histology
• Is not influenced by hyperbilirubinemia (not binding)
• No biliary excretion
• Not suitable for the evaluation of biliary obstruction
Hoekstra L: Annals of Surgery. 257(1):27-36, January 2013
Takeuchi: Hepatogastroenterology. 1999
Satoh K: Ann Nucl Med. 2003
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From morphology to function
• Tests based on stiffness assessment
–Fibroscan
–MRI based
• Histology / Macroscopy (Laparoscopy)
• Volumetry
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Liver stiffness correlates with ICG Clearance Acoustic radiation force impulse (ARFI) imaging in patients with liver tumors
Sun XL: World J Gastroenterolog 2015
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Liver stiffness with different degrees of fibrosis measured using
magnetic resonance elastography
In correlation with indocyanine green retention rate at
15 min and indocyanine green plasma clearance rate
A-C: LS, 2.9 kPa; ICGR-15, 0.003; ICG-K, 0.398
D-F: LS, 4.4 kPa; ICGR-15, 0.057; ICG-K, 0.191
G-I: LS, 5.1 kPa; ICGR-15, 0.083; ICG-K, 0.166
J-L: LS, 10 kPa; ICGR-15, 0.252; ICG-K, 0.092
ICGR-15: Indocyanine green retention rate at 15 min;
ICG-K: Indocyanine green plasma clearance rate; LS: Liver
stiffness.
Native Stiffness ICGR-15
Bin L: World J Gastroenterol 2015
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Computer based Volumetry with risk analysis
Examples of Clinical Cases University Hospital Bern
calculated with MEVIS System
MEVIS Medical Solutions AG, Bremen, Germany
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Clinical scenarios
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Highlight: Small for Size Syndromes
• High flow small volume SFS syndrome.
• Poor function small volume small for size syndrome
Standard liver Volume ca. 25- 30%
Correction: Steatosis - Drug damage, Fibrosis, Resection margins
Portal Perfusion – venous Obstruction – biliary
obstruction – arterial flow
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Assessing Chemotherapy associated liver damage
SOS (sinusoidal obstructive Syndrome)
In a clinical Case
post Neoaduvant Chemotherapy
University Hospital Bern
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day 0 day 7
Seg II/III 720ml 950ml
Patient M 69 J – 105 kg – post Chemo with SOS Syndrom
Pictures courtesy to PD Martin Maurer, Radiologie Inselspital
ASSOCIATING LIVER PARTITION WITH PORTAL VEIN LIGATION FOR
STAGED HEPATECTOMY (ALPPS )
Plus 31%
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‘Marginal’ liver donor
One or more of the following:
–Adverse history • Alcohol abuse, Drug overdose, Severe cardiovascular disease
–severely deranged LFTs –severe steatosis – lengthy hypotension –high-dose inotropes –prolonged ITU stay –sepsis
Mirza D, Lancet 1994
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Steatosis of the liver and transplantation
• Macroscopic greasy, yellow
• Microscopic
macro- microvesicular
Mild <30% save save
Moderate 30-60% IPF ok
Severe >60% PNF ! IPF
Adapted from D’Alessandro 1991
Fishbein 1997 and Barbier 2016
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Preservation injury and severe steatosis
deterioration in
mitochondrial function
Decreased plasma
membrane fluidity
ATP depletion Bleb formation Sinusoidal lining
cell injury
Sinusoidal microcirculatory disorder
Poor graft function
Fukomori, Tranplantation 1999
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Conclusions
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0
10
20
30
40
50
60
26% 60% 75%
% liver resected
% B
rdU
po
sitiv
e c
ells
We know: The liver regenerates !
60%
75%
26%
Inderbitzin D, Studer P, Candinas D: Personal communication
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0
10
20
30
40
50
60
26% 60% 75% 83%
% liver resected
% B
rdU
po
sitiv
e c
ells
... but not always!
60%
75%
26%
83% Inderbitzin D, Studer P, Candinas D: Personal communication
Pushing the margin of safety
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In clinical pratice
• A «sound» combination of more than one liver function test
is needed
• In critical cases protocols for dynamic tests should be
established and working in institutions
• In doubt surgeons use either minimally invasive methods
(e.g. ablations and local resections) rather than large
anatomical resections
• In doubt for small for size syndrome surgeons favour
staged procedures and protocols that induce hypertrophy
• Nothing replaces a interdisciplinary evaluation of patients
at risk