Novel Technologies for Organ Assessment Detoxification Immune control Metabolism . 5 Some Metabolic

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Transcript of Novel Technologies for Organ Assessment Detoxification Immune control Metabolism . 5 Some Metabolic

  • Novel Technologies for Organ Assessment

    • Assessment of liver function

    Vanessa Banz, MD, PhD

    Daniel Candinas, MD

  • 2

    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


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  • 4




    Immune control


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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..

  • 6

    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


    Hepatic artery

    thrombosis after


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    The liver as an immune organ

    • Infection and Sepsis are dominant causes of death in liver


    – 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


    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:


    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:


    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

  • 15

    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


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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


    –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

  • 22

    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


    • GEC is calculated from serial serum samples 20 - 50 min


    Goresky CA: J Clin Invest. 1973

    Holden HM: J Biol Chem. 2003

  • 23

    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


    • 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