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

    cadaveric)

  • 3

  • 4

    Synthesis

    Vasoregulation

    Detoxification

    Immune control

    Metabolism

  • 5

    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

  • 7

    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

  • 8

    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?

  • 9

    Breaching Barriers.

    Franz J. Zemp et al., Sci Transl Med 2014;6:237fs22

  • 10

    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

  • 11

    Fig. 4. Disturbance of host-microbial mutualism in human patients with liver dysfunction.

    Maria L. Balmer et al., Sci Transl Med 2014;6:237ra66

  • 12

    Immune functions (numerous interactions)

    Hepatology. 2014 Dec;60(6):2109-17. doi:

    10.1002/hep.27254.

    Immune tolerance in liver disease

    https://www.ncbi.nlm.nih.gov/pubmed/24913836 https://www.ncbi.nlm.nih.gov/pubmed/24913836

  • 13

    And the hepatocyte as the agent

    J Immunol. 2016 Jan 1;196(1):17-21. doi:

    10.4049/jimmunol.1501668.

    Hepatocytes as Immunological Agents.

    https://www.ncbi.nlm.nih.gov/pubmed/26685314 https://www.ncbi.nlm.nih.gov/pubmed/26685314 https://www.ncbi.nlm.nih.gov/pubmed/26685314

  • 14

    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

  • 16

    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

  • 17

    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

  • 18

    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

  • 19

    Scoring Systems in Chronic liver failure

    • Bleeding

    • Jaundice

    • Malnutrition

    • Ascites

    • Oedema

    • Pruritus

    • Encephalopathy

    • Malignoma

    Synthetic failure and

    portal hypertension

    Child Pugh

    MELD

  • 20

    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

  • 21

    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

    enzymes

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

    postinjection

    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

  • 24

    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

  • 25

    Validation: 99mTc-Galactosyl Serum Albumin Scintigraphy