47: Ischemia Reperfusion Injury after Liver Transplantation



Overall Bottom Line


  • LT, by necessity, subjects the liver allograft to ischemia followed by reperfusion.
  • The pattern and severity of IRI that ensues may be clinically irrelevant in the majority of the cases; however, IRI may cause a spectrum of liver dysfunction resulting in DGF or PNF.
  • The clinical consequences of IRI may range from prolonged length of stay, post-operative complications, re-transplantation, and ultimately recipient death.
  • Recent research has elucidated many molecular pathways involved in hepatic IRI; however, only a few experimental interventional modalities currently exist.






Section 1: Background



Definition of disease



  • IRI is a pathologic state characterized by:

    • Ischemic phase injury resulting in significant reduction of microcirculatory blood flow on reperfusion, perpetuating ischemic injury.
    • Inflammatory response, activated during the ischemic phase (initiated by Kupffer cells), which is amplified during the reperfusion phase.
    • Hepatocyte injury and death occurring via inflammatory response (neutrophil activation, complement activation, T cell-mediated apoptosis), as well as directly via ROS resulting in perturbation of ionic homeostasis, depletion of ATP, mitochondrial permeability and transition.
    • Distant organ dysfunction (cardiovascular, lung, kidney) may occur as a direct consequence of hepatic IRI.

  • Therefore, IRI is the pathologic state behind DGF and PNF, regardless of cause.
  • However, the terminology of IRI is often used to describe the clinical state of DGF where no obvious etiology (i.e. vascular thrombosis) can be identified – therefore, it is a diagnosis of exclusion!


Disease classification



  • Normal graft function after LT is characterized by:

    • Intraoperative restoration of hemostasis.
    • Stabilization of hemodynamics.
    • Rapid resolution of encephalopathy.
    • Normalization of INR within 24 hours.
    • Decrease in AST and ALT within 24–48 hours (AST before ALT, AST t½ ∼18 hours, ALT t½ ∼48 hours).
    • Delayed decrease in bilirubin within 48–72 hours.

  • DGF is a clinical state characterized by:

    • Delayed restoration of hemostasis.
    • Delayed stabilization of hemodynamics – may require transient inotropic support.
    • Delayed resolution of encephalopathy.
    • Delayed normalization of INR.
    • Increase in AST and ALT during the first 24–48 hours, followed by decrease.

  • PNF = post-operative fulminant hepatic failure:

    • Complete lack of hemostasis, requiring blood product support.
    • Hemodynamic instability, requiring inotropic support.
    • Unresolving encephalopathy.
    • Multisystem organ failure ensues.
    • Continual rise in LFT, bilirubin and lactic acidosis.
    • Massive graft necrosis.


Incidence/prevalence



  • Although IRI is a relatively frequent clinical phenomenon in LT, little is known about the incidence of DGF, probably because it is not reported. The incidence of PNF is about 5%.


Etiology



  • LT, by necessity, subjects the liver graft to ischemia followed by reperfusion. The transplant liver graft undergoes three phases of ischemia:

    • Warm ischemia – donor ischemic events (codes, “down time”) and in donation after cardiac death, from extubation to aortic cross-clamp.
    • Cold ischemia – during cold preservation, from cross-clamp until off ice.
    • Warm ischemia – during vascular anastomoses, from off ice until reperfusion.

  • During cold ischemia, sinusoidal endothelial cells are vulnerable, while hepatocytes are relatively protected. During warm ischemia, all cell types are vulnerable; thus, cold ischemia is better tolerated than warm ischemia.


Pathology/pathogenesis



Perfusion abnormality during reperfusion worsens ischemic injury



  • Lack of oxygen results in failure of ATPase, leading to intracellular swelling.
  • Increase in vasoconstrictors (endothelin and thromboxane A2) and decrease in vasodilators (nitric oxide).
  • Results in sinusoidal narrowing.
  • During reperfusion, platelet and neutrophil adhesion and sinusoidal narrowing result in reduction of microcirculatory blood flow leading to some areas without reperfusion (“no-reflow”).


Inflammatory activation leads to hepatocyte injury



  • Kupffer cells initiate inflammatory cascade during the ischemic phase – releasing pro-inflammatory cytokines (TNF-α and IL-1β) – recruiting CD4+ lymphocytes during reperfusion, which in turn recruit neutrophils via IL-17.
  • Natural killer cells and platelets are recruited; sinusoidal endothelial cells and hepatocytes are activated.
  • Complement pathways are activated leading to membrane attack complex formation.
  • Toll-like receptor 4 are activated on Kupffer cells and dendritic cells by danger-associated molecular patterns, resulting in further release of pro-inflammatory cytokines (TNF-α and IL-1β via MyD88 dependent pathway) and IP-10 (leukocyte chemoattractant via MyD88 inde­pendent pathway).


ROS cause direct hepatocyte injury



  • Kupffer cells release ROS.
  • ROS cause oxidative damage to hepatocyte membrane lipids, enzyme complexes of the respiratory chain and DNA.
  • ROS injury causes further release of ROS from nearby hepatocyte mitochondria (known as ROS-induced ROS release), self-propagating mitochondrial damage.
  • Ionic homeostasis of hepatocyte Ca2+, Na+ and H+ is perturbed.
  • Mitochondrial Ca2+ overload and ATP depletion result in increased permeability of inner mitochondrial membrane via mitochondrial permeability transition.
  • When the majority of mitochondria undergo mitochondrial permeability transition, hepatocyte necrosis ensues.


Predictive/risk factors



Donor factors



  • Older donors >60 years. May be explained by decreased expression of protective factors (i.e. Nrf2) in older donors.
  • Graft macrovesicular steatosis >30%.
  • Other underlying liver disease.
  • Donation after cardiac death.


Operative factors



  • Poor flushing during procurement.
  • Mottled reperfusion: may be intraoperative evidence of “no-reflow.”
  • Increased cold ischemia time.
  • Increased warm ischemia time. Higher risk than cold ischemia.


Recipient factors



  • Underlying sepsis.

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Aug 12, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on 47: Ischemia Reperfusion Injury after Liver Transplantation

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