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Liver Regeneration

  • Surgical resection - Growth of hepatocyte population
  • TNF alpha, IL-6,
  • Hepatocyte growth factor
  • LPS
  • Bile acids
  • Laminin to fibronectin and collagen type IV and I

Doctutorials ( Liver Physiology class)

Liver Regeneration

Key Points

  1. Hepatocyte Proliferation:
    • Hepatocytes can repopulate a whole damaged liver in approximately 69 doublings.
    • After resection, hepatocyte proliferation starts in the periportal areas of the lobules and then proceeds to the pericentral areas by 36 to 48 hours.
  2. Oval Cells:
    • In response to toxic liver damage, "oval cells" proliferate to replace the hepatic parenchyma.
    • These cells are also known as hepatic progenitor cells and are important for regeneration when hepatocyte replication is impaired.
  3. Earliest Factors Triggering Regeneration:
    • Interleukin (IL)-6 and tumor necrosis factor (TNF)-Ξ± are the earliest factors triggering the activation of several transcription factors during regeneration.
    • TNF signaling through TNF receptor (TNFR)-I initiates liver regeneration after partial hepatectomy (PHx) with IL-6 as the key target.
    • TNF-Ξ± acts as the initiator of IL-6.
  4. Signaling Pathways:
    • IL-6 activates the Janus kinase (JAK)/STAT3 and MAPK signaling pathways via the gp130/IL-6R complex.
    • This activation leads to an array of immediate and delayed early genes required for normal liver-specific metabolic functions, repair, and hepatoprotection from injury.
    • STAT3 is crucial for cells to progress from G1 to S phase and for activating the c-myc gene, necessary for cell-cycle progression.

Summary:

  • Hepatocyte Proliferation: Starts in the periportal areas after resection.
  • Oval Cells: Proliferate in response to toxic liver damage.
  • (MCQ) Earliest Factors: TNF-Ξ± > IL-6.
  • Signaling Pathways: IL-6 activates JAK/STAT3 and MAPK, crucial for liver regeneration.

Multiple Choice Question

Answer:

  • Correct Answer: D. After resection, hepatocyte proliferation starts in the pericentral to periportal areas.

Explanation:

  • A: True. Hepatocytes can indeed repopulate the whole damaged liver in 69 doublings.
  • B: True. "Oval cells" proliferate to replace the hepatic parenchyma in response to toxic liver damage.
  • C: True. Interleukin (IL)-6 and tumor necrosis factor (TNF)-Ξ± are the earliest factors triggering regeneration.
  • D: False. After resection, hepatocyte proliferation starts in the periportal areas and then proceeds to the pericentral areas by 36 to 48 hours.

Additional Note:

  • The process of liver regeneration involves a complex interplay of cellular and molecular events. TNF-Ξ± acts as the initiator of IL-6, which then activates the JAK/STAT3 and MAPK signaling pathways. These pathways are crucial for the activation of genes necessary for liver-specific metabolic functions, repair, and protection from injury. The initial proliferation of hepatocytes begins in the periportal areas because these regions are closest to the blood supply and thus have immediate access to nutrients and oxygen necessary for rapid cell division.

Liver Atrophy

Key Points

  1. Portal Vein (PV) Ligation:
    • Portal Vein = Liver atrophy due to decrease in hepatotrophic substances BUT WILL NOT NECROSE d/t HA FLOW
  2. Biliary Obstruction:
    • Atrophy occurs mainly via apoptosis which is Fas-mediated.
  3. Hepatic Artery (HA) Occlusion:
    • depend on collateral flow
    • Necrosis = if no collateral flow
    • Atrophy = if collateral flow is present and seldom happens
  4. Lobar Radioembolization:
    • Yttrium-90 or Holmium-166 can cause atrophy of a lobe through beta emission, leading to necrosis.

Summary:

  • PV Ligation: Causes ischemic centrilobular necrosis.
  • Biliary Obstruction: Causes Fas-mediated apoptosis.
  • HA Occlusion: Alone cannot induce atrophy.
  • Radioembolization: Causes lobe atrophy through beta emission necrosis.

Multiple Choice Question

Answer:

  • Correct Answer: C. Occlusion of the hepatic artery alone can induce atrophy.

Explanation:

  • A: True. PV ligation causes ischemic centrilobular necrosis induced atrophy.
  • B: True. In biliary obstruction, atrophy mainly occurs via apoptosis which is Fas-mediated.
  • C: False. Occlusion of the hepatic artery alone cannot induce atrophy.
  • D: True. Lobar radioembolization with Yttrium-90 or Holmium-166 can cause atrophy of a lobe through beta emission causing necrosis.

Effects of Chemotherapy on Liver Resection

Key Points

  1. Oxaliplatin:
    • Leads to Sinusoidal Obstruction Syndrome (SOS).
  2. Irinotecan:
    • Leads to Chemotherapy-Associated Steatohepatitis (CASH).
  3. Bevacizumab:
    • False Statement: Bevacizumab aggravates SOS in patients on Oxaliplatin.
    • In reality, Bevacizumab decreases SOS and increases the pathologic response of Oxaliplatin.
    • The anti-VEGF monoclonal bevacizumab has a long half-life and inhibits wound healing and theoretically should be stopped 6-8 weeks before surgery, necessitating close collaboration with the medical oncologist in the timing of surgery.
  4. Neoadjuvant Chemotherapy:
    • The deleterious effect of chemotherapy on regeneration seems to increase with the total number of cycles given and shows a sharp rise after five courses.
    • No more than six cycles of FOLFOX/FOLFIRI should be given before liver resection for colorectal metastases.
    • A three-week gap is recommended between chemotherapy and surgery.
  5. Future Liver Remnant (FLR):
    • Should be greater than 30%.
  6. Which is more Dangerous?? SOS vs Steatohepatitis?
    • Oxaliplatin induced sinusoidal injury is associated with Increased bleeding and blood transfusion during surgery.
    • But overall ,the risk is less than steatohepatitis.

Summary:

  • Oxaliplatin: Causes SOS.
  • Irinotecan: Causes CASH.
  • Bevacizumab: Decreases SOS, increases pathologic response of Oxaliplatin.
  • Neoadjuvant Chemotherapy: Limited to six cycles, three-week gap before surgery.
  • FLR: Should be >30%.

Multiple Choice Question

Answer:

  • Correct Answer: C. Bevacizumab Decreases SOS, increases pathologic response of Oxaliplatin.