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Post-Hepatectomy Liver Failure (PHLF)

Introduction

  • Post-Hepatectomy Liver Failure (PHLF) specifically describes a decrement in liver function after liver resection.
  • Hepatic failure, often manifested as encephalopathy, hyperbilirubinemia, development of ascites, and coagulopathy, can lead to:
    • Acute respiratory failure
    • Renal failure with/without hepatorenal syndrome
    • Bleeding complications
  • Decompensation of cirrhosis can occur after abdominal procedures or illness.

Risk Factors and Predictors of PHLF

Size and Health of Liver Remnant

  • The development of PHLF depends on the size and health of the liver remnant remaining after hepatectomy.
  • Patients who had insufficient volume based on Total Estimated Liver Volume (TELV) had significantly higher rates of PHLF and mortality.
  • TELV (i.e., sFLR) is considered a better measure of postoperative hepatic insufficiency risk.

Predictive Criteria

50-50 Criteria

  • Combines prothrombin time of less than 50% (or PT-INR ≥ 1.7) and serum bilirubin greater than 50 μmol/L (or ≥ 2.9 mg/dL).
  • Validated as an excellent predictor of death on days 3 and 5 for patients admitted to the ICU for PHLF.

Mullen Criteria

  • Bilirubin peak ≥ 7 mg/dL on postoperative days 1–7.
  • Found to be more accurate than the 50-50 criteria in predicting death from hepatic failure after liver resection.

Classification Systems

  • Various methods exist to diagnose PHLF based on laboratory values.

  • A classification system describes the clinical impact of PHLF, focusing on:

    • Increased INR and hyperbilirubinemia on or after postoperative day 5.
    • Rising levels after surgery in cases of elevated preoperative values.

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  • Gradation of liver failure is based on:

    • Impact on postoperative care
    • Location of care
    • Additional measures used to treat symptoms

Scoring Systems

Child-Pugh and MELD Scores

  • Provide good measures of global liver function in patients with cirrhosis being considered for partial hepatectomy.
  • Surgeons should approach patients with Child-Pugh class B/C or MELD score greater than 8 with caution and consider alternative treatment approaches.

Albumin-Bilirubin (ALBI) Score

  • Categorizes patients into three risk groups (A1, A2, or A3) based on serum albumin and bilirubin.
  • Developed from 1313 patients with hepatocellular carcinoma (HCC) in Japan.
  • ALBI score was better able to predict both PHLF and survival after hepatectomy compared with Child-Pugh and MELD scores.
  • Adds precision in predicting the risk for PHLF within Child-Pugh A patients.
  • Clinical scoring systems are not sensitive enough to detect background liver injury and subsequent risk of postoperative liver dysfunction in patients without cirrhosis.
    • Other methods of functional liver assessment are needed in these patients.

Imaging and Functional Assessment Techniques

Indocyanine Green (ICG) Clearance

  • ICG clearance is a quantitative measure of liver function that can assist in preoperative planning.

99mTc-Galactosyl Serum Albumin (GSA) Scintigraphy and SPECT-CT

  • 99mTc-GSA uptake is limited by inter-operator and inter-institutional differences and does not measure regional liver function.
  • Combined with static Single-Photon Emission Computed Tomography–CT (SPECT-CT) for three-dimensional measurement.
  • Dynamic SPECT-CT may help predict postoperative liver failure but suffers from interobserver variability.
  • Single-arm prospective trial of 185 patients:
    • SPECT-CT calculated ICG clearance specific to the predicted FLR.
    • Demonstrated good correlation with postoperative bilirubin and INR levels.
    • PHLF rate of 8% and 90-day mortality of 0.5%.
    • Showed the importance of measuring the function of the Future Liver Remnant (FLR) rather than the Total Liver Volume (TLV).

99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBS)

  • 99mTc-Mebrofenin is an organic IDA derivative similar to ICG:
    • High hepatic uptake
    • Low displacement by bilirubin
    • Low urinary excretion
  • Administered similarly to 99mTc-GSA scintigraphy using a gamma camera.
  • Uptake ratio is divided by the patient’s Body Surface Area (BSA).
  • HBS correlates well with ICG clearance and is a good marker of post-resection liver function.
  • Combined with SPECT-CT to calculate both function and volume of the FLR.
  • FLR function cutoff value of 2.7%/min/m²:
    • Negative Predictive Value (NPV) of 97.6%
    • Positive Predictive Value (PPV) of 57.1% for PHLF
  • Main limitation: Inter-observer and inter-institution variability.
  • Further research is needed for reproducibility across different settings.

MRI Techniques

  • MRI has been shown to be superior to sFLR volume and ICG-R15 at predicting PHLF.
  • Precise predictors use a combination of:
    • Relative Liver Enhancement (RLE): Difference in signal intensity between unenhanced and hepatobiliary phases.
    • Hepatocellular Uptake Index (HUI): Difference in signal intensity between liver parenchyma and the spleen.
  • Asenbaum et al. calculated an Area Under the Curve (AUC) of 0.9 for predicting PHLF using functional FLR.
  • Studies performing MRI before and after Portal Vein Embolization (PVE) showed:
    • Increase in RLE from baseline to 14 days post-PVE is an excellent predictor of PHLF.
    • Beyond 14 days, minimal improvements in FLR, KGR, and RLE.
  • MRI provides information on both the volume and function of the FLR.
  • Early studies show a relationship between Gd-EOB-DTPA uptake and clinical outcomes post-resection.
  • Larger trials are needed to determine NPV and PPV for PHLF and mortality.

Transient Elastography

  • Ultrasound Transient Elastography (TE) estimates the extent of liver fibrosis.
  • Advantages:
    • Noninvasive
    • Fast
  • Limitations:
    • Significant inter-observer variability
    • Anatomic variations
  • Studies in patients with HCC undergoing hepatectomy found:
    • High NPV of 98%
    • Relatively poor PPV
  • TE may help in screening patients at low risk for PHLF.
  • Positive tests should prompt further investigations.

CT Texture Analysis

  • Texture analysis characterizes regions based on spatial variations in pixel intensity.
  • On CT imaging, it quantifies regional variations in enhancement not visible on inspection.
  • Studies have shown potential utility for:
    • Tumor diagnosis
    • Characterization
    • Prognostication
  • Texture variables of preoperative CT scans show promise for predicting postoperative hepatic failure.
  • May represent a new means of preoperative risk stratification.

Preoperative Strategies to Reduce PHLF Risk

Portal Vein Embolization (PVE)

  • In patients at increased risk for PHLF, hypertrophy of the FLR may be induced by preoperative ipsilateral PVE.
  • PVE is used to induce hypertrophy of the FLR before major liver resection.
  • Studies have shown that the increase in RLE from baseline to 14 days post-PVE is an excellent predictor of PHLF.
  • Beyond 14 days post-PVE, there are minimal improvements in FLR, Kinetic Growth Rate (KGR), and RLE.

Parenchymal-Sparing Techniques

  • The primary rationale is maximizing the volume of liver remaining to maximize functional parenchyma.
  • Highly predictive of postoperative morbidity, mortality, and liver dysfunction.
  • Resections removing up to 80% of functional parenchyma can be safely performed in patients with normal liver function.
  • An FLR of at least 40% is often necessary in patients with underlying liver disease (e.g., cirrhosis, steatohepatitis, chemotherapy-induced liver injury).
  • Accurate calculation of the volume and function of the FLR is imperative to:
    • Determine resectability
    • Discuss perioperative risk with the patient
    • Predict postoperative outcomes
  • Quantitative measures of liver function, including ICG clearance and lidocaine conversion tests, assist in preoperative planning.
  • Systematic measurement of liver remnant volume and careful assessment have improved the safety of major resections.
  • Studies have found a decreased risk of PHLF after hepatic resection through parenchymal-sparing techniques, especially in patients with impaired liver function.
  • Fisher et al. reported:
    • A right posterior sectionectomy was associated with a significantly lower rate of PHLF (1% vs. 8.5%) compared to formal right hepatectomy.
  • Parenchymal-sparing techniques decrease the risk of PHLF compared with more extensive resections.

Postoperative Management of PHLF

Phosphate Metabolism After Hepatectomy

  • Hypophosphatemia is frequent in the early days after hepatectomy and should be corrected.
  • Failure to develop hypophosphatemia is a marker of postoperative hepatic insufficiency and mortality.
  • May be evident in the early postoperative period before traditional markers defining PHLF become evident.
  • In patients who develop PHLF, the later development of hypophosphatemia may signal the beginning of recovery.

Liver Support Devices

  • The application of liver support devices in PHLF is an emerging indication.
  • Need for liver support is based on increased rates of severe postoperative mortality and liver-related morbidity with major hepatectomies.
  • Major hepatectomy (resection of three or more segments) is associated with:
    • Reduced synthetic, detoxification, and immune responses
    • Life-threatening complications:
      • Hepatic encephalopathy
      • Increased susceptibility to infections and sepsis
      • Renal failure
      • Coagulopathy
      • Hemodynamic instability
  • Indications for major hepatectomies have expanded to include high-risk patients with:
    • Steatosis
    • Fibrosis
    • Chemotherapy-induced liver injury
  • Treatment options include:
    • Intensive medical care focused on treating complications until the remnant liver recovers
    • Patients may require prolonged ICU stays and protracted recovery
    • Liver support devices
    • As a last resort, (rescue) liver transplantation
  • Reports of the use of:
    • Molecular Adsorbent Recirculating System (MARS)
    • Prometheus system
  • Only one study reported the use of a biologic support system for PHLF.
  • Preliminary results are promising.
  • Randomized Controlled Trials (RCTs) are warranted to evaluate liver support devices in PHLF.
  • Future studies should address:
    • When to initiate liver support therapy
    • Duration of therapy

Conclusion

  • Accurate calculation of the volume and function of the Future Liver Remnant (FLR) is imperative.
  • Nuclear imaging techniques such as:
    • 99mTc-Galactosyl Serum Albumin Scintigraphy
    • 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBS)
  • These techniques measure both volume and sectorial FLR function.
  • Potentially identify patients at higher risk for PHLF.
  • MRI provides information on both volume and function and shows promise in predicting PHLF.
  • Parenchymal-sparing techniques and preoperative strategies like PVE are essential in reducing the risk of PHLF.
  • Ongoing research and advancements in imaging and liver support devices hold promise for improving patient outcomes after hepatectomy.