A systematic review of small for size syndrome after major hepatectomy and liver transplantation

 

Executive Summary

Small for Size Syndrome (SFSS) is a critical and potentially reversible complication resulting from a significant reduction in liver mass relative to portal venous return. While well-documented in the context of liver transplantation (LT)—particularly living-donor (LDLT) and split-liver procedures—it remains under-recognized following major hepatectomy (MH). This briefing document synthesizes findings from a systematic review of 24 studies involving 2,728 patients to delineate the incidence, pathophysiology, and management of SFSS.

Critical Takeaways:

• Pathophysiology: SFSS is primarily driven by portal hypertension. A reduction in liver mass combined with constant portal venous return leads to a reciprocal rise in portal venous pressure (PVP), causing sinusoidal shear stress, endothelial damage, and ischemia.

• Incidence: Approximately 12% of patients in the reviewed studies met the criteria for SFSS or post-hepatectomy liver failure (PHLF). In LDLT, the incidence can reach up to 20%.

• Predictors: Graft-to-recipient weight ratio (GRWR) < 0.8% is a traditional marker, but elevated PVP (specifically >15–20 mmHg) is a more reliable predictor of SFSS and poor survival.

• Management: Portal inflow modulation (PIM) through surgical (splenectomy, ligation) or pharmacological means can successfully reduce PVP, lower the incidence of SFSS, and improve patient survival to levels comparable with size-matched recipients.

Overview of the Systematic Review

The systematic review followed 2010 PRISMA guidelines, identifying 5,093 records and ultimately including 24 studies published between 2000 and 2019.

Study Characteristics

Pathophysiology and Definition

The Mechanism of SFSS

The syndrome is initiated by a reduction in liver mass (via resection or small graft) while the volume of portal venous return remains constant. This leads to:

1. Portal Hypertension: Defined as a hepatic vein pressure gradient >6 mmHg.

2. Shear Stress: High portal pressures cause mechanical damage to sinusoidal endothelial linings.

3. Cellular Damage: Leads to capillary leakage, hepatocyte swelling, and sinusoidal dilatation.

4. Ischemia: High portal pressures trigger the "hepatic artery buffer response," which reduces hepatic artery pressure and flow.

5. Bacterial Translocation: Endothelial damage increases the risk of infection and sepsis.

Challenges in Definition

There is no universal consensus definition for SFSS. Current clinical benchmarks include:

• Dahm et al. (2005): GRWR <0.8% plus two of the following for three consecutive days: bilirubin >100 mmol/l, INR >2, or grade 3/4 encephalopathy.

• Alternative Criteria: Bilirubin >10 mg/dL on post-operative day (POD) 14 and intractable ascites (>1000 ml/day on POD 14 or >500 ml/day on POD 28).

• MH Context: SFSS is often miscategorized as PHLF. While PHLF can be caused by sepsis or inadequate hepatocytes, SFSS specifically points to portal hypertension and intra-hepatic congestion as the underlying cause.

Key Outcomes and Clinical Predictors

Portal Venous Pressure (PVP) as a Primary Metric

Research indicates that PVP thresholds are more clinically significant than graft size alone.

• Thresholds: Studies generally aim for PVP <15 mmHg or <20 mmHg.

• Mortality: High PVP (>15 mmHg) is significantly associated with worse 90-day and 1-year survival. One study reported 1-year survival at 71% for SFSS patients compared to 87% for those without.

• Predictive Power: GRWR and GV/SLV (Graft Volume/Standard Liver Volume) are inconsistent predictors. However, combining GRWR <0.8% with PVP >15 mmHg significantly increases SFSS risk (OR 10.0).

Liver Regeneration

An increase in PVP is necessary to stimulate physiological liver regeneration. However, excessively high PVP is counterproductive:

• Patients with PVP <20 mmHg showed significantly greater regeneration in volume and function.

• High PVP at the completion of ALPPS Stage 1 was associated with diminished regeneration of the future liver remnant (FLR).

Post-Operative Morbidity

• Infection Risks: GRWR <0.7 is associated with higher infection rates (chest, urinary, wound, and peritonitis).

• Sepsis: Poorly controlled PVP increases the risk of sepsis through endothelial damage and bacterial translocation. Successfully modulating PVP reduces this risk.

Management and Treatment Modalities

Management focuses on Portal Inflow Modulation (PIM) to reduce PVP while maintaining enough flow to stimulate regeneration.

Treatment Summary Table

Category	Intervention Type	Mechanism/Evidence
Surgical	Splenectomy	Successfully reduces PVP; no adverse effect on survival noted in several studies.
	Splenic Artery Ligation (SAL)	Common prophylactic or reactive measure to reduce portal inflow.
	Porto-systemic Shunt (PSS)	Negates SFSS but carries risk of "steal syndrome" (reduced flow leading to graft failure).
Radiological	Splenic Artery Embolisation (SAE)	Pre-operative or early post-operative intervention to reduce flow.
Medical	Non-selective Beta Blockers	Modulates splanchnic blood flow to reduce portal pressure.
	Somatostatin / Octreotide	Infusions used to reduce PVP following major liver resection.
	Plasmapheresis	Utilized in some clinical settings for SFSS management.

Conclusion

The review concludes that SFSS is a critical, under-recognized cause of post-hepatectomy liver failure. While traditionally associated with liver transplantation, the physiological drivers—reduced mass and reciprocal portal hypertension—apply equally to major hepatectomy.

Recommendations for Clinical Practice:

1. Routine Measurement: Intra-operative measurement of PVP should be considered for extensive resections. If PVP >15 mmHg, immediate surgical modulation may be required.

2. Post-operative Monitoring: Use of Doppler ultrasound and hepatic vein wedge pressure measurements for early detection of portal congestion.

3. Balanced Approach: Interventions must strike a balance between reducing PVP to prevent SFSS and maintaining sufficient pressure to facilitate necessary liver regeneration.