Small-for-size syndrome in a 9.7 kg pediatric recipient with a whole liver graft.

BACKGROUND: Small-for-size syndrome (SFSS) in pediatric liver transplant recipients, particularly those weighing less than 10 kg, is rare. This report describes a case of a 15-month-old whole liver transplant recipient who suffered SFSS, and systematic literature review was performed to identify outcomes of such cases and potential risk factors for SFSS. CASE PRESENTATION: A 15-month-old toddler with a history of biliary atresia underwent a deceased donor whole liver transplant. The graft weighed 160 g, resulting in a graft-to-recipient weight ratio (GRWR) of 1.6%. The post-operative course was complicated by SFSS, characterized by massive ascites causing hemodynamic instability and compromised hepatic artery flow. Pharmacological intervention with octreotide was initiated, and the patient eventually recovered. CONCLUSION: In small pediatric recipients, especially those weighing less than 10 kg, the native liver body weight ratio (LBWR) is significantly higher. When selecting an appropriately sized graft for these recipients, this higher ratio should be taken into consideration. The literature review suggests that a GRWR of less than 2% is associated with a higher incidence of small-for-size syndrome in small pediatric recipients weighing less than 10 kg.

Volume-Assisted Estimation of Remnant Liver Function Based on Gd-EOB-DTPA Enhanced MR Relaxometry: A Prospective Observational Trial.

In the context of liver surgery, predicting postoperative liver dysfunction is essential. This study explored the potential of preoperative liver function assessment by MRI for predicting postoperative liver dysfunction and compared these results with the established indocyanine green (ICG) clearance test. This prospective study included patients undergoing liver resection with preoperative MRI planning. Liver function was quantified using T1 relaxometry and correlated with established liver function scores. The analysis revealed an improved model for predicting postoperative liver dysfunction, exhibiting an accuracy (ACC) of 0.79, surpassing the 0.70 of the preoperative ICG test, alongside a higher area under the curve (0.75). Notably, the proposed model also successfully predicted all cases of liver failure and showed potential in predicting liver synthesis dysfunction (ACC 0.78). This model showed promise in patient survival rates with a Hazard ratio of 0.87, underscoring its potential as a valuable tool for preoperative evaluation. The findings imply that MRI-based assessment of liver function can provide significant benefits in the early identification and management of patients at risk for postoperative liver dysfunction.

Dual Graft Living Donor Liver Transplantation for High Acuity Patients: A Single-Center Experience.

Background: The outcomes of dual graft living donor liver transplantation (DGLDLT) in high acuity patients remain underreported. The objective of this study was to report long-term outcomes from a single center in this select group of patients. Methods: This was a retrospective review of patients who underwent DGLDLT between 2012 and 2017 (n = 10). High acuity patients were defined as patients with model for end stage liver disease (MELD) ≥30 or Child Pugh score ≥11. We looked at 90-day morbidity and mortality and 5-year overall survival (OS). Results: The median MELD score and Child Pugh score were 30 (26.7-35) and 11 (11-11.2). The median recipient weight was 105 (95.2-113.7) and ranged from 82 to 132 kg. Out of 10 patients, 4 (40%) required perioperative renal replacement therapy, and 8 (80%) required hospital admission for optimization. The estimated graft to recipient weight ratio (GRWR) with right lobe graft alone was <0.8 in all patients, between 0.75 and 0.65 in 5 (50%) patients, and <0.65 in 5 (50%) patients. The 90-day mortality was 3/10 (30%), and there were 3/10 (30%) deaths during long-term follow-up. Among 155 high acuity patients, the 1-year OS with standard LDLT, standard LDLT with GRWR <0.8, and DGLDLT was 82%, 76%, and 58%, respectively (P = 0.123). With a median follow-up of 40.6 (1.9-74.4) months, the 5-year OS for DGLDLT was 50%. Conclusion: The use of DGLDLT in high acuity patients should be prudent and low GRWR grafts should be considered a viable alternative in selected patients.

Platelets mediate acute hepatic microcirculatory injury in a protease-activated-receptor-4-dependent manner after extended liver resection.

BACKGROUND: Small-for-size syndrome (SFSS) is a major complication following extended liver resection. The role of platelets in the early development of SFSS remains to be cleared. We aimed to investigate the impact of platelets and PAR-4, a receptor for platelet activation, on the acute phase microcirculatory injury after liver resection by in vivo microscopy analyzing the changes in leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis-induced perfusion failure. METHODS: Sixty-percent partial hepatectomy (PH) models using C57BL/6 mice receiving platelet depletion with anti-GPIbα, PAR-4 blockade with tcY-NH2, or vehicle treatment with saline were used. Sham-operated animals served as controls. Epifluorescence microscopic analysis was performed 2 h after PH to quantify the leukocyte recruitment and microcirculatory changes. Sinusoidal neutrophil recruitment, platelet-neutrophil interaction, and microthrombosis were evaluated using two-photon microscopy. ICAM-1 expression and liver liver injury were assessed in tissue/blood samples. RESULTS: The increments of leukocyte recruitment in post-sinusoidal venules and sinusoidal perfusion failure, the upregulation of ICAM-1 expression, and the deterioration of liver function 2 h after 60% PH were alleviated in the absence of platelets or by PAR-4 blockade. Intensified platelet-neutrophil interaction and microthrombosis in sinusoids were observed 2 h after 60% PH, which significantly attenuated after PAR-4 blockade. CONCLUSION: Platelets play a critical role in acute liver injury after extended liver resection within 2 h. The deactivation of platelets via PAR-4 blockade ameliorated liver function deterioration by suppressing early leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis in hepatic sinusoids.

Small-For-Size Syndrome and Graft Inflow Modulation Techniques in Liver Transplantation.

BACKGROUND: Partial liver transplantation has recently been proposed to alleviate organ shortages. However, transplantation of a small-for-size graft is associated with an increased risk of posttransplant hepatic dysfunction, commonly referred to as small-for-size syndrome (SFSS). This review describes the etiology, pathological features, clinical manifestations, and diagnostic criteria of SFSS. Moreover, we summarize strategies to improve graft function, focusing on graft inflow modulation techniques. Finally, unmet needs and future perspectives are discussed. SUMMARY: In fact, posttransplant SFSS can be attributed to various factors such as preoperative status of the recipients, surgical techniques, donor age, and graft quality, except for graft size. With targeted improvement measures, satisfactory clinical outcomes can be achieved in recipients at increased risk of SFSS. Given the critical role of relative portal hyperperfusion in the pathogenesis of SFSS, various pharmacological and surgical treatments have been established to reduce or partially divert excessive portal inflow, and recipients will benefit from individualized therapeutic regimens after careful evaluation of benefits against potential risks. However, there remain unmet needs for further research into different aspects of SFSS to better understand the correlation between portal hemodynamics and patient outcomes. KEY MESSAGES: Contemporary transplant surgeons should consider various donor and recipient factors and develop case-specific prevention and treatment strategies to improve graft and recipient survival rates.

Serine proteases mediate leukocyte recruitment and hepatic microvascular injury in the acute phase following extended hepatectomy.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is the main limitation of extended liver resection. The molecular mechanism and the role of leukocytes in the development of PHLF remain to be unveiled. We aimed to address the impact of serine proteases (SPs) on the acute phase after liver resection by intravitally analyzing leukocyte recruitment and changes in hemodynamics and microcirculation of the liver. METHODS: C57BL/6 mice undergoing 60% partial hepatectomy were treated with aprotinin (broad-spectrum SP inhibitor), tranexamic acid (plasmin inhibitor), or vehicle. Sham-operated animals served as controls. In vivo fluorescence microscopy was used to quantify leukocyte-endothelial interactions immediately after, as well as 120 min after partial hepatectomy in postsinusoidal venules, along with measurement of sinusoidal perfusion rate and postsinusoidal shear rate. Recruitment of leukocytes, neutrophils, T cells, and parameters of liver injury were assessed in tissue/blood samples. RESULTS: Leukocyte recruitment, sinusoidal perfusion failure rate, and shear rate were significantly increased in mice after 60% partial hepatectomy compared to sham-operated animals. The inhibition of SPs or plasmin significantly attenuated leukocyte recruitment and improved the perfusion rate in the remnant liver. ICAM-1 expression and neutrophil recruitment significantly increased after 60% partial hepatectomy and were strongly reduced by plasmin inhibition. CONCLUSIONS: Endothelial activation and leukocyte recruitment in the liver in response to the increment of sinusoidal shear rate were hallmarks in the acute phase after liver resection. SPs mediated leukocyte recruitment and contributed to the impairment of sinusoidal perfusion in an ICAM-1-dependent manner in the acute phase after liver resection.

Advances in the study of small-for-size syndrome / 中华肝胆外科杂志

Small-for-size syndrome is one of the most common and dangerous complications of partial liver transplantation. With the accumulation of clinical experiences and basic researches developed in recent years, new knowledge about the pathogenesis, pathophysiological process, prevention and treatment of small-for-size syndrome has been established. This article summarizes the progress of research on the small-for-size syndrome in recent years to help better diagnosis, prevention and treatment, thus improving the prognosis and long-term survival of patients.

Left liver graft in adult-to-adult living donor liver transplantation with an optimal portal flow modulation strategy to overcome the small-for-size syndrome - A retrospective cohort study.

BACKGROUND: Adult-to-adult living donor liver transplantation (LDLT) is a notable type of liver transplantation. Several centers prefer the right liver graft (RLG) over the left liver graft (LLG) for better recovery of recipients. We compared the outcomes of donors and recipients between LDLT using LLGs and RLGs. MATERIALS AND METHODS: The study cohort comprised of 25 patients in the LLG group and 93 in the RLG group. When both hemiliver grafts met the selection criteria, an LLG was preferred. When portal flow (≥300 ml/min/100gLW) and hepatic venous pressure gradient (≥10 mmHg) were increased, intraoperative splenic artery ligation was performed for portal modulation. Postoperatively, somatostatin was administered when small-for-size syndrome (SFSS) was highly suspected. RESULTS: The graft-to-recipient weight ratio was lower in the LLG group than in the RLG group. There was no significant complication above Clavien-Dindo grade IIIA in donors. Regarding recipient outcomes, SFSS occurred in four (16.0%) patients in the LLG group and three (3.2%) in the RLG group (P = 0.036). Splenic artery ligation was frequently performed in the LLG group than the RLG group (5 [20.0%] vs. 12 [12.9%], P = 0.035) and 5 patients received intravenous continuous somatostatin for 7 (5-12) days. SFSS-related hospital mortality did not occur. There was no significant difference in the short-term and long-term outcomes between the groups. CONCLUSION: This study demonstrates the comparable outcomes of donors and recipients between the LLG and RLG groups although with a higher risk of SFSS that needs high experience to avoid severe complications and graft loss. We expect LLG to be used more actively in adult-to-adult LDLT with portal flow modulation strategies to overcome fatal SFSS.

Anatomical limits in living donor liver transplantation.

We review the anatomical limits of living donor liver transplantation. Graft size is the fundamental challenge in partial liver transplantation. Insufficient graft size leads to small-for-size syndrome, graft failure, and graft loss. However, smaller grafts can be used safely with surgical techniques to optimize outflow and modulate inflow, thereby minimizing portal hyperperfusion. Meanwhile, anatomical variations are common in the vascular and biliary systems. These variants pose additional challenges for vascular and biliary reconstruction. Recognition and appropriate management of these variants ensure donor safety and reduce recipient morbidity. The ultimate principle of partial liver transplantation is to ensure a sufficient graft volume with unimpeded outflow and reconstructable vascular and biliary systems. On this basis, the anatomical limits of living donor liver transplantation can be safely expanded.

Splenic Artery Ligation: An Ontable Bail-Out Strategy for Small-for-Size Remnants after Major Hepatectomy: A Retrospective Study.

It has been reported that the prevention of acute portal overpressure in small-for-size liver grafts leads to better postoperative outcomes. Accordingly, we aimed to investigate the feasibility of the technique of splenic artery ligation in a case series of thirteen patients subjected to major liver resections with evidence of small-for-size syndrome and whether the maneuver results in the reduction of portal venous pressure and flow. The technique was successful in ten patients, with splenic artery ligation alleviating portal hypertension significantly. Three patients required the performance of a portocaval shunt for the attenuation of portal hypertension. Portal inflow modulation via splenic artery ligation is a technically simple technique that can prove useful in the context of major hepatectomies as well as in liver transplantations and the early evaluation and modification of portal venous pressure post hepatectomy can be used as a practical tool to guide the effect of the intervention.

PD-1/PD-L1 inhibition promotes hepatic regeneration in small-for-size liver following extended hepatectomy.

BACKGROUND: Small-for-size syndrome following liver surgery is characterized by compromised liver regeneration. Liver macrophages play key roles in initiating liver regeneration, and modulation of the immune microenvironment through macrophages may accelerate liver regeneration. In our current study, we aimed to explore the involvement of innate immunity after extended hepatectomy in rats and humans, and to test the effect of immunity modulation on small-for-size liver regeneration in rats. METHODS: Serum programmed cell death protein ligand 1 (PD-L1) was measured after major hepatectomy and minor hepatectomy in humans and rats. Liver regeneration in rats was assessed using liver-to-body weight ratio and kinetic growth rate, antigen Ki67 and proliferating cell nuclear antigen (PCNA), and macrophage polarization was assessed by inducible nitric oxide synthase (iNOS), cluster of differentiation protein 163 (CD163) expression by immunohistochemistry (IHC) and iNOS/CD163 ratio. Rat hepatocyte BRL or human hepatocyte LO2 were co-cultured with rat bone marrow-derived macrophages or human macrophages THP-1. BMS-1 or Nivolumab were used to block programmed cell death protein 1 (PD-1)/PD-L1 in vitro and in vivo. RESULTS: PD-L1 expressions were significantly higher following major hepatectomy compared to minor resection in both humans and rats; compromised liver regeneration after extended hepatectomy in rats was associated with PD-L1 upregulation and M2 macrophage polarization. M1 macrophages increased proliferation of hepatocytes through interleukin-6 (IL-6), and M2 macrophages decreased hepatocyte proliferation; blocking PD-1/PD-L1 reversed the effect of M2 macrophages on the survival of hepatocytes in vitro and promoted liver growth in rats through M1 macrophage polarization. CONCLUSION: Compromised hepatic regeneration following extended hepatectomy is characterized by M2 macrophage polarization and upregulated PD-L1 expression. Blocking PD-1/PD-L1 may enhance small-for-size liver regeneration by inducing M1 macrophage polarization.

A systematic review of auxiliary liver transplantation of small-for-size grafts in patients with chronic liver disease.

Background & Aims: The shortage of liver grafts continues to worsen. Because the expanded use of small-for-size grafts (SFSGs) would substantially alleviate this shortage, we aimed to analyse the available knowledge on auxiliary liver transplantation (ALT) with SFSGs in patients with chronic liver disease (CLD) to identify opportunities to develop ALT with SFSGs in patients with CLD. Methods: This is a systematic review on ALT using SFSGs in patients with CLD. The review was completed by updates obtained from the authors of the retained reports. Results: Heterotopic ALT was performed in 26 cases between 1980 and 2017, none for SFGS stricto sensu, and auxiliary partial orthotopic liver transplantation (APOLT) in 27 cases (from 1999 to 2021), all for SFSG. In APOLT cases, partial native liver resection was performed in most of cases, whereas the second-stage remnant native liver hepatectomy was performed in 9 cases only. The median graft-to-body weight ratio was 0.55, requiring perioperative or intraoperative portal modulation in 16 cases. At least 1 complication occurred in 24 patients following the transplant procedure (morbidity rate, 89%). Four patients (4/27, 15%) died after the APOLT procedure. At the long term, 19 (70%) patients were alive and well at 13 months to 24 years (median, 4.5 years) including 18 with the APOLT graft in place and 1 following retransplantation. Conclusions: Despite high postoperative morbidity, and highly reported technical variability, the APOLT technique is a promising technique to use SFSGs in patients with CLD, achieving satisfactory long-term results. The results need to be confirmed on a larger scale, and a standardised technique could lead to even better results. Lay summary: At the cost of a high postoperative morbidity, the long-term results of APOLT for small-for-size grafts are good. Standardisation of the procedure and of portal modulation remain needed.

Do Natural Portosystemic Shunts Need to Be Compulsorily Ligated in Living Donor Liver Transplantation?

BACKGROUND: Natural portosystemic shunt ligation practices in liver transplant vary widely across transplant centres and are frequently undertaken to prevent the serious consequence of portal steal phenomenon. No concrete indications have so far been convincingly identified for their management in living donor liver transplant. METHODS: We retrospectively studied the outcome of 89 cirrhotic patients who either did (n = 63) or did not (n = 25) undergo shunt ligation during living donor liver transplantation between 2017 and 2020. RESULTS: The incidence of early allograft dysfunction/nonfunction (P = 1.0) and portal venous complications (P = 0.555) were similar between the two groups. Although overall complications, biliary complications, and the composite of Grade III and IV complications were significantly higher in the nonligated group (P = 0.015, 0.052 and 0.035), 1- year graft and patient survival were comparable between them (P = 0.524). CONCLUSION: We conclude that shunt ligation in living donor liver transplantation may not always be necessary if adequate portal flow, good vascular reconstruction, and good graft quality have been ensured.

Early Allograft Dysfunction After Live Donor Liver Transplantation: It's Time to Redefine?

BACKGROUND: An ideal definition of early allograft dysfunction (EAD) after live donor liver transplantation (LDLT) remains elusive. The aim of the present study was to compare the diagnostic accuracies of existing EAD definitions, identify the predictors of early graft loss due to EAD, and formulate a new definition, estimating EAD-related mortality in LDLT recipients. METHODS: Consecutive adult patients undergoing elective LDLT were analyzed. Patients with technical (vascular, biliary) complications and biopsy-proven rejections were excluded. RESULTS: There were 19 deaths due to EAD of a total of 304 patients. On applying the existing definitions of EAD, we revealed their limitations of being either too broad with low specificity or too restrictive with low sensitivity in patients with LDLT. A new definition of EAD-LDLT (total bilirubin >10 mg/dL, international normalized ratio [INR] > 1.6 and serum urea >100 mg/dL, for five consecutive days after day 7) was derived after doing a multivariate analysis. In receiver operator characteristics analysis, an AUC for EAD-LDLT was 0.86. The calibration and internal cross-validation of the new model confirmed its predictability. CONCLUSION: The new model of EAD-LDLT, based on total bilirubin >10 mg/dL, INR >1.6 and serum urea >100 mg/dL, for five consecutive days after day 7, has a better predictive value for mortality due to EAD in LDLT recipients.

Minimizing the risk of small-for-size syndrome after liver surgery.

BACKGROUND: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant (FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-for-size syndrome (SFSS). DATA SOURCES: This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specific modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. RESULTS: Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. CONCLUSIONS: With those techniques the indications of radical treatment for patients with liver tumors have significantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modification of interventions and the right timing of surgery.

Clinical application of split liver transplantation technique / 器官移植

Currently, multiple difficulties exist in clinical liver transplantation, such as shortage of donor liver, increasing quantity of patients waiting for liver transplantation and lack of matching donors, etc. Some children and adult patients have little chance of undergoing liver transplantation, which also limits the development of liver transplantation. In this context, split liver transplantation emerges, in which 1 donor liver can be applied to 2 or even more recipients. It may effectively increase the utilization rate of donor liver and alleviate the shortage of donor liver. With the development of split liver transplantation, the survival rate of split liver transplantation is comparable to that of total liver transplantation. Multiple transplantation centers have routinely adopted split liver transplantation. In this article, the development of split liver transplantation, the selection and matching of donors and recipients, the split and reconstruction techniques of donor liver and postoperative complications were reviewed, aiming to provide reference for subsequent development of split liver transplantation in clinical practice and increase the chance of liver transplantation for more patients diagnosed with end-stage liver diseases.

Impact of graft/recipient weight ratio on the prognosis of infants with whole liver transplantation / 中华器官移植杂志

Objective:To explore the impact of graft recipient weight ratio(GRWR)on pediatric whole liver transplantation in infants aged under 1 year.Methods:From January 2014 to December 2019, clinical data were retrospectively reviewed for 140 children aged under 1 year with whole liver transplantation.They were divided into 3 groups of low GRWR(GRWR<2.5%, 48 cases), middle GRWR(2.5%≤GRWR<5%, 73 cases)and high GRWR(GRWR≥5%, 19 cases). Basic profiles, major postoperative complications and survival rate of graft/recipient were compared.Results:There were 62 males and 78 females with an average age of (7.34±1.81)months and an average weight of(6.81±1.09)kg.The median GRWR was 3.27%(1.33%~8.12%). The higher level of GRWR, the greater age, weight and graft weight of donor in three groups and there was statistical difference ( P<0.05); operative duration, postoperative ICU stay and hospital stay were longer in low GRWR group than those in middle GRWR group and there was statistical difference( P<0.05); The incidence of postoperative hepatic artery thrombosis was higher in low GRWR group than that in middle GRWR group(31.3%vs 8.2%)and there was statistical difference( P<0.05); 4 cases of small-for-size syndrome occurred in low GRWR group, it was significantly different from the other two groups and there was statistical difference( P<0.05); the median follow-up period was(50.7±23.4)months.The survival rates of grafts at 3-month and 1/5-year were 89.6%, 91.8%, 100%; 87.5%, 87.7%, 100%; 87.5%, 87.7%, 100%and there was no inter-group difference( P>0.05). The survival rates of recipients at 3 months, 1 year and 5 years post-operation were 93.8%, 91.8%, 100%; 91.7%, 87.7%, 100%; 91.7%, 87.7%, 100%and there was no inter-group difference( P>0.05). Conclusions:Different from pediatric living donor transplantation, GRWR≥5%does not affect the survival rate of recipient/graft during whole liver transplantation.And GRWR<2.5%may boost the postoperative incidence of hepatic artery thrombosis and small liver syndrome.

Perioperative management of split liver transplantation / 器官移植

In the context of shortage of donor livers, split liver transplantation has achieved the goal of "one donor liver for two recipients", which effectively alleviates the shortage of donor livers and has promising development prospect. With the advancement of liver transplant techniques, split liver transplantation may yield clinical prognosis equivalent to total liver transplantation. However, perioperative management of split liver transplantation still encounters multiple challenges, with demanding techniques requirement and high-risk postoperative complications. Besides, there is a possibility of dividing one high-quality donor liver into two marginal donor livers, which will affect the development of liver transplantation. In this article, perioperative management of split liver transplantation was discussed from the perspectives of preoperative evaluation, recipient management and postoperative complication management, aiming to provide reference for promoting the development of split liver transplantation and enhancing clinical prognosis of recipients after split liver transplantation.

Hierarchical Modeling of the Liver Vascular System.

The liver plays a key role in the metabolic homeostasis of the whole organism. To carry out its functions, it is endowed with a peculiar circulatory system, made of three main dendritic flow structures and lobules. Understanding the vascular anatomy of the liver is clinically relevant since various liver pathologies are related to vascular disorders. Here, we develop a novel liver circulation model with a deterministic architecture based on the constructal law of design over the entire scale range (from macrocirculation to microcirculation). In this framework, the liver vascular structure is a combination of superimposed tree-shaped networks and porous system, where the main geometrical features of the dendritic fluid networks and the permeability of the porous medium, are defined from the constructal viewpoint. With this model, we are able to emulate physiological scenarios and to predict changes in blood pressure and flow rates throughout the hepatic vasculature due to resection or thrombosis in certain portions of the organ, simulated as deliberate blockages in the blood supply to these sections. This work sheds light on the critical impact of the vascular network on mechanics-related processes occurring in hepatic diseases, healing and regeneration that involve blood flow redistribution and are at the core of liver resilience.