Graft inflow modulation in adult-to-adult living donor liver transplantation: A systematic review
Introduction
Living donor liver transplantation (LDLT) is a worldwide established alternative to standard liver transplantation. Initially conceived for pediatric recipients, LDLT was successively extended to adult patients with end-stage liver diseases including cancer [1], [2], [3], [4]. Despite its success, adult LDLT is still associated with controversial issues such as risks to the donor and the morbidity linked to the recipient's graft size mismatch [5]. Sufficient graft volume to support the recipient's metabolic demands according to his clinical state (Child-Pugh or MELD score) is a fundamental requisite [5], [6], [7].
More than two decades ago, increased risks of graft loss and a complicated postoperative period following transplantation of pediatric liver grafts into adults were reported; however, the least possible consequences that would be later described in adult LDLT were not imagined [8]. Initially, concerning anatomic–pathological features (low mitosis rate, enhanced cholestasis and necrosis) were described by Emond et al. [9] in a small series of small-for-size graft (SFSG) transplantations. The Kyoto group first reported in 1999 a significantly lower graft survival in cases of LDLT using small grafts [7]. The combination of prolonged cholestasis, intractable ascites, encephalopathy and decreased prothrombin time was thereafter acknowledged and reported as a specific clinical/anatomic–pathological entity termed small-for-size syndrome (SFSS) [8], [10].
To date there is no universal definition of SFSS. The first proposal came from Dahm et al. [11] in 2005, who proposed a dysfunction of a partial graft with a graft-to-recipient body weight ratio (GRBWR) < 0.8% during the first post-operative week after the exclusion of other causes, by the presence of two of the following parameters on 3 consecutive days: INR >2, total bilirubin >5.8 mg/dl and encephalopathy grade 3 or 4. They furthermore defined the “small-for-size non-function” as the failure of a small graft, with graft loss, re-transplantation or death during the first post-operative week after the exclusion of other causes. The Kyushu University termed SFSS the occurrence of prolonged cholestasis (total bilirubin >10 mg/dl on postoperative day 14) with intractable ascites (>1 L on postoperative day 14 or >0.5 L on postoperative day 28) [12]. Subsequently, Hill et al. [13] defined SFSS as the continuous increase in total bilirubin up to 10 mg/dl after postoperative day 7, combined with a PT-INR >1.5 and ascites >2 L, after exclusion of mechanical or technical problems. The most recent definition was proposed in 2012 by Ikegami et al. [14] who depicted SFSS as an evolving situation of graft dysfunction termed “delayed functional hyperbilirubinemia”: a condition with total bilirubin >20 mg/dl for more than 7 consecutive days after the first postoperative week, excluding technical, immunological and infectious factors.
Currently, a donor liver is considered a small-for-size graft when the GRBWR is less than 0.8 or when the ratio between graft volume to standard liver volume (GV/SLV) is less than 40% [15]. Accordingly, an SFSG is a graft with a GV/SLV <35% [16] or <30% [17]. This could be associated with higher recipient complication rates [7]. Although recipients of smaller grafts are at higher risks of SFSS, SFSGs are not always solely responsible [18]. Factors other than the graft volume can potentially influence the outcome; these include recipient-related factors (disease clinical status and portal hypertension), graft-related factors (donor age, elevated percentage of macroscopic fatty content, cold and warm ischemia times, ischemia/reperfusion injury, and immunological factors), and technical factors (vascular reconstruction and adequate outflow, vascular inflow, and pressure gradients) [19].
Although a careful preoperative graft volume assessment is one of the most important steps when planning an LDLT, the incidence of SFSS can vary between 0 and 43% in SFSG with a GRWR of less than 0.8 and between 0 and 5% in SFSG with a GRBWR higher than 0.8 [20], [21], [22].
Portal hypertension following reperfusion and the hyperdynamic splanchnic state are reported as the major triggering factors of SFSS [23], [24], [25], [26], [27]; this is even more a matter of concern in LDLT because of the partial graft transplantation that is associated with increased resistance [28], [29], [30].
The first experimental data showing sinusoidal line disruption and mitochondrial swelling resulted from an SFSG mouse model. [31] Subsequently, the role of portal hypertension was successively shown in a larger animal model [32] and in the clinical setting where enhanced cholestasis and hepatocyte ballooning, disruption of sinusoidal line and transformation of activated Ito cells into fibroblasts were observed [14], [33], [34].
Conservative pharmacological methods in animal models targeting vascular regulation to modulate the portal inflow have been studied, including prostaglandin E1, FK409, a nitric oxide donor, an endothelin receptor-A antagonist, an adenosine A2a receptor agonist and several other options [35]. To date, the most promising drug with a decreasing effect on portal perfusion, preserving the hepatocyte structure and improving outcomes is somatostatin. However, data on the effects of this drug in the clinical setting of liver transplantation are still being evaluated [36], [37], [38], [39].
Surgical techniques to reduce portal overperfusion (graft inflow modulation—GIM) have been described in the past decade, including mesocaval and portocaval (PCS) shunts, splenic artery ligation (SAL), and splenectomy (SPL) [21], [40], [41], [42], [43], [44]. These surgical techniques reduce graft loss and SFSS incidence as described in the literature, although satisfactory outcomes have been reported without GIM in well-selected recipients [45], [46].
The aim of this review is to evaluate the worldwide published experience on graft inflow modulation, analyzing the indications, efficacy of the available techniques, changes in hemodynamics and outcomes.
Section snippets
Literature search
PRISMA statement guidelines for conducting and reporting systematic reviews were followed. The research protocol was registered at the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO) with the following registration number: CRD42015020427.
A systematic literature search was performed independently by two of the manuscript's authors (GB and FT) using PubMed, EMBASE, Scopus and the Cochrane Library Central. The search was limited to studies in humans
Study selection
The literature search yielded 563 articles; after duplicate removal, 376 titles and abstracts were reviewed (Fig. 1). Of these, 344 papers were excluded for the following reasons: 342 not concerning inflow modulation for LDLT, 1 temporary shunt procedure and 1 article reporting outcomes of deceased donor grafts. Finally, 32 articles were selected for full-text review, and of these, 20 more were excluded: 2 did not report outcomes of patients undergoing inflow modulation [46], [48], 3 were case
Discussion
Small-for-size syndrome, although infrequent, is a specific clinical feature that could be encountered in recipients with or without an unfavorable graft size mismatch. Its incidence ranges between 0 and 43% in cases of LDLT with SFSG (GRWR <0.8), and between 0 and 5% in recipients with a GRWR higher than 0.8 [20], [22], [73].
The expanded use of small-for-size grafts in LDLT led to the improvement of surgical techniques aiming to decrease complication rates. Because portal hypertension and
Conflict of interest
All of the authors declare no conflict of interest and no financial and personal relationships possibly influencing the manuscript to disclose.
Authors' contributions
Study conception and design: R. I. Troisi
Acquisition of data: G. Berardi; F. Tomassini
Analysis and interpretation of data: G. Berardi; F. Tomassini; R.I. Troisi; M. Sainz-Barriga
Drafting of manuscript: G Berardi, R.I. Troisi
Critical revision: M Sainz-Barriga
References (84)
- et al.
Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe
Liver Transpl
(2000) - et al.
Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient's disease
Liver Transpl
(2001) - et al.
Small-for-size syndrome in living donor liver transplantation
Hepatobiliary Pancreat Dis Int
(2012) - et al.
Small-for-size syndrome after partial liver transplantation: definition, mechanisms of disease and clinical implications
Am J Transplant
(2005) - et al.
Feasibility of left lobe living donor liver transplantation between adults: an 8-year, single-center experience of 107 cases
Am J Transplant
(2006) - et al.
Primary graft dysfunction after living donor liver transplantation is characterized by delayed functional hyperbilirubinemia
Am J Transplant
(2012) - et al.
Small-for-size grafts in living-related liver transplantation
J Am Coll Surg
(2001) - et al.
Adult-to-adult living donor liver transplantation at the Asan Medical Center, Korea
Asian J Surg
(2002) - et al.
Effects of hemi-portocaval shunts for inflow modulation on the outcome of small-for-size grafts in living donor liver transplantation
Am J Transplant
(2005) - et al.
Graft selection algorithm based on congestion volume for adult living donor liver transplantation
Am J Transplant
(2007)
Impact of right lobe with middle hepatic vein graft in living-donor liver transplantation
Am J Transplant
Significance of portal venous flow in graft regeneration after living related liver transplantation
Transplant Proc
Excessive portal venous inflow as a cause of allograft dysfunction in small-for-size living donor liver transplantation
Transplant Proc
Small-for-size syndrome: what is the problem?
Liver Transpl
Somatostatin therapy protects porcine livers in small-for-size liver transplantation
Am J Transplant
Selective hemi-portocaval shunt based on portal vein pressure for small-for-size graft in adult living donor liver transplantation
Am J Transplant
Impact of a left-lobe graft without modulation of portal flow in adult-to-adult living donor liver transplantation
Am J Transplant
Graft-to-recipient weight ratio lower to 0.7% is safe without portal pressure modulation in right-lobe living donor liver transplantation with favorable conditions
Hepatobiliary Pancreat Dis Int
Modulation of graft vascular inflow guided by flowmetry and manometry in liver transplantation
Hepatobiliary Pancreat Dis Int
Portal hyperperfusion injury as the cause of primary nonfunction in a small-for-size liver graft-successful treatment with splenic artery ligation
Liver Transpl
Living donor liver transplantation with left liver graft
Am J Transplant
Portal venous pressure in adult living donor liver transplantation
Transplant Proc
Modulation of liver graft hemodynamics by partial ablation of the splenic circuit: a way to increase hepatic artery flow?
Transplant Proc
Adult-to-adult living donor liver transplantation using left lobes: the importance of surgical modulations on portal graft inflow
Transplant Proc
Early modulation of portal graft inflow in adult living donor liver transplant recipients with high portal inflow detected by intraoperative color Doppler ultrasound
Transplant Proc
Clinical relevance of adapting portal vein flow in living donor liver transplantation in adult patients
Liver Transpl
Splenectomy and liver transplantation
Transplant Proc
Small-for-size partial liver graft in an adult recipient; a new transplant technique
Lancet
Strategies for successful left-lobe living donor liver transplantation in 250 consecutive adult cases in a single center
J Am Coll Surg
Right lobe graft in living donor liver transplantation
Transplantation
Should we use living donor grafts for patients with hepatocellular carcinoma? Ethical considerations
Liver Transpl
Living donor liver transplantation and tolerance: a potential strategy in cholangiocarcinoma
Transplantation
Ambivalence in living liver donors
Liver Transpl
Impact of graft size mismatching on graft prognosis in liver transplantation from living donors
Transplantation
Transplantation of small donor livers in adult recipients
Transplant Proc
Functional analysis of grafts from living donors. Implications for the treatment of older recipients
Ann Surg
Graft weight/recipient weight ratio: how well does it predict outcome after partial liver transplants?
Liver Transpl
The durability of small-for-size living donor allografts
Liver Transpl
Small-for-size graft: not defined solely by being small for size
Liver Transpl
Successful transplantation of small-for-size grafts: a reappraisal
Liver Transpl
New prediction factors of small-for-size syndrome in living donor adult liver transplantation for chronic liver disease
Transpl Int
Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation
Transpl Int
Cited by (44)
Living donation in liver transplantation: Overview of history, indications, and specific aspects of living donation in liver transplantation
2023, The Liver Graft Before Transplantation: Defining Outcome After Liver TransplantationEnhanced recovery for liver transplantation: recommendations from the 2022 International Liver Transplantation Society consensus conference
2023, The Lancet Gastroenterology and HepatologyThe care of donors and recipients in adult living donor liver transplantation
2022, BJA EducationCitation Excerpt :Graft inflow may need to be modulated to protect the graft; this can be achieved in many ways. Ligating the splenic artery, thereby increasing hepatic artery flow, which in turn decreases portal flow by means of the hepatic artery buffer response, is a popular first choice surgically.10 Many other portosystemic shunts are possible, the choice of which is patient-specific and based on the centre's experience.
Minimizing the risk of small-for-size syndrome after liver surgery
2022, Hepatobiliary and Pancreatic Diseases InternationalCitation Excerpt :Obtaining intraoperative measurement of pre- and post-resection portal vein pressure and flow, and portal vein-hepatic veins/central venous pressure gradient (usually using direct fine gauge catheters introduced to the portal vein), is a key step. Portal vein pressure > 15–20 mmHg or PV/CVP gradient > 15 mmHg or portal flow > 250–360 mL/min/100g liver, are usually suggestive of a hyperperfused liver remnant, indicating that patient will benefit from inflow modulation [267,280]. The type of intervention is influenced by local expertise and surgeon preference and depends on initial pressure values and response to each treatment as there is no consensus favoring a specific technique.
RAPID procedure for colorectal cancer liver metastasis
2020, International Journal of SurgerySmall-for-size syndrome in liver transplantation: Definition, pathophysiology and management
2020, Hepatobiliary and Pancreatic Diseases International