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Introduction
Liver transplantation (LT) is a definite and ultimate treatment alternative for
end-stage and metabolic liver diseases [1-3]. Donor shortages push the
boundaries of marginal donors in deceased donor liver transplantation and living
donors worldwide. In living donor liver transplantation (LDLT), the safety of both
recipients and donors is in line [4].
Definitions of Small for Size Syndrome
Small-for-size syndrome (SFSS) is a critical complication of LT using a partial
graft, particularly in cases of adult-to-adult ALDLT using a small graft (Fig. 1). In general, small-for-size graft (SFSG)
corresponds to a graft weight <0.8% of recipient weight or a graft volume
<40% of recipient’s standard liver volume (SLV) [5-8]. Recent progress in
perioperative care and technical improvement in partial LT, minimally required liver
graft volume for successful transplantation is an ongoing debate and has decreased
to 0.6% graft versus recipient weight ratio (GRWR) (approximately 25% of the
recipient’s SLV).
Fig. 1.
A small partial graft during adult-to-adult living donor liver transplantation. The patient has undergone a small right liver graft with a 0.7% graft-versus-recipient weight ratio.
The definition of SFSS varies among transplant centers. Persistent portal
hypertension and hyperperfusion after SFSG transplantation have been identified as
the main factors in this clinical syndrome [9,10]. Nevertheless, the SFSS is
a multifaceted event. Typical clinical manifestations of SFSS are consequences of
portal hypertension and graft dysfunction, presenting as more than two of the
following on 3 consecutive days: (1) long-standing uncontrolled ascites (>1
L/day), (2) hyperbilirubinemia (total bilirubin >5 mg/dL), (3) coagulopathy
(International normalized ratio >2), and (4) encephalopathy (≥grade 3)
during the first postoperative week after transplantation and after the exclusion of
other causes, such as vascular or biliary complications or rejection. Other symptoms
or signs of portal hypertension can also be addressed. These manifestations can
disappear or improve compared with the pre-transplantation status after graft
functioning.
The factors associated with SFSS include preoperative patient condition, the natural
development of varices, medical or surgical efforts to reduce portal pressure, no
pressure gradient between the hepatic vein and inferior vena cava (or right atrium),
graft quality, and graft size.
Small for Size Syndrome Pathophysiology
The main pathophysiology of SFSS is shear stress, which leads to sinusoidal
microcirculatory disturbances caused by excessive portal pressure [11]. In the case of a small graft, repair and
regeneration cannot overcome the damage and maintain liver function very early after
transplantation. If this damage is permanent or severe, the outcome of SFSS is poor,
leading to graft failure and patient death.
The early microscopic features of SFSS are ischemia related to arterial vasospasm
and/or thrombosis and render hepato-cytes vulnerable to the subsequent oxidative
stress leading to endothelial damage, cholestasis, hepatocyte ballooning, and
ductular reaction, as well as bile duct necrosis. The late features include nodular
regenerative hyperplasia [8,12,13].
Outcomes of Small for Size Syndrome
Early reports on SFSS demonstrated poor patient and graft survival outcomes. Patients
with both elevated portal pressure (≥20 [range 18-25] mmHg) and SFSG
(≤0.8% GRWR) showed significantly worse survival outcomes, bacteremia, and
longer hospital stays. If the pre-transplant patient’s condition is worse,
such as old age and high model for end-stage liver disease (MELD) score,
post-transplant outcomes would be much worse [5,8,11,14].
Recent reports regarding the outcomes of SFSG have shown promising results (Table 1). Small grafts are associated with poor
short-term outcomes. However, the long-term outcome was not inferior in patients
with small grafts [15]. Therefore,
prevention, early detection, and interventions to attenuate SFSS are important.
Various approaches have been explored to modulate inflow and pressure to a small
graft and to decrease the outflow block to alleviate this SFSS. Along with these
efforts, strict matching criteria for patient and donor pairs are also
important.
Table 1.
The outcomes of liver transplantations using a SFSG
| Year of study | Study | Country | Definition | Number of SFSG group | Number of control group | Incidence of SFSS (%) | Short-term mortality in SFSG | Long-term mortality (OR, 90% CI) |
|---|---|---|---|---|---|---|---|---|
| 2008 | Yi | Korea | <0.8% GRWR | 29 | - | - | 0% in Right 33% in Left | - |
| 2008 | Ikegami | Japan | <35% GV/SLV | 33 | 87 | 0 | 12.5% (1 yr) | 3.25 (1.29-8.18) |
| 2009 | Selzner | Canada | <0.8% GRWR | 22 | 249 | 9 | 4.5% (30 days) | 0.82 (0.27-2.60) |
| 2010 | Moon | Korea | <0.8% GRWR | 35 | 392 | 5.7 | - | 1.33 (0.60-2.95) |
| 2014 | Lee | Korea | <0.8% GRWR | 50 | 267 | 8 | 2% (1 yr) | 1.61 (0.72-3.63)* |
| 2015 | Au | HongKong | <35% GV/SLV | 21 | 212 | - | - | 1.61 (0.51-5.15) |
| 2015 | Liu | China | <0.8% GRWR | 65 | 181 | 11 | 7.7% (30 days) | 1.23 (0.65-2.34) |
| 2016 | Ikegami | Japan | <35% GV/SLV | 88 | 119 | 11.4 | - | 0.69 (0.28-1.72) |
Prevention and Management to Improve the Outcome of Small for Size Graft
1. Prevention of small for size syndrome
The management goal of the SFSS is to avoid SFSS. SFSS does not always occur in
patients with SFSG. This can be prevented by cautiously matching the donor and
recipient and applying surgical or medical modifications. Prevention of
damage-related SFSG on portal hypertension is an ideal solution [8,16].
The principles for avoiding SFSS are as follows: First, it does not consider
multiple risks of SFSS at once. There are several known factors related to SFSS:
aged donor, graft steatosis, longer ischemic time, left small liver than right
small liver, and recipient with a high MELD score [8,14,16]. For example, if the patient’s
condition is poor, sufficient graft volume from a young donor with a short
ischemic time rather than a small left liver graft is a better alternative
[11,14,17].
Second, portal pressure is attenuated after accurate measurement of portal
pressure during transplantation [14,16,17-20]. Several surgical
procedures can reduce the portal pressure and alleviate potential SFSS.
Remaining natural varices or creating transient portosystemic shunts can reduce
portal hypertension during the early period of graft regeneration. However,
portal steal syndrome can sometimes ruin sufficient inflow to the graft.
Accurate measurement of portal pressure and flow via the inferior mesenteric
vein or the direct portal puncture technique helps decide whether to proceed
with these procedures [18]. After
regeneration of a small graft, surgical or interventional shunt occlusion can be
performed to improve the long-term graft outcomes and prevent variceal
complications. An indirect method to reduce portal pressure is to reduce splenic
venous inflow to the portal vein. Splenomegaly and splenic artery hypertrophy
are common in patients with end-stage liver disease and portal hypertension. In
that case, splenectomy, splenic artery ligation, or splenic devascularization
can reduce portal pressure [9,16,21,22].
Third, we used the entire transplanted graft without ischemia or congestion, as
possible [9,23,24]. To avoid
ischemia of the small graft, the surgeon should reconstruct all the inflows.
During hepatectomy and graft implantation, meticulous surgery is mandatory to
prevent the use of inotropic agents. To avoid congestion of the small graft,
drain all the outflow of the area >20% of the graft, segment 5 veins,
segment 8 veins, and right inferior hepatic veins in the right graft, and
segment 1 vein in the left graft with the caudate lobe. To improve outflow, the
outlet of the hepatic vein should be sufficiently large to transfer the
oscillation of the heartbeat. Additionally, physiological obstruction related to
hemodynamic changes such as high right atrial pressure or central venous
pressure should be properly managed during the reperfusion period.
Finally, dual graft implantation and auxiliary orthotopic partial liver
transplantation (APOLT) or heterotopic auxiliary partial liver transplantation
(HALT) with future native liver hepatectomy, the so-called resection and partial
liver segment 2/3 transplantation with delayed total hepatectomy (RAPID), can be
another option to avoid SFSS [24-32]. The APOLT technique was applied to
chronic liver disease in the late 90s during ALDLT to avoid SFSS and to protect
donor safety using a small graft for sufficient future remnant volume in Asian
countries (Fig. 2). Recently, this
technique has been applied to patients with colorectal liver-only metastasis
without portal hypertension who do not receive an adequate volume of deceased
donor graft but can get a split left lateral section.
Fig. 2.
Auxiliary partial orthotopic liver transplantation to prevent the small-for-size syndrome. A 36-yr-old patient with Wilson’s disease has undergone living-donor liver transplantation from a 54-yr-old mother using a right posterior section graft. The graft-versus-recipient weight ratio is 0.64%. He has undergone a native liver hepatectomy 11 mo after transplantation. (A) A preoperative recipient computed tomography (CT) scan. (B) A CT scan of postoperative day 9. (C) A CT scan of postoperative 11 mo.
2. Management after small for size syndrome development
Regardless of these efforts during the operation, the SFSS can develop.
Management goals include medical management of portal hypertension and graft
support for acute liver failure. The medical reduction of portal pressure is
similar to that of the pretransplant management of portal hypertension. Fluid
balance and ascites control are basic concepts. Intervention radiology can play
a role in splenic artery embolization by reducing portal pressure via flow
reduction (Fig. 3).
Fig. 3.
Post-transplant splenic arterial embolization to reduce portal hypertension. A 40-yr-old woman with hepatitis B-related liver cirrhosis with the hepatorenal syndrome and uncontrolled ascites underwent living-donor liver transplantation from his 35-yr-old wife using a right liver graft. He underwent gastrorenal shunt occlusion before transplantation to control variceal bleeding and encephalopathy. One mo after transplantation, the patient underwent partial occlusion of the splenic artery because of uncontrolled ascites related to small-for-size syndrome (arrow, material for gastrorenal shunt occlusion). (A) A preoperative recipient computed tomography (CT) scan. (B) A CT scan of postoperative day 7. (C) A CT scan 2 yrs after transplantation.
The SFSS can be overcome after the early period of graft regeneration. If varices
or shunt flow remains, we should wait for a minimum of 2 weeks (10-21 days after
transplantation) for graft regeneration. Delayed closure would be helpful for
the restoration of graft function. Delayed native liver hepatectomy in cases of
APOLT (or HALT, RAPID) can be performed during this period [25-31].
Conclusion
SFSS can occur in any case when using a small partial graft. However, a better
understanding of SFSS and the recent progress in perioperative management and
surgical techniques can push the boundary of a small graft. Before permanent damage
of a small graft, prevention and early detection of SFSS can save patients with only
the alternative for a small graft.
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