Small‐for‐size syndrome in LT

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Abbreviations

GRWR

graft‐to‐recipient weight ratio

LDLT

living donor liver transplantation

PVP

portal venous pressure

SFS

small‐for‐size

SFSS

small‐for‐size syndrome

Definition and Clinical Implication of Small‐for‐Size Syndrome

Kiuchi et al.1 first described that the use of small‐for‐size (SFS) grafts [graft‐to‐recipient weight ratio (GRWR) of <1.0%] in living donor liver transplantation (LDLT) was associated with a significantly lower 1‐year graft survival rate of 50% to 76% than that of >80% for middle‐ and large‐size grafts. This phenomenon was considered to occur because of reduced metabolic and synthetic capacity, causing delayed recovery of bilirubin clearance and prothrombin time, and putting recipients at higher risk for surgical and/or septic complications. Shortly after the report by Kiuchi et al.,1 Sugawara et al.2 demonstrated that recipients of SFS grafts (defined as having a graft volume/standard liver volume ratio of <40%) had a significantly lower survival rate of 80% than that of 96% for recipients of large‐size grafts. Currently, the acceptable lower threshold of the graft size used in LDLT remains at the discretion of each institution. Kyoto University has recently proposed that the GRWR, in combination with portal inflow modulation, can be as low as 0.6%, which is probably the smallest liver graft to date.3

Small‐for‐size syndrome (SFSS) was initially described as a number of clinical manifestations resulting from the use of SFS grafts. SFSS is characterized by persistent hyperbilirubinemia, coagulopathy, intractable ascites, and encephalopathy; however, the definition varies among centers. Dahm et al.4 defined SFSS as a dysfunction of a partial liver graft (GRWR < 0.8%) based on the presence of two of the following three criteria on 3 consecutive days during the first postoperative week, after the exclusion of other causes: (1) total bilirubin > 5.8 mg/dL, (2) prothrombin international normalized ratio > 2, and (3) encephalopathy grade ≥ 3. Other centers have defined SFSS regardless of graft size and have integrated intractable ascites (Table 1). Accumulating evidence supports that SFSS is not only induced by graft size mismatch between the donor and the recipient, but also by several other factors. Survival outcomes of recipients with SFSS are variable. Whereas Ikegami et al.5 reported a significantly decreased 5‐year graft survival rate of 42.9% in left lobe LDLT recipients with severe SFSS (n = 21) compared with those without (n = 186, 94.3%), Moon et al.6 found no statistical difference in the incidence of SFSS (3%–6%) and graft survival (74%–80% at 5 years) between recipients of a right lobe graft with a GRWR <0.8% (n = 35) versus those with a GRWR ≥0.8% (n = 392). The reasons why graft survival rates are diverse among these two studies are multifactorial: difference in the definition of SFSS, mean GRWR (0.71 in Ikegami et al.'s5 series and 1.10 in Moon et al.'s6 series), the method used for survival analyses (patient deaths unrelated to graft function were excluded in Moon et al.'s6 series), small sample size, among others.

Table 1.

Definitions of SFSS

Institution (Year)	Terminology	Definition
University Hospital Zurich4 (2005)	SFS dysfunction	Dysfunctiona of a “small” partial liver graft (GRWR < 0.8%) during the first postoperative week after the exclusion of other causesb
	SFS nonfunction	Failurec of a “small” partial liver graft (GRWR < 0.8%) during the first postoperative week after the exclusion of other causesb
University of Minnesota12 (2009)	SFSS	Total bilirubin >10 mg/dL (and continuing to increase) after postoperative day 7, coagulopathy with an international normalized ratio >1.5, and ascites with drain output >2 L/day in the absence of an obvious technical problem such as vascular thrombosis or stenosis
Kyushu University5 (2016)	Severe SFSS	Total bilirubin >20.0 mg/dL within a month after LDLT, without technical, anatomical, immunological, or hepatitis‐related issues

^aGraft dysfunction: the presence of two of the following on 3 consecutive days: bilirubin >5.8 mg/dL (100 μmol/L), international normalized ratio >2, or encephalopathy grade 3 or 4.

^bExclusion criteria: technical (e.g., arterial or portal occlusion, outflow congestion, bile leak), immunological (e.g., rejection), and infectious (e.g., cholangitis or sepsis).

^cGraft failure: retransplantation or death of recipient.

Pathophysiology and Risk Factors

Portal hyperperfusion plays a central role in the development of SFSS.7 Consistent hyperdynamic splanchnic circulation in LDLT recipients with long‐standing cirrhosis results in increased portal flow to the partial liver graft. The shear stress in hepatic microcirculation caused by elevated portal venous pressure (PVP) gives rise to liver regeneration to a certain extent; however, excessive portal flow or PVP (they do not necessarily correlate with each other) provokes sinusoidal endothelial cell injury, which leads to SFSS and subsequent graft loss in extreme situations. Decreased hepatic arterial flow caused by portal hyperperfusion occurs through a phenomenon called the hepatic arterial buffer response and has been demonstrated to contribute to ischemic biliary injury. Experimental studies have shown the increased mucosal permeability of the congested and edematous intestine secondary to portal hypertension following SFS graft transplantation.8 An intestinal mucosal injury predisposes recipients to bacterial translocation, further compromising their survival. Histopathological manifestations of SFSS (Fig. 1) include zonal extravasation of red blood cells into the periportal sinusoids, hepatocyte ballooning, hepatocanalicular cholestasis, among others.

Figure 1.

Histopathological findings of SFSS: (A) zonal extravasation of red blood cells (arrowhead) in the periportal sinusoids (Rappaport's zone 1), (B) hepatocyte ballooning, and (C) hepatocanalicular cholestasis (arrows).

Regarding the precipitating factors of SFSS, Ikegami et al.5 reported recipients with a model for end‐stage liver disease score of ≥19, donor age ≥48 years, and end PVP of ≥19 mm Hg as independent predictive factors for severe SFSS (defined as hyperbilirubinemia with a total bilirubin concentration of ≥20.0 mg/dL within a month after LDLT using left lobe grafts). Moon et al.6 described that an SFS right lobe graft (GRWR < 0.8%) can be safely used if the donor's age is younger than 44 years. In addition, it is well‐known that severe steatosis is significantly associated with poor outcomes in LDLT. The development of SFSS is multifactorial; therefore, judicious donor and recipient matching is the cornerstone for preventing SFSS.

Management

Right lobe liver grafts are potentially associated with a higher incidence of morbidity and mortality in donors; therefore, vigorous attempts have been made to shift the risk from the donor to the recipient by the more liberal use of left lobe liver grafts in combination with surgical and medical interventions. In 2002, Boillot et al.9 first described a mesocaval shunt with downstream ligation of the superior mesenteric vein. Thereafter, various methods for portal inflow modulation, such as splenectomy, splenic arterial ligation, and portocaval shunts (including the placement of a transjugular intrahepatic portosystemic shunt), combined with the measurement of PVP and/or portal flow have been described.7 It is equally important to maintain an adequate hepatic venous outflow, and surgeons should always pay attention to whether venoplasty of the graft hepatic vein and inferior vena cava is needed. Meanwhile, portal infusion of prostaglandin E1 for SFS grafts in LDLT has effectively lowered the PVP and demonstrated significantly improved liver function in the early postoperative period, suggesting that pharmacological approaches are promising in the prevention of SFSS.10 Only a few publications have discussed treatment options after the occurrence of SFSS, once the graft is in the recipient. Delayed splenic artery embolization was reported to be effective in small case series.11, 12 One patient who developed SFSS despite splenic artery ligation at the time of transplant successfully recovered with the use of intravenous octreotide combined with oral propranolol.13 To date, there are no established criteria regarding the predictors of graft failure in SFSS patients to help identify those who eventually will require retransplantation.

Future Perspectives

From a global viewpoint, live donation remains an important organ resource for end‐stage liver disease patients who require liver transplantation, particularly in Asia, as well as in the Middle East and Africa. It is also being revisited both in the United States and in Europe because of persistent organ shortage. Donor safety always comes first in LDLT, and there is a growing momentum for detailed discussions on the increased use of SFS grafts with refinements on donor and recipient matching, and countermeasures for SFSS within an international framework. In addition, novel strategies for SFSS, such as hepatocyte transplantation and extracorporeal liver support, are theoretically attractive and await clinical validation. We should strive to consolidate global efforts to eradicate donor complications and safely perform LDLT as the last hope for patients who would otherwise have died.