Liver Pathology

Portal Hyperperfusion or Small-for-size Syndrome (PHP/SFSS)

Lisa M. Yerian
Cleveland Clinic
Cleveland, OH


Clinical History
The patient presented with early post-operative graft failure after receiving a left lobe liver graft. The graft appeared to function well over post-operative days (POD) one and two, but on POD 3 the patient developed mental status changes and his bilirubin began to increase. CT revealed patent vessels including a patent left portal vein to inferior vena cava shunt. A small collection of right subphrenic fluid was noted, and the patient was taken to the operating room for exploratory laparotomy and abdominal washout. No evidence of bleeding, bile leak or abscess was found; all anastomoses were intact. A liver biopsy was taken, which showed marked steatosis and canalicular cholestasis. The hepatic lobules contained scattered collections of neutrophils. Occasional hepatocyte mitoses were noted, and there was scattered hepatocyte swelling. The portal tracts also exhibited variable, mild neutrophilic infiltrates and focal bile plugs. The portal vein profiles contained blood, fibrin, and demonstrated focal wall disruption and hemorrhage into portal spaces. Hepatic arterioles appeared intact with no evidence of vasculitis.


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Differential Diagnosis:
At this point in the patient's course, the differential diagnosis in any liver transplant recipient would include
  • Preservation injury

  • Infection

  • Immune-mediated complications: Rejection

  • Technical complications: Biliary and/or vascular

  • Small-for-size syndrome

Discussion:
In a cadaveric graft, evidence of preservation injury is commonly seen in early post-transplant biopsies. These changes vary in severity but are characterized by hepatocyte swelling, canalicular cholestasis, and foci of hepatocyte necrosis [1]. Cholangiolar proliferation may be seen, and hepatocyte mitoses may be prominent. However, since transport times are greatly reduced in living donor liver transplantation (LDLT), manifestations of preservation injury are much less frequent and less likely to be clinically significant. This patient had warm and cold ischemia times of 48 minutes and two hours, 21 minutes, respectively. Infection was considered, particularly sepsis. The patient was afebrile with a slightly elevated white count (12.1 k/uL) and on antibiotics. Evidence of viral infection was not seen in the biopsy, and cultures were taken from the abdominal fluid collection. Sepsis alone can present a spectrum of abnormalities including canalicular cholestasis, cholangiolar proliferation and inspissated bile. In the early post-transplant period these alterations can be difficult to distinguish from technical complications, particularly biliary obstruction, and the clinical findings are critical in guiding management.

Acute rejection most frequently occurs between days 5 and 30 post transplantation but can occur earlier or later [2]. In this case was excluded based on the absence of typical cellular infiltrates, endotheliitis or lymphocyte-mediated bile duct damage [2]. There was no histologic evidence of chronic or ductopenic rejection, which would be unusual in this time frame [3, 4].

Antibody-mediated (humoral) rejection occurs in the setting of pre-formed or de novo anti-donor antibodies, usually occurring in the setting of blood group ABO-incompatibility or lymphocytotoxic antibodies. LDLT recipients appear to be at greater risk than recipients of cadaveric livers [5]. In rare cases, antibody-mediated rejection presents with severe and early graft failure ("hyperacute" rejection) characterized by widespread endothelial cell injury with neutrophilic exudation, fibrin thrombi in central and portal veins, congestion and hepatocyte necrosis [1, 6]. Most cases of lymphocytotoxic antibody-mediated rejection are less florid, presenting with spotty hepatocyte necrosis or swelling with cholestasis and ductular proliferation in the first week after transplantation. A necrotizing arteritis is rarely seen. Deposition of complement C4d in portal vessels can be demonstrated by immunostaining and aids in distinguishing the changes from preservation injury but is also seen in patients with acute cellular rejection. Hence, the diagnostic significance of this finding is uncertain [7]. Our patient was blood group-compatible and tested negative for T-cell and B-cell antibodies, making antibody-mediated rejection extremely unlikely as a cause for this patient's early graft failure.

The greater technical demands of LDLT lead to a greater risk of technical complications [8]. Given the dependence of the biliary tree on hepatic arterial flow and the physiologic balance of portal and arterial flow (discussed further below), biliary and vascular complications can co-exist. This patient underwent multiple vascular anastomoses and a Roux-en-Y biliary anastomosis. Imaging studies performed on POD 1 and 2 revealed patent liver vasculature with anterograde flow, and there was no evidence of bleeding or a bile leak at exploratory laparotomy. Possible biliary complications include biliary obstruction, acute ascending cholangitis, ischemic cholangitis and bile leaks. Although the patient's biopsy exhibited cholestasis and mild duct injury, there was no portal edema to suggest biliary obstruction, signs of duct ischemia were not evident at this time, and although rare neutrophils were seen in association with bile ducts, intraluminal collections were not identified. Other possible vascular complications include decreased portal vein flow and impaired venous outflow. Decreased portal flows may occur due to portal vein thrombosis or shunting of portal flow away from the liver. In living donor transplantation, vascular shunts can direct high portal flows away from the liver graft in attempt to avoid complications of portal hyperperfusion. Hepatic venous outflow impairment occurs due to any mechanical impingement on hepatic vein flow but is less common with left lobe grafts than right lobe grafts because the left lobe retains the middle hepatic vein in addition to the left hepatic vein.

For recipients of split-liver grafts, portal hyperperfusion or small-for-size syndrome (PHP/SFSS) is an important diagnostic consideration. This complication occurs when the graft is unable to meet the demands of the recipient. It most frequently affects grafts that do not meet the graft to recipient weight ratio (GRWR) threshold of 0.8% but is also seen in larger grafts in very ill recipients, with severe recipient portal hypertension, and with suboptimal grafts [9, 10, 11, 12, 13]. In this case, the 78 kg recipient received a 620 gram graft, yielding a GRWR of 0.8%. However, the patient was known to have severe portal hypertension with high portal pressures prior to liver transplantation (mean hepatic wedge pressure 24mm Hg and mean right atrial pressure 1 mm Hg, for a calculated portoatrial gradient of 23 mm Hg [normal <10 mmHg]). It is likely that high portal pressures predisposed the recipient to portal hyperperfusion. That said, adequate portal pressures are important for liver regeneration [11], and satisfactory portal vein, hepatic artery and hepatic vein flows are all important for graft outcome [14]. Strategies to reduce the risk of PHP/SFSS are largely focused on reducing portal flows by splenic artery ligation, portal banding, and portosystemic shunts [10, 15]. However, given the requirement of adequate portal pressures for liver regeneration, it is important to maintain adequate portal and arterial inflow and venous draining while avoiding high portal flows.

Further Clinical Course:
Over the next two days, the patient's condition continued to deteriorate. He was re-listed and on POD 7 underwent orthotopic liver transplantation. At re-transplantation the liver graft was congested and hard. There was no evidence of bile leakage. Histologic examination of the explanted graft demonstrated steatosis and extensive canalicular cholestasis as seen in the prior needle biopsy. At this time there were more prominent portal neutrophilic infiltrates and infiltration of interlobular bile ducts by neutrophils. Large septal ducts exhibited epithelial necrosis with bile leakage into the adjacent stroma. Extensive confluent hepatocyte necrosis was present. In some areas the necrosis was panlobular, and in less severely affected regions the distribution was predominantly centrilobular. The explanted liver showed more prominent portal vein endothelial disruption, injury and focal thrombus formation. The hepatic artery branches were unremarkable with no evidence of vasculitis.

Although there is no uniform definition of PHP/SFSS, it is generally characterized by post transplantation complications including persistent cholestasis, ascites, and coagulopathy [9, 16]. Diagnosis requires that other causes of graft dysfunction including rejection, infection (including cholangitis and sepsis) and technical complications have been excluded. Early histologic features of SFSS reported in needle biopsies include hepatocanalicular cholestasis, steatosis, and a mild ductular reaction associated with mild neutrophilic infiltrates [9]. Endothelial cell alterations including denudation and hypertophy may be subtle and difficult to identify in needle biopsies. More well-developed features seen on examination of failed allografts include hemorrhage into portal tract connective tissue, in some cases extending in periportal hepatic parenchyma. Other late findings of PHP/SFSS such as small portal vein branch thrombosis, luminal obliteration or recanalization, or nodular regenerative hyperplasia [9].

Also present in this patient's explanted graft are features of hepatic artery ischemia including ischemic bile duct injury with bile duct necrosis and parenchymal infarcts. Evaluation of hepatic artery branches revealed no evidence of thrombotic occlusion. In PHP/SFSS, "functional dearterialization" occurs as a compensatory decrease in arterial flows in response to high portal flow as mediated by the "hepatic arterial buffer response." This response yields an overall balance of blood flow to the liver by regulating local adenosine concentrations. In the setting of high portal flow, local adenosine concentrations fall leading to increased hepatic arterial resistance reduced arterial flow [17]. This patient's bile ducts did show features of ischemic injury. Because the bile ducts are exclusively perfused by the hepatic artery, this loss of arterial flow can lead to ischemic bile duct injury, bile leakage, and perihilar parenchymal necrosis. Whereas the native liver is somewhat protected from hepatic artery obstruction by an extensive and anastomosing arterial system, a transplanted liver lacks this arterial redundancy and is much more susceptible to impaired arterial flow. Ongoing arterial ischemia may lead to ischemic bile duct strictures in surviving grafts [9].

Summary and Talking Points:
This patient's risk factors for PHP/SFSS included the left lobe graft of marginal size (GRWR 0.8%) and pre-existing high portal pressures in the recipient. The risks posed to the patient were recognized at the time of LDLT, and portal decompression was performed via creation of a portocaval shunt and splenic artery ligation. Early signs of graft failure included hyperbilirubinemia and mental status changes. The histopathologic changes on early post-transplant biopsy are somewhat nonspecific, whereas the findings seen on explant demonstrate features of portal vein hyperperfusion in addition to hepatic arterial insufficiency. Diagnosis requires knowledge of the risk factors PHP/SFSS and understanding of the complex interrelatedness of graft portal, arterial and venous flows.

References:
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  2. International Panel. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658-663.

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  4. Demetris AJ, Adeyi O, Bellamy CO, et al. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology 2006;44:489-501.

  5. AstarciogluI,CursioR,ReynesM,et al. Increased risk of antibody-mediated rejection of reduced-size liver allografts. J Surg Res1999;87:258-262.

  6. DemetrisAJ,MuraseN,NakamuraK,et al.Immunopathology of antibodies as effectors of orthotopic liver allograft rejection. Semin Liver Dis1992;12:51-59

  7. Neuman UP, Neuhaus P. C4d immunostaining in acute humoral rejection after ABO blood group-incompatible liver transplantation. Liver Transpl 2006;12:356-7.

  8. GhobrialRM,BusuttilRW: Challenges of adult living-donor liver transplantation. J Hepatobiliary Pancreat Surg2006;13:139-145.

  9. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Path 2006;30:986-993.

  10. Ikegami T, Shimada M, Imura S, et al. Current concept of small-for-size grafts in living donor liver transplantation. Surg Today 2008;38:971-982.

  11. Dahm F, Georgiev P, Clavien P. Small-for-size syndrome after partial liver transplantation: Definition, mechanisms of disease and clinical implications. Am J Transpl 2005;5:2605-2610.

  12. Hill MJ, Hughes M, Jie T, et al. Graft weight/recipient weight ratio: how well does it predict outcome after partial liver transplants? Liver Transpl 2009;15:1056-62.

  13. Sanefuji K, Iguchi T, Ueda S, et al. New prediction factors of small-for-size síndrome in living donor adult liver transplantation for chronic liver disease. Transpl Int 2009 Epub ahead of print.

  14. Marcos A, Orloff M, Mieles L, et al. Functional venous anatomy for right-lobe grafting and techniques to optimize outflow.

  15. Kelly DM, Miller C. Understanding the splenic contribution to portal flow: the role of splenic artery ligation as inflow modification in living donor liver transplantation. Liver Transp 2006;12:1186-8.

  16. Kelly DM, Demetris AJ, Fung JJ, et al. Porcine partial liver transplantation: a novel model of the "small-for-size" liver graft. Liver Transpl 2004;10:253-63.

  17. Kelly DM, Zhu X, Shiba H, et al. Adenosine restores the hepatic artery buffer response and improves survival in a porcine model of small-for-size syndrome. Liver Transpl 2009;15:1448-57.