Case 1 -
Portal Hyperperfusion or Small-for-size Syndrome (PHP/SFSS)
Lisa M. Yerian
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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
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At this point in the patient's course, the
differential diagnosis in any liver transplant recipient would include
- Preservation injury
- Immune-mediated complications: Rejection
- Technical complications: Biliary and/or vascular
- Small-for-size syndrome
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 . 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 . In this case was excluded based on the absence of
typical cellular infiltrates, endotheliitis or lymphocyte-mediated bile duct damage . There was no
histologic evidence of chronic or ductopenic rejection, which would be unusual
in this time frame
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 . 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
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
. 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 . 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
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
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 , and satisfactory portal vein, hepatic artery and hepatic vein
flows are all important for graft outcome . Strategies to reduce the risk of PHP/SFSS are largely
focused on reducing portal flows by splenic artery ligation, portal banding, and portosystemic shunts
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
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
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 . 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 .
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 . 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 .
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.
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