Keywords
hepatic venous outflow obstruction - liver transplant - stent - stenosis
Chronic liver disease is the 12th leading cause of mortality in the United States,
responsible for approximately 40,545 deaths in 2016.[1] Liver transplantation provides definitive treatment to address acute or chronic
end-stage liver disease and its complications once medical therapy is no longer effective.[2] Improvements in immunosuppression and surgical techniques have led to contemporary
graft failure rates below 10% at 1 year, and 5-year survival rates for living donors
nearing 75%.[3] Surgical techniques have also evolved over time to address the rising need for liver
transplantation in the setting of a relatively stable deceased donor pool.[4] Transplant graft options include whole, partial, or split deceased donor liver transplant
(DDLT), and living donor liver transplant (LDLT). Donor type (deceased vs. living),
graft type (whole vs. partial), and surgeon/center experience determine the surgical
anastomoses of the hepatic venous outflow. The overall rate of hepatic venous outflow
dysfunction in adult recipients is between 1 and 4%,[5] and the type of anastomosis impacts its prevalence.[6] This review specifically addresses the current understanding of posttransplant venous
outflow complications, their diagnosis, and management.
Hepatic Venous Outflow Obstruction Pathophysiology
Hepatic Venous Outflow Obstruction Pathophysiology
Post liver transplant vascular complications can be categorized based on the location
of the lesion within either the inflow or outflow vessels. Inflow lesions affect vascular
supply via the transplant hepatic artery or portal vein and impact graft survival
via ischemia. Outflow lesions involve the transplant hepatic veins and inferior vena
cava (IVC), and affect graft survival via a phenomenon termed hepatic venous outflow
obstruction (HVOO).
Patients experiencing HVOO commonly present with congestive symptoms including ascites,
pleural effusion, peripheral edema, abdominal pain, elevated liver enzymes, new onset
splenomegaly, renal dysfunction, intestinal congestion, and, ultimately, fulminant
graft dysfunction, hypotension, and multi-organ failure.[6]
[7]
[8]
[9]
[10]
[11]
[12] Mortality rates with HVOO have been reported up to 24%.[13]
[14]
HVOO can be subdivided by time frame: early and late postoperative. Early postoperative
phase HVOO occurs within 28 days of surgery and is typically secondary to surgical
technical factors such as tight anastomotic sutures, kinking or twisting of the outflow
tract, and compression from the graft or adjacent fluid collection.[5]
[7]
[15]
[16]
[17]
[18] Unlike the native recipient liver, which has multiple natural points of fixation
in the abdomen such as the falciform ligament, the transplanted liver can rotate on
its vascular pedicle leading to kinking or twisting of the outflow tract, and may
be more common in liver donor or split liver transplants.[13] Late postoperative phase HVOO likely results from neointimal hyperplasia, fibrosis
due to inflammation, or anastomotic compression due to graft maturation.[10]
[15]
[16]
[19]
[20]
Surgical Technique for Hepatic Venous Outflow
Surgical Technique for Hepatic Venous Outflow
Various surgical techniques are used to reconstruct the hepatic venous outflow during
liver transplant, with the two most common being conventional orthotopic liver transplant
(OLT) and piggyback liver transplant (PBLT).[21] The choice of surgical technique has implications with respect to venous outflow
complications, imaging diagnosis, and endovascular treatment approaches.
Conventional OLT is utilized in the setting of whole liver DDLT. Operative technique
involves complete hepatectomy with or without veno-venous bypass, and cross-clamping
of the recipient retrohepatic IVC for resection and creation of new end-to-end caval
anastomoses[21]
[22] ([Fig. 1]). Hypotension during the anhepatic phase, retroperitoneal bleeding, longer vascular
reconstruction times, and complications of veno-venous bypass are classic shortcomings
of conventional OLT.[23]
[24] These end-to-end drainage pathways tend to be adequately sized; however, outflow
complications involving the superior and inferior caval anastomoses may still occur.
Fig. 1 Schematic illustration of the conventional venous outflow surgical technique demonstrates
separate supra-hepatic and infra-hepatic end-to-end caval anastomoses. The retrohepatic
inferior vena cava (IVC) is removed en-bloc during the recipient hepatectomy.
The PBLT technique shortens the anhepatic phase and obviates the need for veno-venous
bypass by preserving the recipient IVC through the construction of a venous cuff between
the recipient hepatic veins and the donor outflow venous tract.[21]
[23]
[24]
[25]
[26] The most common iterations of this technique include a venous cuff incorporating
the right hepatic vein and middle hepatic vein, the middle hepatic vein and left hepatic
vein, or all three hepatic veins.[21]
[27] This venous cuff is then fashioned into an end-to-end[26] or side-to-side caval anastomosis[28]
[29] ([Fig. 2]), sometimes with an additional anastomosis-enlarging cavotomy.[21]
[30]
[31]
[32] PBLT is commonly performed in LDLT, split or reduced graft placement, and pediatric
transplants, as anatomic variations and size mismatch between graft and recipient
can make conventional technique difficult[33]
[34]
Fig. 2 Schematic illustrations of the piggyback venous anastomotic techniques. (A) The end-to-end piggyback technique preserves the native retrohepatic inferior vena
cava (IVC) via an anastomosis between donor cava and a venous cuff created from the
native hepatic veins. (B) Side-to-side piggyback technique also preserves the native retrohepatic IVC with
an anastomosis between the donor IVC and venous cuff created from the native hepatic
veins. The superior and inferior donor IVC are surgically ligated.
Overall, HVOO is a rare complication of OLT. In adults, recent rates of HVOO vary
between 1 and 4%,[5]
[35]
[36]
[37] while historical rates vary widely and are reported to be between 0.5 and 13%.[4]
[13]
[14]
[23]
[30]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48] Comparatively, HVOO occurs with a slightly higher frequency in the pediatric population.
Recent rates vary between 0 and 5%,[49]
[50]
[51]
[52]
[53]
[54] with historical rates reported to be 5 to 27%.[55]
[56]
[57]
[58]
[59]
[60] Prospective data on outflow complications for specific combinations of graft types
and donor types are challenging to generate given the complexity of transplant interventions,
technical factors, operator variability, and evolving center experience. While a recent
randomized clinical trial[61] and prior analysis of randomized clinical trials reported no difference in vascular
complications between conventional and piggyback transplantation methods,[27] retrospective analyses demonstrate that conventional OLT has a lower rate of HVOO
compared to PBLT. As PBLT is more often utilized in LDLT, split graft placement, and
pediatric transplantation, it has been implicated in higher rates of HVOO in these
instances.[5]
[23]
[42]
[62] For example, a review of 600 pediatric liver transplants revealed HVOO rates of
1% for whole liver grafts, 2% for living-related grafts, and 4% for reduced or split
liver grafts.[6] Discrepant and/or small size of the venous anastomoses and varying drainage patterns
to the IVC have been suspected in these settings.[5]
[18]
[49]
[63]
[64] Moreover, anatomical variations such as torsion or kinking that coincide with graft
maturation may promote physical obstruction.[4]
[5]
[65]
It is important to recognize that there are many variant drainage patterns within
the liver. In the setting of LDLT and split liver transplant, these variations can
require individualized anastomoses between the donor graft and recipient. For example,
a cryopreserved iliac vein conduit and/or polytetrafluoroethylene (PTFE) graft may
be necessary with separate segment 5 and 8 tributaries, or a donor accessory inferior
right hepatic vein draining separately into the IVC.[66] While specific anastomotic variants are beyond the scope of this paper, it is essential
to understand the anatomy prior to interpreting diagnostic studies or intervening
on any patient post liver transplant.
Noninvasive Diagnosis
Noninvasive modalities, such as Doppler ultrasound (DUS) and computed tomography (CT),
play an important role in the detection of posttransplant complications. DUS is an
excellent screening tool in the evaluation of posttransplant liver dysfunction secondary
to its widespread availability, portability, lack of ionizing radiation or iodinated
contrast, and relative affordability compared to CT and magnetic resonance imaging.
Although widely available, DUS is heavily dependent on the operator performing the
exam, and evaluation can be limited in obese patients as well as in the setting of
overlying bowel gas. CT will frequently be used to confirm DUS findings prior to intervention,
or in the setting of a limited DUS evaluation.
The preservation of a biphasic or triphasic waveform on DUS essentially excludes the
possibility of HVOO,[67] which can present as a dampened, monophasic waveform with a pulsatility index of
0.45 or less. These findings are nonspecific, however, and often seen in the posttransplant
setting.[67]
[68]
[69] Ancillary findings may include a visible stenosis on grayscale imaging, color aliasing
at the stenosis, reduced hepatic venous velocities below 10 cm/s,[70] and reversal of normal antegrade flow within the hepatic and/or portal venous system.
Similar findings are present when the IVC is involved. Velocities may increase up
to fourfold in the diseased segment with associated Doppler aliasing artifact. Moreover,
associated dilation of the proximal hepatic veins can be observed along with loss
of phasicity and dampening of the expected biphasic or triphasic waveform.[69]
[71]
CT has a reported sensitivity of 100% with a positive predictive value of 81% in patients
with HVOO.[20] Furthermore, CT has demonstrated better sensitivity and specificity in comparison
with DUS (97 vs. 87% and 86 vs. 68%, respectively) with the benefit of attenuation
differences, which may suggest vascular congestion.[72] Coronal reconstructions of the IVC may be particularly useful for the detection
of caval complications.[73]
Venography and Endovascular Intervention
Venography and Endovascular Intervention
Hepatic Veins
Conventional venography allows for assessment of anastomotic narrowing, relative vascular
flow, and measurement of venous pressures. Additionally, therapeutic intervention
can then be performed immediately following confirmation of suspected HVOO. Transjugular
access is typically utilized to perform venography within the hepatic veins and IVC,
although anatomy can occasionally favor a transfemoral approach. If a severe anastomotic
stenosis or occlusion precludes transjugular selection of the hepatic veins, ultrasound-guided
percutaneous transhepatic puncture of a dilated hepatic vein can be performed to assist
with catheterization.[74]
Measurement of a pressure gradient across the anastomosis can support diagnosis of
a venographic stenosis; however, a validated threshold gradient remains to be determined.
Some authors suggest a more stringent threshold gradient of >10 mm Hg,[40]
[75] while others have argued that gradients >3 mm Hg can be symptomatic,[31] reporting clinical improvements with treatment of gradient ranges between 3 and
5 mm Hg.[20]
[42]
Treatments for HVOO are primarily endovascular, with surgical revision infrequently
performed secondary to the difficult exposure required to reach the outflow anastomosis.
Venoplasty is often the initial intervention. Although high rates of initial patency
are described,[4]
[33]
[76] HVOO often recurs following venoplasty, requiring serial dilation or stent placement.
After identification of the stenotic segment, prolonged inflation of an angioplasty
balloon is performed until the stenotic waist is reduced ([Fig. 3]). The balloon size should be slightly oversized by 1 to 2 mm with respect to the
diameter of the hepatic vein. Kubo et al demonstrated restenosis in 55% of patients,
a primary patency rate of 60% at 5 years, and an assisted patency rate of 100% at
the end of the 5 years follow-up period in the patients with restenosis.[4] Similar assisted patency rates (95–100%) are reported in pediatric patients with
HVOO,[62]
[77] with 76 to 79% of patients requiring no more than two to three dilations.[53]
[77]
Fig. 3 A patient with ascites and hydrothorax, 8 months after piggyback technique liver
transplant. (A) Coronal postcontrast computed tomography demonstrates a high-grade stenosis of the
hepatic venous anastomosis with associated abdominal ascites and right pleural effusion.
(B) Selective digital subtraction venogram with catheter positioned in the right hepatic
vein demonstrates the high-grade anastomotic stenosis (arrow). A trans-anastomotic
pressure gradient of 20 mm Hg confirms the venographic findings. The inferior vena
cava is not opacified with contrast as the catheter is occlusive across the stenosis
and there is intraparenchymal reflux (white asterisk) through the sinusoids and into
the portal vein (arrowhead). Notably, pathology from concomitant transjugular liver
biopsy demonstrated zone-three congestion and necrosis, consistent with hepatic venous
outflow obstruction. (C) Venoplasty is performed with a 12 mm plain balloon, demonstrating a waist at the
anastomotic stenosis (black asterisk). (D) After venoplasty, antegrade flow in the hepatic vein and across the anastomosis
is reestablished, and the pressure gradient across the stenosis improves to 4 mm Hg.
Some favor angioplasty over primary stent placement because indwelling stents are
inherently thrombogenic, promote neointimal hyperplasia, and their presence may complicate
future surgical intervention or retransplantation.[42]
[53]
[77] These considerations are particularly important in the pediatric population in which
an initially appropriately sized stent may become a fixed stenosis as the child and
graft grow.[53]
[60] For this reason, stent placement may be deferred in pediatric liver patients until
maturity in favor of serial angioplasty.
Emerging data highlight a role for primary stenting ([Fig. 4]) in the setting of HVOO with promising long-term stent patency rates at 5 to 10
years ([Table 1]). Early postoperative HVOO may provide a unique scenario for primary stent placement
as venoplasty can theoretically disrupt the newly created transplant anastomosis.[42] Moreover, the causes of early postoperative HVOO may not respond well to venoplasty
alone, given its inability to address kinking, vascular torsion, or ongoing compression.
Even with these considerations, Kim et al recently reported lower patency rates after
stent placement than other cohorts, attributing their findings to high rates of kinking
that were not amenable to stenting.[37]
Fig. 4 A 59-year-old male 3 months after split liver transplant with piggyback anastomosis
presents with rising bilirubin and liver enzymes. (A) Transplant hepatic venous Doppler examination demonstrates a monophasic waveform
with decreased velocities and diminished pulsatility indices in the right and middle
hepatic veins. (B) Selective venogram with catheter positioned in the hepatic vein demonstrates a high-grade
anastomotic stenosis with catheter occlusion across the stenotic segment (arrow).
The measured trans-stenotic gradient is 23 mm Hg. (C) After primary stent placement across the anastomotic stenosis with a 14 mm x 4 cm
self-expanding nitinol stent, there is improved hepatic venous flow and a significantly
reduced gradient now measuring 5 mm Hg. The stent is appropriately oversized with
respect to the size of the hepatic vein and is well positioned across the stenosis
without excessive protrusion into the inferior vena cava. (D) At 2-year follow-up, a Doppler ultrasound demonstrates stent patency with an improved,
biphasic waveform, and a sustained improvement in hepatic vein velocities.
Table 1
Long-term stent patency rates in hepatic venous outlet obstruction
|
1-year patency (%)
|
3-year patency (%)
|
5-year patency (%)
|
10-year patency (%)
|
|
Ko et al[42]
|
82
|
75
|
72
|
NA
|
|
Chu et al[35]
|
94
|
94
|
94
|
NA
|
|
Jang et al[20]
Early
Late
|
88
70
|
88
70
|
88
70
|
88
70
|
|
Kim et al[37]
Early
Late
|
76
40
|
46
20
|
56
20
|
NA
|
Comparison between balloon-expandable and self-expanding stents in the setting of
HVOO is yet to be performed. Balloon-expandable stents are often utilized to treat
hepatic venous stenosis given their higher radial strength and ease of precise placement.[74] Wang et al utilized short balloon-expandable stents in the setting of HVOO and saw
high patency rates.[33] Ko et al and Chu et al demonstrated high patency rates with self-expanding stents[35]
[42] with increased stent diameter demonstrating an association with patency.[42] Reported stent diameters range from 8 to 14 mm within the hepatic veins.[74] In the pediatric population, utilization of large self-expanding stents may allow
the stent to grow with the patient, potentially reducing concern for future stenosis
or stent migration.[62]
[77] Data on pediatric stent placement is lacking although high rates of clinical success
and patency have been previously reported.[77]
[78] Recent data show high rates of stent patency up to 13.5 years (median 6 years)[62] and 17 years (median 7.5 years)[54] in low-powered studies.
Complications related to hepatic vein angioplasty and stent placement are rare.[42] While there is a theoretical risk of anastomotic rupture after angioplasty in the
early posttransplant setting, multiple studies cite a rate of 0%.[4]
[53] Bleeding complications following angioplasty at later time points are very unlikely
given the retroperitoneal location and postoperative scarring.
Another rare, albeit feared, complication is stent migration, which can occur secondary
to respiratory (and cardiac) motion, or due to the complex and dynamic anatomy of
the hepatic venous anastomoses. In one retrospective study involving 152 pediatric
liver transplant patients, 18 of whom required intervention for HVOO, no stent placements
were complicated by stent migration.[62] In two additional retrospective studies, stent migration occurred in only one patient
per study—in one case, the stent migrated slightly into the IVC requiring no further
intervention,[76] and in the second case, migration occurred into the right atrium, requiring retrieval
over the wire with balloon assistance.[37] At the authors' institution, general anesthesia is often used to limit respiratory
motion, as deep inspiration during stent deployment can result in maldeployment necessitating
stent retrieval from the IVC or right atrium. Selection of the appropriate stent size
is also critical in preventing migration. In the event that a stent migrates or is
minimally misplaced into the IVC, the stent can be stabilized by placement of an overlapping
stent.[74] However, if a stent migrates or extends too far centrally into the right atrium,
the consequences can be severe and life threatening, potentially requiring cardiac
surgery for removal if it cannot be retrieved through standard endovascular techniques.
Inferior Vena Cava
Caval complications posttransplantation most frequently result from stenosis of the
suprahepatic IVC or infrahepatic IVC anastomoses in standard technique liver transplants.
Historically, venoplasty ([Fig. 5]) has been successful but resulted in recurrence rates near 50%.[75]
[79]
[80]
[81]
[82] Small retrospective studies utilizing caval stent placement show high rates of technical
and clinical success with primary assisted patency rates of 94[83] and 100%[82] reported at 1 and 7 years, respectively. Given these rates of success, caval stenting
is often considered to be a first-line intervention[39]
[84] with stent sizes ranging between 14 and 24 mm.[74] Additionally, Parvinian and Gaba[85] proposed the utilization of a cutting balloon over stepwise sessions to augment
caval luminal caliber, reporting successful luminal expansion from 2 to 3 mm to 10
to 11 mm. This technique, akin to addressing biliary strictures, would provide an
alternative route when caval stenting is undesirable.[85]
Fig. 5 A 35-year-old man with piggyback technique liver transplant 10 years prior developed
new enlarged abdominal wall collaterals. (A) Coronal image from the venous phase of a computed tomographic scan of the abdomen
demonstrates a high-grade stenosis (arrow) of the suprahepatic inferior vena cava
(IVC). There is hepatic congestion evidenced by heterogeneous enhancement of the liver.
(B) Digital subtraction venogram with 5 French pigtail catheter positioned in the infrahepatic
IVC from right internal jugular venous access demonstrates a 90% stenosis involving
the suprahepatic IVC (arrowheads) with a trans-stenotic gradient of 14 mm Hg. Contrast
refluxes into the hepatic veins (asterisk) and multiple collateral varices (arrow)
are opacified. (C) Serial venoplasty is performed, first with a 14 mm balloon, demonstrating a waist
(arrowheads) at the stenosis. (D) Prolonged venoplasty with an 18 mm balloon demonstrates resolution of the waist.
(E) Post venoplasty digital subtraction venogram demonstrates improved luminal gain
with a residual stenosis of < 50%, and an improved trans-stenotic pressure gradient
of 1 mm Hg. After venoplasty, abdominal wall collaterals resolved.
Complication profiles for venoplasty and stenting of IVC stenosis are similar to those
seen with hepatic venous stenosis. While there is a theoretical risk of anastomotic
rupture after venoplasty, particularly in the early postoperative setting, there are
no documented cases of rupture in the literature.[39] Stent migration, while potentially serious, is rare.[39] The open architectural design and high radial force of the Gianturco Z-stent (Cook
Medical, Bloomington, IN) make it a desirable choice for use in the IVC. The stent
interstices do not obstruct the hepatic outflow when placed across the confluence
([Fig. 6]). This also allows future venoplasty and stenting of the hepatic veins if a concomitant
hepatic venous stenosis warrants treatment. Additionally, anchoring barbs are incorporated
into the struts, a design feature intended to reduce migration.[74]
Fig. 6 A 33-year-old woman with abdominal and lower extremity edema and hyperbilirubinemia
10 days after deceased donor liver transplant. (A) Digital subtraction venography performed with CO2 contrast agent demonstrates near complete occlusion of the infrarenal inferior vena
cava (IVC) (black circle) and a 16 mm Hg gradient from the IVC to the right atrium.
Additionally, there is reversal of flow into the portal venous system (not pictured)
through an existing gastrorenal shunt (black arrowheads) via the left renal vein (LRV).
(B) Angiogram postplacement of a 2.5 × 5.0 cm nitinol Z-stent within the IVC demonstrates
resolution of the obstruction and reduction of the IVC to right atrium gradient to
2 mm Hg. Note that there is no filling of the gastrorenal shunt following stent placement.
(C) Axial computed tomography image demonstrates a Z-stent strut across the hepatic
vein origin (circle); however, flow is preserved as expected given the large Z-stent
interstices.
Conclusion
HVOO is an infrequent complication of liver transplantation that affects graft survival
by compromising outflow via transplant hepatic veins or IVC. While conventional OLT
creates end-to-end drainage pathways between the native and transplant IVC, PBLT technique
involves creation of an anastomotic cuff between the recipient hepatic veins and donor
outflow tract. PBLT is commonly used in LDLT, split/reduced graft transplant, and
pediatric transplant, and is implicated in higher rates of HVOO due to the complex
and variable anatomy encountered in these scenarios. HVOO can occur in the early postoperative
phase or in a delayed manner, resulting in clinical signs and symptoms of venous congestion,
renal failure, and graft dysfunction or failure. Ultrasound is the best noninvasive
screening tool to evaluate the venous anastomoses, and may demonstrate a monophasic
hepatic waveform, a visible stenosis, reduced hepatic venous velocities, or reversal
of flow within the hepatic and/or portal venous system. Conventional venography is
the gold standard for confirming the diagnosis of HVOO, providing both visual assessment
of a stenosis and manometric evaluation of a significant pressure gradient. Furthermore,
it facilitates endovascular treatment of significant lesions with either serial angioplasty
or stent placement, both of which demonstrate efficacy and high rates of long-term
assisted-patency in adult and pediatric populations.
