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PORTAL HYPERTENSION 417
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CONCLUSION
Portal hypertension from intrahepatic causes is definitively managed by transplant. Failing medical therapy and endoscopic banding, when bleeding varices and ascites occur as a consequence of
portal hypertension, they are usually well managed by TIPS placement. Shunt surgery is rarely utilized in the setting of acute bleeding
but remains an excellent, life-saving therapy, particularly when
portosystemic shunting is caused by extrahepatic portal venous
obstruction with a patent mesenteric vein and intact liver function,
or when transplant and TIPS placement are either unavailable or
not feasible.
Liver Transplantation
Benjamin Philosophe, MD, PhD, and Kiara A. Tulla, MD
HISTORY
The evolution of liver transplantation has been relatively rapid.
The first human liver transplant was performed by Thomas Starzl
in 1963. Between March 1 and October 4, 1963, Starzl performed
five human liver transplants, with the longest survival at 23 days.
The patients died with functioning grafts that had little evidence
of rejection at autopsy. There was also a single failed attempt in
Boston in 1963 and in Paris in 1964 before the operation came to a
halt, perceived then to be too difficult. It was not until 1967 that the
first liver transplant recipient survived 1 year. Immunosuppression
consisted of azathioprine, prednisone, and antilymphocyte globulin.
After cyclosporine was introduced in 1980, 1-year survival began to
be consistently achieved (Fig. 1).
As a result of these successes, the surgeon general initiated a
consensus conference in 1983. It was then concluded that liver
transplantation has become a “clinical service” and was no longer
considered an experimental procedure. This led to a rapid expansion
in the number of centers performing liver transplantation. As the
waiting list for liver transplantation grew exponentially, surgical fellows flocked to train under Starzl who had moved to the University
of Pittsburgh. The resulting growth of qualified surgeons eventually
caught up with the national and international need for liver transplants. The introduction of tacrolimus in 1989 pushed the 1-year
survival rates even higher, exceeding 80%, leading to approval by
the US Food and Drug Administration (FDA) in 1994. As surgical
techniques have progressed, there has been gradual improvement
in outcomes; current 1-year patient survival for deceased or living
donor transplantation is 92%.
IMMUNOSUPPRESSION
Indications for Liver Transplantation
Acute Liver Failure
Acute liver failure (ALF) is a rare but potentially fatal syndrome
characterized by sudden loss of hepatic function in a person without
preexisting liver disease. Acute liver failure can also occur in patients
with known diseases, such as Wilson’s disease, autoimmune hepatitis,
or hepatitis B. ALF affects approximately 2000 to 3000 Americans
each year. It is commonly classified as fulminant or subfulminant.
S U G G E S T E D R E A D I N G S
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive
bleeding in cirrhosis: Risk stratification, diagnosis, and management:
2016 practice guidance by the American Association for the Study of
Liver Diseases. Hepatology. 2017;65(1):310–335 Erratum in: Hepatology.
2017;66(1):304.
Orloff MJ. Fifty-three years’ experience with randomized clinical trials of
emergency portacaval shunt for bleeding esophageal varices in cirrhosis:
1958–2011. JAMA Surg. 2014;149(2):155–169.
Zeppa R, Warren WD. The distal splenorenal shunt. Am J Surg.
1971;122(3):300–303.
Fulminant liver failure is defined as the development of encephalopathy within 8 weeks of the development of symptoms such as
jaundice. Subfulminant hepatic failure is reserved for patients with
liver disease for up to 26 weeks before the development of hepatic
encephalopathy.
Whether fulminant or subfulminant, encephalopathy is an essential component in the definition. The most common cause of ALF in
the United States and western Europe is drug-induced liver injury,
which accounts for 50% of the cases. Acetaminophen is the leading
cause of ALF. Patients who are at increased risk for acetaminophen-induced ALF include those with concomitant alcohol use, malnutrition, or use of medications known to induce CYP450 enzymes
(e.g., phenytoin, carbamazepine, or rifampin). In 308 consecutive
patients from 17 tertiary care centers participating in the US Acute
Liver Failure Study Group, acetaminophen was identified as the etiology of ALF in 40% of patients. The other etiologies identified (in
ascending order of prevalence) were malignancy (1%), Budd-Chiari
syndrome (2%), pregnancy (2%), Wilson’s disease (3%), hepatitis A
virus infection (4%), autoimmune hepatitis (4%), ischemic hepatitis
(6%), hepatitis B virus infection (6%), and idiosyncratic drug-induced
liver injury (13%); 17% of cases were found to be indeterminate.
Patients suspected of having ALF should be immediately transferred to a liver transplant center because this can progress very
rapidly to fulminant liver failure and then death. The development
of complications, including cerebral edema, hemodynamic abnormalities, coagulopathy, renal failure, infection and sepsis, acidbase disturbances, and pulmonary dysfunction, requires immediate
attention.
The common cause of death in patients with fulminant hepatic
failure is cerebral edema. Hyperammonemia is considered a critical
factor in the development of cerebral edema and herniation. The
grades of encephalopathy correlate with the degree of herniation.
Cerebral edema develops in about 80% of patients who develop
grade 4 hepatic encephalopathy. The resultant increased ICP results
in decreased cerebral perfusion pressure, in turn leading to ischemic
brain damage and herniation. This accounts for more than one-half
of ALF-associated mortality.
ALF-induced encephalopathy, however, is different from that of
cirrhosis despite the fact that ammonia levels are elevated in both.
Cerebral edema does not develop in the setting of chronic liver
disease. As such, lactulose, a nonabsorbable disaccharide used to
decrease ammonia levels in cirrhotics, has never been shown to
improve survival in the setting of ALF. Rather, therapeutic measures
are focused on decreasing intracranial pressure (ICP), including
elevation of the head of the bed and minimizing patient stimulation
through sedation or paralysis.
418 LIVER TRANSPLANTATION
IMMUNOSUPPRESSION AND OUTCOME
1989 – Starzl introduces FK-506 (Lancet)
0
One year patient survival
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Survival in the history of liver transplantation
1963 – First human liver transplant
1967 – First 1- year liver transplant survival
1970’s – 1- year survival 25% with imuran and prednisone
1981 – Cyclosporine A introduced (NEJM)
100
90
80
70
60
50
40
30
20
10
The development of increased ICP is an ominous sign. Clinical
changes on examination occur only after significant cerebral edema
has developed and as such are not helpful. Head CT is equally insensitive in the early stages of edema but is helpful with more advanced
encephalopathy to rule out other pathology such as intracranial
hemorrhage. If cerebral edema is evident on CT, the likelihood of
irreversible brain injury or uncal herniation is high, and transplantation is contraindicated at this point. ICP monitoring can help diagnose intracranial hypertension and optimize management. There
are various types of ICP monitors, but all carry a significant risk of
intracranial hemorrhage following their placement. Whether the
benefits of ICP monitoring are worth the risks remains controversial.
Some transplant centers routinely utilize ICP monitors, while others
do not and rely on clinical signs.
Without a doubt, predicting which patients with fulminant
hepatic failure will require a time-sensitive life-saving transplant and
1994 – FK-506 FDA approved
FIG. 1 Historical survival data for liver
transplantation.
BOX 1 King’s College Criteria for Medical
Management of Fulminant Liver Failure
Acetaminophen
pH <7.3 or
INR >6.5 and serum Cr >3.4 mg/dL
Nonacetaminophen
INR >6.5 or any three of the following variables:
INR >3.5
Bilirubin >17.6 mg/dL
Age <10 or >40 years
Cause: drug toxicity
Time from onset of jaundice to encephalopathy greater than
7 days
which will recover with medical management alone can be very difficult. Many studies have attempted to identify prognostic indicators
to guide this clinical decision. The most widely applied is from King’s
College Hospital in London. The King’s College criteria are depicted
in Box 1. The positive predictive value of the King’s College criteria
is 80% to 100% according to most studies, which is higher than many
other criteria proposed.
In patients that meet the King’s College criteria, liver transplantation is the only definitive treatment option for patients with
fulminant liver failure. Farmer et al. performed a single-center retrospective analysis of 204 patients undergoing liver transplantation
in an 18-year span. They showed a 73% 1-year patient survival and a
67% 5-year patient survival. Graft survival was 63% and 57%, respectively. More recent registry data showed significant improvement;
1-year and 5-year graft survival was 80% and 73%, respectively.
Chronic Liver Disease
The indications for transplantation have changed over time. Figure 2
shows the diagnosis at the time of listing over the past 15 years.
Alcoholic hepatitis has always been a major cause of chronic liver
disease and remains so today. Although alcohol is listed as a primary
diagnosis around 20% of the time, it is often a secondary diagnosis,
with an overall incidence of 40% to 50%. Interestingly, during the
COVID-19 pandemic, the percent of patients listed with a primary
diagnosis of alcoholic cirrhosis increased drastically in 2020 (34%)
and 2021 (37%). As such, alcoholic cirrhosis is currently the number
one diagnosis at the time of listing.
Since hepatitis C was discovered in the early 1980s, it has been a
primary cause of chronic liver disease and a leading indication for
liver transplantation. For some transplant centers, hepatitis C was
the cause in up to 60% of the patients transplanted. However, with
the advent of direct-acting antiviral agents with near 100% cure rates,
hepatitis C has essentially been eradicated, and in 2021 was a cause in
only 7% of the patients listed.
Nonalcoholic steatohepatitis (NASH) is rapidly becoming a major
cause of cirrhosis. NASH, often a “silent” liver disease, histologically
resembles alcoholic liver disease, but occurs in people who drink
little or no alcohol. Steatosis with inflammation and cellular damage
including ballooning of hepatocytes is the hallmark of NASH. People
with NASH feel well and are not symptomatic until the cirrhosis is
more advanced. NASH affects 2% to 5% of Americans. An additional
10% to 20% of Americans have fatty liver, but no inflammation
PORTAL HYPERTENSION 419
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FIG. 2 Diagnosis of liver disease at the time of listing.
or liver damage, a condition called nonalcoholic fatty liver disease
(NAFLD). It is unclear why 25% of patients with NAFLD go on
to develop NASH. Both NASH and NAFLD are becoming more
common, possibly because of the greater number of Americans with
obesity. In the past 15 years, the rate of obesity has doubled in adults
and tripled in children. NASH is now the second leading indication
for liver transplantation in the United States in 2021 (19%).
Hepatocellular carcinoma (HCC) is the third leading cause of
cancer-related death worldwide and the one of the leading causes of
death in patients with cirrhosis. The incidence has more than doubled in the past two decades and will continue to increase over the
next 20 years. HCC is the third most common indication for liver
transplantation in 2021. HCC is associated with cirrhosis in nearly
90% of the cases in the United States, and when caught early, liver
transplantation is the best chance for cure. A landmark paper in 1996
showed that for small HCCs, the outcomes following transplantation
are excellent if they fall within certain criteria. Since the publication
came from a group in Milan, it has become known as the Milan
criteria. Milan criteria includes HCC candidates with stage T1 (one
lesion <2 cm) or stage T2 (one lesion ≥2 cm but <5 cm, or as many
as three lesions less than 3 cm each without any vascular invasion).
These favorable results established early HCC as a viable indication
for transplantation, resulting in changes in organ allocation that have
favored transplanting patients with HCC. Even in patients who may
appear to be resectable, 5-year disease-free survival is vastly better
following transplantation (82%) compared with resection (40%, P
<0.001).
In 2002, the United Network of Organ Sharing (UNOS) changed
the allocation of livers from a Child-Pugh categorized system to
a Model for End-Stage Liver Disease (MELD)-based system that
focuses on severity of disease and de-emphasizes waiting time. With
the new policy, HCC candidates with stage T1 or stage T2 HCC have
priority beyond the degree of hepatic decompensation. The MELD
“upgrade” given to HCC patients increases their MELD score at
listing reflecting a mortality associated with their cancer rather than
liver disease. Currently, there is a 6-month mandatory waiting period
for eligible patients meeting criteria. Although HCC upgrades have
undergone several revisions, in 2021 a MELD upgrade is defined as
the median MELD score at transplant (MMaT) within a 250–nautical
mile radius of the transplant center minus 3. In other words, if the
median MELD at transplant is 31 for a specific area, the patient with
HCC would receive 28 MELD points after a 6-month waiting period
no matter what his or her calculated laboratory MELD score is.
Cholangiocarcinoma, long considered a contraindication to
transplantation, is reemerging as an indication, especially in patients
with primary sclerosing cholangitis (PSC). Early publications in the
1990s showed a 20% to 25% 5-year survival, with no improvement
of neoadjuvant or adjuvant therapy. A sentinel paper from the Mayo
clinic appeared in 2005 that showed an 82% 5-year survival for
patients who underwent a neoadjuvant chemo/radiation protocol
followed by transplantation. The protocol was very selective and
included only patients with small hilar tumors and excluded patients
with previously attempted resections or those with extrahepatic
disease on a protocol exploratory laparotomy. The study was criticized because of the loose diagnostic criteria that may have included
PSC patients without cancer. In this study, 16 of the 38 patients
(42%) transplanted showed no evidence of cancer on the explant.
Skepticism was abated, however, when a multicenter trial with 12
participating centers showed similar results. This trial included a
larger number of non-PSC patients (71) and PSC patients (143) who
underwent liver transplantation for perihilar cholangiocarcinoma.
The 10-year recurrence-free survival was 51% and 62%, respectively
(P =0.06). Although not as impressive as the initial Mayo Clinic
report, the outcomes are significantly more favorable than most of
the surgical resection reports. The 5-year survival for the cohort is
even better (72%) if UNOS criteria are met (initial hilar mass <3 cm,
no evidence extrahepatic or lymph node disease on protocol exploration). Based on these two studies, UNOS now assigns a MELD
upgrade for patients with hilar cholangiocarcinoma who meet criteria, similar to HCC patients.
MELD
The MELD was first developed to predict survival in patients with
complications of portal hypertension undergoing elective placement of transjugular intrahepatic portosystemic shunts. The MELD
score uses objective variables and has been shown to be an accurate
predictor of survival among different populations of patients with
advanced liver disease. The formula to calculate MELD is based on 3
420 LIVER TRANSPLANTATION
ee
×
()
+×
()
+
×
()
+×
()
41
Predicted Probability of Death
1.0
https://t.me/med1917
variables found to significantly impact survival and their regression
coefficients, the creatinine, bilirubin, and INR:
0.957 LogCr0.378 Logbili1.120
LogINR 0.643 10e]
Since the MELD accurately predicts survival in patients with
cirrhosis who have infections, variceal bleeding, cholestatic diseases,
acute liver failure, and alcoholic hepatitis, it has been modified by
UNOS and used to prioritize patients for liver transplantation. The
modification for transplant maximizes the score at 40 and assigns
a creatinine of 4 mg/dL for patients on renal replacement therapy.
The 3-month predicted mortality associated with the MELD score is
depicted in Table 1.
Several studies have since shown that the addition of serum
sodium into the MELD score (MELD-Na) predicts waiting list mortality better than the MELD alone. The inclusion of serum sodium
into the MELD score allowed for a predictive increase in 7% fewer
TABLE 1 MELD Mortality Equivalents
MELD 3-Month Mortality
7 1%
20 8%
24 10%
26 15%
29 20%
31 30%
33 40%
35 50%
37 60%
38 70%
40 90%
MELD, Model for End-Stage Liver Disease.
deaths with transplantation eligibility for the end-stage liver population. Therefore, in January 2016, the UNOS listing policy was
updated to include serum sodium as a factor in the calculation of
the MELD score:
MELD NaMELDNa0.025 MELD 140 Na 140=−−× ×−
+
A recent study used the largest UNOS database of listed patients
with decompensated cirrhosis in the United States to demonstrate the
MELD-Na. MELD-Na carries a strong predicted value for 6-month
mortality with a c-statistic of 0.83, similar to its predicted value for
90-day mortality. This finding is important as it includes patients
with severe complications of portal hypertension that are often
excluded from prior calculations and who carry increased mortality
(Fig. 3).
Waiting List Additions, Removals, and Transplantation
In the past 15 years, the number of patients added yearly to the transplant waiting list has increased from 8055 in 1996 to 13,803 in 2021.
The number of deceased donor transplants performed increased
initially as acceptable donor criteria expanded, but remained flat
between 2005 and 2013. As a result, mortality on the waiting list
increased during this time. However, when allocation of livers
changed in 2013 to include broader regional sharing of donors
for patients with MELD 35 or higher, mortality decreased and the
number of deceased donor transplants increased (Fig. 4). In 2021,
there were 8667 deceased donor transplants and 569 living donor
transplants performed in the United States.
LIVER TRANSPLANTATION
Techniques
The techniques of hepatectomy and implantation have changed over
time. The first attempts at liver transplantation utilized venous-venous bypass (VVP), which in itself has evolved to include a centrifugal pump and heparin-coated cannulas, thereby eliminating some
of the fatal pulmonary embolisms initially encountered. In 1998,
Chari et al. reported that 95% of the centers were using VVP at least
during the anhepatic phase. However, VVP is fading away as more
and more centers successfully adopt caval preservation and partial
clamping techniques.
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
6111621
26 31 36
MELD-Na
FIG. 3 Predicted probabilities of death at 6 months against
the new Model for End-Stage Liver Disease (MELD-Na)
scores.
PORTAL HYPERTENSION 421
AB
cava
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FIG. 4 Waitlist additions, deaths, and liver transplants over time. (Data from the United States Organ Procurement and Transplantation Network [OPTN]).
Diseased
liver
removed
Gall
bladder
removed
Inf.
vena
FIG. 5 Classic bicaval anastomosis. The native liver is resected together with the retrohepatic inferior vena cava (IVC) and orthotopically replaced by a
donor liver that includes the IVC. (Illustration Copyright 1998–2003 by The Johns Hopkins Health System Corporation and The Johns Hopkins University; from the
Johns Hopkins Division of Gastroenterology and Hepatology [www.hopkinsmedicine.org/gi]. Illustration created by Mike Linkinhoker.)
Hepatic a.
Portal v.
Common
bile duct
Bicaval anastomosis
With this conventional technique, the native liver is resected
together with the retrohepatic inferior vena cava (IVC) and
orthotopically replaced by a donor liver that includes the IVC (Fig.
5). The native hepatectomy begins with dissection of the hepatic
hilum. The dissection isolates the left and right hepatic arteries,
which are divided separately. The proper hepatic artery (HA) is
dissected beyond the gastroduodenal artery to the common HA
because a patch of the gastroduodenal artery and the common HA
is often used for subsequent arterial anastomosis. The cystic duct
is divided followed by the division of the common duct closer to
the hilum to obtain maximal length on the duct. What is left at this
point is the portal vein (PV) with surrounding lymphatic tissue.
The vein is skeletonized from its bifurcation toward the pancreas,
often to the first pancreatic branch. Several centimeters of vein are
necessary to allow placement of a clamp or for cannulation with
Donor liver
transplanted
Anastomoses
VVP. PV division is not performed until the liver is completely
mobilized. This includes dividing the left and right triangular ligaments, mobilizing the right lobe off the diaphragm, and dissecting
the retrohepatic IVC to completely mobilize it posteriorly. The
adrenal vein is often divided to obtain adequate mobility of the
IVC for clamping.
Complete venous clamping with or without VVP is necessary.
Complete IVC and PV clamping can result in important hemodynamic consequences with decreased venous return, congestion in
the caval and splanchnic bed, as well as decreased renal function.
This should be performed when the hepatectomy is nearly complete
because the congestion leads to increased bleeding during hepatectomy. For this reason, VVP was introduced in the mid-1980s.
However, as anesthetic conditioning improved, VVP can be avoided,
especially when the vascular anastomoses are done expediently. Two
IVC anastomoses are required: one suprahepatic and one infrahepatic end to end.
422 LIVER TRANSPLANTATION
Altered anatomy
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Piggyback Technique
In 1989, Tzakis et al. popularized the technique of orthotopic liver
transplantation (OLT) with preservation of the IVC, called the
piggyback technique. This technique involves complete mobilization of the liver off the IVC, including the hepatic veins that are
individually oversewn. In the Tzakis report, the transplant was still
performed with the use of a VVB. Venous outflow reconstruction
was performed between the suprahepatic donor IVC and a common orifice created by opening of the native right, middle, and left
hepatic veins, or just the middle and left. Several studies, including
a randomized trial, favored the piggyback technique over the traditional bicaval technique, with a shorter anhepatic phase, reduced
blood loss, and reduced cost of the procedure in favor of the piggyback technique.
Modified Piggyback Technique
Several reports describing a venous outflow complication rate of
up to 5% appeared. These complications included graft congestion
and stenosis of the caval anastomosis. For this reason, modifications of the piggyback technique became more popular. In 1992, a
Piggyback transplant
side-to-side anastomosis between donor and recipient IVC without
the routine use of VVB was described. In this modification, both
the suprahepatic and infrahepatic end of the donor IVC is closed,
and the anastomosis is created between two new incisions—one
made on the recipient IVC and another on the donor IVC (Fig. 6).
Cherqui introduced another venous outflow reconstruction. He
enlarged the common orifice of three hepatic veins by a caudal
incision on the anterior wall of the recipient IVC and anastomosed
it with the suprahepatic end of the donor IVC (end-to-side anastomosis). This technique was further modified by closing all hepatic
veins and creating an anastomosis between a new incision on the
anterior wall of recipient IVC and a V-shape incision on the donor
IVC to avoid stricturing of the outflow anastomosis. In certain
situations when the suprahepatic IVC cuff is very short, such as
in domino LT or in case of outflow complications after piggyback
implantation, some authors advocate the use of the infrahepatic
cavocaval anastomosis.
Although there are studies comparing the different piggyback
techniques, the essential message is to extend the cavostomy on
the recipient to create a wide caval anastomosis and avoid some of
FIG. 6 Modified piggyback technique. In this modification, both the suprahepatic and infrahepatic ends of the donor inferior vena cava (IVC) are closed,
and the anastomosis is created between two new incisions—one made on the recipient IVC and another on the donor IVC. In this modification, all
hepatic veins are sewn over, and a new incision on the anterior wall of recipient IVC is made. (From Elyssa Siegel, Art as Applied to Medicine, Johns Hopkins
University.)
PORTAL HYPERTENSION 423
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the venous stricturing complications that ultimately lead to BuddChiari syndrome. One thing is clear however; avoiding VVB with
caval-preserving techniques is becoming the norm in many liver
transplant centers.
Vascular Reconstruction
The PV reconstruction is usually performed end to end with
fine polypropylene suture. There are several important technical
considerations to uphold to avoid either stenosis or kinking that
can ultimately lead to portal vein thrombosis (PVT). A technique
that Starzl initially described is allowing for a “growth factor”
when tying after circumferentially running the suture. This allows
expansion of the anastomosis to accommodate the distention
that occurs when flow is reestablished. Failure to incorporate the
growth factor will result in an “hourglass” anastomosis that may
be prone to stenosis and thrombosis. The second concept is related
to the length. Typically during a liver transplant the operative
field is expanded with the use of surgical retractors. This must
be taken into account in assessing the length of the donor PV. It
is not uncommon to find the PV kinking once the retractors are
removed because it was sewn with too much donor length. To
avoid this problem, many surgeons will minimize the retraction
inferiorly and place laparotomy pads above the liver to bring the
liver down before performing the PV anastomosis. If this problem
does occur, then it is important to redo the anastomosis after
cutting an adequate amount of donor PV. This can be done with
minimal hepatic sequelae if performed expediently in the presence
of arterial perfusion.
PV Reconstruction in the Presence of Native PV
Thrombosis
PVT is being increasingly recognized in patients with advanced
cirrhosis and in those undergoing liver transplantation. Reduced
portal flow and hypercoagulability that occurs with advanced liver
disease is probably responsible for clotting in the spleno-porto-mesenteric venous system. The prevalence of PVT in patients without
hepatocellular carcinoma has been reported to be as high as 25%
in ultrasound-based studies, with the overall incidence increasing
to nearly 40% with time. PVT was long considered a contraindication to liver transplantation, but as reports with favorable outcomes
appeared, this is no longer the case. Techniques of native PV thrombectomy have been well described with success rates exceeding 95%.
The thrombus often extends to the confluence of the splenic and
mesenteric veins often sparing at least the SMV. For this reason,
thrombectomy is more successful when the dissection during the
hepatectomy is carried out beyond the confluence to reach the tail
of the thrombus. Although some authors advocate the use of Fogarty
balloons, the clot is often organized and adherent to the vein wall.
The extent of the clot can be manually and visually examined. If the
thrombus completely occludes portal flow, the PV can be divided at
the right and left confluence with the edges held apart using tonsil
clamps. This allows the surgeon to separate the clot and the attached
intimal layer from the media of the vein circumferentially using a
dura elevator. This maneuver is extended as far as necessary, frequently entering the splenic and superior mesenteric veins (SMVs).
The free edge of the clot is then clamped with a tonsil or ring clamp
and gently rotated and pulled out. Because hypercoagulability is
considered a risk factor for PVT, the recipients are often placed on
full-dose daily aspirin before discharge. With this technique, a bypass
graft from the SMV utilizing a donor iliac vein to reestablish PV
inflow is rarely necessary.
In cases of massive portal system thrombosis that involves the
SMV and splenic vein, salvage revascularization techniques have
been described. Cavoportal hemitransposition has been described
by Tzakis when no portal inflow can be achieved. This technique
involves ligating (either completely or partially) the infrahepatic
recipient IVC. The PV anastomosis is either done end to end inferior
to the point of ligation or end to side with partial ligation. Overall
survival was poor, so this should be reserved only as a salvage procedure intraoperatively.
Arterial Reconstruction
The arterial reconstruction is usually a direct anastomosis between
the donor and recipient HA in an end-to-end fashion. The anastomosis should involve Carrel patches on the donor and recipient ends
to decrease the incidence of hepatic artery thrombosis (HAT). The
donor artery typically involves the entire celiac trunk with a patch of
aorta. This is sewn to a Carrel patch created by the recipient gastroduodenal artery and the proper HA coming off the common HA. In
cases in which donor arteriopathy exists, it is important to shorten
the artery to a segment free from disease. A donor patch can also be
made using the splenic artery takeoff if the remainder of the artery
is disease free.
In other cases, the recipient HA is unsuitable for use because of
poor inflow from more proximal stenosis, atherosclerosis, or intimal
dissection. Options include dissecting more proximally on the recipient artery beyond the takeoff of the splenic artery. If the inflow is
adequate at that point, an end-to-side anastomosis to both the celiac
and splenic artery confluence can be achieved while preserving flow
to the spleen. Alternatively, an end-to-end anastomosis to the celiac
can be performed while sacrificing the splenic artery. Although this
is an appropriate alternative especially in re-transplants, splenic
infarcts and abscesses can result. The most common method to deal
with poor arterial inflow is the use of arterial conduit directly from
the aorta using a donor iliac artery graft. For this reason, a donor
iliac graft is always procured with the liver. The anastomosis can
be done to either the supraceliac or infrarenal aorta. The infrarenal
aorta is more commonly used because it is safer and easier to access.
The graft is commonly tunneled antepancreatic and retrogastric/
retrocolic. The infrarenal aorta, however, is more prone to calcification and atherosclerotic disease, especially in older adult patients.
The supraceliac aorta is easy to access after the hepatectomy, so it
may be used in cases in which arterial reconstruction is planned
(e.g., retransplantation with HAT). However, the supraceliac aorta
does not hold sutures as well as the infrarenal aorta, and any complications with this segment can result in disastrous consequences.
The use of arterial conduits is associated with excellent long-term
outcomes and low HAT rates.
Aberrant donor arterial anatomy is present up to 25% of the
time and must be recognized during the procurement. An accessory
or replaced right HA arising from the SMA is often preserved by
procuring the SMA trunk with the celiac. The artery can then be
reconstructed on the backtable before implantation. A left accessory or replaced HA arising from the left gastric should also be
preserved, although no reconstruction is necessary because it arises
from the celiac trunk. Backtable preparation of the accessory left
HA requires careful dissection of the left gastric with ligation of all
of its branches.
Biliary Anastomosis
The two main techniques of biliary tract reconstruction are direct
duct-to-duct and Roux-en-Y hepatico or choledochojejunostomy. If
the recipient duct is normal, a duct-to-duct anastomosis is preferable.
This preserves the native physiology and anatomy and allows future
biliary access via endoscopic retrograde cholangiopancreatography
(ERCP). The end-to-end anastomosis is commonly performed with
either running or interrupted dissolvable sutures. When a significant
size discrepancy exists, a side-to-side anastomosis can be used. Both
techniques are acceptable and yield equivalent results.
Roux-en-Y reconstruction is often needed in retransplantation or
for patients with PSC. The routine use of Roux-en-Y anastomosis for
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TABLE 2 Patient and Graft Survival Following Liver
Transplantation
1 Year 3 Year 5 Year
PATIENT SURVIVAL (%)
Deceased donor 91.2 82.8 75.1
Living donor 92.3 88.4 83.9
GRAFT SURVIVAL (%)
Deceased donor 89.1 80.0 71.8
Living donor 88.0 82.0 77.3
advocating direct duct-to-duct anastomosis in PSC patients with
normal-appearing ducts.
The routine use of T-tubes during biliary anastomosis has been
challenged for over a decade and has lost favor in the majority of
transplant centers. Several pivotal trials have shown that the incidence of biliary complications is actually lower when T-tubes are not
used. Duct-to-duct biliary anastomosis, whether end to end or side
to side, should be done without any biliary tubes.
OUTCOMES
Despite a progressive increase in the severity of liver disease in transplant recipients, graft survival continues to improve. The national
1-year, 3-year, and 5-year graft and patient survival for patients
transplanted between 2008 and 2015 is depicted in Table 2.
The incidence of acute rejection following liver transplantation is
lower than in other groups, decreasing below 10% in most reports.
The decline is likely related to increased efficacy of immunosuppression and better monitoring.
is associated with a significant increase in the incidence of primary
nonfunction. Information on volumetric flow at the time of operation can either be reassuring or may indicate an unexpected problem,
which can be fixed at this time.
Hepatic artery stenosis (HAS) occurs 2% to 10% of the time.
Chen et al. reported an overall HAS incidence of 2.8%, with an early
(<30 days) HAS incidence of 40% versus a late HAS incidence of
60%. The mean time elapsed between transplantation to diagnosis
was 91 days. HAS can lead to an insidious form of graft disorder,
both in the early and later postoperative stages. Many patients with
HAS are asymptomatic and most commonly present only with mildly
elevated liver function tests. Because of the insidious nature of HAS,
some centers perform routine screening ultrasound examinations at
regular time intervals.
The therapeutic management of HAS includes either surgical
revision or percutaneous endovascular interventions, such as percutaneous transluminal angioplasty (PTA) with or without stent placement. In one study treating 42 cases of HAS, 81% were successfully
treated by PTA, with an incidence of immediate complication of
7% including dissection and arterial rupture. These results compare
favorably to surgical approaches, so PTA has become first line therapy for HAS.
Venous
Venous complications are less frequent than arterial complications
but can also result in graft failure, especially if they occur in the early
postoperative period. Endovascular management has become the
treatment of choice for the majority of venous complications.
Portal Vein
The incidence of PV complications is low, estimated around 1%. It is
more common in pediatric and living donor transplants. The most
common complications are portal vein thrombosis (PVT) and portal
vein stenosis (PVS).
VASCULAR COMPLICATIONS
Arterial
The interruption or reduction of arterial flow during liver transplantation is frequently associated with biliary ischemia and complications including bile duct necrosis, liver abscesses, and graft
dysfunction. This occurs because of the absence of collaterals in liver
transplant recipients. In the native liver, HA thrombosis or ligation
is usually well-tolerated because of the abundant arterial collateral
sources that avoid ischemia of the liver parenchyma. In contrast,
disruption of these collaterals inevitably occurs when performing
total hepatectomy for transplant. In cases of hepatic artery thrombosis (HAT), the allograft often survives as a result of portal flow
and portal oxygen. The biliary tree, however, is dependent primarily
on arterial flow and is therefore especially sensitive to interruption
of arterial blood. Recognition and prompt management of HAT is
of great importance for graft and patient survival. The incidence of
HAT is 2% to 5%, with about one-half occurring early within the
perioperative period, and one-half occurring late. Early HAT inevitably leads to graft loss and a high mortality rate. For this reason, when
diagnosed, patients often have to be retransplanted. Rarely HAT can
be caught shortly after it occurs, and graft failure can be thwarted
with thrombectomy and revision or reconstruction of the artery.
Measurement of hepatic arterial flow can be easily accomplished
using flowprobes (e.g., Transonic). The flowprobes are placed on the
reconstructed artery to gently surround the vessel excluding extraneous tissue. By immersing it in saline, a good acoustic contact occurs,
and the readings stabilize rapidly with little fluctuation. Hepatic
arterial flow is dependent on both cardiac output and portal venous
flow. However, it has been shown that arterial flow <200 cc/min is
associated with a six fold increase in HAT, and a flow <100 cc/min
PVT
The risk factors for PVT include technical issues (kinking of the
PV caused by excess length), preoperative PVT in the recipient
requiring intraoperative thrombectomy, hypercoagulability, small
PV diameter, and reconstruction with a vein conduit. Early PVT can
be devastating and leads to early graft dysfunction and loss, and it is
generally less well tolerated than early HAT. Excess length of the PV
following anastomosis can easily occur as a result of the presence of
retraction during the anastomosis. Once the retractors are released,
the operative field collapses, and kinking of the PV can occur. To
account for this, laparotomy pads are typically placed behind the
dome of the liver, essentially bringing the liver down and facilitating
an anastomosis that will not have redundancy. In addition, a “growth
factor” is included when tying the final knot to prevent wasting of the
anastomosis when flow is reintroduced and the PV expands.
If flow is compromised as a result of any of the aforementioned
reasons, then the risk of PVT is increased. It is therefore important
to ensure once the retractors are removed that the PV is not kinked
or redundant. In addition, measurement of portal venous flow can
be easily accomplished using flowprobes. Portal venous flow is
dependent on cardiac output and graft size. The range is wide, but
in general PV flow should exceed 1 L/min to minimize the risks of
PVT. PV hyperperfusion can affect arterial flow, but it is usually only
problematic with small grafts and living donor liver transplantation
(LDLT).
PVS
PVS is a rare complication of liver transplantation primarily because
the majority of patients with PVS are asymptomatic. PVS is a bigger
problem in pediatric and living donor transplants because size mismatch is more likely to lead to technical issues that result in PVS.
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When PVS does occur, the management is dependent on the timing.
Early PVS within the perioperative period should be approached
surgically. Late PVS is more amenable to percutaneous approaches,
either transhepatic or transjugular. Percutaneous balloon dilation
has been reported with good success and has become the treatment
of choice. Asymptomatic PVS noted on ultrasound without any graft
dysfunction should be observed without any intervention necessary.
Biliary Complications
The most common type of biliary reconstruction is a choledochocholedochostomy (duct-to-duct anastomosis). Choledochojejunostomy is sometimes necessary in cases in which the native bile duct
is diseased or unusable, such as with patients with PSC or redo
liver transplants. Duct-to-duct anastomosis has several advantages.
The sphincter of Oddi function is preserved, which plays a role in
decreasing the risk of ascending cholangitis, and it also allows easy
endoscopic access to the biliary tree for diagnostic and therapeutic
purposes.
Bile Leak
Bile leaks occurs early up to 20% of the time following liver transplantation. The majority are self-limiting and seal within a few
days without any further intervention as long as the leaks are well
drained. If the leaks are not well drained, patients could present
with abdominal pain, fever, or any sign of peritonitis. Ultrasound
or CT scan can often identify a biloma or fluid collection near the
porta hepatis, which should raise the suspicion highly. Once bile
leak is suspected, ERCP with sphincterotomy and stent placement
becomes the diagnostic and therapeutic procedure of choice, assuming there are no intraoperatively placed biliary tubes at the time of
anastomosis. The success rate often exceeds 85%, and no further
treatment is necessary. In the event that a bile leak is more extensive
or involves necrosis of the distal donor duct, surgical reconstruction
is necessary to avoid biliary strictures that will become problematic
in the future.
Bile Duct Strictures
Biliary stricture is also a common biliary complication, occurring up
to 15% of the time with deceased donor transplants. Strictures are
classified as anastomotic strictures and non-anastomotic strictures.
The approach to each is markedly different, so it is important to
distinguish the two. Anastomotic strictures early in the postoperative period are often related to technical issues, including surgical
techniques, small-caliber ducts, or burn injury from electrocautery.
Later-onset anastomotic strictures are most likely related to ischemia at the end of the donor duct, leading to fibrotic healing.
Non-anastomotic strictures are likely caused by ischemia secondary
to preservation injury, donation after cardiac death, prolonged use of
vasopressors, rejection, HA insufficiency, or recurrent disease.
Although magnetic resonance cholangiopancreatography
(MRCP) has high sensitivity and specificity, the diagnostic procedure
of choice is ERCP because therapeutic options are often required.
For anastomotic strictures, balloon dilation with stent placement is
more successful than without stent placement. The stents are generally replaced by larger stents every 3 months to prevent clogging,
cholangitis, or stone formation. Serial dilation with dual or multiple
stents will prove successful in the vast majority of patients. Surgical
intervention is rarely necessary.
Management of patients with nonanastomotic strictures is more
difficult as these are prone to developing sludge, casts, and stones,
rendering plastic stents less effective. The recent use of metallic wall
stents may improve the success of endoscopic management of these
strictures. If the disease is limited to the extrahepatic ducts, surgical
revision is necessary and requires conversion to a Roux-en-Y hepaticojejunostomy. If the intrahepatic ducts are also involved, retransplantation may be necessary.
LIVING DONOR LIVER
TRANSPLANTATION
LDLT for pediatric recipients was introduced in 1989 to overcome the
severe shortage of deceased donor organs across the world. In 1993,
Tanaka et al. reported the first adult-to-adult right liver LDLT using a
right lobe, making liver transplantation feasible for adults in areas of
the world where deceased donors are very limited. Since then, living
donor grafts for adults have expanded to include right lobes with
the middle hepatic vein and left lobes. The centers embarking on
LDLT often face ethical issues regarding donor safety when a healthy
adult must undergo a complicated major surgery without receiving
any health benefit. The complication rate after LDLT ranges widely
in the literature between 10% and 50% depending on the severity.
Unfortunately, there have been a number of deaths after living donation. The risk of death is estimated to be 0.2% to 0.5% with left lobe
donation and 0.3% to 1% with right lobe donation. Because of this
as well as a highly publicized death of a living donor in New York
City, enthusiasm in the United States waned in 2001 and remained
flat for the next 13 years. As the world experience for adult-to-adult
LDLTs increased exponentially, the added knowledge and improved
techniques resurrected living donation in the United States, resulting
Geometry analysis of
hepatic vein
FIG. 7 Three-dimensional reconstruction to assess a living donor liver graft.
RT lobe Vol. (cm3)
LT lobe Vol. (cm
RT Middle HV Branches Vol. (cm
3
)
3
)
505.52 (31%)
658.77 (40%)
480.99 (29%)
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in a two fold increase in the number performed annually (see Fig. 4).
The 5-year survival is the same for LDLTs and deceased donor transplants (see Table 2).
Graft function following LDLT is highly dependent on graft
volume. Although left lobe donation is associated with a lower mortality rate, left lobe volumes are typically smaller, and small-for-size
syndrome is more prevalent, especially in the face of significant
portal hypertension. As a result, right lobe grafts have been used
more commonly in adults. Previous literature has suggested that a
graft weight/recipient weight ratio ≥0.8% and a graft weight/standard
liver volume ratio of 40% are the safe limits for donor graft size to
avoid small-for-size syndrome. Small-for-size syndrome is defined as
prolonged cholestasis with ascites void of technical issues. Imaging
techniques to predict vascular anatomy and graft weight include
MRI with IV contrast and or fine-cut CT with IV contrast. There
are multiple software companies that reconstruct the CT or MRI
images three-dimensionally to allow the surgeon to more precisely
assess graft volume including which segmental drainage of the liver
(Fig. 7). These three-dimensional analyses enable the surgical team
to better plan resection lines and need for venous reconstruction.
Parenchymal transection for right lobe grafts is typically performed
immediately to the right of the middle hepatic vein (Fig. 8). Large
branches from segment V or VIII draining to the middle hepatic vein
may need to be reconstructed to avoid hepatic congestion (Fig. 9).
FIG. 8 Parenchymal transection to the right of the middle hepatic vein.
FIG. 9 Right lobe graft after reperfusion with reconstruction of segment
V vein.
Biliary complications have been the Achilles heel of LDLTs. Biliary anatomy is highly variable, and the need to anastomose two bile
ducts is not uncommon. As a result, the leak and stricture rate can be
as high as 30%, higher than for deceased donor transplants.
Despite the technical challenges and higher graft complications,
LDLT remains a life-saving procedure for patients with end-stage
liver disease.
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