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TABLE 1 Transarterial-Related Complications
Toxicities Risk (%) Mitigating Factors Comment
Acute liver failure Rare Subselective embolization Higher risk with bilobar treatment or underlying liver
parenchymal disease
Liver decompensation <1 Selective embolization Increased risk with underlying liver parenchymal
disease
Encephalopathy <1 Selective embolization Increased risk with concurrent cirrhosis or a prior
episode of encephalopathy
Liver abscess 2–4 If intact sphincter of Oddi
10–20
>60
Cholangitis 10–15 Symptomatic treatment Higher risk with smaller drug-eluting beads
Renal failure <2 Hydration and possibly dialysis in severe
Nontarget embolization <1 Perform diagnostic arteriogram, cone
If pretreated with antibiotics
If not pretreated
cases
beam CT, and selective embolization
If compromised sphincter of Oddi, colonized biliary
system
Most likely in chronic renal insufficiency
Variant anatomy increases risk
with DEB) could result in ischemic strictures and hyperbilirubinemia, particularly in patients without underlying liver parenchymal
disease or when using smaller beads with BE or DEB-TACE, specifically in NETs. If the sphincter of Oddi has been violated (hepatojejunostomy or biliary stent), there is a very high risk of intrahepatic
abscess formation. Bacterial colonization becomes an abscess as a
result of embolization-related biliary ischemia in more than 60% of
such patients. Pre- (1 week) and post-TACE (2 weeks) treatment with
broad-spectrum antibiotics (i.e., moxifloxacin 400 mg, by mouth
every day) reduces the risk to less than 10%. Another potentially
serious complication is inadvertent embolization of nontarget vessels. This specifically plays an important role in SIRT since nontarget
embolization could result in serious adverse reactions, such as pneumonitis, gastritis, or skin necrosis. Performing a detailed diagnostic
arteriogram before embolization and a selective embolization nearly
eliminates this risk. Aberrant vascular anatomy further increases this
risk, with the vessels most at risk being left or right gastric arteries,
the supraduodenal artery, and the umbilical artery.
OUTCOMES
Lesion-Based Response
With the introduction of precision medicine, an assessment of early
response to transarterial therapies is essential for “go” versus “no
go” decisions for these treatments. The standard response criteria
requires a critical interrogation, cross-verification, and update.
Many new criteria have been developed to address these evolving
paradigms. There are 1D, 2D, and 3D methods to measure postintervention response, each subdivided into two more subcategories,
based on the ratio of total size to the size of the enhancing component. The Response Evaluation Criteria in Solid Tumors (RECIST)
measurements are based on the sum of the longest one-dimensional (1D) diameter, whereas the modified Response Evaluation
Criteria in Solid Tumors (mRECIST) criteria suggest measuring
changes in tumor enhancement as a biomarker of tumor viability.
The World Health Organization (WHO) introduced an evaluation
system for solid liver tumors based on the sum of the product of
the two-dimensional (2D) diameters of tumor lesions, whereas
the European Association for the Study of the Liver (EASL) has
recommended measuring tumor response based on changes in the
uptake of contrast medium by the tumor tissue. Yet, all 1D and 2D
evaluation methods are flawed, with a limited reproducibility and
an essential inaccuracy when assessing the entity of necrotic and
heterogenic tumor lesions. These clinically relevant limitations have
led to the development of three-dimensional (3D) quantitative image
analysis techniques that are able to achieve a reproducible, biologically accurate, and clinically practicable tumor evaluation. Although
volumetric analysis (vRECIST) considers the height component of
the tumor, assessing the changes in enhancing tumor volume using
quantitative EASL (qEASL)goes beyond these boundaries. The PET
Response Criteria in Solid Tumors (PERCIST) is another response
assessment criteria developed for PET scans.
Imaging Response Criteria
Based on the chosen response criteria (see earlier), the response of
the lesion(s) to the transarterial therapy could be categorized based
on the operator or study preference, according to Table 2.
Overall Survival, Progression-Free Survival, and
Hepatic Progression-Free Survival
Overall survival (OS) has long been considered by the FDA and the
European Medicines Agency as the gold standard for the evaluation
of new oncologic therapies. Progression-free survival (PFS) is the
length of time during and after the treatment of a disease, such as
cancer, that a patient lives with the disease, but the disease does not
worsen. In a clinical trial, measuring the PFS is one way to determine
TABLE 2 Definition of Different Terminologies for
Image-Based Changes in Tumor After Intervention
Detailed Standard
Response
Complete response
Partial response
Stable disease Stable disease
Progressive disease Progressive
Simplified
Response Control-Based
Response Controlled disease
Uncontrolled disease
disease
410 TRANSARTERIAL THERAPIES FOR PRIMARY AND METASTATIC LIVER TUMORS
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how well a new treatment works. Hepatic progression-free survival
(HPFS) is calculated at the time from the first regional treatment
until the first date of documented progression in the liver.
CANCER-SPECIFIC OUTCOMES
Intrahepatic Cholangiocarcinoma
ICC is the second most common primary liver malignancy, accounting for up to 20% of primary liver cancers. Up to 70% of these patients
are diagnosed at an advanced stage, precluding curative surgical intervention. A recent systematic review and met-analysis by Mosconi et al.
showed a median survival of 14.2months after TACE and 13.5months
after SIRT in patients with unresectable ICC, confirming a beneficial
effect when compared with traditional systemic chemotherapy regimens. Another comparative effectiveness analysis by Boehm et al.
also revealed survival of 12.4 months for cTACE, 12.3months for
DEB-TACE, and 13.9months for SIRT without a significant difference
between these modalities. A recent Phase II clinical trial on 38 patients
with unresectable ICC treated with HAI of floxuridine in combination
with systemic gemcitabine and oxaliplatin reached a 58% objective
radiographic response and 84% disease control.
Metastatic Colorectal Cancer
Synchronous colorectal cancer (CRC) liver metastases are present at
the time of diagnosis in 15% to 20% of patients, and 50% of patients
will develop metachronous metastases. In up to 40% of patients, the
liver is the sole site of metastasis, but the lesions are resectable in only
<20% of patients. A recently published meta-analysis by Zhao et al.
showed that transarterial therapies have been underappreciated in
the context of liver-dominant metastatic CRC. A study by Vogl et al.
in 2009 reported 14.7% of patients with a partial response and 48.2%
with stable disease in a cohort of 463 patients with unresectable CRC
liver metastases that were refractory to systemic chemotherapy and
who were treated with TACE. The 1- and 2-year survival rates after
TACE was 62% and 28%, respectively. Meta-analyses by Levy et al.
demonstrated the relative advantage of TACE among transarterial
therapies, with nonrandomized and randomized studies (median
OS DEB-TACE, 17.6 months), and Zacharias et al. demonstrated
that TACE appears to be more effective in the second-line setting
(median OS, 21.0 months). Both DEB-TACE and HAI, when combined with systemic regimens, appear to provide approximately one
in three patients the chance for resection. Compared with HAI,
DEB-TACE offers the additional benefit of enhancing cytotoxic
effects through ischemia, without the need for port implantation.
DEB-TACE loaded with irinotecan in 28 patients with metastatic
CRC resulted in 15% with a complete response, 30% with a partial
response, and 20% with stable disease, thus achieving a median OS
of 13 months. A major network meta-analysis showed that SIRT,
90
using
Y resin microspheres, is effective compared with the best
supportive care in patients with mCRC. A multicenter review of a
large cohort of patients with CRC liver metastases who were treated
with SIRT
are not only consistent with, but nearly identical to, previous reports
of patients treated with resin microspheres, with a median OS of
10.5 months. This was in accordance with a structured meta-analysis
by Vente et al., which showed, in a salvage setting, a response rate of
79% for SIRT combined with 5-fluorouracil/leucovorin (5-FU/LV)
and a rate of 79% SIRT combined with 5-FU/LV/oxaliplatin or 5-FU/
LV/irinotecan, and, in a first-line setting, both showed a rate of 91%.
Metastatic Neuroendocrine Tumors
NETs are the second most common gastrointestinal malignancy after
colon cancer. Up to 90% of patients with NETs develop liver metastases, which are a major determinant of symptoms and survival.
Carcinoid and pancreatic islet cells have a predilection to metastasize
90
Y glass microspheres indicates that survival outcomes
to the liver, and those patients with liver metastases have a poorer
prognosis and quality of life. Surgical resection is curative but is
possible only in less than 10% of patients. Progression to hepatic
metastases is accompanied by hormonal synthesis and released into
the circulation that can lead to a constellation of systems known as
carcinoid syndrome (rash, flushing, diarrhea, and electrolyte disorders). With this development, treatment of the liver would be for
palliation of the carcinoid syndrome symptoms. TACE can be used
in patients with unresectable, hormonally active NETs and strongly
contributes to the elimination of hormonal symptoms. A report by
de Mestier et al. reported a 76% chance of symptom control, a 56%
chance of biomarker response, and a 50% chance of objective tumor
response. TACE was very well-tolerated, and disease progression
was delayed by 12 to 18 months. A prominent meta-analysis of 23
studies reporting response outcomes after SIRT in NETs reported
an objective response rate of 51% and a mean disease control rate of
88%. The median OS after SIRT was 32 months. The RETNET trial
is an open-label, prospective, multicenter randomized controlled
trial designed to determine the optimal embolotherapy technique
for NET liver metastases, initially comparing three embolotherapy
techniques, BE versus cTACE versus. DEB-TACE. However, the
DEB-TACE arm of the trial was closed because it was associated with
a high rate of serious hepatobiliary complications.
Metastatic Renal Cell Carcinoma
About 20% of renal cell carcinoma(RCC) patients have metastatic
spread at the time of diagnosis, and of patients who have already
undergone curativenephrectomy, 20% to 40% develop RCC metastases. The liver is one of the common sites for metastasis, which could
result in a dramatic drop in the 5-year survival rate to 20%. A retrospective analysis of 14 patients with metastatic liver RCC who had
undergone cTACE (n = 9) and SIRT(n = 5) revealed a median OS of
11.6 months. Another retrospective review by Kis et al. of18 patients
with liver-dominant metastatic RCC showed a complete response in
16 patients and a partial response in one patient, as evaluated according to the mRECIST criteria after SIRT.
Metastatic Breast Cancer
Liver metastases eventually develop in approximately 20% of patients
with breast cancer, which carry a poor prognosis. Most of these
patients with metastasis are not surgical candidates and have chemoresistant and multiorgan disease. A recent meta-analysis of transarterial therapies by Rivera et al. in patients with liver metastasis
from breast cancer reported 7.2% complete responders and 38.1%
partial responders in patients who underwent TACE. Median OS
from six studies showed a median of 19.6 months, with 1-year survival ranging from 32% to 88.8%.N0 status, stage I or II disease, and
Child-Pugh A at the diagnosis of liver metastasis were predictors of
improved outcomes. The same meta-analysis reported the cumulative results of nine SIRT studies. In total, there were 2.3% complete
responders, 37.6% partial responders, and 36.5% with stable disease after SIRT. The SUVmax response, a lower volume of hepatic
parenchyma involvement, chemotherapy after SIRT, the presence of
the PI3K mutation, and the radiologic response to treatment were
positive predictive factors for improving OS. This meta-analysis
also reported 1.2% complete response in the pooled cohort of 158
patients, followed by 30.4% partial response, and 31% stable disease. ECOG status, hormone receptor status, maximum size of liver
metastasis, and response to systemic chemotherapy were reported as
factors that contributed to OS.
Metastatic Melanoma
For patients with metastatic melanoma, the median OS falls to
approximately 6 to 10 months, with only 8% of patients surviving
up to 2 years. A recent meta-analysis and systematic review by
LIVER 411
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Rodriguez-Vidal et al. successfully collected and reported the results
for transarterial therapies for melanoma. The average survival of the
TACE studies is about 10 months, but this option has never been
used as a first-line treatment, which could result in bias when interpreting the results. SIRT could offer a median OS of about 18 months
when used as the first-line therapy. When combined with immunotherapies, the OS increased to 26 months in the study by Levey et
al. The reported median OS of the HAI studies was approximately
15 months. The multicenter trial of Leyvraz et al., which studied HAI
with fotemustine, reached an OS of 14 months. However, the study
by Boone et al. barely achieved 3 months of OS with melphalan HAI.
Metastatic Sarcomas
Sarcomas are a heterogeneous group of solid tumors and account
for 1% of all cancers in adults. Resection with or without radiation
therapy is the mainstay treatment for localized primary or oligometastatic liver disease. However, many intermediate- and high-grade
sarcomas are not amenable to surgery. A retrospective analysis
showed that liver-directed transcatheter therapies are safe and may
have a role in the elective management of unresectable primary and
metastatic liver sarcomas.
NEW DEVELOPMENTS AND FUTURE
DIRECTIONS
Radiopaque Beads
In recent years, the development and use of imageable beads,
rendered radiopaque by the incorporation of a radio-absorber,
such as iodine, zinc, tantalum, bismuth, or barium, have provided
direct real-time feedback during the embolization procedure or on
follow-up imaging.
Various Drug-Loaded Beads
Multiple studies have reported the successful loading of other chemotherapy or cytotoxic agents to drug-eluting beads, such as arsenic,
idarubicin, irinotecan, or sorafenib.
Immunoembolization
Immunoembolization is the embolization of the hepatic artery
with granulocyte-macrophage colony-stimulating factor (GM-CSF).
In theory, immunoembolization could attract and stimulate
antigen-presenting cells in liver tumors and improve the uptake of
tumor antigens released from necrotic tumor cells. Inflammatory
responses that develop in or near the tumor may eliminate residual
tumor cells. In addition, local stimulation of the immune system
may produce a systemic immune response against tumor cells, which
thereby suppresses the growth of extrahepatic metastases.
Nanoparticles
The introduction of novel theranostic nanoparticles into the interventional radiology field can help diagnose disease, report the location, identify the stage of the disease, and provide information about
the treatment response. Such nanoparticles can carry therapeutic
agents to the tumor, which can provide the necessary concentrations
of the carried agents via molecular and/or external stimuli.
Combination with Systemic Therapies
The targeted therapies that have been studied have been mostly
MAPK inhibitors, including sunitinib, sorafenib, imatinib, cabozantinib, and selumetinib, in combination with transarterial therapies.
Some other studies have looked into combining transarterial therapies with other therapies, such as immunotherapy (ipilimumab,
nivolumab, pembrolizumab, or IL-2). All studies have shown positive
results with improved outcomes.
Combination with Percutaneous Therapies
Combining embolization techniques with liver ablation may enhance
the therapeutic benefit of each and result in improved patient survival. The majority of studies have demonstrated the safety and
efficacy of a combined, two-step, single-session transarterial and
percutaneous ablation treatment for unresectable hepatic metastases,
specifically for lesions >3 cm in diameter.
Preoperative TACE
Preoperative TACE was correlated with an improved prognosis after
surgical resection for patients with hepatocellular carcinoma (HCC)
beyond the Milan criteria, whereas there was no significant difference in perioperative complications. Among the patients with ICC
with microvascular invasion who were undergoing curative-intent
partial hepatectomy, postoperative adjuvant TACE improved OS and
time to recurrence in those who had an elevated CA19-9, or who did
not undergo lymphadenectomy.
SUMMARY
Although there is level I evidence about the efficacy of transarterial
therapies for the treatment of unresectable primary liver cancer,
including HCC or ICC, a growing body of lower-level evidence
confirms the benefit of transarterial therapies in selected patients
with metastatic liver disease. A multidisciplinary approach for the
selection of appropriate patients and tumors has an important role
in optimizing outcomes and the success of transarterial therapies.
These approaches could not only help downstage lesions for resection in some diseases, such as CRC, but also could halt liver disease
and provide stability when other curative treatment options cannot
be offered to patients. Transarterial therapies also play a crucial role
in both symptom and hormonal control, along with objective tumor
response in metastatic NETs. Finally, the search for new transarterial
therapy approaches and planning for level I evidence is mandated,
given the complexity and variability of metastatic liver diseases and
the continuously emerging novel therapies.
S u g g e S t e d R e a d i n g S
Aliberti C, Carandina R, Sarti D, et al. Hepatic Arterial Infusion of
Polyethylene Glycol Drug-eluting Beads for Primary and Metastatic Liver
Cancer Therapy. Anticancer Res. 2016;36(7):3515–3521.
Boehm LM, Jayakrishnan TT, Miura JT, etal. Comparative effectiveness of
hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213–220.
Chen JX, Wileyto EP, Soulen MC. Randomized Embolization Trial for
NeuroEndocrine Tumor Metastases to the Liver (RETNET): study protocol for a randomized controlled trial. Tr ial s. 2018;19(1):390.
Cheng Z, Lei Z, Jin X, et al. Postoperative adjuvant transarterial chemo-
embolization for intrahepatic cholangiocarcinoma patients with microvascular invasion: a propensity score analysis. J Gastrointest Oncol.
2021;12(2):819–830.
Frilling A, Clift AK, Braat AJAT, etal. Radioembolisation with 90Y micro-
spheres for neuroendocrine liver metastases: an institutional case series,
systematic review and meta-analysis. HPB (Oxford). 2019;21(7):773–783.
Guo C, Zou X, Hong Z, etal. Preoperative transarterial chemoembolization
for barcelona clinic liver cancer stage A/B hepatocellular carcinoma
beyond the milan criteria: a propensity score matching analysis. HPB
(Oxford). 2021 Feb.
Laface C, Laforgia M, Molinari P, et al. Hepatic Arterial Infusion of
Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art.
Cancers (Basel). 2021;13(12):3091.
Mosconi C, Solaini L, Vara G, etal. Transarterial Chemoembolization and
Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma-a
Systemic Review and Meta-Analysis. Cardiovasc Intervent Radiol.
2021;44(5):728–738.
412 TRANSARTERIAL THERAPIES FOR PRIMARY AND METASTATIC LIVER TUMORS
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Rivera K, Jeyarajah DR, Washington K. Hepatectomy, RFA, and Other Liver
Directed Therapies for Treatment of Breast Cancer Liver Metastasis: A
Systematic Review. Front Oncol. 2021;11:643383.
Rodriguez-Vidal C, Fernandez-Diaz D, Fernandez-Marta B, etal. Treatment
of Metastatic Uveal Melanoma: Systematic Review. Cancers (Basel).
2020;12(9):2557.
Subbiah V, Chuang HH, Gambhire D, et al. Defining Clinical Response
Criteria and Early Response Criteria for Precision Oncology: Current
State-of-the-Art and Future Perspectives. Diagnostics (Basel). 2017;7(1):10.
Vogl TJ, Gruber T, Balzer JO, etal. Repeated transarterial chemoembolization
in the treatment of liver metastases of colorectal cancer: prospective study.
Radiology. 2009;250(1):281–289.
P H
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Portal Hypertension:
Role of Shunting
Procedures
Eliza J. Lee, MD, and Russel N. Wesson, MBChB
INTRODUCTION
Defined as a portal venous pressure gradient greater than 5 to 7
mm Hg, portal hypertension develops when resistance to portal
blood flow increases. Although the etiology of portal hypertension
is broad, it is classified as prehepatic, intrahepatic, or posthepatic
(Table 1). In instances of prehepatic and posthepatic portal hyper-
tension, mechanical obstruction of the portal or hepatic veins is the
causative event. In contrast, underlying liver disease with resultant
cirrhosis is the primary cause of intrahepatic portal hypertension. In
North America, cirrhosis remains the leading cause of portal hypertension, with noncirrhotic etiologies accounting for approximately
10% of all cases. Worldwide, Budd-Chiari, schistosomiasis, and portal vein thrombosis are more frequent etiologies.
As resistance to portal flow increases, a number of physiologic
changes occur. Important among these is splanchnic vasodilation
and increased flow through portosystemic venous collaterals. The
pathophysiology of portal hypertension results in increased cardiac
output and total blood volume with decreased systemic vascular
resistance. Subsequent volume expansion occurs with sodium and
water retention. As a result of these changes, complications arise
and include ascites, hepatorenal syndrome, and the development of
portosystemic collaterals or varices. Fifty percent of patients with
cirrhosis have gastroesophageal varices, and approximately onethird of these patients will go on to develop variceal hemorrhage.
The progression from varices to hemorrhage is directly correlated
with hepatic function and mortality. Hemorrhage from portal hypertensive gastropathy and esophageal varices may be life threatening.
Mortality from variceal bleeding ranges from 5% to 68% among
Child-Turcotte-Pugh class A and C cirrhotic patients, respectively.
Surveillance and management of portal hypertension and varices can
avoid considerable morbidity and mortality.
The management of patients with portal hypertension involves
treating the underlying etiology when it is reversible; reducing
pressure within the portal system via medical, interventional radiographic, or surgical means; or removing and replacing the diseased
liver. When portal hypertension is caused by cirrhosis, liver transplantation remains the gold standard for both curing the underlying
liver dysfunction and the complications of portal hypertension.
Although liver transplantation remains a curative therapy, it is not
appropriate for all individuals, specifically those with noncirrhotic
etiologies of portal hypertension and those who are not suitable
transplant candidates. In such instances, or while awaiting transplantation, medical and procedural interventions are available to minimize symptoms related to portal hypertension. In current practice,
these therapies consist of β-blockers, diuretics, endoscopic control
of esophageal and gastric varices, transjugular intrahepatic portosystemic shunt (TIPS) placement, and surgical shunt placement.
Although the TIPS procedure has largely replaced surgical shunt
placement, surgical shunts provide a safe and effective tool in select
patient populations.
COMPLICATIONS OF PORTAL
HYPERTENSION
Portal hypertension is associated with several complications including hepatic encephalopathy, ascites, and the formation of esophageal
and gastric varices. Of these complications, the most immediately
life-threatening is variceal bleeding.
Varices generally develop as the hepatic venous pressure gradient
increases above 12 mm Hg (Table 2). Nearly one-half of cirrhotic
patients have esophageal varices, and one-third of patients with
varices experience a variceal bleed within the first year following
diagnosis. Although variceal hemorrhage may resolve spontaneously
in some patients, bleeding events are associated with significant risks
including rebleeding, infection, progressive liver decompensation,
and death, which may occur in more than 50% of patients with
severe liver disease.
To prevent morbidity and mortality associated with variceal
bleeding, patients with newly diagnosed cirrhosis or portal hypertension undergo endoscopic screening surveillance at the time of
diagnosis and every 6 to 12 months thereafter. Primary prevention
of bleeding is a priority. As mentioned, nonspecific β-blockade (propranolol, nadolol) achieving target reduction in heart rate is important and reduces the risk of bleeding, the development of ascites and
spontaneous bacterial peritonitis, and the risk of death. Endoscopic
variceal banding is useful for patients with medium to large varices.
Sclerotherapy is less effective in prevention and associated with
complications.
In instances of active variceal bleeding, management in conjunction with resuscitation includes vasoconstrictive agents such as
octreotide, somatostatin, or vasopressin plus vasodilator (e.g., nitroglycerin) infusions. Endoscopic band ligation is highly effective, with
sclerotherapy useful when visualization is difficult. When endoscopic
therapy is either not available or is ineffective, hemorrhage may
be temporarily halted by balloon tamponade using the Sengstaken-Blakemore or Minnesota tubes. Complications such as aspiration
as well as esophageal and gastric necrosis may occur with incorrect
use of these tubes, and placement should be limited to 24 hours.
In the 10% to 20% of cases in which hemorrhage episodes
are refractory to medical and pharmacologic intervention, TIPS
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placement is highly effective. These are successful in over 90% of
cases. Historically, surgical shunts were shown to be very effective. In
select cases when TIPS placement is not feasible, such as in patients
with noncirrhotic portal hypertension or well-compensated cirrhosis
where patients have a limited ability to assume appropriate follow-up
care, surgical shunts may still provide the means of reducing portal
pressures and the associated risk of future variceal bleeding.
TRANSJUGULAR INTRAHEPATIC
PORTOSYSTEMIC SHUNT
Widely adopted in the late 1980s and 1990s in the treatment of
complications related to portal hypertension, the TIPS procedure is
accomplished by initially accessing the hepatic veins via the internal
jugular vein under fluoroscopic guidance. The portal vein is subsequently accessed, creating a tract through the liver parenchyma
across which a stent is placed. This stent effectively creates a sideto-side portocaval shunt. This shunt lowers portal venous pressure
and as a result decreases ascites formation, decompresses varices,
and reduces the risk of bleeding. TIPS is not without risk. Because
TABLE 1 Causes of Portal Hypertension by
Location
Location Etiologies
Prehepatic Portal vein thrombosis
Splenic vein thrombosis
Congenital thrombosis of the portal vein
Arteriovenous fistula, resulting in excessive
inflow
Intrahepatic Presinusoidal
Primary biliary cholangitis (primary biliary
cirrhosis)
Sinusoidal
Cirrhosis
Infiltrative liver diseases
Idiopathic portal hypertension
Congenital hepatic fibrosis
Nodular regenerative hyperplasia
Polycystic liver disease
Postsinusoidal
Veno-occlusive disease
Posthepatic Budd-Chiari syndrome
Inferior vena cava webs or thrombosis
Congestive heart failure
Constrictive pericarditis
Tricuspid valve disease
of the increased portosystemic shunting that occurs as a result of
this procedure, there is an approximate 20% to 30% risk of hepatic
encephalopathy. Selection of well-compensated cirrhotic patients
and subsequent medical management of encephalopathy with agents
including lactulose and rifaximin can minimize the incidence and
consequences of this adverse event.
Although historically TIPS procedures were complicated by
occlusion requiring repeated intervention, the incidence of shunt
dysfunction along with the risk of variceal rebleeding have improved
with the introduction of polytetrafluoroethylene (PTFE) stents. In
addition to safely managing symptoms in patients awaiting transplantation, TIPS has the added advantage of being removed entirely
with the explanted liver at the time of transplantation. This is in contrast with surgically placed shunts, which require ligation or revision
during liver transplantation.
Although the timing and application of TIPS remains an area of
active investigation in patients with liver failure, its primary indications remain refractory ascites, acute variceal hemorrhage, and prevention of recurrent variceal hemorrhage. Contraindications include
unfavorable anatomy resulting from thrombosed hepatic or portal
veins, severe liver dysfunction (i.e., a Model for End-Stage Liver Disease [MELD] score >18), severe pulmonary hypertension, congestive
heart failure, and preexisting hepatic encephalopathy.
The advantages of TIPS placement are well-documented and
include improved secondary prevention of variceal bleeding compared with endoscopic or medical therapies, reduced ascites production, and better optimization of liver function than medical therapy
alone, making it a useful tool in symptom control and in bridge to
transplant. Although rebleeding is reported to occur in 5% to 15% of
patients post-TIPS placement, the majority of such episodes occur in
the setting of stent occlusion caused by stenosis or thrombosis. With
reported 1- and 3-year patency rates of 93% and 75%, respectively,
TIPS placement requires frequent Doppler ultrasound examinations
to evaluate patency and determine the need for subsequent intervention. As many as 80% of patients may require at least one postprocedure intervention to ensure adequate shunt patency and function.
Because of this requirement for postprocedure care, TIPS placement
may not be the best choice in patients with difficulty accessing
medical care. Surgically created shunts can provide more favorable
outcomes given the need for fewer postoperative interventions, with
similar outcomes in terms of ascites management and in the prevention of variceal rebleeding.
SURGICAL SHUNTS
Although the TIPS procedure has provided a useful and far less
invasive means of decompressing the portal system in patients suffering from complications of portal hypertension, surgical shunts
remain an important treatment option in patients who are not eligible for TIPS placement, particularly those with prehepatic causes
of portal hypertension. Surgical shunts are well-suited for patients
who (1) have well-compensated cirrhosis without access to TIPS
or who are unable to access the required follow-up care; (2) have
TABLE 2 Common Sites of Varices
Portal Inflow Systemic Outflow Collaterals
Left gastric vein, short gastric veins Intercostal, diaphragmatic, and esophageal
Superior hemorrhoidal vein Middle and inferior hemorrhoidal veins Hemorrhoids
Left portal vein via falciform ligament Umbilicus and abdominal wall veins Caput medusa
Liver via lienorenal ligament Left renal vein Retroperitoneal collaterals
Gastroesophageal varices
veins
PORTAL HYPERTENSION 415
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portal hypertension without cirrhosis and thus would not benefit
from liver transplant; or (3) require decompression as a bridge to
transplantation after failing medical, endoscopic, and interventional
therapies.
As the primary goal of surgical shunts is to decompress the portal
venous system by diverting a proportion of portal inflow to the systemic circulation, surgically placed shunts are classified by the extent
and selectivity of portal venous diversion. Shunts are therefore classified as either total or partial and selective or nonselective.
Total nonselective shunts completely divert all blood flow from
the portal vein to the systemic circulation. Although these shunts
are very effective at decompressing the portal venous system, they
can result in significant encephalopathy and liver dysfunction after
placement. In contrast, partial nonselective shunts and selective
shunts decompress the portal venous system while still maintaining
flow to the liver, reducing the risk of hepatic encephalopathy and
Duodenum
Superior mesenteric vein
decompensation as a result.
‘‘C’’ graft
Total Nonselective Shunts
Created to entirely divert all portal venous blood flow into the lower
resistance systemic circulation, totally diverting nonselective shunts
are 10 to 12 mm or greater in diameter and are created between the
portal venous system and the inferior vena cava. Examples of these
shunts include the end-to-side and large side-to-side portacaval
shunts, as well as interposition mesocaval and central splenorenal
shunts. The end-to-side shunt procedure can be performed with
moderate speed and little blood loss and may be better tolerated
when there is retrograde flow from the liver within the portal vein.
Although the resolution of portal hypertension resulting from
these shunts is an effective means of treating bleeding esophageal
varices in as many as 90% of cases (as well as in treating refractory
ascites in the case of side-to-side shunts), they may result in significant complications. Because of such significant portosystemic
shunting, significant encephalopathy may occur in as many as 40%
of patients, while diversion of hepatotropic substrates present in
the mesenteric blood and diminished antegrade hepatic flow may
accelerate hepatic decompensation, resulting in progressive liver
failure and sometimes death. These shunts are seldom performed as
definitive therapy in the current era.
Partial Nonselective Shunts
Because of the consequences of total nonselective shunts, narrower
diameter conduits were developed to refine portosystemic shunting
and control consequences including encephalopathy. With conduits
of 8 mm in diameter, partial shunts may be created in a variety of
configurations. Traditionally, these configurations have consisted of
side-to-side mesocaval and portacaval (Sarfeh or interposition “H”
graft) shunts. Either an autologous graft (e.g., internal jugular vein)
or prosthetic graft (e.g., PTFE) is used to create a conduit between
either the portal vein or superior mesenteric vein and the inferior
vena cava (Fig. 1). The interposition mesocaval shunt is the easiest,
quickest, and safest of all mesenteric systemic decompression operative procedures, and has been frequently chosen as the means of
managing portal hypertension in the emergent or semi-emergent
situation. Construction of a functional side-to-side total shunt, such
as the mesocaval interposition shunt, is an effective treatment for
ascites, whereas a selective shunt is not.
The interposition “H” portacaval shunt requires ligation of portosystemic collaterals. The umbilical vein within the falciform ligament, the coronary (left gastric) vein, the gastroepiploic vein along
the greater curve of the stomach, and the inferior mesenteric vein are
usually divided. Unlike total nonselective shunts, smaller-diameter
conduits allow for persistent portal perfusion of the liver in approximately 80% of patients, resulting in a lower incidence of postoperative encephalopathy and liver failure without compromising results
Inferior vena cava
FIG. 1 Mesocaval shunt using ringed PTFE to create a “C” graft.
(From Cameron J, Sandone C. Shunts. Atlas of Gastrointestinal Surgery. 2nd ed.
Vol 1. Hamilton, ON: BC Decker Inc; 2007:193–222.)
in terms of control of variceal bleeding and ascites. Because of the
smaller nature of these shunts, however, thrombosis may occur and
require percutaneous intervention.
Randomized trials have not demonstrated any difference in outcome between interposition mesocaval and side-to-side portocaval
shunts. Although patients undergoing mesocaval shunts are reported
to have a higher thrombosis risk compared with portocaval shunts
(particularly as smaller-diameter shunts are used), mesocaval shunts
remain a good option for those awaiting liver transplantation as dissection within the porta hepatis is avoided.
Finally, an important but uncommon population are patients
who present with Budd-Chiari syndrome (BCS) caused by hepatic
vein thrombosis. BCS is caused by mechanical obstruction of the
hepatic venous outflow and can gradually result in cirrhosis and
portal hypertension. Presentation can be fulminant however, and
treatment in this scenario is liver transplantation, although anticoagulation may help prevent disease progression. TIPS placement has
proven to be a valuable tool to bridge such patients to transplantation. If access to completely occluded hepatic veins is not possible,
direct intrahepatic portosystemic shunt (DIPS) placement can be
performed. Surgical shunting using a mesocaval interposition or
side-to-side portocaval shunt may also be performed but has been
replaced by TIPS placement. The compensatory hypertrophied caudate lobe present may make performance of a surgical side-to-side
portocaval shunt difficult or impossible. Finally, of historic interest
in BCS, a mesoatrial shunt has been used effectively when the inferior vena cava is obstructed and consequently not a suitable target
recipient of portal flow. This was particularly helpful in the situation
in which bridging fibrosis was absent and liver function remained
adequate.
Selective Shunts
Designed to avoid total portal venous diversion and its associated
complications, selective shunts create two separate drainage systems
416 PORTAL HYPERTENSION: ROLE OF SHUNTING PROCEDURES
R gastroepiploic
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Short gastric vv.
Paraesophageal vv.
Spleen
IVC
Coronary v.
Portal v.
Pancreas
v.
(divided)
Splenic v.
L. gastroepiploic v.
Renal v.
within the portal venous network. This results in a decreased esophagogastric pressure while still maintaining adequate mesenteric
portal flow and liver perfusion. The most traditional and favored of
these shunts is the distal splenorenal shunt of Warren (Fig. 2). This
shunt functions by retrograde decompression into the spleen of the
gastroesophageal varices via the vasa brevia and left gastroepiploic
vessels. Subsequent flow is into the systemic circulation after the
creation of an end-to-side anastomosis between the distal splenic
vein and the left renal vein. Collaterals are ligated as described earlier as in the smaller caliber, nonselective shunts. Overall, the distal
splenorenal shunt is effective at controlling variceal bleeding in over
90% of patients, with low rates of postoperative encephalopathy and
liver failure. Importantly, because portal flow and sinusoidal pressure is not decreased, ascites is not relieved and may in fact progress
postprocedure, making this shunt contraindicated in patients with
massive ascites. The Warren shunt does not require dissection within
the porta hepatis, making it an attractive option for patients awaiting
liver transplantation.
may be approached via either an upper midline or bilateral subcostal
incisions. The lesser sac is opened and extended toward the spleen.
Care is taken not to injure the spleen as preservation of the spleen
is essential for success of this procedure. The right gastroepiploic
vessels and coronary vein are ligated, taking care to preserve the vasa
brevia (short gastrics) throughout this dissection. The inferior border of the distal pancreas is mobilized and reflected cephalad after
mobilization from its retroperitoneal attachments. When entering
the splenic vein, the inferior mesenteric vein is divided, and the
splenic vein is carefully mobilized from the pancreas. Attention is
then turned to the left renal vein, which is dissected free and mobilized by dividing the adrenal branch. Both vessels are controlled, and
the splenic vein is divided and anastomosed to the renal vein in an
end-to-side fashion. Some surgeons advocate for a more extensive
separation of the splenic vein from the pancreas with ligation of all
tributaries as they argue this prevents future dilatation and flow via
these collaterals.
selective shunts have been demonstrated to be equally effective
SMV
Kidney
Operatively, the technically challenging distal splenorenal shunt
Both nonselective side-to-side shunts and distal splenorenal
FIG. 2 Completed distal splenorenal shunt with ligated collaterals.
(From Cameron J, Sandone C. Shunts. Atlas of Gastrointestinal Surgery.
2nd ed. Vol 1. Hamilton, ON: BC Decker Inc; 2007:193–222.)
(>90%) in controlling hemorrhage with similar, low rates of rebleeding and no difference in survival. However, the incidence of hepatic
encephalopathy is significantly lower following creation of a distal
splenorenal shunt compared with nonselective shunts.
Other Surgical Shunts and Devascularization
Procedures
Although infrequently performed in current practice, several shunt
and devascularization procedures are mentioned as they remain useful in select patient populations or of historic interest in the case of
devascularization procedures.
The meso-left portal venous bypass (Rex shunt) involves the use
of an autologous jugular vein graft or a transposed, dilated coronary
vein to serve as a conduit for blood from the superior mesenteric
vein to the intrahepatic portion of the left portal vein. The Rex
shunt has been mostly employed in the treatment of children with
portal hypertension caused by extrahepatic portal vein thrombosis.
This shunt is an effective means of restoring portal flow to the liver
and improving complications related to portal hypertension, with a
reported success rate of 91% to 93%.
In contrast with shunt procedures, devascularization procedures
are aimed at controlling bleeding caused by esophagogastric varices
by ligating the veins that drain the stomach and esophagus. These
procedures vary in complexity, ranging from esophageal transection
with end-to-end anastomosis to the Sugiura procedure. The Sugiura procedure consists of ligation of all gastroesophageal collateral
veins, devascularization of the proximal stomach and esophagus,
transection and re-anastomosis of the esophagus, and splenectomy.
Although rebleeding episodes following these procedures have been
reported to occur in as few as 5% of patients, such outcomes are
not consistent throughout the literature. Additionally, the morbidity and mortality following devascularization procedures may be
high, with mortality rates as high as 35% in some series. Overall,
as medical, procedural, and surgical care for patients with portal
hypertension and cirrhosis has improved over the past several
decades, the utility of devascularization procedures has become
increasingly limited.
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
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