Embolization Therapy: Principles and Clinical Applications, 1 Ed.

Transcatheter Arterial Embolization of Benign Liver Disease

Chang Jin Yoon • Jae Hyung Park

Transcatheter arterial embolization (TAE) has been commonly used in treatment of malignant liver tumors. Although rare, however, it can be indicated in various benign liver diseases including benign liver tumors, iatrogenic vascular injury, polycystic liver disease, and congenital vascular lesions.

Owing to the widespread use of imaging analyses, either routinely or to evaluate symptomatic patients, benign liver tumors are diagnosed with increasing frequency.1 Most benign liver tumors are incidentally discovered in otherwise healthy individuals. However, some of them are associated with serious complications, which require prompt treatments. Surgical resection has been considered a standard treatment for large or symptomatic lesions. TAE has been used as an alternative treatment for patients who cannot undergo surgery due to poor clinical conditions. It is also indicated to achieve hemostasis in cases of tumor rupture or as a preoperative procedure before surgical resection.26

TAE also plays an essential role in treatment of focal vascular abnormality of the liver. They are most commonly caused by iatrogenic injury following radiologic or surgical liver interventions.79 Recently, as percutaneous transhepatic procedures are more frequently carried out, such vascular lesions are becoming more prevalent. Common vascular lesions include arterial pseudoaneurysm, arterioportal fistula, and arteriobiliary fistula. Small lesions are asymptomatic and may not need any specific treatment. However, a large aneurysm or fistulas with large amount of blood flows can lead to hemobilia, gastrointestinal bleeding, and portal hypertension. Congenital portosystemic shunt or vascular malformations are rare but can be associated with serious and potentially fatal complications.10 In the past, most symptomatic vascular lesions required surgical treatment, but TAE has currently emerged as a valuable minimally invasive treatment option.11

TECHNIQUES AND EMBOLIC MATERIALS

Angiographic access is gained on either a femoral or a left axillary artery using Seldinger technique. Visceral arteriography is performed using a preshaped 4-Fr or 5-Fr angiographic catheter. In the liver, arterial anatomic variations are common. Selective examination of the celiac and superior mesenteric arteries is often necessary. Common variants include the left hepatic artery arising from the left gastric artery and the right hepatic artery replaced to the superior mesenteric artery. It is important to scrutinize the arteriogram for defects in hepatic parenchymal enhancement, which might alert one to the presence of anatomic variants or accessory vessels. Two or more projection hepatic angiograms including the portal venous phase may be required to identify the location of lesion and feeding vessels identified. The vessels to be embolized are catheterized as selectively as possible with use of a 2-Fr or 3-Fr microcatheter.

The liver is well suited to TAE because of its dual blood supply. Arterial embolization is unlikely to result in tissue infarction unless there is concomitant injury to the portal venous system. To minimize normal hepatic parenchyma, it is preferable to place the embolic agent as close to the target lesions as possible. The major considerations for selecting an embolic agent are lesion type and location, individual vascular anatomy, reliability of delivery, and preservation of normal tissue. For benign liver tumors, particulate embolic agents such as polyvinyl alcohol (PVA) and gelatin sponge particles have been frequently employed.12 However, PVA particles are known to clump, resulting in more proximal vessel occlusion. Recently, calibrated microspheres (trisacryl gelatin microspheres) are used to achieve distal vessel blockade, leading to ischemic tumor necrosis.13 For embolization of hepatic vascular injury such as arterioportal/arteriobiliary fistulas and pseudoaneurysms, microcoils, gelatin sponge pledgets, and N-butyl cyanoacylate (NBCA) are typically used either alone or in combination.79 Coils are ideal for precise single-vessel occlusion. They provide controlled delivery with rapid occlusion and are available in various sizes. When using coils, they should be tightly packed without interstices to avoid late recanalization and coil migration. When treating arterial pseudoaneurysm, coils should not be placed inside the aneurysmal sac because there is risk of late rupture. The proximal and distal vessels to the pseudoaneurysm should be embolized so that revascularization by backflow may not occur (sandwich technique). Recently, NBCA has been gaining interest as a useful embolic material for TAE. It occludes target vessels rapidly and completely, which results in more reliable embolization and may reduce fluoroscopic and procedure time. By adjusting the ratio of NBCA and iodized oil, polymerization time and, accordingly, the level of embolization within target vessels can be controlled. This unique character of NBCA is especially useful when a microcatheter is not able to be advanced to desirable intravascular position due to tortuous vascular anatomy or arterial stenosis. In spite of these advantages, the use of liquid embolic agents including NBCA has been limited in TAE because of the concern that they carry a high risk for severe complications such as tissue necrosis and nontarget embolization secondary to uncontrolled reflux.14 In embolization of a large, high-flow arteriovenous shunt, a more durable embolic device with large diameter such as Amplatzer Vascular Plug (St. Jude Medical, Inc., St. Paul, Minnesota) may be required to prevent migration.

CLINICAL APPLICATIONS

Benign Liver Tumors

Hepatocellular Adenoma

Hepatocellular adenoma (HA) is a rare hepatic tumor that is strongly associated with use of oral contraceptives or anabolic steroids and glycogen storage disease.15 Unlike other benign liver tumors, approximately 80% of patients with HA have clinical symptoms; of these, half present with acute-onset abdominal pain due to hemorrhage and half present with symptoms related to mass effect. Only 20% of HAs are found as incidental findings.16 Malignant transformation of HA is rare and associated with β-catenin mutations that are also found in hepatocellular carcinoma.17 There are controversies with regard to the optimal treatment for HA because the potential for hemorrhage or malignant transformation of tumor is difficult to estimate. The patients with lesions smaller than 5 cm and normal α-fetoprotein levels are typically treated conservatively. Discontinuation of oral contraceptives may lead to regression of the tumor.18 Patients with lesions larger than 5 cm should be considered for surgical resection because lesion size is an important indicator of potentials for hemorrhage or progression to hepatocellular carcinoma.19 However, surgery carries an increased risk of postoperative morbidity and a longer recovery time and may not be practical in patients with multiple bilateral HAs.20

TAE, on the contrary, is minimally invasive. It can be applied to multiple and bilateral tumors. It can safely be repeated and is effective in decreasing the lesion size (Fig. 33.1). The data from literatures on embolization of HAs are summarized in Table 33.1. Currently, TAE is commonly indicated in patients presenting with acute hemorrhage from HAs. In several studies, TAE has been successfully performed to obtain adequate hemostasis without the need for urgent laparotomy.5,21,22 Stoot et al.21 treated 11 patients with ruptured HAs. Ten of the patients were stabilized after a single TAE, whereas one other patient needed three TAE sessions. No emergency resections were needed and only minor complications were found. In all patients, tumor size decreased after follow-up, with secondary resection being indicated only in a minority of patients. Because an emergency surgical resection inevitably involves considerable morbidity and mortality, TAE is proposed as the first treatment in hemodynamically unstable patients with ruptured HAs. In addition to the emergency indication, several reports have focused on the elective use of TAE for HAs larger than 5 cm with the aim of reducing the tumor mass by complete cessation of the arterial blood flow.13,23,24 Kim et al.23 performed TAE in 7 patients with large HAs and achieved tumor regression more than 50% in 6 patients. Complete resolution of the tumor was seen in 2 patients. No serious complication was reported except self-limiting postembolization syndrome. In past several years, TAE has been increasingly used in patients with unruptured HAs.25 A randomized controlled study comparing surgical resection versus selective TAE is now going on.26

Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) is the second most common benign liver tumor next to hemangioma and usually affects women of childbearing or middle age.27 It is more often a solitary subcapsular lesion measuring less than 5 cm in size. Histologically, FNH is composed primarily of Kupffer cells and hepatocytes. It is believed to result from the response to a preexisting vascular abnormality. Patients with FNH are typically asymptomatic and may be managed conservatively because there is no predisposition to hemorrhage or malignant transformation. However, up to 30% of patients present with a vague abdominal pain due to mass effect, hepatomegaly, and/or abdominal mass.28Treatment should be considered in cases with a progressive increase in size or compressive symptoms. Surgical resection is currently the treatment of choice for FNH when indicated. TAE is considered to be an alternative to surgery when there is considerable surgical risk because of localization or poor clinical condition. Given FNH’s genesis in abnormal arterial flow, embolization is a feasible strategy.29 Angiographic findings are fairly characteristic. Hepatic angiogram shows a hypervascular mass with dense tumor blush in the capillary and portal venous phases. Lucent septations can be seen within the blush corresponding with the fibrous septations. A single central feeding artery penetrating the tumor mass is usually seen in a large FNH, which makes TAE more feasible. When the lesion is supplied by multiple small feeding vessels, the need for repeat TAE should be anticipated.29 Several small case series reported successful application of TAE in patients with symptomatic FNHs. Microspheres 150 to 750 µm were the most commonly employed embolic agent. TAE relieved symptoms in most patients and led to substantial shrinkage of the tumors (20% to 90%).12,29,30

Cavernous Hemangioma

Cavernous hemangioma is the most common benign tumor affecting the liver, with an estimated prevalence of 3% to 20%.27 It occurs in all age groups but is more frequently discovered between the third and fifth decade, with a mean age of 50 years at diagnosis and is seen more often in females (female-to-male ratio 6:1).27 Most hemangiomas are small, asymptomatic, and usually require no treatment or follow-up. However, giant hemangiomas (diameter >4 cm) may present with abdominal pain or discomfort (23% to 57%) caused by displacement of other organs, capsular stretch, partial infarction, or intralesional hemorrhage. A spontaneous or traumatic rupture is rare (1% to 4%), but mortality in this patient group is high (36% to 39%).3 Kasabach-Merritt syndrome is also a rare but well-known complication of giant hemangiomas. It is characterized by the combination of a vascular tumor and consumptive coagulopathy, which can progress to disseminated coagulopathy. There is no consensus regarding the optimal management of giant hemangiomas, but presence of established complications, diagnostic uncertainty, and incapacitating symptoms are generally considered indications for surgical enucleation or resection.

TAE has been suggested as a good alternative treatment of symptomatic hemangiomas, either alone or as a preoperative procedure before surgical resection.3134 TAE can be successfully applied in tumors with extensive hilar involvement that makes surgical procedures difficult,34 in patients with ruptured hemangiomas,33 or to reduce blood loss at the time of surgery.31 TAE rapidly and safely corrects the coagulopathy caused by Kasabach-Merritt syndrome, which is essential because these patients are poor surgical candidates.35 Various embolic materials are being used, such as gelatin particle, steel coils, PVA particles, and NBCA. Typically, vascular interstices within the lesion are first embolized with PVA particles, followed by embolization of the principal arteries with steel coils.36 In a multicenter study from China, hepatic hemangiomas of 98 patients were treated with chemoembolization using pingyangmycin-Lipiodol emulsion. Pingyangmycin has been found, like bleomycin, to reduce the DNA synthesis of cancer cells and cut off the DNA chain. The presumable mechanism of this treatment relies on pingyangmycin’s ability to destroy the endothelial cells, resulting in the formation of microthrombi in sinuses and causing atrophy and fibrosis of the tumor. The tumor diameters decreased significantly from 9.7 to 3.0 cm at 12 months follow-up. Clinical symptoms were relieved in all patients. The most severe potential complication caused by pingyangmycin is pulmonary fibrosis. However, no pulmonary fibrosis has been observed in used dosage (8 to 24 mg).

Iatrogenic Vascular Injury

Iatogenic hepatic vascular injury is by far most commonly caused by radiologic transhepatic procedures including percutaneous liver biopsy, percutaneous transhepatic biliary drainage (PTBD), transjugular intrahepatic portosystemic shunt (TIPS), and radiofrequency ablation (RFA).37 The incidence of clinically significant vascular injury following RFA and liver biopsy is estimated to be 0% to 0.5% and 0.06% to 1%, respectively. PTBD carries a higher risk (2% to 10%) because of the use of larger catheters and the presence of bile stasis.3840 Most common clinical presentation is gastrointestinal bleeding due to hemobilia.41 This is due to close proximity of the hepatic arteriole and portal venule along with the biliary radical in the portal triad. Thus, an injury to the artery and vein makes the adjacent biliary duct prone to injury. In up to 90% of the patients with iatrogenic hemobilia, a vascular abnormality is found on angiography.41 The most common finding is a pseudoaneurysm, followed by an arteriobiliary or an arterioportal fistula. Some arterioportal fistulas may remain quiescent for long periods, up to many years, but a large arterioportal fistula can lead to dynamic portal hypertension with gastroesophageal varices, ascites, or mesenteric ischemia.42

Nowadays, TAE is the preferred method to treat intrahepatic iatrogenic vascular injuries, which gives satisfactory results; success rates of 80% to 100% have been reported in the literature.9,4348 An overview of the embolization results for iatrogenic hepatic vascular injuries in the literature is presented in Table 33.2. Surgery is usually employed secondarily for unsuccessful embolization and complex lesions. The aim of embolization is to achieve selective and complete thrombosis of pseudoaneurysm or fistula closure with preservation of the adjacent normal vasculature. To achieve this, a microcatheter should be positioned as close as possible to the lesion site to limit hepatic devascularization. For hepatic arterial pseudoaneurysm, microcoils are most commonly used to embolize hepatic arteries just distal and proximal to the lesion, which allows for thrombosis (Fig. 33.2). When embolizing the right or left hepatic arteries, contralateral peripheral vascular bed is filled through intrahepatic collateral vessels immediately; thus, hepatic infarction is unlikely to occur. For embolization of arterioportal fistulas, the embolic agents should be chosen according to the size of the vascular communication. For high-flow fistulas, microcoils are most commonly selected embolic agent.8,9,49 However, the use of microcoils has a potential risk of migration of the coil into the portal vein, especially when fistula is larger than 8 mm.37 Detachable coils, such as the interlocking detachable coil or Guglielmi detachable coil, can avoid the risk of coil migration, but they may not cause thrombosis in high-flow fistula. Hirakawa et al.8 suggested the use of detachable coil as a first anchoring coil and subsequent fibered coils to avoid coil migration and to achieve complete occlusion of large, high-flow fistula. Liquid embolic agent such as NBCA has not been widely used due to its higher risk of migration into the portal venous system. However, it can be a useful embolic agent when there is the presence of multiple small fistulae, all of which had to be embolized,7or proper placement of a microcatheter at the desirable intra-arterial position is impossible.8 Particles such as gelatin sponge or PVA can be used in small, slow-flow fistulas.11

Miscellaneous Benign Liver Diseases

Polycystic Liver Disease

Polycystic liver is the most common extrarenal manifestation associated with autosomal dominant polycystic kidney disease (ADPKD), presenting in 80% of all ADPKD patients.50 Most patients are asymptomatic and require no treatment. However, because of lengthened lifespan of ADPKD patients, recent patients often suffer from hepatic symptoms including abdominal discomfort, dyspepsia, or dyspnea. Surgical interventions to relieve these symptoms include laparoscopic or open cyst fenestration, partial hepatectomy, and hepatic transplantation.51,52 However, these treatments are associated with significant morbidity and mortality, reported as high as 42%.53 Recently, Ubara et al.54 suggested that TAE may be an option for symptomatic patients who are not candidates for surgical treatment. Hepatic cysts in ADPKD patients are mostly supplied from hepatic arteries; therefore, embolization of hepatic artery branches that supply major hepatic cysts may lead to shrinkage of the cyst (Fig. 33.3). Thereafter, several investigators embolized the hepatic arteries supplying the dominant hepatic segments replaced by cysts using microcoils55,56or NBCA57 and achieved symptomatic relief in 50% to 86% of their patients. Total liver volume and intrahepatic cyst volume substantially decreased. No serious complications were reported except mild transient elevation of the liver enzyme.5557

Infantile Hemangioendothelioma

Infantile hemangioendothelioma (IHE) is the most frequent liver tumor in infants, which can occur as solitary or multifocal lesions. Although it is a benign tumor, potentially fatal complications can result from congestive heart failure and consumptive coagulopathy (Kasabach-Merritt-Syndrome). The mortality rate of untreated symptomatic IHE is reported up to 90%.58 In these cases, immediate treatment is crucial for the outcome of the patients. Medical treatment consists of steroids, α-interferon, and symptomatic treatments. Surgical procedures include ligation of feeding vessels, hepatic resection, and liver transplantation. TAE has been considered an important alternative treatment because the patients are often at high surgical risk.5961 As the procedure involves percutaneous arterial access in infants, there is a risk of thrombotic occlusion of the femoral artery. This can be avoided if a venous approach is used with passage to the arterial side via the persistent ductus arteriosus or the oval foramen of right atrium.61 In newborns, feeding vessels from the portal venous system can be embolized via the umbilical vein.59 Warmann et al.61performed coil embolization in four patients with symptomatic IHE and achieved good clinical outcomes in three patients. Signs of heart failure resolved within 8 days after TAE and tumor size was reduced from a mean of 544 mL to 4 mL. Even in cases with incomplete regression of the tumors, the clinical improvement can be achieved shortly after embolization in most patients. Thus, if necessary, a surgical resection might follow after cardiopulmonary stabilization with reduced tumor size.61

Congenital Portosystemic Shunt

Congenital portosystemic shunts are rare (1/30,000) anomalies that result from developmental abnormalities of the portal venous system. They are classified into two types: extrahepatic (type I) and intrahepatic (type II, including patent ductus venosus). Intrahepatic type may be also divided into four different findings: single large tube connecting right portal vein to inferior vena cava, segmental peripheral portal and hepatic venous connection, aneurysmal connection, and diffuse connection in both lobes.62 The clinical course is determined by the diameter of the shunt. Patients with large shunts may have severe related complications including hypoxia owing to hepatopulmonary syndrome, dyspnea caused by pulmonary arterial hypertension, heart failure, encephalopathy, neonatal cholestasis, or liver tumor,63 whereas those with small shunts may develop recurrent episodes of portosystemic encephalopathy that initiate in adulthood.64

Treatment in symptomatic patients consists of surgical or laparoscopic ligation of the shunt or endovascular embolization. Although surgical ligation prevailed for managing most cases in the past, with modern technologic advances of intravascular devices and radiologic techniques, it has been largely replaced by radiologic intervention.65,66 However, because of the anatomical proximity of the vascular structures involved (portal vein and hepatic vein or vena cava), stable placement of a large embolic device inside of a short-length fistulous tract can be challenging. In addition, shunt closure can lead to acute portal hypertension when the hypoplastic portal system does not adapt rapidly. Therefore, an occlusion test with temporary balloon occlusion of the shunt with recording of the portal pressure is recommended before complete closure of the shunts. When portal pressure rises above 30 mm Hg with shunt occlusion test, shunt closure should be avoided, and an alternative two-step procedure (surgical or radiologic) or liver transplantation should be considered.67 Steel coils has been successfully used for shunt closure but carries the risk of migration.63,65 In the case of large, high-flow fistula, an Amplatzer Vascular Plug with a diameter 30% to 50% larger than the shunt is recommended to reduce the risk of device migration68 (Fig. 33.4).

POTENTIAL COMPLICATIONS

The procedures of TAE for benign liver disease are essentially same as those of TAE for malignant liver tumors. Therefore, theoretically, TAE for benign liver disease can be associated with all complications that occur following TAE for malignant liver tumors. Major complications include liver abscess, parenchymal infarction, intrahepatic aneurysm, ischemic cholecystitis or gallbladder infarction, and gastric or duodenal ulcerations. There are well-known predisposing factors for these complications, including major portal vein obstruction, compromised hepatic functional reserve, biliary obstruction, and previous biliary surgery. However, as the patients with benign liver disease usually have a good liver function and unlikely to have the predisposing factors, complications following TAE in benign liver diseases are rare and mostly consist of postembolization syndrome, vascular injury from catheter manipulation, and complications from use of contrast medium.

The postembolization syndrome is the most common complication that occurs in approximately 80% of patients after TAE. It is characterized by pain at the site of embolization, nausea and vomiting, malaise, fever, and leukocytosis, which usually occurs within 24 to 48 hours of embolization and lasts 3 to 7 days. Severity depends on the extent of the embolized liver tissue. Possible causes of the pain are acute ischemia of liver parenchyma, distension of the liver capsule, and/or gallbladder ischemia due to inadvertent embolization of the cystic artery. It is essentially a self-limited condition, which hardly requires any specific treatment. Nevertheless, it may be considered an important complication because it prolongs hospitalization and postpones additional treatment. The relevant systemic symptoms can be controlled by antiemetics, analgesics, antipyretics, and hydrocortisone.

Liver abscess and infarction rarely develops after TAE for benign liver diseases; only a few case series reported these complications. Savader et al.46 experienced two liver abscesses and one infarction following 12 TAE procedures for iatrogenic hemobilia. Liver abscess is usually successfully managed with parenteral antibiotics and percutaneous drainage, but in some cases, it may result in fatal outcome if it is detected too late or managed inappropriately. As biliary-enteric bypass surgery is a well-known predisposing factor, aggressive prophylactic antibiotics administration before TAE is recommended in case of previous bile duct surgery or systemic disorders vulnerable to infection.

Nontarget embolization is the most dreaded complication of hepatic embolization but occurs infrequently if diagnostic angiogram has been carefully evaluated and the appropriate technique of embolization has been followed. The gallbladder is the most common “nontarget” organ because the cystic artery is often not opacified on arteriogram. Inadvertent embolization of the cystic artery causes prolonged postembolization syndrome with fever, pain, and nausea/vomiting. Most cases have self-limited clinical course, but more serious conditions have been reported such as gallbladder perforation and gangrenous or emphysematous cholecystitis, in which cholecystectomy or percutaneous cholecystostomy is required.69 Gastroduodenal ulcer can occur due to inadvertent embolization of the accessory left gastric arteries that arise from the left hepatic artery and the right gastric artery that arises from the proper hepatic artery.70 If these gastric branches are not recognized before the procedure, and appropriate protective measures are not taken, gastric complications are unavoidable. Embolization of gastric branches with coil or balloon occlusion of proper hepatic artery can redirect the blood flow.

When performing embolization for arterioportal fistula, there is a potential risk of the migration of embolic agents to the portal veins. This may cause the blockage of portal vein branches, leading to subsequent thrombosis. Hirakawa et al.8 reported four cases in which portal vein thrombosis developed after TAE. Although portal vein thrombosis is frequently asymptomatic and hepatopetal portal flow maintained by cavernous transformation, this complication should be kept in mind when embolizing a large and high-flow fistula.

During hepatic embolization procedure, iatrogenic arterial injury, such as dissection, may occur in the visceral arteries. The two most common sites of dissection are the celiac artery and the proper hepatic artery. Although iatrogenic dissection of the arteries heals spontaneously in most patients, it may result in complete obstruction or pseudoaneurysm formation.7173

TIPS AND TRICKS

Benign Liver Tumors

• To minimize damage of normal hepatic parenchyma, hepatic arterial embolization should be as close to the target lesions as possible.

• Particulate embolic agents are commonly used. Typically, vascular interstices within the lesion are first embolized with PVA particles, followed by embolization of the principal arteries with steel coils.

• When using coils, they should be tightly packed without interstices to avoid late recanalization.

Iatrogenic Vascular Injury

• In patients with iatrogenic hemobilia, vascular abnormalities such as pseudoaneurysm and arteriobiliary or arterioportal fistula can be demonstrated on angiography in most cases.

• When treating hepatic arterial pseudoaneurysm, coils should not be placed inside the aneurysmal sac because there is risk of late rupture. The proximal and distal vessels to the pseudoaneurysm should be embolized so that revascularization by backflow may not occur.

• When treating large, high-flow fistulas, the use of pushable microcoils has a potential risk of migration. Consider use of detachable coil as a first anchoring coil to prevent coil migration and subsequent pushable fibered coils to achieve complete occlusion of fistula.

• When a microcatheter is not able to be advanced to desirable intravascular position, consider use of NBCA. By adjusting the ratio of NBCA and iodized oil, the level of embolization within target vessels can be controlled.

Miscellaneous Benign Liver Diseases

• Hepatic cysts in ADPKD patients are mostly supplied from hepatic arteries; therefore, embolization of hepatic artery branches that supply major hepatic cysts may lead to shrinkage of the cyst.

• When the procedure involves percutaneous arterial access in infants, consider venous approach with passage via the persistent ductus arteriosus or the oval foramen of right atrium to avoid risk of arterial access related complications.

• When congenital portosystemic shunt is large, high-flow, with short-length fistulous tract, the use of coil carries risk of migration. Amplatzer Vascular Plug with a diameter 30%–50% larger than the shunt is recommended.

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