Arterial and biliary complications after transarterial chemoembolization for hepatocellular carcinoma

Abstract

Transarterial chemoembolization is a common treatment modality that significantly improves prognosis in patients with intermediate-advanced hepatocellular carcinoma. However, this procedure is associated with a spectrum of potential arterial and biliary complications, ranging from mild self-limiting ones to those severely affecting patient outcomes. This review systematically integrates recent studies to explore the epidemiological characteristics, risk factors, and management strategies of these two groups of complications. Arterial complications, primarily hepatic artery stenosis, pseudoaneurysm, and arterial rupture hemorrhage, exhibit a biphasic distribution pattern with the majority occurring within 72 hours postoperatively, while a notable portion occurs within 1-4 weeks. Biliary complications, including biliary fistulas, biliary strictures, and ischemic cholangitis, exhibit higher incidence rates and more insidious clinical manifestations than arterial complications. Risk factors include the severity of cirrhosis, tumor location, procedural technique, and chemotherapeutic drug toxicity. Management strategies emphasize careful preoperative planning (primarily with computed tomography angiography), standardized intraoperative procedures (like superselective embolization), and multi-pronged postoperative monitoring (imaging combined with laboratory indicators of liver function). Interventional embolization or surgical reconstruction is used for arterial complications, while endoscopic therapy or surgical drainage is selected based on the severity of injury for biliary complications. Future research should further explore individualized treatment regimens and novel embolic materials to reduce complication rates and enhance the safety of transarterial chemoembolization.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Arterial complications; Biliary complications; Management strategies

Core Tip: Transarterial chemoembolization for intermediate-advanced hepatocellular carcinoma carries arterial (stenosis, pseudoaneurysms, hemorrhage) and biliary (fistulas, strictures, cholangitis) complications, with biliary ones more prevalent (hilar tumors/cirrhosis as risk factors). Management involves preoperative imaging, intraoperative superselectivity, and postoperative surveillance, with targeted interventions for each complication type. This review synthesizes recent data to provide a holistic, updated framework for understanding and managing these issues.

INTRODUCTION

Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors worldwide, with persistently high incidence and mortality rates. Owing to the lack of specific clinical manifestations in the early stages, most patients are diagnosed at an advanced stage, often accompanied by tumor metastasis or local invasion, thereby losing the optimal opportunity for surgical resection[1,2]. For such patients with unresectable HCC, transarterial chemoembolization (TACE) has become a globally recognized effective treatment modality. It is not only one of the standard therapies for advanced HCC but also the first-line palliative treatment option for patients with Barcelona Clinic Liver Cancer stage B disease[3].

The therapeutic principle of TACE is based on the unique dual blood supply system of HCC: Tumors primarily rely on the hepatic artery for blood supply, while normal liver tissue is mainly perfused by the portal vein. Through interventional radiological techniques, a catheter is superselectively placed into the tumor-feeding artery to infuse high-concentration chemotherapeutic agents and embolic materials to block blood flow. This approach simultaneously achieves the goals of “local chemotherapy-induced tumor cell killing” and “ischemia-hypoxia-induced tumor necrosis”[4]. Conventional TACE (c-TACE) typically involves mixing chemotherapeutic drugs with lipiodol to form an emulsion. The selective deposition property of lipiodol in HCC vessels is leveraged for targeted drug delivery. This is subsequently supplemented with particulate embolic agents such as gelatin sponges to further occlude the feeding artery, maximizing tumor ischemia[5]. In recent years, the application of drug-loaded microspheres has led to the development of drug-eluting bead TACE (DEB-TACE). This technique enables the slow release of chemotherapeutic drugs by microspheres at the tumor site, which theoretically increases the local drug concentration at the tumor site, prolongs the drug action time, and reduces systemic toxicity[6]. Additionally, balloon-occluded TACE (B-TACE) temporarily dilates a balloon at the proximal end of the target artery to alter hemodynamics, which can effectively prevent embolic reflux and promote the deposition of embolic agents in the distal tumor vascular bed, further improving embolization effectiveness[7].

Although TACE exhibits significant efficacy in controlling tumor progression and prolonging patient survival, with added advantages of minimal invasiveness and safety, this procedure is commonly complicated by post-embolization syndrome, characterized by fever, right upper quadrant pain, and nausea/vomiting. Yet, post-embolization syndrome is mostly self-limiting and can be relieved within a few days after symptomatic supportive treatment[8]. However, rare but severe arterial and biliary complications may still occur after TACE. If such complications are not promptly identified and intervened, they may not only impair patient prognosis but also lead to treatment-related mortality in severe cases, offsetting the survival benefits of TACE and limiting the implementation of subsequent treatments. These complications remain a major challenge in clinical research on TACE[9,10].

Currently, existing studies on post-TACE arterial and biliary complications exhibit significant heterogeneity in their reports, and no consensus has been reached on the incidence, risk factors, and optimal management strategies of these complications. Therefore, this review systematically retrieves and synthesizes high-quality studies published in recent years, conducts an in-depth analysis of the epidemiological characteristics, key risk factors, pathophysiological mechanisms, clinical manifestations, and diagnostic essentials of these two types of complications, and summarizes the existing preventive and therapeutic strategies. The aim is to provide evidence-based medical references for clinical practice and further improve the safety of TACE treatment.

ARTERIAL COMPLICATIONS

As an interventional therapeutic modality making use of the arterial system, TACE inevitably entails the risk of arterial injury during the procedure. Although arterial complications are not the most common adverse reactions of TACE, they present a broad spectrum, with reports ranging from mild vasospasm to life-threatening organ infarction or massive hemorrhage. Based on the pathogenesis and location, these complications can be classified into direct arterial injury and extrahepatic organ injury caused by the unintended migration of embolic agents into non-target arteries (Figure 1).

Figure 1 Schematic diagram illustrating the classification, pathogenesis, risk factors, and management strategies of arterial and biliary complications associated with different transarterial chemoembolization modalities. TACE: Transarterial chemoembolization; DEB-TACE: Drug-eluting bead transarterial chemoembolization; B-TACE: Balloon-occluded transarterial chemoembolization.

Epidemiological characteristics of arterial complications

Reports of the incidence of arterial complications after TACE for HCC demonstrate significant heterogeneity[11-13]. Current epidemiological data demonstrate that the pooled incidence ranges from 1.1% to 7.2%[6,7,14-18]. This variation may be associated with factors such as study sample size, standardization of surgical procedures, diagnostic criteria for complications, and follow-up duration. Multiple studies have suggested that centers adopting superselective TACE technology have a significantly lower incidence of postoperative arterial complications than those using c-TACE, indicating that innovations in surgical techniques may be a key factor in reducing the risk of complications[19,20]. In addition, the onset time of complications shows a biphasic distribution pattern: Approximately 62% of arterial complications occur within 72 hours after the procedure (mainly puncture-related bleeding and arterial spasm), another 28% occur 1-4 weeks after the procedure (mainly pseudoaneurysm and arterial thrombosis), and only 10% occur more than 1 month after the procedure (mostly delayed vascular stenosis)[21].

In terms of the distribution of complication types, puncture-related complications account for the highest proportion, among which femoral artery puncture site bleeding/hematoma is the most common, followed by arterial spasm and pseudoaneurysm. The occurrence of femoral artery puncture site bleeding/hematoma is mostly related to premature ambulation of patients after the procedure and deficiency of coagulation factors[22]. Among vascular injury-related complications, the incidence of hepatic artery-portal vein fistula is relatively low; however, once it occurs, it is likely to cause deterioration of liver function. The overall incidence of thromboembolic complications (including distal arterial embolism and pulmonary embolism) is less than 1%, but the risk of mortality is relatively high[23,24]. Notably, with the popularization of DEB-TACE, the incidence of postoperative arterial dissection is slightly higher than that of c-TACE. This may be attributed to the larger diameter of drug-eluting beads and the increased pressure on the vascular wall during the delivery process, a phenomenon that requires focused attention in clinical practice[25,26].

In terms of risk factors, age ≥ 65 years, complicated with atherosclerosis, and coagulation dysfunction are independent predictors for arterial complications after TACE[27-29]. Elderly patients have decreased vascular elasticity and increased vascular wall fragility, making them more prone to vascular injury during surgery; for patients with atherosclerosis, the integrity of vascular endothelium is impaired, leading to a significantly increased risk of postoperative thrombosis[30]. In addition, a higher tumor burden (maximum tumor diameter ≥ 5 cm) is positively correlated with the risk of complications. The incidence of hepatic artery rupture in such patients is significantly higher than that in patients with small tumors[31]. This may be due to the more severe erosion of the hepatic artery wall by large tumors, and the larger dose of embolic agent required during the treatment process, which causes more irritation to blood vessels. Moreover, the incidence of arterial complications in patients with liver cirrhosis of Child-Pugh class B/C is significantly higher than that in patients with class A[32], suggesting that liver function reserve may indirectly regulate the occurrence of complications by affecting vascular repair capacity. Patients with poor liver function have a reduced ability to synthesize vascular repair-related factors [such as vascular endothelial growth factor (VEGF)], resulting in delayed healing after vascular injury.

In recent years, as combination regimens incorporating TACE (such as TACE combined with targeted drugs and immunotherapy) become more widely utilized, their impact on arterial complications has gradually garnered attention. A comparison between patients receiving TACE alone and those receiving TACE combined with sorafenib showed that the incidence of arterial complications in the combined treatment group was slightly higher than that in the TACE alone group, among which the increase in the incidence of arterial thrombosis was more significant[33]. It is speculated that this may be due to the inhibitory effect of targeted drugs on vascular endothelium, which increases the risk of thrombosis. In addition, among patients treated with TACE combined with immune checkpoint inhibitors, although no significant increase in the incidence of arterial complications was found, rare cases of delayed arteritis have been reported[34]. Such complications have insidious clinical manifestations and are easily misdiagnosed, requiring prolonged follow-up to clarify their true incidence and clinical outcomes. The characteristics of complications related to the above-mentioned new treatment modalities provide important references for optimizing combined treatment regimens and formulating targeted prevention and control measures.

Pathogenesis

The pathophysiological mechanisms of arterial complications after TACE are complex, and they can be mainly categorized into two major types: Direct mechanical vascular injury and non-target embolization. These two types are often interrelated and collectively cause damage to local blood vessels and distal organs. Direct mechanical vascular injury refers to the physical damage to the vascular wall caused by interventional devices such as catheters and guidewires during the procedure. Arterial dissection mostly occurs when the tip of a catheter/guidewire penetrates the intima while passing through tortuous, sclerotic, or plaque-laden arteries[35]; blood then flows into the medial layer of the vascular wall to form a false lumen, which compresses the true lumen and leads to impaired blood flow or even occlusion. Vascular perforation and bleeding are common during superselective catheterization of small tumor-feeding arteries; overly aggressive manipulation may penetrate the full thickness of the blood vessel, causing contrast medium extravasation and active bleeding, and failure to handle this promptly can result in massive intra-abdominal hemorrhage. Thrombosis occurs when vascular intimal injury (e.g., catheter friction, dissection) exposes collagen tissue, activating platelets and the coagulation cascade to form a thrombus at the injury site, thereby leading to acute occlusion of the target or non-target artery[36]. Arterial spasm is the reflexive contraction of vascular smooth muscle after the vascular wall is subjected to mechanical stimulation, resulting in temporary luminal stenosis that affects the delivery of embolic agents. Pseudoaneurysm is formed when the hepatic arterial wall is injured by a guidewire/catheter (especially when vascular conditions are poor) or by excessive balloon dilation during bland TACE (B-TACE), which causes blood leakage and subsequent encapsulation by surrounding tissues[6].

Non-target embolization is the main cause of extrahepatic organ complications after TACE. It refers to the entry of chemotherapeutic drugs or embolic agents into the arterial vascular bed of non-tumor target areas, and is affected by the interplay of multiple factors. Extrahepatic collateral arteries (EHCs) serve as an important anatomical basis: When patients have anatomical abnormalities, tumor invasion, previous surgery, or hepatic artery trunk stenosis/occlusion caused by repeated TACE, the body forms EHCs through vascular remodeling to supply blood to the tumor. Misplacement of the catheter tip or regurgitation of the embolic agents may unintentionally embolize EHCs such as the hepatic falciform artery (which supplies periumbilical skin), leading to skin ischemia, rash, or even necrosis[37,38]. Regurgitation of embolic agents is a known mechanism of inadvertent embolization caused by excessively fast injection speed, excessively high pressure, or increased resistance of the target vascular bed. This leads to the retrograde flow of embolic agents toward the proximal end and their entry into non-target branches of the same trunk as the target artery (e.g., gastroduodenal artery, right gastric artery), causing complications such as gastrointestinal ulcers and pancreatitis[39]. Drug toxicity can also cause injury, for example, epirubicin has been shown to be associated with cutaneous adverse events from local extravasation from inadvertent delivery of the chemotherapeutic agent through abdominal wall arteries originating from the chemoembolized hepatic arteries[40]. This drug primarily induces cell apoptosis and necrosis by intercalating into DNA strands and inhibiting topoisomerase II, thereby hindering DNA and RNA synthesis. In addition, arteriovenous shunts within the tumor may allow lipiodol-chemotherapeutic drug complexes to directly enter the hepatic vein and subsequently be carried to the lungs via the blood flow; lipiodol is then decomposed by pulmonary lipase into toxic free fatty acids, triggering toxic reactions[41]. Arteriovenous shunts may also shunt lipiodol and chemotherapeutic drugs directly into the hepatic vein or non-target vessels, and allow its distribution throughout the body via the circulation[11,36,41]. Hematogenous migration is a rare mechanism, referring to the migration of chemotherapeutic drugs (e.g., doxorubicin) from microspheres through the microcirculation to the abdominal subcutaneous tissue; this process occurs at the microscopic level and is therefore difficult to observe via angiography[42]. Cisplatin used in TACE may induce the body to produce autoantibodies against coagulation factor V (FV), leading to FV inactivation or degradation and impairment of coagulation function[43]. Cholesterol crystal embolism occurs when catheter manipulation disturbs unstable plaques in patients with atherosclerosis; cholesterol crystals detach to form microemboli, which embolize the small arteries of distal organs such as the skin and kidneys, causing ischemic injury[44].

Risk factors

The risk factors for arterial complications after TACE can be classified into three categories: Patient-related factors, intervention procedure-related factors, and tumor biological behavior-related factors. Among patient-related risk factors, baseline liver function and systemic status are crucial. Patients with Child-Pugh class B/C have poor liver function reserve, low tolerance to ischemia and chemotherapeutic drugs, and a high risk of postoperative liver failure; impaired function of vital organs such as the heart, lungs, and kidneys also increases perioperative risks[45]. Vascular anatomical variations are key risk factors for severe complications: Extrahepatic collateral blood supply (especially abnormal feeding arteries originating from the renal artery) can expand the diffusion range of chemotherapeutic drugs, and tiny collateral vessels (connecting the embolized area to the feeding arteries of abdominal wall skin) undetectable by angiography are also prone to inducing complications[37,40]. A history of abdominal surgery or hepatic artery trunk stenosis raises the risk of non-target embolization[38]. Patients with a history of HCC rupture and bleeding have a significantly higher incidence of arterial complications[46]. A platelet count < 100000/μL is a high-risk factor for puncture site hematoma[12]. Liver cirrhosis and portal hypertension can slow portal vein blood flow, increasing the risk of thrombosis[36]. Tumors with a diameter > 5 cm, located in the hepatic bare area/subdiaphragmatic region, with exophytic growth, or rich in blood supply are more likely to form shunts[41,46]. Elderly patients, as well as those with long-term hypertension or diabetes, are often complicated with systemic atherosclerosis; their hepatic arteries may be tortuous, stenotic, or plaque-laden, which increases the difficulty of catheter manipulation and the risk of vascular injury[39].

Various procedure related risks are also detailed. Repeated TACE increases the risk of arterial injury[47]. Lipiodol dose exceeding 20 mL is associated with significant increased risk of complications[46]. Arteriovenous shunts within the tumor or other sites allow embolic agents/drugs to bypass the liver, increasing the risk of systemic dissemination[6,36,41]. Liquid-form chemotherapeutic drugs are more easily absorbed systemically than powder-form ones, increasing systemic side effects[42]. Failure to advance the catheter tip deep into the tumor-feeding branch (with microspheres injected at the proximal end) significantly raises the risks of regurgitation and non-target embolization[6,37,39]. Excessively rapid injection speeds or high pressures (especially when aiming for complete blood flow stasis) easily causes embolic agent regurgitation or diffusion through unrecognized collateral vessels[39]. Microspheres such as DC beads are not visible under fluoroscopy, making it difficult to identify regurgitation and increasing the risk of accidental embolization[39]. Insufficient operator proficiency with new devices (in the early stage of technique implementation) leads to a higher incidence of complications[6]. Excessive balloon dilation during bland TACE (B-TACE) may damage small arteries, resulting in pseudoaneurysm[6].

Clinical manifestations and diagnosis

The clinical manifestations of arterial complications after TACE vary depending on the involved vascular bed and the degree of organ injury: Intra-abdominal hemorrhage, mostly caused by hepatic artery perforation or tumor rupture, presents as sudden severe abdominal pain, abdominal distension, accompanied by signs of hemorrhagic shock (tachycardia, hypotension, pallor). Hepatic infarction manifests as persistent severe right upper abdominal pain after the procedure, along with high fever and a sharp increase in serum transaminases (often reaching several thousand U/L). Cutaneous complications typically present as erythematous papules and purpura, which may be accompanied by pruritus or pain, and in severe cases, progress to skin necrosis, eschar, and deep ulcers[37,38]. Systemic dissemination of chemotherapeutic drugs can cause immediate severe pain in the right trunk after TACE, accompanied by livedo reticularis-like cutaneous reactions from the right flank to the upper abdomen, followed by manifestations of multiple organ involvement such as acute liver injury, respiratory distress, and myelosuppression[40]. Acute pancreatitis presents as sudden persistent severe pain in the middle-upper abdomen, radiating to the back; patients often assume a flexed posture to relieve pain, accompanied by frequent nausea and vomiting, and significantly elevated serum/urinary amylase and serum lipase (exceeding 3 times the upper limit of normal values)[39]. Acute lung injury (ALI) mostly occurs within 24-72 hours after the procedure, presenting with dyspnea, dry cough, decreased blood oxygen saturation, reduced bilateral lung breath sounds, and audible wheezing[41]. Spinal ischemia occurs immediately or within a few hours after the procedure, manifesting as acute paraplegia below the level of injury, sensory loss, and urinary and fecal incontinence[48].

In terms of diagnosis: The typical rash and pain that occur immediately after the procedure are key to diagnosing systemic dissemination of chemotherapeutic drugs[40]. Digital subtraction angiography (DSA) is the “gold standard” for diagnosing vascular injuries and identifying extrahepatic collaterals; intraoperative multi-angle angiography can real-time detect contrast medium extravasation (vascular rupture), intimal tear (dissection), vascular spasm, and abnormal collaterals, guiding intraoperative decision-making[38]. Computed tomography (CT) can assess the extent of injury of systemic chemotherapeutic drug dissemination (e.g., lipiodol deposition in the extrahepatic liver lobes, diaphragm, and lungs, abdominal wall thickening, pleural effusion, etc.)[40], and also diagnose non-target organ injuries such as pancreatic injury[39]. Contrast-enhanced CT is also key to confirming thrombosis, which can accurately evaluate organ injury and the range of infarction[36], and is helpful in differentiating arterial dissection, occlusion, pseudoaneurysm, etc., cone-beam CT (CBCT), a standard configuration of the DSA system, can acquire three-dimensional volumetric images intraoperatively. Its “CT-like” tomographic imaging and three-dimensional reconstruction functions can clearly delineate complex networks of tiny blood vessels and occult extrahepatic collaterals, helping to avoid risks before embolization and prevent non-target embolization[38]. Magnetic resonance imaging (MRI) is an important basis for diagnosing spinal ischemic injury; T2-weighted imaging within 24 hours after the procedure can show hyperintensity in the spinal cord parenchyma at the T1-T12 segments[48]. For subcutaneous erythematous tender nodules of unknown cause, biopsy can confirm the tissue nature[42]. When drug-induced FV inhibitors are suspected, laboratory tests show a significant decrease in FV activity (e.g., 4%, with normal range 70%-135%), while the activities of other coagulation factors remain normal[43].

Management strategies

The management of arterial complications after TACE should be centered on prevention while incorporating effective treatment strategies. In terms of preventive measures, preoperatively, multi-phase contrast-enhanced CT/MRI should be used to evaluate the tumor, while arterial-phase images are reviewed to determine the presence of high-risk EHCs (e.g., perihilar abnormal blood vessels, tumors located near the diaphragm/hepatic ligaments)[40,46]. Preoperative DSA is the gold standard for diagnosing EHCs. Peripheral tumor staining defects and a smaller tumor size on angiography than on imaging indicate the presence of EHCs[46]. For high-risk patients (e.g., tumors in the hepatic bare area, history of previous abdominal surgery), intraoperative routine angiography of the subphrenic artery, intercostal artery, etc., should be performed, and CBCT should be a standard procedure for complex cases[38]. For confirmed high-risk non-target arteries (e.g., poorly positioned gastroduodenal artery, thick hepatic falciform artery), if safe superselective avoidance is not feasible, prophylactic embolization with metal coils can be adopted[38,49]. For hepatic artery-portal vein shunts, small low-flow shunts can first be embolized with gelatin sponge particles to occlude the shunt tract, and tumor embolization is performed only after confirmation of shunt disappearance. For large high-flow shunts that can be avoided, superselective embolization of the tumor-feeding artery is conducted; if avoidance is impossible, large gelatin sponges and coils are used to embolize both the shunt tract and the tumor-feeding artery[50,51]. Preoperatively, technetium-99m macroaggregated albumin can also be injected to calculate the shunt fraction - if it exceeds 20%, chemoembolization should be suspended[41]. Intraoperatively, microcatheters are routinely used, combined with angled catheter and guidewire techniques, to place the catheter tip at the distal end of the tumor-feeding artery, maximizing protection of normal tissues and non-target vessels[6,46]. Embolic agents must be injected slowly, with close fluoroscopic monitoring - if regurgitation is detected, injection should be stopped immediately[46]. For embolization of intercostal/Lumbar arteries in which the spinal artery cannot be spared, forced embolization should be avoided to prevent spinal infarction[46]. Some patients may receive intraoperative heparin (2500 IU) to prevent thrombosis, and nitroglycerin or verapamil after arterial sheath placement to prevent spasm[12]. Postoperatively, an elastic bandage should be used to compress the puncture site for 2-4 hours to prevent bleeding and hematoma[52].

Regarding treatment methods: Minor complications (e.g., post-embolization syndrome, mild liver injury, skin erythema) only require bed rest, fluid replacement, antiemetics, and analgesics; mild cutaneous complications can be treated with topical/oral glucocorticoids and antihistamines[38,53]. In cases of systemic dissemination of the chemotherapeutic drug epirubicin, dexrazoxane (an antidote) should be administered immediately for 3 consecutive days, combined with pain management, infection control, and respiratory support[40]. For intestinal obstruction complicated with thrombosis without intestinal necrosis, intensive combined anticoagulant therapy should be initiated[36]. If drug-induced toxic side effects are suspected, the chemotherapeutic dose should be adjusted, or the drug should be discontinued or replaced based on the adverse reaction[43,54]. Pseudoaneurysms can be treated with detachable coil embolization[6]. Extensive skin necrosis requires debridement to promote healing[37]. If interventional treatment fails to control tumor rupture and bleeding, surgical hemostasis is necessary[55].

BILIARY COMPLICATIONS

Epidemiological characteristics of biliary complications

Similar to arterial complications, the reported overall incidence of biliary complications after TACE varies significantly, generally ranging from 0.26% to 6.5%[6,7,10,12,15,16,55-65]. This variation arises from inconsistencies in study design, definitions of complications, and monitoring standards. In terms of the distribution of complication types, intrahepatic bile duct dilatation accounts for approximately 57.1%, biloma for 25.7%, and hilar bile duct stenosis for 17.1%[62]; bilomas are further divided into round cystic (55%), branching (30%), and mixed types (15%)[64]. Specific patient populations and treatment modalities significantly influence the incidence of complications - for instance, the incidence of postoperative biliary injury in patients with a history of hepatobiliary surgery can reach 8%, which is significantly higher than that in patients without a surgical history[62].

Compared with arterial complications, biliary complications have a later onset, with an average of 3.9 ± 2.7 months after the procedure, and most occur within 3 weeks to 1 year[62,66]. However, the time to onset differs remarkably among various types of complications: Acute cholecystitis can occur within 24 hours after the procedure, the average diagnosis time of liver abscess is 13 days (10-19 days) postoperatively[56], while some cases of biliary stenosis may not be detected until 1 year or even later after the procedure due to inconspicuous clinical manifestations. Additionally, the type of embolic agent also affects the onset time: For patients embolized with polyvinyl alcohol particles or gelatin sponges, the average onset time of biliary injury is 1.67 ± 1.65 months; for those embolized with lipiodol alone, the interval to injury is 4 ± 3.34 months[62].

Biliary complications after TACE represent different stages of pathological evolution following ischemic injury to the biliary system. Intrahepatic bile duct dilatation manifests as abnormal tubular or cystic dilatation of intrahepatic bile ducts on imaging (CT/MRI), which is caused by ischemic injury to the peribiliary vascular plexus (PVP)[10]. Biliary duct necrosis (BDN) is the core pathological change of biliary ischemic injury and the basis for subsequent complications; it mostly occurs when the hepatic arterial blood supply is suddenly and completely interrupted (such as hepatic artery thrombosis after liver transplantation), this results in biliary epithelial necrosis and bile leakage[63]. Biloma is formed when the integrity of the necrotic bile duct wall is damaged and bile extravasates into the hepatic parenchyma, forming a well-defined cystic or branching fluid-filled space-occupying lesion; the average onset interval of intrahepatic biloma is 69.1 days (19-155 days)[10,64]. Bile duct necrosis should be contrasted with biliary stenosis caused by gradual hepatic arterial injury[63]. Biliary stenosis is a chronic manifestation of biliary ischemic injury; ischemia leads to fibrotic hyperplasia and scar contraction of the bile duct wall, resulting in luminal narrowing, which further causes distal bile duct dilatation and obstructive jaundice[10,62]. Bronchobiliary fistula (BBF) is a rare but severe complication; after multiple TACE procedures, necrosis and infection of the hepatic tissue at the top of the diaphragm erode the diaphragm and lung tissue, forming an abnormal fistula between the biliary tract and bronchial tree[67]. Cholecystitis is caused by the accidental entry of chemotherapeutic drugs or embolic agents into the cystic artery supplying the gallbladder, leading to chemical or ischemic injury of the gallbladder, which can result in infarction in severe cases[46,61]. Liver abscess is formed on the basis of cholestasis and necrotic tissue, caused by retrograde infection of intestinal bacteria through the portal vein or biliary tract[67].

Pathogenesis

In the normal liver, the blood supply to the biliary system has unique characteristics: The nutrient vessels of larger intrahepatic bile ducts (segmental and lobar bile ducts) are entirely derived from tiny branches of the hepatic artery, which form an elaborate PVP outside the bile duct wall; the tiny terminal bile ducts are partially supplied by portal venous sinusoids. Notably, the PVP is crucial for maintaining the structure, function, and integrity of biliary epithelial cells[63]. TACE exerts its therapeutic effect by embolizing hepatic arterial branches, which inevitably affects the blood supply to the PVP. When PVP perfusion is interrupted or reduced beyond the minimal levels required for basic cellular metabolism, a series of pathophysiological responses are triggered.

Ischemic injury is the core mechanism of biliary complications. Most studies have confirmed that the biliary system relies almost entirely on branches of the hepatic artery for blood supply (which forms the PVP). Ischemia of the PVP impairs the protective mechanism of biliary epithelium, leading to coagulation in surrounding tissues and fibrinolytic necrosis. Combined with the detergent effect of bile acids, this ultimately results in bile duct necrosis and biloma formation[10,58,63,64]. Chemotherapeutic drugs can directly cause necrosis of biliary epithelial cells, exacerbating biliary injury[59]. During the pathological process of biliary ischemic injury after TACE, the ischemic and hypoxic state also activates the liver’s endogenous repair mechanism, in which the regulatory role of angiogenesis-related factors is particularly critical. Following TACE, ischemia and hypoxia induce the liver to produce VEGF, which promotes new vessel formation, while angiopoietin-2 acts as a key regulator that, in the presence of VEGF, facilitates vascular remodeling and maturation. Their synergistic action helps to restore PVP, thereby alleviating ischemic injury. Thus, the levels of VEGF and angiopoietin-2 are considered key biomarkers for evaluating the liver’s capacity for vascular repair after ischemia. One study showed that hepatic artery ischemia-reperfusion induced biliary damage and was associated with increased expression of angiogenic factors, including VEGF-A/C and angiopoietin-1/2, possibly as a compensatory mechanism in response to the biliary injury[68]. Additionally, the systemic inflammatory response triggered by TACE-induced ischemia may further mediate distant organ injury, as sustained inflammatory activation can disrupt vascular barrier function and promote the release of pro-inflammatory cytokines, leading to multi-organ involvement beyond the liver. The ischemia induced by embolization and the toxicity of chemotherapeutic drugs produce a “two-hit” effect: First, the protective barrier of the biliary epithelium is damaged, allowing cytotoxic bile acids to further injure the biliary epithelium and aggravate pathological changes[59]. After biliary injury, secondary chronic biliary infection is likely to occur; repeated cholangitis stimulates the proliferation of fibrous tissue, which worsens biliary stenosis and forms a vicious cycle of “injury-infection-stenosis”[62]. As the main organic solute in bile, bile acids can disrupt cell membranes through their detergent effect, promote the production of reactive oxygen species, and cause cell necrosis and apoptosis. After bile duct necrosis, the absorbed bile acids can continuously damage the surrounding bile ducts and may also induce portal vein thrombosis[63]. Taking BBF as an example, its progression reflects the continuous development of complications: After TACE, hilar bile duct stenosis and biloma formation lead to increased biliary pressure, inducing subphrenic inflammation and liver abscess; the abscess further erodes the diaphragm, enters the thoracic cavity, and communicates with the bronchial tree to form a fistula, allowing bile and pus to flow into the lungs[67]; alternatively, increased pressure in the biloma cavity combined with infection exacerbates the inflammatory response, damages the diaphragm, and pushes bile into the thoracic cavity[69].

Risk factors

The risk factors for biliary complications after TACE can be divided into anatomical and tumor-related factors and treatment-related factors. Among anatomical and tumor-related factors, tumor location is a key influencing factor: Tumors near the diaphragmatic dome complicated with liver abscess or biloma may further progress to BBF[67,69]. Tumors adjacent to the gallbladder fossa (e.g., liver segments S4 and S5) are prone to recruiting blood supply from the cystic artery, increasing the risk of gallbladder-related complications[46]. Lesions near the hepatic hilum, large blood vessels, and bile ducts are susceptible to biliary bleeding or bile leakage due to thermal injury when TACE is combined with microwave coagulation therapy[50]. Hypovascular tumors are a high-risk factor for biliary injury, with a significantly higher proportion of biliary injury in such patients[59]. Regarding the impact of tumor diameter, current evidence is inconclusive, but some studies suggest that large tumors may protect normal bile ducts by concentrating chemotherapeutic drugs within the tumor via a “siphon effect”, while small tumors may increase the risk - this theory requires further research verification[10,62]. TACE for liver metastases is more likely to induce BDN than for HCC. The reasons include: Liver metastases are mostly hypovascular, leading to more accumulation of chemotherapeutic drugs/embolic agents in normal liver tissue and subsequent injury to the PVP; additionally, the background liver of patients with liver metastases is mostly normal (non-cirrhotic), and the PVP has poorer tolerance to ischemia[63]. In patients with liver cirrhosis, the PVP undergoes dilatation and hyperplasia (collateral circulation) due to portal hypertension, whereas the PVP network in normal livers is underdeveloped and more vulnerable to arterial therapeutic insults, making PVP injury more likely[63]. Distal bile duct stenosis causes cholestasis, and increased pressure in the bile duct at the necrotic site exacerbates the leakage of toxic bile acids, expanding the necrotic range and forming bilomas[63]. Patients with preexisting bile duct dilatation have a significantly higher risk of liver abscess after bland TACE (B-TACE)[7].

Several treatment related factors have also been established as risk factors for biliary complications. Repeated TACE or hepatic arterial infusion chemotherapy leads to cumulative biliary injury, as each treatment may exacerbate the damage[47,63]. In early studies, biliary injuries all occurred during procedures using only 4F/5F large-caliber catheters without microcatheters. With the popularization of microcatheter technology and improved operational experience, such complications have decreased significantly[10]. Patients post-hepatectomy, have impaired blood supply to intrahepatic bile ducts, and chemotherapeutic drugs are more likely to enter normal liver parenchyma, increasing the probability of biliary injury[59,62]. Additionally, some studies have shown that the incidence of biliary injury in the DEB-TACE group is significantly higher than that in the c-TACE group, and small-sized microspheres may be more likely to damage bile duct-feeding vessels due to deeper penetration into normal liver parenchyma. However, other studies suggest that microsphere size does not affect the occurrence of complications, and this remains controversial[6,59,70-72]. Lipiodol dosage is a risk factor for biliary injury - it is hypothesized that when the dosage is 5-10 mL, the “siphon effect” of the tumor is weak, making lipiodol prone to regurgitation into bile duct-feeding arteries[59]. The proportion of patients using gelatin sponges in the biliary injury group is higher, as gelatin sponges can block blood flow more completely, reduce lipiodol clearance, and increase the risk of injury[59]. Patients undergoing lobar-level embolization have a significantly higher risk of biliary injury than those undergoing superselective segmental/subsegmental embolization. Embolization at proximal sites such as the proper hepatic artery or left/right hepatic artery leads to excessive perfusion of chemoembolic agents into normal liver parenchyma and can cause ischemic injury to bile ducts[10,59,62].

Clinical manifestations and diagnosis

In the early stage of biliary complications after TACE, clinical manifestations are mostly non-specific and often overlap with those of “post-embolization syndrome”, such as fever, abdominal pain, nausea, jaundice, and transient elevation of liver function indicators, which are easily overlooked[59,64]. Typical specific manifestations are only seen in some complications - for example, patients with BBF may cough up bitter bile-like sputum, accompanied by intermittent cough and yellow purulent secretions[67,69,73]. Long-term complications include recurrent biliary infection, gallbladder stones, intrahepatic bile duct stones, and liver atrophy with portal vein stenosis[62].

The diagnosis of biliary complications after TACE mainly relies on imaging examinations during postoperative and long-term follow-up, and a multimodal imaging strategy is required for comprehensive judgment: CT is a commonly used initial screening tool, but it is prone to confusing BDN with intrahepatic bile duct dilatation. On CT, BDN presents as linear/tubular hypodense lesions along the course of the portal vein, with irregular diameters and a “beaded appearance” (similar to primary sclerosing cholangitis), while bile duct dilatation is mostly regular and tubular[63]. For bilomas, CT shows well-defined hypodense lesions (CT value < 20 HU) with no enhancement on both plain and contrast-enhanced scans; these lesions can be round, multiple, or branching along the Glisson’s capsule, and some communicate with intrahepatic bile ducts[10,64]. CT also has extremely high diagnostic value for BBF[69].

Ultrasound can make up for the misdiagnosis of BDN by CT: Bile duct dilatation appears as a typical anechoic tubular structure on ultrasound, while the portal area in BDN regions shows isoechoic or slightly hyperechoic signals without internal dilated bile ducts. This “CT hypodensity-ultrasound non-liquid” mismatch is an important clue for diagnosing BDN[63]. Ultrasound can also identify bilomas: Sterile bilomas present as anechoic cystic masses, while those with infection/hemorrhage show internal echoes[10].

MRI: BDN shows mild hyperintensity on T2-weighted imaging (reflecting necrotic tissue infiltrated by bile), which contrasts with the marked hyperintensity (filled with fluid) of bile duct dilatation/bilomas[63]. Bilomas present as hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, with no enhancement[64]. In magnetic resonance cholangiopancreatography (MRCP), the BDN region has variable and blurred signal intensity on T2-weighted MRCP due to the absence of flowing bile, which contrasts with the clear surrounding dilated bile ducts[63]. Hepatocyte-specific contrast-enhanced MRI with gadoxetate disodium has unique diagnostic value: In the hepatobiliary phase 20 minutes after injection, the BDN region shows hypointensity because necrotic hepatocytes cannot take up the contrast agent; in the ultra-delayed phase 70 minutes later, the contrast agent excreted from normal liver into the biliary tract leaks from the necrotic bile duct wall into the surrounding necrotic tissue, making the BDN region “turn from dark to bright” and show marked hyperintensity[63].

Percutaneous transhepatic cholangiography can show rough bile duct walls and filling defects when diagnosing BDN[62]. If the aspirated yellow bile-like fluid has the same characteristics as bronchial secretions, or if the contrast agent enters the lungs, BBF can be confirmed[69,73]. Hepatobiliary iminodiacetic acid scan is a functional nuclear medicine imaging technique. After intravenous injection of 99mTc-hepatobiliary iminodiacetic acid (which is taken up by hepatocytes and excreted through the biliary tract), BBF can be confirmed if abnormal entry of radionuclides from the biliary tract into the thoracic cavity, bronchi, or lung parenchyma is observed[74].

In summary, a single CT examination is prone to missed diagnosis or misdiagnosis of biliary complications. Accurate diagnosis requires combining multiple imaging modalities such as ultrasound, MRI (including hepatocyte-specific contrast agents), and MRCP, and identifying the “inconsistency” and “specificity” of imaging features[63].

Management strategies

Prevention is the key for managing biliary complications. Preoperatively, techniques such as MRCP should be used to clarify the anatomy of the biliary system and identify vascular and biliary variation. Before embolization, the microcatheter should be advanced deep into the terminal branches of the tumor-feeding artery to avoid the gallbladder-feeding vessels[46]. During the operation, vascular angiography should be used to carefully identify anatomical structures and prevent embolic agents from accidentally entering the biliary-feeding arteries[46]. A ≥ 2-fold increase in serum γ-glutamyl transferase and alkaline phosphatase (ALP) is a predictive indicator of biliary injury[59]; if plain CT scan 1 week after TACE shows lipiodol deposition along the bile duct wall, or serum ALP rises sharply to > 200 U/L, it also indicates a risk of biliary injury[62]. Postoperatively, choleretic drugs such as ursodeoxycholic acid and liver-protective drugs should be routinely used to promote bile excretion, reduce cholestasis, and lower the risk of cholangitis and liver function damage. For delayed complications (e.g., bile leakage, biliary stenosis), serum biochemical indicators should be rechecked weekly, and CT or MRI should be rechecked every 4-6 weeks[59].

Once biliary complications are suspected or confirmed, patients should be regarded as ‘high risk’ regardless of whether they have symptoms. Multimodal imaging should be used for confirmation, and a tiered treatment approach under multidisciplinary team collaboration should be initiated[62,63]. The core principle is to discontinue any additional intra-arterial treatment (e.g., TACE, hepatic arterial infusion chemotherapy) on the affected liver area to avoid aggravated ischemia leading to biloma or liver abscess[10,63]. For asymptomatic BDN or localized biloma with only mild liver function abnormalities, conservative observation can be adopted first; antibiotics may be used to prevent infection if necessary, and imaging changes should be closely followed up[53,63,64]. When obvious symptoms (e.g., abdominal pain, jaundice), moderate to severe infection, or an increase in biloma size occur, percutaneous puncture and drainage of biloma or liver abscess are required; for obstructive jaundice caused by biliary stenosis, biliary stent placement should be performed[62,63]. For BBF, endoscopic retrograde cholangiopancreatography can be attempted to reduce common bile duct pressure, or a covered stent can be placed to close the fistula[67,74]. If a large amount of bile is still drained after biloma drainage and angiography confirms no communication with the biliary system, absolute ethanol can be injected into the cyst cavity for sclerotherapy to promote biloma shrinkage[59]. For huge bilomas unresponsive to percutaneous transhepatic biliary drainage, partial hepatectomy is required[64]; for BBF unresponsive to interventional treatment, surgical ligation of the fistula can be performed[69].

SPECIAL POPULATIONS AND COMPLEX SCENARIOS

Patients with hepatic arteriovenous fistula

Hepatic arteriovenous fistula is a critical risk factor for secondary ALI and acute respiratory distress syndrome after TACE. Its pathophysiological mechanism lies in that hepatic arteriovenous fistula acts as an “abnormal pathway”: A portion of lipiodol, which should have been retained in liver tumors, directly enters the venous system through the fistula. This lipiodol then travels with the bloodstream and deposits in the lungs, causing lipiodol pulmonary embolism[41]. The lipiodol particles entering the lungs are decomposed into toxic free fatty acids, which induce severe chemical injury and inflammatory responses, damage the alveolar-capillary membrane, and ultimately lead to ALI or acute respiratory distress syndrome[2,75].

Additional risk factors for this population include: Comorbid chronic respiratory diseases, large hypervascular HCC with a diameter > 10 cm complicated by arteriovenous shunts, lipiodol infusion dose > 14.5 mL, and embolization via the subphrenic artery. The most common clinical symptom is dyspnea, followed by cough and fever; symptoms typically occur at an average of 2.4 ± 1.6 days after TACE. In imaging examinations, pleural effusion is the most common abnormal finding, while diffuse pulmonary infiltration and lipiodol accumulation in the lung fields are relatively specific. Laboratory tests often show elevated D-dimer[2,75].

In terms of treatment: Routine oxygen therapy and empirical antibiotic treatment should be administered; systemic glucocorticoid intervention may be considered when obvious symptoms appear; mechanical ventilation support is required for critically ill patients. Regarding prognosis, once these patients develop secondary ALI, their short-term mortality rate increases significantly, long-term quality of life decreases, and only a small number of patients can tolerate subsequent anti-tumor treatment[75-77].

Patients with preoperative leukopenia or thrombocytopenia

Preoperative leukopenia or thrombocytopenia was once classified as a relative or absolute contraindication for TACE in some guidelines[78]. However, recent studies have shown that the incidence of biliary complications after TACE in this patient population is extremely low; the main arterial complication is puncture site bleeding, with an incidence of only 2.22%[78]. Further subgroup studies revealed that there is no statistical correlation between preoperative platelet count and the incidence of postoperative puncture site bleeding. The bleeding is mainly associated with improper local compression rather than directly caused by low platelet count - after adjusting the pressure and position of the arterial compressor, the bleeding gradually stops. The use of radial artery access and modified vascular closure devices may further reduce the risk of bleeding. Meanwhile, the study found no association between preoperative low white blood cell count and infection risk, suggesting that the strict restrictions on performing TACE in this patient group may be appropriately relaxed[78].

HCC patients undergoing TACE after external radiotherapy

For HCC patients who have received external radiotherapy and subsequently require TACE for tumor recurrence or progression, clinical practice should focus on the additive liver injury effect of radiotherapy and TACE. A study by Hamada et al[79] has demonstrated that TACE performed after radiotherapy does not increase the risk of biliary complications, and no obvious arterial complications have been observed. This study suggests that subsequent TACE is technically feasible for such patients, and the incidence of liver function injury and severe complications is comparable to that of patients who have not received radiotherapy. However, potential risks should be vigilantly monitored - especially for patients with poor preoperative liver function reserve, high previous liver radiotherapy doses, or those who need TACE within a short period (< 3 months) after radiotherapy - in these groups, strengthened preoperative evaluation and postoperative monitoring are required[79].

HCC patients with celiac axis occlusion

HCC patients with celiac axis occlusion cannot undergo hepatic artery cannulation via conventional approaches, and special techniques are required to reduce the risk of arterial complications. In clinical practice, the following techniques can effectively minimize catheter manipulation-related injuries: (1) Guidewire preshaping: The tip of the microguidewire is shaped into a smooth, wide curve to facilitate passage through narrow and tortuous vascular segments, avoiding damage to the vascular wall; (2) Guidewire reshaping: When encountering acute-angle branches, the guidewire is retracted and reshaped according to the vascular angle to adapt to the vascular course; and (3) Microcatheter loop technique: When direct access from the gastroduodenal artery to the proper hepatic artery (which forms an acute angle) is difficult, the microcatheter can be formed into a “loop” in the common hepatic artery; the loop shape allows the tip to enter the proper hepatic artery in the reverse direction[80].

The main risk factors for arterial complications in this patient group stem from the anatomical characteristics of alternative pathways (e.g., pancreaticoduodenal arterial arcade) - extremely tortuous course, acute-angle branches, and small caliber. Excessive catheter/guidewire manipulation can directly cause vascular injury. The aforementioned techniques reduce complication risks by lowering manipulation difficulty and vascular irritation, thus playing a key role[80].

HCC patients with portal vein tumor thrombus

Advanced HCC patients with portal vein tumor thrombus (PVTT) have an extremely poor prognosis and are regarded as a population with relative contraindications to TACE in multiple guidelines, posing great challenges for treatment[81,82]. Research data show that the incidence of liver function-related biochemical toxicity after TACE is relatively high in this population: Hyperbilirubinemia occurs in 20.6% of patients in the cTACE group and 10.6% in the DEB-TACE group; ALP elevation is observed in 6.5% of the cTACE group and 10.6% of the DEB-TACE group. This indicates that PVTT is a critical risk factor for severe liver function biochemical toxicity after TACE[82].

Further studies have shown that the difference in surgical approaches between cTACE and DEB-TACE is not a key factor affecting the survival of this population; the independent prognostic factors are Child-Pugh class C liver function and tumor burden > 50%[82]. Some studies on TACE combined with portal vein stenting + I-125 seed brachytherapy have demonstrated that this combined regimen does not increase the incidence of arterial or biliary complications, nor does it significantly alter the incidence of post-embolization syndrome[81,83].

However, attention should be paid to the association between PVTT classification and complication risk: Patients with type III PVTT have a significantly higher incidence of adverse events after TACE (e.g., liver function injury, upper gastrointestinal bleeding related to elevated D-dimer, thrombotic events) than those with type I or II PVTT, indicating that type III PVTT is a significant risk factor for severe postoperative complications[14]. In addition, the use of small-caliber microspheres (< 100 μm) in this population requires caution - although they have a strong embolization effect, they block both the portal vein (already occluded by tumor thrombus) and the hepatic artery, leading to severe ischemic necrosis of large areas of liver tissue (including tumor and non-tumor regions) and easily inducing fatal acute liver failure[70]. Meanwhile, patients with portal vein invasion are more prone to biloma formation[64]. In general, with the development of interventional technology, radiotherapy technology, and advances in combined treatment methods, TACE can be performed relatively safely in PVTT patients after strictly controlling indications and avoiding high-risk factors[81,83].

Patients with ruptured HCC

Spontaneous rupture and bleeding of HCC is one of the most critical complications of HCC. It is a life-threatening condition with high in-hospital mortality. Patients usually present to the hospital with sudden acute abdominal pain or hepatic region pain, and most are accompanied by signs of peritoneal irritation. A definite diagnosis can be made based on clinical manifestations, diagnostic abdominal paracentesis, and imaging examinations. The treatment principle is to first stabilize vital signs, followed by emergency hemostasis. Transarterial embolization or gelatin sponge microsphere TACE are the core hemostatic methods - by accurately injecting gelatin sponge microspheres into the bleeding tumor artery, the blood vessel is mechanically occluded to quickly terminate active bleeding[84]. Recent studies have shown that the success rate of transarterial/TACE as an emergency hemostatic measure exceeds 90%; if bleeding cannot be effectively controlled, emergency open surgery is required for hemostasis[84]. This group of patients has a relatively high risk of postoperative complications and is prone to severe artery-related complications such as shock, pulmonary embolism, and heart failure[55]. Recurrent tumor rupture and bleeding is a unique postoperative complication, with an incidence of 5.1%-7.6%, mostly occurring within 3 months after the initial treatment. It is associated with incomplete initial embolization or changes in internal tumor pressure after embolization, and re-performing gelatin sponge microsphere-TACE can still achieve successful hemostasis[55,85].

CONTROVERSIES AND CUTTING-EDGE ISSUES

Standardization of incidence statistics

A core challenge in the current field of TACE complication research is the significant heterogeneity in reported incidence rates. This heterogeneity is not coincidental; it stems from a lack of unified reporting standards. Specifically, significant differences exist among studies regarding complication definitions, severity grading (e.g., the adoption of the internationally accepted CTCAE v5.0 standard), diagnostic confirmation methods, and follow-up time points. These inconsistencies make direct inter-study comparisons difficult and critically impair the accuracy and reliability of meta-analyses. For instance, a meta-analysis comparing c-TACE and DEB-TACE explicitly identified the high heterogeneity of included studies as its main limitation[8]. Therefore, establishing an internationally recognized standardized reporting guideline is of paramount importance for accurately evaluating TACE safety, comparing the advantages and disadvantages of different techniques, and more effectively guiding clinical practice.

Complementary profiles of emerging technologies

CBCT represents a pivotal technological innovation in TACE procedures, enhancing treatment precision and safety through multiple dimensions: CBCT can instantly generate CT-like three-dimensional images in the interventional operating room, clearly presenting a “three-dimensional roadmap” of hepatic blood vessels. This overcomes the anatomical identification difficulties of traditional two-dimensional DSA caused by vascular overlap and poor imaging angles - studies have confirmed that the sensitivity of CBCT in identifying tumor-feeding arteries (81%) is significantly higher than that of non-selective DSA (38%). When combined with automated navigation software such as Flight Plan for Liver and EmboGuide, CBCT data can be further analyzed to highlight tumor-feeding vessels with color-coded pathways, achieving an identification sensitivity of over 90% and reducing the difficulty of identifying target arteries in complex vascular networks. Furthermore, by clearly distinguishing target vessels from non-target vessels requiring protection (e.g., arteries supplying the gastrointestinal tract or normal tissues), CBCT facilitates the precise placement of microcatheters, significantly lowering the risk of complications related to accidental embolization of embolic agents. Secondly, immediate contrast-free CBCT scanning after cTACE can clearly display the distribution of lipiodol deposition within the tumor, equivalent to intraoperative plain CT scanning. This allows real-time assessment of embolization completeness and detection of omissions, thereby optimizing the embolization endpoint[9].

The development of visible microspheres (e.g., LC Bead LUMI™) marks a significant advancement in TACE technology. These microspheres enable operators to directly observe microsphere distribution in real time under fluoroscopy, facilitating the determination of the embolization endpoint. Additionally, they allow proactive detection of microspheres that may flow into non-target areas, prompting timely cessation of injection. This significantly improves treatment safety and reduces the incidence of arterial complications[6].

DEB-TACE using small-caliber microspheres (< 100 μm) was originally designed to reduce systemic chemotherapy toxicity, but its complication spectrum has gradually attracted attention. Although small-diameter microspheres may enhance tumor-killing efficacy, there remains considerable controversy regarding whether they significantly increase the risk of biliary injury. Some studies suggest that small-diameter microspheres tend to penetrate deeper into normal liver parenchyma, making them more likely to damage bile duct-feeding vessels[70]. However, other studies have shown no association between microsphere size and the incidence of biliary complications[71,72]. More high-quality studies are needed to clarify their safety profile.

Application of artificial intelligence in risk prediction

Artificial intelligence (AI) technology has demonstrated tremendous application potential in the field of TACE, particularly models based on radiomics and deep learning. By integrating pre-operative CT radiomic features and patients’ clinical risk factors through machine learning algorithms, these models can be developed into tools for accurately predicting the survival prognosis of HCC patients after TACE, thereby providing support for individualized treatment decision-making[86,87]. Notably, some AI models not only focus on the tumor itself but also target the peritumoral liver parenchyma. This indicates that the changes in the “microenvironment” or “systemic environment” induced by tumors contain key prognostic information. Such information is difficult to identify with the naked eye but can be effectively captured by deep learning models[88]. Currently, the application of AI in the TACE field mainly concentrates on efficacy and survival prediction. The focus of future research will shift toward the development of risk prediction models for specific severe complications (e.g., biliary tract injury, post-embolization liver failure, non-target embolization). By inputting patients’ pre-operative imaging and clinical data, the model can output the probability of complication occurrence. This provides support for clinicians to formulate individualized risk mitigation strategies (such as selecting safer embolic agents and performing prophylactic embolization of high-risk blood vessels), and promotes the transformation of TACE from “passive management of complications” to “active prevention of complications”[89].

Imbalance of regional representation in TACE complication research

HCC exhibits a pronounced geographical heterogeneity, with the majority of cases concentrated in Asia and Africa[33]. However, a key finding of this review is that the literature we cited is predominantly from Asia (particularly China, Japan, and Korea) and parts of Europe and the United States. While these studies provide robust evidence for understanding TACE application and its associated complications in these high-incidence populations, a significant publication gap exists for comparable high-quality research from regions such as South America and Africa, as revealed by our bibliometric and systematic review analyses.

This geographic disparity in the research landscape is not incidental; it reflects an imbalance in the global allocation of resources for liver cancer research. It is also intrinsically linked to regional differences in HCC etiology, patient characteristics, and TACE procedural practices, which may fundamentally alter the complication risk profiles across different populations. Consequently, while the findings of this review offer valuable insights for clinical practice in the aforementioned regions, their generalizability awaits confirmation from future global studies. We hope that forthcoming research will prioritize multinational collaborations to bridge this literature gap, thereby providing more universally applicable risk assessment and management strategies for HCC patients worldwide (Table 1).

Table 1 Literature review on arterial and biliary complications following transarterial chemoembolization for hepatocellular carcinoma.

Ref.	Research type	Results	Conclusion
Arterial complications
Borrego Rivas et al[37], 2024	Case reports	A 73-year-old male patient presented with right hypochondriac pain and reticular erythematous lesions following the second TACE. Abdominal CT revealed changes caused by embolization and subcutaneous tissue swelling, without other relevant complications. The final diagnosis was livedo purpura, which resulted from microsphere migration of doxorubicin or unrecognized collateral vessels leading to microcirculatory occlusion and necrosis of the skin and subcutaneous tissue	This study reports in detail a case of livedo purpura, a significant arterial complication. It proposes that to reduce the incidence of such complications, the optimal strategy is to ensure the tip of the embolization catheter is positioned as close as possible to the tumor-feeding vessels. Additionally, preventive and therapeutic measures are discussed, such as local ice application prior to TACE to induce vasoconstriction, or local steroid injection after the appearance of skin rashes. However, it is also noted that local use of corticosteroids may lead to the exacerbation of lesions
Hieu et al[48], 2023	Case reports	A 76-year-old male patient with hepatocellular carcinoma developed sudden onset of motor weakness in both lower limbs and sensory impairment below the T10 dermatome following the second TACE. Spinal magnetic resonance imaging revealed intramedullary signal enhancement in the T1-T12 segments. The patient received supportive care, continuous rehabilitation, and high-dose steroid pulse therapy. Nearly complete recovery of sensory function was achieved, while motor function remained unchanged	This study reports in detail a case of spinal cord ischemia, a critical arterial complication. The proposed pathogenesis is that the embolic agent accidentally entered the spinal artery through the connection between the right inferior phrenic artery collaterals and the intercostal arteries, leading to spinal cord infarction. It is emphasized that to prevent these severe consequences, formulating individualized treatment strategies is crucial, including careful consideration of shunts and selection of vessels for lipiodol injection prior to TACE
Giampreti et al[40], 2022	Case reports	A 56-year-old male patient developed right-sided pain and a rapidly progressive livedo reticularis-like cutaneous reaction following epirubicin chemoembolization. CT imaging showed significant extrahepatic dissemination of epirubicin, which led to signs of systemic organ involvement in the patient. After receiving dexrazoxane therapy, both the cutaneous lesions and organ involvement in this critically ill patient were significantly improved, and laboratory parameters returned to normal	This study reports in detail a case of systemic dissemination of chemotherapeutic agents, a critical arterial complication. Systemic dissemination of chemotherapeutic agents during TACE may lead to severe consequences. For extensive cutaneous toxic reactions and severe systemic effects caused by the dissemination of anthracyclines during TACE, dexrazoxane infusion may serve as an effective therapeutic approach
Golfieri et al[15], 2021	Retrospective study	Propensity score matching was used to analyze 182 patients, aiming to compare the tumor response rates between B-TACE and TACE in patients with HCC	The study reported that the incidence of hepatic abscess in the B-TACE group was 2.2% (2/91), while the incidence of hepatic arterial pseudoaneurysm was 1.1% (1/91) in both the B-TACE group and the non-B-TACE group
Ruan et al[2], 2020	Retrospective study	A total of 2200 TACE procedures were performed in 816 patients with HCC, among whom 6 patients developed ARDS after TACE. The diameter of the lesions in these patients ranged from 5.0 cm to 10.2 cm, and 4 of them had lesions predominantly located in the left lateral segment of the liver. All patients underwent chemoembolization with a suspension of nedaplatin, epirubicin, and lipiodol. Symptoms of ARDS occurred in all patients within 24-48 hours postoperatively. Chest radiographs showed diffuse exudative changes in both lungs	The incidence of ARDS was provided in this study. It is proposed that the development of ARDS may be associated with the decomposition of lipiodol particles into toxic free fatty acids after their entry into lung tissue. Early administration of corticosteroids may be beneficial for improving prognosis and reducing mortality
Kim et al[41], 2020	Case reports	A 42-year-old male patient with HCC developed iohexol-induced pneumonia following TACE treatment. On the second post-TACE day, the patient presented with acute respiratory symptoms, including dyspnea and cough, accompanied by decreased oxygen saturation. Chest radiography and CT scans revealed multiple patchy infiltrates. The patient showed gradual improvement with supportive care and oxygen therapy, but failed to achieve complete recovery	This study reports in detail a case of iohexol-induced pneumonia, a critical arterial complication. It provides the imaging features, therapeutic approaches, and treatment efficacy of this complication. It is proposed that the presence of arteriovenous shunts within HCC may lead to the accidental entry of iohexol into the pulmonary vasculature
Fang et al[75], 2019	Retrospective study	Fourteen cases of TACE-related ALI were included. The patients had a mean age of 60.9 years, with a mean onset time of 2.4 days after TACE. Among them, 8 patients (57.1%) progressed to ARDS. Seven patients (50%) had underlying chronic respiratory diseases, and 6 patients (42.6%) were detected with hepatic arteriovenous fistulas; both indicators were significantly higher than those in the control group (P < 0.05). The most common symptom was dyspnea (92.9%). Common imaging abnormalities included pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and lipiodol deposition in the lungs (42.9%). Eleven patients (78.6%) achieved remission after treatment, with a 30-day mortality rate of 21.4%	This study provides important information regarding patients with ALI, including clinical manifestations and their frequencies, imaging findings and their frequencies, as well as mortality rate. It is proposed that chronic respiratory diseases and hepatic arteriovenous fistulas may be important risk factors, and pulmonary lipiodol embolism may be the main cause of TACE-related ALI. For high-risk patients with HCC, close evaluation and monitoring should be performed during TACE to avoid this potentially fatal complication
Yamaguchi et al[39], 2018	Case reports	A patient with HCC developed fatal acute necrotizing pancreatitis and upper gastrointestinal ulcer as complications following TACE	This study reports in detail a case of acute necrotizing pancreatitis, a critical arterial complication. It is proposed that this complication is directly associated with embolic agent reflux and non-targeted embolization
Elsayed et al[42], 2018	Case reports	A 73-year-old patient with HCC underwent DEB-TACE using doxorubicin-loaded microspheres. Three days after the procedure, subcutaneous, erythematous, and tender nodules appeared in the abdomen. Positron emission tomography/CT scans showed mild avidity of these nodules, and biopsy confirmed fat necrosis. The nodules began to improve spontaneously two weeks after onset and stabilized at eight weeks	This study reports in detail a case of subcutaneous fat necrosis, a critical arterial complication. DEB-TACE may lead to the development of subcutaneous erythematous and tender nodules, which are manifestations of subcutaneous fat necrosis
Zhou et al[78], 2017	Retrospective study	Medical records of 1461 patients with HCC were reviewed. The main perioperative complications included hepatic decompensation (n = 66), puncture site bleeding (n = 45), infection (n = 33), severe thrombocytopenia (n = 8), upper gastrointestinal bleeding (n = 6), tumor bleeding (n = 4), and agranulocytosis (n = 3). A χ2 test showed that postoperative infection was not associated with preoperative white blood cell count, and puncture site bleeding was also not associated with thrombocytopenia caused by hypersplenism	It details the incidence rates of artery-related complications, such as puncture site bleeding (2.22%) and upper gastrointestinal bleeding (0.3%). The article indicates that puncture site bleeding is not associated with preoperative platelet count, but is mainly related to improper local compression
Nagpal et al[38], 2016	Case reports	A 54-year-old male patient developed periumbilical maculopapules after an uneventful TACE procedure. Retrospective imaging review revealed that this condition was consistent with non-targeted embolization of the hepatic falciform artery. The patient showed improvement after 3 weeks of treatment with oral nonsteroidal anti-inflammatory drugs	This study reports in detail a case of non-targeted embolization of the hepatic falciform artery, a critical arterial complication
Nakajima et al[36], 2016	Case reports	A 69-year-old male was admitted to the hospital due to abdominal pain. One month prior to admission, he had undergone the 8th transcatheter arterial intervention. Abdominal radiography and contrast-enhanced CT revealed a large amount of pneumatosis intestinalis in the small intestine, as well as venous thrombosis extending from the portal vein to the superior mesenteric vein. The thrombosis was reduced after anticoagulant therapy	This study reports in detail a case of paralytic ileus, a critical arterial complication. Abdominal imaging examinations confirmed that this complication was caused by thrombosis of the portal vein and superior mesenteric vein. For patients with HCC complicated with arteriovenous shunts, repeated transarterial injection therapy may be a risk factor for ileus. During transarterial injection, the accidental flow of lipiodol into the portal vein may induce thrombosis. Anticoagulant therapy administered to this patient achieved a favorable outcome
Biliary complications
Lu et al[59], 2024	Retrospective study	The incidence of biliary tract injury after TACE was 6.5% (55/847). Compared with patients without biliary tract injury, those in the biliary tract injury group showed statistically significant differences in preoperative ALP levels, history of hepatobiliary surgery, intraoperative lipiodol dosage, use of gelatin sponge particles, hypovascular tumors, and embolization sites. Additionally, the postoperative levels of total bilirubin, gamma-glutamyl transferase, and ALP in the biliary tract injury group were significantly higher than those in the group without biliary tract injury	It provides a clear incidence rate of biliary tract injury (6.5%). It is proposed that the risk factors for biliary tract injury after TACE include lipiodol dosage, gelatin sponge supplementation, embolization sites, and hypovascular tumors
Fang et al[67], 2023	Case reports	A 68-year-old male patient developed a bronchobiliary fistula following TACE for HCC. Two months after the initial TACE, the patient presented with a hepatic abscess and underwent drainage. Six months later, he developed cough with yellow sputum production, and magnetic resonance imaging confirmed hepatopulmonary abscesses complicated by a bronchobiliary fistula. Despite treatment with endoscopic retrograde cholangiopancreatography, drainage, and antibiotics, the patient’s condition deteriorated, and he eventually died of sepsis and multiple organ failure	This study reports in detail a case of bronchobiliary fistula, a critical biliary complication. It also indicates that bronchobiliary fistula should be immediately considered when a patient presents with biliary sputum expectoration. Bile accumulation in the liver and lungs may lead to tissue necrosis and chronic infection, necessitating early diagnosis and aggressive treatment
Xu et al[62], 2021	Retrospective study	A total of 693 TACE procedures were performed in 483 patients, from which 21 patients (4.3%) with biliary tract injury were identified. The results showed that patients who had undergone prior hepatectomy or received proximal arterial chemoembolization had a higher risk of postoperative biliary tract injury. The article also indicated that on non-contrast CT one week after the procedure, 14.3% (3/21) of the patients showed hyperdense shadows around the bile duct wall, while 76.2% (16/21) had an ALP level > 200 U/L. On CT, biliary tract injury manifested as intrahepatic bile duct dilatation (57.1%), biloma (25.7%), and hilar bile duct stenosis (17.1%), among other findings	It provides a clear incidence rate of biliary tract injury (4.3%) and explicitly mentions several types of biliary tract injury. It is proposed that biliary tract injury is not caused by a single factor, but rather the result of the combined effect of multiple factors, which is closely associated with the damage to biliary microvessels and subsequent chronic biliary infection, as well as the occurrence probability observed in imaging examinations. The main risk factors for biliary tract injury are identified, including a history of prior hepatectomy and proximal arterial embolization. Lipiodol deposition in the bile duct wall on postoperative CT and a significant increase in ALP levels are indicators for predicting biliary tract injury
Zhang et al[64], 2017	Retrospective study	This study retrospectively analyzed 1923 patients with HCC who underwent a total of 4695 TACE procedures. The results showed that the incidence of intrahepatic biloma was 1.04%. The 20 patients who developed biloma underwent an average of 2.75 TACE procedures. Among these patients, 11 cases were cystic or multiple cystic bilomas, 6 cases were branching bilomas, and 3 cases presented with both cystic and branching features	It clearly identifies the incidence of intrahepatic biloma as 1.04% and explicitly mentions several types of bilomas. It describes in detail the imaging features of bilomas on CT and magnetic resonance imaging. It is proposed that although intrahepatic biloma is rare, it still requires cautious management. Once signs of infection appear, timely administration of antibiotics, drainage, or even partial hepatectomy should be implemented
Dhamija et al[10], 2015	Retrospective study	A total of 305 TACE procedures were performed in 168 patients with HCC, among whom 6 patients (3.6%) developed biliary complications of varying severity, resulting in an overall complication incidence of 1.9%. The specific complications included 3 cases of mild intrahepatic bile duct dilatation, 1 case of bile duct stenosis, and 2 cases of intrahepatic biloma. Supportive treatment was administered to patients with intrahepatic bile duct dilatation, while percutaneous aspiration and nasobiliary drainage were performed for patients with infected biloma	It provides specific incidences of biliary complications based on the number of patients and procedures, which are 3.6% and 1.9% respectively. Several types of biliary complications are listed, such as intrahepatic bile duct dilatation, bile duct stenosis, and intrahepatic biloma

TACE: Transarterial chemoembolization; CT: Computed tomography; B-TACE: Balloon-occluded transarterial chemoembolization; HCC: Hepatocellular carcinoma; ARDS: Acute respiratory distress syndrome; ALI: Acute lung injury; DEB-TACE: Drug-eluting bead transarterial chemoembolization; ALP: Alkaline phosphatase.

CONCLUSION

TACE serves as the cornerstone for the treatment of unresectable HCC with promising clinical outcomes. However, its associated arterial and biliary complications are major obstacles that limit therapeutic efficacy, affect patient safety, and impair quality of life. Through a systematic review of relevant literature, this review puts forward three key viewpoints: First, the risk of complications requires individualized assessment. The risk of arterial complications is mainly determined by vascular anatomical features (especially extrahepatic collateral circulation) and interventional operation techniques; the primary cause of biliary complications is ischemic injury to the PVP, and its risk is closely related to the type of embolic agent (e.g., lipiodol), particle size (e.g., small-diameter microspheres), dosage, and cumulative number of treatments. Thus, clinical decisions must comprehensively evaluate these factors. Second, prevention is the primary strategy for complication management, and multidisciplinary collaboration is crucial - preoperative detailed imaging evaluation is used to identify high-risk anatomical structures, intraoperative careful and precise superselective catheterization techniques are adopted, and intraoperative three-dimensional imaging technologies such as CBCT have irreplaceable value in preventing non-target embolization; once complications occur, a stepped comprehensive management model involving multidisciplinary team collaboration (interventional, endoscopic, pharmaceutical, and surgical approaches) should be initiated based on the type and severity of the complication. Third, salvage therapy should be considered in special cases. The application of TACE is limited by lack of patent vascular access: In a few special situations (e.g., occlusion of both the celiac trunk and superior mesenteric artery, or patients with ruptured HCC who refuse surgery and have extremely complex vascular anatomy), ultrasound-guided percutaneous direct puncture of the hepatic artery for drug perfusion may serve as an effective salvage treatment[90].

Future research should focus on three aspects: First, promote standardization and high-quality clinical trials. There is an urgent need to establish internationally unified definitions, grading systems, and reporting standards for TACE complications; on this basis, conduct large-sample, multi-center prospective randomized controlled trials to scientifically evaluate the real safety profiles of emerging technologies (e.g., new-type microspheres, B-TACE, transarterial radioembolization) and combined treatment regimens. Second, deepen mechanistic research. Further explore the molecular pathological mechanisms of complications, such as identifying promising biomarkers like VEGF and angiopoietin-2 for predicting the susceptibility to biliary ischemic injury. Third, push for an in-depth application of AI technology. Develop and validate AI early warning models for accurately predicting specific severe complications after TACE (e.g., biliary injury, liver failure), enabling clinicians to formulate individualized TACE protocols with the lowest risk and maximum benefit based on patients’ preoperative imaging and clinical data, and realizing the transformation from “passive management” to “active prevention” of complications.

In summary, by deepening the understanding of the mechanisms of post-TACE complications, accurately identifying high-risk patients, and actively applying advanced technologies and multidisciplinary collaboration models, it is expected to continuously improve the safety and efficacy of TACE treatment, thereby bringing longer survival and better quality of life to HCC patients.