Diagnostic value of ultrasonography for post-liver transplant hepatic vein complications

Abstract

Liver transplantation (LT) is the most effective treatment for patients with end-stage liver disease, and maintaining vascular patency of the transplanted liver is one of the crucial prerequisites for surgical success. Despite hepatic vein complications following LT occurring at a relatively low frequency, ranging between 2% to 11%, delayed diagnosis and treatment may lead to graft dysfunction and even patient mortality. Clinical manifestations of hepatic vein complications are often subtle and nonspecific, posing challenges for early diagnosis. Signs may initially present as mild abnormalities in liver function, delayed recovery of liver function, unexplained ascites, lower limb edema, and perineal edema. Prolonged duration of these complications can lead to hepatic sinusoidal dilatation and eventual liver failure due to prolonged hepatic congestion. Ultrasonography has become the preferred imaging modality for post-liver transplant evaluation due to its convenience and non-invasiveness. Although hepatic vein complications may manifest as disappearance or flattening of the hepatic vein spectrum on routine ultrasound imaging, these findings lack specificity. Contrast-enhanced ultrasound that visualizes the filling of contrast agent in the hepatic veins and dynamically displays blood flow perfusion information in the drainage area can, however, significantly improve diagnostic confidence and provide additional information beyond routine ultrasound examination.

Key Words: Liver transplantation; Hepatic congestion; Vascular complication; Hepatic vein complication; Ultrasound

Core Tip: Clinical manifestations of hepatic vein complications are often subtle and nonspecific. Signs may initially present as mild abnormalities in liver function, delayed recovery of liver function, unexplained ascites, and perineal edema. Prolonged duration of these complications can lead to hepatic sinusoidal dilatation and eventual liver failure due to prolonged hepatic congestion. Ultrasonography has become the preferred imaging modality for post-liver transplant evaluation. Contrast-enhanced ultrasound that visualizes the filling of contrast agent in the hepatic veins and dynamically displays blood flow perfusion information in the drainage area can, however, significantly improve diagnostic confidence and provide additional information beyond routine ultrasound examination.

INTRODUCTION

Among vascular complications following liver transplantation (LT), hepatic vein complications occur at a relatively low rate, estimated between 2% to 11%[1]. Due to the complex reconstruction of hepatic veins during living donor LT (LDLT) and split LT (SLT), factors such as significant diameter discrepancies at venous anastomosis sites and roughness of the intimal surface may lead to hepatic venous stenosis or occlusion, also known as hepatic venous outflow obstruction (HVOO). Mild cases of HVOO can result in congestion and necrosis within the drainage area of the liver, while severe cases may lead to graft failure[2]. HVOO represents a severe vascular complication, clinically manifested by abnormal liver function tests, splenomegaly, intestinal congestion, and renal dysfunction, leading to refractory liver dysfunction or mortality[3].

Digital subtraction angiography of the hepatic veins is considered the gold standard to diagnose HVOO. Nonetheless, due to its invasive nature and potential for radiation-induced damage to the body, non-invasive imaging modalities are preferred in clinical practice for patients presenting with clinical symptoms and signs of HVOO[4]. Color Doppler imaging (CDI), as the most commonly used ultrasound technique, provides information regarding blood flow direction and velocity[5]. Its results can be obtained immediately without radiation exposure and can be conveniently performed at the bedside[6]. However, CDI is prone to false-positive or false-negative diagnoses. This susceptibility arises from the proximity of the hepatic veins to the heart, making hepatic venous blood flow spectra susceptible to masking by cardiac pulsations. Also, large angles between the course of the hepatic veins and the ultrasound beam can result in the absence of hepatic venous blood flow signals.

Contrast-enhanced ultrasound (CEUS), however, is safe, convenient, and unaffected by the course of the hepatic veins or overflow of color Doppler signals. It dynamically displays blood flow perfusion information in the affected area, facilitating the diagnosis of HVOO[7]. CEUS not only clearly delineates the specific location of stenosis or thrombosis, but also accurately measures the length and diameter of the stenotic segment. Furthermore, it can delineate the areas and extent of hepatic tissue congestion and necrosis secondary to HVOO, providing crucial imaging information for the selection of appropriate clinical treatment strategies.

NORMAL HEPATIC VENOUS ANATOMY

The hepatic veins serve as the primary conduits for blood return from the liver, responsible for draining hepatic blood and conveying it back to the inferior vena cava. They mainly consist of three branches: (1) The right hepatic vein; (2) the middle hepatic vein; and (3) the left hepatic vein. Additionally, several shorter reflux veins, collectively referred to as the short hepatic veins, are present. The right hepatic vein primarily drains a segment of the blood flow from the right posterior and right anterior lobes, whereas the middle hepatic vein predominantly drains the left medial lobe and the remaining portions of the right anterior lobe. The left hepatic vein drains the left lateral lobe and a segment of the left medial lobe blood flow. The short hepatic veins mainly include the veins of the caudate lobe and the right posterior lobe[8,9]. Under physiological conditions, hepatic veins exhibit a predominantly negative flow (outflow from the liver) on spectral Doppler ultrasound, characterized by a triphasic waveform pattern comprising four phases: (1) A wave; (2) S wave; (3) V wave; and (4) D wave, each corresponding to different phases of the cardiac cycle. The S wave originates from atrial filling during ventricular systole, as blood flow returns from the inferior vena cava to the right atrium and hepatic venous outflow occurs away from the liver. This represents the first negative wave and is associated with the fastest flow velocity. The D wave originates during early to mid-diastole, with rapid blood flow from the right atrium into the right ventricle, and continued hepatic venous flow into the inferior vena cava, generating the second negative wave. The A wave is produced by partial blood return from the right atrium to the inferior vena cava during right atrial contraction, which temporarily changes the direction of hepatic venous blood flow, resulting in a positive wave. The ascent of the V wave is correlated with the opening of the tricuspid valve[10,11]. In the early post-liver transplant period, hepatic swelling leads to decreased hepatic venous compliance, resulting in changes in the hepatic venous spectrum. Early hepatic vein waveforms show decreased amplitude, replaced by a sawtooth-shaped negative wave group, but this typically returns to a normal triphasic waveform change at approximately 2 weeks post-transplant[12] (Figure 1). Several factors can influence spectral morphology, including the examinee’s emotional state, respiratory status, and instrument settings[13].

Figure 1 Normal hepatic veins. A: Color Doppler imaging shows the right hepatic vein (blue arrow) and the middle hepatic vein (red arrow) draining into the inferior vena cava. Both the right and middle hepatic veins can be visualized simultaneously below the right costal margin. The left hepatic vein is difficult to display in the same plane due to its angle; B: Spectral Doppler imaging shows waveforms of the right hepatic vein. Post-liver transplantation, normal hepatic vein waveforms can appear triphasic, biphasic, or even monophasic. Greater variability in the amplitude of hepatic vein waveforms suggests fewer hepatic vein abnormalities. Blood flow velocity also varies significantly, influenced by the measurement location, patient respiration, and the degree of hepatic vein filling.

Hepatic vein stenosis

The incidence of hepatic vein stenosis (HVS) ranges from 0.5% to 3.2%[14]. Early HVS is typically attributed to surgical factors such as inadequate fixation, deformation, or displacement of the graft, while late HVS may result from intimal hyperplasia or fibrosis around the anastomosis[3]. Clinical presentations are often nonspecific, with some patients exhibiting abnormal liver function, hepatic congestion, and ascites in the abdominal and thoracic cavities. Untreated cases may lead to graft failure[15]. Ultrasonography is the preferred modality for early postoperative assessment and longitudinal follow-up, although there are currently no definitive ultrasound diagnostic criteria for HVS[16]. Huang et al[17] reported that a monophasic hepatic vein waveform with an average velocity below 10 cm/second suggests HVS. Luo et al[18] suggested that hepatic vein outflow obstruction should be suspected when the ratio of stenosis to pre-stenosis velocity exceeds 4:1, and a flattened hepatic vein spectrum is observed at the proximal segment of the stenosis (Figure 2). Hepatic vein spectral waveform analysis aids in the diagnosis of HVS, with the normal waveform characterized by three phases. In a study by Lee et al[19], using monophasic hepatic vein waveform as a diagnostic criterion, the accuracy of diagnosing HVS after LDLT was 66.2%. However, Ko et al[20] reported that the specificity of the monophasic waveform in diagnosing HVS is low, but a continuous triphasic waveform can exclude the possibility of HVS. CEUS not only provides visual depiction of the site and degree of HVS, but also evaluates blood flow perfusion in the hepatic parenchyma of the drainage area, with congested areas manifesting as uneven hepatic parenchymal perfusion.

Figure 2 Hepatic vein stenosis in a 2-year-old girl with congenital biliary atresia. A: Grayscale ultrasound shows a reduced diameter (2.4 mm) at the hepatic vein anastomosis site (red arrow). While grayscale ultrasound can reveal a narrowed diameter at the hepatic vein anastomosis site, the diagnosis of hepatic vein stenosis cannot be based solely on the reduced diameter; B: Color Doppler and spectral Doppler imaging demonstrate aliasing of blood flow signals and increased flow velocity (202 cm/second) at the hepatic vein anastomosis site; C: Spectral Doppler imaging shows decreased blood flow velocity in the main hepatic vein (18 cm/second). When the velocity ratio at the stenotic site to the pre-stenotic site exceeds 4:1, and there is a flattened hepatic vein waveform distal to the stenosis, hepatic vein outflow stenosis should be suspected. Surgical procedure: Left lobe living donor liver transplantation. Ultrasound examination: 2 years postoperatively. No abnormal clinical indicators.

Hepatic vein thrombosis

Hepatic vein thrombosis (HVT) primarily occurs in pediatric patients undergoing LDLT, SLT, and other forms of piggyback LT, with a low incidence in patients who have undergone classic orthotopic LT[21]. Risk factors for HVT include hepatic vein anastomotic stenosis, hepatic vein torsion or elongation, excessive compression of the outflow tract due to oversized grafts, hepatic sinusoidal obstruction syndrome, and hypercoagulable states. Without timely intervention, HVT may progress to complete hepatic vein occlusion (HVO)[22]. Clinical manifestations of HVT vary depending on severity. Mild cases may present with unexplained ascites and liver enlargement, while severe cases may manifest symptoms indicative of portal hypertension. Diagnosis via routine ultrasound alone is straightforward. Grayscale ultrasound typically reveals complete or incomplete hypoechoic filling within the hepatic vein lumen, accompanied by enhanced parenchymal echoes in the affected hepatic vein drainage area, forming distinct boundaries with normal liver tissue. CDI shows filling defects in the blood flow signal, with absent blood flow spectra detected at the thrombus site. The primary characteristic of CEUS is filling defects within the hepatic vein lumen[23], where the contrast agent travels along the vein wall and surrounds the thrombus, resulting in a consistent filling defect image. Loose thrombi appear as columnar or strip-shaped filling defects, sometimes centralized or skewed to one side, and typically lack contrast agent surrounding them, indicating adhesion of the thrombus to the vessel wall. Abrupt interruption of contrast agent columns or partial non-enhancement of the hepatic vein suggests complete thrombus filling within the vein lumen. Hepatic parenchymal perfusion on CEUS shows early arterial hyperenhancement in the drainage area liver tissue, forming a wedge-shaped enhancement with the apex pointing toward the inferior vena cava. This enhancement sharply contrasts with the normally enhanced liver tissue. Contrast enhancement synchronously fades or prematurely diminishes during the portal venous phase and delayed phase.

HVO

HVO is a rare yet fatal complication following LT, which can lead to graft failure and death[24]. While its pathogenesis remains unclear, several factors have been implicated, including the surgical technique of LT[25], medications such as azathioprine or tacrolimus[26], acute rejection reactions[27,28], chemotherapy containing oxaliplatin[29], exposure to radiation[30], and ingestion of pyrrolizidine alkaloid-containing plants[31]. Ultrasonographic findings indicative of HVO include: (1) Significant hepatomegaly; (2) thickening and increased echogenicity of the hepatic parenchyma, presenting as “patchy” hypoechoic areas; (3) partial or complete narrowing of the hepatic veins, with thickened walls and increased echogenicity; (4) normal or indistinct hepatic vein blood flow; and (5) CEUS showing non-filling of occluded hepatic veins (Figure 3). Time-intensity curve parameters analysis of CEUS can aid in the diagnosis of HVO following LT[32].

Figure 3 Hepatic vein occlusion in a 72-year-old male with decompensated hepatitis B cirrhosis. A: The liver is significantly enlarged with coarse, dense parenchymal echotexture and patchy hypoechoic areas. The right hepatic vein appears narrowed with thickened, hyperechoic walls. Hepatic vein occlusion results in impaired hepatic blood outflow, leading to liver congestion and enlargement. Ultrasound can measure the maximum oblique diameter of the right lobe to assess liver size. One year post-transplantation, the liver size typically normalizes, with a right lobe maximum oblique diameter not exceeding 140 mm. In this patient, the liver is markedly enlarged. Chronic hepatic congestion can lead to increased parenchymal echogenicity and fibrosis, with patchy hypoechoic areas representing focal congestion; B: Contrast-enhanced ultrasound shows no enhancement within the right hepatic vein, confirming the diagnosis of right hepatic vein occlusion; C: Contrast-enhanced computed tomography reveals no enhancement in the right hepatic vein and heterogeneous liver density. Surgical procedure: Piggyback liver transplantation. Ultrasound examination: 14 years postoperatively. Clinical presentation: Massive ascites.

Bridging vein thrombosis

In the selection of right lobe liver donors for LDLT/SLT, there are two types of donors: (1) Those with the middle hepatic vein; and (2) those without the middle hepatic vein[9]. The drainage area of the middle hepatic vein includes segments 4, 5, and 8. Improper dissection of vessels during surgery may result in reflux obstruction in any of these liver segments. In some cases, reconstruction of one or more branches of the middle hepatic vein is required[33,34]. To prevent reflux obstruction in segments 5 and 8, several techniques are used to bridge the larger branches of the middle hepatic vein, including autogenous great saphenous veins, cadaveric donor vessels, or artificial vessels, collectively referred to as bridging veins[35]. Bridging vein occlusion is a common complication following LDLT/SLT surgery, primarily due to: (1) The bridging vein being located on the surface of the liver section, making it susceptible to compression by abdominal pressure and surrounding fluid accumulation, leading to stenosis; (2) limited blood volume in the drainage area resulting in blood stasis; and (3) the angle formed at the anastomosis between the bridging vein and branches of the middle hepatic vein affecting blood reflux[36]. Bridging vein occlusion may result in focal congestion in the drainage area or the formation of extensive collateral circulation between branches of the middle hepatic vein and the right hepatic vein, with blood flow draining into the right anterior lobe of the liver[37]. Due to their small caliber and deep location, bridging veins are often difficult to detect by grayscale and Doppler ultrasound. CEUS is a superior method for observing bridging veins and detecting collateral formation within the liver after bridging vein occlusion. Ultrasonographic features of bridging vein occlusion include: (1) Solid echogenicity filling the lumen of the bridging vein; (2) absence of blood flow signals on color and spectral Doppler; (3) decreased or reversed portal vein flow velocity; (4) markedly enhanced hepatic parenchyma in the drainage area of the occluded vein, with clear demarcation from adjacent normal liver segments; and (5) complete occlusion of the bridging vein on CEUS, showing uniformly low enhancement throughout the hepatic tissue in the drainage area[38]. In cases of incomplete occlusion of the bridging vein, arterial hyperenhancement in the drainage area of the liver tissue is observed during the arterial phase, with a wedge-shaped or irregular shape, synchronous or premature fading during the parenchymal phase (Figures 4 and 5).

Figure 4 Bridging vein thrombosis in a 37-year-old female with primary sclerosing cholangitis and decompensated cirrhosis. A: Grayscale ultrasound shows the bridging vein lumen filled with medium to low echogenic material; B: Color Doppler ultrasound shows no significant blood flow signal within the bridging vein lumen, suggesting occlusion due to bridging vein thrombosis; C: Contrast-enhanced ultrasound (CEUS) shows no enhancement within the bridging vein lumen, confirming complete occlusion. An interesting phenomenon observed on CEUS is arterial phase hyperenhancement in the drainage area of the bridging vein (segment 4, indicated by the arrow); D: CEUS shows delayed phase hypoenhancement in the drainage area of the bridging vein (segment 4, indicated by the arrow). The abnormal arterial phase enhancement of the hepatic parenchyma in the drainage area is associated with local liver sinusoidal congestion due to impaired hepatic outflow. Surgical procedure: split liver transplantation (including left hemiliver with the middle hepatic vein). The donor liver was from a dextran-binding domain adult, split along the middle hepatic vein, with the left liver graft allocated to this patient. Intraoperative reconstruction of the proximal end of the middle hepatic vein was performed. Ultrasound examination, 1 month postoperatively. Biochemical indicators show elevated transaminases and bilirubin.

Figure 5 Hepatic vein thrombosis in a 53-year-old female with decompensated hepatitis B cirrhosis. A: Grayscale ultrasound shows a solid hypoechoic mass within the middle hepatic vein lumen, not completely filling the vein; B: Color Doppler ultrasound shows no significant blood flow signal in parts of the hypoechoic mass within the middle hepatic vein lumen, with blood flow bypassing around the mass, suggesting hepatic vein thrombosis with incomplete luminal occlusion; C: Contrast-enhanced ultrasound (CEUS) shows a filling defect within the middle hepatic vein, with contrast agent flowing along the vein wall and encircling the thrombus, resulting in a consistent filling defect image; D: CEUS shows arterial phase hyperenhancement in the drainage area of the middle hepatic vein (segment 4, indicated by the arrow); E: CEUS shows delayed phase hypoenhancement in the drainage area of the middle hepatic vein (segment 4, indicated by the arrow). In this case, CEUS confirmed the presence of a middle hepatic vein thrombus, with hepatic parenchymal perfusion characteristics demonstrating arterial phase hyperenhancement and delayed phase hypoenhancement in the hepatic parenchyma of the drainage area. Surgical procedure: split liver transplantation (including right hemiliver with the middle hepatic vein). The donor liver was from a dextran-binding domain adult, split along the middle hepatic vein, with the right liver graft allocated to this patient. Ultrasound examination: 3 days postoperatively. Biochemical indicators showed elevated transaminases and bilirubin.

CONCLUSION

The clinical manifestations of hepatic vein complications after LT are often atypical, and early diagnosis is crucial for timely implementation of targeted treatment strategies. Such prompt interventions can help improve surgical success rates and transplant recipient prognosis. While conventional ultrasound remains the preferred diagnostic modality, the presence of morphological abnormalities in the hepatic vein (such as luminal narrowing, wall thickening, thrombosis, and enhanced parenchymal echoes in the drainage area), or abnormal blood flow patterns (such as flat spectral waveforms and localized peak flow velocity increases) necessitates the use of CEUS as a valuable adjunct imaging technique. CEUS significantly improves diagnostic accuracy and helps avoid unnecessary invasive angiography procedures[39].