Objectives: This study was designed to investigate the frequency of computed tomography features indicating progression of portal hypertension and their clinical relevance in patients who experienced acute cellular rejection after liver transplantation.
Materials and Methods: This retrospective study included 141 patients with pathologically diagnosed acute cellular rejection following liver transplant. Patients were divided into early and late rejection groups according to the time of diagnosis. Two radiologists analyzed the interval changes in spleen size and variceal engorgement on computed tomography images obtained at the times of surgery and biopsy. Aggravation of splenomegaly and variceal engorgement were considered computed tomography features associated with the progression of portal hypertension. Clinical outcomes, including responses to treatment and graft survival, were compared between patients with and without these features.
Results: The frequency of progression of portal hypertension was 31.9% and did not differ signifi-cantly in patients who experienced early (30.8% [28/91]) and late (34.0% [17/50]) rejection (P = .694). In the late rejection group, computed tomography features indicating progression of portal hypertension were significantly associated with poor response to treatment (P = .033). Graft survival in both the early and late rejection groups did not differ significantly in patients with and without progression of portal hypertension.
Conclusions: Computed tomography features suggesting the progression of portal hypertension were encountered in about one-third of patients who experienced acute cellular rejection after liver transplant. Progression of portal hypertension was significantly related to poor response to treatment in the late rejection group.
Key words : Graft rejection, Imaging, Vascular complications
Acute cellular rejection is a common event after liver transplant (LT), occurring in up to 40% of these patients.1 Although improvements in immunosup-pression regimens have reduced the incidence of acute cellular rejection, it is still reported in 10% to 30% of LT recipients.2,3 Elevation of hepatic enzymes and/or bilirubin is considered suggestive of acute cellular rejection; however, these are not sufficiently sensitive or specific in differentiating acute cellular rejection from other causes of graft dysfunction.4,5 Imaging methods, such as Doppler ultrasonography (US) and computed tomography (CT), can exclude other major vascular and biliary complications of LT and increase suspicion of acute cellular rejection.6-10 In particular, several CT features, including globular swelling, nonanastomotic stenosis of the major draining vein, and heterogeneous enhancement of the graft, were reported to be significantly associated with acute cellular rejection.10 Nevertheless, a definitive diagnosis of acute cellular rejection requires liver biopsy. Most acute cellular rejection episodes respond to bolus doses of steroid or escalation of immunosuppression and generally do not affect long-term graft or patient survival.2,11 However, the risks of chronic rejection and graft loss can be increased in patients who experience repeated episodes of severe acute cellular rejection12,13 and in those with late-onset acute cellular rejection.14-16
Portal hypertension, an indicator of end-stage liver disease, usually resolves in patients who do not experience significant complications after transplant. Decreases in spleen size and varices are well-recognized phenomena after LT.17-19 However, posttransplant portal hypertension can occasionally be present as a result of various causes, including vascular complications (such as portal vein stenosis or venous outflow obstruction) and parenchymal diseases (such as acute cellular rejection).20,21 Among the radiologic findings of acute cellular rejection, decreased portal blood flow velocity on Doppler US may be caused by portal hypertension. Moreover, hepatofugal flow at the main portal vein, which can also be diagnosed by Doppler US, represents an extremely severe form of portal hypertension and may be indicative of a fatal condition.22,23 To our knowledge, however, the frequency of CT features associated with the progression of portal hyper-tension in patients with acute cellular rejection after LT has not been determined, nor has the clinical relevance of these features, as evaluated by treatment response to immune suppression and graft survival. The present study was therefore designed to determine the frequency of CT features indicating progression of portal hypertension and their clinical relevance in patients who experience acute cellular rejection after LT.
Materials and Methods
The study protocol was approved by the institutional review board of Asan Medical Center, which waived the requirement for informed consent because of the retrospective nature of this study.
Between January 2012 and June 2017, 2135 patients aged >18 years underwent deceased donor LT (n = 378, 17.7%) or living related donor LT (n = 1757, 82.3%) at our center for various liver diseases. Of living related donors, the relationships were first degree in 1359 (77.3%), family-in-law including spouse in 203 (11.6%), second degree in 101 (5.7%), and third degree in 94 patients (5.4%). All patients underwent CT scans before LT and regularly after LT for the surveillance of posttransplant complications. Of these patients, 190 were diagnosed with acute cellular rejection pathologically by transjugular or percutaneous liver biopsy. However, 49 were excluded: 20 because of absence of contrast-enhanced CT scans within 7 days before acute cellular rejection diagnosis; 14 because of coexisting major vascular (n = 8) or biliary (n = 6) complications on CT or Doppler US; and 15 because of coexisting liver diseases on pathologic examinations, including 9 patients with hemodynamic derangement and 6 with recurrent viral hepatitis. The remaining 141 patients, all of whom had undergone contrast-enhanced CT imaging within 7 days of pathologic acute cellular rejection diagnosis and did not have any coexisting posttransplant diseases, were included in our analyses (Figure 1). The 141 patients enrolled in this study included 97 men (68.8%) and 44 women (31.2%) with mean age of 51.8 ± 10.2 years (range,
20-73 years). The mean interval between LT and acute cellular rejection diagnosis was 212.7 ± 501.2 days (range, 4-3931 days). Patients were divided into 2 groups: early rejection (≤90 days after LT) and late rejection (>90 days after LT).
Computed tomography techniques
Computed tomography was performed using a
64- or 128-detector row CT scanner (Somatom Definition, Somatom Definition AS, and Somatom Definition Edge; Siemens Healthineers). Computed tomography images were obtained using the breath-hold technique at end-expiration at 120 kV and 200 to 220 mA, with automated dose modulation using the maximum allowable tube current. After unenhanced CT scans were acquired, intravenous contrast medium, consisting of 150 mL iopromide (Ultravist 370; Schering AG), was administered at a flow rate of 3 mL/s using a mechanical injector (Percupump II; E-Z-Em, Inc.). Arterial phase images were acquired 15 seconds after the attenuation of the descending thoracic aorta reached 100 Hounsfield units. Portal venous-phase images were obtained 75 seconds after administration of contrast medium. Images were reconstructed with filtered back projection at slice thicknesses of 3 mm.
Computed tomography images were reviewed independently by 2 radiologists (KWK, with 20 years of experience in LT imaging, and JYC, with 1 year of experience in LT imaging). Both radiologists were blinded to pathologic information. Disagreements between the 2 readers were resolved by consensus evaluations.
Contrast-enhanced CT images at baseline and at the time of acute cellular rejection diagnosis were analyzed to determine the interval changes in spleen size and variceal engorgement. Baseline contrast-enhanced CT was defined as the first postoperative CT scan, obtained within 1 week after LT or, if unavailable, the preoperative CT scan. Interval changes in spleen size were categorized by S score, with NA defined as splenectomy or procedures potentially affecting spleen size, such as splenic artery/vein embolization/ligation or splenic devascularization; S0 as not enlarged originally or decreased over the interval; S1 as equivocally unchanged splenomegaly; and S2 as an increase over the interval. Interval changes in variceal engorgement were categorized by V score, with V0 defined as originally absent or disappeared following surgical ligation, radiological embolization, or spontaneously; V1 as slightly decreased with residual engorgement or equivocally unchanged; and V2 as interval aggravated. Progression of portal hypertension was considered in patients with scores of S2 or V2.
Histologic assessment of acute cellular rejection
Transjugular or percutaneous liver biopsy samples were obtained from patients with clinical suspicion of acute cellular rejection, such as elevated liver enzyme levels, no response to routine immunosup-pressive treatment, or rebounding of liver enzyme level. Acute cellular rejection was histologically diagnosed using the Banff method.24 The rejection activity index was calculated as the sum of the scores for the following criteria: (1) portal inflammation, (2) bile duct inflammation damage, and (3) venous endothelial inflammation, with the severity of involvement of each component scored on a scale of 0 to 3. Clinically relevant acute cellular rejection was diagnosed if the rejection activity index score was greater than 4.
Clinical outcomes of patients with acute cellular rejection were investigated by reviewing their electronic medical records. Patients were grouped as good or poor responders depending on their response to immune suppression treatment. Patients were defined as good responders if they recovered without the need for additional liver biopsy or when follow-up biopsy showed a decreased rejection activity index. All other patients were considered poor responders, showing histological progression (no interval change/increase in rejection activity index or development of chronic rejection on follow-up biopsy) or graft failure (retransplant or graft-related death).
The demographic and clinical characteristics of patients who experienced early and late rejection were compared using t tests for continuous variables and the chi-square test or Fisher exact test for categorical variables. Interobserver agreement in CT scoring for interval changes in portal hypertension was assessed using Cohen’s kappa coefficients with 95% confidence intervals. Kappa coefficients were interpreted by using the following convention: less than 0.20 indicated poor, 0.21 to 0.40 indicated fair, 0.41 to 0.60 indicated moderate, 0.61 to 0.80 indicated substantial, and 0.81 to 1.00 indicated nearly perfect. Subsequent analyses were performed using consensus review results. Differences in CT scores and clinical outcomes between the early and late acute cellular rejection groups were compared using Fisher exact tests. The relationships between the progression of portal hypertension (CT score of S2 or V2) and responses to treatment were compared in the early and late acute cellular rejection groups using Fisher exact tests. The relationship between the progression of portal hypertension and graft survival at 6 months, calculated from the date of acute cellular rejection diagnosis to the date of graft failure, was assessed by the Kaplan-Meier method and compared by the log-rank test. All statistical analyses were performed using SPSS Statistics for Windows (version 23.0; IBM Corp). Two-sided P values < .05 were considered statistically significant.
The characteristics of the patients are shown in Table 1. Ninety-one patients (64.5%) were diagnosed with early rejection and 50 patients (35.5%) with late rejection. A total of 62 patients (44.0%) underwent surgical or radiological intervention, which can affect the portosplanchnic circulation. Thirty-seven patients (26.2%) underwent ligation/embolization of the portosystemic shunt, 20 (14.2%) underwent ligation/embolization of the splenic artery or splenic devascularization, and 15 (10.6%) underwent splenectomy, with 10 of these patients (7.1%) undergoing 2 or more of these procedures. There were no significant differences in age, sex, rejection activity index, type of graft, and incidence of intraoperative/perioperative procedures between the early and late rejection groups.
Interobserver agreement between the 2 readers in CT scoring for interval change of portal hypertension at the time of acute cellular rejection diagnosis was substantial for both S score (κ = 0.72; 95% CI, 0.62-0.80) and V score (κ = 0.76; 95% CI, 0.67-0.86) (Table 2).
The CT scores for interval changes in portal hypertension and clinical outcomes in the early and late rejection groups are summarized in Table 3. Although the frequency of S2 did not differ significantly (P = .43) in the early rejection group (27.5% [25/91]) and late rejection group (24.0% [12/50]), the frequency of V2 was significantly higher (P = .047) in the late rejection group (18.0% [9/50]) than in the early rejection group (6.6% [6/91]). The frequency of progression of portal hypertension (S2 or V2), however, did not differ significantly (P = .694) between the early rejection group (30.8% [28/91]) and late rejection group (34.0% [17/50]).
Of the 141 patients with acute cellular rejection, 84 (59.6%) were good responders and 57 (40.4%) were poor responders to immune suppression therapy. The poor responders included 21 patients (14.5%) with steroid-resistant acute cellular rejection on follow-up biopsies, 19 patients (13.1%) who were pathologically diagnosed with chronic rejection, and 30 patients (21.3%) who underwent retransplant or died as a result of graft failure, including 13 with and 17 without steroid-resistant acute cellular rejection or chronic rejection. There was no significant difference in response to immune suppression therapy between the early and late rejection groups (P = .778).
Of the 28 patients with early rejection who showed progression of portal hypertension, 16 (57.1%) were good responders and 12 (42.9%) were poor responders. Of the 63 patients in this group without progression of portal hypertension, 39 (61.9%) were good responders and 24 (38.1%) were poor responders. There was no significant relationship between progression of portal hypertension and response to immune suppression therapy in the early rejection group (P = .820). In the late rejection group, poor response to immune suppres-sion therapy was significantly more likely in patients who did than did not show progression of portal hypertension (P = .033) (Table 4). Findings in represen-tative patients are illustrated in Figure 2 and Figure 3.
Graft survival at 6 months between patients with and without progression of portal hypertension did not differ significantly in both the early (P = .608) and late (P = .318) rejection groups (Figure 4).
Our findings showed that CT features suggesting the progression of portal hypertension, such as progressive splenomegaly and variceal engorgement, were occasionally observed in patients with both early and late rejection after LT. Although progressive variceal engorgement was more frequently seen in patients with late than with early rejection, the frequencies of progressive splenomegaly and overall progression of portal hypertension did not differ significantly in the early and late rejection groups. Subgrouping of patients as good or poor responders to immune suppression therapy showed that the frequency of progression of portal hypertension in the late rejection group was significantly more frequent in poor than in good responders, whereas this incidence did not differ significantly between good and poor responders in the early rejection group. Nevertheless, graft survival was not significantly affected by the frequency of progression of portal hypertension in either group.
Portal hypertension after LT can reduce portal flow and impair or delay graft regeneration and can even be life-threatening.25 Acute cellular rejection, one of the most common complications of LT, as well as various other complications (including small graft size, hepatic venous outflow obstruction, and portal vein stenosis), may be the cause of portal hypertension and decrease portal inflow to the liver graft, particularly in those with persistent portosystemic shunt.26 Evaluation of the pathophysiologic mecha-nism of acute cellular rejection has shown that severe periportal inflammation can progress to centrolobular venule obstruction and increased intrasinusoidal pressure, eventually causing portal hypertension.27 Indeed, decreased portal flow on Doppler US may be a marker for acute cellular rejection after LT. Patients with acute cellular rejection have been reported to experience a marked reduction in portal blood flow velocity, with a 40% reduction7 and an absolute portal blood flow velocity <20.2 cm/s,8 proposed as cutoffs for the diagnosis of clinically relevant acute cellular rejection. Reversed portal flow has also been reported during acute cellular rejection episodes after LT.22,23,28 Consistent with these findings, the present study showed that CT features suggesting the prog-ression of portal hypertension were not uncommon in patients with acute cellular rejection.
Several factors during the early postoperative period may affect portal pressure. For example, graft size can be an important factor in patients who undergo living donor LT. Small-for-size grafts can lead to a sudden increase in intrasinusoidal pressure due to the relatively low capacity of the hepatic sinusoid.29 Postoperative volume overload or congestion can also lead to high intrahepatic vascular resistance, and variations in the degree of portal vein stenosis can increase portal pressure. Interactions among these various factors can result in the improvement, persistence, or development of portal hypertension during the early postoperative period, making it difficult to interpret results in the early rejection group. Huge portosystemic shunts are usually interrupted surgically or radiologically in our institution. These procedures can have a greater effect on portal pressure than acute cellular rejection-associated changes in graft parenchyma during the early postoperative period, possibly leading to the underestimation of portal hypertension. This may account for the lower frequency of progressive variceal engorgement shown in the early versus the late rejection group.
In contrast, confounding factors may have minimal effects during the late posttransplant period. Liver transplant recipients have had more time to adapt to the sizes of the grafts. Moreover, because most patients who experience late rejection do so in an outpatient setting, problems such as volume overload due to fluid therapy are less likely. In the present study, CT features of progressive portal hypertension were occasionally observed in the late rejection group and were more frequent in poor than in good responders to immunosuppressive treatment. The progression of portal hypertension during this period likely reflects the acute cellular rejection-associated parenchymal changes in the graft.
This study had some limitations. First, because of its retrospective design, there may have been selection bias in the study populations. Acute cellular rejection is common after LT, and patients with suspected mild acute cellular rejection were empirically treated with immune suppressants before pathologic confirmation. There are no definitive guidelines for performing liver biopsy, with the choice to obtain biopsy samples being at each clinician’s discretion. Therefore, patients with mild acute cellular rejection were not included in our study population, suggesting that our findings are applicable only to patients with clinically relevant acute cellular rejection. Second, some patients in the present study underwent procedures to change portal flow, which could have influenced the development or regression of portal hypertension. Therefore, it is hard to generalize the results of this study to patients treated using a different surgical strategy. Third, the present study is a cohort study. Comparisons with a control group are necessary to determine whether the progression of portal hypertension is diagnostic for acute cellular rejection. Fourth, although we analyzed CT features in these patients, we did not assess the consistency between CT features and changes in portal flow on Doppler US. Paired Doppler US scans were not always available, particularly during the late postoperative period. Doppler parameters such as portal blood flow velocity can better show the presence of portal hypertension as decreased or reversed values. Further studies pairing CT and Doppler US features are needed.
Computed tomography features suggesting the progression of portal hypertension are occasionally encountered in patients with acute cellular rejection. In patients with late rejection, the progression of portal hypertension is more frequently associated with poor than with good response to immune suppression treatment. Nevertheless, graft survival is not significantly affected.
Volume : 20
Issue : 8
Pages : 742 - 749
DOI : 10.6002/ect.2022.0142
From the 1Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul; the 2Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; and the 3Department of Surgery, Division of Hepatobiliary and Liver Transplantation Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Acknowledgements: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (No. 2017R1E1A1A03070961). The authors have no declarations of potential conflicts of interest.
Corresponding author: Kyoung Won Kim, Department of Radiology and Research Institute of Radiology, Asan Medical Cqenter, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
Figure 1. Patient Flow Diagram
Table 1. Demographic and Clinical Characteristics of the Study Patients
Table 2. Interobserver Agreement on S Scores and V Scores
Table 3. Computed Tomography Scores and Clinical Outcomes in Patients With Early and Late Acute Cellular Rejection
Table 4. Relationship Between Progression of Portal Hypertension and Clinical Outcomes in Patients With Late Acute Cellular Rejection
Figure 2. Images From 45-Year-Old Man Diagnosed With Acute Cellular Rejection (Rejection Activity Index = 6) 309 Days After Living Donor Liver Transplant With Right Hemiliver Graft for Hepatitis B Virus-Associated Liver Cirrhosis
Figure 3. Images From 56-Year-Old Man Diagnosed With Acute Cellular Rejection (Rejection Activity Index = 7) 243 Days After Living Donor Liver Transplant With Right Hemiliver Graft for Hepatitis B Virus-Associated Liver Cirrhosis
Figure 4. Graft Survival at 6 Months in Late Rejection Patients