Sinistral portal hypertension (SPH) is a localized form of portal hypertension that usually occurs as a result of isolated obstruction of the splenic vein (1). Since the splenic vein is contiguous with the pancreas, pancreatic disorders, include pancreatitis and pancreatic neoplasms, are the most common etiology (2). Because most patients with SPH in acute pancreatitis (AP) are asymptomatic, in the past, SPH has been easily ignored clinically (3). However, due to the increased awareness of the entity and recent advances in the diagnostic approaches, especially the wide application of computed tomography (CT) for assessing pancreatic pathology, SPH is often found incidentally on investigation (3). SPH was detected in 3.3% of AP patients and in 12.5% of patients with moderate and severe AP (3, 4). For patients without any symptoms, correct prognostic judgment and advice on the follow-up are important for the medical consultation. In addition, very few patients with SPH run the risk for gastrointestinal bleeding from gastric varices, which is usually serious and potentially fatal (5–7). Thus, understanding of the diagnosis, risk stratification, and prognosis of SPH imposes important clinical significance, and this understanding may help with developing suitable discharge plan and improving outpatient management.

Splenic venous occlusion secondary to thrombosis formation, inflammatory stenosis, or external compression results in venous hypertension in collateral pathways that carry the splenic blood to the superior mesenteric and portal veins, mainly including the short gastric, coronary, and gastroepiploic veins (8). Xie et al. (3) reported 633 AP patients, including 21 patients diagnosed with SPH, and found that isolated gastric varices detected included gastroepiploic varices (100%), short gastric varices (61.9%), coronary varices (42.9%), and fundal varices (19.0%). However, the dynamic changes in varices have not been reported, which is critical for SPH due to its complex, prolonged clinical course. In addition, few studies have focused on the risk factors for SPH in patients with AP. Li et al. (4) demonstrated that males, recurrent AP, hypertriglyceridemia, high glucose, and infection of walled-off pancreatic necrosis were independent risk factors for SPH in patients with moderate and severe AP. However, the predictive value of these factors was not assessed, which made it difficult to derive consistent clinical guidance. There is potential significant benefit in using the clinical and imaging indicators determined at early stage of disease to predict SPH as early as possible, but this type of data has rarely been reported. A weighted risk score that can assist physicians in distinguishing high-risk patients from low-risk patients with SPH is still urgently needed clinically.

Thus, in this case-control study, we aimed to (1) investigate the imaging features and dynamic changes of gastric varices in patients with AP on contrast-enhanced CT; (2) analyze the relationship between the patency of portosplenomesenteric veins and the development of SPH; and (3) clarify the independent risk factors and develop a novel nomogram for the early prediction of SPH.

SPH is a common, prolonged complication in patients with moderate and severe AP, and it is associated with high incidence and heavy medical burden (4). Studies on dynamic changes in gastric varices and prognostic models in SPH have rarely been reported. In this observational study based on contrast-enhanced CT imaging using a long-term follow-up, we clarified that the development of gastric varices in SPH patients was a long-term, slowly progressing disease course. The patency of splenic vein was strongly associated with the development of SPH, with persistent occlusion and stenosis of splenic vein being the main factors. Male sex, high BMI, prolonged PT, and abnormal splenic vein were independent risk factors for SPH. The nomogram based on these risk factors could greatly predict SPH with good discrimination, calibration and clinical utility.

Normal liver condition, isolated gastric varices, and splenomegaly are characteristics of SPH, among which the radiological evaluation of gastric varices plays an important role in assessing the cause of SPH and can allow for the identification of SPH (8). However, the definition of gastric varices is often subjective and indistinct without a uniform standard, which brings difficulties and inconsistences to clinical evaluations and scientific research (13). In this long-term follow-up study, we reviewed all CT images and measured maximum diameter of involved veins, which provided an objective evaluation of the extent of varicose veins. Occlusion of splenic vein results in venous hypertension in the collateral pathways, which carry splenic blood to the superior mesenteric and portal veins. It was reported that the collateral pathways mainly occurred through gastroepiploic vein into superior mesenteric vein or short gastric vein through gastric fundus vein, and gastric coronary vein drained into the portal vein (3). Our results were in accordance with the literature. In addition to these common varices, some rarely reported varices were observed, including middle colonic, omentum branch of the gastroepiploic, pancreaticoduodenal, right gastric, left adrenal, and dorsal pancreatic veins, which deserve the attention of clinicians and radiologists, especially for the left adrenal varices. Portal-systemic shunt was rarely observed in patients with SPH due to the low pressure, however, we detected formation of spontaneous gastro-systemic shunt suggested by the enlargement of the left adrenal vein. Most SPHs are asymptomatic and often found incidentally on investigation; thus, their exact time of onset is unknown (14). There was a large difference between different studies in the median time to the detection of SPH, and this time ranged from 12 days to 8 months, which might be a result of different participants and CT detection times among these studies (3, 4). Thus, studying the dynamic changes in gastric varices is very helpful to understand the whole natural history of SPH. In this study, we confirmed that the dynamic changes in gastric varices in SPH patients were associated with a long-term, slowly progressing disease course, and the median time to reach the diagnostic criteria of SPH was 9 weeks. Long-term dynamic monitoring is necessary for the patients with suspicious varices.

Splenic venous thrombosis or occlusion is strongly associated with the occurrence and development of SPH. Varices were identified in 53% of patients with pancreatitis-induced splenic vein thrombosis (15). We also found that the proportion of splenic venous thrombosis was significantly higher in patients with SPH. However, the rate of occlusion or stenosis was even higher than that of thrombosis (75.4% vs. 23.4%). This result indicated that patency of splenic vein was affected not only by thrombosis but also by other factors, such as the stimulation of pancreatin and inflammatory mediators, coagulation dysfunction, and compression of necrotic tissue (12). Additionally, dynamic observations have showed that thrombosis of splenic vein was detected within 1 month after the onset of AP but undetected 3 months after the onset of AP. The condition of undetected thrombosis might be as a result of disappearance of the thrombosis or difficulty on detection by imaging due to the influence of occlusion of veins. Unlike thrombosis, stenosis or occlusion of splenic vein tended to appear at the early stage of the disease and persist during the one-year follow-up period, and the dynamic changes of stenosis or occlusion were more relevant to the changes in SPH, with the proportion of patients diagnosed with SPH increasing over time. Furthermore, multivariable analysis demonstrated that occlusion and stenosis of the splenic vein, but not splenic vein thrombosis, were independent risk factors for SPH.

Investigating risk factors and developing predication models are important steps to distinguish high-risk cases from low-risk cases. It was reported that male sex, local complications, recurrent AP, hypertriglyceridemia, glucose level >10 mmol/L, smoking, and infection of walled-off necrosis were risk factors for SPH (4). Part of our results was basically inconsistent. We found that male sex, high BMI, prolonged PT, and patency of splenic vein were independent risk factors for SPH. The specific reason why SPH was more common in males needs further exploration (3, 4). Obese patients were more prone to have a more serious disease with larger extent of pancreatic necrosis (16). The presence, location, and extent of pancreatic necrosis were strongly related to stenosis or occlusion of splenic vein due to the anatomical location (17). Coagulation dysfunction, which was manifested as prolonged PT, was reported to be a risk factor for splenic vein thrombosis, and the use of anticoagulation therapy is controversial (18, 19). Currently, no studies have reported scores or prediction models for SPH in AP patients. We developed a novel nomogram based on male sex, high BMI, prolonged PT, and the patency of splenic vein and validated that the model could predict SPH with good discrimination, calibration and clinical utility. This is clinically important because it provides a simple model for identifying patients at high risk for SPH at early stage of the disease. Based on this information, a clinician might provide suitable medical consultation, correct judgment on the prognosis and proper advice regarding the follow-up schedule, and clinicians can identify the suspicious cause as soon as possible when gastrointestinal bleeding or other complications happen during the follow-up.

Watchful waiting is an acceptable course of management in asymptomatic individuals (8). However, how clinicians should monitor these patients is still an important clinical issue. Herein, we reported a case with regular and frequent follow-up for as long as 3 years. The patient was a 39-year-old male diagnosed with SAP complicated with SPH involving gastric fundus vein, short gastric vein, and gastric coronary vein, as well as stenosis and occlusion of splenic vein (Figure 5 and Supplementary Figure 1). We observed that both SPH and the occlusion of splenic vein had developed slowly and did not resolve over 3 years, but the patient did not have any symptoms, indicating that frequent follow-up might be unnecessary. Because of the following reasons: (1) most SPHs are asymptomatic; (2) dynamic changes in varices are slow and don’t usually recover for a long time; and (3) frequent follow-up and CT increase the patients’ financial burden and medical cost, we advise that the follow-up interval should not be frequent. In total, for patients with MSAP and SAP, especially males and obese patients with abnormal splenic vein and coagulopathies, prolonged and close monitoring with CT examinations every 3 months within the first year of AP onset may be suggested in order to identify SPH as early as possible. For those patients with known SPH, one CT per year may be enough, while more importantly, preventive measures such as appropriate dietary restrictions and patient education for an early recognition of gastrointestinal bleeding should be provided. Further studies are needed to validate the feasibility of the follow-up plan.

This study has several limitations. First, although CT imaging was objective, the results might be affected by the radiologists’ subjective judgments. To reduce the bias, the imaging analysis was conducted by two experienced radiologists who were blinded to other clinical data, and interobserver agreement was considered to be good. It would be more accurate if both magnetic resonance imaging (MRI) and constrast-enhanced CT could be used to assess the imaging features. Second, although the model was derived from our data and internal validation showed good performance, an external validation is still needed. Third, confounding factors were also considered in all observational and retrospective studies. Although we attempted to account and adjust for potential confounding variables, the possibility of unmeasured risk factors still existed.

We confirmed that the dynamic changes in varices in SPH were long-term, slowly progressing, and we developed a novel nomogram for the early prediction of SPH with good discrimination, calibration and clinical utility. A flexible follow-up plan was suggested in male obese patients with abnormal splenic veins and coagulopathies. Additional prospective studies with larger sample sizes are needed to confirm our findings.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of The First Affiliated Hospital of Nanchang University. Written informed consent was waived due to the retrospective nature of the study.

CY reviewed the all CT images. LD designed the study, analyzed the data, and wrote the manuscript. MJ collected the clinical data. CY, LD, and MJ contributed equality to this work and then should be considered co-first authors. QL helped in reviewing CT images. XH, YL, and HK helped in finishing follow-up. HX, WH, and LX participated in its design and helped in analyzing data. XZ revised the manuscript. NL and YZ made substantial contributions to conception, design and coordination of the study. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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