Downhill esophageal varices: a systematic review of the case reports

Aim: The etiologies, presentation, and management of downhill varices in the era of modern medicine are relatively under-explored and mostly limited to case reports or case series. Methods: Published case reports/series of patients ≥ 18 years old with proven/probable downhill esophageal varices were searched on Ovid MEDLINE and Ovid EMBASE for all published cases up to January 2021. Results: The mean age was 50.9 (standard deviation ± 17.6) years old for all downhill variceal cases. End-stage renal disease was the most common comorbidity (43.9%), followed by thyroid disease (12.2%), Behçet’s disease (9.8%), and pulmonary hypertension (7.3%). Dialysis catheters, central venous grafts, or additional catheters were additional risk factors (51.2%). Variceal bleeding presenting as hematemesis, melena, or both was the most common presenting symptom (80.5%). Conclusions: Dialysis catheter-associated superior vena cava obstruction resulted in an increased risk of downhill varices. Other causes include thyroid malignancies, pulmonary hypertension, and Behçet’s disease.

from the portal system to the SVC via portosystemic anastomosis resulting in "uphill" varices [4]. In contrast, downhill varices develop in the upper two thirds of the esophagus due to increased pressure or obstruction of the SVC in the cervical esophagus. This results in the blood flowing from the SVC to the azygos vein and transmits pressure to the esophageal venous plexus. Esophageal veins, which are typically not visible, can become visible due to obstructions in portal blood flow or of the SVC, leading to dilation of intramural and paraesophageal veins. They work as a collateral circulation between the portal vein, the azygos system, and the vena cava system [2,3]. Augmented SVC pressures were thought to be the only cause for downhill varices, but recently cases have been reported due to non-obstructive SVC . Several causes of downhill varices have been reported in literature, most common of which is SVC syndrome and associated vascular occlusion. Other causes include mediastinal fibrosis, Behçet's syndrome, catheter manipulation, retrosternal goiter and other thyroid masses, thymomas, bronchial carcinomas, metastases, pulmonary hypertension, and lymphomas.
Downhill varices are diagnosed with upper endoscopy and magnetic resonance imaging (MRI) or computed tomography (CT) which are used to visualize underlying etiology [45]. Therapeutic means are directed towards controlling the bleeding via sclerotherapy or banding [22]. Etiology-specific therapies that relieve the pressure in the venous system are employed for definitive treatment. These may include thyroidectomy, balloon angioplasty, vascular stenting, or conservative management [9,21,28]. A brief of the esophageal venous system is provided in Figure 1. Previously, augmented SVC pressures were thought to be the only cause for downhill varices ( Figure 2).  No previous systematic review or meta-analysis exists per our literature search of the epidemiology, diagnosis, treatment, and outcomes of downhill esophageal varices. Therefore, a systematic review of cases of downhill esophageal varices published from January 1970 to January 2021 was conducted, to explore the contemporary etiologies, clinical manifestations, presenting symptoms, diagnosis, and therapeutic regimens of this phenomenon.

Materials and methods
This review was initiated and summarized per the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [46]. The PRISMA checklist can be seen in the supplementary materials. Published case reports and series of downhill varices, as defined by the International Classification of Diseases-Tenth Revision-Clinical Modification (ICD-10-CM) code I85.00 for esophageal varices in patients ≥ 18 years old were reviewed from January 1970 to January 2021. A systematic search using search strategies that comprised of keywords including "downhill varices", "SVC syndrome", "goiter", and "Behçet's disease" was carried out in Ovid MEDLINE/PubMed and Ovid EMBASE. The search was limited to studies involving human participants and published in English. The final search was performed on January 2021. Bibliographies of relevant articles were also searched. Inclusion criteria required that the published cases had documentation of (i) presenting symptoms, (ii) predisposing factors or underlying medical conditions, (iii) endoscopic results, and (iv) management. Letters to the editors were included if they met the inclusion criteria. Any editorials, cases with inadequate details, review articles, or case series where the analysis was pooled without the description of individual patient data were excluded.
One author implemented search strategies and initial search results revealed 89 texts which were then filtered based on relevance to keywords after reviewing abstracts and titles only. Duplicates were removed and the remaining titles and abstracts were assessed for inclusion. Full texts of relevant articles were retrieved and independently assessed by two authors. Out of 64 articles selected, 12 were excluded due to non-English, and the remaining 52 articles were assessed by full-text review, among which 12 articles were additionally removed as they did not fulfill the inclusion criteria. Forty articles were selected in the final review ( Figure 3) (Table 1). Any disagreements over study inclusion were resolved by consensus.  Using standardized data extraction forms, data were extracted independently by the two authors and compared. Discrepancies were discussed with the third author as adjudicator. Data extracted included patient demographics, underlying conditions/comorbidities, presenting symptoms, diagnosis or endoscopic findings, predisposing etiologies, probable causes, and interventions during the hospitalization for downhill varices. The authors reviewed each case report to deduce whether other causes of variceal bleeding in each case were sufficiently excluded. Potentially overlapping causes, for example, patients with goiter and ESRD/dialysis catheter placement, both, etc. were also looked at and no such cases were reported or included in present study.
Underlying conditions that may predispose to downhill variceal bleeding were extracted and include the following: central venous catheter placements, grafts, ESRD, vasculitis, tumors, and goiter. All reported cases were also screened for duplication to ensure unique cases. Recently, Murad et al. [47] proposed a tool to evaluate the methodological quality of case reports and case series in systematic reviews. They proposed explanatory questions to assess ascertainment, casualty, and reporting. This is quite similar to our search strategy, and therefore, a separate risk of bias evaluation was not conducted. Additionally, as the data were derived from case reports, the data of interest were not subject to bias.
Data analysis was conducted using STATA statistical software. Patient demographics, predisposing factors, endoscopic findings, and therapeutic regimens were summarized descriptively. Illustrations were generated electronically.
The majority of cases underwent management based on the etiology. Patients not undergoing any invasive interventions other than medications were defined as conservative therapy. Among all cases, there were twelve angioplasties with or without stent placement, eleven esophageal bandings for variceal bleeding, one sclerotherapy and four thyroidectomies. Fourteen patients underwent conservative management. While a total of 21 cases had SVC obstruction as reported earlier, all patients who underwent angioplasty had underlying SVC obstruction secondary to dialysis catheters 12/21 (57.14%). About 3/21 (14.9%) cases of variceal bleeding underwent banding and angioplasties, 3/21 (14.9%) cases of variceal bleeding underwent banding only, 1/21 (4.8%) underwent sclerotherapy with angioplasty, and 4/21 (19%) of the patients were managed conservatively. In the present study, 9/21(42.8%) cases had angioplasties only. Three fifth (60%) patients with underlying etiology of retrosternal thyroid underwent thyroidectomies and only 1/5 (20%) underwent conservative treatment. Concurrently, only 1/5 (20%) patient underwent variceal banding and thyroidectomy. All four cases of Behçet's disease underwent conservative management with steroids and tumor necrosis factor (TNF) inhibitors. One patient also underwent variceal banding. Pulmonary hypertension was managed conservatively except for one case for which esophageal variceal banding was performed.

Discussion
This is a contemporary systematic review of downhill esophageal varices providing an insight into presenting symptoms and an increasing spectrum of etiologies of downhill varices. The current review was undertaken and reported using the PRISMA guidelines. Downhill varices bleeding has been reported to bleed less than uphill varices. This could be explained by the fact that variceal bleeding secondary to portal hypertension is associated with coagulopathy in decompensated stages of cirrhosis and due to the squamous lining of the distal esophagus having an increased gastric acid reflux exposure. Additionally, the veins in the distal part of the esophagus run in the mucosal layer whereas those in the upper esophagus are deeper and run in the submucosa [9].
There was an increased incidence of downhill esophageal varices in ESRD patients. This could be secondary to patients having underlying SVC obstruction besides dialysis catheters (Table 1). Variceal bleeding presenting as hematemesis or melena was the most common presenting symptom in downhill varices. Possible mechanisms by which the catheters contribute to the development of SVC obstruction include endothelial damage during insertion, blood turbulence due to a catheter, decreased limb movement, and other overlapping comorbidities [48]. Anticoagulant prophylaxis may be used to reduce the risk of symptomatic and asymptomatic catheter-associated thrombosis and obstruction [48]. Previous prophylactic treatments that have been studied include heparin infusions, vitamin K antagonists and low molecular weight heparin. A recent meta-analysis comparing prophylactic modalities did not include patients with ESRD or dialysis catheters and the implications of prophylactic anticoagulation in patients with ESRD is not widely studied [49,50]. However, a systematic review of individuals with atrial fibrillation receiving dialysis found similar efficacy in preventing venous thromboembolic events with direct oral anticoagulants (DOACs) versus warfarin [51]. Some of the other predisposing factors that are found less happened included retrosternal thyroids [16,21,23,40,41], Behçet's disease [6,22,32,42] and pulmonary hypertension [7,24,25,34].
Downhill varices in retrosternal goiter develop due to a similar obstruction in the thyroid veins resulting in the blood re-routing via the deep esophageal veins [16]. In the absence of any obstruction, blood from the thyroid plexus passes within the inferior thyroid veins into the brachiocephalic vein [23]. Imaging reveals that there could be obstruction of blood flow to the thyroid veins due to excessive pressure of retrosternal thyroid growth and improvement in varices after thyroidectomy [16,21,23,40]. The definitive diagnosis is made via neck imaging and management mainly involves thyroidectomy to relieve the obstruction and resume normal blood flow. In addition, a mechanical obstructive mechanism increased blood drainage in the esophageal veins due to malignancy as well as pulmonary hypertension leading to venous backflow have also been proposed as etiologies for downhill varices [26,34,38].
The establishment of a diagnosis almost always includes an endoscopic evaluation which may or may not include endoscopic management. However, a diagnostic workup is required to identify the etiology. Patients can undergo imaging studies including x-rays, barium swallows, CT angiograms, and/or MRIs. While esophageal banding or sclerotherapy can be temporizing for acute variceal bleeding definitive treatment, which alleviates the underlying SVC obstruction. Based on the etiology, some of the management strategies were catheter removal, angioplasty with or without stenting, thyroidectomy, tumor resection, or conservative therapy. Conservative therapy involves DMARDs or steroids is most used in Behçet's disease or vasculitis [6,7,20,22,24,25,32,34,42]. The impact of dialysis catheters on the incidence of downhill varices is a preventable cause and further comparative data are required to avert unwanted complications.
The current review provides the most recent and most extensive overview of the predisposing factors, diagnoses, and causes of downhill varices. Cases covered in this systematic review were identified from a thorough search of databases using a well-organized search strategy. Despite having stringent inclusion criteria, authors cannot rule out the possibility of missing cases given that some individual patient data were unavailable. Publication bias is a limiting factor in the present study as case reports often represent rare observations that are more likely to be published which potentially excludes some of the more common cases.
Although rare, downhill esophageal varices are an established cause of upper gastrointestinal hemorrhage. This review revealed that ESRD patients might be at an increased risk of downhill variceal bleeding compared to other etiologies. Dialysis catheter-associated SVC obstruction remains the most known cause in ESRD patients. It would be helpful for prospective future trials to study novel precautionary measures to avoid SVC obstruction in ESRD patients. No data are currently available regarding the use of anticoagulation to prevent SVC thrombosis and downhill varices in ESRD patients.

Abbreviations
DMARDs: disease-modifying antirheumatic drugs ESRD: end-stage renal disease PRISMA: preferred reporting items for systematic reviews and meta-analyses SD: standard deviation SVC: superior vena cava

Supplementary materials
The supplementary material for this article is available at: https://www.explorationpub.com/uploads/ Article/file/100196_sup_1.pdf.

Author contributions
HA, RP and EA contributed conception and design of the study; HA organized the database; HA and RP performed the statistical analysis; HA wrote the first draft of the manuscript; HA, RP, EA, SP and DK wrote sections of the manuscript. NLB edited the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest
The authors declare that they have no conflicts of interest.

Ethical approval
Not applicable.

Consent to participate
Not applicable.