Morphological study of incompetent saphenous veins: apoptosis and ultrastructural changes of smooth muscle cells.

BACKGROUND: Varicose veins affect approximately 25% of people in industrialized countries. METHODS: The study aimed at detecting apoptotic cells and histopathological changes in varicose vein walls. Patients (N.=41) with varicose veins and 30 control group patients were divided into two groups according to their age (younger and older than 50 years). Apoptosis was determined by the TUNEL assay, elastin and collagen IV expression by immunohistochemistry and ultrastructural changes by transmission electron microscopy. RESULTS: The results show that the number of apoptotic cells in the layers of varicose veins increased, in particular in a group of patients aged over 50 years. In the varicose veins as compared to control veins the elastic fibers were found to be thinner, more fragmented and disorderly arranged. Elastin and collagen IV expression was found to decline in the intima and the media of varicose veins in both age groups. Electron microscopy demonstrated hypertrophy and degeneration of smooth muscle cells. Furthermore, cells with ultrastructural feature of apoptosis were noted. In the disorganized and expanded extracellular matrix membrane-bound vesicles, ghost bodies with different size and electron density were observed. Ghost bodies seem to bud off from smooth muscle cells and are likely to be involved in extracellular matrix remodeling as they are seen in close contact with collagen fibers. CONCLUSIONS: The study demonstrates increase of apoptotic cells in the wall of varicose veins along with vein wall structural abnormalities including alterations of smooth muscle cells and decline of elastin and collagen IV expression.

Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs.

One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. There are many etiological environmental factors influencing the development of chronic venous insufficiency (CVI), although genetic factors and family history of the disease play a key role. All these factors induce changes in the hemodynamic in the venous system of the lower limbs leading to blood stasis, hypoxia, inflammation, oxidative stress, proteolytic activity of matrix metalloproteinases (MMPs), changes in microcirculation and, consequently, the remodeling of the venous wall. The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. Particular emphasis has been placed on describing the role of inflammation and oxidative stress and the involvement of extracellular hemoglobin as pathogenetic factors of VV. Additionally, active substances used in the treatment of VV were discussed.

[Risk factors and construction of a nomogram model for cirrhotic portal vein thrombosis combined with esophagogastric variceal bleeding].

Objective: To investigate the risk factors and construct a nomogram model for predicting the occurrence of cirrhotic portal vein thrombosis in patients combined with esophagogastric variceal bleeding (EVB). Methods: Clinical data on 416 cirrhotic PVT cases was collected from the First Hospital of Lanzhou University between January 2016 and January 2022. A total of 385 cases were included after excluding 31 cases for retrospective analysis. They were divided into an esophagogastric variceal bleeding group and a non-esophagogastric variceal bleeding group based on the clinical diagnosis. The esophagogastric variceal group was then further divided into an EVB group and a non-bleeding group. All patients underwent gastroscopy, serology, and imaging examinations. The risk factors of PVT combined with EVB were identified by univariate analysis using SPSS 26. The prediction model of cirrhotic PVT in patients combined with EVB was constructed by R 4.0.4. The prediction efficiency and clinical benefits of the model were evaluated by the C-index, area under the receiver operating characteristic curve, calibration plots, and decision curve. The measurement data were examined by a t-test or Mann-Whitney U test. The counting data were tested using the χ(2) test or the Fisher exact probability method. Results: There were statistically significant differences in the etiology, Child-Pugh grade,erythrocyte count, hematocrit, globulin, and serum lipids between the esophageal and non-esophageal varices groups (P < 0.05). There were statistically significant differences in etiology, erythrocyte count, hemoglobin, hematocrit, neutrophil percentage, total protein, globulin, albumin/globulin, urea, high-density lipoprotein cholesterol, calcium, and neutrophil lymphocyte ratio (NLR) between the EVB and non-bleeding groups (P < 0.05). Multivariate logistic regression analysis showed that etiology (OR = 3.287, 95% CI: 1.497 ~ 7.214), hematocrit (OR = 0.897, 95% CI: 0.853 ~ 0.943), and high-density lipoprotein cholesterol (OR = 0.229, 95% CI: 0.071 ~ 0.737) were independent risk factors for cirrhotic PVT patients combined with EVB. The constructed normogram model predicted the probability of bleeding in patients. The nomogram model had shown good consistency and differentiation (AUC = 0.820, 95% CI: 0.707 ~ 0.843), as verified by 10-fold cross-validation (C-index = 0.799) and the Hosmer-Lemeshow goodness of fit test (P = 0.915). The calibration plot and the decision curve suggested that the prediction model had good stability and clinical practicability. Conclusion: The risk factors for EVB occurrence include etiology, erythrocyte, hemoglobin, hematocrit, percentage of neutrophils, total protein, globulin, albumin/globulin, urea, high-density lipoprotein cholesterol, calcium, and NLR in patients with cirrhotic liver. The constructed prediction model has good predictive value, and it can provide a reference for medical personnel to screen patients with high bleeding risk for targeted treatment.

Prevalence and clinical characteristics of advanced portal vein thrombosis in cirrhotic patients with gastroesophageal variceal hemorrhage.

OBJECTIVES: Portal venous thrombosis (PVT) in cirrhotic patients is usually asymptomatic and diagnosed incidentally. In this study we aimed to investigate the prevalence and characteristics of advanced PVT in cirrhotic patients with a recent episode of gastroesophageal variceal hemorrhage (GVH). METHODS: Cirrhotic patients with recent GVH at one month before their admission for further treatment to prevent rebleeding were retrospectively recruited. Hepatic venous pressure gradient (HVPG) measurements, contrast-enhanced computed tomography (CT) scan of the portal vein system, and endoscopy were performed. PVT was diagnosed by CT examination and classified as none, mild and advanced. RESULTS: Of the 356 patients enrolled, 80 (22.5%) had advanced PVT. Elevated levels of white blood cells (WBC) and serum D-dimer were observed in advanced PVT patients compared with those with no or mild PVT. Moreover, HVPG was lower in patients with advanced PVT, with fewer patients having HVPG exceeding 12 mmHg, while grade III esophageal varices and varices with red signs were more prevalent. Multivariate analysis showed that WBC count (odds ratio [OR] 1.401, 95% confidence interval [CI] 1.171-1.676, P < 0.001), D-dimer level (OR 1.228, 95% CI 1.117-1.361, P < 0.001), HVPG (OR 0.942, 95% CI 0.900-0.987, P = 0.011), and grade III esophageal varices (OR 4.243, 95% CI 1.420-12.684, P = 0.010) were associated with advanced PVT. CONCLUSIONS: Advanced PVT, which is associated with a more severe hypercoagulable and inflammatory status, causes severe prehepatic portal hypertension in cirrhotic patients with GVH.

Cyanoacrylate glue reactions: A systematic review, cases, and proposed mechanisms.

OBJECTIVE: Cyanoacrylate glue closure was first used in humans 10 years ago to treat venous reflux of the axial veins. Studies have since shown its clinical efficacy in vein closure. However, great need exists to elucidate further the types of specific adverse reactions that cyanoacrylate glue can cause for better patient selection and to minimize these events. In the present study, we systematically reviewed the literature to identify the types of reported reactions. In addition, we explored the pathophysiology contributing to these reactions and proposed the mechanistic pathway with inclusion of actual cases. METHODS: We searched the literature for reports of reactions following cyanoacrylate glue use in patients with venous diseases between 2012 and 2022. The search was performed using MeSH (medical subject headings) terms. The terms included cyanoacrylate, venous insufficiency, chronic venous disorder, varicose veins, vein varicosities, venous ulcer, venous wound, CEAP (clinical, etiologic, anatomic, pathophysiologic), vein, adverse events, phlebitis, hypersensitivity, foreign body granuloma, giant cell, endovenous glue-induced thrombosis, and allergy. The search was limited to the literature reported in English. These studies were evaluated for the type of product used and the reactions noted. A systematic review, in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) method, was performed. Covidence software (Melbourne, VC, Australia) was used for full-text screening and data extraction. Two reviewers reviewed the data, and the content expert served as the tiebreaker. RESULTS: We identified 102, of which, 37 reported on cyanoacrylate use other than in the context of chronic venous diseases and were excluded. Fifty-five reports were determined appropriate for data extraction. The adverse reactions to cyanoacrylate glue were phlebitis, hypersensitivity, foreign body granuloma, and endovenous glue-induced thrombosis. CONCLUSIONS: Although cyanoacrylate glue closure for venous reflux is generally a safe and clinically effective treatment choice for patients with symptomatic chronic venous disease and axial reflux, some adverse events could be specific to the properties of the cyanoacrylate product. We propose mechanisms for how such reactions can occur based on histologic changes, published reports, and case examples; however, further exploration is necessary to confirm these theories.

Progression of Portal Hypertension in Acute Cellular Rejection After Liver Transplantation.

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 significantly 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.

Quantitative and structural characteristics of mitochondrial DNA in varicose veins.

OBJECTIVE: We examined quantitative (in terms of mtDNA/nuclear DNA) and structural (in terms of common deletions in the MT-ND4 gene region) characteristics of mitochondrial DNA (mtDNA) in varicose veins (VVs) and venous wall layers by comparing mitochondrial genome parameters, as well as mitochondrial function (in terms of mitochondrial membrane potential (MtMP)), in varicose vein (VV) vs. non-varicose vein (NV) tissue samples. METHODS: We analyzed paired great saphenous vein samples (VV vs. NV segments from each patient left after venous surgery) harvested from patients with VVs. Relative mtDNA level and the proportion of no-deletion mtDNA were determined by a multiplex quantitative PCR (qPCR), confirming the latter with a more sensitive method - droplet digital PCR (ddPCR). Mitochondria's functional state in VVs was assessed using fluorescent (dependent on MtMP) live-staining of mitochondria in venous tissues. RESULTS: Total mtDNA level was lower in VV than in NV samples (predominantly in the t. media layer). ddPCR analysis showed lower proportion of no-deletion mtDNA in VVs. Because of the decrease in relative MtMP in VVs, our results suggest a possible reduction of mitochondrial function in VVs. CONCLUSION: Quantitative and structural changes (copy number and integrity) of mtDNA are plausibly involved in VV pathogenesis. Future clinical studies implementing the mitochondrial targeting may be eventually fostered after auxiliary mechanistic studies.

Vein ablation is an effective treatment for patients with bleeding varicose veins.

BACKGROUND: Bleeding is a rare but potentially life-threatening complication of varicose veins. There is paucity of literature about patients with varicose veins that present with bleeding and the effectiveness of vein ablation as therapy to prevent recurrent bleeding. This study compares patients treated with vein ablation for bleeding varicose veins with patients treated for venous symptoms other than bleeding. We hypothesize that vein ablation is safe and effective in preventing recurrence of bleeding from varicose veins. METHODS: A retrospective single-centre review of consecutive patients undergoing vein ablation using radiofrequency in an outpatient office was performed. Patients presenting with bleeding were identified. A random (3:1) group of patients undergoing vein ablation for other venous symptoms and no bleeding was selected as a comparative group (control). The medical records were reviewed for patient characteristics and outcomes. A telephone survey inquiring about intensity of symptoms on a numeric rating scale of 0 to 10 prior and after treatment as well as recurrence of bleeding was also conducted. Patient characteristics and outcomes were compared between the two groups. RESULTS: The incidence of patients with bleeding varicose veins was 3.6% (13/362) of all patients undergoing vein ablation at our center. A total of 26 ablations and 60 ablations were performed in patients with bleeding (n = 13) and controls (n = 39), respectively. There was no difference in age and race, but there was a trend for bleeding to occur more commonly in male patients (61.5% vs 33.3%; P = .073). Patients with bleeding from varicose veins were more likely to have congestive heart failure (P = .013) and present with more advanced venous disease based on CEAP classification (P = .005) compared with the control group. There was no difference between the 2 groups in vein closure (P = .246) or complications (P = .299) after vein ablation. With mean follow-up of 2.26 ± 1.17 years, 85% of patients (n = 11) remained free from bleeding episodes. One patient with recurrent bleeding required additional vein ablation and the second patient had a concomitant ulcer that was treated with compression therapy. CONCLUSIONS: Bleeding from varicose veins is rare and more common in patients with congestive heart failure. Bleeding affects patients with higher CEAP scores. Vein ablation is a safe and effective treatment to prevent the recurrence of bleeding.

Long-term follow-up of biliary atresia using liver transient elastography.

OBJECTIVE: Liver transient elastography (TE) using FibroScan® has gained popularity as a non-invasive technique to assess hepatic fibrosis by measuring liver stiffness. This study focused on biliary atresia patients post Kasai operation for more than 10 years to prospectively correlate the hepatic fibrosis score to the biochemical changes of liver fibrosis and clinical development of portal hypertensive complications. METHODS: TE was performed in 37 patients who had biliary atresia post Kasai operation done at median age of 60 days. Biochemical indices of liver fibrosis including aspartate aminotransferase/platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score based on age, platelet count, alanine aminotransferase and aspartate aminotransferase level were calculated at the time of TE. Platelet count, spleen size, varices, ascites and hepatic encephalopathy were evaluated as clinical markers of portal hypertension. RESULTS: There were 22 female and 15 male with TE done at median age of 17.0 years. Median FibroScan® fibrosis score was 11.4. Fibrosis score of 6.8 kilopascal (kPa) was taken as the upper reference limit of normal. Nine patients (24%) had normal fibrosis score. Score above or equal to 6.8 kPa was significantly associated with lower platelet level (p = 0.001), higher INR (p = 0.043), higher APRI (p = 0.021), higher FIB-4 score (p = 0.013), and larger splenic diameter (p = 0.004). Higher FibroScan® fibrosis score was also significantly associated with portal hypertensive complications (p = 0.001). CONCLUSIONS: The FibroScan® fibrosis score correlated well with the biochemical changes of liver fibrosis and development of portal hypertensive complications clinically. Screening of portal hypertensive complications such as varices is recommended for patients with raised fibrosis score upon long-term follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities.

Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (ßMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 ×10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial.

Comparison of sequential CT arterioportography-arteriosplenography with standard cross-sectional imaging and endoscopy in children with portal hypertension.

In this study the diagnostic capability and additional value of sequential CT arterioportography-arteriosplenography (CT AP-AS) in comparison to standard cross-sectional imaging and upper gastrointestinal endoscopy (UGE) in pediatric portal hypertension (PH) was analyzed. Patients with clinical signs of PH who underwent CT AP-AS in combination with additional contrast-enhanced magnetic resonance imaging (CE-MR) and/or contrast-enhanced computed tomography (CE-CT) were included. Two radiologists reviewed independently imaging regarding the capability to prove patency of (1) extrahepatic and intrahepatic main stem portal vein (PV), (2) intrahepatic PV system and (3) splenomesenteric venous axis. Imaging was reviewed for detection of abdominal varices and results were compared to UGE. Main venous supply of varices (PV and/or splenic vein system) and splenorenal shunting were evaluated. 47 imaging studies (20 CT AP-AS, 16 CE-MR, 11 CE-CT) and 12 UGE records of 20 patients were analyzed. CT AP-AS detected significantly more splenorenal shunts (p = 0.008) and allowed more confident characterization of the extra-/intrahepatic PV-system and splenomesenteric veins in comparison to CE-MR (p < 0.001). Extra- and intrahepatic PV-system were significantly more confidently assessed in CT AP-AS than in CE-CT (p = 0.008 and < 0.001 respectively). CT AP-AS was the only modality that detected supply of varices and additional gastric/duodenal varices. In this retrospective study CT AP-AS was superior to standard cross-sectional imaging concerning confident assessment of the venous portosplenomesenteric axis in pediatric patients. CT AP-AS detected additional varices, splenorenal shunting and supply of varices.

Ultrasonic spleen thickness-based indexes surpass Baveno VI criteria in high-risk gastroesophageal varices detection.

AIMS: To evaluate the efficiency of ultrasonic spleen thickness (UST), routine variables and (expanded) Baveno VI criteria for high-risk gastroesophageal varices (HRGOV) detection in cirrhotic patients. METHODS: In total, 305 cirrhotic patients were retrospectively enrolled in the deriving cohort and 328 cirrhotic patients with hepatitis B sustained viral response were prospectively enrolled in the validation cohort. HRGOV was defined as medium and severe gastroesophageal varices (GOV), mild GOV with red signs or Child-Pugh C. The cut-offs for HRGOV were determined by likelihood ratio indicating strong evidences. Algorithms of Spleen thickness-Age-Liver stiffness measurement (LSM, by Fibroscan®)-Albumin (SALA) and Spleen thickness-Platelet-Albumin (SPA) were derived by multivariate analyses. RESULTS: The area under receiver operating characteristics curve of SALA, SPA, UST, platelet, and LSM were 0.849, 0.835, 0.808, 0.746, and 0.655 in the deriving cohort, and improved to 0.901, 0.904, 0.858, 0.876, and 0.811 in the validation cohort, respectively. While SALA, SPA, UST, platelet, Baveno VI criteria (BVI), and expanded BVI spared 46.6%, 38.0%, 29.2%, 21.0%, 12.1%, and 23.6% esophagogastroduodenoscopy in the deriving cohort, these numbers were improved to 68.1%, 66.8%, 27.1%, 37.8%, 36.0%, and 61.0% in the validating cohort, respectively; however, the negative likelihood ratio of expanded BVI was up to 0.16. SPA spared less esophagogastroduodenoscopy than SALA, which can be supplemented by stepwise applying UST and SPA. Sequentially combining UST and SALA, BVI and SALA exempted additional 10-5% endoscopies. CONCLUSIONS: SPA, without LSM, improves HRGOV detection comparing with BVI. UST based algorithms combination can achieve the best efficiency especially in sustained virus response hepatitis B.

What is the relationship of varicose vein pathogenesis with collagen fibers?

Aims and Background: In this study, the densities of collagen 1 and collagen 4, which are an effective vascular component in the remodelling of varicose veins, were investigated. Materials and Methods: The study included primary varicose vein samples of 20 patients and vein samples of 20 healthy controls. Immunohistochemical staining was performed using collagen 1 and collagen 4 antibodies. Histochemical staining was performed using Masson Trichrome. Results: In the immunohistochemical analysis of varicose samples, collagen 1 immunostaining was negative in 17 cases (85%) and positive in 3 cases (15%). In healthy venous tissue samples, collagen 1 immunostaining was negative in 12 cases (60%) and positive in 8 cases (40%). There was no statistically significant difference between both groups concerning collagen 1 immunostaining (p > 0.05). In varicose samples, collagen 4 immunostaining was negative in 4 cases (20%) and positive in 16 cases (80%). In healthy venous tissue samples, collagen 4 immunostaining was negative in 13 cases (65%) and positive in 7 cases (35%). Statistical comparison of healthy veins and varicose veins concerning collagen 4 immunostaining showed a significant difference (p = 0.03). In the histochemical analysis of varicose samples, Masson Trichrome staining was negative in 4 cases (20%) and positive in 16 cases (80%). In healthy venous tissue samples, Masson Trichrome staining was negative in 18 cases (90%) and positive in 2 cases (10%). Statistical comparison of healthy veins and varicose veins concerning collagen 4 immunostaining showed a significant difference (p = 0.01). Conclusion: The change in the density of collagen types plays an important role in vein wall remodeling.

Clinical and Pathological Correlations in Chronic Venous Disease.

BACKGROUND: Chronic Venous Disease (CVD) has a high prevalence in the western world. Varicose veins (VVs) are the main signs of this disease that is characterized by important pathological vessel wall changes. The aim of this study is to correlate the main histopathological abnormalities with related clinical issues of CVD. METHODS: A cohort of patients with VVs scheduled for open surgical treatment namely stab avulsion of VVs was recruited. Subsequently, venous tissue from stab avulsion was collected in order to evaluate the following biomarkers: Vascular-Endothelial Growth Factor (VEGF), Protein Gene Product 9.5 (PGP 9.5), Fibronectin (FN), and Matrix Metalloproteinase-9 (MMP-9). The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) criteria were used to classify CVD. RESULTS: Fourteen tissue fragments were processed for histological and immunohistochemical studies. Of these, 43% were from CEAP C2 patients, 36% from CEAP C3 patients, and 21% from CEAP C4 patients. CEAP Class C2 had few to moderate structures positive to VEGF; occasional structures positive to Fibronectin, numerous structures positive to MMP9, few to moderate structures positive to PGP 9.5. CEAP Class C3 had moderate structures positive to VEGF; few to moderate structures positive to Fibronectin; many structures positive to MMP9; few to moderate structures positive to PGP 9.5. CEAP Class C4 had numerous structures positive to VEGF; numerous structures positive to Fibronectin; abundant structures positive to MMP-9; few structures positive to PGP 9.5. CONCLUSIONS: In this study, positive VEGF, FN, and MMP-9 structures were found with increasing trends in relation to the disease staging. VEGF and FN are associated with a progressive increase from C2 to C4. The MMP-9 marker has an important positivity even at early stage of the disease, being higher in CEAP C4 patients. PGP 9.5 decreases in CEAP C4 patients and this is concordant to decreased vein wall innervation.

Endoscopic findings unrelated to portal hypertension in patients with liver cirrhosis undergoing a varicose vein screening programme. / Hallazgos endoscópicos no relacionados con hipertensión portal en pacientes con cirrosis hepática sometidos a un programa de cribado de varices.

AIM: To determine the prevalence of endoscopic lesions unrelated with portal hypertension in patients with cirrhosis. PATIENTS AND METHODS: Cross-sectional study including a consecutive cohort of patients with liver cirrhosis enrolled in a screening program of oesophageal varices who underwent an upper gastrointestinal endoscopy from November, 2013, to November, 2018. Clinical predictors of endoscopic lesions unrelated to portal hypertension were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 379 patients were included. The most frequent aetiology of liver disease was alcohol consumption (60.4%). The prevalence of endoscopic lesions unrelated with portal hypertension was 39.6% (n=150). Among 96 patients with peptic lesions, urease was obtained in 56.2% of patients (positive in 44.4% of them). The prevalence of endoscopic lesions unrelated to portal hypertension was not associated with age, gender, liver function or ultrasound findings of portal hypertension. The prevalence of endoscopic lesions unrelated to portal hypertension was not associated with age, gender, liver function or ultrasound findings of portal hypertension. Smokers had a trend to increased prevalence of endoscopic lesions unrelated to portal hypertension (43.2% vs. 34.6%; p=0.09), particularly peptic ulcer (6.4% vs. 0.6%; p=0.05) and peptic duodenitis (17.3% vs. 6.3%; p=0.002). Active smoking was the only independent predictor of peptic ulcer or duodenitis (OR=2.56; p=0.017). CONCLUSION: Active smoking is a risk factor for endoscopic lesions unrelated to portal hypertension. This finding should be further investigated to reassess endoscopic screening programs in cirrhotic smokers.

Liver stiffness by two-dimensional shear wave elastography for screening high-risk varices in patients with compensated advanced chronic liver disease.

OBJECTIVES: To investigate the usefulness of the criteria with liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT) for ruling out high-risk varices in patients with compensated advanced chronic liver disease (cACLD). METHODS: A total of 661 patients with cACLD had successfully undergone 2D-SWE and endoscopy screening. We analyzed risk factors for the presence of high-risk varices and compared proportions of patients who were spared endoscopy when used the predicting criteria with LS (ranged from 16 to 25 kPa) and PLT (ranged from 80 × 109/L to 150 × 109/L). RESULTS: PLT, albumin, LS were found to be independent predictors of high-risk varices. The LS values for ruling out and ruling in high-risk varices were 14.0 kPa and 24.8 kPa, respectively. When the Baveno VI criteria LS < 20 kPa and PLT > 150 × 109/L were used, the high-risk varices miss rate was 2.1%, while the saved endoscopy rate only was 19.2%. The new criteria that LS < 16 kPa and PLT > 100 × 109/L saved 30.4-34.6% endoscopy with 0-3.2% high-risk varices miss rate in the subgroup analysis stratified according to the types of underlying liver disease. CONCLUSIONS: The Baveno VI criteria can be applied to LS measurement by 2D-SWE. The new criteria that LS < 16 kPa and PLT > 100 × 109/L could be a potential model to spare more endoscopy screening with < 5% high-risk varices miss rate. KEY POINTS: • LS measured by 2D-SWE is reliable predictive factor for predicting all-size varices and high-risk varices in patients with compensated advanced chronic liver disease. • LS measured by 2D-SWE < 16 kPa and PLT > 100 × 109 /L, which can spare more endoscopy than Baveno VI criteria with < 5% high-risk varices miss rate. • The Baveno VI criteria can be applied to LS measurement by 2D-SWE.

Phenotypic and Functional Transformation in Smooth Muscle Cells Derived from a Superficial Thrombophlebitis-affected Vein Wall.

BACKGROUND: Superficial thrombophlebitis (ST) is a frequent pathology, but its exact incidence remains to be determined. This study tested the hypothesis whether relationships exist among smooth muscle cells (SMCs) derived from ST, varicose great saphenous veins (VGSVs), and normal great saphenous veins (GSVs). METHODS: Forty-one samples of ST, VGSVs, and GSVs were collected. SMCs were isolated and cultured. Proliferation, migration, adhesion, and senescence in SMCs from the three vein walls were compared by various methods. Bax, Bcl-2, caspase-3, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 messenger RNA (mRNA) and protein expressions were detected by fluorescence quantitative PCR and Western blot. RESULTS: An obvious decrease in cytoskeletal filaments was observed in thrombophlebitic vascular smooth muscle cells (TVSMCs). The quantity of proliferation, migration, adhesion, and senescence in TVSMCs was significantly higher than in varicose vascular smooth muscle cells and normal vascular smooth muscle cells (NVSMCs) (all P < 0.05). Bax and caspase-3 mRNA and protein expression were decreased, while Bcl-2 mRNA and protein expression were increased in the TVSMCs compared with the varicose vascular smooth muscle cells and the NVSMCs (all P < 0.05). MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA and protein expression were significantly increased in the TVSMCs compared with the VVGSVs and the NVSMCs (all P < 0.05). CONCLUSION: SMCs derived from ST are more dedifferentiated and demonstrate increased cell proliferation, migration, adhesion, and senescence, as well as obviously decreased cytoskeletal filaments. These results suggest that the phenotypic and functional differences could be related to the presence of atrophic and hypertrophic vein segments during the disease course among SMCs derived from ST, VGSVs, and GSVs.

The presence of a pathologic perforator may be predictive of central venous pathology and multilevel disease in severe chronic venous insufficiency.

OBJECTIVES: The treatment of a refluxing perforator is indicated in the setting of severe chronic venous insufficiency, but there are limited data on the presence of multilevel disease in these patients. This study sought to evaluate whether the presence of a pathologic perforator is predictive of the presence of central venous pathology. METHODS: This study was a retrospective review of the institutional Vascular Quality Initiative database. Consecutive patient limbs were identified that underwent intervention of refluxing perforators. The patients who underwent imaging, including magnetic resonance imaging or computed tomography (group A), were compared with those who did not undergo imaging (group B). The treated limbs in group A were also compared with the contralateral limbs as an internal control. Anatomical findings on imaging were analyzed by two independent investigators. The primary outcome was the presence and degree of central venous stenosis as measured by an orthogonal diameter reduction of >50% by axial imaging. Secondary outcomes included demographic and clinical differences between the two groups, frequency of central venous intervention, and duration of ulcer healing. Standard statistical analysis was performed. RESULTS: Ninety-three patient limbs underwent treatment of a pathologic perforator, with 30 in group A and 63 in group B. The following demographic and clinical variables were higher in group A compared with group B: male sex, body mass index, deep venous thrombosis history, recent or active anticoagulation use, perforator diameter, Clinical Etiology Anatomy Pathophysiology class 4, 5, or 6, and Venous Clinical Severity Score. Radiographic analysis of group A revealed concordance of a treated pathologic perforator with an ipsilateral central venous stenosis in 53.3% of patients, and a higher frequency of common iliac vein stenosis (50% vs 21.4%, P = .024) and external iliac vein stenosis (20% vs 0%, P = .012) compared with the contralateral limbs. When separated by the left or right limb, the left limbs exhibited a greater degree of common iliac vein stenosis as compared with the contralateral limbs (50.7% ± 20.9% vs 16.3% ± 16.5%, P < .001) as well as a greater frequency of >50% common iliac vein stenosis (46.7% vs 13.3%, P = .046). The right limbs exhibited a greater frequency of >50% external iliac vein stenosis as compared with the contralateral limbs (33.3% vs 0%, P = .022). CONCLUSIONS: This study suggests that patients with severe chronic venous insufficiency who undergo treatment for a pathologic perforator may have additional ipsilateral central venous pathology, supporting the presence of multilevel disease. Additional axial imaging might unmask central venous pathology and provide another option for treatment.

Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins.

Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFß inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins via activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.