Portal Hypertensive Vasculopathy Research Articles

Portal hypertensive vasculopathy - An entity worth remembering with non-neoplastic gastrointestinal lesions.

Portal hypertensive vasculopathy (PHV) represents an increase in the pressure in the portal circulation. This increased pressure leads to changes in the mucosa that can be appreciated endoscopically as well as histopathologically. Lesions can be observed in the entire gastrointestinal tract (GIT) including stomach, duodenum, jejunum and colon. The histological changes are appreciated mainly in the mucosal and submucosal blood vessels. A knowledge of these lesions as well as the changes helps in separating them from other close differentials with specific treatment to be instituted. The pathogenesis of the hemodynamic changes is not well-understood. The underlying factor is increased portal pressure. Studies indicate, that besides increased portal pressure other factors in combination led to the observed changes. Portal hypertensive gastropathy (PHG) is seen in the gastric body and fundus, while varices are noted in the cardia and fundus. Changes may be seen in the small intestine and throughout the colon with anorectal varices. Histopathological changes include dilated, congested and ectatic capillaries and edema in the lamina propria besides a large spectrum of other histopathological changes. Mucosal capillaries with thick irregular wall show absence of red blood cells in the lumen. Thickening of the vessel wall serves as a better marker than the vascular diameter when portal hypertension (PHT) is considered. Long standing cases may show fibrosis in lamina propria. At times, these changes may lead to occult gastrointestinal bleeding. Important differentials need to be ruled out in all the cases as the treatment and the outcome of all differs. Endoscopically or histopathologically if the mucosal changes are observed they should not be overlooked and a detailed work-up must be carried out.

Pathological abnormalities in splenic vasculature in non-cirrhotic portal hypertension: Its relevance in the management of portal hypertension.

BACKGROUNDPortal hypertension (PH) is associated with changes in vascular structure and function of the portosplenomesenteric system (PSMS). This is referred to as portal hypertensive vasculopathy. Pathological abnormalities of PSMS has been described in the literature for cirrhotic patients. Raised portal pressure and hyperdynamic circulation are thought to be the underlying cause of this vasculopathy. In view of this, it is expected that pathological changes in splenic and portal vein similar to those reported in cirrhotic patients with PH may also be present in patients with non-cirrhotic PH (NCPH).AIMTo investigate pathological abnormalities of splenic vein in patients with NCPH, and suggest its possible implications in the management of PH.METHODSA prospective observational study was performed on 116 patients with NCPH [Extrahepatic portal vein obstruction (EHPVO): 53 and non-cirrhotic portal fibrosis (NCPF): 63] who underwent proximal splenorenal shunt (PSRS), interposition shunt or splenectomy with devascularization in JIPMER, Pondicherry, India, a tertiary level referral center, between 2011-2016. All patients were evaluated by Doppler study of PSMS, computed tomography porto-venogram and upper gastrointestinal endoscopy. An acoustic resonance forced impulse (ARFI) scan and abdomen ultrasound were done for all cases to exclude cirrhosis. Intraoperative and histopathological assessment of the harvested splenic vein was performed in all. The study group was divided into delayed and early presentation based on the median duration of symptoms (i.e. 108 mo).RESULTSThe study group comprising of 116 patients [77 (66%) females and 39 (34%) males] with NCPH had a median age of 22 years. Median duration of symptoms was 108 mo. The most common presentation in both EHPVO and NCPF patients was upper gastrointestinal bleeding (hematemesis and melena). The ARFI scan revealed a median score of 1.2 (1.0-1.8) m/s for EHPVO and 1.5 (0.9-2.8) m/s for NCPF. PSRS was performed in 84 patients (two of whom underwent interposition PSRS using a 10 mm Dacron graft); splenoadrenal shunt in 9; interposition mesocaval shunt in 5; interposition 1st jejunal to caval shunt in 1 patient and devascularization with splenectomy in 17 patients. Median pre-splenectomy portal pressure was 25 (range: 15-51) mm Hg. In 77% cases, the splenic vein was abnormal upon intraoperative assessment. Under macroscopic examination, wall thickening was observed in 108 (93%), venous thrombosis in 32 (28%) and vein wall calcification in 27 (23%) cases. Upon examination under a surgical magnification loupe, 21 (18%) patients had intimal defects in the splenic vein. Histopathological examination of veins was abnormal in all cases. Medial hypertrophy was noted in nearly all patients (107/116), while intimal fibrosis was seen in 30%. Ninety one percent of patients with intimal fibrosis also had venous thrombosis. Vein wall calcification was found in 22%, all of whom had intimal fibrosis and venous thrombosis. The proportion of patients with pathological abnormalities in the splenic vein were significantly greater in the delayed presentation group as compared to the early presentation group.CONCLUSIONPathological changes in the splenic vein similar to those in cirrhotic patients with PH are noted in NCPH. We recommend that PH in NCPH be treated as systemic and pulmonary hypertension equivalent in the gastrointestinal tract, and that early aggressive therapy be initiated to reduce portal pressure and hemodynamic stress to avoid potential lethal effects.

Extrahepatic Portal Venous Obstruction: What Should be the Mainstay of Treatment?

The two cornerstones of management for Extrahepatic portal vein obstruction (EHPVO) are endotherapy and surgery [Porto-systemic shunts (PSS)/Mesorex bypass (MRB)]. Endotherapy is the mainstay of treatment for acute variceal bleed control and has also been used extensively for secondary prophylaxis till variceal eradication is achieved. However, long-term follow-up beyond endoscopic eradication of esophageal varices (EEEV) indicates that there are numerous delayed bleed and non bleed sequelae of EHPVO, which merit surgery as a definitive procedure to decompress the hypertensive portal venous system. While endotherapy obliterates natural porto-systemic collaterals in the gastroesophageal region, persistently raised portal pressures manifest as an increase in secondary isolated gastric varices, ectopic varices, portal hypertensive vasculopathy, issues related to massive splenomegaly, portal biliopathy, growth retardation and hence impaired quality of life (QOL). An ideal management strategy should address both bleed and non-bleed consequences of EHPVO and translate into a near normal QOL. Further, MRB has opened up new dimensions to the management philosophy of EHPVO. This review article critically evaluates the role of surgery and endotherapy based on available literature and authors' own experience.Surgery and endotherapy are complementary. However, with increasing duration of follow-up post EEEV, it is evident that there is resurgence in the role of surgery (PSS/MRB) as a single one time definitive procedure for alleviating all bleed and delayed non bleed sequelae of EHPVO.Surgery for EHPVO (PSS/MRB) should not be allowed to become a dying art and future generations of surgeons should continue to receive training in this specialized area of surgery.

Protective effects of hydrogen sulfide on portal hypertensive vasculopathy in rabbits by activating AKT-NF-κB pathway.

The role of hydrogen sulfide (H2S) in portal hypertension (PH)-induced esophagus-gastric junction vascular lesions in rabbits was observed. The rabbit PH models were established. The animals were randomly divided into the following groups: normal, PH, PH+sodium hydrosulfide (PH+S), PH+propargylglycine (PH+PPG). The plasma H2S levels, apoptosis of esophageal-gastric junction vascular smooth muscle cells, and the expression of nuclear transcription factor-κB (NF-κB), p-AKT, IκBa and Bcl-2 were detected. The cystathionine γ lyase (cystathionine-gamma-splitting enzyme, CSE) in the junction vascular tissue was measured. The results showed that the plasma H2S levels and the CSE expression levels had statistically significant difference among different groups (P<0.05). As compared with PH group, plasma H2S levels were declined obviously (11.9±4.2 vs. 20.6±4.5, P<0.05), and CSE expression levels in the junction vascular tissue were notably reduced (1.7±0.6 vs. 2.8±0.8, P<0.05), apoptosis rate of vascular smooth muscle cells per unit area was significantly decreased (0.10±0.15 vs. 0.24±0.07, P<0.05), and the expression levels of p-AKT and NF-κB were significantly decreased (2.31±0.33 vs. 3.04±0.38, P<0.05; 0.33±0.17 vs. 0.51±0.23, P<0.05), however, IκBa and Bcl-2 expression increased obviously (5.57±0.17 vs. 3.67±0.13, P<0.05; 0.79±0.29 vs. 0.44±0.36, P<0.05) in PH+PPG group. As compared with PH group, H2S levels were notably increased (32.7±7.3 vs. 20.6±4.5, P<0.05), the CSE levels in the junction vascular tissue were significantly increased (6.3±0.7 vs. 2.8±0.8, P<0.05), apoptosis rate of vascular smooth muscle cells per unit area was significantly increased (0.35±0.14 vs. 0.24±0.07, P<0.05), and the expression levels of p-AKT and NF-κB were significantly increased (4.29±0.49 vs. 3.04±0.38, P<0.05; 0.77±0.27 vs. 0.51±0.23, P<0.05), yet IκBa and Bcl-2 expression decreased significantly (3.23±0.24 vs. 3.67±0.13, P<0.05; 0.31±0.23 vs. 0.48±0.34, P<0.05) in PH+S group. It is concluded that esophagus-gastric junction vascular lesions happen under PH, and apoptosis of smooth muscle cells is declined. H2S can activate NF-κB by the p-AKT pathway, leading to the down-regulation of Bcl-2, eventually stimulating apoptosis of vascular smooth muscle cells, easing PH. H2S/CSE system may play an important role in remission of PH via the AKT-NF-κB pathway.

Celiac disease suspected at endoscopy in patients with chronic liver disease

Endoscopic findings of celiac disease have high specificity and sensitivity. We evaluated records of 137 consecutive patients who had endotherapy for variceal hemorrhage, and who had features of celiac disease at endoscopy; patients who had such markers at endoscopy had undergone duodenal histology and serology. Thirty-one patients had changes of portal hypertensive vasculopathy in the duodenum, 8 had scalloping, and 6 had mosaic pattern; 3 patients also had decreased fold height or sparse folds in the descending duodenum. Six of these 8 patients had positive serology and histology suggestive of celiac disease. Endoscopic evaluation resulted in diagnosis of CD in 4.37% patients of chronic liver disease undergoing endotherapy.

Resultados de la realización de colonoscopia en la evaluación de pacientes cirróticos candidatos a trasplante hepático

To assess the presence of preneoplastic and neoplastic colonic lesions, as well as those related to portal hypertensive vasculopathy, and their association with liver disease in cirrhotic patients who are candidates for orthotopic liver transplantation (LT).Between October 2004 and December 2005, colonoscopy was performed in 92 patients who were LT candidates, aged >50 years old or aged <50 years old but with clinical indications.Eighty-eight percent of the patients were > 50 years old, the mean age was 55.3 years (29-69) and 81.5% were males. The main etiology of cirrhosis was alcoholic (46.7%), and 21% were Child-Pugh class A. No abnormalities were detected in 20.7%. Polyps were discovered in 38% (35/92) of patients (adenomatous 65.2%; tubular type 86.7%). Six patients with adenomatous polyps had mild dysplasia, and one asymptomatic patient had a well-differentiated adenocarcinoma. An association was found between polyps and male sex (44% males vs 17.6% females; p=0.044) and Child-Pugh grade (63.2% Child A vs 32.9% Child B/C, p=0.016) but not with serum levels of carcinoembryonic antigen (CEA), age or etiology of liver disease. Portal hypertensive colopathy was found in 23.9%, rectal varices in 7.6% and internal or mixed hemorrhoids in 52.3%.The prevalence of preneoplastic and neoplastic colonic lesions may support the use of colonoscopy in LT candidates aged >50 years-old or with a history suggesting lower gastrointestinal bleeding or other abnormalities.

Splenic vasculopathy in portal hypertension patients

To investigate the interaction between portal hypertension, splanchnic hyperdynamic circulation and splanchnic vasculopathy by observing splenic arterial and venous pathological changes and the ro1e of extra-cellular matrix in the pathogenesis of portal hypertensive vasculopathy by measuring the expression of type I and type III procollagen mRNA in splenic venous walls of portal hypertensive patients. Morphological changes of splenic arteries and veins taken from portal hypertensive patients (n=20) and normal controls (n=10) were observed under optical and electron microscope. Total RNA was extracted and the expression of type I and type III procollagen mRNA in splenic venous walls of portal hypertensive patients (n=20) was semi-quantitatively detected using reverse transcription-polymerase chain reaction (RT-PCR). Under optical microscope, splenic arterial intima was destroyed and internal elastic membrane and medial elastic fibers of the splenic arterial walls were degenerated and broken. Splenic venous intima became remarkably thick. Endothelia1 cells were not intact with formation of mural thrombus. The tunica media became thickened significantly due to hypertrophy of smooth muscles. Fibers and connective tissues were increased obviously. Under electron microscope, smooth muscle cells of the splenic arteries were degenerated and necrotized. Phenotypes of smooth muscle cells changed from constrictive into synthetic type. Red blood cells and platelets accumulated around the damaged endothelial cells. Synthetic smooth muscle cells were predominant in splenic veins and their cytoplasma had plentiful rough endoplasmic reticulum ribosomes and Golgi bodies. Along the vascular wall, a lot of collagen fibers were deposited, the intima was damaged and blood components accumulated. There was no significant difference in the expression of type I procollagen mRNA in splenic venous wall between the patients with portal hypertension and those without portal hypertension (P>0.05), but the expression of type III procoagen mRNA was significantly stronger in the patients with portal hypertension than in those without portal hypertension (P<0.01). Type III procollagen and collagen might be important extra-cellular matrix resulting in neointimal formation and vascular remodeling in the pathogenesis of portal hypertensive vasculopathy. The pathological changes in splenic arteries and veins exist in portal hypertension patients. There might be an interaction between portal hypertension, splanchnic hyperdynamic circulation and splanchnic vasculopathy.

Expression of local angiotensinogen mRNA and activation of local nuclear factor-kappaB in vasculopathy of portal hypertension

To investigate the expression of local angiotensinogen mRNA and activation of local nuclear factor-kappaB in vasculopathy of portal hypertension and to discuss their role in the pathogenesis of portal hypertensive vasculopathy. RT-PCR was used to detect the expression of local angiotensinogen mRNA in 28 specimens of splenic artery and vein obtained during operation of elective separation and amputation on 28 portal hypertension (PH) patients, 20 males and 8 females, aged 51.7 +/- 10 (30 - 65), and in 12 specimens of normal vessel from 12 patients undergoing splenectomy due to traumatic rupture of spleen. Chemiluminescent electrophoretic mobility shift assay (EMSA) was used to detect the activation of NF-kappaB in splenic artery and vein. The levels of local angiotensinogen mRNA in the splenic artery and vein of PH group were 0.48 +/- 0.21 and 0.43 +/- 0.16 respectively, both significantly higher than those in the control group (0.23 +/- 0.12 and 0.18 +/- 0.10, both P < 0.05). There was no significant difference between the splenic artery and vein in the expression of local angiotensinogen mRNA in PH group. The activation levels of NF-kappaB in splenic artery and vein of the PH patients were 1.44 +/- 0.23 and 1.38 +/- 0.18 respectively, both significantly higher than those of the control group (0.19 +/- 0.20 and 0.25 +/- 0.16 respectively, both P < 0.05). However, there was no significant difference in the activation levels of NF-kappaB between the splenic artery and vein in the PH patients (P > 0.05). Local angiotensinogen and activation of NF-kappaB maybe one of the factors in the pathogenesis of portal hypertensive vasculopathy, which can cause and advance portal hypertensive vasculopathy.

Acute gastrointestinal bleeding from portal hypertensive gastropathy: prevalence and clinical features.

The clinical and endoscopic features of patients diagnosed with acute bleeding due to portal hypertensive gastropathy (PHG) were evaluated. Acute bleeding from PHG was diagnosed in 12 patients (0.8%) of 1496 patient admissions prospectively evaluated by our Gastrointestinal Bleeding Team over a 3-yr period, and accounted for 8% of nonvariceal bleeding diagnosed in patients with liver disease. The median age of PHG patients (8M:4F) was 66 yr (range, 37-72). The most common underlying liver disease was alcoholic cirrhosis (five patients). The majority of patients presented with melena. There was no hemodynamic instability. Six patients had prior sclerotherapy. Esophageal varices, grades 1 (five patients) and 2 (three patients), were present. Severe PHG was encountered in seven patients. There was no correlation between the presence or absence of varices, the grade of esophageal varices, and prior sclerotherapy on the severity of PHG or continued bleeding. The mean hospital stay was 6 days. An average of 4 units of blood was transfused per patient (range, 2-8). Continued bleeding occurred in nine patients (75%), one of whom had mild PHG. Two patients with continued bleeding subsequently were diagnosed with portal hypertensive vasculopathy distal to the stomach. There was one episode of encephalopathy and no related mortality. Acute (overt) bleeding from PHG is uncommon, likely to recur, and can evolve into a pattern of chronic blood loss.