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  Table of Contents    
REVIEW ARTICLE  
Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 32-42
Portal hypertensive vasculopathy – An entity worth remembering with non-neoplastic gastrointestinal lesions


1 Department of Pathology and Gastroenterology, MLN Medical College, Prayagraj, Uttar Pradesh, India
2 Department of Pathology, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India

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Date of Submission22-Feb-2021
Date of Acceptance18-May-2021
Date of Web Publication7-Jun-2021
 

   Abstract 


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.

Keywords: Colopathy, enteropathy, gastropathy, mucosa, portal hypertension, vasculopathy.

How to cite this article:
Misra V, Agrawal R, Misra SP. Portal hypertensive vasculopathy – An entity worth remembering with non-neoplastic gastrointestinal lesions. Indian J Pathol Microbiol 2021;64, Suppl S1:32-42

How to cite this URL:
Misra V, Agrawal R, Misra SP. Portal hypertensive vasculopathy – An entity worth remembering with non-neoplastic gastrointestinal lesions. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jun 23];64, Suppl S1:32-42. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/32/317906





   Introduction and Background Top


Portal hypertensive vasculopathy (PHV) is a condition that describes the pathologic changes and mucosal abnormalities observed in the GIT of patients with PHT. Advent of video capsule endoscopes (VCE) made the possibility of better visualisation of the changes in the GIT. PHT is defined as increased pressure in the portal circulation, as estimated by measurement of hepatic venous pressure gradient (HVPG) which is the difference between the wedge and the free hepatic venous pressures. HVPG of more than 6 mmHg is considered abnormal.[1],[2] It is considered to be clinically significant when the reading is more than 10 mmHg and becomes severe when the HVPG is more than 12 mmHg.[3],[4] PHT results due to a combination of two hemodynamic changes occurring simultaneously–increased intrahepatic resistance to flow of blood following liver cirrhosis and, increase in the splanchnic blood flow following vasodilatation of the splanchnic vascular bed.[4]

McCormack et al.,[5] in 1985, first described the microcirculatory changes observed on endoscopy and histopathology in the gastric mucosa, due to PHT and termed it as congestive gastropathy. Later, the term portal hypertensive gastropathy (PHG) was coined. PHG is a distinct entity that was recognized as an important cause of upper gastrointestinal hemorrhage in patients with PHT (8-7% episodes of bleeding) in the West.[5–7] Further more terms like portal hypertensive intestinal vasculopathy and colopathy were also used for describing changes in the small intestine and colon respectively.[6]


   Epidemiology and Clinical Presentation Top


PHV should be suspected when there is gastrointestinal bleeding or anemia without any associated finding along with signs of PHT such as ascites, splenomegaly, thrombocytopenia, or if the HVPG is more than 10 mmHg.[8],[9] Prevalence of PHV ranges between 15%-25% when traditional endoscopic modalities like duodenoscopy, push enteroscopy or colonoscopy with ileal intubation were used but increased to 40%-82% in studies where VCE was used.[8],[9],[10],[11],[12],[13],[14],[15],[16] Prevalence of each finding also varies depending on the type of endoscope use.

PHV may remain asymptomatic or can present as anemia, melena, hematochezia and, hematemesis. Red spots (22.2%-62.2%) and angiodysplasia-like lesions (24.3%-55.7%) were more common than inflammatory-like lesions (5.6%-13%) or varices (8.1%-38.9%). Mixed lesions were reported in up to 22.3% patients.[11],[12],[14],[16] Small bowel varices accounted for 12%-35% of all ectopic varices.[17] Polyps were rare and less common in the small intestine (0.3%) as compared to stomach (0.6%). The bleeding risk associated with mild PHG is nearly 3.5–31%, which increases to 38–62% in severe cases. Fatal or life threatening small intestine variceal hemorrhage with a classic triad of hematochezia (without hematemesis), PHT, and previous intra-abdominal surgery can be present.[8],[9],[11],[17] Large esophageal varices, history of sclerotherapy, endoscopic variceal ligation, portal hypertensive colopathy (PHC), PHG, anemia, thrombocytopenia, splenomegaly, multiple signs of PHT can be observed on computerized tomographyscan, and, more commonly in child Pugh type C patients.[11],[12],[16],[18]

Active bleeding has been reported in 17.8% patients.[8] In some of the patients with cirrhosis, mild but chronic hemorrhage may occur into the GIT. Both esophageal and gastric varices associated with PHG may lead to long standing but gradual loss of blood leading to iron deficiency anemia.[19] Diagnosis of iron-deficiency anemia poses great difficulty especially in patients with cirrhosis because the RBC indices such as MCV and MCH are less reliable since deficiency of other vitamins and the altered lipoprotein composition of the RBC membrane also plays a role. Serum ferritin levels are helpful in diagnosing iron-deficiency anemia but, being an acute phase reactant its level falsely rises in chronic inflammatory condition of liver cirrhosis.[20] Portal hypertensive duodenopathy (PHD) is an uncommon feature and is the least common gastrointestinal manifestation of the PHT syndrome.

Primignani et al.,[21] observed that the prevalence of PHG was only 56% in patients with newly diagnosed cirrhosis which rose to 75% in patients with previously diagnosed cirrhosis and no prior variceal bleeding, and further rose to 91% in patients with previously diagnosed cirrhosis and prior variceal bleeding treated with sclerotherapy. Esophageal varices may progress from small to large with high chances of bleeding. The onset of bleeding may be marked by the variceal size, severity of cirrhosis falling into child B or C class, pressure in the varices more than 12 mm Hg and endoscopy showing presence of red spots.[22]

The diagnosis of PHV should not be made on histopathology alone, but rather in conjunction with other clinical and endoscopic findings. CT scan findings of PHT such as esophageal and, gastric varices, peri umbilical varices, PHG, PHE, PHC, portal hypertensive cholecystopathy, splenomegaly, and ascites are the radiologic predictors of PHV. Each of the CT findings is given one point with a maximum score of 6 points. A CT score of >3 is associated with PHE. CT and magnetic resonance angiographies can also aid in the evaluation of vascular origin of the ectopic varices.[11]


   Pathogenesis Top


Several researchers using VCE laser-Doppler flowmetry and/or reflectance spectrophotometry observed gastric mucosal perfusion to be increased in patients with PHG. The pathogenesis of the hemodynamic changes in PHV is inadequately understood.[23] Patients with cirrhosis have persistent vasodilation of the arterial vessels causing increased portal venous inflow leading to PHT.[24] The entire GIT can be affected by PHT causing esophageal varices, gastric varices, PHG, PHE and PHC.[5],[25],[26]

Hyperdynamic congestion with a change in the gastric mucosal blood flow causes activation of cytokines, growth factors, and hormones that further enhance the hyperdynamic gastric circulation.[27] This vascular congestion alters the gastric microcirculation which is characterized by increased intrahepatic vascular resistance, generalized splanchnic vasodilatation, decreased mean arterial pressure, decreased systemic vascular resistance, increased gastric blood flow and, decreased gastric mucosal flow.[28] Cirrhotic patients have dilated and small gastric blood vessels including arterioles, pre-capillaries, capillaries, submucosal veins, and subserosal veins, with a decrease in the arteriovenous resistance and straightening of the arterioles.

The hyperdynamic circulation impairs the gastric mucosal defense mechanism causing release of proinflammatory mediators, and inhibition of growth factors rendering the gastric mucosa more susceptible to injury, impaired healing, increased erosions, ulcerations and bleeding.[29],[30],[31],[32],[33] Gastric mucosa is highly susceptible especially to hypoxia and noxious factors such as aspirin and alcohol.[27],[34] Cirrhosis with consequent increased hepatic vascular resistance and portal venous inflow remains the most common etiology of PHT. However, reports in patients with non–cirrhotic PHT such as in polycystic liver disease, congestive heart failure, Budd-Chiari syndrome, portal vein thrombosis, Schistosomiasis are also available. Many a times the cause remains idiopathic [Figure 1].[26],[27],[28],[35],[36],[37],[38],[39]
Figure 1: Showing the possible mechanism of pathogenesis of portal hypertension

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PHV shows three phenotypes during development: ischemia-reperfusion, inflammatory cell infiltration, and angiogenesis. In the ischemia-reperfusion phenotype, PHT and venous stasis are associated with mucosal hypoxia, muscularis vasodilation, and opening of arteriovenous shunts leading to a redistribution of the blood flow within the intestine.[40] In experimental rats, mast cell protease-II induced degranulation of mucosal mast cells leading to increased intestinal permeability, enhanced uptake of antigens and bacteria and bacterial translocation to the mesenteric lymph nodes were observed.[41] Furthermore, there is induction of mesenteric adenitis and small bowel inflammatory response. In the angiogenic phenotype, goblet cell hyperplasia representing epithelial remodeling leads to submucosal angiogenesis and fibrosis of muscularis mucosa.[42]

The mechanism by which mucosal red spots and gastric vasodilatation appear in patients with PHT remains unknown. PHG is more pronounced in patients having esophageal varices but is uncommon in patients with varices in the gastric fundus or with splenorenal shunt. A possible reason could be that due to angio-architectural differences there is a much higher collateral blood flow resulting in a significant portal decompression. The severity of PHG directly correlates with the rise in portal pressure. Variceal pressure is similar in patients with or without PHG and not all patients with PHT show features of PHG. So it can be postulated that other factors besides PHT may contribute to these mucosal lesions.[43]

Humoral factors are also known to be involved in the pathogenesis of PHG. Increased circulating levels of vasodilators, or a reduced sensitivity to endogenous vasoconstrictors play an important role. This hypothesis is supported by the increased plasma levels of vasodilators such as glucagon, norepinephrine, VIP, gastrin and secretin. Glucagon significantly increases the portal pressure causing splanchnic vasodilation and also renders the gastric mucosa more susceptible to toxins especially ethanol.[29] However, it has no role in the pathophysiology of PHG. Few endothelial factors such as prostaglandins especially PGE2, Nitric Oxide (NO) and vascular endothelial growth factor (VEGF) may cause increased vascularity of stomach and intra-abdominal viscera.[44],[45] Tumor necrosis factor alpha (TNF-α) stimulates the release of NO and prostacyclins thus directly contributing to the hyperdynamic circulation as observed in PHG. Prostacyclin, a vasodilator that inhibits gastric acid secretion, has been proposed as a mediator of the hyperdynamic circulation in PHG. Low prostaglandin levels caused marked decrease in the gastric perfusion velocity whereas Misoprostol, a PGE2 analogue, significantly increases the gastric perfusion.

A high serum level of Autotaxin, involved in liver fibrosis has been associated with advanced stage of cirrhosis, presence of esophageal varices, and PHG [Figure 2].[46] Helicobacter pylori (H. pylori) infection has not been linked with PHG.[28],[39],[40],[41],[43],[47],[48],[49],[50],[51],[52]
Figure 2: Showing various factors implicated in portal hypertensive gastropathy

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Edema of the gastric lamina propria secondary to chronic mucosal ischemiaon endoscopy shows a “mosaic” pattern. Impaired oxygenation, lower gastric mucosal oxygen saturation and, decreased mucosal blood flow have been reported.[53],[54],[55] Makhija et al.,[29] reported a decrease in gastric mucosal blood flow, an increase in blood flow in the submucosal and muscular layers, and a net increase in the total gastric blood flow. Increased gastric mucosal apoptosis and decreased mucosal proliferation are likely to promote mucosal injury. Pan et al.,[48] believed that the severity of PHG strongly correlated with hypersplenism.

The angiogenic and vasoactive chemicals released play important role in causing vascular syndromes including PHT, overflow of the splanchnic vessels leading to fatal hepatorenal syndrome, abnormal angiogenesis, development of shunts, porto-pulmonary syndrome, hepatopulmonary syndrome and systemic hyperdynamic circulation.[56] Porto-pulmonary hypertension (PoPH) is a life-threatening condition with increases pressure in the pulmonary arteries in the background of PHT. It is defined as raised pulmonary arterial pressure with mean pressure at rest more than 25 mmHg and 30 mmHg on exertion, raised pulmonary vascular resistance of more than 240 dynes s-1 cm-5 along with pulmonary capillary wedge pressure less than 15 mmHg.[57] Both cirrhotic and non-cirrhotic patients can be affected. The exact etiology is unknown but role of genetics, shear stress of the pulmonary vessel wall and various mediators has been emphasized. Nearly 3-10% of end stage liver disease patients may develop PoPH.[58]

Furthermore, POPH has been reported in patients with PHT of non-hepatic etiology so it has been postulated that the underlying pathology is that of PHT rather than liver disease per se.[59] Combined portal and pulmonary vasculopathies lead to complicated hemodynamics and therapeutic issues. Hepatopulmonary syndrome is a trial of hepatic disease, ectasia of the pulmonary vessels and impaired oxygenation. It is defined as a difference in the alveolar – arterial oxygen in the room air of more than 15 mmHg in patients aged 64 years or elder, associated with or without hypoxemia following intrapulmonary vasodilatation in the presence of hepatic dysfunction.[60]

In experimental animals with PHT, reduced acid secretion, increased hydrogen ion back diffusion, reduced prostaglandin biosynthesis, decreased gastric mucosal blood flow, decreased bicarbonate output, increased gastric permeability, reduced gastric epithelial proliferation and a thinner layer of gastric mucosa have been observed. Elevated levels of injurious free radicals and lysosomal enzymes along with decreased levels of protective antioxidant enzymes in gastric mucosal biopsies have been demonstrated.[31] Kawanaka et al.,[61] observed impaired endoplasmic reticulum serine/threonine kinase-2 (ERK2) activation after oxidative stress in rats. ERK2 normally protects against cellular stress by inducing cell proliferation in the gastric mucosa. Decreased mucin production impairs gastric mucosal protection, decreased thickness of mucosal gel layer, surface epithelial cell intracellular pH, and oxygenation of gastric mucosal surface in experimental rats with PHG. A decrease in the number of angiogenic buds after injury to PHG mucosa has been shown.


   Endoscopic Findings Top


Different scoring and grading systems have been put forward to classify the endoscopic findings observed in PHV. Depending on the site of obstruction to the blood flow, PHT can be divided into pre-hepatic, intrahepatic or post-hepatic types. De Palma et al.,[12] reported a landmark study using VCE on lesions in the small bowel in patients with PHT and anemia. They categorized grades 1 and 2 lesions as mucosal inflammatory like abnormalities (edema, erythema, atrophy, granularity, friability, and/or spontaneous bleeding) and, vascular lesions (cherry red spots, telangiectasias, angiodysplasia-like lesions, and varices), respectively. Abdelaal et al.,[18] classified PHT lesions into 4 subtypes: inflammatory-like lesions, red spots, angio-ectasia, and small bowel varices. They created a scoring system based on VCE findings, giving each type one point with an additional point for multiple i.e. more than two lesions. [Table 1]
Table 1: Endoscopic Findings Observed and Reported by Different Authors

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Kodama et al.,[62] proposed a PHT scoring system based on double balloon enteroscopy findings classifying them into 2 categories: villous abnormalities and vascular lesions. They further subclassified each category into 3 subtypes: edema, atrophy and reddening for villous abnormalities, and angiodysplasia-like lesions, dilated/proliferated vessels, and varices for vascular lesions. A single point was given for each type, resulting in a scoring system with a maximum of 6 points. [Table 1] However, this scoring system was not significantly associated with any of the clinical variables except for the presence of ascites.

The vascular lesions carry a higher chance of profuse bleeding as compared to the inflammatory lesions.[11],[18] Duodenal varices are most common in the duodenal bulb and the second portion of duodenum. Jejunal and ileal varices are common in patients with previous abdominal surgery due to development of porto-systemic collaterals after bowel anastomosis. Other endoscopic observations include mucosal edema, granularity, patchy erythematous mucosa, and herring roe appearance (rounded blunted villi in a background of congested mucosa with granularity) [Figure 3]a, friability, loss of vascularization, hyperthermia, flat red spots, angiodysplasia-like lesions, pigmented black-brown spots, mucosal granularity, ulcers, reticulated mosaic-like pattern of the mucosa [Figure 3]b, protruding red bumps, inflammatory polyps, and varices.[8],[11],[13],[15],[52],[63],[64] Erosions and ulcers are the most common findings [Figure 3]c.[65] There has been a single report of solitary duodenal polyp [Figure 3]d.[66] Multiple sessile polyps in the duodenum have been reported by Pillai et al.[67]
Figure 3: (a) Endoscopy showing portal colopathy with friable congested mucosa, (b) Endoscopy showing classical snake skin and mosaic pattern in stomach, (c) Showing severe gastropathy with bleeding spots, (d) duodenal polyp in a patient of portal hypertension

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Grade 2+ or larger esophageal varices, PHG, PHC and Childs–Pugh class C cirrhosis were found to be significantly associated with PHE.[21] A fine pink speckling or scarlatina rash, superficial erythema on the surface of the gastric rugae giving a striped appearance, also termed as snake-skin appearance or “mosaic pattern” were classified as mild changes. Presence of discrete cherry-red spots and diffuse hemorrhagic gastritis are labeled as severe changes [Figure 3].

PHT produces changes in the colorectal mucosa similar to those seen in the mucosa of upper GIT. Histological changes of PHC were found to be distributed throughout the colon without any predilection to a specific site. Gonzalez et al.,[68] in an experimental study, mainly found lesions in the ascending colon and rectum. This further illustrates the dissociation between endoscopic and histological appearances in PHV. Solitary vascular ectasias were observed predominantly in the transverse and ascending colon while, diffuse vascular ectasias are observed mainly in the right colon. Redness has been observed in the entire colon and blue vein in the rectum.[69] Colonoscopy revealed ectasia, mucosal edema, friability, mosaic – pattern mucosa irregularity and dilatation of the vessels, solitary and diffuse red spots and, colorectal varices. However, these findings are not specific and do not correlate with the etiology, degree of cirrhosis, effect of treatment or associated risk factors. Rectal varices are present more than 4 cm above the anal verge. They are dark blue in color, and do not prolapse on endoscopy. These varices are different from hemorrhoids, due to their origin proximal to the dentate line.

Different endoscopic findings may require different therapeutic interventions.[9] Treatment of polypoid enteropathy depends on the number of polyps and endoscopic accessibility. A polypectomy can be safely performed if the polyp is single, accessible and amenable for endoscopic removal. Band ligation and variceal obturation are endoscopic interventions of choice for hemostasis in variceal rupture.[17],[70],[71]


   Differential Diagnosis Top


The differential diagnosis based on the endoscopic findings include ischemia, inflammatory bowel disease, radiation changes, celiac disease, arteriovenous malformations, familial adenomaous polyposis and, hereditary hemorrhagic telangiectasia. A detailed clinical history and examination are helpful. Histopathology however remains the gold standard.

Angiodysplasia-like lesions in patients with PHV may pose difficulty in differentiating from angioectasia of the small bowel secondary to degenerative changes following chronic renal disease, aortic stenosis, or elderly age. The former are multiple and diffuse, while the latter are usually fewer in number, smaller, and less widely distributed.[72]

The most important differential of PHG is gastric antral vascular ectasia (GAVE) since they have distinct pathologic, clinical, and endoscopic features, and treatment protocol. PHG can present at any age and mainly involves the gastric body. The main predictors of PHG are PHT and severe liver disease.[73] GAVE typically affects the antrum and can present in patients not suffering from PHT or liver diseases. It manifests as longitudinal red stripes that are flat or slightly raised, i.e. 'striped-type' or 'watermelon stomach.' 'Diffuse-pattern GAVE' occurs in patients with PHT involving the gastric cardia, duodenum, and small bowel. Another change observed in GAVE as compared to severe PHG is an increase in the number of mucosal vessels exhibiting fibrin thrombi, ectasia and spindle cell proliferation due to increased number of smooth muscles and myofibroblasts. Fibrohyalinosis is more frequent in GAVE than in severe PHG and is an important diagnostic criterion for differentiating between the two entities.[74]

It is important to differentiate the vascular changes of colopathy from angiodysplasia of the colon which may lead to massive lower GI bleeding. Lesions of angiodysplasia occur in elderly and are fewer, smaller, and less widely distributed as compared to those of PHT. Angiodysplasia are secondary to degenerative changes, while PHT occurs mainly due to increased venous pressure. Histopathology shows dilatation of blood vessels and edema in the mucosa, along with increased lymphoplasmacytic infiltration in the lamina propria. Association with cirrhosis and endoscopic appearances may also help in the differentiation.


   Histopathology Top


The endoscopic features of the gastrointestinal mucosa have been well documented, but the histologic changes are still confusing lacking well-defined and distinct diagnostic criteria.[6],[43],[50],[75],[76] PHT leads to hemodynamic disturbances throughout the GIT with predominant changes in the mucosal vessels especially venules and capillaries.[77],[78] These changes resembling congestion may be due to the use of pinch avulsion technique in the biopsy forceps.[6]

The full spectrum of pathology findings is still unknown. The pathological changes in stomach may be secondary to impairment of gastric microcirculation. Different reports on the gastric mucosal capillaries are available. Misra et al.,[78] reported thicker capillary walls, while, Ichikawa et al.,[79] reported a narrower diameter and lesser capillary angiogenesis. Prominent cytoplasm in the endothelial cells of mucosal micro-vessels leading to narrowing of the capillary lumina was confirmed by electron microscopy which showed significantly larger cytoplasmic and pinocytic vesicular areas and increased thickness of the capillary basement membrane. Additionally, there was observed arterialization of submucosal veins and thickening of arterioles in the muscularis mucosae and submucosa.[80]

Microscopy shows angiogenesis, congestion, edema, apoptosis, fibrosis, and villous change. Angiogenesis and neovascularization are important vascular phenomenon that mediate adaptation and accommodation of the high portal pressure.[65] Non-helicobacter pylori gastritis is the most common finding on histology. Hyperplastic polyp was more common in patients with PHT than in the control group. Malignancy is however rare.

The frequency and severity of PHG strongly correlates with the severity of PHT as indicated by HVPG, esophageal intra-variceal pressure and presence or size of esophageal varices.[21],[38],[81] Patients with severe PHG had elevated HVPG, high hepatic sinusoidal resistance, and low hepatic blood flow, all markers of severity. Resolution of PHG after a reduction in PHT following therapy proves that the changes observed were secondary to the raised pressure. The unique histological feature of PHG is a marked dilatation of the capillaries and collecting venules in the gastric mucosa which serves as an important histological marker [Figure 4]a,[Figure 4]b,[Figure 4]c.[5],[77] Submucosal veins appear ectatic and irregular with foci of thickening of tunica intima [Figure 5]a.[5] The most common location for PHG is the fundus and body of stomach.[82]
Figure 4: (a). Section from PHG showing numerous dilated, congested and empty ectatic capillaries with mucosal edema (H and E × 100), (b). Deeper area from gastric mucosa showing dilated, congested and ectatic capillaries lying in between the glands (H and E × 100), (c). Gastric mucosal fold showing congested thick-walled capillaries with fibrosis of lamina propria at the tip (H and E × 400)

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Figure 5: (a) Gastric biopsy showing numerous ecstatic and congested capillaries with irregularly thickened wall and mucosal oedema. 5 (b). PAS stain highlighting thickened blood vessel wall in a gastric biopsy (PAS × 400), 5 (c). Numerous dilated and thick walled empty capillaries (IHC for CD 34 × 100)

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The maximum capillary wall thickness and the maximum diameter of the mucosal capillaries especially in the duodenum were significantly greater in patients with PHT as compared to that in the control group. In PHT, since the splanchnic blood flow cannot revert back to the systemic circulation, vasodilation results giving rise to congestion of small intestinal mucosa. Additional findings on histopathology include capillary dilatation and edema in the lamina propria (mean vascular diameter of 380 μm), increased capillary wall thickness, thickened muscularis mucosae, fibromuscular proliferation, decreased villous/crypt ratio, neovascularization, vascular ectasia, vessels with fibrin thrombi, lympho-plasmatocytic cells infiltration in the lamina propria, epithelial cells exhibiting reactional nucleocytoplasmicatypia and crenulated glands [Figure 5]a,[Figure 5]b,[Figure 5]c.[8],[37],[63],[75],[78],[83],[84],[85]

Thickening of the wall of ectatic capillaries has been attributed to perivascular stromal condensation or fibrosis.[6] Saperas et al.,[86] concluded that specimens obtained with large biopsy forceps were not useful for histological diagnosis of vascular ectasia in cirrhotics. However, they did not comment on the thickness of the capillary wall. The thickened wall is considered to be a better marker of PHT than the vascular diameter. Morphometry reveals the mean cross-sectional area to be higher in patients as compared to the control group. On histomorphometry, the thickness of the vessel wall observed was significantly more in patients with cirrhosis who underwent sclerotherapy.[77],[87] These histopathological changes are however non-specific but carry an increased propensity of occult GI bleeding.

The characteristic mosaic pattern observed in mild PHG on endoscopy have been variously termed as inflammatory gastritis, mucosal vasculopathy, portal hypertensive mucosa, and PHG.[5],[21],[53],[77],[83],[88] However, the previous categorisation of these changes as gastritis indicating an inflammatory etiology has been proved to be incorrect since the observed histological changes are without any associated inflammation or erosion.[89] Chaves et al.,[90] reported that the mosaic pattern was significantly more prevalent in patients with cirrhosis. However, the underlying etiology of cirrhosis did not affect the frequency or severity of PHG.[27],[91],[92] Hepatitis C, hepatitis B, cryptogenic cirrhosis, hepatitis C and hepatitis B co-infection, duration of liver disease correlated with the development of PHG.[43]

In severe PHG, besides the mosaic pattern, discrete cherry-red spots or fine pink speckling referred as the 'red marks' are present.[5] These spots may mimic eosinophilic gastritis.[93] Vascular ectasia appears as a flat lesion arising from the dilated mucosal and submucosal capillaries and veins. PHG is typically observed in the gastric body and fundus whereas gastric varices are observed around the cardia and fundus.[26] Dilated capillaries in the submucosa and lamina propria may be observed in hyperplastic-like polyps.[94] Subepithelial granulation tissue and vascular proliferation are non-specific, and non- diagnostic.[95] Increased number of mucosal capillaries along with thickened walls were more marked in the antrum than in the fundus.

Increased portal pressure leads to increased collagenization further strengthening the hypothesis that the changes observed in PHT patients should be termed PHG and not congestive gastropathy as was named earlier. Dilatation and congestion of the blood vessels are a transient and reversible phenomenon. Long standing increase in the luminal pressure may lead to mucosal edema and loss of villous architecture. In cirrhotic patients, erosive gastritis is attributed to PHT induced venous back-pressure rather than any toxic factor playing a role. This hypothesis is supported by the reversal of changes after portal decompression following surgical shunts. PHG can portal hypertensive vasculopathy occur even in patients with non-cirrhotic portal fibrosis, extrahepatic portal vein obstruction, hepatic veno-occlusive disease, and schistosomiasis.[43],[48],[90],[96],[97]

The histological changes in the jejunum are associated with changes in the duodenum followed by gastric antrum and fundus in that order. A unique feature noted in the PHV biopsies was that the mucosal capillaries have thickened walls but are without red blood cells (RBCs) probably because the capillaries in PHT being thickened and rigid cannot collapse [Figure 5]c. These changes are more commonly seen in biopsies from duodenum and jejunum as compared to stomach and colon. A similar picture is observed in splenic chronic venous congestion due to PHT where the pulp is suffused with RBCs during the early phase but becomes more fibrous and cellular with passage of time [Figure 6]a. The increased portal pressure leads to exudation and deposition of proteins in the sinusoidal basement membrane, of dilated blood vessels The thickened blood vessel wall stains positive with PAS [Figure 5]b. There is mild fibrous proliferation in lamina propria secondary to oedema and mild inflammation. These fibers are seen mainly encircling the dilated and ecstatic capillaries and can be highlighted by Van Gieson's stains [Figure 6]b.[78] Bella et al.,[98] in their study concluded that histopathology and endoscopic findings had a low correlation in the diagnosis of PHV. Furthermore, CD34 also does not provide any additional support to the histopathological finding.
Figure 6: (a). Gastric biopsy from a case of PHT showing congested and ectatic capillaries along with moderate fibrosis in the lamina propria (H and E × 400), 6 (b). Van Gieson's stain highlighting fibrosis in the lamina propria (Van Gieson × 400)

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Awareness of the association between PHT and histological changes due to vasculopathy in the submucosal and mucosal vessels is important from the treatment point of view. Earlier these changes were described as dilatation, congestion, and ectasia.[5],[43],[75],[76] The vascular changes can be divided into two groups: 'Dilated and congested' irrespective of the vessel wall thickness and, 'dilated and thick-walled' irrespective of the presence or absence of red blood cells in the lumen. The latter were more common and specific than the former. Capillary dilatation per se has been observed to be non-specific and may be due to other transient and artifactual factors.[6]

Not all researchers agree on these findings. Some authors observed that dilated and congested vessels were more common in the control group than in the patient group.[43],[75] This difference was however not statistically significant. Focal and diffuse increase in the number of capillaries has also been reported, However, it was not possible to count the number of capillaries, because in few areas the numbers were so marked giving it a granulation-tissue-like appearance [Figure 7]a,[Figure 7]b,[Figure 7]c. Mild mononuclear cell inflammatory infiltrate, oedema and fibromuscular proliferation in the lamina propria leading to altered arrangement of crypts without branching or distortion in the morphology have been reported in patients with PHT. Severe cases may give agranulation tissue like appearance with ulceration of lining epithelium [Figure 8].[99],[100]
Figure 7: (a) Biopsy from duodenum in a case of PHE showing superficial mucosa with numerous dilated and congested capillaries, mucosal oedema with sieve like appearance near the tip of mucosal fold (H and E x100). (b) and (c) Higher magnification from highlighted areas showing numerous congested and ecstatic blood vessels with irregular lumen and thickening of walls (x400)

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Figure 8: Biopsy from colon in a case of Portal hypertensive colopathy showing dilated, ectatic, congested and irregularly thickened capillaries, with mild inflammation and fibrosis in the lamina propria (H and E × 400)

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In resected specimens, marked vascular ectasia was observed in the entire small bowel extending from the duodenum to the ileum. Polypoid enteropathy due to PHT appears as red bumps or polyps in the small bowel.[37],[63] Anorectal varices commonly seen in the cirrhotic may cause fresh lower GI bleeding. Occult bleeding may also be due to PHG which is more common than colopathy. These mucosal changes if present, should not be overlooked and a report on colonic biopsies from patients with PHT should include comments on these parameters.[101] Capillary angiogenesis is an important vascular mechanism for adaptation to PHT. Non-vascular changes included increased apoptosis, fibrous proliferation and, villous changes. In dyspeptic patients, only minimal histopathologic changes were noted.[71],[78],[96],[101],[102]


   Conclusion Top


Increased hepatic venous pressure gradient is an important factor leading to mucosal changes especially in the capillaries. Lesions occur in the entire intestine. Depending on the severity, the changes have been variably classified and distinguished. A unique feature observed in the biopsies specimens from duodenum and jejunum was thickened mucosal capillaries with absence of RBCs in the lumen, probably due to non-collapsing capability of these vessels. Major histopathology changes seen in biopsies of patients with PHT are dilated and tortuous mucosal capillaries with irregular wall thickening, edema of lamia propria and mild chronic inflammatory infiltrate.



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Correspondence Address:
Vatsala Misra
Department of Pathology, MLN Medical College, Prayagraj - 211 001, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_201_21

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