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PORTAL HYPERTENSIVE GASTROPATHY

PORTAL HYPERTENSIVE GASTROPATHY/ CONGESTIVE GASTROPATHY

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PORTAL HYPERTENSIVE GASTROPATHY

  1. 1. PORTAL HYPERTENSIVE GASTROPATHY PRATAP SAGAR TIWARI, DM RESIDENT, DEPARTMENT OF HEPATOLOGY, NAMS
  2. 2. Contents of Part1  Background & History  Introduction & Epidemiology  Pathogenesis  Risk factors: Correlation of PHG with PHTN/ with Etiology / liver disease duration & severity/ varices
  3. 3. Background  Gastric inflammatory diseases can be broadly categorized into gastritides and gastropathies.  Gastritis is predominantly an inflammatory process while gastropathy demonstrates minimal to no inflammation.  The term gastritis is used to denote inflammation associated mucosal injury. However, epithelial cell injury and regeneration are not always accompanied by mucosal inflammation. This distinction has caused considerable confusion since the term "gastritis" is often used to describe endoscopic or radiologic characteristics of the gastric mucosa rather than specific histologic findings. A gastric mucosal biopsy is necessary to establish a definitive diagnosis of gastritis versus gastropathy. Epithelial cell damage and regeneration with minimal or no associated inflammation is properly referred to as "gastropathy."
  4. 4. History: PHG  Palmer[1], in 1957, proposed that the pathogenesis of erosive gastritis in cirrhotic pts was different than that in non-cirrhotic pts and that erosive gastritis in cirrhotic pts resulted from mechanical venous back-pressure from PHTN, rather than a circulating, mucosal, or intraluminal toxic factor.  This proposal was supported by successful reversal of erosive gastritis in cirrhotic pts with portal decompression by surgical shunts[1].  In 1984, Sarfeh et al[2] recognized a distinct form of gastric mucosal hemorrhage in pts who had PHTN, demonstrated by cirrhosis and GEV, which they called “portal hypertensive gastritis”. They proposed that gastric mucosa in PHTN reacts differently from gastric mucosa without PHTN and these pts with PHTN may benefit from portal decompressive surgery.  One year later, McCormack et al[3] reported that the gastritis in pts with PHTN differed from that in pts without PHTN in mucosal histology, nonresponse to standard therapy for conventional gastritis, and in occasionally having very similar histological changes in other GI organs such as the colon. They called these gastritis-like changes in patients with PHTN “congestive gastropathy”or which we called as “Portal Hypertensive Gastropathy” [3], and classified it as “mild” or “severe”, using criteria described by Taor et al[4]. 1 Palmer ED. Erosive gastritis in cirrhosis; influence of portal hypertension on the gastric mucosa. Am J Dig Dis 1957; 2: 31-36 2 Sarfeh IJ, Tarnawski A. Portal hypertensive gastritis. Gastroenterology 1984; 86: 592 3 McCormack TT, Sims J, Eyre-Brook I, Kennedy H, Goepel J, Johnson AG, Triger DR. Gastric lesions in portal hypertension:inflammatory gastritis or congestive gastropathy? Gut 1985; 26: 1226-1232 4 Taor RE, Fox B, Ware J, Johnson AG. Gastritis: gastroscopic and microscopic. Endoscopy 1975; 7: 209-215
  5. 5. Introduction: PHG  PHG is diagnosed by characteristic endoscopic findings of small polygonal areas of variable erythema surrounded by a pale, reticular border in a mosaic pattern in the gastric fundus/body in a patient with cirrhotic or non-cirrhotic portal hypertension.  Histologic findings include capillary and venule dilatation, congestion, and tortuosity, without vascular fibrin thrombi or inflammatory cells in gastric submucosa. Pic taken from : http://www.patientcareonline.com/articles/%E2%80%9Csnakeskin%E2%80%9D-gastric-muc
  6. 6. Epidemiology  PHG can present at any age, including pediatric or adult pts.  The reported prevalence of PHG varies greatly from 7% to 75% in pts with PHTN (Table 1)[1,8- 25], and varies greatly from about 35% to 98% in pts with cirrhosis (Table 2)[2,26-68]. References are at the end of slides Notes: • Prevalence in epidemiology is the proportion of disease found to have been affecting a particular population (typically a disease or a risk factor. • Point prevalence is the proportion of a population that has the condition at a specific point in time. • Period prevalence is the proportion of a population that has the condition at some time during a given period (e.g., 12 month prevalence), and includes people who already have the condition at the start of the study period as well as those who acquire it during that period. • Lifetime prevalence (LTP) is the proportion of a population that at some point in their life (up to the time of assessment) have experienced the condition. • The difference between prevalence and incidence can be summarized thus: prevalence answers "How many people have this disease right now?" and incidence answers "How many people per year newly acquire this disease?". • Incidence in epidemiology is a measure of the probability of occurrence of a given medical condition in a population within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.
  7. 7. 5472/9712=56.34%
  8. 8. HEPATOLOGY UNIT, BIR HOSPITAL CASES OF 89 DAYS DURATION N PHG % Alcoholic cirrhosis 80 51 63.75 Alcohol + hbv/hcv related 9 2 22.22 Alcohol + HCV+ HCC 2 0 0 Alcohol + HBV+ HCC 1 1 100 Cryptogenic 4 2 50 NASH related 1 0 0 NCPH 3 2 66.66 TOTAL 100 58 58 %
  9. 9. Epidemiology  PHG is usually mild as reported by McCormack et al[3] or in the NIEC study[5,7]. The prevalence of mild PHG in pts with PHTN ranges from 29%-57%, and of severe PHG ranges from 9%- 46%[6].  This wide variability likely reflects variability in classification criteria, interpretation of endoscopic lesions, study populations, and natural history of PHG[4,5,6]. References are at the end of slides Note: During the diagnosis of cirrhosis, the prevalence of PHG is approximately 30% and its incidence is approximately 12% per year. However, pts with severe liver dysfunction and large EV are at higher risk of developing PHG, whereas large fundal varices may have a protective role, particularly when they are associated with spontaneous gastrorenal shunt. Overall, during the course of cirrhosis, mild PHG may be observed in up to 50–70% of patients and severe PHG in 20–40%. Ref: Schiff’s Disease of Liver
  10. 10. Pathogenesis: PHG  The pathogenesis of PHG is inadequately understood[1].  Hemodynamic changes, especially increased PP, are the suspected underlying causes because PHG develops only with established PHTN[2]. However, PHTN cannot be the sole factor because all pts with PHTN do not develop PHG [3,4]. 1. Feldman M, Lee EL. Gastritis. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 10th ed. Philadelphia: Elsevier Saunders, 2010: 868-883 2. Cubillas R, Rockey DC. Portal hypertensive gastropathy: a review. Liver Int 2010; 30: 1094-1102 3. Merkel C, Schipilliti M, Bighin R, Bellini B, Angeli P, Bolognesi M, Vescovi F, Gatta A. Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study. Dig Liver Dis 2003; 35: 269-274 4. Bayraktar Y, Balkanci F, Uzunalimoglu B, Gokoz A, Koseoglu T, Batman F, Gurakar A, Van Thiel DH, Kayhan B. Is portal hypertension due to liver cirrhosis a major factor in the development of portal hypertensive gastropathy? Am J Gastroenterol 1996; 91: 554-558
  11. 11. Pathophysiology: PHG PHTN Cirrhosis Hyperdynamic circulation PHG Inc IHR Inc PBF Hemodynamic change
  12. 12. Notes on previous slide: Pathophysiology: PHG • Most common coz of PHTN is cirrhosis In cirrhosis, there is increased Intrahepatic resistance that occurs as a result of several mechanical factors that leads to reduction in vessel diameter. • In addition to the architectural disturbances caused by formation of regenerative nodules and fibrotic bands, there are several mechanical factors that includes capillarization of the sinusoids ie Transformation of normal liver sinusoidal endothelial cells into vascular type with addition of basement membrane. We know that The unique arrangement of the normal sinusoidal endothelium lacks basement membrane and helps to facilitate the large exchanges that take place between hepatocytes and the blood. But With the formation of basement membrane and changes in LSECs will interfere with the bi-directional exchange of molecules and therefore have deleterious effects on liver physiology, such as decreased sinusoidal compliance with increased resistance to blood flow, and may contribute to development of portal hypertension.) and swelling of cells, including hepatocytes and Kupffer cells. • Hemodynamic changes in the hepatic circulation also contribute to increase intrahepatic resistance. These changes are characterized by impaired responses to vasodilatory stimuli and hepatic vasoconstriction. thus even with small decrease in vessel radius will cause prominent increases in resistance. • In noncirrhotic causes of PHTN, the increase in resistance may occur at sites upstream (prehepatic) or downstream (posthepatic) of the liver, as in portal vein thrombosis and hepatic vein thrombosis, respectively.
  13. 13. Notes on previous slide: Pathophysiology: PHG • Most evidences suggests that a decrease in the production of the vasodilator NO and an increase in the production of the vasoconstrictor ET-1 jointly contribute to the increase in hepatic vascular resistance. Other increased vasoconstrictors include norephinephrine, thromboxane A2, angiotensin Ⅱ,leukotrienes . • In cirrhosis, this increase in intrahepatic vascular resistance is only the initiating factor that leads to PHTN, whereas there is addition of another important factor ie the increase in portal blood flow which is a secondary phenomenon that maintains and worsens the increased portal pressure, giving rise to the hyperdynamic circulation syndrome. • And in the splanchnic circulation, as mediated by several vasodilators like NO, PROSTACYCLIN, GLUCAGON and others and in addition to reduced vasoconstrictive effect, there is vasodilation of arterioles in splanhnic organs, This increase in blood flow in splanchnic organs and the subsequent increase in portal venous inflow, and now together with an increased resistance to portal inflow, this aggravates the PP. • The hyperdynamic circulatory state of PHTN which is mediated in part by arterial vasodilation, but this vasodilation alone is not sufficient to cause the circulation to become hyperdynamic. It is the combination of arterial vasodilation and blood volume expansion that produces optimal conditions for maintaining the hyperdynamic circulatory state in PHTN. • As there is arterial vasodilation in the peripheral and splanchnic circulation leads to a decrease in central blood volume. And creates the relative arterial hypovolemia which ultimately leads to the stimulation of cardiopulmonary volume receptors and arterial baroreceptors, activating the sympathetic nervous system, the renin-angiotensin-aldosterone system and arginine-vasopresin (antidiuretic hormone). • Mediators from these systems result in sodium and water retention by the kidneys, and consequently, plasma volume expansion. • Sodium retention is due to increased tubular reabsorption of sodium, mediated by receptors for aldosterone, angiotensin and alpha-adrenergic stimuli. • The decrease in water excretion is due to increased secretion of antidiuretic hormone. Thus the hyperdynamic state is created. • The harmful effects of hyperdynamic circulation are not restricted to the hepatosplanchnic circulation.
  14. 14. Reduced NO in liver  An increased expression of caveolin (an eNOS inhibitory protein).  A decrease in eNOS phosphorilation due to abnormal Akt (protein kinase B) signalling, are the mechanisms that might explain the reduced eNOS activity in liver cirrhosis.  In addition to a decreased NOS activity, an increased NO degradation has also been suggested to be responsible for the diminished NO bioavailability.  Since superoxide (O2 -) is able to react with NO to generate peroxinitrite (ONOO-), NO bioavailability can be substantially reduced if the O2- levels are increased as a consequence of a decrease in superoxide dismutase activity.
  15. 15. Hypothesized mechanism of PHG Portal HTN ↑ gastric bld flow/ ↓ Gastric mucosal bld flow Hyperdynamic Circulation Release of cytokines Gastric mucosal injury ↓ gastric mucosal perfusion Hypoxic Gastric mucosal injury Increased NO PHG Bleeding from PHG • increased gastric mucosal apoptosis and decreased mucosal proliferation • Free radical injury • Decreased Mucin • Increase TNF a Impaired mucosal Repair Overexpressed NO synthase
  16. 16. Notes of the previous slides…  So we have hyperdynamic circulation in PHTN. And this leads to increase in gastric blood flow and decrease gastric mucosal blood flow. (explained in next slides)  Hemodynamic changes in pts with PHTN lead to hyperdynamic congestion with a change in gastric mucosal blood flow, that leads to activation of cytokines, growth factors, and hormones that perpetuate this hyperdynamic gastric circulation.  This release of proinflammatory mediators, makes gastric mucosa more susceptible to injury and impair mucosal healing.  Abnormal regulation of the gastric microcirculation in PHG may render gastric mucosa more vulnerable to hypoxia, and more susceptible to noxious gastric factors, such as aspirin and ethanol  This vulnerable mucosa becomes predisposed to bleeding.  Decreased gastric mucosal perfusion may explain the increased rate of erosions, ulcers, and bleeding in PHG.  …………please correlate with other explaiantions……..
  17. 17. Gastric mucosal blood flow in PHG  The level of gastric mucosal blood flow in PHG is controversial. Most studies reported decreased mucosal blood flow in patients with PHG[1,2,3,4,5], whereas several studies reported increased gastric mucosal blood flow in experimental animals and in humans with PHG[6-10].  Makhija et al [11] described in PHG a ↓ in gastric mucosal blood flow, an ↑ in the submucosal and muscular layer blood flow, and a net ↑ in TGBF.  Mezawa et al [1] using a laser Doppler flowmeter to measure gastric BF reported ↓ mucosal blood flow and ↑ TGBF in pts with PHG. These results reversed after undergoing TIPS, with an ↑ in mucosal blood flow and a ↓in TBF.  These finding support the hypothesis of decreased mucosal blood flow in patients with PHG. References are at the end of slides Note: The gastric mucosal changes of PHG are associated with increased gastric mucosal and submucosal perfusion and, therefore, are hyperemic not “congestive” – changes. The term congestive gastropathy is not adequate and should not be used. Ref: Schiff’s Disease of Liver
  18. 18.  Misra et al [1] showed that gastric mucosal capillaries, obtained by endoscopic mucosal biopsies, have a much thicker wall in pts with cirrhosis than in healthy volunteers.  Ichikawa et al [2] reported a narrower diameter in gastric mucosal capillaries and less capillary angiogenesis, after exposure to ethanol in individuals with PHG as compared to healthy controls. 1. Misra V, Misra SP, Dwivedi M. Thickened gastric mucosal capillary wall: a histological marker for portal hypertension. Pathology 1998; 30: 10-13 2. Ichikawa Y, Tarnawski A, Sarfeh IJ, Ishikawa T, Shimada H. Distorted microangioarchitecture and impaired angiogenesis in gastric mucosa of portal hypertensive rats. Gastroenterology 1994; 106: 702-708
  19. 19. Decreased level of Mucin:  Wang et al [146] reported significantly reduced expression of mucin mRNA in rat models of PHTN induced by partial portal vein ligation.  Decreased mucin production may impair gastric mucosal protection. Rats with PHTN had significantly greater injury to gastric mucosa than healthy controls after exposure to gastrotoxic compounds. 1. Wang JY, Hsieh JS, Lin SR, Huang TJ. The effect of portal hypertension on expression of gastric mucin mRNA in rats. Hepatogastroenterology 2001; 48: 667-671
  20. 20. Tumor necrosis factor alpha:  TNF-α may directly contribute to the hyperdynamic circulation in PHG.  Patients and animal models with PHTN had an elevated TNF-α level which stimulated release of NO and prostacyclin, important mediators of a hyperdynamic circulation[1].  Kaviani et al [2] reported that TNF-α increased by 50% and inducible nitric oxide synthase (iNOS) mRNA levels increased by 300% in gastric strips after ligating the PV in rats (P < 0.01 for both). These data are consistent with TNF-α playing a role in the hyperdynamic circulation in PHG via NO and prostacyclin. 1. Muñoz J, Albillos A, Pérez-Páramo M, Rossi I, Alvarez-Mon M. Factors mediating the hemodynamic effects of tumor necrosis factor-alpha in portal hypertensive rats. Am J Physiol 1999; 276: G687-G693 2. Kaviani A, Ohta M, Itani R, Sander F, Tarnawski AS, Sarfeh IJ. Tumor necrosis factor-alpha regulates inducible nitric oxide synthase gene expression in the portal hypertensive gastric mucosa of the rat. J Gastrointest Surg 1997; 1: 371-376
  21. 21.  Ohta et al [1] similarly successfully used TNF-α antibody to normalize gastric mucosal blood flow in rats with PHG and to significantly reverse overexpression of gastric NOS . In PHG rats, treatment with TNF-α antibody significantly reduced the elevated NOS by 48% (P < 0.01).  Moreover, administration of thalidomide, which enhances TNF-α mRNA degradation, decreased levels of TNF-α and NOS in animals with PHTN produced by partial PV ligation[2]. 1. Ohta M, Tarnawski AS, Itani R, Pai R, Tomikawa M, Sugimachi K, Sarfeh IJ. Tumor necrosis factor alpha regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats. Hepatology 1998; 27: 906-913 2. Lopez-Talavera JC, Cadelina G, Olchowski J, Merrill W, Groszmann RJ. Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats. Hepatology 1996; 23: 1616-1621
  22. 22. Correlation of PHG with PHTN??? 1. Does the Severity of PHG correlated with the severity of PHTN as determined by HVPG ? 2. Is there correlation with presence & size of varix ?
  23. 23. Correlation of PHG with PHTN  Merkel et al [2] reported that the severity of PHG was correlated with the severity of PHTN as determined by HVPG, but this correlation was significant only for severe PHG (HVPG = 20.5 ± 4.0 mmHg) vs no PHG (HVPG = 17.4 ± 5.2 mmHg, P = 0.0004), and not for mild PHG (HVPG = 16.1 ± 3.2 mmHg) vs no PHG [17.4 ± 5.2 mmHg, not significant (NS)].  In a prospective study of 331 cirrhotic pts, Kim et al [3] found that pts with severe PHG had significantly higher HVPG (15.6 ± 4.6 mmHg) than pts with mild PHG (10.7 ± 4.1 mmHg) or no PHG (4.9 ± 1.7 mmHg) (P < 0.001). 1. Merkel C, Schipilliti M, Bighin R, Bellini B, Angeli P, Bolognesi M, et al. Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study.Dig Liver Dis 2003; 35: 269-274 2. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55:3561-3567
  24. 24. Correlation of PHG with PHTN  Primignani et al [1] confirmed the correlation of PHG with severity of PHTN, by correlating PHG with presence and size of EV. The rate of PHG was significantly higher in pts with EV [80 of 104 pts (76.9%)] than in pts without EV[51 of 84 (60.7%), P < 0.007].  The rate of PHG also significantly increased with increasing variceal size (P = 0.0003).  Abbasi et al [2] reported a significantly positive correlation between EV size and rate of PHG (r = 0.46; P < 0.001).  Taranto et al [3] reported more severe PHG in cirrhotic pts with more severe PHTN, as measured by esophageal intravariceal pressure. 1. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC).Gastroenterology 2000; 119: 181-187. 2. Abbasi A, Bhutto AR, Butt N, Munir SM, Dhillo AK. Frequency of portal hypertensive gastropathy and its relationship with biochemical, haematological and endoscopic features in cirrhosis.J Coll Physicians Surg Pak 2011; 21: 723-726 3. Taranto D, et al. Gastric endoscopic features in patients with liver cirrhosis: correlation with esophageal varices,intra-variceal pressure, and liver dysfunction. Digestion 1994; 55:115-120.
  25. 25. Correlation of PHG with PHTN  Other data supporting an association between PHG and PHTN include resolution of PHG after intervention to decrease PHTN , including pharmacotherapy[1-5], transjugular intrahepatic portosystemic shunt (TIPS), or liver transplantation[5]. 1. Trevino HH, Brady CE, Schenker S. Portal hypertensive gastropathy. Dig Dis 1996; 14: 258-270 2. Kamath PS, et al. Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 2000; 118: 905-911 3. Mezawa S, et al. Effect of transjugular intrahepatic portosystemic shunt formation on portal hypertensive gastropathy and gastric circulation. Am J Gastroenterol 2001; 96:1155-1159 4. Urata J, et al. The effects of transjugular intrahepatic portosystemic shunt on portal hypertensive gastropathy.J Gastroenterol Hepatol 1998; 13: 1061-1067 5. Kamath PS, Shah VH. Portal hypertension and bleeding esophageal varices. In: Boyer TD, Manns MP, Sanyal AJ, editors.In: Zakim and Boyer’s Hepatology: A textbook of liver disease. 6th ed. Philadelphia: Elsevier Saunders, 2012: 296-326
  26. 26. Correlation of PHG with PHTN ?  Contrariwise, a minority of studies showed no significant association between severity of PHTN and rate of PHG [1,2,3,4,5,6,7,8,9,10].  Curvêlo et al [2] found no significant difference in HVPG in cirrhotic pts with vs without PHG.  Bellis et al [1] demonstrated similar findings.  Among pts with PHTN from cirrhosis without EV, Zardi et al [10] reported that patients with PHG vs pts without PHG had similar mean PV diameter, SV diameter, and portal flow volume, all markers of severity of PHTN.  Erden et al [3] showed that the mean diameters of the left gastric and azygos veins, which are also markers of PHTN, were not significantly different between pts with vs without PHG. NOTE: (NORMAL VALUES) PVD :13mm, SVD: 11 mm, IMVD:7 mm SMVD:10 mm LGVD:5-6 mm Ligamentum Teres N <3mm Hepatic A: 5+/1 1 mm Hepatic V N <10 mm PV mean velocity 15 cm/s. Mean diameter of Azygos V: (at origin: 4.05±1.03 mm. At its termination: 8.56±1.26 mm, Mean diameter of Hemiazygos V: (at its origin : 3.17±0.7 mm, at its termination was 5.65±1.17 mm )
  27. 27. Conclusion  Portal hypertension: Most studies show that the frequency and severity of PHG is strongly correlated with the severity of PHTN, as indicated by multiple parameters, including HVPG [1,2], esophageal intravariceal pressure[3], and presence or size of EV [2,4,5,6,7]. 1. Merkel C, Schipilliti M, Bighin R, Bellini B, Angeli P, Bolognesi M, et al. Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study.Dig Liver Dis 2003; 35: 269-274 2. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55:3561-3567 3. Taranto D, et al. Gastric endoscopic features in patients with liver cirrhosis: correlation with esophageal varices, intra-variceal pressure, and liver dysfunction. Digestion 1994; 55:115-120 4. Primignani M,et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC).Gastroenterology 2000; 119: 181-187 5. Fontana RJ, et al. Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial. Am J Gastroenterol 2006;101: 983-992 6. Abbasi A, Bhutto AR, Butt N, Munir SM, Dhillo AK. Frequency of portal hypertensive gastropathy and its relationship with biochemical, haematological and endoscopic features in cirrhosis.J Coll Physicians Surg Pak 2011; 21: 723-726 7. Hou MC, et al. Changes in portal hypertensive gastropathy after endoscopic variceal sclerotherapy or ligation: an endoscopic observation. Gastrointest Endosc 1995; 42: 139-144 The main predictors of PHG is portal hypertension.
  28. 28. Cirrhotic vs non-cirrhotic portal HTN:  Primary liver disease usually occurs in PHG, but is not a prerequisite for PHG provided another cause of portal hypertension exists.  PHG can occur among patients with non-cirrhotic portal fibrosis (NCPF), extrahepatic portal vein obstruction (EHPVO), hepatic veno-occlusive disease, and schistosomiasis[1,2,3,4,5]. 1. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 2. Sogaard KK, et al. Portal vein thrombosis;risk factors, clinical presentation and treatment. BMC Gastroenterol 2007; 7: 34 3. Chaves DM, et al.Comparative study of portal hypertensive gastropathy in schistosomiasis and hepatic cirrhosis. Endoscopy 2002; 34: 199-202 4. Kamath PS, et al. Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 2000; 118: 905-911 5. Pan WD, Xun RY, Chen YM. Correlations of portal hypertensive gastropathy of hepatitis B cirrhosis with other factors. Hepatobiliary Pancreat Dis Int 2002; 1: 527-531
  29. 29. Cirrhotic vs non-cirrhotic portal HTN:  Sarin et al [1] reported that pts with cirrhosis had a significantly higher frequency of PHG (37.1%) than that in pts with NCPF (16.7%; P < 0.05), or non-cirrhotic EHPVO (8.7%; P < 0.01) and had a more aggressive course of PHG with progression to more severe PHG with time.  Chaves et al [2] similarly reported a higher incidence of PHG in pts with cirrhosis vs pts with PHTN from etiologies including schistosomiasis or postsinusoidal hypertension. Chaves et al[2] reported that PHG occurred in 18 (81.8%) of 22 pts with cirrhosis vs only 7 (33.3%) of 21 pts with PHTN from schistosomiasis (P < 0.05). 1. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 2. Chaves DM, Sakai P, Mucenic M, Iriya K, Iriya Y, Ishioka S.Comparative study of portal hypertensive gastropathy in schistosomiasis and hepatic cirrhosis. Endoscopy 2002; 34: 199-202 The frequency of PHG appears to be higher in PHTN with cirrhosis than in PHTN without cirrhosis.
  30. 30. Cirrhosis etiology:  Abbasi et al [1] reported among 217 pts with cirrhosis that PHG was unassociated with cirrhosis etiology (r = 0.056;P = 0.414), among 144 pts with hep C, 36 pts with hep B, 21 pts with cryptogenic cirrhosis, 15 pts with hep C and hep B coinfection, and 1 pt with hep B and hep D coinfection.  Kim et al [2] similarly did not find a correlation between cirrhosis etiology and severity of PHG in a prospective study of 331 pts with cirrhosis, including cirrhosis etiologies of alcohol in 250, hep B in 68, hep C in 15, and cryptogenic cirrhosis in 8.  Gupta et al [3] in a study of 230 pts with cirrhosis and EV found no significant difference in the rate of PHG between pts with cirrhosis from alcohol [32 of 52 pts (62%)] vs cirrhosis from other causes [110 of 178 pts (62%), P = NS].  Iwao et al [4] in an endoscopic study of 47 pts with histologically-proven cirrhosis reported no significant differences in etiology of cirrhosis between pts without PHG vs pts with mild or severe PHG. 1. Abbasi A, Bhutto AR, Butt N, Munir SM, Dhillo AK. Frequency of portal hypertensive gastropathy and its relationship with biochemical, haematological and endoscopic features in cirrhosis.J Coll Physicians Surg Pak 2011; 21: 723-726 2. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55:3561-3567 3. Gupta R, Saraswat VA, Kumar M, Naik SR, Pandey R. Frequency and factors influencing portal hypertensive gastropathy and duodenopathy in cirrhotic portal hypertension. J Gastroenterol Hepatol 1996; 11: 728-733 4. Iwao T, et al. Portal-hypertensive gastropathy develops less in patients with cirrhosis and fundal varices. J Hepatol 1997; 26: 1235-1241
  31. 31. Cirrhosis etiology: On basis of Several research groups reported that the underlying etiology of cirrhosis did not affect PHG frequency or severity.
  32. 32. Liver disease duration:  Merli et al [1] reported a cumulative incidence of 3% at 1 year, 10% at 2 years, and 24% at 3 years. Most cases were mild, with only 10% of cases reported as severe PHG in cirrhotic pts undergoing EGD to screen for EV.  Primignani et al [2] reported that the prevalence of PHG was only 56% in pts with newly diagnosed cirrhosis, rose to 75% in pts with previously diagnosed cirrhosis and no prior variceal bleeding, and rose further to 91% in pts with previously diagnosed cirrhosis and prior variceal bleeding treated with sclerotherapy (P < 0.0001). The frequency of PHG increased by 46% after 5 years of follow-up in pts with cirrhosis[2].  Child-Pugh stage C cirrhosis was associated with faster progression of PHG[2]. 1. Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 2004; 99: 1959-1965 2. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC).Gastroenterology 2000; 119: 181-187 Duration of liver disease positively correlates with development of PHG.
  33. 33. Liver disease severity:  The reported strength of this correlation is variable.  Some studies showed correlation between all stages of cirrhosis and PHG, whereas other studies showed correlation only for specific stages of cirrhosis.  Sarin et al [1] reported an 87% prevalence of PHG in pts with CP C, vs only 13% prevalence in pts with CP A.  Another study reported that only CP C was independently associated with PHG (OR = 2.68; 95%CI: 1.16-6.20, P = 0.021)[2].  Merli et al [3] reported, in a study of 48 pts with PHG among 222 pts with cirrhosis, that CP B or C, and presence of EV were independent RF for developing PHG.  De Lisi et al [4] reported a significantly higher prevalence of PHG in CP B or C, as compared to stage A. 1. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 2. Kumar A, Mishra SR, Sharma P, Sharma BC, Sarin SK. Clinical, laboratory, and hemodynamic parameters in portal hypertensive gastropathy: a study of 254 cirrhotics. J Clin Gastroenterol 2010;44: 294-300 3. Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 2004; 99: 1959-1965 4. De Lisi S, Peralta S, Arini A, Simone F, Craxì A. Oesophagogastroduodenoscopy in patients with cirrhosis: Extending the range of detection beyond portal hypertension. Dig Liver Dis 2011; 43:48- 53
  34. 34. Correlation with other markers of Liver dysfunction  In another study that included 331 cirrhotics (55 % had PHG), the MELD score was significantly correlated with PHG severity (mean MELD score in pts without PHG = 7.6 ± 1.7, in pts with mild PHG = 10.2 ± 4.0, and in pts with severe PHG = 11.3 ± 3.5; P < 0.001)[1].  In the HALT-C trial, hypoalbuminemia and hyperbilirubinemia, biochemical markers of advanced liver disease, were independent predictors of PHG. 1. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55:3561-3567 Extra note: Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial Results: of 232 pt, Rates of SVR were 18-26% in patients with good function by QLFTs, but ≤6% in patients with poor function. Hepatic metabolism, measured by caffeine k elim (P = 0.02), antipyrine k elim (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cl oral (P = 0.0002) and cholate shunt (P = 0.0003) and PHM (P = 0.03) improved after SVR. Conclusion: Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM.
  35. 35. Liver disease severity:  Contrariwise, a minority of studies found no correlation between liver disease severity, as determined by CP stage, and presence or severity of PHG [1,2,3,4,5,6,7,8].  Primignani et al [1] reported the prevalence of severe PHG was lowest in CP C. In the NIEC study, patients with CP B had a higher prevalence of PHG than pts with stages A or C.  Zardi et al [9] reported no significant differences in CP score or in MELD score among cirrhotic pts with vs without PHG. 1. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 2000; 119: 181-187 2. Merkel C, et al. Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study. Dig Liver Dis 2003; 35: 269-274 3. Menchén L, et al. Prevalence of portal hypertensive duodenopathy in cirrhosis: clinical and haemodynamic features. Eur J Gastroenterol Hepatol 2006; 18: 649-653 4. Bellis L, et al. Hepatic venous pressure gradient does not correlate with the presence and the severity of portal hypertensive gastropathy in patients with liver cirrhosis. J Gastrointestin Liver Dis 2007; 16: 273-277 5. Curvêlo LA, et al. Underlying mechanism of portal hypertensive gastropathy in cirrhosis: a hemodynamic and morphological approach. J Gastroenterol Hepatol 2009; 24: 1541-1546 6. Abbasi A, Bhutto AR, Butt N, Munir SM, Dhillo AK. Frequency of portal hypertensive gastropathy and its relationship with biochemical, haematological and endoscopic features in cirrhosis.J Coll Physicians Surg Pak 2011; 21: 723-726 7. Spina GP, et al. Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy, September 19, 1992. J Hepatol 1994; 21: 461-467 8. Pan WD, Xun RY, Chen YM. Correlations of portal hypertensive gastropathy of hepatitis B cirrhosis with other factors. Hepatobiliary Pancreat Dis Int 2002; 1: 527-531 9. Zardi EM, Ghittoni G, Margiotta D, Viera FT, Di Matteo F, Rossi S. Portal hypertensive gastropathy in cirrhotics without varices: a case-control study. Eur J Gastroenterol Hepatol 2015; 27: 91-96
  36. 36. Correlation of PHG with Liver disease severity: PHG is correlated with liver disease severity, as measured by CP stage .
  37. 37. Correlation with varices:  Among the 188 of 373 pts with cirrhosis not undergoing variceal sclerotherapy in the NIEC study, the prevalence of PHG was significantly higher in pts with EV [80 of 104 pts (77%)] than in pts without EV[51 of 84 pts (61%); P = 0.007]; and the prevalence of PHG significantly increased with increasing variceal size (P < 0.0003)[1].  Numerous other studies also demonstrated significant correlation between presence of EV and PHG, and several studies also demonstrated significant correlations between variceal size and PHG[2,3,4,5,6,7,8]. 1. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 2000; 119: 181-187 2. Parikh SS, Desai SB, Prabhu SR, Trivedi MH, Shankaran K, Bhukhanwala FA, Kalro RH, Desai HG. Congestive gastropathy: factors influencing development, endoscopic features, Helicobacter pylori infection, and microvessel changes. Am J Gastroenterol 1994; 89: 1036-1042 3. El-Rifai N, et al. Gastropathy and gastritis in children with portal hypertension. J Pediatr Gastroenterol Nutr 2007; 45: 137-140 4. Taranto D, et al. Gastric endoscopic features in patients with liver cirrhosis: correlation with esophageal varices, intra-variceal pressure, and liver dysfunction. Digestion 1994; 55:115-120 5. Fontana RJ, et al. Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial. Am J Gastroenterol 2006; 101: 983-992 6. Kumar A, Mishra SR, Sharma P, Sharma BC, Sarin SK. Clinical, laboratory, and hemodynamic parameters in portal hypertensive gastropathy: a study of 254 cirrhotics. J Clin Gastroenterol 2010; 44: 294-300 7. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55:3561-3567 8. Abbasi A, Bhutto AR, Butt N, Munir SM, Dhillo AK. Frequency of portal hypertensive gastropathy and its relationship with biochemical, haematological and endoscopic features in cirrhosis. J Coll Physicians Surg Pak 2011; 21: 723-726
  38. 38. Correlation with varices:  However, a few studies showed no correlation between presence or size of varices and PHG[1,2,3,4].  All these negative studies but one were relatively small.  Gupta et al [3] reported no significant association between frequency of PHG and size of EV among 230 cirrhotic pts.  Similarly, in a study of 59 pts with cirrhosis, Bellis et al [4] showed a non-significant trend towards more severe PHG in pts with large vs small varices. For example, 3(50%) of 6 pts without EV had PHG, 6 of 10 pts (60%) with small varices had PHG, 19 of 25 pts (76%) with medium sized varices had PHG, and 16 of 18 pts (89%) with large varices had PHG (NS).  Iwao et al [2] (47 pts) further reported that the frequency of PHG was not correlated with EV size. The mean grade of GEV was 1.4 ± 0.9 for no PHG, 2.0 ± 0.9 for mild PHG, and 1.9 ± 1.0 for severe PHG (all NS), and the mean grade of GV was 0.5 ± 0.8 for no PHG, 1.3 ± 1.3 for mild PHG, and 0.9 ± 1.2 for severe PHG (all NS). 1. Calès P, et al. Gastroesophageal endoscopic features in cirrhosis. Observer variability, interassociations, and relationship to hepatic dysfunction. Gastroenterology 1990; 98: 156-162 2. Iwao T, et al. Portal hypertensive gastropathy in patients with cirrhosis. Gastroenterology 1992; 102: 2060-2065 3. Gupta R, Saraswat VA, Kumar M, Naik SR, Pandey R. Frequency and factors influencing portal hypertensive gastropathy and duodenopathy in cirrhotic portal hypertension. J Gastroenterol Hepatol 1996; 11: 728-733 4. Bellis L, et al. Hepatic venous pressure gradient does not correlate with the presence and the severity of portal hypertensive gastropathy in patients with liver cirrhosis. J Gastrointestin Liver Dis 2007; 16: 273-277
  39. 39. Many studies report a correlation between the presence and size of EV and severity of PHG.
  40. 40. Location of varices:  Regarding variceal location, Sarin et al [1] reported in a study of 107 pts with cirrhosis, NCPF or EHPVO, that PHG was significantly more common in pts with coexistent gastric and EV as compared to solely EV. PHG occurred in 15 (42%) of 36 pts with concomitant esophageal and GV, but occurred in only 8 (11%) of 71 pts with solely EV (P < 0.01).  Likewise, Gupta et al [2] reported a significantly higher prevalence of PHG in patients with esophageal and GV [74 of 107 pts (69%)] compared to solely EV [68 of 123 pts (55%), P < 0.05]. 1. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 2. Gupta R, Saraswat VA, Kumar M, Naik SR, Pandey R. Frequency and factors influencing portal hypertensive gastropathy and duodenopathy in cirrhotic portal hypertension. J Gastroenterol Hepatol 1996; 11: 728-733
  41. 41. Location of varices:  Iwao et al [1] reported a significantly higher incidence of PHG in cirrhotic pts with EV as compared to fundal GV.  PHTN is usually associated with porto systemic collateral circulation, commonly including EV, GV, and abdominal or umbilical or hemorrhoidal vein dilatation; and uncommonly including splenorenal, gastric, renal, retroperitoneal, or cardiac angle venous shunts.  Wu et al [2] reported that the rate of moderate or severe PHG was higher in pts with common collaterals [296 of 439 pts (67.4%)] vs uncommon collaterals [70 of 118 pts (59.3%)], but this difference was not statistically significant. 1. Iwao T, et al. Portal-hypertensive gastropathy develops less in patients with cirrhosis and fundal varices. J Hepatol 1997; 26: 1235-1241 2. Wu Q, et al. Characterization of uncommon portosystemic collateral circulations in patients with hepatic cirrhosis. Oncol Lett 2015; 9: 347-350
  42. 42. Location of varices:  In 2007, Zardi et al [1] proposed that PHG is promoted by minimal collateral circulation because a significant collateral circulation would otherwise reduce PP and gastric mucosal congestion. They found that the PV diameter in cirrhotic pts was larger in pts with PHG and no EV(13.0 ± 2.6 mm) than in pts with F1 EV(12.6 ± 2.3 mm) or F2 EV(12.9 ± 2.0 mm) (NS).  They further supported this concept by finding that pts with PV diameter < 12 mm have a significantly higher prevalence of F1 and F2 EV than pts with a portal diameter between 12-13 mm[1]. Seems to indicate that EV may unload portal pressure in the initial phases of portal hypertension 1. Zardi EM, Uwechie V, Gentilucci UV, Dobrina A, Petitti T, Laghi V, Picardi A, Afeltra A. Portal diameter in the diagnosis of esophageal varices in 266 cirrhotic patients: which role? Ultrasound Med Biol 2007; 33: 506-511
  43. 43. Extranote : p value  When you perform a hypothesis test in statistics, a p-value helps you determine the significance of your results. Hypothesis tests are used to test the validity of a claim that is made about a population. This claim that’s on trial, in essence, is called the null hypothesis.  The alternative hypothesis is the one you would believe if the null hypothesis is concluded to be untrue. All hypothesis tests ultimately use a p- value to weigh the strength of the evidence (what the data are telling you about the population).  The p-value is a number between 0 and 1 and interpreted in the following way: 1. A small p-value (typically ≤ 0.05) indicates strong evidence against the null hypothesis, so you reject the null hypothesis. 2. A large p-value (> 0.05) indicates weak evidence against the null hypothesis, so you fail to reject the null hypothesis. 3. p-values very close to the cutoff (0.05) are considered to be marginal (could go either way).  For example, suppose a pizza place claims their delivery times are 30 minutes or less on average but you think it’s more than that. You conduct a hypothesis test because you believe the null hypothesis, Ho, that the mean delivery time is 30 minutes max, is incorrect. Your alternative hypothesis (Ha) is that the mean time is greater than 30 minutes. You randomly sample some delivery times and run the data through the hypothesis test, and your p-value turns out to be 0.001, which is much less than 0.05. In real terms, there is a probability of 0.001 that you will mistakenly reject the pizza place’s claim that their delivery time is less than or equal to 30 minutes. Since typically we are willing to reject the null hypothesis when this probability is less than 0.05, you conclude that the pizza place is wrong; their delivery times are in fact more than 30 minutes on average, and you want to know what they’re gonna do about it! (Of course, you could be wrong by having sampled an unusually high number of late pizza deliveries just by chance.)
  44. 44.  Abstract  The aim was to evaluate the predictability of PD in the diagnosis of EV and of large size EV (F3EV) in a large series of pts with cirrhosis.  266 persons with cirrhosis (M:F = 153:113; mean age 65.4 ± 10 y) were studied by USG and EGD. PHG was found in 16.1% and EV was found in 60.9% of pts.  Only Child’s class (B vs. A: OR 3.4, p < 0.0001; C vs. A: OR 10.3, p < 0.0001; C vs. B: OR 3.1, p = 0.01) and age (OR 1.04, p = 0.03) were independent predictors of EV, whereas PD was not (p = 0.4).  Child’s class and age were also the only independent predictors of F3EV. Mean PD showed a slight and not significant increase in PHG pts compared with pts with negative endoscopy, a reduction in F1EV pts and then a progressive increase in F2EV and F3EV pts.  Pts with PD <12 mm showed a significantly higher prevalence of F1-F2EV (p < 0.05) and a near- significant lower prevalence of endoscopies negative for EV (p = 0.06) than pts with 12 ≤ PD ≤ 13 mm. PD was not able to predict EV or F3EV in a large series of pts with cirrhosis.  The oscillatory trend of PD, proceeding from patients with negative endoscopy to F3EV pts, seems to indicate that EV may unload portal pressure in the initial phases of PHTN.
  45. 45. 1. PHG was significantly more common in pts with coexistent gastric and EV. 2. Significantly higher incidence of PHG in cirrhotic pts with EV as compared to fundal GV. 3. PHG was higher in pts with common collaterals. 4. Relation with PVD ????
  46. 46. Esophageal variceal eradication:  Poddar et al [11,12] reported in a prospective study of 274 children undergoing surveillance EGD after endoscopic sclerotherapy for EHPVO that the number of pts with PHG increased from 46 (24.7%) to 95 (51.6%) after sclerotherapy among 186 pts completing the study (P < 0.001).  Itha et al [8] reported that the rate of PHG increased from 12% to 41% after endoscopic sclerotherapy (P < 0.001) in a prospective study of 163 children undergoing surveillance EGD at 3 and 6 mo after endoscopic sclerotherapy.  In the study by Sarin et al [7], 86 (9%) of 967 pts with prior variceal bleeding treated with endoscopic sclerotherapy, had PHG at EGD, of whom 22 (26%) had PHG before variceal eradication and 64 (74%) developed PHG after variceal eradication. References are at the end of slides Extra note: Sclerotherapy for esophageal varices has a 20-40% incidence of complications and a 1–2% mortality rate. The procedure controls acute bleeding in about 90% of patients, but it may have to be repeated within the first 48 hours to achieve this success rate.
  47. 47. Extranote  Prospective A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). The study usually involves taking a cohort of subjects and watching them over a long period..  Retrospective A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Many valuable case-control studies, such as Lane and Claypon's 1926 investigation of risk factors for breast cancer, were retrospective investigations. Most sources of error due to confounding and bias are more common in retrospective studies than in prospective studies.
  48. 48. Extranote Case-Control studies  Case-Control studies are usually but not exclusively retrospective, the opposite is true for cohort studies. The following notes relate case-control to cohort studies:  outcome is measured before exposure  controls are selected on the basis of not having the outcome  good for rare outcomes  relatively inexpensive  smaller numbers required  quicker to complete  prone to selection bias  prone to recall/retrospective bias  Cohort studies  Cohort studies are usually but not exclusively prospective, the opposite is true for case-control studies. The following notes relate cohort to case-control studies:  outcome is measured after exposure  yields true incidence rates and relative risks  may uncover unanticipated associations with outcome  best for common outcomes  expensive  requires large numbers  takes a long time to complete  prone to attrition bias (compensate by using person-time methods)
  49. 49. Esophageal variceal eradication:  Duan et al [1] reported PHG developed in 13 of 34 pts (38%) after percutaneous transhepatic variceal embolization for massive esophagogastric variceal hemorrhage.  These phenomena are attributed to increased PP and flow after eradication of EV because of redistribution of residual blood flow that had passed through the previously patent varices[2,3,4,5,6,7,8,9,10].  Itha et al [11] concluded that the significant increase in frequency and severity of PHG after variceal eradication resulted from decreasing collateral blood flow through EV causing increasing PHG from gastric mucosal congestion. This mechanism is supported by finding that gastric mucosal blood flow increases after variceal ligation[12]. References are at the end of slides
  50. 50. Esophageal variceal eradication:  Most studies showed no differences in frequency or severity of PHG after variceal ligation vs sclerotherapy[1,2,3,4,5,6], but some studies showed worse outcomes after variceal ligation[6,7,8], while some other studies showed worse outcomes after sclerotherapy[9]. 1. dos Santos JM, et al. Endoscopic and pharmacological secondary prophylaxis in children and adolescents with esophageal varices. J Pediatr Gastroenterol Nutr 2013; 56: 93-98 2. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 2000; 119: 181-187 3. Yüksel O, et al. Effects of esophageal varice eradication on portal hypertensive gastropathy and fundal varices: a retrospective and comparative study. Dig Dis Sci 2006; 51: 27-30 4. Hou MC, Lin HC, Kuo BI, Perng CL, Lee FY, Lee SD. Changes in portal hypertensive gastropathy after endoscopic variceal sclerotherapy or ligation: an endoscopic observation. Gastrointest Endosc 1995; 42: 139-144 5. Balan KK, Grime JS, Sutton R, Critchley M, Jenkins SA. Do alterations in the rate of gastric emptying after injection sclerotherapy for oesophageal varices play any role in the development of portal hypertensive gastropathy? HPB Surg 1999; 11: 141-148; discussion 148-150 6. Sarwar S, Khan AA, Alam A, Butt AK, Shafqat F, Malik K, Ahmad I, Niazi AK. Effect of band ligation on portal hypertensive gastropathy and development of fundal varices. J Ayub Med Coll Abbottabad 2006; 18: 32-35 7. de la Peña J, Rivero M, Sanchez E, Fábrega E, Crespo J, Pons-Romero F. Variceal ligation compared with endoscopic sclerotherapy for variceal hemorrhage: prospective randomized trial. Gastrointest Endosc 1999; 49: 417-423 8. Lo GH, Lai KH, Cheng JS, Hwu JH, Chang CF, Chen SM, Chiang HT. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995; 22: 466-471 9. Sarin SK. Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence. J Hepatol 1997; 26: 826- 832
  51. 51. Esophageal variceal eradication:  PHG after variceal obliteration is often transitory and less severe than PHG that predated the variceal obliteration[1,2].  Sarin et al [1] reported in a study of 84 pts followed for a mean of 25 ± 14 mo that PHG resolved in 28 (44%) of 64 pts who developed PHG after sclerotherapy, but resolved in only 2 (9%) of 22 pts who had PHG present before sclerotherapy (P < 0.05).  Hou et al [2] similarly reported that the increased severity of PHG after variceal obliteration was generally transitory and returned to baseline status. The return to baseline severity of PHG was significantly faster after variceal ligation than after sclerotherapy (P = 0.03), [1]. 1. Sarin SK, Shahi HM, Jain M, Jain AK, Issar SK, Murthy NS. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol 2000; 95: 2888-2893 2. Hou MC, Lin HC, Chen CH, Kuo BI, Perng CL, Lee FY, Lee SD. Changes in portal hypertensive gastropathy after endoscopic variceal sclerotherapy or ligation: an endoscopic observation. Gastrointest Endosc 1995; 42: 139-144
  52. 52. Esophageal variceal eradication:  Primignani et al [1,4] demonstrated an almost identical increase in frequency of PHG with time in pts undergoing vs not undergoing sclerotherapy, and suggested that PHG evolved identically with time regardless of performance vs nonperformance of sclerotherapy.  Some investigators believe the higher rate of PHG in pts undergoing endoscopic variceal sclerotherapy merely reflects a longer duration of PHTN, more advanced liver disease, or more severe PHTN in pts selected to undergo variceal sclerotherapy compared to controls rather than the performance of sclerotherapy [1,2,3]. 1. Primignani M, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 2000; 119: 181-187 2. Kamath PS, Shah VH. Portal hypertension and bleeding esophageal varices. In: Boyer TD, Manns MP, Sanyal AJ, editors. In: Zakim and Boyer’s Hepatology: A textbook of liver disease. 6th ed. Philadelphia: Elsevier Saunders, 2012: 296- 326 3. Feldman M, Lee EL. Gastritis. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 10th ed. Philadelphia: Elsevier Saunders, 2010: 868- 883 4. Primignani M, Materia M, Preatoni P, Carta A, Morbin T. Does endoscopic treatment of esophageal varices with sclerotherapy (ES) or ligation (EL) influence the evolution of portal hypertensive gastropathy (PHG) in cirrhotic patients? Gastroenterology 1998; 114; A1324
  53. 53. Esophageal variceal eradication 1. Yüksel O, Köklü S, Arhan M, Yolcu OF, Ertuğrul I, Odemiş B, Altiparmak E, Sahin B. Effects of esophageal varice eradication on portal hypertensive gastropathy and fundal varices: a retrospective and comparative study. Dig Dis Sci 2006; 51: 27-30 2. Hou MC, Lin HC, Chen CH, Kuo BI, Perng CL, Lee FY, Lee SD. Changes in portal hypertensive gastropathy after endoscopic variceal sclerotherapy or ligation: an endoscopic observation. Gastrointest Endosc 1995; 42: 139-144 3. Elnaser MS, Elebiary S, Bastawi MB, El Shafei A, Elmagd IM, Hamza MM. The prevalence of portal hypertensive gastropathy and duodenopathy in some Egyptian cirrhotic patients. J Egypt Soc Parasitol 2004; 34: 915- 923 4. Lo GH, Lai KH, Cheng JS, Hsu PI, Chen TA, Wang EM, Lin CK, Chiang HT. The effects of endoscopic variceal ligation and propranolol on portal hypertensive gastropathy: a prospective, controlled trial. Gastrointest Endosc 2001; 53: 579-584 5. de la Peña J, Rivero M, Sanchez E, Fábrega E, Crespo J, Pons-Romero F. Variceal ligation compared with endoscopic sclerotherapy for variceal hemorrhage: prospective randomized trial.Gastrointest Endosc 1999; 49: 417-423 6. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 7. Sarin SK, Shahi HM, Jain M, Jain AK, Issar SK, Murthy NS. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol 2000; 95: 2888-2893 8. Itha S, Yachha SK. Endoscopic outcome beyond esophageal variceal eradication in children with extrahepatic portal venous obstruction. J Pediatr Gastroenterol Nutr 2006; 42: 196-200 9. D’Amico G, Montalbano L, Traina M, Pisa R, Menozzi M, Spanò C, Pagliaro L. Natural history of congestive gastropathy in cirrhosis. The Liver Study Group of V. Cervello Hospital. Gastroenterology 1990; 99: 1558-1564 10. Gupta R, Saraswat VA, Kumar M, Naik SR, Pandey R. Frequency and factors influencing portal hypertensive gastropathy and duodenopathy in cirrhotic portal hypertension. J Gastroenterol Hepatol 1996; 11: 728-733 11. Poddar U, Bhatnagar S, Yachha SK. Endoscopic band ligation followed by sclerotherapy: Is it superior to sclerotherapy in children with extrahepatic portal venous obstruction? J Gastroenterol Hepatol 2011; 26: 255-259 Numerous studies demonstrated that PHG increased in incidence and that preexistent PHG increased in severity after eradication of EV by either endoscopic variceal ligation (Table 3)[1,2,3,4,5] or endoscopic variceal sclerotherapy (Table 4)[4,5,6,7,8,9,10,11] in cirrhotic pts with PHTN.
  54. 54. Conclusion 1. PHG increased in incidence and that preexistent PHG increased in severity after eradication of EV by either endoscopic variceal ligation or endoscopic variceal sclerotherapy in cirrhotic pts with PHTN. 2. Both phenomena also occurs after endoscopic variceal eradication in pts with NCPH.
  55. 55. Additional risk factors:  PHG severity is significantly associated with thrombocytopenia & splenomegaly [1,2,3].  In a prospective study of 331 cirrhotic pts performed in South Korea, PHG severity was correlated with splenic diameter: Splenic diameter with severe PHG = 13.1 ± 2.4 cm, diameter with mild PHG = 12.2 ± 2.5 cm, and diameter with no PHG = 10.7 ±2.9 cm, P < 0.001)[2]. In this study, PHG severity was inversely correlated with plt count: count with no PHG = 174600 ± 109400 plts/mm3, count with mild PHG = 132000 ± 100700 plts/mm3, count with severe PHG = 102800 ± 68800 plts/mm3 (P< 0.001).  Among 1016 pts with bridging fibrosis or compensated cirrhosis undergoing EGD in the HALT-C trial, including 374 (37%) with PHG, PHG was negatively correlated with plt count (P = 0.0007)[1]. 1. Fontana RJ, Sanyal AJ, Mehta S, Doherty MC, Neuschwander-Tetri BA, Everson GT, Kahn JA, Malet PF, Sheikh MY, Chung RT, Ghany MG, Gretch DR. Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial. Am J Gastroenterol 2006; 101: 983-992 2. Kim MY, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55: 3561-3567 3. De Lisi S, Peralta S, Arini A, Simone F, Craxì A. Oesophagogastroduodenoscopy in patients with cirrhosis: Extending the range of detection beyond portal hypertension. Dig Liver Dis 2011; 43: 48-53
  56. 56. References are at the end of slides
  57. 57. 1. Sarin SK, Sreenivas DV, Lahoti D, Saraya A. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992; 102: 994-999 2. Sogaard KK, Astrup LB, Vilstrup H, Gronbaek H. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol 2007; 7: 34 3. Iwao T, Toyonaga A, Sumino M, Takagi K, Oho K, Nishizono M, Ohkubo K, Inoue R, Sasaki E, Tanikawa K. Portal hypertensive gastropathy in patients with cirrhosis. Gastroenterology 1992; 102: 2060-2065 4. Gupta R, Saraswat VA, Kumar M, Naik SR, Pandey R. Frequency and factors influencing portal hypertensive gastropathy and duodenopathy in cirrhotic portal hypertension. J Gastroenterol Hepatol 1996; 11: 728-733 5. Chaves DM, Sakai P, Mucenic M, Iriya K, Iriya Y, Ishioka S. Comparative study of portal hypertensive gastropathy in schistosomiasis and hepatic cirrhosis. Endoscopy 2002; 34: 199-202 6. Fontana RJ, Sanyal AJ, Mehta S, Doherty MC, Neuschwander-Tetri BA, Everson GT, Kahn JA, Malet PF, Sheikh MY, Chung RT, Ghany MG, Gretch DR. Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial. Am J Gastroenterol 2006; 101: 983-992 7. Poddar U, Thapa BR, Singh K. Frequency of gastropathy and gastric varices in children with extrahepatic portal venous obstruction treated with sclerotherapy. J Gastroenterol Hepatol 2004; 19: 1253-1256 8. Mori T, Aisa Y, Yajima T, Shimizu T, Kato J, Nakazato T, Hibi T, Ikeda Y, Okamoto S. Esophageal varices and portal hypertensive gastropathy associated with hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation. Int J Hematol 2008; 87: 231-232 9. Urso G, Interlandi D, Puglisi M, Abate G, Bertino G, Raciti C, Sciacca C, Bruno M, Panarello A, Di Prima P, La Rosa G. Role of Helicobacter pylori in patients with portal hypertensive gastropathy by liver cirrhosis hepatitis C virus- related. Minerva Gastroenterol Dietol 2006; 52: 303-308 10. Al Mofleh IA. Does Helicobacter pylori affect portal hypertensive gastropathy? Saudi J Gastroenterol 2007; 13: 95-97
  58. 58. References are at the end of slides
  59. 59. Helicobacter pylori:  Numerous studies demonstrated that Helicobacter pylori (H. pylori) infection is not associated with PHG[1,2,3,4,5,6,7,8,9,10,11,12].  Indeed, several studies reported that patients with PHG less frequently have H. pylori infection than controls. H.pylori does not appear to play a pathogenic role in ulcers associated with PHG[13].  Contrariwise, Sathar SA[14] reported an association between H. pylori infection and PHG in cirrhotic pts, but this study apparently had limitations, including low specificity and low sensitivity of H. pylori serology in cirrhotic pts, and underreporting of H. pylori seroprevalence[14-18]. References are at the end of slides
  60. 60. End of Part 1  Diagnosis  Endoscopy & classification  Capsule Endoscopy  Dynamic CT  Differentiation from GAVE  Differentiating GI bleeding from varices vs PHG:  Clinical Presentation  Management:  Pharmacotherapy  Endoscopic therapy  Invasive therapy  Surgery  Prevention  Mortality  Lesions resembling PHG in other GI regions: Part 2
  61. 61. PHG: Contents of part 2  Diagnosis  Endoscopy & classification  Capsule Endoscopy  Dynamic CT  Differentiation from GAVE  Differentiating GI bleeding from varices vs PHG:  Clinical Presentation  Management:  Pharmacotherapy  Endoscopic therapy  Invasive therapy  Surgery  Prevention  Mortality  Lesions resembling PHG in other GI regions:
  62. 62. Diagnosis: Endoscopy  PHG is diagnosed by EGD[1]. The characteristic appearance is a mosaic-like pattern or a diffuse, erythematous and reticular cobblestone pattern of gastric mucosa consisting of small polygonal areas, with superimposed red punctate lesions, > 2 mm in diameter and a depressed white border[2,3,4].  These findings occur predominantly in the gastric body and fundus, and rarely in the antrum[1,6,8].  Toyonaga et al [9] reported in a meta-analysis of 6 studies that the mosaic-like pattern had high specificity at 98% , but low sensitivity at 38% for PHG, with an accuracy of 78% .  In severe PHG numerous petechiae and bleeding spots present as a diffuse hemorrhagic gastropathy [7,8]. References are at the end of slides
  63. 63. Figure 2 illustrates a pt with classic endoscopic findings of PHG. Figure 2 A 60-year-old man presented for routine endoscopic screening for esophageal varices due to a history of CP B cirrhosis, with a MELD = 18, from HCV secondary to former IV drug use. The pnt denied a history of GIB. The hematocrit was 40.1%. EGD revealed the classic findings of PHG, including a pale white reticular (mosaic) pattern surrounding small polygonal areas of mucosa, with variable erythema, in the entire stomach, but most prominently in the gastric fundus and body. B is a relatively close-up view of the lesions seen in A.
  64. 64. Endoscopic classification:  Endoscopic classification of PHG severity is clinically important because severity is correlated with bleeding risk [1,2,3,4].  PHG can be simply categorized as mild with a mosaic-like pattern without red spots, or as severe, with superimposed red lesions present[5,6].  Multiple formal endoscopic classifications exist, with no consensus as to which classification is the best[7,8,9,10].  The following classifications are commonly used: Classifications by McCormack et al [11], Tanoue et al [12], the New Italian Endoscopic Classification (NIEC) [13], and the Baveno scoring system [14]. References are at the end of slides Note: Red mucosal spots are due to extravasation of red cells through damaged endothelium or to passage of red cells through interendothelial spaces. These changes are not accompanied by an inflammatory reaction. Ref: Clinical Hepatology. Henryk
  65. 65. Classification system for PHG Mild Moderate Severe Mc Cormack et al (1) Fine pink speckling (scarlatina like rash) Fine white reticular pattern separating areas of raised edematous mucosa (snake skin) Discrete red spots (analogous to cherry red spot in esophagus) Diffuse hemorrhagic gastritis McCormick et al (2) Mosaic or snake skin appearance Presence of erythema Presence of erosions or hemorrhagic gastritis Tanoue et al (3) Mild reddening ,congestive mucosa, no mosaic like pattern Severe redness and fine reticular pattern separating the area of raised edematous mucosa( mosaic like pattern) Point bleeding+ grade 2 Spina et al NIEC (4) Mosaic pattern: presence of small polygonal area surrounded by whitish yellow depressed border Red point lesion (1 mm d flat) Cherry red spots (2 mm slight protrusion) black brown spots(irregularly shaped persistently present after washing) References are at the end of slides
  66. 66. 1. Sarin, SK. Diagnostic issues: Portal hypertensive gastropathy and gastric varices. In: DeFranchis R, editor. Portal hypertension II. Proceedings of the second Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Oxford: Blackwell Science, 1996: 30-55 2. Yoo HY, Eustace JA, Verma S, Zhang L, Harris M, Kantsevoy S, Lee LA, Kalloo AN, Ravich WJ, Thuluvath PJ. Accuracy and reliability of the endoscopic classification of portal hypertensive gastropathy. Gastrointest Endosc 2002; 56: 675-680 3. Burak KW, Beck PL. Diagnosis of portal hypertensive gastropathy. Curr Opin Gastroenterol 2003; 19: 477-482
  67. 67. Endoscopic classification: NIEC 1. Mosaic-like pattern (MLP): small polygonal areas, slightly protruding in the centre, surrounded by a whitish- yellow depressed border. A. Mild: the colour of the central areola is pink. B. Moderate: a fiat red spot, not reaching the white border, is seen in the centre of a pink areola. C.Severe: the colour of the central areola is diffusely red. The NIEC produced a better definition in 1992 of mild and severe PHG[1]. Elementary lesions of PHG according to the NIEC classification include: 1. Spina GP, Arcidiacono R, Bosch J, Pagliaro L, Burroughs AK, Santambrogio R, Rossi A. Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy, September 19, 1992. J Hepatol 1994; 21: 461-467
  68. 68. Fig. 2. Red point lesions (RPL): small, fiat, red point-like lesions (i.e., with diameters less than 1 mm), showing either discrete or confluent distribution. Fig. 3. Cherry red spots (CRS): slightly protruding red-coloured round lesions, with diameters larger than 2 mm, either rare or diffusely distributed. Fig. 4. Black brown spots (BBS): few or multiple flat spots, black or brown in colour, persistent after washing, results of intramucosal haemorrhage. Endoscopic classification: NIEC 1. Spina GP, Arcidiacono R, Bosch J, Pagliaro L, Burroughs AK, Santambrogio R, Rossi A. Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy, September 19, 1992. J Hepatol 1994; 21: 461-467
  69. 69. Endoscopic classification:  The Baveno scoring system uses point calculations to define PHG as mild (≤ 3 points) vs severe (≥ 4 points)[1].  This system adds gastric antral vascular ectasia (GAVE) into the classification.  Stewart et al [2] showed that this scoring system was reproducible and accurately reflected the risk of PHG-related bleeding in cirrhotic patients. 1. Sarin, SK. Diagnostic issues: Portal hypertensive gastropathy and gastric varices. In: DeFranchis R, editor. Portal hypertension II. Proceedings of the second Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Oxford: Blackwell Science, 1996: 30-55 2. Stewart CA, Sanyal AJ. Grading portal gastropathy: validation of a gastropathy scoring system. Am J Gastroenterol 2003; 98: 1758-1765
  70. 70. MP: Small polygonal areas demarcated by a distinct white to-yellow border and with or without a slight central bulge, which had a mosaic, fish scale-like appearance upon endoscopy. The MP was considered to be mild when the color of the mucosa was pink, whereas diffuse erythema (redness) of the mucosa was considered to represent severe MP. RED MARKS. Flat or slightly bulging red lesions seen in the gastric mucosa. Such lesions included fine punctate hemorrhagic spots and discrete red spots corresponding to the red point lesions and cherry red spots described by the NIEC group. BLACK–BROWN SPOTS. These were believed to represent old submucosal hemorrhage and not scored. These definitions are identical to those proposed by the NIEC (9) and by Sarin (10) to develop the scoring systern for PHG presented at the Baveno conference. GAVE was diagnosed by the presence of flat or slightly raised red stripe-like lesions radiating from the pylorus to the antrum and body of the stomach for a variable distance (11). In those with E or GV, bleeding was considered to be caused by PHG if the varices lacked stigmata of recent hemorrhage and fresh oozing from the gastric mucosa was present. The presence of marked mucosal friability, as defined by the ability to induce fresh oozing by squirting water on the mucosa through a catheter passed via the biopsy channel, was considered to be evidence of bleeding from the gastric mucosa. 9.Spina GP, Arcidiacono R, Bosch J, et al. Gastric endoscopic features in portal hypertension: Final report of a consensus conference, Milan, Italy, Sept. 19,1992. J Hepatol 1994;21:461–7. 10.Sarin SK. Diagnostic issues: PHG and gastric varices. In: DeFranchis R, ed. Portal hypertension II. Proceedings of the second Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Oxford: Blackwell Science, 1996:30–55. 11.Gostout CJ, Yiggiano TR, Ahlquist DA, et al. The clinical and endoscopic spectrum of the watermelon stomach. J Clin Gastroenterol 1992;15:256–63.
  71. 71. OBJECTIVE: The specific aim of this study was to independently evaluate the reproducibility and validity of the Baveno PHG grading system. METHODS: This is a prospective study of 100 consecutive pts with cirrhosis and PHG. An EGD was performed at entry on all subjects and on 70 pts during follow-up (median 15 mnths). Interobserver reproducibility was assessed by the statistic. Pts with PHG-related bleeding were compared with those without bleeding. The relationship of PHG-related bleeding to the PHG score was assessed by a receiver operating characteristic curve and by multiple logistic regression analysis. RESULTS: Interobserver agreement about the presence of the mosaic pattern and red marks was high (0.75). However, the agreement about the extent of the lesion was poorer (0.4–0.45). There was a stepwise increase in PHG-related bleeding risk with increasing PHG scores. Multiple logistic regression confirmed that the PHG score independently correlated with PHG-associated bleeding (OR 2.5, 90% CI 1.4–4.6, p 0.009). During follow-up, red marks developed de novo in one of 70 pts. The severity of red marks worsened in five of 25 pts, whereas they disappeared in eight of 62 individuals. Nodular lesions in the antrum were found in 5 subjects. The risks of recurrent bleeding during F/U were related to severe PHG scores (4), presence of GAVE, and nodular lesions in the antrum. CONCLUSIONS: The PHG scoring system is reproducible and accurately reflects the risks of PHG-related bleeding in patients with cirrhosis. (Am J Gastroenterol 2003;98: 1758–1765. © 2003 by Am. Coll. of Gastroenterology)
  72. 72. Capsule endoscopy:  Several studies evaluated the diagnostic accuracy of capsule endoscopy.  In a study of 50 pts with cirrhosis undergoing both EGD and CE for screening or surveillance of EV, CE had an accuracy of 57%, SN of 96%, and SP of 17% compared to EGD. The researchers concluded that more data are required to assess accuracy of CE for DX and staging of PHG[1].  In another study of 50 pts with PHTN undergoing EGD and CE, only 24 of 35 pts with PHG diagnosed by EGD had PHG detected by CE(SN = 69%)[2]. CE was somewhat more sensitive at detecting severe than mild PHG (82% vs 63%), but this difference was not significant (P = 0.44). The accuracy was significantly higher in diagnosing PHG in the gastric body (100%) than the fundus (48%) (P = 0.0009). 1. Frenette CT, Kuldau JG, Hillebrand DJ, Lane J, Pockros PJ. Comparison of esophageal capsule endoscopy and esophagogastroduodenoscopy for diagnosis of esophageal varices. World J Gastroenterol 2008; 14: 4480-4485 2. Aoyama T, et al. Is small-bowel capsule endoscopy effective for diagnosis of esophagogastric lesions related to portal hypertension? J Gastroenterol Hepatol 2014; 29: 511-516
  73. 73. Dynamic CT: PHG  Kim et al [1] proposed using dynamic CT to diagnose PHG by demonstrating the transient perfusion defect sign, defined as the presence of transient segmental or subsegmental hypo- attenuating mucosa in the gastric fundus or body during hepatic arterial imaging that returns to normal attenuation on portal venous or equilibrium-phase imaging.  This sign had a SN of 75%, SP of 88.6%, PPV of 90%, and NPV of 72.1% for diagnosing PHG in pts with cirrhosis.  Further prospective trials are required to validate this diagnostic modality. 1. Kim TU, Kim S, Woo SK, Lee JW, Lee TH, Jeong YJ, Heo J. Dynamic CT of portal hypertensive gastropathy: significance of transient gastric perfusion defect sign. Clin Radiol 2008; 63: 783-790
  74. 74. Predictors of PHG  Screening for PHG is currently not recommended in pts with liver disease[1].  To identify predictors of PHG and varices noninvasively in pts with CLD to increase the cost- benefits of EGD, Min et al [2] combined three independent parameters in a “Varices and PHG” (VAP) score.  The score = platelets/mm3 × albumin in g/Dl /multidimensional index for spleen volume (M- Index) in cm3. The M-Index is calculated from spleen length, width, and thickness, as determined by helical CT, which is designed to reflect Splenomegaly as a predictor of EV and PHG.  A VAP cut-off value of 861 had a SN of 85%, PLR of 3.17, and NPV of 86%. This scoring system requires prospective validation[2]. 1. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-938 2. Min YW, et al. A clinical predictor of varices and portal hypertensive gastropathy in patients with chronic liver disease. Clin Mol Hepatol 2012; 18: 178-184
  75. 75. Extranote Interpreting likelihood ratios: general guidelines  The first thing to realize about LR's is that an LR > 1 indicates an increased probability that the target disorder is present, and an LR < 1 indicates a decreased probability that the target disorder is present. Correspondingly, an LR = 1 means that the test result does not change the probability of disease at all! The following are general guidelines, which must be correlated with the clinical scenario: LR Interpretation  > 10: Large and often conclusive increase in the likelihood of disease  5 - 10:Moderate increase in the likelihood of disease  2 - 5: Small increase in the likelihood of disease  1 - 2: Minimal increase in the likelihood of disease  1:No change in the likelihood of disease  0.5 - 1.0:Minimal decrease in the likelihood of disease  0.2 - 0.5:Small decrease in the likelihood of disease  0.1 - 0.2:Moderate decrease in the likelihood of disease  < 0.1:Large and often conclusive decrease in the likelihood of disease  When evaluating the feasibility or the success of a screening program, one should also consider the positive and negative predictive values. These are also computed from the same 2 x 2 contingency table, but the perspective is entirely different.  Positive predictive value is the probability that subjects with a positive screening test truly have the disease.  Negative predictive value is the probability that subjects with a negative screening test truly don't have the disease.
  76. 76. Differentiation from GAVE:  Differentiation of PHG from GAVE is important because they have distinct pathologic, clinical, and endoscopic characteristics, and different therapies .  Treatments that reduce PP are effective for PHG but ineffective for GAVE[1].  PHG and GAVE also affect different gastric locations. PHG generally affects the proximal stomach ( but can extend throughout the stomach. Ref: Sherlock’s DOL), whereas GAVE generally affects the distal stomach[2].  A mosaic-like pattern surrounding polygonal areas of erythema is typical for PHG, but GAVE has erythema most commonly arranged linearly along folds in the antrum, less commonly arranged as diffuse erythema in the antrum.[3,4,5].
  77. 77. GAVE GAVE (gastric antral vascular ectasia) is a particular form of gastropathy that can cause chronic GI bleeding and IDA. It consists of dilated small blood vessels in the antrum, which can present at endoscopy as watermelon stomach (parallel longitudinal stripes converging to the pylorus) or as diffuse ectasia of vessels. Note: This is marked by increased arteriovenous communications between the muscularis mucosa and dilated precapillaries and veins. Gastric mucosal perfusion is increased. Ref: Sherlock’s DOL
  78. 78. GAVE  Its cause is unknown, although it has been proposed that gastric peristalsis causes prolapse of the loose antral mucosa with consequent elongation and ectasia of the mucosal vessels. Ref: Sleisenger  The pathophysiology of GAVE does not appear to involve PHTN because it does not respond to therapies directed at reducing PP. Given case reports of GAVE resolution after LT, however, it is possible that liver insufficiency may play a role in its pathophysiology. Ref: Sleisenger
  79. 79. Differences between PHG and GAVE Parameter Portal hypertensive gastropathy GAVE Associated conditions Conditions associated with portal hypertension: cirrhotic or non-cirrhotic portal hypertension Cirrhosis, autoimmune disorders, and connective tissue diseases (scleroderma, pernicious anemia, hypothyroidism) Chronic Gastritis (Schiff’s DOL) CKD, CVD, BMT (Sleisenger) Association with portal hypertension Strong association Only 30% of cases 40 % (Sleisenger) Sex Mildly more common in males (alcoholic cirrhosis more common in males than females) Much more common in females (80%) Age Can occur at any age in patients with portal hypertension or cirrhosis Typically elderly (average age > 70 years old) Location Proximal stomach: Fundus, body Distal stomach: Antrum
  80. 80. Differences between PHG and GAVE Parameter Portal hypertensive gastropathy GAVE Diagnosis Endoscopy (endoscopic biopsy sometimes useful). Radiologic imaging usually not helpful Endoscopy (endoscopic biopsy sometimes useful) Appearance at endoscopy Mosaic/snakeskin mucosa with red or brown spots Tortuous columns of ectatic vessels in "watermelon" or diffuse pattern; erythematous or hemorrhagic Histology Ectatic capillaries, mildly dilated mucosal and submucosal veins; no vascular inflammation, no vascular thrombi Marked dilation of capillaries and venules in gastric mucosa and submucosa with areas of intimal thickening, fibrin thrombi, fibromuscular hyperplasia and spindle cell proliferation Clinical presentation/ complications Gastrointestinal bleeding: Usually chronic, but sometimes acute Almost exclusively chronic gastrointestinal bleeding with guaiac positive stools
  81. 81. Differences between PHG and GAVE Parameter Portal hypertensive gastropathy GAVE Primary prophylaxis Not indicated Not indicated (unless associated with large varices) Medical therapy Non-selective β-adrenergic receptor antagonists (propranolol), octreotide (for acute bleeding) No benefit of β-adrenergic receptor antagonists Oral contraceptive pills to temporarily control bleeding Questionable benefit of octreotide Tranexamic acid, Thalidomide(Sleisenger) Endoscopic therapy Occasionally helpful (for focal bleeding) Argon plasma coagulation Local hemostasis with hemospray Very helpful at reducing risk of bleeding: Argon plasma coagulation; EBL; Radiofrequency ablation; YAG laser therapy TIPS Significantly reduces severity and risk of bleeding by reducing PHTN. Option for very severe bleeding from PHG or for moderate PHG in patients with variceal bleeding Not recommended. Does not affect severity of GAVE or risk of bleeding
  82. 82. Differences between PHG and GAVE Parameter Portal hypertensive gastropathy Esophageal varices Liver transplantation Resolves. Ultimate therapy mostly reserved for patients with end-stage liver disease Improves or resolves with liver transplantation (However, the data are insufficient to recommend this therapy unless the patient is otherwise a LT candidate. Ref: Sleisenger) Other surgery Usually resolves with shunt surgery that lowers portal pressure. Partial gastrectomy not recommended Limited surgical resection (partial gastrectomy) recommended for refractory cases. Shunt surgery not recommended Prognosis from bleeding Bleeding rarely severe and very rarely fatal Bleeding occasionally severe
  83. 83. Differentiating GIB from varices vs PHG:  PHG may occasionally resemble GV at EGD. PHG can be prominent on gastric rugae in the gastric body and fundus. The intraluminal linear projections of gastric rugae might superficially resemble that of GV.  However, GV tend to be more serpiginous than linear and tend to be grayish due to the presence of deoxygenated venous blood within varices, whereas the lesions of PHG on gastric rugae tend to be erythematous and surrounded by a prominent mosaic pattern.  It is also important to distinguish between GI bleeding from EV vs PHG in patients having both lesions.
  84. 84. Differences in gastrointestinal bleeding from PHG vs EV Parameter Portal hypertensive gastropathy Esophageal varices Etiology Portal hypertension: Cirrhotic or non-cirrhotic Portal hypertension: Cirrhotic or non-cirrhotic Concurrence Frequently occur simultaneously with EV because the two diseases share common risk factors Frequently occurs simultaneously with PHG because the two diseases have common risk factors Location Stomach: Predominantly fundus and body Distal esophagus: Also can have gastric varices or ectopic varices in other gastrointestinal regions, particularly duodenum Diagnosis Esophagogastroduodenoscopy Esophagogastroduodenoscopy Endoscopic appearance Erythematous small polygonal areas of mucosa surrounded by a fine, whitish, reticular or mosaic/ snakeskin mucosa with red or brown spots Serpiginous mucosal greyish luminal projections in distal esophagus
  85. 85. Differences in gastrointestinal bleeding from PHG vs EV Parameter Portal hypertensive gastropathy Esophageal varices Clinical presentation Mild acute or chronic bleeding Acute gastrointestinal bleeding-typically massive Severity of bleeding Typically mild and not life- threatening Typically severe and life-threatening Histology Not biopsied at endoscopy Endoscopic therapy Limited role Variceal ligation recommended as initial therapy. Sclerotherapy an alternative therapy Medical therapy Octreotide, Propranolol Vasopressin or vasopressin analogues -infrequently recommended any more Octreotide, Propranolol Vasopressin or vasopressin analogues- infrequently recommended any more
  86. 86. Differences in gastrointestinal bleeding from PHG vs EV Parameter Portal hypertensive gastropathy Esophageal varices Angiographic therapy TIPS used as a last resort TIPS recommended if endoscopic therapy fails Transfusion of packed erythrocytes Transfuse only to hematocrit of about 28. Overtransfusion may increase portal pressure and induce greater bleeding Transfuse only to hematocrit of about 28. Overtransfusion may increase portal pressure and induce greater bleeding Liver transplantation Improves or resolves with liver transplantation Improves or resolves with liver transplantation Prognosis Rarely fatal Frequently fatal
  87. 87. Clinical presentation :Acute GI bleeding  GI bleeding is the only known clinically relevant complication of PHG. PHG is responsible for < 1% of UGIB in the general population, and for about 8% of non-variceal upper GI bleeding in pts with liver disease[1].  The reported frequency of acute UGIB in pts with PHG ranges in incidence from 2%-20%.  Diagnosis of PHG as the cause of bleeding can be challenging if a bleeding point is not visualized at EGD[2]. 1. Gostout CJ, Viggiano TR, Balm RK. Acute gastrointestinal bleeding from portal hypertensive gastropathy: prevalence and clinical features. Am J Gastroenterol 1993; 88: 2030-2033 2. Thuluvath PJ, Yoo HY. Portal Hypertensive gastropathy. Am J Gastroenterol 2002; 97: 2973-2978 Note: • 10 to 50% of all UGIB in cirrhotic patients are assumed to arise from PHG. 66 to 75% of these pts experience recurrent bleeding from PHG within 1 year. Ref: Clinical Hepatology . Henryk • The incidence of overt bleeding in pts with mild PHG is approximately 5% per year, as compared to 15% for severe PHG. Ref: Schiff’s Disease of Liver. • The incidence of minor mucosal blood loss, without overt bleeding, is approximately 8% per year in pts with mild PHG and up to 25% in those with severe PHG, in whom severe chronic IDA may result, requiring frequent hospital admissions and blood transfusions. Ref: Schiff’s Disease of Liver.
  88. 88. References are at the end of slides
  89. 89. Risk Factor  Major risk factors for bleeding from PHG are increasing PHG duration, extent, and severity[1,2].  > 90% of acute bleeding occurs with severe PHG[1,3,4,5], and < 10% of acute bleeding occurs with mild PHG[6].  Other risk factors for bleeding from PHG include advanced cirrhosis, and prior endoscopic eradication of EV[7,8,3,9,2,10,11].  Unlike bleeding from GAVE, acute bleeding from PHG is rarely severe, very rarely fatal, and typically requires transfusion of only one-to-two units of packed erythrocytes or less[12,13,14]. References are at the end of slides
  90. 90. Chronic GI bleeding from PHG  The incidence of chronic GIB from PHG is difficult to determine precisely because of variable definitions of chronic GIB[1,2].  Common definitions include: (1) > 2 g/dL decrease in hemoglobin level during > 6 mo in pts without acute GI bleeding and not receiving NSAID therapy; (2) presence of anemia in patients with cirrhosis; and (3) positive fecal occult blood (Baveno II)[3].  Moreover, chronic GIB can be overestimated if hb decline is solely used for the diagnosis. Pts with CLD frequently have anemia without GIB, from causes including alcoholism, hypersplenism, or bone marrow suppression. No studies have objectively quantified chronic blood loss from PHG.  Chronic bleeding from PHG is usually mild to moderate but occasionally severe[4,5].  Pts after EVL have a higher incidence of chronic GIB from PHG[6,7,8].  Chronic GI bleeding from PHG can cause IDA[9,10]. References are at the end of slides
  91. 91. Pharmacotherapy for PHG  Current pharmacologic therapies aim to reduce PP to decrease bleeding from PHG[1,2].  β-adrenergic receptor antagonists: NSBB reduce PP and gastric mucosal blood flow, and thereby reduce bleeding from PHG[3,4,5,6,7,8,9].  Several studies evaluated the efficacy of propranolol, in primary and secondary prevention of bleeding from PHG[4,10].  Pérez-Ayuso et al [3] reported in a multi-center, randomized, controlled trial of 57 pts with acute or chronic bleeding from severe PHG with cirrhosis that the 26 pts administered propranolol at 20-160 mg bd rebled significantly less frequently than the 31 controls receiving only iron therapy as needed at 12 mo (38% vs 65%; P < 0.05), and at 30 mo follow-up (7% vs 52%, P <0.05). Pts receiving propranolol were transfused less units of packed erythrocytes than the controls, but this difference was not statistically significant [0.10 ± 0.06 (SD) units/mo vs 0.60 ± 0.20 (SD) units/mo, P = 0.08] References are at the end of slides
  92. 92. Extranote  Primary prevention aims to prevent disease or injury before it ever occurs.  Secondary prevention aims to reduce the impact of a disease or injury that has already occurred. This is done by detecting and treating disease or injury as soon as possible to halt or slow its progress, encouraging personal strategies to prevent reinjury or recurrence, and implementing programs to return people to their original health and function to prevent long-term problems.
  93. 93. Pharmacotherapy for PHG: NSBB  Propranolol also reduced the risk of developing PHG after esophageal variceal eradication[1].  Lo et al [1] reported in a randomized, controlled trial that 40 pts receiving placebo had a significant increase in PHG severity after variceal ligation (P < 0.01), but the 37 pts receiving propranolol [mean dose = 96 ± 20 (SD) mg/d] had no significant increase in PHG severity.  The frequency of PHG 6 mo after variceal ligation was significantly less in pts receiving propranolol than in the controls (48% vs 85%, P = 0.002).  This difference gradually decreased over time and became not significant at 12 mo. (P < 0.05). 1. Lo GH, Lai KH, Cheng JS, Hsu PI, Chen TA, Wang EM, Lin CK, Chiang HT. The effects of endoscopic variceal ligation and propranolol on portal hypertensive gastropathy: a prospective, controlled trial. Gastrointest Endosc 2001; 53: 579-584
  94. 94. Pharmacotherapy for PHG: NSBB  Propranolol at 240-480 mg/d has been used to arrest acute bleeding from PHG.  Bleeding stopped within 3 d in 13 (93%) of 14 pts with PHG administered propranolol in one study[1]. None of these pts rebled while receiving propranolol during a median of 23 mo of follow- up, but 4 out of 7 pts rebled after electively discontinuing propranolol therapy[2].  Nonresponse to β-adrenergic receptor antagonists, defined as continued bleeding despite this therapy and transfusion-dependency despite iron replacement therapy, should prompt consideration of interventional therapies[3].  NSBB are a first line therapy for secondary prophylaxis of PHG bleeding[4,5].  Nadolol alone was as effective as nadolol with isosorbide mononitrate in preventing the first episode of PHG bleeding[6].  No studies have analyzed the efficacy of carvedilol, another nonspecific β-adrenergic receptor antagonist, in controlling bleeding from PHG[7]. 1. Soin AS, Acharya SK, Mathur M, Sahni P, Nundy S. Portal hypertensive gastropathy in noncirrhotic patients. The effect of lienorenal shunts. J Clin Gastroenterol 1998; 26: 64-67; discussion 68 2. Hosking SW, et al. The role of propranolol in congestive gastropathy of portal hypertension. Hepatology 1997; 7: 437-441 3. Ripoll C, Garcia-Tsao G. Management of gastropathy and gastric vascular ectasia in portal hypertension. Clin Liver Dis 2010; 14:281-295 4. Patwardhan VR, Cardenas A. Review article: the management of portal hypertensive gastropathy and gastric antral vascular ectasia in cirrhosis. Aliment Pharmacol Ther 2014; 40: 354-362 5. Turon F, Casu S, Hernández-Gea V, Garcia-Pagán JC. Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol 2013; 27: 649-664 6. Merkel C, et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000; 31: 324-329 7. Abid S, Ali S, Baig MA, Waheed AA. Is it time to replace propranolol with carvedilol for portal hypertension? World J Gastrointest Endosc 2015; 7: 532-539
  95. 95. Somatostatin and octreotide:  Somatostatin and octreotide, a synthetic somatostatin analogue, cause splanchnic vasoconstriction, reduce PP, reduce portal blood flow, and decrease gastric perfusion in animal models and in pts with PHG [1,2,3,4,5,6,7].  Chan et al [4] found octreotide infusion, compared to placebo, significantly increased systemic vascular resistance [3.4 ± 0.2 (SD) mmHg/mL/min per 100 g vs 2.7 ± 0.2 (SD) mmHg/mL/min per 100 g, P < 0.05], and significantly decreased PP[9.9 ± 0.5 (SD) mmHg vs 12.5 ± 1.2 (SD) mmHg, P < 0.05] in cirrhotic rats.  Another study found that somatostatin only modestly reduced PP in PHG[8].  Octreotide treatment also significantly reduced mean cross-sectional area of gastric mucosal vessels compared to placebo [1810 ± 101 (SD) microns vs 2290 ± 145 (SD) microns, P < 0.05], and significantly inhibited release of several vasoactive gastrointestinal polypeptides, gastric acid, and pepsinogen[2,9]. References are at the end of slides Normal svr is 9–20 mg/ml/min Systemic Vascular Resistance = 80x(Mean Arterial Pressure - Mean Venous Pressure or CVP) / CO
  96. 96. Octreotide  Octreotide is a first-line treatment for acute bleeding from PHG.  In a RCT, octreotide, at 100 mcg bolus followed by infusion of 25 mcg/min for the first 24 h and then 20 mcg/min for the second 24 h, controlled bleeding from PHG in 20 (83%) of 24 pts at 24 h and in 24 (100%) of 24 pts at 48 h[1].  Octreotide significantly more frequently controlled the bleeding than vasopressin (64%, P < 0.005), or omeprazole (59%, P < 0.005), and tended to be more effective than both vasopressin and omeprazole (88%)[1].  Octreotide also controlled the bleeding significantly faster and required significantly less transfusions of packed erythrocytes than vasopressin or omeprazole[1].  Octreotide even successfully stopped bleeding within 48 h in the pts with bleeding refractory to vasopressin and omeprazole therapy. 1. Zhou Y, Qiao L, Wu J, Hu H, Xu C. Comparison of the efficacy of octreotide, vasopressin, and omeprazole in the control of acute bleeding in patients with portal hypertensive gastropathy: a controlled study. J Gastroenterol Hepatol 2002; 17: 973-979
  97. 97. Somatostatin and octreotide  Kouroumalis et al [1] reported that somatostatin or octreotide infusion for 3 d stopped severe bleeding from PHG in all 26 study pts. Only 3 pts experienced recurrent bleeding which stopped after retreatment with somatostatin, and only one pt required gastrectomy for refractory bleeding.  Somatostatin and octreotide only temporarily reduce PP.  Escorsell et al [2] reported rapid desensitization to the effects of octreotide with prolonged administration in cirrhotic pts with PHTN.  Therefore somatostatin and octreotide are useful for acute bleeding but not for preventing chronic bleeding from PHG. 1. Kouroumalis EA, Koutroubakis IE, Manousos ON. Somatostatin for acute severe bleeding from portal hypertensive gastropathy. Eur J Gastroenterol Hepatol 1998; 10: 509-512 2. Escorsell A, Bandi JC, Andreu V, Moitinho E, García-Pagán JC, Bosch J, Rodés J. Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Gastroenterology 2001; 120: 161-169
  98. 98. Vasopressin and Octreotide:  Vasopressin, a systemic vasoconstrictor, reduces splanchnic blood flow, lowers PP, and decreases gastric mucosal blood flow[1].  In a RCT, vasopressin, administered IV at a rate of 1 unit/min for the first 10 min, followed by continuous infusion at 0.1 unit/min for 48 h, arrested bleeding from PHG in 14 (64%) of 22 pts[1].  However, as aforementioned, this result was inferior to that achieved by octreotide, possibly because vasopressin does not inhibit release of peptides, including glucagon and vasoactive intestinal polypeptide, and does not inhibit gastric acid secretion[1].  Concomitant omeprazole therapy may modestly increase vasopressin efficacy[1].  Vasopressin is considered an alternative therapy to octreotide.  Vasopressin causes significantly more frequent side effects (41%) than octreotide, especially abdominal pain[1]. 1. Zhou Y, Qiao L, Wu J, Hu H, Xu C. Comparison of the efficacy of octreotide, vasopressin, and omeprazole in the control of acute bleeding in patients with portal hypertensive gastropathy: a controlled study. J Gastroenterol Hepatol 2002; 17: 973-979
  99. 99. Vasopressin and its analogue: terlipressin:  Vasopressin reduces oxygen saturation of gastric mucosa, but this reduction can be partly reversed by administering supplemental oxygen[1,2].  Terlipressin may be useful in controlling acute bleeding from PHG, especially when used at a dose of 1 mg IV every 4 h for 5 d[3,4,5]. 1. Iwao T, Toyonaga A, Shigemori H, Oho K, Sumino M, Sato M, Tanikawa K. Vasopressin plus oxygen vs vasopressin alone in cirrhotic patients with portal-hypertensive gastropathy: effects on gastric mucosal haemodynamics and oxygenation. J Gastroenterol Hepatol 1996; 11: 216-222 2. Panés J, Piqué JM, Bordas JM, Llach J, Bosch J, Terés J, Rodés J. Reduction of gastric hyperemia by glypressin and vasopressin administration in cirrhotic patients with portal hypertensive gastropathy. Hepatology 1994; 19: 55-60 3. Pérez-Ayuso RM, Piqué JM, Bosch J, Panés J, González A, Pérez R, Rigau J, Quintero E, Valderrama R, Viver J. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991; 337: 1431-1434 4. Bruha R, Marecek Z, Spicak J, Hulek P, Lata J, Petrtyl J, Urbanek P, Taimr P, Volfova M, Dite P. Double-blind randomized, comparative multicenter study of the effect of terlipressin in the treatment of acute esophageal variceal and/or hypertensive gastropathy bleeding. Hepatogastroenterology 2002; 49: 1161-1166 5. Ripoll C, Garcia-Tsao G. Treatment of gastropathy and gastric antral vascular ectasia in patients with portal hypertension. Curr Treat Options Gastroenterol 2007; 10: 483-494

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