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Effect of transjugular intrahepatic portosystemic shunt formation on portal hypertensive gastropathy and gastric circulation
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 4, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02257-2
Effect of Transjugular Intrahepatic Portosystemic Shunt Formation on Portal Hypertensive Gastropathy and Gastric Circulation Shinichi Mezawa, M.D., Hisato Homma, M.D., Hidetoshi Ohta, M.D., Eiichi Masuko, M.D., Tadashi Doi, M.D., Koji Miyanishi, M.D., Koichi Takada, M.D., Takehiro Kukitsu, M.D., Tsutomu Sato, M.D., and Yoshiro Niitsu, M.D. Department of Gastroenterology, Tokeidai Hospital; and Fourth Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
OBJECTIVES: The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics. METHODS: A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure. RESULTS: TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure. CONCLUSIONS: It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG. (Am J Gastroenterol 2001;96: 1155–1159. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Bleeding from esophageal varices is a major complication in cirrhotic patients. Gastric mucosal lesions are known to occur widely in such patients and sometimes cause lethal hemorrhage resistant to therapy (1). Since the report of McCormack et al. in 1985, the occurrence of these gastric mucosal lesions has been termed congestive gastropathy or portal hypertensive gastropathy (PHG) (2, 3). The study of
their pathogenesis has focused on the relationship between the hepatic and gastric circulation. Much effort has been devoted to the clarification of gastric mucosal hemodynamics in cirrhotic patients and to the pathogenesis of PHG. Nevertheless, some controversies remain (4 –7). First, it is unclear whether gastric mucosal blood flow increases or decreases in patients with cirrhosis. Second, it is not clear how gastric mucosal blood flow (GMBF) is involved in the pathogenesis of PHG. Many studies have reported values for GMBF associated with PHG (4 – 8), but there are very few studies on gastric perfusion deeper than the mucosal layer. Transjugular intrahepatic portosystemic shunt (TIPS) is considered to be effective in treating endoscopically uncontrollable variceal bleeding and refractory ascites (9 –13). However, there have been only a few reports describing the effect of TIPS on PHG (14, 15). One of these reports described the effect of TIPS on gastric mucosal hemodynamics, but there have been no reports mentioning deeper gastric perfusion, which is also presumed to be related to the pathogenesis of PHG. In this study, we evaluated the effects of TIPS on PHG, measured gastric mucosal and submucosal hemodynamics, and investigated the relationship between portal and gastric circulation in cirrhotic patients.
MATERIALS AND METHODS Patients The study population included 16 cirrhotic patients who underwent TIPS between March 1996 and September 1999. The clinical characteristics of these patients are summarized in Table 1. The etiology of cirrhosis was hepatitis B virus infection in four patients, hepatitis C virus infection in nine, and alcohol abuse in three. The severity of liver disease according to the ChildPugh’s grade was A in five patients, B in eight, and C in three. TIPS was performed for endoscopically uncontrollable variceal bleeding in 12 patients and for refractory ascites in four. Patients gave their written informed consent to
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Table 1. Patient Characteristics No. of patients Age (yr) Male/female Etiology HBV HCV Alcohol Child-Pugh grade A B C
16 59.3 3/1 4 9 3 5 8 3
HBV ⫽ hepatitis B virus; HCV ⫽ hepatitis C virus.
participate after an explanation of the nature and purpose of the study. TIPS Procedure TIPS was performed according to the standard methods using a Roshe-Uchida Transjugular Liver Access Set (Cook, Bloomington, IN). We used the Wallstent (Boston Scientific, Natick, MA) with a diameter of 1 cm in 14 patients and of 0.8 cm in two. Portal venograms and venous measurements were obtained before and after the procedure. Portal venous pressure (PVP) was directly measured with a transducer (MCS-5500; Fukuda Denshi, Tokyo, Japan) with a catheter placed in the portal vein before and after the shunt placement. Endoscopic Finding of PHG After an overnight fast, all patients underwent upper GI endoscopy (GIF Q-230; Olympus, Tokyo, Japan) before and 2 wk after TIPS. The severity of PHG in cirrhotic patients was classified into no, mild, and severe PHG according to the classification of McCormack et al. (2). Measurements of Gastric Mucosal Blood Flow Gastric mucosal blood flow was measured by a laser Doppler flowmeter (LDF) (ALF21; Advance, Tokyo, Japan) passed through the biopsy channel of the endoscope. The LDF probe was placed in gentle contact with the gastric mucosa of the corpus along the greater curvature. We kept the probe angle within 30 degrees on either side of perpendicular because our preliminary experiment with oral mucosa showed that the LDF signal did not significantly change if the probe angle was kept within this range (16). Measurements were taken using the recorder (ALF-R1; Advance), and to provide a steady state for accurate recording, the subjects were instructed to hold their breath for 10 s throughout the procedure. LDF was performed at five points in every patient, and the average was taken as the representative value of the site. As the directly obtained LDF data contained high frequency noise, they were processed and smoothed by a 5-s time average. Throughout the study, all endoscopy and measurments were performed by the same endoscopist who was blinded to the results obtained during data acquisition.
Figure 1. PVP before and after TIPS. PVP was significantly reduced after TIPS (*p ⬍ 0.01).
Measurements of Total Blood Flow in Gastric Mucosa and Submucosa Total blood flow (TBF) in gastric mucosa and submucosa was measured by near-infrared endoscopy. The system consists of two units: an infrared electronic endoscope (Fujinon 7-HR2; Fuji Photo Optical, Omiya, Japan) with its infrared cut filter removed, and an image processing unit (Nexus 6800; Nexus, Tokyo, Japan). The light source was a high output diode laser with a wavelength of 805 nm, an output of 200 mW, and a band width of 30 nm. The light was guided by a quartz optical fiber through the biopsy channel of the scope. Near-infrared endoscopy was performed at the corpus along the greater curvature, as was LDF. After intravenous administration of indocyanin green (0.5 mg/kg), near-infrared endoscopy can visualize mucosal and submucosal blood vessels (17, 18). The endoscopic image was obtained 10 s after the administration. The change of the spectrophatometric absorption of the endoscopic image was plotted logarithmically, and the infusion velocity of the indocyanine green was obtained from the graph. Statistical Analysis Values are expressed as means ⫾ SD. Differences between the mean values were evaluated by Student’s t test. Significance was established at p ⬍ 0.05.
RESULTS Changes in Portal Venous Pressure and Child-Pugh Score The result of portal venous pressure is shown in Figure 1. The portal venous pressure decreased from 23.4 to 14.0 mm
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Figure 2. GMBF before and after TIPS. Data show increase in GMBF after TIPS (*p ⬍ 0.05).
Figure 3. TBF in gastric mucosa and submucosa before and after TIPS. Data show reduction in TBF after TIPS (*p ⬍ 0.05).
Hg (p ⬍ 0.01) after TIPS. The left gastric vein was recognized in 12 patients on portography before TIPS, but after TIPS it was not clearly visible in all patients. There was no significant difference in Child-Pugh score before and after TIPS (data not shown). Hepatic encephalopathy developed in three patients after TIPS, but was successfully managed with medical treatment such as protein restriction and administration of lactulose and branched-chain amino acids. No lethal complications occurred on TIPS procedure.
DISCUSSION
Endoscopic Findings and Gastric Mucosal and Submucosal Blood Flow After TIPS, GMBF increased from 49.0 ml/min/100 g to 55.6 ml/min/100 g (Fig. 2), and TBF decreased from 0.35/s to 0.27/s (Fig. 3). Among 16 patients with PHG, four had severe PHG and 12 had mild PHG. PHG improved in seven of 16 patients after TIPS. PHG improved in all four patients with severe PHG (reduced to mild PHG). TIPS stopped bleeding from PHG in one patient who had recurrent bleeding from PHG despite the administration of propranolol, which has been reported to reduce the incidence of bleeding. In five of 12 patients with mild PHG, PHG disappeared after TIPS. There were no cases of PHG worsening after TIPS (Fig. 4).
Recently, PHG has been recognized as an important source of lethal hemorrhage. Many investigators have focused their efforts on the clarification of the pathogenesis of PHG, but it is still not clearly understood. Gastric mucosal blood flow has been measured by employing various techniques such as reflectance spectrophotometry, hydrogen gas clearance, and LDF (19, 20). Among these techniques, LDF has several advantages by virtue of its reliability, reproducibility, noninvasive nature, and ease of use (21, 22). Casadevall et al. stated that laser Doppler measurements in the stomach are highly influenced by serum Hb levels (23). However, in our study, there was no significant difference in serum Hb levels before and after TIPS. We therefore believe that the values measured by LDF in our study are reliable. Many investigators have discussed the pathogenesis of PHG by measuring GMBF, but there have been few reports about gastric submucosal hemodynamics in cirrhotic patients with PHG. This is because there have been very few noninvasive methods available to measure gastric submucosal blood flow in humans. As blood flow into the mucosal microvascular system is regulated mainly at the arteriolar level in the submucosal layer (24), we surmised that not only gastric mucosal hemodynamics but also submucosal hemodynamics could be related to the pathogenesis of PHG. The submucosal blood flow was therefore measured with
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Figure 4. Endoscopic findings of PHG before and after TIPS. Among 16 patients with PHG, four had severe PHG and 12 had mild PHG [according to classification of McCormack et al. (2)]. After TIPS, PHG improved in all four patients with severe PHG (reduced to mild disease) and in three of 12 patients with mild PHG (reduced to none).
near-infrared endoscopy, which was able to show the vessels in the mucosal and submucosal layer. There are some reports that the degree of liver dysfunction is correlated to the severity of PHG in cirrhotic patients (1, 25). In our study, PHG improved in many cases after TIPS, although there were no significant differences in the Child-Pugh score before and after the procedure. As a result, we assumed that the severity of PHG is closly related not to the severity of liver disease but to the PVP in the short term. Because severe PHG can cause lethal hemorrhage, much effort has been concentrated on the treatment of PHG. Propranolol has been reported to decrease portal venous pressure and was effective for PHG (26 –28). However, there are some cirrhotic patients who do not respond to propranolol administration because of its insufficient portal decompression (27–30). Portosystemic shunt surgery effectively reduces portal venous pressure and is useful in the treatment of bleeding from PHG (31). Nonetheless, there are inevitable operative risks in treating advanced liver disease. Recently, a few reports have shown the effect of TIPS on PHG (14, 15). Because TIPS effectively reduced portal venous pressure, PHG was improved in all four patients with severe PHG in our study. We have not experienced any lethal complication with the TIPS procedure. Portosystemic
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encephalopathy can occur after TIPS, but all were controlled easily with medical treatment. Shunt dysfunction is another frequent complication after TIPS. Within 1 yr, stenosis of the shunt occurs in a large proportion of patients and may lead to the development of PHG. Such a stenosis must be treated with balloon dilation and placement of another stent within the first one to shore up the narrowed segment after dilation (32, 33). TIPS has been also reported to worsen liver function in some cases, such as in advanced liver disease and hyperbilirubinemia, because of the reduction in effective portal perfusion. In the treatment of PHG, TIPS should be used in situations in which medical treatments such as propranolol have failed or in cases of active bleeding, as the long-term effect of TIPS on PHG has not been confirmed. The pathogenesis of PHG is poorly understood. No agreement has been reached as to whether GMBF is increased or decreased in cirrhotic patients with PHG (4 –7). In our study, TIPS reduced PVP and increased GMBF, resulting in an improvement of PHG. It is therefore assumed that the pathogenesis of PHG is related to the reduction of GMBF caused by congestion due to portal hypertension. Hashizume et al. carried out morphological studies on the stomach of cirrhotic patients and found an increased number of arteriovenous anastomosis in the submucosal layer (34). We assume that in cirrhotic patients with PHG, not only congestion caused by portal hypertension but also increased number of arteriovenous shunts in submucosal layers reduces gastric mucosal perfusion. TBF measured by nearinfrared endoscopy decreased although GMBF measured by LDF increased in our study. This is probably caused by decreased submucosal blood flow in contrast to the increment of GMBF after TIPS. Thus it was suggested that TIPS may bring about decompression of portal vein and reduction of the blood flow in the submucosal layer, probably because of the reduction of the arteriovenous anastomosis. However, to clarify the mechanism underlying this reduction effect of submucosal blood flow by TIPS, further study is needed. In conclusion, we suggest that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG. Randomized controlled trials should be performed to evaluate the long-term effect of TIPS on PHG. Reprint requests and correspondence: Shinichi Mezawa, M.D., Department of Gastroenterology, Tokeidai Hospital, 2-3 North-1 East-1, Chuo-ku, Sapporo 060-0031, Japan. Received Mar. 8, 2000; accepted Oct. 12, 2000.
REFERENCES 1. D’Amico G, Montalbano L, Traina M, et al. Natural history of congestive gastropathy in cirrhosis. Gastroenterology 1990; 99:1558 – 64. 2. McCormack TT, Sims J, Eyre-Brook I, et al. Gastric lesions in
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portal hypertension: Inflammatory gastritis or congestive gastropathy? Gut 1985;26:1226 –32. Tarnawski AS, Sarfeh IJ, Stachura J, et al. Microvascular abnormalities of the portal hypertensive gastric mucosa. Hepatology 1988;8:1488 –94. Panes J, Bordas JM, Pique JM, et al. Increased gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy. Gastroenterology 1992;103:1875– 82. Iwao T, Toyonaga T, Ikegami M, et al. Reduced gastric mucosal blood flow in patients with portal hypertensive gastropathy. Hepatology 1993;18:36 – 40. Ohta M, Hashizume M, Higashi H, et al. Portal and gastric mucosal hemodynamics in cirrhotic patients with portal hypertensive gastropathy. Hepatology 1994;20:1432– 6. Kotzampassi K, Eleftheriadis E, Aletras H. Gastric mucosal blood flow in portal hypertension patients: A laser Doppler flowmetry study. Hepatogastroenterology 1992;39:39 – 42. Chung RS, Bruch D, Dearlove J. Endoscopic measurement of gastric mucosal blood flow by laser Doppler velocimetry: Effect of chronic esophageal variceal sclerosis. Am Surg 1988; 54:116 –20. Ferral H, Bjarnason H, Wegryn SA, et al. Refractory ascites. Early experience in treatment with transjugular intrahepatic portosystemic shunt. Radiology 1993;189:795– 801. Somberg KA, Lake JR, Tomlanovich SJ, et al. Transjugular intrahepatic portosystemic shunt for refractory ascites: Assesment clinical and hormonal response and renal function. Hepatology 1995;21:709 –16. Quiroga J, Sangro B, Nunez M, et al. Transjugular intrahepatic portal-systemic shunt in the treatment of refractory ascites: Effect on clinical, renal, humoral and hemodynamic parameters. Hepatology 1995;21:986 –94. Garcia-Villarreal L, Martinez-Lagares F, Sierra A, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal rebleeding after recent variceal hemorrhage. Hepatology 1999;29:27–32. Banares R, Casado M, Rodriguez-Laiz JM, et al. Urgent transjugular intrahepatic portosystemic shunt for control of acute variceal bleeding. Am J Gastroenterol 1998;93:75–9. Sezai S, Ito M, Sakurai Y, et al. Effects on gastric circulation of treatment for portal hypertension in cirrhosis. Dig Dis Sci 1998;43:1302– 6. Urata J, Yamashita Y, Tsuchigame T, et al. The effects of transjugular intrahepatic portosystemic shunt on portal hypertensive gastropathy. J Gastroenterol Hepatol 1998;13:1061–7. Masuko E, Homma H, Ohta H, et al. Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis. Gastrointest Endosc 1999;49:371–9. Ohota H, Kohgo Y, Goto Y, et al. The near-infrared electronic endoscope for diagnosis of esophageal varices. Gastrointest Endosc 1992;38:330 –5. Ohota H, Kohgo Y, Takahashi Y, et al. Computer-assisted data processing of images of mucosal, and submucosal vessels of stomach obtained by visible, and infrared endoscopy using directional contrast filter. Gastrointest Endosc 1992;38: 3430 –5.
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19. Leung FW, Morishita T, Livingston EH, et al. Reflectance spectrophotmetry for the assessment of gastroduodenal mucosal perfusion. Am J Physiol 1987;252:G797– 804. 20. Murakami M, Moriga M, Miyake T, et al. Contact electrode method in hydrogen gas clearance technique: A new method for determination of regional gastric mucosal blood flow in animals and humans. Gastroenterology 1982;82:457– 67. 21. Iwao T, Toyonaga A, Ikegami M, et al. Observer agreement and variability in measuring gastric mucosal blood flow by laser Doppler flowmetry in humans. Endoscopy 1993;25: 274 –7. 22. Gupta R, Sawant P, Parameshwar R, et al. Gastric mucosal blood flow and hepatic perfusion index in patients with portal hypertensive gastropathy. J Gastroenterol Hepatol 1998;13: 921– 6. 23. Casadevall M, Panes J, Pique JM, et al. Limitations of laserDoppler velocimetry and reflectance spectrophotometry in estimating gastric mucosal blood flow. Am J Physiol 1992;263: G810 –5. 24. Zweifach BW, Lipowsky HH. Pressure-flow relations in blood and lymph microcirculation. In: Renkin EM, Michel CC, eds. Handbook of physiology, section 2: The cardiovascular system. Vol. 4. Microcirculation, part 1. Bethesda, MD: American Physiological Society, 1984:251–307. 25. Sarin SK, Sreenivas DV, Lahoti D, et al. Factors influencing development of portal hypertensive gastropathy in patients with portal hypertension. Gastroenterology 1992;102:994 –9. 26. Lebrec D, Poynard T, Hillon P, et al. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. A controlled study. N Engl J Med 1981;305:1371– 4. 27. Hosking SW, Kennedy HJ, Seddon I, et al. The role of propranolol in congestive gastropathy of portal hypertension. Hepatology 1987;7:437– 41. 28. Perez-Ayuso RM, Pique JM, Bosch J, et al. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991;337:1431– 44. 29. Vorobioff J, Picabea E, Villavicencio R, et al. Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients. Hepatology 1987;7:648 –53. 30. Luca A, Garcia-Pagan JC, Feu F, et al. Non invasive measurement of femoral blood flow and portal pressure response to propranolol in patients with cirrhosis. Hepatology 1995;21: 83– 8. 31. Orloff MJ, Orloff MS, Orloff SL, et al. Treatment of bleeding from portal hypertensive gastropathy by portocaval shunt. Hepatology 1995;21:1011–7. 32. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996;111:138 – 46. 33. Casado M, Bosch J, Garcia-Pagan JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: Correlation with hemodynamic findings. Gastroenterology 1998;114: 1296 –303. 34. Hashizume M, Tanaka K, Inokuchi K. Morphology of gastric microcirculation in cirrhosis. Hepatology 1983;3:1008 –12.
Vol. 96, No. 4, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02257-2
Effect of Transjugular Intrahepatic Portosystemic Shunt Formation on Portal Hypertensive Gastropathy and Gastric Circulation Shinichi Mezawa, M.D., Hisato Homma, M.D., Hidetoshi Ohta, M.D., Eiichi Masuko, M.D., Tadashi Doi, M.D., Koji Miyanishi, M.D., Koichi Takada, M.D., Takehiro Kukitsu, M.D., Tsutomu Sato, M.D., and Yoshiro Niitsu, M.D. Department of Gastroenterology, Tokeidai Hospital; and Fourth Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
OBJECTIVES: The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics. METHODS: A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure. RESULTS: TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure. CONCLUSIONS: It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG. (Am J Gastroenterol 2001;96: 1155–1159. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Bleeding from esophageal varices is a major complication in cirrhotic patients. Gastric mucosal lesions are known to occur widely in such patients and sometimes cause lethal hemorrhage resistant to therapy (1). Since the report of McCormack et al. in 1985, the occurrence of these gastric mucosal lesions has been termed congestive gastropathy or portal hypertensive gastropathy (PHG) (2, 3). The study of
their pathogenesis has focused on the relationship between the hepatic and gastric circulation. Much effort has been devoted to the clarification of gastric mucosal hemodynamics in cirrhotic patients and to the pathogenesis of PHG. Nevertheless, some controversies remain (4 –7). First, it is unclear whether gastric mucosal blood flow increases or decreases in patients with cirrhosis. Second, it is not clear how gastric mucosal blood flow (GMBF) is involved in the pathogenesis of PHG. Many studies have reported values for GMBF associated with PHG (4 – 8), but there are very few studies on gastric perfusion deeper than the mucosal layer. Transjugular intrahepatic portosystemic shunt (TIPS) is considered to be effective in treating endoscopically uncontrollable variceal bleeding and refractory ascites (9 –13). However, there have been only a few reports describing the effect of TIPS on PHG (14, 15). One of these reports described the effect of TIPS on gastric mucosal hemodynamics, but there have been no reports mentioning deeper gastric perfusion, which is also presumed to be related to the pathogenesis of PHG. In this study, we evaluated the effects of TIPS on PHG, measured gastric mucosal and submucosal hemodynamics, and investigated the relationship between portal and gastric circulation in cirrhotic patients.
MATERIALS AND METHODS Patients The study population included 16 cirrhotic patients who underwent TIPS between March 1996 and September 1999. The clinical characteristics of these patients are summarized in Table 1. The etiology of cirrhosis was hepatitis B virus infection in four patients, hepatitis C virus infection in nine, and alcohol abuse in three. The severity of liver disease according to the ChildPugh’s grade was A in five patients, B in eight, and C in three. TIPS was performed for endoscopically uncontrollable variceal bleeding in 12 patients and for refractory ascites in four. Patients gave their written informed consent to
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Table 1. Patient Characteristics No. of patients Age (yr) Male/female Etiology HBV HCV Alcohol Child-Pugh grade A B C
16 59.3 3/1 4 9 3 5 8 3
HBV ⫽ hepatitis B virus; HCV ⫽ hepatitis C virus.
participate after an explanation of the nature and purpose of the study. TIPS Procedure TIPS was performed according to the standard methods using a Roshe-Uchida Transjugular Liver Access Set (Cook, Bloomington, IN). We used the Wallstent (Boston Scientific, Natick, MA) with a diameter of 1 cm in 14 patients and of 0.8 cm in two. Portal venograms and venous measurements were obtained before and after the procedure. Portal venous pressure (PVP) was directly measured with a transducer (MCS-5500; Fukuda Denshi, Tokyo, Japan) with a catheter placed in the portal vein before and after the shunt placement. Endoscopic Finding of PHG After an overnight fast, all patients underwent upper GI endoscopy (GIF Q-230; Olympus, Tokyo, Japan) before and 2 wk after TIPS. The severity of PHG in cirrhotic patients was classified into no, mild, and severe PHG according to the classification of McCormack et al. (2). Measurements of Gastric Mucosal Blood Flow Gastric mucosal blood flow was measured by a laser Doppler flowmeter (LDF) (ALF21; Advance, Tokyo, Japan) passed through the biopsy channel of the endoscope. The LDF probe was placed in gentle contact with the gastric mucosa of the corpus along the greater curvature. We kept the probe angle within 30 degrees on either side of perpendicular because our preliminary experiment with oral mucosa showed that the LDF signal did not significantly change if the probe angle was kept within this range (16). Measurements were taken using the recorder (ALF-R1; Advance), and to provide a steady state for accurate recording, the subjects were instructed to hold their breath for 10 s throughout the procedure. LDF was performed at five points in every patient, and the average was taken as the representative value of the site. As the directly obtained LDF data contained high frequency noise, they were processed and smoothed by a 5-s time average. Throughout the study, all endoscopy and measurments were performed by the same endoscopist who was blinded to the results obtained during data acquisition.
Figure 1. PVP before and after TIPS. PVP was significantly reduced after TIPS (*p ⬍ 0.01).
Measurements of Total Blood Flow in Gastric Mucosa and Submucosa Total blood flow (TBF) in gastric mucosa and submucosa was measured by near-infrared endoscopy. The system consists of two units: an infrared electronic endoscope (Fujinon 7-HR2; Fuji Photo Optical, Omiya, Japan) with its infrared cut filter removed, and an image processing unit (Nexus 6800; Nexus, Tokyo, Japan). The light source was a high output diode laser with a wavelength of 805 nm, an output of 200 mW, and a band width of 30 nm. The light was guided by a quartz optical fiber through the biopsy channel of the scope. Near-infrared endoscopy was performed at the corpus along the greater curvature, as was LDF. After intravenous administration of indocyanin green (0.5 mg/kg), near-infrared endoscopy can visualize mucosal and submucosal blood vessels (17, 18). The endoscopic image was obtained 10 s after the administration. The change of the spectrophatometric absorption of the endoscopic image was plotted logarithmically, and the infusion velocity of the indocyanine green was obtained from the graph. Statistical Analysis Values are expressed as means ⫾ SD. Differences between the mean values were evaluated by Student’s t test. Significance was established at p ⬍ 0.05.
RESULTS Changes in Portal Venous Pressure and Child-Pugh Score The result of portal venous pressure is shown in Figure 1. The portal venous pressure decreased from 23.4 to 14.0 mm
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Figure 2. GMBF before and after TIPS. Data show increase in GMBF after TIPS (*p ⬍ 0.05).
Figure 3. TBF in gastric mucosa and submucosa before and after TIPS. Data show reduction in TBF after TIPS (*p ⬍ 0.05).
Hg (p ⬍ 0.01) after TIPS. The left gastric vein was recognized in 12 patients on portography before TIPS, but after TIPS it was not clearly visible in all patients. There was no significant difference in Child-Pugh score before and after TIPS (data not shown). Hepatic encephalopathy developed in three patients after TIPS, but was successfully managed with medical treatment such as protein restriction and administration of lactulose and branched-chain amino acids. No lethal complications occurred on TIPS procedure.
DISCUSSION
Endoscopic Findings and Gastric Mucosal and Submucosal Blood Flow After TIPS, GMBF increased from 49.0 ml/min/100 g to 55.6 ml/min/100 g (Fig. 2), and TBF decreased from 0.35/s to 0.27/s (Fig. 3). Among 16 patients with PHG, four had severe PHG and 12 had mild PHG. PHG improved in seven of 16 patients after TIPS. PHG improved in all four patients with severe PHG (reduced to mild PHG). TIPS stopped bleeding from PHG in one patient who had recurrent bleeding from PHG despite the administration of propranolol, which has been reported to reduce the incidence of bleeding. In five of 12 patients with mild PHG, PHG disappeared after TIPS. There were no cases of PHG worsening after TIPS (Fig. 4).
Recently, PHG has been recognized as an important source of lethal hemorrhage. Many investigators have focused their efforts on the clarification of the pathogenesis of PHG, but it is still not clearly understood. Gastric mucosal blood flow has been measured by employing various techniques such as reflectance spectrophotometry, hydrogen gas clearance, and LDF (19, 20). Among these techniques, LDF has several advantages by virtue of its reliability, reproducibility, noninvasive nature, and ease of use (21, 22). Casadevall et al. stated that laser Doppler measurements in the stomach are highly influenced by serum Hb levels (23). However, in our study, there was no significant difference in serum Hb levels before and after TIPS. We therefore believe that the values measured by LDF in our study are reliable. Many investigators have discussed the pathogenesis of PHG by measuring GMBF, but there have been few reports about gastric submucosal hemodynamics in cirrhotic patients with PHG. This is because there have been very few noninvasive methods available to measure gastric submucosal blood flow in humans. As blood flow into the mucosal microvascular system is regulated mainly at the arteriolar level in the submucosal layer (24), we surmised that not only gastric mucosal hemodynamics but also submucosal hemodynamics could be related to the pathogenesis of PHG. The submucosal blood flow was therefore measured with
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Figure 4. Endoscopic findings of PHG before and after TIPS. Among 16 patients with PHG, four had severe PHG and 12 had mild PHG [according to classification of McCormack et al. (2)]. After TIPS, PHG improved in all four patients with severe PHG (reduced to mild disease) and in three of 12 patients with mild PHG (reduced to none).
near-infrared endoscopy, which was able to show the vessels in the mucosal and submucosal layer. There are some reports that the degree of liver dysfunction is correlated to the severity of PHG in cirrhotic patients (1, 25). In our study, PHG improved in many cases after TIPS, although there were no significant differences in the Child-Pugh score before and after the procedure. As a result, we assumed that the severity of PHG is closly related not to the severity of liver disease but to the PVP in the short term. Because severe PHG can cause lethal hemorrhage, much effort has been concentrated on the treatment of PHG. Propranolol has been reported to decrease portal venous pressure and was effective for PHG (26 –28). However, there are some cirrhotic patients who do not respond to propranolol administration because of its insufficient portal decompression (27–30). Portosystemic shunt surgery effectively reduces portal venous pressure and is useful in the treatment of bleeding from PHG (31). Nonetheless, there are inevitable operative risks in treating advanced liver disease. Recently, a few reports have shown the effect of TIPS on PHG (14, 15). Because TIPS effectively reduced portal venous pressure, PHG was improved in all four patients with severe PHG in our study. We have not experienced any lethal complication with the TIPS procedure. Portosystemic
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encephalopathy can occur after TIPS, but all were controlled easily with medical treatment. Shunt dysfunction is another frequent complication after TIPS. Within 1 yr, stenosis of the shunt occurs in a large proportion of patients and may lead to the development of PHG. Such a stenosis must be treated with balloon dilation and placement of another stent within the first one to shore up the narrowed segment after dilation (32, 33). TIPS has been also reported to worsen liver function in some cases, such as in advanced liver disease and hyperbilirubinemia, because of the reduction in effective portal perfusion. In the treatment of PHG, TIPS should be used in situations in which medical treatments such as propranolol have failed or in cases of active bleeding, as the long-term effect of TIPS on PHG has not been confirmed. The pathogenesis of PHG is poorly understood. No agreement has been reached as to whether GMBF is increased or decreased in cirrhotic patients with PHG (4 –7). In our study, TIPS reduced PVP and increased GMBF, resulting in an improvement of PHG. It is therefore assumed that the pathogenesis of PHG is related to the reduction of GMBF caused by congestion due to portal hypertension. Hashizume et al. carried out morphological studies on the stomach of cirrhotic patients and found an increased number of arteriovenous anastomosis in the submucosal layer (34). We assume that in cirrhotic patients with PHG, not only congestion caused by portal hypertension but also increased number of arteriovenous shunts in submucosal layers reduces gastric mucosal perfusion. TBF measured by nearinfrared endoscopy decreased although GMBF measured by LDF increased in our study. This is probably caused by decreased submucosal blood flow in contrast to the increment of GMBF after TIPS. Thus it was suggested that TIPS may bring about decompression of portal vein and reduction of the blood flow in the submucosal layer, probably because of the reduction of the arteriovenous anastomosis. However, to clarify the mechanism underlying this reduction effect of submucosal blood flow by TIPS, further study is needed. In conclusion, we suggest that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG. Randomized controlled trials should be performed to evaluate the long-term effect of TIPS on PHG. Reprint requests and correspondence: Shinichi Mezawa, M.D., Department of Gastroenterology, Tokeidai Hospital, 2-3 North-1 East-1, Chuo-ku, Sapporo 060-0031, Japan. Received Mar. 8, 2000; accepted Oct. 12, 2000.
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