Original article 91
Portal hypertensive gastropathy in cirrhotics without varices: a case–control study Enrico Maria Zardia, Giorgia Ghittonib, Domenico Margiottaa, Francesca Torello Vierab, Francesco Di Matteoa and Sandro Rossib Objective Information is lacking on portal hypertensive gastropathy (PHG) in cirrhotics without varices; our aim it is to evaluate whether clinical and sonographic parameters are associated with PHG and may provide information suitable for the management of these patients. Patients and methods After endoscopic selection of 145 cirrhotics without varices, 75 with PHG and 70 without PHG, clinical and sonographic characteristics were assessed. Results Forty portosystemic shunts were present in 27 patients. The mean Child–Pugh score was 6.3 ± 1.4 and 5.6 ± 0.5 in patients with severe and mild PHG, respectively (P = 0.004). The mean portal vein diameter was 10.4 ± 1.7 and 11.6 ± 2.0 mm in cirrhotics without and with PHG, respectively (P = 0.0002). Conclusion A link between the presence of PHG and a more advanced phase of cirrhosis was found. Duplex
Introduction Portal hypertensive gastropathy (PHG) appears on endoscopy as a mosaic-like pattern with or without red spots and is histologically characterized by the presence of dilated capillaries and venules in the mucosa and submucosa of the stomach without signs of erosion, inflammation, or fibrinous thrombi [1]. Its pathogenesis is not completely understood, although evidence suggests a close association with gastric congestion caused by the blockade of gastric blood drainage because of portal hypertension [1]. Patients with cirrhotic or noncirrhotic portal hypertension frequently have PHG, with prevalences ranging from 3 to 46% for mild PHG and from 29 to 57% for severe PHG [2,3]. Acute and chronic bleeding may consequently occur, with incidences of less than 3% and 10–15% at 3 years, respectively [4].
Doppler sonography was confirmed to be a valuable diagnostic method in monitoring cirrhosis. Management of these patients cannot be performed on the basis of a single diagnostic method, and a multimodal diagnostic approach is required. Eur J Gastroenterol Hepatol 27:91–96 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:91–96 Keywords: color Doppler ultrasonography, endoscopy, gastroesophageal varices, portal vein, portosystemic shunts a Department of Clinical Medicine, ‘Campus Bio-Medico’ University, Rome and bVI Department of Internal Medicine and Interventional Ultrasonography, Policlinico ‘S. Matteo’ Foundation, IRCCS, Pavia, Italy
Correspondence to Enrico Maria Zardi, MD, PhD, Department of Clinical Medicine, ‘Campus Bio-Medico’ University, Via Àlvaro del Portillo, 200-00128 Rome, Italy Tel: + 39 062 254 11540; fax: + 39 062 254 1456; e-mail: [email protected] Received 20 July 2014 Accepted 1 October 2014
The prevailing opinion in the literature is that portal hypertension is the key factor that leads to the development and worsening of PHG [1]. A large amount of research has focused on portal hemodynamics and on the severity of liver disease in cirrhotic patients with varices and PHG [9–13], whereas information is lacking on cirrhotics without varices who are affected by PHG. Therefore, we carried out a sonographic duplex Doppler study in cirrhotics without varices with the aim of evaluating whether there is any sonographic parameter that may be associated with PHG and that may be useful in the clinical and therapeutic management of these patients.
Patients and methods Sample
Indeed, after variceal obliteration, the increased flow and pressure within the gastric vascular bed causes PHG [8].
From a weekly liver outpatient screening over the period between January 2008 and August 2011, we consecutively selected a total of 145 cirrhotic patients in whom an endoscopic examination had been performed over the past 2 months and who had no gastroesophageal varices; of these patients, 75 had PHG and 70 did not have PHG. These cirrhotics were prospectively enrolled for the clinical and color Doppler study.
However, PHG may also be observed in cirrhotic patients without gastroesophageal varices.
The diagnosis of cirrhosis in these patients was made on the basis of the results of histological liver examinations
Interestingly, several studies have shown that the development and severity of PHG are correlated with the treatment and eradication of esophageal varices [2,4–7].
0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
DOI: 10.1097/MEG.0000000000000234
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92 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
or a combination of clinical, biochemical, and sonographic criteria (most patients were in Child–Pugh class A). The interval between the endoscopic and sonographic examinations was, for each patient, less than 2 months. The following exclusion criteria were used: (i) antibodies against the human immunodeficiency virus; (ii) a history of stroke or myocardial infarction; (iii) terminal liver failure; (iv) gastric antral vascular ectasia; (v) a history or signs of upper digestive bleeding; (vi) previous endoscopic treatment for gastroesophageal varices; (vii) treatment with β-blockers, nonhormonal anti-inflammatory agents, vasoactive drugs, proton pump inhibitors; (viii) thrombosis of the portal vein; (ix) gastric neoplasia; and (x) previous surgical correction of portal hypertension, gastrectomies, and/or vagotomies. Data collection
Basic demographic data (age, sex, and cause of cirrhosis), biochemical profiles (complete blood counts, biochemical data, coagulation profiles, and serologic data), sonographic evaluations (portal vein diameter, portal flow velocity and volume, splenic diameter, presence or absence of portosystemic shunts, presence or absence of ascites), and endoscopic findings (grade of PHG) were recorded for all patients in a unique database for statistical evaluation. The functional grading of cirrhosis was determined using both the Child–Pugh scoring system and the MELD score; both were used for statistical evaluation. Gray scale and duplex Doppler sonography
At two university Medical Departments, sonographic studies were carried out by two experienced sonographers blinded to the endoscopic diagnosis. To minimize interobserver variations, they worked together for 2 months in a liver sonographic outpatient department. Before starting the study, an interim analysis of interobserver variability was carried out. Both medical doctors performed independent and blinded evaluations of each patient for a total of 34 patients and their concordance was very significant, with a κ of 0.89 (unpublished results). Their interobserver variability among 34 patients for the measurement results of portosystemic shunts was 6.1%; for portal vein diameter measurements, it was 8.1%; and for portal flow velocity and volume, it was 9.5%. Both sonographers carried out the examination as follows: the patients were examined in a supine position after an 8-h fast using two sonographic instruments [Sonoline Ultrasound Logiq E9 Machine (General Electric, Fairfield, Connecticut, USA) and Esaote AU5 (Ansaldo, Genova, Italy)] equipped with a multifrequency convex 2.5–5 MHz probe.
The portal vein diameter (mm) was measured from a longitudinal scan at the site where the portal vein crossed the hepatic artery. At the same time, after positioning the sample volume cursor in the middle of the portal vein (where it crossed the hepatic artery) and correcting for the angle of insonation, the portal flow velocity (cm/s) and portal flow volume (l/min) were calculated automatically using the duplex Doppler system of the sonographic instrument. Portosystemic shunts were considered to be present when tortuous vessels were viewed at the origin of the portal vein and the peripheral portal branch or around the splenic vein. Several particular features were noted: (i) the umbilical vein was recognized as a vein with a hepatofugal flow running from the left branch of the portal vein to the anterior abdominal wall; (ii) the left gastric vein was recognized as a vein with a hepatofugal flow originating from or adjacent to the splenoportal junction; and (iii) splenorenal shunts were recognized when a firm adhesion was observed between the splenic and renal veins when aliasing and high hepatofugal venous flows were also present. If two or more shunts were simultaneously present in the same patient, they were defined as a combined shunt. An arteriovenous shunt was considered to be present when a patent communication between an hepatic arterial branch and a portal or a hepatic vein was observed on color Doppler. The splenic length (the maximum length of the spleen) was calculated after visualizing the organ in a plane passing through the splenic hilum; the spleen was considered to be enlarged when the splenic diameter was at least 12 cm. The mean value of two measurements of portal vein diameter, portal flow volume and splenic diameter, was used for statistical evaluation.
Endoscopic examination
All cirrhotic patients had undergone an endoscopic examination in the 2 months before gray scale and duplex Doppler sonography; therefore, the two investigators were unaware of the sonographic results. The diagnosis of PHG was made in accordance with the known criteria of the Third Baveno International Consensus Workshop [14]. Specifically, PHG was graded according to the following criteria: (1) mild with a score of 1 if there were diffuse pink polygonal, scale-like areas with no signs of red or black–brown spots or when focal flat or slightly bulging red marks were present in isolated areas;
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Portal hypertensive gastropathy Zardi et al. 93
(2) severe with a score of 2 if a mosaic-like mucosal pattern with red point lesions and/or cherry red spots or black–brown spots were present throughout the mucosa or when focal flat or slightly bulging red marks were present throughout the mucosa. Two experienced endoscopists were always present to discuss among themselves the endoscopic images and the score to assign to the PHG, when present. In both departments involved in this study, a control is in place to ensure the quality of the endoscopic examination: all of the endoscopists undergo periodic training programs to control for general agreement on endoscopic diagnoses. Compliance with ethical requirements
This study was approved by the departmental review boards of the two participating centers, and informed consent was obtained from the patients. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
Table 1
Baseline features of the study population (n = 145)
Age (mean ± SD) (years) Males/females Etiology [n (%)] Hepatitis C Hepatitis B Alcohol Cryptogenic Othera Child–Pugh class [n (%)] A B C Ascites [n (%)] Present Absent Portosystemic shunts [n (%)] Left gastric vein Umbilical vein Splenorenal shunts Arteriovenous shunt Portal hypertensive gastropathy [n (%)] None Mild Severe
Comparisons of continuous variables between the groups were performed using the Mann–Whitney U-test. Twosided P values less than 0.05 were considered statistically significant. The 75th percentile portal vein diameter (12 mm) in the 145 cirrhotic patients was defined as the cut-off value for predicting the presence and absence of PHG.
Selected clinical and demographic characteristics of the patients enrolled in this study are listed in Table 1. Baseline data between cirrhotics with and without PHG are compared in Table 2, and data between cirrhotics with severe and mild PHG are compared in Table 3. The hepatitis C virus was the most frequent cause of cirrhosis, and Child–Pugh class A was the most prevalent classification in our patients. PHG was documented by upper endoscopy in 75 cirrhotic patients (51.7%) [mild grade, 45 patients (31%); severe grade, 30 patients (20.7%)], whereas the other 70 cirrhotic patients did not have PHG (48.3%). Portosystemic shunts were detected in 27 cirrhotics (18.6%) and not detected in 118 (81.3%) (Table 1); the simultaneous presence of more than one portosystemic
(57.3) (6.8) (9.7) (9.7) (16.5)
125 (86.2) 19 (13.1) 1 (0.7) 13 132 40 in 27 cirrhotics 6 (4.1) 17 (11.7) 16 (11) 1 (0.68) 70 (48.3) 45 (31) 30 (20.7)
Baseline features of the cirrhotics with and without portal hypertensive gastropathy (n = 145)
Table 2
Age (mean ± SD) (years) Males/females Etiology [n (%)] Hepatitis C Hepatitis B Alcohol Cryptogenic Other Child–Pugh class [n (%)] A B C Ascites [n (%)] Present Absent
Results
83 10 14 14 24
a Autoimmune hepatitis, 4 (2.7%), primary biliary cirrhosis, 2 (1.4%), hemochromatosis, 1 (0.7%), cardiac cirrhosis 0 (0%), and metabolic origin, 17 (11.7%).
Statistical analysis
The data were analyzed using a software for statistical analysis (Prism 5.0; GraphPad Software Inc., San Diego, California, USA).
73 ± 9 70/75
With PHG (75 cirrhotics)
Without PHG (70 cirrhotics)
74 ± 8 39/36
71 ± 11 31/39
49 4 9 4 9
(34) (2.7) (6.2) (2.8) (6.2)
34 6 5 10 15
(23) (4.1) (3.4) (6.9) (10.3)
67 (46.2) 7 (4.8) 1 (0.7)
58 (40) (P = 0.5) 12 (8.3) (P = 0.5) 0 (0) (too low sample size)
6 (4.2)
7 (4.8) (too low sample size) 63 (43.4) (P = 0.6)
69 (47.6)
PHG, portal hypertensive gastropathy.
shunt in the same patient was found in five cirrhotics without PHG and in four cirrhotics with PHG (one with mild PHG and three with severe PHG). No significant differences were found among cirrhotic patients with or without PHG with respect to the presence of portosystemic shunts (Table 4). No differences were found in Child–Pugh class among cirrhotics with or without PHG and among those with mild and severe PHG (Tables 3 and 4). There was also no significant difference in the Child–Pugh score among cirrhotics with or without PHG (P = 0.5), but there was a difference on comparing cirrhotics with mild PHG and those with severe PHG (the mean Child–Pugh score was 5.6 ± 0.5 and 6.3 ± 1.4, respectively) (P = 0.004) (Fig. 1).
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94 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
44 (58.7) 1 (1.3) 0 (0)
1 (1.3)
Absent
44 (58.7)
16 2 8 1 3
(21)a (2.7) (10.7) (1.3) (4)
23 (30.7) (P = 0.5) 6 (8) (P = 0.5) 1 (1.3) (too low sample size)
6 4 2 0
5 (6.7) (too low sample size) 25 (33.3) (P = 0.2)
G
(44)a (2.7) (1.3) (4) (8)
PH
33 2 1 3 6
8
Se ve re
75 ± 9 16/14
G
73 ± 8 23/22
P =0.004
10
PH
Ascites Present
With severe PHG (30 cirrhotics)
M ild
Age (mean ± SD) (years) Males/females Etiology Hepatitis C Hepatitis B Alcohol Cryptogenic Other Child–Pugh class A B C
With mild PHG (45 cirrhotics)
Fig. 1
Mean child score (points)
Baseline features of the cirrhotics with mild and severe portal hypertensive gastropathy (n = 75)
Table 3
a
The percent is reported in brackets.
Mild PHG
Cirrhotics with or without PHG and cirrhotics with severe and mild PHG showed no statistically significant differences in the MELD score (P = 0.7 and 0.5, respectively). The mean portal flow volume was 1.1 ± 0.49 l/min in cirrhotics without PHG and 1.2 ± 0.38 l/min in cirrhotics with PHG (P = 0.1). The mean portal flow volume was 1.15 ± 0.37 l/min in cirrhotics with severe PHG and 1.28 ± 0.39 l/min in cirrhotics with mild PHG (P = 0.09). Cirrhotics with or without PHG showed no statistically significant differences in splenic diameter (P = 0.07) and in the presence of ascites (P = 0.65). Cirrhotics with severe and mild PHG showed no statistically significant differences in splenic diameter (P = 0.4). As ascites was found in very few cirrhotics (Table 3), a statistical analysis was not carried out. No statistically significant differences in thrombocyte count were found on comparing cirrhotics with or without PHG (P = 0.09) and cirrhotics with severe and mild PHG (P = 0.4). The mean portal vein diameter was 10.4 ± 1.67 mm in cirrhotics without PHG and 11.6 ± 2.0 mm in cirrhotics with PHG (P = 0.0002) (Fig. 2); we did not find any Table 4
Severe PHG
The mean Child–Pugh scores are shown. The Child–Pugh score is expressed in points. The bar chart is a plot of summarized data showing the mean; the error bars represent the SD. Patients with severe portal hypertensive gastropathy (PHG) present higher mean Child–Pugh scores compared with patients with mild PHG.
statistically significant differences in the mean portal vein diameter between cirrhotics with mild PHG and cirrhotics with severe PHG. When the 75th percentile portal vein diameter (12 mm) was used as a cut-off level, it achieved a sensitivity of 48.1%, a specificity of 82.4%, a positive predictive value of 75.5%, and a negative predictive value of 58.3% for predicting the presence of PHG. When a portal vein diameter of 11 mm was used as a cutoff level, it achieved a sensitivity of 67%, a specificity of 60%, a positive predictive value of 64%, and a negative predictive value of 63% for predicting the presence of PHG.
Discussion In this study, we examined cirrhotic patients without varices who were affected or unaffected by PHG. This inclusion criteria favored a selection of cirrhotics in class A of Child–Pugh (86%), thus limiting the value of findings to this class of cirrhosis.
Portosystemic shunts in 27 cirrhotics with and without portal hypertensive gastropathy
Type of portosystemic shunts
Number of portosystemic shunts in cirrhotics without PHG
Number of portosystemic shunts in cirrhotics with PHG
Total number
10 4 9 0 23
7 2 7 1 17
17 6 16 1 40
Umbilical vein Left gastric vein Splenorenal shunts Arteriovenous shunt Total number PHG, portal hypertensive gastropathy.
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Portal hypertensive gastropathy Zardi et al. 95
mean Child–Pugh score between cirrhotics with mild and severe PHG and in the mean portal vein diameter between cirrhotics with and without PHG.
Fig. 2
P =0.0002
Mean portal vein diameter (mm)
15
Conflicting results have been found in previous studies on cirrhotics with varices: some authors reported that the portal venous pressure was not significantly different between cirrhotics with and without PHG [12,22], whereas other authors reported more severe portal hypertension in cirrhotics with PHG compared with cirrhotics without PHG [13,24].
10
5
PH
N
o
PH
G
G
0
No PHG
PHG
The mean portal vein diameter values are shown. The portal vein diameter is expressed in millimeters. The bar chart is a plot of summary data showing the mean; the error bars represent the SD. We found a higher mean portal vein diameter in patients with portal hypertensive gastropathy (PHG) than in patients without PHG.
Interesting functional hemodynamic studies showed that cirrhotic patients did not have increased portal flow volumes after meals [15–17]. This lack of variation was attributed to the presence of portal microcirculation hypertension, which is hemodynamically defined as a portal pressure gradient greater than 5 mmHg [18,19]. Indeed, portal microcirculation hypertension develops as a consequence of the destructive alterations to the liver microvascular architecture predominantly favored by the transformation and constriction of hepatic stellate cells [20,21]. It was reported some years ago that patients with PHG had significantly higher gastric mucosal congestion and perfusion compared with patients without PHG [22]. It is now known that the pathogenesis of PHG is the functional consequence of an increased portal pressure causing a passive gastric mucosal congestion, which can impair gastric mucosal defense mechanisms and render the stomach susceptible to mucosal injury [23]. An epidemiological study showed that 40% of cirrhotic patients with PHG had varices compared with only 17% of patients without PHG [2]; furthermore, PHG represents a strong risk factor for bleeding because patients with PHG are significantly more likely to have medium or large varices compared with patients without PHG [2]. Our current study considered only cirrhotics without varices affected or unaffected by PHG. Interestingly, no significant differences were found when comparing cirrhotics without varices affected or unaffected by PHG, except for a significant difference in the
Our previous study on cirrhotics with and without gastroesophageal varices also did not show any significant increase in the mean portal vein diameter in cirrhotics with PHG compared with cirrhotics without PHG [10]. Low positive predictive values have been found in the search for noninvasive surrogate markers of PHG in cirrhotics with varices, but the results of our current study are not comparable with the results of the abovementioned studies because, for the first time, they were obtained in cirrhotics affected and unaffected by PHG, none of whom had varices. The fact that a higher mean portal vein diameter value, which is generally considered an important sign of portal hypertension, was associated with the presence of PHG might be interesting. It is likely that the presence of varices and portosystemic shunts decompresses the portal system [25], which may have influenced the results of previous studies. In this study, no significant difference was observed between cirrhotics with and without PHG with respect to the presence of portosystemic shunts; therefore, because portosystemic shunts were distributed equally between cirrhotics with and without PHG, their presence was unimportant in determining the portal flow volume. The fact that the Child–Pugh score for cirrhotics with PHG and without PHG was not significantly different, but that there was a mildly significant increase in the Child–Pugh score was found in cirrhotics with severe PHG compared with those with mild PHG shows that the former were at a more advanced stage of cirrhosis. Of note, an increased mean portal vein diameter value could be the first sign of portal hypertension that may be useful to identify cirrhotics with PHG. Further studies should be planned to confirm the relationship between increased portal vein diameter and PHG also because this might have therapeutical implications. Although the risk of acute bleeding from PHG is negligible in cirrhotic patients without varices, it is known that PHG causes anemia because of chronic blood loss. The use of beta blockers, preventing portal hypertension and thus bleeding, may help improve the quality of life of cirrhotics.
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96 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
PHG is a dynamic condition, which may worsen from mild to severe, but may also improve and even disappear completely through a reduction in portal hypertension by the use of β-blockers. Although an association between PHG and portal vein diameter has been shown, the sensitivity and specificity are not compelling for use in clinical practice; therefore, our opinion is that decisions to modify management and treatment in cirrhotics depend on several clinical and diagnostic factors [19]. Conclusion
Here, we confirm that duplex Doppler sonography is a valuable diagnostic method to monitor and screen cirrhotics and also to push for further investigations, but not sufficient on its own to plan or modify the clinical and therapeutic management of these patients. Clinical and therapeutic decisions for cirrhotics require a multimodal diagnostic approach.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
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Portal hypertensive gastropathy in cirrhotics without varices: a case–control study Enrico Maria Zardia, Giorgia Ghittonib, Domenico Margiottaa, Francesca Torello Vierab, Francesco Di Matteoa and Sandro Rossib Objective Information is lacking on portal hypertensive gastropathy (PHG) in cirrhotics without varices; our aim it is to evaluate whether clinical and sonographic parameters are associated with PHG and may provide information suitable for the management of these patients. Patients and methods After endoscopic selection of 145 cirrhotics without varices, 75 with PHG and 70 without PHG, clinical and sonographic characteristics were assessed. Results Forty portosystemic shunts were present in 27 patients. The mean Child–Pugh score was 6.3 ± 1.4 and 5.6 ± 0.5 in patients with severe and mild PHG, respectively (P = 0.004). The mean portal vein diameter was 10.4 ± 1.7 and 11.6 ± 2.0 mm in cirrhotics without and with PHG, respectively (P = 0.0002). Conclusion A link between the presence of PHG and a more advanced phase of cirrhosis was found. Duplex
Introduction Portal hypertensive gastropathy (PHG) appears on endoscopy as a mosaic-like pattern with or without red spots and is histologically characterized by the presence of dilated capillaries and venules in the mucosa and submucosa of the stomach without signs of erosion, inflammation, or fibrinous thrombi [1]. Its pathogenesis is not completely understood, although evidence suggests a close association with gastric congestion caused by the blockade of gastric blood drainage because of portal hypertension [1]. Patients with cirrhotic or noncirrhotic portal hypertension frequently have PHG, with prevalences ranging from 3 to 46% for mild PHG and from 29 to 57% for severe PHG [2,3]. Acute and chronic bleeding may consequently occur, with incidences of less than 3% and 10–15% at 3 years, respectively [4].
Doppler sonography was confirmed to be a valuable diagnostic method in monitoring cirrhosis. Management of these patients cannot be performed on the basis of a single diagnostic method, and a multimodal diagnostic approach is required. Eur J Gastroenterol Hepatol 27:91–96 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:91–96 Keywords: color Doppler ultrasonography, endoscopy, gastroesophageal varices, portal vein, portosystemic shunts a Department of Clinical Medicine, ‘Campus Bio-Medico’ University, Rome and bVI Department of Internal Medicine and Interventional Ultrasonography, Policlinico ‘S. Matteo’ Foundation, IRCCS, Pavia, Italy
Correspondence to Enrico Maria Zardi, MD, PhD, Department of Clinical Medicine, ‘Campus Bio-Medico’ University, Via Àlvaro del Portillo, 200-00128 Rome, Italy Tel: + 39 062 254 11540; fax: + 39 062 254 1456; e-mail: [email protected] Received 20 July 2014 Accepted 1 October 2014
The prevailing opinion in the literature is that portal hypertension is the key factor that leads to the development and worsening of PHG [1]. A large amount of research has focused on portal hemodynamics and on the severity of liver disease in cirrhotic patients with varices and PHG [9–13], whereas information is lacking on cirrhotics without varices who are affected by PHG. Therefore, we carried out a sonographic duplex Doppler study in cirrhotics without varices with the aim of evaluating whether there is any sonographic parameter that may be associated with PHG and that may be useful in the clinical and therapeutic management of these patients.
Patients and methods Sample
Indeed, after variceal obliteration, the increased flow and pressure within the gastric vascular bed causes PHG [8].
From a weekly liver outpatient screening over the period between January 2008 and August 2011, we consecutively selected a total of 145 cirrhotic patients in whom an endoscopic examination had been performed over the past 2 months and who had no gastroesophageal varices; of these patients, 75 had PHG and 70 did not have PHG. These cirrhotics were prospectively enrolled for the clinical and color Doppler study.
However, PHG may also be observed in cirrhotic patients without gastroesophageal varices.
The diagnosis of cirrhosis in these patients was made on the basis of the results of histological liver examinations
Interestingly, several studies have shown that the development and severity of PHG are correlated with the treatment and eradication of esophageal varices [2,4–7].
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DOI: 10.1097/MEG.0000000000000234
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92 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
or a combination of clinical, biochemical, and sonographic criteria (most patients were in Child–Pugh class A). The interval between the endoscopic and sonographic examinations was, for each patient, less than 2 months. The following exclusion criteria were used: (i) antibodies against the human immunodeficiency virus; (ii) a history of stroke or myocardial infarction; (iii) terminal liver failure; (iv) gastric antral vascular ectasia; (v) a history or signs of upper digestive bleeding; (vi) previous endoscopic treatment for gastroesophageal varices; (vii) treatment with β-blockers, nonhormonal anti-inflammatory agents, vasoactive drugs, proton pump inhibitors; (viii) thrombosis of the portal vein; (ix) gastric neoplasia; and (x) previous surgical correction of portal hypertension, gastrectomies, and/or vagotomies. Data collection
Basic demographic data (age, sex, and cause of cirrhosis), biochemical profiles (complete blood counts, biochemical data, coagulation profiles, and serologic data), sonographic evaluations (portal vein diameter, portal flow velocity and volume, splenic diameter, presence or absence of portosystemic shunts, presence or absence of ascites), and endoscopic findings (grade of PHG) were recorded for all patients in a unique database for statistical evaluation. The functional grading of cirrhosis was determined using both the Child–Pugh scoring system and the MELD score; both were used for statistical evaluation. Gray scale and duplex Doppler sonography
At two university Medical Departments, sonographic studies were carried out by two experienced sonographers blinded to the endoscopic diagnosis. To minimize interobserver variations, they worked together for 2 months in a liver sonographic outpatient department. Before starting the study, an interim analysis of interobserver variability was carried out. Both medical doctors performed independent and blinded evaluations of each patient for a total of 34 patients and their concordance was very significant, with a κ of 0.89 (unpublished results). Their interobserver variability among 34 patients for the measurement results of portosystemic shunts was 6.1%; for portal vein diameter measurements, it was 8.1%; and for portal flow velocity and volume, it was 9.5%. Both sonographers carried out the examination as follows: the patients were examined in a supine position after an 8-h fast using two sonographic instruments [Sonoline Ultrasound Logiq E9 Machine (General Electric, Fairfield, Connecticut, USA) and Esaote AU5 (Ansaldo, Genova, Italy)] equipped with a multifrequency convex 2.5–5 MHz probe.
The portal vein diameter (mm) was measured from a longitudinal scan at the site where the portal vein crossed the hepatic artery. At the same time, after positioning the sample volume cursor in the middle of the portal vein (where it crossed the hepatic artery) and correcting for the angle of insonation, the portal flow velocity (cm/s) and portal flow volume (l/min) were calculated automatically using the duplex Doppler system of the sonographic instrument. Portosystemic shunts were considered to be present when tortuous vessels were viewed at the origin of the portal vein and the peripheral portal branch or around the splenic vein. Several particular features were noted: (i) the umbilical vein was recognized as a vein with a hepatofugal flow running from the left branch of the portal vein to the anterior abdominal wall; (ii) the left gastric vein was recognized as a vein with a hepatofugal flow originating from or adjacent to the splenoportal junction; and (iii) splenorenal shunts were recognized when a firm adhesion was observed between the splenic and renal veins when aliasing and high hepatofugal venous flows were also present. If two or more shunts were simultaneously present in the same patient, they were defined as a combined shunt. An arteriovenous shunt was considered to be present when a patent communication between an hepatic arterial branch and a portal or a hepatic vein was observed on color Doppler. The splenic length (the maximum length of the spleen) was calculated after visualizing the organ in a plane passing through the splenic hilum; the spleen was considered to be enlarged when the splenic diameter was at least 12 cm. The mean value of two measurements of portal vein diameter, portal flow volume and splenic diameter, was used for statistical evaluation.
Endoscopic examination
All cirrhotic patients had undergone an endoscopic examination in the 2 months before gray scale and duplex Doppler sonography; therefore, the two investigators were unaware of the sonographic results. The diagnosis of PHG was made in accordance with the known criteria of the Third Baveno International Consensus Workshop [14]. Specifically, PHG was graded according to the following criteria: (1) mild with a score of 1 if there were diffuse pink polygonal, scale-like areas with no signs of red or black–brown spots or when focal flat or slightly bulging red marks were present in isolated areas;
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Portal hypertensive gastropathy Zardi et al. 93
(2) severe with a score of 2 if a mosaic-like mucosal pattern with red point lesions and/or cherry red spots or black–brown spots were present throughout the mucosa or when focal flat or slightly bulging red marks were present throughout the mucosa. Two experienced endoscopists were always present to discuss among themselves the endoscopic images and the score to assign to the PHG, when present. In both departments involved in this study, a control is in place to ensure the quality of the endoscopic examination: all of the endoscopists undergo periodic training programs to control for general agreement on endoscopic diagnoses. Compliance with ethical requirements
This study was approved by the departmental review boards of the two participating centers, and informed consent was obtained from the patients. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
Table 1
Baseline features of the study population (n = 145)
Age (mean ± SD) (years) Males/females Etiology [n (%)] Hepatitis C Hepatitis B Alcohol Cryptogenic Othera Child–Pugh class [n (%)] A B C Ascites [n (%)] Present Absent Portosystemic shunts [n (%)] Left gastric vein Umbilical vein Splenorenal shunts Arteriovenous shunt Portal hypertensive gastropathy [n (%)] None Mild Severe
Comparisons of continuous variables between the groups were performed using the Mann–Whitney U-test. Twosided P values less than 0.05 were considered statistically significant. The 75th percentile portal vein diameter (12 mm) in the 145 cirrhotic patients was defined as the cut-off value for predicting the presence and absence of PHG.
Selected clinical and demographic characteristics of the patients enrolled in this study are listed in Table 1. Baseline data between cirrhotics with and without PHG are compared in Table 2, and data between cirrhotics with severe and mild PHG are compared in Table 3. The hepatitis C virus was the most frequent cause of cirrhosis, and Child–Pugh class A was the most prevalent classification in our patients. PHG was documented by upper endoscopy in 75 cirrhotic patients (51.7%) [mild grade, 45 patients (31%); severe grade, 30 patients (20.7%)], whereas the other 70 cirrhotic patients did not have PHG (48.3%). Portosystemic shunts were detected in 27 cirrhotics (18.6%) and not detected in 118 (81.3%) (Table 1); the simultaneous presence of more than one portosystemic
(57.3) (6.8) (9.7) (9.7) (16.5)
125 (86.2) 19 (13.1) 1 (0.7) 13 132 40 in 27 cirrhotics 6 (4.1) 17 (11.7) 16 (11) 1 (0.68) 70 (48.3) 45 (31) 30 (20.7)
Baseline features of the cirrhotics with and without portal hypertensive gastropathy (n = 145)
Table 2
Age (mean ± SD) (years) Males/females Etiology [n (%)] Hepatitis C Hepatitis B Alcohol Cryptogenic Other Child–Pugh class [n (%)] A B C Ascites [n (%)] Present Absent
Results
83 10 14 14 24
a Autoimmune hepatitis, 4 (2.7%), primary biliary cirrhosis, 2 (1.4%), hemochromatosis, 1 (0.7%), cardiac cirrhosis 0 (0%), and metabolic origin, 17 (11.7%).
Statistical analysis
The data were analyzed using a software for statistical analysis (Prism 5.0; GraphPad Software Inc., San Diego, California, USA).
73 ± 9 70/75
With PHG (75 cirrhotics)
Without PHG (70 cirrhotics)
74 ± 8 39/36
71 ± 11 31/39
49 4 9 4 9
(34) (2.7) (6.2) (2.8) (6.2)
34 6 5 10 15
(23) (4.1) (3.4) (6.9) (10.3)
67 (46.2) 7 (4.8) 1 (0.7)
58 (40) (P = 0.5) 12 (8.3) (P = 0.5) 0 (0) (too low sample size)
6 (4.2)
7 (4.8) (too low sample size) 63 (43.4) (P = 0.6)
69 (47.6)
PHG, portal hypertensive gastropathy.
shunt in the same patient was found in five cirrhotics without PHG and in four cirrhotics with PHG (one with mild PHG and three with severe PHG). No significant differences were found among cirrhotic patients with or without PHG with respect to the presence of portosystemic shunts (Table 4). No differences were found in Child–Pugh class among cirrhotics with or without PHG and among those with mild and severe PHG (Tables 3 and 4). There was also no significant difference in the Child–Pugh score among cirrhotics with or without PHG (P = 0.5), but there was a difference on comparing cirrhotics with mild PHG and those with severe PHG (the mean Child–Pugh score was 5.6 ± 0.5 and 6.3 ± 1.4, respectively) (P = 0.004) (Fig. 1).
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94 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
44 (58.7) 1 (1.3) 0 (0)
1 (1.3)
Absent
44 (58.7)
16 2 8 1 3
(21)a (2.7) (10.7) (1.3) (4)
23 (30.7) (P = 0.5) 6 (8) (P = 0.5) 1 (1.3) (too low sample size)
6 4 2 0
5 (6.7) (too low sample size) 25 (33.3) (P = 0.2)
G
(44)a (2.7) (1.3) (4) (8)
PH
33 2 1 3 6
8
Se ve re
75 ± 9 16/14
G
73 ± 8 23/22
P =0.004
10
PH
Ascites Present
With severe PHG (30 cirrhotics)
M ild
Age (mean ± SD) (years) Males/females Etiology Hepatitis C Hepatitis B Alcohol Cryptogenic Other Child–Pugh class A B C
With mild PHG (45 cirrhotics)
Fig. 1
Mean child score (points)
Baseline features of the cirrhotics with mild and severe portal hypertensive gastropathy (n = 75)
Table 3
a
The percent is reported in brackets.
Mild PHG
Cirrhotics with or without PHG and cirrhotics with severe and mild PHG showed no statistically significant differences in the MELD score (P = 0.7 and 0.5, respectively). The mean portal flow volume was 1.1 ± 0.49 l/min in cirrhotics without PHG and 1.2 ± 0.38 l/min in cirrhotics with PHG (P = 0.1). The mean portal flow volume was 1.15 ± 0.37 l/min in cirrhotics with severe PHG and 1.28 ± 0.39 l/min in cirrhotics with mild PHG (P = 0.09). Cirrhotics with or without PHG showed no statistically significant differences in splenic diameter (P = 0.07) and in the presence of ascites (P = 0.65). Cirrhotics with severe and mild PHG showed no statistically significant differences in splenic diameter (P = 0.4). As ascites was found in very few cirrhotics (Table 3), a statistical analysis was not carried out. No statistically significant differences in thrombocyte count were found on comparing cirrhotics with or without PHG (P = 0.09) and cirrhotics with severe and mild PHG (P = 0.4). The mean portal vein diameter was 10.4 ± 1.67 mm in cirrhotics without PHG and 11.6 ± 2.0 mm in cirrhotics with PHG (P = 0.0002) (Fig. 2); we did not find any Table 4
Severe PHG
The mean Child–Pugh scores are shown. The Child–Pugh score is expressed in points. The bar chart is a plot of summarized data showing the mean; the error bars represent the SD. Patients with severe portal hypertensive gastropathy (PHG) present higher mean Child–Pugh scores compared with patients with mild PHG.
statistically significant differences in the mean portal vein diameter between cirrhotics with mild PHG and cirrhotics with severe PHG. When the 75th percentile portal vein diameter (12 mm) was used as a cut-off level, it achieved a sensitivity of 48.1%, a specificity of 82.4%, a positive predictive value of 75.5%, and a negative predictive value of 58.3% for predicting the presence of PHG. When a portal vein diameter of 11 mm was used as a cutoff level, it achieved a sensitivity of 67%, a specificity of 60%, a positive predictive value of 64%, and a negative predictive value of 63% for predicting the presence of PHG.
Discussion In this study, we examined cirrhotic patients without varices who were affected or unaffected by PHG. This inclusion criteria favored a selection of cirrhotics in class A of Child–Pugh (86%), thus limiting the value of findings to this class of cirrhosis.
Portosystemic shunts in 27 cirrhotics with and without portal hypertensive gastropathy
Type of portosystemic shunts
Number of portosystemic shunts in cirrhotics without PHG
Number of portosystemic shunts in cirrhotics with PHG
Total number
10 4 9 0 23
7 2 7 1 17
17 6 16 1 40
Umbilical vein Left gastric vein Splenorenal shunts Arteriovenous shunt Total number PHG, portal hypertensive gastropathy.
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Portal hypertensive gastropathy Zardi et al. 95
mean Child–Pugh score between cirrhotics with mild and severe PHG and in the mean portal vein diameter between cirrhotics with and without PHG.
Fig. 2
P =0.0002
Mean portal vein diameter (mm)
15
Conflicting results have been found in previous studies on cirrhotics with varices: some authors reported that the portal venous pressure was not significantly different between cirrhotics with and without PHG [12,22], whereas other authors reported more severe portal hypertension in cirrhotics with PHG compared with cirrhotics without PHG [13,24].
10
5
PH
N
o
PH
G
G
0
No PHG
PHG
The mean portal vein diameter values are shown. The portal vein diameter is expressed in millimeters. The bar chart is a plot of summary data showing the mean; the error bars represent the SD. We found a higher mean portal vein diameter in patients with portal hypertensive gastropathy (PHG) than in patients without PHG.
Interesting functional hemodynamic studies showed that cirrhotic patients did not have increased portal flow volumes after meals [15–17]. This lack of variation was attributed to the presence of portal microcirculation hypertension, which is hemodynamically defined as a portal pressure gradient greater than 5 mmHg [18,19]. Indeed, portal microcirculation hypertension develops as a consequence of the destructive alterations to the liver microvascular architecture predominantly favored by the transformation and constriction of hepatic stellate cells [20,21]. It was reported some years ago that patients with PHG had significantly higher gastric mucosal congestion and perfusion compared with patients without PHG [22]. It is now known that the pathogenesis of PHG is the functional consequence of an increased portal pressure causing a passive gastric mucosal congestion, which can impair gastric mucosal defense mechanisms and render the stomach susceptible to mucosal injury [23]. An epidemiological study showed that 40% of cirrhotic patients with PHG had varices compared with only 17% of patients without PHG [2]; furthermore, PHG represents a strong risk factor for bleeding because patients with PHG are significantly more likely to have medium or large varices compared with patients without PHG [2]. Our current study considered only cirrhotics without varices affected or unaffected by PHG. Interestingly, no significant differences were found when comparing cirrhotics without varices affected or unaffected by PHG, except for a significant difference in the
Our previous study on cirrhotics with and without gastroesophageal varices also did not show any significant increase in the mean portal vein diameter in cirrhotics with PHG compared with cirrhotics without PHG [10]. Low positive predictive values have been found in the search for noninvasive surrogate markers of PHG in cirrhotics with varices, but the results of our current study are not comparable with the results of the abovementioned studies because, for the first time, they were obtained in cirrhotics affected and unaffected by PHG, none of whom had varices. The fact that a higher mean portal vein diameter value, which is generally considered an important sign of portal hypertension, was associated with the presence of PHG might be interesting. It is likely that the presence of varices and portosystemic shunts decompresses the portal system [25], which may have influenced the results of previous studies. In this study, no significant difference was observed between cirrhotics with and without PHG with respect to the presence of portosystemic shunts; therefore, because portosystemic shunts were distributed equally between cirrhotics with and without PHG, their presence was unimportant in determining the portal flow volume. The fact that the Child–Pugh score for cirrhotics with PHG and without PHG was not significantly different, but that there was a mildly significant increase in the Child–Pugh score was found in cirrhotics with severe PHG compared with those with mild PHG shows that the former were at a more advanced stage of cirrhosis. Of note, an increased mean portal vein diameter value could be the first sign of portal hypertension that may be useful to identify cirrhotics with PHG. Further studies should be planned to confirm the relationship between increased portal vein diameter and PHG also because this might have therapeutical implications. Although the risk of acute bleeding from PHG is negligible in cirrhotic patients without varices, it is known that PHG causes anemia because of chronic blood loss. The use of beta blockers, preventing portal hypertension and thus bleeding, may help improve the quality of life of cirrhotics.
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96 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
PHG is a dynamic condition, which may worsen from mild to severe, but may also improve and even disappear completely through a reduction in portal hypertension by the use of β-blockers. Although an association between PHG and portal vein diameter has been shown, the sensitivity and specificity are not compelling for use in clinical practice; therefore, our opinion is that decisions to modify management and treatment in cirrhotics depend on several clinical and diagnostic factors [19]. Conclusion
Here, we confirm that duplex Doppler sonography is a valuable diagnostic method to monitor and screen cirrhotics and also to push for further investigations, but not sufficient on its own to plan or modify the clinical and therapeutic management of these patients. Clinical and therapeutic decisions for cirrhotics require a multimodal diagnostic approach.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
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