Abstract
Background and aim:
Portal hypertensive gastropathy (PHG) most commonly occurs in the setting of increased portal pressure in patients with cirrhosis. Here, we aimed to understand the correlation between hepatic venous pressure gradient (HVPG) and the presence and severity of PHG in patients with cirrhosis.
Methods:
We examined patients with cirrhosis who underwent HVPG measurement at the Medical University of South Carolina between 2014 and 2020. Extensive demographic, clinical, laboratory, procedural (including precise grading of PHG severity using standard definitions), and outcome data were abstracted at the time of HVPG measurement.
Results:
Three hundred and ten patients with HVPG measurements and cirrhosis were identified. Seventy-three patients having endoscopy within 6 months of HVPG measurement were included (mean age 54 ± 11, 44% female). The most common causes of cirrhosis were alcohol (41%) and non-alcoholic steatohepatitis (32%). The average HVPG was 15 mmHg (±6) and 62 patients had clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mmHg). Of the 73 patients with HVPG measured, 45 (62%) had PHG, including 40 (89%) of whom had CSPH. Out of the 45 patients with PHG, 41 and four had mild or severe PHG, respectively. MELD scores were similar in patients with and without PHG [15 ± 9 (SD) and 17 ± 9, respectively; p=.37]. HVPG was higher in patients with PHG (17 ± 7 mmHg) than those without PHG (13 ± 4 mmHg) (p=.01) but did not differ between mild and severe PHG.
Conclusion:
A weak correlation exists between HVPG level and the presence of PHG.
Keywords: Portal hypertension, non-alcoholic steatohepatitis, cirrhosis, alcohol, fibrosis
Introduction
Portal hypertensive gastropathy (PHG) is a condition defined by ‘snakeskin mosaic’ appearance of the gastric mucosa that is visualized endoscopically [1]. It is most commonly associated with portal hypertension in the setting of cirrhosis of the liver and other associated conditions, such as schistosomiasis, and cardiac failure [1]. The prevalence of PHG varies widely; studies have reported PHG to occur in up to 98% of patients with cirrhosis while others report only a 20% prevalence [1].
The pathogenesis of PHG remains poorly understood. It is believed that PHG occurs as a result of congestion and hyperemia due to the hemodynamic changes that occur when portal pressure increases [1,2]. Another possible explanation includes mucosal ischemia and increased nitric oxide synthase activity associated with abnormal blood flow due to portal hypertension [3–8]. Patients with PHG are most often asymptomatic and the indication for endoscopy is usually unrelated to PHG, rather, for indications, such as screening for esophageal varices [1]. In a small minority of patients, the state of inflammation causes the gastric mucosa to be friable and may predispose to chronic bleeding and less commonly acute hemorrhage [1]. Although it is widely accepted that portal hypertension is a prerequisite [1], data supporting its association with the severity of portal hypertension are conflicting [9,10].
Here, we hypothesized that a correlation exists between the severity of portal hypertension, assessed using the hepatic venous pressure gradient (HVPG), and the presence and severity of PHG in patients with liver cirrhosis.
Methods
Study population and design
We identified 310 consecutive patients with a hepatic venous pressure gradient measurement (HVPG) assessed during a liver biopsy for suspected cirrhosis at the Medical University of South Carolina (MUSC) between January 2014 and January 2020. Patients who were <18 years of age or those who did not have an endoscopy within 6 months of HVPG measurement were excluded. Patients were identified using the MUSC clinical data warehouse which searched for 9th and 10th revisions clinical modifications (ICD-9 and ICD-10, respectively). Patients who met inclusion criteria were then manually reviewed for HVPG measurement and the presence and severity of PHG. The study was approved by the MUSC institutional review board (IRB) and met all guidelines for good clinical practice [11].
Data collection
Data were abstracted from the electronic medical record at the time of HVPG measurement and included the following: complete demographic information, past medical history, adjusted Charlson Comorbidity Index (CCI) for cirrhotic patients, cirrhosis complications (ascites, non-bleeding esophageal varices, bleeding esophageal varices, hepatic encephalopathy), etiology of cirrhosis, and mortality. HVPG was measured using standard techniques [12,13]. The presence of hepatic encephalopathy was defined as altered mental status in a patient with cirrhosis after exclusion of other causes of mental status change. Ascites were defined based on readily available guidelines [14,15].
PHG is typically categorized based on appearance at endoscopy by using either a two or three category classification, mild and severe or mild, moderate and severe [16–19]. In the current study, PHG was defined by a review of endoscopic images using the validated ‘mild’ and ‘severe’ endoscopic descriptors for PHG [16–19]. The primary outcome was the presence of PHG at endoscopy within 6 months of HVPG measurement. The secondary outcome was the severity of PHG using the two-category method as described above. In brief, mild PHG was defined as changes consisting of a snakeskin mosaic pattern whereas severe PHG was characterized by a mosaic-like pattern with flat or bulging red or black-brown spots and/or active bleeding [1].
Statistical analysis
The sample selected included all patients undergoing HVPG measurement. We predicted that patients with severe PHG would have a higher HVPG than those with mild PHG and no PHG. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 27. Comparisons between groups were evaluated using the Fisher exact test for categorical variables and the Student t-test for continuous variables, with results presented as percentages or mean values with standard deviation (SD), where appropriate. All statistical tests were two-sided, and a p-value <.05 was considered statistically significant. Patient variables across demographic, comorbidity, laboratory, and cause of cirrhosis were screened for an association with the presence of PHG using univariate models. Any variable with a univariate p-value <.05 were included in the multivariate regression analysis. Multivariate regression analysis included the following variables: alcoholic cirrhosis, NASH cirrhosis, past history of ascites, past history of hepatic encephalopathy (HE), beta blocker use, and HVPG level. The exponentiation of the B coefficient was used as an odds ratio.
Results
Between 2014 and 2020, 310 patients with HVPG measurement and cirrhosis were identified (Figure 1). Within this group, 73 patients had an upper endoscopy within 6 months of HVPG measurement. Thirty-two (44%) patients were women, and the most common cause of cirrhosis was alcohol (41%) and non-alcoholic steatohepatitis (NASH) (32%) (Table 1). Of this group, 45 (62%) had PHG as defined in the methods section. Patients with PHG and no PHG had similar comorbidities, CCI (5.4 ± 2.0 and 4.6 ± 2.7, respectively). Of the 45 patients with PHG, four patients had severe PHG, and 41 patients had mild PHG (graded as in the methods).
Figure 1.
Consort diagram. The flowchart highlights inclusion and exclusion criteria and the final sample included. HVPG: hepatic venous pressure gradient; EGD: esophagogastroduodenoscopy; PHG: portal hypertensive gastropathy.
Table 1.
Demographic and clinical characteristics.
| Patients with PHG | Patients without PHG | |
|---|---|---|
| n = 45 | n = 28 | |
| Characteristic | [n (%) or mean ± SD] | [n (%) or mean ± SD] |
|
| ||
| Female | 20 (44%) | 12 (43%) |
| Age | 55 ± 10 | 53 ± 13 |
| Race | ||
| White | 38 (84%) | 22 (78%) |
| Black | 6 (13%) | 6 (21%) |
| Hispanic or Latino | 1 (2%) | 0 |
| Cirrhosis etiology | ||
| Alcohol | 13 (29%) | 17 (61%) |
| NASH | 20 (44%) | 3 (11%) |
| HCV | 6 (13%) | 4 (14%) |
| Other | 6 (13%) | 4 (14%) |
| Hepatic encephalopathy | 6 (13%) | 10 (39%) |
| Esophageal varices | 13 (28%) | 7 (25%) |
| Ascites | 7 (15%) | 13 (50%) |
| CP Score: A, B, C | ||
| A | 14 (31%) | 4 (14%) |
| B | 22 (49%) | 13 (46%) |
| C | 9 (20%) | 11 (40%) |
| Carlson Comorbidity Index | 5.4 ± 2.0 | 4.6 ± 2.7 |
MELD scores were similar in patients with PHG and those without PHG [15 ± 9 (SD) and 17 ± 9, respectively; p=.37] (Table 2). Likewise, Child-Pugh scores were similar in those without and without PHG (Table 1).
Table 2.
Laboratory data.
| Patients with PHG | Patients without PHG | |
|---|---|---|
| n = 45 | n = 28 | |
| (Mean ± SD) | (Mean ± SD) | |
|
| ||
| Mean | Mean | |
| Hgb (g/dL) | 11.7 ± 2.6 | 10.7 ± 2.7 |
| Hct (%) | 35 ± 7 | 32 ± 8 |
| WBC (k/uL) | 6.6 ± 5.0 | 8.8 ± 6.2 |
| Plts (k/uL) | 120 ± 69 | 154 ± 87 |
| BUN (mg/dL) | 20 ± 16 | 22 ± 18 |
| Creatinine (mg/dL) | 1.3 ± 0.9 | 2.2 ± 3.3 |
| Sodium (mmol/L) | 136 ± 6 | 133 ± 6 |
| ALT (U/L) | 44 ± 34 | 45 ± 46 |
| AST (U/L) | 80 ± 56 | 67 ± 51 |
| Total bilirubin (mg/dL) | 6.7 ± 11.1 | 5.3 ± 8.4 |
| ALP (U/L) | 149 ± 91 | 145 ± 96 |
| Albumin (g/dL) | 2.9 ± 0.6 | 8.9 ± 33.6 |
| INR (s) | 1.6 ± 2.0 | 1.4 ± 0.5 |
| MELD | 15 ± 9 | 17 ± 9 |
We performed multivariate regression analysis to identify independent variables associated with PHG; out of five variables (etiology of cirrhosis, treatment with beta blockers, ascites, hepatic encephalopathy, and HVPG) only NASH cirrhosis, ascites, and HVPG were independently associated with PHG (p=.008, p=.02, p=.009).
Relationship between HVPG and PHG
The average HVPG was 15 mmHg (±6) and 62/73 patients had clinically significant portal hypertension (CSPH) (HVPG ≥10 mmHg). Of the 45 patients with PHG, 89% had CSPH. Notably, 5 of 11 patients (44%) with HVPG < 10 mm Hg had PHG, while 40 of 73 patients (65%) of patients with HVPG ≥10 mm Hg had PHG (Table 3).
Table 3.
Varices and PHG.
| Varices Alone | Varices + PHG | PHG Alone | No PHG/No Varices | ||
|---|---|---|---|---|---|
| n = 7 | n = 13 | n = 32 | n = 21 | ||
| n (%) | n (%) | n (%) | n (%) | Total | |
|
| |||||
| HVPG <10 | 2 (18%) | 0 (0%) | 5 (46%) | 4 (36%) | 11 |
| HVPG ≥ 10 | 5 (8%) | 13 (21%) | 27 (44%) | 17 (27%) | 62 |
Interestingly, although no patient with an HVPG < 10 mm Hg had both EVs and PHG, in the 45 patients with PHG, 13 (29%) had varices while in patients without PHG, 7 (25%) had varices (Table 3); there was no difference between the presence of esophageal varices and the presence of PHG (p=.7).
The average HVPG in patients with mild PHG was 16 ± 7 and 17 ± 7 in those with severe PHG (p=.8). There was no difference in HVPG among the different etiologies of cirrhosis (p=.88). HVPG values differed between the 28 patients without PHG (13 ± 4) and the 45 who had PHG (17 ± 7) (p=.01) (Table 4). In addition, the odds ratio for the presence of PHG and HVPG was 1.125 (CI = 1.02, 1.24). The Spearman’s rank correlation between the presence of PHG and an increasing HVPG was 0.2 (p=.1) (Figure 2).
Table 4.
HVPG and PHG.
| Overall | Patients w/PHG | Patients w/o PHG | ||
|---|---|---|---|---|
| (n = 73) | (n = 45) | (n = 28) | ||
| Characteristic | [n (%) or mean ± SD] | [n (%) or mean ± SD] | [n (%) or mean ± SD] | p-Value |
|
| ||||
| Hepatic venous pressure gradient (mmHg) | 15 ± 6 | 17 ± 7 | 13 ± 4 | .01 |
| Clinically significant portal hypertension (HVPG >10) | 62 (85%) | 40 (89%) | 22 (78%) | .23 |
Figure 2.
HVPG and PHG severity. Each dot in the scatter plot represents an individual patient with their respective HVPG measurement and PHG severity. The line represents the mean HVPG level in each category. Spearman’s rank-order correlation revealed a positive correlation between HVPG and PHG severity [rho(71) = 0.2].
We additionally assessed the possible effect of beta-blockers on PHG and HVPG (Table 5). Out of the 73 patients, 29 patients were on non-selective beta-blockers before HVPG measurement, and of those 17 (59%) had PHG with a mean HVPG of 15 ± 6 vs. 14 ± 4 in patients on beta-blockers with no PHG (p=.6). Of the 44 patients not on beta-blockers at the time HVPG was measured, 28 (64%) had PHG with a mean HVPG of 17 ± 6 vs. 13 ± 4 in patients, not on beta-blockers who did not have PHG (p=.01). Overall, the mean HVPG for patients on beta-blockers was 15 ± 5 and 16 ± 7 in patients not on beta-blockers (p=.4) (Table 5). In aggregate, these data suggest that the use of non-selective beta-blockers had no effect on the presence of PHG.
Table 5.
PHG and HVPG in patients on nonselective beta-blockers.
| On beta-blocker |
Not on beta-blocker |
|||||
|---|---|---|---|---|---|---|
| (N = 29) |
(N = 44) |
|||||
| Characteristic | No PHG | Mild PHG | Severe PHG | No PHG | Mild PHG | Severe PHG |
|
| ||||||
| N | 12 | 15 | 2 | 16 | 26 | 2 |
| Hepatic venous pressure gradient (mean ± SD) | 14 ± 4 | 14 ± 6 | 21 ± 7 | 13 ± 4 | 18 ± 7 | 14 ± 6 |
Discussion
In this study, we demonstrated that a relationship between increased HVPG and the presence of PHG exists and that it appears to be independent of liver disease severity based on MELD and Child-Pugh scores. However, we could not draw any conclusions on the correlation between the severity of PHG and the degree of HVPG abnormality due to the limited number of patients with severe PHG in our population.
Our results are consistent with previous studies demonstrating a correlation between HVPG and the presence of PHG [20–23]. However, while we found no clear correlation between the severity of PHG and the degree of elevation in HVPG, others have reported such a relationship to exist. In one such study of 49 patients with PHG, portal pressure was greater in patients with severe PHG (HVPG = 20) compared to those without PHG (HVPG = 17, p=.0004) [20]; these data are likely skewed because of the great number of patients with severe PHG, which is in fact uncommon when rigorous PHG grading is utilized—such as was done in our study. In a larger prospective study [23] of 298 PHG patients, increasing HVPG levels were found in patients categorized as having no PHG, mild PHG, and severe PHG and (p = <.001). Conversely, there are a few [2,9] who found no association at all between the severity or presence of PHG and HVPG.
Several studies [21,24,25] have examined the correlation between PHG and portal hypertension by comparing esophageal variceal presence and size (which presumably are only present in the setting of CSPH) with PHG. Overall, the data suggest that the rate of PHG is significantly higher in those with varices. In one study, patients with esophageal varices had a significantly higher rate of PHG [80 of 104 (76.9%)] than those without esophageal varices [51 of 84 (60.7%)] (p=.007) [24]. Our study found that varices had no effect on the presence of PHG (p=.7). Although not significant, the prevalence of PHG was higher in those with varices [13 out 20 (65%)].
Previous literature has reported no correlation between the etiology of cirrhosis and PHG [25,26]. Interestingly, we found that PHG was present in 20 of 23 (87%) patients with NASH cirrhosis, while it was found in only 25 of 50 (50%) of patients with other etiologies of cirrhosis (Table 1). Out of those with CSPH 17 out of 20 NASH patients had PHG (p=.02). This contrasts with other studies [23,25,27,28] which showed that cirrhosis etiology had no effect on the presence of PHG. One possibility for this discrepancy is that previous studies did not specifically examine patients with NASH cirrhosis. However, we urge caution in the interpretation of this potentially novel finding because our sample size is small and suggests that this association should be examined in further studies.
The notion that liver disease severity may be important in the pathogenesis, and thus, the presence of PHG, is controversial [20,24,29]. One study showed that the prevalence of PHG was 87% in patients with Child-Pugh stage C but only 13% in patients with Child-Pugh stage A [30]. Another showed no significant differences in Child-Pugh stage or in MELD score among patients with and without PHG [29]. Although we failed to find a clear association between MELD score or Child-Pugh class, we urge caution in concluding that there is not an association between liver disease severity and the presence or severity of PHG; this is because we did not examine a substantial number of cirrhosis patients with minimally severe disease (i.e., those with an HVPG <10 mm Hg or Child-Pugh class A). Ideally, a prospective examination of patients with early-stage disease, followed over time would best address this issue.
We recognize the limitations of this study. First, this is a retrospective study, and as such may contain ascertainment bias. We believe that this is mitigated however by the careful curation of the data set, in particular by the careful and rigorous standardization of the presence or absence, and severity of PHG—as previously described [16–19]. We intentionally used the validated ‘mild’ and ‘severe’ endoscopic descriptors for PHG instead of the three category descriptors to reduce the risk of discrepancy in assigning PHG severity. This is in part responsible for the identification of only four patients with severe PHG, and did not permit us from drawing any conclusions about the relationship between the severity of PHG and portal hypertension, even though we found no relationship to exist with the small number of severe cases we have. Since this study was a pragmatic study in which data were obtained in ‘real time’ and under different management circumstances, we were unable to control for certain confounding variables. Perhaps the most important of these is the use of non-selective beta-blockers to reduce portal pressure. In our population, beta-blockers had no effect on either the presence of PHG (p=.4) or HVPG level (p=.4), although we cannot rule out the possibility of lead time bias in that patients may have been started on a non-selective beta-blocker before HVPG due to some unmeasured clinical feature reflecting elevated HVPG. Additionally, this study is from a single-center, and thus our results might not be generalizable to other centers. However, since our center is typical of most other large academic medical centers, we suspect that the findings are. Lastly, the lack of objective uniform criteria to assess PHG severity could account for disagreements between reviewers in assessing the severity of PHG, leaving room for different interpretations of PHG severity. Nonetheless, these potential concerns were addressed by using the two category descriptors of PHG.
In summary, despite the fact that PHG is a common finding in patients with cirrhosis, conflicting views on its association with portal hypertension continue to exist. Our findings support the notion that portal hypertension drives, at least to some extent, PHG. Further, our data demonstrating the extremely high prevalence of PHG in patients with NASH and portal hypertension raises the possibility that NASH may contribute to the pathogenesis of PHG. Further studies with larger sample sizes will be needed to better delineate the pathophysiological relationship between PHG, PHG severity, and portal pressure.
Acknowledgments
Funding
D.C.R. was supported by the NIH (P30 DK123704).
Abbreviations:
- ALT
alanine transaminase
- AST
aspartate transaminase
- CCI
Charlson comorbidity index
- CSPH
clinically significant portal hypertension
- Exp(B)
exponentiation of the B coefficient
- HE
hepatic encephalopathy
- HVPG
hepatic venous pressure gradient
- ICD
international classification of disease
- IRB
Institutional Review Board
- MELD
model for end-stage liver disease
- mmHG
millimeters of mercury
- MUSC
Medical University of South Carolina
- NASH
non-alcoholic steatohepatitis
- PHG
portal hypertensive gastropathy
- Rho
Spearman’s rank correlation coefficient
- SD
standard deviation
- SPSS
Statistical Package for the Social Sciences
Footnotes
Disclosure statement
No potential conflict of interest was reported by the author(s).
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