Hsu et al., 1
Long-term risk of recurrent peptic ulcer bleeding in patients
with liver cirrhosis: a 10-year nationwide cohort study
Short title: Recurrent PUB in cirrhosis
Yao-Chun Hsu1,2, Jaw-Town Lin1,3,4, Tzu-Ting Chen5, Ming-Shiang Wu3, Chun-Ying Wu2,5-7
1
Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung;
2
Graduate Institute of Clinical Medicine, China Medical University, Taichung;
3
Division of Gastroenterology, National Taiwan University Hospital, Taipei;
4
Center for Health Policy Research and Development, National Health Research Institutes; Miaoli;
5
Division of Gastroenterology, Taichung Veterans General Hospital, Taichung;
6
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei;
7
Department of Life Sciences, National Chung-Hsing University, Taichung; all in Taiwan
* Correspondence: Chun-Ying Wu, MD, MPH, PhD
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
155, Sec. 2, Linong Street, Taipei 112, Taiwan
E-mail: chun@vghtc.gov.tw
Tel: +886-4-23592525 # 3304;
Fax: +886-4-23741331
Hsu et al., 2
ABSTRACT
Peptic ulcer bleeding leads to substantial morbidity and mortality in patients with liver
cirrhosis, whose long-term risk of recurrent bleeding remains elusive. In order to elucidate
the association between cirrhosis and peptic ulcer rebleeding, we conducted this nationwide
cohort study by analyzing the Taiwan National Health Insurance Research Database. From
all patients (n=271,030) hospitalized because of peptic ulcer bleeding between January 1997
and December 2006, we identified 9,711 patients with liver cirrhosis and selected 38,844
non-cirrhotic controls matched with 1:4 proportion in age, gender, and use of
gastroprotective agents. Cumulative incidences and hazard ratios were analyzed. The
cumulative incidences of recurrent bleeding were significantly higher in cirrhotic patients
than in controls (1 year: 17.0% vs. 11.9%, 5 year: 36.2% vs. 24.9%, and 10 years: 42.2% vs.
31.0%, all p<0.001). The excessive risk of rebleeding associated with cirrhosis was
consistently found in stratified analyses. However, the hazard ratio diminished with age
because the rebleeding incidence was high regardless of age in cirrhotic patients, whereas it
rose incrementally with age in controls. The multivariate Cox regression analysis verified
cirrhosis as an independent risk factor for recurrent peptic ulcer bleeding with an adjusted
hazard ratio of 1.43 (95% confidence interval: 1.36-1.50). Conclusion: Liver cirrhosis is
independently associated with higher risk of recurrent peptic ulcer bleeding. The high
rebleeding rate found in all cirrhotic patients with different demographic characteristics
Hsu et al., 3
highlights the urgent needs for effective therapies to reduce this long-term risk.
Keywords: peptic ulcer, bleeding, cirrhosis, age, national health insurance research database
Hsu et al., 4
INTRODUCTION
Acute upper gastrointestinal (UGI) bleeding frequently occurs in patients with liver
cirrhosis, with acute variceal hemorrhage (AVH) and peptic ulcer bleeding (PUB)
accounting for 60-70% and 20-30% of all episodes respectively (1-3). Not only is AVH a
lethal complication of cirrhosis, but PUB has also been associated with substantial morbidity
and mortality in cirrhotic patients (1, 4). A multi-center prospective research from Italy
demonstrated that 10% of cirrhotic patients re-bled and 15% of them died within 6 weeks
after an episode of acute non-variceal UGI bleeding (1). However, in contrast to AVH that
has been extensively studied (5), existing literature focusing on cirrhotic patients with PUB
remains strikingly sparse. Little is known about the natural history of PUB in patients with
liver cirrhosis.
Several factors are likely to predispose cirrhotic patients to hemorrhage from peptic
ulcers. In addition to the acquired bleeding diathesis as a result of thrombocytopenia,
dysregulated coagulopathy, endothelial dysfunction, bacterial infection, renal insufficiency,
and hemodynamic alterations may also render these patients susceptible to bleeding from
ulcers (6-10). Hospital-based studies have demonstrated consistently that cirrhosis was
independently associated with risk of recurrent bleeding as well as mortality in patients with
acute UGI hemorrhage, irrespective of the bleeding source (11-13). By prospectively
following a PUB cohort of 738 individuals recruited from a single institute, Guglielmi and
Hsu et al., 5
colleagues identified cirrhosis as an independent predictor for the short-term recurrent
bleeding (12). Nevertheless, data from population-based research remained unavailable and
the long-term risk of recurrent PUB has not been elucidated for patients with liver cirrhosis.
In order to address the paucity of current knowledge regarding the natural history of
cirrhotic patients with PUB as well as to explore the role of cirrhosis in determining the
long-term risk of peptic ulcer rebleeding, we conducted this nationwide cohort study by
analyzing a comprehensive national database over a 10-year period.
PATIENTS AND METHODS
Study design and population:
This is a population-based retrospective cohort study using data from the Taiwan
National Health Insurance Research Database (NHIRD), a comprehensive healthcare
database covering 99.9% of the entire 23.74 million population of Taiwan. Details of the
NHIRD were described in our previous research (14-17). This study has been approved by
the National Health Research Institutes, Taiwan.
By using the international classification of disease-9 (ICD-9) codes to define the
presence of diseases, we first identified all hospitalized patients who were admitted with a
primary diagnosis of PUB (ICD-9 codes: 531.0, 531.2, 531.4, 531.6, 532.0, 532.2, 532.4,
532.6, 533.0, 533.2, 533.4, and 533.6) for the first time between January 1, 1997 and
Hsu et al., 6
December 31, 2006. Those who were admitted again or transferred to another hospital
within 3 days of discharge from the index hospitalization were considered in the same
course of bleeding episode. Patients aged less than 20 years and those who had received
gastric resection or vagotomy prior to discharge of the index admission were excluded.
Cirrhotic cohort and matched cohort:
The diagnosis of cirrhosis was based on the specific admission code (ICD-9: 571) and
the cirrhotic cohort comprised PUB patients who had been diagnosed with liver cirrhosis
before the index hospitalization. With regard to the control cohort, we matched each
cirrhotic patient with four non-cirrhotic controls selected from the PUB population
according to age ( 2 years), gender, and the frequency of taking gastroprotective
medication which was defined as proton pump inhibitor (PPI) and histamine type 2 receptor
antagonist (H2RA).
Definition of recurrent peptic ulcer bleeding
Recurrent PUB was defined as re-hospitalization with a primary diagnosis of PUB after
the index bleeding episode during the study period. Cumulative incidences of recurrent PUB
over 1-, 5-, and 10-year periods were determined for the cirrhotic patients and their matched
controls. We also calculated the hazard ratio (HR) associated with cirrhosis for PUB
recurrence.
Definition of and adjustment for probable confounding factors
Hsu et al., 7
We defined presence of co-morbidities according to the diagnoses coded on admissions
prior to the index hospitalization. We considered acute coronary syndrome, cerebral
infarction, hypertension, diabetes mellitus, chronic obstructive pulmonary disease,
dyslipidemia, and end stage renal disease (ESRD) as potentially important confounding
factors. We adjusted the factor of ulcerogenic drugs which included non-steroidal
anti-inflammatory drugs (NSAID), cyclooxygenase-2 (COX-2) specific inhibitors, aspirin,
clopidogrel, ticlopidine, warfarin, dipyridamole, cilostazol and cerenin. We also considered
non-selective beta blocker and nitrates, which were frequently prescribed to cirrhotic
patients for reduction of portal hypertension (18), as probable confounders. Prescription
information of medication such as the dosage, frequency, duration, and administration route
was retrieved from the NHIRD.
Enrolled patients who received eradication therapy for Helicobacter pylori before or
after the index hospitalization were defined as having H. pylori-associated peptic ulcers. The
definition of H.pylori eradication therapy was the combination regimen containing a PPI or
H2RA plus two or more compatible antibiotics (amoxicillin, clarithromycin, metronidazole,
tetracycline, etc.), with or without bismuth, in the same prescription order with treatment
duration lasting from 7 to 14 days. All combination regimens eligible for H.pylori
eradication have been detailed in our previous research (14, 15).
Statistical analysis:
Hsu et al., 8
Cumulative incidences of recurrent PUB were estimated by using the Kaplan-Meier
method and compared by the log-rank test between the two cohorts. The influence of
cirrhosis on PUB recurrence was examined in different strata according to age, gender,
comorbidity, therapeutic agents, and H,pylori status. For stratified analysis, patients were
defined as users of a certain medication if they received this drug with duration longer than
10% of the observation period. We further applied the Cox proportional hazard model to
verify whether cirrhosis was an independent risk factor for recurrent PUB. With all probable
confounders included initially, we performed the analysis using step-down method and
assessed goodness-of-fit of the models. We used SAS 9.1 software (SAS Institute., Cary, NC,
USA) for data management, and SPSS program for Windows 11.0 (SPSS Inc. Chicago,
Illinois, USA) to calculate cumulative incidence and HR. For each calculated HR, 95 %
confidence interval (CI) was estimated. All statistical tests were two-sided with significance
set at p value <0.05.
RESULTS
Baseline characteristics of PUB patients with cirrhosis and matched cohort
We identified 9,711 patients with liver cirrhosis among a total of 271,030 patients who
were hospitalized for the first time with a primary diagnosis of PUB between 1997 and 2006.
This cirrhotic cohort was matched to 38,844 non-cirrhotic PUB patients in terms of age,
Hsu et al., 9
gender, and use of gastroprotective agents. Demographic data, H.pylori status, prescription
frequency of drugs that might protect or induce peptic ulcers and medication that might
influence portal pressure, major comorbidities, and follow-up duration of the two study
cohorts were summarized in the Table 1.
Cumulative incidences of recurrent PUB between the cirrhotic cohort and controls
The cumulative incidence of recurrent bleeding in the cirrhotic cohort was 42.2% (95%
CI, 39.9-44.6%) during the 10-year study period (Figure 1), significantly higher than 31.0%
(95% CI, 30.2-31.8%) in the matched controls (p<0.001, by the log rank test). The number
needed to have one case of recurrent PUB (number needed to harm, NNH) for being
cirrhotic was 9 in 10 years. Cirrhotic patients were also more likely to re-bleed within 1 and
5 years after an index admission for PUB, with significantly higher 1-year (17.0% vs. 16.7%
p<0.001) and 5-year (36.2% vs. 24.9%, p<0.001) cumulative incidences of rebleeding
respectively (Table 2). The corresponding NNH were 20 and 9 in 1 and 5 years respectively.
Cirrhosis as an independent risk factor for recurrent PUB
In the multivariate stratified analysis, cirrhosis was associated with increased risk of
recurrent PUB in all subgroups according to age, gender, medication, H.pylori status, and
comorbidities (Figure 2). The effect of cirrhosis on increased risk of rebleeding appeared to
be modified by age, gastroprotective agents, and ESRD in that the effect was greater if the
patients were younger, not protected by PPI or H2RA, and not comorbid with ESRD. The
Hsu et al., 10
interesting interaction between cirrhosis and age was further illustrated by the cumulative
incidences of recurrent PUB in different age groups (Figure 3A). In contrast to the
non-cirrhotic controls whose risk of recurrent bleeding significantly increased with age
(from 23.6% in the age group of 20-39 years to 37.2% if aged >60 years), the cirrhotic
cohort had similarly high risks of rebleeding across ages (Figure 3B). Even in the age
stratum of 20-39 years, the cumulative incidence of recurrent bleeding was as high as 40.9%
(95% CI, 37.4%-44.7%).
Cirrhosis remained an independent risk factor for PUB recurrence with a hazard ratio of
1.43 (95% CI, 1.36-1.50; p<0.0001) after adjustment for age, gender, use of gastroprotective
or ulcerogenic drug, propranolol, nitrate, H.pylori status, and comorbidities.
DISCUSSION
This is the first population-based research to evaluate the long-term risk of recurrent
peptic ulcer bleeding in patients with liver cirrhosis. We revealed in this nationwide cohort
study that PUB commonly recurred in cirrhotic patients. The cumulative incidences of
recurrent bleeding were 17.0%, 36.2%, and 42.2% in 1, 5, and 10 years respectively among
the 9,711 cirrhotics, significantly higher than the corresponding 11.9%, 24.9%, and 31.0% in
the 38,844 non-cirrhotic matched controls. The role of cirrhosis as an independent risk factor
for peptic ulcer rebleeding was further confirmed by the multiple stratified analyses and the
Hsu et al., 11
multivariate Cox regression modeling, both of which took age, gender, medication, H.pylori
status, and comorbidity into account. These findings point out an important issue that has
escaped attention for years in the management patients with liver cirrhosis. In view of the
detrimental consequences of UGI bleeding on these vulnerable patients, effective measures
for long-term risk reduction should be urgently sought.
Intriguingly, the stratified analysis revealed that the excessive risk attributable to
cirrhosis decreased with age (Figure 2). This finding resulted from the high cumulative
rebleeding incidences regardless of ages among cirrhotic patients, in contrast to the controls
whose rebleeding risk rose dramatically with age (Figure 3). It implicated that cirrhosis was
more determinant than age in compromising the mucosal defense. Accordingly, not even in
those cirrhotic patients younger than 40 years should the risk of recurrent bleeding be
overlooked. We also found that the hazard ratios associated with liver cirrhosis differed
according to the use of gastroprotective agents. Although cirrhosis consistently enhanced the
risk of rebleeding in both subgroups, the magnitude was greater in patients with than in
those without using these drugs. Since PPIs and H2RAs are reimbursed by the Taiwan
national health insurance only in patients with proven endoscopic lesions such as ulcers or
erosive esophagitis, their use might actually represent a preexisting UGI pathology.
Therefore, our analysis explicitly matched the cirrhotic cohort with controls in
gastroprotective medication to avoid its potentially confounding effect. Moreover, because
Hsu et al., 12
ESRD also independently adds to the long-term risk of recurrent PUB (17), the impact of
cirrhosis on magnifying this risk was reasonably less pronounced in patients with ESRD.
Our results were consistent with previous studies showing that as compared with the
general population, cirrhotic patients had more complicated outcomes of peptic ulcers.
Earlier studies have revealed peptic ulcers not only healed more slowly but also recurred
more frequently in patients with liver cirrhosis as compared with controls (19, 20). Moreover,
there was evidence to suggest that cirrhosis was a predictive factor for PUB recurrence in
the short term (12). The exact mechanism underlying the association between liver cirrhosis
and risk of peptic ulcer rebleeding remains elusive, but may be related to impaired mucosal
defense (6), bleeding tendency (7, 8), endovascular dysfunction (9, 21), and hyperdynamic
circulation (22). The presence and severity of portal hypertension, the hallmark of the
pathophysiology of cirrhosis, has been shown to induce gastric mucosal ulceration and
hemorrhage in experimental models and to correlate with occurrence and recurrence of
peptic ulcer diseases in clinical observations (23-28). Therefore, it stands to reason that the
pathophysiological derangements of cirrhosis directly contribute to the pathogenesis of the
higher recurrent bleeding rate.
There was emerging evidence indicating that PUB patients whose pathogenesis was
unrelated to H.pylori or NSAIDs were more likely to re-bleed or die (29, 30). The major
characteristic that distinguished these patients with so-called “idiopathic” ulcers from those
Hsu et al., 13
with NSAID- or H.pylori-related ulcers was the severity of underlying illness (29). Since
H.pylori status and ulcerogenic drugs, along with other covariates, were adjusted, results of
this study add to elucidating how patient’s underlying comorbidity affects the outcomes of
PUB. The lower proportion of H.pylori-associated ulcers and less frequent use of
ulcerogenic drugs (Table 1) also suggested that the majority of ulcer recurrences in the
cirrhotic cohort were unrelated to these two well-recognized ulcer inducers.
How to reduce the recurrence rate of peptic ulcers remains unknown and has scantly
been investigated for patients with liver cirrhosis. Although H.pylori eradication is
unequivocally effective in preventing peptic ulcer recurrence in the general population (31),
such effectiveness was not demonstrated in patients with cirrhosis (28, 32). After
prospectively following up 104 cirrhotic patients with duodenal ulcer for one year, Luo and
colleagues reported that duodenal ulcer recurred in 21 of the 36 (58%) patients who
achieved successful H.pylori infection, 8 of the 18 (44%) patients who remained
H.pylori-positive despite eradication therapy, and 24 of the 50 (48%) patients who were
H.pylori-negative at the enrollment (p=0.53) (28). Similarly, it remains unexplored whether
anti-secretory medication effectively lowers recurrence rate of ulcer bleeding in cirrhotic
patients. The efficacy of acid suppression for patient with cirrhosis appears questionable
because cirrhotic patients are characterized by marked gastric hypoacidity (33), and
therefore gastric acid may not play a crucial role in the ulcerogenesis of this unique
Hsu et al., 14
population. On the other hand, cirrhosis-related pathophysiological alterations may be
considered as potential therapeutic targets. Agents that can decrease portal hypertension,
increase gastric mucus lining, correct endothelial dysfunction, or restore mucosal integrity
merit examination in the setting of clinical trials.
Major strengths of this study are attributed to the comprehensiveness of NHIRD that
allows our analysis to cover a nationwide population for a period of 10 years. We ascertain
definition of diseases and outcomes by investigating only hospitalized patients, because
admission diagnoses are strictly scrutinized by the insurance system for the purpose of
reimbursement. Although it is possible in theory that PUB may be managed on an outpatient
basis, such an event is most likely insignificant clinically. Furthermore, the consistency of
subgroup analyses stratified by various covariates supports that cirrhosis per se raises the
risk of peptic ulcer rebleeding. We believe there are no unmeasured confounders that could
have distorted the analysis because such factors would have to be either strongly linked to
both the presence of cirrhosis and a heightened risk of PUB or would have to be very
common, given the size of our cohort.
Our study may have the following limitations. The source of UGI bleeding sometimes
is difficult to determine in cirrhotic patients, and therefore PUB might have been
insufficiently coded as unspecified UGI hemorrhage or erroneously as AVH. However, such
misclassification probably would have underestimated the exact incidence of recurrent PUB
Hsu et al., 15
in the cirrhotic patients and biased the results toward no difference. Second, we can only
estimate exposure to medications by data of filled prescriptions, but cannot ascertain the
amount each individual exactly takes. However, any difference in drug compliance is
probably random and unrelated to cirrhosis or not. Furthermore, medication at the patient’s
own expense cannot be analyzed, but substantial exposure to unrecorded drug is very
unlikely in either cohort thanks to the widespread coverage of our national health insurance.
Finally, endoscopic stigmata of bleeding ulcers are not available in the NHIRD and cannot
be included into our analysis. Nevertheless, despite their values in predicting short-term
recurrent bleeding, ulcer stigmata probably are not related to long-term risk prediction.
In conclusion, we demonstrate in this nationwide cohort study that PUB recurs in more
than 40% of cirrhotic patients within 10 years regardless of their ages. The association
between cirrhosis and risk of recurrent PUB is independent to H.pylori infection,
ulcerogenic agents, and other relevant factors. It implicates that cirrhosis along with its
pathophysiological consequences may have important roles in the pathogenesis of ulcer
bleeding. Our findings underline the unmet needs for a therapeutic option with proven
efficacy in lowering long-term risk of peptic ulcer rebleeding among patients with liver
cirrhosis.
Hsu et al., 16
ACKNOWLEDGEMENT
This work was supported in part by the National Health Research Institutes of
Taiwan (Grant numbers: PH-099-PP-26 and PH-099-PP-16) and Taichung
Veterans General Hospital, Taiwan (Grant numbers: TCVGH-1003304C).
REFERENCES
1.
D'Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Post-therapeutic
outcome and prognostic indicators. Hepatology 2003;38:599-612.
2.
Lecleire S, Di Fiore F, Merle V, Herve S, Duhamel C, Rudelli A, Nousbaum JB, et al.
Acute upper gastrointestinal bleeding in patients with liver cirrhosis and in noncirrhotic
patients: epidemiology and predictive factors of mortality in a prospective multicenter
population-based study. J Clin Gastroenterol 2005;39:321-327.
3.
Hsu YC, Liou JM, Chung CS, Tseng CH, Lin TL, Chen CC, Wu MS, et al. Early risk
stratification with simple clinical parameters for cirrhotic patients with acute upper
gastrointestinal bleeding. Am J Emerg Med 2010;28:884-890.
4.
Afessa B, Kubilis PS. Upper gastrointestinal bleeding in patients with hepatic
cirrhosis: clinical course and mortality prediction. Am J Gastroenterol 2000;95:484-489.
5.
Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis.
N Engl J Med 2010;362:823-832.
6.
Weiler H, Weiler C, Gerok W. Gastric mucosal prostaglandin E2 levels in cirrhosis
Hsu et al., 17
and portal hypertension. J Hepatol 1990;11:58-64.
7.
Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK.
Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J
Hepatol 2002;37:463-470.
8.
Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, Tripodi A,
et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical
assessment of current management. Hepatology 2006;44:1039-1046.
9.
Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol
2007;46:927-934.
10.
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med
2011;365:147-156.
11.
Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper
gastrointestinal haemorrhage. Gut 1996;38:316-321.
12.
Guglielmi A, Ruzzenente A, Sandri M, Kind R, Lombardo F, Rodella L, Catalano F, et
al. Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer.
Endoscopy 2002;34:778-786.
13.
Marmo R, Koch M, Cipolletta L, Capurso L, Pera A, Bianco MA, Rocca R, et al.
Predictive factors of mortality from nonvariceal upper gastrointestinal hemorrhage: a
multicenter study. Am J Gastroenterol 2008;103:1639-1647; quiz 1648.
Hsu et al., 18
14.
Wu CY, Wu CH, Wu MS, Wang CB, Cheng JS, Kuo KN, Lin JT. A nationwide
population-based cohort study shows reduced hospitalization for peptic ulcer disease
associated with H pylori eradication and proton pump inhibitor use. Clin Gastroenterol
Hepatol 2009;7:427-431.
15.
Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT. Early Helicobacter pylori
eradication decreases risk of gastric cancer in patients with peptic ulcer disease.
Gastroenterology 2009;137:1641-1648 e1641-1642.
16.
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Effective reduction of gastric
cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter
pylori-infected patients. J Clin Oncol 2010;28:2952-2957.
17.
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Long-term peptic ulcer
rebleeding risk estimation in patients undergoing haemodialysis: a 10-year nationwide
cohort study. Gut 2011;60:1038-1042.
18.
Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic
response to pharmacological treatment of portal hypertension and long-term prognosis of
cirrhosis. Hepatology 2003;37:902-908.
19.
Siringo S, Burroughs AK, Bolondi L, Muia A, Di Febo G, Miglioli M, Cavalli G, et al.
Peptic ulcer and its course in cirrhosis: an endoscopic and clinical prospective study. J
Hepatol 1995;22:633-641.
Hsu et al., 19
20.
Di Mario F, Gottardello L, Germana B, Dotto P, Grassi SA, Vianello F, Battaglia G, et
al. Peptic ulcer in cirrhotic patients: a short- and long-term study with antisecretory drugs.
Ital J Gastroenterol 1992;24:122-125.
21.
Cahill PA, Redmond EM, Sitzmann JV. Endothelial dysfunction in cirrhosis and portal
hypertension. Pharmacol Ther 2001;89:273-293.
22.
Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases:
from the patient to the molecule. Hepatology 2006;43:S121-131.
23.
Calatayud S, Ramirez MC, Sanz MJ, Moreno L, Hernandez C, Bosch J, Pique JM, et
al. Gastric mucosal resistance to acute injury in experimental portal hypertension. Br J
Pharmacol 2001;132:309-317.
24.
Tsugawa K, Jones MK, Akahoshi T, Moon WS, Maehara Y, Hashizume M, Sarfeh IJ,
et al. Abnormal PTEN expression in portal hypertensive gastric mucosa: a key to impaired
PI 3-kinase/Akt activation and delayed injury healing? FASEB J 2003;17:2316-2318.
25.
Wu CS, Lin CY, Liaw YF. Helicobacter pylori in cirrhotic patients with peptic ulcer
disease: a prospective, case controlled study. Gastrointest Endosc 1995;42:424-427.
26.
Chen LS, Lin HC, Hwang SJ, Lee FY, Hou MC, Lee SD. Prevalence of gastric ulcer
in cirrhotic patients and its relation to portal hypertension. J Gastroenterol Hepatol
1996;11:59-64.
27.
Kitano S, Dolgor B. Does portal hypertension contribute to the pathogenesis of gastric
Hsu et al., 20
ulcer associated with liver cirrhosis? J Gastroenterol 2000;35:79-86.
28.
Lo GH, Yu HC, Chan YC, Chen WC, Hsu PI, Lin CK, Lai KH. The effects of
eradication of Helicobacter pylori on the recurrence of duodenal ulcers in patients with
cirrhosis. Gastrointest Endosc 2005;62:350-356.
29.
Hung LC, Ching JY, Sung JJ, To KF, Hui AJ, Wong VW, Leong RW, et al. Long-term
outcome of Helicobacter pylori-negative idiopathic bleeding ulcers: a prospective cohort
study. Gastroenterology 2005;128:1845-1850.
30.
Wong GL, Wong VW, Chan Y, Ching JY, Au K, Hui AJ, Lai LH, et al. High incidence
of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic
bleeding ulcers. Gastroenterology 2009;137:525-531.
31.
Van der Hulst RW, Rauws EA, Koycu B, Keller JJ, Bruno MJ, Tijssen JG, Tytgat GN.
Prevention of ulcer recurrence after eradication of Helicobacter pylori: a prospective
long-term follow-up study. Gastroenterology 1997;113:1082-1086.
32.
Tzathas C, Triantafyllou K, Mallas E, Triantafyllou G, Ladas SD. Effect of
Helicobacter pylori eradication and antisecretory maintenance therapy on peptic ulcer
recurrence in cirrhotic patients: a prospective, cohort 2-year follow-up study. J Clin
Gastroenterol 2008;42:744-749.
33.
Savarino V, Mela GS, Zentilin P, Mansi C, Mele MR, Vigneri S, Cutela P, et al.
Evaluation of 24-hour gastric acidity in patients with hepatic cirrhosis. J Hepatol
Hsu et al., 21
1996;25:152-157.
FIGURE LEGENDS:
Figure 1. Cumulative incidences of recurrent peptic ulcer bleeding in cirrhotic patients
and matched controls. Cirrhotic patients as compared with non-cirrhotic controls had
significantly higher 10-year cumulative incidence of recurrent peptic ulcer bleeding; CI,
confidence interval.
Figure 2. Stratified analyses for the association between liver cirrhosis and peptic ulcer
rebleeding. Cirrhosis was associated with higher risk of peptic ulcer rebleeding in all
stratified analyses according to age, gender, medication, H.pylori status, and comorbidities.
Note that the effect of cirrhosis on rebleeding risk was more prominent in those who were
younger, not protected by gastroprotective drugs, or not comorbid with chronic renal failure;
PPI, proton pump inhibitor; H2RA, histamine type 2 receptor antagonist; ACS, acute
coronary syndrome; ESRD, end stage renal disease; CI, confidence interval.
Figure 3. Cumulative incidence of recurrent peptic ulcer bleeding stratified by age.
Hsu et al., 22
Rebleeding incidence was similarly high in the cirrhotic patients regardless of their ages,
whereas the incidence rose incrementally with age among controls (Panel A). The difference
of rebleeding rates between the cirrhotic and non-cirrhotic cohorts was greater in the
younger than in the older subgroup (Panel B); CI, confidence interval.