Perforated peptic ulcers (PPUs) count among the most frequent emergency conditions globally.1–3 According to data from the 2010 Global Burden of Disease study, there were 896,000 deaths, 20 million years of life lost, and 25 million disability-adjusted life-years from 11 emergency general surgical conditions reported individually in the study.3 Notably, the most common cause of death was complicated peptic ulcer disease, followed by aortic aneurysm, bowel obstruction, biliary disease, mesenteric ischemia, peripheral vascular disease, abscess and soft tissue infections, and appendicitis. Thus, while PPU may be outnumbered in terms of absolute frequency of occurrence compared with other emergency conditions, it makes for one of the most lethal emergency surgery conditions on a global scale.
Consequently, when considering the health impact and widespread occurrence of PPU, it comes as a puzzle that perforation mechanism is so poorly understood, with few recent efforts or progressions reported in both medical and surgical research terms. Although perforations make up somewhere between 5% and 20% of complicated ulcers (the majority of complications in peptic ulcer disease being bleeding ulcers), the contribution to ulcer mortality from perforations is 70% or more.2,3 In comparison with the high mortality observed in perforations, mortality from bleeding ulcers is now approaching numbers well less than 5% because of improvements in modern endoscopic techniques and interventional radiology,4 making emergency surgery now a rare option for bleeding compared with only a few decades ago.
Thus, one should think that the rate of research followed the priority for public health, but such is not the case. Indeed, when reviewing the literature, one is stunned by the pause in objective, high-quality evidence for the overall management of patients with PPU,5 where randomized trials make the exception rather than the rule. Furthermore, one would envision this kind of disease entity particularly amenable to international, multicenter research collaboration through observational studies, registries, or clinical trials6 because of its widespread occurrence globally. Again, there is a paucity of multicenter collaboration in PPU.
PPU represents one of the most frequent causes of free air obtained on imaging studies of an acute abdomen and thus is a frequent challenge to modern surgeons.7 Still, very little is known about the mechanisms that lead to perforation in gastroduodenal ulcers. Thus, the aim of this article was to review the current insight into the pathophysiology of perforation in gastroduodenal ulcers.
Disparities in Research Attention and Funding of Ulcer Complication Research
Peptic ulcer disease as a whole has received tremendous amounts of research attention because of the historical impact and medical disease burden in the western world. Moreover, attention attributable to the 1982 discovery and description of the role of the Helicobacter pylori (eventually Nobel prize given to Warren and Marshall in 2005) and the development of effective acid-depressing drugs (H2-receptors and later proton pump inhibitors) as well as the development of endoscopic techniques and equipment has led to a intense investigations and trials in peptic ulcer disease in general. This has mainly concerned trials and investigations into bleeding ulcer management, with less attention to perforations. The reasons for this may be manifold; for one, the medical community may have had greater interest in the ulcer disease and its related developments (drugs and endoscopy) with easier access to funding (industry). In contrary, the surgical scope has been more on adequate and timely care—which is a more generic approach constituted for all emergency general surgery disorders and thus less amenable for funding. The one “intervention” receiving most attention in trials has been laparoscopic repair (compared with open) for which the few trials have demonstrated few, if any, highly clinically relevant differences but the evidence is weak at best.
Peptic Ulcer Development and Perforation Mechanisms
Obviously, while hard data are missing, there is no lack of theories as to how a perforation may occur (Fig. 1), but real data to support these ideas are few and virtually nonexistent. The number of associations, risk factors, and ulcerogenic components makes for a long read.5,8 It is clear that there is an imbalance between ulcerogenic and protective factors that lead to ulcer development, as well as facultative modifiers (e.g., stress and smoking) that increase the risk of severity. Yet, these associations cannot explain why one person go on to have a perforation that is literally the size of a punch hole, with no or only minor ulcer bed in the stomach or duodenal side, while another patient may present with an ulcer of several centimeters followed by gross abdominal contamination.
Why is it that some perforate in what seems to be a very localized and rapid pattern of penetration, while others have large ulcer beds that dig through larger areas of the enteric layers before eventual perforation ensues? More than half of patients with PPU have no history of ulcer disease or no ensuing symptoms, so it is a first event for the majority of those who experience a perforation.
Notably, if clinical data are scarce, proper studies into the pathogenesis of ulcer disease and perforation mechanisms are even fewer and far between. That is, the ulcerogenesis and role of H. pylori is certainly well investigated, and data on ulcers in the mucosa per se are well investigated. However, H. pylori alone is also not sufficient for perforation, as up to half of all patients with PPU may be H. pylori negative.9 Cofactors such as smoking and alcohol may be related but vary in intake across populations. These factors may increase acidity and directly affect the protective mechanisms in the mucosa. Hypergastrinemia (Zollinger-Ellison syndrome) is the rare disease example of how high acidity contents may give risk to ulcers and even perforation.10
Change in Epidemiology—Any Clues?
There are epidemiologic studies to demonstrate the change in disease prevalence that comes with an altered population demography.11 For example, in the western world, a shift in PPU frequency occurs toward higher ages (>60 years), with a female dominance, more often with a gastric location of the ulcer perforation, and a higher likelihood of association with drugs, including steroids and nonsteroidal anti-inflammatory drugs or low-dose aspirin.12–14 On the contrary, in developing countries, the median age is almost 2 decades younger, heavily skewed toward men (up to a 10:1 distribution for men to women), highly associated with H. pylori infections, and a predominant duodenal location. Indeed, this reflects the situation in the western world half a century ago. Of notice, almost half of the global population is infected with H. pylori, yet only 10% to 20% develop ulcer disease.15 Of those with ulcer disease, only a minor share of these develop complications, usually in the form of bleeding followed by perforation as the second most frequent complication. While the “psychogenic stress” theory of the past in ulcer genesis was almost abandoned completely with the discovery of H. pylori as a main causative bacteria, current evidence points toward a role of psychosocial risk factors and decreased stress resilience and increased risk for peptic ulcer in population-based studies.16
Do Location and Size Matter?
As some perforated ulcers are small as punch holes, while others are several centimeters in size, this suggest that ulcer size is not related to risk of perforation. Indeed, the majority of ulcers have a mean size of 6 mm to 8 mm. Where in the past big perforations were considered to be greater than 2 cm, the size for “big” now frequently involves perforations greater than 1 cm because of the higher risk with laparoscopic repair in those greater than 1 cm. Of interest is the thought that, even though only 2 mm to 5 mm in size, the perforation mechanism should be fairly similar to those who have 30-mm to 50-mm perforations. The moment the penetration occurs and exposes acid into the abdominal cavity is when peritonitis symptoms first occur. At least that is what is believed. However, knowledge as to why some have very large perforations while others have really small holes is largely not understood. Apparently, there must be some process that allows not only the mucosa to be injured but also digestion of muscular and stromal tissue before eruption occurs. Thus, this process must be able to happen in a very narrow area in most and in larger surfaced parts in others.
The vast majority of perforations occur on the anterior side (only a few perforate on the posterior side and are covered perforations) and usually in the distal part (stomach) or the bulbous region (duodenum). Thus, the immediate pyloric region is at highest risk, for unknown reasons. Some have eluded this risk to body position, such as sleeping position in patients, as the nocturnal acidity is highest, but no clear association has been made.17 Likely, most people would have to sleep on the belly, which is not the case.
A vascular component, with either vasoconstriction or thrombosis, may be present with smoking, and this theory is enhanced with the report of cocaine- or amphetamine-induced PPU.18,19 However, these latter drug-related causes are exceptions rather than the rule and cannot explain the vast majority of PPUs. However, the use of low-dose aspirin has been associated with a reduced expression of vascular endothelial growth factor (VEGF) and increased mucosal injury, partly explaining changes at the molecular level that may contribute to ulcerogenesis. Adding to the line of evidence here is the associated risk of perforation seen with the use of bevacizumab, an antiangiogenic drug for colorectal cancer, that inhibits VEGF.20,21 While the risk is not very large (gastrointestinal perforations occur in less than 1–2% of those with bevacizumab use), the mechanisms of VEGF inhibition or decreased expression may be a molecular mechanism that contributes to the understanding of an increased risk of perforation. The vascular component is also supported by the rare coincidence in patients with Bechet’s disease.22
Immune System Components
Several components of the immune system, including interleukins and toll-like receptors, have been investigated in relation to the risk of peptic ulcer development. The toll-like receptor 4 (TLR-4) is a part of the innate immune system and recognizes H. pylori lipopolysaccharide. One study23 investigated specific polymorphisms in TLR-4 and suggested a role for TLR-4 in gastric acid regulation and that the polymorphisms TLR-4 +896 and +1196 wild-type homozygozity increased peptic ulcer risk via gastrin secretion. However, nothing could be noted of perforation risk. Other parts of the immune system, such as interleukin polymorphisms,24,25 have been investigated in relation to H. pylori infection and ulcer risk as well, thus addressing the role of the host genetic contribution to pathogenesis. While several molecular aspects of the immune system have been investigated and associated toward the risk of ulcer, none has specifically been pointed to perforation risk. However, one study investigated the genotype of H. pylori strains and found that there was ethnic difference between Estonians and Russians living in Estonia and that patients with PPU were mainly infected with cagA (82%) and s1 (98%) genotypes of H. pylori.26
In addition, as fungal infection is fairly common in PPU,27,28 it has generally been thought of as a secondary event after perforation—often complicating the intra-abdominal infection and associated with abscesses and prolonged antibiotic therapy. However, some have discussed whether fungal infection, such as candidiasis, has a putative role in ulcerogenesis per se and may even particularly contribute to the development of perforation.29–31 Despite limited clinical causation data, experimental models in rat have examined this further. In one study of cysteamine-induced duodenal ulcer perforation in rats, the presence of Candida albicans aggravated duodenal ulcer perforation in the experimental model.32 Compared with a control group of normal saline, rats infected with C. albicans had a significantly higher rate of perforations, and colonization by C. albicans was recognized at the ulcer base, surrounded by marked granulocytic infiltration, higher eosinophil count and expression of secretory aspartyl protease. The findings suggest that proteases and host-parasite relationships, including granulocyte-dependent mechanisms, may be involved in the aggravation of ulcer perforation by C. albicans.32 The same group also demonstrated that the effect can be reversed by giving an antifungal drug.33 Again, causation has not been clinically firmly established, and because fungal infection is not found in all patients, it is most likely a modifier rather than a strong contributor. However, further investigation into potential mechanisms should be warranted.
The Way Forward
Patients with PPU represent a heterogeneous population with an outcome notoriously difficult to predict.34,35 In an era where much focus and big money are put into diseases amenable to “omics” technology in search for genetic explanation of a disease, there seems to be a void of research into “traditional” areas of the surgical disease spectrum and particularly for emergency surgery conditions.36,37 Understanding disease mechanisms is a first step in the direction toward improved care, and PPU seems to be a stepchild in peptic ulcer research based on the global disease burden and otherwise focus on “nonperforation” issues in peptic ulcer disease. It is hoped that new or revitalized research models38–40 and proper investigations may lead to novel findings of clinical relevance for patients with PPU.
K.S. planned, drafted, revised and finalized all aspect of this paper.
The author declares no conflict of interest.
1. Ng-Kamstra JS, Dare AJ, Patra J, Fu SH, Rodriguez PS, Hsiao M, Jotkar RM, Thakur JS, Sheth JK, et al. Deaths from acute abdominal conditions and geographic access to surgical care in India: a nationally representative population-based spatial analysis. Lancet
. 2015; 385(Suppl 2): S32.
2. Wang YR, Richter JE, Dempsey DT. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006. Ann Surg
. 2010; 251: 51–58.
3. Stewart B, Khanduri P, McCord C, Ohene-Yeboah M, Uranues S, Vega Rivera F, Mock C. Global disease burden of conditions requiring emergency surgery. Br J Surg
. 2014; 101: e9–e22.
4. Lau JY, Barkun A, Fan DM, Kuipers EJ, Yang YS, Chan FK. Challenges in the management of acute peptic ulcer bleeding. Lancet
. 2013; 381: 2033–2043.
5. Søreide K, Thorsen K, Harrison EM, Bingener J, Møller MH, Ohene-Yeboah M, Søreide JA. Perforated peptic ulcer. Lancet
. 2015; 386: 1288–1298.
6. Søreide K, Alderson D, Bergenfelz A, Beynon J, Connor S, Deckelbaum DL, Dejong CH, Earnshaw JJ, Kyamanywa P, Perez RO, et al. Strategies to improve clinical research in surgery through international collaboration. Lancet
. 2013; 382: 1140–1151.
7. Kumar A, Muir MT, Cohn SM, Salhanick MA, Lankford DB, Katabathina VS. The etiology of pneumoperitoneum in the 21st century. J Trauma Acute Care Surg
. 2012; 73: 542–548.
8. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet
. 2009; 374: 1449–1461.
9. Gisbert JP, Calvet X. Review article: Helicobacter pylori
–negative duodenal ulcer disease. Aliment Pharmacol Ther
. 2009; 30: 791–815.
10. Poitras P, Gingras MH, Rehfeld JF. The Zollinger-Ellison syndrome: dangers and consequences of interrupting antisecretory treatment. Clin Gastroenterol Hepatol
. 2012; 10: 199–202.
11. Lau JY, Sung J, Hill C, Henderson C, Howden CW, Metz DC. Systematic review of the epidemiology of complicated peptic ulcer disease: incidence, recurrence, risk factors and mortality. Digestion
. 2011; 84: 102–113.
12. Thorsen K, Søreide JA, Kvaløy JT, Glomsaker T, Søreide K. Epidemiology of perforated peptic ulcer: age- and gender-adjusted analysis of incidence and mortality. World J Gastroenterol
. 2013; 19: 347–354.
13. Ishikawa S, Inaba T, Mizuno M, Miyake Y, Okada H, Ishikawa H, Hori K, Wato M, Kawai K, Yamamoto K. Characteristics of serious complicated gastroduodenal ulcers in Japan. Hepatogastroenterology
. 2012; 59: 147–154.
14. Wysocki A, Budzynski P, Kulawik J, Drozdz W. Changes in the localization of perforated peptic ulcer and its relation to gender and age of the patients throughout the last 45 years. World J Surg
. 2011; 35: 811–816.
15. De Falco M, Lucariello A, Iaquinto S, Esposito V, Guerra G, De Luca A. Molecular mechanisms of Helicobacter pylori
pathogenesis. J Cell Physiol
. 2015; 230: 1702–1707.
16. Melinder C, Udumyan R, Hiyoshi A, Brummer RJ, Montgomery S. Decreased stress resilience in young men significantly increases the risk of subsequent peptic ulcer disease—a prospective study of 233 093 men in Sweden. Aliment Pharmacol Ther
. 2015; 41: 1005–1015.
17. Pinck RL, Held BT. Giant ulcers or walled-off perforations of the duodenum. N Engl J Med
. 1961; 264: 541–543.
18. Schuster KM, Feuer WJ, Barquist ES. Outcomes of cocaine-induced gastric perforations repaired with an omental patch. J Gastrointest Surg
. 2007; 11: 1560–1563.
19. Jones HG, Hopkins L, Clayton A, McKain E. A perforated duodenal ulcer presenting as inferior lead ST elevation following amphetamine use. Ann R Coll Surg Engl
. 2012; 94: e144–e145.
20. Tol J, Cats A, Mol L, Koopman M, Bos MM, van der Hoeven JJ, Antonini NF, van Krieken JH, Punt CJ. Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation. Invest New Drugs
. 2008; 26: 393–397.
21. Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol
. 2007; 14: 1860–1869.
22. Honne K, Kohsaka H, Kaneko H, Komano Y, Nakanishi S, Kitagawa M, Miyasaka N. A case of Behçet’s disease with widespread perforating enteric ulcers preceded by a long history of peripheral gangrene. Mod Rheumatol
. 2011; 21: 651–654.
23. Pohjanen VM, Koivurova OP, Huhta H, Helminen O, Makinen JM, Karhukorpi JM, Joensuu T, Koistinen PO, Valtonen JM, Niemela SE, et al. Toll-like receptor 4 wild type homozygozity of polymorphisms +896 and +1196 is associated with high gastrin serum levels and peptic ulcer risk. PLoS One
. 2015; 10: e0131553.
24. Guerra JB, Rocha GA, Rocha AM, de Castro Mendes CM, Saraiva IE, de Oliveira CA, Queiroz DM. IL-1 gene cluster and TNFA-307 polymorphisms in the risk of perforated duodenal ulcer. Gut
. 2006; 55: 132–133.
25. Datta De D, Roychoudhury S. To be or not to be: the host genetic factor and beyond in Helicobacter pylori
mediated gastro-duodenal diseases. World J Gastroenterol
. 2015; 21: 2883–2895.
26. Sillakivi T, Aro H, Ustav M, Peetsalu M, Peetsalu A, Mikelsaar M. Diversity of Helicobacter pylori
genotypes among Estonian and Russian patients with perforated peptic ulcer, living in Southern Estonia. FEMS Microbiol Lett
. 2001; 195: 29–33.
27. Shan YS, Hsu HP, Hsieh YH, et al. Significance of intraoperative peritoneal culture of fungus in perforated peptic ulcer. Br J Surg
. 2003; 90: 1215–1219.
28. Lee SC, Fung CP, Chen HY, Sy ED, Lee JC, Lin PW. Candida peritonitis due to peptic ulcer perforation: incidence rate, risk factors, prognosis and susceptibility to fluconazole and amphotericin B. Diagn Microbiol Infect Dis
. 2002; 44: 23–27.
29. Cascio A, Bartolotta M, Venneri A, Musolino C, Iaria C, Delfino D, Navarra G. A case of Candida krusei
peritonitis secondary to duodenal perforation due to Candida duodenitis
. 2011; 171: 51–55.
30. Ukekwe FI, Nwajiobi C, Agbo MO, Ebede SO, Eni AO. Candidiasis, a rare cause of gastric perforation: a case report and review of literature. Ann Med Health Sci Res
. 2015; 5: 314–316.
31. Enani MA, Alharthi BN, Dewanjee N, Bhat NA, Fagih M. Spontaneous gastric ulcer perforation and acute spleen infarction caused by invasive gastric and splenic mucormycosis. J Glob Infect Dis
. 2014; 6: 122–124.
32. Nakamura T, Yoshida M, Ishikawa H, Kameyama K, Wakabayashi G, Otani Y, Shimazu M, Tanabe M, Kawachi S, Kumai K, et al. Candida albicans
aggravates duodenal ulcer perforation induced by administration of cysteamine in rats. J Gastroenterol Hepatol
. 2007; 22: 749–756.
33. Nakamura T, Yoshida M, Kitagawa Y, Jin L, Ishikawa H, Kameyama K, Wakabayashi G, Tanabe M, Kawachi S, Shinoda M, et al. Intravenous injection of micafungin counteracts Candida albicans
–induced aggravation of duodenal ulcers caused by cysteamine in rats. Dig Dis Sci
. 2008; 53: 2422–2428.
34. Søreide K, Thorsen K, Søreide JA. Predicting outcomes in patients with perforated gastroduodenal ulcers: artificial neural network modelling indicates a highly complex disease. Eur J Trauma Emerg Surg
. 2015; 41: 91–98.
35. Thorsen K, Søreide JA, Søreide K. What is the best predictor of mortality in perforated peptic ulcer disease? A population-based, multivariable regression analysis including three clinical scoring systems. J Gastrointest Surg
. 2014; 18: 1261–1268.
36. Bergenfelz A, Søreide K. Improving outcomes in emergency surgery. Br J Surg
. 2014; 101: e1–e2.
37. Søreide K. The research conundrum of acute appendicitis. Br J Surg
. 2015; 102: 1151–1152.
38. Okabe S, Roth JL, Pfeiffer CJ. A method for experimental, penetrating gastric and duodenal ulcers in rats. Observations on normal healing. Am J Dig Dis
. 1971; 16: 277–284.
39. Kristt DA, Freimark SJ. Histopathology and pathogenesis of behaviorally induced gastric lesions in rats. Am J Pathol
. 1973; 73: 411–424.
40. Selye H, Szabo S. Experimental model for production of perforating duodenal ulcers by cysteamine in the rat. Nature
. 1973; 244: 458–459.