Since the discovery of Helicobacter pylori (H. pylori) infection in the stomach, the bacteria infection and non-steroidal anti-inflammatory drugs (NSAIDs) use had been considered to be the 2 main causes of peptic ulcers. However, there have been recent reports of an increase in the proportion of peptic ulcers without these known risk factors; these are termed idiopathic peptic ulcers. Such trend was firstly indicated in 1990s from some reports in North America. In Asia, numerous studies reported that idiopathic ulcers accounted for a small percentage of all ulcers in the 1990s, but in the 2000s, multiple studies reported that the proportion of idiopathic ulcers had reached 10%-30%, indicating that the incidence of idiopathic ulcers in Asia has also been rising in recent years. While a decline in H. pylori infection rates of general population in Asia is seen as the main reason for the increased incidence of idiopathic ulcers, it is also possible that the absolute number of idiopathic ulcer cases has increased. Advanced age, serious systemic complication, and psychological stress are considered to be the potential risk factors for idiopathic ulcers. Management of idiopathic ulcers is challenging, at present, because there is no effective preventative measure against recurrence in contrast with cases of H. pylori-positive ulcers and NSAIDs-induced ulcers. As it is expected that H. pylori infection rates in Asia will decline further in the future, measures to treat idiopathic ulcers will also likely become more important.

After Helicobacter pylori (H. pylori) was discovered in 1982, it was considered to be the cause of a large number of peptic ulcers (90%-95% of duodenal and 70%-90% of gastric ulcers)[1]. H. pylori, aspirin, and other non-steroidal anti-inflammatory drugs (NSAIDs) comprise the causes of a large proportion of peptic ulcers. A subsequent rise in global NSAID use and a relative increase in the proportion of NSAID-caused ulcers[2,3] led to wide acceptance that H. pylori infection and NSAID use are the 2 main causes of peptic ulcers[4]. Other causes include Zollinger-Ellison syndrome, Crohn’s disease, and viral infections such as cytomegalovirus and herpes.

However, there have been recent reports of an increase in the proportion of peptic ulcers without these known risk factors; these are termed idiopathic peptic ulcers. By the 1990s, several studies reported that idiopathic ulcers comprised 20%-40% of all peptic ulcers in North America[5-7]. In this region, 20% of H. pylori-positive ulcers recurred after bacterial elimination[8], a markedly higher percentage than that reported in other areas. This finding indicated that a large number of “bystander” cases existed, wherein a patient is positive for H. pylori but the bacteria are not directly involved in causing the ulcer. In the 2000s, increases in the proportion of idiopathic ulcers were also reported in Europe and Asia (Table 1). However, a few studies still report low idiopathic ulcer proportions (4%), including a recent report from Italy[6].

Detailed reviews of idiopathic ulcers were published in 2002[37] and 2008[38]. Here, we examine more recent trends in the incidence of idiopathic ulcers, particularly in Asia.

When diagnosing idiopathic ulcers, H. pylori infection and history of NSAID use, the 2 main causes of peptic ulcers, must be completely ruled out. Otherwise, one will naturally find a high proportion of idiopathic ulcers.

Various methods are used to diagnose H. pylori infection, none of which is 100% accurate alone. Thus, the absence of H. pylori can be determined only when several tests are combined and the results of all are found to be negative[38]. Diagnostic methods that use endoscopic biopsy specimens-histology, culture, and rapid urease tests (RUT)-can show false negatives due to sampling errors caused by non-uniform distribution of H. pylori inside the stomach[39]. Therefore, biopsies must be obtained from several locations. Further, these methods can show false negatives immediately after acute upper digestive tract hemorrhage[40]. In these situations, other diagnostic methods must be used in combination. The urea breath test (UBT) examines urease activity throughout the stomach due to H. pylori, and is used to compensate for sampling errors in tests using biopsy specimens. However, care is needed when using UBT, as false negatives can result when bacterial concentrations decrease during administration of proton pump inhibitors (PPIs)[41], similar to other tests using biopsies. The serum antibody method is not affected by PPI administration or acute upper digestive tract hemorrhage; therefore, it is useful for diagnosing H. pylori infection in these situations. However, this method continues to show positive results for some time after bacterial elimination[42], making it difficult to differentiate between current and past infections. Nevertheless, it is a useful test because it provides a precise diagnosis of idiopathic ulcer (as few false negatives as possible). There are several tests for even more precise diagnosis of H. pylori-negative patients; although these tests do not directly confirm the presence of H. pylori, they eliminate the diagnosis of idiopathic ulcer based on tissue findings associated with infection, such as neutrophil infiltration into the gastric mucosa or atrophy of the gastric mucosa[28,30].

Another important factor in diagnosing idiopathic ulcers is careful elimination of NSAID users. Aspirin and other NSAIDs can be purchased without a doctor’s prescription in many countries. A large number of surreptitious NSAID users likely exist; therefore, patients must be questioned scrupulously about their drug history. Indeed, several previous studies have clarified the existence of surreptitious NSAIDs users. Lanas et al[43] examined patients with gastrointestinal perforation using platelet cyclooxygenase activity in the blood as an objective marker of aspirin usage. They identified 13% more aspirin users with this method than were found through investigation of medical history. Moreover, based on measurements of blood salicylic acid concentrations, Hirschowitz et al[44] reported that 50% of intractable peptic ulcer patients who denied using aspirin were in fact aspirin users. These findings underscore the necessity of carefully eliminating NSAID users when diagnosing idiopathic ulcers. Retrospective studies, which can only determine NSAID usage from past medical records, would be inevitably too lenient in eliminating NSAID users. The result would be a tendency to report higher rates of idiopathic ulcers; therefore, care must be taken when interpreting such data.

Six reports of the proportion of idiopathic ulcers in Asia were published in 1999-2003 based on patient data from the 1990s[19-24], 5 of which reported low rates of 1.3%-4.1%[19-23]. In 9 studies from 2005-2006 based on patient data from the 2000s[28-36], almost all reported that the proportion of idiopathic ulcers was 10%-30%, indicating that the proportion of these ulcers among all peptic ulcers in Asia is increasing. A decline in H. pylori infection rates among background healthy individuals is likely a cause of this increase. This trend is common among Asian countries[45], and indicates that recent improvements in sanitation and the increased use of H. pylori elimination therapies have decreased the H. pylori infection rates in the region. Even if the increase in idiopathic ulcers is merely a relative rise accompanying a decline in H. pylori-positive ulcers, or if H. pylori has only been coexisting as a bystander in many cases, the decline in H. pylori infection rates among the overall population has given prominence to the issue of idiopathic ulcers. Further, it has been reported that not only the proportion of idiopathic ulcers has increased but also the actual number of cases has been increasing annually[28]. This trend suggests the existence of not just a relative cause but also some other direct factor that is contributing to the incidence of idiopathic ulcers. Next, we will examine the incidence of idiopathic ulcers in various Asian countries in detail.

Although a clear cause of idiopathic ulcers hasn’t yet to be shown, several factors related to the condition have been proposed.

Psychological stress

A link between psychological stress and peptic ulcers has long been suggested[65], but once H. pylori infection and damage from NSAID use were identified as the 2 main causes of peptic ulcers, it became unclear whether psychological stress should be considered an independent cause of peptic ulcer[4,21]. However, there have been reports of ulcer formation in the victims of the Great East Japan Earthquake that struck in 2011[67,68]. Kanno et al[67] compared the ulcer incidence 3 mo after the disaster with the ulcer incidence in the same period during the previous year; they found a 1.5-fold rise in ulcer cases after the disaster. Further, the proportion of H. pylori- and NSAID-negative (that is, idiopathic) ulcers rose significantly from 13% in 2010 to 24% after the disaster in 2011 (Figure 1)[67]. This study excluded cases complicated by severe trauma due to the disaster, showing indirectly that psychological stress can be an independent cause of peptic ulcers among disaster victims. Interestingly, the H. pylori-, NSAID-negative ulcers that arose after the disaster were in patients who were significantly older than those with other ulcer types[67]; this finding is consistent with the characteristic of idiopathic ulcers described above.

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Figure 1 Changing pattern of the etiology of peptic ulcers before (2010) and after (2011) the Great East Japan earthquake. In the analysis of etiologic factors of the ulcers, cases from each year were classified into four groups according to the Helicobacter pylori (H. pylori) status and non-steroidal anti-inflammatory drugs (NSAIDs) intake. The proportion of H. pylori-negative non-NSAIDs takers among PU patients after the earthquake (2011) was significantly higher than in the previous year (13% in 2010 vs 24% in 2011, P < 0.05). The date available from reference[67].

Bacterial elimination therapy is often effective for preventing the recurrence of H. pylori-positive ulcers and does not require subsequent maintenance therapy with acid-suppressive agents[4]. In NSAID-induced ulcers, changing therapy to COX-2-selective NSAIDs or other alternative medications that do not cause as much damage to the gastrointestinal mucosa can be expected to suppress recurrences[4]. However, for idiopathic ulcers, although acid-suppressive agents can produce temporary relief, they are not an effective preventative measure against recurrence. It has been shown that recurrence rates are high when patients remain unmedicated after such temporary cures. A study from Denmark observed 32 unmedicated patients with H. pylori-negative duodenal ulcers for 2 years, and reported a 35% recurrence rate[12]. Additionally, a prospective study from Hong Kong that observed unmedicated patients with idiopathic, hemorrhagic gastroduodenal ulcers for 7 years found that 42% experienced a relapse of ulcer hemorrhage. This is 4 times the percentage found while observing patients with H. pylori-positive ulcers who were unmedicated after bacterial elimination[69]. Further, a recent report from South Korea found that compared to H. pylori-positive ulcers and NSAID-induced ulcers, idiopathic ulcers showed more recurrences, which led to increased medical costs[36].

Although it has been shown that recurrences can easily occur when patients with idiopathic ulcer are not treated, there is no consensus on whether maintenance therapy with acid-suppressive agents can effectively prevent these recurrences. In the aforementioned study from Denmark, PPI administration was found to have an effect on preventing the recurrence of H. pylori-negative duodenal ulcers[12]. However, a recent major follow-up study from Hong Kong that examined 663 patients with idiopathic hemorrhagic gastroduodenal ulcers did not find H₂-blocker or PPI administration to be effective in preventing ulcer hemorrhage relapse[35]. Around 50% of the cases in the Hong Kong study were gastric ulcers[35], and it was found that gastric ulcers, even idiopathic cases, might show different reactivity to acid-suppressive agents than duodenal ulcers. Until it is determined which medications can effectively prevent the recurrence of idiopathic ulcers, the most realistic choice appears to be continuous PPI therapy.

Numerous studies reported that idiopathic ulcers in Asia accounted for a small percentage of all ulcers in the 1990s, but in the 2000s, multiple studies reported that the proportion of idiopathic ulcers had reached 10%-30%. Despite limitations such as difficulties in precise diagnosis of H. pylori infection and identification of surreptitious NSAID users, it is clear that the incidence of idiopathic ulcers in Asia has been rising in recent years. While a decline in H. pylori infection rates in Asia is seen as the main reason for the increased incidence of idiopathic ulcers, it is also possible that the absolute number of idiopathic ulcer cases has increased. As it is expected that H. pylori infection rates in Asia will decline further in the future, measures to treat idiopathic ulcers will also likely become more important. Further multicenter studies from many different countries, with the same protocol, are necessary to investigate the real incidence of idiopathic ulcers and the real causes.