Inflammatory bowel disease

Over the past few decades, inflammatory bowel disease (IBD) has become increasingly recognized in diverse populations around the world. The prevalence and incidence rates of IBD have historically been higher in developed countries, with a decreasing prevalence from north to south latitudes. These demographics have started to change recently as a significant portion of underdeveloped countries have begun to modernize. The increase in incidence and prevalence of IBD has paralleled the social and economic development and adoption of the Western lifestyle.

The incidence of ulcerative colitis (UC) has been increasing in developed countries since World War II; however, over the past few decades studies have suggested that it may be starting to plateau or even decrease. The highest prevalence rates of IBD worldwide have been documented in the Israeli Jewish population. In a recent study that surveyed physicians in Israel, the prevalence of Crohn disease (CD) was found to be 113 per 100,000, and the prevalence of UC in the same population was noted to be 216.6 per 100,000. The United States and the northern and western countries of Europe have also traditionally documented high prevalence rates of IBD, especially when compared with southern European countries. A study conducted in Northern California found the point prevalence per 100,000 of CD and UC to be 96.3 and 155.8, respectively. Similar rates have been documented in western Europe. A study that prospectively identified patients who were newly diagnosed with IBD in 20 European centers between 1991 and 1993 showed that the incidence rates for UC and CD were 40% and 80% higher in the northern centers than in the southern centers. This previously described north to south gradient of IBD seems to be changing over the past few decades, as shown in more recent studies performed in European populations. Recent studies suggest that Europe has seen a stabilization of IBD incidence rates in northern and western countries with a corresponding increase in incidence rates of southern and eastern countries. A prospective study published in 2005 reported the incidence of UC in central Greece to be 11.2 per 100,000. This finding suggests an increase in the incidence of IBD in this previously low-incidence area of the world. A similar increase was documented in the Croatian population in a recent prospective study. The incidence rates for UC and CD were found to be 4.3 and 7 per 100,000, respectively, in this study performed from 2000 to 2004, suggesting a threefold increase in the incidence of UC and a tenfold increase in the incidence of CD in Croatia over the past 24 years.

Similarly, studies indicate that previous low-incidence areas of eastern Europe, Asia, and Central and South America have demonstrated a recent increase in the incidence and prevalence of IBD. One of the first studies on the prevalence and incidence of IBD in the Indian population was conducted in Punjab, India by Sood and colleagues. Almost 52,000 people were screened for signs or symptoms of UC using a questionnaire. Anyone who was suspected to have UC received further workup with a sigmoidoscopy/colonoscopy and biopsies. The incidence rate of UC in this population was determined to be 6.0 per 100,000 inhabitants with a prevalence rate of 44.3 per 100,000 inhabitants. This study was the first published to document prevalence rates of UC in this population, and it noted a surprisingly high rate in this previously “low-prevalence” country. The incidence of IBD has also been noted to increase in South Korea and Japan over the past few decades. A large population-based study was performed in South Korea over a period of 20 years between 1986 and 2005. The mean annual incidence rates of CD and UC increased significantly from 0.05 and 0.34 per 100,000 in 1986 to 1990, to 1.34 and 3.08 per 100,000 in 2001 to 2005. Studies also show that the presenting features may vary based on geography. In India, colonic involvement in CD is more common and fistulization is less common. In Pakistan, few patients with CD have perianal or fistulizing disease, and there is much less extraintestinal disease compared with what is reported in the West.

During the past few decades, there have been large migrations from the Indian subcontinent into western Europe and the United States. This unique population of immigrants and their children, or first-generation immigrants, provides an opportunity to ponder possible environmental etiologic factors that may play a role in the pathogenesis of IBD. These environmental factors may also help to explain why the incidence of IBD seems to be higher among these immigrant populations when compared with data from studies conducted in their native countries. Of interest, it seems that individuals who migrate to developed countries before adolescence, who initially belong to traditionally low-incidence populations, have a higher incidence of IBD, this being comparable with that of the developed country to which they migrated. Multiple studies report that those who move from an area of low prevalence to one of high prevalence after childhood retain a similar rate of IBD as before, but their children (first-generation immigrants) have an increased risk of IBD. Changes in diet and the changing prevalence of previously common infections are 2 proposed mechanisms that may explain the increasing incidence of IBD in not only migrant populations but also in native populations in what were previously considered “low-incidence” countries.

It has long been accepted that immune dysregulation is a large contributory factor to the onset and pathogenesis of many allergic disorders. IBD likely results from dysregulated immune responses to intestinal contents. Some common pathogens have been proposed to stimulate the normal development of regulatory immune mechanisms. Examples of such organisms include saprophytic mycobacteria, bifidobacteria, lactobacilli, and helminths. These organisms are recognized by the immune system as innocuous, and they therefore gear immune responses toward regulatory modulation. Helminths are multicellular worm parasites that infect more than 1 billion people around the world, but helminth carriage is much less frequent in westernized societies. Most helminths stimulate the production of Th2 cytokines. IBD, along with a few other immunodysregulatory disorders, is predominantly a Th1-driven disease. In addition, helminthiasis also prevents Th2-driven allergic reactions. Therefore, the ability of some helminths to induce regulatory cytokines, including interleukin-10 and transforming growth factor β, via stimulation of both regulatory T cells and regulatory type non-T cells suppresses both Th1 and Th2 arms of immunity. A combination of these factors probably accounts for the seemingly protective and possibly therapeutic role played by helminths in patients with IBD. Genetically susceptible people who are never exposed to helminths may lack a counteractive Th2 response, and this may be vital in preventing the onset of IBD.

The possibility that intestinal helminths might protect against development of IBD led to the consideration by one group in Iowa to use helminths in the treatment of IBD. These investigators chose Trichuris suis , as it is not a human parasite but the ova are capable of colonizing a human host for several weeks and then are eliminated from the body on their own without any specific therapy. A single dose of 2500 live T suis eggs was administered to a small number of patients with active CD and UC, following which a majority of subjects entered remission. The worldwide distribution of Trichuris trichiura (a human parasite) is chiefly tropical, with infection being more common in Asia, Africa, and South America than in Western nations. Within the United States, infection is rare overall, with the highest infection rate affecting the southeastern area of the country. Infection with T trichiura is associated with poor hygiene and consumption of soil or food that may have been fecally contaminated. There have been mass public health initiatives worldwide to decrease the incidence of T trichiura infections in underdeveloped countries, and this may correspond to the increase in IBD in these countries.

Changing diet in developing countries has been proposed as a risk factor for the development of IBD in certain populations, and this has been most extensively documented in South Asian populations. Almost 2 decades ago, Chuah and colleagues reported that westernization of the Indian diet may be linked to IBD. In a questionnaire study conducted in the United Kingdom, investigators found that Hindu patients with IBD were less likely to use spices and eat flour than age-matched and ethnicity-matched controls. One spice that may play an integral role is turmeric, a spice used in cooking by most South Asians. Turmeric is derived from the herb Curcuma longa , a member of the ginger family. Curcuminoids are polyphenolic compounds that give turmeric its yellow color, and curcumin is the principal curcuminoid in turmeric. Several studies have shown that curcumin has both anti-inflammatory and antioxidant properties. It has also been shown to reduce colonic inflammatory responses. A few studies to date have also studied curcumin’s therapeutic potential in patients with IBD. Investigators in a pilot study published in 2005 administered curcumin to 10 patients with either UC or CD, and reported a marked improvement of symptoms and disease activity in 9 of the 10 patients. In addition, a slightly larger randomized placebo-controlled trial from Japan reported significantly lower recurrence rates among patients with quiescent UC who were administered curcumin when compared with placebo controls. These studies suggest that curcumin, the active ingredient in the commonly known spice termed turmeric, may have significant therapeutic benefits in the treatment of IBD. However, large randomized controlled studies should be performed to better determine whether curcumin can actually play a significant role in the management of IBD.

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is classified as a functional bowel disorder, and is one of the most frequent reasons for consultation with a gastroenterologist. However, it remains an underdiagnosed entity, especially in developing societies. Assessment of the prevalence of IBS based on studies conducted over the past 20 years is difficult given the varying populations and assessment criteria used by researchers. The Manning criteria were introduced in the 1970s, which identified 4 symptoms thought to differentiate patients with IBS from those with other disorders: visible abdominal distention, pain relieved by bowel movement, more frequent stools with the onset of abdominal pain, and looser stools with the onset of pain. Investigators also found that IBS sufferers were more likely to suffer from rectal passage of mucus and sensation of incomplete evacuation. An international committee met to specify time dimensions to this symptom classification system, and this became known as the Rome criteria. Over time, this classification has been revised and currently the Rome III questionnaire is used.

The prevalence of IBS ranges from 3% to 20%, and is quoted as being between 10% and 15% in most studies conducted in the Western population. It is commonly recognized to have a high female to male ratio (2:1 in most studies), with a typical onset of symptoms before age 45 years and an increase in prevalence again in the elderly. Some studies use both the Manning and Rome criteria and report a markedly different prevalence (20.4% with Manning vs 8.5% with Rome criteria). Saito and colleagues concluded that the prevalence of IBS varied substantially depending on the specific definition of IBS used.

The global picture of IBS is far from complete, with limited data, if any, available from certain regions of the world. It is clear, however, that significant global differences in demographics and clinical presentation of IBS do exist. Based on the literature, the prevalence of IBS seems to be higher than previously thought in Asian countries. By Rome II criteria, the prevalence of IBS in places like Singapore and Japan are 8.6% and 9.8%, respectively, which is comparable to Europe (9.6%), though not as high as in the Unites States, Canada, and England (12%). Interpretation of some of these data is problematic, due to the use of varying diagnostic criteria already mentioned, with many studies reporting varying prevalence rates based on different diagnostic criteria. The largest and most recent study in Japan, which surveyed 10,000 subjects, estimated the prevalence of IBS to be 13% by Rome III criteria. This figure represents a notable increase compared with the prevalence of IBS based on Rome II criteria of 6.1%, which was reported 4 years earlier. South Asian prevalence rates are slightly lower when compared with data available on other Asian countries. A prospective national study conducted in India recently estimated the prevalence of IBS in India to be 4.2%. However, this study did not use the standard Rome II or III criteria in its assessment. In a population-based survey from Pakistan, 13% of subjects met Rome II criteria for IBS. It is unclear whether these seemingly rising prevalence rates in recent studies from Asia reflect a true increase in prevalence, or whether IBS is now becoming more easily recognized and diagnosed in these countries.

Although IBS is more prevalent among women in Western societies, this trend has not proved to be true in other countries. For example, a recent large population-based study from Mumbai, India reported a significant male predominance. Another study conducted in Hong Kong, a telephone survey that used the Rome II diagnostic criteria, revealed there was no significant difference between men and women regarding prevalence of IBS. In one of the most recent and largest studies from India, investigators again reported a higher prevalence of IBS in men (4.3% vs 4.0%). However, the diagnostic criteria used to classify patients as having IBS were less well defined. These statistics do not hold true for a majority of studies published in Asian countries, however. Several studies from other Asian countries did not report a male predominance, but rather no significant difference in prevalence between genders. Similar to much of the Western data, a Japanese study published in 2008 documented a predominant female to male ratio (16% vs 10%) that was statistically significant. Although apparent differences in gender distribution may arise from the use of varying diagnostic criteria, one must ponder why there seems to be such a lack of female predominance in most Asian IBS studies while data from the West suggest that IBS has consistently been more common among women. Are these true gender differences, or are these data a manifestation of cultural factors that make it easier for men to seek medical care? And if cultural factors in these male-dominated societies are not influencing the apparent gender disparity, are there other factors that may make men in these cultures more prone to developing IBS?

There also appear to be differences in socioeconomic status and clinical presentation between Asians and westerners with IBS. Asian patients with IBS tend to come from more affluent classes of their society and are better educated when compared with patients without IBS. By contrast, data from the Unites States reveal that patients with functional bowel disorders are more likely to belong to a lower household income group. Studies reveal that location of abdominal pain is also a factor that seems to vary between Asian and non-Asian IBS patients. Lower abdominal pain is more frequently reported in Western studies, whereas Asian patients are much more likely to present with upper abdominal pain. Clinical overlap between functional dyspepsia and IBS is more common in certain Asian countries. This overlap may result in an underestimation of IBS prevalence in some studies, especially if patients are being classified as having dyspepsia rather than a combination of dyspepsia and IBS. Overall, pain seems to play a bigger role than bowel function in disease perception in Asian societies. What may be perceived as normal in certain Asian populations may really be “abnormal” based on standard Western criteria. For example, a national Indian study found there was a wide mismatch between patient perception of constipation and diarrhea and physicians’ rating based on standard Western diagnostic criteria. A majority of their control population admitted to having bowel movements once or twice a day. On average, this is significantly higher than what is deemed as normal according to Western criteria whereby 3 or more movements per week is considered normal. Similarly, in a study conducted in Singapore, when subjects were asked to describe their bowel habits over the preceding 3 months, a majority of those who met diagnostic criteria for IBS believed they had normal bowel habits. Even if the defecatory disturbances were relatively mild in subjects who participated in these two studies, their data suggest that IBS may be missed in certain populations where the threshold for perception of altered bowel habits is higher.