Inflammatory bowel disease (IBD) encompasses two chronic inflammatory disease entities - ulcerative colitis (UC) and Crohn's disease (CD). The diagnosis is essentially based on classical symptomatology, endoscopy and radiological and histological findings12. In 10-15 per cent of cases, it is difficult to distinguish between the two and referred to as unclassified IBD and when diagnosis is not possible even in a resected bowel specimen, this is referred to as indeterminate colitis12.
IBD causes significant burden to the healthcare set up of the country as both UC and CD require long-term treatment and constant monitoring. In this review, focus is placed on the changing trends of IBD in the Indian subcontinent, risk attribution and the financial teething issues in the management of this morbid entity.
Changing epidemiological trends of inflammatory bowel disease (IBD)
IBD in migrants
IBD is a major health problem around the world. Earlier, it was reported in high proportions from northern and western Europe, North America and Australia34, however, it now has a considerably wider geographic distribution, with an increasing prevalence even in countries that were initially considered as low-risk areas. In addition, there is an increase in IBD burden amongst children and adults in developing nations56. Migrant studies in the early 1990s among South Asians residing in Leicestershire, UK, showed that the standardized incidence of UC in South Asian migrants was significantly high (10.8/100,000 vs. 5.3/100,000 among locals), with the highest incidence amongst Sikhs (16.5/100,000) followed by Hindus (10.8/100,000)7. The same group also reported that the incidence of CD increased over time in both Europeans as well as South Asians, but was significantly low amongst South Asians8. Another single-centre study from England made similar observation of a high frequency of IBD amongst South Asian migrants to the UK9. Subsequently, an increased risk of IBD has been reported in the first- and second-generation South Asian migrants in the UK and Canada, suggesting the influence of environmental factors on the development of IBD101112. The migrant study from Canada13 in 2015 found a significantly lower incidence of 7.3/100,000 amongst migrants compared to the indigenous population (23.9/100,000). However, the incidence of IBD amongst the children of these immigrants approached that of non-immigrants. A systematic review in 2012 confirmed an increased incidence of IBD amongst migrants from Asia to the West14. Population-based studies in the Middle East (Kuwait and Saudi Arabia) reported an increase in the prevalence of IBD, especially amongst children151617.
IBD in South Asians: Epidemiological studies from China, Hong Kong, Japan, Korea, Malaysia, Singapore, Thailand, India and Sri Lanka have shown UC to be more prevalent than CD14. However, a trend towards an increasing incidence of CD was observed14. Gender wise, CD is frequent amongst men with no gender difference for UC. Extraintestinal manifestations of IBD are uncommon in Asians14.
IBD in India: Regional differences in UC and CD have been reported from India. The first prevalence figure of 42.8/100,000 patients for UC from Haryana was reported in 1986 by Khosla et al18. Subsequently, Sood et al19, in 2003, reported a similar prevalence of 44.3/100,000 while screening 51,910 people from Punjab. Both these population-based studies are, however, from select North Indian population and do not in any way represent the true burden of IBD in the Indian subcontinent. But these figures are only one-third to one-sixth of the population-based studies from Canada, North America or the UK202122. In a national survey from India in 201223, UC was equally prevalent in the northern and southern States of the country.
Although, population-based studies for CD are lacking from India, a multicentric hospital-based study24 from the northern and eastern States of the Indian subcontinent reported a fourfold increase in referrals for CD from the late 1990s onwards and also a higher frequency from the southern States of India23.
Overall, hospital-based studies in the recent past have reported an increasing number of IBD cases25. This may be the result of increasing awareness amongst physicians, improved diagnostic techniques and enhanced access to specialized healthcare systems.
Risk attributions to IBD: Urbanization together with changes in dietary pattern i.e., westernization of Indian diet, an improvement in hygienic and environmental conditions and the underlying genetic predisposition, are likely factors responsible for an increase in IBD burden2627.
The results of various genetic studies from India are summarised in the Table. Transethnic studies from India, East Asian and Iranian populations in Asia40, have shown a significant genetic heterogeneity. The nucleotide oligomerization domain (NOD2) variants described in Caucasians are not seen amongst Indians41, but have been reported amongst Malaysians42.
Environmental factors in IBD
Smoking is a factor which is consistently associated with IBD in the West, increasing the risk of CD but reducing the risk of UC434445. However, this is contrary to the trend seen among Asians where despite higher smoking prevalence (65%) among men, the incidence of CD is low46. Some predisposing factors to IBD include food rich in animal protein47, fats, sugar, meat48 and excess tea and coffee49 particularly in the West, whereas high-fibre fruits and vegetables50 are thought to decrease the risk to IBD51. In a case–control, population-based study (ACCESS), 12 months of breastfeeding had a marked protective effect against IBD52.
Rural dwelling, higher education, professionals, an annual income of 100,000 or more, history of appendectomy and family history of IBD are some observed risk factors for IBD in the Indian setting50.
Gut microbiome and IBD
The gut microbiome and influence of antibiotics on the gut flora have been extensively deliberated in IBD. Studies from North India have shown microbiome signature in the Indian IBD population to be similar to that in the West5354. Butyrate-producing bacteria such as Clostridium coccides and C. leptum were found to be significantly decreased in UC5455, with an increase in anaerobes and facultative aerobes (Proteobacteria), in severe UC56. There is a heightened mucosal adherence of Escherichia coli in colonic CD57. Organisms such as cytomegalovirus58, C. difficile5960, Giardia, Strongyloides, hookworm, herpes simplex, Entamoeba histolytica, Cryptosporidium and Salmonella5861 were also found to be associated with an exacerbation of UC. A recent Asian study reported that the use of antibiotics decreased the odds for development of both, UC and CD49.
Indian data regarding the effect of improving hygiene standards on the prevalence of IBD have been conflicting. A study of 200 CD patients from Vellore, India, showed that regular fish consumption and rearing cattle had a protective association with CD, whereas safe drinking water was associated with greater risk for CD62. A study from North India showed that better toilet facilities and use of a separate beds in a household were protective, whereas owning a pet and stressful life events were found to be potential risk factors for UC63.
Demographic profile and clinical presentation
Age: IBD in the West has a bimodal presentation with peaks at 20-39 and 60-79 yr64. The median age at the diagnosis of CD is a decade earlier than that of UC. The age distribution in India is similar to that of other Asian countries65. With the mean age at the time of diagnosis of UC and CD being closer to 40 yr66, with no bimodal distribution2324. In a multicentric study from Kerala, in adults, CD occurred at a younger age compared to UC, whereas this was reversed in children25.
Gender: Data from the West indicate a female preponderance, more so in CD than UC2267, however, most studies from India have shown a male preponderance for both UC and CD232467. However, a study from Central India showed no significant gender difference68. The higher prevalence in men has been ascribed to a large migration of male folks from villages to cities and more frequent visits to the hospital vis-a-vis lower attendance by women due to social inhibitions and genetic susceptibility.
Family history: The Indian IBD experience reportedly includes a positive family history2369, which is significantly lower than that reported from the West (10%-25%)70.
Disease location: The extent of disease in 714 patients from the Indian subcontinent with UC was pancolitis in 306 (42.8%) patients, left-sided colitis in 277 (38.8%) and proctitis in 131 (18.3%) patients23. In a study from Central India, left-sided colitis was more common than pancolitis68 similar to other Asian countries and the West65.
A multicentric study on 182 patients from three centres and the IBD national survey observed near-similar disease location for CD2324. In CD, the disease location was L1 (terminal ileal) in 32 and 29 per cent, L2 (colon) in 41 and 31 per cent, L3 (ileocolonic) in 23 and 40 per cent and L4 (proximal small intestinal) in 4 and 6 per cent in these two studies2324. Seventeen per cent of patients in the multicentric study had perianal disease23. Other studies from Mumbai (178 patients)71 and Vellore (200 patients)62 had similar disease locations. Uniformly, L3 appeared to be the most prevalent in the Indian subcontinent.
Disease behaviour: IBD in India is of milder phenotype compared to the West. One-third of the patients have a chronic active course; one-half, a relapsing remitting course; and four per cent require surgery. In a single-centre study from North India, out of 161 UC cases, 44 and 66 per cent were in complete remission at 1 and 3 yr, respectively. Less than 10 per cent (6.2%) required surgery in the following three years72.
The large variations may be secondary to a referral bias or genetic variations among the populations. Most patients (76%) had an inflammatory phenotype23. A retrospective study from Mumbai noted an aggressive progression of IBD in 20 per cent over a 10 yr follow up71 ; the temporal progression was, however, relatively slow compared to the West.
In a questionnaire based study from India23, the prevalence of extraintestinal manifestation (EIM) was similar to that reported from the West; 38 per cent had at least one, whereas 20 per cent had multiple EIMs. The most frequent EIM was peripheral arthritis in 33 per cent followed by ankylosing spondylitis in 18 per cent and ocular symptoms in 13 per cent. Mucocutaneous manifestations, aphthous stomatitis and pyoderma gangrenosum constituted nine per cent. These aforesaid figures may not reflect the true prevalence as no specific radiological or biochemical investigations were done to confirm the diagnosis. Female gender, Hinduism, severe disease and use of steroids were significantly associated with EIMs73. In a study from North India, the overall prevalence of any EIM and multiple EIMs in UC and CD was 33.2 per cent versus 38.3 per cent and 6.9 per cent versus 4.7 per cent, respectively74. In a large cohort from Kerala, EIMs occurred in 28 per cent cases with CD and 18 per cent cases with UC25. Primary sclerosing cholangitis was less frequent amongst Indians, and this may be due to the overall low prevalence of autoimmune liver disease in India7576.
Colorectal cancer: Earlier hospital-based studies from India found low risk of colorectal cancer (CRC) among Indian patients7778, however, studies from Mumbai79 and New Delhi80 observed that the risk rates of CRC were similar to that of the West81. The incidence density of IBD in Mumbai79 was 3/1000 in the first 10 yr, 3.3/1000 at 10-20 yr and 7/1000 at >20 yr, with an overall prevalence of 2.8 per cent. Similarly, Bopanna et al80 quoted an annual incidence of 0.3 per cent, with an overall prevalence of 1.9 per cent, and the cumulative probability of developing cancer was reported to be 1.5, 7.2 and 23.6 per cent in the first, second and third decades, respectively.
Treatment options in IBD: In a nationwide IBD survey, approximately two-thirds of all UC patients received steroids, a third were on azathioprine (30%) and less than one per cent received biologicals23. The infrequent use of biologicals in Indians may be a reflection of either a less severe disease or economic constraints. The overall colectomy rate in South Asian and Indian patients is relatively low compared to the West1472.
5-ASA (64%), steroids (69%) and azathioprine (63%) were the preferred medications and biologics in 2 per cent of all CD patients23. Two other studies reported use of biologicals in 37 per cent24 to 55 per cent71 respectively.
Impact of tuberculosis in the diagnosis and management of Crohn's disease (CD): Differentiation between CD and intestinal tuberculosis (TB) is important considering the risk of reactivation of latent TB, especially while initiating biologicals in severe IBD.
Despite advances in diagnostic procedures, differentiating CD and intestinal TB remains a major issue in India. Both the diseases often occur in the fourth decade and present with similar clinical features2482. Systemic symptoms such as fever, anorexia and shorter duration of symptoms (less than one year) are frequent presentations of TB24. CD patients have longer duration of symptoms. Diarrhoea, bleeding per rectum, anaemia and EIMs are more frequent in CD patients666883.
Diagnostic tools such as erythrocyte sedimentation rate (ESR)66 and Anti-Saccharomyces cerevisiae antibodies (ASCA)6684 are not always helpful in distinguishing CD from TB. ASCA has a good specificity in distinguishing CD from TB and helps in diagnosing small bowel involvement in CD55. The role of quantiferon TB gold remains controversial in the Indian setting85. At best, Mantoux and quantiferon TB gold provide supportive evidence but are not definitive for TB. Gene Xpert test is highly specific for TB, but has low sensitivity.
On computed tomography or magnetic resonance enterography, presence of lymph nodes greater than 1 cm in size with central necrosis favours a diagnosis of TB. On the other hand, the presence of skip lesions (>3), long-segment involvement (>3 cm), comb sign, fibro-fatty proliferation, left colonic involvement and asymmetric thickening favour CD86. Studies have highlighted the role of visceral fat quantification as a useful marker in the differential diagnosis of CD and TB87.
On endoscopy, involvement of the left side of the colon, involvement of multiple segments of the intestine, presence of longitudinal ulcers, isolated ileal involvement, apthous ulcers, perianal disease, long segment strictures and cobblestoning of the mucosa favour a diagnosis of CD8889.
Demonstration of acid-fast bacilli on histology or on culture is diagnostic of TB but is rarely documented85. Granulomas in TB and CD are distinctive9091. They are often multiple, large, confluent and with caseating necrosis in TB. In CD, these are infrequent, small and poorly organized. TB polymerase chain reaction (PCR)92 ‘in situ PCR’93 and faecal sample PCR testing94 have also been studied, but data on their role in routine screening are inconclusive.
Mycobacterium tuberculosis can be cultured from mucosal biopsies only in a third of the patients with colonic TB92. The isolation of Mycobacteria from culture can be reduced to 2-3 wk with the BACTEC, Mycobacteria growth indicator tube, MB/BacT mycobacterial detection system (Organon Teknika) and the ESP culture system II (ESP II; Trek Diagnostics, Inc., Westlake, USA). These tests have an additional benefit of identifying drug-resistant TB. Ultrastructural and molecular differentiation using claudin 295 and mesenchymal cell marker CD7396 and increased expression of growth-related oncogene alpha mRNA in biopsy specimen and of interleukin (IL) IL-17 in peripheral blood mononuclear cells have been used as markers of intestinal TB97. Both TB and CD can coexist in rare situations98.
Seven susceptibility loci for infection with Mycobacterium leprae, including NOD2, IL23R, RIPK2 and TNFSF15, are known to be associated with CD99.
In 20 per cent of cases, despite all attempts, the diagnosis remains elusive. Under these circumstances, there is a role for an empirical therapeutic trial with ATT66100. Those with intestinal TB are likely to show symptomatic response to antituberculous therapy (ATT) within 2-3 months of initiation of therapy; failure to do so would favour a diagnosis of CD101.
Surgery in inflammatory bowel disease (IBD)
The surgical rates in India, in different series for UC and CD, range from 4 to 12 per cent and 19 to 100 per cent102 respectively. Rai et al103 reported that during a three year follow up of 161 patients, surgery was required in 6.2 per cent. Even though a significant number of Indians are anaemic and have low haemoglobin levels, Truelove and Witt's criteria are still viable in ascertaining the severity of colitis104. Surgery in CD has been reported to range from 37 to 55 per cent of cases71.
For CD, the current indications are partial small bowel obstruction (53%), enteroenteric and enterocutaneous fistulae (10.7%), chronic gastrointestinal (GI) blood loss (7%) and protein losing enteropathy (7%). Surgical emergencies include perforation with peritonitis (14%), massive GI bleed (4%) and gastric outlet obstruction105.
IBD in children: IBD in children and adolescents is a cause of great concern in the Indian population, more so for CD. The disease is more severe and penetrating requiring biologicals. Paediatric patients account for nearly seven per cent of new cases of IBD seen annually106. In a retrospective study from Chennai, ten cases of CD aged between five and 15 yr were detected over a period of eight years and 90 per cent were girls. Five had taken ATT in the past. Complications such as perianal fistulae, rectovaginal fistula, ileal and oesophageal stricture were noted separately in four children107.
In a questionnaire survey across seven centres in India that included 221 children and adolescents with IBD, the mean age of presentation for UC and CD was almost similar with no gender difference. EIMs were noted in 23.6 and 36.1 per cent of UC and CD, respectively72. Pancolitis was predominant in UC (70.9%) and 88 per cent of the cases required steroids. Ileocolonic CD was common in three-fourths of the cases and 76.2 per cent required azathioprine for maintenance. In UC, complications such as massive haemorrhage and toxic megacolon were noted in 11.8 per cent of cases. Among the patients with CD, 27 per cent had fistulae, perianal abscess, stricture and perforation. Biologicals were used in only in a minority (0.8% of severe UC and in 12.2% of CD). In UC, 4.3 per cent of cases required surgical intervention. The authors concluded that paediatric IBD in India shares similarities with adult-onset IBD. However, growth failure and severe disease were distinctive for children108.
Cost and adherence to treatment: Indian experience with IBD: In India, the major economic burden of disease treatment is borne by the patient and family members. Economic constraints affect not only the patient care, but also adherence to treatment. Although diagnostic and treatment expenses make up a significant portion of the cost of IBD management, other factors such as inappropriate treatment, lack of adherence to therapeutic regimens or suboptimal treatment also add to the cost burden. There is indeed a need to evolve beyond symptom control and move towards sustained control of inflammation109. Use of pill cards, patient information booklets and active participation by government and other public agencies can improve adherence to treatment.
The way forward: A multidisciplinary model: Integrating various disciplines in the care of IBD patients will improve patient satisfaction and decrease healthcare costs. In essence, this would mean central referral centres which cater to all aspects of patient care110. Such centres should include nurse practitioners, physicians, surgeons and psychologists. A model is proposed to achieve these goals (Fig. 1).
To conclude, IBD is being increasingly diagnosed in India (Fig. 2). Population-based studies from different parts of the country are the need of the hour to ascertain the magnitude of the problem of IBD in the Indian subcontinent. In the West, Indian immigrants behave like residential Indians, whereas their children show IBD prevalence similar to the West, highlighting the role of environmental triggers. However, the environmental and genetic factors amongst Indians with IBD are not well understood. IBD occurs at the same age as the West, but there is no bimodal peak. Men appear to be more frequently affected than women and disease severity is milder, but with a risk of CRC similar to the West. Paediatric IBD is increasing and would require special attention. Other issues such as cost of medication, poor adherence to treatment, problems in differentiating TB from CD and timing of screening for CRC in patients with IBD need to be addressed.
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Conflicts of Interest: None.