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REVIEW ARTICLE
Year : 2021 | Volume
: 153
| Issue : 4 | Page : 421-430
Inflammatory bowel disease: An Indian perspective
Mayank Jain, Jayanthi Venkataraman
Department of Medical Gastroenterology, Gleneagles Global Health City, Chennai, India
Correspondence Address:
Mayank Jain
Department of Medical Gastroenterology, Gleneagles Global Health City, Chennai 600 100, Tamil Nadu
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijmr.IJMR_936_18
Abstract Inflammatory bowel disease (IBD) in recent times is causing a significant healthcare burden as both ulcerative colitis and Crohn's disease (CD) require lifelong therapy and constant monitoring. The current review highlights the concerns in a country like India with special reference to the changing trends of IBD, risk attribution and the financial issues. 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 in Indians with IBD are not well understood. Men appear to be more frequently affected than women in India. The disease severity is milder in the patients, both males and females, but the risk for colorectal cancer (CRC) is similar to the West. The incidence of paediatric IBD is on the rise. The major burden of IBD in the Indian subcontinent at present is in children, adolescents and teens. Cost towards the management of complications, non-adherence to treatment, differentiating tuberculosis from CD and finally screening for CRC in patients with IBD are the points to ponder in the Indian scenario.
Keywords: Burden - Crohn's disease - epidemiology - inflammatory bowel disease - prevalence - ulcerative colitis
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 Australia[3],[4], 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 nations[5],[6]. 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 Asians[8]. Another single-centre study from England made similar observation of a high frequency of IBD amongst South Asian migrants to the UK[9]. 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 IBD[10],[11],[12]. The migrant study from Canada[13] 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 West[14]. Population-based studies in the Middle East (Kuwait and Saudi Arabia) reported an increase in the prevalence of IBD, especially amongst children[15],[16],[17].
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 CD[14]. However, a trend towards an increasing incidence of CD was observed[14]. Gender wise, CD is frequent amongst men with no gender difference for UC. Extraintestinal manifestations of IBD are uncommon in Asians[14].
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 al[18]. Subsequently, Sood et al[19], 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 UK[20],[21],[22]. In a national survey from India in 2012[23], 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 study[24] 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 India[23].
Overall, hospital-based studies in the recent past have reported an increasing number of IBD cases[25]. 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 burden[26],[27].
Genetic predisposition The results of various genetic studies from India are summarised in the [Table 1]. Transethnic studies from India, East Asian and Iranian populations in Asia[40], have shown a significant genetic heterogeneity. The nucleotide oligomerization domain (NOD2) variants described in Caucasians are not seen amongst Indians[41], but have been reported amongst Malaysians[42].
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 UC[43],[44],[45]. However, this is contrary to the trend seen among Asians where despite higher smoking prevalence (65%) among men, the incidence of CD is low[46]. Some predisposing factors to IBD include food rich in animal protein[47], fats, sugar, meat[48] and excess tea and coffee[49] particularly in the West, whereas high-fibre fruits and vegetables[50] are thought to decrease the risk to IBD[51]. In a case–control, population-based study (ACCESS), 12 months of breastfeeding had a marked protective effect against IBD[52].
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 setting[50].
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 West[53],[54]. Butyrate-producing bacteria such as Clostridium coccides and C. leptum were found to be significantly decreased in UC[54],[55], with an increase in anaerobes and facultative aerobes (Proteobacteria), in severe UC[56]. There is a heightened mucosal adherence of Escherichia More Details coli in colonic CD[57]. Organisms such as cytomegalovirus[58], C. difficile[59],[60], Giardia, Strongyloides, hookworm, herpes simplex, Entamoeba histolytica, Cryptosporidium and Salmonella More Details[58],[61] 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 CD[49].
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 CD[62]. 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 UC[63].
Demographic profile and clinical presentation Age: IBD in the West has a bimodal presentation with peaks at 20-39 and 60-79 yr[64]. 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 countries[65]. With the mean age at the time of diagnosis of UC and CD being closer to 40 yr[66], with no bimodal distribution[23],[24]. In a multicentric study from Kerala, in adults, CD occurred at a younger age compared to UC, whereas this was reversed in children[25].
Gender: Data from the West indicate a female preponderance, more so in CD than UC[22],[67], however, most studies from India have shown a male preponderance for both UC and CD[23],[24],[67]. However, a study from Central India showed no significant gender difference[68]. 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 history[23],[69], 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%) patients[23]. In a study from Central India, left-sided colitis was more common than pancolitis[68] similar to other Asian countries and the West[65].
A multicentric study on 182 patients from three centres and the IBD national survey observed near-similar disease location for CD[23],[24]. 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 studies[23],[24]. Seventeen per cent of patients in the multicentric study had perianal disease[23]. 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 years[72].
The large variations may be secondary to a referral bias or genetic variations among the populations. Most patients (76%) had an inflammatory phenotype[23]. A retrospective study from Mumbai noted an aggressive progression of IBD in 20 per cent over a 10 yr follow up[71]; the temporal progression was, however, relatively slow compared to the West.
Extraintestinal manifestations
In a questionnaire based study from India[23], 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 EIMs[73]. 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, respectively[74]. In a large cohort from Kerala, EIMs occurred in 28 per cent cases with CD and 18 per cent cases with UC[25]. Primary sclerosing cholangitis was less frequent amongst Indians, and this may be due to the overall low prevalence of autoimmune liver disease in India[75],[76].
Colorectal cancer: Earlier hospital-based studies from India found low risk of colorectal cancer (CRC) among Indian patients[77],[78], however, studies from Mumbai[79] and New Delhi[80] observed that the risk rates of CRC were similar to that of the West[81]. The incidence density of IBD in Mumbai[79] 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 al[80] 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 biologicals[23]. 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 West[14],[72].
5-ASA (64%), steroids (69%) and azathioprine (63%) were the preferred medications and biologics in 2 per cent of all CD patients[23]. Two other studies reported use of biologicals in 37 per cent[24] to 55 per cent[71] 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 features[24],[82]. Systemic symptoms such as fever, anorexia and shorter duration of symptoms (less than one year) are frequent presentations of TB[24]. CD patients have longer duration of symptoms. Diarrhoea, bleeding per rectum, anaemia and EIMs are more frequent in CD patients[66],[68],[83].
Diagnostic tools such as erythrocyte sedimentation rate (ESR)[66] and Anti-Saccharomyces cerevisiae antibodies (ASCA)[66],[84] 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 CD[55]. The role of quantiferon TB gold remains controversial in the Indian setting[85]. 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 TB[87].
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 CD[88],[89].
Demonstration of acid-fast bacilli on histology or on culture is diagnostic of TB but is rarely documented[85]. Granulomas in TB and CD are distinctive[90],[91]. 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 testing[94] 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 TB[92]. 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 2[95] and mesenchymal cell marker CD73[96] 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 TB[97]. Both TB and CD can coexist in rare situations[98].
Seven susceptibility loci for infection with Mycobacterium leprae, including NOD2, IL23R, RIPK2 and TNFSF15, are known to be associated with CD[99].
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 ATT[66],[100]. 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 CD[101].
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 cent[102] respectively. Rai et al[103] 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 colitis[104]. Surgery in CD has been reported to range from 37 to 55 per cent of cases[71].
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 obstruction[105].
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 annually[106]. 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 children[107].
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, respectively[72]. 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 children[108].
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 inflammation[109]. 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 care[110]. Such centres should include nurse practitioners, physicians, surgeons and psychologists. A model is proposed to achieve these goals [Figure 1].
Figure 1: Suggested multidisciplinary approach to inflammatory bowel disease care in India. Source: Ref 110.To conclude, IBD is being increasingly diagnosed in India [Figure 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.
Figure 2: Inflammatory bowel disease in India: The known, the unknown and the challenges. Source: Refs 23, 56-64, 68-74, 104-106Conflicts of Interest: None.
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