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Introduction
Gastrointestinal (GI) and hepatic disorders are major sources of morbidity and mortality and are associated with substantial healthcare expenditure.1,2,3 GI diseases have demonstrated an age-standardised death rate (ASDR) of 28.4 deaths per 100,000 population in Western countries and 17-19.45 per 100,000 population in India.4 These disorders are widespread in general practice and account for about 10% of general practitioner (GPs) consultations in Western countries (UK) and ~25% in India.5,6 Thus, for a fairly large section of the population in India, the GP is the first contact point, and their role is therefore crucial in correct diagnosis. In clinical practice, the spectrum of consequences related to diagnostic errors (misdiagnosis, a missed diagnosis, or a delayed diagnosis at any stage in the diagnostic process) could be averted with the appropriate identification of patients at risk.7 Serious health consequences particularly occur if the patient has a malignancy or an aggressive form of a disease.8 Evidence demonstrates that there has been a progressive rise in diagnostic errors, these being reported generally in 5% of out-patients, 10% of in-hospital fatalities, and 7–17% of in-hospital adverse events.9 Some illustrations of diagnostic challenges in GI disorders reported in the literature are depicted in Figure 1. These diagnostic errors could generally be attributed to limited access to diagnostic testing resources, lower doctor-patient ratios, limited availability of specialists and insufficient record-keeping systems.

Apart from these technical challenges, another important decisive factor leading to deviation from guideline practice is the absence of health insurance coverage for a large subset of the population in countries like India.10 It leads to hesitation among physicians and patients, hindering the conduct of required tests to restrict out-of-pocket expenditure. Figure 2 Specific challenges in managing GI diseases also include the failure to obtain sufficient information on patients medical-, travel- and medication history. Treatment based on such incomplete data is likely to delay referral to specialist centres, develop complications, poor prognosis, and higher rates of negative outcomes.11,12 To overcome these challenges in real-life clinical settings and reduce the GI disease burden, clinicians well equipped with effective strategies for skilful diagnosis are critical. Among the various approaches, Gastrovigilance, which includes disease-specific training for recognition of risk factors, algorithms and referral pathways, could prove highly beneficial. In this narrative review, we present a summary of literature supporting the concept of gastrovigilance for GI and hepatic conditions.

FIGURE 1. Illustrative Clinical Evidence Depicting Factors Associated with Diagnostic Errors and its ConsEQUENCes (Disease-Related)13,14,15,16,17

FIGURE 2. Causes of Errors and Delays in Diagnosis10,11,12,18 

Methodology
Literature published in English and the supporting concept of gastrovigilance for GI and hepatic conditions were included. From a wide range of GI conditions, the list included in this article was narrowed down by a group of senior gastroenterologists from India. A draft of the summary of literature supporting the concept of gastrovigilance for GI and hepatic conditions was shared with experts after a virtual/expert group deliberation. In this paper, we have included common challenges in managing these conditions in Indian clinical practice along with their proposed solutions. 

Gastroesophageal Reflux Disease (GERD) Definition, Prevalence in India
GERD is defined as a syndrome due to reflux of gastric content into the oesophagus, resulting in symptoms more than once a week or more than a month and/or complications.19 As per a recent meta-analysis, the pooled prevalence of GERD in the Indian population is 15.6 (5%-28.5%).20

Challenges in Diagnosis and Treatment
Among the various obstacles, incorrect diagnosis is an important one that impacts the successful treatment of GERD patients in clinical practice.21 These challenges, along with probable causes and their remedies based on best practices and guideline recommendations, have been elucidated in Table 1. 

Table 1. GERD- Challenges in Diagnosis and Treatment: Evidence-based practical approach

adysphagia, odynophagia, GI bleeding, anorexia, and weight loss

Dyspepsia and H. pylori Infection Definition, Prevalence in India
Dyspepsia is defined as predominant epigastric pain lasting at least 1 month, which may be associated with any other upper GI symptom such as epigastric fullness, nausea, vomiting, or heartburn.42 There is a wide variation in the prevalence of dyspeptic symptoms (7.6 to 49%) among the Indian population due to the lack of uniform criteria used for the diagnosis. Similarly, a recent meta-analysis of global data found a variation in pooled prevalence according to Rome I criteria (17.6%) and Rome IV criteria (6.9%).43

Challenges in Diagnosis and Treatment
Overlap of symptoms, lack of uniform criteria used for diagnosis and wide variation in occurrence due to ethnicity, and frequently changing epidemiology are the predominant challenges in the management of dyspepsia. The details have been outlined in Table 2. 

Table 2. Dyspepsia- Challenges in Diagnosis and Treatment: Evidence-based practical approach

b gastric oesophagus reflux syndrome c peptic ulcer disease

Irritable Bowel Syndrome (IBS) Definition, Prevalence in India
Patients with IBS should report symptoms of abdominal pain at least once weekly (on average) in association with a change in stool frequency, a change in stool form, and/or relief or worsening of abdominal pain related to defecation.54 Population-based studies have shown the prevalence of IBS between 4.2%-7.5% in India compared to a global pooled prevalence of 11.2%.55 However, epidemiology, clinical presentation, and management of IBS may vary in different geographical regions due to differences in diet, gastrointestinal infection, sociocultural and psycho-social factors, religious and illness beliefs, symptom perception and reporting.55

Challenges in Diagnosis and Treatment
Awareness of alarm symptoms of IBS is crucial to facilitate early diagnosis.56 Diagnosing IBS can be challenging and uncertain for several reasons, as depicted in Table 3. 

Table 3. IBS- Challenges in Diagnosis and Treatment: Evidence-based practical approach

Inflammatory Bowel Disease (IBD) Definition, Prevalence in India
IBD is a broad term that includes conditions characterised by chronic inflammation of the gastrointestinal tract. IBD includes Crohns Disease (CD) and Ulcerative Colitis (UC).66 A comparison of incidence and prevalence rates with other countries suggests that among Asian countries, the disease burden is highest in India.67 With a population of more than 120 million, the total IBD population in India is among the largest globally.67 A multicenter study from India has reported An increasing incidence of CD, with the number of patients diagnosed per year increasing from < 16 patients in 2000 to 57 in 2006.68 A population study found the incidence of UC to be 6.02/100,000.69 A recent multicenter, cross-sectional, prospective national registry showed that the UC:CD ratio was 5.1:1 in India across four zones.70

Challenges in Diagnosis and Treatment
For physicians, both early diagnosis and proper treatment are a real challenge in their effort to ensure the best quality of life in patients with IBD. Table 4 Moreover, recognition of extra-intestinal manifestations of IBD, such as arthralgia, uveitis and erythema nodosum, which could increase the possibility of early diagnosis, could help avoid unnecessary referrals to other specialities.71 

Table 4. IBD- Challenges in Diagnosis and Treatment: Evidence-based practical approach

ITB- Intestinal TB, ATT-Antitubercular therapy, d finding that could be difficult to differentiate from an attack of acute appendicitis

Optimal management of IBD requires a multidisciplinary approach with many key players involving Physicians, GEs, surgeons, radiologists, pathologists, psychologists, rheumatologists and dietitians.74,75 The Physicians play an active role in managing IBD via monitoring patients treatment compliance and, if necessary, making dose adjustments in close cooperation with the specialist.76 Recognising risk factors, monitoring the patient for prevention and treatment of osteoporosis, infections using necessary vaccinations, and regular laboratory investigations is necessary since IBD management involves chronic therapy with aminosalicylates, corticosteroids, or immunosuppressive drugs.75,77,78

Chronic constipation (CC) Definition, Prevalence in India
Constipation is one of the major gastrointestinal disorders diagnosed in clinical practice.79 Primary constipation includes constipation-predominant irritable bowel syndrome (IBS-C), functional constipation, slow transit constipation like myopathy, neuropathy, and functional defecation disorders. Secondary constipation may be a result of metabolic disorders (hypercalcemia, hyperthyroidism and diabetes), medications (calcium channel blockers or opiates), primary colonic disorders (bowel obstructions, myopathies, anal stenosis, anal atresia, megacolon, cancer and proctitis), psychiatric disorders (depression, eating disorders and obsessive disorders) and neurological disorders (multiple sclerosis, spinal cord injury, autonomic neuropathy and Parkinsons disease). 79,80,81,82 Limited data from available studies indicate chronic constipation as a common health problem in India, challenging the general belief of its uncommonness due to a high-fibre diet and vegetarianism. Studies from India have reported a prevalence ranging from 8.6% to 24.8%.83,84,85,86 While studies excluding India suggested a global prevalence of chronic constipation to be 14%.87

Challenges in Diagnosis and Treatment
There are several challenges with chronic constipation, including the definition and identifying the pathophysiology. The average daily stool frequency is higher than the Western population, so the definition from Western countries may not apply to the Indian population (< 3/week vs 14/week) to diagnose CC.84,88 Further, uncertainty about which treatment to use and when is still a challenge in clinical practice.89 Table 5 

Table 5. Chronic Constipation- Challenges in Diagnosis and Treatment: Evidence-based practical approach

Celiac disease (CeD) Definition, Prevalence in India
Celiac disease is estimated to affect about 1% of the worlds population. It is thought to be unusual not only in India but also in Asia.91 Studies from India have found a prevalence of 8.53/1,000 in the northern, 4.66/1,000 in the northeastern, and 0.11/1,000 in the southern part of India. Thus, CeD is more common than is recognised in India, affecting primarily the wheat-consuming population.

Challenges in Diagnosis and Treatment
The predominant challenges include difficulty in diagnosis and patient adherence to dietary restrictions. Table 6 

Table 6. Celiac disease- Challenges in Diagnosis and Treatment: Evidence-based practical approach

GI cancers (Colorectal Carcinoma, Gastric Cancer, Esophageal Cancer)

A. Colorectal Cancer
Definition, Prevalence in India
In India, the annual incidence rate for colorectal cancer ranges between 4.1 to 4.4 per 100000.97,98 Colorectal cancer (CRC) in  India is distinct compared to that in Western countries. Patients from India are younger, and a higher proportion of signet ring carcinomas is noted; more sites are anorectal compared to colonic reported worldwide.99 Besides, patients usually present at an advanced stage. These differences, at least in part, could be attributed to insufficient access to healthcare and socioeconomic factors.99

Challenges in Diagnosis and Treatment
Early detection (Dukes A and B) represents the only chance for increasing 5-year survival rates. Evidence from countries with effective CRC prevention programs shows that early endoscopic detection and removal of preexisting colorectal polyps diminish the incidence of neoplasm. Further, CT colonoscopy (CTC) is the gold standard for managing bowel pathology. Nevertheless, widespread screening and technical expertise for CTC is inadequate in India, resulting in advanced disease stage at presentation.100,101

B. Gastric Cancer
Definition, Prevalence in India
As per the National Cancer Registries (NCR)— population-based tumor registries and Hospital- based cancer registries, the prevalence of gastric cancer (GC) ranges from 0.5/100,000 in Western India to 12.2/100,000 in Southern to 64.2/100,000 in Eastern Indian population.102 Thus, though the prevalence of gastric cancer is low compared to Western counterparts, there is immense regional diversity. Besides, the majority of patients are at an advanced stage of presentation which poses a significant challenge.102 Challenges in Diagnosis and Treatment Preventing the formation of premalignant lesions, either by reducing (eliminating) risk factors or by surveillance and management of premalignant (precancerous) conditions, should be the ideal practice. However, early diagnosis and treatment remain challenging. Table 7 

Table 7. GI Cancers: Challenges in Treatment and Diagnosis with Solutions

e ≥ three risk factors: age 50 or older, white race, male sex and obesity).

C. Esophageal Cancer
Definition, Prevalence in India
Squamous cell carcinoma (SCC) is currently the most common type of oesophagal cancer (EC) in the Indian subcontinent, with the distal third of the oesophagus being the most common site. Approximately 47,000 new cases are reported each year in India.123 About 1 in 300 patients with Barretts oesophagus (BE) are estimated to develop EC annually.121 There has been an association between adenocarcinoma and BE due to chronic inflammation from GERD.121,122

Challenges in Diagnosis and Treatment
Nonspecific complaints like progressive dysphagia and weight loss, limited risk factors for identification delay the diagnosis.1,118,119 Table 7

Hepatic Disorders
A. Viral Hepatitis
Viral hepatitis is a cause for major healthcare burden in India and is now paralleled as a threat to the trio of HIV/AIDS, malaria and tuberculosis.124 While Hepatitis A virus (HAV) and Hepatitis E virus (HEV) cause both sporadic infections and epidemics of acute viral hepatitis (AVH), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) cause chronic hepatitis. Though earlier prevalent in young children, currently there has been a sero- epidemiological shift in HAV infection in India, with increasing incidence of infection in the adult and adolescents (aged 15–24 years: 4.6%) when compared to subjects aged population compared with children (5–14 years: 3.1%).125,126 HEV is a major aetiology for AVH in the paediatric population and is reported to be responsible for over 70% of cases of acute hepatitis.127 During an HEV epidemic, the secondary attack rate among the household contacts is estimated to be lower than HAV (0.7–2% vs 50-75%).128 During an outbreak, pregnant women are at a greater risk of getting infected (12-20% and developing acute liver failure compared to the non-pregnant population (10-22% vs 1-2%).129 India has intermediate to high endemicity for Hepatitis B surface antigen and an estimated 40 million chronic HBV-infected people, constituting nearly 11% of the global burden. The population prevalence of chronic HBV infection in India is around 3-4 %. The estimated prevalence of HCV infection in India is about 1–1.9%.124

B. Non-viral Hepatitis
Definition, Prevalence in India
Non-viral hepatitis can be caused by exposure to some medications, drugs, alcohol, toxins or autoimmune disease. Other possible causes of non- viral hepatitis include contaminated water or food, dietary and herbal supplements, traditional or home remedies, wild-growing mushrooms and plants, and chemicals such as metals, solvents, paint thinners, or pesticides. The drugs causing drug‐ induced liver injury (DILI) tend to differ geographically based on specific disease states.130 In India, it is intensified by the widespread use of traditional and complementary medicines.130 The actual incidence of DILI in India is not known but is probably higher than in Western countries. The idiosyncratic form of DILI includes ~99% of all DILI cases in India, and intrinsic DILI, as it occurs in acetaminophen/paracetamol hepatotoxicity, accounts for <1% of cases.130 Autoimmune hepatitis (AIH) prevalence in India is around 5% of all patients with chronic liver disease.131

Challenges in the Diagnosis and Treatment of Hepatitis
Clinicians should maintain a high index of suspicion for non-viral hepatitis in the differential diagnosis of acute hepatitis in patients presenting with compatible clinical findings.132 Table 8 Patient exposure history should be collected in a more detailed manner to identify the aetiology for non- viral hepatitis.132 Awareness of differential diagnosis and identification of prognostic risks associated with the condition could be an approach for managing patients. 

Table 8. Hepatitis- Challenges in Diagnosis and Treatment: Evidence-based practical approach

C. Non-alcoholic steatohepatitis (NASH)
Definition, Prevalence in India
A diagnosis of NASH is made when the presence of hepatic steatosis in >5% of hepatocytes in the absence of alcohol abuse or any other hepatic disease accompanied by ballooning and inflammation in the liver is detected.146,147 It is a progressive stage of NAFLD which may lead to cirrhosis, hepatic malignancy or fibrosis.146,148 It is currently the second commonest indication for liver transplantation in India.149,150 The prevalence of NAFLD ranges from 9% to 32% in India.151,152 The wide variation in NAFLD prevalence across India could be attributed to the urban-rural divide.153,154 Challenges in

Diagnosis and Treatment
Non-invasive detection of NASH and accurate determination of fibrosis stage remain key diagnostic challenges.155 Table 9 Correctly diagnosing and staging NAFLD and distinguishing the subset of NASH patients is not only critical for disease monitoring and prognostication but also holds potential implications for therapies. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far.156

Gallstones
Definition, Prevalence in India
In India, the prevalence of gallstones is approximately 4%, whereas it is 10% in the Western world.157 The prevalence of asymptomatic gallstones is relatively high in central India.157

Challenges in Diagnosis and Treatment
The challenge is a diagnosis of asymptomatic gallstones and a dilemma with treatment. Recommendations for initial and periodic follow-up screening are also inadequate. Table 10

Table 9. NASH- Challenges in Diagnosis and Treatment: Evidence-based practical approach

Table 10. Gall stones-Challenges in Diagnosis and Treatment: Evidence-based practical approach

Importance of Patient-Physician Interaction/Relationship
The patient-physician relationship and patient participation are the cornerstone of care in managing several GI and hepatic diseases like IBD, UC, GERD and NASH. The Chronic nature of most diseases often demotivates the patient and affects outcomes. Patient education or counselling is effective only when the clinician provides adequate time to understand concerns/questions and provide satisfactory responses. Therefore, reassuring patients to voice their diagnostic concerns or fears is essential. Since most of these diseases necessitate dietary and lifestyle modifications, a clear understanding of these details is necessary to design a patient-centric approach to ensure adherence and improve outcomes. Therefore, there is a need to improve communication strategies for enhancing disease outcomes and improving health- related QoL. There is a need to empower patients so that they transition from passive care recipients to partners in care. Implementing longitudinal-care plans and patient follow-up outside the consultation is specifically important in primary care due to the nonspecific presentation and progression of serious diseases eventually.162

Methods to Improve Screening
Similar to Western countries screening should be performed primarily by physicians. Subjects should be selected based on risk score stratification, which also requires adequate disease knowledge among clinicians. Innovative strategies to maximise adherence to screening recommendations need to be deciphered. Some of these which have been evaluated and found to be successful include use of electronic reminders, best practice alerts, electronic medical record (EMR) prompts.163,164 For the section of the population not generally engaged with primary care, other testing opportunities such as testing in emergency room departments, retail pharmacies, and prenatal clinics should be explored. Nevertheless, though these settings appear reasonable for screening, completing the follow-up steps in the cascade of care is questionable. Thus, robust and persistent screening practices could play a major role in preventing aggressive form of disease states by adopting timely measures.
 
Moreover, these methods could identify subtle symptoms and attenuate the disease progression at early stages, which has a better prognosis, especially in liver cirrhosis, CRC, and GC. These are associated with poor survival rates due to presentation in advanced stages and limited treatment alternatives. Thus, screening based on risk stratification could enhance the window for prevention and early diagnosis, even in asymptomatic or the presence of nonspecific signs and symptoms, which is indeed a major challenge in most of the diseases discussed. This shall also help in the optimisation of the referral process.

Conclusions
GI and hepatic disorders are highly prevalent and are associated with significant mortality and morbidity. Although many evidence-based consensuses for individual conditions are available, the effective management of GI and hepatic disorder relies on effective diagnosis and monitoring of the conditions. Differential diagnosis plays a major role in reducing diagnostic errors and helps reduce long-term malignancy risk in patients with GI and hepatic disorders. Early diagnosis in cases of FGID plays a crucial role in detecting associated overlapping GI conditions. Physicians have a primary role compared to gastroenterologists for diagnosis and treating the patient with early symptoms. However, evidence suggests that the lack of awareness and knowledge of diagnosis among Physicians and limited facilitation of diagnostic resources in clinical settings leads to inefficient treatment of patients. Therefore, optimising knowledge access in primary care is needed. Moreover, there are also gaps between patient and clinician communications which lead to poor patient education. An in-depth understanding of symptoms and differential diagnosis can result in improved diagnosis and better treatment outcomes. Besides the large population, sociodemographic profiles and challenges in health expenditure are major obstacles to implementing guideline-based screening and diagnostic approaches.

Acknowledgements
Medical writing support is provided by Miss Seema Kalel at Intersect Kommunications in Mumbai, India, and is funded by Pfizer.

Disclosure
None of the authors have any conflicts of interest to declare. All authors received an honorarium from Pfizer for their services as a member of the expert group meeting. Dr. Pratyusha, Dr. Akshay, and Dr. Charles are employees of Pfizer Ltd.

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