Microbiome and metabolome in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease of unknown etiology, involving complex interactions between the gut microbiome and host immune response. The microbial dysbiosis is well documented in IBD and significantly influences the host metabolic pathways. Thus, a metabolomic fingerprint resulting from the influence of gut dysbiosis in IBD could aid in assessing the disease activity. PubMed, Medline, Science Direct, and Web of Science were searched for studies exploring the association between microbiome and metabolome in IBD patients in the last 5 years. Additionally, references of cited original articles and reviews were further assessed for relevant work. We provide a literature overview of the recent metabolomic studies performed on patients with IBD. The findings report alterations in the metabolite levels of these patients. We also discuss the gut dysbiosis observed in IBD and its influence on host metabolic pathways such as lipids, amino acids, short-chain fatty acids, and others. IBD, being a chronic idiopathic disease, requires routine monitoring. The available non-invasive markers have their limitations. The metabolite changes account for both dysbiosis and its influence on the host's immune response and metabolism. A metabolome approach would thus facilitate the identification of surrogate metabolite markers reflecting the disease activity.

Personalized Dosing of Infliximab in Patients With Inflammatory Bowel Disease Using a Bayesian Approach: A Next Step in Therapeutic Drug Monitoring.

Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.

Emerging inflammatory bowel disease demographics, phenotype, and treatment in South Asia, South-East Asia, and Middle East: Preliminary findings from the Inflammatory Bowel Disease-Emerging Nations' Consortium.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) is emerging in the newly industrialized countries of South Asia, South-East Asia, and the Middle East, yet epidemiological data are scarce. METHODS: We performed a cross-sectional study of IBD demographics, disease phenotype, and treatment across 38 centers in 15 countries of South Asia, South-East Asia, and Middle East. Intergroup comparisons included gross national income (GNI) per capita. RESULTS: Among 10 400 patients, ulcerative colitis (UC) was twice as common as Crohn's disease (CD), with a male predominance (UC 6678, CD 3495, IBD unclassified 227, and 58% male). Peak age of onset was in the third decade, with a low proportion of elderly-onset IBD (5% age > 60). Familial IBD was rare (5%). The extent of UC was predominantly distal (proctitis/left sided 67%), with most being treated with mesalamine (94%), steroids (54%), or immunomodulators (31%). Ileocolic CD (43%) was the commonest, with low rates of perianal disease (8%) and only 6% smokers. Diagnostic delay for CD was common (median 12 months; interquartile range 5-30). Treatment of CD included mesalamine, steroids, and immunomodulators (61%, 51%, and 56%, respectively), but a fifth received empirical antitubercular therapy. Treatment with biologics was uncommon (4% UC and 13% CD), which increased in countries with higher GNI per capita. Surgery rates were 0.1 (UC) and 2 (CD) per 100 patients per year. CONCLUSIONS: The IBD-ENC cohort provides insight into IBD in South-East Asia and the Middle East, but is not yet population based. UC is twice as common as CD, familial disease is uncommon, and rates of surgery are low. Biologic use correlates with per capita GNI.

Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach-an Indian experience.

PURPOSE: Infliximab (IFX) therapy in inflammatory bowel disease (IBD) is associated with loss of response in half the patients, due to complex pharmacokinetic and immunological factors. Dashboard's Bayesian algorithms use information from model and individual multivariate determinants of IFX concentration and can predict dose and dosing interval. AIM: To compare measured IFX concentrations in our laboratory with values predicted by iDose dashboard system and report its efficacy in managing patients not responding to conventional dosing schedule. METHOD: Clinical history, demographic details, and laboratory findings such as albumin and C-reactive protein (CRP) data of IBD patients (n = 30; median age 23 years (IQR: 14.25 - 33.5)) referred for IFX drug monitoring in our laboratory from November 2017 to November 2019 were entered in iDose software. The IFX concentration predicted by iDose based on this information was compared with that measured in our laboratory. In addition, a prospective dashboard-guided dosing was prescribed in 11 of these 30 patients not responding to conventional dosing and was followed to assess their clinical outcome. RESULT: IFX monitoring in our 30 patients had shown therapeutic concentration in 12, supratherapeutic in 2 and subtherapeutic concentration in 16 patients. The iDose predicted concentration showed concordance in 21 of these 30 patients. Of 11 patients managed with iDose-assisted prospective dosing, 8 achieved clinical remission, 2 showed partial response, and one developed antibodies. CONCLUSION: Retrospective data analysis showed concordance between laboratory measured and iDose-predicted IFX level in 70% of patients. iDose-assisted management achieved clinical remission and cost reduction.

Clinical efficacy of infliximab level and anti-infliximab antibody measurement in patients with inflammatory bowel disease: An audit.

BACKGROUND AND AIMS: Infliximab (IFX) monitoring has been proposed for effective therapeutic management of inflammatory bowel disease (IBD). There is no data on infliximab levels and its antibody measurement in Indian patients. We assessed the clinical efficacy of IFX level and antibodies to infliximab (ATI) monitoring in IBD patients. METHODS: Infliximab trough level and antibody testing was done in 50 and 30 IBD patients, respectively using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The levels were correlated with the disease status, albumin, and C-reactive protein (CRP) levels. The clinical efficacy of level-based change in patient management was evaluated. RESULTS: Of 50 patients, IFX levels were therapeutic in 8, sub-therapeutic in 40, and supra-therapeutic in 2. High ATI titer was present in 8/30 patients. The IFX level did not correlate with the dose of 5 or 10 mg/kg. Based on IFX level and ATI estimation, management was changed in 35 patients: increase in dose in 7, decrease in dosing interval in 17, increase in interval in 2, surgery in 2, change in biologic in 5, and cessation of IFX in 2 patients. Therapy modification based on IFX level improved the clinical response in 25 patients, of whom 5 are in remission at a median duration of 2 years. CONCLUSION: Most (80%) of the IBD patients had subtherapeutic IFX levels while high ATI titers were found in 27% of the patients. There was no correlation between infliximab dose and drug levels. Therapy modification based on drug level benefitted the majority. Our results suggest that measurement of IFX level assists in attaining therapeutic levels and improves clinical response.

Rate of recurrence in Indian patients presenting with acute pancreatitis and identification of chronicity on follow up: Possible risk factors for progression.

BACKGROUND: To study the profile and long-term outcome of Indian patients presenting with acute pancreatitis and the possible risk factors for progression. METHODS: Consecutive patients with acute or recurrent acute pancreatitis seen in our department during July 2013 to December 2014 were included. Details of past episodes were collected and patients were followed up till March 2015. RESULTS: In the 97 patients included (mean age 47.2 [SD 16.9] years; 74 men), gallstones (37 [38.1%]) and alcohol (19 [19.6%]) were the major identified etiologies; the idiopathic (31 [32%]) group constituted a third of patients. Recurrences were more common with idiopathic etiology (14 patients out of 30 had recurrences [46.7%]) as compared to alcoholic (5 out of 19 [26.3%]) and biliary (4 out of 37 [10.8%]) pancreatitis and with mild index episode. Following the episode of acute pancreatitis, identification of chronic pancreatitis was more common with alcoholic (6 out of 18 [33%]) and idiopathic (9 out of 30 [30%]) etiology as compared to other etiologies. Longer duration of follow up, but not number of recurrent episodes, was associated with identification of chronicity in patients presenting as acute pancreatitis. CONCLUSIONS: Out of 97 patients with acute pancreatitis, 27 (27.8%) developed recurrences with risk factors being idiopathic etiology and mild index episode. Eighteen of 97 (18.6%) patients had evidence of chronic pancreatitis on follow up, risk factors being the alcoholic and idiopathic varieties, and longer duration of follow up.

Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity.

BACKGROUND: Thiopurine methyltransferase (TPMT) gene variants have achieved limited success in predicting the outcome of thiopurine therapy, which shows wide inter-individual variations. The literature indicates a strong association between the NUDT15 gene variant and thiopurine-induced toxicity in Asian patients. The present study intends to explore the role of the NUDT15 variant (C415T) in Indian patients on thiopurine therapy. METHODS: NUDT15 and TPMT genotyping were performed using amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) and the restriction fragment length polymorphism (RFLP) technique. RESULTS: Of 370 samples received for TPMT testing, 206 samples were available for NUDT15 genotyping. The NUDT15 risk allele frequency was 10.7%, with the frequency of wild, heterozygous and mutant genotypes being 80.6%, 17.5% and 1.9%, respectively. TPMT variants were seen in 13 of 370 (3.5%) patients, whereas the NUDT15 variant was seen in 40 of 206 (19.4%) patients. Thiopurine-induced toxicity information was available for 101 patients, among whom 10 developed leukopenia and all harbored the NUDT15 variant (p<0.0001). NUDT15 was clinically more relevant than TPMT in terms of sensitivity and specificity, as well as with a statistically significant difference in thiopurine dose requirement for patients with the NUDT15 variant. CONCLUSIONS: A preemptive NUDT15 genotyping approach can therefore help identify high-risk patients (NUDT15 C415T positive) who could benefit from thiopurine dose reduction, thereby preventing fatal thiopurine-induced toxicity.

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease.

BACKGROUND AND AIM: A lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients. METHODS: In this prospective study, 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose-related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature. RESULTS: Of the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non-compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6-TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6-methylmercaptopurine levels ranged up to 4971 pmol/8 × 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose-based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12-39%). CONCLUSION: Half of the patients in this study had low and a quarter had high 6-TGN levels. One-fourth of the patients needed dose modification. The dose-based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients.

Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance.

BACKGROUND: Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine/6-mercaptopurine (6-MP). Mutations in the enzyme lead to generation of excess thioguanine, which causes suppression of various cell lineages, especially neutrophils. Data on the prevalence of TPMT polymorphism are available from Western and some Asian countries; such data from India are sparse. AIMS: The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodulator therapy and its relation to the development of neutropenia on azathioprine therapy. METHODS: In this retrospective study, data of all patients who underwent TPMT genotyping by PCR-RFLP and allele-specific PCR prior to immunomodulator therapy were analyzed. The frequency of on-treatment development of neutropenia (total neutrophil count <1,500 per cubic millimeters) was noted. RESULTS: Data were available on 126 patients (mean age, 42 [SD 13.6] years; 73 men and 53 women). The disease indications included ulcerative colitis (61), Crohn's disease (43), indeterminate colitis (1), autoimmune hepatitis (16), and others (5). TPMT genotype was wild in 120 patients (95.23 %) and heterozygous in 6 patients (4.77 %); no patient had homozygous mutation. Seven of 87 patients (6.8 %) who received azathioprine developed neutropenia; blood counts normalized on cessation of the drug in all. The incidence of neutropenia in patients with wild type was 6/84 (7.14 %) and with heterozygous type 1/3 (33 %) (p = 0.5764). CONCLUSION: Nearly 5 % of this population of patients requiring immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation.

Indian Society of Gastroenterology consensus on ulcerative colitis.

In 2010, the Indian Society of Gastroenterology's Task Force on Inflammatory Bowel Diseases undertook an exercise to produce consensus statements on ulcerative colitis. This consensus, produced through a modified Delphi process, reflects our current understanding of the definition, diagnostic work up, treatment and complications of ulcerative colitis. The consensus statements are intended to serve as a reference point for teaching, clinical practice, and research in India.

Survey of inflammatory bowel diseases in India.

INTRODUCTION: Inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), once thought to be uncommon, is now seen commonly in India. The Indian Society of Gastroenterology (ISG) Task Force on IBD decided to collate data on the clinical spectrum of IBD currently prevailing in India. METHODS: An open call to members of ISG was given through publication of a proforma questionnaire in the Indian Journal of Gastroenterology and the web portal of ISG. The proforma contained questions related with demographic features, family history, risk factors, clinical manifestations and characteristics, course of disease, and pattern of treatment of IBD. RESULTS: Of 1,255 filled questionnaires received, 96 were rejected and 1,159 (92.3 %) were analyzed. This comprised data on 745 (64.3 %) patients with UC, 409 (35.3 %) with CD, and 5 with indeterminate colitis. The median duration of illness was longer in patients with CD (48 months) compared to those with UC (24 months) (p = 0.002). More than one half of patients (UC 51.6 %, CD 56.9 %) had one or more extraintestinal symptoms. A definite family history of IBD was present in 2.9 % (UC 2.3 % and CD 4.6 %; p = 0.12). The extent of disease in UC was pancolitis 42.8 %, left-sided colitis 38.8 %, and proctitis alone in 18.3 %. The extent of disease involvement in CD was both small and large intestine in 39.6 %, colon alone in 31.4 % and small intestine alone in 28.9 %. Stricturing and fistulizing disease were noted in 18.8 % and 4.4 % of patients with CD respectively. Chronic continuous and intermittent disease course were present in 35.5 % and 47.2 % of UC patients respectively, and in 23.1 % and 68.8 % of CD patients. Four percent of patients with UC had undergone colectomy, while 15.2 % of patients with CD underwent surgical intervention. CONCLUSIONS: The present survey provides a reasonable picture of the demographic features and clinical manifestations of Indian patients with IBD, their risk factors, course of disease, and the treatment given to them.

Whipple's disease.

A 74 year old male patient with weight loss, diarrohea, loss of appetite, anemia, thrombocytopenia and culture negative endocarditis was diagnosed to have Whipple's disease. We are reporting this case, as it is a rare disease with fewer than 1000 validated cases reported in literature.

Choledochal cysts with chronic pancreatitis in adults: report of two cases with a review of the literature.

CONTEXT: Choledochal cysts, rarely present with chronic calcific pancreatitis. We report two patients with choledochal cysts who had concomitant chronic pancreatitis. CASE REPORT #1: A 27-year-old female with a history of recurrent abdominal pain, fever and jaundice presented with a type I choledochal cyst with calcifications in the uncinate process of the pancreas on CT scan. Her magnetic resonance cholangiopancreatogram (MRCP) revealed calcifications in the region of the uncinate process of the pancreas, the presence of a type I choledochal cyst with dilatation of the right and left hepatic ducts at their confluence suggesting an anomalous pancreaticobiliary ductal junction. She underwent choledochal cyst excision with a Roux-en-Y hepaticojejunostomy. CASE REPORT #2: A 35-year-old male with colicky abdominal pain of four months duration whose CT scan was suggestive of an atrophic pancreas with a 1 cm dilatation of the pancreatic duct and a calculus in the pancreatic duct near the ampulla. MRCP showed significant atrophy of the pancreas with an isointense filling defect seen in the pancreatic duct at its distal end near the ampulla. A diagnosis of chronic calcific pancreatitis with type I choledochal cyst was made. He underwent choledochal cyst excision with a cholecystectomy, hepaticojejunostomy (end-to-side) and side-to-side pancreaticojejunostomy. CONCLUSION: Chronic calcific pancreatitis is a rare occurrence in patients with choledochal cysts and only six cases have been reported in the literature. Our two patients with choledochal cysts associated with chronic pancreatitis were treated surgically.

Comparison of Mycobacterium tuberculosis culture using liquid culture medium and Lowenstein Jensen medium in abdominal tuberculosis.

BACKGROUND: Traditionally, the Lowenstein Jensen (LJ) medium has been used for culturing Mycobacterium tuberculosis. In abdominal tuberculosis (TB), the reported yield from tissue culture is between 20% and 60%. Liquid cultures are reported to give a higher yield but there is little data available in abdominal TB. AIM: To compare the yield of TB culture with BACTEC 460TB liquid medium and LJ medium for patients with suspected abdominal TB and determine cost effectiveness. METHODS: This prospective study was done in consecutive cases with clinical, radiological, endoscopic/surgical, and histological suspicion of abdominal TB. Tissue biopsies obtained at colonoscopy or surgery were processed and plated on LJ medium as well as the BACTEC 460TB system. NAP (ρ-nitro-α-acetylamino-ß-hydroxy-propiophenone) differentiation was carried out to determine species. The cost of each method and cost per yield were calculated. RESULTS: Of the 29 cases, 22 cases (76%) were positive on BACTEC 460TB culture while 14 (48%) were positive on LJ medium giving a 64% increment in yield. However, the culture of one patient grew on LJ medium, where the BACTEC 460TB was negative. The additional cost of BACTEC 460TB is Rs. 460 and LJ is Rs. 40. CONCLUSIONS: Samples from patients with abdominal TB should be processed on both liquid and LJ medium. For high yield, the use of a liquid culture medium system is essential.

An Indian family of multiple endocrine neoplasia type 1 (MEN1): molecular diagnosis, treatment and follow up.

BACKGROUND/OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal, dominant syndrome, characterized mainly by the combination of tumors involving the parathyroid, pancreatic and pituitary glands. Genetic sequencing leading to early treatment of family members has not yet been reported in Indian patients. METHODS: We performed molecular analysis of the MEN1 gene to identify mutations in an Indian family with MEN1 syndrome. The proband was identified with multiple peptic ulcers because of multifocal recurrent gastrinomas, as well as parathyroid and pituitary adenomas. All the 10 exons of the MEN1 gene were amplified using the polymerase chain reaction (PCR). The MEN1 gene was then screened by direct DNA sequencing. RESULTS: The proband is asymptomatic 3 years after total pancreatectomy and removal of parathyroid adenomas. DNA sequencing revealed the presence of a heterozygous Y227X mutation in exon 4 of the MEN1 gene in the proband. Four of the seven mutant-carrying family members are at present asymptomatic. Following screening, one asymptomatic child has been identified with and treated for insulinoma and parathyroid adenoma. CONCLUSION: Detection of the MEN1 gene mutation enables selection of family members for screening and long-term follow up.

Hepatic tuberculosis in absence of disseminated abdominal tuberculosis.

Liver involvement in tuberculosis in absence of miliary tuberculosis is rare. This study was performed to analyse the spectrum and response to treatment of hepatic tuberculosis in the absence of miliary abdominal tuberculosis. Retrospective analysis of seven cases of hepatic tuberculosis without miliary abdominal tuberculosis who presented at the single tertiary referral center were analyzed. All patients presented with fever and hepatomegaly. Five of them had pain in upper abdomen and vomiting. HIV serology was positive in one patient. All patients had normocytic normochromic anaemia, raised erythrocyte sedimentation rate (Mean 65). Mild elevation of liver enzymes and low albumin (Mean 2.4 gm%) with reversal of albumin globulin ratio (Mean 0.6) were seen in all. Two had jaundice. Prothrombin time was normal in all and lactate dehydrogenase values were elevated in all (Mean 794 IU/L). On ultrasonography, 2 had multiple hypodense lesion, 1 had coarse echotexture of liver, 1 had hyperechoic pattern and 3 had just hepatomegaly. Complete resolution of liver lesions on treatment with 4-drug anti-tuberculosis drug chemotherapy was seen. In conclusion, liver tuberculosis has protean manifestations with nonspecific alteration of liver function tests and is best diagnosed on liver biopsy. Overall response to therapy is satisfactory.