Pathogenesis of tropical sprue A pilot study of antroduodenal manometry, duodenocaecal transit time & fat-induced ileal brake.

Background & objectives: Small intestinal bacterial overgrowth (SIBO) due to ileal brake-induced hypomotility may cause tropical sprue (TS). We evaluated effect of infusion of fat or placebo in duodenum randomly in patients with TS and healthy controls on antroduodenal manometry (ADM) and mediators of ileal brake, and duodenocaecal transit time (DCTT). Methods: ADM and DCTT (lactulose hydrogen breath test, HBT) were evaluated with placebo and fat in eight controls and 13 patients with TS (diagnostic criteria: tests showing malabsorption of two unrelated substances, abnormal duodenal histology, absence of other causes, response to antibiotics and folate). Results: Patients with TS (6 had SIBO by glucose HBT) were similar in age and gender with controls. After fat infusion, proximal gut motility index (MI) was reduced compared to fasting state in TS, and DCTT was longer in TS than controls (200 min, 120-380 vs. 130, 70-160, P=0.001), though comparable after placebo (70 min, 30-140 vs. 60, 40-90). TS patients had higher PYY and neurotensin than controls after fat infusion. DCTT after fat infusion correlated with plasma level of PYY in TS but not in controls. Post-fat PYY and neurotensin levels were higher in TS with lower BMI (<16 kg/m2) than those with higher BMI. Parameters of ileal brake (post-fat DCTT, PYY and neurotensin) were higher in patients with than without SIBO. Interpretation & conclusions: Fat infusion reduced proximal gut MI, increased DCTT, PYY, and neurotensin among patients with TS. Malabsorbed fat might cause exaggerated ileal brake reducing gut motility, promoting SIBO and bacterial colonization and malabsorption in TS.

Spectrum of malabsorption syndrome among adults & factors differentiating celiac disease & tropical malabsorption.

Background & objectives: Aetiology of malabsorption syndrome (MAS) differs in tropical and temperate countries over time; clinical and laboratory parameters may differentiate between various causes. This study was undertaken to investigate the spectrum of MAS among Indian adults and to find out the features that may help to differentiate between TM and celiac disease. Methods: Causes of MAS, and factors differentiating tropical malabsorption (TM) from celiac disease (CD) were determined in 275 patients. Results: Using standard criteria, causes in 275 patients [age 37.5+13.2 yr, 170, (61.5%) male] were, TM 101 (37%), CD 53 (19%), small intestinal bacterial overgrowth 28 (10%), AIDS 15 (5.4%), giardiasis 13 (5%), hypogammaglobulinemia 12 (4%), intestinal tuberculosis 7 (2.5%), strongyloidiasis 6 (2%), immunoproliferative small intestinal disease 5 (2%), Crohn's disease 6 (2%), amyloidosis 4 (1.5%), intestinal lymphangiectasia 3 (1%) and unknown 22 (8%). On univariate analysis, patients with CD were younger than TM (30.6+12 vs. 39.3+12.6 yr, P<0.001), had lower body weight (41.3+11.8 vs. 49.9+11.2 kg, P<0.001), longer diarrhoea duration (median 36 inter-quartile range 17.8-120 vs. 24-months, 8-48, P<0.01), lower stool frequency (6/day, 5-8 vs. 8, 5-10, P<0.05), lower haemoglobin (9.4+3.2 vs. 10.4+2.7 g/dl, P<0.05), higher platelet count (2,58,000, range 1,35,500-3,23,500 vs. 1,60,000, 1,26,000-2,58,000/mm3, P<0.05), and more often had hepatomegaly (9/53, 17% vs. 4/101, 4%, P<0.01), and subtotal or partial villous atrophy (36/50, 72% vs. 28/87, 32%, P<0.001). Younger age (<35 yr), longer diarrhoea duration, higher platelet count and villous atrophy were significant on multivariate analysis. Interpretation & conclusions: TM and CD are common causes of MAS among Indian adults. Younger age (<35 yr), longer diarrhoea duration, higher platelet count and villous atrophy were found to be associated with CD.

Chronic diarrhea and malabsorption due to hypogammaglobulinemia: a report on twelve patients.

Hypogammaglobulinemic sprue (HGS), which may predispose to infection, is uncommon. Twelve patients (all men; median age 29 years, 15–50) with HGS (4%) of 296 with chronic small bowel diarrhea and malabsorption syndrome (MAS) during a 10-year period were analyzed. Treatment of HGS was delayed due to misdiagnosis as intestinal tuberculosis (n=7) and diarrhea-predominant irritable bowel syndrome (n=1). All had diarrhea and weight loss (median loss 12 Kg). Associated conditions were clubbing, bronchiectasis, and seizure (2 patients each), and hypothyroidism (n=1). Laboratory parameters were urinary D-xylose median 0.46 g/5 g/5 h (range 0.2–1.6; normal ≥1), fecal fat 11.9 g/day (3.8–16.7; normal ≤7 g), serum IgA, IgG, and IgM: 23.5 mg/dL (17–114; normal 90–450), 584 mg/dL (145–1051; normal 800–1800), and 23 (0–40.3; normal 60–280). IgA, IgG, and IgM were low in 10, 10, and 11, respectively. Duodenal biopsy was normal in 6 patients and showed partial villous atrophy in 6 and nodular lymphoid hyperplasia in two. Associated infections were giardiasis (n=1), disseminated strongyloidiasis (1), small intestinal bacterial overgrowth (3), septicemia (2), and septic arthritis (1). Two patients died of sepsis, five are well on immunoglobulin and specific antiinfective treatment, and five are lost to follow up. Approximately 4% patients with MAS have hypogammaglobulinemia, which is often associated with infection and is diagnosed late.

Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population.

Aim To find out the association of common HFE mutations (viz., C282Y and H63D) with primary iron overload (PIL) in liver cirrhosis (CLD) patients of Indian origin. Methods Polymerase chain reaction-restriction fragment length polymorphism method was used for screening C282Yand H63D mutation in 496 CLD patients (hepatitis B virus associated cirrhosis (HBVc)=74, hepatitis C virus associated cirrhosis (HCV)=50, alcoholic cirrhosis with hepatitis (ALcW) = 38, alcoholic cirrhosis without hepatitis (ALc)=92, cryptogenic cirrhosis (CC)=242) and 502 healthy controls. Transferrin saturation of >45 or serum ferritin of >300 ng/mL (males)/>200 ng/mL (females) with normal total exogenous iron intake was suggestive of PIL. Histological liver iron grading was done by Perl’s Prussian blue stain. Results Of 496 patients, 13 (2.6; 9 CC, 2 ALc, 1 HBVc, 1 AlcW) had PIL. However, only two (15.3) of 13 patients (1 CC and 1 HBVc) were positive for H63D heterozygous mutation. All the subjects were found to be C282Y wild type, except a single case of double heterozygous (C282Y/H63D) who however, did not have PIL. Overall frequency of H63D allele in patients and controls was not significantly different (5.95 and 4.58 respectively, p=0.17). A highly significant H63D allele frequency (p<0.005) was observed in HBVc (10.82) and ALcW (11.84) groups but they were not associated with PIL. Conclusion The frequency of PIL, and the HFE gene mutaion (C282Y) are both rare in Indian patients and explain why hemochromatosis is a rare cause of liver cirrhosis in India. A highly significant H63D allele frequency in HBV and alcohol-related cirrhosis suggest a possible predisposing role for liver fibrosis of this allele.

Epidemiology and symptom profile of gastroesophageal reflux in the Indian population: Report of the Indian Society of Gastroenterology Task Force.

Background Gastroesophageal reflux disease (GERD) and its complications are thought to be infrequent in India; there are no data from India on the prevalence of and risk factors for GERD. The Indian Society of Gastroenterology formed a task force aiming to study: (a) the frequency and profile of GERD in India, (b) factors including diet associated with GERD. Methods In this prospective, multi-center (12 centers) study, data were obtained using a questionnaire from 3224 subjects regarding the frequency, severity and duration of heartburn, regurgitation and other symptoms of GERD. Data were also obtained regarding their dietary habits, addictions, and lifestyle, and whether any of these were related or had been altered because of symptoms. Data were analyzed using univariate and multivariate methods. Results Two hundred and forty-five (7.6%) of 3224 subjects had heartburn and/or regurgitation at least once a week. On univariate analysis, older age (OR 1.012; 95% CI 1.003–1.021), consumption of non-vegetarian and fried foods, aerated drinks, tea/coffee were associated with GERD. Frequency of smoking was similar among subjects with or without GERD. Body mass index (BMI) was similar in subjects with and without GERD. On multivariate analysis, consumption of non-vegetarian food was independently associated with GERD symptoms. Overlap with symptoms of irritable bowel syndrome was not uncommon; 21% reported difficulty in passage of stool and 9% had mucus in stools. About 25% of patients had consulted a doctor previously for their gastrointestinal symptoms. Conclusion 7.6% of Indian subjects have significant GERD symptoms. Consumption of non-vegetarian foods was an independent predictor of GERD. BMI was comparable among subjects with or without GERD.

Long term efficacy and safety of N-butylcyanoacrylate in endoscopic treatment of gastric varices.

Introduction: Endoscopic glue (N-butyl-2-cyanoacrylate) injection has emerged as promising therapy for bleeding gastric varices (GV). We evaluated safety and long term efficacy of this technique in patients with portal hypertension and large bleeding GV. Patient and Methods: 170 patients (mean age 40.9±14y; 132 male; 142 had cirrhosis, 40 Child A, 62 Child B, 40 Child C) underwent glue injection into GV (F3 140, F2 30; fundal 114) as emergency procedure for active bleeding in 62 and electively for prevention of rebleeding in 108. Glue was injected intra-variceally under endoscopic vision, 0.5-4ml/aliquot, repeated at 3 weeks till varices were eradicated/solidified. The efficacy was assessed by hemostasis at 48 h, primary, secondary, definitive success and treatment failure. Results: The overall hemostasis rate at 48h was 82.3% (51/62). Follow up was available in 158 patients for mean of 30.7 + 17.2 months. Repeat injections were performed in 76. The mean number of injections were 1.9±1.0 (1-4); total volume was 2.5±1.7 ml / patient. The status of GVs at last follow up was : disappeared in 32 (22.6%); F1 solidified in 46 (32.3%); F2 solidified in 64 (45.0%). Bleeding recurred in 14.5% (23/158); 60% within 2 weeks of injection. The primary, secondary and definitive success rates were 85.4% (135/158), 4.4% (7/158) and 89.9% (142/158) respectively and treatment failure rate was 10% (16/158). No significant complications were noticed except for injection site ulceration in 32. Twenty patients died on follow up (9 died of uncontrolled bleeding, 11 died of liver failure) Conclusion: Endoscopic glue injection into bleeding GVs was effective in achieving hemostasis in 82% with a definitive success rate of 90% and had a good safety profile on long term follow up.

Alterations of p53 gene in gallbladder cancer patients of North India.

Background: Mutations in p53 gene are found in a majority of human malignancies and usually occur in the exons 5, 6, 7 and 8. Mutated p53 protein is more stable and gets accumulated in the cells that induce the host to develop anti-p53 antibodies in sera of cancer patients. Aim: This study is aimed to observe the frequency and nature of mutations in exons 5-8 of p53 gene and to evaluate its correlation with prevalence of serum p53 antibodies in Indian patients with gallbladder cancer (GBC). Methods: Mutation studies were done in cancer tissues obtained from 62 patients with proven GBC (40 cytologically proven cases and 22 resected gallbladder cancer tissues) by polymerase chain reaction (PCR), restriction fragment length analysis (RFLP) and single strand conformation polymorphism (SSCP). Presence of serum p53 antibodies was determined using highly specific enzyme linked immunosorbent assay (ELISA) kit in 50 patients with GBC and 30 patients of cholelithiasis. Clinicopathologic characteristics of these patients were given attention. Results: Antibodies to p53 protein was present in the serum in 34% (17/50) of GBC patients and in 3.3% (1/30) patients with cholelithiasis (p<0.018). RFLP failed to detect common mutations in the exons 5- 8 of the p53 gene in 62 samples. Using SSCP analysis we could detect frameshift mutation in p53 gene in 2 of 22 (9.1%) GBC cases. Mutated samples were sequenced and found to have insertion of adenine at codon 271 (GAG) in exon 8 region. Conclusion: Our results show that 1/3rd of the north Indian patients with GBC have antibodies to p53 protein. The commonest identifiable alteration in the p53 gene was a frameshift mutation at codon 271.

Pancreatic diabetes.

Pancreatic endocrine insufficiency secondary to destruction of acinar cells is a well known complication of chronic pancreatitis (CP). Of all patients with diabetes mellitus, 0.5-1% is secondary to CP. The frequency of occurrence of diabetes in CP is about 40-60%. This figure varies according to the aetiology, extent of calcification, and duration of the disease. Pancreatic diabetes is more commonly associated with alcoholic and tropical calcific pancreatitis of long duration. The pathophysiology of pancreatic diabetes is related to beta cell failure and reduced insulin secretory capacity. The development of pancreatic diabetes calls for careful evaluation and management to prevent long term complications. Pancreatic cancer is a known complication of chronic pancreatitis and sometimes manifests with new onset diabetes. As destruction of pancreatic tissue in CP leads to depletion of both insulin and glucagonproducing cells of the islets of Langherhans, pancreatic diabetics are usually not prone to ketoacidosis. A trial of oral hypoglycemic agents followed by insulin therapy when the need arises has been the line of management thus far in these patients. This review focuses on the prevalence, unique pathophysiological aspects, clinical features and special issues in the management of diabetes secondary to chronic pancreatitis.

Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force.

AIMS: To study the profile of irritable bowel syndrome (IBS), and the frequency of such symptoms among the general population, in India. METHODS: In this prospective, multi-center study, data were obtained from 2785 patients with chronic lower gastrointestinal symptoms (complainants) with no alarm feature and negative investigations for organic causes visiting physicians at 30 centers, and from 4500 community subjects (non-complainants), using separate questionnaires. RESULTS: Most complainants were middle-aged (mean age 39.4 years) and male (1891; 68%). The common symptoms were: abdominal pain or discomfort (1958; 70%), abdominal fullness (1951; 70%); subjective feeling of constipation (1404 of 2656; 53%), or diarrhea (1252 of 2656, 47%), incomplete evacuation (2134; 77%), mucus with stools (1506; 54%), straining at stools (1271; 46%), epigastric pain (1364; 49%) and milk intolerance (906; 32%). Median stool frequency was similar in patients who felt they had constipation or those who felt they had diarrhea. Information to subtype symptoms using standard criteria was available in 1301 patients; of these, 507 (39%) had constipation-predominant IBS ( 3 <or= stools/week), 50 (4%) had diarrhea-predominant IBS (>3 stools/day) and 744 (57%) had indeterminate symptoms. Among non-complainants, most subjects reported daily defecation frequency of one (2520 [56%]) or two (1535 [34%]). Among non-complainants, 567 (12.6%) reported abdominal pain, 503 (11%) irregular bowel, 1030 (23%) incomplete evacuation, 167 (4%) mucus and 846 (18%) straining at stools; a combination of abdominal pain or discomfort relieved by defecation, and incomplete evacuation was present in 189/4500 (4.2%) community subjects. CONCLUSIONS: Most patients with IBS in India are middle-aged men, and have a sense of incomplete evacuation and mucus with stools. Abdominal pain or discomfort is frequent but not universal. Importantly, stool frequency was similar irrespective of whether the patients felt having constipation or diarrhea. Most (90%) non-complainant subjects had 1 or 2 stools per day; symptoms complex suggestive of IBS was present in 4.2% of community subjects.

Acute hemorrhagic ascites: look beyond the gastrointestinal tract.

A 33-year-old alcoholic man presented with acute abdominal pain and hemorrhagic, high serum-ascitic albumin gradient ascites following an alcoholic binge, accompanied by hyperkalemia and azotemia. Spontaneous rupture of urinary bladder was diagnosed. The patient recovered uneventfully with conservative management.

Gastric adenocarcinoma presenting with intestinal pseudoobstruction, successfully treated with octreotide.

Intestinal pseudoobstruction has been reported as a paraneoplastic manifestation of several cancers, including those of gastrointestinal tract. Octreotide, a somatostatin analogue, has been used successfully in the treatment of idiopathic and scleroderma-associated intestinal pseudoobstruction. We report a 65-year-old man with carcinoma stomach presenting with intestinal pseudoobstruction, which responded to octreotide.

Molecular mechanisms of pancreatic cancer.

Pancreatic cancer is a deadly disease with no effective therapy short of surgical resection. Unfortunately, only a minority of patients are candidates for potential curative surgery as the tumor spreads early to extrapancreatic sites. Patients with metastatic pancreatic cancer survive less than 1 year following diagnosis. The current challenge for both clinicians and scientists is to translate the growing body of knowledge of the molecular basis of this disease into effective strategies for early diagnosis and systematic treatment. Molecular studies of pancreatic cancer have revealed that this cancer is associated with several genetic mutations. Although our knowledge of the molecular alterations in pancreatic cancer has grown significantly, there is still much to learn. It is clear that oncogenes, tumor suppressor genes, growth factors and DNA mismatch repair genes all play a role in pancreatic tumorigenesis. However, a better understanding of the relative contribution of each of these molecular alterations is necessary and will aid the development of more effective diagnostic and therapeutic strategies to deal with this deadly and aggressive cancer.

Profile of liver involvement in dengue virus infection.

BACKGROUND: Data are scarce on liver involvement in adult patients with dengue virus infection. METHODS: During a recent outbreak of dengue fever in Uttar Pradesh, India, we looked for evidence of liver dysfunction among patients with dengue fever. RESULTS: A total of 45 patients with dengue fever (age 7-65 [median 33] years; 29 men; 39 adults) were studied, including 23 with uncomplicated dengue fever, 15 with dengue haemorrhagic fever and 7 with dengue shock syndrome. The median platelet count was 34 x 10(9)/L (9-99 x 10(9)). Seven patients (15%) had jaundice, 11 (24%) hepatomegaly and 9 clinically detectable ascites; none had splenomegaly. Twelve patients (30%) had hyperbilirubinaemia. Serum alanine and aspartate aminotransferase activities were elevated in 43 patients (96%) each; 5-fold elevated levels were more frequent in severe disease. Hypoalbuminaemia was found in 31/41 patients (76%). Seven patients died, including 2 with acute liver failure. CONCLUSION: Our data show that liver injury is common in adult patients with dengue infection. Further studies are needed to determine the mechanism of liver injury in this disease.

Occult hepatitis B virus infection as a cause of cirrhosis of liver in a region with intermediate endemicity.

BACKGROUND: Serological tests may fail to identify hepatitis B virus (HBV) infection as a cause of liver cirrhosis in a proportion of patients. The frequency of such occult infection in regions with intermediate HBV endemicity is not known. Such cases may be diagnosed by incremental testing for IgG anti-HBc, serum HBV DNA, and HBV DNA in liver tissue. METHODS: We tested sera of 111 patients with cirrhosis, including 39 with history of significant alcohol ingestion, for HBsAg, anti-HBc and serum HBV DNA. In addition, in a subset of 14 patients, HBV DNA was looked for in liver tissue. RESULTS: On HBsAg and anti-HBc testing, 66 patients had HBV infection. Serum HBV DNA testing identified HBV infection in 13 additional cases. Of 18 patients labeled as 'cryptogenic' on serological testing, HBV DNA was detected in the serum in 7 patients. Of 14 patients in whom paired liver tissue and serum specimens were tested, 4 additional patients with HBV infection were detected after liver biopsy analysis. CONCLUSIONS: Serological tests for HBsAg and anti-HBc antibody are insensitive in identifying HBV infection in patients with liver cirrhosis. HBV DNA testing in serum and liver can help in establishing HBV infection as etiology, either alone or in addition to another cause.