Niklaus Gyr

SPINK1 Is a Susceptibility Gene for Fibrocalculous Pancreatic Diabetes in Subjects from the Indian Subcontinent

Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease.

SPINK1/PSTI Mutations Are Associated with Tropical Pancreatitis in Bangladesh

Background/Aims: Tropical pancreatitis (TP) refers to a severe type of idiopathic chronic pancreatitis that develops in children in tropical regions of Africa and southern Asia. Phenotypically TP is subdivided into fibrocalculous pancreatic diabetes (FCPD) and tropical calcific pancreatitis without diabetes mellitus (TCP). Recently an association was identified between idiopathic pancreatitis in the USA and Europe and mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene (previously termed pancreatic secretory trypsin inhibitor, PSTI). Our aim was to determine if either form of TP has a genetic basis. Methods: We studied 8 well-characterized patients from Bangladesh with FCPD, 4 with TCP and 4 controls without pancreatic disease. The entire SPINK1 gene was sequenced in these patients. Results: We detected two disease-associated SPINK1 mutations (N34S/IVS1–37T>C and IVS3 + 2T>C) in 6 of 8 patients from Bangladesh with FCPD but not in 4 patients with TCP (p < 0.03) or 4 controls (p < 0.03). Conclusions: We conclude that SPINK1 mutations are associated with FCPD in Bangladesh. Since SPINK1 mutations in Europeans and North Americans are associated with idiopathic chronic pancreatitis that is phenotypically different from FCPD, we further conclude that mutated SPINK1 markedly increases the risk of developing a variety of pancreatic diseases possibly through a chronic elevation of active trypsin within the pancreas.

Causal Relationship of Helicobacter pylori With Iron-Deficiency Anemia or Failure of Iron Supplementation in Children

BACKGROUND & AIMS We investigated Helicobacter pylori (H pylori)-infection as a cause of iron deficiency (ID) and iron-deficiency anemia (IDA) or treatment failure of iron supplementation. METHODS We randomized 200 Hp-infected children (positive urea breath test) 2-5 years of age with IDA (hemoglobin level <110 g/L; serum ferritin level <12 microg/L; and soluble transferrin receptor >8.3 mg/L) or ID (serum ferritin level <12 microg/L or soluble transferrin receptor level >8.3 mg/L) to 1 of 4 regimens: 2-week anti-Hp therapy (amoxicillin, clarithromycin, and omeprazole) plus 90-day oral ferrous sulfate (anti-Hp plus iron), 2-week anti-Hp therapy alone, 90-day oral iron alone, or placebo. Sixty noninfected children with IDA received iron treatment as negative control. RESULTS Hp-infected children receiving iron had significantly less frequent treatment failure compared with those with no iron in correcting IDA (11% [95% confidence interval (CI), 2%-20%] for anti-Hp plus iron, 0% for iron alone vs 33% [95% CI, 26%-46%] for anti-Hp and 45% [95% CI, 31%-59%] for placebo; chi(2) = 127; P < .0001), ID (19% [95% CI, 8%-30%] for anti-Hp plus iron, 7% [95% CI, 0%-14%] for iron alone vs 65% [95% CI, 52%-78%] for anti-Hp alone, and 78% [95% CI, 66%-90%] for placebo; chi(2) = 124; P < .0001), or anemia (34% [95% CI, 20%-40%] for anti-Hp plus iron, 27% [95% CI, 14%-40%] for iron alone vs 65% [95% CI, 52%-78%] for anti-Hp alone and 78% [95% CI, 66%-90%] for placebo; chi(2) = 46; P < .0001). Cure rates of IDA, ID, or anemia with iron were comparable with that of the negative control group. Improvements in iron status also were significantly greater in groups with iron. CONCLUSIONS H pylori is neither a cause of IDA/ID nor a reason for treatment failure of iron supplementation in young Bangladeshi children.

Prevalence and risk factors of hepatitis B and C virus infections in an impoverished urban community in Dhaka, Bangladesh.

BackgroundViral hepatitis is a serious global public health problem affecting billions of people globally, and both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are rapidly spreading in the developing countries including Bangladesh due to the lack of health education, poverty, illiteracy and lack of hepatitis B vaccination. Also there is lack of information on their prevalence among the general population. So, a population-based serological survey was conducted in Dhaka to determine the prevalence and risk factors of HBV and HCV infections.MethodsHealthy individuals were selected for demographic and behavioural characteristics by stratified cluster sampling and blood tested for hepatitis B surface antigen (HBsAg), antibody to HBV core antigen (anti-HBc), and anti-HCV antibodies (anti-HCV).ResultsFrom June 2005-November 2006, 1997 participants were screened for HBsAg, anti-HBc and anti-HCV, 738 (37%) were males with mean (SD) age of 24 (14) years. HBV-seropositivity was documented in 582 (29%) participants: 14 (0.7%) were positive for HBsAg, 452 (22.6%) for anti-HBc and 116 (5.8%) for both HBsAg and anti-HBc. Four (0.2%) participants were positive for anti-HCV, and another five (0.3%) for both anti-HBc and anti-HCV. Ninety-six/246 (39%) family members residing at same households with HBsAg positive participants were also HBV-seropositive [74 (30.1%) for anti-HBc and 22 (8.9%) for both HBsAg and anti-HBc], which was significantly higher among family members (39%) than that of study participants (29%) (OR 1.56; p < 0.001). In bivariate analysis, HBV-seropositivity was significantly associated with married status (OR 2.27; p < 0.001), history of jaundice (OR 1.35; p = 0.009), surgical operations (OR 1.26; p = 0.04), needle-stick injuries (OR 2.09; p = 0.002), visiting unregistered health-care providers (OR 1.40; p = 0.008), receiving treatment for sexually transmitted diseases (STD) (OR 1.79; p = 0.001), animal bites (OR 1.73; p < 0.001); ear-nose-body piercing in females (OR 4.97; p < 0.001); circumcision (OR 3.21; p < 0.001), and visiting community barber for shaving in males (OR 3.77; p < 0.001). In logistic regression analysis, married status (OR 1.32; p = 0.04), surgical operations (OR 1.39; p = 0.02), animal bites (OR 1.43; p = 0.02), visiting unregistered health-care providers (OR 1.40; p = 0.01); and ear-nose-body piercing in females (OR 4.97; p < 0.001) were significantly associated with HBV-seropositivity.ConclusionsThe results indicate intermediate level of endemicity of HBV infection in Dhaka community, with much higher prevalence among family members of HBsAg positive individuals but low prevalence of HCV infections, clearly indicating need for universal hepatitis B vaccination. The use of disposable needles for ear-nose-body piercing need to be promoted through public awareness programmes as a preventive strategy.

Partially hydrolysed guar gum supplemented comminuted chicken diet in persistent diarrhoea: a randomised controlled trial.

Background: Partially hydrolysed guar gum (Benefiber) added to a diet is fermented in the colon, producing short chain fatty acids, which improve intestinal function, including colonic salt and water absorption. Aims: To evaluate the effect of Benefiber supplemented comminuted chicken diet in the treatment of persistent diarrhoea. Methods: One hundred and sixteen children (aged 5–24 months), presenting to Dhaka Hospital with a history of watery diarrhoea for more than 14 days (persistent diarrhoea), were randomised to receive either: (1) comminuted chicken diet with Benefiber (study diet); or (2) comminuted chicken diet without Benefiber (control diet). The study period was seven days. Results: Of 116 children, 57 received the study diet and 59 received the control diet. Diarrhoea resolved in a greater number of children with the study than with the control diet (46/55 (84%) v 36/58 (62%); odds ratio 3.12, 95% CI 1.19 to 8.4). Survival analysis for the duration of diarrhoea also showed a reduced duration of diarrhoea in children receiving the study diet. There was also a trend in daily stool reduction in children receiving the study diet, significant on days 4–7. Conclusion: Results show that Benefiber supplemented comminuted chicken diet enhances recovery of children with persistent diarrhoea, indicating its therapeutic potential.

Lack of R117H mutation in the cationic trypsinogen gene in patients with tropical pancreatitis from Bangladesh

The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Although environmental factors may play a role in its pathogenesis, a specific genetic predisposition may be necessary. The genetic mutation responsible for hereditary pancreatitis was described recently. Unlike in patients with hereditary pancreatitis, we found a lack of the R117H mutation in the cationic trypsinogen gene in all patients with tropical pancreatitis from Bangladesh.

Efficacy of Partially Hydrolyzed Guar Gum-Added Oral Rehydration Solution in the Treatment of Severe Cholera in Adults

Background: Partially hydrolyzed guar gum (PHGG) is a water-soluble fiber if added to oral rehydration solution (ORS) and undergoes fermentation in the colon liberating short chain fatty acids (SCFAs). SCFAs potentiate the effect of ORS, reducing the severity of diarrhea. Aim: To examine the effect of PHGG-added ORS in reducing the stool output and duration of diarrhea in adult cholera. Methods: 195 male patients were studied in a randomized controlled trial: (a) 65 received ORS + 25 g PHGG; (b) 65 received ORS + 50 g PHGG, and (c) 65 received ORS alone (control). Major outcomes were stool weight and duration of diarrhea. Results: No significant differences were found in mean ± SD stool weight (g/kg b.w.) during the first and second 24 h. In the subgroup analysis (excluding very high purging patients, stool weight in the first 24 h was >10 kg), the stool weight (g/kg b.w.) was significantly reduced in the first 24 h in both groups receiving PHGG (PHGG 25 g, 136 ± 68 vs. PHGG 50 g, 144 ± 49 vs. control, 176 ± 43, p = 0.01). Conclusion: PHGG-added ORS might have a beneficial effect in moderately purging adult cholera. However, further studies are warranted to confirm the preliminary findings.

Long-Term Re-Infection Rate after Helicobacter pylori Eradication in Bangladeshi Adults

Background and Aim: Bangladesh is a developing country with a very high prevalence of Helicobacter pylori infection, which has been ascribed to overcrowding and poor sanitary conditions. It has generally been accepted that the re-infection rate is higher in countries with a high prevalence of H. pylori infection. Short-term follow-up studies support this assumption but no long-term studies are available to confirm or refute this assertion. The present study was aimed to define the long-term H. pylori re-infection rate (6 years after successful eradication) in duodenal ulcer patients. Methods: In a previous study, 90 patients were successfully eradicated for H. pylori and followed-up for 24 months. 17/90 were found to be re-infected (18% re-infection rate per year in the first 12 months) [Gastroenterology 2001;792–798]. The remaining 73 patients were targeted for long-term follow-up. 26/73 were lost to follow-up; 6 symptomatic patients were tested H. pylori positive in the period between 24 and 60 months post-eradication. The remaining 41 patients were evaluated 72 months after successful eradication. The evaluation included clinical history taking, a 13C-urea breath test (UBT), and endoscopy. Results: Of the 41 H. pylori-eradicated patients analyzed after 72 months, 16 were H. pylori-positive. If the 6 patients, who were tested positive between 24 and 60 months, are added, the total re-infection cases amount to 22 subjects in the period between 24 and 72 months. Therefore, an overall annual re-infection rate 6 years after eradication of 5.02% can be calculated. Six of the 23 symptomatic patients had duodenal ulcer relapse, 5/6 were H. pylori re-infected and one was H. pylori-negative at 72 months post-treatment. Conclusion: The long-term annual H. pylori re-infection rate in Bangladeshi adults is markedly higher than in Western countries but lower than anticipated. In this study, duodenal ulcer relapse is clearly related to H. pylori re-infection.

A follow-up experience of 6 months after treatment of children with severe acute malnutrition in Dhaka Bangladesh.

AIM As there is lack of information about what happens to children after recovery from severe acute malnutrition (SAM), we report their relapse, morbidity, mortality and referral during follow-up period. METHODS From February 2001 to November 2003, 180 children completing acute and nutrition rehabilitation (NR) phases of protocolized management were advised for 6-months follow-up. The mean (SD) age was 12 (5) months, 55% were infants, 53% were male and 68% were breast-fed. RESULTS The follow-up compliance rate dropped from 91% at first to 49% at tenth visit. The common morbidities following discharge included fever (26%), cough (24%) and diarrhoea (20%). Successful follow-up done in 124 children [68.9% (95% CI 61.8-75.2%)], partial follow-up in 45 [25% (95% CI 19.2-31.8%)], relapse in 32 [17.8% (95% CI 12.9-24%)] and 5 [2.8% (95% CI 1.2-6.3%)] died. CONCLUSION Our findings highlight need for follow-up as part of overall management of SAM and recommend an effective community follow-up.

Diabetes mellitus in Tropical Chronic Pancreatitis Is Not Just a Secondary Type of Diabetes

Aims: In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes mellitus are unknown. Some consider these cases a straightforward secondary type of diabetes, while others suggest selective β-cell impairment. Testing pancreatic function, we investigated whether selective β-cell impairment triggers diabetes associated with tropical pancreatitis. Methods: At a Bangladeshi research institute, 8 chronic tropical pancreatitis and no diabetes mellitus subjects, 14 fibrocalculous pancreatic diabetics and 27 matched healthy controls underwent arginine (endocrine pancreatic function) and secretin (exocrine pancreatic function assessment) stimulation tests. Results: All patients with clinically-diagnosed, chronic pancreatitis demonstrated pronounced exocrine pancreatic dysfunction with β-cell functioning differing significantly between the two groups. Compared to controls, patients having tropical pancreatitis and no diabetes showed normal plasma C-peptide values at baseline and after arginine stimulation, while fibrocalculous pancreatic diabetics demonstrated a typical diabetic pattern for plasma C-peptide levels. In contrast, pancreatic α-cell functioning (glucagon response to arginine) was preserved in both pancreatitis groups. Conclusion: A preserved pancreatic α-cell function in diabetics with advanced chronic pancreatitis of the tropics supports the concept of two different pathogenic mechanisms, one eliciting chronic pancreatitis and the other selective pancreatic β-cell impairment and subsequent diabetes mellitus.