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Diarrhoea of unknown cause: medical treatment in a stepwise mannerManagement of Idiopathic Diarrhoea Based on Experience of Step-Up Medical Treatment.
Jansson-Rehnberg, AS, Drewes, AM, Sponheim, J, Borgfelt, C, Münch, A, Graf, W, Simrén, M, Lindberg, G, Hellström, PM
Scandinavian journal of gastroenterology. 2024;:1-4
Abstract
The basic principle for the treatment of idiopathic diarrhoea (functional diarrhoea K59.1) is to delay transit through the gut in order to promote the absorption of electrolytes and water. Under mild conditions, bulking agents may suffice. With increasing severity, antidiarrhoeal pharmaceuticals may be added in a stepwise manner. In diarrhoea of unknown aetiology, peripherally-acting opioid receptor agonists, such as loperamide, are first-line treatment and forms the pharmaceutical basis of antidiarrheal treatment. As second-line treatment opium drops have an approved indication for severe diarrhoea when other treatment options fail. Beyond this, various treatment options are built on experience with more advanced treatments using clonidine, octreotide, as well as GLP-1 and GLP-2 analogs which require specialist knowledge the field.
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Pseudo-obstruction, enteric dysmotility and irritable bowel syndrome.
Lindberg, G
Best practice & research. Clinical gastroenterology. 2019;:101635
Abstract
New diagnostic techniques have advanced our knowledge about the irritable bowel syndrome. The majority of patients that we believed to have a psychosomatic disorder have received other diagnoses explaining their symptoms. Endoscopy makes it possible to diagnose celiac disease before it leads to malnutrition and allows the detection of microscopic colitis as a cause of watery diarrhea. At the severe end of the symptom spectrum enteric dysmotility marks the border at which IBS ceases to be a functional disorder and becomes a genuine motility disorder. Joint hypermobility or Ehlers-Danlos syndrome is present in a substantial proportion of patients with enteric dysmotility. Chronic intestinal pseudo-obstruction is the end-stage of a large number of very rare disorders in which failed peristalsis is the common denominator. Nutritional needs and symptom control are essential in the management of pseudo-obstruction. Home parenteral nutrition is life saving in more than half of patients with chronic intestinal pseudo-obstruction.
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3.
Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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Plain language summary
Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.
Abstract
OBJECTIVE IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.
Garcia-Etxebarria, K, Zheng, T, Bonfiglio, F, Bujanda, L, Dlugosz, A, Lindberg, G, Schmidt, PT, Karling, P, Ohlsson, B, Simren, M, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(10):1673-1676
Abstract
Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.
Bonfiglio, F, Zheng, T, Garcia-Etxebarria, K, Hadizadeh, F, Bujanda, L, Bresso, F, Agreus, L, Andreasson, A, Dlugosz, A, Lindberg, G, et al
Gastroenterology. 2018;(1):168-179
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Abstract
BACKGROUND & AIMS Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M.
Henström, M, Hadizadeh, F, Beyder, A, Bonfiglio, F, Zheng, T, Assadi, G, Rafter, J, Bujanda, L, Agreus, L, Andreasson, A, et al
Gut. 2017;(9):1725-1727
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Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.
Ek, WE, Reznichenko, A, Ripke, S, Niesler, B, Zucchelli, M, Rivera, NV, Schmidt, PT, Pedersen, NL, Magnusson, P, Talley, NJ, et al
Gut. 2015;(11):1774-82
Abstract
OBJECTIVE IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN We conducted a GWA study (GWAS) of IBS in a general population sample of 11,326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.
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Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
Beyder, A, Mazzone, A, Strege, PR, Tester, DJ, Saito, YA, Bernard, CE, Enders, FT, Ek, WE, Schmidt, PT, Dlugosz, A, et al
Gastroenterology. 2014;(7):1659-1668
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Abstract
BACKGROUND & AIMS SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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Can sulphonylurea addition to lifestyle changes help to delay diabetes development in subjects with impaired fasting glucose? The Nepi ANtidiabetes StudY (NANSY).
Lindblad, U, Lindberg, G, Månsson, NO, Ranstam, J, Tyrberg, M, Jansson, S, Lindwall, K, Svärdh, M, Kindmalm, L, Melander, A
Diabetes, obesity & metabolism. 2011;(2):185-8
Abstract
The Nepi ANtidiabetes StudY (NANSY) is a 5-year randomized, double-blind, placebo-controlled trial in Swedish primary care, examining whether the development of type 2 diabetes (T2D) and retinopathy (separately reported) would be delayed in 40- to 70-year-old subjects with impaired fasting glucose (IFG) who, in addition to lifestyle changes, were treated with either placebo or low-dosage sulphonylurea (SU) (1-mg glimepiride; Amaryl). Of 274 subjects (163 men, 111 women), 138 were allocated to placebo (46.0% men, 56.8% women) and 136 to glimepiride (54.0% men, 43.2% women). The primary endpoint was conversion to diabetes. Average follow-up time was 3.71 years; 96 subjects converted to diabetes, 55 allocated to placebo and 41 to glimepiride (absolute difference 9.8%; p = 0.072). In conclusion, the study failed to support the notion that low-dose SU added to lifestyle changes in IFG subjects would help to delay the conversion to diabetes.
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Satiety drinking tests: effects of caloric content, drinking rate, gender, age, and body mass index.
Abid, S, Anis, MK, Azam, Z, Jafri, W, Lindberg, G
Scandinavian journal of gastroenterology. 2009;(5):551-6
Abstract
OBJECTIVE To compare the maximum tolerated volumes (MTVs) of drinking water and a nutrient liquid at different rates of drinking and to assess the best drinking test correlating with the symptom scores. MATERIAL AND METHODS Healthy volunteers were requested to drink water at a rate of 10 ml/min or a nutrient liquid drink at 100 and 20 ml/min on three separate occasions. Symptoms of bloating, nausea, and abdominal pain were assessed 30 min after the cessation of drinking using visual analogue scales. RESULTS The MTV of water was 1595 +/- 405 in males and 1327 +/- 308 in females (p<0.05). In rapid nutrient drinking, the MTV was 945 +/- 376 ml in males, whereas females tolerated 760 +/- 174 ml (p<0.05). In slow nutrient drinking, the MTV was 692 +/- 184 ml in males and 594 +/- 131 ml in females (p=0.051). Multiple regression analysis showed no influence of body mass index (BMI), age, or gender in slow nutrient drinking. However, drinking capacity was significantly influenced by gender, age, and BMI in rapid water drinking and by gender in rapid nutrient drinking. When the tolerated volumes for satiety drinking tests were compared, only males showed some significant positive correlations. Symptom scores were higher after slow nutrient drinking compared to the other two drinking tests. CONCLUSIONS The rate of drinking and the caloric content affect the MTVs in satiety drinking tests. Slow nutrient drinking appears to be the best choice among the different satiety drink tests, as MTV in this test was not influenced by BMI or age and was associated with higher symptom scores.