Bile Acid Malabsorption in Patients with Neuroendocrine Tumors.

BACKGROUND: Chronic diarrhea in patients with neuroendocrine tumors (NET) may be caused by bioactive products of NET, bile acid malabsorption (BAM), ileal resection (IR) or steatorrhea. AIM: To quantitate BA and fat malabsorption in NET with diarrhea. METHODS: Part of evaluation in medical oncology clinical practice, 67 patients [42F, 25 M; median age 64.0 y (17.0 IQR)] with well-differentiated NET and diarrhea underwent clinically indicated measurements of 48-h fecal BA [(FBA), fecal weight (normal < 400 g/48 h), fecal fat (normal < 7 g/day) in n = 52] and fasting serum 7αC4 (marker of hepatic BA synthesis, n = 30) between 01/2018 and 11/2020. IR had been performed in 45 patients. BAM diagnosis was based on FBA criteria: elevated total FBA (> 2337 µmol/48 h) or > 10% primary FBA or combination > 4% primary FBA plus > 1000 µmol total FBA/48 h. We also measured fecal elastase (for pancreatic insufficiency) in 13 patients. RESULTS: BAM was present in 48/52 (92%) patients with NET. There were significant correlations between total FBA and 48-h fecal weight (Rs = 0.645, P < 0.001). Mean length of IR was 47 cm; in patients with IR < 25 cm, total FBA was elevated in 85% and primary FBA > 10% in 69%. In 22 patients with no IR, 13/15 tested (87%) had BAM. Among 6 patients with pancreatic NET and no IR, 80% had BAM. Fecal fat was ≥ 15 g/day in 18/42 (43%). In 4/17 (24%) with IR < 25 cm and 8/19 (42%) patients with IR > 25 cm fecal fat was 44.0 (40.5) and 38.0 (38.0)g/day, respectively. CONCLUSION: A majority of patients with NET and diarrhea had BAM, even with < 25 cm or no IR.

The pathophysiology of bile acid diarrhoea: differences in the colonic microbiome, metabolome and bile acids.

Bile acid diarrhoea (BAD) is a common disorder resulting from increased loss of bile acids (BAs), overlapping irritable bowel syndrome with diarrhoea (IBS-D). The gut microbiota metabolises primary BAs to secondary BAs, with differing impacts on metabolism and homeostasis. The aim of this study was to profile the microbiome, metabolic products and bile acids in BAD. Patients with BAD diagnosed by SeHCAT testing, were compared with other IBS-D patients, and healthy controls. Faecal 16S ribosomal RNA gene analysis was undertaken. Faecal short chain fatty acid (SCFA) and urinary volatile organic compounds (VOCs) were measured. BAs were quantified in serum and faeces. Faecal bacterial diversity was significantly reduced in patients with BAD. Several taxa were enriched compared to IBS-D. SCFA amounts differed in BAD, controls and IBS-D, with significantly more propionate in BAD. Separation of VOC profiles was evident, but the greatest discrimination was between IBS-D and controls. Unconjugated and primary BA in serum and faeces were significantly higher in BAD. The faecal percentage primary BA was inversely related to SeHCAT. BAD produces dysbiosis, with metabolite differences, including VOC, SCFA and primary BAs when compared to IBS-D. These findings provide new mechanistic insights into the pathophysiology of BAD.

Brief report: length of ileal resection correlates with severity of bile acid malabsorption in Crohn's disease.

PURPOSE: Bile acid malabsorption (BAM) is a common cause of diarrhoea in Crohn's disease (CD) patients with ileal resection. BAM is usually diagnosed by selenium-labelled homotaurocholic acid test (75SeHCAT) but its availability is limited. Consequently, a large proportion of patients either remain undiagnosed or subject to empirical therapy. There is a paucity of studies examining the correlation between length of ileal resection and severity of BAM, which will be of use to clinicians with no recourse to diagnostic testing for BAM. METHODS: We tested the correlation between length of resected ileum and percentage retention on 75SeHCAT of all CD patients with a prior surgical resection who underwent 75SeHCAT testing. Response to treatment with bile salt sequestrant and 75SeHCAT retention values was tested using Fisher's exact test. RESULTS: A total of 91 patients were identified with a median age of 47 (IQR 21-80). The median length of resected ileum was 24 cm (range 15-165 cm) with a median of 1 resection (range 1-4). Overall, 88 patients (97%) had 75SeHCAT retention values of < 10% and 85 (93%) had retention of < 5%. There was a modest correlation between 75SeHCAT retention and length of ileal resection (Spearman's rho - 0.392, P = 0.0001). Data on response to treatment was available for 57 (63%) patients, of who 38 (67%) responded to bile salt sequestrant. There was no difference in 75SeHCAT retention values between responders and non-responders. CONCLUSIONS: There was a modest correlation between length of ileal resection and severity of BAM as defined by 75SeHCAT retention values. Response to bile salt sequestrant therapy was not dependent on 75SeHCAT retention values.

Risk Factors for Steatorrhea in Chronic Pancreatitis: A Cohort of 2,153 Patients.

This study aimed to investigate the occurrence of and determine the risk factors for steatorrhea in chronic pancreatitis (CP). It was based on analysis of both retrospectively and prospectively acquired database for CP patients admitted to our center from January 2000 to December 2013. Demographic data, course of disease, medical history, and follow-up evaluations of patients were documented in detail. Cumulative rate of steatorrhea was calculated by using the Kaplan-Meier method. For risk factor analysis, multivariate analysis by Cox proportional hazards regression model was performed. A total of 2,153 CP patients were included with a mean follow-up duration of 9.3 years. Approximately 14% (291/2,153) of CP patients presented with steatorrhea at diagnosis of CP. Cumulative rates of steatorrhea at 1, 5, 10, and 20 years after diagnosis of CP were 4.27% (95% CI: 3.42%-5.34%), 12.53% (95% CI: 10.74%-14.59%), 20.44% (95% CI: 17.37%-23.98%) and 30.82% (95% CI: 20.20%-45.21%), respectively. Male gender (HR = 1.771, p = 0.004), diabetes (HR = 1.923, p < .001), alcohol abuse (HR = 1.503, p = 0.025) and pancreaticoduodenectomy (HR = 2.901, p < 0.001) were independent risk factors for steatorrhea while CP in adolescents (HR = 0.433, p = 0.009) was a protective factor. In conclusion, male gender, adult, diabetes, alcohol abuse and pancreaticoduodenectomy lead to increased risk of steatorrhea in CP patients.

Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy.

Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance.

Bile acid malabsorption in inflammatory bowel disease.

Bile acid malabsorption (BAM) is a common but an underestimated and often neglected sign of inflammatory bowel diseases (IBDs), especially those affecting the distal ileum. Clinically relevant BAM is most often present in patients with Crohn's ileitis and particularly in ileal-resected Crohn's disease patients. However, deterioration of bile acid (BA) metabolism occurs also in patients with IBD without ileal disease or in those in clinical remission, and the role of BAM in these patients is not well appreciated by clinicians. In a majority of cases, BAM in IBD is caused by impaired conjugated BA reabsorption, mediated by apical sodium/BA cotransporting polypeptide, localized at the luminal surface of the ileal enterocytes. As a consequence, numerous pathological sequelae may occur, including the malfunction of lipid digestion with clinical steatorrhea, impaired intestinal motility, and/or significant changes in the intestinal microflora environment. In this review, a detailed description of the pathophysiological mechanisms of BAM-related diarrhea is presented. Although BAM is present in a significant number of patients with Crohn's disease, its laboratory assessment is not routinely included in diagnostic workups, partially because of costs, logistical reasons, or the unavailability of the more sophisticated laboratory equipment needed. Simultaneously, novel findings related to the effects of the BA signaling pathways on immune functions (mediated through TGR5, cell membrane G protein-coupled BA receptor 1, nuclear farnesoid X receptor, nuclear pregnane X receptor, or nuclear vitamin D receptor) are discussed along with intestinal metabolism in its relationship to the pathogenesis of IBD.

Valores normales de la prueba Sudan III en niños sanos menores de un año de edad / Normal range for Sudan III test in under children under one year of age

La esteatorrea es la pérdida de grasa en las heces. Se manifiesta clínicamente con heces fétidas, grasosas y abundantes. Se puede determinar por el método Van de Kamer, el esteatocrito acidificado y la tinción sudan III en heces. El objetivo del presente trabajo es precisar el valor normal de la prueba Sudan III en heces. Se incluyeron las muestras de heces de 2000 niños sanos (recién nacidos pre-término, recién nacidos a término, lactantes de 1-4 meses y de 5-12 meses de edad), 500 muestras por grupo. Se realizó en el Hospital Universitario de los Andes, en Mérida-Venezuela, durante los años 1999-2009. En la prueba se utilizó la tinción sudan III y el reactivo de Saathoff, con lente microscópico de 40 y se tomaron en cuenta las gotas grandes y medianas de grasa por campo. Es una investigación clínica con enfoque epidemiológico, observacional de tipo aleatoria. Del total de niños 53% fueron varones y 47% niñas. El promedio de evacuaciones por día fue de 3 en los recién nacidos, de 2 a 3 en los lactantes menores de 4 meses y de 1 a 2 en los de 5 a 12 meses de edad. El valor normal de la prueba Sudan III en heces varía dependiendo de la edad. En RN pre-término un promedio de 5.4 gotas (12-0 gotas)de grasa por campo, en RN a término 7.9 gotas (16-0), en lactantes menores de 4 meses de edad 4.3 gotas (10-0) y en los lactantes de 5-12 meses 3.8 gotas (6-0) de grasa por campo. La prueba Sudan III orienta en el diagnostico de esteatorrea en niños, en pacientes con mala absorción intestinal y en la evaluación del uso de enzimas pancreáticas. Es una técnica sencilla, económica y fácil de realizar. El conocer los valores normales dependiendo de la edad pediátrica permite al médico tratante plantear la existencia de esteatorrea patológica.Palabras claves: esteatorrea, prueba Sudan III en heces

Steatorrhea is the loss of fat through the stools. It becomes clinically apparent with the presence of increased amounts of foul and fatty stools. It can be determined through the Van de Kamer method, the acid steatocrit and the Sudan III stain test of stools. The objective of this paper is to specify the normal value of the Sudan III Stain Test of stools. 2000 healthy children stools samples were included. Age groups were preterm’s, newborns, and infants between 1-4 and 5-12 months of age, 500 samples were collected for every group. The study was performed at the Hospital Universitario de los Andes, in Mérida-Venezuela, during years 1999 through 2009. The Sudan III Stain Test and the Saathoff reactive were employed, as well as a highpower objective lens. The number of large and medium fat drops by field was considered for the classification. This is a prospective, observational, randomized clinical trial. For the total number of children (53% males and 47% females) the average of evacuations per day showed a total of 3 times inthe newborns, from 2 to 3 times in the infants between 1-4 months of age and from 1 to 2 times in the infants between 5 and 12 months of age. The normal value of the Sudan III Stain Test of stools varies according to age: in preterm newborns this test shows an average of 5,4 drops (12-0) of fat per field, in full term newborns 7,9 drops (16-0), in infants from 0 to 4 months 4,3 drops (10-0) and in infants between 5 and 12 months 3,8 drops (6-0) of fat per field. Sudan III Stain Test guides in the diagnosis of steatorrhea in children, in patients with intestinal malabsorption syndrome and in the evaluation of the indication of pancreatic enzymes. This is a cheap, simple and easy technique .To know the normal values in the different pediatric age groups, allows to establish the presence of steatorrhea

Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence.

BACKGROUND: Anderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the SAR1B gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal SAR1B gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7). METHODS AND RESULTS: The patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the SAR1B gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes. CONCLUSIONS: This patient with AD/CMRD has a normal SAR1B gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine.

Somatostatinoma: collision with neurofibroma and ultrastructural features.

The clinical presentation, histopathology and immunoelectron microscopic features of two cases of duodenal somatostatinoma are described, one of which is a hitherto unreported example of a collision tumour with a neurofibroma. Ultrastructural morphometric immunoelectron microscopy studies revealed the presence of four types of cells in both tumours, but there was no difference in the proportions of these cells between the collision tumour and the non-collision tumour. Neurosecretory granules ranging in size from 255-815 nm were generally larger than those previously reported for somatostatinomas and somatostatin was identified in granules of all sizes across this range. Neither tumour was associated with the somatostatinoma syndrome comprising associated diabetes mellitis, steatorrhoea and cholelithiasis.