Utility of Fecal Elastase-1 to diagnose severe exocrine insufficiency in chronic pancreatitis: Real world experience.

INTRODUCTION: Quantitative fecal fat estimation is the gold standard test to diagnose steatorrhea (fecal fat >7 g/day) in chronic pancreatitis (CP), but cumbersome and inconvenient. So, fecal elastase-1 (FE) is proposed as a good alternative but the data on the diagnostic utility of FE to diagnose steatorrhea is variable. METHODS: This retrospective study included adult CP patients evaluated with both 24-h fecal-fat and FE tests within a 3-month period. The objective was to evaluate the diagnostic performance of FE to diagnose steatorrhea and to evaluate the FE progression over 9-month period. RESULTS: Among the 147 included patients, the frequency of steatorrhea (fecal fat >7 g/day) was 34%. The sensitivity, specificity, and negative likelihood ratio (LR) of FE was 90%, 28.9% and 0.35 at cut-off of <100 µg/g stool to diagnose steatorrhea; and 96%, 11.3% and 0.35 at cut-off of <200 µg/g stool, respectively. The optimal cut-off of FE was <20 on receiver operating characteristic curve (sensitivity 66%; specificity 69%; positive LR 2.14). There was no statistically significant variation in FE levels over 9 months interval among a hundred patients. CONCLUSION: Compared to FE ≥ 200 µg/g stool, FE ≥ 100 can used to exclude steatorrhea (better specificity and negative LR). FE < 20 alone cannot replace fecal fat estimation to confirm steatorrhea but to be interpreted with clinical features. Repeat FE testing for exocrine insufficiency progression can be done at least a year later.

Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study.

INTRODUCTION: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. METHODS: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. RESULTS: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. CONCLUSION: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

Staging exocrine pancreatic dysfunction.

Digestive capacity of the gastrointestinal tract, largely but not wholly, depends on exocrine pancreatic function to achieve near complete digestion and absorption of ingested food. Coefficient of fat absorption (CFA), the proportion of ingested fat absorbed (normal >93%), reflects digestive capacity. Exocrine pancreatic insufficiency (EPI) is the state of insufficient digestive capacity (CFA <93%) caused by severe loss of pancreatic exocrine function despite variable compensation by upregulation of extra-pancreatic lipolysis. Fecal elastase 1 (FE1) level is the most widely used, though imperfect, non-invasive test of pancreatic enzyme output. Decline in pancreas enzyme output, or pancreatic exocrine dysfunction (EPD), has a variable correlation with measurable decline in CFA. EPI results in steatorrhea, weight loss and nutrient deficiency, which are mitigated by pancreatic enzyme replacement therapy (PERT). We propose a staging system for EPD, based on measurement of fecal elastase (FE1) and, if necessary, CFA and serum fat-soluble vitamin levels. In Stage I (Mild) EPD, FE1 is 100-200 mcg/gm; if steatorrhea is present, non-pancreatic causes are likely. In Stage II (Moderate) EPD), FE1 is < 100 mcg/gm without clinical and/or laboratory evidence of steatorrhea. In Stage III, there are marked reductions in FE1 and CFA, but vitamin levels remain normal (Severe EPD or EPI without nutritional deficiency). In Stage IV all parameters are abnormal (Severe EPD or EPI with nutritional deficiency). EPD stages I and II are pancreas sufficient and PERT may not be the best or first approach in management of early-stage disease; it needs further study to determine clinical utility. The term EPI refers strictly to EPD Stages III and IV which should be treated with PERT, with Stage IV requiring micronutrient supplementation as well.

Maldigestion Versus Malabsorption in the Elderly.

PURPOSE OF REVIEW: To evaluate recently published information about the frequency of maldigestion and malabsorption in older individuals, likely diagnoses causing these problems, and the diagnostic scheme when these diagnoses are being considered. RECENT FINDINGS: Although the prevalence of malnourishment and frank malnutrition may be increasing among older adults admitted to the hospital, this appears to be due to reduced food intake rather than maldigestion or malabsorption. The mechanisms of food digestion and absorption seem to be resilient, even in old age, but concurrent illness may produce malabsorption in older individuals. Illnesses that may be more common among the elderly include small intestinal bacterial overgrowth, exocrine pancreatic insufficiency, enteropathies, vascular disease, diabetes, and certain infections, such as Whipple's disease. In addition, older adults may have had previous surgeries or exposure to medicines which may induce malabsorption. The presentation of maldigestion and malabsorption in the elderly may be different than in younger individuals, and this may contribute to delayed recognition, diagnosis, and treatment. Diagnostic testing for maldigestion and malabsorption generally is similar to that used in younger patients. Maldigestion and malabsorption occur in older individuals and require a high level of suspicion, especially when weight loss, sarcopenia, or nutrient deficiencies are present.

Serum Concentrations of 7α-hydroxy-4-cholesten-3-one Are Associated With Bile Acid Diarrhea in Patients With Crohn's Disease.

BACKGROUND & AIMS: Patients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7α-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD. METHODS: We collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19 <60 pg/mL. RESULTS: Patients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with CD and IR with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (P compared to UC < .0001) and patients with CD and IR without ileitis had a median concentration of 51.6 ng/mL (P compared to UC < .001). Patients with CD without IR did not have a significantly higher median concentration of C4 than patients with UC (P = .71), regardless of ileitis (P = .34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhea (72.0% vs 0 patients with inactive UC; P < .001), but their median concentrations of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; P = .3). A cutoff concentration of C4 of 48.3 ng/mL or greater identified patients with diarrhea attributable to bile acid malabsorption with 90.9% sensitivity, 84.4% specificity, and an AUROC 0.94. A significantly higher proportion of patients with concentrations of C4 above this cutoff had BAD (50.0%) than below this cutoff (1.8%) (P < .001). When we analyzed only patients with diarrhea, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC, 0.99). Above this cutoff, 83.3% of patients had a serum concentration of FGF19 <60 pg/mL compared to 4.5% below this threshold (P < .0001). C4 concentrations correlated with the number of daily bowel movements (r = 0.41; P = .004) and correlated inversely with FGF19 concentrations (r = -0.72; P<.0001). CONCLUSION: We observed significantly increased serum concentrations of C4 in patients with CD with IR, compared to patients with UC. A cutoff concentration of C4 above 48.3 ng/mL identifies patients with diarrhea likely attributable to bile acid malabsorption (BAD) with an AUROC value of 0.94. Increased serum levels of bile acid precursors identify patients with diarrhea and a low serum concentration of FGF19, and concentrations of C4 correlate with daily liquid bowel movements and correlate inversely with FGF19 concentrations. C4 may be a biomarker to identify patients with diarrhea attributable to bile acid malabsorption.

Organic solute transporter-ß (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis.

Primary bile acid malabsorption is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2) can cause primary bile acid malabsorption but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric organic solute transporter alpha-beta (OSTα-OSTß; SLC51A-SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTß deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma-glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. CONCLUSION: The findings identify OSTß deficiency as a cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα-OSTß's key role in the enterohepatic circulation of bile acids in humans. (Hepatology 2017).

Chronic diarrhoea in adults: what not to miss.

PURPOSE OF REVIEW: Chronic diarrhoea remains a diagnostic challenge, with numerous causes and few effective symptomatic treatments. This review focuses on new methods for diagnosis of common disorders and alerts readers to rarer causes through a systematic approach to the underlying mechanisms. RECENT FINDINGS: New strategies are emerging to stratify the need for endoscopic investigation. Faecal immunochemical testing, combined with standard blood tests, shows promise in excluding colorectal cancers, adenoma and inflammatory bowel disease, challenging the current use of faecal calprotectin. Serum analysis for markers of bile acid synthesis has been refined, potentially streamlining diagnostic pathways of bile acid malabsorption for those who are unable to access nuclear medicine scans, but the positive predictive value of faecal elastase in low prevalence populations has been questioned. Novel markers such as volatile organic compounds and stool DNA analyses continue to develop. SUMMARY: A systematic approach to investigation of chronic diarrhoea will ensure all relevant causes are considered and minimize the chance of a missed diagnosis. Combination of clinical features with noninvasive testing supports a judicious approach to endoscopic investigations but further innovation will be needed to resolve the diagnostic challenge that diarrhoea poses.

Clinical decision-making in managing changes in gastrointestinal function following cancer therapies: Is experience enough?

In patients with gastrointestinal (GI) disorders, identical symptoms may occur for many different reasons. This prospective study assessed whether experienced clinicians can predict accurately the underlying diagnosis or diagnoses contributing to specific symptoms based on the history and physical examination. Three clinicians assessed 47 patients referred for management of troublesome GI symptoms identified after treatment for cancer. Investigations were requested following our comprehensive, peer-reviewed algorithm. The clinicians then recorded their predictions as to the results of those investigations. After each patient had completed all their investigations, had received optimal management and had been discharged from the clinic, the predicted diagnoses were compared to those made. The clinicians predicted 92 diagnoses (1.9 per patient). After investigation, a total of 168 unique diagnoses were identified (3.5 per patient). Of the 92 predicted diagnoses, 41 (43%) matched the diagnosis. Of the 168 actual diagnoses identified, only 24% matched the prediction. None of the clinicians predicted the correct combination of diagnoses contributing to bowel symptoms. Clinical acumen alone is inadequate at determining cause for symptoms in patients with GI symptoms developing after cancer therapy.

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.

[Structural state of the pancreas and coprogram parameters for assessment patients with chronic pancreatitis after cholecystectomy].

Reviewed by a structural condition of the pancreas by ultrasound and scores from the Marseille-Cambridge classification in patients with chronic biliary pancreatitis, including those who had a history of cholecystectomy. Found that after cholecystectomy gland size decreased slightly, but significantly fibrosis is increased. Chronic inflammation and fibrosis of the gland leads to inhibition of both acinar and ductal secretory function, leads to its external and internal secretion deficiency. In assessing coprogram found that most patients with CP present with signs of exocrine insufficiency, including steatorrhea and kreatorrhea that are most pronounced in patients with CP after open cholecystectomy.

Recycling rate of bile acids in the enterohepatic recirculation as a major determinant of whole body 75SeHCAT retention.

Measurement of the whole body retention of orally administered (75)SeHCAT is used to investigate patients with unexplained diarrhoea. Retention values of <15 % at 7 days post-administration are taken to indicate bile acid malabsorption (BAM). Whilst idiopathic BAM is frequently diagnosed with (75)SeHCAT, functional and morphological studies of the terminal ileum rarely show any abnormality, so the disorder may be more appropriately termed bile acid diarrhoea (BAD). In addition to malabsorption, excess bile acid may reach the colon, where the events leading to diarrhoea take place, as a result firstly of increased bile acid synthesis and secondly of an increased recycling rate of bile acids. Increased recycling has been largely ignored as a cause of BAD, but, as shown in this study, can readily result in excess bile acids reaching the colon even when ileal absorption efficiency is normal (i.e. 95-97 %). There needs to be a re-evaluation of the causes of BAD in patients without a history of previous intestinal resection or evidence of ileal pathology, such as Crohn's disease.

Fecal elastase-1 is useful in the detection of steatorrhea in patients with pancreatic diseases but not after pancreatic resection.

BACKGROUND: Fecal elastase-1(FE-1) has been suggested as an alternative to steatorrhea quantification to evaluate pancreatic insufficiency, but its diagnostic performance has not been compared with steatorrhea in chronic pancreatitis or after pancreatic resection. METHODS: The relationship between steatorrhea and FE-1 was studied in patients with chronic pancreatic disorders or pancreatic resection. Student's t test and ANOVA were used for statistical analysis, accepting 0.05 as limit for significance. RESULTS: Eighty-two patients were studied (42 non-operated; 40 previously submitted to pancreatic resection). Fat output was higher in operated than non-operated patients (29.2 ± 3.1 vs 9.9 ± 2.2 g/day, p < 0.001) FE-1 was more severely reduced in operated patients (202 ± 32.3 µg/g in non operated vs 68.6 ± 18.2 in operated patients; p < 0.001). Steatorrhea was significantly more severe in operated patients across different levels of FE-1. The relationship between FE-1 and steatorrhea was described by a power regression model, with a regression line significantly different in operated and non-operated patients (p < 0.001). A steatorrhea of 7 g (upper limit of normal range) was calculated by this regression line when FE-1 is 15 µg/g in non-operated, but as high as 225 µg/g in operated patients. CONCLUSION: FE-1 is useful to identify pancreatic insufficiency. Steatorrhea is anticipated in non-operated patients only when FE-1 is below the limit for a confident measurement of our assay. In operated patients, steatorrhea may be present even if FE-1 is only slightly reduced, that suggests a role for non pancreatic factors. FE1 is not useful to identify operated patients at risk of malabsorption.

Application of a novel tool for diagnosing bile acid diarrhoea.

Bile acid diarrhoea (BAD) is a common disease that requires expensive imaging to diagnose. We have tested the efficacy of a new method to identify BAD, based on the detection of differences in volatile organic compounds (VOC) in urine headspace of BAD vs. ulcerative colitis and healthy controls. A total of 110 patients were recruited; 23 with BAD, 42 with ulcerative colitis (UC) and 45 controls. Patients with BAD also received standard imaging (Se75HCAT) for confirmation. Urine samples were collected and the headspace analysed using an AlphaMOS Fox 4000 electronic nose in combination with an Owlstone Lonestar Field Asymmetric Ion Mobility Spectrometer (FAIMS). A subset was also tested by gas chromatography, mass spectrometry (GCMS). Linear Discriminant Analysis (LDA) was used to explore both the electronic nose and FAIMS data. LDA showed statistical differences between the groups, with reclassification success rates (using an n-1 approach) at typically 83%. GCMS experiments confirmed these results and showed that patients with BAD had two chemical compounds, 2-propanol and acetamide, that were either not present or were in much reduced quantities in the ulcerative colitis and control samples. We believe that this work may lead to a new tool to diagnose BAD, which is cheaper, quicker and easier that current methods.

Chylomicron retention disease: report of two cases from a Greek Island.

Chylomicron retention disease (CRD), or Anderson disease, is a rare, hereditary cause of fat malabsorption. It is one of the familial hypocholesterolaemia syndromes, along with homozygous hypobetalipoproteinaemia (HBL) and abetalipoproteinaemia (ABL). We report clinical, laboratory and histological data as well as molecular DNA analysis in the case of a 4-month-old boy with failure to thrive and steatorrhea who was diagnosed with CRD. His mother's first cousin, who was diagnosed as hypobetalipoproteinaemia 30 years ago, was also reviewed and his diagnosis was revised to CRD. Both patients were treated with a low fat diet and supplementation with fat-soluble vitamins resulting in significant improvement. In conclusion, CRD is a well-defined cause of fat malabsorption and can be distinguished from other forms of familial hypocholesterolaemia because of its specific lipid profile.

Oral pancreatic enzyme substitution therapy in chronic pancreatitis: is clinical response an appropriate marker for evaluation of therapeutic efficacy?

CONTEXT: Malnutrition secondary to pancreatic exocrine insufficiency plays a prognostic role in chronic pancreatitis. Enzyme substitution therapy is generally prescribed to avoid diarrhea and weight loss, although it is unknown whether this is associated with normal absorption of nutrients and a normal nutritional status. OBJECTIVE: We aimed to evaluate whether an adequate clinical response to enzyme therapy can be used to predict a normal nutritional status in patients with chronic pancreatitis. PATIENTS: Thirty-one consecutive patients (25 males, 6 females; mean age 52 years,) with severe chronic pancreatitis and steatorrhea were enrolled in the study. INTERVENTION: Enzyme substitution therapy was indicated in cases with severe steatorrhea (more than 15 g/day), diarrhea and/or weight loss. Therapy was optimized in individual patients to obtain complete symptom relief. MAIN OUTCOME MEASURE: A nutritional evaluation including body mass index and serum levels of retinol-binding protein, prealbumin and transferrin was carried out. RESULTS: Ten out of ten patients with asymptomatic steatorrhea, who did not fulfill the criteria for enzyme substitution therapy, and 11 out of 21 patients (52.4%) with symptomatic or more severe steatorrhea, who were under enzyme substitution therapy, showed a deficient nutritional status. CONCLUSIONS: An appropriate clinical response to enzyme substitution therapy does not allow the prediction of a normal nutritional status in patients with chronic pancreatitis.

Novel CFTR mutations in a Korean infant with cystic fibrosis and pancreatic insufficiency.

Cystic fibrosis (CF) is an autosomal recessive disease that is very rare in Asians: only a few cases have been reported in Korea. We treated a female infant with CF who had steatorrhea and failure to thrive. Her sweat chloride concentration was 102.0 mM/L. Genetic analysis identified two novel mutations including a splice site mutation (c.1766+2T >C) and a frameshift mutation (c.3908dupA; Asn1303LysfsX6). Pancreatic enzyme replacement and fat-soluble vitamin supplementation enabled the patient to get a catch-up growth. This is the first report of a Korean patient with CF demonstrating pancreatic insufficiency. CF should therefore be considered in the differential diagnosis of infants with steatorrhea and failure to thrive.

Ultrastructural aspects of enterocyte defects in infancy and childhood.

Although there has been substantial progress in the identification of diarrheal diseases in infancy and childhood, electron microscopy may be still required for establishing diagnosis, staging, and response to therapy. This review describes severe conditions in which histopathologic examination alone cannot provide a firm diagnosis needed for therapeutic decisions. Microvillus inclusion disease, in its several variants, typifies this category. In certain forms of congenital disorders of glycosylation with gastrointestinal involvement, electron microscopic diagnosis is helpful. Among disorders due to abnormal immune-mediated reactions, celiac disease and cow's milk protein intolerance show fine structural changes of both diagnostic and staging value. Likewise, protein-losing enteropathies, including lymphangectasia, reveal information on the nature and extent of intestinal involvement.

Long-Term Functional Outcome After Pancreatoduodenectomy for Periampullary Carcinoma With Morphological Correlation.

OBJECTIVE: The aim of the study was to evaluate the long-term functional outcome (exocrine and endocrine) and morphological changes in remnant pancreas after pancreatoduodenectomy and its clinical impact. METHODS: Periampullary carcinoma patients with minimum follow-up of 2 years and without recurrence were included (N = 102). Exocrine insufficiency includes clinical steatorrhea and fecal elastase-1 (FE-1) levels; endocrine insufficiency, glucose levels and glycated hemoglobin; and morphological changes, main pancreatic duct (MPD) diameter and thickness of remnant pancreas. RESULTS: The mean (standard deviation) follow-up period was 59 (26) months. Of the 102 patients, 81 (80%) had severely deficient FE-1 (0-100 µg/g). The preoperative MPD was significantly more and thickness of remnant pancreas was significantly less in patients with severely deficient FE-1. Overall, 15.6% (16/102) developed steatorrhea and improved on enzyme replacement therapy. The presence of MPD stricture (P = 0.008) and weight loss (P = 0.001) were significantly associated with steatorrhea. New-onset diabetes was seen in 17% (15/90) patients, of whom 3 of 5 developed it after 4 years (range, 4-7 years). The blood glucose was controlled on oral hypoglycemics in 2 (10/15) of 3 patients. CONCLUSIONS: The assessment by FE-1 indicates loss of exocrine function in more than 90%, whereas only 1 of 6 developed steatorrhea and new-onset diabetes. Morphological changes especially MPD stricture affect the functional status of remnant pancreas.

Bile and fat excretion are biomarkers of clinically significant diarrhoea and constipation in irritable bowel syndrome.

BACKGROUND: Biomarkers in irritable bowel syndrome (IBS) may guide targeted therapy in this multifactorial disease. It has been suggested that 75% accuracy and cost <$500 categorise biomarkers as cost-effective. AIM: To identify differences in faecal bile acids, faecal fat and fasting serum C4 (7a-hydroxy-4-cholesten-3-one) and fibroblast growth factor 19 (FGF19) among patients with IBS-D, IBS-C and healthy controls and to determine accurate, cost-effective biomarkers for clinically relevant diarrhoea and constipation. METHODS: We assessed daily stool frequency and consistency (Bristol Stool Form Scale) from validated bowel diaries, 48 hours total and individual faecal bile acids, 48 hours faecal fat and weight, fasting serum C4 and FGF19, and colonic transit by scintigraphy from healthy volunteers (HV) and patients with IBS-D and IBS-C (Rome III criteria). We utilised multivariate logistic regression to determine biomarkers of clinically significant diarrhoea or constipation based on stool frequency, consistency and weight. RESULTS: Among the 126 HV (44M/82F, 37.5 ± 10.9 years [SD]), 64 IBS-D (5M/59F, 41.9 ± 12.2 years), and 30 IBS-C (0M/30F, 44.6 ± 10 years) patients, there were significant differences between all groups in stool weight, frequency, and consistency; in addition, there were differences in colonic transit at 48 hours, faecal fat, and total and individual faecal bile acids between IBS-D and IBS-C. Reduced total and primary faecal bile acids and increased faecal lithocholic acid were significant predictors of decreased faecal weight, frequency and consistency with AUC > 0.82 (sensitivity >76%, specificity >72%). Total and primary faecal bile acids and faecal fat were significant predictors of increased stool weight, frequency and consistency with AUC > 0.71 (sensitivity >55%, specificity >74%).The faecal parameters had a 11.5 positive likelihood ratio in predicting elevated faecal weight. CONCLUSIONS: Faecal bile acids and faecal fat are cost-effective and accurate biomarkers associated with significant bowel dysfunction among IBS-D and IBS-C patients.

SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.

OBJECTIVES: Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort. METHODS: We performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model. RESULTS: We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups. CONCLUSIONS: We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.