Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors.

BACKGROUND: Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI. PATIENTS AND METHODS: A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start. RESULTS: Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01). CONCLUSION: ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.

Risk factors for developing hyperoxaluria in children with Crohn's disease.

BACKGROUND: For the purpose of a better understanding of enteric hyperoxaluria in Crohn's disease (CD) in children and adolescents, we investigated the occurrence and risk factors for development of hyperoxaluria in those patients. METHODS: Forty-five children with CD and another 45 controls were involved in this cross-sectional study. Urine samples were collected for measurement of spot urine calcium/creatinine (Ur Ca/Cr), oxalate/creatinine (Ur Ox/Cr), and citrate/creatinine (Ur Citr/Cr) ratios. Fecal samples were also collected to detect the oxalyl-CoA decarboxylase of Oxalobacter formigenes by PCR. Patients were classified into 2 groups: group A (with hyperoxaluria) and group B (with normal urine oxalate excretion). The disease extent was assessed, and the activity index was calculated. RESULTS: According to the activity index, 30 patients (66.7%) had mild disease and 13 patients (28.9%) had moderate disease. There was no significant difference in Ur Ox/Cr ratio regarding the disease activity index. O. formigenes was not detected in 91% of patients in group A while it was detected in all patients in group B (p < 0.001). By using logistic regression analysis, the overall model was statistically significant when compared to the null model, (χ2 (7) = 52.19, p < 0.001), steatorrhea (p = 0.004), frequent stools (p = 0.009), and O. formigenes (p < 0.001). CONCLUSION: Lack of intestinal colonization with O. formigenes, steatorrhea, and frequent stools are the main risk factors for development of enteric hyperoxaluria in CD patients. Identifying risk factors facilitates proper disease management in future studies. A higher resolution version of the Graphical abstract is available as Supplementary information.

[Clinical phenotypes and genotypic spectrum of cystic fibrosis with pancreatic insufficiency in children].

Objective: To investigate the clinical phenotypes and genotypic spectrum of exocrine pancreatic insufficiency in children with cystic fibrosis. Methods: This was a retrospective analysis of 12 children with cystic fibrosis who presented to Children's Hospital of Fudan University from December 2017 to December 2021. Clinical features, fecal elastase-1 level, genotype, diagnosis and treatment were systematically reviewed. Results: A total of 12 children, 7 males and 5 females, diagnosis aged 5.4 (2.0, 10.6) years, were recruited. Common clinical features included chronic cough in 12 cases, malnutrition in 7 cases, steatorrhea in 7 cases, bronchiectasis in 5 cases and electrolyte disturbance in 4 cases. Exocrine pancreatic insufficiency were diagnosed in 8 cases,the main clinical manifestations were steatorrhea in 7 cases, of which 5 cases started in infancy; 6 cases were complicated with malnutrition, including mild in 1 case, moderate in 2 cases and severe in 3 cases; 3 cases had abdominal distension; 2 cases had intermittent abdominal pain; 4 cases showed fatty infiltration or atrophy of pancreas and 3 cases showed no obvious abnormality by pancreatic magnetic resonance imaging or B-ultrasound. All 8 children were given pancreatic enzyme replacement therapy, follow-up visit of 2.3 (1.2,3.2) years. Diarrhea significantly improved in 6 cases, and 1 case was added omeprazole due to poor efficacy. A total of 20 variations of CFTR were detected in this study, of which 7 were novel (c.1373G>A,c.1810A>C,c.270delA,c.2475_2478dupCGAA,c.2489_c.2490insA, c.884delT and exon 1 deletion). Conclusions: There is a high proportion of exocrine pancreatic insufficiency in Chinese patients with cystic fibrosis. The main clinical manifestations are steatorrhea and malnutrition. Steatorrhea has often started from infancy. Pancreatic enzyme replacement therapy can significantly improve the symptoms of diarrhea and malnutrition.

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.

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.

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.

The efficacy of a low-fat diet to manage the symptoms of bile acid malabsorption - outcomes in patients previously treated for cancer.

Dietary fat ingestion triggers bile secretion into the gastrointestinal tract. Bile acid malabsorption affects >1% of the population, causing loose stool and other gastrointestinal symptoms. The diagnosis is frequently missed. Treatments are often considered ineffective. We evaluated low-fat diets for managing gastrointestinal symptoms in these patients. All patients reporting type 6 or 7 stool were offered a selenium-75 homocholic acid taurine (SeHCAT) scan. Prospective data in patients with 7-day scan retention <20% were analysed. -Patients requiring a bile acid sequestrant were given this before receiving dietary advice. Patients completed a 7-day food diary before dietetic consultations. Personalised dietary interventions, providing 20% of daily energy from fat, were prescribed. Symptoms were assessed using a modified gastrointestinal symptom rating scale questionnaire before and 4-12 weeks after dietary intervention. A total of 114 patients (49 male, median age 64 years, median body mass index 27 kg/m2) were evaluated. 44% of these patients were taking colesevelam. After dietary intervention, there was statistically significant improvement in abdominal pain and nocturnal defecation (0.2% alpha, p=0.001). Improvement in bowel frequency, urgency, flatulence, belching, borborygmi and stool consistency were seen, but did not reach statistical significance (p≤0.004-0.031). Dietary intervention is an effective treatment option for patients with symptomatic bile acid malabsorption and should be routinely considered.

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.

Clinical profile of calcific and noncalcific chronic pancreatitis in north India.

GOALS: To compare the clinical profile of calcific and noncalcific chronic pancreatitis (CP) in north India. BACKGROUND: The profile of calcific CP has not been adequately studied. STUDY: Detailed demographic data were recorded; hematologic, biochemical, and radiologic investigations were carried out on 225 patients with CP. The patients were divided into calcific and noncalcific groups based on the presence of pancreatic calcification, which was detected on computed tomography. RESULTS: Calcific CP was reported in 46.7% of the patients and noncalcific CP in 53.3%. The mean age, duration of symptoms before presentation, sex ratio, body mass index, and frequency of various symptoms and complications including abdominal pain, ascites, pleural effusion, and segmental portal hypertension was not statistically different between the 2 groups. However, pseudocysts occurred more frequently in noncalcific CP, whereas jaundice because of bile duct stricture, diabetes mellitus, and steatorrhea occurred more frequently in patients with calcific CP (P<0.05). On comparing calcific and noncalcific alcoholic pancreatitis, only steatorrhea was reported more frequently in patients with calcific alcoholic CP. However, pseudocysts and segmental portal hypertension occurred more frequently in noncalcific idiopathic CP, whereas diabetes mellitus occurred more frequently in patients with calcific idiopathic CP (P<0.05). On comparing calcific alcoholic CP with calcific idiopathic CP, we found significantly lower mean age in patients with idiopathic CP and a higher frequency of male patients and pseudocysts in alcoholic CP (P<0.05). CONCLUSION: Calcific CP has a higher frequency of bile duct stricture, diabetes mellitus, and steatorrhea, whereas noncalcific CP has higher frequency of pseudocysts and segmental portal hypertension.

Acid steatocrit determination is not helpful in cystic fibrosis patients without or with mild steatorrhea.

BACKGROUND: Most methods used for the assessment of severe steatorrhea in cystic fibrosis (CF) are sensitive. In fact, the tests show their usefulness in a borderline zone of the results. Yet, the existing data related to acid steatocrit (AS) are still contradictory. Therefore, in the present study we have aimed to assess CF patients without or with mild steatorhea (<10 g/day) and evaluate the applicability of AS in such a subset of patients. PATIENTS AND METHODS: In fifty-five CF patients, AS, fecal fat concentration (FFC) and fecal fat excretion (FFE) in 1-day stool collection were assessed from one to three times (149 samples). In 50 subjects, FFC, FFE, and AS were available for 3 subsequent days. It allowed for the calculations based upon 3-day fecal fat balance study. RESULTS: The correlations between FFE/FFC and AS based upon 1-day stool collection, although statistically significant, were rather weak (r = 0.208, P < 0.011; r = 0.362, P < 0.000006, respectively). The correlations between FFE/FFC and AS based upon the 3-day stool collection, although stronger, did not show values a linear relationship (r = 0.394, P < 0.005; r = 0.454, P < 0.001, respectively). With no regard to the cut-off level for AS (10% and 20%), sensitivity, specificity, negative, and positive predictive values in the determination of abnormal FFC and FFE were not satisfactory. The flow charts describing the accuracy of AS to determine FFE and FC revealed a high level of uncertainty. CONCLUSIONS: AS does not reflect in a reliable way FFE in CF patients without or mild steatorrhea. Its applicability in the assessment of FFC in such patients has therefore limited practical value.

Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is essential for maintaining adequate nutrition in children with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). The US Food and Drug Administration regulations now require all PERT products to undergo clinical efficacy and safety studies before they can be considered for marketing approval. OBJECTIVE: This study was conducted to compare the efficacy of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules with placebo in children with EPI due to CF. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover, superiority study of the new formulation of pancrelipase delayed-release 12,000-lipase unit capsules in children aged 7 to 11 years with CF and EPI. In each period, pancrelipase or identical placebo capsules were taken for 5 days. The primary outcome measure was the coefficient of fat absorption (CFA); secondary outcome measures were the coefficient of nitrogen absorption (CNA) and clinical symptoms. The latter were assessed based on patient-reported daily stool frequency, stool consistency (hard, formed/normal, soft, or watery), flatulence (none, mild, moderate, or severe), and abdominal pain (none, mild, moderate, or severe). Safety measures included vital signs, physical examinations, standard laboratory safety tests (hematology and biochemistry), and adverse events. RESULTS: Seventeen patients were randomized to treatment and 16 completed the study; 1 patient withdrew consent during the first treatment period and was not included in the efficacy analysis. Patients' median age was 8.0 years (range, 7-11 years); 12 patients (70.6%) were male. CFA values were significantly greater for pancrelipase compared with placebo, with least squares mean (SE) values of 82.8% (2.7%) and 47.4% (2.7%), respectively (P < 0.001). The results were similar for CNA, with mean values of 80.3% (3.2%) and 45.0% (3.2%) (P < 0.001). Pancrelipase treatment had significantly greater effects on CFA and CNA in patients with a placebo CFA <50% than in those with a placebo CFA >50% (both parameters, P < 0.001 and P = 0.008, respectively). Significant improvements in stool fat, weight, and nitrogen and a significant reduction in daily stool frequency were observed with pancrelipase compared with placebo (all, P < 0.001). Symptoms of EPI were less severe and remained relatively stable during pancrelipase treatment, but worsened slightly during receipt of placebo. Treatment-emergent adverse events were reported in 5 patients (29.4%) during receipt of pancrelipase and in 9 patients (56.3%) during receipt of placebo; these were predominantly gastrointestinal events. There were no discontinuations due to treatment-emergent adverse events and no serious adverse events. CONCLUSIONS: In this study in children with EPI due to CF, the new formulation of pancrelipase delayedrelease capsules was associated with improvements in CFA, CNA, stool properties, and EPI symptoms compared with placebo. Pancrelipase delayed-release capsules appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00690820. (Clin Ther.

Whipple's disease-generalized stage.

Whipple's disease is a chronic inflammatory systemic disorder in which all organs can be invaded by the rod-shaped bacterium Tropheryma whipplei. It is a rare disease and frequently misdiagnosed, though there is no valid estimate of its actual incidence and prevalence. Only about 1,000-1,500 cases have been reported. The clinical course of untreated Whipple's disease can include three stages: (1) a non-specific prodromal stage which includes migratory polyarthralgias; (2) a classic abdominal manifestation which involves weight loss, weakness, chronic diarrhea, and abdominal pain; and (3) a generalized stage characterized by steatorhea, cachexia, lymphadenopathy, hyper-pigmentation, and cardiovascular, pulmonary, and neurological dysfunction. The authors describe a case of a 39-year-old male patient with about a year's history of generalized adenopathy, inappetence, weight loss, progressive weakness, subfebrilities, and convulsive abdominal pain. Following primary exclusion of a tumor disease, a lymph node biopsy demonstrated a typical picture of a granulomatous inflammation-Whipple's lymphadenitis with partial exemption of the Gram reaction, and stain features corresponding to T. whipplei, which is regarded as the etiological agent causing this disorder. Further tests confirmed the generalized form of the disorder, affecting the lymphatic tissues, gastrointestinal system, respiratory system, and nervous system, with sensory and motor polyneuropathy. HLA-B27 antigen, which is frequent among those with Whipple's disease, was also present. Following treatment for three months with antibiotics a significant reduction of the changes typical of Whipple's disease was found upon follow-up biopsy, hence we assume the applied therapy was successful. In our case study we emphasize the atypical course of the disease with dominant generalized lymphadenopathy and only mild gastrointestinal symptoms.

Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution.

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. beta-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 +/- 100 vs. 425 +/- 80 mM.4 h (mean +/- SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 +/- 1.2 vs. 5.3 +/- 0.6 nM.4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 +/- 7.5 vs. 21.1 +/- 8.3 nM.4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 +/- 4.2 vs. 13.6 +/- 2.9 nM.4 h, P = 0.02; 237 +/- 31.4 vs. 200 +/- 27.4 nM.4 h, P = 0.005; and 595 +/- 82 vs. 497 +/- 80 pmol.kg(-1).4 h, P = 0.01, respectively). beta-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.

Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes.

UNLABELLED: Despite treatment with supra-physiological doses of pancreatic enzyme supplements, residual steatorrhoea is a common problem in patients with cystic fibrosis (CF) and pancreatic insufficiency. Strategies to enhance the activity of pancreatic enzymes include decreasing duodenal acidity. The aim of this study was to evaluate the effect of omeprazole (Losec), a proton-pump inhibitor, on fat absorption in CF patients with residual steatorrhoea despite high dose pancreatic enzyme supplements (> or =10,000 U lipase/kg per day). A random cross-over design was chosen. Fat digestion was evaluated with and without omeprazole by means of chemical fat measurements in 3-day stool collections together with 3-day weighed food records for calculation of fat absorption. The results of 15 patients (3 girls and 12 boys) with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5-15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000-22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5-16.5 g/day) to 5.5 g (quartiles 4.9-8.1 g/day) (P<0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81-89%) without versus 94% (quartiles 90-96%) with omeprazole (P<0.001). CONCLUSION: Omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution.