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.

Untargeted analysis of the serum metabolome in cats with exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI) causes chronic digestive dysfunction in cats, but its pathogenesis and pathophysiology are poorly understood. Untargeted metabolomics is a promising analytic methodology that can reveal novel metabolic features and biomarkers of clinical disease syndromes. The purpose of this preliminary study was to use untargeted analysis of the serum metabolome to discover novel aspects of the pathobiology of EPI in cats. Serum samples were collected from 5 cats with EPI and 8 healthy controls. The diagnosis of EPI was confirmed by measurement of subnormal serum feline trypsin-like immunoreactivity (fTLI). Untargeted quantification of serum metabolite utilized ultra-high-performance liquid chromatography-tandem mass spectroscopy. Cats with EPI had significantly increased serum quantities of long-chain fatty acids, polyunsaturated fatty acids, mevalonate pathway intermediates, and endocannabinoids compared with healthy controls. Diacylglycerols, phosphatidylethanolamines, amino acid derivatives, and microbial metabolites were significantly decreased in cats with EPI compared to healthy controls. Diacyclglycerols and amino acid metabolites were positively correlated, and sphingolipids and long-chain fatty acids were negatively correlated with serum fTLI, respectively. These results suggest that EPI in cats is associated with increased lipolysis of peripheral adipose stores, dysfunction of the mevalonate pathway, and altered amino acid metabolism. Differences in microbial metabolites indicate that feline EPI is also associated with enteric microbial dysbiosis. Targeted studies of the metabolome of cats with EPI are warranted to further elucidate the mechanisms of these metabolic derangements and their influence on the pathogenesis and pathophysiology of EPI in cats.

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy - A multicentre study of 90 patients from the German Dermatooncology Group.

AIM: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. PATIENTS AND METHODS: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. RESULTS: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. CONCLUSION: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

Severe Genotype, Pancreatic Insufficiency and Low Dose of Pancreatic Enzymes Associate with Abnormal Serum Sterol Profile in Cystic Fibrosis.

BACKGROUND: Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation. METHODS: The study involved 55 CF patients and 45 healthy subjects (HS). Sterol concentrations (µg/dL) were measured by gas chromatography/mass spectrometry. CF was characterised by lung function, pancreatic status, liver disease and diabetes coexistence, Pseudomonas aeruginosa colonisation and BMI. CFTR genotypes were classified as severe or other. RESULTS: Campesterol and ß-sitosterol concentrations were lower (p = 0.0028 and p < 0.0001, respectively) and lathosterol levels (reflecting endogenous cholesterol biosynthesis) were higher (p = 0.0016) in CF patients than in HS. Campesterol and ß-sitosterol concentrations were lower in patients with a severe CFTR genotype, pancreatic insufficiency and lower pancreatic enzyme dose (lipase units/gram of fat). In multiple regression analyses, ß-sitosterol and campesterol concentrations were predicted by genotype and pancreatic insufficiency, whereas cholesterol and its fractions were predicted by phytosterol concentrations, age, dose of pancreatic enzymes, nutritional status and genotype. CONCLUSIONS: Independent determinants of lipid status suggest that malabsorption and pancreatic enzyme supplementation play a significant role in sterol abnormalities. The measurement of campesterol and ß-sitosterol concentrations in CF patients may serve for the assessment of the effectiveness of pancreatic enzyme replacement therapy and/or compliance, but further research is required.

Effects of oral cobalamin supplementation on serum cobalamin concentrations in dogs with exocrine pancreatic insufficiency: A pilot study.

The objective of this retrospective study was to evaluate serum cobalamin concentrations before and after oral cobalamin supplementation in dogs with low serum cobalamin concentrations and exocrine pancreatic insufficiency (EPI). Eighteen dogs with serum trypsin-like immunoreactivities between <1.0-2.7 µg/L (reference interval, 5.2-35 µg/L) and serum cobalamin concentrations ≤350 ng/L (reference interval, 244-959 ng/L) were enrolled. All dogs were treated with oral cyanocobalamin according to a previously described protocol (0.25-1.0 mg daily, depending on bodyweight). Median (range) serum cobalamin concentrations at inclusion was 188 ng/L (<111-350 ng/L), which increased significantly to 1000 ng/L (794-2385 ng/L; P < 0.001) after cobalamin supplementation for 19-199 days (median, 41 days). Oral cobalamin supplementation is a potential alternative to parenteral supplementation in dogs with EPI.

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function. AIM: To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP. METHODS: Serum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features. RESULTS: A final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures). CONCLUSIONS: Very low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.

Dysregulated insulin in pancreatic insufficient cystic fibrosis with post-prandial hypoglycemia.

BACKGROUND: Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear. METHODS: To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF). RESULTS: Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120-180min was not different in hypoglycemia[+] vs hypoglycemia[-] with abnormal glucose tolerance (AGT); however, glucose-AUC120-180min was lower in hypoglycemia[+] vs hypoglycemia[-] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120-180min than hypoglycemia[-] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals. CONCLUSION: Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.

Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.

BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.

Zinc deficiency in patients with chronic pancreatitis.

BACKGROUND: Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis (CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency (PEI), which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting results. AIM: To investigate serum zinc levels in patients with CP of various etiologies. METHODS: Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the M-ANNHEIM classification system into the following etiological subcategories: alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal (fecal elastase 1 > 200 µg/g), mildly reduced (100-200 µg/g) and severely reduced (fecal elastase 1 < 100 µg/g). RESULTS: A total of 150 patients were included in the analysis. Zinc deficiency (< 11 µmol/L) was present in 39 (26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency (FE-1 < 200 µg/g). Older age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients < 40 years of age [OR: 3.8, 95%CI (1.08-13.4); P = 0.04]; [OR 6.26, 95%CI (1.94-20.2), P > 0.002]. Smoking and number of pack-years were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher compared to those who had never smoked. Gender, body mass index, etiology of CP, presence of diabetes mellitus, levels of glycated hemoglobin (HbA1c), bone mineral density, alcohol intake and presence of PEI were not associated with low zinc levels. CONCLUSION: Zinc deficiency is common in patients with CP and is significantly associated with age ≥ 60, smoking and the number of pack-years, but not with PEI.

Nutritional markers in patients with diabetes and pancreatic exocrine failure.

AIMS: Altered pancreatic exocrine function can be observed in patients with type 1 or type 2 diabetes. In the present study, we evaluated the potential nutritional consequences of this dysfunction. METHODS: Serum concentrations of nutritional markers, including albumin, cholesterol, triacylglycerol, vitamins A, D, and E, were assessed in a cohort of 468 patients (137 with type 1 diabetes and 331 with type 2 diabetes), after exclusion of the patients with a CRP > 10 mg/l. These patients were compared with 47 patients with diseases of the exocrine pancreas and diabetes (type 3c diabetes or pancreatogenic diabetes). Fecal elastase-1 and chymotrypsin concentrations were measured and patients with type 1 and type 2 diabetes were divided into three groups according to whether zero (group NN), one (group LN), or both (group LL) concentrations were decreased. RESULTS: Several markers differed significantly between the groups of patients, including BMI, albumin, phosphorus, and fat-soluble vitamins. Patients with pancreatogenic diabetes had markedly more profound alterations than patients with type 1 or type 2 diabetes and altered exocrine function. However, patients with type 1 or type 2 diabetes and decreased concentrations of both elastase-1 and chymotrypsin had lower albumin, phosphorus, and vitamin A than patients with normal pancreatic exocrine function. CONCLUSIONS: Modest nutritional alterations were found in patients with type 1 or type 2 diabetes and altered exocrine function. Patients with type 1 or type 2 diabetes and altered exocrine function may thus deserve to be screened for nutritional deficiencies.

Peripheral blood immunophenotyping in a large cohort of patients with Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis from a cohort of 37 SDS patients who display impairment mostly in the myeloid compartment with a deficiency also in the number of B cells and CD4/CD8 double-negative T cells.

Macropolycyte in Pediatrics.

Macropolycytes are tetraploid neutrophils produced during accelerated myelopoiesis. They have been reported in adults with pernicious anemia, sepsis, and after cytotoxic chemotherapy. Two pediatric cases are reported, one after granulocyte colony-stimulating factor treatment and the other following Kawasaki disease, respectively.

Serum Level of D-Lactate in Patients with Cystic Fibrosis: Preliminary Data.

D-Lactate is produced by the intestinal biota and later absorbed into circulation. Some patients with cystic fibrosis (CF) develop exocrine pancreatic insufficiency that may disturb the gut microbiome and enhance the production of D-lactate. However, this concept has not been studied yet. The aim of the study was to assess D-lactate concentration in relation to the occurrence of clinical features, activity of CF, and diet composition in paediatric patients. Patients and Method. Serum concentrations of D-lactate were measured in 38 CF patients (19 girls and 19 boys) from 6 months to 18 years of age. The analysis included age, sex, clinical symptoms, diet (the variety and calorie needs), the laboratory tests for pancreatic efficiency (serum levels of albumin and glucose, faecal elastase activity, and faecal fat index) and faecal calprotectin (the marker of intestinal inflammation), and parameters of liver damage and of cholestasis (the activity of aminotransferases, γ-glutamyltransferase, level of bilirubin, and international normalized ratio). Results. The median level of D-lactate was 0.86 µg/ml (1Q-3Q: 0.48-2.03) and correlated with the CF severity in the Schwachman-Kulczycki score, parameters of pancreatic insufficiency, and the presence of intestinal inflammation. An increased level of D-lactate was observed in the subgroup with pancreas insufficiency (1.05 versus 0.73; p < 0.05), parallel with an elevated level of calprotectin (0.948 versus 0.755; p = 0.08). There was no relationship between energy consumption and diet composition and serum D-lactates. Conclusion. Serum D-lactate concentration in CF patients is a promising new marker of exocrine pancreatic insufficiency probably related to intestinal flora dysbiosis/overgrowth.

Serum concentrations of lipid-soluble vitamins in dogs with exocrine pancreatic insufficiency treated with pancreatic enzymes.

BACKGROUND: In humans, exocrine pancreatic insufficiency (EPI) is associated with deficiencies in lipid-soluble vitamins. Little is reported regarding lipid-soluble vitamin status in dogs with EPI. HYPOTHESIS/OBJECTIVES: Compare serum concentrations of retinol, 25-hydrocholecalciferol (25OHD), and α-tocopherol among dogs with EPI, those with subclinical EPI (sEPI), and healthy dogs. Detect associations between serum concentrations of lipid-soluble vitamins and residual clinical signs in treated dogs with EPI and sEPI. ANIMALS: Twenty dogs with EPI and five dogs with sEPI receiving pancreatic enzyme replacement therapy. Ten healthy dogs sampled before and after 10 days of pancreatic enzyme supplementation. METHODS: Case-control study. Serum retinol and α-tocopherol concentrations were measured by high-performance liquid chromatography. Serum 25OHD concentrations were measured by radioimmunoassay. RESULTS: Serum retinol concentration was significantly lower in dogs with EPI (median, 490 ng/mL; range, 322-990 ng/mL) and serum α-tocopherol concentration was significantly lower in dogs with EPI (median, 11.51 µg/L; range, 4.8-27.1 µg/L) and sEPI (median, 12.66 µg/L; range, 10.21-21.03 µg/L) compared with healthy dogs (median, 1203 ng/mL; range, 637-1768 ng/mL and median, 43.54 µg/L; range, 34.26-53.97 µg/L, respectively). Dogs with weight loss had significantly lower 25OHD (mean, 243.50 nmol/L; standard deviation [SD], 3.54 nmol/L) than dogs with stable weight (314.0 nmol/L; SD, 138.38 nmol/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Altered homeostasis of lipid-soluble vitamins is present in dogs with EPI and sEPI, despite enzyme replacement therapy. Additional studies are needed to determine the clinical relevance of these findings and the therapeutic potential of lipid-soluble vitamin supplementation in dogs with EPI and sEPI.

ß-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL.

BACKGROUND: Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired ß-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired ß-cell secretory capacity, a measure of functional ß-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). METHODS: A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 mg/dL and 2-hour <140 mg/dL [7.8 mmol/L]; n = 13), PI-EGI (1-hour ≥155 mg/dL and 2-hour <140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis-related diabetes, CFRD: 2-hour ≥200 mg/dL; n = 8) participated. Post-prandial glucose tolerance and insulin secretion, and ß-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTTs), and glucose-potentiated arginine (GPA) tests, respectively. RESULTS: PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P < .05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to GPA (P < .01 vs PI-NGT), measures of ß-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P < .05 vs PI-NGT), and correlated with 1-hour glucose in PI-CF (P < .01). CONCLUSIONS: PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired ß-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion.

Validation of a radioimmunoassay of serum trypsin-like immunoreactivity in ferrets.

Measurement of serum trypsin-like immunoreactivity (TLI) is used to assess exocrine pancreatic function in dogs and cats. Ferrets ( Mustela putorius furo) serve as valuable animal models for human diseases such as cystic fibrosis and other pulmonary diseases, and may be a useful model of other diseases including pancreatitis. We developed and analytically validated a competitive radioimmunoassay (RIA) for measurement of TLI in ferret serum by determination of analytical sensitivity, assay linearity, accuracy of spiking recovery, precision, and reproducibility. Analytical sensitivity of the assay was 0.55 µg/L. Observed-to-expected (O/E) ratio for dilutional parallelism was 90.2-127.9% (mean: 108.1 ± 11.9%). The O/E ratio for spiking recovery was 94.5-113.0% (mean: 103.9 ± 7.2%). The intra- and inter-assay coefficients of variation (CVs) were 2.7-5.7% and 3.5-8.2%, respectively. The reference interval (RI) for serum TLI derived from 31 healthy ferrets was 28-115 µg/L; the 90% confidence interval for the lower and upper limits of the RI were 10.0-32.1 µg/L and 103-126 µg/L, respectively. This TLI RIA is analytically sensitive, sufficiently linear, accurate, precise, and reproducible for the measurement of TLI in ferret serum samples.

Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross-Sectional Study.

PURPOSE: As life expectancy in cystic fibrosis (CF) increases, questions regarding its potential impact on cardiovascular health arise. Soluble vascular cell adhesion molecule 1 (sVCAM-1), P-selectin (sP-selectin) are proposed as biomarkers of cardiovascular disease. We aimed to: compare their concentrations in clinically stable CF patients and healthy subjects (HS) and verify whether they independently correlate with CF characteristics. METHODS: Serum sVCAM-1 and sP-selectin levels were measured using ELISA. CF was characterized using: forced expiratory volume in 1 s, exocrine pancreatic and CF-related liver disease status, Pseudomonas aeruginosa colonization, serum high-sensitivity C-reactive protein, and body mass index (BMI). CFTR genotypes were classified as severe (classes I and II) or other. RESULTS: 108 CF patients and 51 healthy subjects volunteered for the study. In the CF group BMI was lower (median [IQR]: 20.5 kg/m2 [18.4-22.2] vs. 21.6 kg/m2 [19.9-23.4], p = 0.02) and hsCRP levels were higher (3.6 mg/L [1.1-7.1] vs. 0.5 mg/dL [0.3-1.0], p < 10-10). While sVCAM-1 concentrations were greater in CF patients (1018 ng/mL [851-1279] vs. 861 ng/mL [806-979], p < 10-4), sP-selectin levels did not differ (155 ng/mL [129-188] vs. 156 ng/mL [144-177], p = 0.48). None of the multivariable regression models was valid for the prediction of sVCAM-1 and sP-selectin in CF. CONCLUSIONS: We found higher sVCAM-1 concentrations in CF patients than in healthy subjects, which were not explained by CF characteristics. Further research is required to check whether sVCAM-1 is a marker of microangiopathy in CF.

Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

OBJECTIVE: The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. DESIGN: Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. RESULTS: A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p<0.00001; I2=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I2=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. CONCLUSIONS: PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.