Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing.

Pediatric patients with exocrine pancreatic insufficiency (EPI) have symptoms that include abdominal pain, weight loss or poor weight gain, malnutrition, and steatorrhea. This condition can be present at birth or develop during childhood for certain genetic disorders. Cystic fibrosis (CF) is the most prevalent disorder in which patients are screened for EPI; other disorders also are associated with pancreatic dysfunction, such as hereditary pancreatitis, Pearson syndrome, and Shwachman-Diamond syndrome. Understanding the clinical presentation and proposed pathophysiology of the pancreatic dysfunction of these disorders aids in diagnosis and treatment. Testing pancreatic function is challenging. Directly testing aspirates produced from the pancreas after stimulation is considered the gold standard, but the procedures are not standardized or widely available. Instead, indirect tests are often used in diagnosis and monitoring. Although indirect tests are more widely available and easier to perform, they have inherent limitations due to a lack of sensitivity and/or specificity for EPI.

Accuracy of simultaneous measurement of serum biomarkers: Carbohydrate antigen 19-9, pancreatic elastase-1, amylase, and lipase for diagnosing pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer is difficult to diagnose early since tumor markers have low sensitivity and specificity. We simultaneously measured serum carbohydrate antigen (CA) 19-9, pancreatic elastase-1, lipase, and amylase, and evaluated the accuracy of a single marker or a combination of two, three, or four markers in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). METHODS: Seventy-six patients with PDAC were included, and 75 patients with non-PDAC diseases were enrolled as the control group. Blood specimens were collected and analyzed for pancreatic elatase-1, CA19-9, amylase and lipase. Sensitivity, specificity, and accuracy for each individual marker and in combination were determined. RESULTS: In PDAC subjects, abnormal CA19-9 was seen most frequently at 80.3%, followed by pancreatic elastase-1 at 57.9%, lipase at 53.9%, and amylase at 51.3%. In non-PDAC subjects, the percentage of abnormal serum pancreatic elastase-1, CA19-9, lipase, and amylase were 50.7%, 41.3%, 40.0%, and 28.0%, respectively. The accuracy rate of amylase and CA19-9 results combined was 64.9% and was higher than the combination of other markers in the intersection set. In the union set, the group of amylase and CA19-9 combined and the group of lipase and CA19-9 combined had the highest accuracy at 66.2%. In the intersection and union set, the area under the curve of CA19-9 was the highest at 0.695. CONCLUSION: CA19-9 as a single marker is the most accurate in the clinical diagnosis of PDAC. Combination of lipase, amylase, or pancreatic elastase-1 results does not significantly increase the accuracy of PDAC diagnosis.

Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview.

Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC50 values in a range from nM to µM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.

[Assessment of exo- and endocrine function of pancreas following distal pancreatectomy].

AIM: The assessment of pancreatic resection volume influence on exo- and endocrine pancreatic functions. MATERIALS AND METHODS: The resected pancreatic volume influence was assessed in 47 patients: 31 (66%) patients after resections of pancreatic body and tail, and 16 (34%) patients after distal resections. The exocrine pancreatic function was assessed by pancreatic fecal elastase 1 as well as endocrine pancreatic function was assessed by C-peptide level measurement. Computed tomography with intravenous contrast enhancement and postprocessing was used for pre- and postoperative pancreatic volume assessment. All tests were performed before and 1, 3, and 6 months after surgery. RESULTS: Type of surgery had no influence on C-peptide and pancreatic fecal elastase 1 levels (p>0.05). Exo- and endocrine pancreatic functions markers tended to decrease in 1st month after surgery with consequent functions restoration towards 6 months after surgery. There were 15 (35.7%) patients from 42 patients with normal exocrine pancreatic function with a fecal elastase 1 level decrease to 114.7±61.8 µg/g; exocrine insuficiency remained only in 2 (4.8%) patients after 6 months after surgery. C-peptide concentration decrease before surgery to less than 1.1 ng/ml was noticed only in 8 (17%) patients. C-peptide concentration decreased in 30 (63.8%) patients in 1st month after surgery, but after 6 months after surgery, C-peptide level decrease was only in 7 (14.9%) patients. CONCLUSION: The exo- and endocrine function of the pancreas is restored in more than 80% of patients after DR. Probably it could be associated with the activation of the pancreatic compensatory abilities.

Preventive and therapeutic effect of anti-IL-17 in an experimental model of elastase-induced lung injury in C57Bl6 mice.

Chronic obstructive pulmonary disease (COPD) is an important health care issue, and IL-17 can modulate inflammatory responses. We evaluated preventive and therapeutic effect of anti-interleukin (IL)-17 in a model of lung injury induced by elastase, using 32 male C57Bl6 mice, divided into 4 groups: SAL, ELASTASE CONTROL (EC), ELASTASE + PREVENTIVE ANTI-IL-17 (EP), and ELASTASE + THERAPEUTIC ANTI-IL-17 (ET). On the 29th day, animals were anesthetized with thiopental, tracheotomized, and placed on a ventilator to evaluate lung mechanical, exhaled nitric oxide (eNO), and total cells of bronchoalveolar lavage fluid was collected. We performed histological techniques, and linear mean intercept (Lm) was analyzed. Both treatments with anti-IL-17 decreased respiratory resistance and elastance, airway resistance, elastance of pulmonary parenchyma, eNO, and Lm compared with EC. There was reduction in total cells and macrophages in ET compared with EC. Both treatments decreased nuclear factor-кB, inducible nitric oxide synthase, matrix metalloproteinase (MMP)-9, MMP-12, transforming growth factor-ß, tumor necrosis factor-α, neutrophils, IL-1ß, isoprostane, and IL-17 in airways and alveolar septa; collagen fibers, decorin and lumican in airways; and elastic fibers and fibronectin in alveolar septa compared with EC. There was reduction of collagen fibers in alveolar septa and biglycan in airways in EP and a reduction of eNO synthase in airways in ET. In conclusion, both treatments with anti-IL-17 contributed to improve most of parameters evaluated in inflammation and extracellular matrix remodeling in this model of lung injury.

Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins.

In order for the intestinal mucosa to absorb dietary proteins they have to be digested into single amino acids or very short peptides of a length of not more than four amino acids. In order to study the efficiency of the digestive endopeptidases to digest folded proteins we have analyzed several target proteins under different conditions, native proteins, heat denatured and acid treated. The three pancreatic serine proteases, trypsin, chymotrypsin, and pancreatic elastase, were found to be remarkable inefficient in cleaving native folded proteins whereas pepsin, which acts at a very low pH (pH 1.2) was much more efficient, possibly due to the denaturing conditions and thereby better accessibility to internal cleavage sites at the low pH. Heat treatment improved the cleavage considerably by all three pancreatic enzymes, but acid treatment followed by return to neutral pH did not have any major effect. Cleavage at the low pH when the protein is in a denatured state, is apparently very efficient. This indicates that pepsin is the prime enzyme cleaving the properly folded native proteins and that the pancreatic enzymes primarily are involved in generating single amino acids or very short peptides for efficient uptake by the intestinal mucosa.

The potential of Atorvastatin for chronic lung diseases therapy.

Atorvastatin (ATO) is of the statin class and is used as an orally administered lipid-lowering drug. ATO is a reversible synthetic competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase thus leading to a reduction in cholesterol synthesis. It has recently been demonstrated that ATO has different pharmacological actions, which are unrelated to its lipid-lowering effects and has the ability to treat chronic airway diseases. This paper reviews the potential of ATO as an anti-inflammatory, antioxidant, and anti-proliferative agent after oral or inhaled administration. This paper discusses the advantages and disadvantages of using ATO under conditions associated with those found in the airways. This treatment could potentially be used to support the formulating of ATO as an inhaler for the treatment of chronic respiratory diseases.

Translational Relevance and Recent Advances of Animal Models of Abdominal Aortic Aneurysm.

Human abdominal aortic aneurysm (AAA) pathophysiology is not yet completely understood. In conductance arteries, the insoluble extracellular matrix, synthesized by vascular smooth muscle cells, assumes the function of withstanding the intraluminal arterial blood pressure. Progressive loss of this function through extracellular matrix proteolysis is a main feature of AAAs. As most patients are now treated via endovascular approaches, surgical AAA specimens have become rare. Animal models provide valuable complementary insights into AAA pathophysiology. Current experimental AAA models involve induction of intraluminal dilation (nondissecting AAAs) or a contained intramural rupture (dissecting models). Although the ideal model should reproduce the histological characteristics and natural history of the human disease, none of the currently available animal models perfectly do so. Experimental models try to represent the main pathophysiological determinants of AAAs: genetic or acquired defects in extracellular matrix, loss of vascular smooth muscle cells, and innate or adaptive immune response. Nevertheless, most models are characterized by aneurysmal stabilization and healing after a few weeks because of cessation of the initial stimulus. Recent studies have focused on ways to optimize existing models to allow continuous aneurysmal growth. This review aims to discuss the relevance and recent advances of current animal AAA models. VISUAL OVERVIEW: An online visual overview is available for this article.

Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children.

OBJECTIVE: The function of the exocrine pancreas is decreased in patients with type 1 diabetes but it is not known when this defect develops. The current study set out to determine whether the reduced exocrine function becomes manifest after the initiation of islet autoimmunity. METHODS: The study was nested in the prospective Type 1 Diabetes Prediction and Prevention study where children with human leukocyte antigen (HLA)-conferred susceptibility are observed from birth. Elastase-1 levels were analyzed from stool samples collected at the time of seroconversion to islet autoantibody positivity and at diagnosis of type 1 diabetes, as well as from samples taken from matched control children of similar age. RESULTS: Elastase levels were lower in case children at the time of the diagnosis of diabetes when compared to the control children. However, elastase concentrations did not differ between cases and controls at the time when autoantibodies appeared. CONCLUSION: The results suggest that the defect in the exocrine function develops after the appearance of islet autoantibodies. Further studies are needed to assess whether reduced elastase levels predict rapid progression of islet autoimmunity to clinical disease.

Fecal pancreatic elastase-1 in the evaluation of pancreatic function after pediatric intestinal transplantation.

Fat malabsorption is common after SBT. To identify whether anatomic variant transplants differ in occurrence of exocrine pancreatic insufficiency that could contribute to fat malabsorption, we measured FPE repeatedly in 54 recipients of a SBT, ages 6.2 to 320 months. FPE determination most distant from SBT was 6.1 years. Of the 54, 39% received an isolated intestinal graft (native pancreas only), 48% received an en bloc liver-intestinal-pancreas graft (native and graft pancreas), and 13% received a multivisceral graft (graft pancreas only). Initial FPE was normal (>200 µg/g) in 15 of the 54 at a median of 22 (11-61) days after SBT. Recipients of a liver-intestine-pancreas transplant were more likely to have normal FPE within 30 days after SBT than were isolated intestinal or multivisceral transplant recipients (47%, 19%, and 0%, respectively, P = .049). Of the remaining 39 patients, 34 eventually demonstrated a normal FPE at a median of 168 (31-943) days after SBT. Type of SBT did not influence the likelihood of achieving a normal FPE level or time when it occurred. Five (9%) patients failed to achieve normal FPE, including 3 who died within 2 years after SBT. In conclusion, possessing both graft and native pancreas as in transplantation of an en bloc liver-intestinal-pancreas graft facilitates early normalization of FPE that eventually occurs in most patients irrespective of transplant type. Failure to recover normal pancreatic function may be associated with severe post-transplant complications.

[The expression of trypsin in serum and vital organs of septic rats].

Objective: Pancreatic enzymes may spread into the injured intestine, bloodstream,and cause the cascade of inflammatory reactions.Our objective was to explore trypsin expression in serum and vital organs in septic rats. Methods: Trypsin levels in serum,heart,lung and jejunum were tested and compared between Escherichia coli endotoxin injected rats(SS), SS treated with a protease inhibitor(ulinastatin) and control group(SHAM).The correlations between serum trypsin,intestinal proteins and inflammation indices were assessed.Two components of mucosal barrier, i.e. mucin-2 and E-cadherin,were measured to evaluate the intestinal mucosal barrier function.The levels of tumor necrosis factor alpha (TNFα),interleukin-6(IL-6) and neutrophil elastase(NE) were measured to determine the inflammation indices. Results: Compared to SHAM group, trypsin levels in serum[(73.71±9.14) ng/ml vs. (12.12±2.36) ng/ml],heart[(51.60±15.06) ng/ml vs. (6.39±3.53) ng/ml],lung [(54.73±5.57) ng/ml vs. (5.24±3.08) ng/ml] and jejunum(1.19±0.48 vs. 0.40±0.12) were significantly higher in SS group (all P<0.05). The level of serum trypsin had negative correlation with mucin-2 and E-cadherin, and positive correlation with TNFα, IL-6 and NE (all P<0.05). In rats treated with ulinastatin, trypsin levels were significantly decreased compared with those in SS group including in serum [(65.79±4.88)ng/ml]], heart [(26.33±12.03)ng/ml], lung [(28.73±14.46) ng/ml] and jejunum (0.80±0.20) (all P<0.05).Serum TNFα[(247.34±16.97)ng/L vs. (178.78±40.81)ng/L] revealed similar changes in ulinastatin and SS group,whereas mucin-2 (0.58±0.14 vs. 0.89±0.17) and E-cadherin (0.11±0.04 vs. 0.23±0.06) were both significantly elevated after administration of ulinastatin (both P<0.05) . Conclusion: Serum and tissue trypsin is elevated in septic rats. Protease inhibitor ulinastatin protects intestinal function by reducing inflammatory reaction.

Emphysema induced by elastase enhances acute inflammatory pulmonary response to intraperitoneal LPS in rats.

Abnormalities in lungs caused by emphysema might alter their response to sepsis and the occurrence of acute lung injury (ALI). This study compared the extension of ALI in response to intraperitoneal lipopolysaccharide (LPS) injection in Wistar rats with and without emphysema induced by elastase. Adult male Wistar rats were randomized into four groups: control, emphysema without sepsis, normal lung with sepsis and emphysema with sepsis. Sepsis was induced, and 24 h later the rats were euthanised. The following analysis was performed: blood gas measurements, bronchoalveolar lavage (BAL), lung permeability and histology. Animals that received LPS showed significant increase in a lung injury scoring system, inflammatory cells in bronchoalveolar lavage (BAL) and IL-6, TNF-α and CXCL2 mRNA expression in lung tissue. Animals with emphysema and sepsis showed increased alveolocapillary membrane permeability, demonstrated by higher BAL/serum albumin ratio. In conclusion, the presence of emphysema induced by elastase increases the inflammatory response in the lungs to a systemic stimulus, represented in this model by the intraperitoneal injection of LPS.

Single amino acid substitutions in recombinant plant-derived human α1-proteinase inhibitor confer enhanced stability and functional efficacy.

BACKGROUND: Human α1-proteinase inhibitor (α1-PI) is the most abundant serine protease inhibitor in the blood and the heterologous expression of recombinant α1-PI has great potential for possible therapeutic applications. However, stability and functional efficacy of the recombinant protein expressed in alternate hosts are of major concern. METHODS: Five variants of plant-expressed recombinant α1-PI protein were developed by incorporating single amino acid substitutions at specific sites, namely F51C, F51L, A70G, M358V and M374I. Purified recombinant α1-PI variants were analyzed for their expression, biological activity, oxidation-resistance, conformational and thermal stability by DAC-ELISA, porcine pancreatic elastase (PPE) inhibition assays, transverse urea gradient (TUG) gel electrophoresis, fluorescence spectroscopy and far-UV CD spectroscopy. RESULTS: Urea-induced unfolding of recombinant α1-PI variants revealed that the F51C mutation shifted the mid-point of transition from 1.4M to 4.3M, thus increasing the conformational stability close to the human plasma form, followed by F51L, A70G and M374I variants. The variants also exhibited enhanced stability for heat denaturation, and the size-reducing substitution at Phe51 slowed down the deactivation rate ~5-fold at 54°C. The M358V mutation at the active site of the protein did not significantly affect the conformational or thermal stability of the recombinant α1-PI but provided enhanced resistance to oxidative inactivation. CONCLUSIONS: Our results suggest that single amino acid substitutions resulted in improved stability and oxidation-resistance of the plant-derived recombinant α1-PI protein, without inflicting the inhibitory activity of the protein. GENERAL SIGNIFICANCE: Our results demonstrate the significance of engineered modifications in plant-derived recombinant α1-PI protein molecule for further therapeutic development.

Elevated permeability of the blood-brain barrier in mice intratracheally administered porcine pancreatic elastase.

Chronic obstructive pulmonary disease (COPD) shows progressive, irreversible airflow limitation induced by emphysema and lung inflammation. The aim of the present study was to determine if COPD conditions induce blood-brain barrier (BBB) dysfunction. We found that the intratracheal administration of porcine pancreatic elastase (PPE; 3 U) induced alveolar enlargement, increased neutrophil number in bronchoalveolar lavage fluid, and decreased blood oxygen saturation in mice at 21 days after inhalation. In parallel with these lung damages, BBB permeability to sodium fluorescein and Evans blue albumin was markedly increased. Our findings demonstrate that COPD conditions are associated with risk for BBB impairment.

In silico and in vitro elastase inhibition assessment assays of rosmarinic acid natural product from Rosmarinus officinalis Linn.

The use of various herbs and their compounds has been a strategy widely used in the fight against various human diseases. For example, rosmarinic acid, a bioactive phenolic compound commonly found in Rosemary plants (Rosmarinus officinalis Labiatae), has multiple therapeutic benefits in different diseases, such as cancer. Therefore, the study aimed to evaluate in silico and in vitro the inhibition potential of the enzyme Elastase from the porcine pancreas by rosmarinic acid isolated from the plant species R. officinalis Linn. Through Molecular Docking, the mechanism of action was investigated. In addition, rosmarinic acid presented a range of 5-60 µg/mL and significantly inhibited Elastase. At 60 µg/mL, there was an inhibition of 55% on the enzymatic activity. The results demonstrate the inhibition of Elastase by rosmarinic acid, which can lead to the development of new enzyme inhibitors that can be an inspiration for developing various drugs, including anticancer drugs.

Clinical and Analytical Comparison of Monoclonal and Polyclonal Immunoassays for Fecal Pancreatic Elastase.

BACKGROUND: Numerous immunoassays have been commercialized to determine pancreatic elastase (PE) in feces in screening for exocrine pancreatic insufficiency (EPI), but how the different assays compare to one another is controversial, especially in the context that all methods use the same cut-off values for interpreting the results obtained on the presence or absence of EPI or the degree of insufficiency if it is present. Our aim was to analytically verify a new method for determining PE, compare the results with a previous method, and verify the declared cut-off values for interpretation of the results. METHODS: PE in the stool was assayed using a previous monoclonal enzyme-linked immunosorbent assay ("ScheBo ELISA") and a new polyclonal particle-enhanced turbidimetric immunoassay ("Bühlmann PETIA"). The direct method comparison of two immunoassays was performed in 40 samples. Clinical comparisons were conducted against each other for the binary determination of "abnormal/normal" elastase levels and the three-way determination of "severe/moderate/no" EPI in 56 samples. The indirect comparison method used external quality assessment (EQA) data to compare the monoclonal and polyclonal immunoassays for PE, and additionally compare the monoclonal ScheBo ELISA to a monoclonal chemiluminescence immunoassay ("DiaSorin CLIA"). RESULTS: Precision in the series and intra-laboratory precision for Bühlmann PETIA met the manufacturer's specifications for the concentration range of limit/lower values and the range of normal values. The Bühlmann PETIA immunoassay on different analytical platforms yielded comparable results and nearly perfect agreement in the case of three-way classification (kappa = 0.89 with 95%CI from 0.79 to 1.00. ScheBo ELISA tends to generate higher values of pancreatic elastase than the Bühlmann PETIA; agreement between the methods was moderate in the case of binary classification (kappa = 0.43; 95% CI 0.25 to 0.62), and substantial in the case of three-way classification (kappa = 0.62; 95% CI 0.50 to 0.75). EQA data analysis showed a statistically significant difference between ScheBo ELISA and Bühlmann PETIA peer groups (p = 0.031), as well as the DiaSorin CLIA and ScheBo ELISA peer groups (p = 0.010). CONCLUSION: The ScheBo ELISA and Bühlmann PETIA do not appear to be commutable in the analytical and clinical context. Our data address a discordance between different mono- and polyclonal immunoassays for pancreatic elastase and the potential of misclassification using its universal cut-off values in screening suspected patients for exocrine pancreatic insufficiency.

Development of a unilateral porcine emphysema model induced by porcine pancreatic elastase.

Emphysema is one of the pathological hallmarks of chronic obstructive pulmonary disease. We have recently reported that radiofrequency therapy improves lung function in rodent models of emphysema. However, preclinical data using large animals is necessary for clinical translation. Here, we describe the work performed to establish a unilateral porcine emphysema model. Different doses of porcine pancreatic elastase (PPE) were instilled into the left lung of 10 Yucatan pigs. Three additional pigs were used as controls. Six weeks after instillation, lungs were harvested. Lung compliance was measured by a water displacement method and plethysmography. Systematic uniform random sampling of the left and right lungs was performed independently to measure alveolar surface area using micro-computed tomography (micro-CT) and histology. In pigs instilled with 725-750 U/kg of PPE (PPE group, n = 6), the compliance of the left lung was significantly higher by 37.6% than that of the right lung (P = 0.03) using the water displacement method. With plethysmography, the volume of the left lung was significantly larger than that of the right lung at 3, 5, and 10 cmH2O. Measurements from either micro-CT or histology images showed a significant decrease in alveolar surface area by 14.2% or 14.5% (P = 0.031) in the left lung compared with the right lung of the PPE group. A unilateral model for mild emphysema in Yucatan pigs has been established, which can now be used for evaluating novel therapeutics and interventional strategies.NEW & NOTEWORTHY For clinical translation, preclinical data using large animal models is necessary. However, papers describing an emphysema model in pigs, which are anatomically and physiologically similar to humans, are lacking. Here, we report success in creating a unilateral mild-emphysema model in pigs with only one single dose of porcine pancreatic elastase. This model will be useful in bringing novel technologies and therapies from small animals to humans with emphysema.

Nivolumab-induced exocrine pancreatic insufficiency.

Immune checkpoint inhibition is the standard-of-care for many advanced cancers. Side effects of therapy may prevent optimal treatment of the cancer. Management of side effects is dominated by recommendations derived from oncological, not gastroenterological practice. We report a patient who developed pancreatic insufficiency during checkpoint inhibitor therapy with a programmed cell death receptor 1 inhibitor, nivolumab, which if not diagnosed would have prevented ongoing treatment. This is a problem which affects approximately 1 in 100 patients treated with this agent but is rarely recognised. Gastroenterologists need to be aware of the spectrum of gastrointestinal disorders which occur after immunotherapy to treat cancer.

What is the significance of a faecal elastase-1 level between 200 and 500µg/g?

Background: Pancreatic exocrine insufficiency is a cause of malabsorption. It is generally diagnosed if faecal elastase-1 (FE-1) levels are below 200 µg/g. Pancreatic function is assumed to be normal when faecal elastase levels are >500 µg/g. The significance of faecal elastase levels above 200 µg/g but less than 500 µg/g is unclear. Methods: This retrospective study reports the response to treatment in patients who had an FE-1 level between 200 and 500 µg/g. Results: Of these 82 patients, 28 were offered pancreatic enzyme replacement therapy (PERT). A clinical response, defined as an improvement in their initial symptoms after commencing PERT, was seen in 20 patients (71%), 7 with potentially predisposing conditions and 13 with functional diarrhoea. PERT particularly abolished or improved diarrhoea, steatorrhoea and flatulence. Conclusion: Clinicians should, therefore, be aware that a trial of PERT given to patients with FE-1 levels between 200 and 500 µg/g may lead to improvement in gastrointestinal symptoms.