GABA Administration Ameliorates Sjogren’s Syndrome in Two Different Mouse Models

Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the salivary and lachrymal glands resulting in oral and ocular dryness. There are no clinically approved therapies to slow the progression of SS. Immune cells possess receptors for the neurotransmitter GABA (GABA-Rs) and their activation has immunoregulatory actions. We tested whether GABA administration has potential for amelioration of SS in NOD.B10-H2b and C57BL/6.NOD-Aec1Aec2 mice, two spontaneous SS models. Oral GABA treatment was initiated (1) after the development of sialadenitis but before the onset of overt symptoms, or (2) after the appearance of overt symptoms. When assessed weeks later, GABA-treated mice had greater saliva and tear production, as well as quicker times to salvia flow, in both SS mouse models. This was especially evident when GABA treatment was initiated after the onset of overt disease. This preservation of exocrine function was not accompanied by significant changes in the number or area of lymphocytic foci in the salivary or lachrymal glands of GABA-treated mice and we discuss the possible reasons for these observations. Given that GABA-treatment preserved saliva and tear production which are the most salient symptoms of SS and is safe for consumption, it may provide a new approach to help ameliorate SS.

Nutritional status of patients undergoing pancreatic resection

Changes in the exocrine function of the pancreas often develops after proximal and distal resections. Exocrine pancreatic insufficiency (EPI) is characterized by a reduced secretion of pancreatic enzymes, because of which the digestion and absorption of nutrients is impaired. Clinical manifestations of EPI and, as a consequence, changes in nutritional status significantly affect the quality of life of patients.

Clinical Efficacy and Safety of Ivacaftor/Lumacaftor Combination in Patients with Cystic Fibrosis: International Studies Review

Cystic fibrosis is an autosomal recessive disease caused by structure abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is characterized by severe course and poor prognosis without or with insufficient treatment. Approval of pathogenetic therapy medications, CFTR modulators (potentiators and correctors), for clinical use in 2012 in the United States has reduced mortality from this disease. This article provides the overview of studies on clinical efficacy and safety of ivacaftor/lumacaftor combination (Iva/Lum) — the first licensed CFTR modulator medication for homozygous patients with F508del variant. It was shown that Iva/Lum increases lung function, reduce the number of acute conditions of bronchopulmonary process (including those that require antibiotics and hospitalization), partially restores pancreas exocrine function, increases body weight and mass growth index, and improves quality of life. It allows considering it as favorable effect on the course and prognosis of cystic fibrosis. It was also noted that the early onset of the drug administration (from the age of two) positively affects the prognosis of the disease, increasing life expectancy and improving quality of life.

P-P17 Casting a Wider NET: Defining PEI in patients with Neuroendocrine Tumours using the 13C-MTG breath test

Background Somatostatin-analogues (SSAs) are the first-line treatment of unresectable, symptomatic neuroendocrine tumours (NETs). However, SSAs inhibit pancreatic secretions which could lead to pancreatic exocrine insufficiency (PEI). There is, however, very limited data regarding the physiologic link between SSAs and PEI. PEI negatively impacts patient quality of life (QoL), nutritional status, and clinical outcomes. This is a prospective, observational, cohort study to establish the impact of SSAs on pancreatic exocrine function in patients with NETs, using the 13C-Mixed-Triglyceride (13C-MTG) breath test. Methods Adult patients commencing SSA therapy for NETs, were recruited from December 2020. Patients were excluded if they had a diagnosis of other pancreatic disease, history of upper-gastrointestinal surgery that may alter pancreatic function, or already on SSA therapy. The impact of SSAs on exocrine function was assessed using the 13C-MTG breath test. A quotient of 13CO2/12CO2 was measured by mass spectrometry and the cumulative percent dose recovered at 6 hours (cPDR) is reported. Secondary endpoints investigated were changes in patient weight and Vitamin D levels. Results Exocrine function reduced in all patients (n = 7) following SSA therapy (median reduction from baseline: -22.2%, range: -5.6- -42.1%; p = 0.018) (Figure 1). Vitamin D levels decreased in all but one patient (median decrease from baseline: -11.7%, range: -29.3-10%; p = 0.126). Change in patient weight did not show any significant change (median decrease from baseline: -0.69%, range: -4.26 – 3.6%, p = 0.933). Conclusions SSA therapy appears to have a consistent impact on exocrine function from early in the treatment course. This suggests that there is a widespread underestimation of PEI in this setting. Whether such decrease in exocrine function leads to weight loss remains to be seen. Further studies are required to confirm this work, determine the clinical relevance of this observation, and optimise medical therapy of PEI in this cohort. The 13C-MTG breath test is a feasible and acceptable measure of pancreatic exocrine function in patients treated with SSA therapy for NETs.

P-P22 NET Profit: Considering quality of life assessment in patients treated with SSAs for NETs

Background Somatostatin Analogue (SSA) therapy of neuroendocrine tumours (NETs) leads to pancreatic exocrine insufficiency (PEI). PEI symptoms include diarrhoea, abdominal discomfort, bloating, and steatorrhea, which negatively impact quality of life (QoL). NETs (and the sequelae of carcinoid syndrome) however, have similar symptomatology to PEI, with a comparably negative impact on QoL. QoL tools exist to assess PEI and its response to enzyme therapy; however, we hypothesise that PEI symptom scale scores will be unreliable in SSA-induced PEI due to the concurrent improvement of the carcinoid symptoms. Methods Adult patients commencing SSA therapy for NETs were recruited from December 2020. Qualitative assessments of the impact of SSAs and pancreatic exocrine function on patient QoL were performed before and during (at 8 weeks) therapy. The Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) was used to capture patient-reported assessment of relevant symptoms. Health-related QoL was assessed using the European Organisation Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLC)-C30, supplemented by the EORTC GI.NET.21. Patients were specifically asked about steatorrhea at both assessments. Results Seven patients completed the study. 5-HIAA levels were raised in 4/7 patients, indicative of carcinoid syndrome, secondary to the NET. Pancreatic exocrine function reduced after SSA therapy in all patients (data reported elsewhere) but paradoxically PEI-Q symptom scale scores reduced (median decrease from baseline: -18.5%, range: -1.5- -55.6%; p = 0.018) (Figure 1). According to PEI-Q, all seven patients would meet the criteria for a mild PEI at baseline, and two would be considered severe. One patient reported steatorrhea after commencing SSA-therapy. No changes in relevant domains of EORTC questionnaires were statistically significant, including functional, symptomatic, and overall health scores. Conclusions The PEI-Q tool is not useful for assessing SSA-related PEI due to substantial symptom overlap with the tumour itself and SSA therapy. The decrease in symptom score is likely due to improvement of carcinoid syndrome, independent of PEI. Although the cardinal PEI symptom is steatorrhea, there is no distinction between that and diarrhoea in the EORTC tool, and confounding aetiologies of diarrhoea in NET patients may further complicate assessment. Current available QoL measures are of limited use in the setting of SSA-related PEI, and care should be taken if evaluating PEI or response of PEI to treatment.

P-P41 Systematic review of Sarcopenia in Chronic Pancreatitis: prevalence, impact on surgical outcomes and survival

Background Chronic pancreatitis(CP) is characterised by progressive inflammatory changes to the pancreas, leading to loss of endocrine and exocrine function. Emerging literature suggests sarcopenia may adversely affect outcomes for chronic pancreatitis patients. This systematic review examines the evidence surrounding the impact of sarcopenia on patients with CP. Methods A systematic literature search of PUBMED, MEDLINE and EMBASE databases identified articles describing body composition assessment in patients with CP. Data collected included definitions of sarcopenia, assessment methodology, baseline demographics, surgery related data and short- and long-term outcomes. Results 9 studies, including 977 patients and a sarcopenia prevalence of 32.3% were included. Alcohol was the predominant aetiology. There was significant heterogeneity in definitions of sarcopenia used. CT was the main modality to assess for sarcopenia in 7 papers, MRI in 2 papers and clinical measurements in 2 papers. 2 papers included patients undergoing total pancreatectomy and Islet cell transplantation. None of the studies found a significant increase in complications with sarcopenia. 1 Year mortality in outpatients from one study of patients with CP was 16% in sarcopenic patients versus 3% (HR:6.69(95%CI:1.79–24.9),p<0.001). Conclusions Sarcopenia is prevalent in patients with CP and has adverse impact on short- and long-term survival.

Image-guided MALDI mass spectrometry for high-throughput single-organelle characterization

Peptidergic dense-core vesicles are involved in packaging and releasing neuropeptides and peptide hormones—critical processes underlying brain, endocrine and exocrine function. Yet, the heterogeneity within these organelles, even for morphologically defined vesicle types, is not well characterized because of their small volumes. We present image-guided, high-throughput mass spectrometry-based protocols to chemically profile large populations of both dense-core vesicles and lucent vesicles for their lipid and peptide contents, allowing observation of the chemical heterogeneity within and between these two vesicle populations. The proteolytic processing products of four prohormones are observed within the dense-core vesicles, and the mass spectral features corresponding to the specific peptide products suggest three distinct dense-core vesicle populations. Notable differences in the lipid mass range are observed between the dense-core and lucent vesicles. These single-organelle mass spectrometry approaches are adaptable to characterize a range of subcellular structures.

Exocrine Pancreatic Function in Girls with Anorexia Nervosa

Objectives: To assess pancreatic exocrine function in patients with anorexia nervosa using a breath test with 13C-labeled mixed triglycerides (MTG-BT) and to determine the relationship between the test results and selected biochemical and hormonal parameters. Material and methods: Anthropometric measurements, biochemical and hormonal parameters (serum leptin, soluble leptin receptor (sLR), acylated and desacylated ghrelin, free leptin index (FLI)), and MTG-BT were performed in a group of 31 girls with the restrictive type of AN, as well as 38 healthy girls (C). Results: The average cumulative dose of 13C-triglycerides recovered with exhaled air (%CD) was similar in both study groups, while the average time from 13C-triglycerides administration to peak 13CO2 excretion in expired air (time to peak (TTP)) was significantly longer in patients with AN compared to C. In both groups, %CD correlated negatively with FLI. TTP correlated negatively with sLR and FLI in the AN and with serum insulin and HOMA-IR values in the C. Conclusions: In girls with AN, the pancreatic efficiency of lipase secretion was found to be normal, while the kinetics of this enzyme secretion were disturbed. These changes may result from disorders in the functioning of the adipose–insular and islet–acinar axes.