Why care about the exocrine pancreas in diabetes?

Transcription

1 Why care about the exocrine pancreas in diabetes? Nils Ewald, MD, PhD Associate Professor of Internal Medicine / Endocrinology and Diabetology Justus-Liebig-University Giessen, Germany and General Hospital Luebbecke

2 Declaration of interests The speaker at this meeting has been selected by Mylan and will receive an honorarium for services provided The speaker at this meeting has also received sponsorship, consulted or lectured on behalf of other pharmaceutical and non-pharmaceutical companies This declaration is made in accordance with clause 23.1 of the ABPI Code of Practice 2016 NON DOP: Nov 2018

3 Close Proximity of the Exocrine and Endocrine Pancreas 03/12/18 Encyclopaedia Britannica Inc.

4 Interactions between the Exocrine and Endocrine Pancreas Anatomy Islet cells are disseminated throughout the whole pancreas organ (enlargement of the area of direct cell-to-cell interactions) No membrane or any other anatomical border separates islet cells and acinar cells Acinar cells in proximity to islets are larger, possess bigger nuclei and more granula, additionally they show increased protein synthesis and increased functional activity Type 1+2 diabetes mellitus patients show an atrophy of acinar cells Existence of a portal blood system within the pancreas organ Physiology Insulin and pancreatic polypeptide (PP): Insulin stimulates protein synthesis and mitosis in acinar cells PP stimulates DNA synthesis in acinar cells Glucagon and somatostatin: Inhibit exocrine function Long-term parenteral application of glucagon leads to acinar atrophy Clinical Practice Review in: Pancreatology 2009;9(4):351-9

5 Endocrine Findings in Exocrine Pathology (Pancreatitis) Prevalence of diabetes mellitus in acute pancreatitis (AP) - Impaired glucose tolerance in approximately 50% of all AP cases - Diabetes mellitus within 3.5 years after first episode of AP = 32% [Pancreas (7): ] - Diabetes mellitus after a severe episode of AP = 39% (follow up 60 months) [J Hepatobiliary Pancreat Surg. 2008;15(4): ] Prevalence of diabetes mellitus in chronic pancreatitis (CP) % [Gastroenterology 2000;119: ; Pancreas Mar;40(2):206-12] - Up to 90% in chronic-calcific disease [Pancreas Mar;40(2):206-12] - Risk factors: duration of the disease, prior partial pancreatectomy, and early onset of calcific disease [Gut 2009; 58: ; Gastroenterol Hepatol 2004; 2: ; United European Gastroenterology Journal 2017; doi: / ] ] Pancreatitis Diabetes

6 Exocrine Findings in Endocrine Pathology (Diabetes Mellitus) Risk of acute pancreatitis is clearly elevated in type 2 DM [Am J Gastroenterol Sep;106(9): ; Diabetes Care Dec;33(12):2580-5] Pancreas is smaller and lighter in patients with DM due to diminished exocrine tissue [Pancreas. 2011; 40(3): ; Diabetes Care Sep;16(9):1296-7; Diabet Med Oct;10(8): ] Atrophy, fibrosis and loss of acinar cells in DM [Pancreas. 2011; 40(3): ; Diabetes Jun;50(6): ] Ductal alterations suggestive of chronic pancreatitis in DM [J Clin Gastroenterol. 2009; 43(2): Am J Gastroenterol May;89(5): Pancreatology. 2002;2(1):30-3.] Diabetes Pancreatitis

7 Metaanalysis: Pancreas Size in T1 Diabetes Pancreatic size and fat content in diabetes: A systematic review and meta-analysis of imaging studies Garcia et al. 03/12/18 PLoS One. 2017; 12(7): e

8 Metaanalysis: Pancreas Size in T2 Diabetes Pancreatic size and fat content in diabetes: A systematic review and meta-analysis of imaging studies Garcia et al. 03/12/18 PLoS One. 2017; 12(7): e

9 Pancreas Volume in Health and Disease Very recent (2018) systematic review and meta-analysis from the Auckland group (18 studies) DeSouza et al., Expert Review of Gastroenterology and Hepatology 2018, 12 (8): /12/18

10 Histopathological Findings (Exocrine Pancreas in Diabetes melitus) 03/12/18 Mohapatra et al., Pancreas 2016, 45 (8):

11 Morphology of the Exocrine Pancreas in Diabetes Mellitus Conclusions of the available studies: Pancreas is generally smaller and lighter in patients with DM due to diminished exocrine tissue (more obvious in T1DM) Atrophy, fibrosis and loss of acinar cells in DM are observed Ductal alterations (suggestive of chronic pancreatitis) in DM are observed There are clear anatomical changes of exocrine pancreatic structure in presence of an endocrine disease such as diabetes mellitus Pancreas 2016, 45 (8): Expert Review of Gastroenterology and Hepatology 2018, 12 (8): PLoS One. 2017; 12(7): e Pancreas. 2011; 40(3): ; Diabetes Care Sep;16(9): Diabet Med Oct;10(8): Diabetes Jun;50(6): J Clin Gastroenterol. 2009; 43(2): Am J Gastroenterol May;89(5): Pancreatology. 2002;2(1):30-3.]

12 Do those morpohological changes translate into an impaired exocrine function in type 1 und type 2 diabetes mellitus? And if so, what are the clinical consequences? 03/12/18

13 Prevalence of Exocrine Pancreatic Insufficiency in Diabetes Mellitus Author Year Subjects Methods Results Pollard H et al Amylase and lipase after pancreozymin-secretin stimulation Chey WY et al diabetic patients; 13 juvenile type Vacca JB et al diabetic patients (22 insulin treated) Amylase and lipase after pancreozymin-secretin stimulation Diastase and bicarbonate after secretin stimulation; fecal fat 62% reduced Low amylase output in diabetes 36% Juvenile diabetes 77% 73% abnormal; correlation with age, no correlation with fecal fat Frier BM et al IDDM, 7 NIDDM, 13 controls Harano Y et al NIDDM, 4 IDDM, 18 controls Stimulation with iv secretin and CCK-PZ Secretin-pancreozymin test PEI: 80% IDDM; correlation with duration Diabetes: 69% deficient enzyme output; correlation with diabetes control Lankisch PG et al IDDM Secretin-pancreozymin test Diabetes: 43% impaired function Bretzke G et al insulin-treated type 2 diabetic patients El Nehwihi H et al type 2 diabetic patients with diarrhea and neuropathy Secretin-pancreozymin test Secretin and CCK test Diabetes 27% mild PEI Enzyme and bicarbonate reduction in all subjects Semakula C IDDM, 303 non-diabetic siblings, 207 controls Serum amylase and lipase Reduced enzyme levels in 18% IDDM, 6% siblings and 2% controls Direct function tests: Exocrine pancreatic insufficiency in 52.4% (18-100%)

14 Prevalence of Exocrine Pancreatic Insufficiency in Diabetes Mellitus Non-invasive testing /screening: Author Year Subjects Methods Results Hardt et al (type 1+2) Fecal chymotrysin Hardt et al type 1 77 type 2 Fecal elastase 1 Fecal elastase 1 Indirect function tests (FEC): 45% <6 U/l 46% < 200 µg/g 74% < 200 µg/g Icks et al type 1 Fecal elastase % < 200 µg/ Rathmann et al type 2 Fecal elastase % < 200 µg/ Hardt et al type type 2 Fecal elastase 1 Exocrine pancreatic insufficiency in type 1 diabetes mellitus: 51% (26-74%) Exocrine pancreatic insufficiency in type 2 diabetes mellitus: 32% (28-36%) 36% 51%< 200 µg/ 35%< 200 µg/ Nunes et al type 1+2 Fecal elastase 1 36% < 200 µg/g Yilmaztepe et al type 2 Fecal elastase 1 28% < 200 µg/ Cavalot et al type 1 Fecal elastase 1 26% < 200 µg/g to be continued until today...

15 Studies on Exocrine Pancreatic Function in Type 1 Diabetes Mellitus (cross sectional studies) Study Patients PEI Factors associated (+) / not-associated (-) with PEI Hardt et al. (2000) 31 <100 µg/g: 25.9% < 200µg/g: 45.5% - diabetes duration Icks et al. (2001) 112 <100 µg/g: 30% < 200µg/g: 56.7% Hardt et al. (2002) 323 <100 µg/g: 28.5% < 200µg/g: 51% Cavalot et al. (2006) 66 <100 µg/g: 10.6% < 200µg/g: 25.8% + male sex, age - Diabetes duration, early diabetes onset + diabetes duration, early diabetes onset, insulin usage - age, sex - age, diabetes duration, early onset, HbA1c Hahn et al. (2008) 33 < 200µg/g: 27.3% - sex, age, diabetes duration, early diabetes onset, HbA1c Larger et al. (2012) 195 <100 µg/g: 19% < 200µg/g: 34% Vujasinovic et al. (2013) 50 <100 µg/g: 2% < 200µg/g: 6% Shivaprasad et al. (2015) 89 < 200µg/g: 31.4% + HbA1c + diabetes duration - early diabetes onset, age, insulin dosage - diabetes duration Oscarsson et al. (2017) 10 < 200µg/g: 33% n.a. 03/12/18

16 Studies on Exocrine Pancreatic Function in Type 2 Diabetes Mellitus (cross sectional studies) Study Patients PEI Hardt et al. (2000) 83 <100 µg/g: 16.9% < 200µg/g: 46% Rathmann et al. (2001) 544 <100 µg/g: 11.9% < 200µg/g: 30.3% Hardt et al. (2003) 697 <100 µg/g: 19.9% < 200µg/g: 35.9% Nunes et al. (2003) 42 <100 µg/g: 22% < 200µg/g: 36% Yilmaztepe et al. (2005) 32 <100 µg/g: 3.1% < 200µg/g: 28.1% Mancilla et al. (2006) 70 <100 µg/g: 19% < 200µg/g: 33% Ewald et al. (2007) 546 <100 µg/g: 21.1% Larger et al. (2012) 472 <100 µg/g: 12% < 200µg/g: 20% Vujasinovic et al. (2013) 100 <100 µg/g: 3% < 200µg/g: 5% Terzin et al. (2014) 101 < 200µg/g: 16.8% Cummings et al. (2015) 288 < 200µg/g: 10% Sivaprasad et al. (2015) 95 < 200µg/g: 29.4% Rathmann et al. (2016) 536 <100 µg/g: 12% < 200µg/g: 17.6 % Kangrga et al. (2016) 315 <100 µg/g: 5.1% < 200µg/g: 5.1% Oscarssonet al. (2017) 38 < 200 µg/g: 33% 03/12/18 Lindkvist et al. (2018) 315 <100 µg/g: 4.9% < 200µg/g: 5.2%

17 Overall Prevalence of PEI in T1 and T2 DM (Recent Review from Zsori et al. 2018, Szeged Group) Most recent review (of 40 studies): PEI in T1 DM: 40% (26-74%) PEI in T2 DM: 27% (10-56%) 03/12/18 Zsori et al., Pancreatology 18 (2018)

18 Pathophysiological Concepts of Exocrine Pancreatic Insufficiency In Diabetes Mellitus Lack of trophic insulin effects on acinar tissue [J Clin Invest Sep;92(3):1113-4]. Islet hormones have regulatory functions on exocrine tissue which may be impaired [Horm Metab Res Jul;7(4):290-6.] Diabetic autonomic neuropathy may lead to impaired enteropancreatic reflexes and exocrine dysfunction [Exp Diabetes Res 2011; ); Dig Dis Sci Jun;33(6):705-10] Diabetic angiopathy may cause local microangiopathy followed by pancreatic fibrosis and atrophy [Ann Intern Med Aug;61:242-7.] Recurring subclinical pancreatitis by means of diabetic acidosis [Ann Intern Med Feb;48(2): ] Viral infections and/or simultaneous autoimmunity against endo- and exocrine tissue [JOP Nov 3;9(6):683-9; Pancreas Jul;27(1):26-30.; Diabetologia Apr; 39(4): ] Inflammatory alterations and/or altered cytokine expression (e.g. TGFβ1, TGFα,TNFα, etc.) in metabolic syndrome and obesity [Pancreas May;40(4): ; Gut.2002;50(4):542-8] Genetic changes affecting both, exocrine and endocrine, tissue [J Biol Chem Oct 7286(40): ]

19 Pathophysiological Concepts of Exocrine Pancreatic Insufficiency In Diabetes Mellitus There definitely is a diabetes associated pancreopathy, however......it is also possible that some of the diabetics are actually patients with chronic pancreatitis. It is this that we would emphasize. [Chey et al.; Ann Intern Med Dec;59: ] Is pancreatogenic diabetes mellitus a frequent phenomenon? [Diabetes Care Feb;31, 165-9, Eur J Intern Med Apr;24(3): ]

20 Problems in Assessing the Prevalence of Pancreatogenic Diabetes Mellitus Lack of awareness of pancreatogenic DM in general Lack of well-defined diagnostic criteria No routine screening for exocrine function/morphology in DM Patients with T1DM und T2DM might develop CP/PDAC Patients with CP/PDAC might develop T1DM or T2DM Patients with pancreatogenic DM due to CP might be clinically and biochemically different from patients with pancreatogenic DM due to PDAC (heterogenous population)

21 Prevalence of Pancreatogenic Diabetes Mellitus Is pancreatogenic diabetes mellitus a frequent phenomenon? [Diabetes Care Feb;31, 165-9, Eur J Intern Med Apr;24(3): ]...Pancreatic diabetes is believed to account for only % of all patients with diabetes mellitus... [Alberti KGMM, 1987; Ganda O, 1994] Two major studies trying to assess the prevalence of pancreatogenic diabetes mellitus: Ewald N, et al. 2012, Diabtes Metab Res Rev Woodmansey C, et. al 2017, Diabetes Care

22 Prevalence of Pancreatogenic Diabetes Mellitus 03/12/18 Diabetes Metab Res Rev May;28(4):338-42

23 Prevalence of Pancreatogenic Diabetes Mellitus Pre-classification and reclassification of the different diabetes types Diabetes Metab Res Rev May;28(4): /12/18

24 Proposed Diagnostic Criteria for Pancreatogenic Diabetes Mellitus Major criteria (must be present) Presence of exocrine pancreatic insufficiency (monoclonal fecal elastase-1 test or direct function tests) Pathological pancreatic imaging (endoscopic ultrasound, MRI, CT) Absence of type 1 diabetes mellitus associated autoimmune markers Minor criteria Absent Pancreatic Polypeptide secretion Impaired incretin secretion (e.g. GLP-1) No excessive insulin resistance (e.g. HOMA-IR) Impaired beta cell function (e.g. HOMA-B, C-Peptide/Glucose-Ratio) Low serum levels of lipid soluable vitamins (A, D, E, and K) Ewald N et al., Eur J Intern Med, 2013

25 Prevalence of Pancreatogenic Diabetes Mellitus Is pancreatogenic diabetes mellitus a frequent phenomenon? [Diabetes Care Feb;31, 165-9, Eur J Intern Med Apr;24(3): ]...Pancreatic diabetes is believed to account for only % of all patients with diabetes mellitus... [Alberti KGMM, 1987; Ganda O, 1994] Answer: Probably pancreatogenic diabetes mellitus is more common than previously thought. It s prevalence seems to be around 5-7% within all patients with diabetes mellitus in Western populations

26 How to Identify Patients with Endocrine and Exocrine Pancreatic Insufficiency? It should not be very hard to identify diabetes mellitus in patient with diagnosed chronic pancreatitis (CP) Screening tools (e.g. fasting-glucose, 75g OGTT, HbA 1c ) are available and well-accepted But one has to... Be aware of it! Screen for it! Classify correctly! Patient with CP (exocrine disease) Screen for DM, Screening-algorithm Classify correctly Be aware of special therapeutic features

27 How to Identify Patients with Endocrine and Exocrine Pancreatic Insufficiency? The greater challenge, however, is to think of a (sub-)clinical exocrine pancreatic disease in a patient first presenting with diabetes mellitus, at least when GI-complaints are present. (Do not only think of side effects of antidiabetic medications such as metformin, incretin-based therapies, etc.) Patient with DM (endocrine disease) 03/12/18 Screen for underlying exocrine pancreatic disease (at least if any GI-complaints are present) 27 Classify correctly Watch out for exocrine pancreatic insufficiency

28 How to Screen for Exocrine Pancreatic Insufficiency in Diabetes Mellitus? Diagnosis of PEI is commonly based on an assessment of the individual s clinical state and a self-report of bowel movements and weight loss in adults or failure to thrive in children 1 03/12/18 Common symptoms: Abdominal pain 1 Flatulence in adults 1 Weight loss 1 Lack of weight gain in children 1 Steatorrhoea 1 Lack of energy 2 Diarrhea Glycaemic control? 1. Australasian treatment guidelines for the management of pancreatic exocrine insufficiency. 2010: Ockenga J. HPB (suppl.3):11-15.

29 How to Screen for Exocrine Pancreatic Insufficiency in Diabetes Mellitus? Recognize the Red Flags! Ask your diabetic patient for those symptoms!...otherwise you may never know... Chong L et al. Poster Presentation, Diabetes UK, 2014

30 Exocrine Pancreatic Function Tests Secretin Test (SPT) is the Gold Standard Evidence 1b, recommendation A In clinical routine, non-invasive tests should be used Evidence 5, recommendation B Faecal elastase-1 is widely available and can be used The 13 C breath test (MTG) is an alternative Test Mild PEI Moderate PEI Severe PEI Sensitivity (%) Sensitivity (%) Sensitivity (%) Specificity (%) f-elastase-1 54% 75% 95% 85% (96% / 79%) $ Qualitative fat 0% 0% 78% 70% Chymotrypsin <50% ca. 60% 80-90% 80-90% 1a/b activity 13 C-breath tests (mixed Triglyceride) % % 80-90% 1b/2b Evidence 1a/b Siegmund et al., Z Gastroenterol 2004, 42:

31 Identifying Exocrine Pancreatic Disease in a Diabetes Clinic Patient with diagnosed hyperglycemia (diabetes mellitus) in a Diabetes Clinic Be aware of frequent exocrine pancreopathy and/or pancreatogenic diabetes mellitus! Thorough medical history with focus on pancreatopathy and GI complaints Basic anthropometric data (weight loss, BMI, waist circumference, etc.) Basic laboratory assessment Diabetes-associated immunology C-peptide / fasting glucose ratio or HOMA-B Pancreatic imaging Concomitant exocrine disease? Pancreatogenic Diabetes mellitus? Exocrine pancreatic function assessment Watch out for special therapeutic features Lipid soluable vitamin status and markers of malnutrition (e.g. prealbumin, retinol-binding protein,25-oh cholecalciferol minerals/ trace elements) 31

32 How to Treat? Treatment Algorithm for Exocrine Pancreatic Insufficiency United European Gastroenterology J, 2013, 1:79-83

33 Why is it Important to Identify and Treat Diabetes Patients with Concomitant Exocrine Dysfunction? PAST: Pancreatic exocrine insufficiency considered as an (isolated) organ defect Treatment of PEI guided by amelioration of symptoms Reversal of weight loss, bloating, steatorrhoea TODAY: Pancreatic exocrine insufficiency is causing malnutrition and long-term morbidity (osteoporosis, immune defects) Treatment of PEI must look beyond symptom control to reduce morbidity and mortality

34 Why is it Important to Identify and Treat Diabetes Patients with Concomitant Exocrine Dysfunction? Special therapeutic features : 1. Disturbed fat digestion - What about the incretin action and incretin-based therapies in those patients? - What about qualitative malnutrition, especially vitamin D and ist (non-classical) actions? 2. Exocrine pancreatic insufficiency - Does exocrine pancreatic insufficiency influence metabolic control in those patients? - Can enzyme replacement therapy influence metabolic control? 3. Anti-diabetic treatment - Which diabetes therapy? Incretin-based? Metformin? OAD vs. Insulin? Brittle -Diabetes? SGLT-II?

35 Implications Key-Questions: What about the incretin effect and incretin-based therapies in T3cDM? Does exocrine pancreatic insufficiency influence metabolic control in T3cDM? Can enzyme replacement therapy influence metabolic control?

36 The addition of pancreatin improves the incretin effect in diabetic patients with exocrine pancreatic insufficiency (EPI) In DM patients with EPI due to chronic pancreatitis, adding pancreatin: Reverses the impaired GIP response Restores the incretin effect of fat Improves glucose tolerance In the absence of PERT a significant rise of IR-GIP was observed after 30 min, reaching peak level of mcg/l With PERT IR-GIP levels rose more rapidly and reached significantly greater peak levels ( mcg/l, p<0.005) In the presence of PERT, the response of serum levels of GIP to the test meal was significantly enhanced (81.2 vs mcg/l x 180 min) Ebert Diabetologia 1980;19: /12/18 Without PERT there was a small meal-induced rise in plasma IRI ( mu/l at 45 min) With PERT IRI levels were significantly higher between 30 and 210 min, reaching mu/l at 45 min At the same time insulin response was augmented (3.4 vs 6.4 U/l x 180 min), resulting in improved glucose tolerance Patients with chronic pancreatitis had impaired glucose tolerance. Mean serum levels were 230 mg/ dl (12.76mmol/L) at 60 min and 242 mg/dl (13.43mmol/L) at 120 min After PERT the serum glucose levels peaked earlier but fell again more rapidly

37 Implications Key-Questions: What about the incretin effect and incretin-based therapies in T3cDM? Does exocrine pancreatic insufficiency influence metabolic control in T3cDM? Can enzyme replacement therapy influence metabolic control?

38 Influence of PERT on Metabolic Control in Diabetes Mellitus Clinical studies: No positive effect on HbA 1c ; less stable control [J Clin Gastroenterol 2001 Apr;32(4): ] Positive effect on HbA 1c, C-peptide, blood glucose and QoL and more stable disease [Int J Pancreatol 1998; 24(1):19-22] No positive effect on HbA 1c, C-peptide, blood glucose, glucagon and PP, but more stable control [Z Gastroenterol 1990; 28: ] No positive effect on HbA 1C, C-peptide, blood glucose no effect, less hypoglycemia [Diabetes Metab Res Rev Jul;23(5): ] Reduced postprandial hyperglycemia, slowed gastric emptying, normalized GLP-1 and GIP- levels [J Clin Endocrinol Metab 99: , 2014]

39 Influence of PERT on Metabolic Control in Diabetes Mellitus Why are the results of the studies so confusing and conflicting? 1. Inadequate enzyme therapy (dosing /pharmacokinetics) Majority of patients on PERT still reports symptoms [Pancreatology Jan;12(1):71-3.] 2. Observation/study period are (often) too short to show differences 3. Heterogeneous study population Diabetes mellitus type 1, type 2, pancreatogenic diabetes (pancreatectomy, chronic pancreatitis, etc.) With and without residual beta function

40 Summary Exocrine pancreatic insufficiency (PEI) is (very) common in patients with type 1 and type 2 diabetes Pancreatogenic diabetes is also more common than previously thought Ask your patients for GI-Symptoms (and screen for PEI), red flags Limited data exists upon the impact of PERT on diabetes control in patients with PEI and diabetes PEI might be essential for qualitative nutrition (Vitamin D, etc.) In some (but not all) studies, PERT has been shown to: a) improve HbA 1C b) decrease post-prandial hyperglycaemia c) decrease hypoglycaemic episodes d) enhance the incretin response 03/12/18

41 Clinical Case Mrs. B.D. 83 year old female, Mrs. B.D. History: Essential hypertension Type 2 diabetes Combined hyperlipidaemia 2007 Chronic Kidney Disease Stage CT-Abdomen: No disease to the pancreas, liver, gall bladder, spleen or kidneys Anterior / posterior vaginal repair Medication: Metformin 500mg Quinapril 20mg Allopurinol 100mg Intolerant to statins and ezetimibe Non smoker No regular alcohol intake 03/12/18 Dr. Roselle Herrring, Cedar Centre / Royal Surrey County Hospital

42 Please Remember the Red Flags Pancreatic Exocrine Insufficiency Red flags ü Steatorrhoea ü Abdominal discomfort or pain ü Bloating or abdominal swelling ü Flatulence ü Unintended weight lose ü Diarrhoea ü Poor glycaemic control 03/12/18

43 2014: Indigestion / Bloating September 2014 February 2015 May 2014 Patient presents to GP with indigestion like symptoms Omeprazole prescribed (1) Weight 74kg June 2014 Patient reattends to GP, minimal improvement in symptoms. Pantoprazole prescribed (2) July 2014 Re-attends to GP. GERD, dysphagia and bloating Referral made for gastroenterologist outpatient review (3) Weight 70kg Appointment with gastroenterologist - OGD arranged (4-6) Diagnosis hiatus hernia, and 11cm segment Barrett's esophagus. Referred back to GP Face to face GP attendance

44 January 2015 Presents with loose motions and stomach cramps HbA1 C increased. Gliclazide added to Metformin 500mg (7) 2015: Poor glycaemic control July 2015 Patient presents to GP with diarrhoea, stomach cramps, bloating Gliclazide stopped (8) 17 th July 2015 Annual Diabetes review HbA1c 64mmol/mol (8.0%) (9) Weight 67.3kg Linagliptan added. Review in 3 months 15 th October 2015 Patient continues to struggle with diabetes medication. Linagliptan stopped and pioglitazone 30mg od commenced. HbA1c 77mmol/ mol (9.2%) Continued weight loss, bloating and cramps (10) GP telephone consultation

45 October 2015 May 2016: Steatorrhoea Oct - Dec 2015 January 2016 Diarrhoea and Continued bloating bloating, and diarrhoea Diagnosed Results inconclusive, negative Weight loss. urinary culture, tract no sign of infection Amoxicillin infection High and HbA1c prescribed plus received No stool sample collected Loperamide recurrent (14) prescriptions for antibiotics Bloods and (11-13) urine Bloods and collected urine. February 2016 Telephone appointment with GP. Symptoms continue Further trimethoprim 200mg bd prescribed plus Loperamide (15-21) May 2016 Severe abdominal / lower chest pains. Diarrhoea, bloating, steatorrhoea. Has to wear incontinence pad (22) Weight 53.4kg

46 July 2016 September 2016: Anaemia June 2016 GP telephone consultation. No improvement GP increases Loperamide (23) July 2016 Telephone consultation with GP for blood results. GP increases Loperamide (24) July 2016 Patient attends appointment with gastroenterologist (25) Anaemia noted. OGD and colonoscopy arranged September 2016 GP attends patient as domiciliary visit Severe bloating, diarrhoea, steatorrhoea Weight lose continues Antibiotics started (26)

47 October 2016 December 2016 October 2016 Telephone consultation with GP Symptoms continue. Further antibiotics prescribed (27) October 2016 Review with gastroenterologist (28) Duodenal Biopsies negative, 2 polyps found. Coeliac screen requested. December 2016 Review appointment. Coeliac screen negative. Diagnosed with IBD and referred back to GP with care plan (29) December 2016 Telephone consultation with GP. IBD diagnosis discussed. Care plan started, blood and urine requested (30)

48 January 2017 PEI Diagnosed January 2017 Presents to GP, symptoms worse and no improvement in glycaemic control GP makes referral to secondary care diabetes team (31) March 2017 Secondary care diabetes clinic High HbA1c, chronic diarrhoea, Weight 47.8kg (BMI: 20) (32) CT: Patient has chronic inflammation and calcification of the pancreas Low vitamin D 12nmol/L, Calcium 2.07nmol/L, Hb 115g/L, MCV 90.6fL Faecal elastase <50 ug/g of stool

49 Treatment Metformin stopped Capillary blood glucose monitoring Started basal insulin (anabolic effects) Started on PERT with meals and snacks. Screened for osteoporosis Dietician support

50 Update Mrs. B.D. moved to a nursing home Bowels have settled. Stopped loperamide. PERT with meals and snacks Dexa-scan showed osteopenia Weight 47.8kg (remember: 74.0kg in May 2014) HbA 1C 46mmol/mol (6.4%) Died in January 2018: Community acquired pneumonia

51 Clinical Case Mrs. B.D. What would have happend if the physicians had been aware of PEI? Do not miss the red flags! Be aware of PEI in diabetes!

52 Visit the Village to find out more about this educational resource This is a Mylan website

53 Thank you for your kind attention! Nils Ewald, MD, PhD Associate Professor of Internal Medicine / Endocrinology and Diabetology Justus-Liebig-University Giessen, Germany and General Hospital Luebbecke