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Pancreatic exocrine insufficiency following pancreatic resection
Pancreatology xxx (2015) 1e7
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Review article
Invited review: Pancreatic exocrine insufficiency following pancreatic resection Mary E. Phillips* Royal Surrey County Hospital, Regional HPB Unit, Egerton Road, Guildford GU2 7XX, United Kingdom
a r t i c l e i n f o
a b s t r a c t
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Background/objectives: Untreated pancreatic exocrine dysfunction is associated with poor quality of life and reduced survival, but is difficult to diagnose following pancreatic resection. Many factors including the extent of the surgery, the health of the residual pancreas and the type of reconstruction must be considered. Patients remain undertreated, and consequently there is much debate to whether or not pancreatic enzyme replacement therapy should be routinely prescribed following pancreatic resection. Methods: A review of the literature was undertaken to establish the incidence of PEI and factors identifying treatment. Results: Forty two to forty five percent of patients undergoing pancreatico-duodenectomy (PD) experience pancreatic exocrine insufficiency pre-operatively, whilst the post-operative incidence is 56e98% in PD, and 12e80% following distal and central pancreatectomy. Conclusions: Routine use of pancreatic enzyme replacement should be considered at a starting dose of 50 to 75,000 units lipase with meals and 25,000 to 50,000 units with snacks in this patient group. Patients who have had a central or distal pancreatectomy should be individually assessed for pancreatic exocrine insufficiency in the post operative period, with those undergoing extensive resection most likely to experience insufficiency. Patients who fail to respond to pancreatic enzyme replacement therapy should be referred to a specialist dietitian, be advised on dose adjustment, and undergo investigation to exclude other gastro-intestinal pathology, including small bowel bacterial overgrowth and bile acid malabsorption. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Pancreatico-duodenectomy Exocrine insufficiency Bacterial overgrowth Bile salt malabsorption Dietetic assessment Pancreatic resection
Introduction Pancreatic exocrine insufficiency (PEI) is multifactorial following pancreatic resection. The degree of insufficiency is influenced by the quantity and quality of the pancreatic remnant [1], the resection of the stomach and duodenum with resultant changes in gut pH [2] and delayed gastric emptying [2]. Other factors include the formation of a pancreatico-jejunostomy and hepatico-jejunostomy on a roux loop, causing potential asynchrony in the delivery of pancreatic secretions and bile [3,4], abnormal cholecystokinin (CCK) secretion [5], obstruction of the pancreatic duct anastomosis [6] and the use of exocrine inhibitory medications such as Octreotide [7]. Consequently the exact type of resection and reconstruction must be considered when assessing patients for PEI.
* Tel.: þ44 1483464119; fax: þ44 01483464868. E-mail addresses: [email protected], [email protected].
In addition, pancreatic resection predisposes patients to other gastrointestinal conditions with symptoms that may mimic those of PEI: this in combination with the limitations of current methods of assessing pancreatic function, results in the potential for misdiagnosis and therefore sub-optimal symptom management. Under-treatment is associated with poor quality of life [8], micronutrient deficiencies [9e11] and in some cases reduced survival [12]. Many units do not have adequate access to specialist dietitians [13], and this is associated with under treatment, and inappropriate dietary restrictions [14]. Assessment of pancreatic insufficiency There are many pancreatic function tests available, however the accuracy of these tests following pancreatic resection is poor, and have been discussed in detail by other authors [15e18]. Function tests can be divided into two categories, those that assess the ability of the pancreas to secrete digestive enzymes, and
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those that assess the efficacy of this by quantifying the nutrients that are not absorbed. This is particularly relevant in assessing malabsorption following pancreatico-duodenectomy (PD) as extrapancreatic factors are present. Assessment of the ability of the pancreas to produce pancreatic enzymes maybe influenced by the reduction in, or removal of, pancreatic stimulatory mechanisms. It could also be hypothesized that the asynchrony of enzyme delivery might result in malabsorption despite an apparently normal secretion of enzymes. The concept of asynchrony of delivery of pancreatic and biliary secretions was first described in the 1950's as a consequence of the Polya gastrectomy with pancreatic enzymes reaching the small bowel sometime after partially digested food particles [19], animal studies confirmed that the degree of steatorrhoea was related to the length of the afferent limb [20]. Thus the quantity and quality of pancreatic tissue does not necessarily reflect absorption following PD. This may in part explain the poor specificity of faecal elastase (FE) following pancreatic resection. Indeed, studies have found significant differences between coefficient of fat absorption (CFA) and FE in patients following PD [8,21]. Coefficient of fat absorption (CFA) and 13C- mixed triglyceride (MTG) breath tests assess fat malabsorption, but cannot quantify the influence of extra-pancreatic factors, nor can they quantify nitrogen and carbohydrate malabsorption. Nitrogen malabsorption occurs in PEI [22], and consequently will also contribute to malnutrition. Whilst compensatory mechanisms exist for carbohydrate malabsorption, by way of colonic fermentation of malabsorbed substrate to short chain fatty acids which the colon can absorb [23], this mechanism would not be present in those with colonic resection, which can be carried out concurrently [24], or as the result of a co-morbidity. Many studies use the onset of steatorrhoea to diagnose PEI, and consequently show a much lower incidence than those using less subjective methods [25,26]. It is widely accepted that the onset of steatorrhoea is a late symptom of PEI, and many patients can exhibit significant malabsorption with an absence of abdominal symptoms [22,27]. Furthermore steatorrhoea will only be apparent in patients consuming adequate dietary fat, and many patients restrict their fat intake in an attempt to help reduce symptoms, or in response to inappropriate advice promoting fat restriction [14]. The use of opiates, iron supplements and anti-diarrhoeals may also mask abdominal symptoms. Consequently, symptom assessment alone is not sufficient to exclude PEI, and a combination of abdominal symptoms, nutritional status and pancreatic function tests must be used to assess pancreatic exocrine function. Specialist dietitians can assess anthropometric and dietary factors in combination with clinical symptoms to assist in the evaluation of exocrine insufficiency. Hence a multidisciplinary approach is likely to provide the most comprehensive assessment of PEI.
disease in the head of the pancreas, and the presence of dilated pancreatic ducts [31] on imaging may suggest PEI, and this will be apparent on pre-operative computerised tomography (CT) or endoscopic ultrasound (EUS). The presence of pre-operative jaundice may mask symptoms of PEI, and is a significant contributory factor toward pre-operative malnutrition. Untreated PEI prior to surgery may cause malnutrition, which in turn increases pancreatic fistula risk [32], morbidity and mortality [33].
Incidence of PEI prior to resection
Symptoms of PEI have a significant impact on quality of life after pancreatic resection [2]. Patients have a prolonged recovery time, and malnutrition and dehydration are common causes of hospital readmissions [34]. Correct identification and management of PEI following pancreatic resection should promote better recovery from surgery, and improved performance status, which is particularly relevant in those due to undergo adjuvant chemotherapy. In patients with chronic pancreatitis, long term survival has been linked to the provision of PERT following pancreatic resection [12].
In patients with operable pancreatic cancer there is often a narrow time frame for assessment in the pre-operative period, with insufficient time to carry out most pancreatic function tests. There is limited data analysing the incidence of PEI prior to pancreatic surgery, with 16% of pre-operative patient's found to have FE < 200 mg/g in a mixed cohort of patients due to undergo distal pancreatectomy [28]. The incidence of PEI was higher in those with pancreatic adenocarcinoma and chronic pancreatitis, compared to those with other benign and pre-malignant disease [28]. There is a significant incidence of PEI prior to pancreaticoduodenectomy documented at 38e45% [3,29,30], with some variation according to underlying disease [30]. The presence of
Incidence of PEI following distal or central pancreatectomy The incidence of PEI following distal pancreatectomy is documented at 19e80% [25,26,28,29], and 11.9% following central pancreatectomy. The majority of these data comes from a large systematic review, however the degree of resection was not specified and the method of assessment was mixed across the included studies including FE, faecal chymotrypsin, p-aminobenzoic acid (PABA), and less objective markers such as onset of symptoms and prescription of PERT [26]. One study using FE included subgroup analysis on those with resection limited to the left of the portal vein compared to that which extended beyond the portal vein. Longitudinal follow up of 70 patients with normal pre-operative pancreatic function demonstrated a return to normal exocrine function by 24 months post operatively [28]. Therefore it is anticipated that the likelihood of PEI would increase with more extensive resection, and in those with poor quality residual pancreatic tissue, but improvements may occur with time. Incidence of PEI following pancreatico-duodenectomy There is much more data surrounding the incidence of PEI following pancreatico-duodenectomy, with a variation in incidence between 56 and 98% in the post operative period [3,8,25,29,30]. Some studies suggest an improvement in pancreatic function over time, however the apparent increase in FE, occurs alongside a reduction in sample size in one study [8] and could be as a result of those with more extensive disease, and therefore potentially more severe pancreatic dysfunction, succumbing to their disease earlier than others. Data using a consistent patient cohort shows a reduction in FE over time, suggesting deteriorating pancreatic function during the post operative period [3] perhaps as a result of atrophy of the residual pancreas. Links with dilated main pancreatic ducts have been assessed, and lower FE was observed in these patients [30]. As with other types of pancreatic resection the incidence of PEI is recorded as lower in those studies using subjective methods of assessment [25], and the extent of pancreatic parenchyma resected is not specified in any of the studies identified. Benefits of PERT
Management of PEI PEI should be treated with PERT at an initial starting dose of 50e75,000 units lipase with each meal, and 20e50,000 units with
Please cite this article in press as: Phillips ME, Invited review: Pancreatic exocrine insufficiency following pancreatic resection, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.06.003
Anthropometric
Biochemical
Clinical symptoms
Dietary
Medical history
Medication
Weight changes assessed in context to energy intake
Fat soluble vitamin status Vitamin A Vitamin D Vitamin E Prothrombin time (or other markers of vitamin K status if available)
Abdominal symptoms Diarrhoea (frequency; consistency; colour; buoyancy; urgency) Bloating Flatulence Post prandial abdominal pain
Dietary adequacy Identification of missing food groups Quantification/adequacy of energy and protein composition of diet Assessment of micronutrient intake/is dietary intake adequate/well balanced
Previous surgery Gastrectomy Duodenal resection Small bowel surgery Colorectal surgery
Presence of medication that influence gut function Anti-diarrhoeals Laxatives Gastric acid suppression Somatostatin Iron supplements Pro-kinetics Opiates Antibiotics Probiotics
Function assessment
Grip Strength Mid arm muscle circumference Tricep skinfold thickness Exercise tolerance/fatigue
Markers of ongoing diarrhoea Magnesium Potassium Bone profile Calcium phosphate Parathyroid hormone Anaemia screen Iron studies Ferritin and CRP Vitamin B12 Folate Haemoglobin Other micronutrients Zinc Selenium Glycaemic control Random Glucose Oral Glucose tolerance test Glycosolated haemoglobin (HbA1c) Incidence of hypoglycaemia in a known diabetic
Symptoms influencing dietary intake Nausea Vomiting Indigestion Post prandial pain Anorexia Early satiety Taste changes Sore mouth Oral thrush
Food avoidances Cultural dietary restriction Identification of foods the patient associates with worsening symptoms History of food allergies/ intolerances
Endocrine function History and type of diabetes Diseases affecting bowel function Coeliac disease Irritable bowel syndrome Inflammatory bowel diseases Food allergies/intolerances Conditions influencing dietary intake (likely following low fat/ low calorie diet) Eating disorders Heart disease Hyperlipidaemia Hypertension Alcohol intake Exocrine function
Medication that influence weight Anti-obesity drugs Steriods Insulin Metformin Recent changes in medication which may suggest reduced absorption Discontinuation of cholesterol lowering medication Reduction in insulin doses
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Please cite this article in press as: Phillips ME, Invited review: Pancreatic exocrine insufficiency following pancreatic resection, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.06.003
Table 1 Dietetic assessment to evaluate PEI.
Extent and type of pancreatic disease Location of disease (head/body/tail) Duration of disease Pancreatic duct dilatation Pancreatic atrophy Pancreatic function test results
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snacks [35,36], and dose escalation may be required [2,4,36e39]. Attention should be given to patient education, and ensuring PERT is used alongside snacks, milky drinks and nutritional supplements. Despite studies showing significant nitrogen losses [22,35], many clinicians still centre management and advice on fat malabsorption, and this practice needs to be amended: PERT should be prescribed alongside all meals, regardless of fat content. Nutritional assessment as part of an evaluation of PEI can be carried out by a specialist dietitian, and the basis of this is summarised in Table 1. Initiation of PERT may unmask diabetes in some patients [40], patients should be regularly screened for both diabetes and micronutrient deficiencies, and routine vitamin and mineral supplementation is recommended [11]. For the minority of patients who require enteral feeding: peptide, medium chain triglyceride (MCT) based enteral feeds should be used [41]. Both peptides and MCT can be absorbed in the brush borders in the absence of pancreatic enzymes, and studies have shown standard polymeric feeds require between four and eight times as much lipase to achieve lipolysis than peptide MCT feeds [42]. Adequate mixing of pancreatic enzymes with standard enteral feeds is difficult to achieve [43], thus peptide MCT feeds should be used to try and minimise malabsorption in this patient group. Patients who have undergone potentially curative surgery should receive long term nutritional follow up in the same manner as is recommended for patients with chronic pancreatitis [44] and coeliac disease [45]. Historically concern has been raised over the potential for fibrosing colonopathy in patients on high dose PERT. There has been very limited incidence of this outside of the cystic fibrosis population, with only one case report identifiable in the literature [46]. Whilst some guidelines have included maximum doses [39], this is based on expert opinion [47], and should not prevent dose escalation in symptomatic patients. However, new onset abdominal pain, or symptoms of bowel obstruction should be investigated to exclude fibrosing colonopathy in patients on high dose PERT. Gastric acid suppression The use of a proton pump inhibitor is currently recommended as second line therapy if the initial dose of PERT is not adequate to control symptoms [2,4,36e39].
Pancreatic enzymes are designed to be released when a pH of >5.5 is achieved [48,49]. It is hypothesised that the reduction in bicarbonate production from the pancreas in pancreatic failure results in a more acidic environment in the duodenum resulting in delayed enzyme release and precipitation of bile salts [50]. The use of a PPI is associated with a reduction in fat losses [51], and may help reduce the precipitation of bile salts. The benefits of gastric acid suppression following pancreatic resection is debated, with studies showing mixed results. Study variables include the potential for variations in gastric emptying, the use of H2 antagonists vs. proton pump inhibitors and the inclusion of subjects who have had gastric/duodenal surgery. A review of the literature identified 14 clinical trials where gastric suppression usage was recorded and of those seven included subjects who had undergone pancreatic resection [52]. Data were summarised by disease state, and in those following pancreatic resection, there was no significant difference in CFA in those receiving gastric suppression (n ¼ 72) and those not (n ¼ 61). However the type of pancreatic resection was not specified and the use of gastric acid suppression is common following PD with the purpose of reducing ulceration at the gastro-jejunostomy. Hence those subjects not receiving gastric suppression may be less likely to have undergone pancreatic head resection. However in those subjects with cystic fibrosis and chronic pancreatitis there was no significant difference in CFA [52]. Differential diagnosis In the event that PEI is not controlled with initial therapy, the majority of clinical guidelines support referral to a specialist dietitian, increasing the dose of PERT, addition of a PPI, followed by investigation of other gastro-intestinal pathology [2,4,36,38,39,53]. Whilst isolated pancreatic resection may be associated with pancreatic insufficiency due to loss of pancreatic parenchyma, and potentially damaged remaining pancreatic tissue, for example as the result of pre-operative pancreatic ductal obstruction, there are likely to be few other contributory factors unless the patient has any co-morbidity. However, in the instance of pancreatico-duodenectomy, the reconstruction itself predisposes patients to bile salt malabsorption [54] and small bowel bacterial overgrowth [55].
Table 2 Management of PEI prior to pancreatic resection.
Preoperative assessment Criteria for commencing PERT: One or more of these symptoms in patients with proven/suspected pancreatic pathology:
Pancreatic function test
Abdominal symptom assessment
Dietetic assessment
Radiological assessment
Pancreatic exocrine insufficiency suggested by: FE < 200ug/g; CFA <93% or 13 C-MTG <58%
Clinical signs of steatorrhoea (oily pale floating stool)
Weight loss despite adequate oral intake
Pancreatic ductal dilatation
Abdominal bloating and flatulence
Micronutrient deficiencies despite adequate intake
Calcified pancreas Atrophied pancreas Tumour replacing pancreatic tissue
Treatment Commence PERT: 50,000e75,000 units lipase with meals 25,000e50,000 units lipase with snacks and nutritional supplements If weight loss or body mass index <20 kg m2 e Specialist Dietitian to advise on high energy high calorie diet Ensure patient is not following a low fat diet (unless required due to other morbidity) Biochemical assessment of endocrine function Correct micronutrient deficiencies Commence vitamin and mineral supplementation Review adequacy of enzyme dose within 2 weeks
Please cite this article in press as: Phillips ME, Invited review: Pancreatic exocrine insufficiency following pancreatic resection, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.06.003
M.E. Phillips / Pancreatology xxx (2015) 1e7
Bile salt malabsorption following pancreatic resection may be attributed to concurrent cholecystectomy or the binding of bile salts to mal-digested protein, carbohydrates and fibre. Precipitation of bile salts may occur due to the change in pH in the small bowel as a result of reduced bicarbonate secretion secondary to diminished pancreatic volume [2]. The presence of a blind loop of bowel within the reconstruction following PD predisposes the patient to bacterial overgrowth, which has been documented in 65% of patients with PEI, with an increased incidence following resection compared to those with pancreatic disease alone [56]. In addition to contributing to gastrointestinal symptoms, this may precipitate further bile salt malabsorption. It is the experience of the author that new presentations of coeliac disease, lactase deficiency and inflammatory bowel disease may become apparent in the post operative period, and there are isolated case reports within the literature of such instances [57e59].
5
Conclusions PEI is under recognised and under treated following pancreatic resection. Given the high incidence of PEI, and potential significant consequences, PERT should be commenced routinely in all patients prior to undergoing PD, and where malnutrition and abdominal symptoms are present in patients prior to distal or central pancreatectomy (See Table 2). In the post operative setting, PERT should be routinely prescribed following PD, and those who have had a central or distal pancreatectomy should be individually assessed in the context of the degree of resection, with both objective assessment of FE, CFA or a 13C-MTG breath test, in addition to the subjective assessment of symptoms (Table 3). Pancreatic function tests lack specificity and need to be interpreted in clinical context following pancreatic resection. It is likely that malabsorption following PD is not solely pancreatic in origin. Patients with pancreatic disease without PEI should be
Table 3 Management of PEI prior following pancreatic resection. Pancreatico-duodenectomy Central/distal pancreatectomy and/or pre-operative PEI Criteria for commencing PERT: Pancreatic function test One or more of these criteria: Pancreatic exocrine insufficiency suggested by: FE < 200 mg/g; CFA <93% or 13 C-MTG <58%
Abdominal symptom assessment Clinical signs of steatorrhoea (oily pale floating stool)
Dietetic assessment Weight loss despite adequate oral intake
Post operative onset of abdominal Micronutrient deficiencies despite bloating and flatulence adequate intake
Treatment Commence PERT: 50,000e75,000 units lipase with meals 25,000e50,000 units lipase with snacks and nutritional supplements If weight loss or body mass index <20 kg m2 e Specialist Dietitian to advise on high energy high calorie diet Ensure patient is not following a low fat diet (unless required due to other morbidity) Biochemical assessment of endocrine function Correct micronutrient deficiencies Commence vitamin and mineral supplementation Review adequacy of enzyme dose within 2 weeks. If
symptoms not resolved Commence gastric acid suppression if not already prescribed Double dose of PERT Refer to Specialist Dietitian to ensure PERT dose appropriate to meal pattern/to ensure high energy diet/to advise on food fortification/prescribe nutritional supplements as necessary. Check PERT being taken and stored correctly (below 25 C; swallowed with cold drink at the same time as eating) Review adequacy within 2 weeks
If
symptoms remain unresolved Consider addition of anti-diarrhoeals Consider further increase in PERT (if some improvement with previous management) Consider changing PERT preparation Exclude bile salt malabsorption Exclude bacterial overgrowth Exclude infectious diarrhoea Consider delayed gastric emptying and other factors that may inhibit PERT Specialist Dietitian to advise on reduced fibre diet, commence peptide/MCT supplements if ongoing weight loss
Long term follow up Regular review of PEI symptoms Review of dietary adequacy Biochemical assessment of endocrine function and micronutrient status Patient education regarding PERT use if dietary intake changes; holidays; meals out; hot weather. Patients to be reassessed if symptoms return/worsen over time
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routinely reassessed as pancreatic function may deteriorate with time, likewise higher doses of PERT are likely to be required over time. As has been suggested by many previous studies it is of paramount importance that patients not responding to PERT, should have their dose and preparation reviewed, be referred to a specialist dietitian, and be investigated for extra-pancreatic causes of malabsorption. Following PD this should specifically mean excluding bile salt malabsorption and small bowel bacterial overgrowth (Table 3). There is a lack of high quality trials examining the incidence and treatment of these conditions following PD, but there is sufficiently defined biological mechanisms supported by individual and small patient cohort case studies to warrant clinical consideration and further investigation. Future research should examine the optimum treatment in the post operative setting, and work needs to continue to educate clinicians in the need for PERT both prior to and following pancreatic resection. The impact of extra-pancreatic factors such as bacterial overgrowth and bile salt malabsorption on FE, 13C-MTG and CFA should be evaluated. . There remains an urgent need to develop a practical, sensitive and specific diagnostic test for PEI in the post operative setting.
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M.E. Phillips / Pancreatology xxx (2015) 1e7 [44] Duggan S, O'Sullivan M, Feehan S, Ridgway P, Conlon K. Nutrition treatment of deficiency and malnutrition in chronic pancreatitis: a review. Nutr Clin Pract: Off Publ Am Soc Parenter Enter Nutr 2010;25:362e70. [45] Ciclitira PJ, Dewar DH, McLauglin SD, Sanders DS. The management of adults with coeliac disease. Br Soc Gastroenterol 2010. [46] Bansi DS, Price A, Russell C, Sarner M. Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements. Gut 2000;46:283e5. [47] Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep 2001;3:101e8. [48] Peschke G. Chapter V: characteristics of a modern pancreatic enzyme preparation. Solvay Pharmaceuticals; 2000. Data on file. [49] Aloulou A, Puccinelli D, Sarles J, Laugier R, Leblond Y, Carriere F. In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability. Aliment Pharmacol Ther 2008;27:283e92. [50] Ghaneh P, Neoptolemos JP. Pancreatic exocrine insufficiency following pancreatic resection. Digestion 1999;60(Suppl. 1):104e10. [51] Proesmans M, De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr 2003;162:760e3. [52] Sander-Struckmeier S, Beckmann K, Janssen-van Solingen G, Pollack P. Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin
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(creon(r)) in patients with pancreatic exocrine insufficiency. Pancreas 2013;42:983e9. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep 2007;9:116e22. Phillips F, Andreyev J. Post-operative chronic diarrhoea in pancreatic and oesophagogastric cancers: the prevalence of bile acid malabsorption (abstract). J Gastroenterol Hepatol 2012;27:0815e9319. Bustillo I, Larson H, Saif MW. Small intestine bacterial overgrowth: an underdiagnosed cause of diarrhea in patients with pancreatic cancer. JOP: J Pancreas 2009;10:576e8. Bordin D, Osipenko Y, Drozdov V, Silvestrova S, Varvanina G. Importance of small intestinal bacterial overgrowth in chronic pancreatitis (abstract). Pancreatol: Off J Int Assoc Pancreatol 2013;13:S2e98. Chedid AD, Kruel CR, Chedid MF, Torresini RJ, Geyer GR. Development of clinical celiac disease after pancreatoduodenectomy: a potential complication of major upper abdominal surgery. Langenbeck's Arch Surg/Dtsch Gesellschaft fur Chir 2005;390:39e41. Stone CD, Klein S, McDoniel K, Davidson NO, Prakash C, Strasberg SM. Celiac disease unmasked after pancreaticoduodenectomy. JPEN J Parenter Enter Nutr 2005;29:270e1. Gebrayel N, Conlon K, Shike M. Coeliac disease diagnosed after pancreaticoduodenectomy. Eur J Surg Acta Chir 2000;166:742e3.
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Review article
Invited review: Pancreatic exocrine insufficiency following pancreatic resection Mary E. Phillips* Royal Surrey County Hospital, Regional HPB Unit, Egerton Road, Guildford GU2 7XX, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Background/objectives: Untreated pancreatic exocrine dysfunction is associated with poor quality of life and reduced survival, but is difficult to diagnose following pancreatic resection. Many factors including the extent of the surgery, the health of the residual pancreas and the type of reconstruction must be considered. Patients remain undertreated, and consequently there is much debate to whether or not pancreatic enzyme replacement therapy should be routinely prescribed following pancreatic resection. Methods: A review of the literature was undertaken to establish the incidence of PEI and factors identifying treatment. Results: Forty two to forty five percent of patients undergoing pancreatico-duodenectomy (PD) experience pancreatic exocrine insufficiency pre-operatively, whilst the post-operative incidence is 56e98% in PD, and 12e80% following distal and central pancreatectomy. Conclusions: Routine use of pancreatic enzyme replacement should be considered at a starting dose of 50 to 75,000 units lipase with meals and 25,000 to 50,000 units with snacks in this patient group. Patients who have had a central or distal pancreatectomy should be individually assessed for pancreatic exocrine insufficiency in the post operative period, with those undergoing extensive resection most likely to experience insufficiency. Patients who fail to respond to pancreatic enzyme replacement therapy should be referred to a specialist dietitian, be advised on dose adjustment, and undergo investigation to exclude other gastro-intestinal pathology, including small bowel bacterial overgrowth and bile acid malabsorption. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Pancreatico-duodenectomy Exocrine insufficiency Bacterial overgrowth Bile salt malabsorption Dietetic assessment Pancreatic resection
Introduction Pancreatic exocrine insufficiency (PEI) is multifactorial following pancreatic resection. The degree of insufficiency is influenced by the quantity and quality of the pancreatic remnant [1], the resection of the stomach and duodenum with resultant changes in gut pH [2] and delayed gastric emptying [2]. Other factors include the formation of a pancreatico-jejunostomy and hepatico-jejunostomy on a roux loop, causing potential asynchrony in the delivery of pancreatic secretions and bile [3,4], abnormal cholecystokinin (CCK) secretion [5], obstruction of the pancreatic duct anastomosis [6] and the use of exocrine inhibitory medications such as Octreotide [7]. Consequently the exact type of resection and reconstruction must be considered when assessing patients for PEI.
* Tel.: þ44 1483464119; fax: þ44 01483464868. E-mail addresses: [email protected], [email protected].
In addition, pancreatic resection predisposes patients to other gastrointestinal conditions with symptoms that may mimic those of PEI: this in combination with the limitations of current methods of assessing pancreatic function, results in the potential for misdiagnosis and therefore sub-optimal symptom management. Under-treatment is associated with poor quality of life [8], micronutrient deficiencies [9e11] and in some cases reduced survival [12]. Many units do not have adequate access to specialist dietitians [13], and this is associated with under treatment, and inappropriate dietary restrictions [14]. Assessment of pancreatic insufficiency There are many pancreatic function tests available, however the accuracy of these tests following pancreatic resection is poor, and have been discussed in detail by other authors [15e18]. Function tests can be divided into two categories, those that assess the ability of the pancreas to secrete digestive enzymes, and
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those that assess the efficacy of this by quantifying the nutrients that are not absorbed. This is particularly relevant in assessing malabsorption following pancreatico-duodenectomy (PD) as extrapancreatic factors are present. Assessment of the ability of the pancreas to produce pancreatic enzymes maybe influenced by the reduction in, or removal of, pancreatic stimulatory mechanisms. It could also be hypothesized that the asynchrony of enzyme delivery might result in malabsorption despite an apparently normal secretion of enzymes. The concept of asynchrony of delivery of pancreatic and biliary secretions was first described in the 1950's as a consequence of the Polya gastrectomy with pancreatic enzymes reaching the small bowel sometime after partially digested food particles [19], animal studies confirmed that the degree of steatorrhoea was related to the length of the afferent limb [20]. Thus the quantity and quality of pancreatic tissue does not necessarily reflect absorption following PD. This may in part explain the poor specificity of faecal elastase (FE) following pancreatic resection. Indeed, studies have found significant differences between coefficient of fat absorption (CFA) and FE in patients following PD [8,21]. Coefficient of fat absorption (CFA) and 13C- mixed triglyceride (MTG) breath tests assess fat malabsorption, but cannot quantify the influence of extra-pancreatic factors, nor can they quantify nitrogen and carbohydrate malabsorption. Nitrogen malabsorption occurs in PEI [22], and consequently will also contribute to malnutrition. Whilst compensatory mechanisms exist for carbohydrate malabsorption, by way of colonic fermentation of malabsorbed substrate to short chain fatty acids which the colon can absorb [23], this mechanism would not be present in those with colonic resection, which can be carried out concurrently [24], or as the result of a co-morbidity. Many studies use the onset of steatorrhoea to diagnose PEI, and consequently show a much lower incidence than those using less subjective methods [25,26]. It is widely accepted that the onset of steatorrhoea is a late symptom of PEI, and many patients can exhibit significant malabsorption with an absence of abdominal symptoms [22,27]. Furthermore steatorrhoea will only be apparent in patients consuming adequate dietary fat, and many patients restrict their fat intake in an attempt to help reduce symptoms, or in response to inappropriate advice promoting fat restriction [14]. The use of opiates, iron supplements and anti-diarrhoeals may also mask abdominal symptoms. Consequently, symptom assessment alone is not sufficient to exclude PEI, and a combination of abdominal symptoms, nutritional status and pancreatic function tests must be used to assess pancreatic exocrine function. Specialist dietitians can assess anthropometric and dietary factors in combination with clinical symptoms to assist in the evaluation of exocrine insufficiency. Hence a multidisciplinary approach is likely to provide the most comprehensive assessment of PEI.
disease in the head of the pancreas, and the presence of dilated pancreatic ducts [31] on imaging may suggest PEI, and this will be apparent on pre-operative computerised tomography (CT) or endoscopic ultrasound (EUS). The presence of pre-operative jaundice may mask symptoms of PEI, and is a significant contributory factor toward pre-operative malnutrition. Untreated PEI prior to surgery may cause malnutrition, which in turn increases pancreatic fistula risk [32], morbidity and mortality [33].
Incidence of PEI prior to resection
Symptoms of PEI have a significant impact on quality of life after pancreatic resection [2]. Patients have a prolonged recovery time, and malnutrition and dehydration are common causes of hospital readmissions [34]. Correct identification and management of PEI following pancreatic resection should promote better recovery from surgery, and improved performance status, which is particularly relevant in those due to undergo adjuvant chemotherapy. In patients with chronic pancreatitis, long term survival has been linked to the provision of PERT following pancreatic resection [12].
In patients with operable pancreatic cancer there is often a narrow time frame for assessment in the pre-operative period, with insufficient time to carry out most pancreatic function tests. There is limited data analysing the incidence of PEI prior to pancreatic surgery, with 16% of pre-operative patient's found to have FE < 200 mg/g in a mixed cohort of patients due to undergo distal pancreatectomy [28]. The incidence of PEI was higher in those with pancreatic adenocarcinoma and chronic pancreatitis, compared to those with other benign and pre-malignant disease [28]. There is a significant incidence of PEI prior to pancreaticoduodenectomy documented at 38e45% [3,29,30], with some variation according to underlying disease [30]. The presence of
Incidence of PEI following distal or central pancreatectomy The incidence of PEI following distal pancreatectomy is documented at 19e80% [25,26,28,29], and 11.9% following central pancreatectomy. The majority of these data comes from a large systematic review, however the degree of resection was not specified and the method of assessment was mixed across the included studies including FE, faecal chymotrypsin, p-aminobenzoic acid (PABA), and less objective markers such as onset of symptoms and prescription of PERT [26]. One study using FE included subgroup analysis on those with resection limited to the left of the portal vein compared to that which extended beyond the portal vein. Longitudinal follow up of 70 patients with normal pre-operative pancreatic function demonstrated a return to normal exocrine function by 24 months post operatively [28]. Therefore it is anticipated that the likelihood of PEI would increase with more extensive resection, and in those with poor quality residual pancreatic tissue, but improvements may occur with time. Incidence of PEI following pancreatico-duodenectomy There is much more data surrounding the incidence of PEI following pancreatico-duodenectomy, with a variation in incidence between 56 and 98% in the post operative period [3,8,25,29,30]. Some studies suggest an improvement in pancreatic function over time, however the apparent increase in FE, occurs alongside a reduction in sample size in one study [8] and could be as a result of those with more extensive disease, and therefore potentially more severe pancreatic dysfunction, succumbing to their disease earlier than others. Data using a consistent patient cohort shows a reduction in FE over time, suggesting deteriorating pancreatic function during the post operative period [3] perhaps as a result of atrophy of the residual pancreas. Links with dilated main pancreatic ducts have been assessed, and lower FE was observed in these patients [30]. As with other types of pancreatic resection the incidence of PEI is recorded as lower in those studies using subjective methods of assessment [25], and the extent of pancreatic parenchyma resected is not specified in any of the studies identified. Benefits of PERT
Management of PEI PEI should be treated with PERT at an initial starting dose of 50e75,000 units lipase with each meal, and 20e50,000 units with
Please cite this article in press as: Phillips ME, Invited review: Pancreatic exocrine insufficiency following pancreatic resection, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.06.003
Anthropometric
Biochemical
Clinical symptoms
Dietary
Medical history
Medication
Weight changes assessed in context to energy intake
Fat soluble vitamin status Vitamin A Vitamin D Vitamin E Prothrombin time (or other markers of vitamin K status if available)
Abdominal symptoms Diarrhoea (frequency; consistency; colour; buoyancy; urgency) Bloating Flatulence Post prandial abdominal pain
Dietary adequacy Identification of missing food groups Quantification/adequacy of energy and protein composition of diet Assessment of micronutrient intake/is dietary intake adequate/well balanced
Previous surgery Gastrectomy Duodenal resection Small bowel surgery Colorectal surgery
Presence of medication that influence gut function Anti-diarrhoeals Laxatives Gastric acid suppression Somatostatin Iron supplements Pro-kinetics Opiates Antibiotics Probiotics
Function assessment
Grip Strength Mid arm muscle circumference Tricep skinfold thickness Exercise tolerance/fatigue
Markers of ongoing diarrhoea Magnesium Potassium Bone profile Calcium phosphate Parathyroid hormone Anaemia screen Iron studies Ferritin and CRP Vitamin B12 Folate Haemoglobin Other micronutrients Zinc Selenium Glycaemic control Random Glucose Oral Glucose tolerance test Glycosolated haemoglobin (HbA1c) Incidence of hypoglycaemia in a known diabetic
Symptoms influencing dietary intake Nausea Vomiting Indigestion Post prandial pain Anorexia Early satiety Taste changes Sore mouth Oral thrush
Food avoidances Cultural dietary restriction Identification of foods the patient associates with worsening symptoms History of food allergies/ intolerances
Endocrine function History and type of diabetes Diseases affecting bowel function Coeliac disease Irritable bowel syndrome Inflammatory bowel diseases Food allergies/intolerances Conditions influencing dietary intake (likely following low fat/ low calorie diet) Eating disorders Heart disease Hyperlipidaemia Hypertension Alcohol intake Exocrine function
Medication that influence weight Anti-obesity drugs Steriods Insulin Metformin Recent changes in medication which may suggest reduced absorption Discontinuation of cholesterol lowering medication Reduction in insulin doses
M.E. Phillips / Pancreatology xxx (2015) 1e7
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Table 1 Dietetic assessment to evaluate PEI.
Extent and type of pancreatic disease Location of disease (head/body/tail) Duration of disease Pancreatic duct dilatation Pancreatic atrophy Pancreatic function test results
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snacks [35,36], and dose escalation may be required [2,4,36e39]. Attention should be given to patient education, and ensuring PERT is used alongside snacks, milky drinks and nutritional supplements. Despite studies showing significant nitrogen losses [22,35], many clinicians still centre management and advice on fat malabsorption, and this practice needs to be amended: PERT should be prescribed alongside all meals, regardless of fat content. Nutritional assessment as part of an evaluation of PEI can be carried out by a specialist dietitian, and the basis of this is summarised in Table 1. Initiation of PERT may unmask diabetes in some patients [40], patients should be regularly screened for both diabetes and micronutrient deficiencies, and routine vitamin and mineral supplementation is recommended [11]. For the minority of patients who require enteral feeding: peptide, medium chain triglyceride (MCT) based enteral feeds should be used [41]. Both peptides and MCT can be absorbed in the brush borders in the absence of pancreatic enzymes, and studies have shown standard polymeric feeds require between four and eight times as much lipase to achieve lipolysis than peptide MCT feeds [42]. Adequate mixing of pancreatic enzymes with standard enteral feeds is difficult to achieve [43], thus peptide MCT feeds should be used to try and minimise malabsorption in this patient group. Patients who have undergone potentially curative surgery should receive long term nutritional follow up in the same manner as is recommended for patients with chronic pancreatitis [44] and coeliac disease [45]. Historically concern has been raised over the potential for fibrosing colonopathy in patients on high dose PERT. There has been very limited incidence of this outside of the cystic fibrosis population, with only one case report identifiable in the literature [46]. Whilst some guidelines have included maximum doses [39], this is based on expert opinion [47], and should not prevent dose escalation in symptomatic patients. However, new onset abdominal pain, or symptoms of bowel obstruction should be investigated to exclude fibrosing colonopathy in patients on high dose PERT. Gastric acid suppression The use of a proton pump inhibitor is currently recommended as second line therapy if the initial dose of PERT is not adequate to control symptoms [2,4,36e39].
Pancreatic enzymes are designed to be released when a pH of >5.5 is achieved [48,49]. It is hypothesised that the reduction in bicarbonate production from the pancreas in pancreatic failure results in a more acidic environment in the duodenum resulting in delayed enzyme release and precipitation of bile salts [50]. The use of a PPI is associated with a reduction in fat losses [51], and may help reduce the precipitation of bile salts. The benefits of gastric acid suppression following pancreatic resection is debated, with studies showing mixed results. Study variables include the potential for variations in gastric emptying, the use of H2 antagonists vs. proton pump inhibitors and the inclusion of subjects who have had gastric/duodenal surgery. A review of the literature identified 14 clinical trials where gastric suppression usage was recorded and of those seven included subjects who had undergone pancreatic resection [52]. Data were summarised by disease state, and in those following pancreatic resection, there was no significant difference in CFA in those receiving gastric suppression (n ¼ 72) and those not (n ¼ 61). However the type of pancreatic resection was not specified and the use of gastric acid suppression is common following PD with the purpose of reducing ulceration at the gastro-jejunostomy. Hence those subjects not receiving gastric suppression may be less likely to have undergone pancreatic head resection. However in those subjects with cystic fibrosis and chronic pancreatitis there was no significant difference in CFA [52]. Differential diagnosis In the event that PEI is not controlled with initial therapy, the majority of clinical guidelines support referral to a specialist dietitian, increasing the dose of PERT, addition of a PPI, followed by investigation of other gastro-intestinal pathology [2,4,36,38,39,53]. Whilst isolated pancreatic resection may be associated with pancreatic insufficiency due to loss of pancreatic parenchyma, and potentially damaged remaining pancreatic tissue, for example as the result of pre-operative pancreatic ductal obstruction, there are likely to be few other contributory factors unless the patient has any co-morbidity. However, in the instance of pancreatico-duodenectomy, the reconstruction itself predisposes patients to bile salt malabsorption [54] and small bowel bacterial overgrowth [55].
Table 2 Management of PEI prior to pancreatic resection.
Preoperative assessment Criteria for commencing PERT: One or more of these symptoms in patients with proven/suspected pancreatic pathology:
Pancreatic function test
Abdominal symptom assessment
Dietetic assessment
Radiological assessment
Pancreatic exocrine insufficiency suggested by: FE < 200ug/g; CFA <93% or 13 C-MTG <58%
Clinical signs of steatorrhoea (oily pale floating stool)
Weight loss despite adequate oral intake
Pancreatic ductal dilatation
Abdominal bloating and flatulence
Micronutrient deficiencies despite adequate intake
Calcified pancreas Atrophied pancreas Tumour replacing pancreatic tissue
Treatment Commence PERT: 50,000e75,000 units lipase with meals 25,000e50,000 units lipase with snacks and nutritional supplements If weight loss or body mass index <20 kg m2 e Specialist Dietitian to advise on high energy high calorie diet Ensure patient is not following a low fat diet (unless required due to other morbidity) Biochemical assessment of endocrine function Correct micronutrient deficiencies Commence vitamin and mineral supplementation Review adequacy of enzyme dose within 2 weeks
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M.E. Phillips / Pancreatology xxx (2015) 1e7
Bile salt malabsorption following pancreatic resection may be attributed to concurrent cholecystectomy or the binding of bile salts to mal-digested protein, carbohydrates and fibre. Precipitation of bile salts may occur due to the change in pH in the small bowel as a result of reduced bicarbonate secretion secondary to diminished pancreatic volume [2]. The presence of a blind loop of bowel within the reconstruction following PD predisposes the patient to bacterial overgrowth, which has been documented in 65% of patients with PEI, with an increased incidence following resection compared to those with pancreatic disease alone [56]. In addition to contributing to gastrointestinal symptoms, this may precipitate further bile salt malabsorption. It is the experience of the author that new presentations of coeliac disease, lactase deficiency and inflammatory bowel disease may become apparent in the post operative period, and there are isolated case reports within the literature of such instances [57e59].
5
Conclusions PEI is under recognised and under treated following pancreatic resection. Given the high incidence of PEI, and potential significant consequences, PERT should be commenced routinely in all patients prior to undergoing PD, and where malnutrition and abdominal symptoms are present in patients prior to distal or central pancreatectomy (See Table 2). In the post operative setting, PERT should be routinely prescribed following PD, and those who have had a central or distal pancreatectomy should be individually assessed in the context of the degree of resection, with both objective assessment of FE, CFA or a 13C-MTG breath test, in addition to the subjective assessment of symptoms (Table 3). Pancreatic function tests lack specificity and need to be interpreted in clinical context following pancreatic resection. It is likely that malabsorption following PD is not solely pancreatic in origin. Patients with pancreatic disease without PEI should be
Table 3 Management of PEI prior following pancreatic resection. Pancreatico-duodenectomy Central/distal pancreatectomy and/or pre-operative PEI Criteria for commencing PERT: Pancreatic function test One or more of these criteria: Pancreatic exocrine insufficiency suggested by: FE < 200 mg/g; CFA <93% or 13 C-MTG <58%
Abdominal symptom assessment Clinical signs of steatorrhoea (oily pale floating stool)
Dietetic assessment Weight loss despite adequate oral intake
Post operative onset of abdominal Micronutrient deficiencies despite bloating and flatulence adequate intake
Treatment Commence PERT: 50,000e75,000 units lipase with meals 25,000e50,000 units lipase with snacks and nutritional supplements If weight loss or body mass index <20 kg m2 e Specialist Dietitian to advise on high energy high calorie diet Ensure patient is not following a low fat diet (unless required due to other morbidity) Biochemical assessment of endocrine function Correct micronutrient deficiencies Commence vitamin and mineral supplementation Review adequacy of enzyme dose within 2 weeks. If
symptoms not resolved Commence gastric acid suppression if not already prescribed Double dose of PERT Refer to Specialist Dietitian to ensure PERT dose appropriate to meal pattern/to ensure high energy diet/to advise on food fortification/prescribe nutritional supplements as necessary. Check PERT being taken and stored correctly (below 25 C; swallowed with cold drink at the same time as eating) Review adequacy within 2 weeks
If
symptoms remain unresolved Consider addition of anti-diarrhoeals Consider further increase in PERT (if some improvement with previous management) Consider changing PERT preparation Exclude bile salt malabsorption Exclude bacterial overgrowth Exclude infectious diarrhoea Consider delayed gastric emptying and other factors that may inhibit PERT Specialist Dietitian to advise on reduced fibre diet, commence peptide/MCT supplements if ongoing weight loss
Long term follow up Regular review of PEI symptoms Review of dietary adequacy Biochemical assessment of endocrine function and micronutrient status Patient education regarding PERT use if dietary intake changes; holidays; meals out; hot weather. Patients to be reassessed if symptoms return/worsen over time
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routinely reassessed as pancreatic function may deteriorate with time, likewise higher doses of PERT are likely to be required over time. As has been suggested by many previous studies it is of paramount importance that patients not responding to PERT, should have their dose and preparation reviewed, be referred to a specialist dietitian, and be investigated for extra-pancreatic causes of malabsorption. Following PD this should specifically mean excluding bile salt malabsorption and small bowel bacterial overgrowth (Table 3). There is a lack of high quality trials examining the incidence and treatment of these conditions following PD, but there is sufficiently defined biological mechanisms supported by individual and small patient cohort case studies to warrant clinical consideration and further investigation. Future research should examine the optimum treatment in the post operative setting, and work needs to continue to educate clinicians in the need for PERT both prior to and following pancreatic resection. The impact of extra-pancreatic factors such as bacterial overgrowth and bile salt malabsorption on FE, 13C-MTG and CFA should be evaluated. . There remains an urgent need to develop a practical, sensitive and specific diagnostic test for PEI in the post operative setting.
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Please cite this article in press as: Phillips ME, Invited review: Pancreatic exocrine insufficiency following pancreatic resection, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.06.003