Dr Nam Nguyen all articles by this author
Neil Merrett all articles by this author
Associate Professor Andrew V Biankin, BMedSc, MBBS (Hons), FRACS, PhD, Surgeon Scientist, is Conjoint Associate Professor in the School of Medicine at The University of New South Wales; Head, Pancreatic Cancer Research, Garvan Institute of Medical Research; and Consultant Gastrointestinal Surgeon, Sydney South West Area Health Service.
Dr Nam Q Nguyen, MBBS (Hons), FRACP, is a Gastroenterology Fellow, Cancer Research Program, Garvan Institute of Medical Research; Department of Gastroenterology, Bankstown Hospital.
Associate Professor Neil D Merrett, MBBS (Hons), FRACS, is Area Director, Gastroenterology and Liver Services, Head of Upper GI Surgery, Consultant Surgeon, Sydney South West Area Health Service.
PANCREATIC cancer is the fourth most common cause of cancer death in our society, with an overall survival of less than 5% at five years.1,2,3 Pancreatic cancer most commonly presents at an advanced stage, and as a consequence surgical resection is only possible in about 20% of patients. Surgery offers the only possibility of cure or long-term survival, which, with chemotherapy, is 20%-25% at five years.
There are now modern approaches to pancreatic surgery, a better understanding, and more appropriate treatment of precursor lesions of pancreatic cancer such as mucinous cystic neoplasms. These factors are improving overall outcomes for pancreatic cancer and increasing the number of patients that require nutritional monitoring and support in the community.
The most common operative techniques used for carcinoma in the pancreatic head are the classic Whipple’s pancreaticoduodenectomy2 (see Figure 1) and the pylorus-preserving pancreaticoduodenectomy procedure.4,5 Left-sided resection (e.g. distal pancreatectomy) is performed for tumours of the body and tail of the pancreas. Although operative mortality rates are relatively low (about 3%) in specialised units,1,6,7 significant morbidity still occurs in about 30% of patients who undergo pancreaticoduodenectomy.8,9,10
The pancreas plays a vital role in food digestion and glucose homeostasis; patients who have had pancreatic resections are at risk of pancreatic (exocrine and endocrine) insufficiency and malabsorption.11
Symptoms of diarrhoea, flatulence, tenesmus and fatty stools may substantially affect quality of life.12 Gastrointestinal dysmotility leading to delayed gastric emptying and enterogastric reflux can also be a significant long-term clinical problem in a small proportion of patients.13,14
Pancreatic insufficiency and gastrointestinal dysmotility after major pancreatic resection can adversely affect oral intake and gastrointestinal absorptive function, and can lead to malnutrition with associated long-term sequelae. GPs can play an important role in the prevention and treatment of these conditions.
Figure 1. The Whipple’s procedure (A). Before the procedure (B). After the procedure; note the anastomosis of the hepatic duct and the remaining pancreas and stomach to the jejunum.
The impact of pancreatectomy on digestive function is in general terms dependent on the extent of the resection and the functional state of the residual pancreas.
Compared to patients with a relatively normal residual pancreas, those with chronic pancreatic disease (e.g. chronic pancreatitis) before resection are more likely to develop pancreatic insufficiency, and thus early and more aggressive treatment may be required.11
As with exocrine insufficiency, diabetes is a well-recognised sequelae in 20%-50% of patients who undergo major pancreatic resections for malignancy,11,15 the management of which is beyond the scope of this article.
Pancreatic enzyme replacement
Most patients who have major pancreatic resections have a degree of exocrine insufficiency. Pancreatic enzyme replacement may be an important part of the long-term management of some of these patients. The key clinical issue is identifying patients that require enzyme replacement. Symptoms of pancreatic insufficiency may not be obvious, and sequelae of malnutrition such as osteo-porosis due to deficiency of the fat-soluble vitamin, vitamin D, may not become apparent for many years.
In patients where pancreatic exocrine insufficiency is identified or suspected, adequate enzyme-replacement therapy reduces malnutrition, normalises biochemical indices of malnutrition, assists a patient to recover much of their original body weight, and improves their overall quality of life.16,17 There is limited information concerning the routine use of pancreatic enzyme-replacement therapy, nor is there data which defines a threshold for the requirement of replacement therapy.
Furthermore, objective measures of pancreatic insufficiency have not proven to be accurate or clinically useful at this point in time.
Patients can have different degrees of exocrine pancreatic insufficiency. The dosage of pancreatic enzymes should therefore be titrated to the individual patient’s symptoms.16,18,19 All patients should be monitored and screened for symptoms and signs of inadequate replacement (see Figure 2 below).
Despite apparently adequate dosage regimens, symptoms may still persist due to inadequate delivery of active enzymes to the small intestine. Of all pancreatic enzymes, lipase is the most sensitive to acidic and proteolytic denaturation, and is therefore the most affected.16,20 As the digestion of fat by lipase is important and cannot be easily compensated by non-pancreatic mechanisms, the key to successful pancreatic enzyme replacement is to achieve sufficient lipase activity in the intestine.20
Contrary to general belief, the relationship between the dose of pancreatic enzymes required and symptoms of maldigestion is not linear. In general, the required amount of lipase to be delivered to the small intestine with each meal is 25,000 to 50,000 units.16,20,21
As unprotected enzyme is rapidly destroyed by gastric acid, the use of acid-suppression therapy may be a useful adjunct therapy and is recommended, especially if severe steatorrhoea continues with adequate dosing of pancreatic enzyme.16,20,22
pH-sensitive pancrelipase microsphere preparations have become increasingly popular and have been recommended as the treatment of choice.18,19,20,23 However, this preparation may be ineffective in patients who underwent pylorus-preserving pancreaticoduodenectomy because
the microspheres are retained in the stomach.24 In these patients, conventional powdered pancreatin enzyme preparations may improve the efficacy of treatment.24
It should be noted that this is not available in Australia.
If symptoms and signs of maldigestion persist despite these therapeutic measures, a trial of pH-sensitive enteric-coated microspheres, restricting the amount of dietary fat and/or replacing fat with medium-chain triglycerides, should be considered.16,25,26,27
Factors influencing the effects of pancreatic enzyme replacements include:28
• Variations in enzyme content
• Size of the enzyme particles and their rate of exit from the stomach
• Dissolution characteristics of the preparation
An overview of pancreatic enzyme replacement preparations available in Australia is shown in Figure 3.
Timing related to meals can also influence the effectiveness of pancreatic enzymes. Dosing during or towards the end of the meal may optimise mixing and enhance the effectiveness of enzymes.29
Adapted from Braga M, et al. Pancreatic enzyme replacement therapy in post-pancreatectomy patients. Int J Pancreatol 1989;5(Suppl):37-44.
Dietary and nutritional management
Apart from pancreatic exocrine insufficiency, poor oral intake from factors such as chronic abdominal discomfort, gastrointestinal dysmotility and persistent steatorrhoea can also lead to malnutrition in these patients. Specific modification to the carbohydrate, protein and fat moieties of the diet, therefore, is an essential adjunct therapy to adequate replacement of pancreatic enzymes.37,38 Frequent small meals with high carbohydrate and protein (1-1.5 g/kg) content are recommended to achieve an adequate intake. Up to 30% of calories of the meal can be given as fat. Management of the patient may include the advice of a dietitian.
In patients who fail to gain or maintain adequate body weight, and/or have persistent steatorrhoea, the amount of dietary fat should be minimised and medium-chain triglycerides (MCT) can be trialled because of the lipase-independent absorption property of MCT.37,39 However, MCTs are poorly tolerated by most patients and may induce side-effects such as abdominal pain, nausea and diarrhoea.39 In addition, a low-fibre diet can be implemented as dietary fibre absorbs enzymes, further decreasing active enzyme delivery.
In summary, major pancreatic resections not only impair pancreatic function, but also the function of the entire upper gastrointestinal tract. This may adversely affect the nutritional status and the overall quality of life of these patients.
Current literature suggests that with advances in surgical techniques and post-operative care (including optimal pancreatic enzyme replacement), most of these patients will have good outcomes with minimal gastrointestinal symptoms, will be able to maintain adequate weight and achieve a high quality of life.
However, it is important that pancreatic enzyme insufficiency after pancreatectomy is suspected, and a patient’s nutritional status (including serum levels of vitamins and minerals) is closely monitored so that appropriate treatment can be provided.
Practical application to general practice
Diagnosing pancreatic enzyme insufficiency can be difficult, but should be suspected after pancreatectomy. As no accurate objective measures of insufficiency are regularly used, a trial of replacement therapy is appropriate.
The dose of enzymes should be titrated to the symptoms of an individual patient. A starting dose of 25,000 to 50,000 IU per meal, with 25,000 IU with snacks, is generally recommended.21 The dose should be increased if symptoms continue; doses of up to 80,000 IU of lipase may be required.40
Dietary adjustment, checking if patients adhere to medications, and further investigations for other possible diagnoses (such as bacterial overgrowth, giardiasis or coeliac disease) may be required if symptoms are not adequately controlled.29
A 40-YEAR-old man presented with fluctuating symptoms of abdominal cramps and diarrhoea for nine months. Eight years previously he underwent a Whipple pancreaticoduodenectomy for a benign insulinoma. He denied any symptoms of significance previous to the past nine months.
He was intensively investigated for these symptoms with ultrasound, CT scanning, gastroscopy, colonoscopy and capsule endoscopy, all of which did not reveal a cause. He did not describe any classic symptoms of fat malabsorption such as floating and difficult-to-flush stools. All routine blood analyses were normal.
He was started on enzyme-replacement therapy at a dose of two pancrelipase (Creon Forte) capsules or 50,000 IU lipase with meals, and had minimal change in his symptoms over a four-week period. This dosage was increased to three capsules or 75,000 IU lipase with meals, with substantial improvement in his cramping and diarrhoea, but intermittent symptoms persisted. Addition of one capsule (25,000 IU lipase) replacement with snacks led to complete resolution of this patient’s symptoms.
This case illustrates that symptoms of pancreatic exocrine insufficiency may manifest a significant period of time after pancreatic resection; that symptoms of fat malabsorption are not always consistent with classical descriptions; and that a dosage of 50,000 IU had no effect, whereas a 50% increase had a dramatic response. Complete resolution of symptoms occurred when 25,000 IU lipase was given in conjunction with snacks. This, therefore, reinforces the importance of individually titrating doses to obtain maximal symptom control.
1. Buchler MW, et al. Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003;138:1310-15.
2. Diener MK, et al. A systematic review and meta-analysis of pylorus-preserving versus classical pancreaticoduodenectomy for surgical treatment of periampullary and pancreatic carcinoma. Ann Surg 2007;245:187-200.
3. Yeo CJ, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 1995;221:613-798.
4. Traverso LW. The surgical management of chronic pancreatitis: the Whipple procedure. Adv Surg 1999;32:23-39.
5. Traverso LW. The pylorus preserving Whipple procedure for the treatment of chronic pancreatitis. Swiss Surg 2000;6:259-63.
6. Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 1990;211:447-58.
7. Yeo CJ, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248-60.
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14. Williamson RC, Bliouras N, Cooper MJ, Davies ER. Gastric emptying and enterogastric reflux after conservative and conventional pancreatoduodenectomy. Surgery 1993;114:82-86.
15. Stone WM, Sarr MG, Nagorney DM, McIlrath DC. Chronic pancreatitis. Results of Whipple’s resection and total pancreatectomy. Arch Surg 1988;123:815-19.
16. Braga M, et al. Pancreatic enzyme replacement therapy in post-pancreatectomy patients. Int J Pancreatol 1989;5(Suppl):37-44.
17. Czako L, et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can J Gastroenterol 2003;17:597-603.
18. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep 2001;3:101-08.
19. Morrow JD. Pancreatic enzyme replacement therapy. Am J Med Sci 1989;298:357-59.
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24. Bruno MJ, et al. Comparative effects of enteric-coated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy. Br J Surg 1997;84:952-56.
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30. Creon approved product information, 23 July 2003.
31. Cotazym-S Forte approved product information, 27 September 2006.
32. Panzytrat 25000 approved product information, 9 July 2003.
33. Creon International Scientific Brochure, 2000.
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35. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut 2005;54:1-28.
36. Nordmark: (Accessed 16 July 2008). Available at: http://p100193.typo3server.info/english/product-range.html
37. Silk DBA. Diet following resections of the small intestine and the pancreas. Pancreatology 2001;1:27-34.
38. Meier RF, Beglinger C. Nutrition in pancreatic diseases. Best Pract Res Clin Gastroenterol 2006;20:507-29.
39. Caliari S, et al. Medium-chain triglyceride absorption in patients with pancreatic insufficiency. Scand J Gastroenterol 1996;31:90-94.
40. Dominguez-Munoz JE, ed. Clinical pancreatology for practising gastroenterologists and surgeons. Blackwell Publishing: Oxford, 2005.
Declaration of interest:
Professor Biankin is the current president of the Australasian Pancreatic Club, which receives support from Solvay Pharmaceuticals. Professor Biankin has presented at medical and clinical meetings through travel grants provided by Solvay Pharmaceuticals.
- Pancreatic enzyme insufficiency should be suspected after pancreatectomy.
- As there are no objective measures of insufficiency which are regularly used, a trial of replacement therapy is appropriate.
- Signs and symptoms of inadequate pancreatic enzyme replacement include weight loss, diarrhoea, steatorrhoea and dyspeptic symptoms with bloating.
- Adequate pancreatic enzyme replacement therapy reduces malnutrition and improves quality of life.
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