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References 429

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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23 Machicado JD, Chari ST, Timmons L etal. A

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based evaluation of the natural history of

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pseudocyst: dilemma of its recent management [Review]. Exp Ther Med 2021;21:159.

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pseudocysts in chronic pancreatitis: endoscopic and surgical treatment. Dig Surg 2003;20:397.e406.

26 Anand A, Gunjan D, Agarwal S etal. Vascular

complications of chronic pancreatitis: a tertiary center experience. Pancreatology 2020;20:1085–1091.

27 Vujasinovic M, Dugic A, Nouri A etal. Vascular

complications in patients with chronic pancreatitis. JClin Med 2021;10:3720.

28 Balachandra S, Siriwardena AK. Systematic appraisal of

the management of the major vascular complications of pancreatitis. Am J Surg 2005;190:489–495.

29 Köklü S, Coban S, Yüksel O etal. Left- sided portal

hypertension. Dig Dis Sci 2007;52:1141–1149.

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portal hypertension: a sinister entity. GE Port J Gastroenterol 2015;22:234–239.

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hypertension: clinical features and surgical treatment of chronic splenic vein occlusion. Med Princ Pract 2012;21:20–23.

32 Bernades P, Baetz A, Lévy P etal. Splenic and portal

venous obstruction in chronic pancreatitis. A prospective longitudinal study of a medical–surgical series of 266 patients. Dig Dis Sci 1992;37: 340–346.

33 Butler JR, Eckert GJ, Zyromski NJ etal. Natural history

of pancreatitissystematic review and meta-

induced splenic vein thrombosis: a

analysis of its incidence and rate of gastrointestinal bleeding. HPB (Oxford) 2011;13:839–845.

34 Agarwal AK, Raj Kumar K, Agarwal S etal. Significance

of splenic vein thrombosis in chronic pancreatitis. Am JSurg 2008;196:149–154.

35 Pandey V, Patil M, Patel R etal. Prevalence of splenic

vein thrombosis and risk of gastrointestinal bleeding in chronic pancreatitis patients attending a tertiary hospital in western India. J Family Med Prim Care 2019;8:818–822.

430

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Nutritional Evaluation andSupport: AnOverview

Sinead N. Duggan1 and Stephen J. O’Keefe

Department of Surgery, School of Medicine, Trinity College Dublin, Ireland

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA

Introduction

Nutrition in chronic pancreatitis has been described as a problem area[1]. There is a high risk of undernutrition, and the etiology is multifactorial. Exocrine pancreatic insufficiency (EPI) results in the malabsorption of macro- and micronutrients. Moreover, pancreatic enzyme replacement therapy (PERT) is often underused and underprescribed[2], and may not fully restore normal digestive function [3]. Poor dietary intake is common due to abdominal symptoms, pain, heavy smoking, fear of eating (due to distressing synptoms), and (for some) alcohol abuse. However, not all patients with chronic pancreatitis are classically underweight (particularly in the earlier stages of diease), and some may be overweight or obese.

Undernutrition

The mean body mass index (BMI) of patients with chronic pancreatitis varies considerably between different countries, reflecting the general nutritional status of the country. Examples of BMI values reported for patients with chronic pancreatitis include: 19.3 India, 21.9 kg/m2 in Italy, 22.1 kg/m2 in Poland, 23 kg/m2 in Denmark, 24 kg/m2 in the Netherlands, and 25.9 kg/ m2/25.5 kg/m2 in males/females in Ireland. Patients with chronic pancreatitis have consistently lower BMIs, lower muscle mass, and handgrip strength than matched controls. The clinical impact of overweight and obesity among patients with chronic pancreatitis is uncertain, but obesity may mask micronutrient deficiencies and sarcopenia. Those who abuse alcohol have an increased risk of undernutrition. High alcohol users tend to have

kg/m2 in

poor nutrient intakes, either due to effects on appetite or due to displacement of food[4]. High alcohol intake also independently increases the risk of osteoporosis, and may be associated with diarrhea and malabsorption[5]. Sarcopenia, a disorder associated with loss of muscle mass, strength and function[6], may develop in patients with chronic pancreatitis, particularly if there is EPI[7].

Nutrient Deficiency

Specific nutrient deficiencies may arise in chronic pancreatitis as a result of steatorrhea (loss of fat- soluble vitamins), alcoholism (increased requirement or loss of water- soluble vitamins), or poor/imbalanced dietary intake. The prevalence of specific nutrient deficiencies varies between studies and countries[8]. They reported that the rate of vitamin A, D, and E deficiency were

16.8%, 57.6%, and 29.2% respectively, with considerable heterogeneity. Another systematic review found that while vitamin D insufficiency and deficiency were highly prevalent in patients with chronic pancreatitits, there was no significant difference between patients and healthy controls[9]. Only one study has investigated the prevalence of vitamin K deficiency, reporting that 63% of chronic pancreatitis patients had low serum levels of vitamin K [10], but vitamin K deficiency is more correctly measured by undercarboxylated osteocalcin or by measurement of proteins of vitamin K absence, and not by measurement of serum vitamin K or prothrombin time, both of which are inaccurate[12]. There have been few studies on other micronutrients, but isolated studies identified low magnesium [13] and zinc levels [14] among chronic pancreatitis patients. In a study from India, folate and vitamin B12 were reportedly lower in

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Dietary Intervention 431

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patients with tropical and alcohol- related chronic pancreatitis than in controls, and low levels correlated with increased oxidative stress. Smoking was associated with much higher risk of folate deficiency[15].

Despite the ostensibly common occurrence of biochemical vitamin deficiency, there are few published reports on the clinical manifestation of such deficiencies in chronic pancreatitis. The exception is vitamin D, which contributes (among other factors) to the welldocumented high prevalence of osteoporosis [16]. Overt vitamin D deficiency resulting in osteomalacia (adult rickets) has also been reported[17]. Neurologic abnormalities associated with vitamin E deficiency have also been rarely reported. One patient out of 13 with biochemical vitamin E deficiency had typical neurologic manifestations along with poorly controlled diabetes[18]. A condition known as brown bowel syndrome (associated with vitamin E deficiency) has also been reported in a deficient patient with chronic pancreatitis, celiac disease, and adenocarcinoma of the colon[19].

Clinical manifestations of vitamin A deficiency tend to manifest as visual defects. One case report[20] described a 45- year- old male with chronic pancreatitis, chronic alcoholism, diabetes, and a history of cholecystectomy. The patient presented with steatorrhea, cachexia, low BMI, and severe weight loss, along with ocular pain, photophobia, and decreased visual acuity. A second report[21] described a patient with chronic pancreatitis, malnutrition, and vitamin A deficiency who developed ulcerative keratitis in one eye and necrotizing stromal ulceration with hyphema in the other eye. In general, clinical deficiencies appear to take years to develop, and occur when there is an additional comorbidity, such as celiac disease or diabetes, or post surgery.

Micronutrient Supplementation

There is a notable research gap regarding the management of nutrient deficiency in chronic pancreatitis, excepting vitamin D. In a study comparing oral vitamin D supplementation to ultraviolet B (UVB) radiation in chronic pancreatitis, oral supplementation (1520 IU/ day) was significantly more effective in increasing serum 25(OH)D, achieving an increase of 32.3 nmol/L (95% 15–50 nmol/L) over 10 weeks [22]. High- dose, single- dose supplementation also appears to be safe and effective in increasing serum 25(OH)D. One study compared 600,000 IU or 300,000 IU single intramuscular injections or intramuscular saline, and found that the higher dose was more effective at increasing serum 25(OH)D, with no reports of hypervitaminosis or hypercalcemia[23].

There are few studies, if any, examining the effectiveness or safety of supplementing vitamins A, E, or K in patients with chronic pancreatitis and biochemical deficiencies. One study documented unexplained excess levels of vitamin A in patients with chronic pancreatitis who were not being supplemented[24]. Therefore, mass supplementation of patients is not recommended, nor is it possible to recommended dosage, administration methods, or specific patient types that warrant supplementation. A precision medicine approach is warranted, with measurement of serum vitamins and attention given to optimizing dietary intake and PERT.

Dietary Intervention

Nutritional status can be improved in chronic pancreatitis with the use of PERT when EPI exists, and by individualized dietary intervention and dietary counseling by an experienced dietitian who specializes in pancreatic disease and works within a multidisciplinary team[25]. In general, interventional studies investigating the effect of various treatments on nutritional status in chronic pancreatitis are scarce, representing a clear research gap. Nevertheless, active treatment works for those who receive it. A systematic review identified eight studies on the long- term nutritional effects of clinical interventions (including input by specialist dietitians, PERT dose escalation, supplementation, or tube feeding) [26]. All studies included in the review demonstrated improved weight gain and pain control compared to a deterioration of nutritional status in patients who were not treated.

Nutritional requirements are up to 35 kcal/kg per day[5,27], and 1.2–1.5 g protein/kg per day[5,27,28]. Particularly in the early stages, very low- fat diets (or fat- free diets) are not recommended as they decrease energy intake and make food less palatable [5,29]. Rather, PERT should be optimized to allow for a moderate fat intake. In the later stages of disease, or where gastrointestinal symptoms are difficult to manage, fat restriction may be necessary. In this case, care must still be taken to optimize PERT along with acid- suppression medications and to exclude other causes of malabsorption (such as small intestinal bacterial overgrowth and giardiasis). There is no evidence that vegetable fat is better tolerated than animal fat as no studies have investigated this [5]. Clinicians must also ensure that patients are compliant with PERT, that they understand how to take it appropriately, and that PERT capsules are suitably stored. For example, high temperatures may denature PERT, reducing their effectiveness. PERT should therefore not be stored in the pockets of tightfitting clothing, on sunny windowsills, or in hot car

Nutritional Evaluation andSupport: AnOverview

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432

glove compartments [30]. If PERT cannot be swallowed, the capsules may be opened and the microspheres placed in an acidic puree (such as apple sauce), and swallowed at intervals throughout the meal. The mouth should be rinsed well with cool water to prevent ulceration. They should not be allowed to touch, or remain in, the mouth[30].

Where malabsorption continues with apparently adequate PERT, a restriction in dietary fiber might improve absorption, as dietary fiber may reduce enzyme availability[5,27]. However, long- term fiber restriction should be avoided as a diet rich in fruit and vegetables should be recommended. For most patients, particularly in the later stages of disease or for those with intractable malabosprtion and distressing symptoms, a frequent, low- volume meal pattern should be advised with the avoidance of large meals at any sitting. A trialmight be required as tolerance to food may be patientspecific. Some patients will require oral nutritional supplements if dietary intake alone is not adequate, and whole- protein types could be tried first before progressing to peptide- based or medium- chain triglyceride (MCT)- enriched supplements. Antioxidant supplementation for the treatment of chronic pancreatic pain was considered a promising treatment option[31], but subsequent studies cast doubt on its effectiveness[32]. A systematic review on the effect of antioxidants in pain reduction, adverse events, and quality of life found 12 studies, 4 of which were included in a meta- analysis[33]. The review found no effects on pain or improvement in quality of life for those taking antioxidants versus placebo, nor were there increased adverse events.

and- error approach

Enteral andParenteral Nutrition

The vast majority of patients with chronic pancreatitis will be maintained on an oral diet, with or without supplementation. Enteral nutrition is indicated for malnourished patients who are unable to meet their requirements orally [28,34,35,36]. Enteral feeding via the jejunal route should be performed in the case of delayed gastric emptying, chronic subacute obstruction of the upper gastrointestinal tract by pancreatic cysts[37], and persistent nausea or vomiting, or pain [28]. Nasojejunal feeding is associated with a reduction in pain, pseudocysts, and inflammation, as well as improvements in nutritional status [38,39]. Where jejunal feeding is required for a prolonged period, a surgical jejunostomy could be considered [28,40]. With regard to the composition of enteral feeds, peptide- based, MCT- based formulas may be trialled where standard feeds are not tolerated[36].

Some patients may require the administration of PERT along with enteral feeds. Enzymes may be flushed via the

feeding tube every 2 hours or added to the feed itself[30]. Parenteral nutrition should be avoided, if possible, as complication rates are higher in chronic pancreatitis due to pancreatic endocrine insufficiency (hyperglycemia) and immunotransnasal endoscopic placement of distal jejunal feeding tubes in chronic pancreatitis usually avoids the need for commonly cited indications of parenteral nutrition, including gastric outlet obstruction secondary to duodenal stenosis, complex fistulating disease, and severe malnutrition prior to pancreatic surgery[34,36,41].

incompetence (catheter sepsis). The use of

Combined Pancreatic Exocrine and Endocrine Deficiency

With end- stage calcific chronic pancreatitis, pancreatic endocrine deficiency exacerbates malnutrition and makes nutritional management even more challenging. Type 3c diabetes (also termed diabetes of the exocrine pancreas [42]) is known as “brittle diabetes” and carries a high risk of hypoglycemia and neuroglycopenia, due to insulin therapy, glycogen deficiency, enhanced peripheral insulin sensitivity, malabsorption, poor dietary intake, and, for some, persistent excess alcohol intake[43]. Rapid swings in blood glucose between hypoglycemia and hyperglycemia are common, the former due to impaired pancreatic glucagon and polypeptide responses, the latter exacerbated by unsuppressed hepatic glucose production [44]. Due to its volatile nature, patients may be wrongly assumed to be noncompliant with guidelines. Attempts to increase dietary intake and the addition of PERT to manage PEI may aggravate hyperglycemia further and have to be carefully covered by increased insulin therapy. Continous glucose monitors may be useful. Patients must be jointly managed with an endocrinologist, and careful dietary monitoring by a specialist diabetes dietitian is essential[29,44].

Structured Nutritional Assessment

Once diagnosed with chronic pancreatitis, patients should undergo thorough and regular nutritional assessment by an experienced, specialist dietitian, working in conjunction with the multidisciplinary team. Figure53.1 summarizes the nutritional assessment of patients with chronic pancreatitis and includes eight key elements:

1) There should be an anthropometric assessment (includ-

ing BMI, mid- upper arm circumference, triceps skinfold). Formal measures of sarcopenia may be useful.

2) A detailed assessment of current and habitual dietary

intake should be undertaken.

Structured Nutritional Assessment 433

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Multidisciplinary

pancreatitis clinic

Dietitian

assessment

Anthropometry and dietary assessment

Muscle and fat stores,

weight / weight

history, BMI, diet

Clinical evaluation

Nausea, vomiting,

diarrhoea,

steatorrhoea, anorexia,

early satiety

Exocrine evaluation

Clinical symptoms (pale, bulky stools,

visible oil), weight loss,

failure to gain weight,

bloating, wind, nausea,

pain, malnutrition

Biochemistry

To include fat-soluble

vitamins, vitamin B12

history

CP diagnosis

supplements (ONS)

Dietary modification

Medication review

Measure exocrine deficiency

Faecal Elastase-1 (µg/g)

- <100 severe PEI

- <200 highly suggestive of PEI

- 200–500 suggests mild PEI, treat if symptomatic

- >500 normal

90% diet + oral

nutritional

5% enteral feeding

<1% parenteral

feeding

Supplement if indicated

Small frequent meals

Energy 30 kcal/Kg/day

Fat 30% of energy

Higher carbohydrate unless DM

Low fibre to increase enzyme

absorption (if indicated)

±Food & symptom diary

Supplementation

±ONS

±MCT supplement

± Antioxidants

Type 3c Diabetes

Dietary modification, avoidance

of hyperglycemia/

hypoglycemia, adequate

glycaemic control. Endocrine

involvement.

PERT± acid suppression

Normal DXA / pre-DXA

-Basic preventative

measures: adequate calcium,

vitamin D, weight-bearing

exercise, alcohol/smoking

cessation

Endocrine evaluation

Fasting glucose, HbA1c

Bone health

25OHD (vitamin D),

PTH

Other

Smoking, alcohol,

physical activity, QOL,

social issues

DXA at baseline, or at least if 1+ additional risk factors

menopausal, > 50 y (men)

Medical social work referral

75g OGTT if any

abnormalities

Previous low-trauma

fracture, intractable

malabsorption, post-

Smoking / alcohol

avoidance

if indicated

Osteopenia

-Basic preventative measures

-Repeat DXA in 2y

Osteoporosis

-Basic preventative measures

-Screen for other causes

-Medication

-Consider bone specialist referral

Vitamin D deficiency

-Vitamin D supplementation, especially during Oct-Mar

-Dietary sources

Figure53.1 Structured nutritional assessment and intervention for patients with chronic pancreatitis (CP). DM, diabetes mellitus; ONS,

oral nutritional supplement; MCT, medium- chain triglyceride; PEI, pancreatic exocrine insufficiency; OGTT, oral glucose tolerance test; DXA, dual X- ray absorptiometry; PTH, parathyroid hormone; QOL, quality of life; PERT, pancreatic enzyme replacement therapy.

Source:Modified from Duggan etal. 2010[5].

Nutritional Evaluation andSupport: AnOverview

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434

3) Clinical evaluation should include the presence of

nausea/vomiting, diarrhea, malabsorption, bloating, wind, anorexia, early satiety, and pain.

4) An assessment of exocrine function should be per-

formed, including the clinical symptoms and signs of malabsorption, as well as an objective measure of EPI.

5) A biochemical assessment of nutritional status should

include measurement of fat- soluble vitamin levels, as well as measurement of fasting glucose and glycated hemoglobin (HbA1c).

6) Endocrine evaluation: A 75 g oral glucose tolerance

test may be required, as some early cases may not be identifiable by fasting glucose and HbA1c alone[45].

7) Bone health should be evaluated by measurement of

serum 25(OH)D and a baseline bone density scan. All

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Exocrine Pancreatic Insufficiency

Chris E. Forsmark

Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA

Introduction

Pancreatic exocrine insufficiency (EPI) is defined by the presence of inadequate pancreatic digestive enzymes in the intestinal lumen to allow normal digestion of fat, carbohydrates, and protein [1]. These digestive enzymes account for the majority of enzymatic digestion in humans under normal circumstances, but there are alternative salvage pathways for starches and complex carbohydrates (salivary amylase), protein (pepsin and brush border peptidases), and fat (gastric lipase), and the colon can absorb up to 500 kcal/day due to bacterial fermentation of soluble fiber to short chain fatty acids, which are then absorbed. The pancreas secretes approximately 10- fold the amount of enzymes required for digestion with each meal, likely an evolutionary advantage when food was scarce and only intermittently available. Whether a reduction in pancreatic enzyme secretion reaches a threshold of being “insufficient” is often difficult to precisely determine, and depends on residual pancreatic secretory capacity, the contents of the meal being digested, intestinal structure and function, and the efficiency of compensatory or salvage mechanisms of digestion [1,2]. EPI most commonly occurs due to acinar cell damage and loss, pancreatic ductal obstruction preventing enzymes reaching the duodenum, and asynchronous or delayed mixing of the meal and enzymes. A number of other conditions are associated with EPI, such as acidenzymes, inadequate hormonal signaling for pancreatic secretion, and some rare genetic syndromes. Many other clinical conditions have been postulated to be associated with EPI, including long- standing type 1 and 2 diabetes, the extremes of age, renal failure, irritable bowel syndrome, smokers, and even otherwise unexplained bloating and gas symptoms.

induced inactivation of

Digestion and absorption of dietary nutrients is a complex process, with many overlapping mechanisms in addition to pancreatic enzyme secretion [1]. Complex carbohydrates are well absorbed in the absence of pancreatic amylase, due to a combination of salivary amylase and brush border enzymes. Similarly, protein digestion and absorption is relatively well preserved in the absence of pancreatic proteases, due to the actions of pepsin and brush border peptidases. Fat digestion and absorption is most dependent on pancreatic lipase and colipase, but gastric lipase can be upregulated and allows nearly 50% of normal fat absorption in the absence of pancreatic lipases. These alternative mechanisms of digestion and absorption, and the physiologic pancreatic enzyme reserve capacity, explain why some individuals with diseases causing EPI seem to suffer no nutritional consequences. A second term, exocrine pancreatic dysfunction (EPD), has been proposed to describe these individuals with diminished pancreatic enzyme secretion that is not sufficient to lead to nutritional consequences[3].

Disease States Associated with EPI (Table54.1)

The most common cause of EPI is chronic pancreatitis (CP). Prevalence estimates for EPI in patients with CP range from 30–50%[4–6]. EPI is typically a late consequence of CP, with a mean time to onset of 10–15 years. The risk of EPI is greater and onset is earlier with CP due to alcohol, smoking, and certain genetic causes (e.g., PRSS1 mutation), compared to other etiologies. Cystic fibrosis patients almost universally have EPI, usually detected at birth.

Pancreatic cancer is another common cause of EPI[7–11]. Around 70% of pancreatic cancer occurs in

Diagnosis andStaging ofEPI 437

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Table54.1 Some disease states associated withEPI.

Disease state Prevalence of EPI Comments

Chronic pancreatitis

Cystic fibrosis >90% Most are pancreas

Pancreatic cancer, ampullary cancer, main duct IPMN

Pancreatic surgery

Nonpancreatic intestinal surgery

Acute pancreatitis

Diabetes Unknown Long-

Aging Unknown Fecal elastase levels drop

Celiac disease Unknown Possibly due to small

Genetic syndromes

IPMN: intraductal papillary mucinous neoplasm.

30–50% Longer duration of

35–75% Depending on location of

Variable, 30–50%

Very common depending on surgery

Variable, 20–45%

Schwachman– Diamond or Johanson– Blizzard

disease and specific etiologies (alcohol, smoking, certain genetic causes) increase risk

insufficient at birth

cancer (head>body>tail) and degree of main pancreatic duct obstruction. Risk increases after any pancreatic resection

Depending on amount of resection, and presence of Roux reconstruction limiting mixing of enzymes and meal

Risk highest after gastrectomy or gastric bypass

Depending on degree of necrosis, but can occur in absence of significant necrosis

standing diabetes associated with reduced fecal elastase. Reduced pancreatic volume and serum levels of trypsin in type 1 DM

in advanced age (>70)

bowel injury leading to diminished CCK release, can improve on gluten-

free diet

Isolated deficiency of pancreatic enzymes

EPI after pancreaticoduodenectomy, for example, is common (40–90%) and most patients require pancreatic enzyme replacement therapy after surgery [11]. Other surgical procedures may also cause EPI by interfering with mixing of enzymes and the meal. Examples include bariatric surgery[12], or Roux- type operations after gastric resections.

Necrotizing pancreatitis can cause EPI in one- third to half of patients, depending on location and extent of necrosis[13–15]. Recent studies document that EPI can also occur acutely in those with milder forms of acute pancreatitis, and can persist in approximately 20%[16].

A number of other conditions have been suggested to cause EPI[17]. The most data are in patients with diabetes. Pancreatic weight and volume are markedly reduced in patients with type 1 DM[18], and even in first- degree relatives of patients with type 1 DM[19]. Autopsy studies in these patients show interacinar fibrosis, and fecal elastase and serum trypsinogen are often reduced. Of note, symptomatic EPI is quite rare in these patients, leading to a proposal to define this as an exocrine pancreatopathy rather than exocrine insufficiency [18]. These findings point to a complex interplay between the exocrine and endocrine pancreas. A few studies have also documented apparent EPI at the extremes of age (<1 or >80), in those with chronic renal failure, in those who are malnourished or critically ill, and in those with otherwise unexplained osteoporosis [17]. Data supporting these etiologies of EPI are meager. Two additional conditions merit mentioning, celiac disease and gastrinoma. In the first, duodenal damage is postulated to cause defective signaling of CCK from the duodenum, and in the second excess acid can denature pancreatic digestive enzymes.

There are also now multiple direct- to- patient offerings on the internet regarding EPI, describing bloating and loose stools and excess flatulence as being consistent with EPI and suggesting patients contact their physician to discuss these symptoms and whether treatment with PERT should be considered. In parallel, many enzyme products of low or unknown potency are available over the counter to treat these symptoms of purported EPI. Of course, with very few exceptions, these patients do not have EPI.

the head of the pancreas, with ductal obstruction and upstream dilation and atrophy of the pancreatic body and tail. In those with unresectable pancreatic cancer, EPI occurs in the majority (50–90%). In those with resectable disease, EPI is present prior to resection in 40–50%, and increases to ≈75% after resection. Pancreatic surgery, for benign or malignant indications, is also commonly associated with postoperative EPI.

Diagnosis andStaging ofEPI

It can be difficult to determine with confidence if EPI is present. While the potential disease associations are known (Table54.1), the lack of an accurate diagnostic test limits diagnostic confidence. EPI is a clinically defined syndrome, which is suspected based on the presence of steatorrhea, weight or muscle mass loss,

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fat- soluble or other vitamin deficiency, or other clinical features in a patient at risk for EPI[1,20]. The confirmation of maldigestion may be achieved by directly measuring inadequate digestion of fat or protein (e.g., 72- hour fecal fat). This type of test requires a diet of precisely known fat content, so that the amount of dietary fat that is digested and absorbed can be calculated (the CFA- coefficient of fat absorption = [dietary fat- stool fat]/dietary fat; with a normal of >93%). By convention, these tests use a high- fat diet (usually 100 gm of fat/day) to gauge maximum pancreatic secretory capacity, but this does not provide insight into the efficiency of fat absorption with routinely consumed or low- fat meals. The presence of an abnormal CFA does not in and of itself prove that EPI is responsible, merely that maldigestion or malabsorption is present. These 72- hour stool collections are challenging, and are rarely done outside of clinical research.

Pancreatic function can also be measured directly, with a tube or endoscope in the duodenum collecting pancreatic secretions after a supraphysiologic stimulus with either secretin (producing ductal secretin of bicarbonate and fluid) or cholecystokinin (CCK; producing acinar secretion of enzymes). It is noteworthy that the results of these direct pancreatic function tests often do not correlate with fecal fat output. As an example, there is no correlation with abnormal bicarbonate output and fecal fat in a secretin-

pancreatozymin (CCK) direct pancreatic function test[3]. This discordance may be related to the fact that these tests do not measure the extrapancreatic sources of lipolysis, hence, there is no way to define a cutoff in a pancreatic function test below which EPI (as opposed to EPD) is likely to occur. These direct pancreatic function tests are complex and invasive, and therefore rarely utilized in clinical settings.

Several tests are being developed which measure digestion that is specifically dependent on pancreatic digestive enzymes. These include a 13C- mixed triglyceride breath test, which measures triglyceride maldigestion by collecting 13CO2 in expired air after ingestion of a test meal[21,22]. The lipids in the meal require pancreatic lipase and colipase for digestion. Another uses measurement of metabolites in blood of lipids digested by pancreatic lipase[1]. Both tests are not currently available to clinicians. An ideal test would measure specific pancreatic enzyme- dependent digestion, be widely available, not require complex collection of stool, and be precise and repeatable. Unfortunately, no such test is currently available to clinicians.

Instead, the most commonly utilized test is the fecal elastase- 1 (FE- 1)[1,20,23,24]. This is actually a misnomer, as elastase- 1 is not expressed in the human pancreas due to transcriptional silencing. The commercial assay actually detects chymotrypsin- like elastases (CELA3A and CELA3B isoforms)[25]. Nonetheless, the

test is conventionally referred to as fecal elastase-

1. Levels of FE- 1 < 100 μg/gm of stool are considered abnormal, and levels of 100–200 μg/gm of stool are considered indeterminate. The test can be measured while patients are taking PERT. Several caveats apply: (i) the stool sample must be solid or semi- solid as watery stool dilutes the elastase; (ii) the results can be variable, so testing more than once is often useful; and (iii) a low elastase alone does not prove EPI is present (it needs to be in the correct clinical setting). In a systematic review and metaanalysis of FE- 1, the sensitivity is 0.96 (95% CI: 0.79–0.99) and specificity 0.88 (95% CI: 0.59–0.97) compared to fecal fat measurement[26]. The wide confidence intervals are noteworthy, and in a low prevalence population (EPI is present in <5% of the population) the test has a substantial false positive rate. A number of clinical conditions have been associated with low levels of FE-

1. In particular, as mentioned above, long- standing diabetes is associated with reduction in pancreatic weight and volume and a decreased FE- 1, but interestingly not often with abnormal fat digestion and EPI[18,19].

There have been proposals to define stages of increasing severity of EPI [3,23]. In one proposal [23], mild EPI is defined as the reduction in secretion of one digestive enzyme without steatorrhea, moderate EPI as a reduction in both digestive enzymes and bicarbonate without steatorrhea, and severe EPI as the presence of steatorrhea. This categorization requires measurement of pancreatic digestive enzyme and bicarbonate output, which is not feasible for clinical use. A second proposal[3] suggests four stages, based on FE- 1 levels, the presence of symptoms, fat- soluble vitamin levels, and the CFA. In this proposal, only those with a CFA < 85% would receive PERT therapy. As in the first proposal, CFA is only very rarely available and so these staging systems are helpful as frameworks but do not have much current utility to clinicians.

Accurate diagnosis of EPI can be challenging, but begins with a clinical assessment of symptoms that might be consistent with the syndrome, such as weight or muscle mass loss, diarrhea, steatorrhea, or increased bloating and flatulence in a patient at risk of possible EPI. Measurement of baseline nutritional markers in these patients (see Chapter53) is also appropriate, and low levels of fat- soluble vitamins can support the diagnosis of EPI. Fecal elastase testing is the next step, with the caveats noted above. Ultimately, a presumptive diagnosis of EPI is made by the clinician, taking into account the clinical setting and ancillary tests, but without a gold- standard test to confirm the clinical impression. A final diagnostic approach merits mention— a therapeutic trial of PERT. There is no standardized approach to determine the degree of clinical symptom improvement needed for a therapeutic trial, and the specificity of these improvements, hence it is not usually helpful in deciding on the presence of EPI.

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