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Management withPERT 439

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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Management withPERT

When enzyme replacement therapy is initiated, a number of important principles must be followed. The normal pancreas produces around 900,000 USP units of lipase with each meal (more than 12,000 units/kg/meal in an average- sized adult). As noted above, a rule of thumb is that approximately 10% of normal pancreatic enzyme secretion can avoid steatorrhea (and presumably the associated nutritional consequences). That would suggest that a typical- sized adult would need 90,000 USP units per meal. Also as noted above, there are alternative and compensatory mechanisms for nutrient absorption, and the pancreas may still be producing some enzymes. In many practice guidelines, a starting dose of 40,000– 50,000 USP units of lipase per meal is suggested[1,2,20,23,24]. Typically, half this amount is taken with snacks. It is entirely appropriate to allow the patient to titrate the dose to the relative fat content of the meal. The enzymes need to be delivered during the meal, to achieve maximal mixing. The enzyme products can also be prescribed in a weightticularly appropriate for infants and children[27].

The enzymes should be taken during the meal or snack, for maximal mixing with the meal. In practice, taking some of the pills during the meal and some with the last bite is often suggested. Many patients do not receive clear instructions on how to take the PERT.

In the United States, five products are currently available (Table54.2). These are of variable potency, and by convention the products are identified by their lipase content. All are of porcine origin. With the exception of one, all are enteric coated and release their enzyme contents at approximately pH 5.5 or greater. In patients with chronic pancreatitis, diminished bicarbonate secretion may acidify the duodenum and proximal jejunum, and delay the release of these enzymes. Some studies, but not all, have noted increased proximal release of enzymes when acid-

suppressing medications (proton pump inhibitor, or H2 receptor antagonist) are also utilized. These are not routinely required when using these enteric- coated formulations, but can be added when response is less than optimal [23]. When using a nonenteric coated product, an acid- reducing medication is required to prevent acid denaturation of the enzymes.

In systematic reviews and meta- analyses of PERT therapy[28,29] in chronic pancreatitis, it is noteworthy that PERT improves but does not normalize fat digestion. The CFA improves from a baseline of 63–67%, to around 83%. Simply put, the current PERT products are not as effective as a normal pancreas. PERT therapy does improve symptoms such as steatorrhea, weight loss, and postprandial bloating and gas. PERT improves quality of life and various nutritional parameters in patients with chronic

based algorithm, which is par-

Table54.2 Enzyme products currently available inthe United

States.

Lipase content/

Product Formulation

Creon® Enteric- coated porcine 3000, 6000, 12000,

Pancreaze® Enteric-

Zenpep® Enteric-

Pertzye® Enteric-

Viokace® Non-

coated porcine 2600, 4200, 10500,

coated porcine 3000, 5000, 10000,

coated porcine

with bicarbonate

enteric coated

porcine

capsule or pill

24000, 36000

16800, 21000

15000, 20000, 25000, 40000

4000, 8000, 16000, 24000

10440, 20880

pancreatitis[1,23,30]. Similar improvements are seen in those with EPI due to pancreatic cancer[30,31]. Limited data support some modest reduction in mortality with the use of PERT as well. These benefits are substantial, but a number of barriers exist preventing the appropriate use of PERT therapy. First and foremost, the lack of a widely available and accurate diagnostic test hampers the ability to identify patients who would benefit.

Many patients with diseases causing EPI are not identified, and many are not treated with adequate dosage. In one survey of 91 European patients with previous pancreatic surgery, the median dosage of lipase was 50,000 U/ meal, but many were on half this dose and the majority had ongoing steatorrhea despite therapy[32]. In a second survey of patients with EPI due to chronic pancreatitis, the median starting dose was 25,000 U/meal, and the majority of patients had ongoing steatorrhea or weight loss[33]. In a large US administrative database[34], only

6.5% of patients with chronic pancreatitis were tested for EPI and only 10% received a PERT prescription of a minimally effective dosage. Only 2% of pancreatic cancer patients had testing for EPI, and only 5% received a prescription for a minimally effective dosage. Taken together, these studies demonstrate that even those at high risk of EPI are infrequently tested and infrequently treated for EPI. An additional impediment to appropriate use of PERT, at least in some countries, is the cost. In the USA, no generic products are available, and the cost without insurance may approach $2000/monthly. In the USA, at least one- third of PERT prescriptions are never filled, likely due to cost.

There are a variety of dietary recommendations[1,2,20,24], but limited science to support these. It is generally recommended to follow a relatively low- fat diet, but very low- fat diets put the patient at risk of fatsoluble vitamin deficiency. Many pancreatologists do

Exocrine Pancreatic Insufficiency

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440

not restrict lipids. Smaller, more frequent meals are also often recommended. A diet rich in complex carbohydrates, low in insoluble fiber, and containing at least

1.5 gm/kg of protein daily is commonly recommended.

Failure toRespond toPERT Therapy

Effective therapy with PERT should stop steatorrhea, allow gain of weight and muscle mass, and correct deficiencies of vitamins and trace elements. EPI is associated with a number of common nutritional consequences, including sarcopenia, weight loss, fat- soluble vitamin deficiency, and osteopenia and osteoporosis, to name just a few. These are discussed in Chapters53 and 55. Adequate PERT therapy is defined by improvement, and hopefully normalization, in these clinical and laboratory features and nutritional consequences. Although measuring the improvement in digestion on PERT with a fecal fat analysis or breath test would be useful to gauge the adequacy of PERT therapy, this is rarely possible. Measuring fecal elastase provides no information on the effectiveness of therapy. The most common reason for failure of PERT is an inadequate dose. As noted above[32–34], this is an exceedingly common problem, likely due to a lack of knowledge in medical professionals writing the prescription. Providing an appropriate dosage, and reinforcing the timing of the PERT is the first step in patients who do not seem to be responding as expected to PERT. In patients who are not responding, increasing the dosage to 90,000 higher) is appropriate as an initial step [23]. In some patients, lipase may be inactivated by gastric acid (a

U/meal (or sometimes

common issue with the uncoated tablets). Some data demonstrate that acid-

reducing medications might allow more proximal release of digestive enzymes from entericcoated preparations as well, and this is recommended for nonresponders in some guidelines[23].

In those who do not respond despite appropriate dosage and timing, consideration should be given to alternative diagnoses. The most common is small intestinal bacterial overgrowth (SIBO), with symptoms and features that are indistinguishable from EPI. In one systematic review, SIBO can be found in 36% of patients with chronic pancreatitis[35]. This is even more common in those with EPI after gastrointestinal surgery [36]. The reason that SIBO is so common is not known, but could reflect a reduction in bactericidal effect of pancreatic digestive enzymes, side effect of opioid therapy, or associated diabetes with enteral neuropathy. Breath testing for SIBO, or empiric antibiotic treatment, can be considered in those who do not respond as anticipated to PERT. In those who do not respond to PERT and have significant weight loss, consideration can also be given to a secondary pancreatic or extrapancreatic malignancy, or to other causes of malabsorption or maldigestion unrelated to the pancreatic disease (e.g., celiac disease).

EPI is common in patients with benign and malignant pancreatic diseases, and in those with previous pancreatic surgery. Appropriate management requires an understanding of compensatory mechanisms that allow digestion and absorption despite EPI, the lack of an accurate diagnostic test, the appropriate dosage and timing of PERT, and the ongoing management of the variety of nutritional consequences of EPI.

References

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PancreasFest Joint Symposium on Exocrine Pancreatic Insufficiency. Gastro Hep Adv 2023, https://doi.org/10.1016/ j.gastha.2022.11.008.

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5 Layer P, Yamamoto H, Kalthoff L etal. The different

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6 Lankisch PG, Lohr- Happe A, Otto J etal. Natural course

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8 Tseng DSJ, Molenaar Q, Besselink MG etal. Pancreatic

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9 Iglesia D, Avci B, Kiriukova M etal. Pancreatic exocrine

insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: a systematic review and meta- analysis. United European GastroenterolJ2020;8:1115–1125.

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insufficiency after pancreatectomy for malignancy: systematic review and optimal management recommendations. J Gastrointest Surg 2021;25:2317–2327.

12 Uribarri- Gonzalez L, Nieto- Garcia L, Martis- Sueiro A

etal. Exocrine pancreatic function and dynamic of digestion after restrictive and malabsorptive bariatric surgery: a prospective, cross-

sectional, and comparative

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Pancreatic exocrine insufficiency following acute pancreatitis: systematic review and study level metaanalysis. Pancreatology 2018;18:253–262.

14 Vujasinovic M, Tepes B, Makuc J etal. Pancreatic exocrine

insufficiency, diabetes mellitus and serum nutritional markers after acute pancreatitis. World J Gastroenterol 2014;20:18432–18438.

15 Tu J, Zhang J, Ke L etal. Endocrine and exocrine

pancreatic insufficiency after acute pancreatitis: long-

up study. BMC Gastroenterol 2017;17:114.

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term

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PM. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol 2017;23:7059–7076.

18 Mohaptra S, Majmunder S, Smyrk TC etal. Diabetes

mellitus is associated with an exocrine pancreatopathy. Conclusions from a review of the literature. Pancreas 2016;45:1104–1110.

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Relative pancreas volume is reduced in first-

degree relatives of patients with type 1 diabetes. Diabetes Care 2019;42:281–287.

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Pancreatitis Study Group et al. Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study. Pancreatology 2022;22(4):457–465.

21 Dominguez- Munoz JE, Iglesias- Garcia J, Vilarino- Insua M,

Iglesias-

Rey M.

C- mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2007;5:484–488.

22 Keller J, Hammer HF, Afolabi PR etal. European guideline

on indications, performance, and clinical impact of

C- breath tests in adult and pediatric patients: an EAGEN, ESNM, and ESPGHAN consensus supported by EPC. United European Gastroenterol J 2021;9:598–625.

23 Lohr JM, Dominguez- Munoz E, Rosendahl J etal. United

European Gastroenterology evidence- based guidelines for the diagnosis and therapy of chronic pancreatitis

(HaPanEU). United European Gastroenterol J 2017;5:153–199.

24 Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor

JR, Whitcomb DC. ACG clinical guideline: chronic pancreatitis. Am J Gastroenterol 2020;115:322–339.

25 Toth AZ, Szabo A, Hegyi E etal. Detection of human elastase

isoforms by the ScheBo pancreatic elastase 1 test. Am J Physiol Gastrointest Liver Physiol 2017;312:G606–G614.

26 Vanga RR, Tansel A, Sidiq S, El- Serag HB, Othman MO.

Diagnostic performance of measurement of fecal elastaseinsufficiency: systematic review and meta-

1in detection of exocrine pancreatic

analysis. Clin

Gastroenterol Hepatol 2018;16:1220–1228.

27 Freeman AJ, Maqbool A, Bellin MD etal. Medical

management of chronic pancreatitis in children: a position paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee. JPGN 2021;72:324–340.

28 Waljee AK, Dimagno MJ, Wu BU etal. Systematic review:

pancreatic enzyme treatment of malabsorption associated with chronic pancreatitis. Aliment Pharmacol Ther 2009;29:235–246.

29 De la Iglesia- Garcia D, Huang W, Szatmary P etal. Efficacy

of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta- analysis. Gut 2017;66:1474–1486.

30 Layer P, Kashirskaya N, Gubergrits N. Contribution of

pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency. World J Gastroenterol 2019;28:2430–2441.

31 Ropeyen G, Berrevoet F, Borbath I etal. Expert opinion on

management of pancreatic exocrine insufficiency in pancreatic cancer. ESMO Open 2022;7(1):100386.

32 Sikkens EC, Cahen DL, van Eijck C etal. Patients with

exocrine insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. Pancreatology 2012;12:71–73.

33 Sikkens EC, Cahen DL, van Eijck C etal. The daily practice

of pancreatic enzyme replacement therapy after pancreatic surgery: a northern European survey: enzyme replacementafter surgery. J Gastrointest Surg 2012;16:1487–1492.

34 Forsmark CE, Tang G, Xu H etal. The use of pancreatic

enzyme replacement therapy in patients with a diagnosis of chronic pancreatitis and pancreatic cancer in the US is infrequent and inconsistent. Aliment Pharmacol Ther 2020;51(10):958–967

35 Capurso G, Signoretti M, Archibugi L etal. Systematic

review and meta-

analysis: small intestinal bacterial overgrowth in chronic pancreatitis. United European Gastroenterol J 2016;4:697–705.

36 DiMagno MJ, Forsmark CE. Chronic pancreatitis and

small intestinal bacterial overgrowth. Pancreatology 2018;18:360–362.

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Bone Disease inChronic Pancreatitis

Sinead N. Duggan

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

Introduction

Patients with chronic pancreatitis have a higher- thannormal risk of developing low bone mineral density (BMD) and osteoporosis[1]. Osteoporosis is characterized by compromised bone strength cause by bone mass loss and bone quality deterioration, resulting in increased fracture risk [2]. In patients with chronic pancreatitis, the high prevalence of osteoporosis translates into a higher prevalence of low- trauma (fragility) fractures compared to healthy controls[3,4]. The etiology of osteoporosis in chronic pancreatitis is multifactorial; low serum 25(OH)D, suboptimal dietary intake, heavy smoking, low physical activity, chronic inflammation, and malabsorption are all likely to contribute[5,6]. Patients with chronic pancreatitis develop osteoporosis despite the absence of additional risk factors (such as long- term steroid use or hypogonadism) that drive bone demineralization in other gastrointestinal conditions [7]. The economic cost of osteoporosis and fracture is considerable. Hip fractures are associated with an 8–36% increase in mortality within 1 year, and approximately a fifth of patients with hip fracture require long-

term nursing care[2,8]. By 2025, in the United States, it is projected that there will be greater than three million fractures annually costing more than $25 billion per year[2].

Measures ofBone Density andBone Metabolism

DXA is considered the clinical gold standard for the measurement of bone mass[9]. DXA works by generating an image of bone mineral content (BMC, g calcium) when the X- ray tube is scanned over the area of interest. Software uses an algorithm to yield BMD (g/cm2) from

BMC and bone area (cm

)[10]. Absolute measurements of BMD are of little value, as they are determined by the site of measurement, the calibration used by the manufacturer and the particular instrument[10]. BMD deteriorates with age; therefore, age- related changes need to be considered. Because of machine and skeletal site differences, BMD results are noted by a derived statistical value, the T- score. Bone density measurements follow a Gaussian distribution, and therefore are described as the number of standard deviations (SD)[11] from the mean for normal controls. Therefore, the T- score is not an absolute value, but the number of SD above or below the BMD average value in young healthy adults[11] (representing “peak bone mass”). For example, a T- score of

- 2.5 indicates that an individual’s BMD is 2.5 SD below (young adult) average. Bone density is divided into several categories: normal (T- score >- 1), osteopenia (T- score - 1 to - 2.5), and osteoporosis (T- score <- 2.5).

Although DXA is the primary diagnostic tool for bone health assessment[12], it is limited by the fact that bone mineral density changes so slowly that DXA is not always suitable for monitoring the effects of treatment. Bone remodeling in the adult skeleton is a dynamic and continuous process with a tightly coupled balance between resorption of old micro-

damaged bone and formation of new bone. The bone remodeling cycle is a coordinated action between osteoclasts (bone resorption cells) and osteoblasts (bone formation cells), and an imbalance of either formation or resorption can lead to substantial deterioration in bone strength over time. Biochemical markers of bone metabolism (bone turnover markers, BTM) can provide an accurate, noninvasive assessment of bone formation, resorption, and turnover. BTM include serum carboxy- terminal telopeptide of type I collagen (CTX- I) for bone resorption and serum procollagen 1 amino- terminal propeptide

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

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(P1NP) and osteocalcin for bone formation [5,13]. In chronic pancreatitis, the chronic inflammatory state (characterized by high levels of proinflammatory cytokines) is associated with higher bone turnover [7]. Therefore, in addition to DXA, these measures of bone activity may have a role in the overall management of bone health in chronic pancreatitis.

The Risk ofDeveloping Osteoporosis andFracture inChronic Pancreatitis

In the only meta- analysis on this topic to date (published in 2014), two- thirds (65%) of 513 patients who had undergone dual X- ray absorptiometry (DXA) had osteoporosis or osteopenia[1]. Only two of the included studies were controlled, with osteoporosis prevalence among healthy controls of 8.6–10.2% [14,15]. These findings have been largely corroborated by more recent reports confirming that most patients with chronic pancreatitis have either osteoporosis or osteopenia[16–18], although in the first report from China, just over a third of those with chronic pancreatitis had low BMD [19]. Importantly, low BMD translates into a real risk of lowtrauma fracture. A US study[4] reported that the risk of fracture in chronic pancreatitis (4.8%) was similar (or higher), than in other gastrointestinal disorders such as celiac disease (5%), Crohn’s disease (3%), postgastrectomy (5.4%) or cirrhosis (4.8%). The rate among healthy controls was 1.1%. Similarly, a European study[3] reported a higher fracture rate among chronic pancreatitis compared to controls (adjusted hazard ratio of 1.7 [95% CI: 1.6, 1.8]).

Management

Given that osteoporosis is costly and largely preventable— coupled with the lack of clinical trials investigating

treatments for osteoporosis in chronic pancreatitis— clinicians must focus on prevention[6,20]. The high risk of developing osteoporosis dictates that basic preventative measures should be advised for all chronic pancreatitis patients. Although some risk factors are nonmodifiable (increasing age, female sex, history of previous low- trauma fracture, and family history of osteoporosis), the modifiable risk factors should be addressed [5]. This includes correcting poor diet (particularly adequate calcium and vitamin D intake), recognizing and treating malabsorption with adequate pancreatic enzyme replacement therapy, preventing/ treating underweight body mass index, ensuring regular weight- bearing exercise, and emphasizing the importance of smoking and alcohol avoidance for bone health. Vitamin D supplementation may be required to optimize levels of serum 25(OH)D, and safe sunshine exposure should also be encouraged. According to the HaPanEU guidelines [20], all patients with chronic pancreatitis should undergo regular serum 25(OH)D assessment and a baseline DXA at diagnosis, with a follow- up DXA every 2 years. Particular attention should be given to those at higher risk including post- menopausal women, those who have had previous low- trauma fractures, men >50 years, and those with malabsorption.

For those with confirmed osteoporosis (or who have vertebral fractures), appropriate osteoporosis medication such as bisphosphonates should be prescribed (although the lack of published interventional studies on therapeutic agents for osteoporosis in chronic pancreatitis constitutes a critical research gap). As well as ensuring that the basic measures for bone health (described above) are implemented, referral to a bone specialist is highly recommended. In the United States, there is evidence that pancreas specialists are more likely than primary care physicians or gastroenterologists to address bone health [21], therefore ongoing education, awareness campaigns, and promotion of bone health for chronic pancreatitis is vital.

References

1 Duggan SN, Smyth ND, Murphy A, Macnaughton D, O’Keefe

SJ, Conlon KC. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and metaanalysis. Clin Gastroenterol Hepatol 2014;12(2):219–228.

2 Cosman F, de Beur SJ, LeBoff MS etal. Clinician’s guide to

prevention and treatment of osteoporosis. Osteoporos Int 2014;25(10):2359–2381.

3 Bang UC, Benfield T, Bendtsen F, Hyldstrup L, Beck Jensen

JE. The risk of fractures among patients with cirrhosis or chronic pancreatitis. Clin Gastroenterol Hepatol 2014;12(2):320–326.

4 Tignor AS, Wu BU, Whitlock TL etal. High prevalence of

low- trauma fracture in chronic pancreatitis. Am J Gastroenterol 2010;105(12):2680–2686.

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endocrine dysfunction in chronic pancreatitis. Proc Nutr Soc 2017;76(4):484–494.

6 Duggan SN, Conlon KC. Bone health guidelines for patients

with chronic pancreatitis. Gastroenterology 2013;145(4):911.

7 Duggan SN, Purcell C, Kilbane M etal. An association

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11 Katz S, Weinerman S. Osteoporosis and gastrointestinal

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scans in the diagnosis and treatment of osteoporosis. Postgrad Med J 2007;83(982):509–517.

13 Ghishan FK, Kiela PR. Advances in the understanding of

mineral and bone metabolism in inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 2011;300(2):G191–201.

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Ridgway PF, Conlon KC. Patients with chronic pancreatitis are at increased risk for osteoporosis. Pancreas 2012;41(7):1119–1124.

15 Joshi A, Reddy SV, Bhatia V etal. High prevalence of low

bone mineral density in patients with tropical calcific pancreatitis. Pancreas 2011;40(5):762–777.

16 Hart PA, Yadav D, Li L etal. High prevalence of

osteopathy in chronic pancreatitis: a cross-

sectional analysis from the PROCEED study. Clin Gastroenterol Hepatol 2022;20(9):2005–2013.

17 Stigliano S, Waldthaler A, Martinez- Moneo E etal.

Vitamins D and K as factors associated with osteopathy in chronic pancreatitis: a prospective multicentre study (P-

BONE study). Clin Transl Gastroenterol

2018;9(10):197.

18 Vujasinovic M, Nezirevic Dobrijevic L, Asplund E etal.

Low bone mineral density and risk for osteoporotic fractures in patients with chronic pancreatitis. Nutrients 2021;13(7).

19 Tang XY, Ru N, Li Q etal. Prevalence and risk factors for

osteopathy in chronic pancreatitis. Dig Dis Sci 2021;66(11):4008–4016.

20 Lohr JM, Dominguez- Munoz E, Rosendahl J etal. United

European Gastroenterology evidence-

based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J 2017;5(2):153–199.

21 Srivoleti P, Yang AL, Jin DX, Banks PA, McNabb- Baltar J.

Does provider type affect bone health surveillance in chronic pancreatitis? Dig Dis Sci 2021;66(7):2235–2239.

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Diabetes fromExocrine Pancreatic Disease

Nao Fujimori1, Tetsuhide Ito

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Neuroendocrine Tumor Centre, Fukuoka, Sanno Hospital, Fukuoka, Japan

Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Fukuoka, Japan

2,3

, and Yoshihiro Ogawa

445

Introduction

Pancreatic diseases frequently induce not only pancreatic exocrine insufficiency (PEI) but also endocrine impairment, which result in the development of diabetes mellitus. Diabetes from exocrine pancreatic disease, namely, pancreatic diabetes or type 3c diabetes, is categorized as secondary diabetes that is associated with various pancreatic diseases, such as acute or chronic pancreatitis and pancreatic cancer, as well as pancreatic resection[1–9]. Although type 1 diabetes and type 2 diabetes are well studied, research on pancreatic diabetes is limited, and its characteristics remain unclear. Sustained inflammation and fibrotic change due to pancreatic diseases lead to β- cell loss and reduced insulin secretion, and this is the most common pathogenesis of pancreatic diabetes. In addition, the levels of pancreatic counterregulatory hormones, such as glucagon, are decreased in these patients. Malnutrition resulting from PEI should also be monitored. Therefore, recognizing the differences between pancreatic diabetes and other types of diabetes is very important to achieve good glycemic control and ensure an appropriate quality of life in patients with pancreatic diabetes.

Definition, Prevalence, andEtiology ofPancreatic Diabetes

The American Diabetes Association (ADA) categorizes pancreatic diabetes as a “specific type of diabetes due to other causes” and distinct from type 1, type 2, and gestational diabetes. Pancreatic diabetes includes both structural and functional loss of glucose- normalizing insulin

secretion due to pancreatic exocrine dysfunction [1]. It has been called “type 3c diabetes” that is derived from diverse etiologies including pancreatitis (acute, chronic, or hereditary), pancreatic trauma, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, and fibrocalculous pancreatopathy. However, the most common cause of pancreatic diabetes is chronic pancreatitis. In routine clinical practice, patients with pancreatic diabetes have been misdiagnosed as having type 2 diabetes.

The prevalence of pancreatic diabetes among all types of diabetes in Western populations has been reported to be 5–10%[4,6]. Ewald etal.[10] studied 1868 patients diagnosed as having diabetes over a 2-

year period and reported that 172 of these patients (9.2%) could be classified as having pancreatic diabetes. In contrast, a nationwide survey in Japan revealed that patients with true pancreatic diabetes (newly developed diabetes associated with pancreatic disease) who received treatment in 2005 accounted for only 0.8% of all patients with diabetes [11]. A more recent large retrospective cohort study from England revealed 559 out of 31,789new diagnoses of adult-

onset diabetes were cases of diabetes following pancreatic disease (1.8%) [12]. Although the prevalence of pancreatic diabetes differs among studies, clinicians should always consider the possibility of pancreatic diabetes when they first make a diagnosis of diabetes. If the accurate diagnosis of pancreatic diabetes and prognosis of pancreatic disease improve, the prevalence of pancreatic diabetes may increase in the future.

Chronic pancreatitis has been well recognized as a major cause of pancreatic diabetes, but a cohort study in New Zealand found that acute pancreatitis is the most frequent preceding disease. In that study, acute pancreatitis

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accounted for 61% of the overall prevalence of diseases of the exocrine pancreas [13]. In another study by Ewald et al. [10], the underlying pancreatic diseases included chronic pancreatitis (78.5%), pancreatic cancer (8.1%), hereditary hemochromatosis (7.0%), and cystic fibrosis (4.1%), as well as pancreatic resection (2.3%). Ito etal.[11] reported that the causal factors of pancreatic diabetes were chronic pancreatitis (40.0%), pancreatic cancer (24.6%), pancreatectomy (10.2%), acute pancreatitis (7.5%), and autoimmune pancreatitis (6.1%).

Patients with chronic pancreatitis frequently have diabetes as a comorbidity, even though its occurrence varies widely from 5% to >80% [2,14–16]. In a study conducted in the United States, 383 out of 1171 patients (32.7%) with chronic pancreatitis had diabetes [17]. A multicenter Italian survey also reported endocrine insufficiency in 31% of patients with chronic pancreatitis[18]. The duration of chronic pancreatitis is a well- known and significant risk factor for the development of diabetes. A large- scale study from China that included 1633 patients revealed a cumulative rate of diabetes mellitus of 21.7% at 10 years after the diagnosis of chronic pancreatitis[19]. In a follow up survey of patients with chronic pancreatitis without diabetes, 121 of 418 patients (28.9%) were newly diagnosed as having diabetes over a period of 8 years[20]. A recent nationwide epidemiological survey of chronic pancreatitis in Japan also showed that patients with advanced- stage chronic pancreatitis (definite/probable cases) had a higher proportion of diabetes than did those with early- stage chronic pancreatitis (42.3% vs.

19.3%) [21]. A systematic review and meta- analysis involving 8970 patients from 15 studies reported that the incidence of new- onset diabetes after chronic pancreatitis diagnosis was 30%. The prevalence of newly diagnosed diabetes was 15% within 36months, and it increased to 33% after 60months from the diagnosis of chronic pancreatitis[22]. Therefore, the prevalence of pancreatic diabetes and chronic pancreatitis as an underlying disease seems far underestimated because many patients with diabetes do not undergo any evaluation of pancreatic exocrine diseases and many patients with chronic pancreatitis do not undergo any evaluation of diabetes.

Alcohol consumption was the most common cause of chronic pancreatitis, and it accounted for 72.0% of cases in a recent nationwide survey in Japan[21]. Ito etal. also reported that alcohol consumption was the main causal factor for chronic pancreatitis in patients with pancreatic diabetes (77.3%, 231/299)[11]. In a long- term study of 2037 patients with chronic pancreatitis, 28.8% (587/2037) developed diabetes during a median follow up period of 7.6 years [24]. Furthermore, the development of diabetes was significantly earlier and more common in alcoholic chronic pancreatitis than in idiopathic chronic pancreatitis. The cumulative rates of diabetes development at 10 years after the onset of chronic pancreatitis was 29.7% and 21.7% in patients with alcoholic and idiopathic chronic pancreatitis, respectively.

Smoking is another important factor associated with the development of diabetes in chronic pancreatitis. Many reports have documented a relationship between smoking and the progression of chronic pancreatitis [21,25–29], which is inevitably associated with the development of diabetes. Maisonneuve et al. reported that smoking was associated with a significant increase in the risk of developing diabetes (hazard ratio, 2.3) after the diagnosis of pancreatitis [26]. Therefore, patients with chronic pancreatitis and diabetes should take steps to improve their lifestyle via abstinence from alcohol and smoking cessation.

Pancreatic calcification is a key finding in the diagnosis of chronic pancreatitis and is involved in disease progression. Several studies have revealed a correlation between pancreatic calcification and the development of diabetes[7,20,23,30]. The risk of diabetes increased 1.32fold after the onset of pancreatic calcification [20]. A study from China also revealed pancreatic calcification as a risk factor for the development of diabetes mellitus (hazard ratio, 2.326) [30]. Therefore, it is important to recognize pancreatic calcification not only as an indicator of advanced chronic pancreatitis (exocrine insufficiency) but also as an indicator of impaired pancreatic endocrine function.

Clinical Characteristics ofPancreatic Diabetes

Risk Factors forthe Development of Diabetes inChronic Pancreatitis

The risk factors for diabetes in patients with chronic pancreatitis include alcohol consumption, smoking, and pancreatic calcification, which are also the risk factors for the progression of chronic pancreatitis[11,21,23,24].

Pancreatic diabetes is characterized by the impaired synthesis and secretion of insulin from β cells and glucagon from α cells because of primary pancreatic diseases [20]. Furthermore, PEI resulting from the decreased secretion or outflow obstruction of pancreatic juice induces the impaired absorption of glucose. Since the degree of impairment in pancreatic endocrine and exocrine functions differs in each patient,

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the pathophysiology and treatment of pancreatic diabetes are complicated. Pancreatic diabetes is also known as “brittle diabetes” because the fluctuations in blood glucose levels result in unstable glycemic control.

Recently, Fukuda etal. reported that the incidence of diabetes was significantly higher in patients who underwent distal pancreatectomy than in those who underwent pancreatoduodenectomy despite no significant difference in the volume of the resected pancreas between the two groups[31]. They also revealed significant alterations in the gut microbiome and increased secretion of glucagon- like peptide- 1 (GLP- 1) in patients who underwent pancreatoduodenectomy, which possibly protected against the development of diabetes. This study shed light on the pathogenic mechanism of pancreatic diabetes, but further validation studies are warranted in the future.

Evaluation andDiagnosis ofPancreatic Diabetes

PEI

Patients with pancreatic diabetes, especially those with chronic pancreatitis, frequently have accompanying PEI, which results in some degree of fat malabsorption and malnutrition[16]. Severe PEI can lead to overt steatorrhea and weight loss that may decrease the quality of life of patients with pancreatic diabetes. Therefore, the evaluation of pancreatic exocrine function and appropriate pancreatic enzyme replacement therapy (PERT) are mandatory for these patients. Although accurate evaluation of PEI is difficult, diagnostic tests including the fecal elastase- 1 or N- benzoyl- - tyrosyl- p- aminobenzoic acid test are recommended if available [16]. Evaluating the patient’s symptoms, including abdominal bloating or discomfort, diarrhea, and weight loss, at each follow- up visit and performing blood tests, including those for hemoglobin, total protein, albumin, and total cholesterol levels, are important for the evaluation of PEI.

Diagnosis ofPancreatic Diabetes

As in other type of diabetes, pancreatic diabetes is diagnosed on the basis of plasma glucose (PG) levels and hemoglobin A1c (HbA1c) analysis. A fasting PG level ≥126 mg/dL, 2- h PG level ≥200 mg/dL during a 75- g oral glucose tolerance test (OGTT), random PG level ≥200 mg/dL, or HbA1c level ≥6.5% may indicate the presence of diabetes [1]. In patients with symptoms related to diabetes or those with significantly high PG levels, the OGTT should be avoided because of the

increased risk of hyperglycemia. The evaluation of insulin secretory capacity, such as by using the insulinogenic index (30min) calculated from a 75-

g OGTT test, fasting C- peptide immunoreactivity (CPR), 24- h urinary CPR, or ΔCPR after glucagon injection, is also important in pancreatic diabetes, as it could help differentiate “insulin- dependent” and “noninsulin- dependent” diabetes. Determining insulin dependence is essential for choosing the appropriate medical treatment.

Pancreatic diabetes is more common than expected, and patients with pancreatic diabetes are mostly misclassified as having type 2 diabetes owing to poor awareness of this type of diabetes [4]. Moreover, no specific diagnostic criteria are available for pancreatic diabetes. Hart etal. proposed conceptual diagnostic criteria for pancreatic diabetes, which included three components: fulfillment of the diagnostic criteria for diabetes, presence of a pancreatic exocrine disease, and diabetes that is reasonably certain to be secondary to pancreatic exocrine disease [2]. Ewald and Hardt [4] also proposed diagnostic criteria for pancreatic diabetes (type 3c diabetes mellitus) (Table56.1). The major criteria included the presence of exocrine pancreatic insufficiency, pathological pancreatic imaging findings, and absence of autoimmune markers associated with type 1 diabetes mellitus. However, distinguishing pancreatic diabetes from other types of diabetes is sometimes difficult because patients with long-

standing type 1 and type 2 diabetes frequently have accompanying PEI. Therefore, clinicians should always consider the possibility of diabetes when treating pancreatic exocrine diseases, such as chronic pancreatitis and pancreatic cancer, as well as the possibility of pancreatic exocrine diseases when treating diabetes.

Table56.1 Proposed diagnostic criteria for type 3c diabetes

mellitus[4].

Major criteria (must be present)

● Presence of exocrine pancreatic insufficiency (monoclonal

fecal elastase- 1 test or direct function tests)

● Pathological pancreatic imaging (endoscopic ultrasound,

MRI, CT)

● Absence of type 1 diabetes mellitus associated autoimmune

markers

Minor criteria

● Absent pancreatic polypeptide secretion

● Impaired incretin secretion (e.g., GLP- 1)

● No excessive insulin resistance (e.g., HOMA- IR)

● Impaired beta cell function (e.g., HOMA- B, C- Peptide/

glucose- ratio)

● Low serum levels of lipid soluble vitamins (A, D, E and K)

Source: Ewald and Hardt 2013[4], table2.

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Treatment ofPancreatic Diabetes

Lifestyle Improvement andManagement ofPEI

In patients with pancreatic diabetes, lifestyle correction through weight control in overweight patients, abstinence from alcohol, and smoking cessation should be considered as an initial treatment, as in patients with other types of diabetes. When chronic pancreatitis is the underlying cause of pancreatic diabetes, abstinence from alcohol and smoking cessation are especially important to prevent the progression of pancreatitis and achieve better glycemic control. Regarding dietary therapy, stereotypic energy restriction to improve glycemic control is not recommended as it exacerbates nutritional disorders due to PEI, which is frequently present in patients with pancreatic diabetes. The presence of PEI is of great importance, as this feature differentiates pancreatic diabetes from other types of diabetes. Patients with PEI diagnosed on the basis of symptoms, blood tests, and pancreatic exocrine function tests require adequate PERT and sufficient energy intake. The PG level is sometimes elevated after PERT; nevertheless, oral hypoglycemic agents or insulin therapies for patients with pancreatic diabetes should be considered together with appropriate PERT.

Insulin Therapy

Insulin therapy should be considered as the firsttreatment for patients with pancreatic diabetes and advanced stages of pancreatic exocrine diseases, such as chronic pancreatitis or pancreatic cancer, as well as for those who have undergone pancreatectomy[14], because these patients generally develop “insulin- dependent” diabetes. Intensive insulin therapy with long- acting insulin as a basal requirement and preprandial short- or ultra-

short- acting insulin for postprandial hyperglycemia are recommended for pancreatic diabetes because these mimic physiological insulin secretion and are helpful in preventing hypoglycemia[7,9,32]. Insulin dependence in pancreatic diabetes is similar to that in type 1 diabetes mellitus, and both conditions meet the absolute indication for insulin therapy. However, compared to type 1 diabetes, pancreatic diabetes shows more impaired secretion of counterregulatory hormones for hypoglycemia, including glucagon and pancreatic polypeptide. Therefore, fluctuations in blood glucose levels are frequently observed after the injection of small doses of insulin, and this makes it difficult to achieve good glycemic control in these patients. Niwano etal. recently compared the insulin requirement between patients undergoing total pancreatectomy (pancreatic diabetes)

line

and those with type 1 diabetes[33]. They found that the total daily insulin and basal insulin levels were significantly lower in patients undergoing total pancreatectomy than in those with type 1 diabetes. Even in the same “insulin-

dependent” condition, we should pay attention to hypoglycemia more carefully in patients with pancreatic diabetes than in those with type 1 or type 2 diabetes. When good glycemic control is difficult to achieve in pancreatic diabetes, an insulin pump (continuous subcutaneous insulin infusion) could be a treatment option [33]. Moreover, adjusting the insulin dose after the evaluation of pancreatic exocrine function and adequate PERT are very important.

Therapy withOther Hypoglycemic Agents

The degree of insulin deficiency and insulin resistance varies with disease severity and duration[34]. Therefore, as in patients with type 2 diabetes, those with pancreatic diabetes who have not undergone total pancreatectomy and are not “insulin- dependent” can be administered oral hypoglycemic agents. Metformin, which is widely used in patients with type 2 diabetes and insulin resistance, is associated with a decreased risk of various cancers, including pancreatic cancer[35]. Therefore, some studies preferred metformin as the first- line treatment for pancreatic diabetes [2,16,34]; nevertheless, further validation of the effect of metformin is required. Insulin secretory agents, such as sulfonylureas and glinides, are also treatment options in patients with preserved insulin secretory capacity. However, the efficacy of incretinbased therapy using dipeptidyl peptidase- 4 inhibitors and GLP- 1 analogs, which also enhance insulin secretion, for pancreatic diabetes has been controversial [9,14,36]. Moreover, the tendency has been to refrain from these drugs owing to a possibility of pancreatitis[34], but several recent reports have demonstrated no relationship between incretin-

based therapy and pancreatitis or pancreatic cancer[37–39]. Nevertheless, GLP- 1 analogs have been associated with a high frequency of gastrointestinal symptoms as side effects [34]. Sodium- glucose cotransporter 2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption and increase urinary glucose excretion [40], have recently been widely used in patients with diabetes. SGLT2inhibitors may be a treatment option because of their insulin- independent action; however, their side effects include weight loss, which should be considered in patients with pancreatic diabetes. A recent study showed no significantly increased risk of acute pancreatitis associated with the use of SGLT2inhibitors[41]. Although evidence regarding oral hypoglycemic agents for pancreatic diabetes is scarce, clinicians should select

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