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Tests of pancreatic exocrine function


Best Practice & Research Clinical Gastroenterology 23 (2009) 425–439

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Best Practice & Research Clinical Gastroenterology

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Tests of pancreatic exocrine function – Clinical signi?cance in pancreatic and non-pancreatic disorders
Jutta Keller, MD, Head of Laboratory for Performance of GI Function Test a, Ali Alexander Aghdassi, MD, Assistant Doctor/Resident Physician b, Markus M. Lerch, MD, Professor of Medicine, Director of the Medical Clinic A b, Julia V. Mayerle, MD, Professor of Medicine b, Peter Layer, MD a, *
a b

Department of Medicine, Israelitisches Krankenhaus, Hamburg, Germany ¨ Department of Medicine A, Ernst-Moritz-Arndt Universitat Greifswald, Germany

Keywords: pancreatic insuf?ciency steatorrhoea pancreatic enzyme secretion pancreatic function test elastase-1 secretin–caerulein test 13 C-breath test

The pancreas functions as the main factory for digestive enzymes and therefore enables food utilisation. Pancreatic exocrine insuf?ciency, partial or complete loss of digestive enzyme synthesis, occurs primarily in disorders directly affecting pancreatic tissue integrity. However, other disorders of the gastrointestinal tract, such as coeliac disease, in?ammatory bowel disease, ZollingerEllison syndrome or gastric resection can either mimic or cause pancreatic exocrine insuf?ciency. The overt clinical symptoms of pancreatic exocrine insuf?ciency are steatorrhoea and maldigestion, which frequently become apparent in advanced stages. Several direct and indirect function tests are available for assessment of pancreatic function but until today diagnosis of excretory insuf?ciency is dif?cult as in mild impairment clinically available function tests show limitations of diagnostic accuracy. This review focuses on diagnosis of pancreatic exocrine insuf?ciency in pancreatic and non-pancreatic disorders. ? 2009 Elsevier Ltd. All rights reserved.

Introduction For centuries the pancreas was a terra incognita hidden behind the stomach and its pathophysiological role remained in the dark. Only in 1761 Jean-Baptista Morgagni described in his book ‘‘de sedibus

* Corresponding author. Israelitic Hospital, University of Hamburg, Orchideenstieg 14, 22297 Hamburg, Germany. Tel.: ?49 40 51125 5001; Fax ?49 40 51125 5009. E-mail address: layer@ik-h.de (P. Layer). 1521-6918/$ – see front matter ? 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.02.013

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et causis morborum’’ the ?rst case of chronic pancreatitis and it took 60 more years until Kuntzmann was able to connect fatty stool to diseases of the organ. Exocrine insuf?ciency usually results from reduced enzyme synthesis and secretion of the pancreatic juice which consists of a mixture of diverse proteases, lipase, amylase and bicarbonate, or from impaired enzyme function [1,2]. However, other mechanisms may also cause or contribute to pancreatic exocrine insuf?ciency (Table 1). Usually, clinically overt symptoms such as steatorrhoea and weight loss occur late in the clinical course of pancreatic disease as the exocrine pancreas has a high reserve capacity and symptoms arise only when functional reserve is spent by 90% [3]. Recognition of exocrine insuf?ciency is highly important to avoid complications of maldigestion with its related morbidity and mortality. Pancreatic exocrine insuf?ciency Pathophysiology and clinical symptoms Steatorrhoea and azotorrhoea, an excessive discharge of nitrogenous substances in the feces, occur when secretion of lipase and trypsin fall below 5–10% of normal levels. In chronic pancreatitis, fat malabsorption develops earlier than malabsorption of proteins or carbohydrates. This is due to an earlier decrease in lipase secretion compared with amylase and proteases [5], higher susceptibility of lipase to acidic pH caused by concomitant impairment of bicarbonate secretion, higher susceptibility of lipase to proteolytic destruction during small intestinal transit, additional acidic denaturation of bile acids and marked inhibition of bile acid secretion in malabsorptive states [6]. Moreover, gastric lipase, the only extrapancreatic source of lipolytic activity in humans, does not compensate for pancreatic lipase de?ciency ef?ciently although it may be elevated in patients with chronic pancreatitis compared to healthy individuals [7]. By contrast, more than 80% of carbohydrates can be digested and absorbed in the absence of pancreatic amylase activity [8] and the colonic ?ora can further metabolise malabsorbed carbohydrates. In consequence, stools usually do not contain carbohydrates [8]. In Western countries steatorrhoea is diagnosed when daily stool fat content exceeds 7 g during ingestion of a diet containing 100 g fat per day. This corresponds to a decrease of the enteral absorption rate to less than 93% [9]. Often steatorrhoea is accompanied by diarrhoea. This is partly caused by accelerated gastric emptying and intestinal transit in patients with exocrine insuf?ciency that can also be reversed by enzyme supplementation [10]. Fat excretion of patients with pancreatic steatorrhoea frequently exceeds that of patients with other causes of steatorrhoea such as coeliac disease, in?ammatory bowel disease, or short bowel syndrome, with the exception of cystic ?brosis. Leaking oily stool from the anus is virtually pathognomonic of chronic pancreatitis. In general, weight loss is a cardinal symptom of pancreatic exocrine insuf?ciency with steatorrhoea, whereas hypoproteinemia or malabsorption of fat-soluble vitamins is less common. Overt steatorrhoea occurs in approximately 30% of patients with chronic calci?c pancreatitis. Mild to

Table 1 Pancreatic and extrapancreatic mechanisms of exocrine insuf?ciency [6]. Loss of functioning parenchyma  Chronic pancreatitis  Cystic ?brosis  Pancreatic tumours  Pancreatic resections  Diabetes mellitus? Decreased secretion despite intact parenchyma  Obstruction of pancreatic duct (tumour of the papilla)  Decreased endogenous stimulation (coeliac disease, Crohn’s disease, diabetes mellitus)  Intraluminal inactivation (Zollinger-Ellison syndrome, tetrahydrolipstatin) Post-cibal asynchrony  Gastric resections  Short bowel syndrome  Crohn’s disease? Diabetes mellitus?

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moderate steatorrhoea may not alter stool appearance and may not cause weight loss. Such patients may maintain their weight by increasing their appetite and food intake. Due to fat malabsorption fat-soluble vitamins are insuf?ciently resorbed which results in a variety of associated complications. Patients may exhibit low vitamin D levels and develop osteopathy, i.e. osteopenia, osteoporosis and osteomalacia. Reduced fecal elastase is observed in signi?cantly more individuals suffering from osteoporotic bone fractures than healthy controls (reduction by 65%) suggesting that exocrine pancreatic insuf?ciency might play a more important role for the development of osteoporosis than previously expected [11–13]. There are reports on vitamin A de?ciency causing night-blindness, visual impairment and other ocular affections. As a consequence of vitamin E and K de?ciency neurologic symptoms or coagulopathy can occur [4]. General clinical relevance of pancreatic function tests Exocrine function tests are either based on the measurement of secreted pancreatic enzymes and bicarbonate (direct tests) or the assessment of secondary effects due to lack of enzymes (indirect tests) [14– 16]. Collection of duodenal juice via an oro- or nasoduodenal tube and direct measurement of stimulated output of enzymes and bicarbonate is the gold standard for the assessment of exocrine pancreatic function. However, such tests are invasive, cumbersome and expensive procedures that need special technical equipment and trained personnel. Indirect methods evaluate the digestion of (synthetic) substrates by pancreatic enzymes which also indicates impaired exocrine function when reduced. In general, indirect tests are only accurate in advanced stages of exocrine insuf?ciency [14]. The same is true for non-invasive detection of decreased fecal enzyme excretion. For detailed description and limitations of pancreatic function testing we would like to draw the readers attention to chapter 4. More than 20 tests have been developed for the assessment of pancreatic exocrine function but only few are clinically available. Measurement of fecal elastase-1 is the currently preferred pancreatic function test. The test is easy to perform and compared with fecal chymotrypsin, it appears to be more sensitive and speci?c. However, as explained in detail in chapter 4, the test only assesses enzyme concentrations, so that there are numerous false positive results in patients with intestinal diseases and diarrhoea. Moreover, mild to moderate pancreatic exocrine insuf?ciency cannot be diagnosed reliably. Shortcomings of the gold standard for measurement of pancreatic exocrine function, the conventional secretin or secretin–caerulein test have been summarised above. Endoscopy based modi?cations of the secretin or secretin–caerulein test and secretin-enhanced MRI are under investigation but not readily available. Moreover, the non-invasive Pancreolauryl test is no longer available in many European countries and there is no wide spread use of the PABA test. Other non-invasive tests such as 13C-breath tests are becoming more important but have not been established in many institutions, yet. In conclusion, there is an unmet need for improved pancreatic function tests that are widely available. Still, pancreatic function tests are mandatory diagnostic tools for objective diagnosis of pancreatic exocrine insuf?ciency in numerous clinical settings as discussed below. Moreover, veri?cation of pancreatic exocrine insuf?ciency by a pathological pancreatic function test is a prerequisite for reimbursement of enzyme treatment in some countries. Role of pancreatic function tests in pancreatic diseases Chronic pancreatitis Prevalence and aetiology Chronic pancreatitis has an incidence of 8.2 per 100 000 population, a prevalence of 27.4 per 100 000 population, and a frequency of 0.04–5% among all autopsies [17,18]. Moreover, it accounts for substantial morbidity and healthcare costs. The annual treatment costs per patient are approximately $US17 000 [19]. Mortality is 3.6-fold increased in patients with alcohol-induced chronic pancreatitis compared with a population without chronic pancreatitis; 20-year survival rate is 45% [20]. Diagnosis is frequently delayed with a median time interval between onset of symptoms and diagnosis between about 3 an 6 years [17]. In Western countries, alcohol consumption is assumed to be the leading cause (70–90%) of chronic pancreatitis [21]. Overall, the prevalence of chronic pancreatitis clearly correlates with alcohol

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consumption but there seems to be no threshold for toxicity. In most studies the time between onset of alcohol abuse and ?rst pancreatitis symptoms is 18 ? 11 years [22]. The second most common form of chronic pancreatitis (25%) is so-called idiopathic pancreatitis [23,24] in patients without identi?able risk factors. This group has been constantly decreasing as knowledge about (genetic) susceptibility factors has been accumulating [25]. Hereditary pancreatitis represents an autosomal dominant genetic disorder closely associated with mutations in the cationic trypsinogen gene. Disease penetrance is about 80% [26]. Patients with hereditary pancreatitis develop recurrent bouts of pancreatitis that progress to chronic pancreatitis and usually begin in early childhood. Compared with the general population, the risk of developing pancreatic carcinoma is 50–60 times greater in these patients [27]. Other mutations with pathogenic implications for the pancreas involve the SPINK1 gene (encoding the pancreatic secretory trypsin inhibitor, PSTI) and have been associated with idiopathic chronic pancreatitis in children. SPINK1 mutations can be frequently detected in patients without a family history of pancreatitis and who are devoid of classical risk factors for chronic pancreatitis [28,29]. Moreover, it has been shown recently that loss of function mutations within the chymotrypsin C gene (encoding for a trypsin degrading enzyme) probably impair its protective role in pancreatitis by letting prematurely activated trypsin escape its degradation [30]. In a subset of patients with idiopathic pancreatitis mutations of the cystic ?brosis transmembrane conductance regulator (CFTR) gene may predispose to development of the disease. It has been shown recently that not only compound heterozygous carriers of CFTR mutations but also carriers of mild/ uncommon CFTR mutations (8% of the population) carry an increased risk of developing chronic pancreatitis [31]. However, it is important to note that pancreatic exocrine insuf?ciency in patients with cystic ?brosis is a completely different disease entity (compare below). Autoimmune pancreatitis is a recently characterised form of chronic pancreatitis that responds well to corticosteroids [32]. It typically presents with enlargement of the pancreatic gland, diffuse narrowing of the pancreatic duct, elevated serum lipase levels and, in 70–80% of patients, obstructive jaundice. For this reason, most patients are initially suspected as suffering from pancreatic carcinoma. The absence of calci?cation in the gland is regarded as a pathognomonic feature. The disease is found predominantly among men, the gender distribution being 2:1. The incidence of autoimmune pancreatitis increases in the second half of life. Blood tests reveal increased IgG4 levels, antinuclear autoantibodies, autoantibodies against lactoferrin and carbonic anhydrase II, and elevated serum rheumatic factors. Morphologically, ductal and periductal in?ammatory in?ltrates predominantly composed of lymphocytes, plasma cells, and granulocytes are the most constant histopathologic ?ndings. In about 60% of cases the disease is associated with other systemic autoimmune disorders. Metabolic disorders associated with hypertriglyceridemia above 1000 mg/dL can be responsible for the development of recurrent episodes of pancreatitis [33]. In increasingly rare cases, chronic calcifying pancreatitis has been reported due to hypercalcaemia in patients with untreated hyperparathyroidism. The underlying mechanism of hyperparathyroidism-associated pancreatitis is most likely related to the established role of calcium in the premature intracellular activation of digestive proteases. Pancreatic exocrine insuf?ciency in chronic pancreatitis The in?ammatory destruction of pancreatic tissue during chronic pancreatitis leads to reduced synthesis and secretion of pancreatic enzymes in response to food intake. With rare exceptions, clinically overt malabsorption only occurs when enzyme secretion is reduced by more than 90% [3,9]. In alcoholic chronic pancreatitis, this usually takes 10–20 years. Steatorrhoea usually occurs earlier and is more severe than malabsorption of other nutrients (compare above). Different natural courses suggest that pancreatic exocrine function is preserved longer and consequently exocrine insuf?ciency may generally be milder in ‘‘early onset’’ idiopathic chronic pancreatitis compared with alcoholic and ‘‘late onset’’ idiopathic chronic pancreatitis [24]. However, direct comparisons of pancreatic exocrine function in patients with varying etiologies of chronic pancreatitis have hardly been performed, so far [34]. In an unselected group of patients with chronic pancreatitis, 80–90% show some degree of pancreatic exocrine insuf?ciency and mean pancreatic exocrine function is reduced by around 50–80% compared with healthy controls [6]. In about 65–75% of patients, morphologic alterations and

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functional impairment develop in parallel. Pancreatic exocrine insuf?ciency without morphologic alterations is rare (<5%) yet possible [35]. Direct and invasive tests of panreatic exocrine function are considered the most sensitive and accurate to establish the diagnosis of chronic pancreatitis in patients with equivocal imaging ?ndings [24,36] (Table 2). In decompensated chronic pancreatitis with less than 5% of normal enzyme output, about 40% of nutrients from a readily digestible low-calorie meal are malabsorbed and enter the colon [10]. Maldigestion can be decreased by oral enzyme supplementation. However, even with clinically established doses of pancreatic lipase, duodenal enzyme delivery remains far below physiologic levels and lipid malabsorption cannot be completely normalised [35,37]. Role of pancreatic function tests in chronic pancreatitis Initial diagnosis: Often the ?rst signs of chronic pancreatitis that prompt the patient to seek medical attention are belt-like abdominal pain that frequently radiates to the back, loss of body weight (in 80%), and steatorrhoea (in less than 50%) [38]. To propose the diagnosis of chronic pancreatitis an impressive number and variety of diagnostic tests have been developed which only prove that there is not a single test that is adequate to establish the diagnosis. For this reason and furthermore for the fact that there is only an inadequate correlation between different lines of investigation (clinical presentation, imaging studies, laboratory ?ndings and pancreatic functioning tests) it is necessary to combine the complementary tests. The secretin–caerulein test is considered to be the reference standard to detect mildly impaired exocrine function as a surrogate for ?brosis but is hardly available. Measurement of fecal elastase is widely available and widely accepted to be part of the diagnostic work up if chronic pancreatitis is suspected. However as a stand alone test in early chronic pancreatitis the lack of sensitivity (50–93%) and the lack of speci?city (62–93%) limit its diagnostic value [39]. Recently with the aim to combine morphology and pancreatic function but avoid invasive procedures such as ERCP the use of secretin stimulated MRI was evaluated [40]. Duodenal ?lling as a result of secretin stimulation can be compared to duct changes on MRCP [41], but the number of patients with suspected chronic pancreatitis recruited to trials comparing MRI to secretin-stimulated pancreatic function is still too low to allow for ?nal evaluation of this method or to give reliable values for sensitivity and speci?city over the whole spectrum of pancreatic impairment. Measuring pancreatic function is mandatory in the diagnostic work up for chronic pancreatitis. Pancreatic function tests are particularly important in those patients who do not present with typical upper abdominal pain but with signs of malabsorption and/or dyspepsia (about 10–20%, Fig. 1). However, normal results do not rule out chronic pancreatitis and, as discussed above, there is an unmet need for improved, non-invasive pancreatic function tests. Surveillance: Recurrent bouts of chronic pancreatitis will eventually result in exocrine and endocrine insuf?ciency with a variable clinical time course. As enzyme supplements are clinically indicated when patients loose more than 10% of their body weight, excrete more than 15 g/d fat with their stool or complain of dyspepsia and meteorism due to exocrine pancreatic insuf?ciency surveillance of exocrine function is warranted. To closely monitor exocrine pancreatic function in chronic pancreatitis non-invasive indirect pancreatic function tests such as measurement of fecal elastase should be employed and measurement of fecal chymotrypsin can be used to follow patients’ compliance to enzyme supplementation. As an alternative non-invasive test the 13C-mixed triglyceride breath test has been recently introduced to monitor disease progression and enzyme treatment [42,43]. Direct

Table 2 Scoring system for diagnosis of chronic pancreatitis [24]. Finding Pancreatic calci?cation Typical histology Characteristic ERCP ?ndings Pancreatic exocrine insuf?ciency - steatorrhoea - abnormal direct invasive test Diagnosis of chronic pancreatitis is established if a score of !4 is achieved. Score 4 4 3 2

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Leading symptom

Characteristic pain

Symptoms of maldigestion

Screening test: US, X-ray for calcification + CT / EUS / ERP / MRCP* + EUS + FNA** + + Function testing

Function testing*** + Clinical reassessment

Chronic pancreatitis

Pancreatic insufficiency

Differential diagnosis: IBS, incipient CP?

Fig. 1. Chronic pancreatitis: Role of pancreatic function testing in the diagnostic algorithm [96]. If patients present with symptoms of maldigestion as leading symptoms, pancreatic function testing is performed as a ?rst step. In case of abnormal results, imaging procedures should be done. In the majority of patients who present with characteristic pain the evaluation starts with transabdominal ultrasound (US) examination (potentially combined with an abdominal X-ray). If the diagnosis remains unclear *CT or MRCP are preferred to ERP at this stage. If EUS is available Endoscopic Ultrasonography (EUS) is performed. **Biopsy is the gold standard but is rarely available. ***If imaging techniques remain inconclusive and/or for establishment of pancreatic exocrine insuf?ciency in patients with de?nite chronic pancreatitis pancreatic function testing is performed next. IBS: irritable bowel syndrome.

pancreatic function tests should be restricted to clinical trials, medical opinions or if the diagnosis remains uncertain. Treatment indications partly rely on proven exocrine insuf?ciency and clear cut diagnosis of impaired exocrine pancreatic function can support surgery as a treatment option. Acute pancreatitis Data from animal studies revealed that the exocrine function of the pancreas during acute pancreatitis is impaired and the time course of improvement of secretory function after acute experimental pancreatitis depends on the severity of pancreatitis [44–47]. Pancreatographic studies showed that impaired secretion was rather a result of ductal and parenchymal injury than of ductal obstruction [48,49]. Little is known about pancreatic exocrine secretion in humans with acute pancreatitis, in particular during the acute stage [6]. The only study available in humans shows normal interdigestive pancreatic function in non-stimulated patients suffering from mild to moderate acute pancreatitis in the early phase [50]. Exocrine secretion remains within the normal range in most patients during the subacute phase, some individuals show gastric acid hypersecretion and altered inactive duodenal trypsin and lipase [51,52]. During the convalescence period 14–100% of patients show abnormal exocrine function con?rmed by either direct secretin–pancreozymin or indirect PABA tests [53]. In most patients

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pancreatic exocrine function had recovered when they were re-tested but some patients can progress to chronic pancreatitis especially those who had concomitant abnormal ERCP and secretin function test ?ndings after onset [53]. In necrotising pancreatitis functional impairment occurs more often and may be long-lasting. Its severity correlates with the extent of pancreatic necrosis or the occurrence of pseudocysts and endocrine insuf?ciency [54]. Moreover, even 18 months after recovery from acute pancreatitis only 13% of patients had a normal Lundh test [55]. Overall, the data on the duration of abnormal exocrine function after acute pancreatitis range from 3 months to 4 years [56–58]. Since pancreatic exocrine insuf?ciency must be regarded as a much more frequent complication after acute pancreatitis than previously thought, is not con?ned to patients with severe acute pancreatitis and may last for months or even years [6,51,59], it is reasonable to perform pancreatic function tests in patients with abdominal symptoms following acute pancreatitis. However, no studies have been performed that speci?cally address the role of pancreatic function testing for management of these patients so that this recommendation cannot be supported by study data. Pancreatic cancer Pancreatic exocrine insuf?ciency can result from tissue destruction, pancreatic duct obstruction due to the tumour or pancreatic surgery that leads to minimisation or complete loss of the organ. Co-existing chronic pancreatitis further decreases enzyme production [60]. Secretory output of pancreatic enzymes and bicarbonate inversely correlates with the extension of pancreatic duct obstruction resulting in manifest exocrine insuf?ciency when more than 60% of the pancreatic duct is blocked [61]. Weight loss is seen in virtually all patients with pancreatic cancer, fat malabsorption in about 75%, protein malabsorption in approximately 50% of patients. Treatment of patients with pancreatic enzymes resulted in signi?cant improvement of absorption rates, especially in those patients with moderate to severe fat or protein malabsorption [62]. Most patients with pancreatic tumours will have pain and weight loss as leading symptoms. Since these patients may avoid eating, concomitant signs of malabsorption may be obscured and pancreatic function tests are helpful for early detection of pancreatic exocrine insuf?ciency and the need for enzyme supplementation. A minority of patients will present with signs of malabsorption. In these, pancreatic function tests are part of the diagnostic work up. Pancreatic resection The extent of pancreatic resection of course also determines the severity of insuf?ciency. Examination of pre- and post-operative exocrine function revealed a signi?cant loss of secretory function after Whipple’s procedure or pylorus-preserving pancreaticoduodenectomy (PPPD). In less invasive operations like duodenum-preserving pancreatic head resection no decline of PABA test was recorded [63]. In an attempt to operate less radically on pancreatic tumours and to preserve functionally intact tissue, a middle-segment pancreatectomy was performed in patients having cystic or islet cell tumours of the body or tail. No patient required enzyme supplementation after an observation period of 18 months [64]. In patients undergoing pancreatic head resection pancreatic exocrine function dropped within the ?rst 2 months but returned to pre-operative status after long-term follow up (12–31 months). It is notable to mention that reduction of exocrine function was most pronounced in patients with a dilated pancreatic duct. Following pancreatectomy, patients de?nitely need pancreatic enzyme supplementation, of course and pancreatic function tests are not required for diagnosis of exocrine insuf?ciency. Still, indirect pancreatic function tests, e.g. 13C-breath tests may serve to optimise enzyme treatment [65]. In patients with less extensive pancreatic resections and normal pancreatic function preoperatively, function tests should be performed in order to diagnose pancreatic exocrine insuf?ciency at an early stage instead of waiting for clinical signs of overt malabsorption. Cystic ?brosis and other hereditary diseases The most important hereditary disease that is associated with pancreatic exocrine insuf?ciency is cystic ?brosis. Relevant pathomechanisms and the role of pancreatic function tests in patients with

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cystic ?brosis are described in detail below. Information on rare hereditary disorders such as Shwachman-Diamond Syndrome, Johanson-Blizzard Syndrome and pancreatic agenesis or hypoplasia is summarised in Table 3. Among the white population cystic ?brosis is the most common lethal autosomal recessive disease, caused by mutations of the cystic ?brosis transmembrane conductance regulator gene (CFTR). The most frequent mutation is a deletion of phenylalanine at codon 508 (dF508), it accounts for approximately 70% of mutations, but so far more than 1000 other mutations have been reported [66]. The defective chloride channel leads to de?cient ?uid secretion and inspissation of secretes not only in the pancreas, but also in the respiratory tract, kidneys and intestine [66,67]. Pancreatic insuf?ciency is found in approximately 72–100% of cystic ?brosis patients [68]. Patients with pancreatic insuf?ciency also show more severe pulmonary malfunction and diagnosis of cystic ?brosis is made earlier [68]. Several studies show that the severity of pancreatic insuf?ciency is highly dependent on the genotype [69]: Almost all patients who are homozygous for delta F508 or have other severe mutations are pancreatic insuf?cient while patients with one or two mild mutations frequently remain pancreatic suf?cient [69]. For detection of exocrine insuf?ciency in cystic ?brosis fecal elastase and fecal chymotrypsin tests are useful, both showing a high sensitivity. In patient subgroups with mild, moderate or severe exocrine insuf?ciency that was diagnosed by secretin–cholecystokinin test, fecal elastase measurements con?rmed these results and showed abnormal concentrations in all groups with an overall sensitivity of 89.3% for all CF patients [70]. However, sensitivity is limited for detection of mild insuf?ciency. Since a progressive decline of pancreatic function is possible in cystic ?brosis, patients who are (partially) pancreatic suf?cient have to be monitored throughout their life. Fecal elastase measurement is convenient, as it is non-invasive and pathological results can precede the appearance of steatorrhoea. However, positive results in children with diarrhoea do not suf?ce to prove pancreatic exocrine insuf?ciency and/or pancreatic affection due to cystic ?brosis. Chymotrypsin can be used to monitor enzyme substitution therapy as it re?ects the amount of enzymes taken by the patient (fecal excretion will be low in patients who are not compliant). However, diagnostic accuracy of fecal chymotrypsin and of fecal lipase appears to be inferior to that of fecal elastase [71,72].

Table 3 Role of pancreatic function tests in rare hereditary pancreatic disorders. Disease Shwachman- (Bodian-) Diamond Syndrome [89–91] Pathomechanisms Pancreatic alterations Clinical characteristics Short stature, skeletal and haematologic abnormalities Role of function tests Fecal elastase testing useful for screening in childhood: negative predictive value 99%, positive results not always associated with steatorrhoea Mandatory in diagnostic work-up: exocrine pancreatic insuf?ciency is most constant clinical symptom

Autosomal recessive, Fatty tissue mutations in SBDS gene replacement of acini, on chromosome 7q11 preserved ductular architecture, exocrine insuf?ciency in almost all affected children Autosomal recessive disorder associated with de?ciency of UBR1, likely causes intrauterine destruction of acinar these cells Unknown Almost complete lack of acinar cells, replacement by fat and connective tissue, ductal architecture and islets quite well preserved

Johanson-Blizzard Syndrome [92,93]

Pancreatic hypoplasia [94]

Pancreatic agenesis [95]

Genetic background only elucidated in single patients

Obligatory: congenital pancreatic insuf?ciency, nasal wing aplasia; facultative: genitourinary/cardiac malformations, mental retardation Partial agenesis of the Increased risk of pancreas (mostly dorsal diabetes mellitus; part) exocrine function usually maintained (reserve capacity!) Complete absence of Diabetes mellitus, pancreas severe malabsorption, intrauterine growth retardation, rapidly fatal in most cases

Warranted in patients with abdominal symptoms and/or signs of growth retardation Theoretically useful but very rare condition

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Disorders with secondary impairment of pancreatic exocrine function Diabetes mellitus In diabetic patients, marked morphological alterations of the exocrine pancreas are observed, and a considerable number of patients show mild to moderate impairment of bicarbonate and enzyme secretion. The pathophysiological mechanisms leading to pancreatic exocrine insuf?ciency in diabetes mellitus are not fully elucidated but probably include imbalance of stimulatory (insulin) and inhibitory (glucagon, somatostatin) islet hormones, pancreatic ?brosis due to angiopathy, autoimmune mechanisms, autonomic neuropathy and altered release of gastrointestinal regulatory mediators [6]. Prevalence of pancreatic exocrine insuf?ciency is particularly high in IDDM and ranges between about 26 and 80% in these patients. In NIDDM patients, the prevalence of pancreatic exocrine insuf?ciency estimated by direct invasive tests and by non-invasive fecal elastase-1 measurements is somewhat lower and ranges between 12 and 73% [6]. Most of the studies performed so far are hampered by small numbers of highly selected patients. The few studies that have used unselected patients of diabetes mellitus registries suggest relatively low frequencies of impaired pancreatic exocrine function in IDDM (26%) and NIDDM (12%). However, fecal elastase-1 measurements as used in these studies are less sensitive and speci?c compared with invasive pancreatic function testing. Pancreatic exocrine insuf?ciency is usually only mild to moderate and will not lead to clinically overt steatorrhoea in the majority of diabetics concerned. Thus, clinical relevance of pancreatic exocrine impairment and the role of function tests in these patients are questionable. However, patients with diabetes mellitus frequently suffer from a wide range of abdominal symptoms which markedly contribute to impairment of quality of life [73]. At least some of these symptoms such as pain and diarrhoea may be attributable in part to (mild to moderate) pancreatic exocrine insuf?ciency and might respond to enzyme treatment. Thus, pancreatic function tests should be part of the diagnostic work-up in patients with such symptoms who do not respond to simple therapeutic measures and in whom other, more likely causes (e.g. carbohydrate intolerance, bacterial overgrowth) have been excluded. Coeliac disease Malabsorption is a frequent problem in coeliac disease and does not only result from impaired nutrient absorption but also from concurrent pancreatic dysfunction due to decreased release of stimulatory mediators (e.g. cholecystokinin) from the atrophic mucosa in untreated patients. In consequence pancreatic enzyme release is impaired and, since these mediators also in?uence gastrointestinal motility, there may be an asynchrony of intestinal meal transit and pancreatic enzyme secretion (post-cibal asynchrony). It is assumed that in patients with coeliac disease direct pancreatic insuf?ciency can also occur. Defective pancreatic exocrine function is present in about 15–40% of patients with untreated coeliac disease [6,74–77]. If patients are treated suf?ciently exocrine pancreatic function normalises and function tests are likely to be identical to healthy subjects. Thus, pancreatic function tests are usually not performed in patients with new-onset and uncomplicated disease. However, in patients with persisting symptoms despite gluten withdrawal a direct pancreatic function test may reveal pancreatic affection with reduced secretion of one or more enzymes in response to hormonal stimulation [75,78]. Indirect pancreatic function tests such as the 13C-mixed triglyceride breath test may help to con?rm and to quantify nutrient maldigestion and malabsorption. In children with coeliac disease determination of fecal chymotrypsin seems to be a predictor for weight gain under gluten free diet (patients with low chymotrypsin display lower weight gain) [79] and may therefore help to guide therapy. In?ammatory bowel disease Pancreatic disorders are considered to be an extraintestinal manifestation of in?ammatory bowel disease (IBD) and patients have a markedly increased risk for developing acute pancreatitis. Likewise,

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prevalence of chronic pancreatitis and pancreatic exocrine insuf?ciency seems to be increased in IBD patients. Often symptoms are mistakenly attributed to IBD [80]. Fecal elastase is found to be lowered in a number of patients with in?ammatory bowel disease, approximately 17% have abnormal values and prevalence is increased to approximately 50% in patients with a history of pancreatitis. About 7% show a decrease in elastase to less than 100 mg/g suggesting severe exocrine insuf?ciency [80,81]. Furthermore, fecal alpha-1-proteinase inhibitor-bound elastase correlates with disease activity. In ulcerative colitis it is suggested to be even superior for evaluation of disease activity than plasma levels of in?ammatory markers. In 50% of patients under treatment who reach clinical remission fecal elastase returned to normal values [80,82]. However, fecal elastase has limited diagnostic accuracy in IBD patients who suffer from diarrhoea because this may lead to false positive results due to dilution effects. Secondly, an increased bacterial degradation of elastase during intestinal transit can lower values. Thus, fecal elastase-1 may overestimate occurrence and/or degree of pancreatic exocrine insuf?ciency in IBD patients. Still, other studies using secretin and PABA tests could con?rm high prevalence of impaired exocrine pancreatic function in in?ammatory bowel disease. Patients with Crohn’s disease showed a decrease in bicarbonate and enzyme secretion in 35% or an abnormal PABA test in 26%. In ulcerative colitis a pathologic secretin test was present in about half of the patients and PABA test was reduced in 22% [80,83]. Pancreatic duct abnormalities suggesting chronic pancreatitis were detectable in 8% of patients with IBD, a high incidence of pancreatic ?brosis was also observed in autopsy studies [83,84]. Mild to moderate exocrine insuf?ciency as observed in most affected IBD patients usually does not cause clinical symptoms, i.e. there is no steatorrhoea in subjects with an otherwise healthy digestive system. However, we speculate that in Crohn’s disease patients with reduced absorptive capacity due to small intestinal resections, extensive in?ammation or scars, lesser degrees of pancreatic insuf?ciency may suf?ce to induce symptoms [6]. Accordingly, pancreatic function tests can help to select patients who might bene?t from enzyme supplementation. Unfortunately, fecal elastase is little helpful in patients with diarrhoea, as discussed above and the clinically available indirect tests of pancreatic function may also give false positive results in patients with an overall reduction of intestinal absorptive capacities and/or bile acid malabsorption. Consequently, the more cumbersome secretin or secretin–caerulein test would be needed to measure pancreatic exocrine function in these patients reliably. Alternatively, repetition of an indirect test (e.g. 13C-breath test) under treatment with pancreatin might help to clarify whether the patients’ symptoms are due to concurrent pancreatic exocrine insuf?ciency. Zollinger-Ellison syndrome Zollinger-Ellison syndrome is a rare disease characterised by increased synthesis of the hormone gastrin that leads to overproduction of gastric acid and a shift of duodenal pH to acidic milieu causing diarrhoea and malabsorption. Apart from intestinal atrophy and in?ammation, pancreatic enzymes are inactivated due to decreased intraluminal pH causing malabsorption. Differential diagnosis of Zollinger-Ellison syndrome should be considered in patients with large amount of acidic duodenal ?uid and multiple therapy refractive ulcers [6,85]. Though pancreatic function tests may be performed in these patients as part of the diagnostic work-up, particularly in those with steatorrhoea, they are not pivotal for diagnosis. Gastric resections Operations on the stomach are frequently associated with pancreatic exocrine insuf?ciency. This is due to insuf?cient grinding of nutrients, to post-cibal asynchrony, that is an imbalance of gastric emptying, intestinal transit and pancreatic enzyme secretion, and/or pancreatic denervation particularly in cancer surgery. However, pancreatic insuf?ciency is noted in both partial and total gastrectomy. Pancreolauryl tests were pathological in 47–64% after Billroth-I and 64–70% after Billroth-II operation. At least 60% of patients were pancreatic insuf?cient after total gastrectomy [86]. Trypsin and chymotrypsin secretion are most severely affected and reduced by up to 91% after three months in patients who underwent total gastrectomy [87]. Several experts strongly suggest pancreatic enzyme

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therapy in gastrectomized patients even if they have no symptoms of maldigestion [88] but this has not become common clinical practise, yet. The situation is even less clear in patients who have undergone partial gastric resections. Thus, a pancreatic function test should be performed in all patients with equivocal symptoms. Direct tests that use hormonal stimulation would evaluate pancreatic secretory capacity most reliably but are of limited use in this situation. Instead, indirect tests also assess the effects of post-cibal asynchrony on nutrient digestion and are to be preferred. Summary Pancreatic exocrine insuf?ciency is most frequently due to chronic pancreatitis (in adults) or cystic ?brosis (in children). Other pancreatic causes include acute pancreatitis, pancreatic cancer and surgery. However, extrapancreatic disorders such as coeliac disease, IBD and gastric resections can also be associated with pancreatic exocrine insuf?ciency, and patients with diabetes mellitus have decreased exocrine function. In most cases, clinical symptoms (steatorrhoea, signs of decreased availability of lipid soluble vitamins) only occur when the pancreatic secretory capacity is reduced to less than 5–10% of normal. However, the negative impact of milder disturbances on bone metabolism may have been underestimated. Moreover, moderately impaired pancreatic exocrine insuf?ciency may contribute to dyspeptic symptoms and diarrhoea, particularly in patients with additional affections of the gastrointestinal tract. A variety of pancreatic function tests exist. Direct invasive function tests like the secretin test are still the gold standard with highest sensitivity and speci?city. However, their availability is limited to centres, they are costly and uncomfortable for the patient. Determination of fecal elastase is convenient and widely available but its sensitivity is low in mild to moderate cases. Moreover, due to low speci?city, it is of limited value for differential diagnosis in patients with diarrhoea. Other non-invasive tests such as 13C-breath tests are becoming more important but are not widely established, yet. Still, pancreatic function tests are mandatory diagnostic tools for objective diagnosis of pancreatic exocrine insuf?ciency in numerous clinical settings. In chronic pancreatitis, they are particularly important for those 10–20% of patients who present with signs of malabsorption and/or dyspepsia. Moreover, veri?cation of pancreatic exocrine insuf?ciency is a prerequisite for reimbursement of enzyme treatment in some countries.

Practice points  Typical clinical symptoms of pancreatic exocrine insuf?ciency include steatorrhoea, weight loss and signs of vitamin de?ciency. They usually only occur if pancreatic enzyme secretion falls below 5–10% of normal levels.  Only few pancreatic function tests are clinically available. The secretin or secretin–caerulein test is regarded as reference method but is hardly available. Measurement of fecal elastase-1 is currently preferred but has limited sensitivity and speci?ty. 13C-breath tests are becoming more important but have not been established in many institutions, yet.  Despite this dilemma, pancreatic function tests are mandatory diagnostic tools for objective diagnosis of pancreatic exocrine insuf?ciency in numerous clinical settings (compare below).  Moreover, veri?cation of pancreatic exocrine insuf?ciency by a pathological pancreatic function test is a prerequisite for reimbursement of enzyme treatment in some countries.  Chronic pancreatitis: Function tests are particularly important in patients who present with signs of malabsorption and/or dyspepsia (about 10–20%), normal results do not rule out the diagnosis.  Acute pancreatitis: Pancreatic exocrine insuf?ciency is a more frequent complication after acute pancreatitis than previously thought, is not con?ned to patients with severe acute pancreatitis and may be long-lasting. Thus, it is reasonable to perform pancreatic function tests in patients with abdominal symptoms following acute pancreatitis.

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 Pancreatic tumours: Patients with pain may avoid eating so that concomitant signs of malabsorption may be obscured. In these, pancreatic function tests are helpful for early detection of pancreatic exocrine insuf?ciency and the need for enzyme supplementation. In the minority of patients who present with signs of malabsorption pancreatic function tests are part of the diagnostic work up.  Pancreatic resections: Following pancreatectomy pancreatic function tests are not required for diagnosis of exocrine insuf?ciency but may serve to optimise enzyme treatment (13Cbreath tests). In patients with less extensive pancreatic resections and normal pancreatic function preoperatively, function tests should be performed in order to diagnose pancreatic exocrine insuf?ciency at an early stage.  Cystic ?brosis: Almost all patients who have severe mutations are pancreatic insuf?cient while the minority of patients with one or two mild mutations (<20%) may remain pancreatic suf?cient. Patients with pancreatic insuf?ciency also show more severe pulmonary malfunction. Fecal elastase is suitable for monitoring of pancreatic exocrine function in cystic ?brosis patients. However, positive results in children with diarrhoea do not suf?ce to prove pancreatic exocrine insuf?ciency and/or pancreatic affection due to cystic ?brosis.  Disorders with secondary affection of the exocrine pancreas: These include diabetes mellitus, coeliac disease, IBD and gastric resections. Exocrine insuf?ciency tends to be mild to moderate in most cases. However, due to concomitant disturbances of gastrointestinal functions it may still contribute to symptoms. Thus, pancreatic function tests should be part of the diagnostic work-up in patients with such symptoms who do not respond to adequate therapeutic measures and in whom other, more likely causes (e.g. carbohydrate intolerance, bacterial overgrowth) have been excluded.

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