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1 Clin Physiol Funct Imaging (2012) doi: /cpf REVIEW ARTICLE Update of exocrine functional diagnostics in chronic pancreatitis Camilla Nøjgaard 1, Søren Schou Olesen 2, Jens Brøndum Frøkjær 3 and Asbjørn Mohr Drewes 2 1 Department of Internal Medicine, Amager Hospital, Copenhagen, 2 Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, and 3 Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark Summary Correspondence Camilla Nøjgaard, Department of Internal Medicine, Amager Hospital, Copenhagen, Denmark mille@dadlnet.dk Accepted for publication Received 15 June 2012; accepted 07 November 2012 Diagnostics of pancreatic insufficiency rely mainly on tests of pancreatic exocrine function based on either measurement of pancreatic secretion or the secondary effects resulting from lack of digestive enzymes or imaging modalities. These methods have been developing rapidly over the last decades, and the aims of this review were to describe exocrine functional testing and imaging of the pancreas in chronic pancreatitis.. Key words chronic pancreatitis; enzymes; exocrine insufficiency; functional testing; imaging Introduction The pancreas is an organ with an exocrine and endocrine function. Anatomically, it lies in the retroperitoneum and is therefore difficult to biopsy, and imaging may also be cumbersome. Chronic pancreatitis (CP) is a chronic inflammatory condition characterized by irreversible morphological changes in the pancreas. During time, the inflammation leads to destruction of the endocrine and exocrine tissue and thereby exocrine and endocrine insufficiency, development of fibrosis and eventual calcifications. The diagnosis is based on a combination of clinical information, imaging procedures and functional testing but rarely on histology (Layer et al., 1994). The diagnosis is easy when calcifications have developed or if histology is available, but in the early stages, the diagnosis is often challenging. This partly relates to the slow progression of the anatomical and functional changes of the organ, and the fact that the anatomical changes are not necessarily connected to functional impairment. The degree of ductal changes probably plays a larger role than the parenchymal abnormalities (Domınguez-Mu~noz et al., 1995). Hence, diagnostics rely mainly on (i) tests of pancreatic exocrine function based on either measurement of pancreatic secretion or the secondary effects resulting from lack of digestive enzymes or (ii) imaging modalities. These methods have been developing rapidly over the last decades, and the aims of this review were to describe state of the art of exocrine functional testing and imaging of the pancreas in CP. Functional procedures Duodenal intubation tests (invasive procedures) Lundh test meal (also named Borgstr om test) In Scandinavian literature, Lundh test meal has often been considered as the gold standard for the definition of exocrine pancreatic insufficiency. It was described by Borgstr om, Dahlqvist and Lundh in 1962 (Borgstr om et al., 1962), but currently, only centres with special interest in pancreatitis use the test as standard procedure. The procedure takes 2 3 h. In the fasting patient, a tube is placed in the third part of duodenum, and the position is confirmed radiologically. The patient consumes a standard meal, and during the next 80 min, the duodenal juice is aspirated. Volume and ph are noted for each specimen, and concentrations of bicarbonate, lipase and amylase are determined. If the volume of the duodenal aspirate is too small, the patient is stimulated by intravenous cholecystokinin. Afterwards, the aspirate is investigated for the concentration of duodenal amylase and lipase. The pancreatic insufficiency can be divided into mild, moderate or severe insufficiency depending on the concentrations of the enzymes. Lundh test meal is thought to be more sensitive to mild and moderate insufficiency than faecal fat excretion according to the relation between lipase secretion and stool fat, as patients with CP will first develop elevated faecal fat excretion if the lipase secretion is lower than 5 7% of normal (DiMagno et al., 1973). 1

2 2 Update of exocrine functional diagnostics in chronic pancreatitis, C. Nøjgaard et al. The secretin pancreozymin test In non-scandinavian countries, this test is most often used as the gold standard for exocrine pancreatic testing, but primarily in centres specifically interested in pancreatitis (Lankisch, 1993). As the Lundh test meal, it is thought to be more sensitive to mild and moderate insufficiency than faecal fat excretion. In the fasting patient, a double-lumen tube is passed into the third part of duodenum, and the position is confirmed radiologically. The duodenal juice is aspirated for a 15-min baseline period and then for three consecutive 15-min periods after infusion of secretin and pancreozymin cholecystokinin intravenously. The volume and ph are noted for each specimen, and concentrations of bicarbonate, lipase, trypsin, and chymotrypsin are determined (Burton et al., 1960). The endoscopic secretin stimulation test By using this method, it is possible to perform a functional test of the pancreas simultaneously with an upper endoscopy of the patient. The fasting patient is given secretin intravenously. Thirty minutes after administration of secretin, the duodenoscope is passed into the stomach and all gastric fluid present is aspirated and discarded. The tip of the duodenoscope is then placed closely to the ampulla of Vater, and duodenal aspirate is drawn for maximum 10 min and then ph is measured. The measurements are excluded if ph is below 60. The collected fluid is measured and analysed for the concentration of bicarbonate, lipase and elastase (Jensen & Larsen, 2008; Law et al., 2012). Compared with the Lundh test meal, endoscopic secretin stimulation test can differentiate between normal and reduced exocrine function with acceptable accuracy, yielding positive and negative predictive values of 88% and 83%, respectively. It is suggested that a combination of the concentration of bicarbonate and lipase is best to characterize the patient s exocrine pancreatic function into normal, reduced or insufficient (Jensen & Larsen, 2008). This method is, however, not used routinely. Non-invasive exocrine pancreatic function tests Faecal elastase-1 Pancreatic elastase-1 is a pancreas-specific enzyme that is not degraded during intestinal passage. It is approximately sixfold enriched in faeces compared with duodenal juice and can be measured in stool using a sensitive enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies (Sziegoleit et al., 1989). Several studies have evaluated faecal elastase-1 in patients with CP of varying severity based on morphological and/or pancreatic function tests. Excellent correlation has been found between the faecal elastase-1 level and duodenal juice volume, lipase, amylase, trypsin and bicarbonate output as well as morphological changes of the pancreas as determined by endoscopic retrograde cholangiopancreatography (Lankisch et al., 1998; Hardt et al., 2002; Chowdhury & Forsmark, 2003). In a study by L oser et al. (1996), the secretin caerulein test was used as gold standard to categorize pancreatic exocrine insufficiency. Faecal elastase-1 sensitivity was 63% for mild, 100% for moderate, 100% for severe and 93% for all patients with exocrine pancreatic insufficiency, and specificity was 93%. Furthermore, the individual day-to-day variations of faecal elastase-1 concentrations were low (mean CV = 15%; L oser et al., 1996). These numbers are comparable with many of the invasive pancreatic function tests, and the faecal elastase-1 test is increasingly used as the first-line measure of pancreatic exocrine insufficiency. The great success of the faecal elastase-1 test has mainly been attributed to its non-invasive nature. Furthermore, it is relatively cheap, easy to handle for the patient and laboratory staff, and it can be stored at room temperature for more than a week. A few limitations, however, need to be considered when using the faecal elastase-1 test: First, diarrhoea or steatorrhoea of non-pancreatic origin may artificially lower faecal elastase-1 concentration due to dilutional effects (Fischer et al., 2001). Second, faecal elastase-1 cannot be used to assess the response to pancreatic supplement therapy as faecal elastase-1 remains low in stool despite pancreatic supplements. Finally, the relatively low sensitivity in mild pancreatic disease needs to be taken into consideration and limits the use of faecal elastase-1 to identify patients with early and mild CP. Faecal fat excretion The simplest measurement of pancreatic enzyme action is measurement of faecal fat excretion. Prior to faecal fat analysis, the patient has to discontinue use of enzyme substitution and under optimal conditions keep a constant fat intake of 100 g day 1 for 5 days. Then stool samples are collected for analysis. To minimize sample errors, collection of three stool samples is usually employed. The collected stool is homogenized and fat extracted by organic solvent. Finally, the content of free fatty acids is quantified (Van De Kamer et al., 1949). A faecal fat quantity of >7 g day 1 (19 mmol day 1 ) is considered to be abnormal and compatible with a diagnosis of pancreatic exocrine insufficiency. Clinical overt steatorrhoea is typically present at faecal fat quantities >15 g day 1 (4 mmol day 1 ). In addition, the fat absorption coefficient can be calculated as a quantitative index of fat absorption. This is accomplished according to the formula (dietary fat intake stool fat/dietary fat intake) 9 100% (normal >925%; Chowdhury & Forsmark, 2003). Maldigestion of fat only occurs after approximately 90% of pancreatic lipase secretory capacity is lost, and a variety of other gastrointestinal diseases are accompanied by steatorrhoea (DiMagno et al., 1973). Consequently, quantitative faecal fat analysis is neither sensitive nor specific for exocrine pancreatic function. Taken together with the relatively time-consuming procedure and uncomfort for the patient, faecal fat excretion should be no longer used for routine clinical diagnosis of exocrine

3 Update of exocrine functional diagnostics in chronic pancreatitis, C. Nøjgaard et al. 3 pancreatic insufficiency, although it may still be useful in selected cases to test the effectiveness of pancreatic enzyme replacement therapy (Lankisch, 1993). Breath tests Several variations of breath tests with labelled carbon atoms in the fatty acid triglyceride have been developed to measure fat digestion by pancreatic lipase. Exhalation of labelled CO 2 is measured after the ingestion of labelled triglycerides, which are usually given together with a standard meal. Tests vary in terms of the substrate, the standard with which the results are compared and the use of radioactive or non-radioactive material for labelling. Various modifications have been proposed to improve the specificity of breath tests for pancreatic function. One modification involves the introduction of a mixed triglyceride that consists of one medium-chain fatty acid and two long-chain fatty acids ( 13 C-mixed triglyceride breath). The principle of the test is that the two stearyl groups have to be split off the glycerol by lipase before 13 C-octanoyl monoglyceride, a medium-chain fatty acid, can be absorbed. This is then rapidly metabolized and 13 CO 2 exhaled (Vantrappen et al., 1989). The test was applied to patients with CP of variable severity and found to have excellent sensitivity (100%) and specificity (85%) in severe CP, but low sensitivity (46%) and specificity (69%) in mild CP (L oser et al., 1998). Breath tests are unable to differentiate between pancreatic steatorrhoea and other forms of fat malabsorption. However, the test can measure the efficacy of enzyme replacement therapy and can be used to make a judgement on the overall maldigestion. For this reason, they have primarily been used to test the effectiveness of pancreatic enzyme replacement therapy instead of the more time-consuming and unpleasant stool fat collection. In this context, the 13 C-mixed triglyceride breath was shown to be an accurate method to evaluate the effect of enzyme therapy on fat absorption (Domınguez-Mu~noz et al., 2007). The metabolism of triglycerides to CO 2 depends not only on hydrolysis by pancreatic enzymes, but also on intestinal absorption, hepatic metabolism and ventilation where disease affection can interfere with the accuracy of these tests (Chowdhury & Forsmark, 2003). Also, in spite of the many available reports pertaining to diverse variations of breath tests, no single test have been thoroughly validated in larger patient materials and international standardization is lacking. Hence, the use of breath tests mainly relies on local expertise and preference. Functional imaging procedures The development in imaging techniques has dramatically improved the diagnosis and evaluation of CP. Some decades ago, the evaluation was limited to radiography depicting calcifications in severe CP. The ductal morphology has traditionally been assessed with endoscopic retrograde cholangiopancreatography, which is based on intraductal contrast enhancement with severity assessed using the Cambridge classification (Sarner & Cotton, 1984). However, failure of visualization of the entire ductal system due to ductal blockage and the risk of acute pancreatitis are limitations. Nowadays, routine imaging modalities applied in the evaluation of CP are as follows: Computed tomography with one or more contrast enhancement phases, magnetic resonance imaging (MRI) with or without magnetic resonance cholangiopancreatography (MRCP) and ultrasound with a transabdominal or endoscopic approach (Fig. 1). The main focus is typically to describe glandular atrophy and calcifications, duct pathology, pseudocysts and complications such as abscess formation and acute inflammation. For endoscopic ultrasound, a classification system based on both parenchymal and ductal morphology has been proposed, that is, the Rosemont criteria (Seicean, 2010). Finally, tumour formation often has to be ruled out, where positron emission tomography (PET) and PET-computed tomography have a central position (Serrano et al., 2010). Recently, more advanced methods have emerged, which also gives important information on both pancreatic function and tissue characteristics. Table 1 summarizes the advantages and limitations of the methods. Ultrasound Sonoelastography examines the elastic properties of tissues by applying a slight compression to the tissue and comparing the images obtained before and after this compression. The tissue hardness can be evaluated with endoscopic ultrasound-guided elastography to assess the degree of parenchymal fibrosis in CP (Janssen et al., 2007). Elastography is now also possible in transabdominal ultrasound (Erchinger et al., 2011). The technical development has substantially improved the image resolution of transabdominal ultrasound, and using power Doppler and contrast-enhanced ultrasound, more information on the pancreatic tissue structure can be obtained (Erchinger et al., 2011). However, these new ultrasound-based techniques have primarily been evaluated for the ability to detect cancers and not the severity of CP. Magnetic resonance imaging On contrast-enhanced MRI, the degree of parenchymal fibrosis can be assessed as decreased and delayed enhancement on serial contrast-enhanced images (Balcı, 2011). In secretinstimulated MRCP, both the ductal system changes (including side branches) are better visualized and the exocrine function can be evaluated with assessment of duodenal filling, changes in pancreatic duct calibre, change in pancreatic anteroposterior diameter, as well as change in signal intensity ratio between pancreas and spleen on T1-weighted and arterial venous enhancement ratios (Balci et al., 2010). The findings are comparable with endoscopic pancreatic function testing in the evaluation of CP. Quantitative assessment of the pancreatic exocrine reserve by dynamic secretin-stimulated MRCP with

4 4 Update of exocrine functional diagnostics in chronic pancreatitis, C. Nøjgaard et al. (a) (b) (c) (d) Figure 1 Magnetic resonance imaging in chronic pancreatitis: axial T2-weighted (a) and 3D cholangiopancreatography (b) images in a patient with dilated and irregular main pancreatic duct, abnormal side branches and a small pseudocyst (arrow). Diffusion-weighted image (c) and map of the apparent diffusion coefficient (d) with a measuring region positioned in the corpus for assessment of parenchymal fibrosis. Table 1 The most important imaging modalities for the diagnosis of key features in chronic pancreatitis. Glandular atrophy Calcifications Ductal morphology Exocrine function Tissue characteristics Cancer evaluation Biopsy Comment ERCP (+) ++ Can be combined with EUS CT (contrast enhanced) (+) + + CT perfusion PET/CT Transabdominal US (+) ++ Endoscopic US Contrast-enhanced US As supplement to routine US Sonoelastography As supplement to routine US MRI with MRCP ++ + (+) + Secretin-stimulated MRCP (+) + Can be combined with DWI Contrast-enhanced MRI Combined with MRCP MR DWI (with ssmrcp) ++ + Combined with MRCP The usefulness of the respective imaging modality for ascertaining the key features is indicated as ++ (excellent), + (sufficient), (+) (not fully sufficient) and (not possible). CT, computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; US, ultrasound; EUS, endoscopic ultrasound; ERCP, endoscopic retrograde cholangiopancreatography; PET, positron emission tomography; DWI, diffusion-weighted imaging. calculation of the duodenal filling volume correlated with the faecal elastase-1 values in CP patients, making it possible to discriminate impaired and preserved pancreatic exocrine function using secretin-stimulated MRCP (Manfredi et al., 2012). Diffusion-weighted imaging assesses the random motion of the water protons and is an emerging technology that can complement standard MRI to assess the parenchymal changes associated with CP (see Fig. 1). Presence of parenchymal fibrosis in CP causes diffusion restriction and results in lower apparent diffusion coefficient (Akisik et al., 2009). Furthermore, after secretin stimulation, the diffusion coefficients have either delayed or lower peak values in patients with reduced exocrine function (Akisik et al., 2009). This is particularly useful in patients with early-stage CP. Finally, diffusion-weighted images are helpful in the distinction between simple pancreatic cyst, inflammatory cysts and cystic neoplasms (Balci et al., 2009).

5 Update of exocrine functional diagnostics in chronic pancreatitis, C. Nøjgaard et al. 5 Computed tomography New multi-detector scanner generations with up to 256 slices allow computed tomography perfusion studies of the entire pancreas (and liver) assessing the parenchymal contrast enhancement with high temporal resolution. The pancreas can be evaluated with assessment of perfusion, peak enhancement intensity, time-to-peak and blood volume, and these parameters were changed in CP patients with exocrine insufficiency (Arikawa et al., 2012). Conclusions and guidelines for the future The optimal functional testing of the exocrine pancreatic function in CP should be non-invasive, safe, fast, cost-effective and with a high sensitivity and specificity. In patients with severe morphological changes, faecal elastase-1 and breath test are often sufficient screening procedures. In patients with mild or moderate CP, the invasive tests are more sensitive and should be considered. 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