Update of Exocrine Functional Diagnostics in Chronic Pancreatitis Camilla Nøjgaard1, Søren Schou Olesen2, Jens Brøndum Frøkjær3 and Asbjørn Mohr Drewes2
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Clin Physiol Funct Imaging (2012) doi: 10.1111/cpf.12011 REVIEW ARTICLE Update of exocrine functional diagnostics in chronic pancreatitis Camilla Nøjgaard1, Søren Schou Olesen2, Jens Brøndum Frøkjær3 and Asbjørn Mohr Drewes2 1Department of Internal Medicine, Amager Hospital, Copenhagen, 2Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, and 3Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark Summary Correspondence Diagnostics of pancreatic insufficiency rely mainly on tests of pancreatic exocrine Camilla Nøjgaard, Department of Internal Medi- function based on either measurement of pancreatic secretion or the secondary cine, Amager Hospital, Copenhagen, Denmark effects resulting from lack of digestive enzymes or imaging modalities. These E-mail: [email protected] methods have been developing rapidly over the last decades, and the aims of this Accepted for publication review were to describe exocrine functional testing and imaging of the pancreas Received 15 June 2012; accepted 07 November 2012 in chronic pancreatitis.. Key words chronic pancreatitis; enzymes; exocrine insufficiency; functional testing; imaging Introduction Functional procedures The pancreas is an organ with an exocrine and endocrine function. Anatomically, it lies in the retroperitoneum and is Duodenal intubation tests (invasive procedures) therefore difficult to biopsy, and imaging may also be cum- Lundh test meal (also named Borgstrom€ test) bersome. Chronic pancreatitis (CP) is a chronic inflammatory condition characterized by irreversible morphological changes In Scandinavian literature, Lundh test meal has often been con- in the pancreas. During time, the inflammation leads to sidered as the gold standard for the definition of exocrine pan- destruction of the endocrine and exocrine tissue and thereby creatic insufficiency. It was described by Borgstrom,€ Dahlqvist exocrine and endocrine insufficiency, development of fibrosis and Lundh in 1962 (Borgstrom€ et al., 1962), but currently, and eventual calcifications. The diagnosis is based on a combi- only centres with special interest in pancreatitis use the test as nation of clinical information, imaging procedures and func- standard procedure. The procedure takes 2–3 h. In the fasting tional testing but rarely on histology (Layer et al., 1994). The patient, a tube is placed in the third part of duodenum, and diagnosis is easy when calcifications have developed or if his- the position is confirmed radiologically. The patient consumes tology is available, but in the early stages, the diagnosis is a standard meal, and during the next 80 min, the duodenal often challenging. This partly relates to the slow progression juice is aspirated. Volume and pH are noted for each specimen, of the anatomical and functional changes of the organ, and and concentrations of bicarbonate, lipase and amylase are the fact that the anatomical changes are not necessarily con- determined. If the volume of the duodenal aspirate is too small, nected to functional impairment. The degree of ductal changes the patient is stimulated by intravenous cholecystokinin. After- probably plays a larger role than the parenchymal abnormali- wards, the aspirate is investigated for the concentration of duo- ties (Domınguez-Munoz~ et al., 1995). Hence, diagnostics rely denal amylase and lipase. The pancreatic insufficiency can be mainly on (i) tests of pancreatic exocrine function based on divided into mild, moderate or severe insufficiency depending either measurement of pancreatic secretion or the secondary on the concentrations of the enzymes. Lundh test meal is effects resulting from lack of digestive enzymes or (ii) imag- thought to be more sensitive to mild and moderate insuffi- ing modalities. These methods have been developing rapidly ciency than faecal fat excretion according to the relation over the last decades, and the aims of this review were to between lipase secretion and stool fat, as patients with CP will describe state of the art of exocrine functional testing and first develop elevated faecal fat excretion if the lipase secretion imaging of the pancreas in CP. is lower than 5–7% of normal (DiMagno et al., 1973). © 2012 The Authors Clinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine 1 2 Update of exocrine functional diagnostics in chronic pancreatitis, C. Nøjgaard et al. et al., 1998; Hardt et al., 2002; Chowdhury & Forsmark, The secretin–pancreozymin test 2003). In a study by Loser€ et al. (1996), the secretin–caerulein In non-Scandinavian countries, this test is most often used as test was used as gold standard to categorize pancreatic exo- the gold standard for exocrine pancreatic testing, but primarily crine insufficiency. Faecal elastase-1 sensitivity was 63% for in centres specifically interested in pancreatitis (Lankisch, mild, 100% for moderate, 100% for severe and 93% for all 1993). As the Lundh test meal, it is thought to be more sensi- patients with exocrine pancreatic insufficiency, and specificity tive to mild and moderate insufficiency than faecal fat excre- was 93%. Furthermore, the individual day-to-day variations of tion. In the fasting patient, a double-lumen tube is passed into faecal elastase-1 concentrations were low (mean CV = 15%; the third part of duodenum, and the position is confirmed Loser€ et al., 1996). These numbers are comparable with many radiologically. The duodenal juice is aspirated for a 15-min of the invasive pancreatic function tests, and the faecal elas- baseline period and then for three consecutive 15-min periods tase-1 test is increasingly used as the first-line measure of pan- after infusion of secretin and pancreozymin–cholecystokinin creatic exocrine insufficiency. The great success of the faecal intravenously. The volume and pH are noted for each speci- elastase-1 test has mainly been attributed to its non-invasive men, and concentrations of bicarbonate, lipase, trypsin, and nature. Furthermore, it is relatively cheap, easy to handle for chymotrypsin are determined (Burton et al., 1960). the patient and laboratory staff, and it can be stored at room temperature for more than a week. A few limitations, how- ever, need to be considered when using the faecal elastase-1 The endoscopic secretin stimulation test test: First, diarrhoea or steatorrhoea of non-pancreatic origin By using this method, it is possible to perform a functional may artificially lower faecal elastase-1 concentration due to di- test of the pancreas simultaneously with an upper endoscopy lutional effects (Fischer et al., 2001). Second, faecal elastase-1 of the patient. The fasting patient is given secretin intrave- cannot be used to assess the response to pancreatic supple- nously. Thirty minutes after administration of secretin, the ment therapy as faecal elastase-1 remains low in stool despite duodenoscope is passed into the stomach and all gastric fluid pancreatic supplements. Finally, the relatively low sensitivity present is aspirated and discarded. The tip of the duodeno- in mild pancreatic disease needs to be taken into consideration scope is then placed closely to the ampulla of Vater, and duo- and limits the use of faecal elastase-1 to identify patients with denal aspirate is drawn for maximum 10 min and then pH is early and mild CP. measured. The measurements are excluded if pH is below 6Á0. The collected fluid is measured and analysed for the concen- Faecal fat excretion tration of bicarbonate, lipase and elastase (Jensen & Larsen, 2008; Law et al., 2012). Compared with the Lundh test meal, The simplest measurement of pancreatic enzyme action is endoscopic secretin stimulation test can differentiate between measurement of faecal fat excretion. Prior to faecal fat analy- normal and reduced exocrine function with acceptable accu- sis, the patient has to discontinue use of enzyme substitution racy, yielding positive and negative predictive values of 88% and under optimal conditions keep a constant fat intake of À and 83%, respectively. It is suggested that a combination of 100 g day 1 for 5 days. Then stool samples are collected for the concentration of bicarbonate and lipase is best to charac- analysis. To minimize sample errors, collection of three stool terize the patient’s exocrine pancreatic function into normal, samples is usually employed. The collected stool is homoge- reduced or insufficient (Jensen & Larsen, 2008). This method nized and fat extracted by organic solvent. Finally, the content is, however, not used routinely. of free fatty acids is quantified (Van De Kamer et al., 1949). À À A faecal fat quantity of >7 g day 1 (1Á9 mmol day 1) is con- sidered to be abnormal and compatible with a diagnosis of Non-invasive exocrine pancreatic function tests pancreatic exocrine insufficiency. Clinical overt steatorrhoea is À typically present at faecal fat quantities >15 g day 1 Faecal elastase-1 À (4 mmol day 1). In addition, the fat absorption coefficient Pancreatic elastase-1 is a pancreas-specific enzyme that is not can be calculated as a quantitative index of fat absorption. This degraded during intestinal passage. It is approximately sixfold is accomplished according to the formula (dietary fat enriched in faeces compared with duodenal juice and can be intake À stool fat/dietary fat intake) 9 100% (normal measured in stool using a sensitive enzyme-linked immuno- >92Á5%; Chowdhury & Forsmark, 2003). Maldigestion of fat sorbent assay (ELISA) with monoclonal antibodies (Sziegoleit only occurs after approximately