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Chronic pancreatitis Chronic pancreatic (CP) is defined as a continuing inflammatory disease of the pancreas characterized by irreversible morphologic changes, often associated with pain and sometimes with the loss of exocrine and/or en-docrine function.1 Changing patterns of alcohol consumption and the availability of more sensitive diagnostic tests have led to the conclusion that CP is more prevalent than previously suspected.2 Although histology remains the gold standard against which all diagnos-tic approaches are judged, it is not practical in the clinical setting. Diag- nosis currently depends on identifying clinical and morphologic features that characterize the final common pathologic pathway of a variety of pancreatic disorders. Clinical manifestations The primary clinical manifestations of CP are abdominal pain and pancreatic insufficiency but patients occasionally present with the consequences of a complication. 1. Abdominal pain The pain is typically epigastric in location, often radiates to the back, is frequently worse after meals and may be relieved by sitting upright or leaning forward. Pain is not invariably present and in 1 series 20 % of patients with CP presented with pancreatic exocrine or endocrine insufficiency but no pain.3 2. Pancreatic exocrine insufficiency Clinically significant fat and protein deficiencies do not occur until over 90 % of pancreatic function is lost.4 The clinical manifestations of fat malabsorption are steatorrhoea and flatulence. Malabsorption of fat-soluble vitamins and vitamin B12 may also occur but clinically symptomatic vitamin deficiencies are rare.5 3. Pancreatic endocrine insufficiency Overt diabetes mellitus typically occurs late in the course of the disease. A family history of type 1 or type 2 diabetes mellitus, early pancreatic calcification and distal pancreatectomy increase the risk of developing diabetes mellitus.6 Most patients with diabetes mellitus secondary to CP require insulin. Due to the loss of glucagon-producing α-cells, such patients are at increased risk of spontaneous and treatment-related hypoglycaemia. 4. Complications Patients may occasionally present with complications of CP such as duo-denal obstruction, bile duct obstruction, pancreatic pseudocyst, pseudo-aneurysm, splenic vein thrombosis, pancreatic ascites, pleural effusion and pancreatic cancer.7 Recommendation CP is more prevalent than previously suspected and unexplained abdominal pain, a history suggestive of maldigestion and diabetes mellitus should raise the possibility of the diagnosis. Diagnosis The diagnosis of CP can be made by morphologic criteria alone or by a combination of morphologic and functional criteria. Pancreatic function tests (PFTs) alone do not distinguish CP from pancreatic insufficiency without CP. 1. Imaging studies Despite the availability of numerous imaging modalities, early CP remains difficult to diagnose. X-rays of the abdomen Plain films reveal pancreatic calcification in only 30 % of patients with CP. Pancreatic calcification is most common in alcoholic CP and rare in idiopathic pancreatitis. Ultrasonography Transabdominal ultrasonography (TUS) lacks sensitivity and specificity and is of limited value in diagnosing CP. Endoscopic ultrasonography (EUS) is increasingly being used to diagnose CP. Four parenchymal criteria (hyperechoic foci, hyperechoic strands, hypoechoic lobules, cysts) and 5 ductal criteria (dilatation, dilated side branches, main duct irregularity, hyperechoic duct margins, stone) are generally accepted to be indicative of CP.8 Published studies have however been difficult to compare because of variations in the threshold and criteria required to diagnose CP.8,9,10,11,12,13,14 Interpretation is further complicated by the absence of a true gold standard, interobserver variability and the lack of standardized terminology. The publication of minimum standard terminology (MST)15 has been an advance but there is still controversy on the definition of criteria. A recent consensus study aimed correcting these deficiencies led to the development of the so-called Rosemont Criteria.16 Computerized tomography (CT) CT has a sensitivity of 75 – 90 % and a specificity of 85 % 13,17,18 and is currently the screening test of choice. The past decade has seen major advances in CT technology and, when possible, multislice CT should be utilized. Non-enhanced CT findings suggestive of CP are gland atrophy, dilatation of the main PD, ductal calculi, intra- or peripancreatic cysts, thickening of the peripancreatic fascia and splenic vein thrombosis. Focal or diffuse enlargement of the pancreas is occasionally seen and intraductal papillary mucinous neoplasm (IPMN) should always be considered in the different-tial diagnosis. A hypodense mass in the head of the pancreas may simu-late a carcinoma. Enhanced CT findings suggestive of CP include heterogenous enhance-ment of the pancreas and the presence of a mass. Hypoenhancement is indicative of fibrosis whereas isoenhancement suggests the absence of fibrosis. Endoscopic retrograde pancreatography (ERP) ERP not only has a poor sensitivity for diagnosing early or mild CP but a study in elderly patients without pancreatic disease revealed a poor speci-ficity.19 Most centres limit the use of ERP to cases likely to require a thera-peutic intervention. Traditional criteria such as the Cambridge Classification for CP20 are arguably outdated and have lost their relevance. MRI MRI changes suggestive of CP are loss of signal intensity on fat-suppressed T1WI and diminished contrast enhancement. MRCP delineates fluid-filled structures such as the main pancreatic duct and pseudocyst well. As side branches are visualised in only 10 - 25 % of cases,21,22 it is of limited diagnostic value in patients with early CP. At present MRCP does not have the sensitivity and specificity of ERCP and therefore does not have a central role in assessing the pancreatic duct. MRCP with secretin stimulation may eventually replace ERCP but has similar limitations.23 2. Pancreatic function tests (PFTs) PFTs have limited utility in the diagnosis of CP because of a lack of availability, poor patient tolerance and uncertain validation of the test results. They furthermore do not distinguish CP from pancreatic insufficiency without CP. PFT are of value in diagnosing pancreatic insufficiency, in evaluating patients with CP and in providing a basis for rational treatment. Direct PFTs Direct PFTs involve stimulation of the pancreas by means of a meal or hormonal secretagogues and subsequent collection and analysis of the duodenal fluid. The secretin test measures the ability of the ductal cells to produce bicarbonate and the cholecystokinin (CCK) test the ability of the acinar cells to secrete digestive enzymes. The secretin-CCK test provides simultaneous assessment of ductal and acinar secretory capacity. The Lundh test has been abandoned. Indirect PFTs Indirect PFTs measure the consequences of pancreatic exocrine insufficiency and are more widely available than direct PFTs. They are however less sensitive and their main utility is the diagnosis of advanced pancreatic exocrine insufficiency. Faecal fat Quantitative measurement of faecal fat requires a high fat diet, lack of exogenous enzymes and a 72 h collection of stool and is only sensitive for the diagnosis of advanced pancreatic insufficiency.24 Stool for Acid Steatocrit is an attractive alternative to this cumbersome test as it not only compares favourably in terms of sensitivity and specificity but also is also inexpensive.25 Faecal chymotrypsin and elastase-1 Chymotrypsin and elastase-1 remain relatively stable during transit through the gastrointestinal tract. Measurement is easy and relatively inexpensive but these tests lack sensitivity for mild to moderate pancreatic exocrine insufficiency and specificity in several non-pancreatic gastrointestinal disorders.26,27 Pancreolauryl test (PLT) The Pancreolauryl test involves the ingestion of fluorescein dilaurate and measurement of fluorescein in either serum or a 24 h urine collection. As with other indirect tests, several non-pancreatic gastrointestinal disorders may reduce specificity. Breath tests Breath tests involve the oral administration of a 13C-labeled substrate which is hydrolysed within the bowel lumen in proportion to the pancreatic lipase activity. Exhaled 13CO2 is measured by means of mass spectrometry or infrared analysis but, as with other indirect tests, it lacks sensitivity and specificity. Recommendations The diagnosis of CP can be made by morphologic criteria alone or by a combination of morphologic and functional criteria but, despite the availability of numerous imaging modalities, early CP remains difficult to diagnose. X-rays of the abdomen and TUS have poor sensitivities and are not recommended for screening purposes. CT and, increasingly EUS, have become the screening methods of choice. The absence of diag-nostic findings on CT does not exclude CP. PFTs do not distinguish CP from pancreatic insufficiency without CP and have a limited role in the diagnosis of CP. Aetiology Despite numerous attempts, the ideal disease classification system for CP remains elusive. One such classification is The M-ANNHEIM multiple risk factor classification of chronic pancreatitis28 Pancreatitis with Multiple risk factors Alcohol consumption Alcohol accounts for 60 – 70 % of cases of CP in the Western world. The daily alcohol consumption at which persons are at risk of developing CP has not been established but is estimated to be 60 – 80 g/day. Gender and genetic and other co-factors may play pivotal roles and the term alcoholic pancreatitis therefore does not necessarily imply chronic alcoholism or harmful patterns of alcohol use. Cigarette smoking appears to increase not only the risk of CP but also of disease progression. There are several tools that may aid in identifying individuals with harmful patterns of alcohol consumption. Alcohol Use Disorders Identification Test (AUDIT)29 provides a reliable assessment but requires the participant to convert traditional measures into standard drinks. The Paddington Alcohol Test (PAT)30 can be completed in 20 s and compares well with AUDIT. Nicotine consumption The odds ratio for smokers developing CP compared to non-smokers developing CP ranges from 7.8 to 17.3 and the risk increases with the amount of smoking. Tobacco smoking should thus be considered an independent risk factor for the development of CP.31,32 Nutritional factors The relationship between protein calorie malnutrition, hypertriglyceri-daemia and other hyperlipidaemias and CP remains controversial. Hereditary factors Hereditary factors are believed to play a role in hereditary pancreatitis, familial pancreatitis, early-onset idiopathic pancreatitis, late-onset idiopathic pancreatitis and tropical pancreatitis.r> Mutations in the gene coding for cationic trypsinogen cause hereditary pancreatitis.33 Affected individuals usually develop symptoms before the age of 20 years and are at markedly increased risk of developing pancre-atic adenocarcinoma. MuMutations in the genes coding for cystic fibrosis transmembrane conduc-tance regulator (CFTR)34 and pancreatic secretory trypsin inhibitor (PSTI or SPINK1)35 have been identified in patients with idiopathic chronic pancreatitis. Efferent duct factors Entities associated with obstructive CP include trauma, calculi, pseudo-cysts and tumours. It is controversial whether pancreas divisum and sphincter of Oddi dysfunction cause CP. Immunologic factors Autoimmune pancreatitis may be seen in isolation or in association with øgren syndrome, inflammatory bowel disease and a number of other autoimmune disorders. It is an important condition to recognise as the lesion responds to treatment with corticosteroids SeSerologic tests of value in diagnosing autoimmune pancreatitis are hyper-gammaglobulinaemia, elevated IgG, elevated IgG4 and the presence of several autoantibodies (anti-nuclear antibodies, anti-lactoferrin antibo-dies, anti-carbonic anhydrase 11 antibodies and anti-smooth muscle antibodies).36 Miscellaneous and rare metabolic factors Chronic renal failure37 and hyperparathyroidism38 are recognized causes of CP whereas the exact role of medications and toxins remains to be established. Recommendations A detailed history is of crucial importance as it may provide the clue to the tiology. Special attention should be paid to occupation and possible exposure to toxins, nutrition and alcohol and tobacco con-sumption. The use of a validated tool aimed at identifying harmful drinking patterns is encouraged. Renal disease and hyperparathyroidism should be considered in the differential diagnosis and a history of autoimmune disease should raise the possibility of autoimmune pancreatitis. A A detailed family history should be obtained and, if an inherited disorder is suspected, the assistance of a genetic counsellor sought. References 1. ain JE, Pearson RK. Diagnosis of chronic pancreatitis: is a gold standard necessary? Surg Clin North Am 1999;79:829-45. 2. Chocquet M, Menke H, Ledoux S. Self-reported alcohol consump-tion among adolescents and the significance of early onset. A longitudinal approach. Soc Psychiatry Psychiatr Epidemiol 1989; 24:102-12. 3. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP, et al. The different courses of early- and late-onset idiopathic and alcoholic pancreatitis. Gastroenterology 1994;107:1481-7. 4. DiMagno EP, Go VL, Summerskill WH. Relations between pan-creatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288:813-5. 5. Toskes PP, Hansell J, Cerda J, Deren JJ. Vitamin B12 mal-absorption in chronic pancreatic insufficiency. N Engl J Med 1971;284:627-32. 6. Malka D, Hammel P, Sauvanet A, Rufat P, O’Toole D, Bardet P, et al. Risk factors for diabetes mellitus in chronic pancreatitis. Gas-troenterology 2000;119:1324-32. 7. Lowenfels AB, Maisonneuve P Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Eng J Med 1993;328:1433-7. 8. Sahai AV, Zimmerman M, Aabakken , Tarnasky PR, Cunningham JT, van Velse A, et al. Prospective assessment of the ability of en-doscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangio-pancreatography. Gastrointest Endosc 1998;48:18-25. 9. Catalano MF, Lahoti S, Geenen JE, Hogan WJ. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 10. Weirsema MJ, Hawes RH, Lehman G, Kochman ML, Sherman S, Kopecky KK. Prospective evaluation of endoscopic ultrasono-graphy and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic ori-gin. Endoscopy 1993;25:555-64. 11. Kahl S, Glasbrenner B, Leodolter A, Pross M, Schulz HU, Malfert-heiner P. EUS in the diagnosis of early chronic pancreatitis: a pro-spective follow-up study. Gastrointest Endosc 2002;55:507-11. 12. Hollerbach S, Klamann A, Topalidis T, Schmeigel WH. Endosco-pic ultrasonography (EUS) and fine needle aspiration (FNA) cyto-logy for diagnosis of chronic pancreatitis. Endoscopy 2001;33:824-31. 13. Buscail L, Escourrou J, Moreau J, Delvaux M, Louvel D, Lapeyre F, et al. Endoscopic ultrasonography in chronic pancreatitis: a com-parative prospective study with conventional ultrasonography, com puted tomography, and ERCP. Pancreas 1995;10:251-7. 14. Hastier P, Buckley MJ, Francois E, Peten EP, Dumas R, Caroli- Bosc FX, et al. A prospective study of pancreatic diseases in pa-tients with alcoholic cirrhosis: comparative diagnostic value of ERCP and EUS and long-term significance of isolated parenchy-mal abnormalities. Gastrointest Endosc 1999;49:705-9. 15. International Working Group for Minimum Standard Terminology for Gastrointestinal Endoscopy. Reproduction of minimum stan-dard terminology in gastrointestinal endosonography. Dig Endosc 1998:10;158-88. 16. Catalano MF, Sahai A, Levy M, Romagnuolo J, Wiersema M, Brugge W el al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009;69:1262-3. 17. Malfertheiner P, Buchler M, Stanescu A, Ditschuneit H. Exocrine pancreatic function in correlation to ductal and parenchymal mor-phology in chronic pancreatitis. Hepatogastroenterology 1986;33:110-4. 18. Malfertheiner P, Buchler M. Correlation of imaging and function in chronic pancreatitis. Radiol Clin North Am 1989;27:51-64. 19. Nagai H, Ohtsubo K. Pancreatic lithiasis in the aged. Its clini-copathology and pathogenesis. Gastroenterology 1984:86;331-8. 20. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984; 25;756-9. 21. Ueno E, Takada Y, Yoshida I, Toda J, Sugiura T, Toki F. Pan- creatic diseases: Evaluation with MR cholangiopancreatography. Pancreas 1998:16;418-26. 22. Yamaguchi K, Chijiwa K, Shimizu S, Yokohata K, Morisaki T, Tanaka M. Comparison of endoscopic retrograde and magnetic resonance cholangiopancreatography in the surgical diagnosis of pancreatic disease. Am J Surg 1998:175;203-8. 23. Kinney TP, Punjabi G, Freeman M. Technology insight: Appli-cations of MRI for the evaluation of benign disease of the pan-creas. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 148-59. 24. Luk GD. Same questions, different answers. Gastroenterology 1979;76:891-2. 25. Dumasy V, Delhaye M, Cotton F, Deviere J. Fat Malabsorption screeing in chronic pancreatitis. Am J Gastroenterol 2004;99:1350-4. 26. Niederau C, Grendell JH. Diagnosis of chronic pancreatitis. Gastroenterology 1985;88;1973-95. 27. Gullo L, Ventrucci M, Tomassetti P, Migliori M, Pezzilli R. Fecal elastase 1 determinations in chronic pancreatitis. Dig Dis Sci 1999;44:210-3. 28. Schneider A, Löhr JM, Singer, MV. The M-ANNHEIM Classifica-tion of Chronic Pancreatitis: Introduction of a unifying classifica-tion system based on a review of previous classifications of the disease. J Gastroenterol 2007;42:101-119. 29. Reinert DF, Allen JP. The Alcohol Use Disorders Identification Test (AUDIT): A review of recent research. Alcohol Clin Exp Res 2002;2:272-9. 30. Patton R, Hilton C, Crawford MJ, Touquet R. The Paddington Alcohol Test: a short report. Alcohol 2004;39:266-8. 31. Talamini G, Bassi C, Falconi M, Sartori N, Salvia R, Rigo L, et al. Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 1999;44:1301-11. 32. Lin Y, Tamakoshi A, Hayakawa T, Ogawa M, Ohno T. Cigarette smoking as a risk factor for chronic pancreatitis: a case-control study in Japan. Research Committee on Intractable Panreatic Diseases. Pancreas 2000:21;109-14. 33. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a muta-tion in the cationic trypsinogen gene. Nat Genet 1996;14;141-5. 34. Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339:687-8. 35. Pfützer RH, Barmada MM, Brunskil APJ, Finch R, Hart PS, Neoptolemos J, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastro-enterology 2000;119;615-23. 36. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Auto-immune pancreatitis. New Engl J Med 2006;335:2670-6. 37. Akari T, Ueda M, Ogawa K, Tsuji T. Histological pancreatitis in end-stage renal disease. Int J Pancreatol 1992;12;263-9. 3838. Mergener K, Baillie J. Chronic pancreatitis. Lancet 1997;340: 1379- 1385. Paddington Alcohol Test (PAT) 1. Do you drink alcohol? Yes – go to 2.r>No 2. What is the most you will drink in any one day? (Pub measures shown in brackets) Beer/lager/cider _____ Pints (2) _____ Cans (1.5) Strong beer/lager/cider _____ Pints (5) _____ Cans (4) Wine _____ Glasses (1.5) _____ Bottles (9) Fortified wine _____ Glasses (1) _____ Bottles (12) Spirits _____ Singles (1) _____ Bottles (30) Total _____ 3. If this is more than 8 units per day for a man and 6 units per day for a woman, does this happen Once a week or more = PAT +ve Or if less frequent At least once a month = PAT +ve Less than once a month = PAT –ve (trumped by 4) 4. Do you feel your current attendance is related to alcohol? Yes = PAT +ve NoNo = PAT –ve Rosemont Criteria Major criteria for CP (1) perechoic foci with shadowing and main pancreatic duct (PD) calculi and (2) lobularity with honeycombing. MiMinor criteria for CP cysts, dilated ducts ≥ 3.5 mm, irregular PD contour, dilated side branches ≥ 1 mm, hyperechoic duct wall, strands, nonshadowing hyperechoic foci, and lobularity with noncontiguous lobules. EUS diagnosis of CP on the basis of consensus criteria 1. Consistent with CPr> A. 1 major A feature + ≥ 3 minor features B. 1 major A feature + 1 major B feature C. 2 major A features 11. Suggestive of CP A. 1 major A feature + < 3 minor features B. 1 major B feature + ≥ 3 minor features C. ≥ 5 minor features (any) 111. Indeterminate for CP A. 3 to 4 minor features, no major features B. major B feature alone or with < 3 minor features 1V. Normal &#≤ 2 minor features, no major features The Cambridge Classification of Chronic Pancreatitis Group Terminology Findingsr>0 Normal Equivocal Whole gland without abnormal feature Less than 3 abnormal branches 1 Mild More than 3 abnormal braches 2 Moderate Abnormal main duct and branches 3 Marked As above with one or more of the following - Large cavities (> 1 cm) - Intraductal filling defects or calculi - Duct obstruction or strictures - Gross irregularity - - Contiguous organ invasion Sunday, 14 February 2010r> |
