Slides

REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY

Description
1. GASTROENTEROLOGY 2007;132:1557–1573REVIEWS IN BASIC AND CLINICALGASTROENTEROLOGY Wafik El-Diery and David Metz, Section Editors Roland M. Schmid, Guest Section…
Categories
Published
of 17
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Transcript
  • 1. GASTROENTEROLOGY 2007;132:1557–1573REVIEWS IN BASIC AND CLINICALGASTROENTEROLOGY Wafik El-Diery and David Metz, Section Editors Roland M. Schmid, Guest Section Editor (p 1557–1573) K. Rajender Reddy, Guest Section Editor (p 1574 –1594)Chronic Pancreatitis: Challenges and Advances in Pathogenesis,Genetics, Diagnosis, and TherapyHEIKO WITT,* MINOTI V. APTE,‡ VOLKER KEIM,§ and JEREMY S. WILSON‡*Department of Hepatology and Gastroenterology, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany; ‡Pancreatic Research Group,South Western Sydney Clinical School, The University of New South Wales, Sydney, Australia; and the §Medizinische Klinik und Poliklinik II, UniversitätsklinikumLeipzig, GermanyChronic pancreatitis (CP) is characterized by progres- digestion) and diabetes.1 As such, this review is a naturalsive pancreatic damage that eventually results in signif- extension of the report by Pandol et al (See March issueicant impairment of exocrine as well as endocrine func- 2007;132:1127–1151). The reported incidence of CP intions of the gland. In Western societies, the commonest industrialized countries ranges from 3.5 to 10 perassociation of chronic pancreatitis is alcohol abuse. Our 100,000 population. Alcohol abuse is the major associa-understanding of the pathogenesis of CP has improved tion of CP in Western countries, but other factors such asin recent years, though important advances that have genetic mutations, pancreatic duct obstruction caused bybeen made with respect to delineating the mechanisms strictures, hypertriglyceridemia, hypercalcemia, and auto-responsible for the development of pancreatic fibrosis immunity also have been implicated.1–3 Another distinct,(a constant feature of CP) following repeated acute at- non–alcohol-related form of CP that has received increas-tacks of pancreatic necroinflammation (the necrosis- ing attention in recent times is tropical pancreatitis. Thefibrosis concept). The pancreatic stellate cells (PSCs) are pathogenesis of this condition is unknown, although annow established as key cells in fibrogenesis, particularly association with a mutation in a serine protease inhibitorwhen activated either directly by toxic factors associated gene (SPINK1) has been proposed.4 In a minority of caseswith pancreatitis (such as ethanol, its metabolites or of CP, no identifiable cause can be found and a diagnosisoxidant stress) or by cytokines released during pancre- of idiopathic pancreatitis is made.5 However, it is antic-atic necroinflammation. In recent years, research effort ipated that with increasing identification of putative ge-has also focused on the genetic abnormalities that may netic/environmental factors, the numbers of true idio-predispose to CP. Genes regulating trypsinogen activa- pathic cases of CP will diminish further.tion/inactivation and cystic fibrosis transmembrane The key histopathologic features of CP (regardless ofconductance regulator (CFTR) function have received etiology) are pancreatic fibrosis, acinar atrophy, chronicparticular attention. Mutations in these genes are now inflammation, and distorted and blocked ducts.1,6 Addi-increasingly recognized for their potential ‘disease mod- tional distinctive histologic features have been describedifier’ role in distinct forms of CP including alcoholic, in some forms of CP, such as extensive pancreatic calci-tropical, and idiopathic pancreatitis. Treatment of un- fication in tropical pancreatitis4 and a prominent lym-complicated CP is usally conservative with the major phocytic and plasma cell infiltrate in autoimmune pan-aim being to effectively alleviate pain, maldigestion and creatitis.7,8diabetes, and consequently, to improve the patient’squality of life. Surgical and endoscopic interventions Abbreviations used in this paper: ADH, alcohol dehydrogenase; AIP,are reserved for complications such as pseudocysts, ab- autoimmune pancreatitis; CFTR, cystic fibrosis transmembrane con-scess, and malignancy. ductance regulator; CP, chronic pancreatitis; ERCP, endoscopic retro- grade cholangiopancreatography; EUS, endoscopic ultrasonography; FAEE, fatty acid ethyl ester; LPS, lipopolysaccharide; MCT, medium-C hronic pancreatitis (CP) is a condition characterized chain triglyceride; MRCP, magnetic resonance cholangiopancreatog- raphy; PSC, pancreatic stellate cell; SO, sphincter of Oddi. by progressive and irreversible damage to both exo- © 2007 by the AGA Institutecrine and endocrine components of the pancreas, even- 0016-5085/07/$32.00tually resulting in significant exocrine insufficiency (mal- doi:10.1053/j.gastro.2007.03.001
  • 2. 1558 WITT ET AL GASTROENTEROLOGY Vol. 132, No. 4 Clinical Features IV. A final stage, mostly without acute flares and ab- The 3 major clinical features of CP are pain, mal- sence or decreased frequency of pain, possibly asso-digestion, and diabetes. ciated with evidence of endocrine and exocrine in- sufficiency (burnout, see below) Pain Single stages may be skipped, eg, some patients Abdominal pain is the most vexing clinical prob- initially may present with a painless stage IV chroniclem and the most common indication for surgical inter- pancreatitis, showing maldigestion, steatorrhea, orvention in patients with CP. Severe pain decreases appe- diabetes.tite, thereby contributing to malnutrition and weightloss. The pain is usually epigastric in location (although Natural Historymore diffuse pain in the upper abdomen can occur) andmay radiate to the back. Although recurrent (type A) or The natural history of CP has been difficult tocontinuous (type B) pain is considered to be the hallmark characterize because of the variability in presentationof CP, a subgroup of patients may have no pain at all, of the disease and the relative inaccessibility of thepresenting instead with symptoms of pancreatic insuffi- pancreas to histologic assessment. However, severalciency. While the course of pain in CP can be unpredict- studies involving large series of medical and surgicalable, in general it is reported to improve or resolve with cases have provided some important insights in thistime in the majority of patients. Whether the alleviation area.5,9,10,12–14of pain coincides with the onset of exocrine insufficiency Alcohol-induced CP usually develops after a prolonged period (5–15 y) of heavy alcohol consumption and does(burn-out hypothesis, see below) is still a matter of de- not develop after an isolated bout of heavy drinking. In abate.9,10 In patients with known CP, pain also may result recent report (published in 2005), Mullhaupt et al10 an-from an acute attack of pancreatitis, from a pancreatic alyzed a series of 343 patients with CP (265 patients withpseudocyst, portal or splenic vein thrombosis, or bile alcoholic CP, 57 with idiopathic CP, and 11 with hered-duct obstruction (associated with jaundice). Associated itary pancreatitis). They reported that the median age atgastric or duodenal ulcers also may contribute to pain in onset of alcoholic pancreatitis is 36 years, whereas that ofthese patients. hereditary pancreatitis was as early as 10 years. Idiopathic CP has 2 forms of clinical presentation: an early onset Maldigestion and Diabetes (juvenile) form with a median age at onset of 23 years, Steatorrhea and weight loss are further important and a late-onset (senile) form with a median age at onsetfeatures of CP. Steatorrhea is a symptom of advanced of 62 years. Tropical pancreatitis is characterized by andisease and does not occur until pancreatic lipase secre- early onset (mean age, 22 y), rapid progression, and severetion is reduced to less than 10% of normal. Maldigestion pancreatic damage in the absence of a history of alcoholof lipids occurs earlier than that of other nutrients (pro- abuse or biliary disease.4 On the other hand, autoim-teins and carbohydrates) since lipase secretion decreases mune pancreatitis is reported to occur at a later age, withmore rapidly than protease or amylase secretion. In ad- a mean age at onset of 59.4 years.8dition to exocrine insufficiency, diabetes mellitus may The median time to the development of pancreaticdevelop in the long-term course of the disease. The dia- insufficiency after disease onset depends on the type ofbetes is classified as type IIIc according to the American pancreatitis under consideration. In alcoholic and late-Diabetes Association11 and is characterized by destruc- onset idiopathic pancreatitis, exocrine insufficiency de-tion of both insulin- and glucagon-producing cells. The velops earlier than in early onset idiopathic pancreati-diabetic state often is fragile because the co-existing de- tis9,10,15; in alcoholic CP, pancreatic insufficiency canficiency of glucagon synthesis aggravates hypoglycemic develop as early as 6 years after the onset of disease.10situations. Similarly, endocrine insufficiency occurs earlier in alco- holic pancreatitis with a median time of 8 years, com- Classification pared with 27 years in early onset idiopathic pancreatitis. Chronic pancreatitis may be separated into 4 dif- In tropical pancreatitis, both exocrine and endocrine in-ferent stages: sufficiency is reported to be evident at very early stages, often at the time of presentation in the majority (70%) of I. A pre-clinical stage with absent or uncharacteristic patients.4 symptoms With respect to the progression of pancreatic insuffi- II. Recurrent acute episodes of pancreatitis without def- ciency over time, there are conflicting data. Studies by inite signs of CP Lankisch et al12 and other groups16 –18 described noIII. Further recurrent episodes with intermittent or con- change or even slight improvements in pancreatic func- stant pain in between and signs of CP such as duct tion over time in patients with CP. In contrast, Mull- dilatation and pancreatic calcification on imaging haupt et al10 reported a progressive deterioration of pan-
  • 3. April 2007 CHRONIC PANCREATITIS 1559 and digestive system. In their recently reported series of alcoholic and idiopathic CP patients, Mullhaupt et al10 reported that the 3 major causes of death were cardio- vascular disease, severe infection, and malignancy. Pathogenesis of Chronic Pancreatitis Research into the pathogenesis of CP was initially focused on large and small pancreatic ducts and then on the pancreatic parenchymal and nonparenchymal cells. In more recent times, the genetics of CP has attracted considerable attention and has revolutionized our knowl- edge of the possible mechanisms mediating pancreatic injury (this topic is discussed in more detail later in the section titled “Genetics of Chronic Pancreatitis”). The majority of studies related to the pathogenesis of CP haveFigure 1. Necrosis-fibrosis concept of progressive pancreatic injury. focused on alcohol-induced CP. (The focus on alcohol inRepeated attacks of acute pancreatic necroinflammation result in in- this article reflects the large amount of available scientificcreasing residual damage to the pancreas, eventually resulting in irre- literature on the topic. Relatively little is known aboutversible damage to the gland, characterized by acinar atrophy andfibrosis. the pathogenesis of acute episodes in tropical or autoim- mune pancreatitis, although there is a growing body of literature dealing with autodigestive injury in hereditarycreatic function during a median follow-up period of 16 acute pancreatitis.) This is not surprising, given thatyears in patients with alcoholic pancreatitis. The reasons alcohol abuse is the most common association of CP.for these discrepant findings are unclear, but may reflect Traditionally, alcoholic pancreatitis has been thought ofdifferences in study design, duration of follow-up evalu- as a form of CP from the start, punctuated during itsation, and/or differences in the sensitivities of the tests course by acute exacerbations. This notion was based onused to assess pancreatic function. studies showing that histologic and radiologic evidence The course of the pain of CP is unpredictable in indi- of CP was evident in the pancreas of many patients at thevidual patients. However, in general, pain is reported to time of their first attack of pancreatitis.24,25 Furthermore,improve or resolve with time in the majority of patients autopsy studies had reported evidence of pancreatic fi-with CP. In this regard, Mullhaupt et al10 reported that brosis in alcoholics with no clinical history of pancreati-240 of 251 patients (95.6%) with alcoholic pancreatitis tis.26 However, this concept has been challenged in recentachieved pain relief after a median time of 10 years years, with current opinion favoring the necrosis-fibrosis(range, 0 –30 y) and that, in the majority of patients, this hypothesis that alcoholic pancreatitis begins as an acutepain relief coincided with the onset of exocrine and process that progresses to chronic irreversible damage asendocrine pancreatic insufficiency (pancreatic “burn- a result of repeated acute attacks (Figure 1).out”). However, other earlier series reported no correla- The necrosis-fibrosis concept is supported by bothtion of pain relief with pancreatic insufficiency.9,12 Absti- clinical and experimental data. A large prospective studynence from alcohol is another important factor has reported that clinical manifestations of CP (exocrineinfluencing pancreatic dysfunction and pain in patients and endocrine dysfunction) were more likely to occur inwith alcoholic CP. Abstainers have a slower rate of dete- alcoholics with frequent clinical recurrent acute at-rioration of pancreatic function and a better response to tacks.10,15 In addition, a postmortem study of patientspain therapy than nonabstainers.10,15,19,20 with fatal acute alcoholic pancreatitis has shown that in The risk of developing pancreatic cancer is significantly 53% of patients there was no evidence of chronic changeshigher in patients with CP than in the general popula- in the pancreas.27tion.21 Alcoholic CP and tropical pancreatitis are associ- Experimental evidence in support of the necrosis-fibro-ated with a 15-fold and a 5-fold increased risk of pancre- sis hypothesis has accumulated rapidly in recent yearsatic cancer, respectively,21,22 whereas the cumulative and suggests that this concept is applicable not only tolifetime risk of cancer in patients with hereditary pancre- alcoholic CP but also to non–alcohol-related pancreatitisatitis is reported to be as high as 40%.21 (such as hereditary and tropical pancreatitis), in which Mortality in CP, particularly alcoholic pancreatitis, is the clinical course is punctuated with recurrent attacks ofapproximately one-third higher than that in an age- and pancreatic necroinflammation. Animal models of pancre-sex-matched general population.23 However, only one atic fibrosis have now been developed by inducing re-fifth of this excess mortality can be attributed directly to peated episodes of acute necroinflammation in the pan-pancreatitis itself. Most of the deaths in CP are caused by creas using an inhibitor of superoxide dismutase28 or bythe effects of alcohol and/or smoking on the liver, lungs, administration of supraphysiologic doses of cerulein
  • 4. 1560 WITT ET AL GASTROENTEROLOGY Vol. 132, No. 4with or without other measures such as ethanol admin- precipitation within pancreatic ducts precedes acinaristration or pancreatic duct obstruction.29,30 Most re- damage. However, recent reports of an association be-cently, Vonlaufen et al31 have demonstrated that repeated tween mutations of the cystic fibrosis transmembranepancreatic necroinflammation induced by endotoxin ad- conductance regulator (CFTR) gene (which affect ductministration in alcohol-fed animals leads to the changes cell function) and the risk of developing idiopathic CPof CP within the gland. The molecular mechanisms re- have revived interest in the possible role of ductularsponsible for pancreatic fibrosis after necroinflammatory dysfunction in pancreatic injury.41,42 The association be-episodes now are understood better, largely due to the tween CFTR mutations and alcoholic pancreatitis is atcharacterization of the cells that play a critical role in the present uncertain. Nonetheless, the possibility that thefibrogenic process, namely, the pancreatic stellate cells duct cell (in addition to the acinar cell) is an important(PSCs; see below). site of alcohol-induced injury cannot be discounted. In this regard, it is of interest to note that as early as in Alcohol-Induced Pancreatic Injury 1965, Sarles et al43 had reported that patients with alco- Studies in the field of alcoholic pancreatitis often holic pancreatitis manifested increased levels of sweathave been hampered by the lack of suitable animal mod- electrolytes (chloride and sodium), suggesting CFTR dys-els of the disease and the difficulty in obtaining human function in this disease.pancreatic tissue for analysis. Nonetheless, significant There is some evidence to suggest that chronic alcoholadvances have been made in recent years, particularly consumption facilitates protein plug formation withinwith respect to the direct toxic effects of alcohol on the pancreatic ducts. This includes: (i) increased total proteinpancreatic acinar cell, which may predispose the gland to concentration of pancreatic juice in alcoholics44; (ii) annecroinflammation and the role of PSCs in the produc- increased capacity of acinar cells to synthesize lithos-tion of pancreatic fibrosis. tathine on alcohol exposure45 (lithostathine is a known Investigations into the pathogenesis of alcoholic pan- constituent of protein plugs with a propensity for pre-creatitis usually have followed 1 of 2 approaches, based cipitation); and (iii) an alcohol-induced decrease in acinaron 2 fundamental clinical observations. One observation content of glycoprotein GP246 (possibly because of in-is that the incidence of alcoholic pancreatitis is propor- creased secretion into pancreatic juice); this glycoproteintional to the level of alcohol consumption, suggesting has unique self-aggregating properties and is an impor-the presence of dose-related effects of alcohol on the tant constituent of protein plugs. Thus, it is possible thatpancreas.32–34 The other observation is that only a mi- blockage of small intralobular ducts by protein precipi-nority of alcoholics develop pancreatitis, suggesting that tates hinders acinar cell secretion, thereby blocking thean additional cofactor or susceptibility factor is required exit of digestive enzymes and predisposing the cell toto trigger overt disease.35,36 acute autodigestive injury (see below). Effect of alcohol on pancreatic acinar cells. Over Constant Effects of Alcohol on the Pancreas the past 3 decades, the focus of research in alcoholic Effect of alcohol on large ducts. Early research pancreatitis has shifted from pancreatic ducts to theefforts in this area (inspired by Opie’s37 observations pancreatic acinar cell itself. This focus is understandableregarding the mechanism responsible for gallstone pan- given that the cells produce large amounts of digestivecreatitis) were focused on the effects of alcohol on large enzymes (6 –20 g/day), with the potential to cause con-ducts and, in particular, the sphincter of Oddi (SO). The siderable tissue damage. The acinar cell is normally pro-large-duct theories (biliary-pancreatic reflux, duodeno- tected from digesting itself by synthesizing most zymo-pancreatic reflux, and the stimulation-obstruction the- gens as inactive precursors, by segregating zymogens intoory) postulated that altered motility of the SO in re- membrane-bound organelles, and by intracellular anti-sponse to alcohol administration played a central role in proteases. Disruption of these normal protective mecha-the development of the disease. However, unresolved nisms results in premature intracellular activation ofcontroversy about the effects of alcohol on SO function digestive enzymes, leading to autodigestive injury.and pancreatic secretion means that these
  • Search
    Similar documents
    View more...
    Related Search
    We Need Your Support
    Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

    Thanks to everyone for your continued support.

    No, Thanks
    SAVE OUR EARTH

    We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

    More details...

    Sign Now!

    We are very appreciated for your Prompt Action!

    x