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PROGRESSION FROM ACUTE TO CHRONIC PANCREATITIS
ACUTE AND CHRONIC PANCREATITIS
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PROGRESSION FROM ACUTE TO CHRONIC PANCREATITIS A Pathologist’s View Giinter Kloppel, MD
Chronic pancreatitis is the result of fibroinflammatory changes in the pancreas that may be the result of various causes. In Western countries, long-term alcohol abuse is the most common etiologic factor in chronic pancreatitis. Seventy to 80% of the patients presenting with chronic pancreatitis are young to middle-aged men (range, 25-50 y) who are heavy drinkers.2,14, 15, 34, 54 Alcoholic chronic pancreatitis (ACP) is therefore usually meant when the pathogenesis of chronic pancreatitis is discussed. This article focuses on ACP with the aim of reviewing its pathology, discussing the links with acute pancreatitis, and relating the various hypotheses regarding its pathophysiology to the morphologic features of ACP. PATHOLOGY OF ALCOHOLIC CHRONIC PANCREATITIS
In early chronic pan~reatitis:~,29 the pancreas is always unevenly affected. Grossly, the involved parts are enlarged and indurated, showing coarse lobulation or nodular scarring on the cut surface. If the fibrotic area lies in the periphery of the gland, duct irregularities (with occasional calculus formation) may be found solely in the duct tributaries affected by fibrosis. In many cases, extrapancreatic pseudocysts or foci of recent necrosis are found in the vicinity of fibrotic areas.”, 27
From the Department of Pathology, University of Kiel, Kiel, Germany
SURGICAL CLINICS OF NORTH AMERICA
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Histologically, the indurated parts of the pancreas show distinct perilobular fibrosis with occasional involvement of an entire lobule, where most of the acinar cells are replaced by connective tissue (intralobular fibrosis). The ducts within the fibrotic areas between the lobules are distorted and may contain eosinophilic protein plugs. The preserved acinar cells within intact lobuli have a normal appearance and show immunoreactivity to pancreatic stone protein (lithostatin) and pancreatic enzymes, such as trypsin. The inflammatory reaction may vary greatly within a given pancreas and from case to case. Chronic inflammatory changes may be present in the perilobular fibrous tissue, consisting of local collections or more diffuse infiltrates of T lymphocytes admixed with a few plasma cells, or foci of resolving fat necrosis, often associated with an extrapancreatic pseudocyst, may be present. These foci are surrounded by granulation tissue that is associated with a marked fibrocytic reaction (Fig. 1). In patients with advanced ACP;3, 29 the entire pancreas, or most parts of it, has a firm consistency and shows a loss of lobulation; however, some areas may still be only slightly affected. The main duct and its branches are irregularly dilated and distorted and in most cases contain numerous calculi of various sizes. The intrapancreatic part .of the common bile duct may show a tapered stenosis. In general, the extent of the duct changes closely correlates with the extent of the parenchymal fibrosis. Thick-walled pseudocysts, usually attached to the pancreas, are present in one third to one half of cases.27They may be connected to the duct system. Histologically, perilobular and intralobular fibrosis is more widespread and pronounced than in the early stages of the disease, but in some areas acinar cells may still be preserved and
Figure 1. Early-stage alcoholic chronic pancreatitis. Resorption of perilobular necrosis with formation of extensive cell-rich perilobular fibrosis (hematoxylineosin, original magnification X 60).
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Figure 2. Advanced alcoholic chronic. pancreatitis. Extensive perilobular fibrosis and distotted interlobular duct partly lined by hyperplastic mucinous epithelium (hematoxylineosin, original magnification x 60).
arranged in lobuli (Fig. 2). The interlobular ducts are usually all distorted and dilated and are often filled with eosinophilic material or impacted calculi composed of calcium carbonate. Calculus formation seems to start in the center of eosinophilic plugs. The duct epithelium is either normal, mucinous, squamous, atrophic, or completely replaced by fibrous inflammatory tissue. Some severely dilated ducts obstructed by calculi may form small retention cysts. In areas of pronounced intralobular fibrosis, only islands of exocrine and endocrine tissue remain and are composed of disorderly arranged small ducts, remnants of atrophic acinar cells forming tubular complexes, and a few islets. Occasionally, however, the islets may form large ("adenomatoid") aggregates, conOften, the nerves form thick, tortutaining fewer p cells than ous bundles and seem to be increased in n ~ m b e r .The ~ wall of the arteries may be thickened. Inflammatory cell infiltrates are typically scanty, consisting mostly of T lymphocytes. Granulocytic infiltrates may be found around ducts where calculi have damaged the epithelium. In alcoholics who remain free of clinically overt chronic pancreatitis, some particular kind of diffuse (periacinar) fibrosis of the pancreas has been de~cribed.~ Whether this type of fibrosis is distinct from that which can be seen in elderly patients without any known risk factors for chronic pancreatitis has yet to be established. WHAT IS THE EVIDENCE THAT ACUTE PANCREATITIS PRECEDES ALCOHOLIC CHRONIC PANCREATITIS?
Three important points argue that ACP evolves from severe acute pancreatitis. The first argument concerns the fact that long-term alcohol
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conslJmption causes not only chronic but also acute pancreatitis. For a long time, investigators have assumed that alcoholics develop clinically acute pancreatitis only on the basis of preexistent (clinically latent) chronic pancreatitis with distinct fibrosis and protein plugs in the small 42 The long duration of alcohol abuse before onset of pancreatitis33and the demonstration of perilobular fibrosis in autopsy pancreases of alcoholics without ~ancreatitis~~ seemed to support this hypothesis; however, in a large autopsy series of 247 patients who died of alcoholic acute pancreatitis, 131 patients (53%) did not reveal any histologic evidence of chronic pancreatitis,4I and similar findings have been reported in smaller series.25,39 Moreover, according to a recent expert meeting, perilobular fibrosis in alcoholics without clinical and functional signs of chronic pancreatitis should not be interpreted as chronic pancreatiti~~~ because it may also be found in nonalcoholics. The second argument for a relationship between alcoholic acute and chronic pancreatitis is based on the presence of pseudocysts and focal necrosis in both diseases.27Pseudocysts in patients with acute pancreatitis are residues of focal fat necrosis caused by autodigestion by activated pancreatic pro enzyme^.^^ If pseudocysts in chronic pancreatitis have the same cause, focal necrosis and transitions of focal necrosis to pseudocyst should also be present in patients with chronic pancreatitis, at least in some cases. Moreover, focal necrosis and pseudocysts should be more common in pancreatic specimens with little fibrosis and still numerous acinar cells (that can produce enzymes) than in pancreases showing advanced fibrosis and only few remaining acinar cells. The third argument concerns the uneven involvement of the pancreas by both diseases. Careful morphologic analysis has shown that both diseases, at least at the beginning, affect the pancreas focally rather than diffusely. DO PSEUDOCYSTS AND FOCAL NECROSIS IN PATIENTS WITH ALCOHOLIC CHRONIC PANCREATITIS SHOW THE SAME HISTOLOGIC FEATURES AS IN PATIENTS WITH ACUTE PANCREATITIS?
Alcoholic chronic pancreatitis is characterized by a high incidence of pseudocysts, ranging from 11%to 50%.2, 16, Is, 25, 32, 51,52 Their pathogenesis has been the subject of controversy. According to one study, cystic cavities in patients with ACP are retention cysts resulting from cystic dilatations of obstructed pancreatic ducts, which may rupture.l0 In a study reviewing the pathology of 57 pancreas resection specimens and 9 autopsy pancreases of patients with ACP, the authors were unable to confirm these ~bservations.~~ The authors found that pseudocysts in patients with ACP have essentially the same features as those found in patients with acute pancreatitis. Although pseudocysts in patients with ACP may have a thicker wall (because of an increased amount of dense st
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Figure 3. Margin of a pseudocyst in alcoholic chronic pancreatitis. The pseudocyst wall consists of an inner layer composed of granulation tissue and an outer layer showing dense fibrosis that blends into perilobular fibrosis (hernatoxylin-eosin, original magnification x 60).
collagen) than those of acute pancreatitis, their basic structure is identical in both diseases and is composed of an inner layer of granulation tissue followed by connective tissue rich in collagen (Fig. 3). These pseudocysts were present in 42% of patients and were more common in pancreatic specimens with limited fibrosis (56%) than in those with extensive fibrosis (32%). They were usually found outside of the parenchyma of the gland in the peripancreatic fatty tissue. In addition, 33 patients had microscopic autodigestive necrosis, and 19 patients had transitions of large focal necrosis into pseudocyst formation. Taken together, these findings lend strong support to the assumption that the pathogenetic process underlying pseudocyst development in patients with chronic pancreatitis is identical to that in patients with acute pancreatitis.
WHY IS THE PANCREAS UNEVENLY AFFECTED BY ALCOHOLIC CHRONIC PANCREATITIS?
Investigators generally agree that the fibrotic process characterizing ACP affects the pancreas unevenly7,13, 29, 32 In a typical case, areas with some perilobular fibrosis, or even normal acinar parenchyma, alternate with severe perilobular and intralobular fibrosis. If such a patchy pattern of fibrosis is caused by a necrotic process, this process must also be focal. But acute pancreatitis is thought to be a diffuse disease, implying that all parts of the pancreas are evenly affected. This concept is not
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consistent, however, with the distribution pattern of necrosis that is usually found in patients with severe acute pancreatitis. Although the surface of pancreatic specimens with severe acute pancreatitis shows confluent fat necrosis and hemorrhage, suggesting diffuse involvement of the organ, analysis of the parenchyma of the gland generally reveals large areas that are well preserved and only foci of hemorrhage and interstitial fat necrosis.25,29, These focal changes may be confined to only one area of the pancreas, such as the head or tail, leaving the other parts of the gland completely unaffected. Which mechanisms govern the distribution of the necrotic lesions within the pancreas is unclear because the damage patterns differ from patient to patient and do not follow any recognizable rule. These findings are evidence that acute pancreatitis is, morphologically speaking, not a diffuse disease but a focal process, the pattern of which compares well with the irregular fibrosis seen in patients with chronic pancreatitis. This suggests that the primarily focal nature of chronic pancreatitis reflects the intrapancreatic damage pattern observed in severe acute pancreatitis. @
HOW DOES ALCOHOLIC CHRONIC PANCREATITIS EVOLVE FROM ACUTE PANCREATITIS? This question was addressed in a long-term clinicomorphologic study of 73 patients with ACP who were followed up for a mean of 12 years and in whom either surgical or postmortem specimens of the pancreas were a~ailable.~ All patients entering this study were part of a large cohort of 254 ACP patients who initially had at least one documented episode of acute pancreatitis. The investigators found that in surgical specimens, which were obtained at a mean of 4.1 years after onset of the disease, perilobular fibrosis, focal necrosis, and pseudocysts predominated. In postmortem specimens, which were obtained at a mean of 12 years after disease onset, severe perilobular fibrosis, combined with intralobular fibrosis and calcifications, prevailed. Grading of fibrosis allowed a more detailed evaluation of the extent of fibrosis in relation to duration of ACP. This revealed a marked progression of fibrosis with duration of the disease, which was associated with an increased incidence of calcification and correlated with failure of exocrine and endocrine pancreatic function (Fig. 4). The clinicomorphologic correlation was particularly evident in 10 patients with two histologic assessments (surgical resection and postmortem examination) at a mean interval of 8 years. These data document the dynamic progression of alcoholic pancreatitis from early to late stages, starting as acute pancreatitis and ending as full-blown chronic pancreatitis (Fig. 5). Therefore, one can conclude that ACP represents the end stage of damage that has accumulated during multiple relapses of acute pancreatitis. The key factor and driving force of this progressive process is most likely the repeated occurrence of autodigestive fat necrosis and hemorrhagic necrosis characterizing severe acute pan~reatitis.~~ Large necrotic areas and chains of smaller
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Figure 4. Evolution of fibrosis (FS: mean 2 SEM) in relation to duration of alcoholic chronic pancreatitis from onset. Number of patients with histology (numbers in parentheses); percentage of patients with calcifications (white numbers). (From Ammann RW, Heitz PU, Kloppel G: Course of alcoholic chronic pancreatitis: A prospective clinicomorphological long-term study. Gastroenterology 111:224, 1996; with permission.)
interlobular foci of necrosis, particularly when hemorrhagic, seem to induce fibroblast proliferation in the perilobular space during their resolution by macrophages:26If this process takes place repeatedly, always affecting other previously still intact parts of the pancreas and involving the main duct and its branches, it gradually causes sacculations and strictures of the duct system. These ductal changes may hamper the flow of pancreatic secretions and promote precipitation of proteins, with eventual calcification, as was experimentally demonstrated in dogs by Another effect partial pancreatic duct ligation for 4 months and longer.29a of duct obstruction is the induction of acinar atrophy and intralobular fibrosis, which are the hallmarks of end-stage damage in patients with ACP. For this concept to be relevant to patients and the natural course of their disease, the extent and distribution pattern of necrosis in acute pancreatitis must be carefully evaluated with regard to the restitutional processes (i.e., restitutio ad integrum, pseudocyst, intrapancreatic fibrosis) that may follow. WHY DOES EVERY CASE OF RELAPSING ALCOHOLIC PANCREATITIS NOT PROGRESS TO CHRONIC PANCREATITIS?
Investigators have shown that some patients with relapsing alcoholic pancreatitis do not progress clinically to chronic pan~reatitis.~ Re-
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Figure 5. Natural history of alcoholic pancreatitis. Mild acute pancreatitis is characterized by spotty peripancreatic fat necrosis. Resolution of the small foci of peripancreatic fat necrosis results in resfifufioad infegrum (1). Mild acute pancreatitis may proceed to severe acute pancreatitis (2). Severe acute pancreatitis with large confluent areas of peripancreatic necrosis, but little intrapancreatic involvement, leads to an extrapancreatic pseudocyst (3). Relapse of severe acute pancreatitis with intrapancreatic involvement (4). Severe acute pancreatitis with extensive extra- and intrapancreatic foci of necrosis causes irreversible damage to the pancreas, inducing perilobular fibrosis and duct distortions. In addition, there may be extrapancreatic pseudocysts (5). Early-stage chronic pancreatitis evolves into endstage chronic pancreatitis with severe duct changes, diffuse but still patchy fibrosis, and calculi (6). (From Kloppel G, Maillet B: Chronic pancreatitis: Evolution of the disease. Hepatogastroenterology38:408, 1991; with permission.)
cently, investigators suggested that progression of acute pancreatitis to ACP occurs in approximately 1 in 10 patients.31Conversely, many cases 37 To explain these of ACP have a tendency toward self-perpet~ation.~, observations and to get an idea about a patient’s risk for progressive ACP, the possible extent of damage in severe acute pancreatitis, its localization in and around the pancreas, and its consequences for the pancreatic duct system have to be consideredz8(Fig. 6). In many patients, severe acute pancreatitis leads predominantly to massive peripancreatic fat necrosis over the surface of the pancreas, whereas the intrapancreatic regions are virtually unaffected. The massive peripancreatic necrosis (also described as fluid collection on CT)5 is then liquified and transformed into an extrapancreatic pseudocyst that may cause complications, such as bleeding or infection, but does not lead to significant intrapancreatic fibrosis with duct alterations. Consequently,
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Figure 6. Natural history of progressive chronic pancreatitis. The first type is characterized by acute relapses that involve the peripancreatic tissue and the pancreatic parenchyma, including the duct system. The second type is characterized by chronic damage to the pancreatic head, which subsequently induces progressive obstructive changes in the body and tail of the pancreas. The third type is characterized by fibrotic damage to the body and tail that progresses locally but remains restricted to this area. (From Kloppel G, Maillet B: The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 420:1, 1992 0 Springer Verlag; with permission.)
this type of severe acute pancreatitis does not progress to chronic pancreatitis. In a second group of patients with severe acute pancreatitis, peripancreatic necrosis is associated with some small foci of intrapancreatic necrosis. The sequelae of these lesions are an extrapancreatic pseudocyst and small foci of scarring within the pancreas. If the intrapancreatic fibrotic foci do not involve the main pancreatic duct and its branches, progression of the disease is unlikely to occur. It will, however, progress if a patient continues to abuse alcohol so that further pancreatitis attacks can occur, which now affect regions adjacent to the main pancreatic duct, resulting in significant changes of the entire duct system. A third group of patients shows severe acute pancreatitis with marked extrapancreatic fat necrosis and large foci of intrapancreatic hemorrhagic necrosis. This severe pancreatitis, particularly if relapsing, causes not only pseudocysts but also pancreatic fibrosis that already initially involves the main duct in the affected areas and leads to its distortion. In these patients, progression to chronic pancreatitis is most likely, even after alcohol abstinence. The clinical severity of the resulting chronic pancreatitis then depends on whether the damage was mainly to the head of the pancreas or to the body-tail, or both. If the head was the main target, the resulting duct obstruction causes dilatation of the main duct and its branches in the body and tail of the pancreas, and subsequently also fibrosis. After months or some years these patients,
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apart from pain, suffer from severe exocrine and endocrine pancreatic insufficiency. If the damage was limited to the body or tail, the patient, even with abstinence from alcohol, may suffer from pain but pancreatic insufficiency will not develop because of normal tissue remaining in the head of the pancreas. IS THERE A UNIFYING PATHOGENETIC CONCEPT OF ALCOHOLIC CHRONIC PANCREATITIS?
Although alcohol abuse has a clear etiologic association with chronic pancreatitis, the pathogenesis of this disease process remains poorly understood.' Four distinct hypotheses exist regarding the pathogenesis of ACP-the "toxic-metabolic," the "oxidative stress," the "proteinplug," and the "necrosis-fibrosis" hypotheses. These four hypotheses are discussed in the light of the earlier mentioned morphologic findings and their interpretations. According to the toxic-metabolic hypothesis, which was put forth by Bordalo and Noronha,3*long-term alcohol consumption exerts direct toxic and metabolic effects on the acinar cells. This induces progressive lipid deposition in the acinar cells, leading to acinar atrophy and inducing intrapancreatic fibrosis. Because the described pancreatic changes, particularly the fatty degeneration of acinar cells, have not been confirmed by others, the significance of this concept for the pathogenesis of ACP seems to be minor. The oxidative stress hypothesis12postulates that oxidative stress in pancreatic acinar cells induced by excess free radicals causes a blockade of intracellular pathways, fusion of lysosomal and zymogenic compartments, and membrane lipid oxidation. These events then trigger an inflammatory response. This hypothesis focuses on possible functional disturbances underlying acute acinar failure but fails to explain the particular fibroinflammatory process that is typical of ACP. The protein-plug hypothesis was introduced by Sarles more than 20 years 45,46 It suggests that long-term ethanol consumption increases the protein concentration in the pancreatic juice, causing protein plugs within the ducts, which later calcify. More recently, Sarled group35,36, 43*44 identified a protein in pancreatic juice that prevented CaCO, precipitation and was therefore called lithostatin (formerly, pancreatic stone protein). Some investigators believe that abnormal secretion of lithostatin caused by either an acquired or an inherited defect in its biosynthesis contributes to the calcification of protein plugs in the pancreatic ducts. The formation of stones leads in turn to duct obstruction and ulceration of duct epithelium, two mechanisms that cause acinar atrophy and fibrosis upstream of the obstruction, as well as periductular inflammation. Although this hypothesis is attractive, it has been criticized for several reasons. First, the findings concerning altered lithostatin biosynthesis and function in patients with chronic pancreatitis have not been univer47 Second, the hypothesis recognizes only chronic pansally confirmed.20,
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creatitis as an alcohol-induced disease and neglects the fact that acute 41, 49 Third, alcoholic acute pancreatitis may also be caused by and chronic pancreatitis have many features in common, as shown earlier. Fourth, in patients with alcoholic acute pancreatitis, no preexistent changes caused by chronic pancreatitis have been found, whereas the pancreas of patients with chronic pancreatitis may show signs of acute pancreatitis, such as autodigestive tissue necrosis.25,29 Fifth, in the early stages of chronic pancreatitis calcifications are u n c ~ m m o n . ~ The fourth hypothesis, the concept of the necrosis-fibrosis sequence, was developed by the authors 10 years ago.22,28 This theory postulates that alcoholic chronic pancreatitis is the result of relapsing severe acute pancreatitis, as originally proposed by Comfort et al.13The resorption of large areas of fat necrosis and hemorrhagic necrosis, which are the main events in severe acute (necrotizing) pancreatitis, induces fibrosis, possibly through the action of mediators, such as transforming growth factor a and p, epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor.17,30, 53 The fibrosis develops primarily in the perilobular space, where fat necrosis and most of the hemorrhagic necrosis occur.27The subsequent changes follow the sequence of events described in the paragraph on the development of ACP. Although the necrosis-fibrosis sequence nicely explains the presence of pseudocysts, the perilobular fibrosis pattern, the patchy distribution of fibrosis, and the late occurrence of calculi in the pancreatic ducts of patients with ACP, certain questions remain unanswered. First, the mechanisms that lead to acinar dysfunction and acute pancreatitis as a result of alcohol toxicity are unknown. Second, the precise factors that govern the progression of alcoholic acute pancreatitis to ACP have to be determined. Third, that the necrosis-fibrosis sequence also holds true for the primary painless chronic pancreatitis that is noted in 5% to 10% of alcoholics is difficult to reconcile.6,l4 Fourth, why biliary acute pancreatitis, which may occasionally be as severe as alcoholic pancreatitis, virtually never progresses to chronic pancreatitis is unclear. Fifth, whether immunologic processes play a major role in the development of ACP, as has recently been suggested?l or are mere epiphenomena has to be clarified. Sixth, whether other types of chronic pancreatitis, such as hereditary or tropical pancreatitis, have a pathogenesis similar to ACP will be interesting to see.
SUMMARY The available morphologic data on ACP are consistent with the view that ACP evolves from acute pancreatitis. How alcohol abuse triggers pancreatic injury and which factors are responsible for the progression to chronic pancreatitis remain to be clarified, however.
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References 1. Adler G, Schmid RM: Chronic pancreatitis: Still puzzling? Gastroenterology 1121762,1997 2. Ammann RW, Akovbiantz A, Largiader F, et al: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 86:820, 1984 3. Ammann RW, Heitz PU, Kloppel G: Course of alcoholic chronic pancreatitis: A prospective clinicomorphological long-term study. Gastroenterology 111:224, 1996 4. Ammann RW, Muellhaupt B, Meyenberger C, et al: Alcoholic non-progressive chronic pancreatitis: Prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976-1992). Pancreas 9:365, 1994 5. Balthazar EJ, Robinson DL, Megibow AJ, et al: Acute pancreatitis: Value of CT in establishing prognosis. Radiology 174331, 1990 6. Bank S: Chronic pancreatitis: Clinical features and medical management. Am J Gastroenterol 81:153, 1986 7. Bardram L: Gastrin in non-neoplastic pancreatic tissue from patients with and without gastrinomas. Scand J Gastroenterol25:935, 1990 8. Becker V Chronische pankreatitis: Klinische morphologie. Gastroenterologie und Stoffwechsel, vol 21. Stuttgart, Thieme, 1984 9. Bockman DE, Biichler M, Malfertheiner P, et al: Analysis of nerves in chronic pancreatitis. Gastroenterology 941459, 1988 10. Bourliere M, Sarles H. Pancreatic cysts and pseudocysts associated with acute and chronic pancreatitis. Dig Dis Sci 34:343, 1989 11. Bradley EL 111: Pseudocysts in chronic pancreatitis: Development and clinical implications. In Beger HG, Biichler M, Ditschuneit H, et a1 (eds): Chronic Pancreatitis. Heidelberg, Springer-Verlag, 1990, p 260 12. Braganza JM: Pancreatic disease: A casualty of hepatic "detoxification"? Lancet ii:lOOO, 1983 13. Comfort MW, Gambill EE, Baggenstoss A H Chronic relapsing pancreatitis: A study of 29 cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 6239, 1946 14. DiMagno EP, Layer P, Clain JE: Chronic pancreatitis. In Go VLW, DiMagno El', Gardner JD, et a1 (eds): The Pancreas: Biology, Pathobiology, and Disease. New York, Raven Press, 1993, p 665 15. Durbec JP, Sarles H Multicenter survey on the etiology of pancreatic diseases: Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein, and lipid consumption. Digestion 18:337, 1978 16. Edmondson HA, Bullock WK, Mehl J W Chronic pancreatitis and lithiasis: 11. Pathology and pathogenesis of pancreatic lithiasis. Am J Pathol 26:37, 1950 17. Friess H, Yamanaka Y, Biichler M, et al: Increased expression of acidic and basic fibroblast growth factors in chronic pancreatitis. Am J Pathol 144:117, 1994 18. Gambill EE, Comfort MW, Baggenstoss A H Chronic relapsing pancreatitis: An analysis of 27 cases associated with disease of the biliary tract. Gastroenterology 11:1, 1948 19. Guy 0, Robles-Diaz G, Adrich Z , et al: Protein content of precipitates present in pancreatic juice of alcoholic subjects and patients with chronic calcifying pancreatitis. Gastroenterology 84:102, 1983 20. Hayakawa T, Naruse S, Kitagawa M, et al: Pancreatic stone protein and lactoferrin in human pancreatic juice in chronic pancreatitis. Pancreas 10137, 1995 21. Hunger RE, Mueller C, ZGraggen K, et al: Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology 121656, 1997 22. Kloppel G: Pathomorphology of chronic pancreatitis. In Malfertheiner P, Ditschuneit H (eds): Diagnostic Procedures in Pancreatic Disease. Heidelberg, Springer-Verlag, 1986, p 135 23. Kloppel G: Chronic pancreatitis: Etiology, pathophysiology, and pathology. In Howard 1, Idezuki Y, Ihse I, et a1 (eds): Surgical Diseases of the Pancreas, ed 3. Baltimore, Williams & Wilkins, 1998, p 321 24. Kloppel G, Bommer G, Commandeur G, et al: The endocrine pancreas in chronic
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pancreatitis: Immunocytochemical and ultrastructural studies. Virchows Arch A Patho1 Anat Histopathol377157,1978 25. Kloppel G, Dreyer T, Willemer S, et al: Human acute pancreatitis: Its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch A Pathol Anat Histopathol 409:791, 1986 26. Kloppel G, Maillet B: Chronic pancreatitis: Evolution of the disease. Hepatogastroenterology 38:408, 1991 27. Kloppel G, Maillet B: Pseudocysts in chronic pancreatitis: A morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 6:266, 1991 28. Kloppel G, Maillet B The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 420:1, 1992 29. Kloppel G, Maillet B: Pathology of acute and chronic pancreatitis. Pancreas 8:659, 1993 29a. Konishi K, Izumi T, Kato 0, et al: Experimental pancreatolithiasis in the dog. Surgery 89:687, 1981 30. Korc M, Friess H, Yamanaka Y, et al: Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor a, and phospholipase Cgamma. Gut 35:1468, 1994 31. Lankisch PG, Assmus C, Petersen M, et a 1 Acute pancreatitis (AP): How many patients progress to chronic pancreatitis (CP)? Gastroenterology 112:A455, 1997 32. Lankisch PG, Koop H, Seelig R, et al: Antinuclear and pancreatic acinar cell antibodies in pancreatic diseases. Digestion 21:65, 1981 33. Marks IN, Bornman PC: Acute alcoholic pancreatitis: A South African view point. In Bradley EL I11 (ed): Acute Pancreatitis: Diagnosis and Therapy, New York, Raven Press, 1994, p 271 34. Mossner J: Epidemiology of chronic pancreatitis. In Beger HG, Buchler M, Malfertheiner P (eds): Standards in Pancreatic Surgery. Berlin, Springer-Verlag, 1993, p 263 35. Multimer I, Sarles H, Lombardo D, et al: Pancreatic stone protein 11: Implication in stone Tormation during the course of chronic calcifying pancieatitis. Gastroenterology 89:387, 1985 36. Multigner L, de Caro A, Lombardo D, et al: Pancreatic stone protein: A phosphoprotein which inhibits calcium carbonate precipitation from human pancreatic juice. Biochem Biophys Res Commun 110:69, 1983 37. Nagata A, Homma T, Tamai K, et al: A study of chronic pancreatitis by serial endoscopic pancreatography. Gastroenterology 815484, 1981 38. Noronha M, Bordalo 0, Dreiling DA: Alcohol and the pancreas: 11. Pancreatic morphology of advanced alcoholic pancreatitis. Am J Gastroenterol 76:120, 1981 39. Payan H, Sarles H, Demirdjian M, et al: Study of the histological features of chronic pancreatitis by correspondence analysis. Revue Europienne d'etudes Cliniques et Biologiques 17:663, 1972 40. Pitchumoni CS, Glasser M, Saran RM, et al: Pancreatic fibrosis in chronic alcoholics and non-alcoholics without clinical pancreatitis. Am J Gastroenterol 79:382, 1984 41. Renner IG, Savage WT, Pantoja JL, et al: Death due to acute pancreatitis: A retrospective analysis of 405 autopsy cases. Dig Dis Sci 30:1005, 1985 42. Sarles H: Definitions and classifications of pancreatitis. Pancreas 6:470, 1991 43. Sarles H, Bernard JP, Gullo L: Pathogenesis of chronic pancreatitis. Gut 31:629, 1990 44. Sarles H, Muratore R, Sarles JC, et al: Aetiology and pathology of chronic pancreatitis. In Sarles H (ed): Pancreatitis (Bibliotheca Gastroenterologica No. 7). Basel, Karger, 1965, p 75 45. Sarles H, Payan H, Tasso F, et al: Chronic pancreatitis, relapsing pancreatitis, calcification of the pancreas. In Bockus HL (ed): Gastroenterology. Philadelphia, WB Saunders, 1976, p 1040 46. Sarles H, Sahel J: Pathology of chronic calcifying pancreatitis. Am J Gastroenterol 66:117. 1976 47. Schmiegel W, Burchert M, Kalthoff H, et al: Immunochemical characterization and quantitative distribution of pancreatic stone protein in sera and pancreatic secretions in pancreatic disorders. Gastroenterology 99:1421, 1990 48. Schmitz-Moormann P: Comparative radiological and morphological study of the
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human pancreas: IV. Acute necrotizing pancreatitis in man. Pathol Res Pract 171:325, 1981 49. Seligson U, Cho JW, Ihse I, et al: Clinical course and autopsy findings in acute and chronic pancreatitis. Acta Chir Scand 148:269, 1982 50. Slater SD, Williamson RC, Foster C S Expression of transforming growth factor-beta 1 in chronic pancreatitis. Digestion 56937, 1995 51. Stolte M: Chronische Pankreatitis: Morphologie, Pankreatographie, Differentialdiagnose. Erlangen, Perimed, 1984 52. Uys CJ, Bank S, Marks IN: The pathology of chronic pancreatitis in Cape Town. Digestion 9:454, 1973 53. van Laethem JL, Deviere J, Resibois A, et al: Localizing of transforming growth factor p l and its latent binding protein in human chronic pancreatitis. Gastroenterology 108:1873, 1995 54. Woming H: Chronic pancreatitis: Pathogenesis, natural history and conservative treatment. Clin Gastroenterol 13:871, 1984
Address reprint requests to Gunter Kloppel, MD Department of Pathology University of E e l Michaelisstrasse 11 D-24105 Kiel Germany e-mail: [email protected]
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PROGRESSION FROM ACUTE TO CHRONIC PANCREATITIS A Pathologist’s View Giinter Kloppel, MD
Chronic pancreatitis is the result of fibroinflammatory changes in the pancreas that may be the result of various causes. In Western countries, long-term alcohol abuse is the most common etiologic factor in chronic pancreatitis. Seventy to 80% of the patients presenting with chronic pancreatitis are young to middle-aged men (range, 25-50 y) who are heavy drinkers.2,14, 15, 34, 54 Alcoholic chronic pancreatitis (ACP) is therefore usually meant when the pathogenesis of chronic pancreatitis is discussed. This article focuses on ACP with the aim of reviewing its pathology, discussing the links with acute pancreatitis, and relating the various hypotheses regarding its pathophysiology to the morphologic features of ACP. PATHOLOGY OF ALCOHOLIC CHRONIC PANCREATITIS
In early chronic pan~reatitis:~,29 the pancreas is always unevenly affected. Grossly, the involved parts are enlarged and indurated, showing coarse lobulation or nodular scarring on the cut surface. If the fibrotic area lies in the periphery of the gland, duct irregularities (with occasional calculus formation) may be found solely in the duct tributaries affected by fibrosis. In many cases, extrapancreatic pseudocysts or foci of recent necrosis are found in the vicinity of fibrotic areas.”, 27
From the Department of Pathology, University of Kiel, Kiel, Germany
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Histologically, the indurated parts of the pancreas show distinct perilobular fibrosis with occasional involvement of an entire lobule, where most of the acinar cells are replaced by connective tissue (intralobular fibrosis). The ducts within the fibrotic areas between the lobules are distorted and may contain eosinophilic protein plugs. The preserved acinar cells within intact lobuli have a normal appearance and show immunoreactivity to pancreatic stone protein (lithostatin) and pancreatic enzymes, such as trypsin. The inflammatory reaction may vary greatly within a given pancreas and from case to case. Chronic inflammatory changes may be present in the perilobular fibrous tissue, consisting of local collections or more diffuse infiltrates of T lymphocytes admixed with a few plasma cells, or foci of resolving fat necrosis, often associated with an extrapancreatic pseudocyst, may be present. These foci are surrounded by granulation tissue that is associated with a marked fibrocytic reaction (Fig. 1). In patients with advanced ACP;3, 29 the entire pancreas, or most parts of it, has a firm consistency and shows a loss of lobulation; however, some areas may still be only slightly affected. The main duct and its branches are irregularly dilated and distorted and in most cases contain numerous calculi of various sizes. The intrapancreatic part .of the common bile duct may show a tapered stenosis. In general, the extent of the duct changes closely correlates with the extent of the parenchymal fibrosis. Thick-walled pseudocysts, usually attached to the pancreas, are present in one third to one half of cases.27They may be connected to the duct system. Histologically, perilobular and intralobular fibrosis is more widespread and pronounced than in the early stages of the disease, but in some areas acinar cells may still be preserved and
Figure 1. Early-stage alcoholic chronic pancreatitis. Resorption of perilobular necrosis with formation of extensive cell-rich perilobular fibrosis (hematoxylineosin, original magnification X 60).
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Figure 2. Advanced alcoholic chronic. pancreatitis. Extensive perilobular fibrosis and distotted interlobular duct partly lined by hyperplastic mucinous epithelium (hematoxylineosin, original magnification x 60).
arranged in lobuli (Fig. 2). The interlobular ducts are usually all distorted and dilated and are often filled with eosinophilic material or impacted calculi composed of calcium carbonate. Calculus formation seems to start in the center of eosinophilic plugs. The duct epithelium is either normal, mucinous, squamous, atrophic, or completely replaced by fibrous inflammatory tissue. Some severely dilated ducts obstructed by calculi may form small retention cysts. In areas of pronounced intralobular fibrosis, only islands of exocrine and endocrine tissue remain and are composed of disorderly arranged small ducts, remnants of atrophic acinar cells forming tubular complexes, and a few islets. Occasionally, however, the islets may form large ("adenomatoid") aggregates, conOften, the nerves form thick, tortutaining fewer p cells than ous bundles and seem to be increased in n ~ m b e r .The ~ wall of the arteries may be thickened. Inflammatory cell infiltrates are typically scanty, consisting mostly of T lymphocytes. Granulocytic infiltrates may be found around ducts where calculi have damaged the epithelium. In alcoholics who remain free of clinically overt chronic pancreatitis, some particular kind of diffuse (periacinar) fibrosis of the pancreas has been de~cribed.~ Whether this type of fibrosis is distinct from that which can be seen in elderly patients without any known risk factors for chronic pancreatitis has yet to be established. WHAT IS THE EVIDENCE THAT ACUTE PANCREATITIS PRECEDES ALCOHOLIC CHRONIC PANCREATITIS?
Three important points argue that ACP evolves from severe acute pancreatitis. The first argument concerns the fact that long-term alcohol
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conslJmption causes not only chronic but also acute pancreatitis. For a long time, investigators have assumed that alcoholics develop clinically acute pancreatitis only on the basis of preexistent (clinically latent) chronic pancreatitis with distinct fibrosis and protein plugs in the small 42 The long duration of alcohol abuse before onset of pancreatitis33and the demonstration of perilobular fibrosis in autopsy pancreases of alcoholics without ~ancreatitis~~ seemed to support this hypothesis; however, in a large autopsy series of 247 patients who died of alcoholic acute pancreatitis, 131 patients (53%) did not reveal any histologic evidence of chronic pancreatitis,4I and similar findings have been reported in smaller series.25,39 Moreover, according to a recent expert meeting, perilobular fibrosis in alcoholics without clinical and functional signs of chronic pancreatitis should not be interpreted as chronic pancreatiti~~~ because it may also be found in nonalcoholics. The second argument for a relationship between alcoholic acute and chronic pancreatitis is based on the presence of pseudocysts and focal necrosis in both diseases.27Pseudocysts in patients with acute pancreatitis are residues of focal fat necrosis caused by autodigestion by activated pancreatic pro enzyme^.^^ If pseudocysts in chronic pancreatitis have the same cause, focal necrosis and transitions of focal necrosis to pseudocyst should also be present in patients with chronic pancreatitis, at least in some cases. Moreover, focal necrosis and pseudocysts should be more common in pancreatic specimens with little fibrosis and still numerous acinar cells (that can produce enzymes) than in pancreases showing advanced fibrosis and only few remaining acinar cells. The third argument concerns the uneven involvement of the pancreas by both diseases. Careful morphologic analysis has shown that both diseases, at least at the beginning, affect the pancreas focally rather than diffusely. DO PSEUDOCYSTS AND FOCAL NECROSIS IN PATIENTS WITH ALCOHOLIC CHRONIC PANCREATITIS SHOW THE SAME HISTOLOGIC FEATURES AS IN PATIENTS WITH ACUTE PANCREATITIS?
Alcoholic chronic pancreatitis is characterized by a high incidence of pseudocysts, ranging from 11%to 50%.2, 16, Is, 25, 32, 51,52 Their pathogenesis has been the subject of controversy. According to one study, cystic cavities in patients with ACP are retention cysts resulting from cystic dilatations of obstructed pancreatic ducts, which may rupture.l0 In a study reviewing the pathology of 57 pancreas resection specimens and 9 autopsy pancreases of patients with ACP, the authors were unable to confirm these ~bservations.~~ The authors found that pseudocysts in patients with ACP have essentially the same features as those found in patients with acute pancreatitis. Although pseudocysts in patients with ACP may have a thicker wall (because of an increased amount of dense st
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Figure 3. Margin of a pseudocyst in alcoholic chronic pancreatitis. The pseudocyst wall consists of an inner layer composed of granulation tissue and an outer layer showing dense fibrosis that blends into perilobular fibrosis (hernatoxylin-eosin, original magnification x 60).
collagen) than those of acute pancreatitis, their basic structure is identical in both diseases and is composed of an inner layer of granulation tissue followed by connective tissue rich in collagen (Fig. 3). These pseudocysts were present in 42% of patients and were more common in pancreatic specimens with limited fibrosis (56%) than in those with extensive fibrosis (32%). They were usually found outside of the parenchyma of the gland in the peripancreatic fatty tissue. In addition, 33 patients had microscopic autodigestive necrosis, and 19 patients had transitions of large focal necrosis into pseudocyst formation. Taken together, these findings lend strong support to the assumption that the pathogenetic process underlying pseudocyst development in patients with chronic pancreatitis is identical to that in patients with acute pancreatitis.
WHY IS THE PANCREAS UNEVENLY AFFECTED BY ALCOHOLIC CHRONIC PANCREATITIS?
Investigators generally agree that the fibrotic process characterizing ACP affects the pancreas unevenly7,13, 29, 32 In a typical case, areas with some perilobular fibrosis, or even normal acinar parenchyma, alternate with severe perilobular and intralobular fibrosis. If such a patchy pattern of fibrosis is caused by a necrotic process, this process must also be focal. But acute pancreatitis is thought to be a diffuse disease, implying that all parts of the pancreas are evenly affected. This concept is not
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consistent, however, with the distribution pattern of necrosis that is usually found in patients with severe acute pancreatitis. Although the surface of pancreatic specimens with severe acute pancreatitis shows confluent fat necrosis and hemorrhage, suggesting diffuse involvement of the organ, analysis of the parenchyma of the gland generally reveals large areas that are well preserved and only foci of hemorrhage and interstitial fat necrosis.25,29, These focal changes may be confined to only one area of the pancreas, such as the head or tail, leaving the other parts of the gland completely unaffected. Which mechanisms govern the distribution of the necrotic lesions within the pancreas is unclear because the damage patterns differ from patient to patient and do not follow any recognizable rule. These findings are evidence that acute pancreatitis is, morphologically speaking, not a diffuse disease but a focal process, the pattern of which compares well with the irregular fibrosis seen in patients with chronic pancreatitis. This suggests that the primarily focal nature of chronic pancreatitis reflects the intrapancreatic damage pattern observed in severe acute pancreatitis. @
HOW DOES ALCOHOLIC CHRONIC PANCREATITIS EVOLVE FROM ACUTE PANCREATITIS? This question was addressed in a long-term clinicomorphologic study of 73 patients with ACP who were followed up for a mean of 12 years and in whom either surgical or postmortem specimens of the pancreas were a~ailable.~ All patients entering this study were part of a large cohort of 254 ACP patients who initially had at least one documented episode of acute pancreatitis. The investigators found that in surgical specimens, which were obtained at a mean of 4.1 years after onset of the disease, perilobular fibrosis, focal necrosis, and pseudocysts predominated. In postmortem specimens, which were obtained at a mean of 12 years after disease onset, severe perilobular fibrosis, combined with intralobular fibrosis and calcifications, prevailed. Grading of fibrosis allowed a more detailed evaluation of the extent of fibrosis in relation to duration of ACP. This revealed a marked progression of fibrosis with duration of the disease, which was associated with an increased incidence of calcification and correlated with failure of exocrine and endocrine pancreatic function (Fig. 4). The clinicomorphologic correlation was particularly evident in 10 patients with two histologic assessments (surgical resection and postmortem examination) at a mean interval of 8 years. These data document the dynamic progression of alcoholic pancreatitis from early to late stages, starting as acute pancreatitis and ending as full-blown chronic pancreatitis (Fig. 5). Therefore, one can conclude that ACP represents the end stage of damage that has accumulated during multiple relapses of acute pancreatitis. The key factor and driving force of this progressive process is most likely the repeated occurrence of autodigestive fat necrosis and hemorrhagic necrosis characterizing severe acute pan~reatitis.~~ Large necrotic areas and chains of smaller
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Figure 4. Evolution of fibrosis (FS: mean 2 SEM) in relation to duration of alcoholic chronic pancreatitis from onset. Number of patients with histology (numbers in parentheses); percentage of patients with calcifications (white numbers). (From Ammann RW, Heitz PU, Kloppel G: Course of alcoholic chronic pancreatitis: A prospective clinicomorphological long-term study. Gastroenterology 111:224, 1996; with permission.)
interlobular foci of necrosis, particularly when hemorrhagic, seem to induce fibroblast proliferation in the perilobular space during their resolution by macrophages:26If this process takes place repeatedly, always affecting other previously still intact parts of the pancreas and involving the main duct and its branches, it gradually causes sacculations and strictures of the duct system. These ductal changes may hamper the flow of pancreatic secretions and promote precipitation of proteins, with eventual calcification, as was experimentally demonstrated in dogs by Another effect partial pancreatic duct ligation for 4 months and longer.29a of duct obstruction is the induction of acinar atrophy and intralobular fibrosis, which are the hallmarks of end-stage damage in patients with ACP. For this concept to be relevant to patients and the natural course of their disease, the extent and distribution pattern of necrosis in acute pancreatitis must be carefully evaluated with regard to the restitutional processes (i.e., restitutio ad integrum, pseudocyst, intrapancreatic fibrosis) that may follow. WHY DOES EVERY CASE OF RELAPSING ALCOHOLIC PANCREATITIS NOT PROGRESS TO CHRONIC PANCREATITIS?
Investigators have shown that some patients with relapsing alcoholic pancreatitis do not progress clinically to chronic pan~reatitis.~ Re-
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Figure 5. Natural history of alcoholic pancreatitis. Mild acute pancreatitis is characterized by spotty peripancreatic fat necrosis. Resolution of the small foci of peripancreatic fat necrosis results in resfifufioad infegrum (1). Mild acute pancreatitis may proceed to severe acute pancreatitis (2). Severe acute pancreatitis with large confluent areas of peripancreatic necrosis, but little intrapancreatic involvement, leads to an extrapancreatic pseudocyst (3). Relapse of severe acute pancreatitis with intrapancreatic involvement (4). Severe acute pancreatitis with extensive extra- and intrapancreatic foci of necrosis causes irreversible damage to the pancreas, inducing perilobular fibrosis and duct distortions. In addition, there may be extrapancreatic pseudocysts (5). Early-stage chronic pancreatitis evolves into endstage chronic pancreatitis with severe duct changes, diffuse but still patchy fibrosis, and calculi (6). (From Kloppel G, Maillet B: Chronic pancreatitis: Evolution of the disease. Hepatogastroenterology38:408, 1991; with permission.)
cently, investigators suggested that progression of acute pancreatitis to ACP occurs in approximately 1 in 10 patients.31Conversely, many cases 37 To explain these of ACP have a tendency toward self-perpet~ation.~, observations and to get an idea about a patient’s risk for progressive ACP, the possible extent of damage in severe acute pancreatitis, its localization in and around the pancreas, and its consequences for the pancreatic duct system have to be consideredz8(Fig. 6). In many patients, severe acute pancreatitis leads predominantly to massive peripancreatic fat necrosis over the surface of the pancreas, whereas the intrapancreatic regions are virtually unaffected. The massive peripancreatic necrosis (also described as fluid collection on CT)5 is then liquified and transformed into an extrapancreatic pseudocyst that may cause complications, such as bleeding or infection, but does not lead to significant intrapancreatic fibrosis with duct alterations. Consequently,
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Relapse
Scarring
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Figure 6. Natural history of progressive chronic pancreatitis. The first type is characterized by acute relapses that involve the peripancreatic tissue and the pancreatic parenchyma, including the duct system. The second type is characterized by chronic damage to the pancreatic head, which subsequently induces progressive obstructive changes in the body and tail of the pancreas. The third type is characterized by fibrotic damage to the body and tail that progresses locally but remains restricted to this area. (From Kloppel G, Maillet B: The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 420:1, 1992 0 Springer Verlag; with permission.)
this type of severe acute pancreatitis does not progress to chronic pancreatitis. In a second group of patients with severe acute pancreatitis, peripancreatic necrosis is associated with some small foci of intrapancreatic necrosis. The sequelae of these lesions are an extrapancreatic pseudocyst and small foci of scarring within the pancreas. If the intrapancreatic fibrotic foci do not involve the main pancreatic duct and its branches, progression of the disease is unlikely to occur. It will, however, progress if a patient continues to abuse alcohol so that further pancreatitis attacks can occur, which now affect regions adjacent to the main pancreatic duct, resulting in significant changes of the entire duct system. A third group of patients shows severe acute pancreatitis with marked extrapancreatic fat necrosis and large foci of intrapancreatic hemorrhagic necrosis. This severe pancreatitis, particularly if relapsing, causes not only pseudocysts but also pancreatic fibrosis that already initially involves the main duct in the affected areas and leads to its distortion. In these patients, progression to chronic pancreatitis is most likely, even after alcohol abstinence. The clinical severity of the resulting chronic pancreatitis then depends on whether the damage was mainly to the head of the pancreas or to the body-tail, or both. If the head was the main target, the resulting duct obstruction causes dilatation of the main duct and its branches in the body and tail of the pancreas, and subsequently also fibrosis. After months or some years these patients,
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apart from pain, suffer from severe exocrine and endocrine pancreatic insufficiency. If the damage was limited to the body or tail, the patient, even with abstinence from alcohol, may suffer from pain but pancreatic insufficiency will not develop because of normal tissue remaining in the head of the pancreas. IS THERE A UNIFYING PATHOGENETIC CONCEPT OF ALCOHOLIC CHRONIC PANCREATITIS?
Although alcohol abuse has a clear etiologic association with chronic pancreatitis, the pathogenesis of this disease process remains poorly understood.' Four distinct hypotheses exist regarding the pathogenesis of ACP-the "toxic-metabolic," the "oxidative stress," the "proteinplug," and the "necrosis-fibrosis" hypotheses. These four hypotheses are discussed in the light of the earlier mentioned morphologic findings and their interpretations. According to the toxic-metabolic hypothesis, which was put forth by Bordalo and Noronha,3*long-term alcohol consumption exerts direct toxic and metabolic effects on the acinar cells. This induces progressive lipid deposition in the acinar cells, leading to acinar atrophy and inducing intrapancreatic fibrosis. Because the described pancreatic changes, particularly the fatty degeneration of acinar cells, have not been confirmed by others, the significance of this concept for the pathogenesis of ACP seems to be minor. The oxidative stress hypothesis12postulates that oxidative stress in pancreatic acinar cells induced by excess free radicals causes a blockade of intracellular pathways, fusion of lysosomal and zymogenic compartments, and membrane lipid oxidation. These events then trigger an inflammatory response. This hypothesis focuses on possible functional disturbances underlying acute acinar failure but fails to explain the particular fibroinflammatory process that is typical of ACP. The protein-plug hypothesis was introduced by Sarles more than 20 years 45,46 It suggests that long-term ethanol consumption increases the protein concentration in the pancreatic juice, causing protein plugs within the ducts, which later calcify. More recently, Sarled group35,36, 43*44 identified a protein in pancreatic juice that prevented CaCO, precipitation and was therefore called lithostatin (formerly, pancreatic stone protein). Some investigators believe that abnormal secretion of lithostatin caused by either an acquired or an inherited defect in its biosynthesis contributes to the calcification of protein plugs in the pancreatic ducts. The formation of stones leads in turn to duct obstruction and ulceration of duct epithelium, two mechanisms that cause acinar atrophy and fibrosis upstream of the obstruction, as well as periductular inflammation. Although this hypothesis is attractive, it has been criticized for several reasons. First, the findings concerning altered lithostatin biosynthesis and function in patients with chronic pancreatitis have not been univer47 Second, the hypothesis recognizes only chronic pansally confirmed.20,
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creatitis as an alcohol-induced disease and neglects the fact that acute 41, 49 Third, alcoholic acute pancreatitis may also be caused by and chronic pancreatitis have many features in common, as shown earlier. Fourth, in patients with alcoholic acute pancreatitis, no preexistent changes caused by chronic pancreatitis have been found, whereas the pancreas of patients with chronic pancreatitis may show signs of acute pancreatitis, such as autodigestive tissue necrosis.25,29 Fifth, in the early stages of chronic pancreatitis calcifications are u n c ~ m m o n . ~ The fourth hypothesis, the concept of the necrosis-fibrosis sequence, was developed by the authors 10 years ago.22,28 This theory postulates that alcoholic chronic pancreatitis is the result of relapsing severe acute pancreatitis, as originally proposed by Comfort et al.13The resorption of large areas of fat necrosis and hemorrhagic necrosis, which are the main events in severe acute (necrotizing) pancreatitis, induces fibrosis, possibly through the action of mediators, such as transforming growth factor a and p, epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor.17,30, 53 The fibrosis develops primarily in the perilobular space, where fat necrosis and most of the hemorrhagic necrosis occur.27The subsequent changes follow the sequence of events described in the paragraph on the development of ACP. Although the necrosis-fibrosis sequence nicely explains the presence of pseudocysts, the perilobular fibrosis pattern, the patchy distribution of fibrosis, and the late occurrence of calculi in the pancreatic ducts of patients with ACP, certain questions remain unanswered. First, the mechanisms that lead to acinar dysfunction and acute pancreatitis as a result of alcohol toxicity are unknown. Second, the precise factors that govern the progression of alcoholic acute pancreatitis to ACP have to be determined. Third, that the necrosis-fibrosis sequence also holds true for the primary painless chronic pancreatitis that is noted in 5% to 10% of alcoholics is difficult to reconcile.6,l4 Fourth, why biliary acute pancreatitis, which may occasionally be as severe as alcoholic pancreatitis, virtually never progresses to chronic pancreatitis is unclear. Fifth, whether immunologic processes play a major role in the development of ACP, as has recently been suggested?l or are mere epiphenomena has to be clarified. Sixth, whether other types of chronic pancreatitis, such as hereditary or tropical pancreatitis, have a pathogenesis similar to ACP will be interesting to see.
SUMMARY The available morphologic data on ACP are consistent with the view that ACP evolves from acute pancreatitis. How alcohol abuse triggers pancreatic injury and which factors are responsible for the progression to chronic pancreatitis remain to be clarified, however.
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References 1. Adler G, Schmid RM: Chronic pancreatitis: Still puzzling? Gastroenterology 1121762,1997 2. Ammann RW, Akovbiantz A, Largiader F, et al: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 86:820, 1984 3. Ammann RW, Heitz PU, Kloppel G: Course of alcoholic chronic pancreatitis: A prospective clinicomorphological long-term study. Gastroenterology 111:224, 1996 4. Ammann RW, Muellhaupt B, Meyenberger C, et al: Alcoholic non-progressive chronic pancreatitis: Prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976-1992). Pancreas 9:365, 1994 5. Balthazar EJ, Robinson DL, Megibow AJ, et al: Acute pancreatitis: Value of CT in establishing prognosis. Radiology 174331, 1990 6. Bank S: Chronic pancreatitis: Clinical features and medical management. Am J Gastroenterol 81:153, 1986 7. Bardram L: Gastrin in non-neoplastic pancreatic tissue from patients with and without gastrinomas. Scand J Gastroenterol25:935, 1990 8. Becker V Chronische pankreatitis: Klinische morphologie. Gastroenterologie und Stoffwechsel, vol 21. Stuttgart, Thieme, 1984 9. Bockman DE, Biichler M, Malfertheiner P, et al: Analysis of nerves in chronic pancreatitis. Gastroenterology 941459, 1988 10. Bourliere M, Sarles H. Pancreatic cysts and pseudocysts associated with acute and chronic pancreatitis. Dig Dis Sci 34:343, 1989 11. Bradley EL 111: Pseudocysts in chronic pancreatitis: Development and clinical implications. In Beger HG, Biichler M, Ditschuneit H, et a1 (eds): Chronic Pancreatitis. Heidelberg, Springer-Verlag, 1990, p 260 12. Braganza JM: Pancreatic disease: A casualty of hepatic "detoxification"? Lancet ii:lOOO, 1983 13. Comfort MW, Gambill EE, Baggenstoss A H Chronic relapsing pancreatitis: A study of 29 cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 6239, 1946 14. DiMagno EP, Layer P, Clain JE: Chronic pancreatitis. In Go VLW, DiMagno El', Gardner JD, et a1 (eds): The Pancreas: Biology, Pathobiology, and Disease. New York, Raven Press, 1993, p 665 15. Durbec JP, Sarles H Multicenter survey on the etiology of pancreatic diseases: Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein, and lipid consumption. Digestion 18:337, 1978 16. Edmondson HA, Bullock WK, Mehl J W Chronic pancreatitis and lithiasis: 11. Pathology and pathogenesis of pancreatic lithiasis. Am J Pathol 26:37, 1950 17. Friess H, Yamanaka Y, Biichler M, et al: Increased expression of acidic and basic fibroblast growth factors in chronic pancreatitis. Am J Pathol 144:117, 1994 18. Gambill EE, Comfort MW, Baggenstoss A H Chronic relapsing pancreatitis: An analysis of 27 cases associated with disease of the biliary tract. Gastroenterology 11:1, 1948 19. Guy 0, Robles-Diaz G, Adrich Z , et al: Protein content of precipitates present in pancreatic juice of alcoholic subjects and patients with chronic calcifying pancreatitis. Gastroenterology 84:102, 1983 20. Hayakawa T, Naruse S, Kitagawa M, et al: Pancreatic stone protein and lactoferrin in human pancreatic juice in chronic pancreatitis. Pancreas 10137, 1995 21. Hunger RE, Mueller C, ZGraggen K, et al: Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology 121656, 1997 22. Kloppel G: Pathomorphology of chronic pancreatitis. In Malfertheiner P, Ditschuneit H (eds): Diagnostic Procedures in Pancreatic Disease. Heidelberg, Springer-Verlag, 1986, p 135 23. Kloppel G: Chronic pancreatitis: Etiology, pathophysiology, and pathology. In Howard 1, Idezuki Y, Ihse I, et a1 (eds): Surgical Diseases of the Pancreas, ed 3. Baltimore, Williams & Wilkins, 1998, p 321 24. Kloppel G, Bommer G, Commandeur G, et al: The endocrine pancreas in chronic
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pancreatitis: Immunocytochemical and ultrastructural studies. Virchows Arch A Patho1 Anat Histopathol377157,1978 25. Kloppel G, Dreyer T, Willemer S, et al: Human acute pancreatitis: Its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch A Pathol Anat Histopathol 409:791, 1986 26. Kloppel G, Maillet B: Chronic pancreatitis: Evolution of the disease. Hepatogastroenterology 38:408, 1991 27. Kloppel G, Maillet B: Pseudocysts in chronic pancreatitis: A morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 6:266, 1991 28. Kloppel G, Maillet B The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 420:1, 1992 29. Kloppel G, Maillet B: Pathology of acute and chronic pancreatitis. Pancreas 8:659, 1993 29a. Konishi K, Izumi T, Kato 0, et al: Experimental pancreatolithiasis in the dog. Surgery 89:687, 1981 30. Korc M, Friess H, Yamanaka Y, et al: Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor a, and phospholipase Cgamma. Gut 35:1468, 1994 31. Lankisch PG, Assmus C, Petersen M, et a 1 Acute pancreatitis (AP): How many patients progress to chronic pancreatitis (CP)? Gastroenterology 112:A455, 1997 32. Lankisch PG, Koop H, Seelig R, et al: Antinuclear and pancreatic acinar cell antibodies in pancreatic diseases. Digestion 21:65, 1981 33. Marks IN, Bornman PC: Acute alcoholic pancreatitis: A South African view point. In Bradley EL I11 (ed): Acute Pancreatitis: Diagnosis and Therapy, New York, Raven Press, 1994, p 271 34. Mossner J: Epidemiology of chronic pancreatitis. In Beger HG, Buchler M, Malfertheiner P (eds): Standards in Pancreatic Surgery. Berlin, Springer-Verlag, 1993, p 263 35. Multimer I, Sarles H, Lombardo D, et al: Pancreatic stone protein 11: Implication in stone Tormation during the course of chronic calcifying pancieatitis. Gastroenterology 89:387, 1985 36. Multigner L, de Caro A, Lombardo D, et al: Pancreatic stone protein: A phosphoprotein which inhibits calcium carbonate precipitation from human pancreatic juice. Biochem Biophys Res Commun 110:69, 1983 37. Nagata A, Homma T, Tamai K, et al: A study of chronic pancreatitis by serial endoscopic pancreatography. Gastroenterology 815484, 1981 38. Noronha M, Bordalo 0, Dreiling DA: Alcohol and the pancreas: 11. Pancreatic morphology of advanced alcoholic pancreatitis. Am J Gastroenterol 76:120, 1981 39. Payan H, Sarles H, Demirdjian M, et al: Study of the histological features of chronic pancreatitis by correspondence analysis. Revue Europienne d'etudes Cliniques et Biologiques 17:663, 1972 40. Pitchumoni CS, Glasser M, Saran RM, et al: Pancreatic fibrosis in chronic alcoholics and non-alcoholics without clinical pancreatitis. Am J Gastroenterol 79:382, 1984 41. Renner IG, Savage WT, Pantoja JL, et al: Death due to acute pancreatitis: A retrospective analysis of 405 autopsy cases. Dig Dis Sci 30:1005, 1985 42. Sarles H: Definitions and classifications of pancreatitis. Pancreas 6:470, 1991 43. Sarles H, Bernard JP, Gullo L: Pathogenesis of chronic pancreatitis. Gut 31:629, 1990 44. Sarles H, Muratore R, Sarles JC, et al: Aetiology and pathology of chronic pancreatitis. In Sarles H (ed): Pancreatitis (Bibliotheca Gastroenterologica No. 7). Basel, Karger, 1965, p 75 45. Sarles H, Payan H, Tasso F, et al: Chronic pancreatitis, relapsing pancreatitis, calcification of the pancreas. In Bockus HL (ed): Gastroenterology. Philadelphia, WB Saunders, 1976, p 1040 46. Sarles H, Sahel J: Pathology of chronic calcifying pancreatitis. Am J Gastroenterol 66:117. 1976 47. Schmiegel W, Burchert M, Kalthoff H, et al: Immunochemical characterization and quantitative distribution of pancreatic stone protein in sera and pancreatic secretions in pancreatic disorders. Gastroenterology 99:1421, 1990 48. Schmitz-Moormann P: Comparative radiological and morphological study of the
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human pancreas: IV. Acute necrotizing pancreatitis in man. Pathol Res Pract 171:325, 1981 49. Seligson U, Cho JW, Ihse I, et al: Clinical course and autopsy findings in acute and chronic pancreatitis. Acta Chir Scand 148:269, 1982 50. Slater SD, Williamson RC, Foster C S Expression of transforming growth factor-beta 1 in chronic pancreatitis. Digestion 56937, 1995 51. Stolte M: Chronische Pankreatitis: Morphologie, Pankreatographie, Differentialdiagnose. Erlangen, Perimed, 1984 52. Uys CJ, Bank S, Marks IN: The pathology of chronic pancreatitis in Cape Town. Digestion 9:454, 1973 53. van Laethem JL, Deviere J, Resibois A, et al: Localizing of transforming growth factor p l and its latent binding protein in human chronic pancreatitis. Gastroenterology 108:1873, 1995 54. Woming H: Chronic pancreatitis: Pathogenesis, natural history and conservative treatment. Clin Gastroenterol 13:871, 1984
Address reprint requests to Gunter Kloppel, MD Department of Pathology University of E e l Michaelisstrasse 11 D-24105 Kiel Germany e-mail: [email protected]