Alcoholic pancreatitis: is it a priori chronic disease?

Abstract

Chronic pancreatitis clinically refers to a syndrome of destructive inflammatory conditions that result in persistent functional and permanent structural abnormalities of the pancreas. 1 It remains a major source of morbidity worldwide, as well as in the United States. It is believed that a substantial number of cases with chronic pancreatitis are not overt, and the true incidence and prevalence of the disease is underestimated. The major risk factors can be categorized as (1) toxic metabolic, (2) idiopathic, (3) genetic, (4) autoimmune, (5) recurrent and severe acute pancreatitis, or (6) obstructive. The clinical diagnosis depends on identification of defined clinical, functional, and morphologic changes in the pancreas. The functional changes alone are not considered diagnostic, as pancreatic insufficiency may result from noninflammatory pancreatic disorders. 1 Detection of morphologic changes either with imaging studies or histopathologic examination is critical in making a definitive diagnosis. While histopathologic changes have been suggested to be the gold standard against which all other diagnostic modalities should be evaluated, pancreatic biopsies in clinical practice are seldom performed for this purpose. 1 There is still lack of consensus in the diagnostic criteria and classification of chronic pancreatitis, and the treatment options of established disease are limited. Alcohol has been recognized as an important etiologic factor in both acute and chronic pancreatitis worldwide. The etiopathogenesis of alcoholic pancreatitis is poorly understood, and it is unclear what factors modify or aid the disease progression. Although toxic metabolic factors are likely to contribute toward disease, the roles of genetic factors and other contributory factors (e.g., smoking) remain undetermined. It is unclear why only a small percentage of heavy alcohol abusers develop clinical disease, while some develop the disease while drinking in moderation. It is also unclear if only recurrent acute pancreatitis leads to chronic pancreatitis or if alcoholic pancreatitis is a priori chronic disease. It is hotly debated whether acute pancreatitis develops in a normal pancreas or occurs superimposed on an already chronically diseased pancreas. Several approaches have been undertaken, including clinical, pathologic, and experimental, to answer these question. Histologically, acute pancreatitis is characterized by hemorrhagic necrosis involving pancreatic parenchyma and peripancreatic fat accompanied by acute inflammatory infiltrate. 2 Chronic pancreatitis is characterized by intralobular and perilobular fibrosis, acinar atrophy, calcification, duct dilatation, chronic inflammatory infiltrate, and duct lithiasis. 2 Pseudocyst formation and fat necrosis are common to both acute and chronic pancreatitis. Large, autopsy-based studies have shown that a significant number of patients (approximately 30–100%) with features of acute alcoholic pancreatitis have no histologic evidence of chronicity in the pancreas. 3–7 However, it should be recognized that postmortem autoactivation of enzymes in pancreas leads to marked autolytic changes, and histologic assessment of pancreas at autopsy is often difficult. Pancreas removed at the time of surgery with immediate fixation provides the best opportunity for proper histologic evaluation. Only few studies have evaluated pancreatic tissue excised at the time of surgery for acute pancreatitis. 5,7 Kloppel et al in their study of 367 autopsy cases also included 3 pancreatic resections obtained from patients operated for acute pancreatitis and found that none of the cases showed any evidence of underlying chronic pancreatitis. 5 The findings supported the view that acute alcoholic pancreatitis can occur in a normal pancreas. Interpretation of histologic changes in pancreas at autopsy is also subject to marked interobserver variability. In an autopsy-based study, review of pathology by an experienced gastrointestinal pathologist confirmed chronic pancreatitis in only 47% of cases initially diagnosed as chronic pancreatitis by a general pathologist. 8 Then, one could also question, what is the minimum evidence of chronicity? Presence of fibrosis has been traditionally taken as minimum evidence suggesting chronicity. The matter is further complicated by the fact that perilobular fibrosis can also be found in nonalcoholic patients without any evidence of chronic pancreatitis. 9,10 Another question that needs to be addressed is, how reliably can one assess delicate fibrosis in the background of acute necrosis without using special techniques or stains for collagen? The current clinical criteria, which rely on pancreatic functional disturbance and morphologic abnormalities detected on imaging studies, are too insensitive to detect mild and early histologic changes suggesting chronicity and cannot adequately address the issue of whether acute alcoholic pancreatitis occurs in a normal or chronically diseased pancreas. 1,11,12 Several clinical studies have shown that acute alcoholic pancreatitis may progress to chronic pancreatitis; however, it is also unclear as to why only some patients develop chronic disease. 13–16 It is also unresolved if severity of initial acute pancreatitis leads to more rapid progression to chronic pancreatitis. 11 Many experimental studies have been performed to study the natural course of acute and chronic pancreatitis. Injection of trypsin has been used in rats and rabbits to induce acute pancreatitis. 17–19 While fibrosis develops (rats: 4 days; rabbits: 4 weeks), all histologic signs soon disappear (rats: 9–14 days; rabbits: 12 weeks), and it has been difficult to produce long-lasting chronic pancreatitis. The experience with other experimental models has also been similar, and attempts to reproduce human disease have been somewhat disappointing. 20,21 One could say without much hesitation that better understanding of the etiopathogenesis of pancreatitis is the key in resolving many of the controversial issues. Several concepts regarding the pathogenesis of chronic pancreatitis have been proposed over the years, most notably the “toxic metabolic,” the “oxidative stress,” the “protein-plug,” or the recent “necrosis–fibrosis” hypotheses. 22,23 Alcohol itself may be directly toxic to pancreas, or it may modify the pancreatic juice to make it more lithogenic and form protein plugs in ducts. 23 It is becoming increasingly clear that genetic predisposition may underlie many cases of acute and chronic pancreatitis. 1,24 Inappropriate activation of the proteolytic enzyme trypsin has been suggested to be the initial step in the development of acute pancreatitis. Gene defects that could enhance autoactivation of trypsin or reduce degradation of the active enzyme could predispose individuals for acute pancreatitis. Few mutations in the key proteins involved in this pathway have already been identified. 25–30 Similarly, mutations in the cystic fibrosis transmembrane conductance receptor (CFTR) gene have been associated with chronic pancreatitis. 31,32 The interaction between different genetic mutations and their role in nonhereditary pancreatitis is being investigated and remains an area of keen interest. It is tempting to postulate that necrosis–fibrosis sequence in genetically predisposed pancreas may lead to a sequence of events resulting in chronic pancreatitis; the observed variability in clinical and histologic manifestations being dependent on the nature of specific underlying gene defects. In the related fields of gastroenterology and hepatology, it has been well established that idiopathic inflammatory bowel disease and autoimmune hepatitis are a priori chronic disorders with acute exacerbations. 33–35 In inflammatory bowel disease and autoimmune hepatitis, it is also widely recognized that while most cases show histologic evidence of chronicity even at the initial presentation, some do not. It is also recognized that some cases achieve complete remission—clinical and pathologic—following the initial episode. 36 A similar phenomenon in alcoholic pancreatitis has been hotly debated as evidence for acute and chronic pancreatitis representing separate entities. The issues in pancreatitis have been complicated because of many reasons. Unlike liver and luminal gastrointestinal tract, it is nearly impossible to follow the disease progression and histopathologic changes in pancreas with sequential biopsies because of medical and ethical issues. Lack of consistent morphologic and clinical criteria makes it difficult to compare results of various studies. It is also unclear what the minimum criteria to suggest chronicity in pancreas are. Histopathologically, presence of fibrosis has been considered an early evidence of chronicity; however, it has not been established what the minimum time required for collagen deposition in human pancreas is and whether it always correlates with clinically chronic disease. Experience with other tissues and organs suggests fibrosis following an acute insult could occur as early as 7 to 10 days. 37 The other issue, which is even more difficult to answer in this setting, is whether fibrosis in pancreas is reversible. 38 If so, how often does it happen, and under what circumstances? In this issue, the study by Gullo et al aims to clarify whether acute alcoholic pancreatitis occurs in a normal pancreas or an already chronically diseased pancreas. The authors reviewed clinical and pathologic data on all cases of acute pancreatitis over a 10-year period. They carefully selected only those cases with first attack of alcoholic pancreatitis (21 cases) for the study. Of these 21 cases, 6 underwent surgery, and adequate pancreatic tissue was obtained for histologic studies. In these cases, the authors found changes of acute pancreatitis superimposed on lesions of chronic pancreatitis, suggesting that acute alcoholic pancreatitis develops in a pancreas already affected by chronic pancreatitis. These results are in sharp contrast to the findings by Kloppel et al 5 and support the view that alcoholic pancreatitis is an a priori chronic disease. In lack of uniformly applied diagnostic histologic criteria for minimal disease, it is difficult to speculate the reasons for such widely discrepant results. Similarly, it is difficult to speculate the role of unidentified genetic factors and controversial comorbid factors, like smoking, in modifying the pancreatic histology in these studies. Undoubtedly, in the past decade, our understanding of the genetic basis, pathogenesis, and natural history of acute and chronic pancreatitis has grown tremendously. However, the distinction between acute and chronic pancreatitis still remains blurred. There is an overlap in the etiologic factors as well as pathologic changes in the acute and chronic pancreatitis, and growing evidence suggests a continuous spectrum of disease rather than 2 separate distinct entities. Roles of underlying genetic abnormalities in alcoholic pancreatitis need to be clarified. Universally accepted diagnostic criteria and classification schemes need to be developed. Prospective multiinstitutional studies applying uniform pathologic and clinical criteria need to be undertaken. Also, animal models that recapitulate human disease by combining genetic susceptibility with susceptibility to alcohol-mediated pancreatitis need to be developed. Better understanding of the genetic factors and the molecular mechanisms of the disease are arguably the most important aspects that may help in resolving these controversies in the future.