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Pathogenesis and the natural course of chronic pancreatitis

Strate, Tim; Yekebas, Emre; Knoefel, Wolfram T.; Bloechle, Christian; Izbicki, Jakob R.

European Journal of Gastroenterology & Hepatology: September 2002 - Volume 14 - Issue 9 - p 929-934
Review in Depth

This article gives an overview about current thinking in pathogenesis and natural course /therapy in chronic pancreatitis. Alcohol consumption is still the most relevant factor in the development of chronic pancreatitis, a disease with enormous personal and social impact, shortening life expectancy up to 10–20 yrs. Pathogenesis of chronic pancreatitis has to be considered for different symptoms. Particularly pain, the most bothering symptom is most likely due to a combination of hypertension in the organ and parenchymal alterations. Pathogenesis of pancreatic head enlargement remains largely elusive. In particular it is not known what triggers growth factors to step into action. Most other symptoms like common bile duct stenosis or portal hypertension are secondary to this enlargement of the head of the pancreas.

Department of General Surgery, University Hospital, Hamburg, Germany

Correspondence to Dr J.R. Izbicki, Department of General Surgery, University Hospital Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany Tel: +49 (0)40 42803 2401; fax: +49 (0)40 42803 4995; e-mail: izbicki@uke.uni-hamburg.de

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Introduction

Chronic pancreatitis is a benign inflammatory pancreatic disease that is difficult to define [1]. Accompanied by severe pain attacks, it leads to progressive destruction of pancreatic parenchyma affecting exocrine and endocrine function. In the past, its pathogenesis, classification and natural course have been discussed controversially [2,3]. Despite extensive research, especially on the pathogenesis of pain, the disease is still not fully elucidated. Since therapeutic options are still modest, a better understanding of the underlying mechanisms would help to establish clear cut indications for existing treatment modalities.

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Definition of chronic pancreatitis

`Chronic pancreatitis’ is a term that has been used for a variety of pancreatic diseases without a generally accepted definition [1]. In 1963 inflammatory pancreatic diseases were divided into:

  • acute
  • relapsing acute (with restitutio ad integrum)
  • chronic relapsing (with acute exacerbations)
  • chronic pancreatitis (anatomical and functional residual damage) [4].

A classification according to morphological changes seen by endoscopic retrograde pancreatography was suggested in the 1980s [5]. The pancreatographic findings were graded as normal (equivocal), mild, moderate, or marked changes of diffuse or local disease. A more recent definition of chronic pancreatitis has been the result of two consensus conferences (held in Marseille and Cambridge 1984): ‘Chronic pancreatitis is a disease of the pancreas with permanent alteration of the anatomical organ structure and/or with functional damage to the pancreas due to progressive inflammation’ [1].

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Symptoms in chronic pancreatitis

In general the disease process starts before the onset of clinical symptoms. The most noticeable symptom is pain; either recurrent abdominal pain similar to pain attacks in acute pancreatitis or rarely permanent abdominal pain. Only very few patients do not suffer from pain throughout the long course of the disease. This pattern is mainly found in idiopathic chronic pancreatitis [2,3,6,7].

Functional deficits are independent of pain sequelae. Exocrine pancreatic function is often impaired in the beginning. It manifests with weight loss due to malabsorption and steatorrhea. Onset of endocrine dysfunction with diabetes mellitus is often a late consequence in chronic pancreatitis [4,8]. Pancreatic pseudocysts with or without ductal alterations occur as a complication due to inflammation and pancreatic calculi in the natural course of chronic pancreatitis with an incidence of up to 60% [9–11]. Other common complications of adjacent organs are stenosis of the common bile duct or duodenum and portal hypertension [12].

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Pathomorphological findings in chronic pancreatitis

Pathomorphological findings in chronic pancreatitis like inflammatory infiltration of the pancreatic tissue, fibrosis, atrophy of the acinar cells, calcifications, pancreatic duct strictures and pseudocysts can be found isolated, segmentally or diffuse in the whole organ to different degrees [10,13,14].

Two main forms can be distinguished histomorphologically: chronic obstructive pancreatitis and chronic calcifying pancreatitis. Chronic obstructive pancreatitis develops on the basis of pancreatic main duct stenosis with prestenotic dilation of the pancreatic duct, but without alterations of the ductal epithelium [15,16]. Pancreatic duct stones or protein plugs are uncommon. Periductal fibrosis and inflammatory infiltration are found mainly around the larger ducts and in the pancreatic head. Diffuse fibrotic changes occur throughout the organ without lobular topography. Pancreatic main duct stenosis might be caused by either papillary stenosis (tumour) or inflammation, duodenal diverticula, pancreatic tumours, congenital or acquired duct abnormalities (pancreas divisum) and, rarely, by pancreatic duct injuries (trauma).

The more common form of chronic calcifying pancreatitis is characterized by intraductal protein plugs, ductal calculi and parenchymal calcifications. These alterations of various degrees in different stages of the disease lead to pancreatic duct stenosis and consequently alternating pre-stenotic dilatations. These impose as ‘chain of lakes’ radiographically (endoscopic retrograde pancreatography). In addition, epithelial alterations, inflammatory periductal infiltrations, parenchymal atrophy, necrosis and fibrosis (lobular and diffuse) can be observed [15,16]. Ductal hypertension and tissue necrosis can lead to the formation of pseudocysts.

In 1997, Ectors et al. defined a third form of chronic pancreatitis as non-alcoholic, duct destructive, chronic pancreatitis [17]. In contrast to alterations seen in alcohol induced chronic pancreatitis, they described periductal lymphocytic inflammatory infiltration of the epithelium, perilobular fibrosis and ductal obstruction mainly affecting interlobular ducts. The main component is ductal destruction due to the mechanisms mentioned above, which are similar to findings seen in patients with autoimmune diseases.

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Aetiology and pathogenesis of chronic pancreatitis

Alcohol induced chronic pancreatitis

By far the most common aetiological factor of chronic pancreatitis in the Western world is chronic alcohol abuse, responsible for up to 80% of all cases [1]. The most common form of alcohol induced chronic pancreatitis is the progressive calcifying form, followed by non-calcifying and slowly progressive chronic pancreatitis. Onset of symptoms is the fourth decinium after a subclinical stage of up to 10 years. There is a clear prevalence of male patients.

Alcohol directly damages acinar as well as liver cells. In addition, it induces a change in microcirculatory perfusion thus altering epithelial permeability. This again predisposes to changes in acinar protein secretion and consequently protein plug and ductal stone formation [1].

Patients suffering from alcohol induced chronic pancreatitis reveal a typical history of recurrent episodes of acute pancreatitis and a history of excessive alcohol intake of > 80 g/day for some years (less in females). Different alcohol tolerance levels or certain risk factor patterns have been suggested for patients developing alcohol induced pancreatitis [15,18]. Long-term alcohol consumption (> 35 years) is associated with increased risk for developing chronic pancreatitis, while intake of saturated fatty acid and vitamin E are negatively associated [18]. High caloric protein and fat nutrition, smoking, lack of vitamins and trace elements have been indicated as additional predisposing risk factors [19].

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Non-alcohol induced chronic pancreatitis

Tropical chronic pancreatitis is a non-alcohol related form of calcifying chronic pancreatitis. It is associated with protein (Kwashiorkor) and trace element malnutrition with additional uptake of tapioca and cassava toxins [15]. Also a lack of the R117H mutation in the cationic trypsinogen has been isolated in patients suffering from tropical chronic pancreatitis [20]. This mutation has also been found in the rare form of hereditary chronic pancreatitis, a disease entity manifesting in the first two decades of life [21].

Hereditary pancreatitis has been described in well over 100 cases. It is an autosomal dominant disorder with 80% penetrance [22]. Several mutations of the cationic trypsinogen have been described so far.

A recent report by Teich et al. described increased amounts of trypsinogen caused by a trypsinogen mutation in the activation peptide of the proenzyme in hereditary pancreatitis [23]. It is concluded that this mutation could initiate pancreatitis.

In up to 20%, the cause for the development remains unclear, thus it is named idiopathic pancreatitis. Two different forms can be distinguished: (1) the juvenile form with an onset in the first two decades, mostly presenting as progressive calcifying chronic pancreatitis, and (2) the often asymptomatic senile form presenting with little pancreatic inflammation and fibrosis [17].

Some patients suffering from juvenile idiopathic chronic pancreatitis display decreased levels of alpha-1 antitrypsin. An imbalance of proteases and antiproteases could support the development of chronic pancreatitis in these patients [19].

Smoking has been indicated as playing a causative role in the development of pancreatic calcification in late onset idiopathic chronic pancreatitis [24]. Excessive calcium blood levels due to hyperparathyroidism, for example, can rarely cause chronic pancreatitis. Interstitial or autoimmune chronic pancreatitis are found after viral infections or associated with systemic diseases. Finally, tumours, diverticula, strictures, pancreas divisum and annulare or pancreatic injury can cause pancreatic duct obstruction, leading to chronic obstructive pancreatitis.

It is hypothesized that chronic pancreatitis is a sequelae of recurrent episodes of acute pancreatitis [13]. Also, pancreatolithiasis is thought to be the underlying cause of chronic pancreatitis [10]. Imbalance of the pancreatic juice due to hypersecretion of proteins from acinar cells and/or decreased fluid or bicarbonate secretion, as well as reduced or increased amounts of lithostatine in the pancreatic juice might lead to formation of protein plugs in ducts and ductuli as seen in early chronic pancreatitis. These protein plugs mainly consist of lithostatine, glycoproteins and pancreatic enzymes. Through these plugs, calcium carbonate precipitates and intraductal stones are formed. Produced in the acinar cells, lithostatine is not only the main component of plugs and stones but also inhibits the development of calcium carbonate precipitations in vivo and in vitro. Lithostatine is reduced in the pancreatic juice of alcoholic patients [25].

Protein plugs are found in most forms of chronic pancreatitis, whereas ductal stones are predominantly found in alcohol induced chronic pancreatitis. Sarles’ theory [10] of pancreatolithiasis being the first manifestation of chronic pancreatitis is supported by findings of increased ductal pressure due to stenosis, with subsequent derangement of fluid exchange and pancreatic oedema. Though this theory can explain pathogenesis in alcoholic chronic pancreatitis it neglects the fact that in the early stages of chronic pancreatitis, calcifications or ductal stones may be absent.

Ammann et al. suggested that acute alcoholic and chronic pancreatitis are probably different stages of the same disease [26]. Klöppel and Maillet described chronic pancreatitis as the result of relapsing severe acute pancreatitis with residual damage to the pancreas (necrosis–fibrosis sequence) [13,16].

Initially, fat and parenchymal necrosis with haemorrhage of the pancreas may induce perilobular fibrosis that subsequently lead to intralobular fibrosis, ductal obstruction and periductal inflammation. Finally, intraductal plugs predispose to calcifications. This sequence of necrosis and fibrosis explains the progressive course of the disease with development of pseudocysts, pancreatic duct stenosis due to relapsing inflammation and relapsing pain attacks.

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Pathogenesis of pain in chronic pancreatitis

The most noticeable and burdening symptom of chronic pancreatitis is pain, with enormous social and economic impact. It is hypothesized that pain is caused by parenchymal and ductal hypertension, a situation frequently found in chronic pancreatitis. But the causative agent is most probably not only ductal hypertension. Parenchymal inflammation is said to be another main factor for the development of pain. Inflammatory changes, like neural alterations, ultrastructural changes of the neurolemm, diameter changes or changes of the area of tissue served per nerve are frequent findings in resected specimen of patients with chronic pancreatitis [27–29]. The pancreatic head has been proposed as being the pacemaker of the disease [30]. Since resection of the altered parenchyma, mainly the pancreatic head, helps in reducing pain and prevent further inflammation, an inflammatory process as an underlying mechanism for the development of pain in chronic pancreatitis can be postulated. In a study on the pathogenesis of pain we found a strong correlation with preoperative pain and pancreatic pressure elevation in the duct, but also in the body and tail. In the head and uncinate process, the main inflammatory focus was seen, whereas no correlation between parenchymal hypertension and pain attacks could be established. This atrophic, fibrotic and non-functional pancreatic tissue may cause pain due to parenchymal and neural alterations. Once major inflammation has occurred in the altered pancreas, the effect of resection on decreasing parenchymal pressure is less pronounced. Direct alterations of pancreatic nerves are a conclusive finding in patients with chronic pancreatitis. Friess et al., for example, report on increased expression of nerve growth factor and tyrosine kinase receptor A in patients with chronic pancreatitis [31].

The pathogenesis of pain in chronic pancreatitis seems to be multifactorial. Pancreatic parenchymal hypertension, and neural alterations due to inflammation are likely to be the two most relevant factors.

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Natural course in chronic pancreatitis

The natural course of chronic pancreatitis is characterized by a progressive loss of parenchyma and subsequently a loss of pancreatic exocrine and endocrine function. Most pronounced and noticeable for the patient is abdominal pain. The morphological findings in chronic pancreatitis, like inflammatory infiltration of pancreatic tissue, fibrosis, atrophy of the acinar cells, calcifications, pancreatic duct strictures etc. can be found in the very beginning of the disease even without any clinical symptoms.

Usually, after a subclinical period without any noticeable pain, the second stage of the disease is characterized by pain to various degree and exocrine, later on endocrine, dysfunction. In the third stage the gland is globally insufficient and pain might subside (burn-out pancreas).

But a pain free course of the disease is still an exception. According to Ammann and others up to 50% of all patients suffering from idiopathic chronic pancreatitis show a pain free course, whereas in a more recent study Lankisch et al. corrected this number to 7% [2,3,6,7].

In a retrospective investigation about the difference in the natural course of alcohol and non-alcohol induced chronic pancreatitis, 10 years after the onset 50–61% still suffered from abdominal pain [32]. Only alcoholic patients had some pain relief with progressive exocrine insufficiency, but 54–73% of the patients still suffered from pain despite pronounced exocrine insufficiency. Endocrine insufficiency did not alter the course of pain. Reduction of alcohol intake did not influence the course of pain in patients with alcohol induced chronic pancreatitis. Patients who quit drinking showed some improvement in exocrine function [2,32]. Pancreatitis associated mortality was 13%. In 315 patients, Layer et al. investigated the natural course of alcohol induced, early onset idiopathic and late onset idiopathic chronic pancreatitis [7]. In idiopathic pancreatitis, there was no gender preference as in alcoholic (male > female) and calcification rate was slower. Pain free disease was found in 50% of patients with late onset of idiopathic chronic pancreatitis. Patients with early onset idiopathic chronic pancreatitis presented with more severe pain that started earlier than in the other forms investigated. Pain relief was achieved independently of exo- and endocrine insufficiency or pancreatic calcification. In this investigation, pancreatitis associated mortality was 15% and pancreatic cancer developed in 3% of investigated patients.

In a prospective long-term study, Ammann et al. enrolled 231 patients with alcohol and non-alcohol induced chronic pancreatitis [3]. Eighty-five per cent of alcoholic patients displayed some pain relief, whereas exo- and endocrine function and calcifications deteriorated. Though survival in the non-alcoholic group was higher, pancreatitis associated mortality was approximately 20% in both groups. Pancreatic cancer was found in 2.8% of investigated patients. In a different investigation there was an association between the onset of calcifications and exocrine insufficiency in alcoholic patients [6]. The progressive pancreatic dysfunction, including diabetes mellitus, was more rapid and pronounced in alcohol induced chronic pancreatitis in both groups. Interestingly, only 30% of patients suffering from idiopathic chronic pancreatitis showed complete and spontaneous pain relief without evidence of exocrine and endocrine dysfunction.

The latest report on Ammann's series of 207 patients (mean follow-up 17 years) with alcoholic chronic pancreatitis has been published recently [33]. Severe persistent pain was found to be associated with local complications like pseudocysts and cholestasis. Again he was able to document lasting pain remission in over 80% of patients within 10 years of onset in association with marked pancreatic dysfunction.

In another report on 140 patients with recurrent acute alcohol induced pancreatitis, 78% developed chronic pancreatitis [34]. This information strongly suggests a natural course of recurrent spells of acute pancreatitis developing into chronic pancreatitis. This is supported further by a clinical–morphological study showing an evolution of alcohol related recurrent attacks of acute pancreatitis evolving into chronic pancreatitis [26]. Mortality of patients with chronic pancreatitis is around 30–40%, with 20% being directly related to the disease [35]. The life expectancy of patients with advanced chronic pancreatitis is shortened by 10–20 years [36].

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Risk of pancreatic cancer in chronic pancreatitis

Patients suffering from chronic pancreatitis have an elevated risk of developing pancreatic cancer [37]. Whether both diseases display the same risk factors, or whether chronic pancreatitis itself is a ‘premalignant’ alteration or a precursor for the development of pancreatic cancer was unclear, but in 1993 Lowenfels et al. [38] reported the results of 2015 patients (mean follow-up of 7.4 years) with chronic pancreatitis, who had an 8-fold higher risk of developing pancreatic cancer when compared to a normal population. Thus, chronic pancreatitis may be considered an independent risk factor for the development of pancreatic cancer [38].

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Complications of adjacent organs in chronic pancreatitis

Complications of adjacent organs are, in general, indications for a surgical approach. The most frequent complications in chronic pancreatitis are stenosis to the common bile duct, segmental duodenal stenosis and segmental portal hypertension by splenic vein thrombosis. They result from fibrotic inflammation caused by the inflammatory alterations/tumour in the pancreatic head or from compression by pancreatic pseudocysts [12]. Whether segmental portal hypertension without coexisting complications of other adjacent organs and without severe pain is an indication for surgery remains controversial [39,40].

Other complications, such as pancreatic ascites, pleura effusion or fistula and inflammation of the colon are only rarely observed.

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Factors influencing the natural course of chronic pancreatitis

Factors influencing the natural course in terms of pain relief, exo- and endocrine insufficiency through alcohol intake reduction showed contradictory results [2,32]. It has been suggested, though, that ongoing alcohol abuse leads to a higher mortality in chronic pancreatitis [3]. New treatment options, despite substitution of enzymes and insulin and analgesics, have been elaborated. Surgical drainage of symptomatic pancreatic pseudocysts leads to pain relief in half of the treated patients, while a delay in the progression into exocrine, but not endocrine dysfunction seems possible [9,41]. In a longitudinal prospective analysis of 143 patients, Nealon et al. report on stable functional status of the pancreas when operated early in the course of the disease (mild to moderate chronic pancreatitis). If no drainage procedure was performed, the disease progressed to severe pancreatitis with functional impairment in 78% vs 13% in the operative group [41].

Interventional endoscopic treatment with papillotomy, stone extraction, ductal stenting and extracorporeal shock wave lithotripsy in order to relieve ductal hypertension has been applied. An improvement of exo- and endocrine dysfunction as well as pain relief has been reported in limited cases using these methods [42,43]. This treatment option mimics the older surgical drainage options by targeting on the theory of ductal hypertension being the only pathophysiological correlate for the development of pain in patients with chronic pancreatitis. But as discussed earlier, the aspect of neural alterations in the pancreatic tissue is not regarded, since ductal drainage does not alter the inflammatory paranchymal changes. Resection, especially duodenum preserving resection, seems to be a promising alternative to drainage procedures. Pain relief is reported to be long lasting, the loss of pancreatic function can be delayed and quality of life can be improved [12,41,44,45].

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Animal models in chronic pancreatitis

Most animal models of pancreatic inflammatory disease are simulating acute pancreatitis, using special diets or infusions into the pancreatic duct. Animal models for chronic pancreatitis are difficult to develop, since it is hard to mimic the characteristically clinical or morphological features. Established models focus on different aspects of chronic pancreatitis, but do not combine alterations observed in humans. Pap and Boros tried to mimic chronic pancreatitis by temporary occlusion of the biliopancreatic ducts with Ethibloc and tube-fed 12 g/kg alcohol daily over a period of 2 months [46]. It is probably the animal model that closely resembles the clinical situation of patients suffering from chronic alcohol induced pancreatitis. Riaz et al. tried to induce chronic pancreatitis in rats by repeatedly inducing spells of acute pancreatitis through a choline deficient diet [47]. They conclude that chronic pancreatitis is a progressive disease caused by recurrent acute pancreatitis. A different model induces chronic obstructive pancreatitis through narrowing of the pancreatic duct in rats [48,49]. Using this model, Karanja found elevated intraparenchymal pressure and reduced pancreatic blood flow. Since he was able to decrease intraparenchymal pressure while increasing blood flow to the organ by surgical ductal decompression, he postulated a compartment syndrome in chronic pancreatitis [49]. However, this finding could not be reproduced in a recent study on microcirculation of the human pancreas in vivo [50].

An interesting variation of this model has been suggested by Satake and Hiura [51]. In rats, they ligated the main pancreatic duct of the splenic lobe and left the gastroduodenal lobe intact. This model produces chronic pancreatitis in one part and normal pancreatic tissue in another part of the same animal, biochemically and histologically. This way, bias (inter-individual variations) were partially excluded.

A reproducible model of chronic pancreatitis is described by Sugiyama et al. They investigated genetically altered rats (WBN/Kob rats) [52]. Though reliably reproducible, clinical relevance is limited, since these alterations are not the cause of human chronic pancreatitis.

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Keywords:

Chronic pancreatitis; pathogenesis; review

© 2002 Lippincott Williams & Wilkins, Inc.