Pathogenesis of Chronic Pancreatitis: An Evidence-Based Review of Past Theories and Recent Developments

Tyler Stevens; Darwin L. Conwell; Gregory Zuccaro


Am J Gastroenterol. 2004;99(11) 

In This Article

Different Etiologies, Different Mechanisms?

Although many of the above theories seek to provide a unifying model, it is more likely that diverse etiologies lead to chronic pancreatitis through unique pathways. For example, most would agree that obstructive chronic pancreatitis occurs through a very different mechanism than alcoholic chronic pancreatitis. Furthermore, the low prevalence of chronic pancreatitis among alcoholics would seem to suggest other cofactors at play in many with diagnosed "alcoholic" pancreatitis. In fact, possession of multiple risk factors may be required for progression to fibrosis.

Various systems have been proposed to classify pancreatitis based on clinical presentation, radiographic features, and etiology. Multiple revisions of the Marseilles-Rome system have classified pancreatitis into acute and chronic forms, with further descriptors applied to subdivide chronic pancreatitis according to morphologic and clinical characteristics ( Table 1 ).[97] The Marseille symposium suggested specific etiologies for each of these morphologic forms of CP. The "TIGAR-O" classification of chronic pancreatitis has recently been proposed to replace the previous Marseilles classification systems.[2] This system proposes risk modifiers –not etiologies–that may interact in any one patient to produce pancreatic disease ( Table 2 ). Each of the listed risk factors may predispose toward pancreatitis through unique mechanisms (Fig. 6). A brief discussion of possible pathogenic mechanisms for each of the etiologies listed in the TIGAR-O classification follows.

Figure 6.

Pathogenic pathways proposed to explain each etiology of CP enumerated in the TIGAR-O classification. It is likely that different pathophysiologic mechanisms may explain the diverse etiologies of CP.

Toxic and Metabolic

Alcohol is the most common etiology of chronic pancreatitis in developed countries. Most of the above models of pathogenesis suggest possible mechanisms of alcohol-related injury, including perturbations in exocrine function, changes in cellular lipid metabolism, induction of oxidative stress, and activation of stellate cells. Interestingly, only 10–20% of chronic alcoholics develop acute or chronic pancreatitis.[98] Though ethanol has been demonstrated to potentiate chronic pancreatitis in a murine model of chronic pancreatitis,[99] animals chronically fed alcohol do not develop chronic pancreatitis. This would seem to suggest the interaction of genetic or other environmental cofactors that amplify the effects of alcohol. In fact, an increased prevalence of genetic mutations known to produce chronic pancreatitis has been found in patients with previously diagnosed alcoholic pancreatitis[100,101] while others have not.[102]

A limited number of other toxins are linked to the development of chronic pancreatitis, but the pathogenic mechanisms are poorly understood. For example, smoking is associated with increased risk for chronic pancreatitis, independent of alcohol use.[103] Tobacco may effect bicarbonate secretion in pancreatic juice,[104] decrease pancreatic secretion,[105] induce oxidative stress,[106] and increases the rate of pancreatic calcification.[107] The interaction and interdependence of smoking and alcohol as risk factors for chronic pancreatitis is not fully understood. Medications are more clearly linked to acute rather than chronic pancreatitis.

Certain metabolic conditions are also associated with acute and chronic pancreatitis:

  1. Hypercalcemia: Severe hypercalcemia produces acute pancreatitis through trypsin-mediated mechanisms. With persistent or recurrent hypercalcemia, chronic pancreatitis may also result. Several studies have shown an association of hyperparathyroidism with chronic pancreatitis.[108,109] The pathogenesis may be explained through recurrent acute pancreatitis progressing to chronic pancreatitis, as described by the necrosis-fibrosis theory. Proponents of the stone and ductal obstruction theory cite that hypercalcemia modifies pancreatic secretion, which may lead to protein plug formation.[110,111]

  2. Chronic renal failure: The prevalence of acute and chronic pancreatitis is increased in patients with renal failure.[112] An autopsy study performed in 78 patients with end-stage renal disease (ESRD) revealed pancreatic fibrosis in 28%.[113] Another study demonstrated an increased prevalence of pancreatic gland changes on ultrasound in patients with chronic pancreatitis.[114] In contrast, another study did not reveal significant pancreatic ultrasonographic changes among ESRD patients.[115] However, this same study did find a decreased fecal chymotrypsin level in ESRD patients compared to controls, suggesting pancreatic insufficiency. The pathogenesis of chronic pancreatitis in renal failure is not known, but suggested mechanisms include:

    (i) Uremic toxicity to the parenchyma,
    (ii) Recurrent volume contraction during hemodialysis, resulting in decreased pancreatic flow and inspissation of pancreatic secretion,[116]
    (iii) Recurrent acute pancreatitis from secondary hyperparathyroidism and hypercalcemia, and
    (iv) An impaired gastrointestinal hormone profile causing pancreatic exocrine dysfunction.[117]


New discoveries of genetic, immune-mediated, and environmental risk factors for chronic pancreatitis have caused this category to dwindle in recent years. However, 10–30% of patients with chronic pancreatitis possess no clear risk factors for the disease. Idiopathic chronic pancreatitis has been classified as early and late onset, given its bimodal age presentation and differences in presentation (Fig. 7).[118,138]

Figure 7.

Bimodal distribution of idiopathic chronic pancreatitis.ICJP-Idiopathic chronit juvenile pancreatitis; ISCP-Idiopathic senile chronic pancreatitis. Adapted from Disorders of the Pancreas: Current Issues in Diagnosis and Management, Editors: Burns GP and Bank S, Ammann RW, Alcohol and non-alcohol induced pancreatitis: Clinical aspects (Chapter 16), pp. 253–71, Copyright 1992, with permission from McGraw-Hill, Inc.

Early-onset idiopathic chronic pancreatitis typically presents in the first two decades of life with severe abdominal pain. Structural changes, exocrine insufficiency, and calcifications occur much later in the course. Late-onset idiopathic chronic pancreatitis occurs in the fourth or fifth decade with minimal pain, often with pancreatic insufficiency at the time of diagnosis. Exocrine and endocrine dysfunction and pancreatic calcifications are much more likely to occur in late-onset idiopathic chronic pancreatitis. Possible mechanisms for both early and late onset idiopathic chronic pancreatitis include occult alcohol use and undiagnosed genetic defects. The serine protease inhibitor Kazal type 1 (SPINK-1) mutation has been noted in many patients previously characterized as having early idiopathic chronic pancreatitis.[119] SPINK-1 is the gene that encodes pancreatic secretory trypsin inhibitor, a protein that plays a primary role in counteracting the effects of activated trypsin. Mutations causing loss of function of this protein increase the risk of development of acute and chronic pancreatitis. It is likely that underlying CFTR mutations exist in many of patients with idiopathic chronic pancreatitis as well.


In recent years, there have been great discoveries in genetic mechanisms for several inherited causes of CP (HP, cystic fibrosis gene, SPINK-1, etc.). These discoveries have provided important insights into the genetics of pancreatic disease, as well as understanding of pathogenesis of acute and chronic pancreatitis. The details of these important genetic discoveries are discussed in a recent, excellent review.[98]


Autoimmune chronic pancreatitis (AIP) is a rare condition, but may account for a substantial proportion of patients with "idiopathic" chronic pancreatitis. The entity known as "non-alcoholic duct-destructive chronic pancreatitis" may actually represent AIP.[120] AIP may occur in isolation or in association with other autoimmune diseases, such as Sjögren's syndrome, PSC, and inflammatory bowel disease.[121–123] Clinical features include minimal pain, hypergammaglobulinemia, autoantibodies (ANA, anti-lactoferrin, anti-carbonic anhydrase I and II, anti-smooth muscle, others), diffuse enlargement of the pancreas on imaging, typical lack of calcifications and cysts, and improvement with steroids (Fig. 8).[124] Histopathological findings include fibrotic changes with infiltration of lymphocytes and plasmacytes, often concentrated around the pancreatic duct.

Figure 8.

CT scan and ERCP appearance of autoimmune pancreatitis, before and after treatment with steroids. Prior to steroids, the gland is enlarged and edematous, and the pancreatic duct is narrowed and irregular (A) and (C). These features improve after steroid therapy (B) and (D). Adapted from Digestive Diseases and Sciences, Vol. 40, Yoshida K, et al. Chronic pancreatitis caused by an autoimmune pancreatitis, pp. 1561–8, Copyright 1995, with permission from Kluwer Academic/Plenum Publishers.

Endoscopic retrograde pancreatography reveals significant pancreatic ductal irregularity and narrowing. Because of the distinct association of AIP with other autoimmune diseases of the exocrine glands, and the presence of auto-antibodies directed against target antigens shared between these organs, it is likely that the pathogenesis of AIP relates to an immune-mediated attack on the ductal cells (primary duct hypothesis). Recent research has revealed a unique cellular and cytokine profile for AIP. Specifically, CD4+ and CD8+ T-cells are increased in the pancreas of patients with AIP.[125] Both cellular and humoral immunity may are likely to play a role in ductal injury.

Recurrent and Severe Acute Pancreatitis Associated Chronic Pancreatitis

One, severe episode of acute pancreatitis may result in permanent pancreatic dysfunction and glandular fibrosis. Severe damage to the gland would allow ample time for both the attraction of stellate cells in the late inflammatory phase, as well as the deposition of excess collagen during a prolonged healing phase. Recurrent acute pancreatitis from any cause may produce chronic pancreatitis through the necrosis-fibrosis and SAPE pathways, however, it remains puzzling why patients with recurrent gallstone or hypertriglyceridemia-associated pancreatitis rarely develop chronic pancreatitis.


Obstructive pancreatitis was codified as an etiologic entity in the second symposium of Marseilles[126] and remains in the present TIGAR-O system. Obstruction of the main pancreatic duct reproducibly produces changes of chronic pancreatitis within weeks in several animal models.[127–129] The pathology of obstructive pancreatitis in humans is somewhat distinct from typical alcoholic pancreatitis. Features include uniform distribution of inter- and intralobular fibrosis and marked destruction of the exocrine parenchyma in the territory of obstruction, notably lacking the presence of plugs and calcifications.[130] Pancreatic malignancies, including pancreatic adenocarcinoma, neuroendocrine tumors, and intrapapillary mucinous tumor, are thought to produce both recurrent acute pancreatitis and chronic pancreatitis. Other disorders such as sphincter of oddi dysfunction and pancreas divisum have a more tenuous connection with chronic pancreatitis.

Main pancreatic duct obstruction may produce stagnation and lithogenicity of pancreatic juice (stone and duct obstruction theory), or acute recurrent pancreatitis and periductular fibrosis (necrosis-fibrosis theory). Intraductal hypertension is another pathogenic factor known to play a role in pathogenesis of pain in chronic pancreatitis, and may also have a role in fibrogenesis and glandular damage. Patients with large duct chronic pancreatitis often have intraductal[131–133] and interstitial[134] hypertension resulting from stones and strictures. A growing literature suggests that pain improves with surgical or endoscopic relief of obstruction.[135] Experiments in cats with obstructive chronic pancreatitis have demonstrated impaired pancreatic blood flow in addition to elevated tissue pressure.[136,137] In contrast to the normal hyperemic response, these cats have a decrease in blood flow after secretin. This constitutes a compartment syndrome, as the normal postprandial augmentation of blood flow is prevented because of decreased tissue compliance and increased interstitial pressures. Pain and progression of fibrosis may result from this mismatch of oxygen supply and demand.


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