Chronic pancreatitis: controversies in etiology, diagnosis and treatment

P. Draganov and P. P. Toskes

Division of Gastroenterology, Hepatology and Nutrition. University of Florida. Gainesville, Florida. USA

 

ABSTRACT

The pathogenesis of idiopathic chronic pancreatitis remains poorly understood despite the high expectations for ascribing the pancreatic damage in affected patients to genetic defects. Mutations in the cationic trypsinogen gene, pancreatic secretory trypsin inhibitor, and the cystic fibrosis conductance regulator gene do not account for the chronic pancreatitis noted in most patients with idiopathic chronic pancreatitis. Small duct chronic pancreatitis can be best diagnosed with a hormone stimulation test. Endoscopic ultrasonography can detect abnormalities in both the parenchyma and ducts of the pancreas. The true value of endoscopic ultrasonography in diagnosing small duct chronic pancreatitis remains to be fully defined and is under active investigation. It is not clear whether endoscopic ultrasonography is more sensitive for early structural changes in patients with small duct disease or is over diagnosing chronic pancreatitis. Pancreatic enzyme supplementation with non-enteric formulation along with acid suppression (H2 blockers or proton pump inhibitors) is an effective therapy for pain in patients with small duct chronic pancreatitis. The role of endoscopic ultrasonography-guided celiac plexus block should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities. Total pancreatectomy followed by autologous islet cell autotransplantation appears to be potential therapeutic approach but for now should be considered experimental.

Key words: Chronic pancreatitis. Abdominal pain. Endoscopic ultrasonography. Islet cell autotransplantation.

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Draganov P, Toskes PP. Chronic pancreatitis: controversies in etiology, diagnosis and treatment. Rev Esp Enferm Dig 2004; 96: 649-659.

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Recibido: 16-06-04.
Aceptado: 30-06-04

Correspondencia: Peter Draganov. Assistant Professor of Medicine. University of Florida. 1600 SW Archer Rd. Division of Gastroenterology, Hepatology and Nutrition. Room HD 602, PO Box 100214. Gainesville, FL 001-32610-0214. Tel: 001-352-392-5046. Fax: 001-352-392-3618. e-mail: dragapv@medicine.ufl.edu

 

INTRODUCTION

Chronic pancreatitis (CP) is one of the greatest challenges in gastroenterology. The etiology of CP remains elusive in 10-30% of all cases (1). A variety of diagnostic tests are available, the clear implication being that no one diagnostic test is sufficient to make the diagnosis in all patients with chronic pancreatitis (2). Once CP is diagnosed, a number of therapeutic options are available. This review of chronic pancreatitis focuses on selected controversial issues of etiology, diagnosis and management of CP.

ETIOLOGY

Despite the perhaps unreasonable expectations, it is becoming quite clear that most cases of idiopathic CP represent a complex interaction of genetic and environmental factors rather than resulting from single gene mutation. Neither mutations in the cationic trypsinogen gene (3,4) nor mutations of the cystic fibrosis conductance regulator gene (5,6) account for the chronic pancreatitis noted in most patients with idiopathic CP.

Mutations involving the cationic trypsinogen gene

Various mutations on the cationic trypsinogen gene (also known as protease serine 1 or PRSS1) have been identified. The first mutation identified in patients with hereditary pancreatitis was a single point mutation in the third exon of the cationic trypsinogen gene (3). This same mutation is called R117H or R122H in various publications (using two different nomenclatures). It was hypothesized that a single amino acid substitution led to a gain of function mutation, in which the mutated trypsin was resistant to inactivation once activated. Under normal conditions, human trypsinogen undergoes a slow autoactivation. Pancreatitis does not occur due to the presence of several protective mechanisms. Pancreatic secretory trypsin inhibitors are able to inhibit the activity of trypsin within the acinar cells and pancreatic duct. Once activated, trypsin may also be inactivated by cleavage at the 117 (or 122, depending on nomenclature) site. The R117H mutation appears to interfere with this inactivation of trypsin once activated. If trypsin is activated within the pancreas at levels sufficient to overwhelm the pancreatic secretory trypsin inhibitors that are present, and if this trypsin is resistant to inactivation by other protective mechanisms, the activated trypsin could activate other proenzymes and produce pancreatitis. This could produce chronic pancreatitis by repeated low-grade pancreatic injury from the activated proteases.

Two other, less frequent mutations (N29I and A16V) may also make trypsin resistant to inactivation (7,8). Other mutations that involve the trypsinogen activation peptide (K23R, D22G), cationic trypsinogen promoter (-delTCC), and cationic trypsinogen gene (L104P, R116C, C139F) have been described (9-11). The penetrance of the best studied mutation R122H is only 80% raising the question of the contribution from environmental factors to the development of hereditary CP. On the other hand a number of studies have failed to show that mutations in the cationic trypsinogen gene are responsible for cases of nonfamilial sporadic idiopathic CP or contribute to the development of alcohol induced CP (11).

Mutations involving the pancreatic secretory trypsin inhibitor gene

The pancreatic secretory trypsin inhibitor (frequently referred in publications as Serine Protease Inhibitor Kazai Type 1 or SPINK 1) is believed to be the first line of defense against injury from activated trypsin within the pancreatic gland. A number of SPINK 1 mutations have been described the most common being N34S (12). The N34S mutation has been demonstrated in 25% of patients with familial pancreatitis (13), 16% of patients with idiopathic pancreatitis (11) and in 20 to 33% of patients with tropical pancreatitis (14,15). The frequency of SPINK 1 mutations was not increased in patients with alcoholic CP (16).

Mutations involving the cystic fibrosis gene

At present it remains unclear whether the cystic fibrosis conductance regulator gene mutations alone can lead to pancreatitis as an autosomal recessive disease or if these mutations operate as part of a polygenic process affecting the susceptibility for developing CP. Cystic fibrosis conductance regulator gene mutations are common in the general population. A recent study tested 39 patients with idiopathic non-familial CP for common cystic fibrosis gene and pancreatic secretory trypsin inhibitor (SPINK 1) mutations (17). Pancreatitis risk was increased approximately 40-fold by having 2 cystic fibrosis mutations (p < 0.0001), 20-fold by having N34S (p < 0.0001), and 900-fold by having both (p < 0.0001).

It appears that the role of genetic factors in the pathophysiology of CP is variable and complex. Numerous genetic, dietary and environmental factors probably act together to determine each individual susceptibility to develop CP. At present we are at the very early stages of identifying these factors and determining their precise role.

DIAGNOSIS

An impressive number and variety of diagnostic tests for CP have been developed. These diagnostic tests are usually separated into those tests that detect abnormalities of pancreatic function and those that detect abnormalities of pancreatic structure. A large number of patients exist who are thought to have idiopathic chronic pancreatitis but are not able to be diagnosed by the tests of structure including conventional abdominal ultrasound (US), computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), or endoscopic retrograde cholangiopancreatography (ERCP) (18). These patients are frequently referred as having small duct chronic pancreatitis (19). What percentage of all patients with chronic pancreatitis this subset represents remains controversial but may be as high as 40% at some centers.

Direct hormonal stimulation tests have been felt to be the most sensitive tests for chronic pancreatitis (20). The reliability of the secretin stimulation test in detecting chronic pancreatitis has been evaluated against histology in over 100 patients by Hayakawa et al. (21). In this study, the peak bicarbonate concentration of pancreatic secretion was the most accurate parameter for the diagnosis of CP. Although it has been widely accepted that the most sensitive and specific test to diagnose CP is a hormone stimulation test like the secretin test, this test has not been widely used (2). Multiple factors may have contributed to that. The procedure is labor and time intensive, demands trained personnel and a designated laboratory. A passage of a large size (26 Fr) oro-duodenal tube is required. The tube has to remain in place for more than one hour because the standard secretin stimulation test in our laboratory requires collection of pancreatic secretions for 60 minutes after injection with secretin. During the insertion of the tube and during sample collection sedation is not used because it can interfere with the test results. The lack of sedation can make the performance of the secretin stimulation test uncomfortable for patients. A significant degree of discomfort rarely may prevent successful completion of the test.

The search continues for a simple, inexpensive, safe, and accurate test to detect structural changes related to chronic pancreatitis. In recent years, endoscopic ultrasonography (EUS) has emerged as the frontrunner among the tests evaluating pancreatic structure. There are distinct advantages of endoscopic ultrasonography in imaging the pancreas. Transabdominal US imaging suffers from low resolution because high-frequency instruments providing high resolution do not penetrate deeply enough to image the pancreas from the skin surface. Furthermore, transabdominal ultrasound is limited by overlying bowel gas. EUS overcomes both of these disadvantages by placing a transducer within the lumen of the bowel in close proximity with the pancreas and removes or displaces bowel gas. Also, endoscopic ultrasonography is significantly safer than ERCP. Overall, the rate of serious complications from diagnostic endoscopic ultrasonography is one per 2000 procedures (22). Finally, whereas ERCP can image only the pancreatic ductal system, endoscopic ultrasonography can evaluate both the pancreatic ducts and the parenchyma.

Nonetheless, there are also several disadvantages of endoscopic ultrasonography. First, in the United States, EUS still remains confined to very few tertiary care centers and is not widely available. Second, the value of endoscopic ultrasonography is directly proportional to the training, skill, and experience of the endosonographer. All of the published information pertaining to EUS is the work of a relatively small group of experts. Third, the principal concern in using EUS for the diagnosis of chronic pancreatitis is the possibility that it may over diagnose chronic pancreatitis, causing patients to be falsely diagnosed with CP when they do not have pancreatic disease. Because experts cannot agree on a gold standard for the diagnosis of chronic pancreatitis, it has been difficult to determine the extent to which over diagnosis occurs. In patients with endoscopic ultrasonographic evidence of changes of chronic pancreatitis but a normal secretin test or a normal ERCP, it is not clear whether the endoscopic ultrasonography is more sensitive for early changes or if it is truly over diagnosing chronic pancreatitis (20).

In the past, a number of studies have compared EUS with various diagnostic modalities. Comparison with function testing and pancreatography obtained via ERCP shows similar results. The main source of disagreement in these studies involved patients with abnormal results of endoscopic ultrasonography and normal function tests or normal ERCP. More recently, EUS was directly compared with the secretin test. The secretin test was used as a gold standard in 21 patients with unexplained abdominal pain. The two endosonographers were blinded to the results of the secretin test. When a cutoff of four criteria for chronic pancreatitis was used, the sensitivity of endoscopic ultrasonography was 57%, and the specificity was 64%. At any chosen cutoff, a substantial number of patients had discordant test results (23).

In general, histology is the most obvious candidate for a diagnostic gold standard. A number of factors have prevented histologic samples from being taken in the case of chronic pancreatitis. The distribution of changes of chronic pancreatitis can be patchy (24). Pancreatic tissue is difficult to obtain, and biopsy of the pancreas is associated with potential risk. Can a technique be developed that can reliably diagnose chronic pancreatitis from needle biopsy samples rather than requiring surgical resection, specimens, or core biopsy samples? Hollerbach et al. attempted to answer this question (25). They prospectively evaluated 37 patients with clinical symptoms and laboratory test results suggestive of chronic pancreatitis. All patients underwent ERCP, indirect pancreatic function testing (fecal chymotrypsin, fecal pancreatic elastase 1, urinary pancreolauryl test), and endoscopic ultrasonography. Twenty-seven underwent fine-needle aspiration (FNA) guided by endoscopic ultrasonography. Thirty-one patients were shown to have chronic pancreatitis on ERCP, and 33 were shown to have chronic pancreatitis on endoscopic ultrasonography. Endoscopic ultrasonography had a sensitivity of 97%, a specificity of 60%, and a negative predictive value of 75% if ERCP served as the gold standard for the diagnosis of chronic pancreatitis. FNA findings increased the negative predictive value to 100%, resulting in a small increase in specificity to 67%. There is poor correlation between endoscopic ultrasonography and indirect function testing, particularly in patients with mild disease. Based on the available findings, FNA cannot be recommended as a routine diagnostic extension of EUS in the diagnosis of CP.

At present, EUS is an important tool in the diagnosis of chronic pancreatitis. There is still controversy regarding the diagnosing of early (small duct) chronic pancreatitis based on endoscopic ultrasonography changes alone. In such cases, one would be well advised to take into account all components of the patient's evaluation, including history, pancreatic function testing, and responsive response to therapy, before diagnosing the patient with chronic pancreatitis (20).

THERAPY

Patients with chronic pancreatitis seek medical attention predominantly secondary to two symptoms: abdominal pain and maldigestion. At present we have an effective therapy for maldigestion in the form of pancreatic enzymes supplementation. On the other hand therapy of pain can be a real challenge to patients and physicians alike. Three pathophysiologic mechanisms have been proposed to explain the pain in CP: acute pancreatic inflammation, increased intrapancreatic pressure, and alterations in pancreatic nerves. Different therapies for CP aim to decrease pain by influencing one of the above mechanisms. Therapy with antioxidants aims to decrease pancreatic inflammation. Pancreatic enzyme supplementation, cholecystokinin (CCK) antagonists, and octreotide aim to decrease pancreatic secretion thus decreasing intrapancreatic pressure. Various endoscopic and surgical techniques attempt to decrease the pressure by providing improved drainage. Celiac plexus block and thoracoscopic splanchnicectomy interrupt neural transmission of pain signals. A relatively new radical approach is to perform pancreatectomy with islet cell autotransplantation. Few therapies have been studied in placebo-controlled trials of adequate sample size, and advocates of specific therapies often forget the substantial placebo response of 35-40% that can be seen in these patients (26). Below we will address the use of pancreatic enzyme supplementation, EUS guided celiac plexus block, and pancreatectomy with islet cell autotransplantation as therapies for pain due to chronic pancreatitis.

The role of pancreatic enzyme supplementation as a therapy for pain due to chronic pancreatitis

It is important to realize that chronic pancreatitis is not one disease, but may have many forms. The differentiation between those patients with chronic pancreatitis and big duct disease and those with chronic pancreatitis and small duct disease is an attempt to tailor the therapeutic approach towards these different groups of patients (19). It is likely that, with the recognition that a CCK releasing factor is important in the feedback control of pancreatic secretion, an appreciation is emerging that there may be forms of pancreatitis that are related to abnormalities in CCK homeostasis (27). Oral pancreatic enzyme preparations appear to inhibit pancreatic exocrine secretion through negative feedback mechanism involving intraduodenal serine proteases and the exocrine pancreas. Intraduodenal serine proteases modulate pancreatic exocrine secretion by regulating CCK release. Because patients with chronic pancreatitis often have decreased intraduodenal protease activity secondary to a damaged gland, they may not be capable of inactivating the intraduodenal peptide (CCK releasing peptide) that stimulates CCK blood levels. Hence, in a subset of patients, the gland is under constant stimulation by CCK. Oral pancreatic enzyme supplements may provide relief of pain by supplementing endogenous protease inactivation of CCK releasing peptide, in patients with chronic pancreatitis pain. Inactivation of this peptide results in decreased CCK release, which decreases pancreatic stimulation, hence may decrease pain. Because this is a proximal small intestine phenomenon, it is mandatory that the pancreatic proteases be delivered to the upper small intestine. This can only be done consistently by the administration of non-enteric coated pancreatic enzyme preparations. Because the non-enteric coated enzyme preparations are not protected against gastric acid in the pass through the stomach, it is appropriate to add an acid-suppressing agent (H2 receptor antagonist or proton pump inhibitor), to allow significant amount of the protease to reach the duodenum. From our clinical experience we have found that Viokase-16 (Axcan Scandipharm, Birmingham, AL) given orally at a dose of 4 tablets with each meal and at bedtime, provides the best clinical response in most patients.

Six randomized trials have evaluated the effectiveness of pancreatic enzymes in reducing the pain of chronic pancreatitis (28). Pancreatic enzymes were effective in reducing pain in two trials (29,30), whereas in 4 studies no statistical improvement in relieving pain was seen. Given our understanding of CCK regulation of pancreatic secretion and mechanism of action of pancreatic enzymes, not surprisingly, the two trials showing positive effect in reducing pain used non-enteric coated preparations and all trials showing no improvement used enteric coated enzymes. Furthermore in patients with big duct disease there was at best a 25% response rate in decreasing abdominal pain, whereas in those with small duct disease there was a response rate of approximately 70%. Results of a meta-analysis of these randomized trials indicated that pancreatic enzyme therapy did not decrease abdominal pain in patients with chronic pancreatitis (31). This meta-analysis, however, has come under criticism because it lumped together the analysis of those patients receiving non-enteric coated enzymes and enteric-coated enzymes (20).

Abundant information now exists, both in randomized trials and clinical experience, indicating that non-enteric coated enzyme preparations are preferable over enteric-coated enzymes for relief of abdominal pain in patients with chronic pancreatitis. Thus, if pancreatic enzyme preparations are to be employed to relieve the pain of chronic pancreatitis, then the appropriate patient should be selected, i.e., one with small duct disease and the appropriate enzyme preparations should be employed, i.e., a non-enteric coated enzyme preparation in the proper dose. Great success is not going to be achieved if one attempts to treat the pain of a patient with big duct disease and steatorrhea with an enteric-coated preparation.

The role of EUS guided celiac plexus block as a therapy for pain due to chronic pancreatitis

A substantial body of literature has accumulated regarding EUS-guided celiac plexus block in the management of pain resulting from pancreatic cancer. A combination of long-acting local anesthetics and steroids injected into the celiac plexus under endoscopic ultrasonography guidance in patients with CP has been used for years (personal communication), yet the published data are scarce. Gress F et al. compared endoscopic ultrasonography-guided versus CT-guided celiac blocks in a prospective, randomized fashion (32). The conclusion of this small study was that EUS-guided celiac block (n=10) provided more persistent pain relief than CT-guided block (n=8). The same group of investigators recently published their prospective experience with endoscopic ultrasonography-guided celiac plexus block in 90 patients with pain resulting from chronic pancreatitis (33). A significant improvement in pain score occurred in 55% of the patients. The benefit persisted beyond 12 weeks in 26% of patients and beyond 24 weeks in only 10%.

The current evidence indicates that endoscopic ultrasonography-guided celiac plexus block is safe and well tolerated, with excellent temporary results in some patients. Unfortunately, reliable predictors of success are lacking. In the absence of long-term studies with follow-up in patients with chronic pancreatitis whose pain is chronic, the role of endoscopic ultrasonography-guided celiac plexus block should be limited to treating flares of chronic pain in patients with otherwise limited therapeutic options.

The role of pancreatectomy with islet cell autotransplantation as a therapy for pain due to chronic pancreatitis

Total pancreatectomy, as a therapy for severe chronic pancreatitis provides good pain control but has been plagued with long-term morbidity and mortality, in particular, related to the ensuing diabetes mellitus (34,35). An elegant alternative is to perform total or nearly total pancreatectomy followed by islet cell autotransplantation. This attractive approach comes with the high expectations that after removing the diseased pancreas pain control will be achieved without paying the price of causing surgical diabetes.

Recently three studies have examined the outcomes of patients undergoing total pancreatectomy followed by autologous islet cell autotransplantation. Twenty two patients underwent the procedure at the University of Cincinnati from February 2000 to February 2003 (36). There were 4 major post-operative complications (acute respiratory distress syndrome, intra-abdominal abscess and pulmonary embolism) and no deaths. All patients were taking opioid analgesics prior to the intervention. After mean follow-up of 19 months (range 3 to 41), 82% of the patients required no opioids analgesia. Forty one per cent were insulin independent and 27% required minimal amount of insulin.

The experience of the Leicester General Hospital in the United Kingdom was recently published (37). Forty patients underwent pancreatectomy with islet cell autotransplantation. The range of follow-up was from 6 months to 7 years. A crude estimation of pain control was done by reporting the use of opiates. Data were not available on all patients. At 6 months all patients for whom data are available (n=6) still required narcotics. That number decreased to 5 out of 10 patients at one year, 4 out of 9 at two. Of the 4 patients followed for 6 years one patient was requiring opioids. Most importantly of the 40 patients, 38 required varying doses of insulin and only one had normal oral glucose tolerance test. The authors noted that over time the function of the islet cell transplant deteriorated.

The largest series to date comes from the University of Minnesota (38). Over a period of 28 years 112 islet cell autotransplants were done at the time of total or subtotal pancreatectomy for chronic pancreatitis. Pain resolved in 40% of the patients, improved in 32% and remained unchanged or worsened in 12%. Complete insulin independence was achieved overall in 38% of the patients and 12% required only one injection daily with long-lasting insulin. Furthermore 71% of the patients who had not undergone previous pancreatic surgery did not require insulin. Not surprisingly, patients who had undergone prior distal pancreatectomy or Puestow drainage procedure had lower islet cell yield and less than 20% were insulin independent.

These studies show that islet cell autotransplantation is technically feasible. As this technology improves total pancreatectomy followed by autologous islet cell autotransplantation one day may become a standard therapy for patients suffering from refractory pain due to chronic pancreatitis.

CONCLUSION

The pathogenesis of idiopathic chronic pancreatitis remains poorly understood. Genetic mutations account for the minority of cases in patients with idiopathic chronic pancreatitis. The true value of endoscopic ultrasonography in diagnosing small duct chronic pancreatitis remains to be fully defined. Non-enteric coated pancreatic enzyme supplementation is an effective therapy for patients with small duct chronic pancreatitis. Endoscopic ultrasonography-guided celiac plexus block can provide excellent short-term pain relief in some patients with chronic pancreatitis. Large, long-term controlled studies are needed to examine the safety and efficacy of celiac plexus block. At present its use should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities. Total pancreatectomy followed by autologous islet cell autotransplantation appears to be a feasible therapeutic approach but for now should be consider experimental.

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