ročník 11,2003 č.4
Kongres

Chronic pancreatitis

Špičák, J.

Department of hepatogastroenterology
Institute for clinical and experimental medicine
Prague

Epidemiology

Epidemiology of chronic pancreatitis is uneasy to assess, particularly because of the confusion between the definitions of acute and chronic pancreatitis, and the methodology of the individual studies. In general, the occurrence of chronic pancreatitis reflects alcohol consumption and the presence of other globally much less important and clear pathogenic factors (tropical pancreatitis).
According to reports from various regions, the mean time to onset of chronic pancreatitis is about 45 years after regular drinking of roughly 20 years. The incidence of chronic pancreatitis has been estimated only in several regions.
Unfortunately, the value of studies older than 20 years is compromised by changes in the classification and by the dramatic advances made in imaging techniques. Data are usually dependent on the activity of several research groups, and the differences among particular regions may be associated with differences in clinical practice, principles of health care, and epidemiological methods rather than with different patterns of occurrence of the disease.
Bernandens et al. assessed the occurrence of chronic pancreatitis in eight French departments using a questionnaire sent to gastroenterologists, endocrinologists, and radiologists over a period of two years in the early 1990s (1). A total of 1,099 cases of chronic pancreatitis were identified, and the incidence was estimated at 4.7/100 000/year. Eighty-six percent of individuals with chronic pancreatitis were alcoholics and 88 % were males.
Ikeda analyzed his findings of ultrasonography as the screening method in 130,951 individuals (2). He found ductal changes in 664 (490/100,000), calcifications in 65 (50/100,000), and cystic lesions in 271 (210/100,000) individuals.
Using the doses of pancreatic enzymes distributed by pharmacies, Schmidt evaluated the occurrence of chronic pancreatitis in Sweden in 1971 - 1987, and in Stockholm in 1983-1987 (3). The number of the defined daily dose was 194/100 000 in 1971 and 110 in 1987. A study from Denmark estimated the prevalence of chronic pancreatitis at 27.4/100,000; however, the disease was demonstrated beyond any doubt in only half of the cases.
Worning et al. assessed the prevalence of chronic pancreatitis at 70/100,000 pop.
in Copenhagen, Denmark, and at 20/100,000 pop. in Zurich, Switzerland (4). Dziniszewski explored the prevalence in Warsaw, Poland reporting 14/100,000 and 17/100,000 population in 1986 and 1987, respectively, with 73 % of alcoholic origin (5).
Lankisch, in North Germany, based his investigation on the population registry in the area of Luneberg with a approximate population of 150,000 (6). The incidence was about 7/100 000 per year.
In the United States, the incidence of chronic pancreatitis was assessed using of hospital discharge reports. The corresponding figures were 5.7 per 100,000 for males and 7.6 per 100,000 females in 1987, which seems to be unreliable since chronic pancreatitis is without any doubt more frequent in males (7). The focus on epidemiological and clinical data has a long-standing tradition in the Czech Republic, dating back to reports of Herfort up to recent data collected by Dítě et al. showing an incidence of 7.9 per 100,000 pop./year (8).
Despite the low value of individual epidemiological studies, the average incidence in the Caucasian civilization can be estimated at somewhere between 6 and 7/100,000/year, with the prevalence varying between 50 and 75/100,000 population / year, with a clear predominance of males and alcoholics (alcoholic origin in 75 %) (9-11).

Genetic abnormalities in chronic pancreatitis

A genetic predisposition to chronic pancreatitis clustering in some families has been known from the studies conducted by Comfort et al. in the early 1950s. The crucial step was the discovery of mutations in the cationic trypsinogen gene (protease, serine, l; PRSI1) by David Whitcomb in 1996 (14). The importance of the genetic background was further underlined by the discovery of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor, Kazal type 1 (SPINK1) mutations [12]. In addition to providing an insight into the molecular pathogenesis of chronic pancreatitis, these findings imply the diagnostic potential of genetic testing.
Genetic polymorphism contributes not only to the development of chronic pancreatitis; it also suggests the severity of attacks and the risk for developing pancreatic cancer. Genetic mutations in the cationic trypsinogen gene either enhance trypsin activation mutations in the activating region, or by loss of inhibition through changes in the process of autolysis.
The severity of pancreatitis depends on the alterations in the promoter regions of cytokines, which lead to an overexpression of proinflammatory mediators or decreased expression of anti-inflammatory cytokines. The interleukin-8 microsatellite allele has been shown to be associated with a three-fold lower likelihood of developing multiple organ dysfunction in severe acute pancreatitis. Likewise, genetically-based low production of interleukin 10 increases susceptibility to severe acute pancreatitis (13). A similar role is played by the overproduction of tissue necrosis factor alpha (TNF-?) due to gene promoter region polymorphism. Protective mechanisms are increased by polymorphismus in the promoter regions of the IL-6 gene.
Mutations in the trypsinogen genes, most usually R122H and N291, predispose both to acute and chronic pancreatitis. Similarly, mutations in the CFTR and SPINK1 (N34S) genes tend to promote the development of chronic pancreatitis.
The pathogenesis can be well defined, at least in hereditary chronic pancreatitis. In other and more common forms of pancreatitis, development of the disease is the result of a combination of both environmental and genetic factors while exact identification of their roles in the each individual is still a task for future research (15).

Fibrosis in chronic pancreatitis and the role of stellate cells

Chronic pancreatitis is characterized by progressive yet irregular destruction of all forms of pancreatic cells; their replacement by pancreatic fibrosis leading to loss of both exocrine and endocrine function, and to scarring which roughly resembles liver cirrhosis (16). The basic pathogenic principles are similar to those associated with chronic inflammation in all human organs. Pancreatic stellate cells (again, similar to the pathogenesis of liver cirrhosis) represent the main source of extracellular matrix in chronic pancreatitis. The main features of pancreatic stellate cells include storage of retinyl palmitate, retinol esterification, expression of cytofilaments vimentin and desmin, and transformation into an active matrix producing myofibroblast-like cells. Transformation of the phenotype of cells includes the development of a prominent endoplasmic reticulum, disappearance of fat droplets and retinyl esters, expression of iso-a-smooth muscle actin, increased cell proliferation, and stimulated production of collagen types I and III and fibronectin. The stellate cells are primarily stimulated by the growth factors TGF-ß, bFGD, PDFG, and TGF-?, which are released by activating macrophages and aggregating platelet cells as the first step in the pathogenesis after pancreatic injury (17). However, the opposite principle in the development of fibrosis is a decreased rate of extracellular matrix degradation by metalloproteinases, which can be obtained using tissue inhibitors. The process of development of chronic pancreatitis reflects the imbalance caused by stimulated fibrosis overwhelming the degradation. Research providing further insight into the whole process for the therapeutic outcome aimed at reversal of this chronic disease is warranted (18, 19, 20).

Diagnosis

The diagnosis of chronic pancreatitis is based on a history of the disease, routine blood tests (which usually do not play a major role), function tests and, most importantly, rapidly evolving imaging methods as the most significant potential contributor.

Function tests

Function tests are classified into invasive and noninvasive ones, the latter including three subgroups: oral, fecal, and breath tests. The most widely spread noninvasive tests include the fecal chymotrypsin test, the fecal elastase test, the pancreolauryl test, and the PABA test. These tests are indirect, not standardized, and their specificity and sensitivity vary. Their accuracy is limited by several extrapancreatic factors such as decreased gastric emptying, decreased bile secretion, intestine and renal dysfunction, and so on. While invasive tests (secretin test) are still recognized as the gold standard, they have in fact never been internationally standardized. They are invasive, cumbersome, time-consuming, expensive, and highly dependent on specific skill and experience. Most centers have completely abandoned these tests and, in my view, those advocating their use can hardly identify the patient in whom these tests can significantly contribute to the patient's management.
To demonstrate their uselessness, we could try to answer the following hypothetical questions:
1. Who should perform function tests? (family physician, a specialist, an internist?)
2. Should we repeat the test in any specific condition?
3. Do we need the function tests in patients with a positive finding when using imaging methods?
4. Are the tests reliable in the patients with malabsorption and a normal pancreatic morphology?
5. Are the tests reliable in patients with a history of pancreatic attacks, without any other symptoms, and inconclusive results of imaging methods?
6. Would you undergo function tests if you have to make partial payment for them (only partial reimbursement) (21, 22, 23, 24, 25)?

Imaging methods

There are five imaging methods, which can be applied in diagnosis of chronic pancreatitis:
Ultrasonography seems to be a less sensitive modality, yet the difference is not dramatic. If its finding is conclusive, no other methods are needed. All the other techniques are slightly more sensitive. Computed tomography (CT) and magnetic resonance pancreatography are recognized as the gold standard today. Endoscopic ultrasonography is more invasive, its advantages being the best resolution of pancreatic cancer, and its therapeutic potential. Endoscopic retrograde cholangiopancreatography is most invasive procedure currently being replaced by other ones. It can only be justified in cases with an unclear anatomy of pancreatic ducts resulting from other methods and before intervention. When considering the best diagnostic algorithm, one should take into account the following constantly evolving factors: universality (ability to be used in other medical fields); invasive nature; costs; and therapeutic potential. It is clear from everyday clinical practice that these techniques are misused and overused (26, 27, 28, 29, 30).

Endoscopic management of chronic pancreatitis

Causal treatment of chronic pancreatitis reflecting the pathogenesis of the disease is unknown (except of abstinence), and current therapeutic modalities are focused on symptom relief and management of complications. Endoscopic treatment is generally based on principles similar to those employed in surgery. Endoscopic treatment has become increasingly important during the last 10 years challenging the results of surgery. There are five indications for endoscopic treatment: 1. Intractable pancreatic pain, 2. Pancreatic duct disruption with pancreatic secretion leakage. 3. Pancreatic pseudocyst. 4. Biliary stricture. 5. Duodenal stricture (31, 32).

The bridging of pancreatic strictures

Similar to surgery, endoscopic treatment is based on the theory of increased intraductal pressure causing pancreatic pain. Thus, the aim of endoscopy is to decrease the high pressure. Suitable candidates for endoscopic treatment include patients with stenosis in the proximal part of the pancreatic duct associated with suprastenotic dilatation. The technique of stent implantation and pancreatic sphincterotomy is not different from that one used in biliary intervention. The success rate of stent implantation in individual studies varies between 82 % and 100 %; the complication rate is rather low. There are two specific problems: The first is induction of fibrotic changes in segmental pancreatic ducts in the early stages of chronic pancreatitis, and the second is rapid pancreatic stent occlusion by pancreatic secretion deposits, occurring in half of the patients within several weeks. Pancreatic strictures usually do not disappear even after long-term stenting, which have to be re-implanted either at regular intervals or as necessary (33, 34, 35, 36, 37).

Treatment of pancreaticolithiasis

Similar to strictures, pancreatic stones can block the flow of pancreatic secretion thus increasing pancreatic pressure. The endoscopic technique is identical with that used in the treatment of biliary stones. A significant proportion of stones cannot be removed using common instruments. Stone fragmentation and their subsequent removal can be obtained with the help of extracorporeal lithotrypsy, which can be performed either under ultrasonographic or radiological guidance. A total of more than 300 patients were enrolled in several studies. Complete elimination of pancreatolithiasis was reported in almost 60 %, symptomatic improvement in 72 % of patients; safety of the procedure is high with zero mortality (38, 39, 40).

Treatment of pancreatic pseudocysts

Pancreatic cysts can develop in both acute and chronic pancreatitis and disappear spontaneously in most cases. Indications for treatment include a pseudocyst greater than 5 cm in diameter without signs of disappearance after well-documented follow-up, a pain-causing pseudocyst, biliary or duodenal obstruction, infection and suspicion of malignancy. In the latter case, surgery is necessary. Besides endoscopic drainage, the options include surgery (drainage or resection) and external drainage under CT guidance. The first endoscopic drainage was performed in 1975; the technique was generally adopted and widely used over the last 15 years. Cysts communicating with pancreatic ducts can be treated by pancreatic sphincterotomy and cyst internal drainage. Transmural (gastric or duodenal) drainage is reserved for pseudocysts, which do not communicate with pancreatic ducts and bulge into the gastric or duodenal lumen. The endoscopic technique is not standardized. The drainage can be undertaken using the lateral scope or endoscopic ultrasound, which is otherwise a most useful (but not absolutely necessary) tool for the precise determination of the thickness of tissue between the cystic and gastric or duodenal lumens, and for identifying the most suitable site of puncture. Before the puncture, the pseudocyst lumen can be visualized by injecting a contrast agent. The first cut use to be performed with a needle-knife sphincterotome often followed by rapid evacuation of the pseudocyst content. The puncture has to be enlarged by dilatation, and maintained by nasocystic or cystogastric (duodenal) drainage. We usually use several stents inserted in parallel. Numerous studies have reported high technical success rates (80 - 99 %), recurrence rates of 10 - 20 %, and low morbidity and mortality. Baron achieved a cyst resolution rate of 82%; the figure was higher with chronic than with acute pancreatitis (41, 42, 43, 44, 45).

Treatment of biliary obstruction

Biliary obstruction may develop in up to 45 % of patients with chronic pancreatitis. Biliary stent implantation can be an alternative to the generally preferred surgical management. The maintain biliary flow, it is critical to exchange stents at regular intervals because stenosis resolution can be expected in only a minority of cases. Long-term use of endoscopy is generally justifiable only in patients at high surgical risk.

Long-term results of endoscopic treatment

In the last decade, the endoscopic approach challenging standard surgery has sparked lively discussion concerning the benefits of endoscopy versus surgery. While both modalities have their specific undoubted indications, the question is what should one prefer under standard conditions: pain as the main indication and a dilated pancreatic duct without additional complications? The answer should to be derived from comprehensive data describing the results of both methods in a large community, but no such data are available at the moment, as are not the results of randomized controlled studies inevitably enrolling selected patients thus biasing the conclusions. Anybody planning a controlled study should analyze separately patients with pseudocysts, biliary obstruction, drinkers, and exclude patients not eligible for one of the two methods (multiple pancreatic duct strictures or high risk of surgical complications). After this selection, the figures can only hardly achieve statistical significance. Extremely valuable are therefore the results of a retrospective multicenter international study published by T. Rösch from Munich. The study involved 1,252 patients, 72 % were alcoholics. The complication rate was 13 %. Technical success rate of endoscopic treatment varied between 48 % and 72 % depending on the pathology. Significant pain relief was achieved in 85 % of patients. The proportion of patients with diabetes mellitus increased during follow-up (mean 4.9 years) from 23 % to 37 %. Surgery had to be performed in 23 % of patients with majority of draining procedures but, surprisingly, 10 % of these patients had to undergo additional endoscopic treatment. Recently, Dítě et al. published a randomized controlled study comparing endoscopic treatment with surgery in 72 patients. Complete absence of pain was more frequent after surgery (34 % vs. 15 %), whereas partial relief was almost identical (52 % vs. 46 %). In the endoscopy group, therapeutic pancreatic sphincterotomy and either stone extraction (23.4%) or stent inertion was performed, with additional biliary sphincterotomy undertaken in 12.5 % of cases. In the surgical group, resection and a draining procedure were performed in 80 % and 20 %, respectively. Neither biliary problems in the surgical group, nor the above selection were mentioned (46, 47).

Conclusion

Despite the lack of lacking evidence-based results, the role of endoscopic interventions in chronic pancreatitis is likely to increase. However, it should by performed only in adequately equipped centers with a large body of experience.

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Address for corespondence:

Julius Špičák, MD, PhD.
Department of hepatogastroenterology
IKEM, Videnska 1958/9
140 00 Prague 4
Czech Republic