Chronic Pancreatitis

Matthew J DiMagno, MD; Eugene P DiMagno, MD

Curr Opin Gastroenterol. 2005;21(5):544-554. 

Abstract and Introduction

Purpose of review: As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. We included articles, including review articles, only if they contained new observations or readdressed old questions and provided new insights into old and new concepts.
Recent findings: Important observations include the following:

  1. Strong association between cystic fibrosis transmembrane regulator dysfunction/mutations and 'recurrent acute pancreatitis', particularly in patients with pancreas divisum

  2. Pancreas divisum may be incidental finding in recurrent acute pancreatitis

  3. Smoking increases risk of chronic pancreatitis

  4. Coxsackie B virus may increase severity of alcoholic chronic pancreatitis

  5. CD4+ T cells and an immune reaction against amylase may play a role in pathogenesis of autoimmune pancreatitis

  6. 2-(18F)-Fluro-2-deoxy-D-glucose positron emission tomography might be useful to detect pancreatic cancer in chronic pancreatitis patients at risk for developing pancreatic cancer, but contrast-enhanced Doppler ultrasound or endosonography may be as sensitive and better than contrast enhanced computed tomography

  7. Superiority of surgery vs endotherapy for long term pain relief and weight gain in painful chronic pancreatitis

  8. Early treatment of pain and malabsorption may improve life quality

  9. Antifibrogenesis and fibrolytic agents as potential therapies.

Summary: Ongoing basic and clinical research this past year has further characterized genetic, molecular and clinical aspects of chronic pancreatitis. The advent of predictable and lasting treatments of chronic pancreatitis is most likely to appear on the wings of carefully conducted studies targeting genetic and molecular mechanisms of chronic pancreatitis, particularly pancreatic fibrogenesis.

This year we review publications that contain important new observations, but also those that readdress old questions and provide insightful interpretations of what is known. Most noteworthy, we discuss differentiation of chronic pancreatitis from pancreatic cancer by positron emission tomography (PET) scanning, identification of cystic fibrosis transmembrane regulator (CFTR) dysfunction and/or gene mutations in recurrent acute pancreatitis associated with pancreas divisum, clearer characterization of genetic and environmental modifiers of alcoholic pancreatitis, recognition that early and successful treatment of pain and malabsorption may improve life quality, assessment of the quality of life in persons with chronic pancreatitis, and investigation of pancreatic fibrogenesis and experimental fibrolytic therapies.


The triggers, thresholds, immunologic response and mechanisms of chronic pancreatitis remain under investigation. In an important review on the pathogenesis of chronic pancreatitis,[1] the authors summarized the traditional theories of chronic pancreatitis (oxidative stress, toxic-metabolic, ductal obstruction, and necrosis-fibrosis), and discussed the newer primary duct and the SAPE (sentinel acute pancreatitis event) hypotheses. According to the primary duct hypothesis chronic pancreatitis begins as a primary autoimmune or inflammatory reaction in pancreatic ducts and alcohol may initiate pancreatitis by altering target antigens in duct epithelium and/or causing direct toxic injury to duct epithelium. As the authors point out, the SAPE hypothesis incorporates many features of traditional hypotheses into a single unifying concept. According to this hypothesis, the first pancreatic insult occurs in acinar cells in response to alcohol, oxidative stress etc. which up-regulate trypsin activation, in turn producing an early inflammatory response consisting of proinflammatory cells, and cytokines. At this point, removal of the inciting factor(s) results in healing. If, however, the pancreatic cytokine secretion continues (see Pancreatic fibrogenesis), activated pancreatic stellate cells (PSCs) secrete collagen and set the stage for fibrosis and chronic pancreatitis.

The authors also review the TIGAR-O (toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, obstructive) etiologic classification of chronic pancreatitis (see ), and suggest, somewhat at odds with the unifying SAPE hypothesis, that different etiologies result in different mechanisms of chronic pancreatitis. Rather, it seems more plausible that different etiologies enter the SAPE hypothesis model but at different points. For example, toxic metabolic factors begin by stimulating the acinar cells to up-regulate trypsin activation whereas the entry point for genetic factors is the up- or down-regulation of trypsin activation or inhibition respectively (e.g. PRSS1 and SPINK1 mutations), and the entry point for autoimmune disease is at the cellular infiltrate stage. The authors comment that 'it remains puzzling why patients with recurrent gallstones or hypertriglyceridemia-associated pancreatitis rarely develop chronic pancreatitis'-the simplest explanation for these observations is that the inciting cause is removed (gallstones) or reduced (hypertriglyceridemia) to levels that do not induce continued secretion of cytokines.

  Etiologic Factors Associated with CP: TIGAR-O Classification System

At present there are three major groups of mutations in chronic pancreatitis (PRSS1, SPINK1, and CFTR). '52-81% of patients with hereditary pancreatitis have cationic trypsinogen or serine protease I (PRSS1) gene mutations, 50% of patients formerly classified as early onset idiopathic chronic pancreatitis have mutations of the serine protease inhibitor, Kazal type 1 (SPINK1) or the cystic fibrosis transmembrane regulator (CFTR), and 20-55% of patients with tropical pancreatitis have SPINK1 gene mutations'.[2] Of note, there is no association withfunctional polymorphisms in the angiotensin converting enzyme (ACE)[3] or with UDP-glucuronosyltransferase genes[4] in familial pancreatitis or sporadic chronic pancreatitis. Thus, currently the value of genetic testing in recurrent acute pancreatitis (RAP) or chronic pancreatitis is limited to screening for cationic trypsinogen gene mutations, which unlike CFTR and SPINK1 mutations, are both diagnostic and predictive of pancreatic disease.[5]

SPINK1 gene mutations may increase the risk of pancreatitis by impairing the ability of pancreatic acinar cells to inhibit and counteract the potentially damaging effects of activated intracellular trypsin. The protective function of trypsin inhibitor was experimentally confirmed by showing that the severity of secretagogue-induced acute pancreatitis in mice was significantly ameliorated by transgenic overexpression of trypsin inhibitor, which inhibited trypsin activity but not trypsinogen activation.[6] Clinically, the association of SPINK1 mutations with early onset ICP and RAP was confirmed[7] by showing a 19.5% prevalence (8/41) vs 2.6% (5/190) in controls and an earlier onset of pancreatitis in those with SPINK1 mutations vs. those without (median years = 12[3-46] vs 38,[4-82] P < 0.0003). The high prevalence of N34S SPINK1 gene mutations (~2%) relative to the low prevalence of chronic pancreatitis (0.006%) suggests that this gene mutation is a disease modifier rather than a primary cause of pancreatitis. In another study, however, this relation appeared to be mutation specific[8]; SPINK1 gene mutations may cause disease[8] because the severe mutations c.87 + 1G > A and c.27delC (causing complete functional loss of the mutant protein) were found in 3/46 families having ≥2 pancreatitis patients.

Overt cystic fibrosis manifestations are lacking in nonclassic cystic fibrosis having a genotype with ≥1 copy of a mutant gene that encodes for a partially functioning CFTR protein. These persons, however, have an increased risk for pancreatitis.[9,10] A recent analysis of prospectively collected data from the Cystic Fibrosis Foundation[11] confirms that pancreatitis is rare in cystic fibrosis patients harboring genotypes associated with pancreatic insufficiency (0.9% of 12,997 patients), is more frequent in cystic fibrosis patients with at least 1 mild cystic fibrosis mutation (11.9% of 868) and is greatest in patients with an R334W mutation (19%), of which 48% were found in Hispanics (n = 79) and patients living in Puerto Rico (n = 13). It remains unknown whether asymptomatic carriers are at risk for pancreatitis and whether the frequency of the R334W CFTR mutation is increased in Hispanics with idiopathic pancreatitis.

Two recent studies establish a strong association between CFTR dysfunction/mutations and what has been labeled 'recurrent acute pancreatitis' (RAP).[12,13] These findings cast doubt on the controversial hypothesis that pancreas divisum triggers RAP and raise serious questions about the rationale for endotherapy in patients with pancreas divisum and RAP. Choudari et al.[12] tested for only 13 common CFTR gene mutations in patients with idiopathic pancreatitis but found a 22% (8/37) mutation frequency in patients with pancreas divisum and idiopathic pancreatitis compared with 0% (0/20) in those with pancreas divisum and no pancreatitis (P = 0.02) and 18.3% (19/104) in those with idiopathic pancreatitis. The similar frequency of CFTR gene mutations in patients with idiopathic pancreatitis with or without pancreas divisum significantly weakens the hypothesis that pancreas divisum is an independent risk factor or disease modifier for pancreatitis. Similar conclusions are drawn from a multicenter North American study[13]; in 12 patients with pancreas divisum and RAP, nasal epithelium CFTR function, in response to isoproterenol, had an intermediate value between normal controls (median 13 vs 22 mV, P = 0.001) and those with classic CF and either pancreas sufficiency (median 13 vs -1 mV, P < 0.0001) or pancreas insufficiency (median 13 vs -3 mV, P < 0.0001). Combined, these studies suggest that pancreas divisum may represent an incidental finding in the setting of RAP or at best is a factor dependent on other predisposing factors for triggering RAP, such as CFTR gene defects.

The association of CFTR mutations with alcoholic pancreatitis is uncertain; absent in several large studies[10,14,15] and present in 23-40% of patients in large Italian,[16] Spanish[17] and Japanese[18] studies. The latter three studies raise the possibilities that an increased frequency of CFTR mutations occurs in patients with idiopathic and alcoholic chronic pancreatitis, there may be regional genetic differences in patients with alcoholic chronic pancreatitis, and as reported by Casals et al.,[17] different CFTR mutational spectrums may be present in patients with alcoholic chronic pancreatitis compared with ICP. Noted in the Japanese study is the rarity of cystic fibrosis in Japan (1/350 000 vs 1/2500 in Western countries). In support of these data, Naruse et al.[19] showed in a pilot study that CFTR dysfunction (indicated by finger sweat test) was present in 52% of patients with chronic pancreatitis (21 alcoholic and 4 idiopathic) vs 16% of controls. It is unsettled if CFTR gene mutations are associated with alcoholic chronic pancreatitis and if the simple finger sweat test is clinically useful to determine CFTR dysfunction in patients with pancreatitis.

Environmental (e.g. smoking,[20] fat/protein rich diet[21]) and genetic (e.g. UDP glucuonosyltransferase gene polymorphisms[22]) cofactors likely contribute to the pathogenesis of alcoholic pancreatitis, because <10% of alcoholics develop pancreatitis.[23] Recently, investigators showed by multivariate analysis of a prospective cohort of 129 000 prepaid health plan members that smoking (1 pack daily vs. never) was a strong, independent risk factor for alcoholic pancreatitis (P < 0.001).[24] Although subclass analysis of acute and chronic pancreatitis groups (the latter indicated by prior symptoms, pancreatic pseudocyst or calcifications, pancreatic insufficiency) was not provided, the authors interpret the data as indicating that the increased risk of alcoholic pancreatitis in smokers applies to acute and chronic pancreatitis groups. The relative risk of idiopathic pancreatitis was also increased in smokers (P < 0.01)[24]; although the age, presence of chronic changes, and clear absence of alcohol history were not provided, these observations parallel previous findings of an increased risk of pancreatic calcification in late onset ICP patients who smoked cigarettes.[25] Other predictors of alcoholic pancreatitis included male gender, black ethnicity, and lower-educational attainment. In contrast to a prior study,[26] drinking coffee but not tea correlated inversely with the risk of alcoholic pancreatitis (P = 0.003),[24] similar to the inverse relation between coffee and cirrhosis[24]; this protection against alcoholic pancreatitis occurred primarily in cigarette smokers. Smoking also accelerates the progression of alcoholic chronic pancreatitis[27]; compared with nonsmokers, smokers had alcoholic CP diagnosed 4.7 years earlier diagnosis (P = 0.001), an increased risk of pancreatic calcifications (hazard ratio 4.9; 95% CI 2.3-10.5) and an increased risk of diabetes (hazard ratio 2.3; 95% CI 1.2-4.2). Presently there is no single unifying explanation to explain how smoking alters the risk of pancreatitis.

Group B coxsackie virus infection, which causes necrotizing pancreatitis in humans, may be an important cofactor in alcoholic pancreatitis. Alone, this virus causes acute pancreatitis in a viral titer dependent fashion,[28,29] which may progress to chronic pancreatitis when there is a lack of tissue repair, a defect associated with preferential activation of (M1) macrophages and T helper 1 (Th1) cells rather than (M2) macrophages and Th2 cells.[30] Short-term (5-14 days) and subchronic (>28 days) oral ethanol potentiates viral-induced pancreatitis and impairs pancreatic regeneration following injury in a dose- and duration-dependent fashion.[29] Thus alcohol may modify rather than trigger acute pancreatic injury, possibly by increasing tissue virus infection or replication, impairing tissue healing and promoting chronic injury.

That ethanol plays a modifying rather than triggering role in pancreatitis is supported by observations that ethanol causes perturbations in pancreatic regulatory processes without causing pancreatitis; chronic ethanol feeding disrupts normal pancreatic neurohormonal control mechanisms,[31] causes dysregulation of the immune system,[32] leads to acinar cell changes, including mitochondrial damage,[33] differentially regulates activation of the inflammatory transcription factor NF-kB[34] and lowers the threshold for initiating acute pancreatitis.[35] An in-vivo study[36] confirms the potentiating effect of alcohol (Lieber-DeCarli protocol) on secretagogue-induced acute pancreatic injury in rats and that onset of pancreatic fibrosis was accelerated by both ethanol exposure and the increased intensity and duration of the pancreatitis trigger, findings which support a relation between acute injury, inflammation and fibrogenesis.

No significant association exists between alcoholic chronic pancreatitis and genes encoding for the detoxifying enzymes glutathione S-transferases (GSTM1, GSTT1, GSTP1), the cytochrome P450 (CYP2E1, CYP1A1) enzymes,[37] and with polymorphisms in genes encoding for TGF-ß1, interleukin-10, interferon-γ, alcohol dehydrogenase 3 or CYP2E1.[2,38] The lack of association between GSTM1 and alcoholic chronic pancreatitis, however, contrasts with a protective effect for the GSTM1 null genotype.[39] This discrepancy partially is accounted for by differences in sample size (n = 14 vs 79 for alcoholic chronic pancreatitis) resulting in different power to discern differences and possibly regional genetic differences (Brazil vs Netherlands).

Most reports last year confirm known features of autoimmune pancreatitis (AIP). To recapitulate our position: we are lumpers rather than splitters and believe AIP includes some forms of idiopathic pancreatitis, idiopathic duct-centric chronic pancreatitis, sclerosing pancreatitis, lymphoplasmacytic sclerosing pancreatitis and a subset of tumefactive chronic pancreatitis, as do prominent pathologists.[40] A major histologic feature is infiltration of lymphocytes, predominantly CD4+ T cells. Clinically, there may be high levels of circulating IgG4, particularly if there is a mass lesion,[41] and the response to steroids is dramatic in most patients.[42-44]

New and somewhat disconcerting information, however, is the report of Takayama et al.[45] that 11 of 36 (26%) patients treated with prednisolone (40 mg/d x 4 weeks followed by 5 mg/wk x 7 weeks, and discontinuation if clinical findings had improved) had recurrent attacks with recurrent irregular narrowing of pancreatic duct and/or stenosis of the common bile duct. Furthermore, in contrast to earlier reports of rare pancreatic calcification in AIP, 6 of 11 patients with relapses developed pancreatic calcifications over a median follow-up of 54.5 months. These authors previously reported that IgG4 serum concentrations remained high even when the disease was clinically inactive. In their current study elevated serum IgG4 levels were closely associated with relapse. Hence, monitoring serum IgG4 concentrations may provide a guide for continuing steroids - cease steroids if IgG4 concentrations are low; continue a maintenance dose if IgG4 remains slightly elevated; and increase steroids if IgG4 levels increase.

Potentially important is that rats develop morphologic features of AIP similar to human AIP after tail vein injection of CD4+ T cells that recognize pancreatic amylase.[40] This experiment lends support to the importance of CD4+ T cells in the pathogenesis of AIP and raises the possibility that an immune reaction against amylase may play a role in human AIP, but potentially conflicts with the primary duct hypothesis (see Pathogenesis).


A persistent question is whether CP varies according to geographic region. Garg and Tandon[46] investigated the prevalence, etiology, clinical presentation, diagnostic work-up, and management of chronic pancreatitis in the Asia-Pacific region by surveying experts from centers in 8 countries. Population based surveys formed part of the data (from India), but the study design is flawed by referral bias that weakens data interpretation, particularly prevalence and management. Also, the total number of patients included in the survey is uncertain - they list an excess of 2165 patients, but provide no numbers for Australia, Malaysia and South Korea. In addition it is unclear whether tropical and idiopathic pancreatitis were considered single or separate entities, and what is meant by idiopathic; is it late onset only or also early and late onset chronic pancreatitis? Therefore, the data reliability is uncertain for the reported 0% proportion of idiopathic chronic pancreatitis in North and South India and for the reported 30-70% prevalence of tropical chronic pancreatitis in China, North and South India, and Malaysia. Furthermore, statements such as '... endotherapy emerged as the mainstay of treatment for pain... some even felt should be offered as the initial therapy...' are biased (see Treatment: pancreatic endotherapy for chronic pancreatitis). In summary, this study suffers from flawed methods and analyses and does not push the frontiers forward.

Migliori et al.[47] revisited the controversy of whether patients presenting with alcoholic pancreatitis have preexisting chronic pancreatitis. They assessed exocrine pancreatic function, at least 4 months following a first attack of alcoholic pancreatitis (n = 36) or with biliary pancreatitis (n = 39). Pancreatic insufficiency was more frequent and severe in the alcoholic chronic pancreatitis group. The authors interpreted these data as evidence that alcoholic pancreatitis patients had preexisting chronic pancreatitis. Unfortunately, this interpretation is somewhat suspect because the authors failed to quantify pancreatic exocrine function with invasive tests in most patients and did not account for the possibility that pancreatic necrosis and subsequent loss of function may have contributed to pancreatic insufficiency. The latter point is important because necrotizing pancreatitis was more frequent in alcoholic pancreatitis (17/36, 47%) vs. biliary pancreatitis (16/39, 41%). Lastly, the authors did not consider that alcohol may suppress regeneration[29] and lead to decreased exocrine pancreatic function (see Etiology: environmental modifiers of alcoholic pancreatitis). Finally, loss of function may occur even in the setting of histologically normal appearing pancreas[29,31,33,35,48] and may not indicate chronic pancreatitis, which also requires clinical and morphologic changes.[49] Thus, the relation between human acute and chronic pancreatitis remains blurred and requires standardization of pathologic and clinical criteria and perhaps examination of animal models that recapitulate human disease.

The mainstay of chronic pancreatitis diagnosis remains imaging. A major advance would be the ability to diagnose chronic pancreatitis at a reversible stage. Clinically apparent chronic pancreatitis is readily diagnosed by endoscopic ultrasonography (EUS); it is uncertain if EUS affords early diagnosis of chronic pancreatitis. Raimondo and Wallace[50] point out that the sensitivity, specificity and predictive values vary greatly among studies and depend upon the number of EUS criteria used to diagnose chronic pancreatitis. Nevertheless, several authors attempted to determine if EUS provides early chronic pancreatitis diagnosis, but unsuccessfully in our opinion for a variety of conceptual, experimental design and analytical problems.

Yusoff et al.[51] performed EUS ≥ 4 weeks after a recurrent (n = 112) or an initial (n = 134) attack of 'idiopathic' acute pancreatitis and found that the EUS diagnosis of CP (based on ≥5 EUS criteria) was 42 vs 22%, (P < 0.0008), respectively. Unfortunately, their definition of idiopathic pancreatitis is problematic ('no alcohol binge drinking [>120 g/d] within 14 days of the episode of pancreatitis'); many patients likely had significant alcohol intake. EUS changes might indicate significant alcohol intake, which, may alter important pancreatic regulatory processes (see Etiology: ethanol perturbs pancreatic regulatory processes without causing pancreatitis) and EUS appearance (≥5 EUS criteria) without causing clinical attacks of pancreatitis.[52] Also, their findings likely were confounded by slow resolution of EUS abnormalities; it is common knowledge that computed tomography (CT) abnormalities persist for weeks to months after an attack of acute pancreatitis, long after clinical resolution, and ethanol exposure may impair pancreatic regeneration following injury (see Etiology: environmental modifiers of alcoholic pancreatitis).[29]

Irisawa et al.,[53] using commercially available software to evaluate echogenicity, claimed 'Computer analysis of EUS images...may be useful in quantitating severity of disease...'. Although, we applaud the approach,[54] the data Irisawa et al.[53] employed to differentiate pancreatic cancer from chronic pancreatitis are not convincing. The only significant difference among normal persons and patients with mild, moderate and severe chronic pancreatitis was the size of the hyperechoic area; surprisingly the mean echogenicity was similar among all groups. Unfortunately, the authors used circular reasoning EUS, the modality under evaluation was used as the gold standard to diagnose chronic pancreatitis. Additionally, the etiology of chronic pancreatitis and ethanol intake were not provided.

Secretin enhanced magnetic resonance imaging (MRI) increasingly is used to diagnose chronic pancreatitis, particularly when ERCP cannot be done or fails to visualize the bile and pancreatic ducts.[55] In the future MRI may become the imaging modality of choice; if it does ERCP may be necessary only if endoscopic therapy is needed.

Differentiation of chronic pancreatitis from pancreatic cancer is a major problem in de-novo patients presenting with a pancreatic mass and in patients with established chronic pancreatitis, all of whom have an increased risk of having pancreatic cancer. Multiple past publications promoted 2-(18F)-Fluro-2-deoxy-D-glucose positron emission tomography (FDG-PET) to address this diagnostic challenge. A recent study[56] showed that FDG-PET differentiated between chronic pancreatitis and pancreatic cancer with 91% sensitivity and 87% specificity. Moreover, they studied 6 patients with established chronic pancreatitis who were suspected of having developed pancreatic cancer; 5 of the 6 had significant accumulation within the pancreas (a positive FDG-PET) and pancreatic cancer was confirmed in all 6 (by histology[3] or by radiological and clinical follow-up[3]). Thus, FDG-PET might be useful to detect pancreatic cancer in chronic pancreatitis patients at a very high risk for developing pancreatic cancer such as hereditary pancreatitis and chronic pancreatitis patients who develop a mass lesion.

In this regard, contrast-enhanced Doppler ultrasound[57,58] with intravenous injection of micrometric microparticles of galactose and microscopic air bubbles (Levovist, Schering, Berlin, Germany) warrants further evaluation. In one report[57] contrast enhanced ultrasound was as sensitive as EUS in detecting pancreatic tumors <2 cm (18/19 patients; 95%) and both were significantly more sensitive than contrast enhanced CT (13/19; 68%); all modalities had similar sensitivities for detecting tumors >2cm (≥93%).

The articles we reviewed of indirect and direct function tests do not provide novel information and have limited clinical utility. The breath test was confirmed as being insensitive,[59] and not recommended for diagnosis of chronic pancreatitis. Steatocrit, a rapid gravimetric method to measure stool fat, when performed on a 72 hour stool collection is as sensitive and specific as a 72 hour quantitative stool fat, and may be as accurate if performed on a 24 hour stool[60] or random stool samples. Steatocrit or any fecal test, however, only has relatively high sensitivity and specificity when there is severe chronic pancreatitis with malabsorption; they cannot and should not be used to diagnose mild to moderate chronic pancreatitis. Similarly, Stevens et al.[61] confirmed an old observation in 5 patients with established chronic pancreatitis and 5 healthy controls that pancreatic elastase-1 concentrations in duodenal aspirates after CCK or secretin stimulation correlate with lipase and bicarbonate. Surprisingly, 3 of 5 chronic pancreatitis patients had pancreatic elastase-1 values within the range of pancreatic elastase-1 concentrations of healthy persons. These data dampen enthusiasm for measuring pancreatic elastase-1 in duodenal samples for diagnosis of chronic pancreatitis, despite the novelty of endoscopic collection of duodenal aspirates. They also studied 8 healthy persons to further validate the porcine synthetic secretin endoscopic test.[62] Although the pattern of bicarbonate concentration and other electrolytes mimicked the patterns observed with the standard Dreiling test, one to two patients (6-13%) had concentrations lower than 80mEq/L, the lower limit of normal to differentiate between health and chronic pancreatitis, as long as 50 minutes after secretin. The endoscopic test must undergo rigorous comparison with standard invasive test(s) of exocrine pancreatic function to determine if the tests have similar accuracy and if the endoscopic test can be completed in a shorter time, and more cheaply than standard tests.

At last there is a report of a randomized trial comparing endotherapy and surgery for treatment of painful chronic pancreatitis.[63] Patients were randomized to surgery (resection [80%], and drainage [20%]) or endotherapy (sphincterotomy and stenting [52%] and/or stone removal [23%]). At one year the pain relief was similar for both groups but at 5 years more patients who underwent surgery had complete absence of pain and greater weight gain than endotherapy (34 vs 15% and 47 vs 29%, respectively). Drawbacks to this study are minor relative to most endotherapy studies but only 50% of the eligible patients underwent random assignment (although the authors report no differences for analyses of the total group vs the randomized group), there is no true control group (no endoscopic or surgical intervention), and the pain pattern is not provided and prevents characterization of patients' pain according to the clinically important descriptions by Amman as 'type A pain' (short relapsing pain episodes [<10 days] separated by long pain-free intervals) or 'type B pain' (continuous pain [>1 month, ≥5 days a week] and requiring continuous analgesics).

Many studies of endotherapy combined with extracorporeal shock wave lithotripsy (ESWL) for treatment of painful chronic pancreatitis report pain relief,[64-66] but lack accounting for the pain pattern[65] and with the exception of the study of Gabrielli et al.,[66] include large numbers of patients with 'type A pain',[64] which obscures the primary endpoint of pain relief, and none are randomized. Type A patients would be managed by most pancreatologists without resorting to endotherapy or surgery. In follow-up of 110 patients (50% with 'type A pain'),[64] the Brussels group maintains that endotherapy 'provides long term benefits for about two thirds of patients with painful chronic pancreatitis', mainly by reducing the number of hospitalizations for pain, even though surgery became necessary in 21% (12 of the 56 surviving patients). In a meta analysis[65] of 17 ESWL studies of 491 patients (123 from the Brussels group) the authors claim that ESWL relieves pain, but do not mention the pain patterns and if patients underwent surgery. The Gabrielli study,[66] even though it is a small retrospective analysis, is commendable for examining patients with 'type B pain'. They report 22 patients treated with endotherapy; clearing of the stones from the duct was successful in all and consisted of sphincterotomy in everyone, ESWL in 15 and stent placement in 13. However, only 6/22 (21%) were pain free at ~5 years, similar to the 15% in the Ditte study,[63] and 4 (18%) required surgery. As pointed out in the accompanying editorial,[67] interpretation of this and other studies is frequently hindered by a significant number of patients lost to follow up (e.g. 6 [21%] in the Gabrielli study) and by failure to recognize and/or control for a high placebo effect. In fact, Dr Wilcox[67] noted an endoscopic placebo response rate of 38% in patients with type 2 and 3 sphincter of Oddi dysfunction and we previously noted a similar placebo response rate in patients who had chronic pancreatitis and severe pain (type B).[68] Until a properly controlled study is done in which only appropriate patients are enrolled (type B), and compared with a control group who are treated conservatively or with surgery, endotherapy ± ESWL remains an unproven therapy, a position taken even by some endoscopists.[67] As middle ground, endoscopists should recognize that pain in most patients with chronic pancreatitis decreases over time, type A patients should be managed with conservative medical treatment (no surgery or endotherapy) and that endotherapy only should be considered for patients with type B pain, particularly if surgery is contraindicated.

One retrospective[69] and 2 prospective follow-up[70,71] studies support Baron's[72] summary on treatment of symptomatic distal common bile duct stenosis secondary to chronic pancreatitis. Surgery is the treatment of choice. As Baron concluded, endoscopic therapy should be used only if immediate surgery is contraindicated due to severe jaundice with cholangitis, a large inflammatory mass in the head of the pancreas or severe comorbid disease. In all but the last situation surgery should be done as soon as the clinical situation allows. Cahen et al.[69] found that endoscopic drainage of the common bile duct (CBD) succeeded (92%) only if the CBD stricture was due to concomitant acute pancreatitis (based on CT findings). Without these CT findings of acute pancreatitis only 24% had resolution of the stricture. Although Pozsar et al.[71] and Catalano et al.[70] found that multiple stents placed sequentially, resulted in stricture diminution, this method accrues major problems. The method requires multiple endoscopic procedures (4-8) that drive cost, which likely is similar to surgery, and, a mortality of up to 7% associated with the endoscopic therapy (septic shock).[71] Lastly, Kahl et al.[73] surprisingly drew the conclusion that biliary strictures do not cause pain in chronic pancreatitis. This assertion is suspect because they treated biliary obstruction endoscopically with variable results, yet ~25% of patients had pain relief. The bottom line: despite the lack of properly controlled studies, surgical bile duct decompression is the treatment of choice to prevent complications such as cholangitis and liver damage and to relieve pain.

Quality of Life in Chronic Pancreatitis

Wehler et al.[74] showed that chronic pancreatitis patients have a reduced physical and emotional quality of life (QOL), but QOL was not associated with the morphology of chronic pancreatitis. Factors contributing to low QOL included severity of abdominal pain, chronic diarrhea, low body weight and unemployment. Consequently, early treatment of pain and malabsorption may improve QOL. The discordance between chronic pancreatitis morphology and QOL likely relates to the incomplete accounting of the impact of co-morbidities such as smoking and alcoholism upon QOL. The authors did not include control groups to differentiate QOL measures separately due to chronic pancreatitis, alcohol, smoking and diabetes. Future QOL studies must address these confounding factors by including gender and age matched control groups without pancreatitis who are lacking all these factors, and smokers, diabetics, alcoholics and who have combinations of these factors.

To emphasize the association of pancreatic exocrine insufficiency to QOL, Dumsay et al.,[60] and the accompanying editorial by Forsmark,[75] pointed out that of the 60 patients with chronic pancreatitis, 47 (78%) had steatorrhea (abnormal steatocrit) but 29 of the 47 (62%) had no clinical symptoms or signs of steatorrhea and were not being treated with pancreatic enzymes. Further, 28 patients who were not treated with pancreatic enzymes lost twice as much weight (~1 kg/m[2] /y) than persons treated with enzymes, implying that early treatment of malabsorption may improve the QOL in chronic pancreatitis patients, and importantly fat malabsorption merits treatment even in the absence of symptoms. Furthermore, pancreatic enzyme treatment may normalize postprandial gastric myoelectrical activity,[76] rapid gastric emptying and slow gallbladder empting,[77] dysmotilities that may contribute to abdominal pain.

Pancreatic Fibrogenesis

Fibrosis is a dynamic and potentially reversible condition. 'Pancreatic' cytokine generation (from activated macrophages, platelets, acinar cells, activated PSCs or sequestered leukocytes) may determine whether a self-limited or prolonged/perpetual type of injury occurs following an acute pancreatitis episode. Increases in many of these 'fibrogenic' cytokines correlate with the severity of episodes of acute pancreatitis[34,78] and possibly the degree/duration of PSC activation. The studies of Apte and Wilson support the hypothesis that necroinflammatory injury but also non-necroinflammatory processes trigger pancreatic fibrogenesis. Ethanol and the oxidative metabolite acetaldehyde (and oxidative stress) may directly activate PSCs,[79] and the non-oxidative ethanol metabolites, fatty acid ethyl esters (FAEEs) inhibit extracellular matrix (ECM) degradation.[80] Increased ductal and tissue pressure may accelerate (but not necessarily precipitate) pancreatic fibrosis and chronic pancreatitis. In an in-vitro model, dispersed PSCs are activated in culture by increased pressure (with compressed helium gas) causing TGF-ß1 and type I collagen secretion, which was prevented by inhibitors of mitogen-activated protein kinase (MAPK) pathways.[81]

Activation of the AP-1 and MAPK pathways may modulate proliferation, migration, ECM protein secretion of activated PSCs and sustain fibrosis rather than trigger activation of PSCs,[82,83] although controversy exists regarding AP-1's ability to activate PSCs.[84] Therefore, successful therapeutic strategies may require eliminating PSCs by inducing apoptosis[85] (an important step in wound healing[86]), rather than inhibiting/inactivating PSCs. Nonetheless, potential anti-fibrotic therapies targeting intracellular pathways responsible for PSC activation hold promise such as inhibiting MAPK pathways (JNK, ERK and p38 MAPK),[81,87-89] which may also participate in angiotensin II[90] and PI3 (phosphatidylinositol 3)-kinase[91] signaling in PSCs. Additional targets include the Rho-Rho kinase (ROCK) pathway,[92] TGF ß1 mediated intracellular signaling,[93,94] and activator protein (AP)-1 activation.[84] Future studies conducted with recently developed PSC cell lines[95,96] may accelerate progress in understanding PSC behavior in health and disease.

Nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists ameliorate inflammatory and fibrotic parameters of chronic pancreatitis in rats,[97] although a PPARγ-independent mechanism may be responsible. That inhibition of the renin-angiotensin system (RAS) ameliorates parameters of chronic pancreatitis, presumably by suppressing induction of TGFß1 expression and PSC activation,[98] was extended further by in vivo studies showing a synergistic effect of angiotensin-converting enzyme (ACE) inhibitors with angiotensin II type 1 receptor (AT1-R) blockers in rats[99] and that genetic deletion of AT1-R in mice attenuated parameters of chronic pancreatitis induced by repetitive caerulein hyperstimulation,[100] although without an effect on parameters of acute pancreatitis. The mechanism of action of these interventions is obscure because in vivo ACE inhibition appears to reduce only circulatory and not pancreatic ACE activity.[98] This raises the question of whether pancreatic RAS has a significant role in pancreatic fibrogenesis even though pancreatic RAS activity increases in response to acute pancreatitis and chronic hypoxia[98] and angiotensin II modulates PSC behavior in vitro.[90,101] Finally, the oral protease inhibitor camostat mesilate, used clinically for the treatment of chronic pancreatitis in Japan, ameliorates pancreatic inflammation, cytokines expression and fibrosis in a rat dibutyltin dichloride model of chronic pancreatitis, which was associated with in-vitro suppression of monocyte and PSC activity.[102] These studies, if corroborated in human chronic pancreatitis, offer the hope that diabetes, malabsorption, calcification and pain may be delayed or aborted.


Several findings this past year may develop into true advances in chronic pancreatitis. Investigation of pancreatic fibrogenesis has led to the identification of potential novel treatments for chronic pancreatitis. Although some claim insurmountable evidence supports pancreatic endotherapy for painful chronic pancreatitis, and decry the 'nihilistic' approach to present management of chronic pancreatitis, the advent of predictable and lasting treatments of chronic pancreatitis is most likely to appear on the wings of carefully conducted studies targeting genetic and molecular mechanisms of chronic pancreatitis, particularly pancreatic fibrogenesis.


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