Modern diagnostics of chronic pancreatitis

Chronic pancreatitis is a well-defined disease on histopathological grounds, but for clinical purposes diagnosis is generally not based on histological specimens. Imaging procedures, non-invasive or with different degrees of invasiveness, and pancreatic function tests are therefore the diagnostic mainstay in patients with suggestive clinical history. The correct diagnosis of chronic pancreatitis is easy in late stages but difficult in an early stage of the disease. A particular challenge is the differentiation between acute or recurrent acute and early chronic pancreatitis. Earlier classifications (Cambridge and Marseille) did not consider the complex interrelationship between (especially alcoholic) acute and chronic pancreatitis. A possible solution is to separate the entities into probable and definite alcoholic chronic pancreatitis, with the assignment into the latter category achieved by follow-up investigations. Up to now the best diagnostic accuracy at an early stage is achieved by the detection of abnormalities of the ductal system in endoscopic retrograde pancreatography or by assessing exocrine function with the secretin-ceruletide test. The endoscopic ultrasound may substitute the endoscopic retrograde pancreatography as superior imaging modality that detects both parenchymal and ductal changes of chronic pancreatitis at an early stage. Magnetic resonance pancreatography is a further promising diagnostic tool without the risk of pancreatitis after endoscopic retrograde pancreatography, but imaging of the side branches, which is crucial for detection of early chronic pancreatitis, is not yet sufficient. Faecal elastase is a progress in non-invasive testing of exocrine pancreatic function, but its value for the diagnosis of chronic pancreatitis under conditions of clinical practice is limited. Several (13)C breath tests have been developed, but their availability and their diagnostic accuracy in chronic pancreatitis is still limited. Light to moderate exocrine pancreatic insufficiency is not detectable with adequate accuracy by tubeless function tests. A specific serum marker of pancreatic fibrosis which would reliably indicate the presence of chronic pancreatitis or its progression to is not available.     

Assessment of exocrine pancreatic dysfunction in chronic pancreatitis

The clinical diagnosis of chronic pancreatitis is usually based on imaging studies, pancreatic function tests, and the presence of characteristic clinical features. In Japan, diagnostic criteria for chronic pancreatitis were established in 1995. The secretin test (a duodenal intubation test) and the combination of noninvasive tests, N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) and fecal chymotrypsin (FCT), have been recommended for evaluating exocrine pancreatic function in patients with chronic pancreatitis. In the present study, the diagnostic value of these two noninvasive tests was compared to the secretin test. Although noninvasive tests are less sensitive and specific for determining exocrine pancreatic dysfunction than the secretin test, greater reliability for diagnosing chronic pancreatitis can be obtained by performing the BT-PABA and FCT simultaneously. Assessment of exocrine pancreatic function is important not only to diagnose chronic pancreatitis but also to decide a treatment method with pancreatic enzyme preparation.     

Is pancreaticoduodenectomy justified for chronic pancreatitis masquerading as periampullary tumor?

BACKGROUND/AIMS: Chronic pancreatitis associated with periampullary mass often presents diagnostic and therapeutic dilemmas. Incidence and justification of pancraticoduodenectomy for chronic pancreatitis masquerading as pancreatic head cancer and sensitivity of frozen-section biopsy in detecting the periampullary malignancy were investigated. METHODOLOGY: Nine patients with chronic pancreatitis masquerading as periampullary tumor were included to study the clinical features, clinical diagnostic rates, and surgical risk. Pathological data of 272 periampullary malignancies were analyzed to evaluate the diagnostic rate of preoperative endoscopic biopsy and the reliability of intraoperative frozen-section biopsy. RESULTS: The incidence of pancreaticoduodenectomy for chronic pancreatitis masquerading as periampullary tumor was 3.2%. The most common symptoms for these 9 chronic pancreatitis patients were epigastric pain (88.9%), jaundice (55.6%) and body weight loss (55.6%), with a median duration of symptom of 9 months. All of these chronic pancreatitis lesions in the periampullary region were considered to be pancreatic head or periampullary cancer by image studies except 1 to be chronic pancreatitis by ultrasound and endoscopic retrograde cholangiopancreatography. No surgical mortality and only 1 minor complication with wound infection occurred. Among the 272 periampullary malignancies, the positive diagnostic rate by preoperative endoscopic biopsy was 26.5%. The overall sensitivity of frozen-section biopsy in detecting the periampullary malignancy was 70.7%. CONCLUSIONS: Pancreaticoduodenectomy may be justified for chronic pancreatitis presenting as periampullary mass, in terms of nonspecific clinical features, unreliable preoperative imaging studies, undependable intraoperative frozen-section biopsy and low surgical risk.     

Endoscopic ultrasonography for evaluating patients with recurrent pancreatitis

Acute recurrent pancreatitis （ARP） is still a complex diagnostic and therapeutic challenge in clinical practice. In up to 30% of cases of ARP, it is not possible to establish the etiology of the disease. In the other 70%, many factors play an etiological role in ARP： microlithiasis, sphincter of Oddi dysfunction （SOD）, pancreas divisum, hereditary pancreatitis, cystic fibrosis, a choledochocele, annular pancreas, an anomalous pancreatobiliary junction, pancreatic tumors or chronic pancreatitis are diagnosed. EUS should be useful in ARP as it is sensitive for diagnosing bile duct stones, gallbladder sludge, pancreatic lesions, ductal abnormalities and chronic pancreatitis. Endoscopic ultrasound （EUS） appears to be diagnostic in the majority of patients with previously unexplained pancreatitis, and offers an alternative to endoscopic retrograde cholangiopancreatography （ERCP） as the initial diagnostic test in patients with ARP.     

Serum cathodic trypsin-like immunoreactivity, pancreatic lipase, and pancreatic isoamylase as diagnostic tests of chronic pancreatitis or pancreatic steatorrhea

We compared serum concentrations of cathodic trypsin-like immunoreactivity, pancreatic lipase, and pancreatic isoamylase as diagnostic tests of chronic pancreatitis (and of pancreatic steatorrhea in the 41 patients with steatorrhea) in 105 patients (57 men, 48 women) consecutively investigated because of clinical suspicion of chronic pancreatitis. Chronic pancreatitis (36 patients), pancreatic steatorrhea (24 patients), and other diseases were diagnosed without knowledge of the serum levels of the three enzymes. When evaluated by means of receiver operating characteristic curves, no differences were found in diagnostic performance of the enzymes with regard to chronic pancreatitis or pancreatic steatorrhea. The sensitivity and specificity for recognition of chronic pancreatitis ranged from 0.306 to 0.444 and from 0.942 to 0.986 when the discrimination values were chosen to give highest efficiencies. The similar ranges for pancreatic steatorrhea were 0.500-0.708 and 0.882-0.941. In conclusion, none of the three enzymes had any advantage over the others as diagnostic tests of chronic pancreatitis or of pancreatic steatorrhea. Only positive test results have clinical importance because of the low sensitivities of the three enzymes.     

Chronic pancreatitis: The problems of diagnostic criteria

The diagnostic criteria for chronic pancreatitis proposed by the Japan Pancreas Society (JPS) classified chronic pancreatitis into (i) definite; (ii) probable, and (iii) possible chronic pancreatitis, excluding obstructive, inflammatory (autoimmune) and tumor-forming pancreatitis from the definition of chronic pancreatitis. In the JPS Criteria, imaging studies, pancreatic function tests, and histological findings are independent of each other, and thus the diagnosis of chronic pancreatitis is made if one of the criteria is satisfied, regardless of the etiology of the chronic pancreatitis. The current diagnostic criteria for chronic pancreatitis depend on abnormalities of the duct system, such as low bicarbonate output, dilation of main pancreatic duct and duct branches, and calculi in the ducts by imaging studies. We revealed that the difference between reversible and irreversible pancreatitis in experimental animals is dependent on the degree of damage of the duct epithelium where pancreas progenitor cells exist. Thus, chronic pancreatitis diagnosed by the current criteria based on abnormalities of the duct system is irreversible. In contrast, the epithelium of the ducts is usually preserved in obstructive and autoimmune pancreatitis in that both structural and functional changes recover almost completely when the obstruction is removed or the inflammatory changes disappear following steroid administration. Even in chronic pancreatitis defined as irreversible, there must be a reversible stage during its clinical course. There is a need to develop biological markers and/or imaging procedure to detect chronic pancreatitis at its reversible stage.     

Molecular diagnosis in pancreatic carcinoma

Present diagnostic possibilities virtually do not make it possible to diagnose early stages of pancreatic cancer. Likewise, it is very difficult to differentiate between pancreatic cancer and chronic pancreatitis. The methods of visualization are insufficiently sensitive and the determination of certain genes could enrich our diagnostic opportunities. Considerable attention in this direction has been devoted to the determination and evaluation of the presence of oncogene K-ras. Our initial experience with the determination of K-ras in preparations from patients with pancreatic cancer or with chronic pancreatitis confirmed that K-ras in an oncomarker associated with adenocarcinoma of pancreas, whereas in patients with chronic pancreatitis it occurs in about 10% of the examined samples.     

SERUM PANCREATIC ISOAMYLASE ESTIMATION BY THE INHIBITOR METHOD AS A DIAGNOSTIC TEST FOR CHRONIC PANCREATITIS

The diagnosis of chronic pancreatitis is often difficult to establish and may involve invasive diagnostic procedures. Serum pancreatic isoamylase has been estimated by the inhibitor method in controls and in 38 patients with known chronic pancreatitis in order to evaluate its use as a diagnostic test. The mean pancreatic isoamylase in those with chronic pancreatitis (68 ± 77 IU/l) was significantly lower (p <0.005) than in controls (113 ± 60 IU/I). The diagnostic sensitivity of pancreatic isoamylase was 50% (compared to total amylase 9%) and had a specificity of 95%. Stimulation tests with cholecystokinin and secretin failed to increase the sensitivity of the test. A low value of pancreatic isoamylase strongly supports a diagnosis of chronic pancreatitis and may obviate the need for further investigation.     

Changes in serum pancreatic enzymes after hormonal stimulation in chronic pancreatitis

Eighteen patients with chronic pancreatitis and 12 healthy controls were subjected to hormonal stimulation by continuous secretin plus cerulein intravenous infusion or a rapid injection of secretin. In both tests total serum amylase, lipase, and TLI (trypsin-like immunoreactive substances) levels were measured. Continuous intravenous infusion does not bring about changes in the serum levels of the enzymes studied; rapid injection of secretin, however, induces changes in the serum levels of TLI and lipase (but not amylase) which makes it possible to distinguish patients with chronic pancreatitis in its early stages from advanced chronic pancreatitis but is of doubtful value in distinguishing healthy subjects from those suffering with chronic pancreatitis.     

Diagnosis of early chronic pancreatitis by endoscopic ultrasound. Are we there yet?

The diagnosis of chronic pancreatitis at an early stage is a clinical challenge. A major limitation is the inability of clinicians to obtain a tissue or histological sample to confirm the clinical diagnosis. Currently available imaging modalities have limited sensitivity or specificity for diagnosing early chronic pancreatitis. Endoscopic ultrasonography (EUS), introduced in the early 1980's, was first developed to image the pancreas. It overcame many of the limitations (abdominal gas and fat) of transabdominal ultrasonography when evaluating patients for possible pancreatic diseases. To date, EUS represents the most promising imaging modality for diagnosing chronic pancreatitis. Contrary to endoscopic retrograde pancreatography (ERCP), EUS has a very low risk of complications and can detect abnormalities suggestive of chronic pancreatitis in the pancreatic parenchyma and ductal system which are not visible on any other imaging modality. The minimal changes in echotexture are difficult to interpret because there is no reliable gold standard confirmatory test. There is now some evidence in the literature suggesting that these early changes detected by EUS correlate with the histological changes of chronic pancreatitis and may predict progression to more advanced disease. The EUS diagnosis of chronic pancreatitis relies on quantitative (more than qualitative) parenchymal and ductal criteria found during evaluation of the pancreas. It is generally accepted that, in the absence of any criteria, chronic pancreatitis is unlikely, whereas in the presence of 5 or more criteria (out of 9-11) chronic pancreatitis is likely although ERCP and pancreatic function tests may still be normal. The diagnostic significance of patients with fewer (1-4) criteria found on EUS is currently unclear, particularly when other diagnostic tests such as ERCP and function testing are normal. In these cases, there is a potential for "over-diagnosis" of chronic pancreatitis, since the EUS changes cannot be confirmed by other modalities. How can we better understand the implications of EUS detected changes when other tests are normal?     

Study of parotid and mixed saliva in the diagnosis of chronic pancreatitis.

A study on the diagnostic value of the parotid and mixed saliva assay after stimulation with 1% pilocarpine hydrochloride was carried out in 36 controls and 26 patients affected with chronic pancreatitis. No statistical difference between the two groups was found as far as saliva volume, bicarbonate and amylase (concentration and output) are concerned. No correlation was found between the results of the saliva test and those of the secretin-pancreozymin test or endoscopic retrograde pancreatography. These data excluded any diagnostic role of the saliva test in chronic pancreatitis.     

Endoscopic ultrasound in the diagnosis and treatment of pancreatic disease

Endoscopic ultrasound(EUS)is an important part of modern gastrointestinal endoscopy and now has an integral role in the diagnostic evaluation of pancreatic diseases.Furthermore,as EUS technology has advanced,it has increasingly become a therapeutic procedure,and the prospect of multiple applications of interventional EUS for the pancreas is truly on the near horizon.However,this review focuses on the established diagnostic and therapeutic roles of EUS that are used in current clinical practice.In particular,the diagnostic evaluation of acute pancreatitis,chronic pancreatitis,cystic pancreatic lesions and solid masses of the pancreas are discussed.The newer enhanced imaging modalities of elastography and contrast enhancement are evaluated in this context.The main therapeutic aspects of pancreatic EUS are then considered,namely celiac plexus block and celiac plexus neurolysis for pain control in chronic pancreatitis and pancreas cancer,and EUS-guided drainage of pancreatic fluid collections.     

Copenhagen Pancreatitis Study

During the past 2 decades an increasing number of patients with pancreatitis have been admitted to the Copenhagen hospitals. For this reason all departments receiving such patients from the city of Copenhagen initiated the Copenhagen Pancreatitis Study (CPS), to provide a prospective recording of all pancreatitis patients from this geographical area and to conduct yearly follow-up studies of the patients. The aims of the CPS were, first, to establish data on the incidence, prevalence, and clinical characteristics of pancreatitis, and, second, to evaluate the accuracy of diagnostic tests applied and to provide data on the natural history and the prognosis under current therapy. The present study is an interim report on 343 patients from the initial 1 1/2 years of the CPS. Pancreatitis patients are listed in four diagnostic groups: I. Possible acute pancreatitis; II. Acute pancreatitis; III. Possible chronic pancreatitis; IV. Chronic pancreatitis. The incidence rates per year per 100,000 citizens aged 20 years or more (population aged 20 years or more: 417,000) were as follows: total, 36.3; I, 6.2; II, 21.9; III, 4.2; IV, 4.0. The prevalence for the chronic types on 31 August 1979 per 100,000 citizens aged 20 years or more was as follows: total, 27.4; III, 14.4; IV, 13.0. Gallstones were found in 1/3 of the acute and 1/10 of the chronic cases. Alcohol consumption was more than 50g/day in nearly half of the patients. Acute pancreatitis was dominated by a high leukocyte count, hyperbilirubinaemia, raised aminotransferases and blood glucose levels, and low albumin and calcium levels in serum. In chronic pancreatitis 1/3 had steatorrhoea; 1/6 regularly used morphine, and 1/4 had impaired liver function. It is concluded that the incidence rates of acute and chronic pancreatitis in Copenhagen seem to be higher than those reported elsewhere; however, differences in diagnostic criteria may play a role. The clinical and laboratory findings are in agreement with other studies.     

Effect of peripheral pancreatic duct obstruction on the progression of chronic pancreatitis]

Experimental chronic pancreatitis model were made in five dogs with chronic pancreatic fistula by injection of microspheres into peripheral pancreatic duct. Sequential changes of pancreatic exocrine and endocrine functions also with morphology were studied. Significant decrease of volume, bicarbonate output, and amylase output of pure pancreatic juice (PPJ) separately collected with stimulation of secretin were detected. While, viscosity of PPJ was significantly increased with concomitant increase of hexosamine concentration. Chronic pancreatitis was demonstrated morphologically also. These results suggest that concentrated PPJ caused by decrease in volume in PPJ and increase in viscosity of PPJ with concomitant increase in hexosamine concentration bring about the progression of chronic pancreatitis in this experimental model.     

Autoimmune pancreatitis versus pancreatic cancer: a comprehensive review with emphasis on differential diagnosis

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis with a discrete pathophysiology occasional diagnostic radiological findings, and characteristic histological features. Its etiology and pathogenesis are still under investigation, especially during the last decade Another aspect of interest is the attempt to establish specific criteria for the differential diagnosis between autoimmune pancreatitis and pancreatic cancer, entities that are frequently indistinguishable. DATA SOURC...     

Recurrent and Relapsing Pancreatitis

Recurrent acute pancreatitis is a common clinical problem. Most cases of pancreatitis are identified by a careful history and physical examination. Despite advanced evaluation, the cause is not apparent in about 10% of cases. The etiology of recurrent acute pancreatitis appears to be multifactorial, with genetic and environmental influences playing a significant role. The strength of evidence for certain etiologies is highly variable, and natural history data are limited. Controversy exists regarding the most appropriate diagnostic and therapeutic approach. Recurrent acute pancreatitis often represents a continuum with chronic pancreatitis.     

Is acute recurrent pancreatitis a chronic disease？

Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis （ARP） seem a casual association. Cystic fibrosis transmembrane con-ductance regulator （CFTR） gene mutation, hereditary and obstructive pancreatitis seem an acute disease that progress to chronic pancreatitis, likely as a consequence of the activation and proliferation of pancreatic stellate cells that produce and activate collagen and therefore fibrosis. From the diagnostic point of view, in patients with acute recurrent pancreatitis Endoscopic ultrasound （EUS） seems the more reliable technique for an accurate evaluation and follow-up of some ductal and parenchymal abnormalities suspected for early chronic pancreatitis.     

Clinical evaluation of pancreatic excretion test with dimethadione and oral BT-PABA test in chronic pancreatitis

Further evaluation of the pancreatic excretion test with 5,5-dimethyl-2,4-oxazolidinedione (dimethadione, DMO) was made in comparison with the pancreozymin-secretin (PS) test on 100 normal subjects, 79 patients with chronic pancreatitis, and 83 patients with nonpancreatic disease. The diagnostic sensitivity of the oralN-benzoyl-l-tyrosyl-PABA (BT-PABA) test was estimated in 42 patients with chronic pancreatitis, on whom both PS and DMO excretion tests were performed as test of reference for exocrine pancreatic function. Pancreatic DMO excretion after secretin injection was significantly diminished in chronic pancreatitis. The DMO excretion test was more sensitive than the PS test to detect chronic pancreatitis and to distinguish between mild to moderate and advanced noncalcific chronic pancreatitis. The specificity of the DMO excretion test was more than adequate to find out pancreatic disease. The 6-hr urinary PABA excretion was significantly reduced in chronic pancreatitis. The BT-PABA test, however, showed the low sensitivity in mild to moderate chronic pancreatitis.     

Argyrophilic Nucleolar Organizer Regions May Help the Differential Diagnostic Distinction between Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma

Mäkinen K, Eskelinen M, Lipponen P, Pasanen P, Nuutinen P, Alhava E. Argyrophilic nucleolar organizer regions may help the differential diagnostic distinction between chronic pancreatitis and pancreatic ductal adenocarcinoma. Scand J Gastroenterol 1994;29:1029-1033.

Background: The aim of this study was to determine whether the number of argyrophilic nucleolar organizer regions (AgNORs) could be of diagnostic significance in differentiating between chronic pancreatitis and pancreatic ductal adenocarcinoma.

Methods: The number of AgNORs was enumerated in biopsy specimens of normal pancreas, chronic pancreatitis, and pancreatic ductal adenocarcinoma.

Results: The number of AgNORs was lower in patients with normal pancreas than in patients with chronic pancreatitis or pancreatic adenocarcinoma. In addition, the number of AgNORs was significantly lower in chronic pancreatitis than in pancreatic ductal adenocarcinoma (p < 0.001).

Conclusions: The diagnosis of pancreatic adenocarcinoma is usually clear. Difficulties can be encountered, however, in cases of chronic pancreatitis, specially when biopsy material is small. Our results suggest that the number of AgNORs may help in distinguishing between chronic pancreatitis and pancreatic ductal adenocarcinoma, especially in diagnostically difficult specimens.     

Alcoholic pancreatitis

Without doubt, alcohol consumption is one of the most important considerations in adults with acute or chronic pancreatitis. Understanding chronic pancreatitis as a complex disorder in which complimentary factors are required for recurrent acute and late chronic pancreatitis to develop in subsets of patients is critical for the early diagnosis and management of these individuals. Recent pathophysiological and genetic findings represent the beginning of major diagnostic and treatment breakthroughs that are likely to continue for the foreseeable future. The information provided in this article should provide the physician with a fresh perspective and remind the clinician of the importance of an accurate and complete history, and the need to document the actual alcohol consumption, pattern of drinking, and raise appropriate concerns if signs of alcoholism are detected. If alcohol-associated pancreatitis is detected, then limitation of pancreatic damage, limitation of progression, or preventative intervention should become the major concern.