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Pancreatitis: An introduction to history, etiology and pathogenesis
... Acute and chronic pancreatitis was long regarded as two separate diseases. However in the 80s and 90s it was recognized, in studies analyzing the pancreatic changes in resection specimens of patients with a long history of recurrent pancreatitis, that chronic pancreatitis, particularly when caused by alcohol abuse, evolves from recurrent episodes of acute pancreatitis, a pathogenetic concept that was termed the necrosis-fibrosis sequence [133][134][135]. In other studies it was noted that the pathology of chronic pancreatitis, which was formerly considered to be uniform and "nonspecific," varies according to the different causative factors of the disease, such as alcohol abuse, inherited gene mutations, autoimmune syndromes, metabolic disturbances, smoking and anatomical abnormalities [136]. ...
The last 50 years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic accuracy and delineate best treatments. As exciting as these many advances are, our knowledge of pancreatic pathology remains incomplete, and there is much to be learned.
Background:
Genetic association studies regarding relationship between PRSS1-PRSS2 rs10273639/CLDN2 rs7057398/MORC4 rs12688220 polymorphisms and pancreatitis yielded conflicting results. We performed this meta-analysis to explore associations between these polymorphisms and pancreatitis in a larger pooled population.
Methods:
A systematic search of the literature was conducted for eligible studies. We used Review Manager to conduct statistical analyses.
Results:
Fifteen studies were included in this meta-analysis. The results of pooled analyses showed that CLDN2 rs7057398, MORC4 rs12688220 and PRSS1-PRSS2 rs10273639 polymorphisms were all significantly associated with susceptibility to acute pancreatitis in Caucasians. Moreover, MORC4 rs12688220 and PRSS1-PRSS2 rs10273639 polymorphisms were also significantly associated with susceptibility to chronic pancreatitis in Asians.
Conclusions:
Our findings suggested that rs7057398, rs12688220 and rs10273639 polymorphisms could be used to identify individuals at an elevated susceptibility to acute pancreatitis in Caucasians. Moreover, rs12688220 and rs10273639 polymorphisms could be used to identify individuals at an elevated susceptibility chronic pancreatitis in Asians.
This study led to the development of monoclonal antibodies and time-resolved immunofluorometric methods recognizing human trypsinogen-1 and -2, respectively. Using these methods in normal sera the concentration of trypsinogen-1 was found to be higher than that of trypsinogen-2. However, in acute pancreatitis the concentration of serum trypsinogen-2 was 50-fold higher than in controls, whereas the difference in trypsinogen-1 concentration was only 15-fold. Serum samples from patients who had undergone pancreatoduodenectomy contained trypsinogen-2, while trypsinogen-1 was detected in only one of nine samples. Furthermore, in human ovarian cyst fluids tumor-associated trypsinogen-2 (TAT-2) is the predominant isoenzyme and in mucinous cyst fluids the levels of TAT-2 were associated with malignancy. These results suggest that (i) trypsinogen-2 could be used as a diagnostic marker for acute pancreatitis, (ii) its expression is not restricted to the pancreas, and (iii) TAT could be involved in ovarian tumor dissemination and breakage of tissue barriers. In ion exchange chromatography, isoelectric variants of the trypsinogen isoenzymes were seen. Mass spectrometric analysis of these revealed that pancreatic trypsinogens are sulfated at tyrosine 154 (Tyr154), whereas TAT-2 from a colon carcinoma cell line is not. Tyr154 is located within the primary substrate binding pocket of trypsin. Thus, Tyr154 sulfation is likely to influence substrate binding. The previously known differences in charge and substrate binding between pancreatic and tumor-associated trypsinogens are suggested to be caused by sulfation of Tyr154 in pancreatic trypsinogens.
Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.
The first international meeting on classification of pancreatitis was held in Marseilles, France in 1963. This meeting classified pancreatic inflammatory diseases into two mutually distinct categories — acute pancreatitis and chronic pancreatitis. In acute pancreatitis the pancreas returns to morphologic and functional normalcy after withdrawal of the acute insult. In chronic pancreatitis the pathologic lesions persist and progress in spite of withdrawal of the etiologic agent. In subsequent years three more international meetings have striven to improve and expand on this classification. The salient features of each of the four classifications are presented in tabular form (Tables 1–4). Even today, however, the classification of pancreatitis is far from perfect. This is to a large extent because of our inability in the early stages of the disease to differentiate acute from chronic pancreatitis. In this review, we analyse the drawbacks of the present classification and look and ahead to the possible improvements in the future.
Pancreatic involvement in primary sclerosing cholangitis (PSC) is an extremely rare condition, and its pathologic features are poorly documented. We report two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, gallbladder, and, in one patient, the lip. Two elderly men presented with waxing and waning obstructive jaundice, and exhibited radiologic and ultrasonographic findings highly suggestive of pancreatic carcinoma. Gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term for this condition, of which a similar lesion has been previously noted in a single case of "PSC involving pancreas". Differences in age, radiologic appearance, and the negative history of ulcerative colitis exist, but the two cases in this study could be considered as a variant of PSC extensively involving pancreas, which can readily be mistaken for pancreatic carcinoma.
"Groove pancreatitis" is a form of segmental pancreatitis affecting the head of the pancreas which is localized within the "groove" between the head of the organ, the duodenum and the common bile duct. We diagnosed this form of pancreatitis in 30 out of 123 surgical duodenopancreatectomy specimens of chronic pancreatitis (24.4%). In a comparison with non-segmental chronic pancreatitis, no differences was observed in age and sex distribution or in alcohol consumption. Clinically, in contrast, preceding diseases of the biliary system, peptic ulcers and gastric resections were more frequently indicated. The cardinal clinical finding is frequently duodenal stenosis; in sonographic and CT examinations, the cicatricial "plate" in the "groove" represents as a "tumor", so that--also on account of the frequent duodenal stenosis--a carcinoma of the head of the pancreas may be suspected. In groove pancreatitis, the pancreatic duct system is grossly normal, calcifications or intraductal protein plugs being rare and an adaptive intimal fibrosis of the intrapancreatic arteries and arterioles is found only within the cicatricial area. Very commonly, scarring of the duodenal wall, stenosis of the duodenum, true duodenal wall and pancreatic cysts are detected. Aetiopathogenetic possibilities are previous diseases of the biliary system, peptic ulcers, gastric resections, true duodenal wall cysts, pancreatic head cysts, pancreatitis in duodenal pancreatic heterotopia, and disturbances of pancreatic juice outflow in Santorini's duct in the absence of the minor papilla, and hyperstimulation in consequence of chronic alcoholism.
Ten patients in whom cystic dystrophy developed in a heterotopic pancreas of the duodenal (nine patients) or gastric (one patient) wall are reported. All were young or middle aged white men, only two of whom were alcoholic. The symptoms were caused by intestinal or biliary stenosis, or both, secondary to the inflammation and fibrosis. Only endosonography provided strong evidence for the diagnosis in three patients. All patients underwent surgery: a pancreaticoduodenectomy was performed in eight patients. The surgical specimen showed cystic lesions of the gut wall, occurring in inflammatory and fibrous heterotopic pancreatic tissue. The pancreas proper was normal in all patients. It is suggested that cystic dystrophy is an uncommon and serious complication of heterotopic pancreas. Similar cases associated with chronic pancreatitis of the pancreas have been observed and it is suggested that this process could be responsible for some of the chronic pancreatitis encountered in young, non-alcoholic patients.
• Acute pancreatitis is a protean disease capable of wide clinical variation, ranging from mild discomfort to apocalyptic prostration. Moreover, the inflammatory process may remain localized in the pancreas, spread to regional tissues, or even involve remote organ systems. This variability in presentation and clinical course has plagued the study and management of acute pancreatitis since its original clinical description. In the absence of accepted definitions for acute pancreatitis and its complications, it has not been possible to devise a clinical classification system useful for case management. Following 3 days of group meetings and open discussions, unanimous consensus on a series of definitions and a clinically based classification system for acute pancreatitis was achieved by a diverse group of 40 international authorities from six medical disciplines and 15 countries. The proposed classification system will be of value to practicing clinicians in the care of individual patients and to academicians seeking to compare interinstitutional data.
Acute pancreatitis is a protean disease capable of wide clinical variation, ranging from mild discomfort to apocalyptic prostration. Moreover, the inflammatory process may remain localized in the pancreas, spread to regional tissues, or even involve remote organ systems. This variability in presentation and clinical course has plagued the study and management of acute pancreatitis since its original clinical description. In the absence of accepted definitions for acute pancreatitis and its complications, it has not been possible to devise a clinical classification system useful for case management. Following 3 days of group meetings and open discussions, unanimous consensus on a series of definitions and a clinically based classification system for acute pancreatitis was achieved by a diverse group of 40 international authorities from six medical disciplines and 15 countries. The proposed classification system will be of value to practicing clinicians in the care of individual patients and to academicians seeking to compare interinstitutional data.
The pathogenesis of alcoholic chronic pancreatitis and its relationship to alcoholic acute pancreatitis are debated. According to our recent clinical long-term study, alcoholic chronic pancreatitis seems to evolve from severe acute pancreatits. The aim of this study was to correlate clinical findings to the pancreatic histopathology at early and advanced stages of the disease.
Morphological changes (pseudocysts, autodigestive necrosis, calcification, and perilobular and intralobular fibrosis) were recorded in 37 surgical and 46 postmortem pancreas specimens of 73 patients from our long-term series, who progressed from clinically acute to chronic pancreatitis (mean follow-up, 12 years). Pancreatic function was monitored at yearly intervals.
Surgical interventions were performed at a mean of 4.1 years from onset. Histologically, focal necrosis (49%) and mild perilobular fibrosis (54%) predominated, Pseudocysts (n = 41, mostly postnecrotic) occurred in 88% within 6 years from onset. Autopsy specimens were obtained at a mean of 12 years. These pancreata often showed severe perilobular and intralobular fibrosis (85%) and calcifications (74%), but rarely necrosis (4%). Fibrosis correlated with progressive pancreatic dysfunction (P < 0.001), particularly in the 10 patients with two histological assessments (mean interval between biopsy and autopsy, 8 years).
The data support an evolution from severe alcoholic acute pancreatitis to chronic pancreatitis.
In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjögren's disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review.
This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis.
As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.
Fibrosis in the pancreas is caused by such processes as necrosis/apoptosis, inflammation or duct obstruction. The initial event that induces fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, the duct cells and/or the acinar cells. Damage to any one of these tissue compartments of the pancreas is associated with cytokine-triggered transformation of resident fibroblasts/pancreatic stellate cells into myofibroblasts and the subsequent production and deposition of extracellular matrix. Depending on the site of injury in the pancreas and the involved tissue compartment, predominantly inter(peri)lobular fibrosis (as in alcoholic chronic pancreatitis), periductal fibrosis (as in hereditary pancreatitis), periductal and interlobular fibrosis (as in autoimmune pancreatitis) or diffuse inter- and intralobular fibrosis (as in obstructive chronic pancreatitis) develops.
Autoimmune pancreatitis seems to be a disease with a heterogeneous appearance. Our intention was to establish key diagnostic criteria, define grades of severity and activity, identify features of potential subtypes and evaluate the diagnostic relevance of biopsy specimens.
Histopathological criteria and clinical features were recorded in pancreatic resection specimens from 53 patients who were found to have chronic pancreatitis lacking pseudocysts, calculi, irregular duct dilatations, pancreas divisum and/or duodenal wall inflammation. The severity of the chronic inflammation was graded, and the activity of the acute inflammatory component and the granulocytic epithelial lesion (GEL) were determined. Additionally, pancreatic biopsy specimens from 9 patients with suspected AIP were assessed.
Periductal lymphoplasmacytic infiltration was identified in all cases, followed in order of frequency by periductal fibrosis and venulitis. These changes were absent in 147 pancreatic specimens that showed chronic pancreatitis associated with pseudocysts, calculi, pancreas divisum and/or duodenal wall inflammation. In 90% of the cases, these chronic changes were graded as 3 or 4. In 81%, the inflammatory process resided in the head of the pancreas and involved the common bile duct. GELs were present in 42% of the patients, who had a mean age of 40.5 years, an almost equal male-female ratio and a high coincidence of ulcerative colitis or Crohn's disease. Patients without GELs were older (mean age 64 years), showed a male preponderance, commonly had Sjogren's syndrome and often developed recurrent bile-duct stenosis. Diagnostically relevant lesions were present in two of five wedge biopsy specimens and three of four fine-needle specimens.
Periductal lymphoplasmacytic infiltration and fibrosis, preferential occurrence in the pancreatic head and venulitis characterize autoimmune pancreatitis. GELs predominantly occur in a subset of patients who are younger, more commonly have ulcerative colitis and Crohn's disease and seem to have fewer recurrences than patients without GELs. Pancreatic biopsy material proved to be a very helpful adjunct for establishing the diagnosis.
Ueber die sog. Fettnekrose
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Pathogenesis: how does acute pancreatitis de-velop? Clinical Pancreatology for Practising Gastroenterologists and Surgeons
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šber die Beziehungen zwischen der Autodigestion des Pankreas und den Fettgewebsnekrosen
- Chiari
Pathologie der Bauchspeicheldrüse (mit Ausnahme der Langerhannschen Inseln und der Diabetesfrage)
- Gruber
Autoimmune pancreatitis
- Klöppel
Fibrosis of the pancreas
- Klöppel