Chronic inflammation and pancreatic cancer

There is a proven association between carcinoma of the pancreas and both the sporadic and hereditary forms of chronic pancreatitis. In chronic pancreatitis the standardised incidence ratio for development of pancreatic cancer is 14-18 and is further increased by cigarette smoking. Underlying mechanisms are unclear but current theories point to the progressive accumulation of genetic mutations as a consequence of repeated DNA damage and cell regeneration in an environment favouring proliferation and neovascularisation. In patients who develop pancreatic cancer, there is interest in the role of the inflammatory response in the development of cancer cachexia and in determining prognosis. Furthermore, markers of a systemic inflammatory response have prognostic significance in both advanced, inoperable pancreatic cancer and in patients undergoing resection. Further understanding of the details of the relationship between inflammation, carcinogenesis and cancer prognosis may lead to new therapeutic possibilities as part of multi-modality management of this difficult disease.     

Systemic lupus erythematosus presenting initially with acute pancreatitis and a review of the literature

A patient with systemic lupus erythematosus is reported whose initial clinical presentation was that of acute pancreatitis, confirmed by pancreatic isoamylase elevation and pancreatic enlargement on computerized tomography. A lack of a correlation with steroid therapy and a need to document pancreatitis in a multisystem disease like lupus with radiographic evidence as well as pancreatic isoamylase elevations is emphasized.     

Pancreatitis coincident with Crohn's ileocolitis

A young woman who developed acute pancreatitis coincident with Crohn's disease is presented. The pancreatitis was documented by pancreatic hyperamylasemia, elevated urine amylase activity, abdominal sonogram, computed tomography, and laparotomy. A cause-and-effect relationship has not been established, however; no etiology other than the Crohn's disease, which was confined to the ileum and colon, could be identified. Surgical removal of the severely involved ileum led to the resolutionof the pancreatitis. A possible relationship between acute pancreatitis and Crohn's disease is proposed, although potential pathophysiologic mechanisms are unknown. The diagnosis of pancreatic involvement in such cases may make an important contribution to therapy.     

Autoimmune pancreatitis

The purpose of this review is to provide a concise view of the existing knowledge of autoimmune pancreatitis (AIP) for practicing clinicians. AIP is a rare disease whose recognition and understanding are evolving. It is a type of chronic pancreatitis that often presents as obstructive jaundice, has a distinctive histology, and is exquisitely sensitive to steroid therapy. This form of chronic pancreatitis has a unique clinical, biochemical, and radiological profile. The term "AIP" encompasses two subtypes: types 1 and 2. Type 1 AIP is the pancreatic manifestation of a systemic fibro-inflammatory disease called immunoglobulin G4-associated systemic diseases. Type 2 AIP has been shown to be associated with inflammatory bowel disease. Existing criteria are geared towards the diagnosis of type 1 AIP. At present, pancreatic histology is a requirement for the definitive diagnosis of type 2 AIP. AIP can mimic most other pancreatic diseases in its presentation, but in clinical practice, it often has to be differentiated from pancreatic cancer. There are established criteria and algorithms not only to diagnose AIP, but also to differentiate it from pancreatic cancer. The utility of these algorithms and the approach to management are discussed here.     

Exocrine pancreatic function in patients with progressive systemic sclerosis

The exocrine pancreatic function was investigated in 16 patients with progressive systemic sclerosis by means of a meal test (Lundh test) and in 9 of the patients by the secretin-cholecystokinin test as well. Gastrointestinal involvement with progressive systemic sclerosis was evaluated by esophageal manometry and by routine roentgenographic series of the small bowel. Fecal fat excretion measurement, the D-xylose absorption test, and a small-intestinal biopsy procedure were carried out. Duodenal juice was cultured and bacterial counts were estimated. One-third of the patients had reduced exocrine pancreatic function, but only four patients had unequivocally a reduction that could be of clinical importance. The results obtained with the meal test were in accordance with the secretin-cholecystokinin test, indicating a preserved capacity for endogenous stimulation.     

Autologous and allogeneic mixed lymphocyte reactions in progressive systemic sclerosis

The autologous and allogeneic mixed lymphocyte reactions (MLR), observed when peripheral blood mononuclear cells from 20 patients with progressive systemic sclerosis were used, were compared with those of age-, sex-, and race-matched normal controls. Such cells were separated by gradient centrifugation of sheep red blood cell (E) rosettes into stimulator (E- or non-T cell) and responder (E + or T cell) populations. The autologous MLR of both the progressive systemic sclerosis and normal peripheral blood mononuclear cells varied widely but there was no statistical difference between the means of each group. In the allogeneic MLR, proliferation between progressive systemic sclerosis non-T cells and normal T cells was significantly less than that of normal non-T cells and progressive systemic sclerosis T cells (P = 0.001). A decreased autologous MLR, while noted with other autoimmune diseases, was lacking in progressive systemic sclerosis. This suggests a different defect. The differences in the allogeneic MLR also suggest that either progressive systemic sclerosis non-T cells were poor stimulators or T cells associated with this disease were better responders when compared with similarly prepared cell populations from normal individuals. The MLR differences could have also resulted from compositional subset alterations or the sharing of a common antigen. HLA-DR5 was found in 9 of the 17 white patients with progressive systemic sclerosis. Although these individuals were evenly distributed as low, medium, and high responders, this finding showed that some progressive systemic sclerosis non-T cells shared a common antigen.     

Antibiotic prophylaxis in severe acute pancreatitis.

Severe acute pancreatitis is considered to be a subgroup of acute pancreatitis with the development of local and/or systemic complications. A significant correlation exists between the development of pancreatic necrosis, the frequency of bacterial contamination of necrosis and the evolution of systemic complications. Bacterial infection and the extent of necrosis are determinants for the outcome of severe acute pancreatitis. The late course of necrotizing pancreatitis is determined by bacterial infection of pancreatic and peripancreatic necroses. Mortality increases from 5-25% in patients with sterile necrosis to 15-28% when infection has occurred. The use of prophylactic antibiotics has been recommended in patients with necrotizing pancreatitis. Several controlled clinical trials demonstrated a significant reduction in pancreatic infections or a significant reduction of hospital mortality. However, the results of these clinical trials are controversial and not convincing. Recently, the largest randomized placebo-controlled, double-blind trial has been able to demonstrate that antibiotic prophylaxis with ciprofloxacin and metronidazole has no beneficial effects with regard to the reduction of pancreatic infection and the decrease of hospital mortality. The clinical data from this placebo-controlled trial do not support antibiotic prophylaxis in all patients with necrotizing pancreatitis, but in specific subgroups of patients with pancreatic necrosis and a complicated course.     

Local and systemic zymogen activation in human acute pancreatitis

BACKGROUND: Activation of trypsinogen and phospholipase A(2) is an early event in pancreatic inflammation, but little is known about zymogen activation and the severity of human pancreatitis. METHODS: Using a new fluoroimmunoassay we measured trypsinogen activation peptide (TAP) and phospholipase A(2) activation peptide (PROP) in plasma and ascites in 25 patients with acute pancreatitis. TAP, PROP, Pro-PROP and pancreatic PLA(2)-I were measured in plasma for 14 days and in pancreatic necroses, ascitic fluid and pleural effusions. RESULTS: All 16 patients with severe acute pancreatitis (SAP) had pancreatic necrosis, 10 developed systemic complications like sepsis, pulmonary or renal failure, 6 had infected necrosis, and 4 died. All 9 patients with mild pancreatitis (MAP) survived. Plasma TAP on admission was higher in patients with SAP than in those with MAP and increased in infected necroses. It did not correlate with systemic complications. Systemic PROP was not increased in complicated courses but was significantly higher in patients with MAP than in those with SAP on admission. Pro-PROP was higher in patients with SAP than in those with MAP but was not correlated with systemic complications. Plasma pancreatic PLA(2)-I was increased but not different in patients with SAP and those with MAP. In patients with pancreatic necrosis, TAP and PROP were highest, while in those with post-acute pancreatic abscess, only PROP and Pro-PROP were high. In patients with pleural effusion, TAP was low and PROP/ Pro-PROP were high. CONCLUSION: Trypsinogen and PLA(2)-I activation are early events in acute pancreatitis and the activation peptides can be detected in plasma. In the pancreas, trypsinogen activation is accompanied by PLA(2)-I activation in patients with pancreatic necrosis. However, in our study, organ complications in SAP patients was not associated with increased plasma PROP.     

Gastrointestinal systemic sclerosis in serologic mixed connective tissue disease

Mixed connective tissue disease is a clinical entity defined by overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, and distinct serologic findings. Esophageal dilatation and dysmotility have been the only gastrointestinal manifestations reported. Three patients with serologic findings of mixed connective tissue disease and extensive gastrointestinal involvement compatible with the changes found in progressive systemic sclerosis are presented. Gastrointestinal manifestations of progressive systemic sclerosis are reviewed and were found to be indistinguishable from the findings in these patients.     

Progressive systemic sclerosis with eosinophilia and a fulminating course

A case of progressive systemic sclerosis, with blood and pleural fluid eosinophilia and a fulminating course, is presented. Wide-mouth colonic diverticula developed within 10 weeks. Death from renal failure occurred five and a half months after the onset of symptoms. The possibility of eosinophilia as a marker of severe disease in progressive systemic sclerosis is raised.     

Pancreatic involvement in celiac disease

Celiac disease (CD) is well recognized as a systemic, chronic autoimmune disease mainly characterized by gluten-sensitive enteropathy in genetically predisposed individuals but with various extraintestinal features. One of the affected organs in CD is the pancreas, consisting of both endocrine and exocrine alterations. Over the last decades there has been increasing interest in the pancreatic changes in CD, and this has been reflected by a great number of publications looking at this extraintestinal involvement during the course of CD. While pancreatic endocrine changes in CD, focusing on type 1 diabetes mellitus, are well documented in the literature, the relationship with the exocrine pancreas has been less studied. This review summarizes currently available evidence with regard to pancreatic exocrine alterations in CD, focusing on risk of pancreatitis in CD patients, association with autoimmune pancreatitis, prevalence and outcomes of pancreatic exocrine insufficiency in newly diagnosed and gluten-free diet treated CD patients, and the link with cystic fibrosis. In addition, we discuss mechanisms behind the associated pancreatic exocrine impairment in CD and highlight the recommendations for clinical practice.     

Anticentromere antibody in patients without CREST and scleroderma: association with active digital vasculitis, rheumatic and connective tissue disease.

This paper looks at the problem confronting a doctor evaluating a patient with anticentromere antibody who does not have evidence of disease along the spectrum from CREST (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) to progressive systemic sclerosis. Of 33 people with anticentromere antibody, 21 had CREST and two had scleroderma. Of the other 10 with a positive anticentromere antibody, three had systemic lupus erythematosus (two with digital vasculitis), three very active seronegative polyarthritis, three Raynaud's phenomenon, and one a claudication syndrome involving the legs. A positive antinuclear antibody test does not always indicate the presence of a connective tissue disease, but the presence of anticentromere antibody without systemic sclerosis or CREST often indicates the presence of another sometimes serious underlying rheumatic or connective tissue disease.     

Influence of PMN Leukocyte-Mediated Pancreatic Damage on the Systemic Immune Response in Severe Acute Pancreatitis in Rats

The outcome of severe acute pancreatitis is determined by the development of the systemic inflammatory response and subsequent multiorgan dysfunction. Using the taurocholate-induced model of acute pancreatitis in rats, we investigated the relationship between early polymorphonuclear (PMN)-mediated pancreatic tissue damage and the systemic inflammatory response. The respiratory burst of PMN leukocytes was increased in animals with acute pancreatitis and was reduced by anti-ICAM-1 antibody and oxygen radical scavenger treatment after 24 hr. In acute pancreatitis a reduced number of peripheral helper T cells was evident, most likely due to L-selectin-mediated increased lymphocyte homing. After 24 hr the CD45RC(high)/CD45RC(low) ratio of helper T cells, a critical factor in T cell-mediated disease was increased due to a reduction of regulatory CD45RC(low) cells. Only the treatment with anti-ICAM-1 mAb affected these changes, indicating that immunological changes in necrotizing pancreatitis are only in part affected by early PMN leukocyte-mediated pancreatic damage.     

Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation

OBJECTIVES:   Autoimmune pancreatitis has been characterized by irregular narrowing of the main pancreatic duct and sonolucent swelling of the parenchyma, both of which are due to lymphoplasmacytic inflammation at the active stage of the disease, and by the absence of pancreatic stone formation. The aim of the present study was to confirm or deny whether or not this disease is progressive with recurrent attacks, resulting in pancreatic stone formation like ordinary chronic pancreatitis.
METHODS:   Forty-two patients, 36 of whom were treated with prednisolone, were followed up for periods longer than 12 months (median follow-up period: 54.5 months, range: 13–111 months) by regular interview and examination of their medical records for laboratory tests and image tests.
RESULTS:   Eleven patients (26.2%) who were treated with prednisolone showed recurrent attacks during median follow-up periods of 22 months. Eight patients (19%) showed the formation of pancreatic stones during the follow-up periods. Because 6 of 11 patients (54.5%) who suffered relapse showed pancreatic stone formation, it is significantly associated with relapse in comparison with nonrelapse ( p = 0.0019).
CONCLUSIONS:   Contrary to previous reports, we observed both relapse and pancreatic stone formation in some patients with autoimmune pancreatitis, which suggests that autoimmune pancreatitis has the potential to be a progressive disease with pancreatic stones.     

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.     

Gallium-67 uptake by the thyroid associated with progressive systemic sclerosis

Although thyroidal uptake of gallium-67 has been described in several thyroid disorders, gallium-67 scanning is not commonly used in the evaluation of thyroid disease. Thyroidal gallium-67 uptake has been reported to occur frequently with subacute thyroiditis, anaplastic thyroid carcinoma, and thyroid lymphoma, and occasionally with Hashimoto's thyroiditis and follicular thyroid carcinoma. A patient is described with progressive systemic sclerosis who, while being scanned for possible active pulmonary involvement, was found incidentally to have abnormal gallium-67 uptake only in the thyroid gland. Fine needle aspiration cytology of the thyroid revealed Hashimoto's thyroiditis. Although Hashimoto's thyroiditis occurs with increased frequency in patients with progressive systemic sclerosis, thyroidal uptake of gallium-67 associated with progressive systemic sclerosis has not, to our knowledge, been previously described. Since aggressive thyroid malignancies frequently are imaged by gallium-67 scintigraphy, fine needle aspiration cytology of the thyroid often is essential in the evaluation of thyroidal gallium-67 uptake.     

The Problem of Classification and Staging of Chronic Pancreatitis: Proposals Based on Current Knowledge of Its Natural History

Chari ST, Singer MV. The problem of classification and staging of chronic pancreatitis. Proposals based on current knowledge of its natural history. Scand J Gastroenterol 1994;29:949-960.

Background: Even though the four international meetings held so far on classification of pancreatitis have helped considerably to further our understanding of the disease, all have serious drawbacks that limit their clinical utility. The main problem with the Marseille classifications is the need for histologic proof, and the Cambridge classification relies on imaging modalities that are not sensitive or specific enough. Results: Chronic pancreatic inflammation (CP) has been observed in association with several systemic diseases (such as autoimmune diseases), and since the natural history of the pancreatic affliction in these conditions is clearly distinct from that seen in other forms of CP, these need to be classified separately. Furthermore, many clinical/aetiologic forms of chronic calcifying pancreatitis (CCP) exist which differ sufficiently in their clinical features and management to deserve individual recognition. Proposal: A subclassification of CCP into alcoholic, tropical, hereditary, hypercalcaemic, hyper-lipoproteinaemic, drug-induced, and idiopathic is proposed. The staging of chronic alcoholic pancreatitis has been a controversial issue, mainly because of the apparent unpredictability of the course of pain. However, several large follow-up studies in the past decade suggest that recurrent acute exacerbations dominate the clinical picture in the first few years after onset of symptoms, and progressive pancreatic insufficiency is the predominant feature in the late stages of the disease. On the basis of the results of these studies it is proposed that alcoholic chronic pancreatitis be divided into four stages: I) latent or subclinical, II) early, or stage of inflammatory complications, III) late, or stage of severe pancreatic insufficiency, and IV) advanced, or stage of secondary painless pancreatitis.     

Acute pancreatitis:The stress factor

Acute pancreatitis is an inflammatory disorder of the pancreas that may cause life-threatening complications.Etiologies of pancreatitis vary,with gallstones accounting for the majority of all cases,followed by alcohol.Other causes of pancreatitis include trauma,ischemia,mechanical obstruction,infections,autoimmune,hereditary,and drugs.The main events occurring in the pancreatic acinar cell that initiate and propagate acute pancreatitis include inhibition of secretion,intracellular activation of proteases,and generation of inflammatory mediators.Small cytokines known as chemokines are released from damaged pancreatic cells and attract inflammatory cells,whose systemic action ultimately determined the severity of the disease.Indeed,severe forms of pancreatitis may result in systemic inflammatory response syndrome and multiorgan dysfunction syndrome,characterized by a progressive physiologic failure of several interdependent organ systems.Stress occurs when homeostasis is threatened,and stressors can include physical or mental forces,or combinations of both.Depending on the timing and duration,stress can result in beneficial or harmful consequences.While it is well established that a previous acute-short-term stress decreases the severity of experimentally-induced pancreatitis,the worsening effects of chronic stress on the exocrine pancreas have received relatively little attention.This review will focus on the influence of both prior acute-short-term and chronic stress in acute pancreatitis.     

Akute Pankreatitis

While interstitial acute pancreatitis usually takes a benign course, necrotizing acute pancreatitis takes a severe course, mainly because of severe local and systemic complications. After a quick diagnosis it is necessary to rapidly assess a degree of severity of the disease and thus the prognosis. The clinical picture and the result of imaging procedures do not always correspond. The management basically includes to treat pain as well as to administer fluid, electrolyte, protein and calories. In addition, systemic treatment of complications such as shock or respiratory and renal insufficiency—if occurring—is necessary. In case of pancreatic necrosis, prophylactic administration of pancreas-penetrable antibiotics is recommended to avoid infection. In the severely ill with infected pancreatic necrosis, surgery is the treatment of choice. In approximately 10% of all patients with alcohol-induced pancreatitis, there is a gradual transition to chronic pancreatitis.     

Acute pancreatitis

While interstitial acute pancreatitis usually takes a benign course, necrotizing acute pancreatitis takes a severe course, mainly because of severe local and systemic complications. After a quick diagnosis it is necessary to rapidly assess a degree of severity of the disease and thus the prognosis. The clinical picture and the result of imaging procedures do not always correspond. The management basically includes to treat pain as well as to administer fluid, electrolyte, protein and calories. In addition, systemic treatment of complications such as shock or respiratory and renal insufficiency--if occurring--is necessary. In case of pancreatic necrosis, prophylactic administration of pancreas-penetrable antibiotics is recommended to avoid infection. In the severely ill with infected pancreatic necrosis, surgery is the treatment of choice. In approximately 10% of all patients with alcohol-induced pancreatitis, there is a gradual transition to chronic pancreatitis.