Impact of etiology on disease course in chronic pancreatitis.

BACKGROUND: Complications in chronic pancreatitis (CP) can be grouped in inflammatory (ICC) and fibrotic (FCC) clusters and pancreatic insufficiency cluster (PIC). However, the association between etiological risk factors and the development of complication clusters remains obscure. In this study, the impact of the etiology and disease duration on disease onset and development of complications was investigated. METHODS: This cross-sectional study recruited patients with CP from Mannheim/Germany (n = 870), Gießen/Germany (n = 100) und Donetsk/Ukraine (n = 104). Etiological risk factors, disease stage, age at disease onset, complications, need for hospitalization and surgery were noted. RESULTS: In 1074 patients diagnosed with CP, main risk factors were alcohol and nicotine abuse. An earlier onset of the disease was observed upon nicotine abuse (-4.0 years). Alcohol abuse was only associated with an earlier onset of the definite stage of CP. Alcohol abuse was the major risk factor for the development of ICC (p < 0.0001, multiple regression modeling). Abstinence of alcohol reduced ICC, whereas abstinence of nicotine showed no association. PIC correlated with efferent duct abnormalities and the disease duration. In contrast, FCC was mainly dependent on the disease duration (p < 0.0001; t-test). The presence of any complication cluster correlated with the need for surgery (p < 0.01; X2-test). However, only ICC correlated with a prolonged hospital stay (p < 0.05; t-test). CONCLUSIONS: ICC is mainly dependent on alcohol abuse. In contrast, FCC and PIC are mainly dependent on the disease duration. The etiology and disease duration can be used as predictors of the course of disease to provide individual treatment and surveillance strategies.

Analysis of the Course of Chronic Pancreatitis: Pancreatic Burnout Rates Are Only Increased in a Subgroup of Patients With Alcoholic Chronic Pancreatitis.

OBJECTIVES: The pancreatic burnout hypothesis postulated an increasing absence of pain with simultaneous functional insufficiency in advanced stages of chronic pancreatitis (CP). However, the underlying data remain scarce and contradictory. We aimed to analyze, first, the frequency of a pancreatic burnout in CP, and, second, its association with etiological risk factors. METHODS: We performed a multicenter, retrospective, cross-sectional study with 741 patients with CP categorized according to the M-ANNHEIM classification. Pancreatic burnout was defined by different combinations of exocrine or endocrine insufficiency with partial or complete absence of abdominal pain. RESULTS: The frequency of a pancreatic burnout increased with prolonged disease duration and was observed in a maximum of 38% of patients after 20 years. Development of a pancreatic burnout was significantly associated with alcohol consumption (P < 0.05, Mann-Whitney U test), but not with other etiological risk factors. After a disease duration of more than 10 years, the likelihood of a burnout was 8 times higher in alcoholic CP than in nonalcoholic CP (95% confidence interval, 1.5-42.0; P = 0.015, logistic regression analysis). CONCLUSIONS: A pancreatic burnout does not regularly occur in CP. Increased burnout rates are only observed in patients with alcoholic CP.

Clinical Course of Chronic Pancreatitis in Elderly Patients.

BACKGROUND: Several guidelines recommend the risk-adapted monitoring of patients with chronic pancreatitis (CP). However, dedicated risk stratification is widely missing in CP. Elderly-CP (disease onset with 60 or more years of age) may represent a subgroup of CP subjects with a distinct course of disease. AIMS: We aimed to investigate the clinical presentation of elderly-CP, and if elderly-CP requires an adapted monitoring. METHODS: Seven hundred forty one patients with CP were analyzed in a multicenter (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104), cross-sectional, retrospective study and classified according to the M-ANNHEIM classification. RESULTS: The frequency of elderly-CP was 20% (148/741). In comparison with non-elderly-CP, elderly-CP was less frequently caused by alcohol and nicotine dependency or genetic mutations. In contrast, the frequency of efferent duct abnormalities (p = 0.009, chi-square test) and idiopathic CP (p < 0.0001, chi-square test) increased significantly. The presence of multiple risk factors was found less frequently in elderly-CP than in non-elderly patients (p < 0.0001; chi-square test). Furthermore, elderly-CP was associated with increased rates of pseudocysts (p = 0.0002; chi-square test), endocrine insufficiency (p = 0.001; chi-square test), and the absence of pain (p = 0.04; chi-square test) in the first year of the disease. CONCLUSION: In elderly-CP, the course of disease significantly differs from non-elderly-CP. Therefore, individualized monitoring strategies for elderly-CP might be necessary.

Clinical evaluation of the M-ANNHEIM classification: Development of the M-ANNHEIM-Surgery-Score as a new tool to monitor patients with chronic pancreatitis.

OBJECTIVES: The M-ANNHEIM classification of chronic pancreatitis (CP) stratifies degrees of disease severity according to the M-ANNHEIM-Severity-Score. We aimed to demonstrate the clinical usefulness of the M-ANNHEIM-Severity-Score in quantifying and predicting the frequency of pancreatic surgery, and to establish the M-ANNHEIM-Surgery-Score as a simplified system for patient surveillance regarding the demand of pancreatic surgery. METHODS: We performed a retrospective, cross-sectional study with 741 CP patients (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104) categorized according to the M-ANNHEIM classification. RESULTS: We observed a significantly higher M-ANNHEIM-Severity-Score in patients that were classified within 7 days preceding pancreatic surgery than in individuals that did not require surgery (p < 0.001, Mann-Whitney-U-test). Using a logistic regression analysis with all variables of the M-ANNHEIM-Severity-Score, we established the M-ANNHEIM-Surgery-Score as a simplified new tool to identify patients that may require surgery. A receiver operating characteristic-analysis revealed a cut-off-value of 9 points within the M-ANNHEIM-Surgery-Score to identify these individuals (sensitivity 78.7 %, specificity 91 %). Based on the M-ANNHEIM-Surgery-Score, we defined three categories for demand of surgery with frequencies of pancreatic operations of 1.6 % (n = 7/440) in the "Baseline-Demand"-category, 7 % (n = 12/172) in the "Low-Demand"-category (p < 0.0001, Chi-square-test, OR 4.6, Confidence Interval (CI) 1.8 - 12), and 54 % (n = 70/129) in the "High-Demand"-category (p < 0.0001, OR 73, CI 32 - 167). Patients that were categorized for the "High-Demand"-category, but were not operated on, had a significantly increased ratio of clinical features that hamper performance of surgery (p < 0.001, Chi-square-test). CONCLUSIONS: The M-ANNHEIM-Surgery-Score represents a useful tool to monitor patients with CP and to estimate the demand of surgery in CP.

Evaluation of a New Technique for iFOBT Utilising a New Sample Collection Device with Increased Buffer Stability.

AIMS: The aims of the present study were: (i) Evaluate specificity and sensitivity of Hb Smart enzyme-linked immunosorbent assay (ELISA) (ScheBo Biotech) compared to colonoscopy results and (ii) assess stability of a new sample collection device containing a newly formulated buffer to extract haemoglobin using buffer and stool samples spiked with defined concentrations of haemoglobin. MATERIALS AND METHODS: Stool samples were quantified with the ELISA method. The stability of haemoglobin in the extraction buffer and in native stool samples, respectively, was determined daily by ELISA during storage for 5 days at 4°C and at room temperature after addition of haemoglobin. RESULTS: Haemoglobin ELISA had a sensitivity of 78.4% for detection of CRC with a specificity of 98%. Haemoglobin extracted in corresponding extraction buffer demonstrated stability throughout storage for 5 days at 4°C and at room temperature. CONCLUSION: Hb Smart represents a very promising tool for large-scale screening of CRC with regard to sample handling, stability and analysis of haemoglobin in faeces.

Potential for Screening for Pancreatic Exocrine Insufficiency Using the Fecal Elastase-1 Test.

The early diagnosis of pancreatic exocrine insufficiency (PEI) is hindered because many of the functional diagnostic techniques used are expensive and require specialized facilities, which prevent their widespread availability. We have reviewed current evidence in order to compare the utility of these functional diagnostic techniques with the fecal elastase-1 (FE-1) test in the following three scenarios: screening for PEI in patients presenting with symptoms suggestive of pancreatic disease, such as abdominal pain or diarrhea; determining the presence of PEI in patients with an established diagnosis of pancreatic disease, such as chronic pancreatitis or cystic fibrosis; determining exocrine status in disorders not commonly tested for PEI, but which have a known association with this disorder. Evidence suggests the FE-1 test is reliable for the evaluation of pancreatic function in many pancreatic and non-pancreatic disorders. It is non-invasive, is less time-consuming, and is unaffected by pancreatic enzyme replacement therapy. Although it cannot be considered the gold-standard method for the functional diagnosis of PEI, the advantages of the FE-1 test make it a very appropriate test for screening patients who may be at risk of this disorder.

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU).

BACKGROUND: There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach. METHODS: Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers. RESULTS: The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as 'strong' and plenary voting revealed 'strong agreement' for 99 (98%) recommendations. CONCLUSIONS: The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research.

Diagnosis and treatment of diabetes mellitus in chronic pancreatitis.

Diabetes secondary to pancreatic diseases is commonly referred to as pancreatogenic diabetes or type 3c diabetes mellitus. It is a clinically relevant condition with a prevalence of 5%-10% among all diabetic subjects in Western populations. In nearly 80% of all type 3c diabetes mellitus cases, chronic pancreatitis seems to be the underlying disease. The prevalence and clinical importance of diabetes secondary to chronic pancreatitis has certainly been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes mellitus, the endocrinopathy in type 3c is very complex. The course of the disease is complicated by additional present comorbidities such as maldigestion and concomitant qualitative malnutrition. General awareness that patients with known and/or clinically overt chronic pancreatitis will develop type 3c diabetes mellitus (up to 90% of all cases) is rather good. However, in a patient first presenting with diabetes mellitus, chronic pancreatitis as a potential causative condition is seldom considered. Thus many patients are misdiagnosed. The failure to correctly diagnose type 3 diabetes mellitus leads to a failure to implement an appropriate medical therapy. In patients with type 3c diabetes mellitus treating exocrine pancreatic insufficiency, preventing or treating a lack of fat-soluble vitamins (especially vitamin D) and restoring impaired fat hydrolysis and incretin secretion are key-features of medical therapy.

Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?

Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus.

Successful treatment of severe hypertriglyceridemia with a formula diet rich in omega-3 fatty acids and medium-chain triglycerides.

BACKGROUND: Patients with highly increased plasma triglyceride levels are at risk of developing serious complications such as pancreatitis, coronary heart disease and stroke. Therefore it is important to rapidly decrease plasma triglyceride levels. A sufficient control of triglyceride levels with drugs like fibrates, statins or nicotinic acid can usually only be attained after a couple of weeks. Plasma exchange appears to be a fast but expensive method to reduce triglyceride levels. In this study we describe the use of a new omega-3 fatty acid and medium-chain triglyceride-rich formula diet as a therapeutic concept to reduce plasma triglyceride levels fast and effectively. METHODS: Thirty-two patients with severe hypertriglyceridemia were treated with the especially composed formula diet for a period of 7 days. RESULTS: Within this period of time, plasma triglycerides decreased from 1,601 (402-4,555) to 554 (142-2,382) mg/dl (p < 0.05). Total cholesterol levels were reduced from 417 (211-841) to 287 (165-457) mg/dl (p < 0.001). Fasting glucose and uric acid levels also slightly decreased (-8%; -12%). The formula diet as a 1-week treatment was well tolerated and accepted by the patients. CONCLUSION: This diet was successfully used as an acute treatment in severe hypertriglyceridemia and showed effectiveness in rapidly and safely lowering plasma triglyceride levels.

Microbiota and SCFA in lean and overweight healthy subjects.

Obesity has recently been linked to the composition of human microbiota and the production of short chain fatty acids (SCFAs). However, these findings rely on experimental studies carried out using rather small and defined groups of volunteers or model animals. Our aim was to evaluate differences within the human intestinal microbiota and fecal SCFA concentration of lean and obese subjects. A total of 98 subjects volunteered to take part in this study. The BMI in kg/m(2) of 30 volunteers was within the lean range, 35 were overweight and 33 were obese. The fecal microbiota was characterized by real-time PCR analyses. With the primers used herein we were able to cover 82.3% (interquartile range of 68.3-91.4%) of the total microbiota detectable with a universal primer. In addition, the concentration of SCFA was evaluated. The total amount of SCFA was higher in the obese subject group (P = 0.024) than in the lean subject group. The proportion of individual SCFA changed in favor of propionate in overweight (P = 0.019) and obese subjects (P = 0.028). The most abundant bacterial groups in faeces of lean and obese subjects belonged to the phyla Firmicutes and Bacteroidetes. The ratio of Firmicutes to Bacteroidetes changed in favor of the Bacteroidetes in overweight (P = 0.001) and obese subjects (P = 0.005). Our results are in line with previous reports suggesting that SCFA metabolism might play a considerable role in obesity. However, our results contradict previous reports with regard to the contribution of various bacterial groups to the development of obesity and this issue remains controversial.

Severe hypertriglyceridemia and pancreatitis: presentation and management.

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is a well recognized cause of acute pancreatitis accounting for approximately up to 10% of all cases and even up to 50% of all cases in pregnancy. Both primary and secondary disorders of lipoprotein metabolism may be associated with hypertriglyceridemic pancreatitis (HTGP). The purpose of this review is to provide an overview of the current studies on presentation and management of HTGP. RECENT FINDINGS/CONCLUSION: Hydrolysis of triglycerides by pancreatic lipase and formation of free fatty acids that induce inflammatory changes are postulated to account for the development of HTGP, yet the exact pathophysiology remains unclear. The clinical features of patients with HTGP are generally not different from patients with acute pancreatitis of other causes, and there is some evidence that HTGP is associated with a higher severity or a higher complication rate. There is no clear evidence as to which HTG patients will develop pancreatitis. Several studies have evaluated the effect of apheresis, the benefit of insulin and/or heparin treatment and the use of different antihyperlipidemic agents in HTGP. Dietary modifications resemble the key features in the long-term management of HTG. Whether HTG may cause chronic pancreatitis in the long-term follow-up remains controversial.

Exocrine pancreatic involvement in critically ill patients.

PURPOSE OF REVIEW: To learn about the prevalence, pathophysiology, and treatment of exocrine pancreatic involvement in critically ill patients. RECENT FINDINGS: Elevations in the levels of pancreatic enzymes are observed in up to 80% of intensive care patients. Most of these patients do not develop clinically relevant pancreatitis. However, elevations in enzyme levels do represent pancreatic damage with a risk of complications. Different factors have been discussed, which may contribute to pancreatic damage in critically ill patients. These include splanchnic hypoperfusion during shock or major surgery, bacterial translocation, elevated triglyceride levels, development of biliary sluge, and biliary pancreatitis, as well as several drugs. Imaging procedures and inflammatory markers help to identify relevant disease. Several therapeutic options have been discussed recently with a focus on early enteral nutrition. SUMMARY: Pancreatic damage is frequently observed in critically ill patients. Although in most of these patients, this is without major clinical consequences, some patients develop relevant pancreatitis, which contributes to morbidity and mortality. Risk factors have been identified and therapeutic strategies have been changed.

Distinct autoantibodies against exocrine pancreatic antigens in European patients with type 1 diabetes mellitus and non-alcoholic chronic pancreatitis.

CONTEXT: Histopathological analysis has demonstrated lymphocytic infiltration in both the endocrine and the exocrine pancreas in some patients with type 1 diabetes and non-alcoholic chronic pancreatitis, suggesting an immune-mediated mechanism which affects both diabetes mellitus and chronic pancreatitis. OBJECTIVE: The examination of exocrine pancreatic humoral markers in Caucasian patients with respect to the interactions between exocrine and endocrine pancreatic diseases. PATIENTS: One hundred and thirty-six European Caucasian subjects subdivided into three groups: type 1 diabetes (n=48); non-alcoholic chronic pancreatitis (n=48); controls (n=40). MAIN OUTCOME MEASURE: Autoantibodies against carbonic anhydrase II (CAIIAb) and lactoferrin (LACAb) (both of which are exocrine pancreatic antigens) were analyzed by enzyme-linked immunosorbent assay. RESULTS: No positivity for CAIIAb and LACAb were found in the controls. Patients with type 1 diabetes had a significantly higher prevalence of CAIIAb (25.0%) than the controls while the prevalence of LACAb (8.3%) was not significantly higher than the controls. The prevalence of CAIIAb (12.5%) and LACAb (20.8%) in the patients with non-alcoholic chronic pancreatitis was significantly higher than that in the controls. A significantly higher prevalence of CAIIAb and/or LACAb was found in patients with type 1 diabetes (29.2%) and non-alcoholic chronic pancreatitis (22.9%) compared to that in the controls (0%). There was a significant association between CAIIAb and LACAb titers both in patients with type 1 diabetes (P=0.042) and in patients with non-alcoholic chronic pancreatitis (P<0.001). CONCLUSION: We have clearly demonstrated that some European Caucasian patients with type 1 diabetes and non-alcoholic chronic pancreatitis have autoantibodies against the exocrine pancreatic antigens CAIIAb and LACAb.

Tumor M2 pyruvate kinase: a tumor marker and its clinical application in gastrointestinal malignancy.

Proliferating cells, in particular tumor cells, express a dimeric isoenzyme of pyruvate kinase, termed Tumor M2 pyruvate kinase. In the last few years, much attention has been paid to this novel tumor marker that can be determined in EDTA-plasma and in the feces. It has been used in diagnosis and surveillance of a variety of malignant diseases. As compared with the established tumor markers, Tumor M2-PK in EDTA-plasma proves to have at least equal sensitivity in pancreatic, gastric, esophageal, colorectal and cholangiocellular cancer. In combination with established tumor markers, EDTA-plasma M2-PK is a useful tool in diagnosis and surveillance of gastrointestinal tumors. In colorectal cancer, M2-PK in EDTA-plasma even proves superiority as compared with CEA. Fecal Tumor M2-PK testing resembles a good noninvasive screening parameter for colorectal cancer with a reported sensitivity of 68.8-91.0% and a specificity of 71.9-100%. It is superior to fecal occult blood testing in colorectal cancer screening. Since it is effective, easy to handle and bears rather low costs, fecal Tumor M2-PK testing is recommended for large-scale CRC screening.

Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases. Castle of Rauischholzhausen of the Justus-Liebig-university, Giessen (Rauischholzhausen), Germany. March 7-8, 2008.

The 'Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases' was organized in order to reflect and discuss recent developments in the field, especially the progress that has been achieved since the first meeting in March 2005. About thirty international specialists were invited to share their experience and thoughts covering the main topics of: A) pancreatic diabetes (type 3c); B) chronic inflammation of the pancreas. The presentations of session A covered an overview about the frequency of exocrine dysfunction in diabetes mellitus, the relation between diabetes, celiac disease and the exocrine pancreas, the prevalence of type 3c diabetes, damage to the pancreas caused by genes, the role of incretins in type 2 and type 3 diabetes, the role of exocrine tissue in beta cell homeostasis, peculiarities in the treatment of type 3c diabetes and a lecture on incretins: from concept to treatment. Session B included presentations about the frequency of chronic inflammation of the pancreas and therapeutical implications, the role of ACE in the pancreas, genomics and the metabolic hypothesis of chronic pancreatitis, nutritional aspects of pancreatic diseases, the stellate cell concept, autoimmunity, genetic background of chronic pancreatitis and the hypothesis of chronic obstruction induced by gallstone disease. The meeting resulted in several new projects that will be started by the participants in the near future.

Successful long-term treatment of severe hypertriglyceridemia by feedback control with lipid self-monitoring.

BACKGROUND/AIMS: Successful treatment of severe hypertriglyceridemia is difficult. Besides therapy with different drugs, dietary intervention is an important approach. However, compliance with dietary recommendations is usually bad. Lipid self-monitoring in patients might improve dietary compliance and control of lipid parameters. METHODS: Thirty-two patients with severe hypertriglyceridemia (>750 mg/dl) were primarily treated with a formula diet reducing the triglyceride levels <600 mg/dl. After this acute treatment, self-monitoring of lipid parameters was performed for 48 weeks. Twenty-five patients completed the whole study. The participants measured their lipid parameters with Accutrend GCT dry chemistry strips. Dietary records were taken and measurements of body composition, BMI, triglycerides, total cholesterol and glucose were performed. RESULTS: Triglycerides remained stable in patients with levels <300 mg/dl at the beginning of the protocol. There was a significant decline in triglycerides in those who started with levels >300 mg/dl. No severe hypertriglyceridemia (>750 mg/dl) could be observed. The energy intake decreased in all patients due to a reduction in total fat and carbohydrate consumption. The relation between carbohydrates and protein remained unchanged. Self-measurement was well tolerated and an improvement in controlling the diet was reported. CONCLUSIONS: Self-control of lipid parameters can improve the dietary compliance of patients with hypertriglyceridemia and is well tolerated.

Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed?

Exocrine pancreatic insufficiency is frequently associated with diabetes, with high prevalence in both insulin-dependent or insulin-independent patients. Exocrine pancreatic failure has often been perceived as a complication of diabetes. In contrast, recent clinical observations lead to the notion that nonendocrine pancreatic disease is a critical factor for development rather than a sequel to diabetes. The incidence of diabetes caused by exocrine pancreatic disease appears to be underestimated and may comprise 8% or more of the general diabetic patient population. Nonendocrine pancreas disease can cause diabetes by multiple mechanisms. Genetic defects have been characterized, resulting in a syndrome of both exocrine and endocrine failure. Regulation of beta-cell mass and physiological incretin secretion are directly dependent on normal exocrine function. Algorithms for diagnosis and therapy of diabetes should therefore address both endocrine and exocrine pancreatic function.