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.

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.

Fecal pyruvate kinase-M2 (tumor M2-PK) measurement: a new screening concept for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a disease with major impact on public health and public health costs. Colonoscopy is purportedly the best screening tool for CRC. However, the acceptance by the general population is very poor. Therefore evaluation of additional screening tools is of great interest. PATIENTS AND METHODS: The use of M2-PK measurement in the feces has been reported in 6 studies to date. The data of these studies were analysed and critically reviewed. Additionally, 1,906 persons undergoing routine health care check-up provided stool samples for M2-PK measurement. RESULTS: The overall sensitivity of M2-PK is 77.9% for CRC. Specificity ranges from 74.3 to 83.3%. Of the 1,906 screened persons, 90.4% had results within the normal range, while 9.6% had elevated results. CONCLUSION: Measurement of tumor M2-PK in feces seems to be the most promising tool for CRC screening at the present time. In combination with colonoscopy, this test should hence be recommended for CRC screening programs.

Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial.

BACKGROUND: Recently, high prevalence of exocrine dysfunction in diabetic populations has been reported. Patients with fecal elastase 1 concentration (FEC) <100 microg/g have also been demonstrated to suffer from steatorrhea in about 60% of cases, indicating the need of pancreatic enzyme replacement therapy. Until now, there have only been a few reports on the use of enzyme replacement therapy in diabetic patients with exocrine pancreatic insufficiency. This investigation was designed to evaluate the impact of enzyme-replacement therapy on glucose metabolism and diabetes treatment in a prospective study of insulin-treated patients with diabetes mellitus. METHODS: A total of 546 patients with diabetes mellitus requiring insulin treatment were screened for exocrine dysfunction by FEC measurements. One hundred and fifteen patients (21.1%) had FEC <100 microg/g (normal >200 microg/g). Of these, 95 patients entered the study and 80 patients were randomized to receive either pancreatin (Creon) (39 patients) or placebo (41 patients) in a double-blind manner. Parameters of glucose metabolism, diabetes therapy and clinical symptoms were recorded in standardized protocols for 16 weeks. RESULTS: During the observation phase of 16 weeks, there were no significant differences between both groups concerning HbA(1c), fasting glucose levels, 2-h pp glucose levels, clinical parameters and safety parameters. A reduction in mild and moderate hypoglycemia was observed in the pancreatin group at the end of the study. CONCLUSIONS: Pancreatin therapy can be used safely in patients with diabetes mellitus and exocrine dysfunction. Parameters of glucose metabolism were not improved by enzyme replacement therapy.

Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study.

OBJECTIVE: The prevalence and main determinants of exocrine pancreatic insufficiency were investigated in a large population-based sample of older adults by measuring pancreatic elastase-1 in stool. MATERIAL AND METHODS: The study comprised 914 participants aged 50 to 75 years recruited by their general practitioner during a general health examination. All participants and their physicians were asked to fill out a standardized questionnaire which contained information on socio-demographic and lifestyle factors as well as medical history. Native stool was examined for pancreatic elastase-1 with a commercially available ELISA (ScheBo Tech, Giessen, Germany). RESULTS: Overall, 524 women and 390 men aged 50 to 75 years (mean age 61.9 years) were included in the analysis. In total, 105 (11.5%) of the 914 subjects showed signs of exocrine pancreatic insufficiency (EPI) with =200 microg elastase-1/g stool, and 47 (5.1%) subjects showed signs of a severe exocrine pancreatic insufficiency (SEPI, < 100 microg elastase-1/g stool). There was a clear increase in EPI with age. Patients taking angiotensin-converting enzyme (ACE) inhibitors had a lower prevalence than subjects without this medication; these associations persisted after adjustment for covariates. CONCLUSIONS: Prevalence of EPI increases with age and seems to be tentatively higher in men than in women. However, smoking seems to be an independent risk factor for EPI and SEPI whereas ACE-inhibitor intake might be a protective factor. The latter finding may even point to new options in the treatment of chronic pancreatitis.

Giessen international workshop on interactions of exocrine and endocrine pancreatic diseases. Castle of Rauischholzhausen of the Justus-Liebig-University, Giessen, Germany. March 18-19, 2005.

The 'Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases' was held on March 18-19, 2005 at the Castle of Rauischolzhausen, Giessen University, Germany. About 50 international clinicians and researchers attended the workshop. It was structured into three sessions: A: Pancreatic Autoimmunity - Interaction Between Exocrine and Endocrine Tissue; B: Diabetes Mellitus - Possible Implications of Exocrine Pancreatic Insufficiency; C: Chronic Pancreatitis - Update on Prevalence, Understanding and Pathophysiological Concepts. Several new aspects of pancreatic diseases were discussed, including new classifications of pancreatitis, new insights into prevalence, pathophysiology and new therapeutical considerations. The meeting resulted in more cooperation and a number of new concepts for clinical study which will provide data for future developments.

Effects of oral fat load on insulin output and glucose tolerance in healthy control subjects and obese patients without diabetes.

OBJECTIVE: Elevated plasma nonesterified fatty acid (NEFA) concentrations cause peripheral and hepatic insulin resistance and may play an important role in regulating glucose-induced insulin secretion. The aim of our study was to investigate the influence of physiologically elevated NEFA levels on glucose-stimulated insulin secretion in order to find evidence that NEFAs are a potential factor predisposing for type 2 diabetes and related metabolic disorders, which are known risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We combined an orally administered fat emulsion with an intravenous glucose tolerance test and measured the time course of NEFA, insulin, and glucose. In order to find pathological conditions we applied the experiment to healthy and obese subjects. RESULTS: The main findings are a significant increase in glucose-stimulated insulin secretion after oral fat load in both groups compared with the condition without preceding fat ingestion and a prolonged insulin secretion after fat load in obese patients compared with control subjects. CONCLUSIONS: The results provide evidence that fat ingestion modulates beta-cell function and that NEFA is a plausible mediator that acts as a link between fat and glucose metabolism by modulating glucose-stimulated insulin secretion. Under the condition of elevated plasma levels of NEFA, this mechanism may be responsible for hyperinsulinemia in obese patients and a potential target of type 2 diabetes prevention strategies.