Clinical signs of early chronic pancreatitis

Clinical signs of early chronic pancreatitis

Abstracts / Pancreatology 16 (2016) S1eS192 S13 IC5-5. IC5-7. Risk factors for CP: Role in diagnosis of CP Clinical signs of early chronic pancre...

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Abstracts / Pancreatology 16 (2016) S1eS192

S13

IC5-5.

IC5-7.

Risk factors for CP: Role in diagnosis of CP

Clinical signs of early chronic pancreatitis

Suresh T. Chari

Dhiraj Yadav, David Clement Whitcomb

Mayo Clinic, USA

Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, USA

The term chronic pancreatitis: “CP” currently encompasses a wide variety of diseases. In the more recent proposal to define CP it has been has described as “a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress”. In this schema persistent fibrosis and acinar/ductal dysfunction are seen only in established or advanced CP. In the other guidelines presence of EUS features and abnormal pancreatic function test are considered sufficient to label as early CP. However, it is unclear how risk factors could play a diagnostic role in early CP. For example, if a smoker or alcoholic with a normal CT/or MRI were to have an abnormal pancreatic structure on endoscopic ultrasound or had abnormal pancreatic function based on lower-than-normal secretin stimulated bicarbonate concentration, could that add up to a diagnosis of early CP? We would like to argue that pathologic tissue responses to risk factors are not restricted to CP. We show that a pathologic response that is distinguishable from CP, that we call pancreatopathy, is not only seen in asymptomatic smokers and alcoholics, but also in conditions not traditionally considered risk factors for CP (e.g., diabetes mellitus). In some of these conditions extensive data on pancreatic function testing is available and shows that a significant proportion of DM subjects have abnormal pancreatic function tests. Thus, at this point, we believe that even in patients with risk factors for CP, abnormal pancreatic structure and function, in the absence of clinical disease is not specific for chronic pancreatitis and, therefore, not sufficient to diagnose it. Biomarkers that distinguish true CP from pancreatopathy are needed to help diagnose early CP.

The two most common clinical signs of early CP are abdominal pain and episode (s) of acute pancreatitis. However, only a subset of patients with these presentations have coexisting early CP or will eventually progress to definite CP. Therefore, identification of patients at high-risk of progression and characterizing their disease trajectory is critically important to advance the field. Patients with early CP have typical pancreatic pain that is often constant, but can also occur as episodes lasting for variable periods of time ranging from a few hours to days at a time. Patients with recurrent acute pancreatitis can be asymptomatic in between the attacks, or can have symptoms of abdominal pain as described above. Features that increase the probability of early CP in these patients include exposure to environmental risk factors (e.g. alcohol consumption, especially if heavy/very heavy; smoking), recurrent acute pancreatitis, abnormalities in serum pancreatic enzymes, presence of genetic susceptibility factors (if tested), family history of pancreatitis, pancreatic cancer or cystic fibrosis, presence of exocrine and/ or endocrine insufficiency, local complications of acute pancreatitis (e.g. pseudocyst, necrosis), history of autoimmune diseases (e.g. inflammatory bowel disease, etc.), and subtle abnormalities on pancreatic imaging (CT scan, MRI/MRCP, EUS) which are suggestive, but not definitive for CP. Appropriately powered studies with longitudinal follow-up are needed to accurately define the risk of progression to definite CP in these patients with abdominal pain and/or recurrent acute pancreatitis with one or more risk factors. Furthermore, collection of annotated and timed biological samples in these subjects during follow-up will help to develop biomarkers of and provide mechanistic insights into disease progression, which will help design strategies/treatments to prevent disease progression.

IC5-6. Genetic susceptibility in chronic pancreatitis

IC5-8.

Miklos Sahin-Toth

Diagnostic biomarkers for early chronic pancreatitis

Department of Molecular and Cell Biology, Boston University, USA

Markus M. Lerch, Peter Simon, F. Ulrich Weiss

Development of recurrent acute pancreatitis and chronic pancreatitis, with or without a family history, is often determined by genetic risk factors. Susceptibility genes identified to date include, in the order of discovery, PRSS1 (serine protease 1, human cationic trypsinogen), CFTR (cystic fibrosis transmembrane conductance regulator), SPINK1 (serine protease inhibitor Kazal type 1, pancreatic secretory trypsin inhibitor), CTRC (chymotrypsin C), CLDN2 (claudin-2) locus, CPA1 (carboxypeptidase A1), and CEL (carboxyl ester lipase). Mutations in PRSS1 such as p.N29I and p.R122H, are strong risk factors which cause autosomal dominant hereditary pancreatitis with incomplete penetrance and variable expressivity. Although less well characterized, CPA1 mutations also confer strong predisposition resulting in early onset disease. In contrast, risk variants of other genes typically result in smaller but significant risk and are often found in the trans-heterozygous state in affected carriers. Common variants in the CLDN2 locus and in the promoter region of PRSS1 increase disease risk marginally. There are at least two pathological pathways mediating increased pancreatitis risk linked to genetic variants. In the trypsin-dependent pathway, increased trypsinogen activation (PRSS1 mutations), impaired trypsin inhibition (SPINK1 mutations) or decreased trypsinogen degradation (CTRC mutations) result in elevated intra-pancreatic trypsin activity. Alternatively, a subset of PRSS1 mutations and pathogenic CPA1 mutations can cause misfolding, intracellular retention and degradation with consequent endoplasmic reticulum stress. The downstream mechanisms by which trypsin and endoplasmic reticulum stress increase risk for chronic pancreatitis remain poorly defined. Importantly, not all genetic variants found in pancreatitis susceptibility genes are pathogenic and clinical relevance of rare variants is often difficult to ascertain. An online database at www.pancreasgenetics.org helps to track all published variants associated with chronic pancreatitis.

Department of Medicine A, University Medicine, Ernst-Moritz-ArndtUniversity of Greifswald, Germany Chronic pancreatitis is, for the most part, a debilitating disease associated with pain, exocrine and endocrine pancreatic insufficiency and various complications. It been shown to burdened patients with a high rate of disability and a 30% reduction in life expectancy. No therapy or interventional measures so far has been found to change the natural history of the disease or its progression from a subclinical form to overt disease. It has been suggested that an earlier detection of chronic pancreatitis may help changing the progression, if only because the recommendation for lifestyle changes would become much more convincing. Various biomarkers have been suggested to be helpful to achieve this but none so far has convincingly been supported by prospective clinical trials. One would be collagen3-peptide, a marker for ongoing fibrogenesis that has claimed some merit in chronic liver disease. Another has been fecal elastase quantification, for which a potential role in screening for chronic pancreatitis has been claimed. Its downside is that early changes appear not to be associated with significant reductions in stool elastase secretion and many non-pancreatic causes of diarrhea can yield false positive results. Endoscopic ultrasound seems currently the most sensitive tool to diagnose early stages of chronic pancreatitis but overstaging, a high inter-investigator variability and the inherent invasiveness of the procedure preclude its use for screening. A recent association study has suggested that mildly elevated serum lipase levels may indicate subclinical pancreatic injury and (Weiss et al. Gut. 2015; 64: 646-56), if confirmed, may indicate that the development of early stage biomarkers for chronic pancreatic injury is not unfeasible and the search should be continued.