Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

Abstract

Chronic pancreatitis (CP) is a progressive inflammatory condition triggered by the loss of exocrine pancreatic acini and fibrosis or scarring of pancreas tissue [1]. The exocrine pancreas comprises about 90 % of total pancreas and releases digestive enzymes such as chymotrypsin, amylase and lipase in response to a meal. CP develops in 16 % of patients presenting with acute pancreatitis, a number which increases to 38 % upon second admission. The most common symptom of CP is abdominal pain, which can be both intermittent and persistent. Furthermore, 95 % of CP patients present with alcoholic or idiopathic disease [1]; however, excessive consumption of alcohol alone may not be the cause of CP. Additional causes of CP include gallstones, exposure to volatile hydrocarbons, viral infection and genetic mutations [2]. There are various genetic forms of CP including gain-of-function mutations in genes such as Prss1 which results in a form of trypsin that is resistant to degradation and can lead to an autosomal-dominant hereditary form of CP [1]. In contrast, loss-of-function mutations in genes such as Spink1 and Cftr, which is involved in the inactivation of pancreatic trypsin, are also associated with CP. The overall survival rate for CP patients is only 50 % at 20–25 years from diagnosis [3], and CP patients also have an increased risk of developing pancreatic cancer [4]. Current treatments for CP involve pain management with paracetamol and non-steroid anti-inflammatory drugs as first line, followed by mild opioids such as tramadol. An important clinical feature of CP is steatorrhea, caused by reduced absorption of fat in the intestine. Supplementation of pancreatic enzymes such as lipase, together with H2 histamine antagonists, is used to reduce this malabsorption of lipids [1]. Micronutrient therapy containing antioxidants such as Antox® (containing methyl and thiol moieties, as well as methionine and vitamin C) is now being tested, as it has been shown to control the pain and attacks associated with CP [1]. The pathogenesis of CP is believed to be associated with inappropriate pancreatic enzyme activation and clearance from the acinar cells. Increased pancreatic Ca levels as a result of excessive consumption of alcohol or other causes is common in CP, with calcifying protein deposits implicated in the blockage of the acinar ducts, leading to digestive enzyme accumulation and subsequent inflammation. Other evidence suggests that noxious agents such as alcohol are directly toxic to the acinar cells and may also trigger the activation of pancreatic stellate cells [5]. An important element of the pathogenesis of CP is fibrosis, which can occur via sustained activation of pancreatic stellate cells that migrate to sites of tissue damage and secrete excess extracellular matrix proteins, causing fibrosis or scarring [6]. Factors that drive this fibrotic response include lipid peroxidation products released by acinar cells and TGF-β1 release by reactive oxygen species (ROS)-activated mast cells that infiltrate the pancreas as part of the inflammatory response to CP [1]. Progression of fibrosis in CP is associated with the loss of acinar and islet cells, leading to both exocrine and endocrine pancreas dysfunction. There are currently no effective therapies to prevent or reverse CP [7]. Given the insidious nature of CP, together with the increased mortality rate and pancreas cancer risk, improved treatment options for reversing the progressive fibrosis associated with this disease are urgently needed. To this end, new molecular targets that are involved in the onset and progression of fibrosis associated with CP need to be identified. * Derek P. Brazil d.brazil@qub.ac.uk