*4.2.4 CTRB*

CTRB1 and CTRB2 genes encode a member of the serine protease family of enzymes. The study by Rosendahl et al. reported the identification of *CTRB1- CTRB2* (chymotrypsin B1 and chymotrypsin B2) as a new chronic pancreatitis (CP) risk locus by means of GWAS. The inversion is found to decrease the CP risk by increasing trypsinogen degradation [34].

## *4.2.5 CELA3B*

Recently, researchers found a new protease mutation linked to hereditary pancreatitis. The missense mutation in the gene encoding pancreas-specific protease elastase 3B (CELA3B), which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis [35].

### **4.3 Ductal dysfunction**

After joining the common bile duct, the main pancreatic duct, after which both ducts perforate the medial side of the second portion of the duodenum. Therefore, any obstruction, compression or inflammation of the pancreatic tissue will increase the pressure within the pancreatic ducts leading to ductal dilation, stenosis and to atrophy of the acinar cells and replacement by fibrous tissue [36]. Long standing ductal obstructions by pseudocyst, calculi or pancreatic division can be a reason for recurrent pancreatitis attacks, which lead to eventually fibrosis and pancreatic insufficiency. Ductal obstruction can be also caused by concretions which increase the viscosity of the secretions and thereby promoting protein plugging [37].

A distinct form is the pancreatitis resulting due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a chloride–bicarbonate channel expressed in the apical plasma membrane of secretory epithelia in many organs such as pancreas. The channel controls transepithelial fluid secretion and hence hydration of the epithelial luminal surfaces. It also controls the pH of the secretions, which is important for the optimal digestion [38]. Genetic variations in CFTR that affect membrane levels or channel activity led to various pancreatic phenotypes including chronic pancreatitis. Aberrant expression of CFTR causes to diminished fluid and HCO3− secretion leading to decreased intraluminal pH, decreased washout of the digestive enzymes, and more viscous protein rich ductal fluid. These changes promote the formation of intraluminal protein plugs [39, 40].

### **4.4 Oxidative distress**

Moreover, a hypothesis is proposed which implies that mutation-induced misfolding, secretory blockage, and consequent endoplasmic reticulum (ER) stress can lead to acinar cell damage and pancreatitis [41]. Some of associated genes are CPA1 and CEL. Recent studies have also reported CLDN2, and MORC Family CW-Type Zinc Finger 4 (MORC4) gene are associated with CP, but the mechanism has not elicited, yet [4, 14].

Pathogenic CPA1 variants are detected both late but especially early onset CP due to proenzyme mis-folding, resulting in a secretion defect and intracellular retention [42, 43]. A deletion mutation in CEL is founded to cause an increasement in ER stress, through activation of the unfolded protein response and causing cell death by apoptosis [44].

The pancreas consists of three critical cell lineages: acinar, ductal and endocrine46. Adjacent to the acinar cells around small pancreatic ducts and blood vessels are pancreatic stellate cells, that compromise around 4–7% of all parenchymal cells [45, 46]. The hypotheses mentioned above lead to cellular injury, which turns into chronic inflammation and then eventually fibrosis.

As explained before, the secretory parenchyma but mainly the acinar cells are destroyed by processes such as toxification, inflammation, duct obstruction or oxidative stress. Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the organ. Fibrosis causes acinar cells and duct cells to injure and disappeared. This process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas resulting in functional impairment of both exocrine and endocrine functions, eventually leading to clinical symptoms such as pain, malnutrition, or diabetes [47, 48]. Furthermore, the pancreatic stellate cells activate into myofibroblast-like phenotypes, proliferate, and secrete collagen I and III and fibronectin [49, 50]. Hence, the initial of the pancreas, leads to cell necrosis and/or apoptosis and consequently release of cytokines/growth factors (e.g., tumor growth factor b1, interleukin-8, platelet-derived growth factor and CC-chemokines), either from immigrating inflammatory cells, especially macrophages, and/or nearby preexistent epithelial or mesenchymal cells [51–54]. Thereafter damaged cells are phagocytosed by macrophages, causing release of cytokines, which in turn causes activation and proliferation of PCS [55]. So, a vicious circle of the irreversible event has started. These metalloproteinases are in return regulated by cytokine tumor growth factor (TGF)-β1s, which through autocrine inhibition enhances pancreatic fibrogenesis by reducing collagen degradation [50].

## **5. Diagnosis**

The diagnosis of the chronic pancreatitis is still challenging especially in the early stages of the disease. Clinician must be suspected chronic pancreatitis in a patient with chronic abdominal pain (especially in upper quadrants), weight loss, steatorrhea, and endocrine pancreatic insufficiency. All patients with suspected chronic pancreatitis should have a dedicated pancreatic protocol to rule out pancreas carcinoma. Clinician should remember that any patient with chronic abdominal pain may also be had suffered from chronic abdominal pain syndrome, history of ERCP-related pancreatitis or any ductal changes. In most cases follow-up with serial imaging and physiological tests are recommended [56]. Once the diagnosis is confirmed, physician should characterize the etiology of chronic pancreatitis. TIGAR-O classification and modified MANNHEIM classification should be evaluated. TIGAR-O classification is a mnemonic for toxic metabolic, idiopathic, genetic mutations, autoimmune, recurrent, and severe acute pancreatitis associated chronic pancreatitis and obstructive etiologies [46]. Modified MANNHEIM classification is a mnemonic for multiple risk factors, alcohol consumption, nicotine consumption, nutritional factors (hyperlipidemia, hypertriglyceridemia), hereditary factors, efferent duct factors, immunologic factors, miscellaneous factors (hypercalcemia, hyperparathyroidism, chronic renal failure, toxins) [45].

### *Current Approaches in Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.98214*

Contrast-enhanced CT should be the initial diagnostic tool. CT scans have an overall sensitivity of 75% for chronic pancreatitis. Enlargement of the main duct (2–4 mm), glandular enlargement, heterogenous parenchyma, small (<10 mm) or lager (>10 mm) cavities, irregular ductal borders, irregular head/body contour and increased echogenicity of main duct wall are the probable pathologies that are seen in CT scan. After seeing these pathologies physician should suspect chronic pancreatitis and follow-up the patient. The other imaging technique for chronic pancreatitis is MRI and MRCP. Current MRI and MRCP technologies can provide high-quality images both parenchyma and ductal system [56]. T1 sequence in MRI is helpful for evaluating parenchymal changes in chronic pancreatitis. MRCP is used for evaluating ductal changes in chronic pancreatitis. Intravenous secretin administration during MRCP imaging stimulates pancreatic fluid secretion and can improve the visualization of ductal tree [57]. The other imaging technique for evaluating chronic pancreatitis is ultrasonography and endoscopic ultrasonography (EUS). EUS finding can be classified as two subgroups which are parenchymal features and ductal features [58]. EUS is one of the most promising imaging techniques for diagnosis and evaluating chronic pancreatitis. However, the EUS imaging needs experienced clinician. EUS is now considered to be the most sensitive CP diagnostic investigation, especially in the early stages of the disease [59, 60].

Blood amylase and lipase levels can help the physician to diagnose acute pancreatitis however, in chronic pancreatitis these levels often normal. The diagnosis of the chronic pancreatitis with blood tests are challenging. There can be some clues like hypertriglyceridemia, hypercalcemia, hyperparathyroidism and hyperlipidemia. On the other hand, fecal elastase levels are often decreased in chronic pancreatitis. Also, diagnosis of type 3c diabetes (defined as pancreatic islet dysfunction and islet loss due to diseases of endocrine pancreas) is helpful for diagnosing the disease. Increased levels of hemoglobin A1c (HbA1c), absence of insulin resistance, loss of incretin secretion and low levels of fat-soluble vitamin concentrations can support the diagnosis of the chronic pancreatitis. The secretin stimulation test can be used with MRCP and for research. Secretin stimulation test is a complex procedure. Firstly, the physician takes a sample from duodenal fluid as a baseline enzyme value then performs intravenous secretin administration after that the second sampling from duodenal fluid is done. Fecal elastase levels and secretin stimulation test results show the damage of exocrine pancreas.
