Chronic Pancreatitis - Term Paper Example

Chronic Pancreatitis Case A 65 year old man with persistent lower abdominal pain and jaundice was detected with elevated levels of hepatobiliary enzymes. Abdominal ultrasonography revealed a diffuse hypoechoic swelling of the pancreas. Contrast enhanced ultrasound (CEUS) exhibited an enhancement of pancreatic parenchyma with inhomogenous staining. Negative results were reported for presence of humoral and anti-DNA antibodies. An endoscopic retrograde cholangiopancreatography (ERCP) showed a marked narrowing of the main pancreatic duct as well as the side branches along with stenosis in the head and tail segments of the pancreas. General Description Chronic Pancreatitis (CP) is a heterogeneous, progressive disorder of the pancreas characterized by a spectrum of symptoms pain, inflammation, diabetes mellitus, and pancreatic damage leading to significant loss of both endocrine and exocrine functions of the pancreas (Witt and associates, 2007; DiMagno & Dimagno, 2006). Pathology involves fibrosis in the pancreatic parenchyma that manifests irregularly. Other organs in vicinity are also affected as consequence of the disease that may commence as an individual or a group of symptoms resulting from functional impairment of pancreas. The major clinical symptom of disease is recurring or persistent pain within the abdomens. The chief cause of CP in western world is alcohol abuse leading to alcoholic calcific pancreatitis (ACP). The other form of CP known as tropical calcific pancreatitis (TCP) prevalent in tropical countries is of uncertain etiology (Lee, 2011). Based on the risk factors CP is classified by the TIGAR-O (Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute, Obstructive) classification system (Nair tet al., 2007). Figure 1: Anatomy of the pancreas (http://www.britannica.com/bps/media-view/68636/1/0/0) Pancreas: Normal Physiology Pancreas is retroperitoneal structure in upper abdomen that can broadly be divided into head, body and tail (figure 1). Major portion of pancreatic tissue comprises of acini (80%) that are responsible for the exocrine functions of the pancreas. Groups of acini form spherical lobules that are interspersed with connective tissue. The central ducts of each lobule in which the secretions of the surrounding acinar cells accumulate, join to extralobular ducts that finally drain in to the main pancreatic duct. The main pancreatic duct carrying the secreted digestive enzymes enters the hepatopancreatic ampulla along with bile duct. At the duodenal papilla the enzymes enter the duodenum (Adda et al., 1984). The endocrine functions of the pancreas are performed by the richly vascularized islets of Langerhans. The islets of Langerhans comprise of beta, alpha and delta cells that secrete hormones insulin, glucagon, somatostatin respectively. The most abundant beta cells (73-75%) are centrally located and are surrounded by alpha cells (18-20%) and delta cells (4-6%). The rich vascularization allows for the transfer of hormones from the islets while the specific arrangement of the alpha, beta and delta cells allows paracrine regulation of hormones. Thus high concentrations of the insulin secreted from the central beta cells inhibit glucagon release from the peripheral alpha cells. The venous blood flow from the islets of langerhans reaches the hepatic portal vein, rendering the liver the prime target for the impact of pancreatic hormones. The rich innervations in the pancreas ensure the release of several neurotransmitters in the pancreas that regulate the release and concentrations of hormones (Case, 2006). During normal physiology, in basal state, the secreted pancreatic fluid is mildly alkaline comprising of small quantity of proteins. Gastric distension and acid production during eating stimulate duodenal S cells causing the release of secretin. Under the influence of the secretin, a large quantity of the bicarbonate rich watery liquid or the hydraulic secretion is released from the ductal cells of the smaller ducts. During the postprandial stages, cholecystokinin (CCK) released by the duodenum stimulates acinar cells of pancreas to secrete enzyme enriched ecbolic secretion into the ducts (Lieb & Draganov, 2008). • Cellular Mechanism of Chronic Pancreatitis The molecular mechanisms underlying the development of cellular modifications in CP are incompletely understood. Genetic factors identified recently provide an insight into the molecular mechanism underlying the histopathology of CP. The three genes identified to be involved in development of CP include cationic trypsinogen (PRSS1) gene, the pancreatic secretory trypsin inhibitor (SPINK1) gene, and the Cystic Fibrosis transmembrane conductance regulator (CFTR) gene. The gain of function mutation in PRSS1, such as R122H mutation causes trypsin autolysis under low calcium conditions as found in acini, the site of synthesis and storage of trypsinogen. Familial CP and ICP in children have been reported to be associated with the loss of function mutation of SPINK1. A normal CFTR gene is involved in movement of pancreatic enzymes out of the pancreas through the pancreatic duct, i.e. in areas of high calcium concentrations and without an active trypsin autolysis mechanism. Mutations in each of these three genes lead to defects that cause the damage to pancreas by premature trypsinogen activation followed by activation of other digestive enzymes. These defects are therefore responsible for pancreatic autodigestion and inflammatory responses that manifest as recurring acute pancreatitis (RAP) (Whitcomb, 2004). Along with these the chemokines, cytokines contribute to the cellular changes that aim to strike a balance between the damaging effects such as necrosis, apoptosis, and fibrosis; and the repair and regenerative processes. These processes are responsible for the fibroblastic growth and fibrosis within the pancreas which may lead to the development of dysplastic ductal cells with high tendency to undergo malignant transformations (Detlefsen et al., 2006). The mechanism of fibrogenesis in CP has recently been elucidated and has been shown to be initiated by the specific response of macrophages and other inflammatory cells to tissue damage or necrosis in pancreas. These together with myofibroblasts are stimulated to synthesize cytokines. This is why in CP patients with negligible or no tissue damage, fibrogenesis is minimal. The transforming growth factors-β (TGF- β), platelet driven growth factor (PDGF) and the fibroblast growth factor- β (FGF- β) have been found to be responsible for the transformation of pancreatic stellate cells into proliferating myofibroblasts or the active stellate cells during in vitro studies. The active pancreatic stellate cells express smooth muscle actin and desmin in contrast to inactive stellate cells that store lipids and vitamin A. Immunohistochemical studies have reported the accumulation of these growth factors along with their receptors and active components in the inflammatory cells, and in the chronically inflamed epithelial tissues in the pancreas (Detlefsen et al., 2006). • Pathophysiology As a consequence of the aforementioned histological changes; a progressive decrease in acinar cells with simultaneous increase in connective tissue results. Pancreas develops into enlarged, irregular structures with extended ducts and may sometimes contain pancreatic cysts. Due to the fibrogenesis the normal of functioning of the pancreas is affected. The replacement of normal tissue with the fibrotic tissue and pancreatic tissue necrosis leads to impairment of the exocrine as well as the endocrine function of the pancreas. Digestive process is impaired due to deregulation of the exocrine functions leading to loss of weight. The overall output of the digestive enzymes drops by 60-90% as a consequence of 5-10 years of CP. Further excretion of undigested, fat-rich food leads to diarrhea which further develops into steatorrhea with fall in lipase activity to less than 5-10% of the normal. The endocrine insufficiency resulting in impairment of insulin production causes elevation of blood sugar levels that is responsible for the development of diabetes mellitus (Giger et al., 2004). Progressive CP leading to fibrosis of the periductal tissue causes ductal obstruction. Stenosis of the bile duct, duodenal stenosis resulting in the compression of the portal venous system follows. Duct obstruction and formation of pseudocysts with elevated pressure within the duct causes pain symptoms. Ductal obstruction leads to accumulation of pancreatic fluid due to its upstream transfer. This causes the formation of pancreatic cysts known as pseudocysts. Compression of bile duct and duodenum due to enlarging pseudocyst and progressive fibrosis leads to pain. In advanced cases of CP, interaction of pseudocysts with surrounding tissues, leads to formation of acsites, fistulas and pleural effusions leading to shortness of breath. Rupture of the pancreatic ducts may also contribute to these symptoms. Besides progressive fibrosis and calcification of pancreatic tissue causes nerve entrapment that is responsible for consistent or episodic pain symptoms during CP (Layer et al., 1994). Finally Notch signaling pathway, the suppression of which is responsible for favored differentiation of pancreatic progenitor cells into endocrine cells, over exocrine cells; has been found to be reinstated in CP (Su et al., 2006). Signs and Symptoms The commonly reported symptoms of CP include pain, weight loss, diarrhea, jaundice with the probable complications being nutrient malabsorption and diabetes mellitus. Abdominal pain, either continuous or episodic is the major symptom of CP reported in 50-80% of the cases. The pain is localized in the epigastric area, and worsens post eating or drinking. It is often associated with nausea and is reported to extend to the back in some cases. Bleeding from gastric vesicles is observed in cases with splenic vein thrombosis (Giger et al., 2004). The levels of secretin and CCK are disturbed in CP with elevated in early stages of CP and being quantifiable form excellent diagnostic criteria for CP. Further in early stages of CP, the levels of pancreatic enzymes in pancreatic juices is high while in the advanced stages, necrosis and fibrosis results in reduction of levels of these enzymes. During laboratory tests total bilirubin, alkaline phosphatase, and hepatic transaminase levels are indicated to be higher than normal as a consequence of ductal obstruction. High levels of autoantibodies such as antinuclear antibody and immunoglobulin G4serum antibody are reported in autoimmune pancreatitis (Lieb & Draganov, 2008). The morphological signs that are observed during the ultrasound examinations enabling diagnosis of the disease include hyperechoic foci and strands in the pancreatic parenchyma, lobularity of gland contour, and collections of pseudocysts. Pancreatic ducts are often seen to be extended with irregular and/or hyperechoic margins. Ductal side branches are also dilated and stones are found in certain advanced cases of CP (Lieb & Draganov, 2008). • Maintenance of Homeostasis The repair and remodeling processes initiated as a consequence of these cellular changes in order to maintain the homeostasis involve overexpression and accumulation of certain growth receptors at specific locations within the pancreas and surrounding tissue. Alterations in Tyrosine kinase receptors and their ligands have been identified to be one of the significant factors contributing to the cellular changes. The overexpression of epidermal growth factor receptors and their ligands, the fibroblast growth factors and their receptors, and the platelet derived growth factors leads to their accumulation in acinar and ductal cells, the islets, fibroblasts, endothelial cells and the inflammatory cells (Ebert et al., 1998). The overexpression of tyrosine kinase A receptors and associated nerve growth factor leads to the accumulation of same in perineurium and the ganglia (Ebert et al., 1998). Diagnosis & Treatment a. Clinical Manifestations & Lab Tests i. Physical Examination Findings The major clinical manifestation of CP is RAP that progresses to chronic condition manifested as midepigastric pain manifested especially during postprandial stages and radiating to back. Besides this steatorrhaea, malabsorption, weight loss, vitamins (A, B12, D, E, and K) deficiency symptoms, diabetes are observed in patients. In some patients (10-20%), exocrine insufficiency without abdominal pain is reported, while in some others spontaneous pain remission due to organ failure is manifested (Nair & Lawler, 2007). ii. Laboratory Blood Test Results The differential diagnosis of CP is based on clinical manifestations and imaging results. No result can exclusively confirm the diagnosis and the choice of tests depends on the condition of patient, clinical manifestations, risks and advantages to the patient (Nair & Lawler, 2007). The commonly used tests and their results in order of preference are presented in table 1. Table 1: Laboratory tests for diagnosis of CP (Nair & Lawler, 2007) Tests Results and comments Blood count Elevated, with infection Total Bilirubin, Alkaline phosphatase, and Hepatic Transaminase, Elevated: Biliary Pancreatitis, Occurs with ductal obstruction Fasting Serum Glucose Elevated: pancreatic diabetes Pancreatic Function Tests Useful in combination with imaging studies Fecal Fat Estimation >7g fat/day abnormal Fecal Elastase Read More