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Introduction to Pancreatic Disease Introduction to Pancreatic Disease: Chronic Pancreatitis Elham Afghani Division of Gastroenterology, Cedars-Sinai Medical Center Los Angeles, CA 90048 e-mail: [email protected] Version 1.0, December 16, 2014 [[DOI: 10.3998/panc.2015.3] 1. What is chronic pancreatitis? In the normal pancreas, there are three types of pancreatic cells: 1) acinar cells, which produce Chronic pancreatitis is a long-standing pancreatic digestive enzymes; 2) ductal cells lining inflammatory disease which leads to scarring of the pancreatic ducts, which secrete a watery fluid to pancreas and irreversible changes. Chronic carry the digestive enzymes into the intestine; and pancreatitis results in abdominal pain and, in some 3) endocrine cells present in the islets of cases, results in diabetes and fatty stools that are Langerhans, which secrete insulin and other large and bulky. Calcification, which is another sign hormones (Figure 2). As the pancreas begins to of chronic inflammation, can develop throughout scar and more than 90% of the tissue is destroyed the pancreas. These calcifications are like stones over time (often over many years) patients develop that are within the tissue itself, or within the fatty stools and fat malabsorption because they do pancreatic duct (Figure 1). not produce enough digestive enzymes; and diabetes due to loss of insulin producing cells. Figure 1. Features of chronic pancreatitis. Chronic pancreatitis is progressive inflammatory process in the pancreas that causes fibrosis (scarring of tissue), calcifications or stones, and dilated pancreatic duct. Adapted from Gorelick F, Pandol, SJ, Topazian M. Pancreatic physiology, pathophysiology, acute and chronic pancreatitis. Gastrointestinal Teaching Project, American Gastroenterological Association. 2003. This work is subject to an International Creative Commons Attribution 4.0 license. Figure 2. Cells of the pancreas. The pancreas has two types exocrine cells which include acinar and ductal cells; and endocrine cells present in the islets of Langerhans. The exocrine portion of the pancreas makes up 85% of the pancreas. Adapted from Gorelick F, Pandol SJ,, Topazian M. Pancreatic physiology, pathophysiology, acute and chronic pancreatitis. Gastrointestinal Teaching Project, American Gastroenterological Association. 2003. The incidence of chronic pancreatitis ranges from pancreatitis (8, 21). However even lesser amounts 4.4 to 11.9 per 100,000 per year, with a higher of alcohol can change the structure of the incidence in Japan compared to the United States. pancreas. Alcohol and smoking together increase (6, 22, 23). Men are up to 1.5 times more likely to the risk of chronic pancreatitis as they often have chronic pancreatitis compared to women in coexist. However recently, it has been found that the United States (22). The incidence may be smoking is independent risk factor for chronic higher in other countries. In 2009, there were pancreatitis. Those who smoke less than one pack 19,724 admissions for chronic pancreatitis in the per day have a 2 fold risk of chronic pancreatitis, United States, and associated with annual those who smoke more than one pack per day hospitalization costs of $172 million (16). The have a 3 fold risk (2), and those with more than 35 incidence has been increasing which may be due smoking pack year history (which is equal to the to improved diagnostic techniques or increased number of packs per day times the years) have a use of alcohol worldwide but more so in the 13 fold risk of chronic pancreatitis (21). Continued developing countries, such as India and China (7). smoking after the development of chronic The incidence of chronic pancreatitis is less in pancreatitis speeds up the progression of the children. The age at presentation varies with disease (19). It also further increases the risk of etiology. Hereditary pancreatitis has a peak age at pancreatic cancer. 10 to 14 years (11), juvenile idiopathic chronic pancreatitis at 19 to 23 years, alcoholic chronic Chronic pancreatitis usually results from recurrent pancreatitis at 36 to 44 years, and senile idiopathic attacks of acute pancreatitis. In addition to alcohol chronic pancreatitis at 56 to 62 years (9, 13). abuse, other causes of acute recurrent pancreatitis include high levels of calcium or triglycerides in the 2. What causes chronic blood, genetic mutations, and congenital pancreatitis? abnormalities of the pancreas. Genetic mutations and cystic fibrosis can cause acute recurrent Figure 3 shows the causes of chronic pancreatitis. pancreatitis or may cause chronic pancreatitis Alcohol abuse and smoking are the most common without prior acute pancreatitis. These are also causes of chronic pancreatitis. Heavy alcohol use, likely the causes of chronic pancreatitis in children. which means 4-5 drinks per day of alcohol over Hereditary pancreatitis due to genetic mutations is years, increases the risk of developing chronic a rare cause of chronic pancreatitis. 2 Figure 3: Causes of chronic pancreatitis. The most common cause of chronic pancreatitis in the United States is alcohol and smoking. Other causes include genetic mutations, cystic fibrosis, hypercalcemia (or elevated calcium levels in the blood), hypertriglyceridemia (or elevated levels of triglycerides in the blood), autoimmune, or idiopathic, meaning that the cause is still unknown. Fibrocalcific pancreatitis, also known as tropical pancreatitis, is more common in India. Figure 4: Mechanism of gene mutations causing pancreatitis. Trypsinogen is a precursor, meaning that it is an inactive form of an enzyme, called trypsin. It becomes activated. A gain of function mutation in PRSS1, is associated with premature and continued activation of trypsinogen into trypsin. Trypsin is flushed into the duodenal to allow for food digestion by bicarbonate rich fluid. A loss of function in CFTR prevents adequate formation of bicarbonate fluid, therefore increasing the amount of trypsin around the pancreas. Trypsin can also cause injury or inflammation of the pancreas. This is usually prevented by normal functioning SPINK1, a pancreatic secretory trypsin inhibitor. However, if there is a loss of function in SPINK1, then trypsin is free to cause inflammation. Trypsin is broken down by one form of the enzyme called chymotrypsin. The gene responsible for this enzyme is CTRC. A loss of function of CTRC prevents trypsin breakdown, therefore allowing more trypsin to cause tissue injury. In the recent years, there has been more research or a loss of function (which occurs in SPINK1, that has found new genes that may be associated CTRC, and CFTR) leads to either the premature with the development of chronic pancreatitis. activation of the enzymes that digest the pancreas These genes include PRSS1, CFTR, SPINK1, and (trypsin) or prevents it breakdown (20). (Figure 4). CTRC. A gain of function (which occurs in PRSS1) 3 Cystic fibrosis affects 1 in 3000 births in people of Due to the lack of pancreatic enzymes that are North European descent (15). Some people with being released by the pancreas, patients may have cystic fibrosis may have pancreatic exocrine fatty stool that is oily appearing and foul smelling. insufficiency while other will have a working This is known as exocrine pancreatic insufficiency pancreas, also known as pancreas sufficient. and is mainly due to a shortage of pancreatic lipase Those who are pancreas sufficient may go on to which is necessary for fat digestion. Patients may develop chronic pancreatitis, with or without also develop diabetes that is due to the loss of discrete attacks of pancreatitis pancreatic tissue and cells that produce insulin, also known as islets of Langerhans. This is known Congenital abnormalities of the pancreas may as endocrine insufficiency. Patients with alcohol become apparent either in childhood or in induced chronic pancreatitis develop exocrine adulthood. These abnormalities include annular insufficiency approximately 4.8-5.5 years after the pancreas, which is an abnormal development of onset of chronic pancreatitis (1). Patients with the pancreas during development while in the hereditary chronic pancreatitis will develop womb. Pancreas divisum is another abnormality. exocrine insufficiency at a younger age (18). This abnormality is present in 10% of the Patients with chronic pancreatitis have a 4% risk of population. The significance of pancreas divisum is developing pancreatic cancer over 20 years (10). unknown since most patients with this do not have However the risk of pancreatic cancer is also symptoms or go on to develop chronic pancreatitis. dependent on the cause of chronic pancreatitis. One study showed that those with pancreas For example, smokers with chronic pancreatitis will divisum and chronic pancreatitis had a genetic develop pancreatic cancer earlier than mutation, more commonly CFTR gene mutation, nonsmokers (12, 17). suggesting that pancreas divisum by itself does not cause pancreatitis (3). 4. How is chronic pancreatitis Other causes of chronic pancreatitis in adults and diagnosed? children include autoimmune pancreatitis and fibrocalcific pancreatitis, also known as tropical Chronic pancreatitis is diagnosed by a combination pancreatitis, which is more common in India. of symptoms and imaging tests, including CT or “CAT” scans and MRIs. CT scans can shows 3. What are the symptoms of calcifications and dilated ducts that occur with chronic pancreatitis? chronic pancreatitis. However CT scan is a poor test for diagnosing mild chronic pancreatitis. MRI Symptoms of chronic
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