PANCREATITIS. By April McMurray. March 14, 2013 NDFS 356

PANCREATITIS By April McMurray March 14, 2013 NDFS 356

INTRODUCTION The pancreas is a small gland that sits behind the stomach and plays an important role in digestion (1). Its head is situated within the curvature of the duodenum of the small intestine, where its secretions flow from the pancreatic duct through the Ampulla of Vater (2). The functional unit of the pancreas is the acinar cell, which is responsible for synthesizing, storing, secreting digestive enzymes into the pancreatic duct (3). The Islet of Langerhans are also an important unit of the pancreas, which have endocrine function and secrete hormones directly into the bloodstream (3). The pancreas has both endocrine and exocrine functions. The Islets of Langerhans produce the hormones insulin and glucagon to regulate the level of glucose in the blood (1). The blood flow in the pancreas follows from the islets to the acinar cells, allowing insulin to even affect the pancreatic exocrine function (3). Somatostatin, also produced by the pancreas, inhibits the release of these hormones, as well as the exocrine functions (3). The exocrine function of the pancreas is involved in digestion, as the digestive enzymes produced by the acinar cells are secreted into the pancreatic duct and into the duodenum (2). The pacreas can secrete up to 2.5 L per day (4). In addition to the digestive enzymes, the ductal epithelial cells secrete bicarbonate, and alkaline secretion which neutralizes the content of the stomach as is enters the small intestine (3). The major digestive enzymes are amylases, which digest starches and glycogen, lipases, which act together with bile salts to break down fat, and proteases, which cleave amino acids for the breakdown of protein (3). The pancreas is stimulated both by neural and hormonal responses, with ingested foods playing an important roll (2). The primary hormonal stimulants are secretin, acetylcholine (Ach), and cholecystokinin (CCK) (3). There are three phases during which the pancreas is stimulated to produce these digestive

enzymes. The cephalic phase is mediated by the vagus nerve and initiated by the sight, smell, taste, or even anticipation of food (2). The Acinar cells are stimulated but no bicarbonate is released (3). The second phase, the gastric phase, is initiated by gastric distention with the presence of food in the stomach (2). The intestinal phase, has the most potent effect on the pancreatic secretions, and is mediated by CCK (2). As food enters the small intestine, amylase, lipase and protease are all released from the pancreas into the duodenum (3). The duodenum is the most important site for lipase secretion, and it acts with bile salts for full digestive activity (3). The proteases, trypsin, chymotrypsin, and elastase, are stored in the pancreas in their inactive form and are activated when they enter the duodenum (3). DISEASE DESCRIPTION Pancreatitis is inflammation of the pancreas and is characterized by pancreatic edema, cellular exudate and fat necrosis (2). The release of active proteases within the pancreas stimulate auto-digestion and an intense inflammatory response (3). With a rapid onset, symptoms and side effects vary from mild to severe (3). Acute pancreatitis (AP) is a sudden attack and a full recovery is typical, whereas chronic pancreatitis (CP) is a more persistent condition and the pancreas can suffer more permanent damage (1). Cases of acute and chronic pancreatitis affect more than 80,000 Americans per year (5). PATHOPHYSIOLOGY The pathophysiology for pancreatitis is not entirely understood. Acinar cell injury is caused by the activation of trypsinogen to trypsin within the cells, enough to overwhelm the regular mechanisms such as pancreatic secretory trypsion inhibitor (PSTI) and alpha-antitrypsin (5). Trypsin in turn catalyzes more proteases to their active forms while still in the pancreas, causing a downward cycle of auto-digestion and protease activation (5). In experimental

pancreatitis, this can occur within 10 minutes of onset (5). It is still unclear as to the cause of the activation of trypsinogen to trypsin; causes include gallstones and alcohol abuse (although the mechanism is not fully understood), cystic fibrosis, genetic mutations and the presence of lysosomes (5). The progression of AP happens in two stages. The first stage typically lasts a week, and is characterized by the initiation of the inflammatory cascade (5). Signs of pancreatic ischemia, edema, and systemic inflammatory response syndrome (SIRS) are noted (5). Extrapancreatic organ failure sometimes occurs secondary to the inflammation, depending on the severity of the case (5). 75-80% of pancreatitis cases will resolve without progressing to the second stage (5). This second stage can last weeks to months, and is characterized by more severe pancreatic damage, necrosis, and multi-organ failure (5). Death can occur rapidly during the first two weeks if the case is severe enough (5). The pathophysiology of pancreatitic episodes in chronic pancreatitis are mostly the same as acute, but it is less understood than AP (6). There are several hypotheses explaining the mechanisms, but most lack evidence. The most supported hypothesis suggests that CP is caused from recurring episodes of acute pancreatitis (6). With similar features of the acute condition edema, inflammation, ischemia, necrosis this causes extensive damage and permanently scarred pancreatic tissue (6). Chronic pancreatitis can take years to develop, and can often have silent symptoms (6). However, with time, several complications can arise from the condition. Microcirculatory injury, inflammation, oxidative stress, bacterial translocation and fibrosis can occur (6). Sometimes pancreatic fluids can leak into other organs, causing damage (6). Other organs that are affected are the kidneys and lungs (6).

Eventually, pancreatitis will lead to both endocrine and exocrine failure. A consequence of exocrine dysfunction is steatorrhea. A feature of advanced conditions of chronic pancreatitis, steatorrhea doesn't occur until lipase secretions are less than 10% of the normal output (6). The poor digestion and absorption of fat causes loose, foul-smelling, fatty stools (6). A complication of endocrine dysfunction is diabetes mellitus. A slightly different condition than either type 1 or type 2, diabetes as a result of chronic pancreatitis is not caused by a complete destruction of the Islet of Langerhans, although some function is lost (6). For unknown reasons, the pancreas will still secrete some insulin if glucagon-like peptide 1 is administered (6). However, the pancreas' ability to secrete glucagon is completely lost, and patients receiving insulin therapy (eventually 50%) must monitor blood glucose carefully to not cause hypoglycemia (6). 40-80% of all CP patients will eventually get diabetes (6). ETIOLOGY The mechanisms of the causes of pancreatitis are still not fully understood, but as understanding increases, the number of idiopathic cases will decrease. The principal cause of acute pancreatitis is gallstones (5). Gallstones account for 40% of AP incidents (5). The small gallstones in particular, which are small enough to leave the gallbladder and get lodged in the pancreatic duct, causing an obstruction (5). AP will affect 3-7% of people with gallstones (5). The best way to treat this problem is to remove the gallstones, and in some cases, the gallbladder (5). Other types of obstructions which are less common causes of pancreatitis are biliary sludge and tumors (5). The next most common cause of acute pancreatitis is alcohol abuse. Accounting for roughly 30% of all AP, there are several hypotheses concerning the mechanism including an affect on the exocrine function of the pancreas, changes in lipid metabolism and oxidative stress

caused by heavy drinking (5). Another significant cause is hypertriglyceridemia, which accounts for 5% of AP, making it the third most common cause (5). AP patients may be found with blood triglyceride levels of 1,000 mg/dl, compared to the normal range of <150 mg/dl (5). Poorly controlled diabetic patients, alcoholics, and non-obese-non-alcoholic patients with drug-induced hypertriglyceridemia are at particular risk for developing AP (5). Other less common conditions that may cause AP include infections, vascular disease, trauma, post-ercp operations, postoperative and hereditary (5). Some of the causes in CP are similar to those of AP. In cases of CP, however, alcohol abuse is the greatest contributor, and accounts for 70% of all CP cases (6). However, pancreatitis is a condition that only affects 3-15% of the heavy drinking population (those who consume more than 14 grams of alcohol daily), so it appears that co-factors in conjunction with heavy drinking are also of significance (6). These co-factors may include genetic mutations, high dietary intake of fat and protein, the type of alcohol consumed, decreased antioxidant and trace elements and smoking (6). Smoking in particular has been found to be a significant co-factor, as 90% of patients with CP from alcohol abuse also smoke (6). The biggest recommendation for alcohol-induced CP patients is to cease drinking alcohol, which cannot stop or reverse damage done to the functioning pancreas, but it will slow the condition's progression (6). Tumors, scars, ductal stones and duodenal wall cysts are obstructions that can cause CP (6). Other causes are tobacco use, some tropical climates, genetic and autoimmune influences (6). Recurrent episodes of AP, regardless of the initial cause, can also eventually lead to CP (6). MEDICAL DIAGNOSIS The biggest symptom of pancreatitis is pain. Pain can reach is maximum intensity in 10-

20 minutes, and is steady and almost unbearable (5). Upper abdominal pain can radiate, belt-like, to the back (2). As the other symptoms of pancreatitis are similar to other GI disorders, such as nausea and vomiting, pain is often the biggest indicator of pancreatitis (5). The pain can be caused by increased pressure and ischemia in the pancreas or an increase innervation of the nociceptive nerves, stimulated by inflammation (6). Ecchymoses occurs in the flanks and is called Grey Turner's sign (5). Jaundice may occur if the bile duct is blocked (1). Hypotension, low urine output and dyspnea may also occur in more severe cases (2). The severe continuous pain, especially as seen with chronic pancreatitis, can cause a decrease in appetite, which can lead to weight loss and malnutrition over time (6). Complications like steatorrhea and diabetes, as mentioned above, are also symptoms of pancreatitis. The diagnosis for acute pancreatitis can be diagnosed by the symptoms, serum enzymes, or radiological imaging (5). Amylase and lipase levels are checked in the blood. The serum amylase test is quickly and easily performed, and is most specific to pancreatitis (7). When the acinar cells are damaged, excess amylase pours into the lymph and is picked up in the blood (7). Levels can rise up to two to three times more than the upper level of normal values within 12 hours of onset (7). Serum lipase is also a valuable diagnostic tool, as pancreatitis is the most common cause for elevated levels (7). Lipase can rise to five to ten times more than the normal values, and stays elevated longer (5-7 days) than amylase (7). There are several tests to determine the severity of pancreatitis. Ranson's criteria is the most commonly used tool, and it identifies 11 signs that can be measured in the first 48 hours of hospital admission to predict the severity and prognosis of the disease (krause). The Bedside Index for Severity in Acute Pancreatitis (BISAP) is a newer test that gives an early identification of at-risk patients and has been shown to be an accurate tool (8). The APACHE score, a

generalized scoring tool for many conditions, can also give a general sense of severity (8). Diagnosis for chronic pancreatitis is more difficult. There is a wide variety of tests, but no one test is better than the rest; different hospitals will run different tests as there is no gold standard (6). Long-term follow-up is often substituted for actual diagnostic tests (6). However, the existing tools that are used are separated into tests of functional or structural abnormalities. Direct tests examine pancreatic function based on direct hormonal stimulation (6). For example, the secretin stimulation test measures pancreatic secretions, particularly bicarbonate, in response to secretin, one of the pancreas' major stimulating hormones (2). A fecal fat test is an example of an indirect test, used to measure pancreatic function based on the total output of fecal fat per 24 hours in a 3-day stool collection (7). Structural abnormalities of the pancreas can be examined with ultrasounds or an endoscopic retrograde cholangiopancreatography (ERCP). An abdominal ultrasound can detect inflammation and abscess of the pancreas (pagana). Acute inflammation will be visualized as an enlarged edematous pancreas, whereas chronic inflammation will appear small and dense (7). An ERCP uses a fiberoptic endoscope to create radiographic visualizations of the bile and pancreatic ducts (7). It can also be used to incise the papillary muscle in the ampulla of Vater to remove gallstones (7). ERCP is a somewhat invasive tool, and is only used during surgical procedures, and not solely for an examination (6). MEDICAL TREATMENT The focus of pancreatitis treatment is often to relieve pain and focus on the patient's nutritional and metabolic needs (1). For AP patients, hydration and analgesia are important in relieving pain (5). In addition to managing pain, maintaining fluid balance can also dilute serum proteins and lower the hematocrit; in order to prevent necrosis, hematocrit should be below 45% (5). Respiratory and cardiovascular care should also be controlled, and blood levels of glucose,

insulin and electrolytes should be monitored carefully (5). To treat nausea and vomiting, AP patients should not consume anything orally for five to seven days (5). Antibiotics may be used for more severe cases where infection is present (5). Endoscopic interventions may also help increase the rate of recovery for severe AP (5). An urgent ERCP can help patients suffering from gallstones, and endoscopic stents placed early have shown to decrease pancreatic duct leakage and necrosis (5). Treatment for pancreatitis is also based on managing pain, although specific therapies should be used to treat individual conditions and complications, such as pseudocysts (6). Analgesics are also used to treat pain in CP, but most patients require more potent drugs (6). Although the risk of addiction is 10-30% if stronger analgesics, or even opoids in cases where analgesics are too weak, pain relief is the first priority (6). Cessation of alcohol and smoking reduces the permanently damaging effects of CP, although not completely, and also decreases pain (6). Some operational interventions may also be used to treat the pain and organ damage of CP. Endoscopic therapy, similar to its use with AP, can be used to improve pancreatic duct drainage, place stents and remove gallstones (6). Surgical therapy can be considered for patients with unbearable abdominal pain or complications of the surrounding organs (6). Surgery can also drain pancreatic ducts to relieve inflammation or take out portions of the pancreas and duodenum, or both, depending on the source of the pain and the ductal anatomy (6). The Whipple procedure is another procedure that can be performed to relieve pain and maintain CP. In this pancreaticduodenectomy, all or part of the pancreas and duodenum may be removed and the GI tract reattached (6). It is successful in its treatment of pain provides pain relief for 65-95% of patients but is also associated with high morbidity and mortality levels (6).

Complications arise in half of these patients. Because of this, some recently developed procedures are being tried, with substantial success, to not disrupt the GI as much as the Whipple procedure (6). MEDICAL NUTRITION THERAPY As some of the pain associated with the secretory mechanisms of the pancreas, following a diet that causes as little stimulation as possible can help manage the pain (2). Medical nutritional therapy also involves replacement of important nutrients lost through poor digestion and malabsorption (4). It was previously considered an acceptable treatment to keep patients NPO in order to stimulate the pancreas as little as possible, (4). However, that recommendation now only remains for milder cases of AP (4). The reason for this is that with the intense inflammatory response stimulated by pancreatitis, nutritional support also needs to address the metabolic needs, such as nitrogen balance, to overcome the inflammation (9). Therefore, the goal of nutritional support for pancreatitis is to provide for the metabolic needs without overstimulating the pancreas (9), and parenteral nutrition should only be maintained long enough to reduce nausea and vomiting (5). Early refeeding, even in severe cases of AP, can improve the outcome if serum lipase can be brought back down to levels no more than three times within the normal range (5). Furthermore, enteral nutrition reduces blood glucose, sepsis, further complications, and overall leads to a shorter hospital stay (5), especially if initiated within 48 hours of admission (4), and does not seem to affect mortality (9). Low-fat or clear liquid diets have appeared to be sufficient in reducing pancreatic stimulations (5), and even a full solid diet as the initial meal can reduce hospital stay for patients with mild AP (10). Some complementary and alternative medicines have been shown to be effective in nutrition intervention. Antioxidants have been shown to help reduce pain in CP patients (6).

Although they do not have a very significant effect, they do reduce oxidative stress, which is a strong activator of CP (6). It is also risk free, and therefore is used at times to at least provide some pain relief (6). Pancreatic enzyme therapy is another alternative treatment. It activates the feedback control to reduce enzyme activity, which in turn decreases pain (6). Enzymes should be administered to the small bowel to decrease CCK release (6). The Cochrane Library suggests that there is evidence that there may be some benefit to using pancreatic enzyme treatment, although more research should be conducted (11). Through the course of 10 trials, a significant reduction of fecal fat was observed, although both the specific enzyme and timing of administration had insignificant outcomes (11). Overall, the benefits of pancreatic enzymes are still debatable and require further research. In CP, the prolonged dysfunction of the pancreas can lead to malabsorption and malnutrition (4). Steatorrhea can be treated with enzymes and lipase supplements (6). However, this has several problems associated with it: lipase supplements are not potent, nor can they survive the gastric acid of the stomach well (6). Larger supplements made to counteract this often take too long and become active too far along the GI tract to do much good (6). The lack of success also leads to difficulty to get patients to comply faithfully with their prescription, but if one appropriately lipase supplementation does show improvement (6). Treatment of diabetes is also important, and it differs from interventions for type 1 or type 2 diabetics. CP patients with diabetes are mainly treated by monitoring urine glucose loss in place of tight control of blood glucose in order to prevent hypoglycemia, due to the fact that glucagon cannot be produced (6) Other nutritional therapy is similar to that of type 1 or 2, and

the same complications, such as neuropathy, retinopathy, nephropathy, should be monitored closely (6). CONCLUSION Despite good adherence to medical and nutritional interventions, complications may be unescapable, but most people with either chronic or acute pancreatitis can have a good prognosis if treatment and nutrition therapy is followed carefully (1).

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