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Updated: 03/13/08 11:26 AM |
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| HOME | HEAL | EDUCATE | RESEARCH | DIRECTORY | OUTREACH |
Authors: G. Leinbach, B.J. Reid, D.R. Saunders, and T.D. Nguyen
Download Chapter ♦ Download Lecture Slides & Notes
Download Chapter ♦ Download Lecture Slides & Notes
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F. Diseases of the Pancreas
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Acute pancreatitis:
Reversible changes
Chronic pancreatitis: Irreversible changes |
Inflammation of the pancreas is called pancreatitis. Because of potentially confusing nomenclature, many international meetings have been convened and it is the current consensus that the distinction between acute and chronic pancreatitis should be based on the reversibility of pancreatic injury rather than on its time course. Acute pancreatitis is defined as being a reversible process once the inciting cause of the pancreatitis is removed whereas chronic pancreatitis implies some irreversible damage.
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1. Acute Pancreatitis
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Causes of pancreatitis:
biliary stones, alcoholism |
Acute pancreatitis is an auto-digestive disease in which pancreatic enzymes are inappropriately activated within the pancreas with resulting digestion of tissue. The exact cause of acute pancreatitis is not well understood, but 2/3 of patients will either have stones in the biliary tract or alcoholism. Of the remaining 1/3, predisposing factors, such as recent surgery near the pancreas or pancreatic trauma, will be found in most. In some cases the cause is idiopathic, i.e., no underlying reason is found. However, the triggering event for this auto-digestive process is unknown. Perhaps in some cases a combination of acinar hypersecretion in the face of blocked pancreatic drainage causes acini to rupture and release activated enzymes which digest pancreatic tissue. For example, stones in the common bile duct may obstruct the pancreatic duct. In other cases, there may be a direct metabolic effect on the pancreas, such as in alcoholism.
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Histology
Importance of ischemia |
A clear histologic picture of the early changes in human pancreatitis is understandably hard to come by, except in experimental animals -- and the exact relation of experimental pancreatitis to the naturally occurring variety is uncertain. In any case the resultant inflammatory changes in the pancreas may vary widely. At one extreme there may be only spotty areas of mild interstitial edema. Variable parenchymatous necrosis involving the ducts, acinar cells, and to a lesser extent the islet cells, may be seen. There may be leukocytic infiltration. In more severe cases, interstitial hemorrhage is seen, along with areas of fat necrosis in the pancreas itself and in the omentum. In patients who die of acute pancreatitis, the gross appearance of the pancreas is a mixture of grey-white areas of necrotic tissue, blue-black areas of hemorrhage, and chalky-white areas of fat necrosis. Ischemia seems to transform mild edematous pancreatitis into a hemorrhagic, necrotic process.
The characteristic clinical finding of acute pancreatic inflammation is steady midline upper abdominal and/or back pain. |
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| Retroperitoneal fluid loss |
Blood or serum often oozes in large quantities (up to 2 liters in hemorrhagic pancreatitis) into the retroperitoneal space or into the peritoneal cavity. Fluid in the abdominal cavity may be aspirated with a needle; and if its amylase content is high this is almost diagnostic of pancreatitis. Retroperitoneal losses may go undetected until shock appears. Inflammation of contiguous loops of small bowel may result in localized or generalized dilatation and paralysis of the bowel. What findings might you expect therefore on physical examination of the abdomen?
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| Remote effects of pancreatic enzymes |
The liberation of digestive enzymes from the pancreas into the neighboring tissues and the blood stream may explain many manifestations of the disease. Lipase released into the pancreas, mesentery and omentum may result in areas of fat necrosis. Hydrolysis of tissue triglycerides results in release of fatty acids which interact with serum calcium to form "soaps" which are deposited throughout the fatty tissue. This may account for acute decreases in serum calcium and occasional tetany (muscle spasms associated with low blood calcium levels) in pancreatitis. Rarely, lipase can be carried by the blood stream to cause fat necrosis and inflammation in the bone marrow, mediastinum, pericardium, joints and skin. This can result in aseptic necrosis of the femur, pericarditis, arthritis and necrotic skin nodules.
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| Serum amylase |
Amylase found circulating in the blood stream under normal conditions is derived principally from the salivary glands, with a smaller contribution from the pancreas. Elevated levels of blood amylase (pancreatic) may be detected early in acute pancreatitis, and if sufficiently high (over 3 times normal), may be diagnostic. However, it is important to remember that such elevated levels of circulating amylase may be seen in a number of other conditions: mumps (combination of increased salivary amylase and associated viral pancreatitis), perforated ulcer (?entry of enzymes into the blood via peritoneal absorption), small bowel obstruction or infarction, acute cholecystitis (mechanism unknown), renal failure (decreased enzyme excretion), salpingitis and ectopic pregnancy (Fallopian tubes synthesize amylase), and opiates administered for any type of pain (increased pancreatic ductal pressure). Furthermore, there may be moderate elevations of serum amylase associated with non-pancreatic abdominal pain. Such cases can be confused with mild attacks of pancreatitis. In some of these conditions the total serum amylase may be elevated to levels identical with those obtained in acute pancreatitis. Such confusion may be overcome by measuring serum lipase.
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| Autodigestion |
Trypsin has been postulated to be the primary auto-digestive enzyme in pancreatic inflammation, but it is likely that all pancreatic enzymes contribute to the severe destruction and hemorrhage which may be seen in the gland. For example, elastase can digest blood vessel walls.
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| Liquefactive necrosis -early: pancreatic necrosis -late: pseudocysts -secondary infection: abscess |
In pancreatitis, autodigestion leads to edema and liquefactive necrosis as pancreatic enzymes seep into the parenchyma, and, sometimes, into adjacent tissue planes. Early in the course, these areas of necrosis (previously known as phlegmons) are identified on computed tomographic (CT) imaging as areas without discrete borders, less dense and less perfused than normal pancreatic parenchyma. Patients who, genetically, have a reduced ability to combat inflammation-induced oxidative stress seem to be more likely to progress from mild to severe pancreatitis.
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cytokines |
Necrosis is an important factor in the severity of the acute pancreatitis episode because it is associated with multisystem organ failure (shock, pulmonary insufficiency, renal failure, disseminated intravascular coagulation, and gastrointestinal bleeding), and because the necrotic area can become secondarily infected. While the hypotension may be partially explained by the intravascular depletion associated with fluid loss into the peritoneal cavity or retroperitoneal space, the multisystem organ failure appears to be mediated by different cytokines and chemokines, such as IL-1, IL-6, IL-8, and tumor necrosis factor, which are released into the circulation by the injured pancreas and the associated monocytes and macrophages. Secondary infection of the necrotic areas results mainly from bacterial translocation from the gut lumen. Overall, the mortality from interstitial edematous pancreatitis is < 2%, with necrosis, it raises to 10%, while with infected necrosis, it is further increased to 30%. Later on, as these necrotic areas become homogenously liquefied and acquire distinct boundaries of connective tissue and surviving parenchyma, they are called pseudocysts because they are not lined by epithelium which is a characteristic of a true cyst. These areas may also become secondarily infected, and become abscesses.
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| Treatment and management |
Here is the rationale for the time-honored treatment for a patient with severe, acute pancreatitis which takes into consideration the following data obtained from patients with a cannulated pancreatic duct:
Critics of the time-honored plan of “putting the inflamed pancreas to rest” might ask if the damaged pancreas were able to respond to secretory stimuli. A patient with acute pancreatitis should continue to fast if eating worsens abdominal (pancreatic) pain. The most important immediate initiatives are to support the systemic blood circulation, and to ameliorate pain. |
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Figure 6 An Outline of Possible Sequelae of Acute Pancreatitis |
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2. Chronic Pancreatitis and Insufficiency
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| Pancreatic calcification |
Although alcoholism is the most common cause of chronic pancreatitis, it is mysterious why only a minority of chronic alcoholics develop pancreatic disease. The association of CFTR mutations with alcoholic pancreatitis is still uncertain. Alcohol increases the permeability of the intestinal epithelium so bacterial lipopolysaceharides may be factors. Metabolites of ethanol (acetaldehyde, ethalesters of fatty acids, reactive oxygen species) have ill-effects on pancreatic acinar cells. Acetaldehyde may activate pancreatic stellate cells (similar to hepatic stellate cells) to elaborate collagen in extra cellular spaces.
Recurrent attacks of pancreatic inflammation may lead to variable degrees of focal or diffuse destruction of acinar cells, islets and ducts along with lymphocytic and plasma cell infiltration and scarring. Dilated ducts secondary to multiple stenoses commonly occur. Calcium may be deposited both within the ducts as stones and within the parenchyma in areas of fat necrosis. Such calcium deposition may be seen on abdominal X-ray films, either as focal collections of calcium, or as a diffuse stippled density outlining the pancreas. This process is known as chronic calcific pancreatitis. In some cases this designation is a misnomer because there may be no inflammation. All that may be present is a gland which is carved up by bands of connective tissue. Patients who have the histologic features of chronic pancreatitis may be asymptomatic or may suffer from recurrent inflammatory attacks. Would the serum and urinary amylase be elevated during such attacks? Why? Other patients may suffer from chronic pain from an obstructed pancreatic duct or pseudocyst, or to ongoing inflammation of peripancreatic nerves. |
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| Endocrine and exocrine insufficiency |
Some patients develop so much glandular destruction that endocrine and exocrine secretions become insufficient to meet the daily demands of carbohydrate metabolism and food digestion. Such patients are said to have "chronic pancreatitis with pancreatic insufficiency". These patients may or may not have pain. Endocrine insufficiency results in diabetes mellitus because of inadequate insulin production and the glycemic state is often fragile because the coexisting deficiency of pancreatic glucagon aggravates hypoglycemic states. Exocrine insufficiency occurs when approximately 80% of the functioning pancreas is destroyed. Impaired digestion of carbohydrates, proteins, and fats diminishes absorption of food and weight loss is frequent. An excessive amount of unabsorbed fat appears in the stool (steatorrhea), and often leads to bulky, frequent, foul-smelling, light-colored stools which may be greasy and have a characteristic odor of rancid fat.
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| Steatorrhea |
In steatorrhea the stool always shows an excessive number of fat globules when stained with lipophilic dyes and examined microscopically. Small fatty droplets are often present normally, and thus, this finding is not always diagnostic. A quantitative estimate of steatorrhea demands a chemical fat analysis of stools collected in a standardized manner. Direct studies of pancreatic function such as the secretin test show marked reduction in volume and concentration of bicarbonate in all patients who have had sufficient destruction of the pancreas to develop exocrine insufficiency with steatorrhea.
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| Treatment |
The treatment of chronic pancreatic exocrine insufficiency is by giving oral pancreatic enzymes with each meal. If necessary, deficient insulin secretion can be replaced with the use of insulin injections. Thus, diabetes can be controlled and malabsorption can be reduced. Occasionally, however, patients with proven pancreatic insufficiency fail to respond to pancreatic enzyme replacement given with meals. Why? How might you approach this problem?
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| Investigation |
As noted above, some patients with chronic pancreatitis suffer severe pain. This may be uncontrollable by medical measures and may occasionally result in addiction to the pain-relieving narcotics prescribed by the physician. Such patients sometimes require one or more operations designed to decrease their pain. What sort of operative procedures might you consider, should you be the surgical consultant on such a case? An endoscopic procedure, endoscopic retrograde cholangiopancreatography (ERCP), can visualize the ductal system and confirm the presence of a potentially correctable abnormality such as localized resectable disease. ERCP is done by passing an endoscope to the papilla of Vater, inserting a catheter through the endoscope into the papilla, and injecting radio-opaque contrast material through the catheter and into the pancreatic and common bile ducts. The ducts can then be visualized radiographically. ERCP may be useful in determining whether a surgically correctable lesion (obstructed pancreatic duct) is present in either patients with chronic pain or in those having recurrent acute attacks of pain.
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3. Carcinoma of the Pancreas
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Carcinoma of the pancreas is increasingly prevalent and is now the fourth most common cause of death in the United States. (After cancers of the lung, colon, and breast.) It usually occurs in patients over 50 years of age, and patients with alcoholic chronic pancreatitis have fifteen fold increased risk of pancreatic carcinoma compared with non-alcoholics. Virtually all pancreatic tumors (other than those of the islet cells) arise from the ductal epithelium, and are most commonly adenocarcinomas growing in a well-differentiated glandular pattern.
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| Steatorrhea and jaundice |
Sixty to 70% of pancreatic cancers involve the head of the pancreas. They may produce pancreatic insufficiency and steatorrhea. How? They may also cause jaundice. How? Carcinoma of the body (20 - 30%) or tail (5 - 10%) of the pancreas, on the other hand, may grow to large size and be widely invasive before being detected, often by virtue of a metastatic lesion in the liver or in the lung.
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| Pain |
Involvement of nerve endings within the pancreas itself gives persistent upper abdominal pain, and involvement of somatic retroperitoneal nerves gives severe back pain. Obstruction of pancreatic and biliary flow can markedly impair digestion of the food with resultant weight loss and steatorrhea.
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| Splenomegaly |
Physical examination of the spleen is of value in diagnosing carcinoma of the pancreas because neoplastic involvement of the splenic vein can cause splenic vein thrombosis and splenomegaly.
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| Diagnosis |
The presence of a mass in the pancreas may be suggested by displacement of the stomach or widening of the duodenal loop upon X-ray examination of these organs after ingesting barium. Such a mass could be a benign cyst or a cancer. Radiographic diagnosis of carcinoma of the pancreas depends primarily upon cross-sectional imaging techniques such as ultrasound and computed tomography, or by Endoscopic ultrasound (EUS). Pancreatic masses larger than 1 2 cm in diameter may be detected in approximately 80 90% of cases. Barium upper GI series and angiography are secondary studies, not frequently used to establish the diagnosis. ERCP can show ductal obstruction suggestive of cancer, but differentiation from benign obstruction caused by pancreatitis may be difficult. Definitive diagnosis of cancer requires recovery of malignant tissue. This is most efficiently done by biopsy guided by EUS, or percutaneously guided by ultrasound or CT. Cytologic demonstration of malignant cells may also be accomplished in pancreatic juice or in an operative biopsy of a metastatic nodule. Direct operative biopsy of the lesion in the pancreas may be hazardous (postoperative fistula or pancreatitis) and still misleading (only fibrous tissue adjacent to the cancer may be sampled). Many surgeons thus prefer to remove a peripancreatic node for histological examination. |
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| Survival |
Pancreatic cancer is extremely difficult to diagnose clinically and usually impossible to treat effectively. Surgical treatment usually involves an extensive resection of the pancreas and surrounding area, and five-year survivals are uncommon. Death usually occurs within 6 to 12 months after the appearance of symptoms.
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4. Cystic Fibrosis (CF)
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| Impaired function of CFTR, a cAMP-activated Cl- channel |
CF is an autosomal recessive disorder. Among people of Northern European origin, approximately 1 in 2,500 live births is affected. It is extremely rare in people of Asian or African origin. The CF gene has been cloned; it encodes a protein, the CF transmembrane conductance regulator (CFTR) which is a chloride channel which also regulates other ion channels. CFTR is expressed in the pancreatic duct epithelial cell and impaired function of this channel leads to decreased bicarbonate secretion. A recent theory postulates that the acid microenvironment in the periacinar regions due to decreased bicarbonate results in the precipitation of GP2, a protein that is excreted by pancreatic acinar cells in conjunction with pancreatic enzymes. These GP2 precipitates result in ductal obstruction. There are now about 900 known mutations of CFTR that result in different types of defects (impaired protein synthesis, impaired protein processing, impaired regulation of the channel, impaired function of the channel, low abundance of the channel). A deletion of a phenylalamine at amino acid position 508 is the most common mutation, accounting for 70% of the alleles in patients with CF; it results in a protein exhibiting both impaired processing and function. Mutations causing impaired protein synthesis or processing are severe mutations that, in the homozygous state, produce pancreatic insufficiency. Milder mutations may not produce pancreatic insufficiency but may be associated with chronic pancreatitis. CF is the major cause of pancreatic insufficiency in children and the majority of adult patients with CF have pancreatic insufficiency. Pancreatic insufficiency in adult CF is becoming more a problem now that 35% of the patients live past the age of 20.
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5. Hereditary Pancreatitis
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| Arginine to histidine mutation in the cationic trypsinogen renders it resistant to catalytic cleavage following auto-activation |
Hereditary pancreatitis (HP) is an autosomal dominant disease with 80% penetrance characterized by recurrent episodes of pancreatitis since childhood and a familial occurrence. The gene for HP has recently been cloned and encodes cationic trypsinogen. Mutations may render this trypsin resistant to catalytic cleavage by trypsin and other proteases. In this manner, when trypsinogen is auto-activated in the pancreatic acinar cell, it can no longer be inactivated by proteases, so that pancreatic autodigestion can result.
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6. Abnormalities of Islet Cells
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Hyperplasia, adenoma, or adenocarcinoma of the beta cells of the islets may cause excessive insulin production and profound hypoglycemia (insulinoma).
Hyperplasia or neoplasia of the non-beta cells of the islets can cause excessive gastrin secretion. The persistent gastrin stimulation causes excessive HC1 and pepsin secretion by parietal and chief cells of the stomach and can lead to severe, unrelenting peptic ulcer disease and diarrhea (Zollinger-Ellison syndrome). An unusual non-beta cell tumor of the islets produces a humoral substance which causes severe diarrhea with marked fluid and electrolyte loss. This hormone has been identified as vasoactive intestinal peptide (VIP). Symptoms are related to water loss and marked hypokalemia (reduction in blood potassium). These patients do not have gastric hypersecretion. VIP, acting via specific receptors on crypt cells of small and large intestines, stimulates cAMP production to activate the CFTR Cl- channel, resulting in marked luminal electrolyte and fluid loss. |
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