IUHS Student-2-Student USMLE Step 1 Recall

                                                    Pancreas

Acute Pancreatitis

acute pancreatitis is characterized by the acute onset of abdominal pain resulting from enzymatic necrosis and inflammation of the pancreas...

 about 80% of cases are associated with two conditions: biliary tract disease and alcoholism...

gallstones are present in about 35-60% of cases of pancreatitis, and about 5% of patients with gallstones develop pancreatitis...

 The enzymes released from the pancreas with acute pancreatitis damage the surrounding fat and form soaps -- localized soft tan to yellow areas of

enzymatic fat necrosis...

liquefactive necrosis of pancreatic parenchyma...

associated with mumps, coxsackieviruses, and mycoplasma pneumoniae...

the morphology of acute pancreatitis stems directly from the action of activated pancreatic enzymes that are released into the pancreatic substance...

the basic alterations are microvascular leakage, to cause edema, necrosis of fat by lipolytic enzymes, and acute inflammatory reaction, proteolytic destruction of pancreatic substance, and destruction of blood vessels with subsequent interstitial hemorrhage...

 the extent and predominance of each of these alterations depend on the duration and severity of the process...

 in the milder form, acute interstitial pancreatitis, histologic alterations are limited to interstitial edema and focal areas of fat necrosis in the pancreatic substance and peripancreatic fat...fat necrosis, as we have seen results from enzymatic destruction of fat cells...the released fatty acids combine with calcium to form insoluble salts that precipitate in situ...

 in the more severe form, acute necrotitzing pancreatitis, necrosis of pancreatic tissue affects acinar and ductal tissues as well as the islets of langerhans...there may be sufficient damage to the vasculature to cause hemorrhage into the parenchyma of the pancreas...macroscopically, the pancreatic substance exhibits areas of blue black hemorrhage interspersed with foci of yellow white, chalky fat necrosis...

the anatomic changes of acute pancreatitis strongly suggest autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes...as is well known, pancreatic enzymes are present in the acini in the proenzyme form and have to be activated to fulfill their enzymatic potential...

among many possible activators, a major role is attributed to trypsin, which itself is synthesized as the proenzyme trypsinogen...once trypsin is generated, it can in turn activate other proenzymes such as prophospholipase and proelastase, which then take part in the process of autodigestion...the activated enzymes so generated cause disintergration of fat cells and damage the elastic fibers of blood vessels...

trypsin also converts prekallikrein to its activated form, thus bringing into play the kinin system, and by activation of hageman factor the clotting and complement systems as well...in this way, the inflammation and small vessel thromboses (which may lead to congestion and rupture of already weakened vessels) are amplified...

thus, activation of trypsinogen is an important triggering event in acute pancreatitis...

(1) Pancreatic duct obstruction...ragardless of whether the common bile duct and pancreatic duct share a  common channel or separate channels, impaction of a gallstone in the region of the ampulla of vater raises intrapancreatic ductal pressure...backage to ductal flow favors the accumulation of an enzyme rich interstitial fluid...this causes local fat necrosis, as lipase is already active...resident tissue leukocytes are stimulated to release proinflammatory cytokines, initiating local inflammation and promoting the development of interstitial edema through a leaky microvasculature...edema compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells...

(2) Primary acinar cell injury...this mechanism is most clearly involved in the pathogenesis of acute pancreatitis caused by certian viruses (mumps), drugs, and direct trauma to the pancreas, as well as that following the ischemia of shock...the mechanisms by which alcohol promotes acinar cell injury remain unclear...

(3) Defective intracellular transport of proenzymes within acinar cells...aberrant acinar cell packaging of digestive enzymes has been shown to occur both when there is pancreatic duct obstruction or exposure to alcohol, and in experimental animal models of metabolic pancreatic injury...in normal acinar cells, digestive enzymes and the lysosomal hydrolases are transported in separate pathways after being synthesized in the endoplasmic reticulum and packaged in the golgi apparatus...the digestive enzymes make their way through zymogen granules to the apical cell surface, while lysosomal hydrolases are transported into the lysosomes...when acinar cells are injured, the pancreatic proenzymes are delivered to an intracellular compartment containing lysosomal hydrolases, thereby permitting proenzyme activation, rupture of the lysosomes, and local release of activated enzymes...

abdominal pain is the cardinal manifestation of acute pancreatitis...its severity varies from mild and uncomfortable to severe and incapacitating...suspected acute pancreatitis is primarily diagnosed by the presence of elevated plasma levels of amylase and lipase, and exclusion of other caues of abdominal pain...

lipase is more specific...

full blown acute pancreatitis is a medical emergency of the first magnitude...these patients usually have the sudden calamitous onset of an acute abdomen that must be differentiated from diseases such as ruptured acute appendicitis, perforated peptid ulcer, acute cholecystitis with rupture, an occlusion of mesenteric vessels with infarction of the bowel...the pain is usually constant and intense and is often referred to the upper back...

explanations for the rapid development of shock include loss of blood volume and electrolyte disturbances, endotoxemia, and release of cytokines and vasoactive agents such as bradykinin, prostaglandins, nitric oxide (NO), and platelet activating factor...laboratory findings include marked elevation of serum amylase and lipase levels during the first 24 hours, followed within 72-96 hours by a rising serum lipase level...glycosuria occurs in 10% of cases...hypercalcemia may result from precepitation of calcium soaps in the fat necrosis; if persistent, it is a poor prognostic sign...direct visualization of the enlarged inflamed pancreas by radiographic means is useful in the diagnosis of pancreatitis...

Chronic Pancreatitis

chronic pancreatitis is a diseae characterized by repeated bouts of mild to moderate pancreatic inflammation, with continued loss of pancreatic parenchyma and replacement by fibrous tissue...the chief distinction between acute and chronic pancreatitis is whether the pancreas is normal before a symptomatic attack or already chronically damaged...this distinction may be impossible to apply in clinical settings...

the disease is protean in its manifestations and most frequently affects middle aged males, particularly alcoholics...biliary tract disease plays a less important role in chronic pancreatitis than in the acute form of the disease; hypercalcemia and hyperlipoproteinemia also predispose to chronic pancreatitis...in up to 12% of patients, recurrent pancreatitisis associated with pancreas divisum, presumably because of the combination of an anomalous ductal system and stenosis of the duodenal papilla...

(1) Ductal obstruction by concretions...hypersecretion of protein from acinar cells in the absence of increased fluid secretion permits the precipitation of proteins that, when admixed with cellular debris, form ductal plugs...such plugs are observed in all forms of chronic pancreatitis, but in alcoholics these plugs may enlarge to form laminar aggregates (stones) containing calcium carbonate precipitates...

(2) Secreted Proteins...it is proposed that a low molecular weight protein, lithostathine, is elaborated by acinar cells and normally inhibits intraluminal precipitation of calcium carbonates...decreased secretion of this protein would promote precipitation and accretion of intraluminal stones...alternatively, alcohol may cause the secretion of abnormal proteins with decreased solubility...

(3) Oxidative stress...alcohol induced stress may generate free radicals in acinar cells leading to abnormal protein secretion, acinar cell necrosis, inflammation, and fibrosis...

(4) Interstitial fibrosis...it is proposed that acute pancreatitis initiates a sequence of perilobular fibrosis, duct distortion, and altered pancreatic secretion and ductal flow, the necrosis hypothesis...abnormal intrapancreatic lipid metabolites may trigger the development of fibrosis...

chronic pancreatitis is characterized by irregularly distributed fibrosis, reduced number and size of acini with relative sparing of the islets of langerhans, and variable obstruction of pancreatic ducts of all sizes...

it may present as repeated attacks of moderately severe abdominal pain, recurrent attacks of mild pain, or persistent abdominal and back pain...again, the local diseaes may be entirely silent until pancreatic insufficiency and diabetes develop, the latter from associated destruction of islets...

gallstone induced obstruction may be evident as jaundice or elevations in serum levels of alkaline phosphatase...a very helpful finding is visualization of calcifications wihin the pancreas by CT and ultrasonography...weight loss and hypoalbuminemic edema may point toward pancreatic insufficiency...

Pseudocysts of Pancreas

often in the tail of the pancreas...

pseudocysts are localized collections of pancreatic secretions that develop after inflammation of the pancreas...they are to be distinguished from sterile pancreateic abscesses, which involve liquefactive necrosis of severely damaged pancreatic parenchyma...

both entities lack a true epithelial lining, unlike congenital cysts...pseudocysts are by far the more common, and virtually all arise after acute or chronic pancreatitis...traumatic injury to the abdomen may also give rise to pseudocysts...

these cysts are usually solitary and may be situated within the pancreatic substance or immediately adjacent to the pancreas...they are formed by drainage of pancreatic secretions from damaged ducts into interstitial tissue, which becomes walled off by fibrous tissue to form a cystic space...

continued fluid drainage may lead to massive enlargement of the cyst to 5-10cm in diameter...

pseudocysts produce abdominal pain; intestinal hemorrhage and infection with generalized peritonitis are potential complications...however, their usual clinical significance lies in their being discovered as an abdominal mass in a location that strongly suggests a primary malignancy...they are usually unilocular, which assists in distinction from neoplastic cysts, which tend to be multiloculated...

Carcinoma of the Pancreas

carcinoma of the pancreas is now the fifth most frequent cause of death from cancer in the U.S., preceded by lung, colon, breast, and prostate cancers...

currently, 28,000 new patients are identified every year, of whom only 1000 are expected to survive 5 years...

"painless jaundice"...elevation of direct bilirubin along with an elevation in alkaline phosphatase...

Trousseau Syndrome - spontaneous venous thrombosis, which may resolve and recur in other areas (migratory thrombophlebitis), associated with a visceral malignancy...

Carcinoembryonic antigen (CEA)...

the strongest environmental influence is smoking, since incidence rates are several times higher in smokers than in nonsmokers...

other environmental factors have been implicated, including chronic alcohol intake and consumption of a high energy diet rich in fats, but these are not consistent risk factors...pancreatic cancer arises with greater frequency in patients with chronic pancreatitis, but a causal role for pancreatitis is not established, since smoking and alcohol usage in this patient population may underlie the association...

a similar argument applies to the association of diabetes with pancreatic cancer, since diabetes may develop as a consequence of chronic pancreatitis...familial clustering of pancreatic cancer has been reported, but no genetic abnormality has been described..a rare form of pancreatitis, familial relapsing pancreatitis, is significantly associated with pancreatic cancer...

point mutations at codon 12 of K-ras are found in over 90% of pancreatic cancers, and 60-80% exhibit mutations in p53...

K-ras mutations appear to be the early event, as they are detected frequently in patients with chronic pancreatitis...however, they do not seem to impart increased risk for pancreatic cancer in screening studies of patients with pancreatitis...

approximately 60% of cancers of this organ arise in the head of the pancreas, 15% in the body, and 5% in the tail; in 20%  the tumor diffusely involves the entire gland...virtually all of these lesions are adenocarcinomas arising in the ductal epithelium...some may secrete mucin, and many have an abundant fibrous stroma...these desmoplastic lesions therefore present as gritty, gray-white, hard masses...in its early stages, the tumor infiltrates locally and eventually extends into adjacent structures...

with carcinoma of the head of the pancreas, the ampullary region is invaded, obstructing the outflow of bile...ulceration of the tumor into the duodenal mucosa may also occur...as a consequence of common bile duct obstruction, there is marked distention of the biliary tree in about 50% of patients with carcinoma of the head of the pancreas...in marked contrast, carcinomas of the body and tail of the pancreas do not impinge on the biliary tract and hence remain silent for some time...they may be quite large and widely disseminated by the time they are discovered...they extend through the retroperitoneal spaces; impinge on adjacent nerves, and occasionally invade the spleen, adrenal, vertebral column, transverse colon, and stomach...

"painless jaundice"...elevation of direct bilirubin along with an elevation in alkaline phosphatase...

carcinomas in the pancreas remain silent until their extension impinges on some other structure...it is when they erode to the posterior wall of the abdomen and affect nerve fibers that pain appears...pain is usually the first symptom, but by the time pain appears, these cancers are usually beyond cure...

obstructive jaundice is associated with most cases of carcinoma of the head of the pancreas, but it rarely draws attention to the invasive cancer soon enough...weight loss, anorexia, and generalized maliase and weakness tend to be signs of advanced disease...

migratory thrombophlibitis known as the Troussesu sign, occurs in about 10% of patients, attributed to the elaboration of platelet aggregating factors and procoagulants from the tumor or its necrotic products...ironically, Trousseau diagnosed his own fatal disease as cancer of the pancreas when he developed these spontaneously appearing and disappearing thromboses...

the symptomatic course of pancreatic carcinoma is typically brief and progressive...despite the tendency of lesions of the head of the pancreas to obstruct the biliary system, less than 15% of pancreatic tumors overall are resectable at the time of diagnosis..there has long been a search for biochemical tests indicative of their presence...the utility of screening tests for K-ras mutations remains unproven...serum levels of many enzymes and antigens have been found to be elevated...

Hyperinsulinism (Insulinoma)

beta-cell tumors (insulinomas) are the most common of islet cell tumors and may be responsible for the elaboration of sufficient insulin to induce clinically significant hypoglycemia...

95% benign...

there is characteristic clinical triad resulting form these pancreatic lesions:

(1) attacks of hypoglycemia occur with blood glucose levels below 50mg/dl of serum;

(2) the attacks consist principally of such central nervous system manifestations as confusion, stupor, and loss of consciousness; and

(3) the attacks are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral adminstration of glucose...

while up to 80% of islet cell tumors may demonstrate excessive insulin secretion, the hypoglycemia is mild in all but 20% , and many cases never becomes clinically symptomatic...

the critical laboratory findings in insulinomas are high circulaing levels of insulin and a high insulin-glucose ratio...surgical removal of the tumor is usully followed by prompt reversal of the hypoglycemia...

it is important to note that there are many other causes of hypoglycemia besides islet cell tumors...the differential diagnosis of this frequently obscure metabolic abnormality includes such conditions as insulin sensitivity, diffuse liver disease, inherited glycogenoses, and ectopic formation of insulin by certain retroperitoneal fibromas and fibrosarcomas...

C-pepitde is increased....c-peptide is what is cleaved when preproinsulin is converted into insulin...

Whipple's Triad

hypoglycemia, symptoms of hypoglycemia, and relief of these symptoms with glucose intake...

Zollinger-Ellison Syndrome (Gastrinomas)

marked hypersecretion of gastrin usually has its origin in gastrin-producing tumors (gastrinomas), which are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas...

ZE arises from pancreatic G cells...

there has been a lack of agreement regarding the cell of origin for these tumors, save that endocrine cells of both the gut and pancreas can undergo dedifferentiation and express a broad array of gene products...

zollinger and ellison first called attention to the association of pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration...

ulcers are present in 90-95% of patients; the ratio of duodenal to gastric ulcers is 6:1...

gastrinomas may arise in the pancreas, the peripancreatic region, or the wall of the duodenum...

over half of gastrin-producing tumors are locally invasive or have already metastasized at the time of diagnosis...

in some instances, multiple gastrin-producing tumors are encountered in patients who have other endocrine tumors, thus conforming to multiple endocrine neoplasia type I...

as with insulin-secreting tumors of the pancreas, gastrin-producing tumors are histologicallly bland and rarely exhibit marked anaplasia...

ZE arises from pancreatic G cells...

in the classic case of the zollinger-ellison syndrome, hypergastrinoma from an islet cell tumor stimulates extreme gastric acid secretion, which in turn causes peptic ulceration... 

the duodenal and gastric ulcers, sometimes multiple, are identical to those found in the general population; they differ only in their intractability to usual modalities of therapy...

in addition, ulcers may also occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, zollinger ellison syndrome should be considered...

more than 50% of the patients have diarrhea; in 30% it is the presenting symptom...

treatment of the zollinger ellison syndrome involves control of gastric acid secretion by use of H2 blockers and excision of the neoplasm...total resection of the neoplasm, when possible, eliminates the syndrome...patients with hepatic metastases have a significantly shorted life expectancy, with progressive tumor growth leading to liver failure usually within 10 years...

ZE arises from pancreatic G cells...

injection of secretin is the most specific and easiest test for gastrinomas and will display increased serum gastrin due to loss of the negative feedback loop...