Pancreas study notes Normal pancreas - the islands make up about 15% of the organ's weight, and that they are concentrated in the tail - fatty ingrowth is common and this can undergo fat necrosis - the exocrine pancreas has great functional reserve, and no symptoms will occur until 85% or so of the gland is gone - trypsinogen is activated only on caontact with enterokinase, and trypsin in turn activates other enzymes - the embryonic pancreas arises as two buds - the annular pancreas is wrapped around the duodenum, and gets blamed for obstruction - cystic fibrosis causes atrophy and malabsorption of the pancreas Acute Pancreatitis - inflammation of the exocrine pancreas with damage to the acinar cells - one of the most common severe intra-abdominal processes in adults - pancreatits is perpetuated by the release of activated digestive enzymes into the organ and surrounding tissues - chronic pancreatitis is a misnomer for pancreatic insufficiency and/or pain which probably is caused by a previous episode of acute pancreatitis - any injury to the acinar cells will release digestive enzymes and result in extensive damage - what damages the exocrine pancreas? - very heavy drinking - the most important cause of pancreatitis in the U.S. - cholelithiasis - accounts for a large majority of cases of pancreatitis - gallstones are thought to cause pancreatitis by: 1) loding in the common bile duct and blocking the pancreatic duct, producing back pressure which pushes enzymes from the duct back into the interstitium 2) damaging the sphincter of Oddi, allowing backwash of enterokinase and/or cell poisons such as lysolecithin into the pancreas - much less common are trauma, gastric ulcer, viruses, ischemia, vasculitis, drugs, hyperlipidemia, hypercalcemia, following cardiopulmonary bypass, familial, and uremia - pateints present with abdominal and/or back pain, fever, and shock - in the acute process, the pancreas undergoes proteolysis and lipolysis, eventually with hemorrhage - pancreas undergoes fat necrosis - after the acute phase is over, liquified areas may be surrounded by fibrous tissue, producing a pseudocyst; if they become infected while forming, a pancreatic abscess results - the duodenum can become obstructed in pancreatitis - chronic pancreatitis is usually seen in chronic problem drinkers, as a pain syndrome associated with nerve involvement - there is loss of acinar cells, atrophy of the remaining cells, and dense fibrous tissue - also look for calcifications - either calcified fat necrosis or pancreatic caniculi - in the late stages, pts can expect to have malabsorption, and perhaps a pseudocyst - pts may have chronic severe pain from involvement of the sensory nerves around the celiac plexus - chronic obstructive pancreatitis - follows obstruction of the pancreatic duct; there is selective atrophy of acini around the head of the pancreas Non-malignant Masses - pancreatic pseudocysts are common after acute pancreatitis from alcoholism or trauma - benign tumors are umcommon; they are almost always some variant of adenoma Cancer of the Pancreas - accounts for about 5% of U.S. cancer deaths; the incidence has tripled in the past 40 years because of smoking and chemicals - virtually all cancers of the pancreas are adenocarcinomas arising from the ducts - mucin positive - risk factors include smoking (3X) and exposure to chemicals (B-naphthylamine and benzidine) - most cancers of the exocrine pancreas have mutated K-ras at hot-spot codon 12 - 60% in head, 15% in body, 5% in tail, and 20 % too late to tell - pts come in with back pain, jaundice, weight loss, GI upsets, depression, and/or migratory thrombophlebitis - cancers in the head can be detected early because they produce jaundice - Courvoisier's law states that a distended gall bladder in a patient with obstructive jaundice means cancer - these patients have diabetes, and the cause is insulin resistence - adenocarcinoma of the pancreas typically metastasizes to lymphatics, and blood-borne metastases to the liver are typically massive Classifying Diabetes Mellitus and Related Conditions - diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized in its fully expressed clinical form by an absolute or relative insulin deficiency, fasting hyperglycemia, glycosuria, and a striking tendency toward the development of atherosclerosis, microangiopathy, nephropathy, and neuropathy - diabetes mellitus - the pt has signs and/or symptoms, and/or elevated fasting blood sugar - type I diabetes and type II diabetes are sometimes called primary diabetes since they seem to be genetic diseases - secondary diabetes is said to exist when the metabolic disturbances are the result of some other identifiable illness, injury, molecular abnormality, etc. - impaired glucose tolerance - fasting blood sugar is normal, but a glucose tolerance test is abnormal Primary Diabetes Type I - 1 in 300 - a child presents with polyuria, polydipsia, and polyphagia of relatively sudden onset; he has very high blood glucose levels causing osmotic diuresis - the child can look forward to a period of fairly good health while taking insulin - after 10-15 years, infections, blindness, peripheral neuropathy, gangrene of the lower extremities, kidney disease, stroke, and heart disease start taking their toll - death usually comes after about 40 years of MI - the essential lesion in type I diabetes is a severe absolute lack of insulin - type I diabetes is a gentically programmed, chronic autoimmune disease that may be triggered by a virus - genetic factors - siblings of those with type I are at 25X risk - identical twins have 50% chance of getting also - strongly associated with HLA-related antigens DR3 and DR4 - the beta cells of these patients express HLA class II histocompatability antigens - autoimmune factors - several types of IgG and anti-beta cell antibodies occur; one or more is present in up to 85% in the acute phase - one has been identified as anti-glutamic acid decarboxylase - there is also cell-mediated immunity directed against beta cells in most patients who have been studied - some diabetics yield no evidence of autoimmunity - viral factors - type I diabetes often follows a viral illness - it is hypothesized that a viral infection triggers autoimmune destruction of the beta cells in genetically-predisposed individuals - some stress apparently causes decompensation at the time of onset; following recovery from the first episode of ketoacidosis, the honeymoon period begins, when control is easy for several years Primary Type II Diabetes - before the era of injectable insulin, nothing much was done for the type II diabetics, even if the disease was detected; the patients got complications and had shorter life spans - the adult today looks forward to dieting, jogging, and possibly insulin or diabetes pills - complications as in type II will occur, and death probably to an MI - identical twins have nearly 100% concordance - there are no good HLA associations or phenomena pointing to autoimmunity - maturity-onset diabetes of the young appears to be an autosomal dominant with 90% penetrance - another important gene is the insulin receptor substrate, which receives the message from the insulin receptor itself - most type II diabetics have insulin resistence in both liver and skeletal muscle, and this appears to be the key lesion. In addition, there is almost always some evidence of beta cell dysfunction - the liver continues to make and put out glucose when blood sugar is high, and fails to take up orally-administered glucose; the skeletal muscles fail to take up glucose in response to insulin - amylin acts on skeletal muscle to increase its resistence to insulin - it has been reported that amylin is greatly increased in type II diabetics - in type II diabetes, basal insulin secretion is generally normal - hyperosmolar nonketotic diabetic coma is the usual cause of diabetic coma in type II diabetics, though most of them never get it - ketoacidosis is uncommon in type II diabetics, but can occur Secondary Diabetes - pancreatic diabetes - destruction of the islets by disease of the pancreas - causes - pancreatitis, carcinoma, hemochromatosis, trauma, surgery - endocrine diabetes - glucose intolerance due to other endocrine disturbances - causes - Cushing's, acromegaly, amylin from pancreatic cancer, obesity, stress, etc. - regardless of the cause of the prolonged hyperglycemia, we now know that the complications in remote organs will be the same Diabetic Blood Vessel Disease - large vessel disease - accelerated atherosclerosis - nonenzymatic glycosylation of lipoproteins seems to be a problem, LDL's stick best to glycosylated collagen, and the disease damages the intima of the arteries in some unidentified manner - the result is the rapid development of atherosclerosis, with stroke, gangrene of the lower extremity, and MI - small vessel disease - arteriolar sclerosis - the basement membranes of the capillaries and the arterioles becomes much thicker, it's expansion eventually compromises the lumen of the vessels - even if the lumen is not compromised, the small vessels of diabetics open and close chaotically, and proper tissue perfusion cannot be assured - the pericytes can proliferate or die off - microangiopathy augments the ischemia caused by atherosclerosis, which is why so many diabetics lose legs - most diabetics eventually become hypertensive Diabetic Kidney Disease (diabetic neuropathy) - renal failure causes much disability and death among type I diabetics; this is now the #1 single cause of end-stage renal disease in the U.S.; type II diabetics generally die off before their kidneys fail - renal vascular lesions - arteriolar sclerosis of both afferent and efferent arterioles at the glomerular pole is highly characteristic of diabetes - glomerular lesions - always present: thickening of glomerular basement membrane because of increased production of GBM - often present - nodular glomerulosclerosis or Kimmelstiel-Wilson disease; big balls of GBM-mesangial matrix material in the glomerular tufts - clinically, the patients have albuminuria, then renal failure - other renal lesions in diabetes include kidney infections and renal papillary necrosis Eyes - diabetes is the commonest cause of blindness before old age in the U.S. - a variety of cataracts; glaucoma is becoming more common - diabetic retinopathy is the most serious eye problem - nonproliferative phase - edema, exudates, hemorrhages, microinfarcts - proliferative phase - new vessels grow, eventually invading the vitreous humor, with hemorrhage, granulation tissue, fibrosis, and retinal detachment Peripheral nerves - manifests as symmetrical sensory loss and as autonomic dusturbances such as diarrhea, bladder problems, orthostatic hypotension, and impotence - axons are lost and Schwann cells take a beating - increased availability of glucose for polyol pathway results in more sorbitol Pancreatic Islets - except when the islands are actually destroyed, the relationship of morphologic lesions to the abnormal metabolic state is usually obscure - in type I, early cases show lymphocytic infiltration; later cases show destruction of beta cells and even whole islets - in type II, the islets most often look normal - in either type, there may be hyalinization of the islets with collagen and/or amyloid - amyloid-laden islets seems to be the result of chronic over-stimulation of beta-cells - babies of diabetic mothers have hyperplastic islets which are infiltrated with lymphocytes Other Problems for Diabetics - infections - bacterial and fungal - gallstones - altered platelet function - complications of pregnancies - all of the common problems are more common, and the babies are bigger - chronic hyperglycemia results in non-enzymatic glycosylation of many body proteins - hemoglobin A1c is glycosylated hemoglobin which can be measured in the blood to assess the quality of diabetic control Hypoglycemia - hypoglycemic coma - when pts come to ER in coma, you'll give them 50 gm glucose by vein after you do the blood work; this brings around the known diabetic who has OD on their insulin, and the undiagnosed type II diabetics who are sick from too much insulin too late - fasting hypoglycemia - rule out beta cell tumor - post-prandial hypoglycemia - seldom serious in non-diabetics - the familiar queezy syndrome probably has nothing to do with refined sugar even when intake exceeds typical dietary levels, neither dietary sucrose nor aspartame affects children's behavior Pancreatic Islet Cell Tumors - the tumors are usually slow-growing, even when malignant - these tumors make one or more of the following - glucagon, insulin, gastrin, somatostatin, vasoactive intestinal polypeptide, and pancreatic polypeptide - the surrounding pancreatic islets may show hyperplasia - metastatic spread remains the only reliable criterion for malignancy in these tumors - beta cell tumors - most common islet cell tumor - look for Whipple's triad 1) low measured plasma glucose 2) mental changes, especially related to fasting or exercise 3) attacks relieved by glucose administration - of the beta cell tumor patients, 70% have a solitary adenoma, while the rest have either hyperplasia of many islands, or a beta cell carcinoma - Zollinger-Ellison syndrome - an especially troublesome syndrome of multiple bleeding ulcers and diarrhea - the majority of gastrinomas are low-grade malignancies - high basal acid secretion plus a marked increase in serum gastrin levels in response to secretin administration strongly suggests gastrinoma - removal of all of the tumor is curative - patients respond well to B2 blockers - alpha-two cell tumors - these produce mild diabetes, sore tongue, and necrolytic migratory erythema - multiple endocrine neoplasia syndromes - some or all of the following in the same family - Wermer's MEN I - pituitary adenoma, parathyroid adenoma, Zollinger-Ellison - Sipple's MEN II(a) - parathyroid adenoma, pheochromocytoma, medullary carcinoma of the thyroid - MEN IIb/III - medullary carcinoma of the thyroid, pheochromocytoma, mucosal neuromas, Marfinoid habitus -