The Pancreas

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The Pancreas
G.
Salaru, M.D.
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Congenital anomalies

• Agenesis
• Hypoplasia
• Pancreas divisum
• Annular pancreas
• Ectopic pancreas

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The Pancreas

• Endocrine pancreas
• Diabetes Mellitus (DM)
• Islet Cell Tumors
• Exocrine pancreas
• Acute pancreatitis
• Chronic pancreatitis
• Carcinoma of the pancreas

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Endocrine Pancreas

• 1 million microscopic units the islets of
  Langerhans
• 4 most important cell types of the islets are
• ? (beta) constitute 70 of the cells and contain
  insulin
• A (alpha) 20 of the cells and elaborate
  glucagon
• D (delta) secrets somatostatin which suppresses
  the insulin and glucagon secretion
• PP (pancreatic polypeptide) unknown physiologic
  function

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Diabetes Mellitus

• several syndromes of abnormal carbohydrate
  metabolism hyperglycemia.
• relative or absolute impairment in insulin
  secretion, along with varying degrees of
  peripheral resistance to the action of insulin.
• no distinction between primary and secondary
  causes of diabetes.
• attempt to classify DM according to the etiologic
  differences and to move away from the description
  based on age of onset or type of treatment.

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Etiologic classification of DM

• Type 1 DM Beta-cell destruction that usually
  leads to absolute insulin deficiency
• Immune-mediated
• Idiopathic
• Type 2 DM predominantly insulin-resistant with
  relative insulin deficiency to a predominantly
  secretory defect with insulin resistance
• Gestational DM
• Other specific types

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Other Specific Types

• Genetic defects of beta cell function
• Genetic defects involving insulin action
• Diseases of exocrine pancreas (pancreatitis,
  trauma, neoplasia, CF etc.)
• Endocrinopathies ( Cushings, acromegaly,
  pheochromocytoma, hyperthyroidism etc.)
• Drug-or chemical-induced (glucocorticoids,
  thiazide diuretics, nicotinic acid, pentamidine,
  etc.)
• Infection-related (congenital rubella, CMV, etc.)
• Other genetic syndromes associated with diabetes
  (Turner, Klinefelter, Down, etc.)

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• Although the 2 major types of diabetes have
  different pathogenic mechanisms and metabolic
  characteristics, the long-term complications are
  the major causes of morbidity and death from
  diabetes.
• These complications include
• Coronary heart disease which can lead to heart
  attacks
• Retinopathy which can lead to blindness
• Nephropathy which can lead to kidney failure and
  the need for dialysis
• Neuropathy which can lead to, among other
  complications, foot gangrene requiring
  amputation.

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Incidence of DM

• In the US, more than 15.4 million persons have
  DM, but only 60 of them have been diagnosed.
• The annual mortality rate is about 54,000.
• In 1998, the cost of diabetes to the medical care
  system in the US was 104 billion, a figure that
  has been increasing yearly by 10-12.
• It is the 7th leading cause of death in the US.

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Criteria for the Diagnosis of DM

• Symptoms of diabetes plus a random plasma glucose
  concentration gt200 mg/dL (11.1 mmol/L).
• Fasting plasma glucose concentration gt126 mg/dL
  (7.0 mmol/dL)
• 2-hour plasma glucose concentration gt200 mg/dL (
  11.1 mmol/dL)during an oral glucose tolerance
  test.

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Normal Insulin Metabolism

• Insulin is a peptide hormone composed of 51
  aminoacids that is synthesized, packaged and
  secreted in the pancreatic beta cells.
• The major regulator of insulin secretion is
  glucose which acts both directly and by
  augmenting the action of other insulin
  secretagogues.
• A rise in the blood glucose levels, causes an
  immediate release of insulin, presumably that is
  stored in the beta-cell granules. If the
  secretory stimulus persists, a delayed response
  follows, which involves active synthesis of
  insulin from the beta-cells.
• Other agents, including intestinal hormones and
  certain aminoacids (leucine and arginine), as
  well as sulfonylureas, stimulate insulin release.

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Functions of Insulin

• Insulin is a major anabolic hormone. It is
  necessary for
• Transmembrane transport of glucose and aminoacids
• Glycogen formation in the liver and skeletal
  muscles
• Glucose conversion to triglycerides
• Nucleic acid synthesis
• Protein synthesis
• Its principal metabolic function is to increase
  the rate of glucose transport into certain cells
  in the body. These are the striated muscle cells,
  including myocardial cells, fibroblasts, and fat
  cells, representing collectively about 2/3 of the
  entire bodyweight.

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Pathogenesis of type 1 DM

• This form of diabetes results from a severe,
  absolute lack of insulin caused by a reduction in
  the beta cell mass.
• It usually develops in childhood, becoming
  manifest and severe at puberty.
• Patients depend on insulin for survival.Without
  insulin, they develop serious metabolic
  complications such as acute ketoacidosis and
  coma.
• Ketoacidosis may also be the first manifestation
  of diabetes in young patients.
• Three interlocking mechanisms are responsible for
  the islet cell destruction
• Genetic susceptibility
• Autoimmunity
• Environmental factors

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Genetic susceptibility

• The precise mode of inheritance of the
  susceptibility genes for type 1 DM remains
  unknown.
• 50 concordance rate among monozygotic twins.
• Only 5-10 of the children of first-degree
  relatives with type 1 DM develop the disease.
• Therefore,environmental factors must play an
  important role in this type of diabetes.

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• At least one of the susceptibility genes for type
  1 DM resides in the region that encodes the class
  II antigens of the major histocompatibility
  complex on chromosome 6 (HLA-D)
• About 95 of caucasian patients with type 1 DM
  have either HLA-DR3 or HLA-DR4 alleles or both,
  whereas in the general population the prevalence
  of these antigens is only 40.
• HLA-DR3 5x greater risk of developing diabetes
• HLA-DR4 7x
• HLA-DR3/DR4 14.3x

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Autoimmunity

• A role for autoimmunity in the pathogenesis of
  diabetes is supported by several morphologic,
  clinical, and experimental observations
• Lymphocytic infiltrate (insulitis) in the islets
  in cases of recent onset. Both CD4 and CD8 T
  cells are found within such infiltrates.
  Furthermore, CD4 T cells from diseased animals
  can transfer diabetes to normal animals, thus
  establishing the primacy of T-cell autoimmunity
  in type 1 DM.
• Type 1 DM results from cell-mediated autoimmune
  destruction of the beta cells of the pancreatic
  islets.Circulatory markers of this destruction
  are autoantibodies to insulin, islet cells,
  glutamic acid decarboxylase (GAD), and several
  tyrosine phosphatases.One or more antibodies are
  present in 85-90 of newly diagnosed patients
  with type 1 disease.

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• In experimental animals and humans the insulitis
  is associated with expression of class II major
  hystocompatibility complex (MHC) molecules on
  beta cells.
• Type 1 patients (aprox.10) are prone to other
  autoimmune disorders such as Graves disease,
  Hashimotos thyroiditis, Addisons disease, and
  pernicious anemia.

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Environmental factors

• Although no definite environmental agent has been
  identified, viruses are suspected as initiators
  of the disease.
• The viral infections implicated include
• Mumps
• Measles
• Rubella
• Coxsackie B
• Epstein-Barr (infectious mononucleosis)
• The most likely scenario is that viruses cause
  mild beta cell injury, which is followed by an
  autoimmune reaction against altered beta cells in
  persons with HLA-linked susceptibility.

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Pathogenesis of type 2 DM

• More than 80 of patients with diabetes in the US
  have type 2 disease which has a strong genetic
  base, as concordance rate among monozygotic twins
  is almost 100.
• There are 2 main defects in patients with type 2
  DM
• Insufficient insulin secretion (relative to the
  glucose load)
• Increased insulin resistance(inability of
  peripheral tissues to respond to insulin)
• Obesity increases insulin resistance and about
  80 of patients with type 2 DM are obese (weight
  loss can improve the diabetic condition).
• Most patients with type 2 disease have a relative
  or absolute deficiency of insulin, which is
  milder than that of type 1, and not an early
  feature of this variant of diabetes.

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Pathogenesis of the Complications of Diabetes

• microvascular complications usually appear 10-15
  years after the onset of DM retinopathy,
  nephropathy, and neuropathy.
• The Diabetes Control and Complication Trial
  (DCCT) reported 30-50 decreased risk of
  development of microvascular complications with
  strict diabetic control. NEJM.1993329977.(previo
  usly it was thought that tight control did not
  have much effect on these complications.)
• Most of the available evidence suggests that the
  complications of DM are a consequence of the
  metabolic derangements, especially hyperglycemia.
• 2 mechanisms are considered important
• Nonenzymatic glycosilation
• Intracellular hyperglycemia with disturbance in
  the polyol pathways

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Nonenzymatic Glycosilation

• glucose attaches to the amino group of proteins
  without the aid of enzymes.
• nonenzymatic glycosylation of hemoglobin A (HbA)
  leads to the formation of HbA1c, which normally
  constitutes about 4 of hemoglobin in the red
  blood cells.
• HbA1c level provides an index of the average
  blood glucose level over the preceding 2-4
  months.
• The results of DCCT trial indicate that a HbA1c
  value in the 7.2 8.0 range (blood glucose
  concentration of 155 mg/dL) significantly reduces
  the appearance and progression of microvascular
  complications.

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• excessive glycosylation advanced glycosylation
  products (AGEs)
• serum albumin, collagen, basic myelin protein,
  and low-density lipoproteins (LDLs).
• AGEs attached to collagen in blood vessel walls
  irreversibly cross-link to plasma proteins, e.g.
  LDLs.
• cross-linking retards the normal efflux of LDLs
  that have entered the vessel wall and enhances
  deposition of cholesterol in the intima and
  accelerates the development of atherosclerosis.

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Intracellular Hyperglycemia with Disturbance in
the Polyol Pathways

• In nerves, lens, kidney and blood vessels,
  hyperglycemia leads to increase in intracellular
  glucose (do not require insulin for glucose
  transport)
• polyol pathway - glucose is reduced to sorbitol
  by the enzyme aldol reductase and then fructose.
• Sorbitol tissue toxin,and has been implicated
  in the pathogenesis of diabetic complications.
  Sorbitol decreases phosphoinositide metabolism
  and signal transduction.
• Aldol reductase inhibition also has been shown to
  prevent experimental cataracts and retinopathy.

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• In the past it has been common to attribute
• microvascular complications (retinopathy,
  nephropathy, neuropathy) to the polyol pathway
• macrovascular complications (stroke, gangrene,
  myocardial infarction) to glycation and AGEs.
• However both pathways contribute to both sets of
  complications.

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Metabolic derangements

• Insulin major anabolic hormone glucose, lipid
  and protein metabolism.
• type 1 DM marked deficiency
• stimulation of glycogenolysis, which is normally
  inhibited by insulin and favored by glucagon.
  Fasting blood glucose may reach levels many times
  greater than normal
• exceeds the renal threshold glycosuria
• glycosuria induces an osmotic diuresis and thus
  polyuria, causing a profound loss of water and
  electrolytes.

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• water loss AND hyperosmolarity depleted
  intracellular water in the osmoreceptors of the
  thirst in the brain intense thirst
  (polydipsia).
• Through poorly defined pathways, increased
  appetite (polyphagia) develops, thus completing
  the classic triad of diabetic findings
  polyuria, polydipsia, and polyphagia.
• With a deficiency of insulin, the scales swing
  from insulin-promoted anabolism to catabolism of
  proteins and fat.
• Two important acute metabolic complications of
  diabetes are ketoacidosis, and non-ketotic
  hyperosmolar coma.

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Morphology of Diabetes

• Three important factors in morphologic changes of
  diabetes are
• The duration of the disease
• The adequacy of metabolic control
• Genetic factors

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Basement Membrane Changes

• Thickening of the BM (BMT) is characteristic of
  DM.
• capillaries microangiopathy
• Skin
• skeletal muscle
• Retina
• renal glomeruli
• renal medulla.
• BMT in nonvascular structures - renal tubules,
  Bowmans capsule, peripheral nerves, placenta and
  possibly other sites.
• single layer BM replaced by concentric layers of
  hyaline material (type IV collagen).
• increased thickness BMT but more leaky than
  normal to plasma proteins.

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Anatomic changes in the pancreatic islets

• Type 1 DM
• Islets are small and beta cells are markedly
  decreased in number or are absent
• insulitis - lymphocytic infiltration is highly
  specific for this form of diabetes.
• Type 2 DM
• islet fibrosis and hyalinization (due to
  deposition of amylin) are characteristic but not
  specific.
• Amylin (also known as islet amyloid polypeptide,
  IAPP) is characteristic of type 2 DM and is
  thought to interfere either with the conversion
  of proinsulin to insulin or with sensing of
  insulin by beta cells.

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Circulatory changes

• In the course of 10-15 years of the disease, most
  diabetics develop significant vascular
  abnormalities.
• Atherosclerosis is more extensive and occurs
  earlier than in general population.
• Coronary artery disease (CAD) accounts for more
  than half of deaths in diabetics. Women with
  diabetes have a risk of cardiovascular death that
  is up to 7.5x that of aged-matched nondiabetic
  women. Silent myocardial ischemia is more common
  in diabetic patients than in general population.
• Peripheral deposits may cause intermittent
  claudication, gangrene, and, in men, organic
  impotence on a vascular basis.
• Surgical repair of large-vessel lesions may be
  unsuccessful because of the simultaneous presence
  of widespread disease of the small vessels.

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Presumed Reasons for Accelerated Atherosclerosis

• Elevated blood lipid levels.
• Qualitative changes in the lipoproteins (low
  levels of HDL, while LDL levels are high-normal
  or high). The atherosclerotic lesion appears to
  be initiated by oxidized LDL (not native LDL).
• Increased platelet adhesiveness to the vessel
  wall (enhanced thromboxane A2 synthesis and
  decreased prostacyclin).
• Increased secretion of endothelin-1 and
  diminished production of nitric oxide (in vitro).
• Increased incidence of hypertension in diabetics.

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Kidneys

• The kidneys are prime targets of DM. Renal
  failure is second only to myocardial infarction
  as a cause of death from this disease. About half
  of the cases of end stage renal disease in the US
  are now due to diabetic nephropathy.
• Diffuse glomerulosclerosis, nodular
  glomerulosclerosis (Kimmelstiel-Wilson),
  arteriolosclerosis, exudative lesions such as
  fibrin cap or drops in Bowmans capsule,
  occlusion of the glomeruli are renal
  manifestations of diabetes. Deposition of albumin
  and other proteins occurs in both glomeruli and
  tubules.
• Pyelonephritis is a frequent complication that
  may be compounded by renal papillary necrosis.
• The most specific lesions of diabetic
  glomerulosclerosis are hyalinization of afferent
  glomerular arterioles and the Kimmelstiel-Wilson
  nodules.

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Eyes

• The ocular involvement in diabetes are
• Retinopathy
• Cataract
• Glaucoma
• Diabetic retinopathy (retinal exudates, edema,
  hemorrhages, and microaneurysms of small vessels)
  is the leading cause of new blindness among
  adults. It correlates with duration and control
  of DM.
• Retinopathy begins to occur 3-5 years after
  diagnosis in patients with type 1 DM, and within
  15-20 years of having the disease almost all
  patients have some retinopathy. After 20 years of
  type 2 DM, 50-80 of patients have retinopathy.

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Nervous System

• The central and peripheral nervous systems are
  not spared in diabetes.
• The most frequent pattern of involvement is a
  peripheral, symmetric polyneuropathy of the lower
  extremities, that affects both motor and sensory
  function but particularly the latter (symptomatic
  paraesthesias of pins and needles).
• Other forms include
• Autonomic neuropathy (gastroparesis, erectile
  dysfunction)
• Diabetic mononeuropathy usually affects the
  third and sixth cranial nerves, the peroneal
  nerve (foot drop), and the radial nerve (wrist
  drop)
• Cerebral vascular infarct and hemorrhages
• Degenerative changes of the spinal cord

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Changes in other organs

• Fatty changes of the liver
• Glycogen vacuolation in the nuclei of the hepatic
  cells
• Degenerative changes of striated muscles
• Skin
• Xanthomas (collections of lipid-laden macrophages
  in the dermis)
• Furuncles and abscesses because of increased
  propensity to infection frequent fungal
  infections, especially with Candida albicans

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Type 1 DM - clinical correlation

• Begins by age 20 in most patients
• Signs and symptoms are polyuria, polydipsia,
  polyphagia, weight loss, muscle weakness.
• Ketoacidosis may be the first manifestation in
  young patients with diabetes.
• Plasma insulin is low or absent, and glucagon
  level is increased.
• Blood glucose level is quite sensitive to
  administered exogenous insulin, deviations from
  normal dietary intake, unusual physical activity,
  infection or other forms of stress.Inadequate
  fluid intake or vomiting may rapidly lead to
  significant disturbances in fluid and electrolyte
  balance.
• Thus , these patients are vulnerable on one hand
  to hypoglycemic episodes and on the other hand to
  ketoacidosis.

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Type 2 DM clinical correlation

• Patients are often older (gt40 years) and
  frequently obese.
• The disorder is often part of a complex metabolic
  syndrome (syndrome X), that constitutes a major
  risk for cardiovascular disease. Obesity,
  dyslipidemia, hypertension and clotting
  abnormalities are other components of the
  syndrome.
• May also present with polyuria and polydipsia in
  some cases unexplained weakness or weight loss.
• Very often, however, the diagnosis is made by
  routine blood or urine testing in asymptomatic
  persons.
• The metabolic derangements are usually
  controllable and less severe.
• In the decompensated state they develop
  hyperosmolar nonketotic coma.

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Characteristics DM 1 DM 2
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Characteristics DM1 DM2
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Islet Cell Tumors

• Tumors of the pancreatic islets are rare in
  comparison with tumors of the exocrine pancreas.
• They may be hormonally functional or
  non-functional, single or multiple, benign or
  malignant.
• The most common are
• Insulinoma (beta cell tumor)
• Gastrinoma (Zollinger-Ellison syndrome)
• Glucagonoma (alpha cell tumor)
• Vipoma

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Exocrine Pancreas

• The disorders of the exocrine pancreas are
  relatively common in clinical practice. The three
  most frequent are
• Acute pancreatitis
• Chronic pancreatitis
• Carcinoma of the pancreas

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Acute Pancreatitis

• In acute pancreatits, activation of the
  pancreatic enzymes causes autodigestion of the
  gland.
• abdominal pain
• associated with raised levels of pancreatic
  enzymes (amylase and lipase) in blood and urine.
• It varies in severity from a mild, self-limited
  condition called acute interstitial pancreatitis
  (interstitial edema and inflamation of the
  pancreas) to a severe life-threatening disorder
  referred to as acute hemorrhagic pancreatitis,
  which exhibits extensive hemorrhage into the
  parenchyma of the pancreas.
• About 80 of cases are associated with
  cholelithiasis and alcoholism.

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Pathogenesis

• Features of pancreatitis include tissue
  proteolysis, lipolysis, and hemorrhage, resulting
  from the destructive effect of pancreatic enzymes
  released from acinar cells.
• mechanisms are as follows
• Pancreatic duct obstruction (by gallstones, with
  impaction in the ampulla of Vater and pancreatic
  duct obstruction). An enzyme-rich interstitial
  fluid accumulates, and the tissue leukocytes
  release proinflammatory cytokines, promoting
  local inflammation and edema).
• Primary acinar cell injury (by viruses mumps,
  drugs, trauma, and the ischemia of shock).
• Defective intracellular transport of the
  proenzymes (acinar cell digestive enzymes are
  misdirected toward lysosomes rather than toward
  secretion lysosomal hydrolysis of the proenzymes
  promotes local release of activated enzymes.

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Morphology

• basic pancreatic alterations
• Leakage of the vasculature to cause edema
• Necrosis of regional fat by lipolytic enzymes
• acute inflammatory reaction
• Proteolytic destruction of the pancreatic
  substance
• Destruction of the blood vessels with subsequent
  interstitial hemorrhage

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Clinical features

• medical emergency with acute abdomen, intense
  abdominal pain with upper back radiation,
  peripheral vascular collapse, and shock from
  explosive activation of the systemic inflammatory
  response.
• Death from shock, ARDS, or acute renal failure
• Laboratory marked elevation of the serum
  amylase during the first 24 hours, followed
  within 72-96 hours by a rising serum lipase.
  Hypocalcemia may result from precipitation of
  calcium soaps in the fat necrosis if persistent
  is a poor prognostic sign.
• Common sequela are a sterile pancreatic abscess
  from liquefaction of the tissue and pancreatic
  pseudocyst from aberrant drainage of pancreatic
  secretions.

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acute pancreatitis
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Chronic Pancreatitis

• repeated bouts of mild to moderate pancreatic
  inflammation, with continued loss of pancreatic
  parenchyma and replacement by fibrous tissue.
• more debilitating than life-threatening because
  of progressive loss of pancreatic function.
• alcoholism and biliary tract disease, and less
  commonly hypercalcemia, and hyperlipidemia.
• Morphologic findings
• fibrosis
• reduced number and size of acini
• sparing of the islets of Langerhans
• variable obstruction of pancreatic ducts

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Chronic pancreatitis

• may be silent, or recurrent attacks of pain may
  occur at scattered intervals.
• precipitated by alcohol abuse, overeating, and
  drug use.
• may have mild elevations of serum amylase and
  lipase in the long run the destruction of acinar
  cells precludes such diagnostic clues.
• Late complications include
• Diarrhea (malabsorbtion)
• Steatorrhea
• Diabetes
• Pseudocyst

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Carcinoma of the Pancreas

• Carcinoma of the pancreas refers to carcinoma of
  the exocrine pancreas, almost always arising from
  ductal epithelial cells (adenocarcinoma).
• It is the fourth most common cause of death in
  the US and accounts for 5 of all cancer death.
• Survival rates are 18 at 1 year and only 2 at 5
  years.
• Incidence rates are higher in smokers (2-3 x)
  than in nonsmokers alcohol consumption imposes a
  modestly increased risk.
• 65-80 y/o, MgtF, BgtW.

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Morphology

• Distribution
• Head 60
• Body 15
• Tail 5
• Diffuse or widely spread 20
• small and ill defined or large (8-10 cm), with
  extensive local invasion and regional metastases.
• Microscopically, more or less differentiated
  glandular patterns (adenocarcinoma) arise from
  ductal epithelium, mucous or non-mucous
  secreting.

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Clinical features

• fatigue, anorexia, weight loss, and painless
  jaundice. Pain may develop later in the course.
• local extension or metastases at the time of
  diagnosis.
• With tumors in the head of the pancreas, the
  ampullary region is invaded, obstructing the
  outflow of the bile patients usually die of
  obstructive jaundice and hepatobilliary
  dysfunction while the tumor is still relatively
  small and not widely disseminated.
• In marked contrast, carcinoma of the body and
  tail of the pancreas remain silent for some time
  and may be quite large and widely disseminated by
  the time they are discovered.
• Migratory thrombophlebitis (Trousseau sign) may
  occur, particularly with carcinoma of the body
  and tail.

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Diagnosis of pancreatic adenocarcinoma

• Tumor markers, including carcinoembryonic antigen
  (CEA), CA 19-9, and CA 125, are associated with
  pancreatic cancer but are not accurate enough to
  rule in or rule out a clinical diagnosis.
• CT is the principal diagnostic test, although
  MRI, endoscopic ultrasonography, and ERCP each
  have a role.
• Cytologic and histologic specimens can be
  obtained by ERCP. The aim is to determine if
  curative resection (pancreaticoduodenectomy
  Whipple procedure) is possible.

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• About half of the patients who are deemed to have
  operable disease by imaging studies are found to
  have unresectable tumors at laparatomy.
• In most instances, therapy is palliative, with
  the aim of relieving jaundice, pain, and duodenal
  obstruction. ERCP with billiary stent placement
  relieves jaundice in most patients with
  unresectable tumors.
• Survival is related to functional status and is
  usually 6-12 months.