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Flashcards in Pancreas Path Deck (72):

Exocrine Pancreas

Acute Pancreatitis
Chronic pancreatitis
Pancreatic tumors


Acute pancreatitis

Acute onset of abdominal pain resulting from enzymatic necrosis and inflammation of the pancreas
An acute inflammatory process that spreads to other areas (retroperitoneal)
-E.g., spleen, duodenum, distal portion of CBD, lesser omental sac, pararenal spaces, and diaphragm
Occurs as a spectrum in both duration and severity


Acute pancreatitis etiology

Most cases due to:
Gallstones (biliary tract disease) at end of CBD
As a complication of alcoholism
-These two causes constitute 80% of cases
The remaining cases are evenly divided between idiopathic and miscellaneous:
-Drugs, metabolic causes, infectious agents (common viruses, mycobacteria)
-Trauma is leading cause in kids
Recurrence high if inciting agent not removed


Acute pancreatitis path

Involves activation of zymogens and increased duct permeability
Three proposed pathways
-Pancreatic duct obstruction
-Primary acinar injury
-Defective intracellular transport of proenzymes in acinar cells
Occurs by intra-acinar activation of trypsin from trypsinogen — THE KEY INITIATING EVENT
Trypsin, in turn activates:
-Prothrombin (potential for DIC)
-Complement (anaphylaxins)
-Phospholipases (potential for ARDS)
-Elastases (destroys vesselshemorrhage)
-Kinin system (shock)
-Lipases (fat necrosis)
Necrotic pancreatic tissue becomes infected 40-60% of time
Increased ductal permeability  gland fibrosis and atrophy


Acute pancreatitis clinical features

A steady, burning, midepigastric pain
-Penetrates straight through to the back
-Radiates to the periumbilical area
-Pain is relieved by bending forward
-Pain worsens when patient is supine
-Bowel sounds  (localized ileus)
*Produces cutoff sign on X-ray
Patient may be in shock
Complications in ~25% of cases
-Most occur in 2nd and 3rd weeks
-Pancreatic necrosis (80%)
-Pseudocyst formation
*Lacks a true cystic lining
*Fluid accumulates in a walled-off area
*Often Dx by persistent  amylase > 1 week


Acute Pancreatitis x-ray

normal or localized ileus ("sentinel loop") or "colon cut-off sign" due to spasm of descending colon from inflammation


Acute Pancreatitis complications

Most multifunction complications occur in 1st week
Mortality rate
-As high as 20-25% in kids
-10% in adults ( usually secondary to pancreatic infection and ARDS)


Acute pancreatitis lab

ELEVATION OF SERUM AMYLASE and SERUM LIPASE beginning in 2-12 hours and remaining for 3-5 days
Absolute neutrophilic leukocytosis (L shift)
Elevated transaminases and cholestasis enzymes
CT scan imaging method of choice for Dx


Chronic pancreatitis

It’s a continuing inflammatory disease
It’s irreversible, painful and causes permanent functional loss
-Need to ascertain status of pancreas prior to any episode of panceatitis
70-80% of cases due to alcoholism
-Oxidative stress related
-40-50% of these cases also have alcoholic liver disease
Cystic fibrosis most common cause in kids
Pseudocysts more common than in acute


Chronic pancreatitis 2 types

Chronic calcifying pancreatitis
Chronic obstructive pancreatitis


Chronic calcifying pancreatitis

More common and alcohol associated
Pathogenesis relates to:
-Deposition of fibrillar protein in ducts


Chronic obstructive pancreatitis

Involves obstruction of major ducts and absence of calcification
Tumor and duct stricture most common associations


Chronic Pancreatitis clinical features

Present with intermittent attacks
Persistent mid-epigastric pain and radiation to back
Weight loss secondary to malabsorption
Diabetes mellitus is a late complication (70%)
Predisposes to pancreatic carcinoma
Diagnosis related to triad of:
-Pancreatic calcification
-Diabetes mellitus
50% of patients are dead in 5-12 years


Chronic pancreatitis lab

More likely encountered with functional tests of pancreas
Enzymes usually not elevated unless acute exacerbation
Dystrophic calcification in ULQ on imaging
ERCP (endoscopic retrograde cholangiopancreatography) for use in equivocal diagnoses


Pancreatic tumors

~ 90% involve the pancreatic duct
-Pancreatic adenocarcinoma (see below)
Remaining 10% affect the islet cells
Most common benign tumors are serous and mucinous cystadenomas


Pancreatic adenocarcinoma

The most common exocrine cancer
More common in men
Generally occurs in the 60-80 year olds
Risk factors: age>60, male sex, tobacco use, chronic pancreatitis (9-fold risk), family history of nonpolyposis cancer syndrome
Involve mutations in TP53 suppressor gene of chromosome 17 and the ras oncogene (75%)
Most carcinomas are located in the HEAD of the pancreas (70%) followed by the body and tail


Pancreatic adenocarcinoma lab

inc CA19-9 and CEA may be elevated
-No single marker specific
Minimal elevation of serum amylase and lipase


Pancreatic adenocarcinoma clinical features

Pain in midepigastrum worsens when supine
Weight loss
Jaundice and clay–colored stools
Glucose intolerance
Palpable gallbladder
Surgery only cure (Whipple’s procedure)



29 million people (10% of the population) have diabetes
21 million diagnosed
8 million undiagnosed
2 million new cases / year
7th leading cause of death
-70,000 death certificates listing it as the underlying cause of death
-230,000 death certificates listing diabetes as an underlying or contributing cause of death


DM is not a single disease entity

It is a group of metabolic disorders sharing the common underlying feature of hyperglycemia
Hyperglycemia results from defects in insulin secretion, insulin action, or (usually), both
The chronic hyperglycemia and attendant metabolic dysregulation may be associated with secondary damage to organs, especially, the kidneys, eyes, nerves and blood vessels


Metabolic syndrome

The term metabolic syndrome (previously called “syndrome X”) has been applied to an increasingly common condition wherein abdominal obesity and insulin resistance are accompanied by a constellation of risk factors for cardiovascular disease like abnormal lipid profiles
Persons with metabolic syndrome benefit greatly from changes in their life style, including dietary modification and weight reduction;
a similar benefit is observed in individuals with frank type 2 diabetes


DM classification

Most common and important forms arise from primary disorders in the islet cell insulin signaling system
May be a result of:
1. An absolute deficiency of insulin (Type 1)
2. Inadequate insulin secretion coupled with insulin resistance in the peripheral tissue (Type 2)
Defective or deficient insulin secretory response
-Impaired CHO (glucose ) use

Less common type (MODY) differs in specific genetic defects of -cell function


Primary DM

subclassified into type 1 insulin dependent DM (formerly, IDDM) and type 2 non-insulin dependent DM (formerly, NIDDM)
-Type 1 (previously called juvenile type DM) accounts for ~10% of cases of primary DM
-Type 2 (previously called adult-onset type DM) accounts for most of the remaining cases
-Maturity onset diabetes of the young (MODY)



An AD inherited DM exhibiting defects in insulin secretion due to genetic defects in B-cell function that result in mild hyperglycemia
while the major types of DM have DIFFERENT pathogenic mechanisms, the long term complications are the SAME and are the major causes of morbidity and mortality


Gestational DM

Glucose tolerance that 1st develops in pregnancy
-inc placental size and anti-insulin effect of human placental lactogen have been implicated
-At 24-28 weeks gestation, pregnant women are screened with a 50g 1-hour glucose challenge test
increased morbidity and mortality of the newborn
-Results in macrosomia, respiratory distress syndrome, open neural tube defects, and transposition of the great vessels
35% of these women will develop overt DM in 5-10 years


DM incidence

~108 (1.3X106 in U.S.) have DM
7th leading cause of death in U.S.
Prevalence  with age
-55% of patients are > 50 yo
Lifetime risk is 5-7% for Type 2 and 0.5% for Type 1


Type I path

Severe absolute lack of insulin caused by  -cell mass
Patients absolutely dependent on exogenous insulin
Three interlocking mechanisms for islet cell destruction:
1. Genetic susceptibility
2. Autoimmunity
3. Environmental insult


Type I path 2

Genetic susceptibility linked to specific alleles of Class II MHC
Autoimmunity develops spontaneously or is triggered by an environmental event such as a viral infection
DM appears when sufficient -cells have been destroyed
Occurs most often in people of Northern European ethnicity
Can aggregate in families
-Clinical disease appears abruptly but only after chronic attack of -cells and subsequent loss


Type I environmental factors

Certain geographic areas have higher incidence
Epidemiology suggests a viral implication
-Seasonal trends
-Common viral infections implicated
-Either viral alteration of B-cells or molecular mimicry
-HLA-linked susceptibility



in most cases, it is hypothesized that a viral infection “triggers” autoimmune destruction of the β cells in genetically-predisposed individuals
-Coxsackie B4 virus destroys the β cells of non-obese diabetic mice
*the mouse has lots of autoreactive (but unactivated) T cells
*Coxsackie B4 produces a mild infection of the β cells, and bystander T cells are activated ("bystander activation")
-Coxsackie B4 has been found commonly as a recent infection in kids coming down with diabetes !!


Early T1D Morphologic Changes

In Type 1, following the initial acute inflammation, there will eventually be a reduction in number and size of islets; thus loss of β-cells. Here we see infiltration of an islet by lymphocytes. Later islet will become hyalinized.


Type 2
Two characteristic metabolic defects:

Derangement of insulin secretion by B-cells
Insulin resistance (B response to insulin by peripheral tissues)


Type 2 path

Pathogenesis is enigmatic
No evidence of autoimmune mechanism
Lifestyle plays a role
Genetic factors very important (> Type 1)
-High concordance among identical twins (60-86%)
-Type 2 is not linked to HLA genes
-Results from polymorphisms (a collection of multiple gene defects)
*Each contributes risk modified by environmental factors


Type 2 Derangement of insulin secretion

At risk populations may have a modest hyperinsulinemia
-Hyper-responsiveness of -cells to physiologic elevations of blood sugar
-With onset of disease, pattern of insulin secretion changes:
* Early on, insulin secretion is normal and plasma levels not reduced (derangement in B-cell response)
* Later on, a mild to moderate insulin deficiency develops


Type 2 insulin resistance

Insulin deficiency present late in Type 2, not of sufficient magnitude to explain metabolic disturbance
Dec responsiveness (insulin resistance) is the major factor
-Seen in obesity and pregnancy as well
-Persistent stimulation may exhaust B-cells
*Ultimately modest dec in B-cell mass


Type 2 obesity

An extremely important environmental influence
~ 80% of Type 2 patients are obese (with intrabdominal obesity)
Definite correlation to DM not demonstrated, but nondiabetic obese persons exhibit insulin resistance and hyperinsulinemia
-Only small portion develop DM
-Weight loss can reverse impaired glucose tolerance


Type 2 Amylin

37 amino acid peptide may be involved in pathogenesis of DM
Co-secreted with insulin in response to food ingestion
Eventually acquires amyloid-like characteristics
Not known if a cause or effect of -cell derangement



These patients demonstrate:
Impaired -cell function
Normal weight
Absence of GAD (glutamic acid decarboxylase) Abs (seen in 70-80% of Type 1 DM patients)
Lack peripheral insulin resistance syndrome


DM morbidity

Morbidity of longstanding DM: stems from

Pathologic abnormalities are the result of nonenzymatic glycosylation (NEG) and osmotic damage


In NEG, glucose combines with amino groups in proteins

E.g., glycosylated hemoglobin HbA1c
Form advanced glycosylation end products (AGEs)
1. Trap LDL in blood vessel walls ( atherogenesis)
2. Trap proteins in vessel wall (hyaline arterio-sclerosis)
3. Enhance production of oxidized LDL ( athero-genesis)
4. Stimulate the release of cytokines from monocytes and mesenchymal cells   type IV collagen deposition in basement membranes
5. Increased vessel permeability


DM Osmotic damage

Assumes prominent role in many DM complications
Hyperglycemia in tissues that do not require insulin for glucose transport
-Lens of the eye, nerves, kidneys, blood vessels
-Glucose is converted to sorbitol and fructose
*These are osmotically active and draw water into tissues and cause permanent damage
*Includes: peripheral neuropathy, (Schwann cell destruction), cataract, microanuerysms in diabetic retinopathy (damaged vessel walls secondary to pericyte damage)


Type 1 clinical features

Generally begins by age 20
Dominated by polyuria, polydipsia, polyphagia and ketoacidosis
Derangement in insulin function affects glucose metabolism as well as muscle and fat metabolism
-Glucose assimilation is severely diminished
-Glycogen stores are depleted


Type 1 path

Severe hyperglycemia and glycosuria occur with profound water and electrolyte loss
-Leads to polyuria from osmotic diuresis
Renal water loss and hyperosmolarity lead to polydipsia
Catabolism of proteins and fats lead to polyphagia
-Results in muscles weakness and weight loss in spite of appetite increase
Patients vulnerable to
-Hypoglycemic episodes from insulin Tx


Type 2 clinical features

May also present with polyuria and polydipsia
Patients usually > 40 yo
-Are frequently obese
Metabolic derangements are less severe and easier to manage (than Type 1)
In the decompensated state, hyperosmolar non-ketotic coma can occur
-Results from sustained hyperglycemic diuresis in patients who do not compensate for urinary water loss


Features common to both Type 1 and 2:

Hyaline arteriolosclerosis
-Main cause of vascular disease in DM
-Prominent in diabetic nephropathy and small vessel disease in general
Macrovascular disease is  secondary to increased atherosclerosis
Coronary artery Dz (predisposes to MI)
Peripheral vascular Dz (e.g., gangrene of lower extremities)
Cerebrovascular Dz (atherosclerotic stroke)


Features common to both Type 1 and 2:

The duration and severity of disease are key factors underlying the clinical presentation
Tight control of glucose reduces the onset and severity of the complications related to nephropathy, retinopathy, and neuropathy
Ideal control of glucose is considered:
-Fasting glucose of 100 mg/dL
-Bedtime glucose of 120 mg/dL  20 mg/dL
-A 1 hour postprandial glucose of 140 mg/ dL
-A glycohemoglobin between 6 and 7 %
Studies show a reduction in risk (with tight control) from retinopathy of 63%, neuropathy of 60%, and nephropathy of 54%


Diabetic ketoacidosis (DKA)

Primarily a complication of Type 1 DM (Type 2 produces enough insulin to prevent it)
50% of cases are associated with a medical illness, 20% from omission of insulin, and 30% are idiopathic
Key abnormalities are


Hyperosmolar non-ketotic coma (HNKC)

Primarily seen in Type 2 DM
-Remember there is usually enough insulin to prevent ketogenesis
Severe dehydration occurs
-Hypovolemic shock is common due to loss of hypotonic salt in urine


Features common to both Type 1 and 2:
Late complications

Accelerated atherosclerosis causes
Ischemic injury to organs (DM most common cause of nontraumatic limb amputations)
 incidence of abdominal aortic aneurysms
Acute MI (most common cause of death in DM)
Atherosclerotic strokes


Macrovascular disease

Accelerated development of atherosclerosis.
Leads to MI, cerebrovascular disease, peripheral vascular disease ( gangrene).
MI is the most common cause of death in diabetics.


Diabetic nephropathy

In general, microalbuminuria is the initial manifestation
Three lesions:
-Glomerular lesions
-Renal vascular lesions
ACE inhibitors used in TX
More common in Type 1
Accounts for most cases of end-stage renal Dz in U.S.



DM associated blindness leading type in U.S.
Non-proliferative stage (microaneurysms)
Proliferative with further progression
-Blood vessel proliferation around disk
-Soft and hard exudates (infarcts and increased vessel permeability
Potential for retinal detachment and blindness
Cataracts common (glucose alters refractive index)
hemorrhagic foci


Diabetic retinopathy classification

Diabetic retinopathy is classified on a spectrum from nonproliferative to proliferative depending on the extent of retinal changes and the degree of microvascular growth. In advanced disease, progressive hemorrhage obscures a patient's visual fields, leading to vision loss. The image shown is an example of what a patient with advanced diabetic retinopathy may see when looking at a scene of 2 young children.



Distal symmetric polyneuropathy
-Result of osmotic damage to Schwann cells affecting sensory and motor nerves
-most common cause of peripheral neuropathy in U.S.


Diabetic Neuropathy

symmetrical peripheral neuropathy most common type
usually sensory nerves involved
“stocking-glove” distribution pattern
Can lead to loss of sensation, abnormal sensations such as burning or tingling, or a combination of both.


Other neurologic abnormalities relate to autonomic abnormalities

Cardiac arrythmias (bradycardia, tachycardia)
Insensitivity to chest pain (silent MIs)
Gastroparesis (slow emptying of the stomach)
Male impotence (erectile dysfunction)
Pressure ulcers


Neuropathic ulcer

Etiology: peripheral sensory neuropathy, trauma, & deformity
ischemia, callus formation, edema
The diabetic foot ulcer shown is the result of longstanding peripheral neuropathy, one of the major microvascular complications of diabetes mellitus.


Increased susceptibility to infection due to

Impaired leukocyte function (chemotaxis, phagocytosis, cell killing)
Poor blood supply
Increased tissue glucose


Two unusual relationships with DM

Mucormycosis of the frontal sinuses ( frontal lobe brain abscesses)
Malignant external otitis (Pseudomonas aeruginosa)



The last photo shows bilateral BKAs (below the knee amputations). The yellowish, tree bark-looking areas of the legs show stasis dermatitis which occurs when there is blood pooling and insufficient return of the blood in the legs to the heart. There are also several necrotic ulcers (gangrene) present, including on the heels and plantar surfaces, which means the arteries bringing blood to the leg are compromised (by atherosclerosis) as well (peripheral vascular disease, PVD). This patient is fairly young but has an extensive history of long-standing uncontrolled diabetes.


In a non-pregnant adult, a diagnosis of diabetes mellitus can be made with

A single random glucose >200mg/dL in a patient with classic signs and symptoms of hyperglycemia
Hemoglobin A1c ≥ 6.5%
A fasting glucose ≥126mg/dL or greater occasion (normal is



Impaired glucose tolerance (IGT) is defined as a 2-h plasma glucose 140-199 mg/dL or above during a 75 g OGTT
Impaired fasting glucose (IFG) is defined more recently as a fasting plasma glucose 100-125 mg/dL or more
Hemoglobin A1c between 5.7 and 6.4%


Criteria for diagnosis of dm

blood glucose values are normally maintained in a very narrow range (usually 70-120 mg/dL)
the diagnosis of diabetes is established by noting elevation of blood glucose by any one of four criteria*:
1. A1C > 6.5% mg/dL
2. a fasting plasma glucose (FPG)  126 mg/dL
3. 2-hour plasma glucose (PG)  200 mg/dL during an oral
glucose tolerance test (OGTT)
4. a random (“casual”) plasma glucose (PG)  200 mg/dL,
in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis


Cystic fibrosis (CF) or mucoviscidosis

Probably most important of the pediatric genetic disorders
Autosomal recessive disease affecting 1:2500 live Caucasian births in the U.S.
-1 in 20 people in the U.S. is an unaffected carrier
Most common genetic disease in whites
-3% of white population in U.S. is a carrier
-Uncommon in blacks and Asians
A fundamentally widespread disorder of epithelial transport affecting fluid secretion in:
-Exocrine glands
-Epithelial lining of the respiratory, GI, and reproductive tracts


CF primary abnormalities

Recurrent pulmonary infections
Pancreatic insufficiency
Malnutrition and failure to thrive
Manifestations may appear anytime from prior to birth to late in childhood and adolescence


CF path

Fundamental defect in transport of chloride ions through certain epithelial cells
-In sweat glands:
Sodium and chloride ions are not reabsorbed from lumen
Na and Cl are lost in sweat (sweat test)


CF in respiratory epithelium:

Cl- not secreted into the lumen
Na+ and water are reabsorbed from lumen
Results in thick secretions
Interferes with mucocilliary action of the epithelial cells


CF clinical features

Leads to abnormally viscid (thick) secretions
-Obstruct organ passages resulting in most clinical features
-I.e., recurrent pulmonary infections  chronic lung disease, pancreatic insufficiency, steatorrhea, etc.


CF in GI tract

Pancreatic abnormalities occur in 90% of cases
-Secretions obstruct ducts
Obstructed ducts lead to dilation and atrophy of exocrine glands
-Leads to malabsorption (especially fats)
-Diabetes mellitus from islet cell destruction
*Late manifestation
*Rarely associated with ketoacidosis
In newborns, meconium ileus with obstructions
-Earliest manifestation
-Virtually pathognomonic
In adults, partial bowel obstruction called meconium ileus equivalent
Cholestasis enzymes commonly elevated
Cholesterol gallstones commonly present


CF In pulmonary system

Progressive respiratory failure most common cause of death
Airway obstruction
Recurrent pneumonias
Cor pulmonale
Chronic sinusitis and nasal polyps


CF In reproductive system

Sterility in males in 95% of cases
-Due to atresia of vas deferens
-Absence of seminal vesicles
-Frequently abnormal sperm
Females can bear children, but reduced frequency of pregnancy
Life expectancy is ~30 years


CF Diagnostic testing

Sweat chloride is the GOLD STANDARD:
Usually done by pilocarpine iontophoresis
Sweat chloride >60mEq/L is diagnostic for CF
Becomes (+) between 3-5 weeks of age
False positive results occur with congenital adrenal hyperplasia and other salt wasting diseases