Path - Endocrine Pancreas Flashcards
major linkage to MHC class II genes, also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs
Type 1 DM
- no HLA linkage
- linkage to candidate diabetogenic and obesity-related genes
Type 2 DM
when is reduction in the number and size of pancreatic islets seen?
most often in T1DM
- particularly with rapidly advancing disease
- most of the islets are small and inconspicuous
when would you see leukocytic infiltrates in the islets (insulitis)?
T!DM
- distribution of insulitis may be strikingly uneven in infants who fail to survive the immediate postnatal period
when would you see a subtle reduction in islet cell mass?
T2DM
when would you see amyloid deposition within islets?
T2DM
- begins in and around capillaries and between cells
- at advanced stages, the islets may be virtually obliterated
- fibrosis may also be observed
- similar lesions may be found in older nondiabetics, as part of normal aging
when would you see an increase in the number and size of islets?
nondiabetic newborns of diabetic mothers
- fetal islets undergo hyperplasia in response to maternal hyperglycemia
what is widespread in diabetes, as a consequence of the deleterious effects of persistent hyperglycemia and insulin resistance on the vascular compartment?
endothelial dysfunction
what is the hallmark of diabetic macrovascular disease?
accelerated atherosclerosis involving the aorta and large/medium sized arteries
- is indistinguishable from nondiabetic atherosclerosis, but is greater severity and earlier onset
what is the most common cause of death in diabetics?
mycardial infarction caused by atherosclerosis of the coronary arteries
what is approx 100x more common in diabetics than the general population?
gangrene of the lower extremities
the larger renal arteries are subject to severe atherosclerosis in a diabetic patient, but where is the most damaging effect of diabetes on the kidneys exerted?
at the level of the glomeruli and the microcirculation
vascular lesion associated with hypertension
- is both more prevalent and more severe in diabetics than in nondiabetics, but is not specific for diabetes and may be seen in older nondiabetics
hyaline arteriosclerosis
- it takes the form of an amorphous hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen
what is one of the most consistent morphologic features of diabetes?
diffuse thickening of basement membranes
- the thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla
- can also be seen in nonvascular structures like renal tubules, the Bowman capsule, peripheral nerves, and placenta
despite the increase in thickness of basement membrane, diabetic capillaries are what?
more leaky than normal to plasma proteins
- the microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy
what are the three lesions encountered in diabetic nephropathy?
- glomerular lesions
- renal vascular lesions, principally arteriosclerosis
- pyelonephritis
what are the most important glomerular lesions in diabetic nephropathy?
capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis
what occurs in virtually all cases of diabetic nephropathy and is part and parcel of the diabetic microangiopathy?
capillary basement membrane thickening
- widespread thickening of the GBM
- can only be detected by electron microscopy
- begins as early as 2 years after the onset of T1DM and by 5 years increases to 30%
- thickening continues progressively and usually concurrently with mesangial widening
- simultaneously there is thickening of the tubular basement membranes
this lesion consists of diffuse increase in mesangial matrix
- there can be mild proliferation of mesangial cells early in the disease process, but cell proliferation is not a prominent part of this injury
- mesangial increase is typically associated with the overall thickening of the GBM
- matrix depositions are PAS-positive
- as the disease progresses, the expansion of mesangial areas can extend to nodular configurations -> correlates with deteriorating renal function
diffuse mesangial sclerosis
these glomerular lesions take the form of ovoid or spherical, often laminated nodules of matrix situated in the periphery of the glomerulus
- PAS-positive
- they lie within the mesangial core of the glomerular lobules and can be surrounded by patent peripheral capillary loops, or loops that are markedly dilated
- the nodules often show features of mesangiolysis with fraying of the mesangial/capillary lumen interface
nodular glomerulosclerosis, aka intercapillary glomerulosclerosis, aka Kimmelstiel-Wilson disease
- as the disease advances, the individual nodules enlarge and may eventually compress and engulf capillaries, obliterating the glomerular tuft
- nodular lesions are frequently accompanied by prominent accumlations of hyaline material in capillary loops (fibrin caps)
what do approximately 15% to 30% of individuals with long-term diabetes develop?
nodular glomerular sclerosis
- in most instances it is associated with renal failure
these lesions constitute part of the macrovascular disease is diabetics
- the kidney is one of the most frequently and severely affected organs, but changes in the arteries and arterioles are similar to those found in other tissues
- hyaline arteriosclerosis affects not only the afferent but also efferent arterioles
renal atherosclerosis and arteriosclerosis
acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules
- both acute and chronic forms are more common in diabetics than in the general population
- once affected, diabetics tend to have more severe involvement
pyelonephritis
what special pattern of acute pyelonephritis is much more prevalent in diabetics than in nondiabetics?
necrotizing papillitis
what body part is profoundly affects by diabetes mellitis?
the eye
- the most intese histopathologic changes are seen in the retina
what does diabetes-induced hyperglyceima lead to in the eye?
acquired opacification of the lens -> cataract
- long-standing diabetes also associated with increased intraocular pressure (glaucoma) and resulting damage to the optic nerve
autoimmune disease characterized by progressive destruction of islet b-cells, leading to absolute insulin deficiency
- the fundamental immune abnormality is a failure of self-tolerance in T cells, and circulating autoantibodies to islet cell antigens (including insulin) are often detected in affected patients
T1DM
no autoimmune basis, but insulin resistance and b-cell dysfunction, resulting in relative insulin deficiency
T2DM
what has an important relationship with insulin resistance?
obesity
- mediated through multiple factors including excess free fatty acids, cytokines released from adipose tissues (adipocytokines) and inflammation
what causes monogenic forms of diabetes?
single-gene defects that result in
- primary b-cell dysfunction (glucokinase mutation)
- or lead to abnormalities of insulin-insulin receptor signaling
what are the four potential mechanisms of long-term diabetic complications?
- formation of advanced glycation end products (AGEs)
- activation of protein kinase C (PKC)
- distrubances in the polyol pathways leading to oxidative overload
- overload of hexosamine pathway
long term complications of diabetes include large vessel diseases such as what?
atherosclerosis, ischemic heart disease and lower extremity ischemia
long term complications of diabetes include small vessel diseases such as?
retinopathy, nephropathy and neuropathy
these tumors are most often found within the pancreas and are generally benign
- most are solitary, although multiple tumors may be encountered
insulinomas
- on rare occasions, they may arise in ectopic pancreatic tissue -> electron microscopy reveals the distinctive granules of b-cells
how are Bona fide carcinomas diagnosed?
on the basis of local invasion and distant metastasis
usually small, encapsulated, pale to red-brown nodules located anywhere in the pancreas
- histologically, these benign tumors look like giant islets, with preservation of the regular cords of monotonous cells and their orientation to the vasculature
solitary tumors
what is a characteristic feature of many insulinomas?
amyloid deposition
what may be caused by focal or diffuse hyperplasia of the islets?
- this change is found occasionally in adults but is far more commonly encountered as congenital hyperinsulinism with hypoglycemia in neonates and infants
- several clinical scenarios may result in islet hyperplasia, including maternal diabetes, Beckwith-Wiedemann syndrome, and rare mutations in the b-cell K-channel protein or sulfonylurea receptor
hyperinsulinism
what is seen in maternal diabetes regarding fetal islets?
fetal islets respond to hyperglycemia by increasing their size and number
- in the postnatal period, hyperactive islets may be responsible for serious episodes of hypoglycemia
