Pathology (endocrine, pancreas, MEN)

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  1. What is the epidemiology of diabetes?
    • 1. The leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputations.
    • 2. 7% of American (20 m)/ lifetime prevalence of 35% (more in female)
    • 3. 54 m of American has prediabetes
    • 4. Non-Hispanic Whites has the lowest risk
    • 5. Obesity is the most important risk factor
  2. How is DM diagnosed?
    • 1. Random blood glucose ≥200 +symptoms (no repeat)
    • 2. FPG≥126
    • 3.2hPPG≥200
    • 4.HbA1c≥6.5%
    • 2-4 requires repeat
  3. How is prediabetes diagnosed?
    • FPG between 100 and 125 (including)
    • 2hPPG between 140 and 199 (including)
    • HbA1c between 5.7 to 6.4%
    • Higher risk of Diabetes (7% per year)
    • Higher risk of CVD
  4. What is the mcc of DM before 20?
  5. What are the major pathophysiological features of DM1 and 2?
    • Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
    • Type 2 diabetes (combination of insulin resistance and β-cell dysfunction)
  6. What are the defective genes in MODY?
    HNF and glucokinase
  7. What is the defect in neonatal DM?
    ATP-sensitive potassium channels
  8. What are the secondary causes of DM?
    • Exocrine pancreatic defects (Hemochromatosis, CF, chronic pancreatitis)
    • Endocrinopathies (Acromegaly, Cushing , Hyperthyroidism, Pheochromocytoma, Somtastatinoma,  Glucagonoma)
    • MODY (HNF, GK)
    • Infections (CMV, CRS, Coxsackie B)
    • Drugs  (Glucocorticoids, Thyroid INFα, PI, β-agonists, Thiazides, Nicotinic acid, Phenytoin, Vacor, diazoxide, pentamidine, calcineurin inhibitors)
    • Genetic syndromes associated with diabetes  (Down syndrome,  Kleinfelter syndrome,  Turner syndrome,  Prader-Willi syndrome, Fredriech Ataxia, Myotonic dystrophy)
  9. What are the genetic syndromes associated with DM?
    Down syndrome,  Kleinfelter syndrome,  Turner syndrome,  Prader-Willi syndrome, Fredriech Ataxia, Myotonic dystrophy
  10. What are the endocrinopathies associated with DM?
    Acromegaly, Cushing , Hyperthyroidism, Pheochromocytoma, Somtastatinoma,  Glucagonoma
  11. What are the drugs associated with DM?
    Glucocorticoids, Thyroid INFα, PI, β-agonists, Thiazides, Nicotinic acid, Phenytoin, Vacor, diazoxide, pentamidine, calcineurin inhibitors
  12. How is insulin synthesized?
    Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate mature insulin and a cleavage peptide, C-peptide. Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation
  13. What is the change in C-peptide in DM1 and 2?
  14. What is the most important regulator of insulin?
  15. How does glucose regulate insulin secretion?
    A rise in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulin- independent glucose-transporter, GLUT-2. β cells express an ATP-sensitive K+ channel on the membrane, which comprises two subunits: an inward rectifying K+ channel (Kir6.2) and the sulfonylurea receptor (SUR1). Metabolism of glucose by glycolysis generates ATP, resulting in an increase in β-cell cytoplasmic ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ channel, leading to membrane depolarization and the influx of extracellular Ca[2]+ through voltage-dependent Ca[2]+ channels. The resultant increase in intracellular Ca[2]+ stimulates secretion of insulin, presumably from stored hormone within the β-cell granules. This is the phase ofimmediate release of insulin. If the secretory stimulus persists, a delayed and protracted response follows that involves active synthesis of insulin.
  16. Factors other than glucose that stimulate insulin do this by primarily increasing insulin.........
    Release (not synthesis)
  17. What is the major metabolic function of insulin?
    To increase the rate of glucose transport into certain cells in the body, thus providing an increased source of energy
  18. What are the major actions of insulin?
    • 1. Skeletal muscle (GLUT-4)--> increase glucose uptake, aa uptake, glycogen synthesis, protein synthesis
    • 2. Liver--> increase lipogenesis, glycogen synthesis, decrease gluconeogenesis
    • 3. Adipose --> (GLUT-4)--> increase glucose uptake, lipogenesis, decrease lipolysis
    • 4. Mitogenic (initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation)
  19. What is the mechanism of action of insulin receptor?
    • The insulin receptor is a tetrameric protein composed of two α- and two βsubunits. The β-subunit cytosolic domain possesses tyrosine kinase activity. Insulin binding to the α-subunit extracellular domain activates the β-subunit tyrosine kinase, resulting in autophosphorylation of the receptor and the phosphorylation (activation) of several intracellular substrate proteins, such as the family of insulin receptor substrate (IRS) proteins, which includes IRS1–IRS4 and GAB1. The substrate proteins, in turn, activate multiple downstream signaling cascades, including the PI-3K and the MAP kinase pathways, which mediate the metabolic and mitogenic activities of insulin on the cell. Insulin signaling facilitates the trafficking and docking of vesicles containing the glucose transporter protein GLUT-4 to the plasma membrane, which promotes glucose uptake. This process is mediated by AKT, the principal effector of the PI-3K pathway, but also independently by the cytoplasmic protein CBL, which is a direct phosphorylation target of the insulin receptor. 
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  20. How can the insulin receptor activity be attenuated?
    Protein tyrosine phosphatase 1B (PTPN1B) dephosphorylates the insulin receptor and inhibits insulin signaling. The phosphatase PTEN can attenuate insulin signaling by blocking AKT activation by the PI-3K pathway.
  21. What is the main mechanism of DM1?
    autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens.
  22. What is the most important susceptibility loci for DM1?
    HLA gene at 6p21
  23. What are the genetic association of DM1?
    • HLA DR3 and 4 (if +DQ8--> highest inheritance)
    • VNTR at promoter of insulin gene
    • Polymorphisms in CTLA4 and PTPN22 (also in autoimmune thyroiditis). Both CTLA-4 and PTPN-22 are thought to inhibit T-cell responses--> decreased activation
    • Polymorphism is in CD25 (α chain of the IL-2 receptor)--> decreased activation
  24. What are the possible explanations of viral involvement in DM1?
    • 1. The first is “bystander” damage, wherein viral infections induce islet injury and inflammation, leading to the release of sequestered β-cell antigens and the activation of autoreactive T cells.
    • 2. The second possibility is that the viruses produce proteins that mimic β-cell antigens, and the immune response to the viral protein cross-reacts with the self-tissue (“molecular mimicry”).
    • 3. The third hypothesis suggests that viral infections incurred early in life (“predisposing virus”) might persist in the tissue of interest, and subsequent re-infection with a related virus (“precipitating virus”) that shares antigenic epitopes leads to an immune response against the infected islet cells. This last mechanism, also known as “viral déj vu,” might explain the latency between infections and the onset of diabetes
  25. What is the fundamental immune abnormality in type 1 diabetes?
    Failure of self-tolerance in T-cells.
  26. Where does the initial activation of autoreactive T cell occur in DM1?
    peripancreatic lymph nodes
  27. What are the major cells that destroy beta cell of pancreas in DM1?
    TH1 cells (which may injure β cells by secreted cytokines, including IFN-γ and TNF), and CD8+ CTLs (which directly kill β cells).
  28. What are the islet auto-antigens that are the targets of immune attack in DM1?
    insulin itself, as well as the β-cell enzyme glutamic acid decarboxylase (GAD), and islet cell autoantigen 512 (ICA512)
  29. Genetic predisposition is stronger for diabetes type.....
  30. What is the most reproducible genetic association for DM2?
    transcription factor 7–like-2 (TCF7L2) on chromosome 10q, which encodes a transcription factor in the WNT signaling pathway.
  31. What are the two metabolic defects that characterize type 2 diabetes?
    • (1) a decreased response of peripheral tissues to insulin (insulin resistance)
    • (2) β-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia
  32. What is likely to be the largest contributor to the pathogenesis of insulin resistance in vivo?
    loss of insulin sensitivity in the hepatocytes
  33. What is the most important RF for insulin resistance in DM2?
  34. How can central obesity increase insulin resistance?
    • 1. Increased nonesterified FA
    • 2. Adipokines (decreased adiponectin/ increase resistin)
    • 3. Inflammatory cytokines (IL-6, TNF, MCP-1)
    • 4. PPAR gamma (reduced activity)
  35. How can nonesterified FA in obesity affect insulin resistance?
    • Inverse correlation between fasting plasma NEFAs and insulin sensitivity.
    • The level of intracellular triglycerides is often markedly increased in muscle and liver of obese individuals, because excess circulating NEFAs are deposited in these organs.
    • Central adipose tissue is more “lipolytic” than peripheral sites, which might explain the particularly deleterious consequences of this pattern of fat distribution.
    • Excess intracellular NEFAs overwhelm the fatty acid oxidation pathways, leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG) and ceramide. Thesetoxic” intermediates can activate serine/threonine kinases, which cause aberrant serine phosphorylation of the insulin receptor and IRS proteins. Unlike tyrosine modification, phosphorylation at serine residues attenuates insulin signaling.
    • Insulin normally inhibits hepatic gluconeogenesis by blocking the activity of PEPCK, the first enzymatic step in this process. Attenuated insulin signaling allows PEPCK to “ramp up” gluconeogenesis.
    • Excess NEFAs also compete with glucose for substrate oxidation, leading to feedback inhibition of glycolytic enzymes, and thereby further exacerbating the existing glucose imbalance.
  36. What are the pro-hyperglycemic and anti-hyperglycemic adipokines?
    • Pro-hyperglycemic adipokines -->resistin, retinol binding protein 4 [RBP4]
    • Anti-hyperglycemic adipokines -->leptin, adiponectin.
  37. How does Adipokines affect insulin sensitivty?
    • Leptin and adiponectin improve insulin sensitivity by directly enhancing the activity of the AMP-activated protein kinase (AMPK), an enzyme that promotes fatty acid oxidation, in liver and skeletal muscle.
    • Adiponectin levels are reduced in obesity, thus contributing to insulin resistance.
    • AMPK is also the target for metformin, a commonly used oral antidiabetic medication.
  38. How does PPAR gamma improve insulin sensitivity?
    • PPARγ is a nuclear receptor and transcription factor expressed in adipose tissue, and plays a seminal role in adipocyte differentiation.
    • Activation of PPARγ promotes secretion of anti-hyperglycemic adipokines like adiponectin, and shifts the deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle.
  39. What is the mechanism of β-Cell Dysfunction in DM2?
    • 1. Intrinsic predisposition to β-cell failure (TCF7L2)
    • 2. Also mechanisms that contribute to IR
    • : excess NEFAs and attenuated insulin signaling (“lipotoxicity”) --> Agents like metformin that enhance fatty acid oxidation through AMPK activation also improve β-cell function
    • 3. Amyloid replacement of islets is a characteristic finding in individuals with long-standing type 2 diabetes. Islet amyloid protein is directly cytotoxic to islets.
  40. What are the major causes of monogenic diabetes?
    • Genetic Defects in β-Cell Function
    • Genetic Defects in Insulin Action
  41. What are the characteristics of monogenetic DM caused by Genetic Defects in β-Cell Function?
    • A primary defect in β-cell function that occurs without β-cell loss, affecting either β-cell mass and/or insulin production.
    • (1) autosomal-dominant inheritance, with high penetrance; (2) early onset, usually before age 25  (3) absence of obesity; and (4) absence of β-cell autoantibodies.
  42. What are the monogeneic causes of Defects in β-Cell dysfunction?
    • 1. MODY (GK in MODY2/ HNF--> all control insulin secretion or beta cell mass)
    • 2. Permanent neonatal diabetes (Gain of function mutation in ATP-sensitive K channels)--> constitutive activation of the K+ channel, membrane hyperpolarization, and hypoinsulinemic diabetes, severe hyperglycemia and ketoacidosis,and epilepsy
    • 3. Maternally inherited diabetes and deafness --> mitochondrial DNA mutations.--> decreased insulin secretion.
    • 4. Mutations within the insulin gene
  43. What are the features of MODY2?
    • Glucokinase, implicated in MODY2, is an enzyme that catalyzes the transfer of phosphate from ATP to glucose, which is the first and rate-limiting step in glucose metabolism.
    • β-cell glucokinase controls the entry of glucose into the glycolytic cycle, which, in turn, is coupled to insulin secretion. Mutations of the glucokinase (GCK) gene increase the glucose threshold that triggers insulin release, causing mild increases in fasting blood glucose
    • As many as 50% of carriers of glucokinase mutations develop GDM.
  44. What are the monogenic Defects in Insulin Action?
    • 1. Insulin receptor mutations that affect receptor synthesis, insulin binding, or receptor tyrosine kinase activity can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance). Such patients often show acanthosis nigricans, polycystic ovaries and elevated androgen levels. 
    • 2. Lipoatrophic diabetes is hyperglycemia accompanied by loss of adipose tissue in the subcutaneous fat. This rare group of genetic disorders has in common insulin resistance, diabetes, hypertriglyceridemia, acanthosis nigricans, and abnormal fat deposition in the liver (hepatic steatosis). Dominant-negative mutations in the DNA-binding domain of PPARG are found in a subset of patients, which interfere with the function of wild-type PPARγ in the nucleus, leading to severe insulin resistance.
  45. What is the key mediator in the pathogenesis of the long-term complications of diabetes?
    Persistent hyperglycemia
  46. What are the mediators of the effect of persistent hyperglycemia on tissues?
    • Formation of Advanced Glycation End Products
    • Activation of Protein Kinase C.
    • Intracellular Hyperglycemia and Disturbances in Polyol Pathways.

  47. What is AGE?
    Nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3deoxyglucosone) with the amino groups of both intracellular and extracellular proteins
  48. How is the effect of AGE mediated?
    • Receptor of AGE (RAGE--> on MQ, EC, SMC, and lymphocytes)
    • Non-receptor mediated crosslinking withECM protein
  49. What are the receptor mediated effects of AGE?
    • (1) release of pro-inflammatory cytokines and growth factors from intimal macrophages
    • (2) generation of reactive oxygen species in endothelial cells
    • (3) increased procoagulant activity on endothelial cells and macrophages
    • (4) enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix.
  50. What are the effects of AGE by Direct cross-linking of extracellular matrix proteins?
    • 1)Cross-linking of collagen type I molecules in large vessels decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury
    • 2)cross-linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid
    • 3)Proteins cross-linked by AGEs are resistant to proteolytic digestion. Thus, cross-linking decreases protein removal while enhancing protein deposition
    • 4)AGE-modified matrix components also trap nonglycated plasma or interstitial proteins. In large vessels, trapping of LDL, for example, retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima, thus accelerating atherogenesis
    • 5)In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the glycated basement membrane, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy.
  51. What are the major complications of DM mediated by AGE?
    Macrovascular, Nephropathy
  52. How is PKC activated in diabetes?
    Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence causes activation of PKC.
  53. What are the effects mediated by activation of PKC in diabetes?
    • 1) VEGF--> neovascularization characterizing diabetic retinopathy
    • 2) Elevated endothelin-1 and decreased NO, due to decreased expression of endothelial nitric oxide synthase  
    • 3) TGF-β, leading to increased deposition of extracellular matrix and basement membrane material  
    • 4) PAI-1, leading to reduced fibrinolysis and possible vascular occlusive episodes  
    • 5) Production of pro-inflammatory cytokines by the vascular endothelium
  54. PKC inhibitors might be beneficial in which diabetic complications?
    Ruboxistaurin have yielded promising results in diabetic retinopathy and nephropathy
  55. What is the major underlying cause of diabetic neuropathy?
    Persistent hyperglycemia
  56. How can disturbances in polyol pathway impair tissue function in DM?
    In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular glucose. This excess glucose is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH as a cofactor. Progressive depletion of intracellular NADPH by aldol reductase compromises GSH regeneration, increasing cellular susceptibility to oxidative stress.
  57. What are the major changes in pancreas of patients with DM1?
    • Reduction in the number and size of islets
    • Leukocytic infiltrates in the islets (insulitis) are principally composed of T lymphocytes. The distribution of insulitis may be strikingly uneven. Eosinophilic infiltrates in diabetic infants who fail to survive the immediate postnatal period.
  58. What are the major changes in the pancreas of patients with DM2?
    • Subtle reduction in islet cell mass, demonstrated only by special morphometric studies.  
    • Amyloid deposition within islets in type 2 diabetes begins in and around capillaries and between cells. fibrosis may also be observed. Similar lesions may be found in elderly nondiabetics, apparently as part of normal aging.
  59. What is the major changes in the pancreas of nondiabetic newborns of diabetic mothers?
    An increase in the number and size of islets
  60. What is the hallmark of diabetic macrovascular disease?
    accelerated atherosclerosis
  61. What is the mcc of death in diabetes?
  62. What are the major consequences of macrovascular complications in DM?
    • MI
    • CVA
    • PAD
    • Hyaline arteriolosclerosis
  63. What is the effect of DM on basement membranes?
    • One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.
    • However, it may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta.
    • Despite the increase in the thickness of basement membranes,diabetic capillaries are more leaky than normal to plasma proteins. 
  64. What does the microangiopathy underlay in DM? 
    nephropathy, retinopathy, and some forms of neuropathy.
  65. What are the renal lesions in diabetes?
    (1) glomerular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis.
  66. What are the most important glomerular lesions in diabetes?
    • Capillary basement membrane thickening
    • Diffuse mesangial sclerosis
    • Nodular glomerulosclerosis.
  67. What is the morphological feature of diabetic nephropathy that is seen in all patients?
    Widespread thickening of the glomerular capillary basement membrane (GBM)
  68. What are the characteristic of deposits of Diffuse Mesangial Sclerosis in diabetes?
    It is PAS+
  69. What are the histological features of Nodular Glomerulosclerosis?
    • Ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus.
    • The nodules are PAS-positive.
    • They lie within the mesangial core of the glomerular lobules
    • The nodules often show features of mesangiolysis with fraying of the mesangial/capillary lumen interface, disruption of sites at which the capillaries are anchored into the mesangial stalks, and resultant capillary microaneurysm
    • Even uninvolved lobules and glomeruli show striking diffuse mesangial sclerosis.
    • As the disease advances, the individual nodules enlarge and may eventually compress and engulf capillaries, obliterating the glomerular tuft.
    • Frequently accompanied by prominent accumulations of hyaline material in capillary loops (“fibrin caps”) or adherent to Bowman's capsules (“capsular drops”).
    • Both afferent and efferent glomerular hilar arterioles show hyalinosis-->ischemia, tubular atrophy and interstitial fibrosis.
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  70. What is unique to arteriolosclerosis of kideny in diabetes?
    Involvement of efferent arterioles
  71. What are the biochemical effects of insulin deficiency?
    • Reduced glucose uptake into adipocytes and muscles
    • Glycogenolysis in muscle and liver
    • Gluconeogenesis in the liver due to increased in aa from protein breakdown
    • Reduced LPL activity--> elevated chylomicron and VLDL
    • Increased HSL--> increased FA--> increased substrate for ketogenesis --> increased fatty a oxidation--> increased Acyl-CoA (together with ketogenic aa)--> increased ketone
  72. What are the RF for diabetic nephropathy?
    • Diabetes Type 1
    • Populations other than non-Hispanic Whites
  73. What is the mc pattern of diabetic neuropathy?
    distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function, but particularly the latter
  74. What are the major infections in diabetes?
    Diabetics are plagued by enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and pyelonephritis
  75. What are the main causes of infection in diabetes?
    • Decreased neutrophil functions (chemotaxis, adherence to the endothelium, phagocytosis, and microbicidal activity)
    • Impaired cytokine production by macrophages
    • Vascular compromise also reduces delivery of circulating cells and molecules that are required for host defense.
  76. What is the relation of retinopathy and nephropathy?
    • In DM1 if nephropathy is related to diabetes, always retinopathy and neuropathy are present. The inverse is not true
    • In DM2 the relationship is less intense
  77. What are the histological features of diabetic neuropathy?
    • Axonal neuropathy + some segmental demyelination.
    • There is a relative loss of small myelinated fibers and of unmyelinated fibers, but large fibers are also affected.
    • Endoneurial arterioles show thickening, hyalinization, and intense PAS positivity in their walls and extensive reduplication of the basement membrane
  78. What is the pathophysiology of mononeuropathy in DM?
    vascular insufficiency, and ischemia of the affected peripheral nerve.
  79. What is the mcc of multiple cranial neuropathy?
  80. Which nerves are most commonly affected in diabetic mononeuropathy?
    CN III and median nerve
  81. What are the drugs that used for painful diabetic retinopathy?
    Amitriptyline, pregabalin, duloxetine, venlafaxine 
  82. What are the major manifestations of diabetic autonomic neuropathy?
    • Gastroparesis
    • Postural hypotension
    • Enteropathy (constipation, diarrhea)
    • Erectile dysfunction
  83. What are the features of  diabetic amyotryphy?
    Acute symmetric focal onset of pain, followed by weakness involving proximal leg, autonomic failure and weight loss--> due to polyradiculopathy
  84. What is the feature of diabetic cranial mononeuropathy?
    Unilateral pain, ptosis, diplopia, and sparing of pupillary function
  85. What is the most important RF for diabetic neuropathy?
    Duration and severity of hyperglycemia
  86. What is the most common peripheral mononeuropathy in DM?
  87. What is the feature of neuropathic edema?
    • Peripheral vascular denervation results in excess peripheral circulation and AV shunting
    • Treat by Midodrine (reduces shunting by activating SANS)
  88. What is the hallmark of diabetic enteropathy?
    Severe nocturnal exacerbations
  89. What is a reliable histologic marker of diabetes mellitus in the eye?
    • Thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body
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  90. What are the hallmarks of diabetic nonproliferative retinopathy?
    • Abnormalities of angiogenesis located within the retina (i.e., confined beneath the internal limiting membrane of the retina).
    • The basement membrane of retinal blood vessels is thickened.
    • The number of pericytes relative to endothelial cells diminishes
    • Microaneurysms (not seen by ophthalmoscopes)
    • Physiologic breakdown in the blood-retinal barrier-->leak-> macular edema Exudates that accumulate in the outer plexiform layer (hard exudate).
    • Although the retinal microcirculation is often hyperpermeable, it is also subject to the effects of micro-occlusion. 
    • Nerve-fiber layer infarct (cotton-wool)
    • Intraretinal hemorrhage
  91. What is the consequence of diabetic non-proliferative retinopathy?
    Up-regulation of VEGF and retinal angiogenesis
  92. What is the hallmark of diabetic proliferative retinopathy?
    Retinal neovascularization (newly formed vessels breach the internal limiting membrane of the retina)
  93. Absence of the ganglion cell and nerve fiber layers are seen in which disorder?
  94. What are the major causes of blindness in DM?
    • Macular edema
    • Hemorrhage (vitreous)
    • Neovascular glaucoma
    • Retinal detachment
  95. What are the earliest changes in diabetic retinopathy?
    • Loss of pericytes and EC
    • Retinal BM thickening
  96. When might retinopathy be exacerbated?
    • Intensive insulin therapy
    • Pregnancy
  97. What is the major abnormal immune cell in DM1?
  98. What are the mcc of diabetic foot infection ?
    • Superficial--> gram+ cocci
    • Deep (fascia)--> gram +cocci and gram - rod
  99. What is the important complication of DKA in children?
    Cereberal edema
  100. What are the main criteria for malignancy of islet cell tumor?
    metastases, vascular invasion, and local infiltration
  101. What is the mc islet cell tumor?
  102. What is the triad of insulinoma?
    • Hypoglycemic episodes, which
    • (1) occur with blood glucose levels below 50 mg/dL of serum;
    • (2) consist principally of central nervous system manifestations such as confusion, stupor, and loss of consciousness; and
    • (3) are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose.
  103. What is the morphology of insulinoma?
    • Most benign
    • Encapsulated and monomorphic (even if malignant)
    • Resemble giant islets
    • Presence of amyloid
  104. What are the major causes of focal or diffuse hyperplasia of the islets?
    • Maternal diabetes
    • Beckwith-Wiedemann syndrome
    • Mutations in the β-cell K+-channel 
  105. What are the features of ZES?
    • >50% invasive
    • No anaplasia
    • PUD, diarrhea
  106. What are the features of glucagonoma?
    • Mild diabetes mellitus
    • Skin rash (necrolytic migratory erythema)
    • Anemia
    • Thromboemboli
  107. What are the features of somatostatinoma?
    • Diabetes mellitus
    • Cholelithiasis
    • Steatorrhea
    • Hypochlorhydria
  108. What are the features of VIPoma 
    • Watery (secretory) diarrhea 
    • Hypokalemia
    • Achlorhydria
  109. What are the common features of MEN?
    • Younger age
    • Multiple endocrine organs
    • Multifocal  
    • Preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin. 
    • More aggressive 
  110. What is the mc manifestation of MEN1?
    Primary hyperparathyroidism (either monoclonal hyperplasia or adenoma)
  111. What is the mcc of death in MEN1?
    Endocrine tumors of the pancreas
  112. What are the clinical features of MEN1?
    • Parathyroid: Primary hyperparathyroidism (MC)
    • Pancreas: Endocrine tumors of the pancreas (most malignant, most functional, most pancreatic polypeptide)
    • Pituitary (prolactinoma)
  113. What is the mc location for ZES in MEN1?
  114. What are the major manifestations of MEN1?
    • Hypoglycemia due to insulinomas
    • Intractable peptic ulcers  due to ZES
    • Nephrolithiasis caused by PTH-induced hypercalcemia
    • Symptoms of prolactin excess from a pituitary tumor
  115. What are the genetic abnormalities in MEN?
    • MEN1--> menin (tumor suppressor)
    • MEN2 --> RET (Proto-oncogene) gain of function
  116. What are the mc manifestation of MEN2?
  117. What disorders are caused by gain and loss of function of RET?
    • MEN2
    • Hirschprung (RET encodes receptor tk for GDNF)
  118. What are the symptoms of MEN2?
    • MEN2A--> MTC (aggressive, mc), pheochromocytoma (multifocal, extraadrenal), parathyroid hyperplasia (least common)
    • MEN2B--> MTC (more aggressive than 2A), pheochromocytoma, marfanoid habitus, mucocutanueous ganglioneuroma
Card Set:
Pathology (endocrine, pancreas, MEN)
2013-09-12 19:23:48

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