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Dr. Paula L. BlancoDr. Paula L. [email protected]@toh.on.ca
Pathology in DiabetesPathology in Diabetes
October 2015October 2015
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[Unit name – Lecture title – Prof name]
Disclosure
• You may only access and use this PowerPoint presentation for educational purposes.
• You may not post this presentation online or distribute it without the permission of the author.
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Objectives• 3711-2 Describe the pathological changes in the pancreas for type I / II diabetes.
• 4619 Understand and recognize the pancreatic pathology in type I diabetes.
• 4620 List, understand and recognize the pathology of the major complications of diabetes: - Microvascular changes general aspects- Microvascular effects in retina- Microvascular changes in nerves- Renal pathology- Atherosclerosis in Diabetes
• 4621 Describe the special aspects of pathology of infection in diabetes.
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Islet of Langerhans
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The endocrine pancreas
Pathologic basis of disease – Robbins 8th
α cells: glucagonβ cells: insulin
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Increased synthesis and reduced degradation of glycogen, lipids and proteinsPathologic basis of disease – Robbins 8th
Insulin: most potent anabolic hormone
Hyperglycemia
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[Unit name – Lecture title – Prof name]
Definition
• Diabetes is not a single disease entity but a
group of metabolic disorders sharing the
common underlying feature of hyperglycemia
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Classification• Type I Diabetes 5-10%
• Type II Diabetes 90-95%
• Genetic defects of β cell function• Maturity-onset diabetes of the young (MODY), Neonatal diabetes
• Genetic defects in insulin action
• Exocrine pancreatic defects• Chronic pancreatitis, Cystic fibrosis, Hemachromatosis, Trauma, Neoplasia
• Endocrinopathies• Acromegaly, Cushing syndrome, Hyperthyroidism, Pheochromocytoma
• Infections• CMV, Coxsackie B virus, Congenital rubella
• Drugs• Glucocorticoids, Thiazides, Thyroid hormone, Interferon-α, β adrenergic agonists, Protease inhibitors
• Genetic syndromes associated with diabetes• Down syndrome, Kleinfelter syndrome, Turner, syndrome, Prader-Willi syndrome
• Gestational diabetes mellitus
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ClassificationClassification• Type I Diabetes 5-10%
• Type II Diabetes 90-95%
• Genetic defects of Genetic defects of ββ cell function cell function• Maturity-onset diabetes of the young (MODY), Neonatal diabetesMaturity-onset diabetes of the young (MODY), Neonatal diabetes
• Genetic defects in insulin actionGenetic defects in insulin action
• Exocrine pancreatic defectsExocrine pancreatic defects• Chronic pancreatitis, Cystic fibrosis, Hemachromatosis, Trauma, NeoplasiaChronic pancreatitis, Cystic fibrosis, Hemachromatosis, Trauma, Neoplasia
• EndocrinopathiesEndocrinopathies• Acromegaly, Cushing syndrome, Hyperthyroidism, PheochromocytomaAcromegaly, Cushing syndrome, Hyperthyroidism, Pheochromocytoma
• InfectionsInfections• CMV, Coxsackie B virus, Congenital rubellaCMV, Coxsackie B virus, Congenital rubella
• DrugsDrugs• Glucocorticoids, Thiazides, Thyroid hormone, Interferon-Glucocorticoids, Thiazides, Thyroid hormone, Interferon-αα, , ββ adrenergic agonists, Protease inhibitors adrenergic agonists, Protease inhibitors
• Genetic syndromes associated with diabetesGenetic syndromes associated with diabetes• Down syndrome, Kleinfelter syndrome, Turner, syndrome, Prader-Willi syndromeDown syndrome, Kleinfelter syndrome, Turner, syndrome, Prader-Willi syndrome
• Gestational diabetes mellitusGestational diabetes mellitus
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Diabetes type I
• Chronic progressive autoimmune disorder
• 5-10% of all cases• Most common subtype in younger patients (<20 y.o.)
• Immune system reacts against endogenous β-cell antigens
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Diabetes type I
Immune cells
“absolute” insulin deficiency
pancreatic β-cell destruction
Failure of self tolerance in T-cells
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Model of Diabetes type I
Adapted from N Rngl J Med 314:1360, 1986
Age (years)
Bet
a ce
ll m
ass
2510
Overt diabetes
Overt immunologic abnormalities
Normal insulin release
Progressive loss of insulin release
Glucose normal
? Precipitating event
Genetic predisposition
• HLA-DR3/DR4
• others
Environmental Factors
? Viral infections
(i.e. mumps, rubella, CMV)
(>90% β-cell destruction)
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Type I pathology
Pathologic basis of disease – Robbins 8th
Insulitis (lymphoid cell infiltrate)
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Insulitis (lymphoid cell infiltrate)
Type I pathology
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Diabetes type II
• 90-95% of all cases (most common type)• Adult onset – increasing in children
• No related to autoimmunity
• Multifactorial
-Genetic (i.e. genes associated with β-cell function / insulin secretion)
-Environmental
o Diet
o Sedentary life style
Obesity (i.e. adipokines, fatty acids, inflammation)
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Diabetes type II
2 metabolic defects:
• Insulin resistance
Failure of target tissues to respond normally to
insulin.
• β-cell dysfunction
Inadequate insulin secretion in states of insulin
resistance and hyperglycemia.
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Diabetes type II
pancreatic β-cell “preserved”
Hypersecretion of insulin
“relative” insulin deficiency
β-cell failure
Diabetes compensatory β-cell hyperfunction
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Type II pathology
library.med.utah.edu
Amyloid replacement of islets
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Amyloid
Fibrils that result from
abnormal folding of
proteins, which
become insoluble,
aggregate and deposit
in extracellular tissues
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Congo Red stain
with polarization
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[Unit name – Lecture title – Prof name]
Objectives• 3711-2 Describe the pathological changes in the pancreas for type I / II diabetes.
• 4619 Understand and recognize the pancreatic pathology in type I diabetes.
• 4620 4620 List, understand and recognize the pathology of the major List, understand and recognize the pathology of the major complications of diabetes: complications of diabetes: - Microvascular changes general aspects- Microvascular changes general aspects- Microvascular effects in retina- Microvascular effects in retina- Microvascular changes in nerves- Microvascular changes in nerves- Renal pathology- Renal pathology- Atherosclerosis in diabetes- Atherosclerosis in diabetes
• 4621 4621 Describe the special aspects of pathology of infection in diabetes.Describe the special aspects of pathology of infection in diabetes.
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[Unit name – Lecture title – Prof name]
Objectives• 3711-2 3711-2 Describe the pathological changes in the pancreas for Describe the pathological changes in the pancreas for type Itype I / II diabetes / II diabetes..
• 4619 Understand and recognize the pancreatic pathology in type I 4619 Understand and recognize the pancreatic pathology in type I diabetes. diabetes.
• 4620 List, understand and recognize the pathology of the major complications of diabetes: - Microvascular changes general aspects- Microvascular effects in retina- Microvascular changes in nerves- Renal pathology- Atherosclerosis in diabetes
• 4621 4621 Describe the special aspects of pathology of infection in diabetes.Describe the special aspects of pathology of infection in diabetes.
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[Unit name – Lecture title – Prof name]
COMPLICATIONS OF DIABETES
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Hyperglycemia is the primary initiating factor for damage of the target tissues
Nature 414:813-820, 2001
Dia
be
tic com
plica
tion
s(Advanced Glycation End products)
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Complications of diabetes
• Macroangiopathy (medium and large sized arteries)
- Accelerated atherosclerosis
• Microangiopathy (small vessels)
- Retinopathy
- Nephropathy
- Neuropathy
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[Unit name – Lecture title – Prof name]
Macrovascular diseaseAccelerated Atherosclerosis
Not specific, just worse
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Atheromatous plaque
Pathologic basis of disease – Robbins 8th
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Predisposition to atherosclerosis
• Increased risk of:
-Myocardial infarction (atherosclerosis of coronary arteries)
o Most common cause of death among diabetics
-Stroke
-Lower extremity gangrene
Persistent hyperglycemia/Insulin resistance on vascular compartment
Endothelial dysfunction
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Ischemic peripheral vascular disease
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Hyperglycemia
Glycosilation of BM proteins(AGE)
Thick and leaky blood vessels
Narrow lumen
Ischemic organ damage
Microvascular disease – general aspects
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Ocular complications
• Glaucoma – increased two fold
• Cataracts – develop at earlier age
• Retinopathy
• Diabetes is the leading cause of blindness among 20-74yo
• Prevalence: ~70-80% diabetics with >10 years of disease
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Thickened basement membrane
Normal
Ciliary body
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Diabetic retinopathy (DR)
• Progressive dysfunction of the retinal blood vessels caused by chronic hyperglycemia
• The best predictor of diabetic retinopathy is the duration of the disease
• After 20 years of diabetes, nearly 99% of patients with type 1 diabetes and 60% with type 2 have some degree of diabetic retinopathy
• Initially asymptomatic, if not treated though it can cause low vision and blindness
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[Unit name – Lecture title – Prof name]
Diabetic retinopathy – 4 stages
• Non-proliferative DR
-Mild, moderate, severe
• Proliferative DR
Tim
e
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Normal retina – Histology
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[Unit name – Lecture title – Prof name]
Diabetic retinopathy - stages
• Non-proliferative DR
- Loss of pericytes and formation of microaneurysms
(most important - early characteristic manifestation)
NormalAntonetti et al NEJM 2012
DR
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Loss of pericytes and microaneurysms
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[Unit name – Lecture title – Prof name]
Diabetic retinopathy
• Non-proliferative DR
- Capillary leakage / Macular edema
- Hemorrhages and hard exudates
- Arteriolovenular shunts
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[Unit name – Lecture title – Prof name]
Diabetic retinopathy
• Proliferative DR
- Neovascularization (up-regulation of VEGF)
- Vitreous hemorrhage
- Fibrovascular tissue proliferation – retinal detachment
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Diabetic retinopathy - fundoscopy
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[Unit name – Lecture title – Prof name]
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Diabetic nephropathy
• Very important!
• Leading cause of end-stage renal disease
• Advance/end-stage kidney disease occurs in ~40% diabetics
• Renal failure: 2nd most common cause of death in diabetics
• Does not happen quickly: progression from microalbuminuria macroalbuminuria end-stage disease over 10-20 years
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Normal glomerulus
Arterioles (afferent and efferent)
Tubules
Mesangial area
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Tubular basement membrane thickening
Capillary basement membrane thickening
Diabetes
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Electron microscopy
Glomerular basement membrane (GBM) thickening
Normal(~280-330 nm)
GBM
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Nodular diabetic glomerulosclerosis
(Kimmelstiel-Wilson)
Tubular basement membrane thickening
Capillary basement membrane thickening
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Diffuse mesangial sclerosis
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Silver stain
Microaneurysm formation
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PAS stain
Arteriolar hyalinosis (both afferent and
efferent)
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Normal
Loss of podocytes
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Pyelonephritis
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Papillary necrosis
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Diabetic nephropathy – summary of findings
• Glomeruli
- Basement membrane thickening (earliest)
- Diffuse mesangial sclerosis
- Nodular glomerulosclerosis
- Microaneurysms
- Loss of podocytes
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Diabetic nephropathy – summary of findings
• Vessels- Arteriolar hyalinosis- Atherosclerosis (larger vessels)
• Tubulointerstitium- Tubular basement membrane thickening- Pyelonephritis- Papillary necrosis
• Final result: Scarring (fibrosis)
Decreased size
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Diabetic neuropathy
• Prevalence: ~50% of diabetics (80% if >15 years of disease)
• Time dependent
• Syndromes:
-Distal symmetric sensory(motor) polineuropathy-Autonomic neuropathy
(postural hypotension, incomplete bladder emptying: infections, sexual dysfunction)
-Focal/multifocal asymmetric neuropathy
(individual peripheral or cranial nerve: mononeuropathy; several individual nerves: mononeuropathy multiplex)
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Distal symmetric sensorimotor neuropathyAxonal neuropathy
Thinly myelinated fibers
Segmental demyelination / Severe loss of myelinated fibers
Endoneurial arteriole wall
thickening
Normal
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Enoch et al, University of Wales UK, 2004
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Diabetic ulcers
• Painless• Surrounded by callus• At pressure points
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Pathologic basis of disease – Robbins 8th
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[Unit name – Lecture title – Prof name]
Objectives• 3711-2 3711-2 Describe the pathological changes in the pancreas for Describe the pathological changes in the pancreas for type Itype I / II diabetes / II diabetes..
• 4619 Understand and recognize the pancreatic pathology in type I 4619 Understand and recognize the pancreatic pathology in type I diabetes. diabetes.
• 4620 4620 List, understand and recognize the pathology of the major List, understand and recognize the pathology of the major complications of diabetes: complications of diabetes: - Microvascular changes general aspects- Microvascular changes general aspects- Microvascular effects in retina- Microvascular effects in retina- Microvascular changes in nerves- Microvascular changes in nerves- Renal pathology- Renal pathology- Atherosclerosis in diabetes- Atherosclerosis in diabetes
• 4621 Describe the special aspects of pathology of infection in diabetes.
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[Unit name – Lecture title – Prof name]
Infections in diabetes
• More frequent, more serious
• Increase morbidity and mortality
• May be the first manifestation of the disease
• Precipitating factor for complications
(i.e. diabetic ketoacidosis, hypoglycemia)
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[Unit name – Lecture title – Prof name]
Pathology of infection in diabetes
• Generalized impairment of immunity
-PMN and lymphocyte dysfunction: migration, phagocytosis and chemotaxis
-Complement deficiency
-Decreased cytokine response
-Glycation of Ig: decreased antibody function
• Non-immunologic anatomically specific factors
-Compromised local circulation – impaired wound healing
-Site specific changes
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Infections – Increased risk
• Lower extremity: Diabetic foot
- Contributors:
o Sensory neuropathy awareness of injury to the foot
o Motor neuropathy intrinsic muscles of the foot foot deformity
maldistribution of weight
o Autonomic neuropathy sweating dry and cracked skin
breaches in integrity of skin entry of microorganism
- Monomicrobial (Staphylococcus aureus/ epidermidis) or polymicrobial
- Bone (osteomyelitis) / articular involvement
- Often leads to amputation
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[Unit name – Lecture title – Prof name]
Infections – Increased risk
• Head and neck
- Mucormycosis
o Rhinocerebral infection / Invasive pulmonary or GI
o Causative agent: Rhizopus, Mucor
- Malignant external otitis
o Extension to soft tissue, mastoid bone and CNS
o Causative agent: Pseudomonas aeruginosa
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[Unit name – Lecture title – Prof name]
Mucormycosis
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[Unit name – Lecture title – Prof name]
Infections – Increased risk
• Genitourinaryo Autonomic neuropathy incomplete bladder emptying urinary colonization by microorganisms
o High glucose concentration in urine growth of microorganisms
-Asymptomatic bacteriuria
-Bacterial pyelonephritis (E. coli, Proteus)
-Emphysematous pyelonephritis (E. coli, Enterobacter aerogenes)
-Emphysematous cystitis (E. coli, followed by Enterobacter, Proteus, Klebsiella, and Candida)
-Fungal cystitis (Candida)
-Perinephric abscess (E. coli, polymicrobial)
-Candida vulvovaginitis
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[Unit name – Lecture title – Prof name]
Fungal cystitis - Candida
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[Unit name – Lecture title – Prof name]
Infections – Increased risk
• Respiratory
-Streptococcus pneumoniae
-Influenza
-H1N1
-Tuberculosis
• Superficial fungal infections (oral candidiasis, onychomycosis, intertrigo)
• Emphysematous cholecystitis
• Necrotizing fasciitis
• Surgical wound infections
Vaccination
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[Unit name – Lecture title – Prof name]
Prevention for type 2 diabetes
• Canadian adults with diabetes are twice as likely to die prematurely, compared to people without diabetes.
• Life expectancy for people with type 1 diabetes may be shortened by as much as 15 years.
• Life expectancy for people with type 2 diabetes may be shortened by 5 to 10 years.
• Reduce risk by 58% by exercising ~20 min/d and losing 7% body weight.
Diabetes Prevention Program