dr. paula l. blanco [email protected] pathology in diabetes october 2015
TRANSCRIPT
Dr. Paula L. BlancoDr. Paula L. [email protected]@toh.on.ca
Pathology in DiabetesPathology in Diabetes
October 2015October 2015
[Unit name – Lecture title – Prof name]
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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.
Islet of Langerhans
The endocrine pancreas
Pathologic basis of disease – Robbins 8th
α cells: glucagonβ cells: insulin
Increased synthesis and reduced degradation of glycogen, lipids and proteinsPathologic basis of disease – Robbins 8th
Insulin: most potent anabolic hormone
Hyperglycemia
[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
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
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
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
Diabetes type I
Immune cells
“absolute” insulin deficiency
pancreatic β-cell destruction
Failure of self tolerance in T-cells
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)
Type I pathology
Pathologic basis of disease – Robbins 8th
Insulitis (lymphoid cell infiltrate)
Insulitis (lymphoid cell infiltrate)
Type I pathology
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)
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.
Diabetes type II
pancreatic β-cell “preserved”
Hypersecretion of insulin
“relative” insulin deficiency
β-cell failure
Diabetes compensatory β-cell hyperfunction
Type II pathology
library.med.utah.edu
Amyloid replacement of islets
Amyloid
Fibrils that result from
abnormal folding of
proteins, which
become insoluble,
aggregate and deposit
in extracellular tissues
Congo Red stain
with polarization
[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.
[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.
[Unit name – Lecture title – Prof name]
COMPLICATIONS OF DIABETES
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)
Complications of diabetes
• Macroangiopathy (medium and large sized arteries)
- Accelerated atherosclerosis
• Microangiopathy (small vessels)
- Retinopathy
- Nephropathy
- Neuropathy
[Unit name – Lecture title – Prof name]
Macrovascular diseaseAccelerated Atherosclerosis
Not specific, just worse
Atheromatous plaque
Pathologic basis of disease – Robbins 8th
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
Ischemic peripheral vascular disease
Hyperglycemia
Glycosilation of BM proteins(AGE)
Thick and leaky blood vessels
Narrow lumen
Ischemic organ damage
Microvascular disease – general aspects
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
Thickened basement membrane
Normal
Ciliary body
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
[Unit name – Lecture title – Prof name]
Diabetic retinopathy – 4 stages
• Non-proliferative DR
-Mild, moderate, severe
• Proliferative DR
Tim
e
Normal retina – Histology
[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
Loss of pericytes and microaneurysms
[Unit name – Lecture title – Prof name]
Diabetic retinopathy
• Non-proliferative DR
- Capillary leakage / Macular edema
- Hemorrhages and hard exudates
- Arteriolovenular shunts
[Unit name – Lecture title – Prof name]
Diabetic retinopathy
• Proliferative DR
- Neovascularization (up-regulation of VEGF)
- Vitreous hemorrhage
- Fibrovascular tissue proliferation – retinal detachment
Diabetic retinopathy - fundoscopy
[Unit name – Lecture title – Prof name]
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
Normal glomerulus
Arterioles (afferent and efferent)
Tubules
Mesangial area
Tubular basement membrane thickening
Capillary basement membrane thickening
Diabetes
Electron microscopy
Glomerular basement membrane (GBM) thickening
Normal(~280-330 nm)
GBM
Nodular diabetic glomerulosclerosis
(Kimmelstiel-Wilson)
Tubular basement membrane thickening
Capillary basement membrane thickening
Diffuse mesangial sclerosis
Silver stain
Microaneurysm formation
PAS stain
Arteriolar hyalinosis (both afferent and
efferent)
Normal
Loss of podocytes
Pyelonephritis
Papillary necrosis
Diabetic nephropathy – summary of findings
• Glomeruli
- Basement membrane thickening (earliest)
- Diffuse mesangial sclerosis
- Nodular glomerulosclerosis
- Microaneurysms
- Loss of podocytes
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
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)
Distal symmetric sensorimotor neuropathyAxonal neuropathy
Thinly myelinated fibers
Segmental demyelination / Severe loss of myelinated fibers
Endoneurial arteriole wall
thickening
Normal
Enoch et al, University of Wales UK, 2004
Diabetic ulcers
• Painless• Surrounded by callus• At pressure points
Pathologic basis of disease – Robbins 8th
[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.
[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)
[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
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
[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
[Unit name – Lecture title – Prof name]
Mucormycosis
[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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Fungal cystitis - Candida
[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
[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