Dr. Paula L. Blanco pblanco@toh.on.ca Pathology in Diabetes October 2015

Dr. Paula L. BlancoDr. Paula L. Blancopblanco@toh.on.capblanco@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

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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

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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

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Diabetic retinopathy – 4 stages

• Non-proliferative DR

-Mild, moderate, severe

• Proliferative DR

Tim

e

Normal retina – Histology

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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

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Diabetic retinopathy

• Non-proliferative DR

- Capillary leakage / Macular edema

- Hemorrhages and hard exudates

- Arteriolovenular shunts

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Diabetic retinopathy

• Proliferative DR

- Neovascularization (up-regulation of VEGF)

- Vitreous hemorrhage

- Fibrovascular tissue proliferation – retinal detachment

Diabetic retinopathy - fundoscopy

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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

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)

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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

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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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Mucormycosis

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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

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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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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