Pathology Of Diabetes
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"Never offer the devil a ride. He will always want to be in the driving seat…!" BK.
Pathology of Diabetes Dr. Venkatesh M. Shashidhar Associate Professor of Pathology
Fiji School of Medicine
Diabetes Mellitus z z z
z
Disorder of metabolism (Carb, Prot & Fat) Due to Absolute/relative deficiency of insulin. Characterized by hyperglycemia. Clinically : Polyuria, Polydypsia, Polyphagia.
Introduction
z
Diabetes mellitus (sweet urine) 3% of world population, 100 million people Incidence is increasing alarmingly (40% in the past decade, more in future. 259 m by 2025. Most Common non communicable disease High Morbidity & mortality.
z
DM shortens life span by 15 years.
z
Leading cause of blindness and Kidney dis. Pacific Islands – leaders in DM & Obesity…!
z z z
z
z
World Statistics:
Normal Pancreatic Islet:
ß
α
ß cells (Insulin) α cells (Glucagon) δ cells (Somatostatin) pp Cells (pan prot)
Insulin - Anabolic Steroid z
Transmembrane transport of glucose
z
Liver, muscle & fat Æ ↓ blood glucose
z
Liver & skeletal muscle - ↑ glycogen
z
Converts glucose to triglycerides
z
Nucleic acid & Protein synthesis
z
Diabetes Æ Increased catabolism.
z
Hyperglycemia, ↓ protein synthesis, Liplysis, wasting, weight loss.
Blood Glucose & Hormones Action Hormone z Insulin z ↓ Glucose z Glucortocoids z ↑ Glucose z Glucagon z ↑ Glucose z Growth Hormone z ↑ Glucose z Epinephrine z ↑ Glucose
Cellular Glucose Uptake Insulin Requiring z Striated Muscle z Cardiac Muscle z Fibroblasts z FAT
Non-Insulin Requiring z Blood Vessels z Nerves z Kidney z Eye Lens
Pathology in Diabetes: z Low glucose inside cell z decreased cell metabolism (muscle, liver) z High glucose outside z Glycosylation damage (BV) z Polyol products – osmotic damage*
Classification z
Primary DM – (primary - no other disease) z z z z
z
Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. MODY – 5% maturity onset - Genetic Gestational Diabetes
Secondary DM – (secondary to other dis.) z z z z
Pancreatitis/tumors/Hemochromatosis. Infectious – congenital rubella, CMV. Endocrinopathy, downs. Drugs – Corticosteroids.
Pathogenesis of Type I DM Genetic HLA-DR3/4 • • • • •
Environment Viral infe..? Autoimmune Insulitis PS Glomerulonephritis Ab to ß cells/insulin Graves, Hashimoto thyroiditis. Rheumatic heart disease SLE, Collagen vascular disease Rheumatoid arthritis.
Type I / IDDM
ß cell Destruction
Insulin deficiency
Progression of Type I
Pathogenesis of Type II DM Genetic / ß cell defect
Obesity / Life style ? Abnor. Secretion Insulin Resistance
IDDM
Relative Insulin Def.
ß cell exhaustion
Type II NIDDM
“Things may come to those who wait, but only the things left by those who hustle.” – Abraham Lincoln
What type? 1. 2. 3. 4. 5. 6.
56 year male obese 30 year female following pregnancy 8 year old boy. 24 year female with Cushing’s sy 68 Year male following Carcinoma of pancreas. 34 year male with extensive tuberculosis.
II NIDDM II GDM I IDDM Sec IDDM
Sec IDDM
Sec IDDM
Type-I z z z z z z z z z z
Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins
Type-II z z z z z z z z z z
More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins
Insulitis – Type I
Insulinitis
Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Complications: z
z
Short term Complications: (metabolic) z Hypoglycemia z Diabetic Ketoacidosis z Non Ketotic hyperosmolar diabetic coma z Lactic acidosis Long term Complications:(Angiopathy) z Microngiopathy - Retinopathy, Nephropathy, Neurophathy, dermatopathy. z Macroangiopathy – Atherosclerosis.
Microangiopathy Pathogenesis: ¾ ¾ ¾ ¾ ¾ ¾
Hyperglycemia chronic. Glycosylation of basement membrane proteins Æ Leaky blood vessels. Excess deposition of proteins – glycosylation cycle. Thick and Leaky blood vessels. Narrow lumen Ischemic Organ damage...
Diabetic Microangiopathy Normal
¾ ¾ ¾ ¾
Glucose Glycosylation BM damage leak ‘AGE’ deposition
Diabetic
Neuropathy z z
Sensory Æ Motor (myelin) Peripheral Neuropathy z z z
z
Bilateral, symmetric Progressive, irreversible Paraesthesia, pain, muscle atrophy
Visceral neuropathy z z z
Cranial nerve – diplopia, Bell palsy GIT- constipation, diarrhoea CVS – orthostatic hypotension
Neuropathy Myelin loss in nerve
Chronic Polyneuropathy Claw foot – Dermopathy & Neuropathy
Diabetic Amyotrophy Painful muscle wasting
Diabetic Neuropathic ulcer
Neuropathic ulcer Etiology: ¾ peripheral sensory neuropathy, Trauma & deformity. Factors: ¾ Ischemia, callus formation, and edema.
Neuropathic ulcers
FEATURES: Painless, surrounded by callus At pressure points. associated with good foot pulses May not be associated with gangrene
Nephropathy z
z
z
z z z
Nodular Glomerulo Sclerosis. Common morbidity & mortality. Deposition of ‘AGE’ Advanced Glycosylation End-products as nodules. Nephrotic syndrome Pyelonephritis End stage renal failure
Diabetic Nephropathy Microangiopathy, atherosclerosis & infections: z Diffuse or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson Sy) z Renal arteriolosclerosis & atherosclerosis z Necrotizing renal papillitis. z Pyelonephritis. z End stage kidney.
Nodular Glomerulosclerosis – KW lesion.
Diabetic Glomerulosclerosis Hyaline nodules
Diabetic Glomerulosclerosis
Retinopathy z
Non Proliferative z z z z z
z
Microaneurysms, Dot blot hemorrhages Hard and soft exudates Cotton wool – infarcts Macular edema.
Proliferative. z z
Neovascularization Retinal detachment.
Normal Retina
Diabetic Retinopathy
Cotton wool spots
Diabetic Retinopathy Dot blot – Hemorrhages / Microaneurysms
Diabetic Retinopathy Pre retinal Hemorrhage - detachment
Diabetic Retinopathy Advanced fibrous plaques
“The past cannot be changed, but the future can.. by actions in the present time.” --BK Past is history, Future is mystery Present is the gift…!
Label the diagram. 1. Hard dep. 2. Optic disc 3. Macula 4. Blot hem 5. Cotton wool
Macroangiopathy Atherosclerosis z
Dyslipidemia
z
↓ HDL
z
Non-Enzymatic Glycosylation
z
↑ Platelet Adhesiveness
z
↑ Thromboxane A2
z
↓ Prostacyclin
z
Endothelial damage Æ Atherosclerosis
z
MI, CVA, Gangrene of Leg (PVD), Renal Insufficiency
Atherosclerosis:
Slide Show
Diabetic Gangrene
Fungal infections: Candidiasis
Macrosomia With Polycythemia
Blood vessel calcification: Amputated thumb
Cataract
Acanthosis Nigricans
¾Insulin resistance…
Acanthosis Nigricans
¾Insulin resistance…
Label the diagram. 1. Capillary 2. Nodule – AGE 3. Bowman caps 4. Hyaline arteriolo sclerosis in arteriole.
Infections in Diabetes:
z
Decreased metabolism – low immunity. Decreased function of lymphocytes & neutrophils – glycosylation. Glycosylation of immune mediators. Ab Capillary thickening – impaired inflammation. Ischemia & infarctions. Increased glucose (alone is not the cause*)
z
Diabetes Æ State of immunosuppression.
z z
z z z
Laboratory Diagnosis: z z z z
z z
Urine glucose - dip-stick –Screening Random or fasting blood glucose (<11) Fasting > 7mmol, Random >11mmol If Fasting level is between 7-11 then OGTT HbA1c - for follow-up, not for diagnosis Fructosamine - for long term maintenance.
Points to remember: z z z
Disorder of metabolism – Insulin Type-I Children, Acute, Metabolic compl. Type-II Adults, Chronic, Vascular compl. z Angiopathy (micro/macro), z
z z z z
Heart, Brain, Kidney, Retina, Skin, BV.
Increased Infections – know reasons. Hypoglycemia is more dangerous. Not hyper Glucose control is critical * FBS, GTT & HbA1C.
Questions.. z z z z z z z z
How – Ketoacidosis? How – hypoglycemia ? Angiopathy – Macro & Micro ? Infections in Types of retinopathy ? Diabetes insipidus ? Nephrotic / Nephritic syndrome ? Kidney damage in Diabetes ?
“It's not that I'm so smart, it's just that I stay with problems longer” --Albert Einstein
Pathology of Diabetes Dr. Venkatesh M. Shashidhar Associate Professor of Pathology
Fiji School of Medicine
Diabetes Mellitus z z z
z
Disorder of metabolism (Carb, Prot & Fat) Due to Absolute/relative deficiency of insulin. Characterized by hyperglycemia. Clinically : Polyuria, Polydypsia, Polyphagia.
Introduction
z
Diabetes mellitus (sweet urine) 3% of world population, 100 million people Incidence is increasing alarmingly (40% in the past decade, more in future. 259 m by 2025. Most Common non communicable disease High Morbidity & mortality.
z
DM shortens life span by 15 years.
z
Leading cause of blindness and Kidney dis. Pacific Islands – leaders in DM & Obesity…!
z z z
z
z
World Statistics:
Normal Pancreatic Islet:
ß
α
ß cells (Insulin) α cells (Glucagon) δ cells (Somatostatin) pp Cells (pan prot)
Insulin - Anabolic Steroid z
Transmembrane transport of glucose
z
Liver, muscle & fat Æ ↓ blood glucose
z
Liver & skeletal muscle - ↑ glycogen
z
Converts glucose to triglycerides
z
Nucleic acid & Protein synthesis
z
Diabetes Æ Increased catabolism.
z
Hyperglycemia, ↓ protein synthesis, Liplysis, wasting, weight loss.
Blood Glucose & Hormones Action Hormone z Insulin z ↓ Glucose z Glucortocoids z ↑ Glucose z Glucagon z ↑ Glucose z Growth Hormone z ↑ Glucose z Epinephrine z ↑ Glucose
Cellular Glucose Uptake Insulin Requiring z Striated Muscle z Cardiac Muscle z Fibroblasts z FAT
Non-Insulin Requiring z Blood Vessels z Nerves z Kidney z Eye Lens
Pathology in Diabetes: z Low glucose inside cell z decreased cell metabolism (muscle, liver) z High glucose outside z Glycosylation damage (BV) z Polyol products – osmotic damage*
Classification z
Primary DM – (primary - no other disease) z z z z
z
Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. MODY – 5% maturity onset - Genetic Gestational Diabetes
Secondary DM – (secondary to other dis.) z z z z
Pancreatitis/tumors/Hemochromatosis. Infectious – congenital rubella, CMV. Endocrinopathy, downs. Drugs – Corticosteroids.
Pathogenesis of Type I DM Genetic HLA-DR3/4 • • • • •
Environment Viral infe..? Autoimmune Insulitis PS Glomerulonephritis Ab to ß cells/insulin Graves, Hashimoto thyroiditis. Rheumatic heart disease SLE, Collagen vascular disease Rheumatoid arthritis.
Type I / IDDM
ß cell Destruction
Insulin deficiency
Progression of Type I
Pathogenesis of Type II DM Genetic / ß cell defect
Obesity / Life style ? Abnor. Secretion Insulin Resistance
IDDM
Relative Insulin Def.
ß cell exhaustion
Type II NIDDM
“Things may come to those who wait, but only the things left by those who hustle.” – Abraham Lincoln
What type? 1. 2. 3. 4. 5. 6.
56 year male obese 30 year female following pregnancy 8 year old boy. 24 year female with Cushing’s sy 68 Year male following Carcinoma of pancreas. 34 year male with extensive tuberculosis.
II NIDDM II GDM I IDDM Sec IDDM
Sec IDDM
Sec IDDM
Type-I z z z z z z z z z z
Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins
Type-II z z z z z z z z z z
More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins
Insulitis – Type I
Insulinitis
Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Complications: z
z
Short term Complications: (metabolic) z Hypoglycemia z Diabetic Ketoacidosis z Non Ketotic hyperosmolar diabetic coma z Lactic acidosis Long term Complications:(Angiopathy) z Microngiopathy - Retinopathy, Nephropathy, Neurophathy, dermatopathy. z Macroangiopathy – Atherosclerosis.
Microangiopathy Pathogenesis: ¾ ¾ ¾ ¾ ¾ ¾
Hyperglycemia chronic. Glycosylation of basement membrane proteins Æ Leaky blood vessels. Excess deposition of proteins – glycosylation cycle. Thick and Leaky blood vessels. Narrow lumen Ischemic Organ damage...
Diabetic Microangiopathy Normal
¾ ¾ ¾ ¾
Glucose Glycosylation BM damage leak ‘AGE’ deposition
Diabetic
Neuropathy z z
Sensory Æ Motor (myelin) Peripheral Neuropathy z z z
z
Bilateral, symmetric Progressive, irreversible Paraesthesia, pain, muscle atrophy
Visceral neuropathy z z z
Cranial nerve – diplopia, Bell palsy GIT- constipation, diarrhoea CVS – orthostatic hypotension
Neuropathy Myelin loss in nerve
Chronic Polyneuropathy Claw foot – Dermopathy & Neuropathy
Diabetic Amyotrophy Painful muscle wasting
Diabetic Neuropathic ulcer
Neuropathic ulcer Etiology: ¾ peripheral sensory neuropathy, Trauma & deformity. Factors: ¾ Ischemia, callus formation, and edema.
Neuropathic ulcers
FEATURES: Painless, surrounded by callus At pressure points. associated with good foot pulses May not be associated with gangrene
Nephropathy z
z
z
z z z
Nodular Glomerulo Sclerosis. Common morbidity & mortality. Deposition of ‘AGE’ Advanced Glycosylation End-products as nodules. Nephrotic syndrome Pyelonephritis End stage renal failure
Diabetic Nephropathy Microangiopathy, atherosclerosis & infections: z Diffuse or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson Sy) z Renal arteriolosclerosis & atherosclerosis z Necrotizing renal papillitis. z Pyelonephritis. z End stage kidney.
Nodular Glomerulosclerosis – KW lesion.
Diabetic Glomerulosclerosis Hyaline nodules
Diabetic Glomerulosclerosis
Retinopathy z
Non Proliferative z z z z z
z
Microaneurysms, Dot blot hemorrhages Hard and soft exudates Cotton wool – infarcts Macular edema.
Proliferative. z z
Neovascularization Retinal detachment.
Normal Retina
Diabetic Retinopathy
Cotton wool spots
Diabetic Retinopathy Dot blot – Hemorrhages / Microaneurysms
Diabetic Retinopathy Pre retinal Hemorrhage - detachment
Diabetic Retinopathy Advanced fibrous plaques
“The past cannot be changed, but the future can.. by actions in the present time.” --BK Past is history, Future is mystery Present is the gift…!
Label the diagram. 1. Hard dep. 2. Optic disc 3. Macula 4. Blot hem 5. Cotton wool
Macroangiopathy Atherosclerosis z
Dyslipidemia
z
↓ HDL
z
Non-Enzymatic Glycosylation
z
↑ Platelet Adhesiveness
z
↑ Thromboxane A2
z
↓ Prostacyclin
z
Endothelial damage Æ Atherosclerosis
z
MI, CVA, Gangrene of Leg (PVD), Renal Insufficiency
Atherosclerosis:
Slide Show
Diabetic Gangrene
Fungal infections: Candidiasis
Macrosomia With Polycythemia
Blood vessel calcification: Amputated thumb
Cataract
Acanthosis Nigricans
¾Insulin resistance…
Acanthosis Nigricans
¾Insulin resistance…
Label the diagram. 1. Capillary 2. Nodule – AGE 3. Bowman caps 4. Hyaline arteriolo sclerosis in arteriole.
Infections in Diabetes:
z
Decreased metabolism – low immunity. Decreased function of lymphocytes & neutrophils – glycosylation. Glycosylation of immune mediators. Ab Capillary thickening – impaired inflammation. Ischemia & infarctions. Increased glucose (alone is not the cause*)
z
Diabetes Æ State of immunosuppression.
z z
z z z
Laboratory Diagnosis: z z z z
z z
Urine glucose - dip-stick –Screening Random or fasting blood glucose (<11) Fasting > 7mmol, Random >11mmol If Fasting level is between 7-11 then OGTT HbA1c - for follow-up, not for diagnosis Fructosamine - for long term maintenance.
Points to remember: z z z
Disorder of metabolism – Insulin Type-I Children, Acute, Metabolic compl. Type-II Adults, Chronic, Vascular compl. z Angiopathy (micro/macro), z
z z z z
Heart, Brain, Kidney, Retina, Skin, BV.
Increased Infections – know reasons. Hypoglycemia is more dangerous. Not hyper Glucose control is critical * FBS, GTT & HbA1C.
Questions.. z z z z z z z z
How – Ketoacidosis? How – hypoglycemia ? Angiopathy – Macro & Micro ? Infections in Types of retinopathy ? Diabetes insipidus ? Nephrotic / Nephritic syndrome ? Kidney damage in Diabetes ?
“It's not that I'm so smart, it's just that I stay with problems longer” --Albert Einstein
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