Pathogenesis-Chronic-Complications-Diabetes

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Pathogenesis - Chronic Complications of Diabetes

                                                                                                                                             Intracellular Hyperglycaemia with
            Non-E nzymatic Glycosylation                            Activation of Protein Kinase C (PKC)
                                                                                                                                               Disturbance of Polyol Pathway
Process where Glucose Attach to Proteins (chemically)                   Intracellular Hyperglycaemia                                Does not require Ins ulin for Glucose Trans port
without aid of Enzyme                                                                     ↓                                         Nerves, Lens, Kidneys, Blood Vessels
                                                            Stimulates de novo synthesis for Diacylglycerol (DAG)
Degree of Glycosylation                                                                                                             During Hyperglycaemia → ↑ Intracellular Glucose
                                                                        from glycolytic intermediates
Directly related to Blood Glucose Level
                                                                (DAG = 2nd messenger in signal transduction)
Glucose + Hb chain = Glycated HbA (HbA1c )                                                ↓
In Diabetics, ↑ HbA 1c                                                       Activate Protein Kinase C
HbA 1c Reflects average level of glucose over 120 days                       ↙           ↓              ↘

Checking Blood Sugar in Pre-Diabetic                             Produce            Produce              Produce Pro-
Monitor Blood Sugar Control in Diabetic Patients              Plasminogen           Vascular              Fibrogenic
Irreversible Advanced Glycosylation End Pr oducts               Inhibitor        Endothelial GF           Molecules
                                                                    ↓                    ↓               (Transforming GF)
(AGEs)                                                                                                                              Many cells contain Aldose Reductase
                                                              ↓ Fibrinolysis         Neo-                       ↓
•     Glycosylation of Collagen, Long-lived Proteins in             ↓            vascularization         ↑ Deposition               Excess Sorbitol Cannot Exit Cell, Coverted to Fructose
      Blood Vessels, Interstitial Tissues                                        (Abnormal Vesse ls)                                      Accumulation of Sorbitol (Polyol), Fructose
                                                                Vascular                                  Of ECM &
•     Accumulate in Blood Vessels and cause                    Occlusion s
                                                                                         ↓
                                                                                                         BM Material                                           ↓

      Microvascular, Macrovascular Lesions                                          Diabetic                                                ↑ Intracellular Osmolality, H2O Influx
                                                                                                                                                               ↓
              AGEs bind to ECM proteins                                            Retinopathy
                                                                                                                                                         Cell Injury
             on Basement Membrane (BM )                                                                                                       Endothelial cells
                           ↓
                 Accumulation of AGEs                                                                                                         Lens (Cataract)
                           ↓                                                                                                                  Nerve (↓ Nerve Conduction)
              Trap Non-Glycosylated                                                                                                        Continuous Aldose Red uctase Pathway
         Plasma Protein, Interstitial Protein                                                                                                                  ↓
             ↙                          ↘                                                                                                             Diminished NADPH
   Trapping of LDL at          Trapping Albumin at                                                                                                             ↓
 Vessel Wall accelerates      BM of capillaries cause                                                                                    ↓ Formation of Reduced Glutathione (GSH)
                                                                                                                                                               ↓
     Atherogenesis              Thickening of BM
                                                                                                                                                Cells prone to Oxidative Stress
                                     (Diabetic
                                 Glomerulopathy)
              Circulating Plasma Protein
                           ↓
             Binds to AGE Receptors on
   Endothelial Cells, Mesangial Cells, Macrophages
                           ↓
         Effects of AGE Receptor Signalling
          Release Cytokines, GF
          ↑ Endothelial Permeability
          Induce Procoagulant Activity
          Enhance ECM Synthesis

Chronic Complications                                                                             Pathophysiol ogy (Macrovascular Complication)
           Macrovascular                               Microvascular                                                           Hyperglycaemia
                                                                                                                                                  ↓
Stroke                                      Diabetic Retinopathy
                                                                                                                    Nonenzymatic Glycosylation of Collagen, Proteins in
IHD                                         Diabetic Nephropathy
                                                                                                                           Interstitial Tissue, Blood Vessel Wall
Peripheral Vascular Disease                 Diabetic Neuropathy                                                                                   ↓
                                                                                                            Formation of Irreversible Advanced Glycosylation End Products
                                                                                                                                        (AGEs)
                                                                                                                                                  ↓
                                                                                                                             Cause Cross Link between Polypeptides
                                                                                                                                                  ↓
                                                                                                                      Trap Plasma, Interstitial Proteins including LDL
                                                                                                                                                  ↓
                                                                                                               Promote deposition of Ch olesterol in blood vessel intima
                                                                                                                                                  ↓
                                                                                                                                     Accelerate Atherogenesis
                                                                                                                                                  ↓
                                                                                                                                    Form Atherosclerotic Plaque
                                                                                                                                                  ↓
                                                                                                                                         Atherosclerosis
                                                                                                                              Insulin Deficiency/ Insulin Resistance
                                                                                                                                                  ↓
                                                                                                                              Impaired Glucose Uptake, Utilization
                                                                                                                                                  ↓
                                                                                                                                             ↑ Lipolysis
                                                                                                                                                  ↓
                                                                                                                                       ↑ Circulating Glucose
                                                                                                                                        ↑ Free Fatty Acid
                                                                                                                                              ↓ HDL
                                                                                                                                                  ↓

Macrovascular Complication                                                                                                                Atherosclerosis
    Cardiovascular           Cerebrovascular               Peripheral Vascular                                                            Atherosclerosis
                                                                                                                                                  ↓
Angina                   Coma                             Gangrene
MI                       Stroke                                                                         Coronary Artery                  Lower Extremities              Brain Vessel
IHD                                                                                                                                           Vessel
                                                                                                                                                  ↓
HPT
                                                                                                                                    Compromise d Blood Supply
                                                                                                                                ↙                 ↓                ↘
                                                                                                       Myocardial Infarction            Coagulative Necrosis       Stroke
                                                                                                                                             Infections
                                                                                                                                                  ↓

                                                                                                                                           Wet Gangrene
                                                                                                                                                             jslum.com | Medicine
Microvascular Complication                                                             Diabetic Retinopathy
Diabetic Microangiopathy                                                               Retinal changes – Long term Diabetes
Diabetic Neuropathy                                                                    Cause Visual Impairment, Total Blindness
Diabetic Retinopathy                                                                   Pathogenesis
Diabetic Neuropathy                                                                                          ↑ Glucose in Non-Insulin Dependent Cels
                                                                                                                  (Nerves, Lens, Blood Vessels)
Diabetic Ulcer                                                                                                                     ↓
                                                                                                                     Activate Polyol Pathway
Diabetic Microangiopathy                                                                                                           ↓
                                                                                                                              ↑ [Sorbitol]
Diffuse Thickening of Capillary Basement Membrane (BM)                                                                             ↓
Diabetic Capillaries are ↑ Leaky to Plasma Proteins (compared to Normal)                                            Inhibit Myoinositol Uptake
Thickening is Most Evident in Capillaries of                                                                          Impair Na+/K+ ATPase
                                                                                                                                   ↓
  Vascular Structures                     Non-Vas cular Structures                                             Damage Pericytes of Retinal Capillary
  Skin                                    Renal Tubules                                                    ↙                                             ↘
  Skeletal Muscle                         Bowman Capsule                                     Retinal Microthrombi formation                    ↑ Vascular Permeability
                                                                                                ↙                    ↘                          ↙                      ↘
  Retina                                  Peripheral Nerve                              Vascular Occlusion      Outpouching             Fluid Infiltration       Leakage of Fat,
  Renal Glomerulus                        Placenta                                              ↓               occur at local                 ↓                    Protein
  Renal Medulla                                                                              Hypoxia          point of weakness              Edema                     ↓

Underlies the development of Diabetic                                                           ↓               due to loss of                                   Hard Exudate
Nephropathy, Retinopathy, Neuropathy (some form)                                        Neovascularization        pericytes
                                                                                                                     ↓

                                                                                                               Microaneurysm
Diabetic Nephropat hy                                                                              Non-Proliferative                                Proliferative
Kidney – Prime Targets of Diabetes                                                     Microaneurysms                                  Consequen ces of Hypoxia due to
Renal Failure 2nd after MI (main cause of death in Diabetics)                          (Dot, Blot Haemorrhage)                         Occluded Vessels
Glomerular Lesions                                                                     Earliest clinical abnormally detected           Neovascularization (hallmark)
    Capillary BM          Diffuse Mesangial
                                                     Nodular Glomerulosclerosis        Resulting from loss of pericytes                Morphology
     Thickening                Sclerosis
                                                                                       Outpouching occur at local point of             Branch Repeated
  BM Thickened         Diffuse ↑ in Mesangial   Kimmelstiel-Wilson Lesion
  throughout           Matrix along with            Glomerular Sclerosis involving     weaknening due to loss of pericytes             Fragile
  entire length        Mesangial Cell              development of nodular lesion in    Morphology                                      Bleed Easily
                       Proliferation                    glomerular capillaries         Tiny Discrete                                   Fibrous Tissue Reaction
                       Thickening BM                              ↓                    Circular/ Saccular                              (due to lack of supportive tissue)
                                                      Impaired Blood Flow with
                       Manifest Nephrotic                                              Dark Red Spots near to retinal vessels
                                                        Progressive Loss of
                       Syndrome (proteinuria,                                          Haemorrhages
                                                          Kidney Function
                       hypoalbuminaemia,                          ↓                    Leakage of blood into deeper layers
                       edema)                             Renal Failure                  Dot                 Blot
           Chronic Hyperglycaemia               Pathognomonic for Diabetic Pt.           Red                 Red
                        ↓
       Non-Enzymatic Glycosylation of                                                    Small               Larger
          Terminal Amino Group                                                           Round               Irregular Shape
                        ↓
                                                                                         Regular             Sharp Margin
                      AGEs
                        ↓                                                                Shape, Margin
    Affect Structure, Function of Capillaries
                 (Vasodilation)                 Nodular Glomerulosclerosis in
                        ↓                       Diabetic Nephropathy
              ↑ in Sheer Forces                 (Kimmelstiel-Wilson Lesion)
              Glomeruli Damage
                        ↓
           ↑ Mesangialhypertrophy
                        ↓
              ↑ Secretion of
        Mesangialextracellular Matrix
          ↑ Collagen Production
                        ↓
         Thickening of Glomerular BM
                        ↓
              Glomerulosclerosis
                        ↓
    Capillaries ↑ Leaky to Plasma Proteins
                        ↓
                   Proteinuria
                        ↓
     Peripheral Edema, Hypoalbuminemia                                                 Retinal Exudates
                        ↓
                   Hypertension                                                        Soft Exudates
                                                                                       Due to Microinfarct (Nerve Fibers)
Renal Vascular Lesion
                                                                                       Morphology
  Principally                                                 DM
                                                               ↓                       •     Greyish white
  Atherosclerosis                                Plasma Proteins penetrate into        •     Indistinct margins
  Arteriolosclerosis                         abnormally permeable wall of arterioles
  Part of Macrovascular disease                                ↓
                                                                                       •     Dull matt surface
                                                    Plasma Proteins trapped                  (Cotton-Wool spots)
  Changes same throughout body                                 ↓                       Similar to Hypertension
  Arteries                                      Vessel Hypertrophy, Hyalinization
  Arterioles                                                   ↓
                                                 Thickening of wall of arterioles
  Morphology                                                   ↓
  Arteriolar lesions with hypertrophy,                 Narrowing of lumen
  hyalinization of vessels                                     ↓
                                                  Ischaemic Damage to Kidney           Hard Exudates
  Hyaline arteriolosclerosis                                   ↓                       Leakage of Plasma from Abnormal
  (affe ct Afferent, Efferent Arteriole)                  Renal Failure
                                                                                       Retinal Capillary
Pyelonephritis                                                                         Morphology
Acute, Chronic Inflammation of Kidneys
                                                                                       •    Bright Yellowish White
Usually begin in Interstitial Tissue (then spread to affect Tubules)
                                                                                       •    Irregular outline
Pathophysiol ogy
                                                                                       •    Sharply defined Margin
Autonomic Neuropathy → Bladder Stasis → VUR → Infection
Untreated Infection
Renal Papillary Necrosis
                                                                   jslum.com | Medicine

Diabetic Maculopathy
↓ Common than Retinopathy
Due to Maculo Edema
(hard exudates within 1 disc width of macula)
Affects
Older Patient with Type 2 Diabetes
Asymptomatic
Important to test Visual Acuity of patients with diabetes yearly
May lead to Blindness




Cataract
Permanent lens opacity
Causes
Intralenticular accumulation of Sorbitol
Non-Enzymatic Glycation of Lens Protein
Most common in Elderly with DM
Young patient with Poorly Controlled Diabetes
Pathogenesis
           Diabetes Mellitus
                    ↓
↑ Glucose in Non Insulin-Dependent Cells
                (Lens)
                    ↓
        Activate Polyol Pathway
                    ↓
    ↑ Sorbitol accumulation in Lens
                    ↓
       ↑ Intracellular Osmolarity
                    ↓
 Influx of H2O, Plasma Protein into cells
                    ↓
         Lens Swelling, Opacity
                    ↓
                Cataract


Glaucoma
↑ Intraocular Pressure
Retinal Neovascularization
Pathogenesis
        Prolong Hyperglycaemia
                    ↓
    Activate Protein Kinase C Pathway
                    ↓
 Develop Neovascular membrane on Iris
               surface
   (2° to ↑ VEGF in Aqueous Humor)
                    ↓
  Contraction of Neovascular membrane
                    ↓
   Adhesions between Iris, Trabecular
              Meshwork
                    ↓
       Occluding Aqueous Outflow
                    ↓
         ↑ Intraocular Pressure
                                                                                                                                        jslum.com | Medicine

Diabetic Neuropathy                                                  Acute Painful Neuropathy
Manifest on Peripheral Nervous System                                Burning, Crawling Pains
Types                                                                Feet, Shins, Anterior Thighs
Symmetrical (mainly Sensory Polyneuropathy)                          Symptoms worse at night
Acute Painful Neuropathy                                             Develop after sudden improvement of Glycaemic control
Mononeuropathy, Mononeuritis Multiplex (Multiple Mononeuropathy)     Remits spontaneously after 3-12 months
Diabetic Amyotrophy
Autoimmune Neuropathy                                                Monone uropathy (Long Standing Diabetes)
                                                                     Any Nerve can be involved (Cranial, Peripheral)
                                                                     Pathogenesis (Adult-Onset Diabetes)
                                                                     Vascular Insufficiency → Ischaemic Injury of Peripheral Nerve
                                                                     Severe, Rapid Onset with Full Spontaneous Recovery
                                                                                 Cranial Nerves                              Peripheral Nerves
                                                                     Isolated Palsies to External Eye          Compression of Median Nerve
                                                                     Muscles (3rd , 6th Nerve)                 (Carpal Tunnel Syndrome)
                                                                     C3, C6 (result in Diplopia)               Lateral Popliteal Nerve Compression
                                                                     Femoral Nerve                             (Foot Drop)
                                                                     Sciatic Nerve                             Lateral Poplitea l Nerve = C ommon Peronea l Nerve


                                                                     Diabetic Amyotrophy
                                                                     Occur in Old Men with Diabetes
                                                                     Period of Poor Glycaemic Control
Pathogenesis                                                         Presentation
                                 Hyperglyc aemia
                                                                     Painful wasting of Quadriceps Muscle (us ually asymmetrical wasting)
                                         ↓
                              ↑ Intracellular Glucose                Tender (affected area)
                                         ↓                           Extensor Plantar Response
                             Stimulate Polyol Pathway                Claw Toes with Wasting of Interosseous muscle
                                         ↓
                 Accumulation Sorbitol + Fructose in Schwann cells   Extensor Plantar response is Abnormal Reflex
                                ↑ IC Osmolality                      (in response to Cutaneous Stimulation of Plantar surface of Foot)
                                         ↓
                                                                     Dorsiflexion of Great Toe
                                   Influx of H2O
                                         ↓                           Abduction of other toes
                                Osmotic Cell Injury
                                         ↓
                              Damage Schwann Cell
                                         ↓
                              Demyeliniation of Axon
                                         ↓
                          Axon degeneration irreversibly
                                         ↓
                             Disrupt Neural Function
                                         ↓
                               Diabetic Neuropathy
                                                                     Claw Toe
Symmetrical Sensory Polyneuropathy                                   Severe Atrophy of Intrinsic Foot Muscles (Lumbricals, Interossei)
Early Signs                              Later Signs                 (due to Motor Neuropathy)
                                                                     (result in Imbalance of Foot Muscles, Cocked -up toes)
Loss of Vibration, Pain, Temperature     Impaired Proprioception
sensation in Feet                                                    Diagnosis of Peripheral Neuropathy can be made (by Inspection alone)
Complication
                                                                     Autonomic Neuropathy
Unrecognized Trauma (Blister → Trauma)
                                                                     May affect Sympathetic, Parasympathetic
Loss of Tend on Reflu x in Lower Limbs
                                                                              CVS                       GIT                                     GUT
Characteristics
                                                                     Vagal Neuropathy                Dysphagia                       Loss of Bladder Sensation
Foot Ulcer                                                           Tachycardia at rest             Gastroparesis                   Neurogenic Bladder
Charcot Neuroathropathy (ankle)                                      Loss of Sinus Arrhythmia        Intractable Vomiting            ↑ Residual Volume
Hands                                                                Heart Den ervated               (esophageal reflux)             ↑ UTI Risk
Small muscle wasting                                                 (later stage)                   Delay gastric emptying          Disturb parasympathetic
Sensory changes (differ with Carpal Tunnel Syndrome)                 Postural Hypotension            (Abdominal fullness)            Penile Vasodilation
Pathophysiol ogy                                                     Loss of Sympathetic tone to     Diarrhoea                       Retrograde ejaculation
                     Occlusion of Vaso Nervorum due to AGEs          peripheral arterioles           (Bacterial Infection)           Impotence
                                         ↓                           Warm Foot                       Autonomic Diarrhoea             Sexual dysfunction
                           Ischaemic damage to Nerves                Bounding Pulse                  At Night
                                         ↓                           Polyneuropathy                  Accompanied by
                           Somatic Motor Neuropathy
                                         ↓
                                                                     Peripheral Vasodilation         •      Urg ency
                          Loss of Innervations of Muscles                                            •      Incontinence
                           (which Maintain Plantar Arch)
                                         ↓
                    Unbalanced traction by long flexor muscles
                                         ↓
                     Exagg erated Plantar Arch (shape altered)
                                         ↓
                  Abnormal distribution of Pressure when walking
                 (↑ Distributed over Head of Metatarsal, Knuckles)
                                         ↓
                           Build up of hard skin (callus)
                                         ↓
                             Callus ↑ Pressure further
                                         ↓
                               Necrosis under callus
                                         ↓
                                 Skin breaks down
                   Leaves clean, punched out Neuropathic Ulcer
                                         ↓
                            Bacteria enter broken skin
                                         ↓
                                      Fever
                                                                                 jslum.com | Medicine

Diabetic Foot
Ulcer
Neuropathic Ulcer
Ischaemic Ulcer
Neuro-Ischaemic Ulcer
Charcot’s Joint
Gangrene
Foot Deformities (Claw Toes)




Ischaemia vs Neuropathy
                 Ischaemia                           Neuropathy
  Symptoms       Claudication                        Usually Painless
                 Rest Pain                           Painful Neuropathy
  Inspection     Dependent Rubor                     ↑ Arch, Clawing of Toes
                 Trophic changes                     No Trophic changes
  Palpation      Cold                                Warm
                 Pulseless                           Bounding Pulse
  Ulceration     Painful                             Painless Plantar
                 Heels, Toes




Ischaemic Foot Ulcer                     Neuropathic Foot Ul cer
Dorsum of 2nd Toe                        Ulcer on 1st Metatarsal Head
Ischaemic lesion                         Healthy Granulation Tissue on its bed
Whitish color on tip due to ischaemia    Callus formation surrounding ulcer




Mixed Etiology
Neuro-Ischaemic Ulcer
                                         Gangrene
                                         Death of Tissue in considerable mass
                                         Due to
                                         •    Loss of Vascular Supply
                                         •    Bacterial Infection




Charcot’s Foot (Neuro-Osteoathropat hy)
Osteolytic destruction of 2rd, 4th Metatarsal Head
Widening 3rd Metatarsophalangeal joint

				
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