Complications of diabetes mellitus Nóra Hosszúfalusi 2011.03.29.
Acute and chronic complications Acute Chronic - Diabetic ketoacidosis - nephropathy (DKA) - retinopathy - Hyperglycemic - neuropathy hyperosmolaris - Macrovascular diseases syndrome (HHS) (CHD, peripheral vascular disease, - hypoglycemia stroke) - metformin associated lactic acidosis, MALT
Chronic complications
Associations between HbA1c and MI and microvascular complications #� �' �����*���+������*)�,����� $� ����������)*�� !" '���(����� �� �� � � $������ %����������# &�������� ��� �� ����������� �� ������������ !" ����������������������������� �������������������� ��������� ����������������� ������������������ ���� ���
Good glycemic control decreases Good glycemic control decreases the diabetic complications the diabetic complications DCCT Kumamoto DCCT UKPDS HbA 1c 9 → → 7% 9 → → 7% 7,9 → → 7% → → → → → → Retinopathy 76% 69% 17-21% Nephropathy 54% 70% 24-33% Neuropathy 60% - - Macrovascular 41%* - 16%* disease * not statistically significant DCCT Study Group. N Engl J Med 329:977-86, 1993 Ohkubo Y. Diabetes Res Clin Prac 28:103-17, 1995 UKPDS Study Group. Lancet 352:837-53, 1998
genetic background repeated acute, reversible changes hyperglycemia functional structural changes changes cumulative, irreversible changes in stable macromolecules other risk factors
Hyperglycemia causes acute reversible and cumulative irreversible changes • Acute, reversible intracellular metabolic changes • Cumulative, irreversible effects on stabile macromolecules
Metabolic changes caused by hyperglycemia
Acute, reversible intracellular metabolic changes • Increased activity of polyol pathway • Modified protein kinase C activity • Early glycation products • Increased production of free radicals
Consequences of increased protein kinase C (PKC) activity
Development of advanced glycation end products (AGE) Early → → → → Intermedier → → → → Advenced (AGE) H fehérje + Amadori Késői glikációs termékek Schiff bázis redukáló cukor (AGE) keresztkötései termékek Pentozidin CML FFI AFPG Pirralin (N ε ε &karboximetil ε ε (2&(2&furoil)&4(5)&(2&furanil)& (1&alkil&2&formil&3,4& lizin) 1H&imidazol) diglűkozil&pirrol)
Effects of advanced glycation end products (AGE) • Crosslinking of extracellular proteins • Interactions with specific AGE receptors • Crosslinking with intracellular DNA
Cells having AGE-receptors • Monocyta, macrophage • Endothel • Pericyta • Podocyta • Astrocyta • Microglia
Interactions with specific AGE receptors
Hemodynamic disturbances in diabetes • Increased blood flow • Increased permeability • Hemorrheological and coagulation abnormalities - increased plasma viscosity - decreased red-cell deformability - increased platelet aggregability
Structural abnormalities in diabetes • Leakage of glycated plasma proteins • Extracellular matrix is increased - BM is thickened - mesangial matrix is expanded - collagen is increased • Hypertrophy and hyperplasia of endothelial, mesangial and arterial smooth muscle cells
Nephropathia
Stages of nephropathy in T1DM Stages GFR PU RR Histology ↑ I. hypertrophy No Normal Glomerular hyperfiltration hypertrophy ↑ / → II. glomerular No, Normal GBM tissue changes thickening, transient mesangium ↑ ↑ / → ↑ within the III. „beginning” MAU + Severe > st. II. persist. normal nephropathy ↓ ↑ IV. manifest macro- glomeruloscl., nephropathy albumin- arterioscler., uria tubulointerst. ↓ ↓ ↓ ↑ V. insuff. renalis Severe > st. IV.
Diagnosis and treatment of microalbuminuria • Screening once a year in T1DM (at least), at diagnosis in T2DM • Urinary albumin excretion 30-300 (299) mg / 24 h • 2 positive out of 3 samples (collected urine) (fever, urinary tract infection, heart failure etc.) • ACE-inhibitors (ARB), good metabolic control • DM + albuminuria increases the CVD mortality with 20 x
NOT characteristic for diabetic nephropathy • Rapid progression (rapid development of nephrotic syndrome) • Considerable hematuria, red-cell casts • Absence of retinopathy • Short disease duration (T1DM)
Diabetic Eye Disease Retinopathy
Stages of diabetic retinopathy Non-proliferative retinopathy • mild non-proliferative (background): microaneurysms, scattered exsudates, haemorrhages (no complains) macular oedema macular ischaemia • severe non-proliferative (preproliferative): multiple previous abnormalities, cotton-wool spots, intraretinal microvascular abnormalities ( IRMA) through the whole retina
Stages of diabetic retinopathy Proliferative retinopathy • Impaired vision, blindness • New vessels, fibrous proliferation, hemorrhages (preretinal vitreous), retinal detachment
Screening! • Screening at least once a year • DR no + good metabolic control 1x a year mild DR + good metabolic control 6 months RD no + bad metabolic control 3-6 months dilated pupil!! cataract glaucoma Visus, pressure, fundus! • Laser photocoagulation!! (FLAG, OCT)
OCT (optical coherence tomographic) image, healthy retina
OCT macular oedema
Diabetic Neuropathies
Classification of diabetic neuropathy • Diffuse neuropathy - somatic np.: sensorimotor - autonomic np.: cardiovascular, gastrointestinal, genitourinary, pupil • Focal syndromes - focal np.: mononeuritis, entrapment syndr. - multifocal np.: proximal neuropathies • Subclinical neuropathy - abnormal electrodiagnostic tests - abnormal quantitative sensory tests - abnormal autonomic function tests
Type Large fiber Small fiber Proximal Acute Pressure motor mononeu. palsies 0 → +++ 0 → + 0 → + 0 → + + → +++ Sensory loss touch, thermal, vibration allodynia + → +++ + → +++ + → +++ + → +++ + → +++ Pain N → ↓↓↓ N → ↓ ↓↓ Tendon N N reflex 0 → +++ + → +++ + → +++ Motor 0 Proximal + → +++ deficit
Diabetic foot syndrome
Contractures → Hammer toe → Improper weight-bearing → Ulcer → Infection → Osteomyelitis → Amputation Hammer toe Ulcer
Quantitative sensory tests • Tuning fork (vibration perception) • Monofilament (touch sensation, predict foot ulceration) • Pain and thermal sensation • Tendon reflexes (Achilles) • Neurometer (áramérzet küszöb)
Classification of diabetic foot ulcer (Meggitt-Wagner Ulcer Classification • Grade 0: No ulcer, but high-risk foot (bony prominences, callus, deformities, previous ulcer) • Grade 1: Superficial, full-thickness ulcer • Grade 2: Deep ulcer, may involve tendons, but without bone involvement • Grade 3: Deep ulcer with osteomyelitis • Grade 4: Local gangrene • Grade 5: Gangrene of whole foot
University Texas Wound Classification System • Grade 0: Pre- or postulcerative lesion, completely epithelialized • Grade 1: Superficial wound not involving tendon, capsule or bone • Grade 2: Wound penetrating to tendon or capsule • Grade 3: Wound penetrating to bone or joint • Stage A: without infection or ischemia • Stage B: with infection • Stage C: with ischemia • Stage D: with infection and ischemia
Treatment of diabetic foot ulcer • Removing necrotic tissue • Removing the pressure (casts, total contact casts) • Antibiotic treatment (1-12 weeks): clidamycin, ciprofloxacin, cephalexin, amoxicillin-clavulanate, impenem, • Revascularisation
Charcot’s neuropathic arthropathy Progressive, relatively painless, destructive
Cardiovascular tests Quantitative autonomic function tests Parasympathic Sympathic function function, heart rate (RR): Variability: • Orthostatic • Valsalva’s maneuver hypotension • Deep breathing • Supine vs. standing Autonomic neuropathy increases the five-year mortality with 3 times!
Macrovascular complications
Cardiovascular risk in diabetes • Peripheral arterial disease 2-4x ↑ (risk of amputation 16x ↑ ) • CHD: risk of AMI 2-3x ↑ , heart failure 5x ↑ • Stroke 2-4 x ↑ • Protection of female gender is disappeared • The macrovascular risk is 10 x ↑ in the presence of microvascular complication
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