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Complications ofdiabetes mellitus
Nóra Hosszúfalusi2011.03.29.
Acuteandchroniccomplications
Acute
- Diabetic ketoacidosis
(DKA)
- Hyperglycemic
hyperosmolaris
syndrome (HHS)
- hypoglycemia
- metformin associated
lactic acidosis, MALT
Chronic
- nephropathy
- retinopathy
- neuropathy
- Macrovascular diseases
(CHD, peripheralvascular disease, stroke)
Chronic complications
Associations betweenHbA1c andMIandmicrovascular complications
Stratton IM, et al. Stratton IM, et al. UKPDS 35.UKPDS 35. BMJ 2000; 321:405BMJ 2000; 321:405––412412
Átlagos HbA1c koncentráció (%)
80
60
40
20
05 6 7 8 9 10 11
Inci
denc
ia10
00 b
eteg
évre
(%)
MIMicrovascularis végpontok
HbA1c
Retinopathy
Nephropathy
NeuropathyMacrovasculardisease
DCCTDCCT9 →→→→ 7%
76%
54%
60%
41%*
Kumamoto9 →→→→ 7%
69%
70%
-
-
UKPDS7,9 →→→→ 7%
17-21%
24-33%
-
16%*
* not statistically significant
Goodglycemiccontrol decreasesthediabeticcomplications
Goodglycemiccontrol decreasesthediabeticcomplications
UKPDS Study Group. Lancet 352:837-53, 1998Ohkubo Y. Diabetes Res Clin Prac 28:103-17, 1995DCCT Study Group. N Engl J Med 329:977-86, 1993
genetic background
repeated acute,reversible changes
hyperglycemia functional structuralchanges changes
cumulative, irreversiblechanges instable macromolecules
other risk factors
Hyperglycemia causesacute reversible and
cumulative irreversible changes
• Acute, reversible intracellular metabolic changes
• Cumulative, irreversible effects on stabile macromolecules
Metabolic changes caused by hyperglycemia
Acute, reversible intracellularmetabolic changes
• Increased activity of polyol pathway • Modified protein kinase C activity• Early glycation products• Increased production of free radicals
Consequences of increasedprotein kinaseC (PKC) activity
fehérje +
redukáló cukor Schiff bázisAmadori
termékek
Késői glikációs termékek (AGE) keresztkötései
CML
(Nεεεε-karboximetillizin)
PirralinPentozidinAFPG
(1-alkil-2-formil-3,4-diglűkozil-pirrol)
FFI
(2-(2-furoil)-4(5)-(2-furanil)-1H-imidazol)
Early →→→→ Intermedier →→→→ Advenced (AGE)
Development of advanced glycationendproducts (AGE)
H
Effects of advanced glycationend 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 abnormalitiesin 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 nephropathyin T1DM
Severe > st. IV. ↑↓↓ ↓V. insuff. renalis
glomeruloscl.,
arterioscler.,
tubulointerst.
↑macro-albumin-uria
↓IV. manifest nephropathy
Severe > st. II. ↑ within the normal
MAU + persist.
↑/→III. „beginning”
nephropathy
GBM thickening, mesangium↑
NormalNo,
transient
↑/→II. glomerulartissue changes
Glomerularhypertrophy
NormalNo↑I. hypertrophy hyperfiltration
HistologyRRPUGFRStages
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 DiseaseRetinopathy
Stages of diabetic retinopathy
Non-proliferative retinopathy• mild non-proliferative (background):
microaneurysms, scattered exsudates, haemorrhages (no complains)macular oedemamacular ischaemia
• severenon-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 monthsRD no + bad metabolic control 3-6 monthsdilated pupil!! cataract glaucomaVisus, pressure, fundus!
• Laser photocoagulation!! (FLAG, OCT)
OCT (optical coherence tomographic)image, healthy retina
OCTmacular 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
+ → ++++ → +++Proximal
+ → +++
00 → +++ Motor
deficit
NN↓↓N → ↓N → ↓↓↓Tendon
reflex
+ → ++++ → ++++ → ++++ → ++++ → +++Pain
+ → +++0 → +0 → +0 → +
thermal,
allodynia
0 → +++
touch,
vibration
Sensory
loss
Pressure
palsies
Acute
mononeu.
Proximalmotor
Small fiberLarge fiberType
Diabeticfoot syndrome
Hammer toe
Ulcer
Contractures → Hammer toe →Improper weight-bearing → Ulcer →Infection → Osteomyelitis → Amputation
Quantitativesensorytests
• Tuning fork (vibration perception)
• Monofilament (touch sensation, predict footulceration)
• 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 arthropathyProgressive, relatively painless, destructive
Cardiovascular testsQuantitative autonomic function tests
Parasympathic
function, heart rate
Variability:
• Valsalva’s maneuver
• Deep breathing
• Supine vs. standing
Sympathic function
(RR):
• Orthostatichypotension
Autonomic neuropathy increasesthe five-year mortality with 3 times!
Macrovascularcomplications
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
Survival (9Survival (9Survival (9Survival (9----years followyears followyears followyears follow----up): up): up): up): HoornHoornHoornHoorn StudyStudyStudyStudyin the 50in the 50in the 50in the 50----75 year old population75 year old population75 year old population75 year old population
DM (WHODM (WHODM (WHODM (WHO----criteria): 8 %criteria): 8 %criteria): 8 %criteria): 8 %
follow-up (years)
1086420
Cu
m S
urv
iva
l1,0
,9
,8
,7
,6
,5
NGT
IGT
NDM
KDM
De Vegt et al: Diabetes Care.2000;23:40
Survival rate with DM and/or AMI
0102030405060708090
100
0 1 2 3 4 5 6 7 8
Year
Nondiabetic without prior MIDiabetic without prior MINondiabetic with prior MIDiabetic with prior MI
Su
rviv
al(%
)S
urv
ival
(%)
Results of OGTTafter AMI
0
10
20
30
40
50
60
70
80
90
100
IGT
At Discharge 3 mo later At Discharge 3 mo later
Newly diagnosed DM
35% 40% 31% 25%
n = 181
% o
f Pat
ient
s
Norhammar A, et al. Lancet 2002;359:2140-44.
Hypertension/bloodpressurecontrol
• Should be measured at every visit
• Repeat RR ≥ 130/80 Hgmmconfirms the diagnosis of hypertension
• Therapeutic goal: RR < 130/80 Hgmm
• 130-139/80-89 Hgmmlifestyle for 3 months
• RR ≥ 140/90 Hgmmdrug therapy
• ACE-I or ARB
Dyslipidemia/lipid management
• At least annually measurement (low risk 2 years)
• Therapeutic goal:
LDL-chol. < 2.6 mmol/l (no CVD)
LDL-chol. < 1.8 mmol/l (with CVD)
TG < 1.7 mmol/l
HDL-chol. > 1.0 (male); > 1.3 mmol/l (female)
Dyslipidemia/lipid management
• Lifestyle modification
• Statin regardless of basal lipid levels!!!! If
- DM + overt CVD
> 40 years of age, + risk faktor(s) for CVD
• < 40 years of age, LDL > 2.6 mmol/l or multiple CVD risk factors
• Contraindicated in pregnancy
Antiplatelet therapy(low dose aspirin)
• Primary prevention (T1, T2)
CV 10-year risk >10 %; male > 50 years, female > 60 years + at least one major CVD risk factor
• Major risk factors: family history of CVD, hypertension, smoking, dyslipidemia, albuminuria
• No aspirin if the 10-year CVD risk < 5 %
• Clinical judgment between 5-10 %
• Secondary prevention
• CVD + aspirin allergy → clopidogrel
• Combination up to one year after ACS
CHD screening in diabetes(ESC andEASD guideline 2007)
• Resting ECG (1x a year)
• Echocardiographia
• Exercise testing ECG
ADA recommendation 2011
• In asymptomatic patients, routine screening for CHD is not recommended, as it does not improve outcomes as long as CVD risk factors are treated (A).
STENO-2 vizsgálat eredménye
HbA1c< 6,5%TC< 4,5 mmol/lTG< 1,7 mmol/lRR< 130/80 aspirin
CV halál,AMI,Stroke,Amputáció> 50 %-kal ↓
Diabetes andinfections
• Infections are more frequent: pneumonia, urinary tract, skin and mucosal infections 1.5-2 x ↑
• Infections are more severe, mortality rate is increased 2-3x ↑.
• Provokes hyperglycemic crisis. • Rare, life threatening infections.• Immunization: annually influenza vaccine,
pneumococcal polysaccharid vaccine > 2 years (repeat > 64 years of age, renal disease, transplantation)
Rare, lifethreatening infections.in diabetes
• Mucormycosis (rhinocerebralis) • Malign otitis externa (Ps. aeruginosa)• Psoas abscessus (St. aureus)• Emphysematosus cholecystitis (E. coli, Cl.
Perfringens)• Emphysematosus urocystitis, pyelonephritis
(E. coli, K. pneumoniae)• Fasciitis necrotisans (polymicrobe)