Complications ofdiabetes mellitus
Nóra Hosszúfalusi2017
Acute and chronic complications
Acute
- diabetic ketoacidosis
(DKA)
Chronic
Microvascular
- nephropathy(DKA)
- hyperglycemic
hyperosmolaris
syndrome (HHS)
- hypoglycemia
- metformin associated
lactic acidosis, MALT
- nephropathy
- retinopathy (eye)
- neuropathy
Macrovascular diseases
- CHD
- peripheral vascular disease
- stroke
Chronic complications
HbA1c
Retinopathy
DCCTDCCT9 →→→→ 7%
76%
Kumamoto9 →→→→ 7%
69%
UKPDS7,9 →→→→ 7%
17-21%
Good glycemic control decreasesthe diabetic complications
Good glycemic control decreasesthe diabetic complications
Nephropathy
Neuropathy
Macrovasculardisease
54%
60%
41%*
70%
-
-
24-33%
-
16%*
* not statistically significant
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 structural hyperglycemia functional structural changes changes
cumulative, irreversiblechanges instable macromolecules
other risk factors
Hyperglycemia causesacute reversible and
cumulative irreversible changes
• Acute, reversible intracellular metabolic changeschanges
• 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• Modified protein kinase C activity• Early glycation products• Increased production of free radicals
Consequences of increasedprotein kinase C (PKC) activity
Early →→→→ Intermedier →→→→ Advenced (AGE)
Development of advanced glycationendproducts (AGE)
H
fehérje +
redukáló cukor Schiff bázisAmadori
termékek
Késői glikációs termékek (AGE) keresztkötései
CML
(Nεεεε-karboximetil lizin)
PirralinPentozidinAFPG
(1-alkil-2-formil-3,4-diglűkozil-pirrol)
FFI
(2-(2-furoil)-4(5)-(2-furanil)-1H-imidazol)
Effects of advanced glycation end products (AGE)
• Crosslinking of extracellular proteins • Interactions with specific AGE receptors• Interactions with specific AGE receptors• Crosslinking with intracellular DNA
Cells having AGE-receptors
• Monocyta, macrophage• Endothel• Pericyta• Pericyta• Podocyta• Astrocyta• Microglia
Interactions with specific AGE receptors
Hemodynamic disturbances in diabetes
• Increased blood flow• Increased permeability• Hemorrheological and coagulation • 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 - BM is thickened - mesangial matrix is expanded- collagen is increased
• Hypertrophy and hyperplasia of endothelial, mesangial and arterial smooth muscle cells
Nephropathia
Glomerular endothelial glycocalyx
Rabelink, T. J. & de Zeeuw, D. (2015) The glycocalyx—linking albuminuria with renal and cardiovascular diseaseNat. Rev. Nephrol. doi:10.1038/nrneph.2015.162
Stages of nephropathy in T1DM
Stages GFR PU RR Histology
I. hypertrophy hyperfiltration
↑ No Normal Glomerular hypertrophy
II. glomerular tissue changes
↑/→ No,
transient
Normal GBM thickening, tissue changes transient thickening, mesangium ↑
III. „beginning”
nephropathy
↑/→ MAU + persist.
↑ within the normal
Severe > st. II.
IV. manifest nephropathy
↓ macro-albumin-uria
↑ glomeruloscl.,
arterioscler.,
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)nephrotic syndrome)
• Considerable hematuria, red-cell casts
• Absence of retinopathy
• Short disease duration (T1DM)
Diabetic Eye DiseaseRetinopathyRetinopathy
Stages of diabetic retinopathy
Non-proliferative retinopathy• mild non-proliferative (background):
microaneurysms, scattered exsudates, haemorrhages (no complains)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, • 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 monthsRD no + bad metabolic control 3-6 monthsdilated pupil!! cataract glaucomaVisus, pressure, fundus!
• Laser photocoagulation!! (FLAG, OCT)
Diabetic Neuropathies
Classification of diabetic neuropathy
• Diffuse neuropathy- somatic np.: sensorimotor- autonomic np.: cardiovascular, gastrointestinal, genitourinary, pupil
• Focal syndromes- focal np.: mononeuritis, entrapment syndr. - 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 PressureType Large fiber Small fiber Proximal motor
Acute
mononeu.
Pressure
palsies
Sensory
loss
0 → +++
touch,
vibration
0 → +
thermal,
allodynia
0 → + 0 → + + → +++
Pain + → +++ + → +++ + → +++ + → +++ + → +++
Tendon
reflex
N → ↓↓↓ N → ↓ ↓↓ N N
Motor
deficit
0 → +++ 0 Proximal
+ → +++
+ → +++ + → +++
Diabetic foot syndrome
Hammer toe
Contractures → Hammer toe →Improper weight-bearing → Ulcer →Infection → Osteomyelitis → Amputation
Ulcer
Quantitative sensory tests
• Tuning fork (vibration perception)
• Monofilament (touch sensation, predict foot ulceration)ulceration)
• Pain and thermal sensation
• Tendon reflexes (Achilles)
• Neurometer (áramérzet küszöb)
University Texas Wound Classification System
• Grade 0:Pre- or postulcerative lesion, completely epithelialized
• Grade 1:Superficial wound not involving tendon, capsule or bonecapsule 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)casts)
• Antibiotic treatment (1-12 weeks): clidamycin, ciprofloxacin, cephalexin, amoxicillin-clavulanate, impenem,
• Revascularisation
Cardiovascular testsQuantitative autonomic function tests
Parasympathic
function, heart rate
Variability:
Sympathic function
(RR):
• Orthostatic Variability:
• Valsalva’s maneuver
• Deep breathing
• Supine vs. standing
• Orthostatic hypotension
Autonomic neuropathy increasesthe five-year mortality with 3 times!
Macrovascular complicationscomplications
Cardiovascular risk in diabetes
• Peripheral arterial disease 2-4x ↑ (risk of amputation 16x ↑)
• CHD: risk of AMI 2-3x ↑, heart failure 5x ↑ • 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): Hoorn Studyup): Hoorn Studyup): Hoorn Studyup): Hoorn Studyin 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 %
Cu
m S
urv
ival
1,0
,9 NGT
follow-up (years)
1086420
Cu
m S
urv
ival
,8
,7
,6
,5
IGT
NDM
KDM
De Vegt et al: Diabetes Care.2000;23:40
Results of OGTTafter AMI
70
80
90
100
IGT Newly diagnosed DM
n = 181
% o
f Pat
ient
s
0
10
20
30
40
50
60
70
At Discharge 3 mo later At Discharge 3 mo later
35% 40% 31% 25%
% o
f Pat
ient
s
Norhammar A, et al. Lancet 2002;359:2140-44.
Hypertension/blood pressure control
• Should be measured at every visit
• Repeat RR ≥ 130/80 Hgmm confirms the diagnosis of hypertension
• Therapeutic goal:
• RR < 140(<130)/<90(<80) Hgmm
• 130-139/80-89 Hgmm lifestyle for 3 months
• RR ≥ 140/90 Hgmm drug 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. < 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- 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• 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 improve outcomes as long as CVD risk factors are treated (A).
STENO-2 study
HbA1c< 6.5%TC< 4.5 mmol/lTG< 1.7 mmol/lRR< 130/80 aspirinaspirin
CV death,AMI,Stroke,Amputation> 50 % ↓
Diabetes and infections
• 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 ↑.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)• Psoas abscessus (St. aureus)• Emphysematosus cholecystitis (E. coli, Cl.
Perfringens)• Emphysematosus urocystitis, pyelonephritis
(E. coli, K. pneumoniae)• Fasciitis necrotisans (polymicrobe)