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)