Complications of diabetes mellitus Nra Hosszfalusi 2011.03.29. - - PowerPoint PPT Presentation

Complications of diabetes mellitus

Nóra Hosszúfalusi 2011.03.29.

Acute and chronic complications

Acute

• Diabetic ketoacidosis

(DKA)

• Hyperglycemic

hyperosmolaris syndrome (HHS)

• hypoglycemia
• metformin associated

lactic acidosis, MALT Chronic

• nephropathy
• retinopathy
• neuropathy
• Macrovascular diseases

(CHD, peripheral vascular disease, stroke)

Chronic complications

Associations between HbA1c and MI and microvascular complications

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)* !" ' *+*),

HbA1c

Retinopathy Nephropathy Neuropathy Macrovascular disease

DCCT DCCT

9 → → → → 7% 76% 54% 60% 41%*

Kumamoto

9 → → → → 7% 69% 70%

• UKPDS

7,9 → → → → 7% 17-21% 24-33%

• 16%*

* not statistically significant

Good glycemic control decreases the diabetic complications Good glycemic control decreases the diabetic complications

UKPDS Study Group. Lancet 352:837-53, 1998 Ohkubo Y. Diabetes Res Clin Prac 28:103-17, 1995 DCCT Study Group. N Engl J Med 329:977-86, 1993

genetic background repeated acute, reversible changes hyperglycemia functional structural changes changes cumulative, irreversible changes in stable macromolecules

• ther 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

fehérje + redukáló cukor Schiff bázis Amadori termékek Késői glikációs termékek (AGE) keresztkötései

CML (Nε ε ε ε&karboximetil lizin) Pirralin Pentozidin AFPG (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 glycation end products (AGE)

H

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

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 ↑ Normal No, transient ↑/→

• II. glomerular

tissue changes Glomerular hypertrophy Normal No ↑

• I. hypertrophy

hyperfiltration Histology RR PU GFR Stages

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

+ → +++ + → +++ Proximal + → +++ 0 → +++ Motor deficit N N ↓↓ N → ↓ N → ↓↓↓ Tendon reflex + → +++ + → +++ + → +++ + → +++ + → +++ Pain + → +++ 0 → + 0 → + 0 → + thermal, allodynia 0 → +++ touch, vibration Sensory loss Pressure palsies Acute mononeu. Proximal motor Small fiber Large fiber Type

Diabetic foot syndrome

Hammer toe Ulcer

Contractures → Hammer toe → Improper weight-bearing → Ulcer → Infection → Osteomyelitis → Amputation

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 function, heart rate Variability:

• Valsalva’s maneuver
• Deep breathing
• Supine vs. standing

Sympathic function (RR):

• Orthostatic

hypotension

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

Survival (9 Survival (9 Survival (9 Survival (9-

• years follow

years follow years follow years follow-

• up):

up): up): up): Hoorn Hoorn Hoorn Hoorn Study Study Study Study in the 50 in the 50 in the 50 in the 50-

• 75 year old population

75 year old population 75 year old population 75 year old population DM (WHO DM (WHO DM (WHO DM (WHO-

• criteria): 8 %

criteria): 8 % criteria): 8 % criteria): 8 %

follow-up (years) 10 8 6 4 2 Cum Survival 1,0 ,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

10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6 7 8 Year

Nondiabetic without prior MI Diabetic without prior MI Nondiabetic with prior MI Diabetic with prior MI

Survival (%) Survival (%)

Results of OGTT after AMI

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 % of Patients

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 < 130/80 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. < 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 and EASD 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/l TG< 1,7 mmol/l RR< 130/80 aspirin CV halál, AMI, Stroke, Amputáció > 50 %-kal ↓

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 ↑.

• 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, life threatening 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)