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)