Acido urico come marker e target del rischio metabolico · infiammatoria nell’uomo ed è una...

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Acido urico come marker e target del rischio metabolicoP. Faggiano, Spedali Civili - Brescia

Perché parlare di uricemia ?

è una malattia metabolica dovuta ad un disordine del

dismetabolismo delle purine che porta alla deposizione di

cristalli di urato monosodico a livello articolare e nei tessuti

extra-articolari con formazione di depositi denominati tofi.

L’iperuricemia cronica con deposito di urato (gotta)

La presenza di iperuricemia, definita dal riscontro di livelli

circolanti di acido urico >6 mg/dL, rappresenta il prerequisito

fondamentale per la deposizione a livello articolare e tissutale

di urato.

NEL PASSATO:“LA MALATTIA DEI RE – LA MALATTIA DEI PAPI”

La gotta era definita come la più comune artropatia

infiammatoria nell’uomo ed è una frequente causa di

infiammazione articolare nella donna, con una

prevalenza che eccede quella dell’artrite reumatoide

E’ stata a lungo etichettata come “la malattia dei re e

dei papi ” a voler evidentemente sottolineare

un’associazione con un tenore di vita elevato tale da

consentire abitudini alimentari piuttosto ricche

Doherty M, Ann Rheum Dis 2012; 71: 1765-1770Marson P, Reumatismo 2011; 63 (4): 199-207

IL PRESENTE:MALATTIA DA DISMETABOLISMO DELL’ACIDO URICO

Nel corso degli ultimi decenni un crescente interesse è

stato rivolto da parte della letteratura al problema della

patologia da dismetabolismo dell’acido urico e delle

condizione morbose ad essa correlate come determinanti

del rischio cardio-nefro-metabolico in ragione del

frequente riscontro di una significativa associazione

tra iperuricemia cronica con e senza deposito di

urato ed aumento del rischio relativo di complicanze

cardiovascolari e/o renali.

Uric Acid (UA)

ipoxanthine

Fructokinase

xanthine

Fructose

ATP

ADPFructose-1-phosphate

AMPIMP

Uric Acid

Xanthine Oxydase

AMP deaminase

PURINESDegradation of

Nucleic Acid

Allantoin + CO2

Uricase+ O2 + H2O

5-hydroxyisourate + H2O2

3D structure of Uric Acid

Aspetti epidemiologici

IPERURICEMIA CON E SENZA DEPOSITO

DI URATO

Confrontro tra la prevalenza della malattia da

depositi di urato rilevata nella popolazione

americana nel NHANES-III (1988-1994) e nel

NHANES 2007-2008

Prevalenza dell’iperuricemia (livelli circolanti

>6 mg/dl) per 1000 abitanti distinti per sesso ed

anno di riferimento

Ann Rheum Dis.2012 Jun 26

1) Dieta squilibrata, con eccesso di 3 elementi

cruciali nell’indurre iperuricemia

2) Incremento delle condizioni che causano

iperuricemia (e da questa sono causate)

3) Invecchiamento popolazione, e/o aumento

delle patologie causanti iperuricemia

Cause dell’aumento nella loro prevalenza dal 1980 ad oggi

Purine (troppa carne)

Proteine (troppa carne)

Fruttosio (addizionato alle bevande)

Obesità centrale

Disglicemia/Diabete mellito di tipo 2

Dislipidemia

Ipertensione arteriosa

Sindrome metabolica

Uso di diuretici (tiazidici, dell’ansa)

ASA basso dosaggio (CHD, etc.)

Insufficienza renale cronica

Iperuricemia cronica con e senza deposito di urato

Epidemiologia

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study S

urv

ival W

itho

ut D

iab

ete

s (

%)

Years

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

ent

Rat

e (x

100

per

son

s-y

ears

)

Ev

ent

Rat

e (x

100

per

son

s-y

ears

) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

Death

Terminal HF

Dementia

ESRD

Endothelial

dysfunction and

activation

Micro-

albuminuria

CHF

Secondary stroke

Nefrotic

proteinuria

Macro-

proteinuria

MI and Stroke

ATS, IVS

LV dilation

Cognitive

impairment

LV

remodelling

Serum Uric Acid and the CV continuum

Cardiovascular

Risk factors

Wellness FrailtyAdapted from Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Risk Target Organ Damage Events

Cu

mu

lative

Eve

nt

Fre

e S

urv

iva

l

Months

lower LVMI and lower UA

lower LVMI and higher UA

higher LVMI and lower UA

higher LVMI and higher UA

Cumulative Event Free Survival in Hypertensive

Patients with and Without Cardiac TOD in relation to

Serum Uric Acid Levels

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551. Feig DI, et al. N Engl J Med 2008; 359: 1811-1821.

Verdecchia P et al. Hypertension. 2000;36:1072-1078.)

Relation Between Serum Uric Acid and Risk of

CVD in Essential Hypertension: The PIUM A Study

TotalCVevents FatalCVevents Allcausedeaths

1720 subjects with EH, untreated, screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Follow-up up to 12 years (mean, 4.0) we followed

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs)

Ev

en

t R

ate

(x

10

0 p

ers

on

s-y

ea

rs) Women (n=800) Men (n=920)

T T T

mg/dL 4.5 5.2 6.2 3.2 3.9 4.6

T T T

n=21,475 healthy volunteers (Vienna health screening project); mean age 46 yrs; F-UP = 7 y; Development of Kidney Disease (eGFR-MDRD stage 3 CKD)

natural cubic spline OR for stage 3 CKD

depending on UA levels

com pared w ith m ean UA levels

( 4 .2 in fem ales, 5 .9 in m en)

ObermayrRP,etal.JASN2008

After adjustment for: baseline

eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol,

blood glucose, triglycerides, and BP)

ViazziFetal.DiabetesCare.2011;34:126-8

Serum Uric Acid Levels Predict New-Onset Type 2

Diabetes in Hospitalized Patients With Primary

Hypertension: The M AGIC Study

Su

rviv

al W

itho

ut D

iab

ete

s (

%)

Years

Shah A, et al. Curr Rheumatol Rep (2010) 12:118–124

Gout, Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect?

Feig DI et al. JAMA. 2008;27;300(8):924-32.

Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension

Mean 24 hour blood pressure

Pretreatment End of placebo phase

Pretreatment End of allopurinol phase

Pretreatment End of placebo phase

Pretreatment End of allopurinol phase

Sy

sto

lic

Blo

od

Pre

ssu

re (

mm

Hg

)

Sy

sto

lic

Blo

od

Pre

ssu

re (

mm

Hg

)

Dia

sto

lic

Blo

od

Pre

ssu

re (

mm

Hg

)

Dia

sto

lic

Blo

od

Pre

ssu

re (

mm

Hg

)

Allopurinol and Cardiovascular Outcomes in Adults With Hypertension

A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were

studied: 10-year period

MacIsaac ML et al. Hypertension 2016

Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients

Dogan A, et al. Blood Press 2011 Jun;20(3):182-7.

100 diabetic normotensive pts randomized to allopurinol (900 mg/die) or placebo for 12 weeks.

Uric acid (mg/dL) HBA1c

P=0.01

P=0.01

Xu X et al. J Card Fail. 2008 ; 14(9): 746–753

Xanthine Oxidase Inhibition with Febuxostat Attenuates Systolic Overload-induced Left Ventricular Hypertrophy

and Dysfunction in Mice

*p<0.05 as compared with sham group; #p<0.05 as compared with vehicle group

TAC = Transverse aortic constriction. VH = vehicle. FBS = febuxostat

Urate lowering therapy to improve renal outcomes in

patients with chronic kidney disease: systematic review

and meta-analysis

Kanji et al. BMC Nephrology (2015) 16:58

Effects of probenecid on endothelial function in patients

with New York Heart Association Class II–III chronic

heart failure

Soletsky B et al, Hypertension 2012

Mortalità cardio-vascolare per quartile di uricemiaThe NHANES I Epidemiologic Follow-up study (1971-

1992)

5926 soggetti ,età 24-75 anni, follow-up medio 16,4 anni

Fang J et al. 2000;283(18):2404-2410

Hazard Ratio (HR) aggiustati per età e pressione

arteriosa per livello sierico di acido urico e malattia

cardiovascolare: The Rotterdam Study

Bos M J et al. Stroke. 2006;37:1503-1507

Quintili di acido urico

Malattia coronarica

(n = 515)

Infarto del miocardio

(n = 149)

Tutti gli ictus

(n = 381)

Ictus ischemici

(n = 205)

Ictus emorragici

(n = 46)

Ndrepepa G et a Am J Cardiol 2012;109:1260 –1265l

Valore prognostico dei livelli circolanti di acido urico nei pazienti con sindrome coronarica acuta

Iperuricemia e cardiopatia ischemica

>6 mg/dl: 14.6%

OR: 1.4 ,2° tertile

2.2 , 3° tertile

Livelli medi di acido urico sierico durante il periodo di investigazione (mg/dl)

0%

20%

40%

60%

80%

100%

5 (0.30) 6 (0.36) 7 (0.42) 8 (0.48) 9 (0.54) 10 (0.60)

Inci

den

za d

i ric

orr

enti

att

acch

i di g

ott

a a

più

di 1

an

no

do

po

ogn

i pri

ma

visi

ta d

el p

azie

nte

(%

) ObservedLogistic regression

Solubilità dell’Acido Urico

37oC

Shoji ,et al. Arthritis & Rheumatism 2004

La frequenza degli attacchi acuti è correlata ai livelli di uricemia

Livelli di uricemia <6,0 mg/dlhanno comportano una ridotta frequenza o la prevenzione dei

futuri attacchi acuti (11)

Target terapeutici

Contenuto in purine Alimenti

150-1000 mg (altissimo)Animelle, molluschi, acciughe, fegato, rene, estratti di carne, insaccati, lievito

50-150 mg (alto)Montone, vitello, tacchino, oca, merluzzo, sgombro, salmone, trota, frutta secca

15-50 mg (moderato)

Bue, coniglio, pollo, maiale, crostacei, fagioli, piselli, lenticchie, spinaci, asparagi, carciofi, formaggi grassi o fermentati, cachi, banane, fichi

<15 mg (basso)Bevande, cereali, latte, burro, formaggi, uova, verdure

Contenuto in purine per 100 gr di pesoLA DIETA

Target terapeutici

Effect of Allopurinol on Cardiovascular Outcomes in

Hyperuricemic Patients: A Cohort Study

N=7127 N=7127

Main outcome: HR 0.89 (95% CI, 0.81-0.97) allopurinol vs control

All-cause mortality: HR 0.68 (95% CI, 0.62-0.74) allopurinol vs

control

Larsen KS et al. The American Journal of Medicine (2016) 129, 299-306

2011; 71:600-607.

Ridurre l’uricemia < 5 mg/dl può offrire ulteriori vantaggi

Niskanen, Arch Int Med 2004

Nell’uomo, l’acido urico è il prodotto finale del catabolismo delle purine, prodotto dall’ossidazione della xantina ad opera dell’enzima xantina

ossidasi

XANTINA-OSSIDASI:

TARGET CRUCIALE NEL MECCANISMO D’AZIONE

DEI FARMACI IPOURICEMIZZANTI

Terapia dell’iperuricemia

Terapia dell’iperuricemia

Efficacia e maneggevolezza di Febuxostat nel ridurre l’uricemia al target minimo di 6 mg/dL in pazienti con malattia da depositi di urato

Jackson RL et al. BMC Geriatrics 2012;12:11

Terapia dell’iperuricemia

Alcune considerazioni conclusive

- Dosaggio dell’uricemia in pazienti con fattori di rischio

cardiovascolare, cardiopatia accertata o sospetta

- Utilizzo del valore di uricemia nella interpretazione

fisiopatologica del quadro clinico, nella stratificazione

prognostica

- Considerare l’uricemia un target di interventi

terapeutici, sia farmacologici, che sugli stili di vita

Brescia Dott. P. FaggianoMilano Dott. F. OlivaBergamo Dott.ssa R. Rossini

Analisi dei dati dott.ssa A. Iorio

Periodo raccolta dati: 1-15 settembre 2016

Acido urico in Unità Coronarica: Survey lombarda

Clinical Characteristic 102 patients

Age (year) 67±14

Male sex (%) 73 (71)

Clinical presentation

Unstable Angina (n,%)

NSTEMI (n,%)

STEMI (n,%)

5 (4.9)

23 (22.5)

24 (23.5)

HF 37 (36.3)

Arrhythmia (n, %) 13 (12.5)

Post-CCH (n, %) 2 (2)

Hypertension 54 (52,5)

Diabetes Mellitus 29 (28.2)

Survey lombardaCaratteristiche basali I

Descriptive Statistics

N Minimum Maximum Mean Std. DeviationCreatinina 102 0.48 9.26 1.58 1.48Azotemia 102 18 423 67 63eGFR 102 5 203 69 44

Glicemia 102 62 999 133 111Emoglobina 102 7.2 16.8 12 2.2

coletot 94 77 273 155 37LDL 94 11 221 108 40

Survey lombardaCaratteristiche basali II

Treatment

Furosemide (n,%) 47, 46.1

Tiazidico (n,%) 3, 2.9

ASA (n,%) 47, 46.1

ACE-I (n,%) 32, 31.2

Sartano (n,%) 13, 12.7

Statine (n,%) 40, 39.1

Survey lombardaTerapia in UTIC

Survey lombardaMisurazione dei valori di acido urico

Uricemia 94 1.9 11.6 5 2N Minimum Maximum Mean

Std. Deviation

Terapia ipouricemizzante alla dimissione

Allopurinolo

Febuxostat

Survey lombardaValori di acido urico e terapia alla dimissione

Call to Action:

“Uricemia nei Reparti di Cardiologia”

Grazie per l’attenzione

Pulse wave velocity Left ventricular mass index

Circulation Journal Vol.77, August 2013

Iperuricemia ed ipertensione arteriosa

Acido urico ed attivazione intrarenale del sistema renina-angiotensina nell’uomo

Perlstein TS et al, Kidney Int 2004

Proposed mechanisms by which uric acid causes hypertension

Johnson R J et al. Hypertension. 2013;61:948-951

Titolo

• Nome dell'autore

• Inserire qui le informazioni

aggiuntive.

Viazzi F, et al. Hypertension 2005;45(5):991-6

Livelli circolanti di acido urico e danno d’organo nell’ipertensione arteriosa

mm

ol/

L

p<0.05p<0.05

p<0.05

Cum

ula

tive E

vent F

ree S

urv

ival

Months

lower LVMI and lower

UA

lower LVMI and higher

UA

higher LVMI and lower

UA

higher LVMI and higher

UA

Sopravvivenza cumulativa libera da eventi in pazienti ipertesi con e senza danno d’organo in relazione ai livelli

circolanti di acido urico

Niskanen LK, et al. Arch Intern Med 2004; 164: 1546-1551Feig DI, et al. N Engl J Med 2008; 359: 1811-1821

Viazzi F et al. Diabetes Care. 2011; 34:126-8

I livelli circolanti di acido urico predicono l’insorgenza di diabete di tipo 2 in pazienti ospedalizzati con

ipertensione arteriosa

Surv

ival

Wit

ho

ut

Dia

bet

es (

%)

Years

Iperuricemia e DIABETE

Iperuricemia e Componenti della Sindrome Metabolica

Semin Nephrol 2005;25:25-31

Path diagram for relations between uric acid, hypertension, cardiovascular disease, and kidney disease

Rischio di insorgenza di scompenso cardiaco in base ai

livelli di ac.urico nella popolazione del Framingham

Offspring Study

Krishnan E. Circ Heart Fail .2009; 2:556-562

Curve di sopravvivenza di Kaplan-Meier distinte per livelli di acido urico in pazienti con scompenso cardiaco lieve-moderato

Anker SD et al. Circulation 2003;107:1991-1997

Livello medio di uricemia durante tutto il periodo preso in considerazione (mg/dL)

0%

20%

40%

60%

80%

100%

5 (0.30) 6 (0.36) 7 (0.42) 8 (0.48) 9 (0.54) 10 (0.60)Inc

ide

nza

di

rec

idiv

e d

i a

tta

cc

hi g

ott

os

i p

iù d

i u

n a

nn

o d

op

o la

p

rim

a v

isit

a (

%)

Osservata

Logistic regression

n=267

Shoji A, et al. Arthritis & Rheumatism (Arthritis Care & Research): 2004; 51(3): 321–325

Studio retrospettivo sulla correlazione tra uricemia

e deposito di cristalli di urato

Sintesi dello studio

1) Uricemia: The lower the better ?

2) Uricemia < 6 (<5.5 ?) è l’obiettivo corretto !

2011 Recommendations for the diagnosis and

management of gout and hyperuricemia.The

target of urate-lowering therapy should be a serum

uric acid level of ≤ 6 mg/dL. Postgrad Med. 2011;123(6

Suppl 1):3-36

Rischio di outcome CV in funzione delle variazioni a 6 mesi dei

livelli circolanti di acido urico nella studio RENAAL

Smink PA et al. J Hypertens 2012 Feb 29. [Epub ahead of print]

_

_

------------------------------------------------------------------------------------------------------ _

_

_

_

_ _ _ _

_

__

-5 -3 0 3 5

_0

50

100

150

Fre

qu

en

cy

Ha

zard

ra

tio

fo

r C

V m

orb

idit

y a

nd

mo

rtality

Change in uric acid after 6 months treatment (mg/dl)

0

1

2

3

4

_5

CV morbidity and mortalityEach initial 0.5 mg/dl reduction in

SUA was independently

associated with a reduction in the

risk of subsequent cardiovascular

outcomes of

5.3% (0.9 to 9.9%; P=0.017)

Il mondo reale - vicino a noi

12.320 Pz in carico a 8 MMG in Provincia di Brescia

Età > 18 anni Follow-up 5 anni

68,3%

31,7%

Valori Uricemia in 4023 pz (32.6%)

ac.urico < 6.8 mg/dl

ac.urico > 6.8 mg/dl

Courtesy of Dr. Bettini

Uric acid in > 18.000 patients referring to the

Centro Cardiovascolare di Trieste

82%

7%

11%

Not available

Uric Acid > 6 mg/dL

Uric Acid < 6 mg/dL

37% vs 63%

Courtesy of Dr. Andrea Di Lenarda

Uric acid in patients referring to theCentro Cardiovascolare di Trieste

Uric acid and CAD

Uric acid and CHF (NYHA class)

-Diuretics- Renal Function

Uric acid and AF

Uric acid and metabolic syndrome

Uric acid and increased CV risk

Uric acid and survival

……… c’è ancora molto da fare !

grazie per l’attenzione

IN CONCLUSIONE

• L’iperuricemia cronica con deposito di urato è una malattia metabolica dovuta ad un disordine del

dismetabolismo delle purine che porta alla deposizione di cristalli di urato monosodico a livello articolare e nei

tessuti extra-articolari con formazione di depositi denominati tofi.

• La presenza di iperuricemia, definita dal riscontro di livelli circolanti di acido urico >6

mg/dL, rappresenta il prerequisito fondamentale per la deposizione a livello articolare e tissutale di

urato

• Progetto CRISTAL: Il progetto è nato con l’obiettivo di generare conoscenza e condivisione al fine

di concentrare nuovi interessi ed entusiasmo intorno ad una materia che racchiude nei livelli

plasmatici di un semplice prodotto del nostro metabolismo un universo di conoscenze complesse

che solo in un ambito di collaborazione multidisciplinare possono trovare la loro interpretazione

Miao Y et al. Hypertension 2011;58:2-7

Studio RENAAL: livelli medi di acido urico durante il follow-

up fra i pazienti nel gruppo losartan e nel gruppo placebo

Studio RENAAL: HR, incidenza dell’outcome renale (raddoppio

delle creatinina o ESRD) in funzione delle variazioni dei livelli

circolanti di acido urico a sei mesi

mean group difference of

−0.16 mg/dL (95% CI −0.30

to −0.01; P=0.031)

8.0 –

7.8 –

7.6 –

7.4 –

7.2 –

7.0 –

6.8 –

6.6 –

6.4 –

6.2 –

6.0 –

n. of pts

Losartan 751 678 606 564 504 461 335 93

Placebo 762 664 590 523 482 425 302 72

0 6 12 18 24 30 36 48Time (months)

Uric A

cid

(m

g/d

L)

Risk reduction per 0.5 mg/dL serum Uric Acid decrement: = 6% (95% CI = 10-3)

2.0 -

1.5 -

1.0 -

0.5 -

0.0 -+2.0 +0.6 0.0 -0.6 -1.7

Month 6 change Uric Acid (mg/dL)

P<0.00

1

Placebo

Losartan

L’iperuricemia senza e con deposito di urati (gotta) è una condizione

estremamente frequente con una prevalenza in progressivo aumento

– Dati del National Health and Nutrition Examination Survey

* Cea Soriano L et al. Arthritis Research & Therapy 2011, 13:R39

21,1

4,7 5,9

2

0

5

10

15

20

25

Maschi femmine

Prevalence of Hyperperuricemia (>7 mg/dl) and Gout - NHANES 2007-208

%

Zhu Y et al. Arthritis Rheum. 201;63(10):3136-41Y

Males Females

sUA

(mean)

4.87 mg/dl

sUA

(mean)

6.14 mg/dl

2007-2008

Prevalence = 3.9%,

8.3 millions of pts with

gout

2007-2008 Versus 1988-1994

+ 1.2% Gout prevalence

(CI 95% 0.6, 1.9)

+ 0.15 mg/dl sUA

(CI 95% 0.07, 0.24)

+ 3.2% Hyperuricemia

prevalence (CI 95% 1.2, 5.2)

6.52-9.81 %60-89 yrs *

2.04-4.45 %60-89 yrs *