Acido urico come marker e target del rischio metabolico · infiammatoria nell’uomo ed è una...
-
Upload
nguyenngoc -
Category
Documents
-
view
213 -
download
1
Transcript of Acido urico come marker e target del rischio metabolico · infiammatoria nell’uomo ed è una...
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 *