Hyperurikämie Unispital Basel Rheumatologie
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Unispital Basel
Rheumatologie
Hyperurikämie
Ulrich Walker
Sogar „Sue“ hatte
Hyperurikämie
Sue starb im Alter von 28 Jahren
Rothschild BM "Tyrannosaurs suffered from gout" Nature 1997
Akute Gichtarthritis Rubor, Tumor, Calor, Dolor, Fieber, Frösteln, Tachykardie, Nausea Extrem schmerzhaft, innert 12 h maximal, in 2/3 als Monarthritis MTP I-Gelenk typisch, untere Extremität : obere Extremität = 10:1 Spontane Resolution innerhalb von Tagen
Mechanism of the inflammation in gout
Entzündung, Fieber
Rekrutierung von Neutrophilen
Kötter I, Z Rheumatol 2009 ; Martinon F Nature 2006 ; Pope RM Arthritis Rheum 2007
Akuter Gichtschub – Therapieoptionen
Rider TG Rheumatology 2010 ; Jordan K Rheumatology 2007
Prävention weiterer Gichtschübe
Lesinurad
Harnsäure Homöostase
Urat Pool: ♂1200 mg, ♀ 600 mg; Turnover 60%/ Tag
Leber
Produziert Harnsäure aus endogenen u. alimentären Purinen
GI Trakt
Entfernt 1/3 der Harnsäure
durch passive Exkretion vom Blut ins intestinale Lumen
Darmbakterien bauen Harnsäure ab (intestinale Urikolyse)
Niere
Eliminiert 2/3 der Harnsäure
durch glomeruläre Filtration, Reabsorption, Sekretion
Ursachen der Hyperurikämie
Hyperurikämie Definition >420uM (7 mg/dl)
90% Untersekretion Überproduktion 10%
Primär Primär
Transporterpolymorphismen HPRT Defekt
(URAT-1 et cet.) PRPP-Synthetase Überfunktion
Glykogenosen
Sekundär
Niereninsuffizienz Sekundär
Art. Hypertonus Exzessive Purinaufnahme
Hypothyreose Hämatologische Erkrankung
Psoriasis
Medikamente
Diuretika Medikamente
Cyclosporin A Zytotoxische Substanzen
Alkohol Alkohol
Rider TG, Rheumatology 2010
Epidemiologie der Gicht
Prävalenz
• 2-4% in westlicher Hemisphäre
• 95% Männer
• Hyperurikämie : Gicht = 10 : 1
Jährliche Peak-Inzidenz
• ♂ 30.-45. Lebensjahr
• ♀ 55.-70. Lebensjahr
Harnsäurespiegel Gichtinzidenz
über 5 Jahre (%)
< 7,0 mg/dl (10 mg/dl (>600 µmol/l) 30,5
Doherty M Rheumatology 2009 ; Campion, Am J Med 1987
BMI: Gout risk
Bariatrische Chirurgie induziert Gewichtsverlust und vermindert die Harnsäure
(um durchschnittlich 100 µmol/L)
Chio KH, Arch Int Med 2005, Dalbeth N, Ann Rheum Dis 2014, Richette P, Arthritis Care Res 2015; Dalbeth N, Ann Rheum Dis 2013Ernährung
Erhöhtes Gichtrisiko
Fleisch RR 1,41
Fisch / Meeresfrüchte RR 1,51
Fruktose (Süssgetränke, Saft, Äpfel, Orangen) RR 1,64-1,85
Protektive Faktoren
Milchprodukte RR 0,56
Kaffee
Vitamin C (>500 mg/ Tag)
Choi HK JAMA 2010 ; Dalbeth N Ann Rheum Dis 2010
Rider TG Rheumatology 2010 ; Choi HK New Engl J Med. 2004 ; Choi HK Arthritis Rheum 2005; Choi HK Arthritis Rheum 2007Alkohol
Alkohol induziert Hyperurikämie u. erhöht das Risiko von
Gichtschüben
Gichtrisiko im Vergleich zu Alkoholabstinenz
10 - 14,9 g Alkohol/ Tag → + 32%
15 - 29,9 g Alkohol/ Tag → + 49%
30 - 49,9 g Alkohol/ Tag → + 96%
>50 g Alkohol/ Tag → + 153%
Bier: höheres Risiko als Spirituosen
Moderater Weinkonsum: Kein Risiko
Choi HK Lancet 2004Allele renaler Urattransporter
Blut Urin
URAT1
Pyrazinamid, Ketonkörper, Laktat, Diuretika stimulieren Anionentransport an URAT-1
Alkohol induziert Anionen durch Dehydration und Azidose
Terkeltaub G, Nat Rev Rheumatol 2010Komorbiditäten bei Gicht
Possible interactions in the association
between gout and cardiovascular disease
Abeles AM Curr Opin Rheum 2019Mechanism of the CVR in gout
Singh JA Ann Rheum Dis 2015Urate is associated with incident hypertension
Mixed race (African-American & White) cohort, established in 1985 with 20
years of follow-up
Men Hazard increase was more pronounced
for men than for women, possibly a
reflection of higher absolute urate
levels in men.
Women
Gaffo AL Ann Rheum Dis 2012Allopurinol decreases blood pressure
Diastolic Systolic
1.4 mmHg 3.3 mmHg
Agarval V J Clin Hypertension 2013Predictors of CVD in patients with gout
700 gout patients and 276 controls
Prevalence of CVD in gout 47%, in controls 24%
Independent predictors of CVD:
• Gout duration ≥ 2 years
• Oligo- or polyarthritis
• Serum urate > 0.55 mmol/l at presentation
• Joint damage
Disveld IJM J Rheumatol 2018Hyperuricemia is an independent CVR factor
in gout
Singh JA Ann Rheum Dis 2015Atrial fibrillation by hyperuricemia
Prospective cohort study of 123 238 Chinese patients from 2006 to
2014.
Serum urate concentrations measured every 2 years
Incident AF cases were identified via biennial 12-lead ECG
High serum urate levels associated with increased risk of
incident AF
Participants with the highest quintile of serum urate had 1.91-
fold higher risk of AF (adjusted hazard ratio)
Li S J Am Heart Assoc 2019Atrial fibrillation by elevated urate
Mechanisms?
Hyperuricemia
• associated with increased left atrial diameter, a known
marker of atrial fibrosis
• promotes development of arrythmogenic substrate by
activation of the renin-angiotensinaldosterone (RAAS)
system and increased xanthine-oxidase mediated
free radical generation.
• Promotes systemic inflammation and atrial fibrosis via
increased TGF-β activity
Elevated risk for AF also in ankylosing spondylitis (HR
1.35), psoriatic arthritis (HR 1.46) and RA (HR 1.29)
Black Maier E Trends in Cardiovascular Medicine 2019Serum urate levels predict outcome
in chronic heart failure
Anker SD Ciculation 2002Allopurinol ameliorates cardiac function in non- hyperuricaemic patients with chronic heart failure Objective: To observe the effects of allopurinol on the cardiac function of non-hyperuricaemic patients with chronic heart failure. Patients and methods: 125 consecutive cases of non-hyperuricaemic patients with chronic heart failure who were randomly divided into allopurinol (300 mg/day) group (n=62) and control group (n=63). During the six months treatment period, levels of cardiac function, brachial artery endothelial function, inflammatory cytokines, and biochemical markers were routinely examined. Results: After three months of allopurinol treatment, patients exhibited an increase in flow- mediated vasodilatation (FMD) of brachial artery, whereas, after six months of treatment, the cardiac function classification was improved; plasma levels of brain natriuretic peptide and tumour necrosis factor-a were decreased; left ventricular internal diameter was diminished; and the ejection fraction was increased (p
Gievertz MM Circulation 201
ULT lowers mortality and strokes
in patients with gout
Retrospective cohort study
Incidence rates (IRs) of hospitalized CAD, stroke, HF, and all-cause mortality
in gout patients who use ULT and those who do not
Yen FS PLOSone 2020Allopurinol is associated with a reduced risk of MI
Population-based case–control study: 3171 cases of non-fatal AMI and
18 525 controls
• AMI cases had a lower prevalence of allopurinol use (0.82%) than
controls (1.03%) OR 0.52 (95% CI 0.33 to 0.83)
• The protective effect of allopurinol was
– only observed at 300 mg or greater (OR=0.30)
– with prolonged treatments >180 days OR=0.21
• Allopurinol also showed a significant reduced risk of AMI
recurrence (OR=0.16)
De Abajo FJ Heart 2015Benefits from ULT on cardiovascular mortality?
Metaanalysis of 18 RCTs
Most of the studies were
• underpowered
• of short duration
• low-risk populations
Zhang T Rheumatology 2017Benefits from ULT on cardiovascular mortality in gout?
Second metaanalysis
• Mostly studies of hyperuricemic patients without gout (only 12 of
93 studies had majority-gout patients)
• Larger, included only studies assessing XOI use, mainly in high-
risk populations.
Allopurinol reduces incident cardiovascular disease
Febuxostat does not
Bredemeyer M Cardiovasc Disord 2018Allopurinol vs. Febuxostat
in CV-disease of gout patients (1)
• Population based cohort study from US Medicare claims data (2008–2013)
• Primary outcome: hospitalization for myocardial infarction or stroke
• Secondary outcome: all-cause mortality
No differences
Zhang MA Circulation 2018Cardiovascular safety of
Allopurinol vs. Febuxostat in gout (2)
CARES RCT in gout patients with major cardiovascular disease
Lack of an untreated control group
impossible to determine if the greater rate of events with febuxostat
represents an actual increase in events, or a less dramatic risk reduction
compared with allopurinol.
White WB New Engl J Med 2018Cardiovascular safety of
Allopurinol vs. Febuxostat in gout (3)
FAST RCT in gout patients with major cardiovascular disease
Hospitalisation for non-fatal myocardial
infarction, acute coronary syndrome; non-
fatal stroke; or cardiovascular death.
Febuxostat is non-inferior to allopurinol with respect to cardiovascular events
Mackenzie IA Lancet 2020FREED RCT:
Febuxostat reduces cerebral, cardiovascular,
and renal events in hyperuricemia
RCT of 1070 patients with hyperuricaemia (serum uric acid >7.0 to
≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease
Febuxostat delays the progression of renal dysfunction
Kojima S Eur Heart J 2019Treating hyperuricemia in chronic kidney disease
Several observational studies showed elevated SUA levels are strong and
independent predictors of early GFR decline and albuminuria
Nephroprotective and absent effects of ULT in CKD-studies
Russo E J Clin Med 2021Colchicine and XOI
both improve endothelial dysfunction in gout
38 untreated gout patients receiving colchicine and staggered XOI (allopurinol
or febuxostat)
• 4 weeks after achieving target sU concentration on colchicine plus an XOI,
FMD was significantly improved
• hsCRP, ESR, IL-1β, and IL-6 also all significantly improved
Toprover M Ann Rheum Dis 2020Colchicine and CVR in gout Single-center retrospective cross-sectional study in gout patients • Colchicine associated with a lower incidence of myocardial infarctions (1.2 vs. 2.6%, hazard ratio 0.46) • Colchicine duration unknown, study was not adjusted for confounders Medicare database study in gout patients • Colchicine had markedly lower rates of cardiovascular events (hazard ratio 0.51) • 73% reduction in all-cause mortality (hazard ratio 0.27) Nidorf SM J Am Coll Cardiol 2013 ; Crittenden DB Arthritis Rheum 2014 ; Solomon DH Ann Rheum Dis 2018
Does Colchicine lower CVR in patients without gout?
Double-blind RCT involving patients within 30 days after myocardial infarction
Colchicine 0,5 mg/d
Death from cardiovascular causes, resuscitated cardiac arrest, myocardial
infarction, stroke, or urgent hospitalization for angina
Tardif JC New Engl J Med 2019Canakinumab and CVR in patients without gout?
CANTOS trial: Patients with a history of myocardial infarction and hsCRP>2mg/L
first definitive proof-of-principle
that an antiinflammatory strategy
can reduce cardiovascular risk
Secondary analysis revealed that canakinumab also reduced incident gout rates
(e.g. prevented first gouty attack)
Ridker PM New Engl J Med 2017Summary (1) • Cardiovascular risk factors are more prevalent in gout than in RA patients. • Gout is an independent risk factor for cardiovascular disease and cardiovascular mortality. • Lowering serum urate may improve cardiovascular outcomes, but data are conflicting. • It remains unclear whether allopurinol confers more favorable outcomes than febuxostat • Other medications, including colchicine, may have salutary effects on cardiovascular disease in patients with gout and non-gout
Gout patients should be screened for
cardiovascular risk factors?
Gout patients older than 35 years should be screened with
• Fasting lipid profile
• HbA1c monitoring
• Blood pressure measurement
• Current smoking status
Singh JA Ann Rheum Dis 2015Warum haben Menschen keine Urikase ? Menschen und höhere Primaten haben keine Urikase Andere Säugetiere: Uratspiegel
Hyperuricemia associated with low risk of
Parkinson’s disease
Higher plasma concentrations of urate predict a reduced risk of Parkinson’s
disease
Weisskopf MG Am J Epidemiol 2007Hyperuricemia associated with low risk of
Parkinson’s disease
Metaanalysis of cohort studies
The pooled rate ratio of Parkinson’s disease associated with a standard
deviation increase in urate (1.32 mg/dl) was 0.80 (p = 0.000074)
Weisskopf MG Am J Epidemiol 2007Hyperuricemia
is associated with incident vascular dementia
A community-based prospective French cohort study of healthy 4931 elderly
people 65 years or older, examined at six clinical visits
Patients on ULT were excluded
Multivariable-adjusted HR with the highest (≥5.8 mg/dL in men, ≥4.9
mg/dL in women) versus the lowest sUA quartile (≤4.37 and ≤3.51 mg/
dL, respectively) was 1.79 for incident dementia (95% CI 1.17 to 2.73;
p=0.007).
Strong association with vascular or mixed dementia (HR=3.66 (95% CI
1.29 to 10.41), p=0.015)
No significant association with Alzheimer’s disease (HR=1.55 (95% CI
0.91 to 2.61), p=0.10).
Latourte A Ann Rheum Dis 2018ULT is not associated with incident dementia
US Medicare claims DB analysis
Singh JA Ann Rheum Dis 2018EULAR guidelines 2016 EULAR gout treatment guideline statew that for patients with gout being treated with ULT, sUA level
Summary (2) • Cardiovascular risk factors are more prevalent in gout than in RA patients. • Gout is an independent risk factor for cardiovascular disease and cardiovascular mortality. • Lowering serum urate may improve cardiovascular outcomes, but data are conflicting. • It remains unclear whether allopurinol confers more favorable outcomes than febuxostat • Other medications, including colchicine and statins, may have salutary effects on cardiovascular disease in patients with gout and non-gout • Hyperuricemia is associated with increased vascular dementia and neuroprotection in Parkinson’s • So far no real signal that ULT has adverse CNS effects
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