RAPID FIRE - Gout with comorbidities - Dr Sourabh Malviya
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Transcript of RAPID FIRE - Gout with comorbidities - Dr Sourabh Malviya
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Dr Sourabh MalviyaConsultant Rheumatologist
Medanta HospitalIndore
GOUT WITH CO-MORBIDTIES
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OutlineBackground-CaseNumber of ComorbiditiesPathophysiologyGout with each comorbidities relationCase – an exampleConclusion
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Background CaseA 28 YR Male,Admitted in CCU as
acute AWMI with LVF On Mechanical
VentilatorWith no comorbiditiesNo addictionNo Family History of
Cardiac illnessRheumatology consult
for joint pain & swelling in hands
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Background CaseInvetigationsCBC- Hb 12gm./dl , TLC- 6500, PC –
4750000LFT- WNLCreat 1.2 mg/dlUA- 10.3 mg/dlDiagnosis – Chronic Tophaceous Gouty Arthritis
Acute AWMI with LVF
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Uric Acid
Intelligence Alzheimer’s
Parkinson’s Disease
Gout Stone
MI
The Good The Bad
The Ugly
Tophi
CVA Dyslipidemia
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Gout and comorbidities – Why to know?
Avg. 4 comorbidities in each gout pt during the course of disease
5% to 10% have 7 or morePrevalance increases with degree
& duration of hyperuricemia & gout
These comorbidities and their treatment may have an effect on the development of gout and on the choice of treatment
1.Stamp LK, Chapman PT., Rheumatology (Oxford). 2013 Jan;52(1):34-44.2.Michael H. Pillinger, et. Al.; Gout and Its Comorbidities: Bulletin of NYH Hospital of Joint Diseases 2010;68(3):199-203
HypertensioCVD
Renal impairmentDiabetesObesity
Hyperlipidaemia
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Comorbidities of Gout & HyperuricemiaNHANES study 2007 – 08, 5,707 pts• 74% Hypertension• 71% CKD stage 2 or >• 53% obese• 26% DM• 14% MI• 11% CHF• 10% CVA
1.Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med. 2012 Jul;125(7):679-87.
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Pathophysiology of Vascular Damage Due to Hyperuricemia
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The Oxidant-Antioxidant Paradox Mechanisms of Uric Acid
1.Changyi Chen,Jian-Ming Lü , Qizhi Yao: Hyperuricemia-Related diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview ;1643-3750 , 2016; 22: 2501-2512
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Schematic Diagram
Experimental models have shown that hyperuricemia-induced vascular dysfunction, inflammation and increased oxidative stress lead to insulin resistance, which later leads to impaired glucose tolerance and predisposes to the other components of the metabolic syndrome.
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Comorbidities
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QuestionFollowing co-morbidities can be seen with
Gout- Best of four1.Metabolic Syndrome, CVD & Stroke2.Metabolic Syndrome, CVD, Stroke & CKD3.Metabolic Syndrome, CVD, Stroke, CKD &
Ocular Abnormalities4.Metabolic Syndrome, CVD, Stroke, CKD,
Ocular Abnormalities & Malignancy
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HypertensionHypertension -74% with gout and 47% with
hyperuricemia in comparison to a population-estimated prevalence of 24% among normouricemic patients. NHANES 2007-08 survey
Hyperuricemia is seen in:• - 25% of patients with untreated hypertension• - 50% of patients on diuretics• - >75% of patients with malignant hypertension
Many medications used have effects on serum urate (SU)
In the LIFE study, lowering of serum uric acid in the losartan grp contributed to about 29% of the intervention effect on cardiovascular end points
Stamp LK, Chapman PT., Rheumatology (Oxford). 2013 Jan;52(1):34-44.Annemans L et al., Ann Rheum Dis 2008; 67:960-6.Chen SY et al., Clin Rheumatol 2007;26:1453-7.Johnson R et al., Hypertension 2003;41:1183-90.
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Does ULT has effect on blood pressure?
ULT may contribute to a reduction in blood pressure. In a study of 48 hyperuricaemic patients-allopurinol 300
mg/day for 3 months resulted in a significant reduction in blood pressure
In another study of 30 adolescents (aged 11-17 years) with essential hypertension, allopurinol 200 mg b.i.d. for 4 weeks resulted in a significant reduction in blood pressure
But Cochrane review concluded that evidence is still insufficient to recommend ULT
Kanbay M et al., Int Urol Nephrol 2007;39: 1227-33Feig D et al., JAMA 2010;300:924-32.Gois PH, Souza ER. Online). 2013; 1:CD008652.
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Peripheral arterial diseaseManifestation of atherosclerosisHigher SU levels were significantly
associated with PAD, independently from traditional cardiovascular risk factors (3987 participants in NHANES 1999–2009)
Shankar A, Klein BE, Nieto FJ, et al. Association between serum uric acid level and peripheral arterial disease. Atherosclerosis. 2008; 196:749–55. [PubMed: 17275005]
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Cardiovascular diseaseCVD risk increases by 60% in Gout Uric acid level - independent predictor of all-cause
death, (hazard ratio of 1.26)• Men with UA levels in the upper 1/3 were 1.7 –
fold more likely to die from any cause• Increase of uric acid > 4 mg/ml ,a “red flag” to the
increase risk of CVD & especially in those already at risk for CVD
1.Krishnan E et al., Arthritis Rheum 2006;54:2688-96.; Krishnan E et al., Arch Intern Med 2008;168:1104-10.; Choi H, Curhan G., Circulation 2007; 116:894-900.; Edwards N.,Curr Opin Rheum 2009;21:132-7.; Kim S et al. Arthritis Care Res 2009;61:885-92.; Baker J et al., Angiology 2007;58:450-7.2.oachimescu AG, Brennan DM, Hoar BM, et al.: Serum uric acid an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiology information system (PreCIS) database cohort study. Arthritis Rheum 2008, 58:623–630.
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What Studies say association between SU, cardiovascular disease, and cardiovascular death ?
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CHF• Gout pts 80%
progressively increases risk of CHF
• Increased XO activity in damaged myocardial tissue
• Increase urate precursors and radical oxygen species
• Cardiac hypertrophy• Myocardial fibrosis• Left ventricular
remodeling and contractility impairmentKrishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open. 2012 Feb 15;2(1):e000282.
Kanbay M et al., Int Urol Nephrol 2007;39: 1227-33.; Norman A et al., Lancet 2010;375: 2161-7.; Rentoukas E et al., Int J Cardiol 2010; 145:257-8.
• ULT may be beneficial• Oxypurinol 405
patients reported a trend toward improved outcomes
• Allopurinol - significant reduction in CHF re-admissions or death (RR 0.69; 95% CI 0.60, 0.79) and reduced all-cause mortality (RR 0.74; 95% CI 0.61, 0.90)
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Uric Acid is a Risk Factor for Myocardial Infarction & Stroke• 4385 participants in Rotterdam, 1990-1993
were > 55 yr, free from CVA & CHD• Average f/u was 8.4 yrs• Relationship betwn SUA & risk of CVD is
linear• High SUA levels assoc with risk of MI & CVA• Age & sex adjusted hazard ratios for highest
vs lowest quintile of UA were• 1.68 CVD• 1.87 MI• 1.57 CVA
• SUA is a strong risk factor for MI & stroke
1.Bos MJ et al. Stroke. 2006;37:1503-1507.2.Weir CJ, Muir SW, Walters MR, Lees KR: Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003, 34:1951–1956.3. Wong KY, MacWalter RS, Fraser HW, et al.: Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J 2002, 23:788–793.
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Hyperuricemia and StrokeHigh normal SU (SU >5.75 mg/dL for men;
>4.8 mg/dL for women) concentrations were associated with a significantly increase in white matter hyperintense signals compared to participants with low to moderate SU levels
Weir CJ, Muir SW, Walters MR, Lees KR: Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003, 34:1951–1956.54. Wong KY, MacWalter RS, Fraser HW, et al.: Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J 2002, 23:788–793.
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Renal impairment & Urate Nephropathy
Renal impairment is associated with hyperuricaemia, which also contributes to renal impairment
Under-excretion of urate is a common cause of hyperuricaemia
Increase -reactive oxygen species leads to activation of the renin angiotensin system (RAS) -- > vasoconstriction of the afferent arteriolar system and glomerular hypertrophy
ArteriolopathyDirect effect of urate in tubular cellsTransition of renal tubular cells leading to renal
fibrosis
Stamp L, Dalbeth N., Semin Arthritis Rheum. 2016 Jul 28. pii: S0049-0172(16)30147-0
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Effect of urate lowering on renal function
In patients with CKD, allopurinol has been
shown to slow the progression of renal
disease
A post-hoc analysis of the FOCUS study demonstrated that febuxostat was
associated with an improvement in renal
functionSiu YP et al., Am J Kidney Dis 2006;47:51-9.; Goicoechea M et al., Clin J Am Soc Nephrol 2010;5:1388-93.; Stamp L, Dalbeth N., Semin Arthritis Rheum. 2016 Jul 28. pii: S0049-0172(16)30147-0; Whelton A et al.,J Clin Rheumatol 2011;17: 7-13.
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Insulin resistance and metabolic syndrome
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Insulin Resistance,and Obesity- Metabolic Syndrome ( MS)
MS commonly seen – UA 10 mg/dL or above than less than 6.0 mg/dL (70.7% and 18.9% respectively).
MS - 62.8% and 25.4% with and without goutUA levels is independently correlated with IR
shown in a Korean study of > 50000Hyperuricemia were more likely to develop IR
and pre-diabetes, HR 1.36 (95% CI 1.23–1.51) and 1.25 (95% CI 1.04–1.52), respectively (A recent 15-year follow-up study on 5,012 US non-diabetic adults)
Insulin resistance increases by 35% in gout patients
1.Yoo HG, Lee SI, Chae HJ, et al. Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis.Rheumatol Int. 2009 Dec 20; Epub ahead of print.2. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007 Aug;293(2):C584-96
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Diabetes and GoutMen with gout are at risk of developing type 2
diabetes compared with men without gout (RR for incident type 2 diabetes 1.34 (95% CI 1.09, 1.64)
Gout - 35% to 65% increase in risk for future incidence of Type II diabetes
Prevalence in pts with gout ( 25.7% ) and 7.8% without gout
Those with established diabetes or significantly increased HbA1c may be at lower risk due to uricosuric effect of glycosuria
Choi H et al., Rheumatology 2008;47:1567-70.
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EYE
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Take Home messagesGout is bigger risk factor for co-morbidities Evaluation and management of co-morbidities
should be done in a pt of GoutTreat-to-target approach Keep UA around 4-5 mg/dl in co-morbid condition
in pts with goutWhen choosing gout therapies, consider
individual patient’s comorbidities and potential drug interactions.
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Surgical -StrikeDe-monetization
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