Asymptomatic hyperuricemia

Dr Sharath Kumar, ISIC hospital, New Delhi,

27th July 2012

??Presymptomatic

Overview

Definition of hyperuricemia What are the risks with asymptomatic

hyperuricemia Why is asymptomtic hyperuricemia, asymptomatic? Asymptomatic hyperuricemia and

Gout Renal stones HTN/CV outcomes CKD Metabolic syndrome

Treatment for Treatment against My Consensus based recommendations

Total of 44 slides 2

Definition of hyperuricemia > 5mg in children > 6mg in women > 7mg in men

How this was derived

Based on original caucasian data from national survey in the US which used greater than 2 SD as cut offs.

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Definition of hyperuricemia

General uric acid levels vary with ethnicity

Supersaturation for urate - 6.4 to 6.8mg/dL.

Uric acid can causes problems by deposition and without deposition (i.e. intracellular uric acid)

associations with cardiovascular and other disorders at concentrations that are subsaturating.

High prevalence of urate values exceeding saturation but within 2 standard deviations of the population mean

For example, an estimated 5 to 8 percent in adult white males in the US and 25 percent in Taiwan Chinese males

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Asymptomatic hyperuricemia Crystal deposition related disorders

Gout Urolithiasis Acute urate nephropathy

Non crystal deposition related disorders CVS Kidney Metabolic

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CV:- prehypertension, hypertension, increased proximal sodium reabsorption, peripheral, carotid and coronary artery disease, endothelial dysfunction, oxidative stress, renin levels, endothelin levels, C-reactive protein levels.

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Kindey:- Microalbuminuria, Proteinuria, Chronic Kidney disease and ESRD

Metabolic Obesity, Hypertriglyceridemia, low HDL, Hyperinsulinemia, Hyperleptinemia, Hypoadiponectinemia

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Hyperuricemia and Gout

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Gout

Crystal deposition

Acute flare

Immune system factors

Asymptomatic hyperuricemia

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Crystal formation

Seed nucleus (particulate)

Immunoglobulin

Phagocytes

Low temperature

Low pH

Cation concentration

Intra-articular dehydration

Other (unknown) macromolecules

Triggering the acute flare (local factors)

Rapid change in urate level

Microcrystal release

IgG coat (apolipoproteins B, E inhibitory)

Complement activation (classical, alternate, MAC)

Inflammasome activation

Cytokine and chemokine release

Endothelial activation (e-selectin, ICAM-1, VCAM-1)

Local trauma?

Presence of susceptible phagocytes, mast cells (systemic events)

Surgery, trauma

Infections, other intercurrent systemic illness

Alcohol, dietary intake

Drugs that raise or lower circulating urate level

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Hyperuricemia and gout Annual incidence rate of gout as per uric acid level < 7.0 mg/dl 0.1% 7.0 to 8.9 mg/dl 0.5% > 9 mg/dL 4.9%

Cumulative incidence of gout in >9mg/dL 22% after 5 years

The American Journal of Medicine 82, 421–426Normative Aging Study 

Uric acid increases in men after puberty and in women after menopause

Gout max incidence in men after 40 years In women after 60 years

So atleast 20 years for gout to develop 11

Urate and pre-gout/crystal deposition MSU crystals in SF of asymptomatic

hyperuricaemia

One out of 19 healthy subjects (5%) and in two of nine (22%) renal failure pts.

Another recent study 9/26 (34.6%), Range of SUA in these patients 7.1–9.9

Ann Rheum Dis 2012 71: 157-158

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Urate and pre-gout Cross-sectional, controlled study non blinded study. Pineda et

al from Mexico Fifty asymptomatic individuals with hyperuricemia and 52

normouricemic subjects Double contour sign in

25% of the first MTPJs from hyperuricemic individuals, none in the control group

17% of Knees from hyperuricemic individuals None in control group

Patellar tophi in 6% hyperuricemic individuals None in control group

Intra-articular tophi were found in eight hyperuricemic individuals None of the normouricemic subjects

Arthritis Research & Therapy 2011, 13:R4In the previous studies all 9/26 with MSU in the SF had Double

contour signs13

Urate and pregout The problem is much bigger than in 1987

NHANES data from 2007 to 2008

Hyperuricemia ≥7 mg/dl prevalence of 21.1% in men and 4.7% in women.

The reported gouty arthritis prevalence in the 2007 to 2008 NHANES data was 5.9% in men and 2% in women.

So problem is more severe than we thought.

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Urate and pregout Can we predict? Dehghan and colleagues developed a risk

score A 40-fold increased risk based on variations of SLC2A9, ABCG2 and

SLC17A3 genes.

If we can’t predict can we prevent?

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Uric acid stones When daily urinary uric acid excretion

exceeds 1100 mg (6.5 micromol), the incidence of urolithiasis approaches 50 percent .

Uptodate 2010

Furthermore, uric acid stones develop in only 20% of hyperuricemic patients.

Cleaveland clinic 2008

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Now we come to non deposition diseases

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Urate and CVS

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Urate and CVS Landmark study by Mazzali et al., Induced mild-to-moderate hyperuricemia in rats

resulted in hypertension. Uric acid elevation treated allopurinol or uricosuric

agent, development of hypertension prevented.

Feig et al. > 5.5 mg/dl in 90% of adolescents with newly diagnosed primary hypertension.

Strong linear correlation between serum uric acid and systolic blood pressure. (r = 0.8, P < 0.001)

Double-blind, placebo-controlled crossover study 30 HTNsive adolescents randomized allopurinol or

placebo for 4 weeks. 86% of the intervention group normotensive only 3% in the control arm.

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Urate and CVS Prospective evidence in adults that

hypertension is associated with an increased risk for gout independent of diet, obesity, renal impairment, and diuretic use.

Subset analysis of a clinical trial of the XO inhibitor oxypurinol showed a favorable response only in patients with a baseline serum urate of greater than 9.5 mg/dL.

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Urate and CVS Independent relationship between SUA and

renal artery resistive index (RI) in HTN subjects LIFE trial association between SUA and CV

outcomes only in women SUA was found to be independently associated

with silent brain infarcts in women, but not in men

SUA correlated with internal carotid RI (r = 0.34; p < 0.001) in women, but not in men,

BMC Cardiovascular Disorders 2012, 12:52

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Urate and CVS 1,579 Japanese ≥65 years {663 men and 916

women} Divided into 4 groups according to UA

quartiles. Odds ratio (OR) in men for carotid

atherosclerosis was 2.01 in the highest quartile of UA

OR in women was 2.10

Cardiovascular Diabetology 2012, 11:2

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Urate and Kidney

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Urate and Kidney Uric acid exerts action on kidney two major

mechanisms. Firstly, induces endothelial dysfunction and

inflammation. Increases monocyte chemoattractant protein (MCP-

1) in cultured vascular smooth muscle cells and human proximal tubular epithelial cells.

MCP-1 is recognized as one of the key chemokines in atherosclerosis and chronic kidney disease.

Second, hyperuricemia alters glomerular hemodynamics. Cortical renal vasoconstriction and increased renin

expression were observed in rats.24

Hyperuricemia and Kidney Historically impaired renal function in up to 40% of gout, pts Death from renal failure in 18% to 25% of gout pts.

Fessel et al. hyperuricemia not important from renal (<13 mg/dL in men; <10 mg/dL in women)

Recent epidemiologic confirmation of associations of hyperuricemia (independent of crystal deposition) with chronic kidney disease 

Experimental data in rats,

? causal role or ? simply a marker

For example, the generation of the ROS superoxide (O2·−) and hydrogen peroxide (above) in the xanthine oxidase reaction may be the culprit

increase in urate level reflects increased enzyme activity and so increased oxidative events

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Hyperuricemia and kidney Correlations between SUA and the development

of CRF in pts with HTN

Incidence of end-stage renal disease in 7 year longitudinal study among Okinawan women with SUA > 6.0 mg/dL was significantly higher

A reciprocal relationship between serum urate levels and renal vascular responsiveness to angiotensin II administration has been reported in rats

? So SUA activates the renin-angiotensin system.

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Hyperuricemia and Kidney Retrospective longitudinal study n = 1,285 Japanese factory

workers annual medical examinations from 1990 to 2007. Cox regression analysis Hazard ratio for new-onset CKD in the participants with

hyperuricemia was 3.99 HR for CKD in participants with hypertension was 2.0

BMC Nephrology 2011, 12:31

Obermayr et al 21,475 participants followed for 7 years Risk of new-onset CKD OR 1.74 in SUA 7.0- 8.9 mg/dL, by 3.12 times in SUA ≥ 9.0 mg/dL.

Iseki et al Hazard ratio for progression to ESRD was 5.77 in women with ≥ 6.0

mg/dL, No significant association between progression to ESRD and uric

acid levels in men with uric acid levels of ≥ 7.0 mg/dL.

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Urate and metabolic syndrome The inverse correlation of serum urate and insulin

sensitivity Positive correlation of urate and triglyceride levels Hyperuricemia simple marker of insulin resistance. Weight loss–inducing medications like

sibutramine and orlistat reduce serum urate levels, Independent association of serum urate and leptin

levels has been reported.  Again urate causative or just bystander not known.

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Treatment for - Urate and pregout “Dirty dishes” strategy of gout treatment

Prospective cohort of 211 gout pts, Urate-lowering therapy withdrawn 5 years after

resolution of the last tophus. (total 5yrs if no tophus)

Follow up time after withdrawal was 33.1 ± 22.6 months (median 27.5 [IQR 16.0—47.5]).

Eighty-two patients (38.9%) had a crystal-proven recurrence of gout during the followup observation period

Arthritis Rheum. 2011 Dec;63(12):4002-6

So if we treat presymptomatic hyperuricemia for some time then we can prevent gout??!!??29

Treatment for - Urate and Urolithiasis Patients with a history of kidney stones,

should be considered for long-term allopurinol treatment esp if they are overproducers i.e. excrete > 1gm per day in the urine

Patients about to undergo Radio or chemo to prevent acute urate nephropathy

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Treatment for - Urate and CVS Adolescent data already discussed RCT

Ongoing trials in adults

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Treatment for - Urate and CKD Hyperuricemia not to be treated until serum urate levels

exceed at least 13 mg/dL in men, and 10 mg/dL in women, (Old data based on supposed safety at levels below this and Expert practice Cleavland clinic )

Siu et al randomized 54 asymptomatic chronic kidney disease patients to placebo or allopurinol

Allopurinol significantly preserved renal function compared to placebo at 1 year.

50 chronic kidney disease patients who were on allopurinol stopped treatment.

Decrease in renal function esp in pts not taking renin-angiotensin system blockers

Kanbay et al allopurinol to 48 hyperuricemic and 21 normouricemic patients, all of whom were asymptomatic and had normal kidney function at the start of the study.

After 3 months calculated GFR increased from 79 to 92 ml/min in hyperuricemic pts not controls.

Blood Purif 2010;30:288–295

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What treatment Substitution of alternative antihypertensives to thiazides, Better control of hypertension, Reduction of obesity, Appropriate changes in diet Alcohol restriction Increased consumption of ascorbate and coffee Decreased consumption of high fructose corn syrup–sweetened

beverages (e.g., soft drinks, energy drinks) A low-carbohydrate weight reduction diet tailored to treat metabolic

syndrome can lower the SUA but only by about 15% at most;

Purine-restricted diets are even less effective and largely unpalatable.

Why less effective? Most uric acid is derived from the metabolism of endogenous

purine, Foods rich in purines contributes only a small portion of the total

pool of uric acid.33

What treatment

????? XO inhibitors

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Treatment against Previous epidemiologic associations have been

proven wrong by well-controlled prospective studies For eg:- the Women’s Health Initiative findings on

estrogen and heart disease Urate-lowering therapies are not devoid of

adverse effects, which are sometimes severe or life-threatening.

Allopurinol hypersensitivity syndrome occurs in 2%.

Xanthine oxidase inhibitors can cause gastrointestinal intolerance, hepatotoxicity, rashes, and gout flares,

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Treatment against (Urolithiasis) Kaiser Permanente study. No increased risk of stone formation in

asymptomatic hyperuricemia. In gout, pts risk of stones increased, But annual risk only 1%, and mean time to the first

stone episode after the diagnosis of gout was 10.8 years.

Not uric acid stones. Many times uric acid is just the nidus. Treatment of the hyperuricemia might not even eliminate this already low risk.

Probably the benefits are lesser in asymptomatic patients

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Treatment against Chemical structure of uric acid similar to

trimethylatedxanthine caffeine Studies in the 1960s and 1970s higher uric

acid level = greater intelligence, achievement-oriented behavior, school performance, and reaction time.

J Rheumatol 2008;35;734-737

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Treatment against Chronic intracellular UA is oxdiative

But acute serum UA is anti oxidative Ames, et al elevated uric acid concentration may

help prolong longevity Epidemiological studies Elevated uric acid levels have a lower frequency

of Multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease

By ability to block the blood-brain barrier, or by effects on astroglial cells

J Rheumatol 2008;35;734-737

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Treatment against Most of the clinical studies suggesting benefit

performed with allopurinol,

A xanthine oxidase inhibitor which itself reduces oxidant load.

Other uric acid-lowering agents are less effective,

So ????? We don’t need to treat asymptomatic hyperuricemia, we need to treat asymptomatic XO hyperactivity.

The Journal of Rheumatology 2008; 35:5

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Treatment against 2011 recommendations for the diagnosis and

management of gout and hyperuricemia.

Donot treat asymptomatic hyperuricemia!!!!

Postgraduate medicine journal

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Mom test

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Latest In the top category (serum urate 10 mg/dL),

86% of subjects had chronic kidney disease stage 2, 66% had hypertension, 65% were obese, 33% had heart failure, 33% had diabetes, 23% had myocardial infarction, and 12% had stroke.

Sex-specific odds ratios tended to be larger among women than men

The American Journal of Medicine (2012) 125, 679-687

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My consensus recommendations

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My consensus recommendations Holistic treatment.

Don’t forget non pharmacological and other pharmacological (Metformin, Orlistat )

When the devil has crossed through the first door i.e. crystal deposition seen by SF or USG then probably better to treat

Urolithiasis point of view >1gm per day excretion only after discussion with patient

When SUA greater than 9mg/dL better to treat. (22% cumulative incidence of gout in 1987 probably much higher now, increased CV and CKD risk)

Lower threshold for treatment in women given higher risks esp with respect to CVS (maybe also CKD)

In patients with pre existing CVS and CKD treat any value >7mg/dL.

We need a risk score determining need for initiation of XO inhibitors like Farmingham or FRAX risk score 45

Thank you for your attention