New Prevention Targets for Gout and Comorbidities: Epidemiologic Perspectives

Hyon Choi, MD, DrPH

Professor of Medicine Boston University School of Medicine

Boston University Medical Center Brigham and Women’s Hospital

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Disclosure

• None

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Gout -“morbus dominorum et dominus morborum”

• “Disease of Kings and King of Diseases,”» Alexander the Great, Henry VIII, Charlemagne, Benjamin

Franklin, Alexander Hamilton, Isaac Newton, Charles Darwin, Leonardo da Vinci, Tennyson, Coleridge, & Voltaire

• Known since antiquity – described by Hippocrates• “the Patrician Malady”• Originally a disease of the affluent; middle aged men

of the wealthy upper class

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Prevalence of Gout in US and Canada

7%5%4%2%1%0.6%0.2%Women13%12%9%6%3%1%0.4%Men≥8070-7960-6950-5940-4930-3920-29Age

• Canada Data (BC): Based on physician codes, 2004

(Total = 0.83 mil [men = 0.58 mil; women = 0.25 mil])

6%5%4%2%0.6%0.1%0.6%Women9%11%9%6%2%2%0.2%Men≥8070-7960-6950-5940-4930-3920-29Age

• US Data: Based on NHANES III (1988-94)

(Total = 8.3 mil) in 2007-2008) Zhu et al. A&R 2011

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

<6 6-6.9 7-7.9 8-8.9 9-9.9 >10

Serum Uric Acid (mg/dL)

Ann

ual I

ncid

ence

of G

out

exponential projection

Relation between Serum Urate Levels and Incidence of Gout.

Choi et al. Ann Intern Med (2005)Campion et al. Am J Med (1987)

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NHANES 1999-2008

Mean Serum Urate Level, mg/dL (µm/l)

Age (y) All Men Women

20-29 5.26 6.12 (364) 4.41 (262)

30-39 5.24 6.09 (362) 4.41 (262)

40-49 5.33 6.10 (363) 4.57 (272)

50-59 5.48 6.26 (372) 4.93 (293)

60-69 5.63 6.14 (365) 5.17 (308)

70-79 5.70 6.10 (363) 5.38 (320)

80+ 5.84 6.11 (363) 5.68 (338)

Ribose-5-P + ATP

: HPRT deficiency(Lesch-Nyhan syndrome & variants)

IMP

Inosine

Hypoxanthine

Xanthine

Urate

ATP

AMP

Adenosine

Adenine

GTP

GMP

Guanosine

Guanine

+ PRPP

PRPP synthetase

xanthine oxidase

xanthine oxidase

5'-nucleotidase

5'-nucleotidase

PNP PNPadenosine deaminase

HPRTAPRT+ PRPP

5'-nucleotidase

PNP

DE NOVO SYNTHESIS

PRPP

: PRPP synthetase superactivity

SALVAGE PATHWAYS

feedback inhibition

EthanolFructose Intolerance or InfusionGlycogen Storage Diseases (Type I, III, V, and VIII)Severe Tissue Hypoxia

Figure 5

Allantoin

Uricase

Choi et al. Ann Intern Med (2005)

Mutation

Man and Great Apes

Other mammals

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Cladogram of hominoid evolution showing the proposed times of the various uricase mutations.

mil mil mil milWu, J of Mol Evol, 1992

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Uricase, Diet, and Gout• Humans – only mammals that develop gout

spontaneously (likely due to hyperuricemia)• Diet of the great apes (SUA, 1.53mg/dl) - vegetation

and fruits, with only small amounts of animal protein» Similar to people in some indigenous human hunting and

gathering societies.• Gout was rare among Africans, esp in rural areas with

agricultural and diary based diets. Now frequency, esp urban communities. (Similar among US blacks now as compared with 1940’s and before)

Johnson & Rideout, NEJM (2004)

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Prevalence - Immigration Studies

• The immigration to Western countries —associated with in serum Uric Acid (UA) levels and risk of gout» E.g. immigration of the Filipino and Japanese to North

America

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0

2.5

7.5

5

% prevalence

8.5

9.4

1969

7.8

4.8

Prevalence (1-y) – US NHIS (per 1,000)

1976 1988 1996

10

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What factors contribute to this increase?

• Dietary and lifestyle trends» Western Diet» Red Meat, Sugary Soda, Refined CHO

• Hyperuricemic conditions: Obesity, metabolic syndrome, HTN, End Stage Renal Diseases

• Increased use of meds that urate levels: diuretics, low-dose ASA, certain organ transplantation medications

Bieber JD, Terkeltaub RA. Arthritis Rheum. 2004;50:2400-2414Saag KG, Choi H. Arthritis Res Ther. 2006;8(suppl):S2

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Prospective Cohort Studies for Gout

• Health Professionals Follow-Up Study (HPFS) : 51,529 male health professionals aged 40-75 from 50 states followed since 1986

• Nurses Health Study (NHS): 121,700 female registered nurses aged 30-55 from 11 states followed since 1976

• By validated questionnaires• Follow-up rate is > 90%

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Purine-Rich Food Group and Gout - HPFS

P for trend = 0.016

Purine-rich Food Group Quintile (serving/d)

Q1 Q3 Q5 Q1 Q3 Q5 Q1 Q3 Q5

Mul

tivar

iate

Rel

ativ

e R

isk

0.0

0.5

1.0

1.5

2.0

P for trend = 0.016 P for trend = 0.779

Total Meat Seafood Purine-rich Vegetables

(0.6) (1.3) (2.3) (0.1) (0.3) (0.7) (0.2) (0.6) (1.4)

Choi et al. NEJM 2004

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Dairy Intake and Gout - HPFS

P for trend = 0.648P for trend < 0.001

Dairy Intake Quintiles (serving/d)

Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5

Mul

tivar

iate

Rel

ativ

e R

isk

0.0

0.5

1.0

1.5 High-Fat Dairy IntakeLow-Fat Dairy Intake

(0.1) (0.4) (0.8) (1.2) (2.6) (0.2) (0.5) (0.8) (1.2) (2.5)

Choi et al. NEJM 2004

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Sweetened Soft Drinks Gout

P for trend =0.002

Sweetened Soft Drinks (servings)

<1/mo 1/mo-1/wk 2-4/wk 5-6/wk 1/day >=2/day

Mul

tivar

iate

Rel

ativ

e R

isk

0

1

2

3

4

Choi et al. BMJ (2008) Choi et al. JAMA (2010)

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Free Fructose Gout

P for trend <0.001

Free Fructose Intake Quintile(% of energy)

Q1 (<3.5) Q2 (3.4-4.4) Q3 (4.5-5.3) Q4 (5.4-6.6) Q5 (>6.6)

Mul

tivar

iate

Rel

ativ

e R

isk

0

1

2

3

Choi et al. BMJ (2008) Choi et al. JAMA (2010)

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Sugary Soda sUA Levels

Choi et al. A&R (2008)

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Fructose-Induced UA Production

Choi et al, JAMA (2010)

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Choi. Current Opinion in Rheumatology 2010,22:165–172

Red meat &

butter

White rice, white bread, potatoes, pasta, & sweets

Fish , poultry and eggs

0 to 2 servings

Nuts and legumes

1 to 3 servings

Vegetables

In abundance

Fruit (Cherries )

2 to 3 servings

Whole grain foods

At Most Meals

Plant oils (olive, canola, soy, sunflower, peanut, & other vegetable oils)

At Most Meals

DAILY EXERCISE AND WEIGHT CONTROL

Multiple Vitamins For Most (vitamin C )

Alcohol in moderationUnless Contraindicated(wine ,beerliquor )

Use Sparingly

Dairy or calcium supplement

1 to 2 servings

( Low-fat dairy products cow High-fat diary products )

Gout Risk and a Healthy Eating Pyramid

Coffee

Sweetened Soda

Tea

Choi et al. NEJM (2004)Choi et al. Lancet (2004)

Choi et al. Ann Intern Med (2005)Choi et al. Arch Int Med (2005)

Choi et al. Arthr & Rheum (2007)Choi et al. BMJ (2008)

Choi et al. Arch Int Med (2009)Choi et al. JAMA (2010)Zhang et al A&R (2012)

Risk Increase

Risk Decrease

Risk Neutral

Symbols for Gout Risk (& Hyperuricemia)

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Co-Morbidities of Gout

• The Metabolic Syndrome: 63% (NHANES)• HTN: 74% (NHANES)• Obesity: 53% (NHANES)• Type 2 Diabetes: 26% (NHANES)• CAD: 25% (GPRD), 18% (HPFS)• CKD (≥ stage 3) : 20% (NHANES)• Kidney Stone: 14% (NHANES); 15% (HPFS)

General Practice Research Database (GPRD) Health Professionals Follow-up Study (HPFS)

Mikuls TR, Ann Rheum Dis 2005; 64: 267-72.Kramer, Am J Kid Dis 2002; 40: 37-42.

The National Health and Nutrition Examination Survey (NHANES)

Choi et al. A&R (2007) and Arch Int Med (2005)Zhu et al. A&R (2011)

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Anti-HTN Agents and Gout Risk

• Risk: » Diuretics: (RR=2.36)» β-blockers: (RR=1.48)» ACE-inhibitors: (RR=1.24)» Non-losartan ARB: (RR=1.29)

• Risk: » Losartan: (RR=0.81)» Calcium channel blockers: (RR=0.87)

Choi. BMJ (2012)

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Potential Novel Targets for Gout Prevention

• Dairy Products (Low-fat)• Decaf. Coffee (or regular coffee)• Vitamin C (>500mg/dL)• Cherries• Weight Loss• Losartan and Calcium Channel Blockers – HTN patients• (Avoiding hyperuricemic risk factors: Red meat and

fructose-rich beverages)

Asymptomatic HyperuricemiaAsymptomatic Hyperuricemia

ULTULT

Intercurrent Gout (Early)Intercurrent Gout (Early)

Intercurrent Gout (Frequent)Intercurrent Gout (Frequent)

Chronic Tophaceous GoutChronic Tophaceous Gout

After Successful ULT After Successful ULT DiscontinuationDiscontinuation

Role of Lifestyle ModificationRole of Lifestyle Modification

AdjunctAdjunct to ULT to to ULT to urate urate and CVD comorbiditiesand CVD comorbidities

The optionThe option to to urate and urate and CVD comorbiditiesCVD comorbidities

The optionThe option to to urate and urate and CVD comorbiditiesCVD comorbidities

AdjunctAdjunct to ULT to to ULT to urate urate and CVD comorbiditiesand CVD comorbidities

The optionThe option to to urate and urate and CVD comorbiditiesCVD comorbidities

Stages of GoutStages of Gout

ULTULT

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Acknowledgements

• Participating Health Professionals & Nurses • NIAMS, CIHR• Arthritis Society of Canada• Takeda (TAP)

Thank You