# Presentation: 000518

## GOUT: THE PROTOTYPICAL CRYSTAL

**GOUT: THE PROTOTYPICAL CRYSTAL**
**                  ****DEPOSITION ARTHROPATHY**

**Monosodium**
**Urate**
**Crystal**

## Uric Acid: A Normal Product of Purine Metabolism

- <date/time>

- Xanthine Oxidase

- Xanthine Oxidase

**Notes:**
Edwards, NH. Arthritis and Allied Conditons, Koopman, WJ, Lippincott Williams Wilkins, p. 2320. 2001

## DELICACY OF URIC ACID BALANCE

- IN HUMANS

- Miscible
- urate
- pool

## Uric Acid Imbalance

- Hyperuricemia
- Increased Total Body Miscible Urate Pool
- Monosodium Urate Crystal Deposition
- Clinical Expression:
**Tophi**
**Gouty Arthritis**
**Uric Acid (and Oxalate) Urolithiasis**
**Interstitial Nephropathy**

## Gout:

- Etiology Well Understood
- Diagnosis & Rx of Arthritis and Hyperuricemia Well-Developed but Often Poorly Applied
- Prevalence > 1% in adults (~ 3-5 million in USA)
- High Prevalence in Certain Minorities
- Disease Growing in Numbers
- Disease Evolving Clinically via Iatrogenic and Socioeconomic Factors
- = MAJOR PUBLIC HEALTH PROBLEM

## GOUT EPIDEMIOLOGY IN RAW NUMBERS

_***GOUT EPIDEMIOLOGY IN RAW NUMBERS***_

## BASES FOR INCREASED GOUT PREVALENCE AND 

- _BASES FOR INCREASED GOUT PREVALENCE AND _
- _CLINICAL COMPLEXITY IN THE USA _
- _FROM 1980’s-PRESENT _

- INCREASED LONGEVITY
- INCREASED HYPERTENSION
- INCREASED DIURETIC AND ASPRIRIN THERAPY
- DIETARY TRENDS
- INCREASED OBESITY &METABOLIC SYNDROME
- DEMOGRAPHIC TRENDS
- IMPROVED CAD, CHF, DM SURVIVAL
- INCREASED ESRD SURVIVAL AND TRANSPLANTS
- LIMITATIONS IN CURRENT ANTIHYPERURICEMICS

## High Blood Pressure Rising In U.S.

- July 8, 2003
-  (Photo: AP / CBS)
**Government data collected to chart the nation's health shows that in 1991, 25 percent of adults surveyed had high blood pressure and in 2000, the number climbed to 28.7 percent.**

## HYPERTENSION TREATMENT PATTERNS ARE CHANGING

**ALLHAT STUDY RESULTS ARE INTERPRETED TO SUPPORT USE OF INEXPENSIVE THIAZIDES**
- 	The Thiazide Chlorthalidone compared to ACE inhibitor, Calcium Channel Blocker, Alpha-Adrenergic blocker in 42,418 USA subjects with mild-moderate hypertension:
***Thiazide had improved stroke, CHF*** ***outcomes****** ***

- Ferdinand KC. Am J Hyp 2003

## SUMMARY OF VA VISN 22 PRESCRIPTION     		REVIEW 1999-2003                 (Population: ~92%male,                         n ~ 250,000)

- ASA                                        UP ~10%
- FUROSEMIDE                      UP 4.7%
- HYDROCHLORTHIAZIDE  UP 74.2%
_*ALLOPURINOL                UP 12.3%*_

## The “American Diet” and its consequences

## Obesity, Metabolic Syndrome and Gout

- ~ 1/3 of Americans meet
-     criteria for obesity, ~2/3 overweight
- Obesity and Increased Body Mass alone associated with Hyperuricemia
- Insulin Resistance Compounds the Problem

## PRINCIPAL FEATURES OF 

_**METABOLIC SYNDROME**_

**ELEVATED CIRCULATING INSULIN LEVELS**
**INSULIN RESISTANCE **
**GLUCOSE INTOLERANCE OR TYPE II DM**
**ABDOMINAL (VISCERAL) OBESITY: defined as waist**
**circumference > 40 inches in men (>35 inches in females)**
**DYSLIPIDEMIA (Hypertriglyceridemia&low HDL chol)**
**HYPERTENSION**
**HYPERURICEMIA**
**INCREASED RISK OF ATHEROSCLEROSIS AND **
**COAGULATIVE ARTERIAL OCCLUSIVE EVENTS**

## Renal Effects of Metabolic Syndrome Pertinent to Gout

**Hyperinsulinemia Stimulates Increased Renal Sodium and      Urate Reabsorption**
**A Mild Defect in Renal Ammonium Excretion Associated with IR Promotes Acid Milieu for Uric Acid Urolithiasis **

- relative risk of urolithiasis
- in men with diagnosis of gout:
- = 2.12

- Kramer et al . Kidney Int 2003

## Slide 15

## Diet and Alcohol-Related Trends Influencing Incident Gout 

- in the “Health Professionals Follow-Up Study”

- Relative risk of incident gout :
- Meat 1.41
- Seafood 1.51
- Dairy 0.56
- Any Alcohol 2.53
- Five 12 oz Beers/Wk To One Beer Daily 1.75
- Two or More Beers Daily 2.51
- Per Shot of Spirits daily 1.15
- Per Glass of Wine Daily 1.04

*n = 47,150 men without gout aged 40-75, *
*12 year follow-up with 730 cases of new gout*
*Choi H et al, NE_x0008_JM and Lancet 2004 *

- Highest intake quintiles

## SEVERAL POPULAR DIETS HIGH IN FAT AND LOW IN CARBOHYDRATES HAVE THE POTENTIAL TO PROMOTE HYPERURICEMIA VIA KETOSIS AND HIGH MEAT AND SEAFOOD INTAKE

## MILLION 

**MILLION**

**The number of **
**Americans on a **
**hard-core low carb**
**diet right now**

- “LOW CARB” MANIA IN THE USA:
-            TIME, May 2004

**$30**
**BILLION**

**Expected sales of **
**low-carb products**
**in 2004. That’s **
**more than Coca-Cola**
**generates in revenue**
**from soft-drink sales**
**worldwide**

## USA TRENDS IN ALCOHOL CONSUMPTION IN 

- USA TRENDS IN ALCOHOL CONSUMPTION IN
- THE LAST 20 YEARS MAY FAVOR INCIDENT GOUT

- Overall alcohol consumption flat or slightly declining
- Beer consumption has risen steadily
- Beer is rich in the readily absorbed purine Guanosine
- Light beer and “Low Carb” Beers markedly increased in
-  market share and promoted as “health-conscious” option

##         GOUT EPIDEMIOLOGY:

-         **GOUT EPIDEMIOLOGY:**
**CLASSIC PROFILE OF GOUT PATIENT.**

**MALE, MIDDLE-AGED, AFFLUENT, EDUCATED, ALCOHOL, HOT PODAGRA**

## EMERGING EPIDEMIOLOGY IN GOUT:

**EMERGING EPIDEMIOLOGY IN GOUT:**

**MORE FEMALES, ++ RISE IN 70-80 AGE GROUP**

## GOUT IN OLDER WOMEN

**INCREASING PREVALENCE ALONG WITH INCREASED LONGEVITY**
**LINKED TO COMMON USE OF DIURETICS (>25% after age 65)**
**LINKED TO CRI AND CHF**
**WILL DECREASED USE OF ESTROGENS RAISE URIC ACID&GOUT PREVALENCE ?**
**MAY BE CLINICALLY SUBTLE AND MASQUERADE AS INFLAMMATORY HAND OSTEOARTHRITIS**

## A COMMON PRESENTATION OF GOUT

**A COMMON PRESENTATION OF GOUT**
**IN OLDER WOMEN:**
**TOPHACEOUS GOUT IN **
**JOINTS WITH PRIMARY OA**

## RENAL INSUFFICIENCY PROMOTES

**HYPERURICEMIA AND GOUT AND **
**MAKES MANAGEMENT OF HYPERURICEMIA**
**AND GOUTY ARTHRITIS **
**SUBSTANTIALLY MORE DIFFICULT**

## Rise in End Stage Renal Disease (ESRD) & Transplants in USA 

**1987: ESRD 156 new cases/million**
**1997: ESRD 303 new cases/million**
-       (ESRD prevalence 4-5 x higher in African- Americans and Elderly)
**1988 Renal Transplants 8,874**
**2002 Renal Transplants 14,777**
- (Improved transplant donor networks and protocols also >> more heart, liver, pancreas transplants)

## EVOLVING EPIDEMIOLOGY OF GOUT:TRANSPLANT/CYCLOSPORINE GOUT

**HYPERURICEMIA IN >80% **
**MEAN SERUM URATE >12 mg%**
**GOUT PREVALENCE >10% BY 3 YEARS**

## TRANSPLANT CYCLOSPORINE (CSA)

**RAPIDLY EXPANDING TOPHI REFRACTORY TO Rx**
**?EXTRARENAL CSA EFFECTS**
**ARTHRITIS REFRACTORY TO STEROIDS AND OTHER Rx’s**
**CSA NEPHROPATHY**
**CRI AND CSA **
** ****CONTRIBUTE TO SERIOUS, ADVERSE DRUG INTERACTIONS**
**INCLUDING COLCHICINE TOXICITIES**

**TRANSPLANT CYCLOSPORINE (CSA)**
** ****GOUT:**

## GOOD NEWS PREDICTION: CYCLOSPORINE GOUT WILL BE A BRIEF FOOTNOTE IN THE LONG HISTORY OF GOUT

**TACROLIMUS (FK506): another calcineurin inhibitor but marginally better for hyperuricemia**
**SIROLIMUS (RAPAMYCIN)**
**MYCOPHENOLATE**
**COMBINATION REGIMENS WITH LOW-DOSE CSA**
**EVENTUALLY: ADVANCES IN THERAPEUTIC IMMUNE TOLERANCE WILL RENDER CSA FULLY OBSOLETE**

**GOOD NEWS PREDICTION: CYCLOSPORINE GOUT WILL BE A BRIEF FOOTNOTE IN THE LONG HISTORY OF GOUT**

## THE PERFECT STORM

**INCREASED GOUT PREVALENCE AND GOUT CLINICAL COMPLEXITY IN THE USA **
**OVER THE LAST 20 YEARS:**

_*THE PERFECT STORM*_

## Gout Epidemiology: Nationwide ~25% Rise in Allopurinol-Treated Patients 1996-2002

- Allopurinol Patients - IMS factored TRx for Gout by 4.7 TRxs per Patient

**Notes:**
Source:  Data from "Allopurinol67-02-IMSnrx_trx"
and "AlloAnnualRoundup-trx-nrx"
2002 Est. through Nov. data
Scripts factored for gout and Allo patients
factored by 6.06 (avg. number of rx purchased per patient)

## EVOLVING EPIDEMIOLOGY OF GOUT:

**EVOLVING EPIDEMIOLOGY OF GOUT:**
**REFRACTORY TOPHACEOUS DISEASE**
**HAS NOT DISAPPEARED AND APPEARS**
**TO BE MAKING A COMEBACK**

## REFRACTORY GOUT IS PAINFUL, DESTRUCTIVE, AND INCAPACITATING

**REFRACTORY GOUT IS PAINFUL, DESTRUCTIVE, AND INCAPACITATING**
**JOINT EROSION CAN PROGRESS EVEN WITH EFFECTIVE URATE LOWERING THERAPY**

## Prevention and Management of Urate Crystal Deposition: Larger Issues and Needs 

**1. Sustained hyperuricemia associated with incident gout in only ~20% by 5 years: **
**	*****Need to determine what factors other than serum uric acid account for clinical crystal deposition as gout; can urate crystallization regulators be harnessed in therapy ? ***
**2. Extent of Effectiveness of Diet and Alcohol/Lifestyle and BP Therapy Modifications Alone ?**
**3. Existing Generation of Antihyperuricemics is Antiquated and Needs Improvement **

## DIETS TO REDUCE URIC ACID LEVELS

***Traditional low purine diets unpalatable and only reduce serum urate by up to 1 mg/dL or 15%**
*** ? Role of Customized 40/30/30 Diet** **with Caloric Reduction for Gout**

## SMALL OPEN STUDY OF “LOW CARB” DIET

- Wt reduction diet tailored for Insulin Resistance
- Caloric restriction to _1600_ kcal/day
- 40/30/30 carbs/protein/fat
- Replaced refined carbs with complex carbs
- Replaced saturated fat with monounsaturates in olive oil, nuts, and seafood
- Mean wt loss 7.7 kg at 16 week endpoint
_**Serum urate levels decreased by 18%**_

- Dessein et al: Ann Rheum Dis 2000

**SMALL OPEN STUDY OF “LOW CARB” DIET**
**FOR URATE LOWERING**

## SIGNIFICANCE:

- NOT ALL LOW CARB DIETS MAY BE ADVERSE FOR
- HYPERURICEMIA
- EFFECTS OF DIET AND ALCOHOL MODIFICATION
- ON HYPERURICEMIA AND GOUT NEED CAREFUL, CONTROLLED
- LONG-TERM STUDY

## URIC ACID LOWERING DRUGS CURRENTLY IN USE

- 1. **XANTHINE OXIDASE INHIBITORS: **
**ALLOPURINOL **_**(> 95% of US Market)**_
**OXYPURINOL (compassionate use basis)**

**XO**

**XO**

## LIMITATIONS OF ALLOPURINOL

**RASH IN ~2%**
**INTOLERANCE IN UP TO 10% **
**MAJOR ALLOPURINOL HYPERSENSITIVITY SYNDROME RARE BUT HAS ~20% MORTALITY**
**OXYPURINOL CROSS-REACTIVITY LIMITS ALTERNATIVE USE **
**TOPHUS REDUCTION OFTEN SLOW**
**OPTIMUM DOSING CONTROVERSIAL, PARTICULARLY WITH CRI**

## CURRENT OPTIONS FOR ALLOPURINOL-HYPERSENSITIVE&REFRACTORY GOUT

- NO CRI, URATE UNDEREXCRETION

***URICOSURIC**

- CRI, URATE OVERPRODUCTION
- *ALLOPURINOL-ALLERGIC

*** ALLOPURINOL **
**DESENSITIZATION (50:50)**
***OXYPURINOL  **

***PUSH ALLOPURINOL**
*** ? COMBINE**
**ALLOPURINOL WITH**
**PROBENECID, LOSARTAN**

***IF ALLOPURINOL-TOLERANT**
**& REFRACTORY GOUT**

## URIC ACID LOWERING DRUGS CURRENTLY IN USE

**2.**** DRUGS USED TO PROMOTE URICOSURIA: **
**PROBENECID**
**SULFINPYRAZONE (problematic)**
**BENZBROMARONE (not FDA-approved, hepatotoxicity can be serious)**
***LOSARTAN, FENOFIBRATE (relatively weak effects,***
***questionable extent of synergy with current drugs)***

##     CAN WE DEVELOP PHARMACOGENOMIC APPROACHES TO OPTIMIZE URATE-LOWERING THERAPY BASED ON RECENT DEVELOPMENTS IN RENAL URATE HANDLING ?

## CLASSIC DISORDER IN RENAL URATE EXCRETION 

**CLASSIC DISORDER IN RENAL URATE EXCRETION **
**IN PRIMARY GOUT**

**Notes:**
Edwards, NH. Arthritis and Allied Conditions, Koopman, WJ, Lippincott Williams Wilkins, p. 2316. 2001

## “OLD 4-COMPONENT MODEL OF RENAL URATE HANDLING”

**“****OLD 4-COMPONENT MODEL OF RENAL URATE HANDLING”**

- SOURCE: DR PAUL DIEPPE

## URAT1

**NH****2**

**COOH**

**TUBULE LUMEN**

**INTRACELLULAR**

_**URAT1**_

**Urate**

**Anion Exchanger **
**Activated**
**by** **Organic Anions**
**(Less so by Inorganic **
**Anions)**

## *

**Distance along the branches is inversely related the degree of sequence identity. For example, sequence identities are 70% between hOCT1 and hOCT2, 32% between hOCT1 and hOCTN1, and 32% between hOCT1and hOAT1. **
***Koepsell, H. and Endou, H. Pflugers Arch  July 2003***** **

**Phylogenetic tree of **
**human transporters**
**of SLC22 **
**family (e.g. URAT1)**

*****

## SNPS AND MUTATIONS

*Koepsell, H. and Endou, H. Pflugers Arch  July 2003 *

-  IN
- MULTIPLE-PASS
- TRANSMEMBRANE
- SLC22
- TRANSPORTERS
- MAY CAUSE DISEASE

## INTRARENAL SLC22 FAMILY

_** **__**MEMBER EXPRESSION **_
_** **__**REGULATED BY: **_

- GENDER
- AGING AND DEVELOPMENT
- HYPERTENSION
- HYPERURICEMIA
- RENAL FAILURE
- CERTAIN DRUGS

## -

**NH****2**

**COOH**

**TUBULE LUMEN**

**INTRACELLULAR**

**EXTRACELLULAR**

**INTRACELLULAR**

**NH****2**

**COOH**

_**UAT**_

_**URAT1**_

********* ******GALACTOSIDE BINDING SITE***

***URATE/OXONATE***
*** ******BINDING SITE***

***ADENOSINE BINDING SITE***

**Urate**

**Anion**

**Urate**

**+**
**+**

**+**

**Urate**

## apical 

**Organic Anion**

**apical **
**membrane**
**(tubule **
**lumen) **

**basolateral**
**membrane**
**(interface with **
**the circulation)**

**URAT1**

**Benzbromarone**
**Probenecid**
**Losartan**
**Sulfinpyrazone**

**     ****(e.g., Lactate, PZA)**
**               **

**Organic**
**Anion**

**Proximal Tubule Cell Urate Reabsorption**

**Urate**

**Urate**

**Urate**

** **

**Urate**

**+**

- _

**UAT**

**Urate**

- _

**+**

**OAT3?**

**Urate**

**Organic Anion**

## Proximal Tubule Cell Urate Secretion

**Proximal Tubule Cell Urate Secretion**

**Urate**** **

**Urate **

**OAT1**
**OAT3?**

**Anion**

**NPT1?**

** ****UAT**** **

**Urate**

**Urate**

**apical **
**membrane**

**basolateral**
**membrane**

**Urate **

**Na****+**

**+**

- _

**+**

- _

**Anion**

**Urate**

## 2004: URATE HANDLING IN THE NEPHRON

- Reabsorption

- Secretion

- Reabsorption Fine Tuning
**                                                   ****? Na****+****/H****+**** **
**                                                    ****antiporter,**
**                                                    ****OATS**

- Excretion:
- Normally ~10%
- of Filtered Load

- Glomerular Filtration: Normally ~99%

- Bidirectional
- Urate Movement
- in Proximal Tubule

- _2004: URATE HANDLING IN THE NEPHRON_

- *

-      Pharmacogenomics and URAT1:
- Probenecid, Pyrazinamide, Benzbromarone Fail to Alter
-  Renal Urate Clearance in subjects with Defective URAT1

- *

## PROBLEM: EFFECTIVENESS OF ALL CURRENT URICOSURICS IS LIMITED

**CRI**
**URATE OVERPRODUCTION IN 10- 25% OF PRIMARY GOUT UROLITHIASIS RISK**
**OTHER SIDE EFFECTS AND DRUG INTERACTIONS**

## POTENTIAL  THERAPEUTICROLE OF URICASE

- URIC ACID + 2.H20+ O2
- ALLANTOIN + H2O2 + CO2

**A critical means to convert relatively insoluble**
**            ****uric acid to highly soluble allantoin**

- URICASE (Uric acid oxidase)

## URICASE GENE SILENCING

**URICASE GENE SILENCING**
**RENDERS HUMAN URATE BALANCE**
**PRECARIOUS**
**Urate Insoluble in vitro at ~7 mg/100 ml**

## RECOMBINANT URICASE FOR URIC ACID LOWERING

**FDA-APPROVED FOR SHORT TERM SINGLE COURSE IN PEDIATRIC HEMATOLOGIC MALIGNANCIES**
**PROFOUND ACUTE URATE-LOWERING**
**	****(e.g. 10-15 --> 1-2 mg/dL) **
**EFFECTIVE URATE-LOWERING IN SHORT TERM STUDIES IN GOUT **
**POTENTIAL FOR ACCELERATED TOPHUS DISSOLUTION (MONTHS)**

## RECOMBINANT URICASE:CURRENT STATUS

**IMMUNOGENICITY LIMITS SAFETY AND EFFICACY**
**H****2****O****2**** GENERATION LIMITS SAFETY:**
***CELL TRANFORMATION ***_***IN VITRO***_***,***
***ANAPHYLAXIS, HEMOLYSIS with G6PD loss, ***
***METHEMOGLOBINEMIA ***_***IN VIVO***_
**POTENTIALLY LETHAL**
**NOT ORALLY BIO-AVAILABLE **
**CLINICAL TRIALS OF LESS IMMUNOGENIC PEGYLATED FORMS IN PROGRESS FOR GOUT**

## PROPOSED THERAPEUTIC NICHE FOR RECOMBINANT URICASE IN GOUT:

-    Limited-term (months) treatment with long-lasting recombinant uricase preparations of low antigenicity for the reduction of macroscopic, destructive tophus burden in carefully selected patients

## ASYMPTOMATIC HYPERURICEMIA AND VASCULAR DISEASE 

**Serum urate correlates with untreated BP in children of 6-18 **
**Hyperuricemia a powerful predictor pf atherosclerosis and arterial occlusive events and adverse outcome in 1****0**** vascular diseases (e.g., 12-fold more cardiac death in stroke survivors at 5 yrs, adjusted for renal function)**
**Serum urate **_**may**_** be an **_**independent**_** risk factor for atherosclerosis and certain atherosclerotic vaso-occlusive complications**

**Feig et al, Hypertension 2003, and Wong et al Eur Ht J 2002 **
**Reviewed in Bieber and Terkeltaub, Arthritis and Rheumatism, 2004**

## ASYMPTOMATIC HYPERURICEMIA AND RENAL AND VASCULAR DISEASE 

**	****Controversial Recent Data Suggest **_**Direct **_**Linkage of Hyperuricemia to:**
**VSMC Dysfunction**
**Increased sodium reabsorption**
**Hypertension**
**Glomerulopathy**
**Cyclosporine Nephropathy**
**CRI**

## IS MARKEDLY ELEVATED “NORMAL” SERUM URATE IN HUMANS A BENEFICIAL OR HARMFUL RESULT OF EVOLUTIONARY HUMAN URICASE GENE SILENCING? 

## EVOLUTION OF

**EVOLUTION OF**
**APES TO HOMINIDS**
**WITH MORE UPRIGHT**
**POSTURE**

## URICASE GENE INACTIVATION BY MUTATION IN THE 

- From*:*   Watanabe et al, Hypertension, 40:355, 2002

- URICASE GENE INACTIVATION BY MUTATION IN THE
- LATE MYOCENE PERIOD COINCIDING WITH A
- MORE UPRIGHT POSTURE OF HIGHER PRIMATES

## URICASE

- URIC ACID + 2 H20 + 02

- ALLANTOIN + C02 + H202

- OXONIC
-   ACID

- rat serum urate rises
- from ~1 mg/dL to
- ~2 to 3 mg/dL

- The Oxonic Acid-Treated Rat Model of “Mild” Hyperuricemia
-                    (developed by Richard Johnson and colleagues)

## From:   Watanabe et al, Hypertension, 40:355, 2002

- From*:*   Watanabe et al, Hypertension, 40:355, 2002

## Flaws in the Oxonic Acid-Treated Rat Model of

-                       “Mild” Hyperuricemia

**EXTRACELLULAR**

**INTRACELLULAR**

**NH****2**

**COOH**

_**UAT**_

***URATE/OXONATE***
*** ******BINDING SITE***

**Urate**

**Urate**

**Oxonate**

**OXONATE HAS THE POTENTIAL **
**TO PROMOTE INTRACELLULAR **
**RETENTION OF URATE AND OTHER**
**SOLUTES**

## OTHER LIMITS ON INTERPRETING 

_**EXISTING DATA OF ADVERSE RENAL **_
_**AND VASCULAR EFFECTS OF HYPERURICEMIA**_

**1. DIRECT URIC ACID INFUSION IN HEALTHY HUMAN **
**ADULTS DID NOT ALTER HEMODYNAMIC **
**OR ENDOTHELIAL FUNCTIONS ***
**2. URATE HANDLING AS WELL AS SERUM URATE LEVELS **
**MAY DIFFER MARKELY IN RAT AND HUMAN**
**3. CELLULAR EFFECTS OF SOLUBLE URIC ACID**
**IN VITRO SUBJECT TO ARTEFACTS **

- *Waring et al, *Heart,* 2004

## URIC ACID IN HUMANS: THE GOOD, THE BAD, AND...

**Soluble uric acid induced Cox-2 and MCP-1 in cultured VSMCs**

**Uric acid is an antioxidant , 8 times more abundant in human serum than ascorbate  **
**Human ascorbate production lost  in evolution in parallel with uricase**
**Uric acid appears to protect against oxidant and hypoxic brain and heart injury**

- Reviewed by Bieber and Terkeltaub, Arthritis and Rheum, 2004

## GOUT IS EVOLVING CLINICALLY 
GOUT AND “REFRACTORY GOUT” ARE RISING
BETTER PREVENTATIVE EFFORTS INCLUDING PATIENT EDUCATION ARE NEEDED 
DEVELOPMENT OF NEW TREATMENTS FOR HYPERURICEMIA HAS NOT KEPT PACE WITH MEDICAL NEEDS
“TYPICAL” ASYMPTOMATIC HYPERURICEMIA HAS NOT BEEN PROVEN TO DIRECTLY  CAUSE RENAL AND VASCULAR DISEASE 
GOUT AND HYPERURICEMIA ARE WELL UNDERSTOOD AND MANAGED BUT NOT WELL ENOUGH

**GOUT AND “REFRACTORY GOUT” ARE RISING**
**BETTER PREVENTATIVE EFFORTS INCLUDING PATIENT EDUCATION ARE NEEDED **
**DEVELOPMENT OF NEW TREATMENTS FOR HYPERURICEMIA HAS NOT KEPT PACE WITH MEDICAL NEEDS**
**“****TYPICAL” ASYMPTOMATIC HYPERURICEMIA HAS NOT BEEN PROVEN TO DIRECTLY  CAUSE RENAL AND VASCULAR DISEASE **
**GOUT AND HYPERURICEMIA ARE WELL UNDERSTOOD AND MANAGED BUT NOT WELL ENOUGH**

_**FOOD FOR THOUGHT**_