Hyperuricemia and Gout

By: Annette Vedelago


1) Natural history of gout

Unusual for gout to occur under age 30 in males or under age 50 in females

Four stages:        -   asymptomatic hyperuricemia
                             -   acute gouty arthritis

                             -   intercritical gout

                             -   chronic tophaceous gout

2) Pathophysiology

• Increase in UA from a decrease in urine  acid excretion or
• increase purine breakdown most commonly secondary to drugs (chemotherapy, diuretics, low dose aspirin), disease (malignancies, renal dysfunction, psoriasis), and dietary (beer, fish, red meat)

3) Asymptomatic hyperuricemia

• > 360 μmoL/L for females
• > 420 μmoL/L for males

The incidence of acute gout after 20 years of sustained hyperuricemia is:

• 0.1% – 0.5% for UA concentrations between 420 - 540 μmoL/L
• 5% for UA > 504 μmoL/L

4) Clinical pearl

Asymptomatic hyperuricemia usually does not require treatment with some exceptions. 

5) Drugs and conditions associated with hyperuricemia ¹

Drugs

•   alcohol
•  cyclosporine
•  cytotoxic chemotherapy
• diuretics
•  ethambutol
•  interferon + ribavirin
•  levodopa
•  nicotinic acid
•  pyrazinamide
•  salicylates, low-dose
•  tacrolimus
•  teriparatide

Conditions

•  alcohol consumption
•  atherosclerosis
•  diabetes
•  hyperlipidemia
•  hypertension
•  intrinsic renal disease
•  ischemic heart disease
•  metabolic syndrome
•  myeloproliferative disorders and some cancers  
•  obesity

What is the concern of diuretics with gout? ²

Loop (e.g. furosemide) and thiazide diuretics decrease the excretion and increase the concentration of uric acid.

hydrochlorothiazide-induced gout:    ~ 1%  increased when dose >25 mg/d

6) Diagnostic rule

• consider male gender
• previous patient reported arthritis attack
• onset within one day
• joint redness
• 1st MTP joint
• hypertension or > CVD risk and UA > 360 μmoL/L

Reference 1

7) What non-pharmacological therapies are recommended? ²

Acute attack: rest, elevate limb, ice, avoid contact

Maintenance: useful and may decrease the need for preventative medications

             Diet: compliance with low purine diets is poor, recommend one less portion of meat or fish per day; drink wine instead of beer; drink a glass of skimmed milk each day. Low fat dairy, fiber, vitamin C, and whole grains are associated with decreased gout.
Low calorie diet more beneficial/acceptable then low purine diet!

               Avoid: liver, kidney, shellfish, gravy, sardine, sweetbread, sugar drinks and yeast extract.

               Lifestyle: Weight loss, Smoking cessation, decrease alcohol binging (especially beer)

                                drink 2 L water/day (unless contraindicated), mild-moderate intensity exercise.

8) Indications for antihyperuricemic therapy ¹

• 2 attacks/year
•  severe or polyarticular attacks
•  presence of tophaceous gout
•  radiographic evidence of joint damage due to gout
•  severe/persistent hyperuricemia (> 720 μmoL/L)
•  hypoxanthine-guanine phosphoribosyl ransferase (HGPRT) deficiency or prhosphoribosyl perophosphate (PRPP) synthetase overactivity ( both ­ uric acid production)
•  uric acid nephropathy, nephrolithiasis (uric acid or calcium stones)
•  24-hour urinary uric acid excretion > 1000 mg, particularly in males < 25 years and premenopausal women
•  prophylaxis of hyperuricemia prior to administration of cytotoxic agents

Reference 1

Reference 1

Reference 1

Reference 1

Clinical pearls  – NSAIDs

• Contraindicated with decreased renal function (Clcr < 30 mL/min), GI) ulcer, heart failure, previous allergy to NSAID.
• Indomethacin is used historically, however others are also effective and cause less CNS adverse effects
• GI prophylaxis should be considered in the presence of a history of PUD/GI bleed or age > 70 (PPI or misoprostol 200 μg TID – QID)
• High doses for 1^st 24-72 hours, then stop or use lowest effective dose x 1-2 weeks

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Clinical pearls  – Colchicine

Dose:  1.2 mg stat then 0.6 mg 1 hour later (FDA); no further doses for 3 days (CPS) other dosing schedules have been used: 0.6 mg bid x 1-3 days, then daily x1-2 weeks

Limiting dose to less than 3 tablets on day 1 then 1-2 tablets/day will greatly decrease diarrhea/GI side effects

Use ½ dose if taking concomitant strong CYP3A4 inhibitor and normal renal/hepatic function (CPS) see CPS for other doses

Monitor:  CBC (neutropenia), CK (rhabdomyolysis may increase with statins/fibrates), renal function q6 months

Prophylaxis when starting allopurinol:  0.6 daily – bid (or 1 mg daily) x 3 – 6 months.

NOT COVERED ON ODB
Vitamin C   

1000 – 1500 mg/day may reduce relative risk of gout by 34 – 45%

However, doses over 1000 mg increases risk of kidney stones (oxalate or uric acid) in those who have had a previous kidney stone

•       May increase excretion of uric acid.

Clinical pearls  – Allopurinol

Wait 1-2 weeks after inflammation subsides before initiating NEVER START OR STOP ALLOPURINOL DURING AN ACUTE ATTACK

Prophylax with colchicine (0.6 daily – bid) or NSAID low dose x 3 – 6 months while titrating allopurinol

D/C if rash since rash may precede serious hypersensitivity reactions (20-30% mortality)

Start low:  100 – 200 mg daily and increase by 100 mg weekly based on UA levels (CPS)  or start at 100 mg daily and increase q2 – 4 weeks (RxFiles)

Maximum 800 mg daily if normal renal function, otherwise reduced.

If eGFR < 50 mL/min, start at 50 mg/day and titrate by 50 mg doses, maximum 300 mg/day.  (http://www.rxfiles.com/)

CrCl 10 – 20 mL/min max. maintenance dose 100 mg daily

CrCl < 10 mL/min max maintenance dose 100 mg q2-3 days

Divided doses if > 300 mg daily (improved GI tolerability)

After food

↑INR possible with warfarin – monitor

↑toxicity of azathioprine

Before starting:  LFT; Cr (CrCl); CBC

Febuxostat (Uloric ©)

80 mg daily more effective than allopurinol 300 mg daily in bringing UA to goal (<360 μmoL/L)

May be used if CrCl > 30 mL/min

Alternative to allopurinol if hypersensitive to allopurinol

BUT – more expensive, NOT COVERED ON ODB, if normal renal function, allopurinol dose may be increased above 300 mg (800 mg max)

Contraindicated with azathioprine, mercaptopurine or theophylline!

Conclusions

Treat acute gout before deciding upon need for UA lowering Tx

Consider iatrogenic causes (ie. Drugs)

Never start or stop allopurinol (or febuxostat) during acute attack

Use prophylaxis with colchicine or NSAID x 3-6 months while titrating dose of allopurinol (or            
               febuxostat

References

1.  Therapeutic choices. Canadian pharmacists Association, 2011

2.  www.RxFiles.ca (Accessed Oct 17, 2011)