GOUT & HYPERURICEMIA

Introduction
 Gout: heterogeneous clinical spectrum of diseases:
 Elevated serum urate concentration (hyperuricemia),
 Recurrent attacks of acute arthritis associated with
monosodium urate crystals in synovial fluid
leukocytes,
 Deposits of monosodium urate crystals (tophi) in
tissues in and around joints, interstitial renal disease,
and uric acid nephrolithiasis.
 Cont’d…

 Hyperuricemia: underlying metabolic disorder of gout.

 Hyperuricemia: serum that is supersaturated with monosodium
urate.
 Hyperuricemia
≥ 7 mg/dL (416 mol/L) for men
6 mg/dL (357 mol/L) for women.
 The mere presence of hyperuricemia itself is often an
asymptomatic condition. 
 Epidemiology

 Historically, gout as the "disease of kings"

 Incidence and prevalence high in Western countries.
 Also in less industrialized Eastern countries.
 Increased longevity, dietary habits, and increasing
prevalence of obesity and the metabolic syndrome.
 Cont’d…

⁌ Serum uric acid ~ incidence and prevalence of gout.

⁌ Serum urate high: increasing age, serum creatinine, blood
urea nitrogen, male gender, blood pressure, body weight,
and alcohol intake
⁌ The incidence high among
 Obese;
 Who consume large amounts of alcohol;
 Use higher amounts of meat/fish. 
 Cont’d…

 Sustained elevated serum urate: single most important risk factor.

 However, hyperuricemia does not always lead to gout.
 Many patients with hyperuricemia remain asymptomatic.
 Affects men about 7 – 9x more often than women.
 Incidence peaking at 30 to 50 yrs of age.
 Etiology & Pathophysiology
 Uric acid: terminal step in the degradation of purines.
 waste product (no known physiologic purpose)
 Normal uric acid levels are near the limits of urate
solubility.
 Because, of the delicate balance that exists between the
amount of urate produced and excreted.
 Humans have higher uric acid levels than other
mammals.
 They do not express the enzyme uricase, which converts
uric acid to the more soluble allantoin.
 A. Overproduction of Uric Acid

 Purines sources:
 Dietary purine;

 Conversion of tissue nucleic acid to purine nucleotides;

 De novo synthesis of purine bases.

 Average ≈600- 800 mg/day of uric acid produced.

Cont’d…
How???
 Increased breakdown of tissue nucleic acids and cell turnover,

as with:
 Myeloproliferative and lymphoproliferative disorders,
 Polycythemia vera, psoriasis,
 Some types of anemias.
 Cytotoxic medications
 Enzyme abnormalities
 An increase in the activity of phosphoribosyl pyrophosphate (PRPP)
synthetase which leads to an increased concentration of PRPP.
 PRPP key determinant of purine synthesis and uric acid
production.
 Cont’d…

 A deficiency of hypoxanthine-guanine phosphoribosyltransferase

(HGPRT).
 HGPRT convert guanine to guanylic acid and
hypoxanthine to inosinic acid.
 A deficiency in the HGPRT Increased metabolism of
guanine and hypoxanthine to uric acid. 
Uric acid pathway and targets of drug action. (HGPRT,
hypoxanthine-guanine phosphoribosyltransferase; PRPP, phosphoribosyl
pyrophosphate.)
 B. Under-excretion of Uric Acid

 Normally, uric acid does not accumulate : production ≈

elimination.
 2/3 excreted in the urine, remainder through the GIT after
enzymatic degradation by colonic bacteria.
 80% to 90% of patients with gout have decrease in the
renal excretion of uric acid for an unknown reason (1°
idiopathic hyperuricemia).
 Condition enhance sodium reabsorption (e.g.,
dehydration) increased uric acid reabsorption. 
Cont’d…
 Drugs that decrease renal clearance of uric acid
 Diuretics
 Nicotinic acid
Ethambutol
 Salicylates (2g/day)
Cytotoxic drugs
 Ethanol Cyclosporine
 Levodopa Pyrazinamide
 By enhancing renal urate reabsorption
Hyperuricemia
Biologically significant hyperuricemia (≥6.8 mg/dL) is less than
laboratory defined hyperuricemia (≥8.0 mg/dL)

The Hyperuricemia Cascade

Tissue Endogenous
nucleic acids Overproduction
purine synthesis
Dietary
purines Urate
Under excretion
Hyperuricemia ≥6.8 mg/dL

Silent Gout Renal Associated

tissue manifestations cardiovascular events
deposition and mortality
 Clinical Presentation

 Diagnosed clinically by symptoms rather than laboratory tests of

uric acid.
 Asymptomatic hyperuricemia discovered incidentally no Rx
 General
 Acute inflammatory monoarthritis.

 The first metatarsophalangeal joint is often involved

("podagra"), also any joint
 Its spectrum: nephrolithiasis, gouty nephropathy, and
aggregated deposits of sodium urate (tophi) in cartilage,
tendons, synovial membranes, and elsewhere. 
 Acute Gouty Arthritis

 Acute gout for peripheral joints of the lower extremity

 Low temperature of these joints + high intra-articular
urate concentration
 Characterized by rapid and localized onset of excruciating
pain, swelling, and inflammation.
 Typically monarticular at first 1st metatarsophalangeal joint
(great toe).
 Then, ankles, heels, knees, wrists, fingers, and elbows.
18

Olecranon Bursa

Elbow
Gout can occur
in bursae, tendons, Wrist
and joints
Fingers

Knee
1st MTP Ankle
(eventually affected in ~90%
of individuals with gout) Subtalar

Midfoot
 Cont’d…
 The development of crystal-induced inflammation
involves a number of chemical mediators causing
 Vasodilation,
 Increased vascular permeability,
 Complement activation, and
 Chemotactic activity for polymorphonuclear leukocytes
Phagocytosis of urate crystals joint pain, erythema,
warmth, and swelling.
 Fever is common, as is leukocytosis.
 Untreated attacks may last from 3 to 14 days before
spontaneous recovery
Cont’d…
 Precipitating factors:
 Stress, trauma, alcohol ingestion, infection, surgery,

 Rapid lowering of serum uric acid by ingestion of uric

acid- lowering agents, and
 Ingestion of certain drugs known to elevate serum uric
acid concentrations.
 Diagnostic Work up
 P/E, lab, clinical signs and symptoms

 Signs and Symptoms

 Fever, intense pain, erythema, warmth, swelling, and
inflammation of involved joints
 Laboratory Tests
 Elevated serum uric acid levels; leukocytosis
 Other Diagnostic Tests
 Observation of monosodium urate crystals in synovial
fluid or a tophus
 For patients with long-standing gout, radiographs may
show asymmetric swelling within a joint on or
subcortical cysts without erosions
 American College of Rheumatology Criteria for the Clinical Diagnosis
of Gout

1. More than one attack of acute arthritis

2. Maximum inflammation developed within 1 day
3. Monoarthritis attack
4. Redness observed over joints
5. First metatarsophalangeal joint painful or swollen
6. Unilateral first metatarsophalangeal joint attack
7. Unilateral tarsal joint attack
8. Tophus (proven or suspected)
9. Hyperuricemia
10. Asymmetric swelling within a joint on x-ray images

11. Subcortical cysts without erosions on x-ray images

12. Monosodium urate monohydrate microcrystals in joint fluid during attack

13. Joint fluid culture negative for organisms during attack

The combination of crystals, tophi, and/or six or more criteria is highly suggestive of
gout
 Cont’d…

 Determine whether the patient overproducing or under

excreting uric acid.
 Put on a purine-free diet for 3 to 5 days measure the
amount of uric acid excreted in the urine in 24 hours.
 >600 mg on a purine-free diet overproducers.
 <600 mg under excreters.

 >1g/24 hrs excretion reflects overproduction; if less, normal. 

 Uric Acid Nephrolithiasis

 Occur in 10% to 25% of patients with gout.

 So suspect hyperuricemic states for patients who present with
kidney stones.

 The frequency of urolithiasis depends on

 Serum uric acid concentrations,
 Acidity of the urine, and
 Urinary uric acid concentration.
 Cont’d…
 Patients with uric acid nephrolithiasis have a urinary pH of < 6.
 Exist as unionized, less soluble form.

 When acidic urine is saturated with uric acid spontaneous

precipitation
 Other factors that predispose individuals to uric acid nephrolithiasis
 Excessive urinary excretion of uric acid

 Highly concentrated urine.

 The risk of renal calculi 50% if renal excretion >1,100 mg/day.

 Increased risk for mixed uric acid–calcium oxalate stones and pure
calcium oxalate stones.
Gouty Nephropathy
Cont’d…
 In acute uric acid nephropathy
 Acute renal failure occurs: As a result of blockage of
urine flow.
 Common after initiation of chemotherapy 
 Chronic urate nephropathy
 Caused by the long-term deposition of urate crystals in
the renal parenchyma.
 The earliest pathophysiologic disturbances
 A decrease in the kidneys' ability to concentrate urine.
 The presence of proteinuria.

 Hypertension and nephrosclerosis: common.

 Renal failure (CKD) will occur
Tophaceous Gout
 Tophi (urate deposits)
 Uncommon in the general population
of gouty subjects.
 Late complication of hyperuricemia.

 Most common sites: base of great toe,

helix of the ear, Achilles tendon, knees,
wrists, and hands.
Cont’d…
 Effects of tophi:
 Deformities
 Damage surrounding soft tissue,
 Cause joint destruction and pain, and
 Nerve compression syndromes (carpal tunnel
syndrome).
Treatment
 Goals of therapy
 Terminate the acute attack.
 Prevent recurrent attacks of gouty arthritis.
 Prevent complications
 Prevent or reverse features commonly associated with
the illness of obesity, elevated triglycerides, and
hypertension.
Treatment
ACUTE GOUTY ARTHRITIS
Nonpharmacologic Therapy
 Reduce intake of foods high in purines (e.g.,

organ meats)
 avoid alcohol

 increase fluid intake and

 lose weight if obese

 Joint rest for 1 to 2 days

 local application of ice may be beneficial.

Acute Gouty Arthritis
 Rx: short courses of high-dose NSAIDs, corticosteroids,
or colchicine.
 NSAIDs: mainstay of therapy
 Excellent efficacy and minimal toxicity with short-
term use.
 Indomethacin , naproxen, and sulindac FDA
approved/gouty flares.
 Cont’d…
 Determinant of therapeutic success with NSAIDs is not what
chosen rather how soon it is initiated.
 Therapy should be initiated with maximum dosages at the
onset of symptoms
 Continued for 24 hrs after complete resolution of an acute
attack.
 Then, tapered quickly over 2 to 3 days.

 Resolution of an acute attack: within 5 to 8 days after

initiating therapy. 
Cont’d…
 A/Es of NSAIDS
 GI system (gastritis, bleeding, perforation),

 Kidneys (renal papillary necrosis, reduced crCL),

 CV system (sodium and fluid retention, increased BP),

Cont’d…
 Caution when using NSAIDs for individuals with a
hx of
 Peptic ulcer disease.
 Congestive heart failure.

 Uncontrolled hypertension.

 Renal insufficiency.

 Coronary artery disease or

 Who are concurrently receiving anticoagulants or anti-

platelets. 
Corticosteroids
 Reserved for Rx of acute gout flares when CI to NSAIDs exist.

 Used either systemically or by intra-articular injection.

 30 to 60 mg PO prednisone /equivalent for 3 to 5 days.

 Good candidates for Patients with multiple joint involvement.

 Dose of corticosteroid should be tapered gradually in 5 mg
decrements over 10 to 14 days and then discontinued.
 Risk for a rebound attack upon steroid withdrawal.
 Cont’d…

 IA triamcinolone acetonide 20 to 40 mg for acute gout

limited to one or two joints.
 A single IM of a long-acting corticosteroid
methylprednisolone is an alternative to the oral route if
patients are unable to take oral therapy.
 If not contraindicated, low-dose colchicine can be used as
adjunctive therapy to injectable corticosteroids.
 To prevent rebound flare-ups. 
Cont’d…
 A/Es of corticosteroids
 Generally dose and duration dependent.
 Short-term use for treatment of acute attacks is well
tolerated.
 Used with caution for patients with diabetes
 Long-term use: osteoporosis, HPA suppression, cataracts,
and muscle deconditioning.
 Colchicine

 Is an antimitotic drug that is highly effective in relieving

acute gout attacks but has a low benefit-toxicity ratio.
 When colchicine is started within the first 24 hours of an
acute attack, most patients respond within several hours.
 Success decreases if treatment is delayed longer than 48
hours after symptom onset.
Cont…

 Oral colchicine causes dose-dependent GI adverse

effects before relief of the attack.
 Non-GI: neutropenia & axonal neuromyopathy,
worsened with myopathic drugs (e.g., statins) or in
those with renal insufficiency.
 After a full IV course, patients should not receive
colchicine by any route for at least 7 days.
Cont…

 The usual oral colchicine dose is 1 mg initially,

followed by 0.5 mg every 1 hour until the joint
symptoms subside, the patient develops abdominal
discomfort or diarrhea, or a total dose of 8 mg has
been given.
XX
Pharmacologic therapy of acute gouty arthritis

Nonpharmacologic Therapy
 Reduce intake of foods high in purines (e.g.,

organ meats)
 avoid alcohol

 increase fluid intake and

 lose weight if obese

 Joint rest for 1 to 2 days

 local application of ice may be beneficial.

 Non-pharmacologic Therapies
 manage the risks: obesity, alcohol intake,
hyperlipidemia, and the insulin resistance syndrome.
 Reduce dietary intake of saturated fats and meats high
in purines (e.g., organ meats).
 Increase fluid intake and decrease salt consumption:
risk of nephrolithiasis.
 Joint rest for 1 to 2 days and local application of
ice.
 Avoid joint exercise and application of heat to

the affected area

 Cont’d…
 Restriction of alcohol intake
 Acute ingestions of alcohol cause lactic acidemia, which
reduces renal urate excretion.
 Long-term alcohol intake promotes production of purines

 As a by-product of the conversion of acetate to acetyl

coA in the metabolism of alcohol.
 Avoid diuretics if other therapy for HTN available.
Nephrolithiasis Management

 Hydration: maintain a urine volume of 2 to 3

L/day.
 Alkalinization of urine to maintain Urine pH 6 to
6.5.
 K+ bicarbonate/ K+ citrate 60 to 80 mEq/day
 Avoidance of purine-rich foods.
 Moderation of protein intake: < 90 g/day.
 Reduction of urinary uric acid excretion.
Cont’d…

 Acetazolamide: 250 mg at bedtime

 Carbonic anhydrase inhibitor.
 Produces rapid and effective urinary alkalinization.
 Used in conjunction with alkali therapy.

 Recurrent uric acid nephrolithiasis: xanthine

oxidase inhibitors (main stay).
 Cont’d…
Xanthine oxidase inhibitors
 Effective in reducing both serum and urinary uric acid
levels of preventing the formation of calculi.
 Prophylactic Rx for patients who will receive
cytotoxic agents (lymphoma or leukemia).
Prophylactic Therapy of Intercritical Gout

 Institute prophylactic therapy

 After the first attack of acute gouty arthritis or;
 After the passage of the first renal stone.
 Cost-effective if patients have ≥2 attacks/year

 Even if the serum uric acid concentration is

normal or only minimally elevated.
Cont…
 Prophylactic treatment, immediately after resolution of the
acute episode if:
 The pt had a severe attack of gouty arthritis
 A complicated course of uric acid lithiasis
 A substantially elevated serum UA (> 10 mg/dL), or
 A 24-hour urinary excretion of UA > 1gm
 Two or more attacks per year
 Cont’d…

 Withheld prophylactic treatment if

 First episode was mild and responded promptly.
 The patient's serum urate concentration was elevated
only minimally.
 The 24-hour urinary uric acid excretion was not
excessive [<1g/24 hours on a regular diet].
 Cont’d…

 Institute prophylactic treatment immediately after

resolution of the acute episode if
 Severe attack of gouty arthritis,
 A complicated course of uric acid nephrolithiasis,
 Elevated serum uric acid level [>10 mg/dL]
 24-hour urinary excretion of uric acid of >1g.
 Patients with tophi.
Cont’d…

 Low-dose oral colchicine (0.6 mg QD): effective in

preventing recurrent arthritis for patients with
 No evidence of visible tophi.
 A normal or slightly elevated serum urate concentration.

 If pts sense the beginning of an acute attack increase the

dose to 1.2 mg, followed by one repeat dose of 0.6 mg
in 1hr.
 Cont’d…
 Discontinue maintenance colchicine if
 Serum urate concentration is within the normal range.
 Patient has been symptom free for 1 year,
 Patients with a history of recurrent acute gouty
arthritis.
 Significantly elevated serum uric acid concentration
 Best managed with uric acid–lowering therapy
 Achieveand maintain a serum uric acid <6 mg/dL (preferably
5 mg/ dL).
 Decreasing the synthesis of uric acid (xanthine oxidase inhibitors)
or
 Increasing the renal excretion of uric acid (uricosurics).
Cont’d…
 Colchicine 0.6 mg QD should be administered for
at least the first 8 weeks of anti-hyperuricemic
therapy.
 To minimize the risk of acute attacks that may occur
during initiation of uric acid–lowering therapy.
 Xanthine Oxidase Inhibitors

 Allopurinol, Febuxostat.
 Prevent conversion of hypoxanthine to xanthine then uric acid.
 Efficacious for prophylaxis (under-excreters and over-producers)
 For the long-term prevention of recurrent attacks of gout.
 Cont’d…
Allopurinol
 Lowers uric acid levels in a dose-dependent.

Long t1/2 of metabolite (oxypurinol): given once daily.
 Initiate: 100 mg/day then titrate to achieve a serum uric acid
level of 6 mg/dL
 Will promote shrinkage of tophi.
 Check serum uric acid levels ≈1 week after initiating or
modifying the dose of allopurinol.
 Typical doses : 100 to 300 mg/day
 Tophaceous gout doses : 400 to 600 mg/day.
 Max. recommended dose: 800 mg/day.
Cont’d…

 Allopurinol A/Es
 Mild: skin rash, leukopenia, GI problems,
headache, and urticaria.
 Severe: severe rash (TEN, erythema, or exfoliative
dermatitis), hepatitis, interstitial nephritis, and
eosinophilia).
Cont’d…
Febuxostat
 40mg/day o≈ 300 mg/day of allopurinol.
 No dose adjustment in liver and renal problems
 Due to the rapid mobilization of urate deposits occurring
with initiation of Febuxostat
 Co-medicate with colchicine or NSAID for at least the
first 8 weeks after initiation of therapy.
 Uricosuric Drugs

Probenecid and sulfinpyrazone.

 Increase the renal clearance of uric acid by inhibiting post- secretory
renal proximal tubular reabsorption.
 Therapy should be started at a low dose to avoid marked uricosuria
and possible stone formation.
 Should be used only for patients with documented under-excretion of
urate:
 (Less than 800 mg/24 hrs on a regular diet or 600 mg/24 hrs on a
purine-restricted diet). 
 Cont’d…

 Uricosuric agents should be avoided for patients with

renal impairment [a creatinine clearance below 50
mL/min], a history of renal calculi, or overproduction of
uric acid.
 Hydrate and alkalinize urine during the first several days of
uricosuric therapy: diminish uric acid stone formation.
Cont’d…
 Probenecid: initial dose of 250 mg Bid for 1 to 2
weeks and then 500 mg Bid for 2 weeks
 Then increase daily by 500 mg every 1 to 2 weeks
until
 Satisfactory
control is achieved or
 A maximum dose of 2 g is reached

Sulfinpyrazone :
 Initial dose 50 mg Bid for 3 to 4 days; then 100 mg
Bid, increasing the daily dose by 100 mg increments
each week up to 800 mg/day.
 Contraindication in pts :
 who are allergic to them
 with impaired renal function (CLcr <50
mL/min) or
 With a history of renal calculi, and
 who are overproducers of uric acid
 Rasburicase and Pegloticase

 Are recombinant uricase that reduces serum UA by

converting UA to allantoin, which is water soluble.
 Are indicated for antihyperuricemic therapy in adults
refractory to conventional therapy.
 The recommended dose of rasburicase is 0.2 mg/kg as
a 30 minute iv daily for up to 5 days.
Pegloticase is a pegylated recombinant uricase
 8 mg by IV infusion over 2 hours every 2 weeks.
 EVALUATION OF THERAPEUTIC OUTCOMES

 Monitor patients with acute gout for symptomatic relief of joint

pain, as well as potential adverse effects.

 Check the serum uric acid level ,however, acute gout can occur
with normal serum uric acid concentrations.

 For patients receiving UALT, baseline assessment of renal

function, hepatic enzymes, CBC, and electrolytes.

 look for possible correctable causes of hyperuricemia (eg,

medications, obesity, malignancy, alcohol abuse).
`