2. Learning objectives
After completing this chapter, you should be able to
Describe the four clinical manifestations of hyperuricemia.
Explain the pathophysiology of gout and hyperuricemia.
Describe Comorbidities that are commonly associated with gout.
Differentiate the clinical presentation of the various forms of gout.
Identify the most common anatomic sites affected in acute gouty
Describe lifestyle modifications that facilitate lowering of serum urate
Formulate a plan for treating gouty arthritis.
3. Mini case
A 54-year-old male presents to your clinic with severe pain in his left wrist and right
great toe. The affected joints are swollen, erythematous and exquisitely painful. He
denies injury to these areas as well as fever. The patient is afebrile with a temperature
of 38.2 °c, all vital signs are within normal limits. The patient has a history of
hypertension and hyperlipidemia. He has been steadily gaining weight over the past
few years and is now about 50 pounds overweight. He states that he drinks four to five
beers each night. On exam, you find that the patient’s wrist and first MTP joint are
erythematous and very tender to even light touch. The patient has limited range of
motion of these joints related to pain. Lab values show a WBC of 5,400 (Normal 4,300-
10,800) and a Uric Acid level of 9.7 mg/dL.
Any information suggesting gout
Risk factors for acute attack?
Any additional information??
How can we treat??
Monitor and evaluate??
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
Hyperuricemia: underlying metabolic disorder of gout.
Hyperuricemia: serum that is supersaturated with monosodium
≥ 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
Historically, gout as the "disease of kings"
Often associated with affluent societies and lifestyles of
overindulgence, gluttony, and intemperance.
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.
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
The incidence high among
Who consume large amounts of alcohol;
Use higher amounts of meat/fish.
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.
10. Etiology & Pathophysiology
Uric acid: terminal step in the degradation of purines.
Uric acid: 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.
Excess accumulation result from overproduction or under-
excretion of uric acid.
12. A. Overproduction of Uric Acid
Conversion of tissue nucleic acid to purine nucleotides;
De novo synthesis of purine bases.
Average ≈600- 800 mg/day of uric acid produced.
Increased breakdown of tissue nucleic acids and excessive rates of cell
turnover, as with:
Myeloproliferative and lymphoproliferative disorders,
Polycythemia vera, psoriasis,
Some types of anemias.
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.
A deficiency of hypoxanthine-guanine phosphoribosyltransferase
HGPRT convert guanine to guanylic acid and hypoxanthine to inosinic
A deficiency in the HGPRT Increased metabolism of guanine and
hypoxanthine to uric acid.
16. 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
Condition enhance sodium reabsorption (e.g., dehydration)
increased uric acid reabsorption.
Drugs that decrease renal clearance of uric acid
By enhancing renal urate reabsorption
19. Clinical Presentation
Diagnosed clinically by symptoms rather than laboratory tests of uric
Asymptomatic hyperuricemia discovered incidentally no Rx
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.
20. Patient’s Chief Complaints
“I woke up in the middle of the
night last evening and my right big
toe felt as if it was on fire. It’s hot,
swollen, and so tender that even
the weight of a blanket on it is
nearly intolerable. And there’s no
way that I can put a shoe on.”
21. Signs and Symptoms
Fever, intense pain, erythema, warmth,
swelling, and inflammation of involved joints
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
22. Acute Gouty Arthritis
X-zed by rapid and localized onset of excruciating pain, swelling,
Typically monarticular at first 1st metatarsophalangeal joint
Then, ankles, heels, knees, wrists, fingers, and elbows.
The predilection of acute gout for peripheral joints of the lower
Low temperature of these joints + high intra-articular urate
Occur at night, patient awakened from sleep by excruciating pain.
Water is reabsorbed from the joint space supersaturated
solution of monosodium urate
The development of crystal-induced inflammation involves a
number of chemical mediators causing
Increased vascular permeability,
Complement activation, and
Chemotactic activity for polymorphonuclear leukocytes
Phagocytosis of urate crystals joint pain, erythema, warmth,
Fever is common, as is leukocytosis.
Untreated attacks may last from 3 to 14 days before spontaneous
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
Later in the disease, tophaceous deposits of monosodium urate
crystals in the skin or subcutaneous tissues may be found.
Tophi can be anywhere, often on the hands/wrists/elbows/knees.
It takes ≥10yrs for tophi to develop.
Inspect for urate crystals +Clinical triad (inflammatory monoarthritis,
elevated serum uric acid level, and response to colchicine) Gout
27. Diagnostic Work up
P/E, lab, clinical signs and symptoms
Definitive dx requires
Aspiration of synovial fluid from the affected joint
Intracellular crystals of monosodium urate monohydrate in
synovial fluid leukocytes.
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
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)
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
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
If an affected joint is tapped, the resulting synovial fluid may have
white cells and appear purulent raise the question of infection.
Diabetes, alcohol abuse, and advanced age increase the likelihood
of septic arthritis.
Determine whether the patient overproducing or under excreting
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.
31. Uric Acid Nephrolithiasis
Occur in 10% to 25% of patients with gout.
So suspect hyperuricemic states for patients who present with
The frequency of urolithiasis depends on
Serum uric acid concentrations,
Acidity of the urine, and
Urinary uric acid concentration.
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
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.
Uric acid stones usually small, round, and radiolucent.
Uric acid stones containing calcium radiopaque.
In acute uric acid nephropathy
Acute renal failure occurs: As a result of blockage of urine
Common after initiation of chemotherapy
36. Chronic urate nephropathy
Caused by the long-term deposition of urate crystals in the
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
37. 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.
Goals of therapy
Terminate the acute attack.
Prevent recurrent attacks of gouty arthritis.
Prevent or reverse features commonly associated with the
illness obesity, elevated triglycerides, and hypertension.
42. 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
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
Continued for 24 hrs after complete resolution of an acute
Then, tapered quickly over 2 to 3 days.
Resolution of an acute attack: within 5 to 8 days after initiating
A/Es of NSAIDS
GI system (gastritis, bleeding, perforation),
Kidneys (renal papillary necrosis, reduced crCL),
CV system (sodium and fluid retention, increased BP),
Caution when using NSAIDs for individuals with a hx of
Peptic ulcer disease.
Congestive heart failure.
Coronary artery disease or
Who are concurrently receiving anticoagulants or anti-
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 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.
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
an alternative to the oral route if patients are unable to take oral
If not contraindicated, low-dose colchicine can be used as
adjunctive therapy to injectable corticosteroids.
To prevent rebound flare-ups.
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
Anti -mitotic drug.
Highly effective at relieving acute attacks of gout.
When begun within the first 24 hrs of an acute attack, it
produces a response in 2/3 of patients within hrs of
Delay in initiation (>48 hrs)probability of success diminishes
Dose-dependent GI symptomsNVD(50% to 80%).
Neutropenia and neuromyopathy (aggravated with statin).
Use carefully for patients with renal insufficiency, with dosing
repeated no more than once every 2 weeks.
Patients undergoing dialysis should receive a reduced dose of
0.6 mg, as a one-time dose only.
Used less often than NSAIDs coz of high incidence of
adverse effects and the low benefit-to-toxicity ratio.
2nd line: when NSAIDs/corticosteroids are CI or ineffective.
IV colchicine has resulted in fatalities.
Bone marrow suppression, hepatic necrosis, AKI, DIC, seizures,
death. Severe sclerotic tissue reactions/extravasation
53. Non-pharmacologic Therapies
Gout is influenced by several dietary factors obesity,
alcohol intake, hyperlipidemia, and the insulin resistance
Reduce dietary intake of saturated fats and meats high in
purines (e.g., organ meats).
Increase fluid intake and decrease salt consumption: risk of
Joint rest for 1 to 2 days and local application of ice.
Avoid joint exercise and application of heat to the affected
Weight loss (caloric restriction and exercise) should be
promoted in all patients with gout or asymptomatic
This may enhance renal excretion of urate.
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.
56. Nephrolithiasis Management
Hydration: maintain a urine volume of 2 to 3 L/day.
Alkalinization of urine 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.
Administration of alkali via sodium salts is a less desirable
option b/c of
Sodium-induced volume expansion increase sodium
excretion 2°rly cause hypercalcemia*****
Calcium passively follows the reabsorption of sodium in
the proximal tubule and loop of Henle.
In the presence of uric acid, the resultant
hypercalcemia calcium oxalate stone formation.
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).
60. 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.
Withheld prophylactic treatment if
First episode was mild and responded promptly.
The patient's serum urate concentration was elevated only
The 24-hour urinary uric acid excretion was not excessive
[<1g/24 hours on a regular diet].
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]
A 24-hour urinary excretion of uric acid of >1g.
Patients with tophi.
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.
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
Achieve and 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).
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.
66. Xanthine Oxidase Inhibitors
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.
Lowers uric acid levels in a dose-dependent.
Long t1/2 of metabolite (oxypurinol): given once daily.
Initiate: 100 mg/day titrate100mg/day at 1-week intervals 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.
An effective urate-lowering agent
Typical doses 100 to 300 mg/day
Tophaceous gout doses 400 to 600 mg/day.
Max. recommended dose 800 mg/day.
Mild: skin rash, leukopenia, GI problems, headache, and urticaria.
Severe: severe rash (TEN, erythema multiforme, or exfoliative
dermatitis), hepatitis, interstitial nephritis, and eosinophilia).
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.
70. 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
(Less than 800 mg/24 hrs on a regular diet or 600 mg/24 hrs
on a purine-restricted diet).
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.
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
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.
Typical Regimen Considerations
Etodolac 300 mg twice daily Avoid for patients with peptic ulcer disease, active bleeding.
Fenoprofen 300–600 mg three to four times daily May cause renal dysfunction, gastritis (worse with concurrent
aspirin), fluid retention, and hypertension. Use caution in
congestive heart failure. Consider coadministration with a
proton-pump inhibitor for patients at risk for gastrointestinal
Ibuprofen 800 mg four times daily
Indomethacin 25–50 mg four times daily initially for 3 days,
then taper to twice daily for 4–7 days
Ketoprofen 75 mg four times daily
Naproxen 500 mg twice daily initially for 3 days, then
250–500 mg once daily for 4–7 days
Piroxicam 20 mg once daily or divided twice daily
Sulindac 200 mg twice daily for 7–10 days
Oral colchicine 1.2 mg initially, followed by 0.6 mg 1 hour
In the presence of renal impairment, dosing should be repeated
no more than once every 2 weeks. Dose-dependent
gastrointestinal side effects (diarrhea, nausea, vomiting). Avoid
coadministration with p-glycoprotein or strong CYP3A4
inhibitors (e.g., clarithromycin).
Oral steroid 30–60 mg prednisone equivalent once daily
for 3–5 days, then taper in 5 mg decrements
spread over 10–14 days until discontinuation
Use with caution in diabetics. Avoid long-term use. May cause
fluid retention and impaired wound healing. Intraarticular
administration is preferred for monoarticular involvement; avoid
use if joint sepsis is not excluded.
IM steroid Triamcinolone acetonide 60 mg IM once, or
methylprednisolone 100–150 mg/day for 1–2
IA steroid Triamcinolone acetonide 10–40 mg (large
joints), 5–20 mg (small joints)
NSAIDs Lowest effective dosage NSAID gastropathy (See above.)
Oral colchicine 0.6 once daily or every other day Reversible axonal neuromyopathy and
Allopurinol 50–300 mg daily [can be titrated
up to 800 mg/day to achieve
serum urate concentration <6.0
mg/dL (<357 mol/L)]
Can be used in both urate overproduction and
urate underexcretion. Dose reduction necessary for
patients with renal insufficiency.
Febuxostat 40–80 mg/daily Can be used for allopurinol-intolerant patients. No
dosage adjustment necessary for patients with
mild-moderate renal dysfunction [creatinine
clearance 30–59 mL/min . Side effects include liver
enzyme elevations, nausea, arthralgias, and rash.
Probenecid 250 mg twice daily, titrated up to
500–2000 mg/day [target serum
urate concentration <6 mg/dL
Useful in urate underexcretion.
Avoid for patients with history of urolithiasis.
Sulfinpyrazone 50 mg twice daily, titrated to
100–400 mg/day [target serum
urate concentration <6 mg/dL