1. Gout

2. The term gout describes a disease spectrum including – hyperuricemia, – recurrent attacks of acute arthritis associated with monosodium urate crystals in leukocytes found in synovial fluid, – deposits of monosodium urate crystals in tissues, – interstitial renal disease, and – uric acid nephrolithiasis. Hyperuricemia may be an asymptomatic condition with an increased serum uric acid level as the only apparent abnormality.

3. Studies have shown that serum urate concentration (and consequently the risk of gout) correlates with age, serum creatinine level, blood urea nitrogen level, male gender, blood pressure, body weight, and alcohol intake. In gout, the mean serum urate concentration values are 6.8 mg/dL for men and 6.0 mg/dL for women.

4. Prevalence Prevalence increases with age, especially in men. Men are affected by gout approximately 10 times more often than women.

5. ETIOLOGY AND PATHOPHYSIOLOGY In humans, uric acid is the end product of the degradation of purines. Uric acid serves no known physiologic purpose and therefore is regarded as a waste product. In lower animals, the enzyme uricase breaks down uric acid to the more soluble allantoin, and thus uric acid does not accumulate. Under normal conditions, the amount of accumulated uric acid is about 1200 mg in men and about 600 mg in women. The size of the urate pool is increased several fold in individuals with gout. This excess accumulation may result from either overproduction or underexcretion.

6. OVERPRODUCTION OF URIC ACID The purines from which uric acid is produced originate from three sources: – dietary purine, – conversion of tissue nucleic acid to purine nucleotides, – and de novo (afresh) synthesis of purine bases. The purines derived from these three sources enter a common metabolic pathway leading to the production of either nucleic acid or uric acid. Under normal circumstances, uric acid may accumulate excessively if production exceeds excretion. The average human produces about 600 to 800 mg of uric acid each day.

7. UNDEREXCRETION OF URIC ACID Uric acid does not accumulate as long as uric acid production is balanced with elimination. Uric acid is eliminated in two ways. About two-thirds of the uric acid produced each day is excreted in the urine. The rest is eliminated through the gastrointestinal tract after enzymatic degradation by colonic bacteria. A decline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate.

8. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption. Approximately 90% of filtered uric acid is reabsorbed in the proximal tubule

9. Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes. Eg-: Diuretics, Ethanol, Ethambutol, Nicotinic acid, Pyrazinamide, Cytotoxic drugs, Salicylates (<2 g/day),Levodopa, Cyclosporine. By enhancing renal urate reabsorption, insulin resistance is also associated with gout.

10. The pathophysiologic approach to the evaluation of hyperuricemia requires determining whether the patient is overproducing or underexcreting uric acid. This can be accomplished by placing the patient on a purine-free diet for 3 to 5 days and then measuring the amount of uric acid excreted in the urine in 24 hours.

11. Normal individuals produce 600 to 800 mg of uric acid daily and excrete less than 600 mg in urine. Individuals who excrete more than 600 mg on a purine-free diet may be considered overproducers. Hyperuricemic individuals who excrete less than 600 mg of uric acid per 24 hours on a purine-free diet may be classified as underexcretors of uric acid. On a regular diet, excretion of greater than 1000 mg per 24 hours reflects overproduction; less than this is probably normal.

12. CLINICAL PRESENTATION Gout is a disease diagnosed by symptoms rather than laboratory tests of uric acid. ACUTE GOUTY ARTHRITIS Acute attacks of gouty arthritis are characterized by rapid onset of piercing pain, swelling, and inflammation. The attack typically is monarticular at first, most often affecting the first metatarsophalangeal joint (great toe) and then, in order of frequency, the insteps (arched middle part of the foot between toes and ankle), ankles, heels, knees, wrists, fingers, and elbows.

13. In one-half of initial attacks, the first metatarsophalangeal joint is affected. Of gouty patients, 90% experience attacks in the great toe at some point in their disease. At night, water is reabsorbed from the joint space, leaving behind a supersaturated solution of monosodium urate, which can precipitate attacks of acute arthritis. Attacks generally begin at night with the patient awakening from sleep in piercing pain.

14. The development of crystal-induced inflammation involves a number of chemical mediators causing vasodilation, increased vascular permeability, and chemotactic activity for polymorphonuclear leukocytes.

15. Phagocytosis of urate crystals by the leukocytes results in rapid lysis of cells and a discharge of proteolytic enzymes into the cytoplasm. The ensuing inflammatory reaction is associated with intense joint pain, erythema, warmth, and swelling. Fever is common, as is leukocytosis. Untreated attacks may last from 3 to 14 days before spontaneous recovery

16. Conditions that precipitate an attack include 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. The diagnosis is best accomplished by aspiration of synovial fluid from the affected joint and identification of intracellular crystals of monosodium urate monohydrate in synovial fluid leukocytes.

17. URIC ACID NEPHROLITHIASIS Nephrolithiasis occurs in 10 to 25% of patients with gout. Factors that predispose individuals to uric acid nephrolithiasis include excessive urinary excretion of uric acid, an acidic urine, and a highly concentrated urine. The risk of renal calculi approaches 50% in individuals whose renal excretion of uric acid exceeds 1100 mg/day.

18. In addition to pure uric acid stones, hyperuricosuric individuals are at increased risk for mixed uric acid–calcium oxalate stones and pure calcium oxalate stones. Uric acid stones are usually small, round, and radiolucent (transparency to X rays). Uric acid stones containing calcium are radiopaque (opacity to x rays).

19. When urine is acidic, uric acid exists primarily in the un-ionized, less soluble form. At a urine pH of 5.0, urine is saturated at a uric acid level of 15 mg/dL. When the urine pH is 7.0, the solubility of uric acid in urine is increased to 200 mg/dL. In patients with uric acid nephrolithiasis, urinary pH typically is less than 6.0 and frequently less than 5.5. When an acidic urine is saturated with uric acid, spontaneous precipitation of stones may occur.

20. GOUTY NEPHROPATHY There are two types of gouty nephropathy: acute uric acid nephropathy and chronic urate nephropathy. In acute uric acid nephropathy, acute renal failure occurs as a result of blockage of urine flow secondary to massive precipitation of uric acid crystals in the collecting ducts and ureters.

21. Chronic urate nephropathy is caused by the long-term deposition of urate crystals in the renal parenchyma. A decrease in the kidney’s ability to concentrate urine and the presence of proteinuria may be the earliest pathophysiologic disturbances. Hypertension and nephrosclerosis are common associated findings.

22. The chronic renal impairment seen in individuals with gout may result largely from the co-occurrence of hypertension, diabetes mellitus, and atherosclerosis.

23. TOPHACEOUS GOUT Tophi (urate deposits) are uncommon in the general population of gouty subjects and are a late complication of hyperuricemia. The most common sites of tophaceous deposits in patients with recurrent acute gouty arthritis are the base of the great toe, helix of the ear, olecranon bursae, Achilles tendon, knees, wrists, and hands.

24. TREATMENT The goals in the treatment of gout are to terminate the acute attack, prevent recurrent attacks of gouty arthritis, and prevent complications associated with chronic deposition of urate crystals in tissues. Patients should be advised to reduce their dietary intake of saturated fats and meats high in purines (e.g., organ meats).

25. ACUTE GOUTY ARTHRITIS Acute attacks of gouty arthritis may be treated successfully with colchicine or any of a variety of nonsteroidal anti-inflammatory drugs (NSAIDs). Colchicine can be given orally or parenterally. The major problem associated with the use of oral colchicine is that it causes gastrointestinal side effects in 50% to 80% of patients before the relief of the attack.

26. This high incidence of gastrointestinal side effects may be controlled by administering colchicine intravenously. Except in patients with renal insufficiency, the initial intravenous dose of colchicine is 2 mg. If relief is not obtained, an additional 1-mg dose may be given at 6 and 12 hours to a total dose of 4 mg for a specific attack. The colchicine should be diluted with 20 mL normal saline before administration to minimize sclerosis of the vein.

27. The intravenous administration of colchicine eliminates most of the gastrointestinal symptoms associated with the oral dose, but subjects the patient to the risk of local extravasation (leakage), which can cause inflammation in and necrosis of the surrounding tissue. Very small, difficult-to inject veins and renal impairment represent relative contraindications to intravenous colchicine therapy.

28. Because of the risk of bone marrow toxicity, colchicine should be discontinued for 7 days following initial therapy with either oral or intravenous administration. Colchicine should not be used intravenously in individuals who are neutropenic, have severe renal impairment (a creatinine clearance of <10 mL/min), or have combined renal and hepatic insufficiency.

29. Indomethacin is as effective as colchicine in the treatment and the acute gastrointestinal toxicity occurs far less frequently with indomethacin than with colchicine. Side effects unique to indomethacin include headache and dizziness. All NSAIDs have been implicated in the cause of gastric ulceration and bleeding, but unlikely with short-term therapy.

30. Indomethacin may be begun with a relatively large dose for the first 24 to 48 hours and then tapered over 3 to 4 days to minimize the risk of recurrent attacks. For example, 75 mg of indomethacin should be given initially, followed by 50 mg every 6 hours for 2 days and then 50 mg every 8 hours for 1 or 2 days.

31. A number of other NSAIDs (e.g., naproxen, fenoprofen, ibuprofen, and piroxicam) are also effective in relieving the inflammation of acute gout. All NSAIDs should be used with caution in individuals with a history of acid peptic disease, heart failure, chronic renal failure, or coronary artery disease.

32. Corticosteroids may be used to treat acute attacks of gouty arthritis, but they are reserved primarily for resistant cases or for patients with a contraindication to colchicine and NSAID therapy. Prednisone may be administered orally in doses of 30 to 60 mg for 3 to 5 days in patients with multiple-joint involvement. Because rebound attacks may occur on steroid withdrawal, the dose should be tapered gradually by 5-mg decreases over 10 to 14 days and discontinued.

33. NEPHROLITHIASIS The medical management of uric acid nephrolithiasis includes – hydration sufficient to maintain a urine volume of 2 to 3 L/day, – alkalinization of urine, – avoidance of purine-rich foods, – moderation of protein intake, and – reduction of urinary uric acid excretion.

34. Maintenance of a 24-hour urine volume of 2 to 3 L with an adequate intake of fluids is desirable for all gouty patients, but especially for those with excessive (>1 g/day) uric acid excretion. Alkalinizing agents should be used with the objective of making the urine less acidic. Urine pH should be maintained at 6 to 6.5.

35. Reduction of urine acidity can be accomplished by the administration of sodium bicarbonate or Shohl’s solution (40 g citric acid and 98 g sodium citrate per liter). With the former(sodium bicarbonate ), 2 to 6 g/day is given in equally divided doses at 6- to 8- hour intervals. A dose of 20 to 60 mL of Shohl’s solution per day, given in three or four divided doses, provides an equivalent amount of alkali. If use of a sodium salt is contraindicated, potassium citrate may be used instead.

36. The mainstay of drug therapy for recurrent uric acid lithiasis ( calculi) is allopurinol. It is effective in reducing both serum and urinary uric acid levels, thus preventing the formation of calculi. One must keep in mind that older patients with uric acid kidney stones also may have hypertension, congestive heart failure, or renal insufficiency, and obviously should not be exposed to overload with alkalinizing sodium salts or unlimited fluid intake.

37. Prophylaxis Recurrences of acute gouty arthritis may be prevented with continuous low-dose daily oral colchicine or by uric acid–lowering therapy with either uricosuric agents or inhibition of xanthine oxidase with allopurinol. Combination therapy consisting of colchicine plus a uricosuric agent or allopurinol may be employed in resistant cases. Prophylactic therapy with low-dose oral colchicine, 0.5 to 0.6 mg twice daily, may be effective in preventing recurrent arthritis

38. Patients do not become resistant to or tolerant of daily colchicine, and if they sense the beginning of an acute attack, they should increase the dose to 1 mg every 2 hours; in most instances the attack will abort after 1 or 2 mg of colchicine. If the serum urate concentration is within the normal range and the patient has been symptom- free for 1 year, maintenance colchicine may be discontinued.

39. Colchicine at a dose of 0.5 mg twice daily should be administered during the first 6 to 12 months of antihyperuricemic therapy to minimize the risk of acute attacks that may occur during initiation of uric acid–lowering therapy.

40. URICOSURIC DRUGS Uricosuric drugs increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. Therapy with uricosuric drugs should be started at a low dose to avoid marked uricosuria and possible stone formation. The maintenance of adequate urine flow and alkalinization of the urine with sodium bicarbonate or Shohl’s solution during the first several days of uricosuric therapy further diminish the possibility of uric acid stone formation.

41. Probenecid is given initially at a dose of 250 mg twice a day for 1 to 2 weeks and then 500 mg twice a day for 2 weeks. Thereafter the daily dose is increased by 500- mg increments every 1 to 2 weeks until satisfactory control is achieved or a maximum dose of 2 g is reached.

42. The initial dose of sulfinpyrazone is 50 mg twice a day for 3 to 4 days and then 100 mg twice a day, increasing the daily dose by 100- mg increments each week up to 800 mg/day.

43. The major side effects associated with uricosuric therapy are gastrointestinal irritation, rash and hypersensitivity, precipitation of acute gouty arthritis, and stone formation. These drugs are contraindicated in patients who are allergic to them and in patients with impaired renal function (a creatinine clearance<50 mL/min), a history of renal calculi, and in patients who are overproducers of uric acid. For such patients, allopurinol should be used.

44. XANTHINE OXIDASE INHIBITOR Currently, allopurinol is the only drug approved for use in inhibiting uric acid synthesis. Both allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and thus impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. An oral daily dose of 300 mg usually is sufficient. Occasionally, as much as 600 to 800 mg/day may be necessary.

45. Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function. The major side effects of allopurinol are skin rash, leukopenia, occasional gastrointestinal toxicity, and increased frequency of acute gouty attacks with the initiation of therapy.