2. Gout Dr. Wael H.Mansy, MD Assistant Professor College of Pharmacy King Saud University

3. Gout Gout is defined as a peripheral arthritis resulting from the deposition of sodium urate crystals in one or more joints. Gout is defined as a peripheral arthritis resulting from the deposition of sodium urate crystals in one or more joints.

4. Uric Acid URIC ACID: Is the final breakdown product of purine degradation in humans URIC ACID: Is the final breakdown product of purine degradation in humans URATE: The ionized forms of uric acid, predominante in plasma, extracellular fluid and synovial fluid. URATE: The ionized forms of uric acid, predominante in plasma, extracellular fluid and synovial fluid. Approximately 98% existing as monosodium urate at pH 7.4 Approximately 98% existing as monosodium urate at pH 7.4

5. Uric Acid Plasma is saturated with monosodium urate at a concentration of 6.8 mg/dl. Plasma is saturated with monosodium urate at a concentration of 6.8 mg/dl. At higer concentrations, plasma is therfore supersaturated, creating the potential for urate crystal precipitation. At higer concentrations, plasma is therfore supersaturated, creating the potential for urate crystal precipitation. Urate production varies with the purine content of the diet and the rates of purine biosyntesis, degradation and salvage. Urate production varies with the purine content of the diet and the rates of purine biosyntesis, degradation and salvage. 2/3 to ¾ of urate is excreted by kidneys, and most of the remainer is eliminated through the intestines. 2/3 to ¾ of urate is excreted by kidneys, and most of the remainer is eliminated through the intestines.

6. Uric Acid Uric acid is more soluble in urine than in water. Uric acid is more soluble in urine than in water. The pH of urine greatly influences its solubility. The pH of urine greatly influences its solubility. pH 5 urine is saturated with uric acid at concentrations ranging from 6 to 15 mg/dl. pH 5 urine is saturated with uric acid at concentrations ranging from 6 to 15 mg/dl. At pH 7 saturation is reached at concentration between 158 and 200mg/dl. At pH 7 saturation is reached at concentration between 158 and 200mg/dl.

7. Uric Acid Serum urate levels vary with age and sex. Serum urate levels vary with age and sex. Children: 3 to 4 mg/dl Children: 3 to 4 mg/dl Adult men: 6 to 6.8 mg/dl Adult men: 6 to 6.8 mg/dl

8. Epidemiology Prevalence of hyperuricemia Prevalence of hyperuricemia 2.3 – 41.4% in various populations. 2.3 – 41.4% in various populations. Corresponds with serum creatinine /BUN levels, body weight, height, age, blood pressure, and alcohol intake. (Taiwan) Corresponds with serum creatinine /BUN levels, body weight, height, age, blood pressure, and alcohol intake. (Taiwan) Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of widely differing races and cultures. Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of widely differing races and cultures. Incidence of Gout Incidence of Gout Varies depending on population studied – 1.8 /1000 – 3.2/1000 Varies depending on population studied – 1.8 /1000 – 3.2/1000 RR for blacks slightly higher (1.3) RR for blacks slightly higher (1.3)

9. Hyperuricemia Defined as a plasma urate concentration > 7.0 mg/dl Defined as a plasma urate concentration > 7.0 mg/dl

10. Hyperuricemia Can result from: Can result from: Increased production of uric acid Increased production of uric acid Decreased excretion of uric acid Decreased excretion of uric acid Combination of the two processes. Combination of the two processes.

11. Increased Urate Production Diet provides an exogenous source of purines and, accordingly, contributes to the serum urate in proportion to its purine content. Diet provides an exogenous source of purines and, accordingly, contributes to the serum urate in proportion to its purine content. Foods high in nucleic acid: liver, red meat and anchovy. Foods high in nucleic acid: liver, red meat and anchovy. Restriction intake: reduces: 1 mg/dl Restriction intake: reduces: 1 mg/dl

12. Endogenous sources: Endogenous sources: De novo purine biosynthesis.Increased phosphoribosyl pyrophosphatase (PRPP) synthetase activity and Hypoxanthine phosphoribosyltransferase (HPRT) deficiency are associated with overproduction of purine, hyperuricemia and hyperuricaciduria. De novo purine biosynthesis.Increased phosphoribosyl pyrophosphatase (PRPP) synthetase activity and Hypoxanthine phosphoribosyltransferase (HPRT) deficiency are associated with overproduction of purine, hyperuricemia and hyperuricaciduria.

13. Decreased Uric Acid Excretion Alterated uric acid excretion could result from: Alterated uric acid excretion could result from: 1. Decreased glomerular filtration. 2. Decreased tubular secretion. 3. Enhanced tubular reabsorption.

14. Decreased tubular secretion of urate causes the secondary hyperuricemia of acidosis. Decreased tubular secretion of urate causes the secondary hyperuricemia of acidosis. Diabetic ketoacidosis, starvation, ethanol intoxication, lactic acidosis, and salicylate intoxication are accompanied by accumulations of organic acids (B- hydroxybutyrate, acetoacetate, lactate or salicylates) that compete with urate for tubular secretion. Diabetic ketoacidosis, starvation, ethanol intoxication, lactic acidosis, and salicylate intoxication are accompanied by accumulations of organic acids (B- hydroxybutyrate, acetoacetate, lactate or salicylates) that compete with urate for tubular secretion.

15. Combined Mechanisms Alcohol intake promotes hyperuricemia: Alcohol intake promotes hyperuricemia: Fast hepatic breakdown of ATP and increases urate production. Fast hepatic breakdown of ATP and increases urate production. Can induce hyperlacticacidemia, and inhibition of uric acid secretion. Can induce hyperlacticacidemia, and inhibition of uric acid secretion. The higher purine content in some alcoholic beverages such as beer may also be a factor. The higher purine content in some alcoholic beverages such as beer may also be a factor.

16. Evaluation of Hyperuricemia Hyperuricemia does not represent a disease. Hyperuricemia does not represent a disease. Is not an specific indication for therapy. Is not an specific indication for therapy. The finding of hyperuricemia is an indication to determine its cause. The finding of hyperuricemia is an indication to determine its cause.

17. The hyperuricemia of individuals who excrete high uric acid amounts while on a purine-free diet is due to purine overproduction The hyperuricemia of individuals who excrete high uric acid amounts while on a purine-free diet is due to purine overproduction Whereas it is due to decreased excretion in those who excrete lower amounts on the purine-free diet. Whereas it is due to decreased excretion in those who excrete lower amounts on the purine-free diet.

18. Complications of Hyperuricemia The most recognized complication of hyperuricemia is gouty arthritis The most recognized complication of hyperuricemia is gouty arthritis Nephrolithiasis Nephrolithiasis Urate Nephropathy Urate Nephropathy Uric Acid Nephropathy Uric Acid Nephropathy

19. Gout = Crystal-induced arthritis MSU (monosodium urate) MSU (monosodium urate) CPPD (calcium pyrophosphate dihydrate) CPPD (calcium pyrophosphate dihydrate) HA (calcium hydroxyapatite) HA (calcium hydroxyapatite) Calcium oxalate (CaOx) Calcium oxalate (CaOx)

20. Monosodiumurate Gout

21. Affecting middle-aged to elderly men. Affecting middle-aged to elderly men. Women represent only 5 to 17% of all patients. Women represent only 5 to 17% of all patients.

22. Monosodiumurate Gout Monosodiumurate Gout Associated with an increased uric acid, hyperuricemia, episodic acute and chronic arthritis, and deposition of MSU crystals in connective tissue tophi and kidneys. Associated with an increased uric acid, hyperuricemia, episodic acute and chronic arthritis, and deposition of MSU crystals in connective tissue tophi and kidneys.

23. Acute and chronic arthritis Acute arthritis is the most frequent early clinical manifestation of MSU gout. Acute arthritis is the most frequent early clinical manifestation of MSU gout. Usually only one joint is affected initially Usually only one joint is affected initially Polyarticular acute gout is also seen in male hypertensive patients with ethanol abuse as well as in postmenopausal women. Polyarticular acute gout is also seen in male hypertensive patients with ethanol abuse as well as in postmenopausal women.

24. The metatarso phalangeal joint of the first toe is often involved. The metatarso phalangeal joint of the first toe is often involved. Ankles, and knees are also commonly affected. Ankles, and knees are also commonly affected. In elderly patients, finger joints may be inflamed. In elderly patients, finger joints may be inflamed. Acute and chronic arthritis

26. The first episode of acute gouty arthritis frequently begins at night. The first episode of acute gouty arthritis frequently begins at night. With dramatic joint pain and swelling. With dramatic joint pain and swelling. Early attacks tend to subside spontaneously within 3 to 10 days. Early attacks tend to subside spontaneously within 3 to 10 days. Most of the patients do not have residual symptoms until next episode. Most of the patients do not have residual symptoms until next episode. Acute and chronic arthritis

27. Signs and Symptoms Chronic: Chronic: Destructive tophacous gout. Destructive tophacous gout. Much greater chance if untreated Much greater chance if untreated Rarely presents as a chronic Rarely presents as a chronic

28. Nephrolithiasis The prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels. The prevalence of nephrolithiasis correlates with the serum and urinary uric acid levels. Serum urate levels 13 mg/dl Serum urate levels 13 mg/dl Urinary uric acid excretion > 1100 mg/d Urinary uric acid excretion > 1100 mg/d

29. Diagnosis Based on history and physical Based on history and physical Confirmed by arthrocentesis Confirmed by arthrocentesis Urate crystals: needle-shaped negatively birefringent either free floating or within neutrophils & macrophages. Urate crystals: needle-shaped negatively birefringent either free floating or within neutrophils & macrophages. Uric acid level non specific. Uric acid level non specific. 30% may show normal level 30% may show normal level Urine collection: Urine collection: <800 mg dl/d underexcertor (<600 purine-free diet) <800 mg dl/d underexcertor (<600 purine-free diet)

30. X-ray Acute Soft tissue swelling Chronic chronic tophaceous gouty arthritis, extensive bony erosions are noted throughout the carpal bones

31. Prognosis Generally good Generally good More severe course when Sx present < 30 y/o More severe course when Sx present < 30 y/o Up to 50% progress to chronic disease if untreated. Up to 50% progress to chronic disease if untreated. Surgical intervention may be required for tophi. Surgical intervention may be required for tophi.

32. Treatment Acute: Acute: NSAID’s anti-inflammatory doses NSAID’s anti-inflammatory doses Colchicine 0.5 mg po q2 hours, may require 6 mg. Colchicine 0.5 mg po q2 hours, may require 6 mg. Stop with response or side effect (diarrhea) Stop with response or side effect (diarrhea) Can be used for chronic disease, increased risk for BM suppression Can be used for chronic disease, increased risk for BM suppression Aspirate followed by administration of corticosteroids Aspirate followed by administration of corticosteroids Prednisone Prednisone ACTH 40-80 IM/IV ACTH 40-80 IM/IV

33. Treatment Chronic: Chronic: Diet will decrease uric acid 1 mg/dL at best Diet will decrease uric acid 1 mg/dL at best Weight loss Weight loss Modification of medications Modification of medications Avoid low dose ASA, diuretics, etc. Avoid low dose ASA, diuretics, etc.

34. Treatment Chronic Chronic Uricosuric: for under-excretors Uricosuric: for under-excretors Probenicid: Probenicid: Sulfinpyrazone: toxic side effects Sulfinpyrazone: toxic side effects Avoid with renal disease Avoid with renal disease Consider NSAIDs to avoid exacerbation of gout. Consider NSAIDs to avoid exacerbation of gout.

35. Treatment Chronic Chronic Indications for Allopurinol Indications for Allopurinol Tophaceous deposites Tophaceous deposites Uric acid consistently >9 mg/dl. Uric acid consistently >9 mg/dl. Persistent Sx with moderate UA levels Persistent Sx with moderate UA levels Impaired renal function Impaired renal function Prophylaxis for tumor-lysis syndrome Prophylaxis for tumor-lysis syndrome Consider NSAID’s to avoid exacerbation Consider NSAID’s to avoid exacerbation