Uric acid


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Uric acid

  1. 1. Case Scenario! • A 45 year old man awoke from sleep with a painful and swollen right great toe. On the previous night he had a meal of fried liver and onions, after which he met with his poker group and drank a number of beers. • He saw his doctor that morning and some tests were ordered. His serum uric acid level was elevated at 8.0 mg/dl. (What is normal value?) • The man recalled that his father and his grandfather, both of whom were alcoholics, often complained of joint pain and swelling in their feet. • What can be his probable diagnosis? Gouty Arthritis
  2. 2. Uric Acid
  3. 3. DNA/RNA (Nucleic Acid) Breakdown Food Malignancy(Cell turnover) Alcohol Uric Acid Energy production
  4. 4. DNA/RNA (Nucleic Acid) Breakdown pancreatic nucleases, non-specific phosphatases , intestinal phosphodiesterases, nucleotidase Adenosine, Guanosine, Thymidine, Cytidine, Uridine Intestine Intestine Nucleic Acid Nucleosides
  5. 5. Purine Catabolism and the necessary enzymes.
  6. 6. PRPP Synthetase DNA/RNA Breakdown Adenine phosphoribosyl transferase (APRT) Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT)
  7. 7. Degradation of Pyrimidines 1. CMP and UMP degraded to bases similarly to purines. A. Dephosphorylation B. Deamination C. Glycosidic bond cleavage 2. Uracil reduced in liver, forming β-Alanine 3. Converted to malonyl-CoA energy metabolism fatty acid synthesis for
  8. 8. Important points about Uric Acid 1. Final breakdown product of purine degradation in humans. 2. Urates, the ionized forms of uric acid, predominate in plasma extracellular fluid and synovial fluid, with ~98% existing as monosodium urate at pH 7.4. 3. Urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine. 4. Two-thirds to three-fourths of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines.
  9. 9. Important points about Uric Acid (Contd..) 1.Daily synthesis 400mg 2.Dietary sources 300mg 3.Normal uric acid pool: 1200mg in males and 600mg in females. 4.75% excreted in urine, remainder in GIT where it’s degraded to Allantoin by bacterial enzymes.
  10. 10. Hyperuricemia Defined as a plasma urate concentration > 7.0 mg/dl Increased production of uric acid Primary • Adenine phosphoribosyl transferase (APRT) • Hypoxanthine-Guanine phosphoribosyl transferase [Lesch-Nyhan Syndrome] • Increased phosphoribosyl pyrophosphatase activity. Secondary • Myeloproliferative disease • Lymphoproliferative disease • Hemolitic anemia • Drugs: Low-doses salicylate, diuretis, pyrazinamide, ethambutol, nicotinamide, ethanol, cytotoxic drugs. Decreased excretion of uric acid • Alterated uric acid excretion could result from decreased glomerular filtration, decreased tubular secretion or enhanced tubular reabsorption. • Diabetic ketoacidosis, starvation, 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.
  11. 11. Lesch-Nyhan Syndrome  A defect in production or activity of HGPRT Causes increased level of hypoxanthine and Guanine (↑ in degradation to uric acid)  Also,PRPP accumulates. Stimulates production of purine nucleotides (and thereby increases their degradation)  Causes gout-like symptoms, but also neurological symptoms  spasticity, aggressiveness, self-mutilation, head banging.  First neuropsychiatric abnormality that was attributed to a single enzyme.  Up to 20 times the uric acid in the urine than in normal individuals. Uric acid crystals form in the urine.  Life expectancy is early- to mid-20s.
  12. 12. ADENOSINE DEAMINASE DEFICIENCY  In purine degradation, adenosine  ADA deficiency results immunodeficiency” in inosine enzyme is ADA. SCID “severe combined  Selectively kills lymphocytes - both b- and t-cells.  Mediate much of immune response.  One of first diseases to be treated with gene therapy.  ADA gene inserted into lymphocytes; then lymphocytes returned to patient.
  13. 13. Glucose-6-phosphatase (G6Pase) deficiency 1. Also known as von Gierke's disease. 2. Unable to dephosphorylate G6P. 3. Glucose-6-P goes into Pentose Phosphate shut. 4. Excess production of ribose-5-phosphate. 5. Cause hypoglcemia as liver fails to form glucose from glycogen. [Glycogen storage disease type I (GSD I)]
  14. 14. Colorimetric determination of uric acid in serum SPECIMEN • Serum is the best, heparinized plasma can be used. • Lipemic and increased bilirubin sample should be avoided. • Drugs such as thiazide and salicyclate cause elevation in uric acid. Why? • Uric acid levels are effected by diet esp. red meat. Why? So will you ask your patient to fast overnight? • Serum should be separated quickly from whole blood. Why?
  15. 15. Method Used 1. Chemical method --- phosphotungstic acid method 2. Enzymatic ---- uricase methods.
  16. 16. Thank you very much!