1. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Dee Unglaub Silverthorn, Ph.D. H UMAN P HYSIOLOGY PowerPoint ® Lecture Slide Presentation by Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University AN INTEGRATED APPROACH T H I R D E D I T I O N Purine degradation & Gout (Musculoskeletal Block) Purine degradation pathway Fate of uric acid in humans Gout and hyperuricemia: Biochemistry Types Treatment 1 Lecture Dr. Sumbul Fatma

2. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Purine degradation pathway The major source of dietary nucleic acids (purines and pyrimidines) is meat Purine and pyrimidine bases are absorbed by the intestine The ingested bases are mostly degraded into different products by degradation pathways These products are then excreted by the body

3. Dietary DNA / RNA Nucleotides Nucleosides Pancreatic nucleases Free purine bases + Ribose Nucleotidases Nucleosidases Uric acid Purine Degradation pathway

4. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Purine degradation pathway Adenosine and guanosine (purines) are finally degraded to uric acid by: Purine degradation pathway

5. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings CATABOLISM OF Purine nucleoside phosphorylase PURINES AMPIMP Adenosine Inosine HypoxanthineXanthine Uric acid Xanthosine XMPGMP Guanosine Guanine AMP Deaminase PNP ADA Xanthine Oxidase GDA Xanthine Oxidase NTDase

6. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Fate of uric acid in humans In humans, primates, birds and reptiles the final product of purine degradation is uric acid Uric acid is excreted in the urine Some animals convert uric acid to other products: Allantoin Allantoic acid Urea Ammonia

7. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Fate of uric acid Uric AcidPrimates, Birds, Reptiles and insects Allantoin Allantoic acid Urea Ammonia Other mammals Teleost Fish Cartilagenous fish and Amphibia Marine invertebrates Urate Oxidase Allantoinase Allantoicase Urease

8. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Fate of uric acid in humans Uric acid is less soluble in water Reptiles, insects and birds excrete uric acid as a paste of crystals To save water Humans excrete uric acid in urine

9. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Fate of uric acid in humans Humans do not have enzymes to further degrade uric acid Excessive production of uric acid causes deposition of uric acid crystals in the joints leading to: Gout Hyperuricemia

10. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout Once fashionable to associate gout with intelligence people with gout: Isaac Newton Benjamin Frankin Martin Luther Charles Darwin Samuel Johnson

11. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Disease of the riches

12. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout Gout is a disease due to high levels of uric acid in body fluids 7.0 mg/dL and above Uric acid accumulates because of: Overproduction or Underexcretion

13. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout prevails mainly in adult males rarely encountered in premenopausal women Sodium urate/uric acid may also precipitate in the kidneys and ureters as stones, resulting in renal damage and urinary tract obstruction

14. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout Painful arthritic joint inflammation due to deposits of insoluble sodium urate crystals (especially big toe) Affects 3 per 1000 persons Sodium urate crystals accumulate in kidneys, ureter, joints leading to chronic gouty arthritis

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16. Voet Biochemistry 3e © 2004 John Wiley & Sons, Inc. Sodium urate crystals in urine

17. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout Inaccurately associated with overeating and drinking Alcohol used to be contaminated with lead during manufacture and storage Lead decreases excretion of uric acid from kidneys causing hyperuricemia and gout Excessive meat comsumption increases uric acid production in some individuals

18. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Gout Two main causes Overproduction of uric acid Underexcretion of uric acid

19. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Hyperuricemia- soft tissues Nodular masses of monosodium urate crystals (tophi) may be deposited in the soft tissues, resulting in chronic tophaceous gout Hyperuricemia is typically asymptomatic and does not lead to gout, but gout is preceded by hyperuricemia

20. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Overproduction of uric acid Primary hyperuricemia is, for the most part, idiopathic (having no known cause) Lesch-Nyhan syndrome also causes hyperuricemia through PRPP accumulation Secondary hyperuricemia is typically the consequence of increased availability of purines, for example, in patients with myeloproliferative disorders or who are undergoing chemotherapy and so have a high rate of cell turnover

21. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Underexcretion of uric acid Underexcretion can be Primary- due to as-yet-unidentified inherent excretory defects secondary to known disease processes that affect how the kidney handles urate, for example lactic acidosis, and to environmental factors such as the use of drugs, for example, thiazide diuretics, or exposure to lead

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23. Diagnostic features usually affect joints in the lower extremities (95%) onset is fast and sudden pain is usually severe; joint may be swollen, red and hot attack may be accompanied by fever, leukocytosis and an elevated ESR

24. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Diagnosis The definitive diagnosis of gout requires aspiration and examination of synovial fluid from an affected joint (or material from a tophus) using polarized light microscopy to confirm the presence of needle-shaped monosodium urate crystals

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26. Monosodium urate crystals

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28. Nonpharmacological Approaches Avoid purine rich foods: red meat and organ meat (liver, kidneys) shellfish, anchovies, mackerel, herring meat extracts and gravies peas and beans, asparagus, lentils alcoholic beverages Weight loss Control alcohol

29. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Treatment of gout- Acute attacks Acute attacks of gout are treated with anti-inflammatory agents. Colchicine, steroidal drugs such as prednisone, and nonsteroidal drugs such as indomethacin are used Colchicine depolymerizes microtubules, thus decreasing the movement of neutrophils into the affected area.

30. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Treatment - Long term Involves lowering the uric acid level below the saturation point, thereby preventing the deposition of urate crystals Uricosuric agents- probenecid or sulfinpyrazone, that increase renal excretion of uric acid Allopurinol, an inhibitor of uric acid synthesis Allopurinol is converted in the body to oxypurinol, which inhibits xanthine oxidase, resulting in an accumulation of hypoxanthine and xanthine—compounds more soluble than uric acid and, therefore, less likely to initiate an inflammatory response

31. Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings References Lippincott 4 th Edition Voet & Voet