Group 3 Sec. A2 BORRICANO, Jayne Nicholei C. BRIONES, Ana Leslie M. BROWN, Sheena Mae B. BUENAVENTURA, Arthur R. BUMALAY, Marivic O. BUNDALIAN, Eder B. BURGOS, Nikki Anne C.

Objectivesy For the students to be able to understand the pathways involved in the development of Gout and predict its progression based on its signs and symptoms. y The students should also be able to: y Discuss the purine catabolic pathway; y Define gout and describe its clinical stages; y Compare gout with pseudo-gout; y Identify the role of the kidneys in producing hyperuricemia; y Understand why joints are the common site for deposition of urate crystals; y Be familiar with the mechanism of action of several pharmacologic agents namely colchicine, probenecid, allopurinol and celecoxib (celebrex) in the treatment of hyperuricemia and gout; y And lastly to appreciate the role of allopurinol as adjunct to chemotherapy.

yPurine Catabolic Pathway yGoutyPathophysiology yClinical stages

Reporter: Buenaventura, Arthur R.

Puriney A purine is a heterocyclic aromatic organic

compound, consisting of a pyrimidine ring fused to an imidazole ring

Purine Metabolism

Purine Catabolic Pathway

Figure 1. Catabolism of Purine Nucleotides. (Lehninger 2005)

Purine Pathway In Other Organisms

Figure 2. Taken from Lehninger s Principles of Biochemistry, 4th Ed

Gouty First identified by the Egyptians in y y y y

2640 BC later recognized by Hippocrates in the 5th century BC, who referred to it as 'the unwalkable disease' from the Latin word gutta (or 'drop') Throughout history, gout has been associated with rich foods and excessive alcohol consumption. a disorder that is related to excess production and deposition of uric acid crystals.

y Uric acid is the byproduct of purine nucleotide

catabolism y occurs when the liver produces more uric acid than the body can excrete or when a diet high in purine rich foods y uric acid in the blood crystallizes and settles in the joint spaces, causing swelling, inflammation, stiffness, and pain.

Incidence and Prevalencey common in men between 40 and 50, and in women, incidence increases after menopause. y The difference is largely a consequence of age because estrogenic hormones have a mild uricosuric effect; therefore, gout is unusual in premenopausal women. y The higher prevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, high rates of diuretic treatment for hypertension and congestive heart failure, and the use of low-dose acetylsalicylic acid.

PATHOPHYSIOLOGYy Gout develops from excessive stores of uric acid in the form of monosodium urate y Uric acid is an end-stage by-product of purine metabolism y Lacking uricase, uric acid are primarily removed by renal excretion y saturation level is 6.8 mg/dL y hyperuricemia may develop and urate can crystallize and deposit in soft tissues

Types of Gouty ArthritisPRIMARY (90%) Overproduction Diet Unknown enzyme defects (80-90%) Known enzyme defects (partial HGPRT deficiency, rare) Increased nucleic acid turnover (leukemia and other aggressive neoplasms) Inborn errors of metabolism (e.g. complete HGPRT deficiency) SECONDARY (10%)

Underexcretion

Reduced excretion of uric acid with normal production

Reduced excretion of uric acid with normal production Chronic renal disease

Primary gouty Decreased filtration and underexcretion of uric acid Two pathways are involved in purine synthesis: 1. de novo pathway 2. salvage pathway - hypoxanthine guanine phosphoribosyl transferase (HGPRT) - deficiency of this enzyme leads to increased synthesis of purine nucleotides through the de novo pathway and hence increased production of uric acid - complete lack of HGPRT occurs in the uncommon Xlinked Lesch-Nyhan syndrome - hyperuricemia, severe neurologic deficits with mental retardation, self-mutilation, and in some cases gouty arthritis

- Hyperuricemia alone is not sufficient in the development of gout. Other factors contribute to the conversion of asymptomatic hyperuricemia into primary gout.Factors contributing to the development of Primary Gout: Age Duration of hyperuricemia (usually after 20 to 30 years) Genetic predisposition (HGPRT deficiency, multifactorial inheritance) Heavy alcohol consumption Obesity (increased risk of asymptomatic gout) Drugs that reduce excretion of urate (e.g. thiazides) Lead toxicity (increased risk of saturnine gout)

y The main factor in the development of arthritis is the precipitation of monosodium urate (MSU) crystals into the joints y solubility of MSU depends upon the temperature and by intra-articular concentration of urate and cations y Crystallization depends on the presence of nucleating agents y synovial fluid is a poorer solvent for MSU than plasma y urates in the joint fluid become supersaturated more easily particularly in the peripheral joints where temperatures are as low as 20C y With prolonged hyperuricemia, crystals and microtophi of urates develop in the synovium and in the joint cartilage

y Events may cause the release of the crystals initiating

cascade of events that intensifies, and sustains a powerful inflammatory response y MSU crystals are phagocytosed by macrophages NALP3 inflammasome are activated y Which then cleaves and activates several cytokines, most notably IL-1 and IL-18 y IL-1 induces the expression of adhesion molecules and the synthesis of the neurophil chemokine CXCL8, which is essential for the localization of neutrophils

y Neutrophils releases toxic free radicals, leukotrienes

(leukotriene B4), and lysosomal enzymes y Repeated attacks of acute arthritis lead eventually to chronic arthritis and the formation of tophi in the inflamed synovial membranes and periarticular tissue y severe damage to the cartilage develops and the function of the joints is compromised

Asymptomatic Hyperuricemia- Appears around puberty in males and after menopause in females. - Most patients will have elevated levels of uric acid in the blood for many years before having their first gout attack and do not need to be treated during this period. - The solubility of uric acid in the serum is about 7 mg/dl.Serum uric acid level (mg/dl) >9.0 7.0-8.9