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Presentation Transcript



Slide 2: 

1)Elevated 5-phosphoribosyl-1-pyrophosphate synthetase (PRPP synthetase) activity. PRPP synthetase is responsible for the synthesis of PRPP (activated ribose) necessary for de novo synthesis of purine nucleotides 2)Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency. HGPRT enzyme involved in salvage of purine nucleotides Decrease salvage leads to increased metabolism increased production of uric acid HGPRT PRPP synthetase

Slide 4: 

Major product of purine catabolism. Daily synthesis 400mg Dietary sources 300mg Normal uric acid pool: 1200mg in males and 600mg in females 75% excreted in urine, remainder in GIT where it’s degraded to allantoin by bacterial enzymes.

Renal handling : 

Renal handling 98-100% reabsorbed in PCT Secretion into distal PCT Further reabsorption in DCT Net excretion is 6-12% PK 5.57 hence above a PH of 5.57 exist as urate ion( more soluble)

hyperuricemia : 

hyperuricemia > 0.42mmol/l in males and >0.36 in females

causes : 

causes Hyperuricemia is generally divided into 3 pathophysiologic categories, ie, uric acid underexcretion, uric acid overproduction, and combined causes. Underexcretion( < 600mg/day)- treat with uricosuric drugs(probenecid/sulfinpyrazone) Idiopathic Familial juvenile gouty nephropathy: This is a rare autosomal dominant condition characterized by progressive renal insufficiency. These patients have a low fractional excretion of urate (typically 4%). Kidney biopsy findings indicate glomerulosclerosis and tubulointerstitial disease but no uric acid deposition.


RENAL DYSFUNCTION THAT RESULTS IN DECREASED IN URIC ACID EXCRETION Uric Acid Transporter (URAT1) : one of the members of the organic anion transporter (OAT) family Uric acid reabsorption URAT 1 exchange uric acid with endogenous and exogenous anions : e.g Lactic acid, Butyric acid, Nicotinic acid, PZA- Polymorphisms or mutations of the URAT1 Uricosuric drugs: Probenecid, Benzbromarone, Sulfinpyrazone, and losartan inhibit the uptake of uric acid by inhibiting URAT 1

Slide 9: 

Renal insufficiency: Renal failure is one of the more common causes of hyperuricemia. In chronic renal failure, the uric acid level does not generally become elevated until the creatinine clearance falls below 20 mL/min, unless other contributing factors exist. This is due to a decrease in urate clearance as retained organic acids compete for secretion in the proximal tubule. In certain renal disorders, such as medullary cystic disease and chronic lead nephropathy, hyperuricemia is commonly observed even with minimal renal insufficiency. Syndrome X: This metabolic syndrome is characterized by hypertension, obesity, insulin resistance, dyslipidemia, and hyperuricemia. This is associated with a decreased fractional excretion of urate by the kidneys.

Slide 10: 

Drugs: Causative drugs include diuretics, low-dose salicylate, cyclosporine, pyrazinamide, ethambutol, levodopa, nicotinic acid, and methoxyflurane. Hypertension Acidosis: Types that cause hyperuricemia include lactic acidosis, diabetic ketoacidosis, alcoholic ketoacidosis, and starvation ketoacidosis. Preeclampsia and eclampsia: The elevated uric acid associated with these conditions is a key clue to the diagnosis because uric acid levels are lower than normal in healthy pregnancies. Hypothyroidism Hyperparathyroidism Sarcoidosis Lead intoxication (chronic): Trisomy 21

Overproduction : 

Overproduction Idiopathic HGPRT(hypoxanthine-guanine phosphoribosyl transferase) deficiency (Lesch-Nyhan syndrome): This is an inherited X-linked disorder. HGRPT catalyzes the conversion of hypoxanthine to inosinic acid, in which PRPP serves as the phosphate donor. The deficiency of HGPRT results in accumulation of PRPP, which accelerates purine biosynthesis with a resultant increase in uric acid production. In addition to gout and uric acid nephrolithiasis, these patients develop a neurologic disorder that is characterized by choreoathetosis, spasticity, growth, mental function retardation, and, occasionally, self-mutilation. Partial deficiency of HGPRT (Kelley-Seegmiller syndrome): This is also an X-linked disorder. Patients typically develop gouty arthritis in the second or third decade of life, have a high incidence of uric acid nephrolithiasis, and may have mild neurologic deficits.

Slide 12: 

Increased activity of PRPP synthetase: This is a rare X-linked disorder in which patients make mutated PRPP synthetase enzymes with increased activity. These patients develop gout when aged 15-30 years and have a high incidence of uric acid renal stones. Purine-rich diet: A diet rich in meats, organ foods, alcohol, and legumes can result in an overproduction of uric acid. Increased nucleic acid turnover: This may be observed in persons with hemolytic anemia and hematologic malignancies such as lymphoma, myeloma, or leukemia. Tumor lysis syndrome: This may produce the most serious complications of hyperuricemia. Glycogenoses III, V, and VII

Slide 13: 

Combined causes Alcohol: Ethanol increases the production of uric acid by causing increased turnover of adenine nucleotides. It also decreases uric acid excretion by the kidneys, which is partially due to the production of lactic acid. Exercise: Exercise may result in enhanced tissue breakdown and decreased renal excretion due to mild volume depletion. Deficiency of aldolase B (fructose-1-phosphate aldolase): This is a fairly common inherited disorder, often resulting in gout. Glucose-6-phosphatase deficiency (glycogenosis type I, von Gierke disease): This is an autosomal recessive disorder characterized by the development of symptomatic hypoglycemia and hepatomegaly within the first 12 months of life. Additional findings include short stature, delayed adolescence, enlarged kidneys, hepatic adenoma, hyperuricemia, hyperlipidemia, and increased serum lactate levels.

Slide 14: 

Glucose-6-phosphatase (G6Pase) deficiency Unable to dephosphorylate G6P Glucose-6-P goes into Pentose shut Excess production of ribose-5-phosphate PRPP  PRPP pathway  increase in uric acid G6PT Purine synthesis


FRUCTOSE INDUCES AN INCREASE IN URIC ACID Fructose rapidly raises uric acid as a consequence of activation of fructokinase with ATP consumption, resulting in intracellular phosphate depletion. AMP deaminase activity is stimulated by low levels of phosphorus, resulting in greater degradation of AMP to uric acid Fructose also competes for uric acid excretion

Slide 17: 

Gout: precipitation of monosodium urate in tissues and joints eliciting an intense inflammatory response. Treatment with allopurinol( xanthine oxidase inhibitor and decrease PRPP concentration). Urate stone ( acidic urine, hyperuricemia)

Lab Studies: : 

Lab Studies: Serum uric acid CBC count: Values may be abnormal in patients with hemolytic anemia, hematologic malignancies, or lead poisoning. Electrolytes, BUN, and serum creatinine values: These are abnormal in patients with acidosis or renal disease. Liver function tests This is part of the general workup for patients with a possible malignancy or metabolic disorders. The results are useful as a baseline if allopurinol is used for treatment. Serum glucose level: This may be abnormal in patients with diabetes or glycogen storage diseases. Lipid profile: Results are abnormal in those with dyslipidemia.

Slide 19: 

Calcium and phosphate levels: This measurement is needed for the workup of hyperparathyroidism, sarcoidosis, myeloma, and renal disease. Thyroid-stimulating hormone level: Obtain this value to help rule out hypothyroidism. Urinary uric acid excretion If uric acid levels are found to be persistently elevated, an estimation of total uric acid excretion may be needed. The estimation of uric acid excretion is recommended in young males who are hyperuricemic, females who are premenopausal, people with a serum uric acid value greater than 11 mg/dL, and patients with gout.

Slide 20: 

One protocol recommends obtaining two 24-hour urine collections for creatinine clearance and uric acid excretion. The first collection is performed while patients are on their usual diet and alcohol intake. At the end of the first 24-hour collection, serum creatinine and urate levels are checked for an estimation of the creatinine clearance. The patient then goes on a low-purine, alcohol-free diet for 6 days, with a repeat 24-hour urine collection performed on the last day, followed by a serum creatinine and uric acid evaluation.

Slide 21: 

Depending on the 24-hour urine uric acid levels before the purine-restricted diet and after the purine-restricted diet, patients who are hyperuricemic can be categorized into 3 groups. High-purine intake - Prediet value greater than 6 mmol/d, postdiet value less than 4 mmol/d Overproducers - Prediet value greater than 6 mmol/d, postdiet value greater than 4.5 mmol/d Underexcretors - Prediet value less than 6 mmol/d, postdiet value less than 2 mmol/d

Slide 22: 

Fractional excretion of urate on a low-purine diet This test should be used to investigate the degree of underexcretion in patients with hyperuricemia or gout in patients for whom the cause cannot be determined. The fractional excretion of urate is calculated by the following formula: Fractional excretion of urate = [(urine uric acid)*(serum creatinine)*(100%)]/[(serum uric acid)*(urine creatinine)] The reference intervals for patients on a low-purine diet and normal renal function are as follows: Males - 7-9.5% Females - 10-14% Children - 15-22% Values less than the lower limits of the reference range indicate underexcretion. The formula also circumvents any inaccuracy that may have occurred during urine collection.

Slide 23: 

Spot urine ratio of uric acid to creatinine If a 24-hour urine collection is not possible, measure the ratio of uric acid to creatinine from a spot urine collection. A ratio greater than 0.8 indicates overproduction. The ratio also helps differentiate acute uric acid nephropathy from the hyperuricemia that occurs secondary to renal failure. The ratio is greater than 0.9 in acute uric acid nephropathy and usually less than 0.7 in hyperuricemia secondary to renal insufficiency.

hypouricemia : 

hypouricemia <0.12mmol/l Causes: hepatocellular disease with reduced purine synthesis Defective tubular reabsorption Over treatment Deficiency of xanthine oxidase( xanthinuria also present)

Analytical methodology : 

Analytical methodology Phosphotungstic acid method Blue reaction as PTA is reduced by urate in alkaline medium. Color read at 650-700nm Protein removal essential(TCA acid, tungstic acid and PTA) Interferences( glucose, AA, glutathione, cysteine from hemolysis), others drugs- acetaminophen, aspirin,purines-caffeine, theophylline They reduce PTA.

Uricase method : 

Uricase method More specific Cheap Little interferences( G,X) Decrease in absorbance as urate is converted to allantoin is measured at 282-292nm Most assays involve a peroxidase system coupled with a number of oxygen acceptors(4-aminophenazone or substituted phenol) to produce a chromogen.

Slide 27: 

Use of phenol helps to reduce interfererances by bilirubin and AA- ascorbate oxidase used to remove it. HPLC- specific, fast Mass spectrometry. Dry chemistry; uricase+ peroxidase in a dry reagent

Reference intervals : 

Reference intervals The levels increase with age_ 10% between 20 and 60 years of age. 0.262-0.452 m, 0.137-0.393 f

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