PURINE AND URATE METABOLISM

Question 1

Introduction [PURINES]

Answer 1

The purine bases include Adenine Guanine and Hypoxanthine
Adenine and Guanine are constituents of nucleic acid DNA and RNA

Theyre derived from breakdown of ingested nucleic acid mostly from cell rich meat

Question 2

De novo Synthesis of PURINES

Answer 2

Enzyme involved in the first step is 
PRPP Synthetase (PhosphoRibosyl PyroPhosphate)

2nd step catalyzed by PRPP-AT
PhosphoRibosyl PyroPhosphate- AmidoTransferase

Question 3

FATE OF PURINES: SALVAGE PATHWAYS

FATE OF PURINES: OXIDATION TO URATE (XANTHINE OXIDASE)

Answer 3

1. REUSED FOR NUCLEIC ACID
   Some purines e.g Xanthine, Hypoxanthine and Guanine can be resynthesized to Purine Nucleotides by Pathways involving Enzymes: HGPRT AND APRT (HYPOXANTHINE GUANINE PHOSPHORIBOSYL TRANSFERASE AND ADENINE PHOSPHORIBOSYL TRANSFERASE)
2. OXIDIZED TO URATE
   Adenine and Guanine are oxidized to Xanthine and Xanthine itself is Oxidized to Urate by Enzyme Xabthine Oxidase in the liver

Question 4

FATE OF URATE

Answer 4

75% excreted via the Kidneys
25% is broken down by intestinal bacteria
Most urate filtered at the glomeruli is reabsorbed
Most urate in urine is via Tubular secretion

Tubular secretion is inhibited by Organic acids and Enhanced by Uricosuric agents
Organic agents e.g Lactate, Ketoacids and Thiazide Diuretics
Uricosuric agents e.g Probenecid, Sulfinpyrazone

Inhibition of Tubular secretion causes Hypouricosuria and Hyperuricemia

While the enhancement will cause Hyperuricosuria and Hypouricemia

Humans are the only mammals predisposed to Hyperuricemia as in most others it is metabolized into a more water soluble form ALLANTOIN by enzyme URICASE

Question 5

Pathology

Answer 5

Hyperuricemia, Gout…

• Reduced solubility at acidic pH:(<6)
• Crystallization in joints: can result in acute gouty arthritis.
• Common site: feet
• In subcutaneous tissue: ears, olecranon and patellae bursae and tendons: gouty tophi
• Renal calculi

The normal serum uric acid level is lower in children than in adults. The upper limit of the reference range for children is 5 mg/dL (0.30 mmol/L). The upper limit of the reference range for men is 7 mg/dL (0.42 mmol/L) and for women is 6 mg/dL (0.36 mmol/L).

Question 6

HYPERURICEMIA

Answer 6

Primary and Secondary Hyperuricemia

Primary is caused by the increased synthesis of purines

The secondary is more commoner than the primary
Caused by increased intake
Increase turnover of nucleic acid (cancer)
Increased Urate formation
Reduced rate of excretion

Question 7

PRIMARY HYPERURICEMIA

Answer 7

Rare in Children and Women of child bearing age

Precipitated by: ( increased meat diet, alcohol intake and thiazide diuretics) and also reduced renal urate excretion

CONGENITAL CAUSES
1. Increased activity of PRPP synthetase (X linked disorder)
2. Deficiency of PRPP-AT ( loss of negative feedback inhibition by purine nucleotides)
3. Lesch Nyhan Syndrome ( X linked disorder)
Reduced activity of HGPRT leading to excess urate production
4. Keely- Seegmiller syndrome
5. Familial juvenile gouty arthropathy

Question 8

SECONDARY HYPERURICEMIA

Answer 8

1. Increased cell turnover:
•malignancy e.g leukamias, lymphomas, polycythemia rubra vera.
•Hemolytic anemia
•Psoriasis
•Tumour lysis syndrome
•Starvation/fasting
•trauma

2. Reduced urate excretion
•Drugs: thiazide diuretics, salicylates, ethambutol and pyrazinamide, nicotinic acid, ciclosporin etc.
•Renal glomerular dysfunction
•Prolonged metabolic acidosis
•Chronic lead intoxication.

3.Combined causes (both increased production and reduced excretion)
•High alcohol intake.
•High fructose diet
•Prolonged and severe exercise.
•Dyslipidaemia and impaired glucose tolerance or type 2 diabetes mellitus.
•Glucose-6-phosphatase deficiency or von Gierke’s disease.

Question 9

Differential Diagnosis

Answer 9

Dm
Hypertension 
Gout
Hyperuricemia 
Obesity
Renal failure
Gall stones or renal stones or calculi
And so on

Question 10

Investigations

Answer 10

Family history
Drug history
Diet history
Serum uric acid
Arthrocentesis
Rft

Rule out secondary conditions
Cbc, eucr, lft

Question 11

Treatment

Answer 11

Probenecid and Sulfinpyrazone
Reduce dietary intake of purine
NSAIDS
Allopurinol and Febuxostat

Rasburicase(elitek) converts to allantoin
High fluid intake

Question 12

HYPOURICEMIA

Answer 12

• Drugs for treating hyperuricemia
• Proximal tubular damage(fanconi’s syndrome)
• Parenteral nutrition
• Pregnancy
• SIADH

Pregnancy and SIADH will cause increased GFR function and thus too much urination

Question 13

XANTHINURIA

Answer 13

This is a very rare inborn error of purine metabolism, inherited as an autosomal recessive disorder, in which there is a deficiency of Xanthine Oxidase in the liver.
•Purine breakdown stops at the xanthine–hypoxanthine stage, and plasma and urinary urate concentrations are very low. Increased xanthine excretion may lead to the formation of xanthine stones.

Question 14

PSEUDOGOUT

Answer 14

not a disorder of purine metabolism; Calcium pyrophosphate precipitates in joint cavities, and calcification of cartilages is demonstrable radiologically (chondrocalcinosis).
•crystals of calcium pyrophosphate may be identified in joint fluid using a polarizing microscope.