PURINE METABOLISM AND GOUT - PowerPoint Presentation

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PURINE METABOLISM AND GOUT

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One of the important specialized pathways of a number of amino acids is the synthesis of purine and pyrimidine nucleotides.

These nucleotides are important for a number of reasons. Most of them, not just ATP, are the sources of energy that drive most of our reactions.

ATPr

GTP

UTP

AMP

NUCLEOTIDES

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Neither the bases nor the nucleotides are required dietary components.

-We can both synthesize them de novo and salvage and reuse those we already have.

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There are two kinds of nitrogen-containing bases - purines and

pyrimidines

.

Purines

consist of a six-membered and a five-membered nitrogen-containing ring, fused together.

Pyridmidines

have only a six-membered nitrogen-containing ring. There are 4 purines and 4

pyrimidines

that are of concern to us.

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Purines include -

Adenine = 6-amino purine

,

Guanine = 2-amino-6-oxy purine

,

Hypoxanthine = 6-oxy purine

,

Xanthine = 2,6-dioxy purine

Adenine and guanine are found in both DNA and RNA

.

Hypoxanthine

and xanthine are not incorporated into the nucleic acids as they are being synthesized but are important intermediates in the synthesis and degradation of the purine nucleotides.

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Humans catabolize the major purine nucleosides adenosine and

guanosine

to uric acid thus:

Adenosine

Adenosine

Deaminase

Inosine

Purine nucleoside

Phosphorylase Guanosine

Purine Nucleoside Phosphorylase

Xanthine Guanase

Hypoxanthine oxidase Xanthine Guanine Uric acid

Adenosine

Adenosine

deaminase

Inosine

Hypoxanthine

Xanthine

Uric acid

Guanine

Guanosine

Purine nucleoside

phosphorylase

Purine nucleoside

phosphorylase

Xanthine oxidase

Guanase

Xanthine oxidase

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Genetic and Biochemical Basis of

Hyperuricemia

There are at least three different inherited defects that lead to early development of severe

hyperuricemia

and gout:

- Glucose-6-phosphatase

(gene symbol: G6PT) deficiency;

Severe and partial

hypoxanthine-guanine phosphoribosyltransferase (HGPRT, gene symbol: HPRT) deficiency; and elevated 5'-phosphoribosyl-1'-pyrophosphate synthetase (PRPP synthetase

) activity

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DISORDERS OF PURINE METABOLISM

 

 

 

 

 

Clinical Disorder

Defective Enzyme

Nature of the Defect

Characteristic of Clinical disorderInheritance patternGout PRPP synthetaseSuperactive (Increased Max)Purine over production and over excretionX-Linked recessiveGoutPRPP synthetaseResistance to feed back inhibitionPurine over production and over excretion

X-Linked recessiveGoutHGPRTase 1Partial deficiencyPurine over production and over excretionX-linked recessiveLesch –

Nyhan SyndromeHGPRTase 1Complete deficiencyPurine over production and over excretion, self mutilation

X-linked recessive

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Von

Gierke’s

disease

In this case purine over production and

hyperuricaemia

(G6P deficiency) occurs secondary to enhanced generation of the PRPP precursor ribose-5-phosphate.

In addition associated lactic acidosis elevates the renal threshold for

urate

elevating total body urates.

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Gout

Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint

.

It is a disorder of purine metabolism and occurs when its final metabolite uric acid crystallizes in the form of monosodium

urate

, precipitating and forming deposits (tophi) in joints, on tendons and in the surrounding tissues.

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Pains typically come on rapidly in less than 12hrs.

The joint at the base of the big toe is affected in about half of cases.

Tophi, kidney stones and

urate

nephropathy, may also result.

Gout occurs due to elevated levels of uric acid in the blood, resulting from a combination of diet and genetic factors.

At high levels, uric acid crystallizes and deposits in joints, and surrounding tissues resulting in an attack of gout

.

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It occurs more commonly in those who eat a lot of meat, drink a lot of beer and are overweight.

Diagnosis may be confirmed by seeing the crystals in joint fluid or tophus.

Blood uric acid levels may be normal during an attack.

Once the acute attack subsides, levels of uric acid can be lowered via life style changes.

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Taking vitamin C and eating a diet high in low fat dairy products may be preventive.

Long standing elevated uric acid levels (

hyperuricaemia

) may result in other symptoms such as hard, painless deposits of uric acid crystal known as tophi (otherwise called crystals of monosodium

urate

).

Extensive tophi may lead to chronic arthritis due to bone erosion.

Hyperuricaemia

may also result in uric acid stones precipitating in the kidneys resulting in urate nephropathy. 

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CAUSES OF GOUT

Diet / lifestyle

accounts for about10 to 12% of cases of gout and is associated with, alcohol, fructose sweetened drinks, meat and seafood, also physical trauma and Surgery.

Consumption of coffee, vitamin C and dairy products as well as physical fitness, appear to decrease the risk.

Genetic predisposition

contributes to about 60% of variability in uric acid level. Mutations in certain genes related to

urate

metabolism can lead to increased risk of hyperuricaemia and gout.

 

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Medical Conditions

- Metabolic syndrome (a combination of abdominal obesity, hypertension, insulin resistance and abnormal lipid levels, occurs in about 75% of cases), other conditions complicated by gout include lead poisoning, kidney failure, hemolytic anemia, psoriasis, solid organ transplants ,

leukaemia

(especially acute

leukaemia

during treatment), starvation,

myeloproliferative

disorders example polycythemia.

Chronic lead exposure is a risk factor for gout due to the harmful effect of lead on kidney function.Lesch – Nyhan syndrome is often associated with gouty arthritis.

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MEDICATION

Diuretics

Niacin

Aspirin

ACE inhibitors

Angiotensin receptor blockers (except losartan)

Beta blockers

etcetera all tend to precipitate gout.

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Under excretion of

urate

is the primary cause of

hyperuricaemia

in about 90% of cases.

Over production is the cause in less than 10%

The risk of developing Gout depends on the degree of

hyperuricaemia

. When levels are between 415 and 530 µmol/l (7 and 8.9g/dl), The risk is 0.5% /year, while in those with a level greater than 535 µmol/l (9mg/dl), the risk is 4.5% / year. Reference range of uric acid – male- 3.4 – 7.2 mg/dl (200 – 430 micromole/L). Female- 2.4 – 6.1 mg/dl (140 – 360 micro mole/L)

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PATHOPHYSIOLOGY

The triggers for precipitation of uric acid are not well understood.

It may precipitate at normal levels.

But it is more likely to do as levels increase

Other triggers include cool temperature, acidosis, extra cellular matrix proteins such as proteoglycans, collagens and chondroitin sulfate.

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DIAGNOSIS

If one has

hyperuricaemia

and the classic acute arthritis of the base of the great toe (known as

podogra

) there may not be any used for further investigations to diagnose gout in the patient.

Synovial fluid analysis (Identification of Monosodium

urate

crystals in S.F or a tophus) SF is obtained by arthrocentesis.

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Blood tests –

inc

(a) plasma uric acid level.

Hyperuricaemia

is defined as a plasma

urate

level greater than 420 µ

mol

/l (7.0 mg/dl) in males and 360 µmol/l (6.0 mg/dl) in females.- WBC counts- Kidney function

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- urine uric acid test (secondary test , to evaluate whether the kidneys are excreting enough uric acid) kidneys filter uric acid out of the blood stream and dispose of it through the urine.

- If the kidneys are unable to do this well, uric acid accumulates in the blood, leading to elevated blood uric acid levels.

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DIFFERENTIAL DIAGNOSIS

The most important differential diagnosis in gout is septic arthritis which should be considered in those with signs of infection or those who do not improve with treatment.

Here a synovial fluid Gram stain and culture may be performed.

Other similar conditions include

psendogout

, rheumatoid arthritis, psoriatic arthritis and reactive arthritis.

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Prevention can be achieved by

Life style changes especially as it concerns dietary changes including reducing intake of purine rich foods of animal origin e.g. meat, seafood, alcohol, fructose (especially high fructose corn syrup) and switching to dairy prods, vitamin C, coffee and cherries may help prevent gout, also losing weight.

Gout may be secondary to sleep apnea via the release of purines from oxygen starved cells. Treatment of apnea can lessen the occurrence of attacks.

Medication can also decrease uric acid levels.

 

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TREATMENT

Aim to settle the symptoms of an acute attack.

Repeated attacks can be prevented by medications that reduce serum uric acid levels.

Drugs include – NSAIDS, colchicine, and steroids.

Options for prevention / prophylaxis include

Allopurinol,

febuxostat

and

probenecid.

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