In this article we will discuss about:- 1. Sources of Uric Acid 2. Stages in the Formation of Uric Acid from Purine 3. Variations.
Sources of Uric Acid:
Uric acid comes from purines in case of man, other primates-Dalmatian dog and birds.
i. From Purines.
These bodies may be derived again from two sources:
(a) Exogenous, and
(a) Exogenous Purines:
(1) Nucleoprotein of food.
(2) Hypoxanthine and xanthine present in meat extracts, meat soup, etc.
(3) Methyl purine-theophylline, theobromine, caffeine; etc., present in tea, coffee, and cocoa.
(b) Endogenous Purines:
(1) The nucleoproteins derived from tissue breakdown,
(2) Several monouncleotides present in the body.
Examples are mentioned below:
i. Adenosine triphosphate found in the muscles,
ii. Inosinic acid, a hypoxandine derivative, found in the muscle.
iii. Guanylic acid, made up of guanine, pentose and phosphoric acid found in glands, viz., the pancreas.
ii. As a synthetic product:
Synthesis of uric acid and proteins is supposed to be a normal process. In birds urea is converted into uric acid in the liver. Moreover, it has been shown that in birds the greater part of uric acid is not derived from purines but by a process of synthesis from lactic acid and ammonia.
Probably the same synthetic processes may take place in the mammals. The human infant which lives and grows on milk only, rapidly increases the nucleoprotein content of the body, although milk is poor in these products. Moreover, it is known that eggs are poor in purine bases but after hatching, the chick contains a large amount of purine-compounds in the body. Histidine is a possible source of purine synthesis. Isotopic experiments with 15N Labelled glycine and 14C labelled acetate show that uric acid is synthesised from them.
These evidences prove that synthesis of purine bases are normal phenomena in our body. Liver is probably the chief site for synthesis although other tissues take part in the synthesis as well.
Uric acid is 2 : 6 : 8 trihydroxypurine. It is derived as an end product of purine metabolism.
Stages in the Formation of Uric Acid from Purine:
It may take place in two ways:
(a) From the free purine bases-adenine and guanine, and
(b) From purine nucleosides.
Uric Acid in Blood:
Blood contains 2-6 mgm uric acids per 100 ml (average 4 mgm).
The form in which uric acid is carried in blood is not yet fully known. Probably, a part of it remains as free uric acid or urate. Another part remains in some colloidal form, combined with the blood colloids. Benedict claims that in the red cells of ox and man major part of uric acid is present in combination with pentose and a small amount in the free form.
Fate of Uric Acid:
1. Destruction of Uric Acid:
Observations of Folin and his associates indicate that nearly 20% of uric acid formed, is destroyed in the body. Liver is the probable site of uric acid destruction. Injection of 15N labelled uric acid definitely proves that some uricolysis occur in the normal human being and that the intestinal floras play very little part. But neither the details of the process nor the end products are known. Allantoin is certainly not the end product.
2. Formation of Allantoin (Uricolytic Index):
In mammals, other than primates excepting the Dalmatian dog, uric acid is further oxidised to allantoin and is excreted as such. If we add together the amounts of allantoin and uric acid excreted and express the allantoin as percentage of this sum, we get what is known as uricolytic index.
It is a measure of the extent of conversion of uric acid into allantoin by the enzyme uricase. In chimpanzee it is 0; in man only 2; in dogs (excepting Dalmatian variety) it is 98. In man and higher apes, therefore, practically no allantoin is formed.
3. Excretion of Uric Acid:
Daily output of uric acid is 0.75-1.0 gm, of which nearly half is endogenous and the other half exogenous. It is excreted either as free uric or as the urates of sodium, potassium, ammonium, etc. Reabsorption of the greater part of the uric acid occurs in the renal tubules, but there is good evidence for tubular secretion of uric acid.
Uric acid is, therefore, cleared from the plasma both by glomerular filtration and by tubular secretion. The urinary excretion of uric acid is increased by the hormones of the adrenal cortex as well as by ACTH. Muscular exercise increases uric acid output.
Variations of Uric Acid Excretion with Different Types of Food:
i. Protein food increases uric acid formation and output.
ii. Calorific value of food. If the calorific value of food be raised keeping the protein content constant, the uric acid output rises. It is interesting to note that this rise is only found if carbohydrates are added to raise the calorific value. With fats this is not seen.
iii. High purine diet. This increases uric acid output.
iv. Fats diminish uric acid output.
Thus proteins, purines, high carbohydrate diet and high calorific value of food raise the formation and output of uric acid, while fats diminish it. Depending upon this observation, it has been suggested that carbohydrates in some unknown way become converted into uric acid.
To diminish uric acid formation, therefore, the diet should be of low caloric value, poor in proteins, purine and carbohydrates but rich in fats. But one should remember that these food-stuffs exert an opposite action on blood uric acid. For instance, proteins (even purine-free substances like egg) and carbohydrates increase uric acid excretion and lower the blood uric acid level. While fats diminish its output and raise its blood level. These facts should be carefully kept in mind while prescribing diet for gout cases.
In gout there is excess of uric acid in the blood and urine. There is also deposition of urate in the articular surfaces of joints and sometimes in particular structures. The joint of the big toe is first affected and in acute attack there appears sudden swelling of joints, which are extremely painful. The blood uric acid (which in the normal subject is about 4 mgm per 100 ml) rises to about 30 to 60 mgm per 100 ml. The urate deposits which occur in the joints, fingers, in the helix of the ear, etc., are known as tophi.
Gout may arise from the following conditions:
i. Increased synthesis of uric acid.
ii. Excessive nucleic acid breakdown, e.g., starvation.
iii. Overproduction as occurs in glycogen storage disease.
iv. Increased nucleic acid turnover, e.g., polycythemia, granulocytic leukaemia.
v. Decreased excretion of uric acid which might arise from interference with secretion of it from kidney tubules.
Significance of Variation of Blood Uric Acid:
Its value in blood is increased in gout where uric acid in larger amounts as monosodium urate may be deposited in the joints and tissues. In leukaemia and pneumonia the blood uric acid is elevated due to increased purine catabolism accompanying with increased destruction of leukocytes and tissue autolysis. It also increases often in arteriosclerosis with hypertension and in cardiac de-compensation in which it may be some time due to renal insufficiency. In some diabetes or in acute infection of children this may increase in blood.