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NITROGENOUS COMPOUNDS

The daily requirement of protein for adults is 0.5-1g/kg body weight. The minimum requirements of protein are about 20g first class protein per day. The protein allowance for children is relatively higher because of the protein needs of growth. The daily requirements for infants and children are 2-3g/kg and 2g/kg body weight respectively.

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Proteins provide 5-10% of the energy requirements; energy value being about 4kcal/g. The dietary intake of protein must consist of adequate quantities of first class proteins (those containing the essential amino acids in the right proportions).

EFFECTS OF DIETARY PROTEIN DEFICIENCY


There are special clinical effects of protein deficiency which are important not only from a diagnostic point of view but also for an understanding of the associated medical and surgical problems. A moderate inadequacy of protein in the diet leads to fatigue and irritability before the symptoms associated with protein deficiency develop. In children, protein deficiency retards growth. Some of the manifestations associated with prolonged periods of protein deficiency are as follows:

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Anorexia- lack of appetite Apathy Muscle wasting Loss of weight Delayed wound healing because of lack of protein and because of anaemia Slow convalescence after illness Hypochromic anaemia (owing to impaired haemoglobin synthesis)

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Liver damage and greater susceptibility of the liver to intoxication by drugs. In growing children, chronic protein and vitamin deficiency may produce chronic hepatitis similar to cirrhosis Protein deficient persons are susceptible to liver damage disease because diets deficient in proteins are also deficient in lipotrophic factors which protect the integrity of the liver cells. The lipotrophic factors are substances which ar responsible for normal hepatic metabolism of lipids eg. Choline and mithionine

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These patients are also susceptible to pulmonary tuberculosis and also show signs associated with vitamin B complex deficiency Increased susceptibility to infection because of diminished concentration the Igs, particularly susceptibility to pulmonary tuberculosis Susceptibility to shock Osteoporosis and delayed union of fractures Decreased ability of the kidneys to concentrate the urine because of diminished amount of urea Oedema (owing to a fall in plasma albumin concentration)

In Africa, such a condition constitutes the principal feature of the nutritional disease known as kwashiorkor. This condition occurs in children who live solely on carbohydrate after weaninig It is characterized by oedema, as well as skin and hair dilutions. In marasmus, a condition which occurs as a result of protein and carbohydrate deficiency, there is less oedema or skin and hair change than in kwashiorkor A biochemical assessment of protein malnutrition may be made by measuring the level of plasma albumin.

NITROGEN BALANCE
Since most of the nitrogen of the diet represents protein, and most of the nitrogenous secretory products are derived from protein catabolism, it is apparent that the balance of the two may reveal significant features of protein metabolism. Nitrogen balance is defined as the quantitative difference between the nitrogen intake and the nitrogen output, both expressed in the same units ( such as grams N/day).

ACTH, glucocorticoids and excess thyroxine enchances protein catabolism and a negative nitrogen balance Growth hormone, the androgens, to a lesser extent the gonadrotrophi8ns, estrogens and thyroxine in physiological doses enhance protein anabolism and there froe a positive nitrogen balance.

FACTORS LEADING TO A POSTIBVE NITROGEN BALANCE


This is usually observed during growth and pregnancy. It may also result from the action of excess protein anabolic hormones which may be give n as treatment eg. Testosterone administration fro the treatment of carcinoma of the breast. In people whose diet contains adequate quantities of energy and the various classes of food substances, high dietary proteins lead to a positive nitrogen balance and increased levels of tissue protein.

FACTORS LEADING TO NEGATIVE NITROGEN PROTEIN BALANCE


Deficient protein intake a negative nitrogen balance ensues within 48 hours after the dietary protein intake has fallen far below the acceptable minimum i.e. 0.5g/Kg body weight. This condition may also result when protein intake is qualitatively inadequate or when total energy intake is low. Diminished protein digestion this condition ensues in the event of pancreatic dysfunction owing to the impaired secretion of proteolytic enzymes (trypsin, chymotrypsin, carboxypeptidase, etc) this impairment also results during kwashiorkor

Increased protein catabolism wasting diseases and diabetic coma led to negative nitrogen balance owing to increased tissue protein catabolism associated with them. Wounds, fractures, surgical operations or chronic infections s may also lead to a negative nitrogen balance partly because of excessive secretion of glucocorticoids- a group of adrenocortical hormones which control metabolism.

Increased loss of protein during menstruation up to about 20g of protein may be lost. This loss leads to negative nitrogen balance only when the dietary protein intake is inadequate. Considerable quantities of proteins may be lost from severely burnt areas (10-50g/day). In the event of nephrotic syndrome, substantial amounts of protein may be lost in the urine.

BIOCHEMICAL ASPECTS OF TREATMENT


A state of prolonged negative nitrogen balance requires treatment. Generally, the patient must be placed on a high protein diet i.e. 150g/day. The diet must also have an adequate vitamin and energy content.

If the patient is unable to digest ordinary protein food, suitably prepared milk protein or protein hydrolysate may be given by continuous intragastric drip in a dose of about 150g/day. If the loss cannot be replaced by oral feeding, a commercial amino acid preparation may be administered intravenously

NON-PROTEIN NITROGENOUS CONSTITUENTS OF BLOOD AND URINE

Blood non-protein nitrogen consists of urea, uric acid, creatine, creatinine, and amino acids. Urea normally constitutes 50% of the plasma non-protein nitrogen.

Urea is solely formed in the liver and is the main excretory product of protein metabolism. The plasma urea level usually increases with age irrespective of the absence of renal disease. The level of plasma urea is higher in men than in women. The reference range of plasma urea in adults is 3.0-8.0mmol/L.

High plasma urea (uraemia) may result from the ff: Increased tissue protein catabolism; which occurs in fevers, wasting diseases. Diabetic coma or after a major surgical operation. Excessive breakdown o blood proteins; which occurs in leukemia as a result of the leukocyte protein breakdown contributes to a high plasma urea. Erythrocyte haemoglobin and plasma may be released into the gut and digested as a result of gastrointestinal disease.

Renal disease as acute and chronic renal failure; which may lead to a fall in the glomerular filtration rate. This may also happen if there is an obstruction to the outflow of urine as in an enlarged prostate gland.

Low plasma urea states result from the following: Pregnancy: - owing to the tendency of increased glomerular filtration rate and diversion of nitrogen to the foetus as well as water retention during late pregnancy, low plasma urea levels are encountered. Acute hepatic necrosis may lead to low plasma urea levels owing to the inability of the liver to further metabolize amino acids and hence impaired urea synthesis.

Cirrhosis of the liver may also lead to low plasma urea level partly because of defective urea synthesis and water retention.

Diminished urea excretion; which may occur when the peripheral blood pressure falls as in venous congestion. This may also result from a low plasma volume which diminishes the renal plasma load.
Renal disease as acute and chronic renal failure; which may lead to a fall in the glomerular filtration rate. This may also happen if there is an obstruction to the outflow of urine a s in an enlarged prostate gland.

Low plasma states result from the following:


Pregnancy: owing to the tendency of increased glomerular filtration rate and diversion of nitrogen to the foetus as well as water retention during late pregnancy, low plasma urea levels are encountered. Acute hepatic necrosis may lead to low plasma urea levels owing to the inability of the liver to further metabolize amino acids and hence impaired urea synthesis.

Cirrhosis of the liver may also lead to low plasma urea level partly because of defective urea synthesis and water retention.

URIC ACID METABOLISM In humans, uric acid is the principal end product of nucleic acid and purine metabolism. The purine: adenine and guanine are nitrogenous bases present in nucleic acids and a large number of lower molecular weight compounds such as ATP and NAD. They may be derived from the diet or by synthesis within the body. Most cells synthesis purines.

The purines sysnthesized in the body, those derived from diet and those released by endogenous catabolism of nucleic acids follow one of two pathways.
1. It is oxidized to urate. Some adenine is oxidized to hypoxanthine, which is then oxidized to xanthine. The guanine is also oxidized to xanthine. The xanthine in turn is oxidized to form urate. The formation of hypoxanthine and xanthine are catalysed by xanthine oxidase activity.

Gout can be treated using Allopurinol, which is an inhibitor of xanthine oxidase.


2. It is reused for nucleic acid synthesis. Some xanthine, hypoxanthine and but less guanine are recycled to form the corresponding nucleotide (inosine monophosphate), which can then be used for nucleic acid synthesis. The enzyme which catalyses this salvage pathway are the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phophoribosyl transferase (APRT).

The level of plasma urate concentration is influenced by the following factors: Sex: plasma urate tends to be higher in males than in females.
Obesity: increased plasma urate concentration tends to occur in the obese. Social Class: the more affluent social classes tend to have higher plasma urate concentration.

Diet Plasma: urate concentration rises in individuals taking a high protein diet (this is rich in nucleic acids) and those who have a high alcohol consumption. Genetic factors.

HYPERURICAEMIA Hyperuricaemia is generally defined as plasma or serum acid concentrations of more than 7.0mg/dl (i.e. 0.42mmol/L) in men; reference range is 2.0-7.0 (0.12-0.42) or 6.0mg/dl (i.e. 0.36mmol/L) in women; reference range is 1.56.0mg/dl (0.09-0.36mmol/l).

Causes of hyperuricaemia Increased rate of urate formation (i.e. overproduction of urate due to Increased synthesis of purines. Increased intake of purines Increased turnover of nucleic acids.
Reduced rate of excretion (i.e. diminished renal excretion).

Steps b, c and 2 are causes of secondary hyperuricaemia. Increased synthesis(i.e. step a) due to impaired feed back control, is probably the most important mechanism causing primary hyperuricaemia. EFFECTS OF HYPERURICAEMIA: GOUT The solubility of urate in plasma is limited; its precipitation in tissues is influenced by pH and trauma. At physiological pH, plasma urate occurs as the monosodium salt.

Crystallization of this salt from supersaturated body fluids particularly in joints results in the classical pictures of gout or gouty arthritis which was first described by Hippocrates in 469 BC. The acute joint manifestation of gout results from the fact that the urate crystals in joint cavities are phagocytosed by leucocytes; the lysosomal membranes of which are destroyed by the crystals causing the release of lactic acid and therefor a full in the local pH.

This converts the urate to uric acid which is even less soluble than urate and a vicious cycle is set up with further precipitation whit subsequent inflammation causing damage to both leucocytes and the surrounding tissues, hence the local inflammatory response. There may be the deposition of urate crystals in cartilaginous tissues such as the ear and subcutaneous tissues like the patellar bursae (knee cap_ and tendons causing a condition called gouty tophi.

There may be precipitation of urate in the kidney leading ultimately to kidney failure if there is an obstruction ot outflow of urine. In the absence of other diseases, gout is a condition of the male, with only 3-7% of the primary cases occurring in women. It often appears in the fourth decade of life. Shortly before and during an acute attack, the plasma urate rises to about 0.9mmol/l.

The biochemical lesions in most cases of gout are not well characterized. Some patients have a partial deficiency of HGPRT leading to reduced synthesis of guanine monophosphate and inosine monophosphate by the salvage route. There is concomitant increase in the concentration of PRPP and thus and elevation of the de novo synthesis of purine nucleotides. In some other cases, the enzymes responsible for the synthesis of PRPP are very high; hence the high levels of PRPP which is observed.

Secondary hyperuricaemia may occur:


In acute or chronic renal disease of any type, as a consequence of administration of drugs such as diuretics (e.g. frusemide, chlorothiazide) or with vasoconstrictive agents e.g. ephedrine whose effect on urate metabolism is by causing renal vasoconstriction. In hypertension, the occurrence is high in patients on antihypertensive agents such as diuretics.

In starvation and any other condition which cause an increased rate of cell destruction or which increase plasma lactate or 3-hydroxybutyrate concentration. These include haemolytic anaemia, toxaemia of pregnancy, endocrine disturbances, etc. In Malignancy because of the high turnover of nulceic acids. This may be aggravated by the use of cytotoxic drugs. In acidotic conditions such as diabetic keto-acidosis or lactic acidosis

The two most important factors which accounts for the high incidence of clinical gout are: Alcohol: this reduces renal excretion of urate owing to tis effects on the enhancements of lactic acid production which lowers the pH, reducing renal urate excretion. A high meat diet owing to the high proportion of purines. Gout is, therefore, common among people in the higher socio-economic group and in the obese. There is considerably variation in serum urate concentration between different ethnic groups.

Other causes of hyperuricaemia are: lesch-Nyhans syndrome (juvenile hyperuricaemia); an X-linked recessive trait in which severe hyperuricaema occurs in young male children. There is the formation of stone early in life followed by gout years later. The biochemical defect of this condition is the deficiency of HGPRT. There is therefore overproduction of urate and an elevation of PRPP. There is also a marked increase ion the de novo synthesis of purine nucleotides.

Children with this condition have grossly distorted behavior. Though capable of warm affection, they usually lapse into excessive aggression, directed at themselves as well as others Glucose-6-phosphate deficiency (von Gierkes Disease) which leads to increased channeling of glucose-6phosphate into the pentose phosphate pathway which ultimately enchances urate production and glycolysis, thus increasing lactic acid production, which reduces renal urate excretion.

Principles for the treatment of gout


Reducing purine uptake. Increasing renal excretion of urate with uricosuric drugs such as probenecid and salicylates wich are administered in high doses Reducing urate production by the use of alloupurinol, an analogue of hyupoxanthine (it therefore acts as a competitive inhibitior of the de novo synthesis of urate) Attacks of gout typially reesponse to colchicines as a specific drug

Creatine/creatinine
Creatine is synthesized mainly in the liver, the kidney and pancreas from amino acids as follows: Transamidination of arginine and glycine forms guanidoacetic acid. The 2nd step is the methylation of guanidoacetic acid with Sadenosyl methionine as the methyl donor to form creatine

Creatine is then transported in the blood to other organs such as muscle and brain where it is phosphorylated to phosphocreatine. Some of the free creatine spontaneously converts to creatinine , the end product of creatine metabolism.

Creatinine, the anhydride of creatine is largely formed the non-enzymatic dephosphorylation of phosphocreatine. The creatinine formed diffuses into the blood and is excreted in the urine. The amount of creatinine synthesized is proportional to the muscle mass. The rate of production, therefore, varies with age, sex and build.

The normal level of plasma creatine is 15-60mmol/L and for plasma creatinine for both male and female is 60120mmol/L. for females only, it is 40-110mmol/L and for males, it is 60-130mmol/L. plasma creatinine concentration is used as a diagnostic tool in the assessment of renal function. Creatinuria This condition is found in patients with muscle disease. When active breakdown of muscle ensues, the conversion of creatine to creatinine is impaired thus leading to increased plasma creatine concentration. Thus ultimaly leads to high levels of creatine in the urine.

Amino acids
Normal fasting levels of plasma amino acid nitrogen is 2.5-4.0mmol/L. this rises after meals. The most dramatic rise of plasma amino acids occurs in acute hepatic necrosis owing to the impaired conversion of amino acids to urea. Levels up to 20mmol/l may be registered during this condition. Marginal increases may be obtained in acute hepatitis, cirrhosis of the liver or after a severe shock.

Amino aciduria The normal amino acids excretion in the urine of adults(healthy) is 4-20mmol/24 hours. The factors which could lead to in creased amounts of amino acids in the urine may be catalogued into two as follwos: primary amino acidurias are a group of inborn errors of metabolism characterized by and enzyme defect either in the pathway by which a specific amino acid si metabolized, eg. Phenylketonuria; or in the specific renal tubular transport system by which the amino acid is reabsorbed eg. cystinuria

Secondary amino aciduria is due to disease of an organ such as the liver, (which is an active site of amino acid metabolism), to generalized renal tubular dysfunction or to protein-energy malnutrition. Amino aciduria may also be overflow or renal overflow amino aciduria which may be either primary eg. Phenylketonuria; or secondary eg. Fulminant hepatic failure, is due to increase in the plasma level of one or more amino acids to such an extent that an excess passes into the urine.

renal amino aciduria may also be primary eg. Cystinuria; or secondary eg. Fanconi syndrome. In this type, though plasma amino acid levels may be normal, a defect in the renal reabsorption of amino acids lead to their increased excretion.