Non-Protein Nitrogenous Constituents of Blood - Urea, Uric Acid Etc

8/13/2019 Non-Protein Nitrogenous Constituents of Blood - Urea, Uric Acid Etc

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NITROGENOUS COMPOUNDS

• The daily requirement of protein for adults is0.5-1g/kg body weight. The minimumrequirements of protein are about 20g first

class protein per day.• The protein allowance for children is relatively

higher because of the protein needs ofgrowth. The daily requirements for infants andchildren are 2-3g/kg and 2g/kg body weightrespectively.



Ctd.

• 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 deficiencywhich are important not only from a diagnostic pointof view but also for an understanding of the associatedmedical and surgical problems.

• A moderate inadequacy of protein in the diet leads tofatigue and irritability before the symptoms associatedwith protein deficiency develop. In children, proteindeficiency retards growth.

• Some of the manifestations associated with prolongedperiods of protein deficiency are as follows:



Ctd.

• Anorexia- lack of appetite

• Apathy

• Muscle wasting

• Loss of weight

• Delayed wound healing because of lack of proteinand because of anaemia

•Slow convalescence after illness

• Hypochromic anaemia (owing to impairedhaemoglobin synthesis)



Ctd.

• Liver damage and greater susceptibility of theliver to intoxication by drugs. In growing children,chronic protein and vitamin deficiency mayproduce chronic hepatitis similar to cirrhosis

• Protein deficient persons are susceptible to liverdamage disease because diets deficient inproteins are also deficient in lipotrophic factorswhich protect the integrity of the liver cells.

• The lipotrophic factors are substances which arresponsible for normal hepatic metabolism oflipids eg. Choline and mithionine



Ctd.

• These patients are also susceptible to pulmonarytuberculosis and also show signs associated withvitamin B complex deficiency

• Increased susceptibility to infection because of

diminished concentration the Igs, particularlysusceptibility to pulmonary tuberculosis

• Susceptibility to shock

• Osteoporosis and delayed union of fractures

•

Decreased ability of the kidneys to concentrate theurine because of diminished amount of urea

• Oedema (owing to a fall in plasma albuminconcentration)



• In Africa, such a condition constitutes the principalfeature of the nutritional disease known askwashiorkor. This condition occurs in children who livesolely on carbohydrate after weaninig

• It is characterized by oedema, as well as skin and hairdilutions. In marasmus, a condition which occurs as aresult of protein and carbohydrate deficiency, there isless 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 mayreveal significant features of protein metabolism.

• Nitrogen balance is defined as the quantitative

difference between the nitrogen intake and thenitrogen 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 positivenitrogen balance.



FACTORS LEADING TO A POSTIBVE

NITROGEN BALANCE

• This is usually observed during growth andpregnancy. It may also result from the action ofexcess protein anabolic hormones which may begive n as treatment eg. Testosterone

administration fro the treatment of carcinoma ofthe breast.

• In people whose diet contains adequatequantities of energy and the various classes of

food substances, high dietary proteins lead to apositive nitrogen balance and increased levels oftissue protein.



FACTORS LEADING TO NEGATIVE

NITROGEN PROTEIN BALANCE• Deficient protein intake

a negative nitrogen balance ensues within 48 hours after thedietary protein intake has fallen far below the acceptableminimum i.e. 0.5g/Kg body weight. This condition may alsoresult when protein intake is qualitatively inadequate or whentotal energy intake is low.

Diminished protein digestion

this condition ensues in the event of pancreatic dysfunctionowing to the impaired secretion of proteolytic enzymes

(trypsin, chymotrypsin, carboxypeptidase, etc) thisimpairment 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 ofglucocorticoids- a group of adrenocortical

hormones which control metabolism.



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 about150g/day.

• If the loss cannot be replaced by oral feeding,

a commercial amino acid preparation may beadministered 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 releasedinto the gut and digested as a result of gastro-

intestinal 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 tothe outflow of urine as in an enlarged prostate gland.



Low plasma urea states result from the following:

Pregnancy: - owing to the tendency of increasedglomerular filtration rate and diversion of

nitrogen to the foetus as well as water retention

during late pregnancy, low plasma urea levels areencountered.

Acute hepatic necrosis may lead to low plasma urealevels 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 alow 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 ofincreased glomerular filtration rate anddiversion of nitrogen to the foetus as well as

water retention during late pregnancy, lowplasma urea levels are encountered.

• Acute hepatic necrosis may lead to lowplasma urea levels owing to the inability ofthe liver to further metabolize amino acidsand 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 twopathways.

1. It is oxidized to urate. Some adenine is oxidized tohypoxanthine, 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 usedfor nucleic acid synthesis.

The enzyme which catalyses this salvage pathway arethe 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 1.5-

6.0mg/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 secondaryhyperuricaemia. Increased synthesis(i.e. step a)due to impaired feed back control, is probably themost important mechanism causing primaryhyperuricaemia.

• EFFECTS OF HYPERURICAEMIA: GOUT

• The solubility of urate in plasma is limited; its

precipitation in tissues is influenced by pH andtrauma. At physiological pH, plasma urate occursas the monosodium salt.



• Crystallization of this salt from supersaturatedbody fluids particularly in joints results in theclassical pictures of gout or gouty arthritis whichwas first described by Hippocrates in 469 BC.

• The acute joint manifestation of gout results fromthe fact that the urate crystals in joint cavities arephagocytosed by leucocytes; the lysosomal

membranes of which are destroyed by thecrystals causing the release of lactic acid andtherefor a full in the local pH.



• There may be precipitation of urate in thekidney leading ultimately to kidney failure ifthere is an obstruction ot outflow of urine.

• In the absence of other diseases, gout is acondition of the male, with only 3-7% of theprimary cases occurring in women. It oftenappears in the fourth decade of life. Shortly

before and during an acute attack, the plasmaurate rises to about 0.9mmol/l.



• The biochemical lesions in most cases of gout arenot well characterized. Some patients have apartial deficiency of HGPRT leading to reducedsynthesis of guanine monophosphate and inosine

monophosphate by the salvage route.• There is concomitant increase in the

concentration of PRPP and thus and elevation ofthe de novo synthesis of purine nucleotides. In

some other cases, the enzymes responsible forthe synthesis of PRPP are very high; hence thehigh 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 whoseeffect on urate metabolism is by causing renal

vasoconstriction.

•

In hypertension, the occurrence is high inpatients on antihypertensive agents such as

diuretics.



• The two most important factors which accounts for thehigh incidence of clinical gout are:

• Alcohol: this reduces renal excretion of urate owing totis effects on the enhancements of lactic acid

production which lowers the pH, reducing renal urateexcretion.

• A high meat diet owing to the high proportion ofpurines. Gout is, therefore, common among people in

the higher socio-economic group and in the obese.There is considerably variation in serum urateconcentration between different ethnic groups.



• Other causes of hyperuricaemia are:• lesch-Nyhan’s syndrome (juvenile

hyperuricaemia); an X-linked recessive trait inwhich severe hyperuricaema occurs in young

male children. There is the formation of stoneearly in life followed by gout years later.

• The biochemical defect of this condition is thedeficiency of HGPRT. There is therefore

overproduction of urate and an elevation of PRPP.There is also a marked increase ion the de novosynthesis of purine nucleotides.



• Children with this condition have grossly distortedbehavior. Though capable of warm affection, theyusually lapse into excessive aggression, directed atthemselves as well as others

• Glucose-6-phosphate deficiency (von Gierke’s Disease)which leads to increased channeling of glucose-6-phosphate into the pentose phosphate pathway whichultimately enchances urate production and glycolysis,

thus increasing lactic acid production, which reducesrenal urate excretion.



Principles for the treatment of gout

• Reducing purine uptake.

• Increasing renal excretion of urate with uricosuricdrugs such as probenecid and salicylates wich are

administered in high doses• Reducing urate production by the use of

alloupurinol, an analogue of hyupoxanthine (ittherefore 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 S-

adenosyl methionine as the methyl donor toform 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 spontaneouslyconverts 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 theurine. The amount of creatinine synthesized is

proportional to the muscle mass. The rate of

production, therefore, varies with age, sex andbuild.



• The normal level of plasma creatine is 15-60mmol/L and forplasma creatinine for both male and female is 60-120mmol/L. for females only, it is 40-110mmol/L and formales, it is 60-130mmol/L. plasma creatinineconcentration 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 conversionof creatine to creatinine is impaired thus leading to

increased plasma creatine concentration. Thus ultimalyleads 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 theimpaired 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 ofadults(healthy) is 4-20mmol/24 hours. The factorswhich 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 errorsof metabolism characterized by and enzyme defecteither in the pathway by which a specific amino acid si

metabolized, eg. Phenylketonuria; or in the specificrenal tubular transport system by which the amino acidis reabsorbed eg. cystinuria



• Secondary amino aciduria is due to disease of an organsuch as the liver, (which is an active site of amino acidmetabolism), to generalized renal tubular dysfunctionor to protein-energy malnutrition.

• Amino aciduria may also be ‘overflow’ or ‘renal’

• ‘overflow’ amino aciduria which may be either primaryeg. Phenylketonuria; or secondary eg. Fulminanthepatic failure, is due to increase in the plasma level of

one or more amino acids to such an extent that anexcess 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 therenal reabsorption of amino acids lead to their

increased excretion.

Non-Protein Nitrogenous Constituents of Blood - Urea, Uric Acid Etc

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