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