Protein Deficiency

In the diagnosis of protein malnutrition, the first steps are determination of the approximate dietary supply of protein from a quantitative and qualitative standpoint and recognition of the pathologic conditions which are prone to lead to protein deficiency. Physical findings common to most protein deficiency syndromes are loss of weight (unless masked by edema), decrease in subcutaneous fat, weakness, muscle wasting, edema and accumulation of fluid in serous cavities. Frequently, hypotension, bradycardia and pigmentary changes in the skin are observed and the basal metabolic rate may decrease. Protein deficiency may lead to fatty infiltration and cirrhosis of the liver. Anemia, which may be normocytic or macrocytic, is a frequent accompaniment of chronic protein deficiency syndromes. Protein deficiency increases the risk of surgery and is associated with poor healing of wounds.

Heart disease of unexplained cause has been reported to be prevalent in certain areas of the world where protein malnutrition is common. Gillanders (27) in South Africa has described heart failure in association with large, hypodynamic, dilated, but often not hypertrophied hearts. Whether protein deficiency is responsible for this syndrome or for the endomyocardial fibrosis which occurs in Uganda remains unknown but is a distinct possibility.

The most important laboratory finding in severe protein deficiency is a decrease in serum proteins, particularly in the albumin fraction. Normal concentration of total proteins in serum is 6.0 – 8.0 gm/100 ml., of albumin, 4.0 to 5.5 gm./100m1. The decrease in concentration in protein deficiency may be masked by a decrease in blood volume. While determination of blood volume is difficult and not always satisfactory, estimation of total circulating serum albumin is a more accurate method of detecting protein depletion than is measurement of concentration of serum albumin. Even small decreases in serum albumin represent loss of tissue protein of considerable magnitude. On the basis of animal experiments, it may be assumed that each gram of decrease in total circulating albumin represents a loss of approximately 30.0 gm. of tissue protein (28).

Several years ago, Harroun and associates suggested estimating extravascular reserves of protein (interstitial fluid and lymph) by determining the response to rapid infusion of one liter of isotonic sodium chloride. Normal persons showed an increase in plasma volume and in total circulating protein, while malnourished subjects showed a smaller increase in plasma volume and a de-crease in total circulating protein. Further evaluation of this procedure seems indicated.

Electrophoretic analysis of serum proteins has not proved of value in the diagnosis of protein deficiency which accompanies caloric undernutrition (30). Studies of antibody response in subjects with abnormal levels of serum protein have failed to show a relationship between the concentration or distribution of serum protein fractions and the ability to form antibodies.

In protein deficiency, nitrogen balance is negative. Since balance studies require special facilities, they are more useful in research than in medical practice. Further-more, many difficulties are inherent in the interpretation of nitrogen balance data. Simultaneous depletion and repletion of various compartments of body protein may not be detected and it is possible to obtain positive balance when some labile protein stores are being depleted.

Recent studies indicate that tissues enzymes respond to changes in dietary protein. It seems likely that measurement of enzyme activity in tissues may prove useful in determining the presence and severity of deficiency and, perhaps, deficiency of specific amino acids. The liver would appear to be a good organ for study as changes in enzyme activity of the liver have been found to accompany variations in exogenous protein intake.

Numerous methods for determining the concentration of amino acids in blood and urine are available. Techniques include chemical and microbiologic assay and chromatography using paper or ion exchange columns. Amino acid determinations have been of value in detecting metabolic derangements but have been of little assistance in evaluating over-all protein nutrition. The amino acid content of plasma during fasting does not fluctuate significantly despite considerable variation in amounts ingeste and does not parallel quantities excreted in the urine due to marked differences in reabsorption of individual amino acids by the renal tubules. Diets high in protein are, however, associated with slight in-creases in 24 hour excretion of amino acids particularly with respect to histidine. Normal plasma levels and pat-tern of urinary excretion are given in Fig. 1. Excretion can be increased by either of two mechanisms, hyperaminoacidemia or changes in renal tubular absorption. Abnormal excretion of amino acids has been reported in advanced liver disease and after radiation injury but not following surgical procedures when nitrogen balance is negativ.

Diseases associated with aminoaciduria have been re-viewed by the Harrison. Specific aminoaciduria of hyperaminoacidemic type occurs in phenylketonuria (phenylpyruvic oligophrenia ), an inborn error of metabolism. In this condition, conversion of phenylalanine to tyrosine is defective, phenylalanine levels in plasma are markedly increased and urinary excretion is correspondingly high. The aminoaciduria of severe liver damage is due to generalized hyperaminoacidemia but taurine, cystine, methionine, ethanolamine and P aminobutyric acid are found in larger amounts than in other types of general aminoaciduria.

Aninoacidurias of renal origin include a number of conditions, some due to inborn metabolic errors, some to toxic agents and others to vitamin deficiency states. In patients with scurvy and in premature infants, the feeding of high protein diets leads to hydroxyphenyluria. The abnormal excretion of hydroxyphenyl derivatives may be prevented by giving ascorbic acid or large amounts of folic acid. Renal aminoaciduria has been reported in infants with vitamin D deficiency. The excretion of free amino acids in rickets is qualitatively similar to that found in the Fanconi syndrome, although less marked. The greatest increases in excretion are in threonine, serine and alanine with slight increases in valine, methionine, leucine, isoleucine and phenylalanine. The Fanconi syndrome, which is characterized by bony changes of rickets or osteomalacia, hypophosphatemia, glycosuria and renal aminoaciduria, may be due to an hereditary metabolic abnormality or occur in older children or adults without familial incidence. The fundamental defect appears to be renal tubular injury, especially of the systems involving amino acids, glucose and phosphate. Treatment of rickets with vitamin D leads to a gradual return of amino acid excretion to normal. Administration of large does of vitamin D results in reduction of the aminoaciduria in the Fanconi syndrome.

Under ordinary dietary conditions, the loss of amino acids in the urine has not been found to be sufficiently great to produce deficiencies. The only significant disturbance directly due to excessive excretion of amino acids is the formation of cystine calculi in the urinary tract in cystinuria (33).

From data just discussed, it is evident that estimation of excretion of individual amino acids is a useful procedure in the diagnosis of a number of diseases associated with metabolic abnormalities. Such determinations are useful, also, in clarifying interrelations among these diseases and among vitamins and amino acids.

SPECIFIC AMINO ACID DEFICIENCIES

Little is known about specific amino acid deficiencies in man. Albanese (36) has suggested that changes in amino acid levels in blood and urine may be useful in detecting certain deficiencies. Further investigation will be needed to substantiate this postulate. Tryptophan is known to be a precursor of the vitamin, niacin, and hence an inadequate dietary supply of tryptophan contributes to the development of niacin deficiency or pellagrA. Methionine metabolism has been widely investigated in animals but little is known about the application of findings to man. Relationships between methionine, choline, vitamin B 12 and folic acid have been observed in animals. Each of these nutrients participates in some way in the metabolism of methyl groups. Such groups are important in the prevention of fatty livers and cirrhosis in animals which are fed diets high in fat, or low in protein and low in fat. It seems likely that methyl groups are of similar importance in human nutrition.