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Metabolism of serum albumin in marasmic infants
TROPICAL PEDIATRICS
Metabolism of sou m albumin in marasmic infants By means of studies with lISl-labeled human serum albumin, the serum albumin half-life of marasmic infants has been shown to be longer than that of normal infants. It is suggested that reduced catabolism of body proteins may contribute to the survival of the infant during prolonged periods of inadequate calorie and protein intake.
Gonzalo Donoso, M.D., Oscar Brunser, M.D., and Fernando M6nckeberg, M.D. SANTIAGO, CHILE
WITH THE TECHNICAL ASSISTANCE o r M a r g a r i t a Gonzfilez
I n patients w i t h kwashiorkor, hypoalbuminemia may be explained by a decrease in the albumin synthesis 6 secondary to diminished intake of amino acids. T h e question arises as to why the low calorie and protein intake, causing marasmus, does not produce a marked decrease in serum protein. I n the mouse, decreased calorie and protein intake leads to decreased synthesis of albumin, but this is compensated for by a significant increase in half-life of albumin. = It may be possible that a similar mechanism occurs in the marasmic infants. I n order to answer this question, we have studied the albumin turnover in a group of marasmic infants in relation to a group of normal infants of the same age.
T w o T Y P E S of malnutrition are generally recognizable in children: one is the marasmic type, in which there is a grossly inadequate: calorie and protein intake, and kwashiorkor, in which the protein intake is very low and there is a reduced, adequate, or even high calorie intake, especially of carbohydrate. F r o m the clinical and biochemical points of view, these two syndromes are clearly different?, 2 Infants suffering from kwashiorkor have as one of the most constant biochemical features markedly reduced levels of serum albumin, whereas, in typical marasmus, an only slightly decreased or even normal serum albumin level is found, even in the most severe cases. '~' 4,
PATIENTS,
From the Laboratorio de Investigaciones Pedidtricas y Centro de Estudios de la Nutrici6n, Universidad de Chile, Hospital Manuel Arriar~n, Santiago, Chile. This work has been supported in part by research Grant A-4226 from the National Institutes of Health, United States Public Health Service.
METHOD
MATERIAL,
AND
G r o u p A. Sixteen infants with severe marasmus, 6 to 14 months old were studied in the Hospital Manuel Arriardm of Santiago. T h e malnutrition of these infants was 306
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Metabolism o[ serum albumin in marasmic in[ants
caused by an insufficient calorie and protein intake due to social and economic factors. These children had received very diluted skimmed milk (some with the addition of carbohydrate and some without) as their sole nourishment. The main clinical characteristics were virtual absence of subcutaneous fat, wasting of the muscles, mental apathy, and considerably less weight and length than normal Chilean infants of the same age. s Hepatomegaly, edema, gross skin lesions, or alterations in the color or texture of the hair (typical signs of kwashiorkor) were not observed in any patient of this group. Up to the time of the study period, there were no associated pathologic conditions that might have interfered with the study, such as dehydration, infections, or parasitism. Prior to the present study, all the malnourished infants were hospitalized and kept under clinical observation for a period of no less than 3 weeks. During this time, they received a powdered milk-carbohydrate formula that provided 130 calories and 5 Gm. of protein per kilogram of body weight per day. Group B. Seven normal infants, whose ages ranged from 4 to 20 months were also studied. Table I shows the principal clinical characteristics of these infants.
30 7
Lugol's drops (5 drops twice a day) were given to all the infants 2 days before and during the entire experimental period. Iodine~aMabeled human serum albumin (Philips-Duphar) was injected intravenously (maximum dose 1.5 ~c per kilogram of weight). Fifteen minutes after the injection was completed, a 5 ml. blood sample was removed and the following determinations performed: hematocrit, radioactivity of 1 ml. of serum (measured in a well-type scintillation counter), and the serum albumin level according to Debro and associates. 9 Blood samples were taken every day for the first 3 days and every 3 days thereafter, for a total of 21 days, and the radioactivity of the serum was measured. The half-life of serum albumin was calculated from the exponential slope of the intravascular radioactivity. 6 In the first 6 children studied, the radioactivity of the trichloroacetic acid precipitate of 1 ml. of serum was measured and found to be 93 to 98 per cent of the total radioactivity. This procedure was discontinued thereafter, inasmuch as it seemed to be unnecessary. Plasma volume and blood volume were calculated by isotope dilution and from the hematocrit data. Total circulating albumin was calculated from the plasma volume and the concentration of albumin in the serum.
Table I. Clinical data of marasmic infants Case No.
Sex
Age (too.)
Weight (Kg.)
Weight deficit (%)
Gain in weight (Gin. per day)*
1 2 3 4 5 6 7 8 9 10 11 t2 13 14 15 16
M M M F F F F M F F F F F F M F
7 6 20 11 6 14 6 13 7 I0 I1 7 14 9 3 7
4.4 2.8 4.1 2.7 4.4 4.1 3.6 4.8 4.1 4.4 2.8 3.2 4.5 4.4 2.8 4.6
48 64 65 71 41 60 50 54 48 50 71 58 53 45 51 41
0 0 4 8 10 10 10 17 18 20 23 27 28 28 4O 40
*Average rate of gain in weight calculated from t~o weeks hefore until the end of the study.
Donoso, Brunser, and M6nckeberg
308
RESULTS
T a b l e I I shows the p l a s m a volume, the blood volume, serum a l b u m i n concentration, a n d total circulating a l b u m i n in the m a l nourished a n d in the n o r m a l infants. T h e p l a s m a volume a n d the blood volume (expressed in milliliters per kilogram weight) are significantly higher (p ~ 0.001) in the m a r a s m i c infant than in the n o r m a l group. Similar results have been reported by Gollan in 1948.1~ T h e concentration of serum a l b u m i n was found to be slightly t h o u g h significantly (p < 0.001) lower in the malnourished infants t h a n in the n o r m a l controls. T h e concentration of a l b u m i n in the serum r e m a i n e d very m u c h the same d u r i n g the experimental period.
August 1965
A l t h o u g h the serum a l b u m i n levels were lower in the m a l n o u r i s h e d group, the size of the intravascular pool (in grams of serum a l b u m i n p e r kilogram of weight) was found to be significantly larger (p < 0.01) in the malnourished infant t h a n in the n o r m a l controls. Serum a l b u m i n half-life, as estimated from the d i s a p p e a r a n c e of the intravascular label, is given in T a b l e I I . A l b u m i n half-life is longer for the m e m b e r s of the malnourished group t h a n for the n o r m a l controls. T h e difference between the m e a n values for groups A a n d B is statistically significant (p < 0.01). Nevertheless, there is a wide scattering of the individual values in the m a r a s m i c group. Even when all the infants u n d e r observa-
T a b l e I I . S e r u m volume, h e m a t o c r i t , blood volume, serum albumin, total circulating a l b u m i n ( T C A ) , a n d serum a l b u m i n half-life, in 16 m a r a s m i c a n d 7 n o r m a l infants
Serum ool.
Case No. Marasmic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean S.D.
(ml./Kg.) 93 93 83 95 59 69 98 63 72 52 77 78 119 88 68 53
Hematocrit
Blood vol. (ml./Kg.)
Serum albumin (Gm. per 100 ml.) l Final Initial
T CA (Gm./Kg.)
Albumin hal/-Ii/ e (days)
34 30 38 33 31 36 35 43 35 35 39 -34 39 28 39
140 118 151 142 92 108 151 110 114 80 126 -179 145 94 87
3.6 3.6 3.3 2.8 3.6 3.0 3.5 4.3 3.4 3.5 3.7 3.6 3.6 4.1 3.4 3.1
3.7 3.6 3.3 2.6 3.8 3.0 3.9 4.0 3.3 3.7. 3.8 3.7 4.3 4.2 3.5 3.3
2.34 3.06 3.07 2.66 2.19 2.07 3.44 2.71 2.46 1.88 2.84 2.82 4.30 3.62 2.22 1.67
17.0 11.1 17.4 13.4 20.5 16.4 12.5 11.4 15.0 12.3 10.4 9.2 12.0 10.0 13.0 13.2
78 18.0
35 3.8
122 29
3.5 0.14
3.6
2.77 0.65
13.4 3.05
51 50 49 61 49 69 66 66 8.7 0.001
38 37 34 36 38 32 39 36 3.8 0.6
86 81/ 74 95 79 100 109 89 13 0.001
3.9 3.9 4.1 4.6 4.4 3.9 3.8 4.1 0.09 0.001
3.9 4.0 4.0 4.5 4.4 3.9 3.8 4.l
2.01 1.97 2.11 2.80 2.15 2.79 2.53 2.34 0.12 0.01
12.0 10.2 11.1 12.0 9.5 11.2 10.9 11.3 0.82 0.01
Normal 1
2 3 4 5 6 7 Mean S.D. p
Volume 67 Number 2
1~ I
Metabolism o[ serum albumin in marasmic in[ants
9
9
:
lO
I
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I
._~ ~,
o [ g. ~
da),l
MARASMATICS
NORMAL$
Fig. l. Serum albumin half-life in normal and marasmic infants. The marasmic infants are separated into three groups according to their response to treatment and weight increase. (The average rate of gain in weight in grams per day was calculated from two weeks before until the end of the study.)
tion presented a severe marasmus, their therapeutic response has been variable, as we have been able to observe. 11 The analysis of the weight curves shows that while some patients gain weight at an average rate of 30 Gm. per day during the period of albumin turnover study, others show a very slow or even no weight gain. If the malnourished infants are grouped according to their mean daily gain in weight, the patients with little improvement present significantly (p < 0.01) longer serum albumin half-life than those with rapid increases in weight (Fig. 1), in which the albumin half-life is similar to that of the normal control group. DISCUSSION albumin
normal one. TM Nevertheless, it can be said that there is no depletion of albumin in the marasmic infant; this is different from the marked depletion that has been reported in kwashiorkor? 3 Albumin t u r n o v e r . Our results s h o w longer serum albumin half-life in the marasmic infants than in the normal controls. Since the total serum albumin represents a balance between synthesis and degradation, a decrease of the latter could explain the lack of albumin depletion. These results are different from those observed in kwashiorkor, where hypoalbuminemia is the rule. Gitlin and associates G could not show any difference between the halflife of serum albumin in children suffering from kwashiorkor before and after treatment, and consequently depletion of albumin in children with low protein intake appears to be due primarily to a decreased rate of albumin synthesis. Similar results have been reported by Garrow and Waterlow? 4 Recently, Picou and Waterlow 15 have reinvestigated the problem and have come to the conclusion that catabolism is also decreased in children with kwashiorkor. According to these authors, all former results would be distorted by the fact that the concentration of serum albumin in children with kwashiorkor is normalized very quickly, and thus, the I T M albumin is progressively diluted in the new albumin which is formed. In our patients, the concentration of serum albumin was slightly lower in the marasmic infants in relation to the normal group, but during the observation period, only small modifications were observed in its concentration. Albumin
The concentration of serum albumin was found to be only slightly lower, while the blood and plasma volume (expressed in milliliters per kilogram of weight) were significantly higher in marasmic infants. This results in an increase in the albumin intravascular pool. However, this increase in the plasma volume could be only a fallacy since it is not legitimate to assume that the body composition of the malnourished infant is similar to that of the Serum
pool.
309
turnover and clinical evaluation
o f m a l n u t r i t i o n . Recovery in children suffer-
ing from severe marasmus is generally slow and difficult. 1~ When hypoalimentation has been of long duration and it has provoked loss of weight of 50 per cent or more, the initiation of recovery takes a long time even when there are no signs of infections, parasitism, or any other concurrent disease. It is frequent that for long periods of time (4 months or more) neither clinical improvement nor recuperation in weight will be ob-
3 1 0 Donoso, Brunser, and M6nckeberg
served in spite of the administration of a diet containing the adequate supply of calories, proteins, and vitamins. During this period, numerous metabolic alterations have been observed, such as decreased nitrogen utilization, 1~ decreased carbohydrate tolerance, 17 decreased lipid absorption, is and decreased oxygen consumption? 2 As soon as the recuperation process is initiated and an increase in weight is observed, all these alterations tend to become normal. T h e group of patients we have studied was not homogenous, although all of them presented signs of severe marasmus (less than 40 per cent of their ideal weight). Some of them had not started recuperation while others responded to treatment satisfactorily and gained at an average rate of 20 or 30 Gin. per day. This would probably account for the wide scattering of the life values of the plasma albumin observed in our malnourished patients. However, when the patients were separated into three groups according to their response to treatment, it can be observed that those children who did not respond to treatment and whose weights remained more or less static, had the longest half-lives (Fig. 1), whereas those who had normal increases in weight had a normal serum albumin half-life. These results lead us to believe that there is an important decrease in the catabolism of albumin in the infant with severe marasmus prior to the initiation of recuperation, and that this prevents an accentuated hypoalbuminemia in spite of the greatly decreased intake of protein and calories. There are other conditions in which a prolonged albumin half-life has been observed, as in myxedematous patients, ~9 and in the hypophysectomized rat. 2~ It is of interest that marasmic infants who have no response to treatment even in the absence of concurrent disease, present similar low iodine uptake 21 by the thyroid, low PBI values, 22 and low basal metabolic rate? 2 These values tend to become normal with the administration of thyroid-stimulating hormone. 2~ It has also been shown that the marasmic infant
August 1965
has increased utilization of protein with the administration of h u m a n growth hormone. 16 Although the reduction in catabolism of serum albumin is perhaps an important factor in maintaining near-normal serum levels, it is not possible to say at the present stage of knowledge that it is representative of w h a t happens with the body proteins as a whole. However, a reduced catabolism of body proteins would contribute to the survival of the child submitted to an inadequate calorie and protein intake. SUMMARY
Albumin metabolism was studied with I131-1abeled h u m a n serum albumin in 16 marasmic and 7 normal infants. T h e albumin half-life was significantly longer in the marasmic infant than in the normal one, especially in those patients who had not begun to gain weight in spite of adequate treatment. It is suggested that the decrease in protein catabolism is an important factor in maintaining a near-normal serum albumin level in infants suffering from marasmus. REFERENCES
1. Jelliffe, D," Protein-calorie malnutrition in tropical preschool children, J. PEDIAT. 54: 227, 1959. 2. Meneghello, J., and M6nckeberg, F.: The adaptation of the infant to malnutrition, International Congress of Pediatrics, Lisbon, September, 1962, p. 123. 3. Chaudhuri, K., and Chaudhuri, A.: Malnutrition in children. A clinical and biochemical study, Indian J. Pediat. 29: 1, 1962. 4. Graham, G., and Morales, E.: Studies in infantile malnutrition. I. Nature of the problem in Peru, J. Nutr. 79: 479, 1963. 5. M6nckeberg, F., Vild6sola, J., Figueroa, M., Oxman, S., and Meneghello, J.: Hematological disturbances in infantile malnutrition. Values for copper, iron, paraphenylene diamine oxidase activity and iron binding capacity in the serum, Am. J. Clin. Nutr. 11: 525, 1962. 6. Gitlin, D., Gravloto, J., Frenk, S. Montano, E., Ramos-Galv~n, R., G6mez, F., and Janeway, C.: Albumin metabolism in children with protein malnutrition, J. Clln. Invest. 37: 682, 1958. 7. Gitlin, D., and Janeway, C.: Plasma protein sparing effect of fats and carbohydrates, Am. J. Dis. Child. 93: 79, 1957. 8. Donoso, G., Undurraga, O., Weshler, A., Barja, I., and S~ez, M.: Estudio del creci-
Volume 67 Number 2
9.
10. 11.
12.
13. 14. t5. 16.
Metabolism of serum albumin in marasmic infants
miento pondoestatural del nifio de O a dos afios, Pediatria (Santiago) 5: 135, 1962. Debro, J., Tarver, H., and Korner, A.: The determination of albumin and globulin by a new method, J. Lab. & Clin. Med. 50: 728, 1957. Gollan, F.: Blood and extracellular fluid studies in chronic malnutrition in infancy, J. Clin. Invest. 27: 352, 1948. Menegbello, J., Niemeyer, H., Rosselot, J., Mardones, F., and Undurraga, O.: Evolucidn intrahospitalaria del lactante distrdfico menor de un afio, Rev. chilena de pediat. 23: 91, 1952. M6nckeberg, F., Beas, F., Horwitz, I., Dabances, A., and Gonz~lez, M.: Oxygen consumption in infant malnutrition, Pediatrics 33: 554, 1964. Cohen, S., and Hansen, J.: Metabolism of albumin and globulin in kwashiorkor, Clin. Sc. 23: 351, 1962. Waterlow, J., Cravioto, C., and Stephen, J.: Protein malnutrition in man, Advances in Protein Chem. 15" 131, 1960. Picou, D., and Waterlow, J.: The effect of malnutrition on the metabolism of plasma albumin, Clin. Sc. 22: 459, 1962. M6nckeberg, F., Donoso, G., Oxman, S.,
17.
18.
19.
20.
21.
22.
311
Pak, N., and Meneghello, J.: Human growth hormone in infant malnutrition, Pediatrics 31: 58, 1963. M6nckeberg, F., Beas, F., and Perretta, M.: Estudio del metabolismo de los hidratos de carbono en el lactante distr6fico, Pediatria (Santiago) 2: 93; 1959. M6nckeberg, F., Manzur, F., and L6pez, M.: Algunos factores que influencian la absorci6n de grasas en el lactante distr6fico, Pediatria (Santiago) 1: 132, 1958. Lewallen, C., Berman, M., and Rail, J.: Studies of iodoalbumin metabolism. II. Effect of thyroid hormone, J. Clin. Invest. 38: 88, 1959. Ulrich, F., Tarver, H., and Li, C.: Effect of growth and adrenocorticotrophic hormone on the metabolism of albumin in the hypophysectomized rat, J. Biol. Chem. 209: 117, 1952. Miinckeberg, F., Barzelatto, J., Beas, F., and Waissbluth, H.: Captaci6n de iodo radioactivo por el tiroides en el lactante distr6fico, Rev. chilena de pediat. 28: 173, 1957. Beas, F., and M6nckeberg, F.: Thyroid response to TSH in infant malnutrition. To be published.
Metabolism of sou m albumin in marasmic infants By means of studies with lISl-labeled human serum albumin, the serum albumin half-life of marasmic infants has been shown to be longer than that of normal infants. It is suggested that reduced catabolism of body proteins may contribute to the survival of the infant during prolonged periods of inadequate calorie and protein intake.
Gonzalo Donoso, M.D., Oscar Brunser, M.D., and Fernando M6nckeberg, M.D. SANTIAGO, CHILE
WITH THE TECHNICAL ASSISTANCE o r M a r g a r i t a Gonzfilez
I n patients w i t h kwashiorkor, hypoalbuminemia may be explained by a decrease in the albumin synthesis 6 secondary to diminished intake of amino acids. T h e question arises as to why the low calorie and protein intake, causing marasmus, does not produce a marked decrease in serum protein. I n the mouse, decreased calorie and protein intake leads to decreased synthesis of albumin, but this is compensated for by a significant increase in half-life of albumin. = It may be possible that a similar mechanism occurs in the marasmic infants. I n order to answer this question, we have studied the albumin turnover in a group of marasmic infants in relation to a group of normal infants of the same age.
T w o T Y P E S of malnutrition are generally recognizable in children: one is the marasmic type, in which there is a grossly inadequate: calorie and protein intake, and kwashiorkor, in which the protein intake is very low and there is a reduced, adequate, or even high calorie intake, especially of carbohydrate. F r o m the clinical and biochemical points of view, these two syndromes are clearly different?, 2 Infants suffering from kwashiorkor have as one of the most constant biochemical features markedly reduced levels of serum albumin, whereas, in typical marasmus, an only slightly decreased or even normal serum albumin level is found, even in the most severe cases. '~' 4,
PATIENTS,
From the Laboratorio de Investigaciones Pedidtricas y Centro de Estudios de la Nutrici6n, Universidad de Chile, Hospital Manuel Arriar~n, Santiago, Chile. This work has been supported in part by research Grant A-4226 from the National Institutes of Health, United States Public Health Service.
METHOD
MATERIAL,
AND
G r o u p A. Sixteen infants with severe marasmus, 6 to 14 months old were studied in the Hospital Manuel Arriardm of Santiago. T h e malnutrition of these infants was 306
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Metabolism o[ serum albumin in marasmic in[ants
caused by an insufficient calorie and protein intake due to social and economic factors. These children had received very diluted skimmed milk (some with the addition of carbohydrate and some without) as their sole nourishment. The main clinical characteristics were virtual absence of subcutaneous fat, wasting of the muscles, mental apathy, and considerably less weight and length than normal Chilean infants of the same age. s Hepatomegaly, edema, gross skin lesions, or alterations in the color or texture of the hair (typical signs of kwashiorkor) were not observed in any patient of this group. Up to the time of the study period, there were no associated pathologic conditions that might have interfered with the study, such as dehydration, infections, or parasitism. Prior to the present study, all the malnourished infants were hospitalized and kept under clinical observation for a period of no less than 3 weeks. During this time, they received a powdered milk-carbohydrate formula that provided 130 calories and 5 Gm. of protein per kilogram of body weight per day. Group B. Seven normal infants, whose ages ranged from 4 to 20 months were also studied. Table I shows the principal clinical characteristics of these infants.
30 7
Lugol's drops (5 drops twice a day) were given to all the infants 2 days before and during the entire experimental period. Iodine~aMabeled human serum albumin (Philips-Duphar) was injected intravenously (maximum dose 1.5 ~c per kilogram of weight). Fifteen minutes after the injection was completed, a 5 ml. blood sample was removed and the following determinations performed: hematocrit, radioactivity of 1 ml. of serum (measured in a well-type scintillation counter), and the serum albumin level according to Debro and associates. 9 Blood samples were taken every day for the first 3 days and every 3 days thereafter, for a total of 21 days, and the radioactivity of the serum was measured. The half-life of serum albumin was calculated from the exponential slope of the intravascular radioactivity. 6 In the first 6 children studied, the radioactivity of the trichloroacetic acid precipitate of 1 ml. of serum was measured and found to be 93 to 98 per cent of the total radioactivity. This procedure was discontinued thereafter, inasmuch as it seemed to be unnecessary. Plasma volume and blood volume were calculated by isotope dilution and from the hematocrit data. Total circulating albumin was calculated from the plasma volume and the concentration of albumin in the serum.
Table I. Clinical data of marasmic infants Case No.
Sex
Age (too.)
Weight (Kg.)
Weight deficit (%)
Gain in weight (Gin. per day)*
1 2 3 4 5 6 7 8 9 10 11 t2 13 14 15 16
M M M F F F F M F F F F F F M F
7 6 20 11 6 14 6 13 7 I0 I1 7 14 9 3 7
4.4 2.8 4.1 2.7 4.4 4.1 3.6 4.8 4.1 4.4 2.8 3.2 4.5 4.4 2.8 4.6
48 64 65 71 41 60 50 54 48 50 71 58 53 45 51 41
0 0 4 8 10 10 10 17 18 20 23 27 28 28 4O 40
*Average rate of gain in weight calculated from t~o weeks hefore until the end of the study.
Donoso, Brunser, and M6nckeberg
308
RESULTS
T a b l e I I shows the p l a s m a volume, the blood volume, serum a l b u m i n concentration, a n d total circulating a l b u m i n in the m a l nourished a n d in the n o r m a l infants. T h e p l a s m a volume a n d the blood volume (expressed in milliliters per kilogram weight) are significantly higher (p ~ 0.001) in the m a r a s m i c infant than in the n o r m a l group. Similar results have been reported by Gollan in 1948.1~ T h e concentration of serum a l b u m i n was found to be slightly t h o u g h significantly (p < 0.001) lower in the malnourished infants t h a n in the n o r m a l controls. T h e concentration of a l b u m i n in the serum r e m a i n e d very m u c h the same d u r i n g the experimental period.
August 1965
A l t h o u g h the serum a l b u m i n levels were lower in the m a l n o u r i s h e d group, the size of the intravascular pool (in grams of serum a l b u m i n p e r kilogram of weight) was found to be significantly larger (p < 0.01) in the malnourished infant t h a n in the n o r m a l controls. Serum a l b u m i n half-life, as estimated from the d i s a p p e a r a n c e of the intravascular label, is given in T a b l e I I . A l b u m i n half-life is longer for the m e m b e r s of the malnourished group t h a n for the n o r m a l controls. T h e difference between the m e a n values for groups A a n d B is statistically significant (p < 0.01). Nevertheless, there is a wide scattering of the individual values in the m a r a s m i c group. Even when all the infants u n d e r observa-
T a b l e I I . S e r u m volume, h e m a t o c r i t , blood volume, serum albumin, total circulating a l b u m i n ( T C A ) , a n d serum a l b u m i n half-life, in 16 m a r a s m i c a n d 7 n o r m a l infants
Serum ool.
Case No. Marasmic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean S.D.
(ml./Kg.) 93 93 83 95 59 69 98 63 72 52 77 78 119 88 68 53
Hematocrit
Blood vol. (ml./Kg.)
Serum albumin (Gm. per 100 ml.) l Final Initial
T CA (Gm./Kg.)
Albumin hal/-Ii/ e (days)
34 30 38 33 31 36 35 43 35 35 39 -34 39 28 39
140 118 151 142 92 108 151 110 114 80 126 -179 145 94 87
3.6 3.6 3.3 2.8 3.6 3.0 3.5 4.3 3.4 3.5 3.7 3.6 3.6 4.1 3.4 3.1
3.7 3.6 3.3 2.6 3.8 3.0 3.9 4.0 3.3 3.7. 3.8 3.7 4.3 4.2 3.5 3.3
2.34 3.06 3.07 2.66 2.19 2.07 3.44 2.71 2.46 1.88 2.84 2.82 4.30 3.62 2.22 1.67
17.0 11.1 17.4 13.4 20.5 16.4 12.5 11.4 15.0 12.3 10.4 9.2 12.0 10.0 13.0 13.2
78 18.0
35 3.8
122 29
3.5 0.14
3.6
2.77 0.65
13.4 3.05
51 50 49 61 49 69 66 66 8.7 0.001
38 37 34 36 38 32 39 36 3.8 0.6
86 81/ 74 95 79 100 109 89 13 0.001
3.9 3.9 4.1 4.6 4.4 3.9 3.8 4.1 0.09 0.001
3.9 4.0 4.0 4.5 4.4 3.9 3.8 4.l
2.01 1.97 2.11 2.80 2.15 2.79 2.53 2.34 0.12 0.01
12.0 10.2 11.1 12.0 9.5 11.2 10.9 11.3 0.82 0.01
Normal 1
2 3 4 5 6 7 Mean S.D. p
Volume 67 Number 2
1~ I
Metabolism o[ serum albumin in marasmic in[ants
9
9
:
lO
I
jr-
I
._~ ~,
o [ g. ~
da),l
MARASMATICS
NORMAL$
Fig. l. Serum albumin half-life in normal and marasmic infants. The marasmic infants are separated into three groups according to their response to treatment and weight increase. (The average rate of gain in weight in grams per day was calculated from two weeks before until the end of the study.)
tion presented a severe marasmus, their therapeutic response has been variable, as we have been able to observe. 11 The analysis of the weight curves shows that while some patients gain weight at an average rate of 30 Gm. per day during the period of albumin turnover study, others show a very slow or even no weight gain. If the malnourished infants are grouped according to their mean daily gain in weight, the patients with little improvement present significantly (p < 0.01) longer serum albumin half-life than those with rapid increases in weight (Fig. 1), in which the albumin half-life is similar to that of the normal control group. DISCUSSION albumin
normal one. TM Nevertheless, it can be said that there is no depletion of albumin in the marasmic infant; this is different from the marked depletion that has been reported in kwashiorkor? 3 Albumin t u r n o v e r . Our results s h o w longer serum albumin half-life in the marasmic infants than in the normal controls. Since the total serum albumin represents a balance between synthesis and degradation, a decrease of the latter could explain the lack of albumin depletion. These results are different from those observed in kwashiorkor, where hypoalbuminemia is the rule. Gitlin and associates G could not show any difference between the halflife of serum albumin in children suffering from kwashiorkor before and after treatment, and consequently depletion of albumin in children with low protein intake appears to be due primarily to a decreased rate of albumin synthesis. Similar results have been reported by Garrow and Waterlow? 4 Recently, Picou and Waterlow 15 have reinvestigated the problem and have come to the conclusion that catabolism is also decreased in children with kwashiorkor. According to these authors, all former results would be distorted by the fact that the concentration of serum albumin in children with kwashiorkor is normalized very quickly, and thus, the I T M albumin is progressively diluted in the new albumin which is formed. In our patients, the concentration of serum albumin was slightly lower in the marasmic infants in relation to the normal group, but during the observation period, only small modifications were observed in its concentration. Albumin
The concentration of serum albumin was found to be only slightly lower, while the blood and plasma volume (expressed in milliliters per kilogram of weight) were significantly higher in marasmic infants. This results in an increase in the albumin intravascular pool. However, this increase in the plasma volume could be only a fallacy since it is not legitimate to assume that the body composition of the malnourished infant is similar to that of the Serum
pool.
309
turnover and clinical evaluation
o f m a l n u t r i t i o n . Recovery in children suffer-
ing from severe marasmus is generally slow and difficult. 1~ When hypoalimentation has been of long duration and it has provoked loss of weight of 50 per cent or more, the initiation of recovery takes a long time even when there are no signs of infections, parasitism, or any other concurrent disease. It is frequent that for long periods of time (4 months or more) neither clinical improvement nor recuperation in weight will be ob-
3 1 0 Donoso, Brunser, and M6nckeberg
served in spite of the administration of a diet containing the adequate supply of calories, proteins, and vitamins. During this period, numerous metabolic alterations have been observed, such as decreased nitrogen utilization, 1~ decreased carbohydrate tolerance, 17 decreased lipid absorption, is and decreased oxygen consumption? 2 As soon as the recuperation process is initiated and an increase in weight is observed, all these alterations tend to become normal. T h e group of patients we have studied was not homogenous, although all of them presented signs of severe marasmus (less than 40 per cent of their ideal weight). Some of them had not started recuperation while others responded to treatment satisfactorily and gained at an average rate of 20 or 30 Gin. per day. This would probably account for the wide scattering of the life values of the plasma albumin observed in our malnourished patients. However, when the patients were separated into three groups according to their response to treatment, it can be observed that those children who did not respond to treatment and whose weights remained more or less static, had the longest half-lives (Fig. 1), whereas those who had normal increases in weight had a normal serum albumin half-life. These results lead us to believe that there is an important decrease in the catabolism of albumin in the infant with severe marasmus prior to the initiation of recuperation, and that this prevents an accentuated hypoalbuminemia in spite of the greatly decreased intake of protein and calories. There are other conditions in which a prolonged albumin half-life has been observed, as in myxedematous patients, ~9 and in the hypophysectomized rat. 2~ It is of interest that marasmic infants who have no response to treatment even in the absence of concurrent disease, present similar low iodine uptake 21 by the thyroid, low PBI values, 22 and low basal metabolic rate? 2 These values tend to become normal with the administration of thyroid-stimulating hormone. 2~ It has also been shown that the marasmic infant
August 1965
has increased utilization of protein with the administration of h u m a n growth hormone. 16 Although the reduction in catabolism of serum albumin is perhaps an important factor in maintaining near-normal serum levels, it is not possible to say at the present stage of knowledge that it is representative of w h a t happens with the body proteins as a whole. However, a reduced catabolism of body proteins would contribute to the survival of the child submitted to an inadequate calorie and protein intake. SUMMARY
Albumin metabolism was studied with I131-1abeled h u m a n serum albumin in 16 marasmic and 7 normal infants. T h e albumin half-life was significantly longer in the marasmic infant than in the normal one, especially in those patients who had not begun to gain weight in spite of adequate treatment. It is suggested that the decrease in protein catabolism is an important factor in maintaining a near-normal serum albumin level in infants suffering from marasmus. REFERENCES
1. Jelliffe, D," Protein-calorie malnutrition in tropical preschool children, J. PEDIAT. 54: 227, 1959. 2. Meneghello, J., and M6nckeberg, F.: The adaptation of the infant to malnutrition, International Congress of Pediatrics, Lisbon, September, 1962, p. 123. 3. Chaudhuri, K., and Chaudhuri, A.: Malnutrition in children. A clinical and biochemical study, Indian J. Pediat. 29: 1, 1962. 4. Graham, G., and Morales, E.: Studies in infantile malnutrition. I. Nature of the problem in Peru, J. Nutr. 79: 479, 1963. 5. M6nckeberg, F., Vild6sola, J., Figueroa, M., Oxman, S., and Meneghello, J.: Hematological disturbances in infantile malnutrition. Values for copper, iron, paraphenylene diamine oxidase activity and iron binding capacity in the serum, Am. J. Clin. Nutr. 11: 525, 1962. 6. Gitlin, D., Gravloto, J., Frenk, S. Montano, E., Ramos-Galv~n, R., G6mez, F., and Janeway, C.: Albumin metabolism in children with protein malnutrition, J. Clln. Invest. 37: 682, 1958. 7. Gitlin, D., and Janeway, C.: Plasma protein sparing effect of fats and carbohydrates, Am. J. Dis. Child. 93: 79, 1957. 8. Donoso, G., Undurraga, O., Weshler, A., Barja, I., and S~ez, M.: Estudio del creci-
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Metabolism of serum albumin in marasmic infants
miento pondoestatural del nifio de O a dos afios, Pediatria (Santiago) 5: 135, 1962. Debro, J., Tarver, H., and Korner, A.: The determination of albumin and globulin by a new method, J. Lab. & Clin. Med. 50: 728, 1957. Gollan, F.: Blood and extracellular fluid studies in chronic malnutrition in infancy, J. Clin. Invest. 27: 352, 1948. Menegbello, J., Niemeyer, H., Rosselot, J., Mardones, F., and Undurraga, O.: Evolucidn intrahospitalaria del lactante distrdfico menor de un afio, Rev. chilena de pediat. 23: 91, 1952. M6nckeberg, F., Beas, F., Horwitz, I., Dabances, A., and Gonz~lez, M.: Oxygen consumption in infant malnutrition, Pediatrics 33: 554, 1964. Cohen, S., and Hansen, J.: Metabolism of albumin and globulin in kwashiorkor, Clin. Sc. 23: 351, 1962. Waterlow, J., Cravioto, C., and Stephen, J.: Protein malnutrition in man, Advances in Protein Chem. 15" 131, 1960. Picou, D., and Waterlow, J.: The effect of malnutrition on the metabolism of plasma albumin, Clin. Sc. 22: 459, 1962. M6nckeberg, F., Donoso, G., Oxman, S.,
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Pak, N., and Meneghello, J.: Human growth hormone in infant malnutrition, Pediatrics 31: 58, 1963. M6nckeberg, F., Beas, F., and Perretta, M.: Estudio del metabolismo de los hidratos de carbono en el lactante distr6fico, Pediatria (Santiago) 2: 93; 1959. M6nckeberg, F., Manzur, F., and L6pez, M.: Algunos factores que influencian la absorci6n de grasas en el lactante distr6fico, Pediatria (Santiago) 1: 132, 1958. Lewallen, C., Berman, M., and Rail, J.: Studies of iodoalbumin metabolism. II. Effect of thyroid hormone, J. Clin. Invest. 38: 88, 1959. Ulrich, F., Tarver, H., and Li, C.: Effect of growth and adrenocorticotrophic hormone on the metabolism of albumin in the hypophysectomized rat, J. Biol. Chem. 209: 117, 1952. Miinckeberg, F., Barzelatto, J., Beas, F., and Waissbluth, H.: Captaci6n de iodo radioactivo por el tiroides en el lactante distr6fico, Rev. chilena de pediat. 28: 173, 1957. Beas, F., and M6nckeberg, F.: Thyroid response to TSH in infant malnutrition. To be published.