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The relationship of tryptophan and albumin in the acute burn patient: preliminary observations
174
Burns, 5, 174-180
Printedin GreatBritain
The relationship of tryptophan and albumin in the acute burn patient: preliminary observations V. R. Pennisi, V. M. Pennisi, J. Wyatt and A. Capozzi St Francis Memorial Hospital. Bothin Burn Center, San Francisco, California INTRODUCTION ONE of the most significant metabolic derangemerits in the acute burn patient is the sharp decrease in albumin synthesis and reversal of the a l b u m i n : g l o b u l i n ratio. This change in albumin heralds the severity of the insult and the catabolic phase, and when the albumin : globulin ratio reverts to normal and increased albumin occurs, the anabolic phase and repair is commenced. It has been demonstrated experimentally that the amino acid tryptophan has a direct influence on the stimulation of albumin synthesis in the liver. Therefore, it was postulated that if the tryptophan intake of the acute burn patient could be adequately supplemented in the diet, then albumin synthesis might be increased and the anabolic phase expedited. In the acute burn, albumin is diminished because of its loss to the interstitial spaces, decreased synthesis by the liver, a negative state of degradation and synthesis and skin losses. It is thought that the skin contains most of the albumin outside of the vascular system. The plasma contains 30-40 per cent of the moveable plasma. Albumin is important to the body and is frequently used by the burn therapist as a prime indicator of inadequate body repair or successful recovery of the burn patient. The chief functions of albumin are: to create homeostasis between the intravascular and extravascular fluids, to carry metals (zinc), ions, amino acids, enzymes and hormones and as a source of nitrogen. Albumin is manufactured in the liver by the hepatocyte at the rate of 12-14 g per day and its half-life is about 20 days. Nutrition is probably
~ mni utrsyptophan
Complete amino acids
/~
(~)
Dsiaggregated I Protesynt in hesis
monosomes
Amino acid supplies
\
Compelami te nacids o
~
Peptlde
or tryptophan alone
mRNA AIgProt gregaeteind
polysomes synthesis
Fig. 1. Diagrammatic representation of the synthesis of protein by the hepatocytes with tryptophan and the lack of protein synthesis without tryptophan. the most important contributor to albumin synthesis. There is protein deficiency in the acute burn case and probably a relative inability to convert amino acids into protein. It has been shown in animals that complete essential amino acids will stimulate albumin synthesis in the liver. However, when tryptophan is not included there is no increased albumin synthesis. Tryptophan apparently regulates the polysome patterns for protein synthesis. Before synthesis can occur, ribosomes must aggregate to form polysomes where messenger R N A is attached and transfer R N A will carry the amino acids into place for
Pennisi et al. : T r y p t o p h a n
[
I--'
Transaminase
L-tryptophan
\
Decarboxylase
Indolepyruvic
acid
Pyrrolase
Tryptamine
I
L-kynurenine
I
:
Nonamine oxidase
Decarboxytase
175
and A l b u m i n
* NAD
t-5-hydroxyr ty ptophan
1
Decarboxylase 5-hydroxytryptamine
Llndol ..... i c j acici
(5HT)
I
Nonamine
oxidase
1
5-hydroxyindoleacetic acid (SHIAA)
Fig. 2. Pathways for tryptophan metabolism. protein synthesis. The supply of complete amino acids which enter the hepatocytes regulates the ribosome aggregates leading to increased polysomes and therefore increased protein synthesis. Tryptophan alone will produce aggregation, but amino acids without tryptophan will not increase protein synthesis (Fig. 1). In rabbits, when dietary tryptophan was increased, there was a corresponding increase in albumin synthesis. We observed a similar phenomenon in the acute burn patient. This tryptophan-albumin relationship may be related to injury stress.
Gm%
Mcq/ml
8-
15
./" 7-
(Try) 14
,,,,,"""
13
5- ;/
2
12 Glob.
~ -
/
• T-Pro "'"
64 3
Tryptophan metabolism follows several pathways depending upon which enzymes are involved (Fig. 2). These enzymes are transaminase, decarboxylase, tryptophan hydroxylase, and pyrrolase (oxygenase). A most significant pathway is by the action of pyrrolase on liver trytophan. It is also reported that tryptophan has an altered diurnal pattern compared to other amino acids. That is, in the rat, amino acids display their maximum and minimum concentrations at 6 a.m. and 6 p.m., while tryptophan high and low occur at 2 a.m. and 2 p.m. This is probably not the result of oral intake, but can be explained by increased action of pyrrolase, increased uptake by tissues or by tryptophan binding to plasma albumin. In the rat during stress, there is increased pyrrolase activity in the liver and is probably mediated from the adrenal cortex. Exogenous tryptophan can increase pyrrolase activity, suggesting that there may be an equilibrium between plasma tryptophan and pyrrolase. This may account for the wide fluctuations of tryptophan when we administered large dietary supplements of this amino acid. Most tryptophan is albumin-bound and not available to tissues or metabolism. Only free tryptophan can be metabolized and free tryptophan can be increased by stress and food deprivation. It has been shown by Binazzi et at. (1974) that
,
~
11 10
AIb.
.1~-....~r
i
9 4
WEEKS a
'
i
4
WEEKS b
s
Fig. 3. a, A 29-year-old male, total burn 15 per cent, l l per cent third-degree and 4 per cent second-degree. No supplementary tryptophan administered. Note the relationship of total protein and albumin with the tryptopban curve (b).
176
Burns Voi. 5/No. 2
Mcq/ml
Gm%
14
T-Pro . - .~'
7
! 13 JF
,"
6
/
b
/
12
i
/
5 4
,.
Y) I
/
11 i
•"
Glob. /,
10
3 2
8
WEEKS a
WEEKS b
Fig. 4. a, A 39-year-old male with a 44 per cent mixed second- and third-degree burn. Note the direct relationships of albumin and tryptophan (b). This too is a control patient without tryptophan supplement. tryptophan metabolism after burns is probably limited to the pyrrolase route. These changes are verified by increased excretion of kynurenines, products of pyrrolase activity, and reduced excretion of anthranilic acids.
METHODS A N D RESULTS It was first necessary to standardize tryptophan determinations. This was done by the method of Denckla and Dewey (1967). Eight non-burned and not chronically ill patients were selected. Their blood samples were analysed for albumin and tryptophan to test the accuracy of the method. We then selected 10 burned patients with moderate second- and third-degree burns. Blood samples were taken from the time of admission twice weekly and determinations of total protein, albumin, globulin and tryptophan were done for a period of 4-6 weeks. These were accurately recorded in each patient's chart. Calorie counts, types of food ingested (tube feedings or oral intake) and dietary tryptophan were recorded. No tryptophan supplements were employed and a moderately high protein diet was administered. This diet contained 1-2 g of tryptophan daily. The results were most consistent. The admission a l b u m i n : g l o b u l i n ratios were relatively normal and the tryptophan levels (pg/ml) were consistent. However, this picture changed in the
first 7-10 days in which case the globulin increased and the albumin and tryptophan levels decreased. The total proteins also generally decreased. As the second and third weeks approached, albumin and tryptophan and total protein levels began to increase and the globulin levels as well. In the fourth and fifth weeks albumin, tryptophan and total protein continued to increase while the globulin level decreased or remained steady (Fig. 3). The relationship of total protein, albumin, globulin and tryptophan was plotted against time and the corresponding linear curves were consistent as stated. In the more severe burns the tryptophan-albumin curves followed the same pattern. Their ups and downs were related but of course the albumin : globulin ratio remained abnormal until much later (Figs. 4, 5). The next objective was to attempt to influence the tryptophan-albumin relationship by administering supplements of oral tryptophan. Tryptophan* is a white powder with a slightly bitter taste and not easily dissolvable. Attempts to disguise the taste in juices were unsuccessful. However, when it was mixed with ice cream it appeared to be very tolerable and patients *Tryptophan supplied by Hospital Diet Products Corporation, Liquidiet Formulas Division, Buena Park, California.
P e n n i s i et al. : T r y p t o p h a n a n d A l b u m i n
177
Mcc /ml
Gm%
6
,* ,, ,, T-Pro
5
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".
/ sS
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~
4
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]
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7
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..~... .....• ----'...
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.~. . . .
.....,
....z
,.." /
J.
|
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....,, .......... ,
.......
5
1
WEEKS
WEEKS
a
b
Fig. 5. a, A 29-year-old male with a 75 per cent burn, 40 per cent third-degree and 35 per cent second-degree. Note the similarity of the albumin curve with the tryptophan curve (b). In this severe burn the albumin : glo6ulin ratio remained reversed during his hospital course. No tryptophan supplement was used.
Gm% Mcq/ml _
T-Pro •
6
, ....
53
t
(~ry)
5 _
,AIb..• ." ",.
",.
.4
7]
j
b
"*.:¢f
WEEKS
a
WEEKS
b
Fig. 6. a, A 50-year-old female with a 35 per cent burn of mixed second- and third-degree. This patient was given 10 g of tryptophan daily after the first week. Note the albumin curve between the fifth or sixth week and the albumin: globulin ratio return to normal. This corresponds to the marked elevations of the plasma tryptophan (53 mEq/ml) (b).
178
Burns Vol. 5/No. 2 Mcq/ml
Gm% T-Pro
7 /
6
J /
5
12
/
,/"
11 .,
~
, / - ~ i ~ii/'~ ,. ~ J " ' J ' .................. :G
2
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'D"
/
4
13
Alb.
(Try)
10
Io b.
./ i4...''"'" v
8
._2
WEEKS a
WEEKS b
Fig. 7. a, A 24-year-old male with a 24 per cent mixed second- and third-degree burn. The patient was started
on 5 g of tryptophan daily shortly after admission. In the third week post burn the tryptophan was increased to 10 g daily. Note the elevated levels of plasma tryptophan (b) and the corresponding increase in albumin and normal albumin:globulin ratio by the fifth week. ingested the concoction easily. The dosage had to be established. The next 3 burn patients with moderately severe burns, primarily second-degree, were given 5 g of tryptophan powder daily in addition to their usual burn centre diet. The diet contained 1-2 g of tryptophan a day. The conclusion was that this amount of supplement had little effect on the tryptophan-albumin relationship and the plotted curves were no different from the previously described controls. In the next 10 patients the tryptophan supplement was increased to 10 g daily. It was soon noted that plasma levels of tryptophan in 8 out of 10 patients became markedly increased. This was 2-5 times that noted in the controls and those patients who were given only 5 g supplements. However, in most patients these drastic plasma levels resembled a septic fever linear curve. Interestingly there was also a corresponding increase and decrease in the albumin level in 8 out of 10 patients. Albumin fluctuations were not at all as drastic as tryptophan changes (Figs. 6, 7,
8), but they were obvious. All 10 patients were studied for periods of 4-8 weeks, or as long as they were hospitalized in the burn unit.
DISCUSSION In analysing the results of this study, we found that in the control burn patients there was a consistent direct relationship between tryptophan and albumin. In the first 7-14 days after a burn there is a period of marked catabolism, so that tryptophan and albumin are decreased and a reverse albumin : globulin ratio occurs. This is immediately followed by the anabolic phase in the third and fourth week as depicted by the gradual increase of albumin and tryptophan and a reversal of a l b u m i n : g l o b u l i n ratio back to normal. This timetable is fairly accurate in the mild to moderately severe burns. In the very severe burns, the same relationship occurs but the catabolic phase is prolonged and the anabolic phase is delayed. It appeared obvious that when the tryptophan supplement of 5 g daily was administered, little
Pennisi et al, : Tryptophan and Albumin
179
/
Mcq/ml
22
Gm%
11
7
,,,"
T-Pro
6
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4
I
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r
.h . . . .
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,
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..............
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i
i
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i
g
g
i
i
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i
i
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a
b
Fig. 8. a, A 25-year-old male with a 70 per cent burn primarily third-degree. This patient was started on 5 g of tryptophan daily, increased to 10 g daily in the fourth week. Note the marked increase in plasma tryptophan levels (b) and the increase in total protein. Albumin remained fairly steady and did not increase until after the eighth week. This patient was very septic which may account for his lack of albumin increase simultaneously with tryptophan. effect was noted. However, when tryptophan was added in amounts of 5-10 times normal or 10g daily, the plasma levels of tryptophan displayed marked peaks and valleys while albumin levels correspondingly increased and decreased, but of course to a lesser degree. The drastic fluctuations of tryptophan can be explained by the elaborate enzyme systems previously described which metabolize tryptophan. This especially applies to pyrrolase which is most active during stress. When tryptophan supplements are used, pyrrolase activity increases to reduce these high levels which may be harmful if allowed to remain elevated. There have been some reports that high doses of L-tryptophan may produce metabolites which may be bladder carcinogens. t-tryptophan is an essential amino acid present in high concentrations in meats and fish. It can be administered either in powder form or as a 250-mg tablet. It has recently been studied extensively as a hypnotic and anti-
depressant and found to be effective. Our overall impression was that patients in our study were generally more tranquil and certainly their nutritional status was better. There was less weight loss noted and sleep patterns appeared better than those not on the study. This observation occurs because tryptophan is a precursor of serotonin (5-hydroxytryptamine), a neurotransmitter that may be active in the sleepregulating mechanism. Nausea and vomiting can occur when high doses are used, although we did not have these adverse reactions in our dosage levels. Other toxic effects can be noted but only in very high doses.
CONCLUSION L-tryptophan is an essential amino acid which has a direct influence on albumin synthesis by the liver. Since albumin is a significant indicator of the repair process in the acute burn patient, this preliminary study was undertaken in an attempt to influence the albumin level and thereby enhance
180
and expedite the anabolic phase of the acute burn case. Although this study encompassed only a small series of patients, certain observations were made. In the acute burn patient, on the average diet containing 1-2 g of tryptophan, there is a direct relationship between plasma tryptophan and albumin. This is observed as decreased in the first and second weeks when hypercatabolism occurs and increased in the third to fifth weeks when the repair phase commences. When daily tryptophan supplements of 10g were administered orally, it was found that albumin levels could be favourably elevated, although only in modest increments. In general, the acute burn patient who was administered tryptophan supplements fared better nutritionally, their tranquillity was enhanced and their apprehension was reduced.
BIBLIOGRAPHY
Binazzi M., Calandra P. and Lisi P. (1974) Tryptophan metabolism in burns. Acta VitaminoI. Enzymol. (Milano) 28, 185. Curzon G. (1975) The control of tryptophan metabolism. Basic Life Sci. 6, 169. Denckla W. D. and Dewey H. K. (1967) The determination of the tryptophan in plasma, liver and urine. J. Lab. Clin. Med. 69, 160.
Burns Vol. 5/No. 2
Dunner D. L. and Goodman F. K. (1972) Effect of L-tryptophan on brain serotonin metabolism in depressed patients. Arch. Gem Psychiatry 26, 364. Harper A. E. (1973) Toxicants occurring naturally in foods. Washington, DC, National Academy of Sciences; National Research Council Committee on Food Protection, p. 142. Hartman E. (1977) L-tryptophan: a rational hypnotic with clinical potential. Am. J. Psychiatry 134, 366. Kirsch E., Saunders S. J., Frith L. et al. (1969) Plasma amino acid concentration and the regulation of albumin synthesis. Am. J. Clin. Nutr. 22, 1559. Rothschild M. A., Oratz M., Mongelli J. et al. (1969) Amino acid regulation of albumin synthesis. J. Nutr. 98, 395. Rothschild M. A., Oratz M. and Schreiber S. S. (1972) Albumin synthesis, Part i. N. Engl. J. Med. 286, 748. Rothschild M. A., Oratz M. and Schreiber S. S. (1972) Albumin synthesis, Part II. N. EngL J. Meal. 286, 816. Sidransky H., Bongiorno M., Sarma D, S. R. et al. (1967) The influence of tryptophan in hepatic polyribosomes and protein synthesis in fasted mice. Biochem. Biophys. Res. Comm. 27, 242. Sidransky H., Sarma D. S. R., Bongiorno M. et al. (1968) Effect of dietary tryptophan on hepatic polyribosomes and protein synthesis in fasted mice. J. Biol. Chem. 243, 1123. Wyatt R. J., Engelman K., Kupfer D. J. et al. (1970) Effects of 5-tryptophan (a natural sedative) on human sleep. Lancet 2, 842.
Requests for reprints should be addressed to: Mr V. R. Pennisi, 490 Post Street, San Francisco, California 94102, USA.
Burns, 5, 174-180
Printedin GreatBritain
The relationship of tryptophan and albumin in the acute burn patient: preliminary observations V. R. Pennisi, V. M. Pennisi, J. Wyatt and A. Capozzi St Francis Memorial Hospital. Bothin Burn Center, San Francisco, California INTRODUCTION ONE of the most significant metabolic derangemerits in the acute burn patient is the sharp decrease in albumin synthesis and reversal of the a l b u m i n : g l o b u l i n ratio. This change in albumin heralds the severity of the insult and the catabolic phase, and when the albumin : globulin ratio reverts to normal and increased albumin occurs, the anabolic phase and repair is commenced. It has been demonstrated experimentally that the amino acid tryptophan has a direct influence on the stimulation of albumin synthesis in the liver. Therefore, it was postulated that if the tryptophan intake of the acute burn patient could be adequately supplemented in the diet, then albumin synthesis might be increased and the anabolic phase expedited. In the acute burn, albumin is diminished because of its loss to the interstitial spaces, decreased synthesis by the liver, a negative state of degradation and synthesis and skin losses. It is thought that the skin contains most of the albumin outside of the vascular system. The plasma contains 30-40 per cent of the moveable plasma. Albumin is important to the body and is frequently used by the burn therapist as a prime indicator of inadequate body repair or successful recovery of the burn patient. The chief functions of albumin are: to create homeostasis between the intravascular and extravascular fluids, to carry metals (zinc), ions, amino acids, enzymes and hormones and as a source of nitrogen. Albumin is manufactured in the liver by the hepatocyte at the rate of 12-14 g per day and its half-life is about 20 days. Nutrition is probably
~ mni utrsyptophan
Complete amino acids
/~
(~)
Dsiaggregated I Protesynt in hesis
monosomes
Amino acid supplies
\
Compelami te nacids o
~
Peptlde
or tryptophan alone
mRNA AIgProt gregaeteind
polysomes synthesis
Fig. 1. Diagrammatic representation of the synthesis of protein by the hepatocytes with tryptophan and the lack of protein synthesis without tryptophan. the most important contributor to albumin synthesis. There is protein deficiency in the acute burn case and probably a relative inability to convert amino acids into protein. It has been shown in animals that complete essential amino acids will stimulate albumin synthesis in the liver. However, when tryptophan is not included there is no increased albumin synthesis. Tryptophan apparently regulates the polysome patterns for protein synthesis. Before synthesis can occur, ribosomes must aggregate to form polysomes where messenger R N A is attached and transfer R N A will carry the amino acids into place for
Pennisi et al. : T r y p t o p h a n
[
I--'
Transaminase
L-tryptophan
\
Decarboxylase
Indolepyruvic
acid
Pyrrolase
Tryptamine
I
L-kynurenine
I
:
Nonamine oxidase
Decarboxytase
175
and A l b u m i n
* NAD
t-5-hydroxyr ty ptophan
1
Decarboxylase 5-hydroxytryptamine
Llndol ..... i c j acici
(5HT)
I
Nonamine
oxidase
1
5-hydroxyindoleacetic acid (SHIAA)
Fig. 2. Pathways for tryptophan metabolism. protein synthesis. The supply of complete amino acids which enter the hepatocytes regulates the ribosome aggregates leading to increased polysomes and therefore increased protein synthesis. Tryptophan alone will produce aggregation, but amino acids without tryptophan will not increase protein synthesis (Fig. 1). In rabbits, when dietary tryptophan was increased, there was a corresponding increase in albumin synthesis. We observed a similar phenomenon in the acute burn patient. This tryptophan-albumin relationship may be related to injury stress.
Gm%
Mcq/ml
8-
15
./" 7-
(Try) 14
,,,,,"""
13
5- ;/
2
12 Glob.
~ -
/
• T-Pro "'"
64 3
Tryptophan metabolism follows several pathways depending upon which enzymes are involved (Fig. 2). These enzymes are transaminase, decarboxylase, tryptophan hydroxylase, and pyrrolase (oxygenase). A most significant pathway is by the action of pyrrolase on liver trytophan. It is also reported that tryptophan has an altered diurnal pattern compared to other amino acids. That is, in the rat, amino acids display their maximum and minimum concentrations at 6 a.m. and 6 p.m., while tryptophan high and low occur at 2 a.m. and 2 p.m. This is probably not the result of oral intake, but can be explained by increased action of pyrrolase, increased uptake by tissues or by tryptophan binding to plasma albumin. In the rat during stress, there is increased pyrrolase activity in the liver and is probably mediated from the adrenal cortex. Exogenous tryptophan can increase pyrrolase activity, suggesting that there may be an equilibrium between plasma tryptophan and pyrrolase. This may account for the wide fluctuations of tryptophan when we administered large dietary supplements of this amino acid. Most tryptophan is albumin-bound and not available to tissues or metabolism. Only free tryptophan can be metabolized and free tryptophan can be increased by stress and food deprivation. It has been shown by Binazzi et at. (1974) that
,
~
11 10
AIb.
.1~-....~r
i
9 4
WEEKS a
'
i
4
WEEKS b
s
Fig. 3. a, A 29-year-old male, total burn 15 per cent, l l per cent third-degree and 4 per cent second-degree. No supplementary tryptophan administered. Note the relationship of total protein and albumin with the tryptopban curve (b).
176
Burns Voi. 5/No. 2
Mcq/ml
Gm%
14
T-Pro . - .~'
7
! 13 JF
,"
6
/
b
/
12
i
/
5 4
,.
Y) I
/
11 i
•"
Glob. /,
10
3 2
8
WEEKS a
WEEKS b
Fig. 4. a, A 39-year-old male with a 44 per cent mixed second- and third-degree burn. Note the direct relationships of albumin and tryptophan (b). This too is a control patient without tryptophan supplement. tryptophan metabolism after burns is probably limited to the pyrrolase route. These changes are verified by increased excretion of kynurenines, products of pyrrolase activity, and reduced excretion of anthranilic acids.
METHODS A N D RESULTS It was first necessary to standardize tryptophan determinations. This was done by the method of Denckla and Dewey (1967). Eight non-burned and not chronically ill patients were selected. Their blood samples were analysed for albumin and tryptophan to test the accuracy of the method. We then selected 10 burned patients with moderate second- and third-degree burns. Blood samples were taken from the time of admission twice weekly and determinations of total protein, albumin, globulin and tryptophan were done for a period of 4-6 weeks. These were accurately recorded in each patient's chart. Calorie counts, types of food ingested (tube feedings or oral intake) and dietary tryptophan were recorded. No tryptophan supplements were employed and a moderately high protein diet was administered. This diet contained 1-2 g of tryptophan daily. The results were most consistent. The admission a l b u m i n : g l o b u l i n ratios were relatively normal and the tryptophan levels (pg/ml) were consistent. However, this picture changed in the
first 7-10 days in which case the globulin increased and the albumin and tryptophan levels decreased. The total proteins also generally decreased. As the second and third weeks approached, albumin and tryptophan and total protein levels began to increase and the globulin levels as well. In the fourth and fifth weeks albumin, tryptophan and total protein continued to increase while the globulin level decreased or remained steady (Fig. 3). The relationship of total protein, albumin, globulin and tryptophan was plotted against time and the corresponding linear curves were consistent as stated. In the more severe burns the tryptophan-albumin curves followed the same pattern. Their ups and downs were related but of course the albumin : globulin ratio remained abnormal until much later (Figs. 4, 5). The next objective was to attempt to influence the tryptophan-albumin relationship by administering supplements of oral tryptophan. Tryptophan* is a white powder with a slightly bitter taste and not easily dissolvable. Attempts to disguise the taste in juices were unsuccessful. However, when it was mixed with ice cream it appeared to be very tolerable and patients *Tryptophan supplied by Hospital Diet Products Corporation, Liquidiet Formulas Division, Buena Park, California.
P e n n i s i et al. : T r y p t o p h a n a n d A l b u m i n
177
Mcc /ml
Gm%
6
,* ,, ,, T-Pro
5
".
".
/ sS
"o
~
4
t
]
/~~lob...
",."
7
(Try)
3,.
2-
..~... .....• ----'...
/
.~. . . .
.....,
....z
,.." /
J.
|
AIb.
....,, .......... ,
.......
5
1
WEEKS
WEEKS
a
b
Fig. 5. a, A 29-year-old male with a 75 per cent burn, 40 per cent third-degree and 35 per cent second-degree. Note the similarity of the albumin curve with the tryptophan curve (b). In this severe burn the albumin : glo6ulin ratio remained reversed during his hospital course. No tryptophan supplement was used.
Gm% Mcq/ml _
T-Pro •
6
, ....
53
t
(~ry)
5 _
,AIb..• ." ",.
",.
.4
7]
j
b
"*.:¢f
WEEKS
a
WEEKS
b
Fig. 6. a, A 50-year-old female with a 35 per cent burn of mixed second- and third-degree. This patient was given 10 g of tryptophan daily after the first week. Note the albumin curve between the fifth or sixth week and the albumin: globulin ratio return to normal. This corresponds to the marked elevations of the plasma tryptophan (53 mEq/ml) (b).
178
Burns Vol. 5/No. 2 Mcq/ml
Gm% T-Pro
7 /
6
J /
5
12
/
,/"
11 .,
~
, / - ~ i ~ii/'~ ,. ~ J " ' J ' .................. :G
2
\
'D"
/
4
13
Alb.
(Try)
10
Io b.
./ i4...''"'" v
8
._2
WEEKS a
WEEKS b
Fig. 7. a, A 24-year-old male with a 24 per cent mixed second- and third-degree burn. The patient was started
on 5 g of tryptophan daily shortly after admission. In the third week post burn the tryptophan was increased to 10 g daily. Note the elevated levels of plasma tryptophan (b) and the corresponding increase in albumin and normal albumin:globulin ratio by the fifth week. ingested the concoction easily. The dosage had to be established. The next 3 burn patients with moderately severe burns, primarily second-degree, were given 5 g of tryptophan powder daily in addition to their usual burn centre diet. The diet contained 1-2 g of tryptophan a day. The conclusion was that this amount of supplement had little effect on the tryptophan-albumin relationship and the plotted curves were no different from the previously described controls. In the next 10 patients the tryptophan supplement was increased to 10 g daily. It was soon noted that plasma levels of tryptophan in 8 out of 10 patients became markedly increased. This was 2-5 times that noted in the controls and those patients who were given only 5 g supplements. However, in most patients these drastic plasma levels resembled a septic fever linear curve. Interestingly there was also a corresponding increase and decrease in the albumin level in 8 out of 10 patients. Albumin fluctuations were not at all as drastic as tryptophan changes (Figs. 6, 7,
8), but they were obvious. All 10 patients were studied for periods of 4-8 weeks, or as long as they were hospitalized in the burn unit.
DISCUSSION In analysing the results of this study, we found that in the control burn patients there was a consistent direct relationship between tryptophan and albumin. In the first 7-14 days after a burn there is a period of marked catabolism, so that tryptophan and albumin are decreased and a reverse albumin : globulin ratio occurs. This is immediately followed by the anabolic phase in the third and fourth week as depicted by the gradual increase of albumin and tryptophan and a reversal of a l b u m i n : g l o b u l i n ratio back to normal. This timetable is fairly accurate in the mild to moderately severe burns. In the very severe burns, the same relationship occurs but the catabolic phase is prolonged and the anabolic phase is delayed. It appeared obvious that when the tryptophan supplement of 5 g daily was administered, little
Pennisi et al, : Tryptophan and Albumin
179
/
Mcq/ml
22
Gm%
11
7
,,,"
T-Pro
6
P,.
[
5 /
4
I
12
r
.h . . . .
10
,
",
9
!
;
Glob.
..............
/i.* ....
8 7 6
i
i
:i
i
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g
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i
i
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WEEKS
a
b
Fig. 8. a, A 25-year-old male with a 70 per cent burn primarily third-degree. This patient was started on 5 g of tryptophan daily, increased to 10 g daily in the fourth week. Note the marked increase in plasma tryptophan levels (b) and the increase in total protein. Albumin remained fairly steady and did not increase until after the eighth week. This patient was very septic which may account for his lack of albumin increase simultaneously with tryptophan. effect was noted. However, when tryptophan was added in amounts of 5-10 times normal or 10g daily, the plasma levels of tryptophan displayed marked peaks and valleys while albumin levels correspondingly increased and decreased, but of course to a lesser degree. The drastic fluctuations of tryptophan can be explained by the elaborate enzyme systems previously described which metabolize tryptophan. This especially applies to pyrrolase which is most active during stress. When tryptophan supplements are used, pyrrolase activity increases to reduce these high levels which may be harmful if allowed to remain elevated. There have been some reports that high doses of L-tryptophan may produce metabolites which may be bladder carcinogens. t-tryptophan is an essential amino acid present in high concentrations in meats and fish. It can be administered either in powder form or as a 250-mg tablet. It has recently been studied extensively as a hypnotic and anti-
depressant and found to be effective. Our overall impression was that patients in our study were generally more tranquil and certainly their nutritional status was better. There was less weight loss noted and sleep patterns appeared better than those not on the study. This observation occurs because tryptophan is a precursor of serotonin (5-hydroxytryptamine), a neurotransmitter that may be active in the sleepregulating mechanism. Nausea and vomiting can occur when high doses are used, although we did not have these adverse reactions in our dosage levels. Other toxic effects can be noted but only in very high doses.
CONCLUSION L-tryptophan is an essential amino acid which has a direct influence on albumin synthesis by the liver. Since albumin is a significant indicator of the repair process in the acute burn patient, this preliminary study was undertaken in an attempt to influence the albumin level and thereby enhance
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and expedite the anabolic phase of the acute burn case. Although this study encompassed only a small series of patients, certain observations were made. In the acute burn patient, on the average diet containing 1-2 g of tryptophan, there is a direct relationship between plasma tryptophan and albumin. This is observed as decreased in the first and second weeks when hypercatabolism occurs and increased in the third to fifth weeks when the repair phase commences. When daily tryptophan supplements of 10g were administered orally, it was found that albumin levels could be favourably elevated, although only in modest increments. In general, the acute burn patient who was administered tryptophan supplements fared better nutritionally, their tranquillity was enhanced and their apprehension was reduced.
BIBLIOGRAPHY
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Dunner D. L. and Goodman F. K. (1972) Effect of L-tryptophan on brain serotonin metabolism in depressed patients. Arch. Gem Psychiatry 26, 364. Harper A. E. (1973) Toxicants occurring naturally in foods. Washington, DC, National Academy of Sciences; National Research Council Committee on Food Protection, p. 142. Hartman E. (1977) L-tryptophan: a rational hypnotic with clinical potential. Am. J. Psychiatry 134, 366. Kirsch E., Saunders S. J., Frith L. et al. (1969) Plasma amino acid concentration and the regulation of albumin synthesis. Am. J. Clin. Nutr. 22, 1559. Rothschild M. A., Oratz M., Mongelli J. et al. (1969) Amino acid regulation of albumin synthesis. J. Nutr. 98, 395. Rothschild M. A., Oratz M. and Schreiber S. S. (1972) Albumin synthesis, Part i. N. Engl. J. Med. 286, 748. Rothschild M. A., Oratz M. and Schreiber S. S. (1972) Albumin synthesis, Part II. N. EngL J. Meal. 286, 816. Sidransky H., Bongiorno M., Sarma D, S. R. et al. (1967) The influence of tryptophan in hepatic polyribosomes and protein synthesis in fasted mice. Biochem. Biophys. Res. Comm. 27, 242. Sidransky H., Sarma D. S. R., Bongiorno M. et al. (1968) Effect of dietary tryptophan on hepatic polyribosomes and protein synthesis in fasted mice. J. Biol. Chem. 243, 1123. Wyatt R. J., Engelman K., Kupfer D. J. et al. (1970) Effects of 5-tryptophan (a natural sedative) on human sleep. Lancet 2, 842.
Requests for reprints should be addressed to: Mr V. R. Pennisi, 490 Post Street, San Francisco, California 94102, USA.