240 Burns, 9.240-248 Printed in Great Britain Serum and erythrocyte amino acid pattern: studies on major burn cases Chang Xiao-jun, Yang Chih-chun, Hsu Wei-shia, Xu Wei-zhen and Shih Tsi-siang Summary Venous serum amino acids were measured in 13 patients with major bums. Erythrocyte amino acids and plasma cortisol, blood sugar and urine catechol- amine were measured in two representative subgroups respectively. After bum injury, serum proline, glycine, valine, isoleucine and arginine were significantly de- creased; phenylalanine, cysteine, methionine, leucine, glutamate, alanine, aspartic acid and tyrosine were significantly increased. Histidine and lysine fluctuated. This serum amino acid profile is considered as a specific pattern for major bums. Serum phenylalanine was markedly elevated in the hypermetabolic bum patients, its fluctuation coincided with the bum course and was negatively correlated with serum albumin level (P<O.OOl). These findings suggest that the ratio of phenylalanine tyrosine is a useful clinical para- meter for assessing the patient’s nutritional condition. Twenty-three simultaneous determinations of both serum and erythrocyte amino acid concentrations show similar changes, suggesting that the serum ammo acid profile might reflect the change of total free amino acid pool. After bum injury, plasma cortisol, blood sugar and urine catecholamine were elevated as well as urine urea nitrogen. However, although the first three returned to normal by the end ofthe second week post bum, urine urea nitrogen remained high. This in- dicates that there are other factors controlling nitrogen loss in patients with major bums. it is also postulated that, due to the abnormal amino acid pattern revealed after major burns, the constituents of commercially available amino acid solutions should be modified. After bum injuries, following a short ebb phase, there is a protracted flow phase of hypermetab- olism (Wilmore et al., 1974; Wilmore, 1979). Profound negative nitrogen balance occurs as a result of marked catabolism. The large nitrogen losses through urine and the bum wound would give rise to acute protein malnutrition so long as intensive nutritional support is not avail- able. This may lead to delayed convalescence, impairment of wound healing, increased sus- ceptibility to infection and defective immuno- competence (Hiebert et al., 1979; Sheldon et al., 1979; Alexander et al., 1980). When the depletion reaches one-quarter to one-third of the lean body mass, a fatal outcome is predicted (Wilmore, 1979). The study of nitrogen balance has been a use- ful way to evaluate post-bum protein metab- olism. The data reported by many authors reached a consensus conclusion in this aspect. Further, the amino acid analyser enabled us to assess the individual amino acids and their dy- namic patterns at large in patients with massive nitrogen loss. The present study was designed to investigate the changes of amino acid pattern and hormone levels and their correlation with nitrogen loss in major bum patients. PATIENTS AND METHODS Thirteen burned patients with 46.1 f 19.5 per cent of total body surface area burned and 18.7_+ 14.8 per cent of third-degree bums were submitted to the present study (Table r). No metabolic disorders could be traced before injury, and none of these patients had other injuries. After resuscitation, they were fed a rou. tine hospital diet as soon as intestinal functior recovered. A total of about 3000 Kcal and 100 g protein was offered per day via enteral and par enteral routes. All patients survived except one who died of pulmonary embolism during the sixth week post bum. Serum amino acid concen trations, serum albumin and urine nitroget levels were determined on fixed days post bum
Transcript
240 Burns, 9.240-248 Printed in Great Britain
Serum and erythrocyte amino acid pattern: studies on major burn cases
Chang Xiao-jun, Yang Chih-chun, Hsu Wei-shia, Xu Wei-zhen and Shih Tsi-siang
Summary Venous serum amino acids were measured in 13 patients with major bums. Erythrocyte amino acids and plasma cortisol, blood sugar and urine catechol- amine were measured in two representative subgroups respectively. After bum injury, serum proline, glycine, valine, isoleucine and arginine were significantly de- creased; phenylalanine, cysteine, methionine, leucine, glutamate, alanine, aspartic acid and tyrosine were significantly increased. Histidine and lysine fluctuated. This serum amino acid profile is considered as a specific pattern for major bums. Serum phenylalanine was markedly elevated in the hypermetabolic bum patients, its fluctuation coincided with the bum course and was negatively correlated with serum albumin level (P<O.OOl). These findings suggest that the ratio of phenylalanine tyrosine is a useful clinical para- meter for assessing the patient’s nutritional condition. Twenty-three simultaneous determinations of both serum and erythrocyte amino acid concentrations show similar changes, suggesting that the serum ammo acid profile might reflect the change of total free amino acid pool. After bum injury, plasma cortisol, blood sugar and urine catecholamine were elevated as well as urine urea nitrogen. However, although the first three returned to normal by the end ofthe second week post bum, urine urea nitrogen remained high. This in- dicates that there are other factors controlling nitrogen loss in patients with major bums. it is also postulated that, due to the abnormal amino acid pattern revealed after major burns, the constituents of commercially available amino acid solutions should be modified.
After bum injuries, following a short ebb phase, there is a protracted flow phase of hypermetab- olism (Wilmore et al., 1974; Wilmore, 1979). Profound negative nitrogen balance occurs as a result of marked catabolism. The large nitrogen losses through urine and the bum wound would give rise to acute protein malnutrition so long
as intensive nutritional support is not avail- able. This may lead to delayed convalescence, impairment of wound healing, increased sus- ceptibility to infection and defective immuno- competence (Hiebert et al., 1979; Sheldon et al., 1979; Alexander et al., 1980). When the depletion reaches one-quarter to one-third of the lean body mass, a fatal outcome is predicted (Wilmore, 1979).
The study of nitrogen balance has been a use- ful way to evaluate post-bum protein metab- olism. The data reported by many authors reached a consensus conclusion in this aspect. Further, the amino acid analyser enabled us to assess the individual amino acids and their dy- namic patterns at large in patients with massive nitrogen loss. The present study was designed to investigate the changes of amino acid pattern and hormone levels and their correlation with nitrogen loss in major bum patients.
PATIENTS AND METHODS Thirteen burned patients with 46.1 f 19.5 per cent of total body surface area burned and 18.7_+ 14.8 per cent of third-degree bums were submitted to the present study (Table r). No metabolic disorders could be traced before injury, and none of these patients had other injuries. After resuscitation, they were fed a rou. tine hospital diet as soon as intestinal functior recovered. A total of about 3000 Kcal and 100 g protein was offered per day via enteral and par enteral routes. All patients survived except one who died of pulmonary embolism during the sixth week post bum. Serum amino acid concen trations, serum albumin and urine nitroget levels were determined on fixed days post bum
Chang et al.: Serum and Etythrocyte Amino Acid Pattern 24
Table !. Clinical data of the patients studied
Age Case Sex (yr) TBSA%
Third-degree burn area ( %j
Burn index Cause
1 M 51 41.5 23 32.3 Flame 2 M 54 76 38 57 Molten steel 3 M 27 34 26.5 30 Flame 4 M 31 30 6 18 Flame 5 M 19 35 18.5 26.8 Flame 6 M 24 49 15 32 Flame 7 M 46 25 19 22 Flame 8 M 29 89 0 44.5 Hot fluid 9 M 23 44 0.5 22.3 Hot fluid
10 M 30 46 37 41.5 Flame 11 F 39 40 0 20 Electric arc 12 M 23 64.5 44 54.3 Flame 13 M 29 25 15.5 20.3 Flame
TBSA%, Percentage total body surface area burned.
The 13 patients were further subdivided into two subgroups to investigate their intracellular amino acid content, serum cortisol, blood sugar and urine catecholamine. Subgroup I consisted of 5 cases (Cases 9-13, Table I). Free amino acid concentrations in red blood cells and RBC/plasma ratios were determined within I month post bum. Subgroup 2 comprised 6 cases (Chsrs 5,6,9-12) whose plasma cortisol, urine catecholamine and blood sugar were measured within 3 weeks post bum.
The serum amino acid concentrations of 22 normal adults and the amino acid concentration of red blood cells of another 8 normal adults were determined: both sets of values served as controls. The age and sex of the controls were compatible with that ofthe patients under study.
Fasting venous blood samples were obtained at 6.0 a.m. Serum samples were obtained by rou- tine treatment of the blood (Bremer et al., 198 1). Amino acid concentrations of erythrocytes were measured using a modified Hagenfeldt’s method (Hagenfeldt et al., 1978). In brief, 4 ml of blood were collected into the heparinized tubes and the sample was divided into 3 parts. The first part, I ml of blood, was diluted with an equal portion of distilled water, and shaken for 40 min on a microvibrator to haemolyse the RBC (Micro- vibrator jb-WII, Medical Analysing Instru- mentation Factory, Shanghai). Protein was precipitated by adding 75 mg of sulfosalicylic acid. Secondly, 1 ml of plasma (from 2 ml of heparinized blood) was treated by adding 40 mg sulfosalicylic acid for deproteinization. Lastly,
I ml of heparinized blood was used for the de- termination of haematocrit. After rapid centri- fugation (2400 R for 30 min), the supematants of the deproteinized samples were submitted for amino acid profile on a LKB 4400 amino acid analyser (LKB Company, Sweden). The concen- trations of free amino acids in erythrocytes were calculated by the following formula:
RBC,, = W B,, - ( I- HCT) P,,
HCT
where aa=amino acid, RBC=red blood cell, WB = whole blood, HCT = haematocrit and P=plasma.
Plasma cortisol was measured by radio- immunoassay (Shanghai Second Medical Col- lege 1978). Urinary catecholamine was measured by Huorophotometry (use epinephrine as standard) (Kuang and Chen, 1979).
RESULTS Normal values of free amino acid concen- trations in serum and erythrocyte The normal values reported by various authors are not consistent since the analysers and methods employed were different. In the present study, certain amino acids cannot be completely separated by using sodium citrate as eluent. Only 16 amino acids were identified. Histidine had been mixed with some other derivatives, so its concentration seemed higher than the results reported by other authors. It has been postulated that the concentrations of some amino acids
Tabl
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N
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137k
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Chang et al.: Serum and Erythrocyte Amino Acid Pattern 243
tend to be somewhat higher in serum than in plasma because of the breakdown of some small peptides during blood coagulation. However, in the present study of 8 normal adults, the values of plasma and serum amino acids were similar, except aspartic acid which showed a higher level in serum.
Most of the amino acid concentrations measured in red blood cells were higher than Hagenfeldt’s values. Since both the values of the RBC and the RBUplasma ratio were close, the results seemed to be reliable.
Dynamic changes of serum amino acids Compared with normal controls, the mean serum concentrations of proline, glycine, valine, isoleucine and arginine were significantly low- ered. Phenylalanine, cysteine, methionine, leu- tine, glutamate, alanine, tryptophan, aspartic acid and tyrosine were significantly elevated; histidine and lysine fluctuated. Significant changes only occurred during certain periods following burning (Tuhle II).
The serum phenylalanine/tyrosine (Phe/Tyr) ratio was dramatically elevated during the period of hypermetabolism. Immediately after the bum, the ratio rose rapidly and reached its peak by the second week, then gradually de- clined to normal following the healing or per- manent coverage of the wound (Fig. I). The linear regression equation showed negative cor- relations between Phe/Tyr ratio and the serum albumin level (P<O.OOl) (Fig. 2).
Serum zr ratio and burn course
0’. 01 3 7 14 21 iWCO”WY
Postburn days
Fix. I. Serum phenylalanine/tyrosine ratio and bum course.
Regression of Serum F$ ratio and albumln
7 = -0.8205 X + 3.8286 . P < 0’001
n = 64
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Serum al bumln ‘/dl
Fig. 2. Regression of serum phenylalanine/tyrosine ratio and albumin.
Relationship between serum and erythro- cyte amino acid concentration In subgroup I, a total of 23 determinations of erythrocyte amino acid concentration and RBUplasma ratio were made within 1 month post bum (Table ZZr). Among the 1 I amino acids assayed, valine was significantly decreased (P-c 0.00 I), isoleucine, leucine and aspartic acid were decreased to a certain degree and pheny- lalanine and glutamate were significantly in- creased (PC 0.00 1, PC 0.05). Methionine, ly- sine, glycine, tyrosine and alanine seemed to be elevated but without statistical significance. The ratios of RBUplasma of glutamate and glycine were elevated (PcO.05, P-cO.01). The ratio of Phe/Tyr in the red blood cells was also markedly elevated.
The changes of serum and erythrocyte amino acid patterns showed compatible changes. For example, in 23 simultaneous determinations of both erythrocyte and serum amino acids,
Tab/
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. E
ryth
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te
amin
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once
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tion
and
RB
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lasm
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tio a
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mol
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agen
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(n
=6)
(n=B
) (n
=23)
P
(n
=6)
(n=8
) (n
=23)
P
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euci
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nyla
lani
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sine
Asp
artic
ac
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Glu
tam
ate
G ly
cine
Ala
nine
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/Tyr
107
0.78
(9
3-12
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264
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713k
261
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19
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350
(258
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3 i8
3 57
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. (1
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1.72
) 2.
03
+ 0.
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f
1 .o
I P
<O.O
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259
(183
-363
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kO.2
5 n.
s.
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0.
79kO
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7 P
<O.O
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heny
lala
nine
/tyro
sine
ra
tio.
ns.,
not
sign
ifica
nt.
89 et al.: Serum and Erythrocyte Amino Acid Pattern 245
Tab/e IV. Comparison of the changes of serum and erythrocyte amino acid concentrations (n=23)
Plasma cortisol, blood sugar. urinary excretion of catecholamine and urea nitrogen
20.
lo-
Normal upper limit
Normal upper limit
01 3 7 14 21 postburn days
n1 =3 n1 =6 n, =6 n4 = 5
nzl = 4
nL =3 “3 =5 n, =5 “,* =4 n2, =4
“1 =2 ns =5 n, =6
n14 = 5
nzl = 5
F;%?_ 3. Plasma cortisol. blood sugar, urinary excretion of catecholamine and urea nitrogen.
246 Burns Vol. g/No. 4
phenylalanine and glutamate were significantly increased, valine was significantly decreased; the changes of other amino acids exhibited a similar tendency (Table ZV).
Plasma cortisol, blood sugar, urine catecho- lamine and urine urea nitrogen During the first 24 h post bum, the plasma cor- tisol and blood sugar levels rose rapidly, and then gradually declined after reaching their peaks. While urine catecholamine was sup- pressed within the first 24 h, it increased and reached its peak on the third day post bum. The levels of all factors tested fell and approached the normal upper limits by the tenth day post bum. At the end of the second week post bum, they returned to normal. Urinary excretion of urea nitrogen, however, remained high throughout the course of study (Fig. 3).
DISCUSSION The changes of plasma amino acids in bums have been reported by many authors (Groves et al., 1978; Aulick and Wilmore, 1979; Gu et al., 1981; Stinnett et al., 1982). Gu et al. (1981) and Stinnett et al. (1982) reported that, after severe bums, most of the plasma amino acids de- creased, including branched-chain amino acids, histidine, proline, threonine, serine, arginine, alanine and glycine; the total amount of amino acids was also decreased. Phenylalanine was constantly elevated; glutamate, aspartate, meth- ionine, hydroxyproline and glycine may also be increased. In the present study, the total amount of I6 amino acids showed no significant changes, indicating that in this category of patients, their serum and RBC amino acid values were within the limit of compensation; no evidence of acute protein malnutrition was revealed clinically.
The findings of the present study show that serum amino aids reveal a specific pattern after major bums. The decrease of proline, isoleu- tine, valine, glycine and arginine is compatible with the reports of other authors. Two weeks post bum, the branched-chain amino acid/total amino acid ratio (BCAA/TAA) was constantly lower than in normal controls, which was attri- buted to the relative decrease in the amount of branched-chain amino acids. The number of amino acids with elevated serum concentrations was greater than the previous reports (Gu et al., 1981; Stinnett et al., 1982), which may be accounted for by the fact that only bum patients of moderate severity were submitted to the present study. The amount of plasma amino
acids comprises only l-6 per cent of the total body amino acid pool (Felig, 1975). The great majority of free amino acids are located within body cells. The coincidence of serum and ery- throcyte amino acid in these cases suggested that the serum amino acid concentrations might reflect the changes of the total amino acid pool.
Cuthbertson (1930) concluded in his original study that the nitrogen lost after traumatic in- sults is derived from a general reserve rather than injured tissues. The studies of other authors documented that the skeletal muscle is the main source responsible for the nitrogen loss. Aulick and Wilmore (1979) found that the release of alanine from the skeletal muscle was very much enhanced after bums. The net release of 10 amino acids assayed reached more than fivefold of the normal control values. These findings illustrate that muscle protein is in a state of increased catabolism following bum injuries. Since branched-chain amino acids are metab- olized mainly in muscle, the oxidation rate de- termines the rate of muscle metabolism (Czaja et al., 1975; Wedge et al., 1976). In muscle, during oxidative degradation, the amino radical of branched-chain amino acid is transferred to pyruvate to form alanine. The latter is released to the circulation with other amino acids which cannot be utilized in muscle. On the other hand, aromatic and sulphur-containing amino acids are exclusively metabolized in the liver. Alanine, the key glucogenic amino acid, is also converted to glucose in liver. These amino acids would be increased in the presence of hepatic insufficiency. In a study of 8 1 bum patients with a bum area covering 4-96 per cent of their tota body surface area (mean 46.8 per cent), Czaja el al. (1975) found that 58 per cent of their patient! had clinical evidence of hepatic impairment probably resulting from a sharp fall of cardiac output, an increase in blood viscosity and di latation of splanchnic vessels, which contributes to the impairment of the hepatic perfusion.
Another characteristic change of amino acic profile in our study group is the decrease c glycine, proline and arginine levels, which i supposed to be the result of accelerated urea genesis. Kagan et al. (1982) demonstrated thz extensive bums are regularly associated wit increased urea production and impaired nitrc gen retention, and considered it to be the const quence of the hypermetabolic response to injur: In experimental animals, a rise of blood an monia was usually accompanied by a high levl of omithine, citrulline and acetyl-glutama (Saheki et al., 1978, 1980) and resulted
Chang et al.: Serum and Erythrocyte Amino Acid Pattern 247
an accelerated ureagenesis. Catalysed by trans- amidinase, glycine and arginine can be con- verted to ornithine and guanidinoacetate in kidney (Montgomery et al., 1977). Smith et al. (1967) showed that proline could be converted to ornithine via glutamic-y-semialdehyde in animal tissues. In brief, the specific post-bum amino acid pattern in major bums may refer to the excessive catabolism of muscle protein, increase of ureagenesis and some additive fac- tors resulting from hepatic insufficiency. This specific amino acid pattern differs from the post- operative pattern which is characterized by the increase of branched chain amino acids (Clifford et al., 1976: Askanazi et al., 1978; Askanazi, Carpentier et al., 1980; Askanazi, Furst et al., 1980).
Askanazi, Carpentier et al. (1980) Herndon et al. (1978) Wannemacher et al. (1976) and Wannemacher (I 977) found that serum Phe/Tyr ratio was elevated in traumatic and infective diseases and considered it to be an indicator of catabolism. The present study justified this find- ing: moreover, it was found that the fluctuation of serum Phe/Tyr coincided with the bum course. A negative correlation with serum albu- min level was also revealed, which indicated that the Phe/Tyr ratio is a reliable clinical parameter for assessing the patient’s metabolic situation. In liver, phenylalanine converted to tyrosine with the help of phenylalanine hydroxylase (Stanbury et al.. 1978). Herndon et al. (1978) showed that following the administration of phenylalanine, serum tyrosine level and the renal clearance of tyrosine were increased both in septic and non- septic bum patients and in normal controls. This fact indicated that there was normal hep- atic conversion of phenylalanine to tyrosine in these patients. The elevation of the serum PheiTyr ratio might be attributed to the in- creased release of phenylalanine from skeletal muscle. The present investigation reveals corre- lations between the bum course, the serum albumin and the dynamics of protein metab- olism.
In the present study. hormonal control of ni- trogen loss was observed. Besides the elevation of the two catabolic hormones (cortisol and cate- cholamine) and hyperglycaemia within IO days post bum. when the catabolic signals of cortisol, catecholamine and blood sugar had returned to normal by the tenth day post bum, the urinary excretion of urea nitrogen still remained high till the twenty-first day post bum. This finding suggested that there were factors other than cortisol and catecholamine which controlled
the nitrogen loss after major bums. Ryan (I 976) believes that there are three main factors affect- ing protein synthesis, namely hormone, amino acid supply and adequate fuel for cellular meta- bolic processes. Protein synthesis requires not only a variety of amino acids, but also a proper proportion of individual amino acids within the body cells, or else the process would be stopped. Under such circumstances, the amino acids will be either degraded as fuel or converted to glucose (Ryan, 1976). In other words, the quality of protein furnished might be more important than its quantity (Alexander et al., 1980). The respec- tive roles of each of the three main factors men- tioned above is still obscure, but the present study suggests that in patients with major bums amino acid therapy should be directed to rectify the abnormal pattern rather than to raise the total amount of free amino acids.
CONCLUSIONS There is a characteristic change of serum amino acid pattern in patients with major bums, which is considered to be the result of increased break- down of muscle protein, accelerated ureagenesis and relative hepatic insufficiency.
The fluctuation of serum Phe/Tyr ratio co- incides well with the bum course, and a negative correlation is found between serum Phe/Tyr and serum albumin concentration. This ratio may be a useful clinical parameter for assessing the patient’s nutritional condition.
The changes of serum and erythrocyte amino acids in patients with major bums are similar, which suggests that serum amino acid profile may reflect the changes of the total amino acid pool.
After major bums, plasma cortisol, blood sugar and urine catecholamine are elevated. The values return to normal by the fourteenth day post bum. Urinary excretion of urea nitrogen, however, remains high and does not return to normal even during the third week post burn. This indicates that there are other factors which control the nitrogen loss of bum patients.
According to the serum amino acid pattern assayed, the commercially available amino acid solutions should be modified to facilitate the rectification of the abnormal amino acid pattern.
Acknowledgements The authors wish to express their sincere thanks to Professor Chen Jia-lun, Dr Chang Da-qing and Associate Professor Li Li-qun for their ad- vice and help in this study.
248 Burns Vol. g/No. 4
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Paper accepted IO September 1982.
Corre.~pondence .shou/d hr urldre.wd 10: Professor C. C. Yang, Shanghai Second Medical College, 280 Chongquin Road Shanghai, People’s Republic of China.
