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Biochemical correlates of illness and recovery in Reye's syndrome.

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Biochemical Correlates of
Illness and Recovery in Reye’s Syndrome
Doris Trauner, M D , Lawrence Sweetman, PhD, Janette Holm, Stanko Kulovich,
and William L. Nyhan, MD, P h D
Eight patients with Reye’s syndrome were followed through the course of their disease with serial measurements of
serum concentrations of ammonia, short-chain organic acids, and amino acids. Correlations were made between
clinical status and biochemical alterations. Elevated short-chain fatty acids, hyperammonemia, and
hyperaminoacidemia were found in all patients studied. Clinical improvement appeared to correlate most closely
with clearance of short-chain fatty acids from the serum. These observations suggest that the clinical symptoms are at
least in part related to organic acidemia and that treatment directed toward the rapid clearance of these compounds
from the system is reasonable.
Trauner D, Sweetman L, Holm J, et al: Biochemical correlates of illness
and recovery i n Reye’s syndrome. Ann Neurol 2:238-241, 1977
A number of biochemical abnormalities have been
described in patients with Reye’s syndrome. These
include hyperammonemia 171, hyperaminoacidemia
[ 5 ] , elevated lipids [ 3 ] ,and abnormal muscle enzymes
[8], all of which have been mentioned as possible
contributors to the disease process or to prognosis.
We have recently reported consistent elevations in
serum concentrations of the short-chain fatty acids
(SCFA) propionate, butyrate, and isobutyrate in patients with Reye’s syndrome early in the course of the
disease [12]. SCFA have been shown to produce
coma, seizures, and electroencephalographic changes
in experimental animals [ I 1, 13, 141. It is possible that
they play a role in the pathogenesis of Reye’s syndrome. With early recognition of the disease, aggressive treatment, and consequent lower mortality, it has
been possible to study biochemical changes throughout the course of the disease and to correlate sequential changes with the clinical state. Serial concentrations of SCFA, amino acids, and ammonia in the
blood have been assayed and liver function tests performed from the time of diagnosis to recovery in 8
patients with Reye’s syndrome and in 2 others who
died. Clinical improvement was found to correlate
better with changes in the concentrations of SCFA
than with other biochemical correlates of illness.
Materials and Methods
A diagnosis of Reye’s syndrome was made in children who
had a history of preceding viral illness followed bp protracted vomiting progressing to seizures and coma, with
elevated blood ammonia concentrations and abnormal
serum glutamic oxaloacetic transaminase (SGOT) levels
From the Departments of Pediatrics and Neurology, University of
California, San Diego, School of Medicine, La Jolla, CA.
Accepted for publication Apr 5 , 1917.
238
(Table 1). Sepsis, meningitis, and ingestion of exogenous
toxins such as salicylates were ruled out with appropriate
laboratory tests. In Patient 8 a liver biopsy was performed
which showed characteristic small-droplet fatty accumulation. In the 2 patients who died, postmortem examination of
the liver confirmed the diagnosis. Five of the patients had
prolonged courses complicated by respiratory arrest. Eight
patients were in stage Ill or IV by the criteria of Huttenlocher 161; 2 were in stage I or I1 (see Table 1). Ages ranged
from 2 months to 7 years.
Serum SCFA were quantitated by the method of Adno et
al [ l ] and amino acids were measured using an amino acid
analyzer [lo].
Results
Serum concentrations of SCFA were elevated in all
patients on admission (Table 2). Initial levels tended
to be higher in the more severely ill patients (stages 111
or IV), although this was not uniformly true. Concentrations of SCFA displayed a gradual improvement
during the course of the illness, and o n the day when
each child was first noted to be clinically awake and
responsive, the levels of SCFA were grcatly decreased
compared to admission values (Table 3). By the time
of discharge from the hospital, concentrations of three
SCFA were no different from control values. Propionate and butyrate concentrations remained slightly
elevated.
Exchange transfusion was inconsistent in its effect
on concentrations of SCFA. In Patient I, for example,
SCFA concentrations were three to five times higher
after exchange transfusion and correlated with some
deterioration in the clinical state. Analysis of the
Address reprint requests ro Dr Trauner, Deparrment of Neurology, AID 8150, University of California Medical Center, San Diego, CA 92 103.
Parienr No.,
Age, and Sex
4 mu, F
1.
2.
3.
4.
5.
4mo,F
2 ino, A4
5 yr, F
2 mo, F
7 yr, F
4 yr, F
,4mo, F
2 yr. M
2 yr, M
6.
7.
8.
9.
10.
NHR
Glucose
( pgi:/dlj
( rngid I)
IV
I11
I
I1
?,ioo
111
111
5ji7
671
IV
IV
IV
356
162
30
11
22
86
18
87
129
Clinical
Stage“
1,200
320
167
[(,I.
NH,
=
ammonia; SGOT
13
33
38 1
1,500
IV
“By rhe criteria of Hutrcnlocher
= serum
36
BUN
SGOT
(IU)
(rngidl)
44 5
622
...
3 30
760
228
31 5
364
’20
840
serum glutamic oxaloaceric transaminase; BZJN
=
Outcome
19
11
28
Survived
Survived
Su wive d
17
Survived
Survived
Survived
21
20
14
81
14
26
___
Survived
Survived
Died
Died
blood urea nitrogen.
Table 2. Short-Chair1 Fatty Acid Concentrations at Admission in 10 Patients with Reyr’j Syndrome
Clinical
Patient
Stage
NO.
9
1V
1V
IV
IV
IV
111
10
8
7
1
2
5
6
IJ
4
I
3
HI
I11
Propionate
/.LIvl/Lj
Isobutyrate
____
( WMiL)
18.52
29.19
27.84
21.30
8.12
15.10
10.80
17.82
7.60
10.56
6.02
6.76
37.14
7.07
4.17
2.42
4.48
5.82
3.75
2.97
Butyrate
( /-lLM/L)
9.74
7.72
12.05
9.24
5.30
112.81
4.16
8.10
‘1.22
3.73
lsovalerate
(W I L )
Valerate
4.48
2.54
11.50
5.18
1.76
2.53
1.16
3.99
1.83
1.59
36.12
11.61
5 .96
5.42
3.72
93.43
7.65
3.24
28.74
14.58
( PWL)
th? Serum at I7arious Stages of Illmss
Table 3. CorzceiitratiotiJ of short-Chain O r g m i r Acids
ti?
Time of
Propionate
Isobutyrate
Dcrermination
( &l/Li
(PWL?
Buryrate
( IcLhliL)
(W I L )
Admission
(N = 8)
Day patient was
clinically awake ( N = 7)
14.89 & 2.51
p < 0.0005
8.87 t 1.29
p < 0.01
8.21 ir 1.18
p < 0.025
8.48 f 4.13
p < 0.05
2.47 +- 0.20
p < 0.025
1.77 0.25
NS
20.70 i 13.20
p == 0.1
5.24 ? 0.66
p < 0.005
5.31 i 0.54
p < 0.005
3.73 i 1.25
p .= 0.025
1.92 2 0.72
NS
1.41 t 0.30
NS
20.34
0.76
1.68 i 0.27
2.61 2 0.42
1.13 2 0.23
7.16
Day of discharge
( N = 6)
C o n t r o l s ( N = 10)
5.11
?
*
Isovalerate
Valerate
UMIL)
p
?
10.86
= 0.1
9.24 2 3.38
NS
7.52 i 2.19
NS
?
1.30
Values are given as mean -C standard error.
All p values represent results of patient versus control values, using the onc-tailed Srudent r-test.
NS
=
not significant
Trauner e t al: Biochemical lndicarors in Keye’s Syndrome 239
peritoneal dialysate in Patient 4 showed the presence
of SCFA in concentrations approximately one-third to
one-fourth those found in the patient’s serum.
In all 10 patients with Reye’s syndrome, initial concentrations of blood ammonia were elevated (see
Table 1). However, these concentrations did not appear to correlate with survival. O n e of the patients
who died had an initial value of 381 ,ug per deciliter,
while 2 survivors had initial levels of 2,500 and 1,200
,ug per deciliter, respectively. In all but 1 patient (No.
1) the blood ammonia concentrations fell to normal
range within one day of institution of therapy.
Serum concentrations of lactic acid were measured
in 3 patients, and initial values were markedly elevated. The mean was 11.52 mEq per liter compared
with a control mean of 1.73 mEq per liter ( p < 0.01).
Indicators of liver function (SGOT, serum glutamic
pyruvic transaminase, and prothrombin time) were
also elevated in all patients on admission and remained abnormal for most of the course. Hypoglycemia was present on admission in 7 of the 10 patients.
T h e concentrations of glucose in the cerebrospinal
fluid were low in 3 of the 4 patients in whom lumbar
puncture was performed initially.
Plasma concentrations of amino acids were measured in 2 of the 10 patients, as well as in 4 patients
studied earlier. Hyperaminoacidemia was present in
all these patients. The concentrations of glutamine
were extraordinarily high in 1 (160 mgidl; normal
range, 4.72 t o 9.20). Concentrations of lysine were
elevated at some time in each of the children studied.
Discussion
The opportunity to study serial biochemical correlates
of disease in patients with Reye’s syndrome has provided data bearing on several questions. It is clear that
a number of biochemical abnormalities occur simultaneously in this disease and may act synergistically to
create the sometimes devastating clinical course seen
in many patients. Five of the present patients were
infants, and in terms of their biochemical abnormalities, it is possible that they d o not reflect the
entire population of children with Reye’s syndrome.
However, ammonia and SCFA concentrations in
these infants were similar to those found in the older
children. The serum ammonia concentration does not
appear to correlate with survival or directly with the
clinical state. I n most cases the concentration of ammonia returned to near normal within 24 to 48 hours
after admission; clinical changes occurred independently. This observation differs from that of Shannon
et a1 [91, who found that arterial blood ammonia concentrations correlated with degree of clinical hyperventilation in patients with Reye’s syndrome. Liver
function tests remained abnormal for variable
periods. They appear to reflect simply the presence of
liver damage rather than specific progression of disease.
Hypoglycemia was present in 7 patients and may
have contributed to the initial symptoms and
biochemical alterations. However, serum glucose
concentrations were quickly returned to normal levels
without improvement in clinical state or reversal of
chemical abnormalities.
As reported earlier with Reye’s syndrome [ 5 ] ,
hyperaminoacidemia was present in 2 of the present
group of patients. Elevated concentrations of
glutamine and alanine appear to be a direct consequence of hyperammonemia, reflecting attempts by
the body to clear ammonia via the conversion of
glutamic acid to glutarnine and of pyruvic acid to
alanine. The elevation of lysine is not readily explained. It is possible that other abnormalities, such
as elevated levels of organic acids, could act as inhibitors of enzymes of amino acid catabolism. In fact,
propionic acid has been shown to inhibit ureageiiesis
in rat liver slices [’t].
The short-chain organic acids propionare, isobutyrate, isovalerate, butyrate, and valerate were consistently elevated in all patients studied. More importantly, in the patients who presented with the most
severe symptoms (stages IJI and 1V) and who had a
slow recovery, the progression from coma to wakefulness appeared to correlate with a sharp decrease in
SCFA concentrations. These observations are consistent with experimental evidence that certain
SCFA-notably buryrate, valerate, and octanoatehave produced coma, seizures, and electroencephalographic abnormalities when administered to
laboratory animals [ I 1, 13, 141.
It is possible that the seizures and coma seen in
Reye’s syndrome are directly related to short-chain
organic acidemia or to a combined effect of SCFA and
ammonia. Such synergistic effects in inducing coma
have been demonstrated in experimental animals
[ 151. Recovery may be partly dependent on clearing
SCFA from the blood. Exchange transfusion failed to
lower fatty acid levels consistently in our study. Insulin is known t o block the release of fatty acids from
adipose tissue and thus would prevent further exacerbation of organic acidemia [ 2 ] .It would seem at present that treatment with insulin and glucose is warranted in these patients. Early introduction of these
agents may block fatty acid release and permit the
body to clear the organic acidemia without the necessity of more vigorous intervention.
Supported in part by US Public Health Service Grant I-ID 04608
from the National Itistitute of Child Health and Developmerlt and
Grant MCT 000224 from the Health Services Division, Department of Health, Education, and Welfare.
W e wish to express our appreciation to Drs David Chadwick and
Alan Schumachcr of the Children's Hospital and Health Cenrer,
San Diego, and to Dr Irvin K a d m d n of U C S D , for their assistance
in obtaining samples. W e wish also to thank M r Jack Leslie for his
rechnical assistance.
References
1. Ando T, Rasmussen K, Nyhan WL, er al: Propionic acidemia in
patierits with ketotic hyperglycemia. J Pediatr 782327,107 1
2. Brown RE, Madge GE: Therapeutic considerations i n Reye's
syndrome. Pediatrics 4X:162-163, 197 1
3. Brown RE, Madge GE, Trauner D A , et al: Lipid and lipoprotein studies in Reye's syndrome. Va Med Mon 99:622, 1972
4. Glasgow A M , Chase HP: Effecrs ofpropionic acid 0 1 1 fiatry acid
oxidation and ureagenesis. Pediatr Res 10:683--686, 1976
5. Hilty MD, Romishe CA, Deiamater PV: Reye's syndrome and
hyperaminoacidemia. J Pediatr 8 4 : 3 6 - 3 6 5 , 1974
6. Huttenlocher PR: Reye's syndrome: relation of outcome to
therapy. J Pediatr 80:845-850, 13'2
7. Huttenlocher PR, Schwartz AD, Klarskin G: Reye's Fyndrome:
ammonia intoxication as a possible factor in the encephalopathy. Pediatrics 43:443-454, 1969
8. Roe CR, Schonberger LR, tielbach SH, et al: Enzymatic alterations in Reye's syndrome: prognostic implicarions. Pediatrics
>5:119-126, 1975
9. Shannon D C , D e h n g R, Bercu B, et al: Studies on the
pathophysiology ofencephahpathy in Reye's syndrome. Pediatrics 56:999-1004, 1775
10. Spackmari DH, Moore S, Stein WH: Automatic recording
apparatus (or use in the ihrornatography of amino acids. Anal
Chem 3O:I 130, 1958
11. Trauner DA, David RR, Madge GE, et al: Reye's syndrome and
free fatty acid induced coma (abstract). Pediatr Rcs 6 3 2 9 ,
1972
12. Trauner D A , Nyhan WL, Sweetman L: Short-chain organic
acidemia and Reye's syndrome. Neurology (Minneap)
25:296-298, 1975
1 3 . Walker CO, AlcCandltss DW, A4cG;lrry JD, et al: Cerebral
energy metabolism in short-chain fatty acid-induced coma. J
Lab Clin Med 76:569-583, 1970
14. White RP, Samson FE: Effects of fatty acid anions on the
electroencephalograms ot unanesthetized rabhirr. Am J
Phpsiol 186:271, 1966
15. Zieve FJ, Zieve L, Doizaki Whf, e t al: Synergism between
arnrnoriia and fatty acids in the production of coma: implicationa for hepatic coma. J Pharmacol Exp Ther 191:10, 1774
Trauner et al: Biochemical Indicators i n Reye's Syndrome 241
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