Encephalopathy of Reye's Syndrome: A Review of Pathogenetic Hypotheses

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Encephalopathy

of Reye’s

Syndrome:

A Review

of Pathogenetic

Hypotheses

G. Robert

DeLong, MD, and Thomas H. Glick, MD

From the Massachusetts General Hospital, Harvard Medical School, Boston

ABSTRACT. The pathogenesis of Reye’s syndrome

en-cephalopathy was analyzed in terms of uniform criteria

designed to clarify and assist evaluation of the leading

hypotheses. Three of these hypotheses derive from

known metabolic sequelae of hepatic mitochondrial dys-function and the severe systemic catabolism of protein,

fats, and carbohydrates that characterize the syndrome

biochemically: hyperammonemia, hyperfattyacidemia,

and hyperlactatemia. In addition, there is a fourth hy-pothesis of generalized mitochondrial insult affecting

brain, muscle, and other organs as well as liver. The

weight of evidence favors hyperammonemia as a

suffi-cient factor while recognizing important

interrelation-ships with the other observed biochemical derangements.

How the catabolism and hepatic mitochondrial

dysfunc-tion are produced by the triggering viral infection remains

unknown. Therapeutic efforts have thus far not succeeded in definitive metabolic intervention. Such reversal of the

clinical syndrome would lead to confirmation of the

nec-essary pathogenetic factors; this type of intervention

re-mains the chief goal of metabolic research in Reye’s

syndrome. Pediatrics 69:53-63, 1982; Reye’s syndrome,

encephalopathogenesis, metabolic derangement, hyper-ammonemia.

The encephalopathy of Reye’s syndrome is re-versible, noninflammatory, and stereotypic in its early progression, and can be characterized as toxic

or metabolic. A characteristic liver pathologic

con-dition and the finding of hyperammonemia

sug-gested

a hepatic

encephalopathy

as the

cause.1

Later, the role of fatty acidemia became the subject

of much investigation.2 Recently, a generalized

in-terference with cell energetics, due to mitochondrial

dysfunction, has received increasing consideration.3

Despite considerable pathophysiologic research in

the last decade, the basis of the encephalopathy remains in contention. In particular, the

hyperam-Received for publication Feb 17, 1981; accepted April 13, 1981. Reprint requests to (G.R.D.) Massachusetts General Hospital,

Harvard Medical School, Boston, MA 02129.

American Academy of Pediatrics.

monemic hypothesis is accepted tacitly by some investigators while being virtually ignored by

oth-ers. For this reason we propose to review critically

the current knowledge of the metabolic

pathophys-iology of the encephalopathy, particularly with re-gard to hyperammonemia and other putative en-cephalopathogenetic factors. Our criteria for eval-uating a factor as a cause of the encephalopathy are as follows: (1) high frequency of occurrence of the factor in classical Reye’s syndrome; (2) positive correlation with the clinical characteristics and course, and, in particular, with (a) the time course of the essential clinical features of the

encephalop-athy, and (b) the severity of the clinical syndrome,

including outcome; (3) correlation with other bio-chemical derangements found in the disease; (4) correlation with pathologic markers; (5) close

anal-ogy with clinical syndromes of established patho-genesis; and (6) close analogy with relevant expen-mental models. Clinical response to a therapy spe-cific for a particular metabolic derangement would provide strong evidence regarding pathogenesis, but no such definitive effect has been documented.

Per-tinent evidence will be reviewed in “Implications for Therapy.”

HYPERAMMONEMIA

Background: Nitrogen Metabolism in Reye’s Syndrome

Patients with Reye’s syndrome are in a profound catabolic state, as shown by high total and urinary nitrogen excretions,4 resulting in a tremendous am-monia load requiring detoxification by the liver. At the same time, ammonia disposal via urea synthesis is impaired due to decreased activity of the two intramitochondrial enzymes of the urea cycle,

car-bamylphosphate

synthetase

(CPS)

and

ornithine

transcarbamylase (OTC).46 In two patients studied,

urea constituted only 20% to 40% of urinary

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extraor-54 REYE’S SYNDROME

dinary demand placed upon the liver, there is im-pairment of urea cycle function. One can invoke the

analogy of a catabolic cloudburst upstream leading

to a deluge of ammonia, at the same time that a

metabolic dam is interposed downstream. The re-sult, predictably, is a systemic hyperaminonemic flood.

Ammonia is taken up by the brain in patients with Reye’s syndrome, as shown by simultaneous

arterial and jugular vein ammonia concentrations

during the course of disease which reveal an acute

uptake of approximately half the ammonia in

cere-bral blood flow.7 CSF ammonia levels increase as

do levels of blood and CSF glutamine,7a the latter

indicating a degree of “buffering” of the cerebral

ammonia load. When the buffering capacity is

over-whelmed, brain function is profoundly affected by the excess ammonia burden, as will be summarized below from clinical and experimental evidence.

Incidence of Hyperammonemia

Hyperammonemia

ranks

as a biochemical

cnte-non for the diagnosis of Reye’s syndrome, is

vir-tually universal in cases of more than minimal

severity, and is a criterion for case ascertainment by the Center for Disease Control.8 Confusion may arise in mild cases from using venous, instead of

arterial, samples.

Correlation with Clinical Characteristics, Course, and Outcome

The time course of hyperammonemia correlates

closely with the course of the disease,1’9 except in

cases in which coma persists, due to irreversible

brain damage, after the ammonia level decreases to normal. Return of consciousness may lag for some hours after ammonia levels return to normal; this is

also seen in experimental hyperammonemia (see below).

The time sequence of events in Reye’s syndrome

helps clarify the pathophysiology. First there is

pernicious

vomiting,

then

confusion,

ataxia,

and

hyperventilation, which can all be explained by

hyperammonemia. At hospital admission the blood ammonia level may be at or near its peak, indicating

that its increase has occurred before or coincident

with the early symptoms. The pathologic condition of the liver, as judged by biochemical and biopsy findings, is well established by the time of admis-sion,’#{176}whereas the encephalopathy may not yet be

severe.”’2

Hyperammonemia correlates better with severity

of disease, as judged by clinical staging, than do

other measures that have been studied adequately. In the Michigan experience,’3 the blood ammonia levels of patients with Reye’s syndrome varied

di-rectly with the depth of coma and the grade of EEG

abnormality.

Hyperammonemia

correlates

closely

with

mor-tality, in the experience of many centers.’9”’5 No other metabolic factor correlates as well with

mor-tality, except possibly the blood levels of the amino

acids glutamate, glutamine, alanine, and lysine,’6

which are all closely related to ammonia metabo-lism. The Center for Disease Control,8 reporting 379

cases occurring in 1974, found that mortality was

21% in patients with peak blood ammonia levels

less than 200 .tg/100 ml, 63% with levels between 401 and 500 ig/100 ml, and 85% with levels greater than 800 g/100 ml. A significant increase in

mor-tality was noted when blood ammonia levels were

greater than 300 tg/10O ml; case fatality ratios were 27% (44 of 136) with peak ammonia levels less than

300 .tg/100 ml, and 65% (53 of 92) with levels greater

than 300 ig/100 ml. In our series of 21 patients,

arterial NH3 (mean ± SE) in 15 survivors was 739

± 613, and in six nonsurvivors 879 ± 399 (not

significantly different). However, half-time for

de-dine of hyperammonemia in the survivors was 9.3

± 4.5 hours, and in the nonsurvivors 19.7 ± 9.2

hours, a highly significant difference, giving evi-dence that greater total exposure to hyperammo-nemia correlated with greater mortality.’7

Hyperventilation in patients with Reye’s

syn-drome is proportional to the ammonia content of arterial blood,7 as is true in experimental

hyper-amm’8 Hyperventilation occurs with

hyper-ammonemia in both clinical7 and experimental’9 situations in the absence of systemic or CSF aci-dosis.

It has only recently become clear that hyperam-monemia produces increased intracranial pressure and cerebral edema. In patients dying of acute hepatic necrosis reviewed by Ware et al,2#{176}cerebral edema was present in the majority of cases, with increased intracranial pressure being the immediate cause of death. Fatal increases in intracranial pres-sure and cerebral edema are found in infants and children with congenital urea cycle enzyme defi-ciencies and severe hyperammonemia,2’ consistent with the experience in Reye’s syndrome. The greater mortality with higher peak ammonia levels is associated with more severe increased intracra-nial pressure.

Correlation with Other Biochemical Parameters

The massive quantitative brain uptake of am-monia correlates directly with calculated excess jugular venous lactate content,7 a measure of lactic acid production by brain. Excess jugular vein lac-tate production

also

correlated with mortality. These findings parallel those of Hindfelt and

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Siesjo22

in animal

studies

of ammonia

intoxication,

who found a marked increase in brain and CSF lactate/pyruvate ratios, proportional to the dose of

administered ammonia. These animal studies were

carefully controlled to rule out effects of

hypoper-fusion, hypoxia, hypocapnia, or increased intracra-nial pressure.2225 Hyperventilation alone can result

in increased CSF lactate content,26 but experimen-tally induced hyperventilation has not resulted in

elevated jugular venous lactate approaching the

magnitude of that seen with hyperammonemia

sec-ondary to ammonia infusion.232427 The distinctive

amino acid pattern in Reye’s syndrome is similar to that seen with congenital OTC deficiency, in which

it is associated with hyperammonemia.28

Neuropathologic Markers of Hyperammonemia

One of the principal arguments against

hyper-ammonemia as the cause of the encephalopathy of

Reye’s syndrome has been the claim that the elec-tron microscopy of brain biopsies in Reye’s syn-drome shows changes different from and

inconsist-ent with those caused by hyperammonemia. There are no adequate electron microscopic studies of human acute hepatic or hyperammonemic enceph-alopathy, although the postmortem observations on

the poorly defined cases of Martinez are not

incon-sistent

with those of experimental acute portal-sys-temic encephalopathy.’3#{176} In a study by Partin et

al,3’-32 patients with Reye’s syndrome in whom

biop-sies were performed not only had marked

hyper-ammonemia (731 and 760 tg/100 ml on admission

in two cases); the biopsies also showed “swollen” astrocytes with normal mitochondria, as in

experi-mental hyperammonemia. In addition, follow-up

biopsies

43 to 75 days later showed numerous re-active protoplasmic astrocytes equivalent in de-scription to Alzheimer type II astrocytes, the neu-ropathologic hallmark of late hepatic and

hyper-ammonemic encephalopathy.’ Myelin blebs, seen

in the biopsies from patients with Reye’s syndrome, were not seen in the comparison material. In sum,

the available brain biopsies from patients with

Reye’s syndrome show changes consistent with

hy-perammonemia,

both acutely and at follow-up, but with the additional finding of myelin blebs.

Analogy to Related Hyperammonemic Syndromes

In congenital ornithine transcarbamylase

defi-ciency,

the clinical

manifestations

are directly cor-related with hyperammonemia. Symptoms of this

disease

are vomiting, coma, hyperventilation, and

increased intracranial pressure, as for Reye’s

syn-drome, with comparable levels of

hyperammone-mia.2’ .34-36 Hyperammonemia secondary to urinary

tract infection with Proteus mirabilis produced the same syndrome, including hyperventilation and res-piratory alkalosis, at comparable levels of

hyper-ammonemia.37 We recently encountered a 5-year-old child with carbamylphosphate synthetase defi-ciency who developed hyperammonemia and lapsed

into coma on three separate occasions. During the

third episode, with protracted hyperammonemia

(360 to 680 zg/1O0 ml) but no acidosis, anionic gap,

or elevated SGOT level, he developed intractable cerebral edema and died. The neurologic manifes-tations were indistinguishable from those of Reye’s syndrome.

Relevant Experimental Models

Experimental hyperammonemia in animals re-produces features of Reye’s syndrome (see above). Hyperventilation is linearly related to brain am-monia content in experimental animals rendered hyperammonemic,’8 and cerebral excess lactate

pro-duction correlates directly with the degree of

by-perammonemia.22

Kindt

et al39

found

in monkeys

and cats that ammonia infusion led to increased intracranial pressure. Intracranial pressure (ICP) increased to two to three times the normal levels when serum ammonia increased to 500 to 800 ig/ 100 ml, and remained elevated for 12 hours beyond the last infusion and six hours after the serum

ammonia level had returned to normal. Sudden

intracranial

pressure

waves

or spikes

were

also

ob-served. Animals that recovered completely follow-ing prolonged infusions of ammonium acetate (3 mEq/kg/hr) demonstrated an exaggerated increase of ICP after only one hour of reinfusion at the same rate. In rats with ammonia infusion leading to in-creased intracranial pressure, they found no in-crease in tissue water content, and suggested that

the increased intracranial pressure was due to

in-creased blood volume caused by impairment of

vascular autoregulation at NH3 levels <750 zg/1O0

nil.4#{176}(This same group has recently reported that

computed tomography [CT] scans in patients with

Reye’s syndrome demonstrated marked increase in

vascularity, suggesting vasodilatation.4’42)

What-ever the mechanism, it seems clear that

experimen-tal hyperammonemia causes increased ICP, that

the severity of increased ICP is related to the

du-ration as well as the severity of hyperammonemia, and that the increased ICP may outlast the hyper-ammonemia.

Implications for Therapy

The hypothesis ofhyperammonemic

encephalop-athy has suggested a range of possible therapeutic

approaches. Unfortunately, these have not been

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none-56 REYE’S SYNDROME

theless worth scrutiny. Therapies aimed at direct removal of ammonia have not been proved

effec-tive.47 Metabolic therapies aim to decrease am-monia production or stimulate its disposal and

de-toxification. Avoiding the use of corticosteroids and

provision

of ample

glucose

may

diminish

protein

catabolism.43

The

use of neomycin

or lactulose

and

prevention of gastrointestinal bleeding minimize ammonia production by the gut.

Measures to increase disposal of ammonia have been, as yet, insufficiently evaluated. Thaler pro-posed that, if ornithine is rate limiting for OTC in patients with Reye’s syndrome, the addition of as-ginine or ornithine would increase ammonia flux into urea. He suggested that patients with high orotic acid excretion have their major block at OTC, and therefore might be helped by administration of ornithine. However, most patients with Reye’s syn-drome do not have increased orotic acid excretion,49 and thus presumably have a block of CPS in addi-tion to OTC. Good et al#{176}infused a patient with

glutamate-arginine; despite elevations of glutamic

acid, argimne, and ornithine, no increase in

citrul-line

was seen-suggesting that OTC block was not overcome by additional ornithine.

Citruffine would appear to have a key metabolic role in ammonia disposal in Reye’s syndrome. It is the product of OTC, which is deficient acutely in Reye’s syndrome,4 and is necessary for transfer of one amine group from aspartate (derived from

am-monia) to urea. Serum citrulline is generally low or undetectable in patients with Reye’s syndrome,5’M and mean serum aspartate is increased fivefold.

Citrulline,

after picking up an ammonia nitrogen from aspartate, is metabolized to arginine, urea, and omithine.4 The net result of adding 1 mole of ci-trulline should be to convert 1 mole of ammonia via aspartate to urea-that is, to permit the urea cycle to function at 50% efficiency. A beneficial effect ultimately depends on the capacity for added ci-trulline nitrogen to find a fate other than generation of ammonia, such as increased pools and excretion

of arginine, ornithine, and glutamate; argimne

di-version to protein synthesis; and ornithine diversion to putrescine and other compounds. Ammonia gen-eration from glutamate, and thus from ornithine via

ornithine-a-ketoglutarate

transaminase,

may

be

blocked because of the decreased activity of

glu-tamic dehydrogenase.55 Increasing the liver content of arginine may increase CPS activity by stimulat-ing the synthesis of N-acetylglutamate, the essen-tial cofactor of mitochondrial CPS. In short, it is not possible to predict a priori the overall metabolic effect of added citrulline in Reye’s syndrome. Our experience with citrulline administration in eight patients demonstrated an accelerated decline of

blood anunonia levels.752u The half-time for de-crease of blood ammonia levels was 8.7 ± 5.6 hours in the treated patients, and 20.3 ± 8.1 hours in a

comparable group of patients treated without ci-trulline. The urine ammonia/urea ratio, elevated in patients with Reye’s syndrome, reverted to normal more rapidly after citrulline administration.’7 The

curves for ammonia decline with citrulline admin-istration-but not without-closely approximated

first-order decay, suggesting that citruffine stimu-lated a first-order removal process. Further quan-titative and dynamic data of this kind are needed to evaluate proposed metabolic treatments.

Sodium benzoate, which may metabolize ammo-nia via the hippuric acid pathway, deserves inves-tigation in Reye’s syndrome,47 as do a-keto acids,

which have been shown to decrease

hyperammo-nemia transiently in congenital hyperammonemic synthomes.57’

FATTY AND ORGANIC ACIDEMIA

Background

The characteristic fatty infiltration in the liver consists of microvesicular droplets of triglyceride and appears to result from increased lipolysis in

adipose

stores

and impaired

hepatic

metabolism

of

the constituent fatty acids. The proffle of elevated serum free fatty acids and the fatty acid moieties of

the accumulated hepatic triglycerides reflect the fatty acid composition of the mobilized adipose stores.59

Incidence of Abnormal Free Fatty Acidemia

Increased serum concentrations of free fatty acids, especially medium- and short-chain fatty acids, are consistently found in Reye’s

syn-thome.’#{176}6’ Trauner et al62 found modest elevations

(approximately

twice

normal)

of the

short-chain

fatty acids propionate, butyrate, isobutyrate, iso-valerate,

and

valerate in all ten patients with Reye’s syndrome studied.

Correlation with Clinical Course

Elevations of free fatty acid levels are found early in the course of the syndrome.62 Initial levels tend to be higher in more severely ifi patients, but this is not uniformly true. Short-chain fatty acid levels tend to decrease concurrently with the progression from coma to wakefulness in children who improve,

but levels also tend to normalize regardless of out-come. As noted below, high fatty acid levels de-crease rapidly almost to the normal range after glucose and insulin infusion, but without

corre-sponding clinical improvement.62

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Correlation with Other Biochemical Abnormalities

We are not aware of studies directly correlating levels of free fatty acids with concentrations of

lactate, degree of abnormality of amino acid

pat-terns, abnormalities of CSF composition or acid-base status, or hyperammonemia.

Correlation with Pathologic Markers

Concentrations of fatty acids have not yet been

studied in relation to cerebral neuropathologic

markers in humans, but there is relevant experi-mental evidence, as indicated below.

Analogy with Other Relevant Clinical Syndromes

Elevated free fatty acid levels are seen in

condi-tions not associated with encephalopathy, including

starvation; if children fast for 20 hours free fatty

acid levels as high as those in Reye’s syndrome are seen, without production of encephalopathy.

There has been some interest in proposing or-ganic acidemias as models or analogues for Reye’s

syndrome. These diseases are characterized by

vomiting, depression of consciousness, acidosis, and

in some cases, by hyperammonemia. Trauner et al62 found that mean serum concentrations of propio-nate and isovalerate in Reye’s syndrome were

two-fold higher on admission than when the child awak-ened. These moderate elevations must be compared with patients having inherited isovalericacidemia in whom a serum level of 340 .tmoles/liter produced only stupor (vs 3.73 .tmoles/liter mean level in patients with Reye’s syndrome on admission). Sim-ilarly, Hommes et al found a serum propionate level of 5400 tmoles/liter, a 1,000-fold elevation above normal, in a neonate with severe propionic-acidemia; by comparison the patients with Reye’s syndrome of Trauner et al62 had a mean serum level at admission of 14.89 tmoles/liter (twice normal).

Hyperammonemia in propionic acidemia may be

related to inhibition of ureagenesis, as shown by Glasgow and Chaseu in vitro with high propionic-acid concentration (5,000 .tmoles/liter); however,

these authors found no specific inhibition of CPS

or OTC, the activities of which are decreased in

Reye’s syndrome. Recently, Stumpf et al67 have

investigated the effect of propionate on

mitochon-drial oxidative metabolism, also using high concen-trations (400 to 4750 zmoles/liter); they found in-hibition of succinate coenzyme A (CoA) ligase, an

enzyme of the citric acid cycle, and suggested this might produce a syndrome similar to Reye’s as seen in propionicacidemia. Of note, no interference was found with pyruvate oxidation, whereas in Reye’s

syndrome such interference is shown both by hy-perlactatemia and decreased activity of pyruvate

dehydrogenase.

The overall biochemical picture of the organic acidemias is quite different from Reye’s syndrome. Symptoms of isovalericacidemia include acidosis with low pH, ketonemia, and ketonuria; the clinical findings including encephalopathy are also milder.’69 Symptoms of propionicacidemia include severe acidosis (a pH of 6.98 has been reported), massive hyperglycinemia, ketosis, and intermittent elevations of leucine, isoleucine, and valine70; none of these is characteristic of Reye’s syndrome.

Pos-sibly several organic acids each at modestly ele-vated levels may produce additive or synergistic effects, but we know of no evidence in this regard.

Relevant Experimental Models

Trauner and Huttenlocher7’ studied the effect of experimental octanoate infusion in rabbits and achieved serum concentrations comparable to those in patients with Reye’s syndrome. EEG changes and changes in consciousness were minimal. Hy-perventilation was marked after 30 minutes of oc-tanoate infusion. There were moderate elevations of ammonia and lactic acid (2#{189}times control). Pathologic studies of brain showed no evidence of cerebral edema. In sum, this study demonstrates a mild pathologic effect of octanoate. However, the

contrast to the overwhelming encephalopathy with

coma and cerebral swelling of Reye’s syndrome is more impressive than the similarities.

Implications for Therapy

Trauner et al62 suggested that insulin and glucose treatment should be given to block the release of free fatty acids; after glucose and insulin infusion, the extremely high fatty acid levels decreased rap-idly almost to the normal range, but without cor-responding clinical improvement. The same inves-tigators found a disproportionate increase in octa-noate which

also

was reduced to a normal

propor-tion after glucose and insulin treatment, again with-out obvious clinical improvement. Insulin treat-ment has not altered the mortality when used in a large group of patients with Reye’s syndrome.’5

Nevertheless, interactions between fatty acids

and ammonia metabolism deserve study in Reye’s

syndrome, and may provide a rationale for therapy to reduce fatty acidemia. Derr and Zieve72 have shown that ammonia and fatty acids act

synergis-tically to produce coma in experimental animals, and demonstrated that added fatty acids inhibited

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impor-58 REYE’S SYNDROME

tant effector of CPS activity.56 The inhibitory effect was greater the longer the fatty acid chain.

Gluta-mate dehydrogenase was likewise inhibited in liver and brain. Thus, the two main processes whereby ammonia is metabolized were inhibited by fatty acids at concentrations that exist pathologically, accounting, at least in part, for the increase in blood ammonia levels in vivo.

GENERALIZED DERANGEMENT OF

MITOCHONDRIAL STRUCTURE AND FUNCTION Background

The pathogenetic hypothesis of a widespread pri-mary mitochondrial disease in Reye’s syndrome implies that the same factor affecting liver mito-chondria also directly affects mitochondria in many organs, including brain. It is noteworthy that most

organs function surprisingly well in patients with

Reye’s syndrome. The concept of general

mitochon-drial disease lacks specificity and is difficult to deal with in practical terms: mitochonch-ia in different organs and cells differ in constituent enzymes and may be differentially affected. Mitochondrial

func-tions are multiple and complex; any one or a corn-bination of enzymes or functions may be impaired, with differing consequences. Furthermore, it is

nec-essary to define whether one is using morphologic,

enzymatic, or metabolic criteria of derangements,

and, finally, whether the mitochondrial dysfunction

in each instance is primary or secondary. Given these difficulties, we will review evidence relating to the mitochondrial hypothesis.

Incidence and Distribution of Mitochondrial

Injury

The mitochondrial changes in hepatocytes, as seen by electron microscopy, can be taken as a reference point, and summarized as follows’0: matrix expansion and disorganization, progressive loss of

matrix dense bodies, mitochondrial pleomorphism,

gross swelling, and late outer membrane rupture. In studies of muscle ultrastructure,73 two separate mi-tochondrial populations could be identified. One group, representing the majority of mitochondria, has moderate matrix swelling and slight to moder-ate alteration of matrix density. A minority of mi-tochondria show more severe effects consisting of frank disruption of the mitochondrial matrix. Lim-ited studies of cardiac muscle and pancreas have

shown mitochondrial changes said to be similar to those reported in liver.74

Whether brain mitochondrial structure and

func-tion are affected in the same way as in liver is obviously a central issue to the problem of

enceph-alopathy. The available ultrastructural evidence comes from studies by Partin et al32 on brain biopsy material from three children with Reye’s syndrome treated by crarnectomy for intractable cerebral edema. All had attendant damage from hypoxia and/or ischemia as judged by residual deficits. Two of these three grade IV patients suffered respiratory arrest, and one was in shock, before the brain

bi-opsy. For comparison, there is available the made-quate postmortem ultrastructural study of Marti-nez’#{176}on two cases of human hepatic encephalopa-thy, and that of experimental primate ammonia

intoxication. In all three materials, astrocytes, al-though prominently swollen, had normal mitochon-dna, and capifiary endothelial cells were normal with normal mitochondria. In neurons, Partin et al’#{176}found the change considered most critical: The mitochondria were described as “pleomorphic, with irregular outline of the mitochondrial outer mem-brane and matrix rarefaction, without cristal alter-ation.” These changes were much milder, with much less disruption of architecture, than those described in hepatic cell mitochondria by the same workers.’#{176} Interpretation of these neuronal changes is obscured by possible hypoxic and ischemic

fac-tors. Despite these uncertainties, it is noteworthy that astrocytes, the cells most affected in the Reye’s syndrome biopsy material, have mitochondria that appear normal, arguing that a primary mitochon-drial lesion is not the cause of astrocytic swelling. Likewise, the finding of normal capifiary endothelial

cell mitochondria is interesting in light of specula-tion that an insult to them might account for cere-bral edema.3

A second line of evidence regarding mitochon-drial derangement derives from direct assays of the activity of intramitochondrial enzymes. In liver, mitochondrial enzymes show decreased activity during the acute phase of ifiness, but later return to normal regardless of the clinical course. In addition to the decreased activity of the mitochondrial en-zymes of the urea cycle,46 Robinson et al55 found that five other hepatic mitochondrial enzymes were well below normal limits in activity; these were citrate synthase, succiic dehydrogenase, glutamic dehydrogenase, pyruvate carboxylase, and pyruvate

dehydrogenase. The activities of two cytoplasmic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, were in the normal range. In both brain and muscle homogenates, the activities of the mitochondrial enzymes citrate synthase, glutamic dehydrogenase, and succinic dehydrogenase were

all within normal limits. Thus, direct enzymatic evidence indicates that most brain mitochondria

.function normally in patients with Reye’s

syn-drome, consistent with the electron microscopy ob-servations discussed above.

(7)

Correlation with Clinical Course and Outcome

The hepatic mitochondrial changes have been found to correlate in a general way with the severity of glycogen depletion and with the stage of enceph-alopathy. As previously indicated, the mitochondria revert to normal morphology if time permits, re-gardless of the cerebral outcome.

Correlation with Other Known Biochemical Derangements

A failure of oxidative metabolism due to

mito-chondrial dysfunction should result in a deficiency of adenosine triphosphate (ATP). One study of hepatic tissue content of ATP indicated no

signif-icant decline,75 but measured levels may have been less than customary controls in at least one other laboratory.3 The blood

$-hydroxybutyrate/aceto-acetate ratio, a measure of mitochondrial

oxidation-reduction potential, was normal in patients with Reye’s synthome.

Stumpf and Parks76 have proposed that hyper-ammonemia is a secondary event, caused by a

mi-tochondrial energy deficiency state, and that it re-sults from removal of orithine from the urea cycle for energy production via ornithine-a-ketoglutarate

transaminase and glutamate dehydrogenase.

Orni-thine is a substrate for OTC, the rate-limiting en-zyme of the urea cycle, and ornithine diversion to

an alternate pathway could limit urea cycle flux.

These arguments may not apply generally to Reye’s syndrome, however, for several reasons: (1) on-thine levels are not low but are elevated in Reye’s

syndrome,’65’ (2) ATP levels in liven may be normal

in Reye’s syndrome,75 and (3) the generalized de-crease in liver mitochondnial enzyme activities in-cludes glutamate dehydrogenase which, as noted

above, is necessary for generation of energy and ammonia from onnithine.

An elevated serum lactate level, a possible con-sequence of impaired oxidative metabolism in mi-tochondria, commonly occurs in Reye’s syndrome, but may be the end result of several different

path-ogenetic mechanisms. For this reason, lactic

aci-dosis will be considered separately.

It has been proposed that false neurotnansmitters

may be significant in the pathogenesis of Reye’s

syndrome as well as hepatic encephalopathy.

In-creased serum tyramine may result from hepatic mitochondnial monamine oxidase deficiency, as

ty-ramine is normally metabolized by this enzyme.77

Octopamine, also metabolized by monamine oxi-dase in liver and in nerve endings, is increased in blood, and in brain at postmortem examination, in

patients with Reye’s syndrome.78 Low

norepineph-nine levels in hypothalamus suggest that octopa-mine may function as a false transmitter, displacing

norepinephrine. As yet, these fragmentary data have not been correlated with the major clinical

features of Reye’s syndrome.

Correlation with Pathologic Markers

The idea of generalized mitochondnial dysfunc-tion begins with the evidence, reviewed above, of morphologic changes in mitochondria. Are there, in addition, histopathologic consequences of mito-chondrial failure and the ensuing energy-deficient

state? Impairment of energy transport and biosyn-thetic functions might lead to a loss of membrane integrity and either sweffing of cellular elements on collection of fluid in interstitial spaces. Astrocytic swelling occurs but is not attributable to

mitochon-drial dysfunction because astrocytic mitochondnia, as previously noted, appear distinctly normal. Cap-ifiary endothelial cells of brain are

also

normal, with normal mitochondria,32 suggesting that cerebral edema cannot be attributed to mitochondrial failure in these cells. Microdroplets of fat, seen in liven, kidney, heart, and muscle, may be a consequence of impaired capacity for fatty acid oxidation by mito-chondria.

Analogous Clinical Syndromes and Experimental Models

Several diseases and toxins affecting mitochon-dna are instructive with regard to the

pathophysi-ology of Reye’s syndrome. Some of these are

dis-cussed below under “Lactic Acidosis;” others are discussed above under “Fatty and Organic Acide-mia.” Systemic carnitine deficiency-causing defi-cient mitochondnial uptake of long-chain fatty acids-shows a superficial similarity to Reye’s

syn-drome79; however, cannitine levels are normal in

patients with Reye’s syndrome. Perhaps most in-tenesting are toxins, such as salicylates, which un-couple mitochondrial oxidative phosphonylation; these agents characteristically produce a respira-tony alkalosis by stimulation of the respiratory cen-ten and a concomitant metabolic acidosis. However, the serum amino acid pattern typical of Reye’s syndrome is not found in salicylism, and salicylate

effects on oxidative enzymes differ from those in Reye’s synthome.#{176} Recent evidence8’ suggests that salicylate ingestion may be a risk factor for occur-nence of Reye’s syndrome.

An agent found in Reye’s syndrome serum that stimulates oxygen consumption in isolated mito-chondria has been identified as uric acid, which was shown not to be a genuine pathogenic factor in Reye’s syndrome.82

Comment

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60 REYE’S SYNDROME

with the task of defining what mitochondrial func-tions are disordered, in what ongans, and in what pathogenic sequence. The process by which the viral illness leads to the pivotal mitochondrial

dys-function in liver is not known. As yet, there is no

coherent and well supported hypothesis of wide-spread primary mitochondrial disease. There is no known treatment for a mitochondnial insult as such.

LACTIC ACIDOSIS Background

Hypenlactatemia is thought to result from an imbalance between lactate production (chiefly by

brain, muscle, skin, and red cells) and utilization

(chiefly by liver and kidney).83’ Lactic acid, corn-pletely dissociated at physiologic pH, is an

impon-tant source of hydrogen ion and thus acidosis. There

are several possible sources of hyperlactatemia in Reye’s syndrome: (1) excess production by brain7 and muscle, (2) impaired hepatic metabolism via gluconeogenesis or the tnicarboxylic acid cycle be-cause of decreased activities of liven enzymes con-trolling metabolism ofpynuvate (and thus lactate),55 (3) hyperventilation reducing hepatic blood flow, thereby causing the liven to produce lactic acid, and (4) hypoxemia, hypopenfusion, and acidosis, as occurring in circulatory failure, causing the liven to produce lactic acid rather than to metabolize it. The relative contributions of these different factons are not known.

Whatever the source of hypenlactatemia, it is possible to make some comments concerning its pathophysiologic consequences. Hypenlactatemia may cause hyperventilation and coma by producing systemic acidosis, but does not cause coma at non-mal pH. Patients with Reye’s syndrome, like those with hepatic encephalopathy, typically are

seen with coma and predominant respiratory

alka-losis, with normal on modestly elevated pH.7 Thus,

one cannot invoke lactic acidosis to explain the

primary cerebral events. However, hyperventilation

and hypocapnia may be central factors for the development of lactic acidosis, much as they are in

liven disease and salicylate toxicity.& This sequence

of events indicates that there must be an important abnormality causing hyperventilation and coma in-dependent of and before the occurrence of lactic acidosis.

Occurrence of Hyperlactatemia and Correlation with Clinical Course

Blood lactate and pyruvate are variably elevated in the ingravescent phase of Reye’s syndrome.’52’ Hyperventilation and obtundation are most often well established with some degree of

uncompen-sated respiratory alkalosis7’; as noted above, this

is inconsistent with lactic acidosis. We had four successive patients with typical Reye’s syndrome (two in stage 2 and two in stage 3) who had no elevation of arterial lactate (unpublished data). In the study of Haymond et al,M mean blood lactate levels were elevated, but were equal in stage 2 and stage 3 patients, whereas glutamate and alanine levels were twofold greater in stage 3 patients; thus,

lactate level did not correlate with severity.

Correlation with Other Biochemical Markers Hyperammonemia and abnormal blood amino acid profiles are occasionally associated with con-genital lactic acidosis,’87 but these findings are exceptional and do not parallel those seen in Reye’s syndrome.

Pathologic Markers

The neuropathology oflactic acidosis, even in the severe fatal congenital cases, is different from that of Reye’s syndrome. Three reports of such cases concur in describing subependymal cystic spaces, widening of lateral ventricles, and spongy

degener-ation and demyelination of white matten.8789

Analogy with Other Clinical Syndromes

One possible clinical analogy for Reye’s syndrome is the group of diseases with congenital lactic

aci-dosis manifested by vomiting, coma, metabolic aci-dosis, hypoglycemia, and fatty livers. This is a het-enogeneous group, with deficiency of any one of several enzymes mediating the disposition of pyru-vate (and thus lactate) in the liver.92 In Reye’s syndrome, there has been direct demonstration by

Robinson et a155 of severely decreased activity in

liven mitochondria of two of these enzymes, pyru-vate carboxylase and pyruvate dehydrogenase.

However, in lactic acidosis, marked acidosis is the

rule with pH reported in the range 6.9 to 7.292;

the uncompensated respiratory alkalosis usually

seen in Reye’s syndrome is absent. Even high and sustained hypenlacticacidemia may be associated with relatively moderate and chronic

encephalopa-thy,89’995 far milder than the fulminant coma of Reye’s syndrome. In some cases, however, congen-ita.l lactic acidosis may be overwhelming and rapidly fatal.87se9

Effects of Specific Therapy and Future

Therapeutic Implications

A promising experimental agent for treatment of lactic acidosis is dichloroacetate, which has been used successfully in humans to reduce elevated levels of blood lactate to normal.95

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tate is thought to work by increasing lactate uptake by peripheral tissues, especially muscles, through an activation of pyruvate dehydrogenase. We are

not aware of this experimental agent having yet been used in Reye’s syndrome, but such use war-rants investigation.

SUMMARY AND CONCLUSIONS

The essential metabolic pathophysiology of Reye’s syndrome appears to consist of two primary

features: (1) a process affecting liver mitochondria, with sharply and transiently decreased activities of

all mitochondrial enzymes that have been mea-sured; and (2) a massive catabolic state. The cause

of these events is presumably related to the trigger-ing viral ifiness, in ways that are totally obscure. The hepatic mitochondrial defect causes impair-ment in metabolism of fat, nitrogenous compounds,

and carbohydrates. The hypotheses that have been put forward to explain the encephalopathy reflect

these classes of metabolites, hyperfattyacidemia, hyperammonemia, and disturbances of carbohy-drate metabolism (hypoglycemia and lactic aci-dosis), have each been singled out as putative en-cephalopathogenic agents, as has a direct mitochon-drial lesion of brain paralleling that of liven cells.

We have systematically analyzed the available evi-dence for and against each of these agents as a cause of the encephalopathy.

The hypothesis relating hypenfattyacidemia to

the encephalopathy is largely based on the circum-stance that fatty acid levels are elevated and this

elevation generally parallels the course of the ifi-ness. However, there are few data directly linking hyperfattyacidemia as a cause of profound coma, massive cerebral swelling, and the neunopathologic

picture of Reye’s syndrome, despite experimental

attempts to demonstrate these links. Hyperfattya-cidemia has not been correlated with other impon-tant biochemical derangements in patients with Reye’s syndrome, such as the distinctive amino acid

pattern, cerebral lactic acid efflux, or acid-base

pat-terns. Furthermore, fatty acid levels are reported to

be equally high in acute starvation, without coma; and therapy using glucose and insulin promptly decreases blood fatty acid levels in patients with

Reye’s syndrome, without evident influence on the

clinical course. Thus, the fatty acid hypothesis is not strongly supported.

Neither hypoglycemia nor lactic acidosis (as

dii-ferentiated from hyperlactatemia) is universal on even common in Reye’s syndrome, and thus does not cause the encephalopathy.

Although there is strong evidence of a severe insult to hepatic mitochondria, there is as yet no evidence for a similar primary mitochondrial

dys-function in the brain.

In contrast, the evidence implicating hypenam-monemia as a cause of the encephalopathy is strong,

based firmly at the present time on a large body of quantitative data. Hypenammonemia fulfills all the major criteria of an agent sufficient to cause the

encephalopathy. It is consistently elevated early in the course of the ifiness. It is capable of causing the encephalopathic symptoms seen, including vomit-ing, hyperventilation, confusion, coma, and in-creased intracranial pressure. Hyperammonemia correlates quantitatively with hyperventilation, with severity of coma, with excess lactate pnoduc-tion by brain, and with mortality. The known effects of hyperammonemia are quantitatively sufficient to account for these effects. The neuropathology of Reye’s syndrome, both acutely and at follow-up, is consistent with effects of hyperammonemia. The

clinical course and features, including biochemical derangements, are congruent with other known dis-eases that are characterized by acute hyperammo-nemia, including congenital urea cycle disorders which, when decompensated, closely resemble Reye’s syndrome.

Important to understanding the encephalopathic

effects of hyperammonemia is the finding of a tre-mendous uptake and metabolism of ammonia by

the brain, which implies that the total burden of ammonia presented to the brain may be more crit-ical than the blood level at any one time. This concept has quantitative support.

We conclude that the ammonia burden in the brain appears to be sufficient to produce the

en-cephalopathy of Reye’s syndrome. It has not yet been possible to test this hypothesis directly be-cause of the lack of an efficient method to reduce the toxic burden of ammonia in the brain. Newer

metabolic therapies give promise of making this possible. In focusing attention once again on the metabolic aspects of the syndrome, we would urge that increased efforts be directed to ways of

mod-ifying the intermediate metabolic derangements.

Gratifying as the results of supportive therapy and

control of intracranial pressure have been in de-creasing mortality, the therapeutic dilemma will not be solved until an effective metabolic interven-tion is found.

ACKNOWLEDGMENTS

We thank Drs Harvey Levy, Ira Lott, and W. Allan

Walker for critical review and comments, and Pamela

Picaniello for faithful secretarial assistance.

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62 REYE’S SYNDROME

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1982;69;53

Pediatrics

G. Robert DeLong and Thomas H. Glick

Encephalopathy of Reye's Syndrome: A Review of Pathogenetic Hypotheses

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