429 Reye’s Syndrome and Aspirin: Epidemiological Associations and Inborn Errors of Metabolism THE LANCET Reye’s syndrome is a rare, acute, self-limiting disorder of childhood causing an encephalopathy that is commonly fatal; and in survivors the neurological damage may be permanent.1,2 Well-characterised pathobiological features are cerebral oedema, a reversible abnormality of mitochondrial structure and of all mitochondrial functions (best seen in liver tissue), and an intense catabolic state. Among the consequences are hyperammonaemia, hypo- glycaemia, and abnormal biochemical tests of liver function (such as raised aspartate aminotransferase activity and long prothrombin time).3 The cause is unknown. In 1982 an editorial4 discussed the possible implication of salicylates in the aetiology and aggravation of Reye’s syndrome and concluded that the epidemiological evidence of three retrospective case-controlled studies was not overwhelming but sufficient to call into question the use of aspirin and other medications in the treatment of benign viral infections in childhood. In the intervening years publicity on Reye’s syndrome has been dominated by controversy over the validity of the association. Potentially serious sources of bias in these earlier studies5 led to claims that the association was spurious.6 A task force was formed by the US Public Health Service to study a possible relation between Reye’s syndrome and medication, with the help of an advisory board from the Institute of Medicine of the National Academy of Sciences, by techniques that avoid the major methodological defects in these earlier studies. Their pilot study published in 1985 showed the feasibility and limitations of the method. The 1. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera: a disease entity in childhood. Lancet 1963; ii: 749-52. 2 De Vivo DC. How common is Reye’s syndrome? N Engl J Med 1983; 309: 179-81. 3. Mowat AP. Reye’s syndrome-twenty years on. Br Med J 1983; 286: 1999-2001. 4. Editorial. Reye’s syndrome—epidemiological considerations. Lancet 1982; i: 941-13. 5. Hall SM. Reye’s syndrome and aspirin: a review. J R Soc Med 1986; 79: 596-98. 6. Daniels SR, Greenberg RS, Ibrahim MA. Scientific uncertainties in the studies of salicylate use in Reye’s syndrome. JAMA 1983; 249: 1311-16. 7. Hurwitz ES, Barrett MJ, Bergman D, et al. Public Health Service Study on Reye’s syndrome and medications: report of the pilot phase. N Engl J Med 1985; 313: 849-57 project has now been ended, with the conclusion that a strong statistical association was observed with the ingestion of salicylates, mainly aspirin, in the antecedent illness of Reye’s syndrome. It is note- worthy, however, that the pilot study comprised 30 patients with 145 controls while the main study comprised only 27 patients and 140 controls, although the protocol had specified that at least 100 patients would be required. The study was stopped prematurely because of the increasing rarity of Reye’s syndrome in the United States and the consequent expense and difficulty of enrolling additional cases in a reasonable period. Epidemiological studies of disorders as rare as Reye’s syndrome must be retrospective. Biases are inevitable.9 Even with the skills and resources available to the task force, essential biases remain. Widespread knowledge of the association may have led to preferential diagnosis and reporting of cases with the diagnostic criteria and a history of aspirin ingestion: parents, guardians, or children themselves may with litigation in mind have reported aspirin use once they knew the diagnosis.s A further difficulty is that the diagnostic criteria used in these studies were non-specific and could have led to the inclusion of children with genetic metabolic disorders that mirnic Reye’s syndrome. 10 This is unavoidable since there is no simple specific diagnostic test for Reye’s syndrome. This criticism is particularly pertinent since in the two task force reports only 15 patients (27%) had histological support for the diagnosis in the form of microvesicular lipid accumulations in the liver-a finding that may have many causes.il We are not told whether the specific mitochondrial abnormality was ever demonstrated on electronmicroscopy. Nor is it clear what steps were taken to exclude genetic disorders. Further data cited as evidence for an association between salicylates and Reye’s syndrome include the occurrence of the syndrome among children on long-term salicylate therapy for connective tissue disorders12 and a reduction in the reported incidence of Reye’s syndrome in USA13 paralleled by a possible decrease in aspirin use as a result of publicity on the possible association in the early 1980s. In contrast, an epidemiological study in Japan failed to confirm the association.14 Despite flaws in the epidemiological evidence, government agencies in many developed 8. Hurwitz ES, Barrett MJ, Bergman D, et al. Public Health Service Study of Reye’s syndrome and medications. Report of the main study. JAMA 1987; 257: 1905-11. 9. Sullivan-Bolyer JS, Corey L. Epidemiology of Reye’s syndrome Epidemiol Rev 1981; 3: 1-31. 10 Kang ES, Crocker JFS, Johnson GM. Reye’s syndrome and salicylates. N Engl J Med 1986; 314: 920-21. 11. Bonnel HJ, Beckwith JB. Fatty liver in sudden infant death. Am J Dis Child 1986; 149: 30-33. 12. Rennebohm RM, Heubi JE, Daugherty CC, Daniels SR Reye’s syndrome and children receiving salicylate therapy for connective tissue disease. J Pediatr 1985; 107: 877-80. 13 Centres for Disease Control. Reye’s syndrome-United States, 1985, CDC. M M W R 1986; 35: 66-74. 14. Heubi JE, Daugherty CC, Partin JS, Partin JC, Schubert WC Grade I Reye’s syndrome—outcome and predictors of progressive coma grades. N Engl J Med 1984; 311: 1539-42
Transcript
429
Reye’s Syndrome and Aspirin:Epidemiological Associations and
Inborn Errors of Metabolism
THE LANCET
Reye’s syndrome is a rare, acute, self-limitingdisorder of childhood causing an encephalopathy thatis commonly fatal; and in survivors the neurologicaldamage may be permanent.1,2 Well-characterised
pathobiological features are cerebral oedema, a
reversible abnormality of mitochondrial structure andof all mitochondrial functions (best seen in liver
tissue), and an intense catabolic state. Amongthe consequences are hyperammonaemia, hypo-glycaemia, and abnormal biochemical tests of liverfunction (such as raised aspartate aminotransferaseactivity and long prothrombin time).3 The cause isunknown. In 1982 an editorial4 discussed the possibleimplication of salicylates in the aetiology and
aggravation of Reye’s syndrome and concluded thatthe epidemiological evidence of three retrospectivecase-controlled studies was not overwhelming butsufficient to call into question the use of aspirin andother medications in the treatment of benign viralinfections in childhood. In the intervening yearspublicity on Reye’s syndrome has been dominated bycontroversy over the validity of the association.
Potentially serious sources of bias in these earlierstudies5 led to claims that the association was
spurious.6 A task force was formed by the US PublicHealth Service to study a possible relation betweenReye’s syndrome and medication, with the help of anadvisory board from the Institute of Medicine of theNational Academy of Sciences, by techniques thatavoid the major methodological defects in these earlierstudies. Their pilot study published in 1985 showedthe feasibility and limitations of the method. The
1. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera:a disease entity in childhood. Lancet 1963; ii: 749-52.
2 De Vivo DC. How common is Reye’s syndrome? N Engl J Med 1983; 309: 179-81.3. Mowat AP. Reye’s syndrome-twenty years on. Br Med J 1983; 286: 1999-2001.4. Editorial. Reye’s syndrome—epidemiological considerations. Lancet 1982; i: 941-13.5. Hall SM. Reye’s syndrome and aspirin: a review. J R Soc Med 1986; 79: 596-98.6. Daniels SR, Greenberg RS, Ibrahim MA. Scientific uncertainties in the studies of
salicylate use in Reye’s syndrome. JAMA 1983; 249: 1311-16.7. Hurwitz ES, Barrett MJ, Bergman D, et al. Public Health Service Study on Reye’s
syndrome and medications: report of the pilot phase. N Engl J Med 1985; 313:849-57
project has now been ended, with the conclusion that astrong statistical association was observed with the
ingestion of salicylates, mainly aspirin, in theantecedent illness of Reye’s syndrome. It is note-
worthy, however, that the pilot study comprised 30patients with 145 controls while the main studycomprised only 27 patients and 140 controls, althoughthe protocol had specified that at least 100 patientswould be required. The study was stoppedprematurely because of the increasing rarity of Reye’ssyndrome in the United States and the consequentexpense and difficulty of enrolling additional cases in areasonable period.
Epidemiological studies of disorders as rare as
Reye’s syndrome must be retrospective. Biases areinevitable.9 Even with the skills and resources
available to the task force, essential biases remain.Widespread knowledge of the association may haveled to preferential diagnosis and reporting of caseswith the diagnostic criteria and a history of aspiriningestion: parents, guardians, or children themselvesmay with litigation in mind have reported aspirin useonce they knew the diagnosis.s A further difficulty isthat the diagnostic criteria used in these studies werenon-specific and could have led to the inclusion ofchildren with genetic metabolic disorders that mirnicReye’s syndrome. 10 This is unavoidable since there isno simple specific diagnostic test for Reye’s syndrome.This criticism is particularly pertinent since in the twotask force reports only 15 patients (27%) hadhistological support for the diagnosis in the form ofmicrovesicular lipid accumulations in the liver-afinding that may have many causes.il We are not toldwhether the specific mitochondrial abnormality wasever demonstrated on electronmicroscopy. Nor is itclear what steps were taken to exclude geneticdisorders.
Further data cited as evidence for an associationbetween salicylates and Reye’s syndrome include theoccurrence of the syndrome among children onlong-term salicylate therapy for connective tissuedisorders12 and a reduction in the reported incidenceof Reye’s syndrome in USA13 paralleled by a possibledecrease in aspirin use as a result of publicity on thepossible association in the early 1980s. In contrast, anepidemiological study in Japan failed to confirm theassociation.14 Despite flaws in the epidemiologicalevidence, government agencies in many developed
8. Hurwitz ES, Barrett MJ, Bergman D, et al. Public Health Service Study of Reye’ssyndrome and medications. Report of the main study. JAMA 1987; 257: 1905-11.
9. Sullivan-Bolyer JS, Corey L. Epidemiology of Reye’s syndrome Epidemiol Rev 1981;3: 1-31.
10 Kang ES, Crocker JFS, Johnson GM. Reye’s syndrome and salicylates. N Engl J Med1986; 314: 920-21.
11. Bonnel HJ, Beckwith JB. Fatty liver in sudden infant death. Am J Dis Child 1986; 149:30-33.
12. Rennebohm RM, Heubi JE, Daugherty CC, Daniels SR Reye’s syndrome andchildren receiving salicylate therapy for connective tissue disease. J Pediatr 1985;107: 877-80.
13 Centres for Disease Control. Reye’s syndrome-United States, 1985, CDC. M M WR 1986; 35: 66-74.
14. Heubi JE, Daugherty CC, Partin JS, Partin JC, Schubert WC Grade I Reye’ssyndrome—outcome and predictors of progressive coma grades. N Engl J Med1984; 311: 1539-42
430
countries15-17 have taken measures to limit the use of
aspirin unless specifically indicated for chronicrheumatic disorders. In Britain, the epidemiology ofReye’s syndrome differs from that in the UnitedStates, the median age of cases being 14 months asopposed to 11 years, and there is no clear associationwith influenza. 18 It remains to be shown whether thesemeasures will reduce the recognition and voluntaryreporting of Reye’s syndrome. Nonetheless, thereseems little reason to challenge these decisions sincethere is equally no evidence that aspirin or any otherantipyretic provides anything other than symptomaticrelief. What country would have the resources toconduct an even more rigorous epidemiologicalstudy?The biological explanation for these observations
may lie in the extensive list of disorders that have beenconfused with Reye’s syndrome. Those publishedinclude five urea-cycle defects, eight differentdisturbances of branched-chain-aminoacid meta-
bolism and six defects in ketogenesis, fructosuria,familial erythrophagocytic reticulosis, cystic fibrosis,and systemic carnitine deficiency, although in reportson the last the whole range of organic acidurias haveseldom been excluded.19,2O Both the urea-cycle defectsand the organic acidurias21 present in an episodicfashion, often developing after an acute viral infection.The clinical, laboratory, and pathological features, atleast at the light microscopy level, are those of Reye’ssyndrome. These disorders are not diagnosed byroutine clinical laboratory tests but diagnosis may beinferred from the relative degree of hyper-ammonaemia, hypoglycaemia, ketosis, and acidosis.Branched-chain-aminoacid defects may be diagnosedfrom the pattern of aminoacids. For the others, evenmore elaborate techniques are required, such as assaysfor the deficient enzyme in white blood cells,fibroblasts, or other tissues. Many of these assays haveserious drawbacks and are available in only a fewlaboratories.21,22 Access to the diagnostically usefultechnique of fast atom bombardment mass
spectroscopy is even more limited. This last techniquehas proved useful because in many of the disorders themetabolic defect produces specific toxic acyl-coAcompounds23 that are detoxified by conjugation withL-camitine or glycine and excreted in the urine in a
15. CSM Update. Reye’s syndrome and aspirin. Br Med J 1986; 292: 1590.16 Mortimer EA. Reye’s syndrome, salicylates, epidemiology and public health policy.
19. Roe CR Metabolic disorders producing a Reye-like syndrome. In: Reye’s syndrome(Royal Society of Medicine Round Table Symposium no 8). London: RSM, 1987.
20. Howat AJ, Bennett MJ, Variand S, Shaw L, Engel PC. Defects of metabolism of fattyacids in sudden infant death syndrome. Br Med J 1985; 290: 1771-73.
21 Editorial. Sudden infant death and inherited disorders of fat oxidation. Lancet 1986; ii:1073-75.
22. Roe CR, Billington DS, Maltby DA, Bohan TP, Kahler SG, Chalmers RA.Diagnostic and therapeutic implications of medium-chain acyl carnitines in
medium-chain acyl CoA dehydrogenase deficiency Pediatr Res 1985, 19: 459-67.23. Kneger I, Tanaka K. Therapeutic effects of glycine in isovalericacidemia. Pediatr Res
1976; 10: 25-28
pattern specific for each disorder. In some conditions,however, such toxic products are seen in the urineonly in acute episodes and only if the patient is notrelatively deficient in L-camitine at the time. In
Reye’s’syndrome the urinary acyl camitines are thenormal form, acetyl camitine, but the excretion rate isincreased. In both Reye’s syndrome and acute
exacerbations of the specific metabolic abnormalities,secondary camitine deficiency can occur. Camitine isdeviated from its primary task of transferring long-chain fatty acid acyl-coA compounds from the
cytoplasm into mitochondria. There may be anadditional load on glycine conjugation which requiresATP and coA in the presence of the mitochondrial
enzyme glycine N-acylase. Aspirin, which is alsometabolised by glycine conjugation, has a greateraffinity for this enzyme than many of the endogenousproducts that accumulate in these genetic disorders.Thus aspirin, particularly in the subject who is
relatively L-camitine deficient, may compromisedetoxification and lead to the accumulation of moretoxic products and precipitate the onset of symptoms- was, for example, in valericacidaemia.24 In Reye’ssyndrome, with both the general defect in mito-chondrial function and an intense catabolic state withan endogenous production of massive amounts ofmetabolites competing for camitine and glycineconjugation, camitine production increases but theremay be a relative deficiency. It could be speculatedthat aspirin given to a child with Reye’s syndrome whohas relative L-camitine deficiency may limit glycineconjugation and change what might have been Reye’ssyndrome stage 114 to a more severe grade thatqualified for inclusion in the task force study.
Before we can obtain further useful informationfrom epidemiological studies we must increase clinicalawareness of these rare genetic disorders. Reye’ssyndrome should not be accepted as a diagnosis in anychild of less than 3 years unless all of the above geneticdisorders have been excluded by definitive tests. Withsome of these disorders the same metabolic
abnormality will present in other family members, notwith Reye’s syndrome but with sudden infant death?sExact diagnosis is thus essential for family guidance aswell as for specific management to preventrecurrences of encephalopathy. Unfortunately, formany clinicians access to the necessary diagnosticfacilities will prove difficult. Faced with a child withthe clinical picture of Reye’s syndrome, the clinicianshould make certain that a specimen of serum andurine is obtained immediately and frozen for
subsequent analysis. Only at the time of presentationmay the diagnostic metabolic effects be present. Thephysician should then try to control endogenousmetabolism by glucose infusion and take care not to
24. Roe CR, Billington DS, Maltby DA, Kinnebrew P. Recognition of medium-chainacyl CoA dehydrogenase deficiency in asymptomatic siblings of children dying ofsudden infant death or Reye-like syndromes. J Pediatr 1986; 108: 13-18.
25. Editorial. Sudden infant death and inherited disorders of fat oxidation. Lancet 1986, ii.1073-75.
431
give drugs that may compromise glycine and camitineconjugation (eg, salicylates, benzoates) or drugs thatinterfere with mitochondrial function (eg, valproate).The role of intravenous L-camitine in preventingor alleviating encephalopathy requires study.Intravenous aminoacids and lipids should be avoideduntil specific genetic disorders of aminoacid or lipidmetabolism have been eliminated. Efforts to promoteearlier recognition of Reye’s syndrome, better
diagnostic facilities allowing specific therapy of thegenetic disorders, and improvements in paediatricintensive care26 should take priority over furtherexpensive in-depth epidemiological investigations.
THE presence of . intraluminal gas creates specialdifficulties for ultrasound diagnosis of the gastrointestinaltract. Despite, alterations in technique and use of real-timeequipment, conventional ultrasound has only limited
application in the evaluation of the gut, and bowel gascontinues to hinder investigation of more deeply placedstructures. 1
The potential of an ultrasound probe introduced
intraluminally in the gut for diagnosis of mucosal diseasewas recognised as early as 1956 when Wilde and Readpresented their results with an intrarectal probe.2 Morerecently, endosonic probes introduced into the rectum andurethra have been used in the diagnosis of diseases of therectum, prostate, and bladder. Upper gastrointestinalendoscopy would appear to provide the perfect opportunityfor extension of simple endosonography into a combinedtechnique of direct visualisation of the mucosa of thegastrointestinal tract and ultrasound assessment of themucosal wall and juxta-intestinal disease. Lutz and Rosch3 3showed that a simple A-mode transducer introduced
through the instrumentation channel of an endoscope coulddifferentiate solid from cystic upper abdominal masseswhich had been shown on endoscopy or contrast radiologyto be causing gastric impression. Some workers haveintroduced small doppler crystals via the biopsy channel ofstandard endoscopes to diagnose flow in varices after
sclerotherapy and to identify the proximity of retroduodenalvessels before endoscopic papillotomy.4 The same
technique has been used to predict re-bleeding when a vesselis detected in proximity to a peptic ulcer at the timeof endoscopy for gastrointestinal haemorrhage.5 Sub-
sequently, real-time B-mode imaging devices have beendeveloped for use with modified endoscopes to view theintestinal wall and adjacent structures directly. Thesemodified echo-endoscopes utilise linear array ultrasoundtechnology or a rotating sector scanner in association witheither end-viewing or side-viewing optics.
26. Jenkins JG, Glasgow JFT, Black JW, et al. Reye’s syndrome: assessment ofintra-cranial monitoring. Br Med J 1987; 294: 337-38.
1 Dubbins PA. Ultrasound in the evaluation of the gastrointestinal tract. In: Kurtz A,Goldberg BB, eds. Gastrointestinal ultrasound. Edinburgh: Churchill Livingstone(in press).
2 Wild JJ, Fodenck JW. The feasibility of echometric detection of cancer in the lowergastrointestinal tract. Part II. Am J Proctol Gastroenterol Colon Rectal Surg 1978;29: 11-20.
3 Lutz H, Rosch W. Transgastroscopic ultrasonography. Endoscopy 1976; 8: 203-05.4. Martin RW, Gilbert DA, Silverstein FE, et al. An endoscopic doppler probe for
assessing intestinal vasculature. Ultrasound Med Biol 1985; 11: 61-69.5 Beckly DB, Casebow MP Prediction of re-bleeding from peptic ulcer. Experience
with an endoscopic doppler device. Gut 1986; 27: 96.
The combination of direct imaging and ultrasound athigh frequency (7-5-10 MHz) may offer major advantagesover transabdominal imaging for evaluation of the
gastrointestinal tract and adjacent organs. Althoughmucosal layers of the gut can be identified on
transabdominal ultrasound, particularly during evaluationof the stomach,l they are more reliably shown by endoscopicultrasound (EUS).6 EUS shows mucosal detail in the
oesophagus, stomach, and duodenum7 and therefore
permits accurate staging of oesophageal and gastric tumoursby demonstrating the extent of invasion of mucosa andsubmucosal layers, and by documenting extra-intestinallymphadenopathy. In addition, high-frequency transducersidentify tiny hepatic metastases unresolved by other imagingtechniques.8
Such techniques might not only assist accurate staging ofupper gastrointestinal tumours but also determine the
operability and nature of operation required before
laparotomy or thoracotomy. Other gastrointestinaltumours-such as leiomyomas-are only detected at
endoscopy or contrast radiology by their deformation of thegastric outline; EUS will identify such tumours and theirrelation to mucosal layers directly. It is also possible to showirregularity of parenchymal pattern and extension outsidethe intestinal wall, thereby indicating malignancy.The pancreas is difficult to investigate with orthodox
imaging techniques. Trans-abdominal ultrasound fails tovisualise the whole organ in up to 30% of patients; thepancreatic tail is commonly obscured by bowel gas.10Moreover, pancreatic lesions are often small and give fewdiagnostic signs. EUS should permit identification of smallpancreatic tumours because of the improved resolution athigh frequency; it is therefore of potential use in
investigation of apudomas and other multiple endocrinetumours of the pancreas. In evaluation of pancreaticcarcinoma it seems unlikely that EUS can yet play a part inearly diagnosis since the size of tumour at the time ofpresentation is almost invariably large enough to be
visualised by a combination of trans-abdominal ultrasoundand computed tomography. However, it may be possible tostage pancreatic carcinoma by means of criteria such asmarginal definition, capsular breach, and adjacentlymphadenopathy. It is difficult to differentiate pancreaticcarcinoma from focal pancreatitis, since both lesions mayappear as focal echo-poor intrapancreatic masses withoutechographic distinguishing features. In patients with apresumptive diagnosis of chronic pancreatic pain,unsubstantiated by other imaging techniques, mild, chronicpancreatitis can be identified by EUS demonstration ofperiductal fibrosis, branch duct ectasia, and lobularinflammation."
Whilst there are considerable advantages in terms ofresolution, there are significant limitations to the technique.Incorporation of an ultrasound probe affects the flexibility
7. Tio TL, Tytgat GN. Endoscopic ultrasonography in the assessment of intra- andtransmural infiltration of tumours in the oesophagus, stomach and papilla of Vaterand in the detection of extraoesophageal lesions. Endoscopy 1984; 16: 203-10.
