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Acute liver disease and encephalopathy mimicking Reye syndrome
December 1975 The Journal o f P E D I A T R I C S
869
Acute liver disease and encephalopathy mimicking Reye syndrome A report of three cases
Three patients are described whose clinical presentation suggested Reye syndrome, and in whom the initial laboratory investigations supported the diagnosis. The subsequent clinical and biochemical evolution of the illness differed from that of Reye syndrome. The liver biopsy of each patient revealed changes in centrilobular hepatocytes rather than the diffuse small droplet fatty change characteristic of Reye syndrome. In each of them normal liver functions were regained The findings in these patients suggest that a firm diagnosis of Reye syndrome cannot be made without histologic examination of the liver.
D. G r a n t Gall, M . D . , * E r n e s t C u t z , M . D . , Toronto, Ont., Canada, H. J u h l i n g M e C l n n g , M . D . , C o l u m b u s , Ohio, a n d M a r k L. G r e e n b e r g , M . D . , Toronto, Ont., C a n a d a
SINCE REYE AND CO-AUTHORS ~ first described acute encephalopathy associated with fatty change of the viscera several authors 2' 3 have suggested that the syndrome can be diagnosed by history and routine laboratory data without confirmation of fatty degeneration of the liver. In fact, Samaha and associates 3 state that routine liver biopsy is contraindicated. Our recent experience suggests that a diagnosis of Reye syndrome based on clinical and biochemical grotmds alone may be unreliable. Between December, 1973, and September, 1974, when we saw ten patients with histologically confirmed Reye syndrome, we encountered three other children initially suspected of having this condition who had, on further examination, what we believe to be a u n i q u e combination of clinical, biochemical, and histologic findings. The three cases form. the basis for this report.
From the Departments of Paediatrics and Pathology, University of Toronto and The Research Institute, The Hospital For Sick Children. *Reprint address: The Hospital For Sick Children, 555 University Ave., Toronto M5G 1X8, Ont., Canada.
CASE REPORTS
Table 1 compares the early clinical and laboratory data and hepatic histologic changes in these patients to those of Reye syndrome.
See related articles, pp. 867 through 887.
Abbreviations used PR: pulse rate RR: respiratory rate CSF: cerebrospinal fluid BUN: blood urea nitrogen SGOT: serum glutamic oxaloacetic transaminase EEG: electroencephalogram IQ: intelligence quotient Case 1. A 6-year-old boy was admitted to a local hospital after being found unconscious in bed. Three days earlier he had developed an upper respiratory infection and had appeared to be recovering. He had received a single 250 mg dose of erythromycin. No history of toxic exposure or trauma was elicited. On transfer to our care two days later he was in Stage III
Vol. 87, No. 6, part 1, pp. 869-874
870
Gall et al.
Table I.
The Journal of Pediatrics December 1975
Comparison
o f cases r e p o r t e d
with
Reye
syndrome
Cases Reye syndrome Early clinical findings" Prodrome Vomiting Seizures Palpable liver Coma grade Decerebrate posturing Tone Deep tendon reflexes Plantar reflexes
+ + _+ + II-IV + * or ~ ~ or ~
+
~
lII +
+ + + III +
+ + + + II +
+ ~
)~
4
)t~
)t~
~
Early laboratory data WBC/mm ~ Prothrombin time ( < 14 see)* SGOT ( < 40 IU)* NH3 ( < 100/~g/ dl)* Bilirubin serum total ( < 1.0 mg/ dl)* fi-l-C ( > 120 mg/ dl) Urinalysis Protein Hemoglobin RBC/HPF BUN ( < 20 mg/ dl) Creatinine (<0.8 mg/dl)
Variable
25,700 22,300 10,700 16 15 22
§ § N or slightly §
-
_+ 0 0 N or ~' N
3,202 142 1.0
850 14 0.5
8J0 56 1.5
66
84
<50
0 0 0 47
2+ 3+ 5-10 67
4+ 3+ 5-10 62
--
4.9
4.2
Hepatic histopathology Diffuse small droplet fatty change of hepatocytes
Centrilobular necrosis
Central hepatocyte nuclei
Minimal fatty change, confined to injured hepatocytes Early signs of liver regeneration No inflammation Normal portal areas
No necrosis
No inflammation Normal portal areas "~Normal values.
coma, 4 with generalized hypertonicity and hyperreflexia; intermittent decerebrate posturing, and extensor plantar responses. Temperature was 39 ~ C, PR 130, RR 60, and BP 130/80 mm Hg. Pupils were dilated and reacted slowly to light. Corneal reflexes
and fundi were normal. He had bilateral otitis media. No hepatomegaly was found. Opening CSF pressure was 228 mm of H20 and no cells were found. Abnormal laboratory studies included elevated white blood cell count with 98% neutrophils and 2% lymphocytes, elevated BUN, SGOT, and blood ammonia levels, prolonged prothrombin time, and depressed fi-l-C globulin (Table I). Blood gas values were consistent with a respiratory alkalosis. Coagulation abnormalities were corrected and a liver biopsy was performed 24 hours after admission. Normal laboratory values included an initial urinalysis, hemoglobin concentration, platelet count, CSF protein and sugar, serum alkaline phosphatase, serum bilirubin, toxicology screen, partial thromboplastin time, and blood sugar. Lipoprotein electrophoresis was normal and demonstrated the presence of a pre-beta fraction. The serum ASO titer was 100 Todd units. Bacterial cultures of blood, CSF, urine, stool, and tracheal aspiration and viral cultures of liver tissue and tracheal aspiration were all negative. Serologic studies for influenza A and B, hepatitis B, cytomegalovirus, Herpes simplex, and EB virus were also negative. The EEG was diffusely abnormal with a generalized excess of slow wave activity but without focal features. Brain scan demonstrated irregular increased cortical uptake bilaterally. On the fourth hospital day rectal bleeding and hematuria occurred. Urinalysis revealed 2 + protein, numerous red blood cells, and granular casts. These abnormalities resolved by day 12 and no evidence of renal failure evolved. Concentration of blood ammonia was normal by the second day and by the third week white blood cell count, BUN, SGOT, a n d / ? - I - C globulin levels had returned to normal. During the second week in hospital the boy gradually regained consciousness. By the time of discharge, on the twenty-second day, he still had symmetrically increased tone and hyperreflexia in all limbs, extensor plantar responses, and cortical blindness. Four months later there was a persistent small defect in the right visual field and a partial right hemiparesis. Repeat laboratory studies were normal. The EEG had improved but continued to show excess slow wave activity, especially on the left. Liver biopsy was repeated. Psychologic assessment eight months after the illness demonstrated severe impairment of visomotor skills with a verbal IQ of 80 and performance IQ o f 53. Assessment prior to his illness had revealed a boy o f above average intelligence. Case 2. A 4-year-old girl seemed to be recovering from an uncomplicated upper respiratory infection o f four days duration when she was found unconscious and convulsing in bed and was taken to the local hospital. She had received phenylephrinehydrocodone compound for two days prior to admission. Seizures were controlled with diazepam and she was transferred to The Hospital For Sick Children. On admission Stage IlI coma was present and temperature was 38.5 ~ C, RR 48, PR 80, BP 110/60 m m Hg. Pupils were dilated and reacted slowly. Corneal reflexes and fundi were normal. She had generalized hypertonicity and hyperreflexia, intermittent decerebrate posturing and extensor plantar responses. Rfiles were heard over the right upper lobe. The liver edge was palpable 2 cm below the right costal margin. Lumbar puncture yielded no abnormal findings. Initial laboratory data are presented in Table
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Liver disease and encephalopathy mimicking Reye syndrome
871
Fig. 1. Case 2. The well-demarcated, pale areas represent zones of centrilobular necrosis of hepatocytes (cv, central vein). Lack of staining is due to loss of glycogen from injured hepatocytes. The portal areas (pa) and rest of the liver parenchyma appear normal. (Periodic acid-Schiffstain; x 60.)
Fig. 2. Case 1. Hepatic tissue in the acute phase of the illness. Higher magnification of the centrilobular area depicts the zone of necrosis with eosinophilic bodies, congestion, and proliferation of Kupffer cells. The adjacent surviving hepatocytes show mild swelling and increase in mitosis. (Hematoxylin-eosin; x 400.)
I. Investigations listed as normal in Case 1 were also normal in this patient. In addition concentration of serum amylase was 3,246 Symogyi units; no evidence of mumps infection was found on examination of acute and convalescent sera. Chest roentgenograms demonstrated a right upper lobe pneumonia consistent with aspiration. Brain scan and EEG findings were identical to those described for Case I. Liver biopsy was performed on the first hospital day. Laboratory evidence of renal failure progressed with peak values of BUN, 140 mg/dl, and serum creatinine, 5.5 mg/dl occurring on the fourth.hospital day. Examination at discharge after 32 hospital days demonstrated cortical blindness and spastic quadraplegia. The renal and hepati c dysfunction had resolved and serum amylase and fl-l-C globulin levels were normal. At re-examination six months later vision was normal, but persistent spastic diplegia of lower limbs was noted and her IQ was 85. Laboratory investigations, of renal and hepatic function were normal. Brain scan and EEG had improved but were still abnormal Case 3. Eight days after the onset of an upper respiratory infection, treated with tetracycline, this 23-month-boy was found convulsing in bed. In his local hospital seizures were controlled with diazepam, but he remained comatose, and vomited coffeeground material several times over the next two days which prompted transfer to our hospital. Past history revealed a convulsive disorder, which developed at six months of age following pneumococcal meningitis and had been well controlled with diphenylhydantoin. He was mildly dehydrated and in Stage II coma with generalized hypertonicity and hyperreflexia and extensor plantar responses. Temperature was 37 ~ C, RR 26, PR 120, and BP 120/ 80 mm Hg. Pupillary and corneal reflexes and fundi were normal. The only other positive physical findings were gum hypertrophy and a liver edge palpable 4 cm below the costal margin. Laboratory data in addition to that presented in Table I included concentration of CSF sugar 40 mg/dl, blood sugar 46 mg/dl, partial thromboplastin time 46 seconds, and bleeding time 18 minutes. Serum amylase concentration was normal as were other
studies listed as normal for Cases 1 and 2. Serum diphenylhydantoin level was within the therapeutic range. Brain scan and EEG revealed findings identical to those seen in the previous two cases. Brain scans prior to this illness had been normal and EEGs had demonstrated seizure activity in the left temporofrontal region. He gradually became anuric during the first week and required peritoneal dialysis for two days. Renal and hepatic function were normal at the time of discharge four weeks later and his mental status had returned to his preillness level. Liver biopsy was performed seven days after admission at which time his SCOT value had decreased to 61 IU and his serum bilirubin and/?-I-C globulin levels had returned to normal. HISTOPATHOLOGY
Materials and methods. N e e d l e biopsies o f liver f r o m all three patients were processed for light ( L M ) a n d electron microscopy ( E M ) by s t a n d a r d procedures. ,The stains for L M in addition to routine staining i n c l u d e d fat stain on frozen sections. Samples for E M were fixed in 1% O,O4 a n d portions o f the same samples in 3% glutaraldehyde followed b y 1% OsO~. Light microscopy. T h e L M histologic changes in C a s e s 1 a n d 2 were similar, b u t differed in severity. T h e r e was extensive coagulative h e p a t o c e l l u l a r necrosis, involving the centrilobular areas o f the liver p a r e n c h y m a . In some lobules, necrosis involved o n e - t h i r d to o n e - h a l f o f the liver cells. These necrotic areas were p r o m i n e n t in sections stained with periodic acid Schiff because of loss of glycogen from the d a m a g e d cells (Fig. 1). Sections stained for fat showed small droplet fatty change, b u t only in hepatocytes s u r r o u n d i n g the necrotic areas. T h e rest o f the p a r e n c h y m a was free o f fat. The degree o f centrilobular h e p a t o c e l l u l a r necrosis was greatest in Case 1 (Fig. 2). T h e hepatocytes a p p e a r e d shrunken, showed m a r k e d cytoplasmic eosinophilia, a n d
872
Gall et al.
contained pyknotic nuclei. In some areas, congestion and extravasation of red blood cells were present. Occasional foci of inflammatory cells and hyperplastic Kupffer cells were seen. Hepatocytes from the marginal zone between necrotic and normal areas showed numerous mitoses. In Case 2 the changes were milder and there were fewer necrotic areas. The centrilobular hepatocytes appeared swollen and had uniformly eosinophilic cytoplasm, but the nuclei appeared intact. Loss of glycogen from these cells, as well as mild. small droplet fatty change in hepatocytes at the margins, outlined the injured areas in a fashion similar to that seen in Case 1. Portal areas in both cases were intact, with no evidence of inflammation. cholestasis, or other lesions. The repeat liver biopsy from Case 1 taken four months later revealed normal histology. The biopsy of liver from Case 3 was taken ten days after the onset of encephalopathy and therefore is not entirely comparable to the other two eases. The hepatocellular changes were less well demarcated but were primarily confined to the centrilobular areas. The hepatocytes appeared swollen, pleomorphic, and. in some areas. formed pseudoacinar structures. Occasional acidophilic bodies and liver cell mitoses were seen. Foci of intracellular and intracanalicular cholestasis were found. predominantiy around the central veins. Stains for fat revealed small and medium-sized droplet fatty change with centrilobular distribution. As in Cases I and 2. the portal areas were normal. Elecwon microscopy. The most striking ultrastructural alterations in Cases 1 and 2 were confined to centrilobular hepatocytes. The periportal and, in some areas, midzonal hepatocytes were essentially normal. In the most severely affected areas, particularly in Case 1, the hepatocytes had disintegra!ed and adjacent Kupffer cells contained phagocytosed cellular-debris. The less involved hepatoeytes showed profound cytoplasmic alterations (Fig. 3). The conspicuous absence of glycogen was accompanied by an increase in smooth endoplasmic reticulum which, in some areas, formed whorllike structures. The rough endoplasmic reticulum showed focal loss of ribosomes and slight dilatation of dsternae. Mitochondria varied in size and were moderately swolle n. There was loss of mitochondrial cristae and dense bodies. The pale and finely granular mitochondrial matrix contained occasional dense floccular deposits. The number of peroxysomes was increased above normal and numerous autophagic vacuoles were scattered in the cytoplasm. Small- and medium-sized fatty droplets were also seen. The nuclei showed rarification of the nucleoplasm. The cell membranes and bile canaliculi were normal. No viral particles were seen. When the biopsy was repeated in
The Journal of Pediatrics December 1975
Case 1, the ultrastructure of hepatocytes had returned to normal. In Case 3 the ultrastructural alterations of hepatocytes differed from those discussed i n Cases 1 and 2 and probably represent the early stages of recovery. The smooth endop!asmic reticulum was prominent but glycogen particles were present. The mitoch0ndria varied slightly in size; but showed normal morphology. PeroxYsomes and autophagic vacuoles, however, were still prominent. The bile canaliculi were dilated and contained occasional bile plugs. The nuclei were normal. DISCUSSION The onset, }ypical history, clinical, and biochemical data in the three patients suggested a diagnosis of Reye syndrome. All had a virallike prodrome with apparent improyement followed by acute encephalopathy and laboratory evidence of liver dysfunction. Case 1 fulfilled all the clinical and biochemical criteria for a nonhistologic diagnosis of Reye syndrome including elevated concentration of blood ammonia. 2, 3 Without benefit of liver histology these patients would have been labeled as having Reye syndrome. Findings unusual for Reye syndrome were lack of vomiting prior to the onset of encephalopathy, sudden onset of coma without preceding delirium, Slow recovery of consciousness with severe neurologic sequel a occurring in two of the children, se.vere renal impairment, normal pre-beta fraction on lipoprotein electrophoresis, 5 decreased levels Of/?-I-C globulin, and normal blood ammonia levels in two patients. The light microscopic histol0gic changes in liver biopsies from these patients differed in manY aspects from those described in Reye syndromer -" In early stages of Reye syndrome, liver histology is characterized by diffuse small droplet fatty change Of hepatocytes without necrosis or associated inflammatory lesions. In our patients the main insult affected the centrilobular hepatocytes which showed eoagulative necrosis. Unlike Reye syndrome, the fatty change was focal and confined to the injured hepatocytes surrounding the necrotic areas, suggesting a degenerative rather than a primary phenomenon. Histopathologic findings similar to Reye syndrome were lack of portal inflammation and return to normal within a short time after the acute insult as shown by th e l%llow-up biopsy in Case 1. In spite of extensive investigations the etiology of acute liver disease in our patients ha s not been established. The central areas of the liver lobule (Zone II! of Rappaport) are considered to be more sensitive to injury than peripheral areas, because of lower oxygen tension in the blood supplying the centrilobular hepatocytes than tl~at supplying the peripheral hepat0cytesY Centrilobuiar necrosis of
Volume 87 Number 6, part 1
Liver disease and encephalopathy mimicking Reye syndrome
873
Fig. 3. Case 2. Electron m!crograph of a portionof cytoplasm from an injured hepatocyte. There is complete dep!etion of glycogen particles. The mitochondria (mi) are swollen and show loss of cristae and dense bodies. There is proliferation of smooth endoplasmic reticulum which forms membranous structures (arrow). Numbers of lysozomes (ly) and peroxysomes (pc) are increased. Fat droplet (fd.) and portion of a nucleus (nu) are seen at upper left. (OsO4fixation; x 30,000.)
liver is a nonspecific lesion and has been described in various conditions such as circulatory failure, carbon tetrachloride poisoning, exposure to various toxins, or drugs and some infectious diseases. 9-14 Recently described Ultrastructural changes in liver biopsies from patients With Reye syndrome were considered characteristic. 1~The most severe changes affected the mitochondria suggesting a disturbance in their oxidative function. Alterations in the fine structure of mitochondria, in our caseS, were confined only to hepatocytes in the injured areas but bore some resemblance to those described in Reye syndrome, where they are diffuse. The complete depletion of glycogen from injured hepatocytes in our patients contrasts with the only moderate char~ges in hepatic glycogen Of patients with Reye syndrome. The ultrastrUctural changes seen in our patients are probably not Specific since similar changes have been described in hypoxia, shock, and in various experimental conditions.16. 17
in our patients there was no history of toxic exposure or clinical evidence of shock. The medications prescribed prior to the onset Of the encephalopathy differed in each case so that drug toxicity seems unlikely; ' There was a prodrome suggestive of viral infection, but cultures and Serologic evaluation at the time of the encephalopathy provided no evidence of a specific viral agent. Group A beta hemolytic streptococcal infections have been assodated with widespread tissue involvement and encephalopathy, '8 but bacterial cultures were negative and serum ASO titers were not indicative of recent infection. The low fi-l-C globulin levels suggested an immunologic process with increased consumption of complement by antigenantibody complexes, and this could also have accounted for the associated renal dysfunction. An alternative possibility for the decreased levels of fi-l-C g l o b u l i n is decreased production, as a result of the hepatocellular damage. We believe these patients suffered from a previously
874
Gall et al.
unrecognized disorder with multiple organ involvement, including brain, liver, kidneys, and possibly pancreas. The clinical and biochemical features could easily be confused with Reye syndrome, a possibility which makes histologic examination of the liver imperative. In the absence o f rigid diagnostic criteria a diagnosis of Reye syndrome should be reserved for children who have typical clinical, biochemical, and histologic features. Our findings suggest that previous studies of Reye syndrome which have not relied on histologic confirmation may include inappropriate cases similar to ours or possibly other disease entities and thus bias evaluation of therapy and prognosis. We wish to thank Dr. J. B. J. McKendry and Dr. D. A. McGreal for permitting us to study their patients and Dr. D. L. Gilday for interpretation of the brain scans. REFERENCES
1. Reye RDK, Morgan G, and Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood, Lancet 2:749, 1963. 2. Glasgow AM, Cotton RB, and Dhiensire K: Reye's Syndrome: I. Blood ammonia and consideration of the nonhistologic diagnosis, Am J Dis Child 124:827, 1972. 3. Samaha EF, Glau E, and Berardinelli JL: Reye's syndrome: Clinical diagnosis and treatment with peritoneal dialysis, Pediatrics 53:336, 1974. 4. Huttenlocher PR: Reye's syndrome: Relation of outcome to therapy, J PEI~IA'rR80:845, 1972. 5. Brown RE, Madge GE, Trauner RB, et al: Lipid and lipoprotein studies in Reye's syndrome, Va Med Mon 99:622, 1972. 6. Schubert WK, Partin JC, and Partin JS: Encephalopathy and fatty liver, in Dopper H, and Schaffner F, editors:
The Journal of Pediatrics December 1975
7.
8.
9.
10.
I I.
12. 13.
14. 15.
16. 17.
18.
Progress in liver disease, New York, 1972, Grune & Stratton, pp 489-510. Norman MG: Encephalopathy and fatty degeneration of the viscera in childhood: I. Review of cases at The Hospital For Sick Children, Toronto (1954-56), Canad Med Assoc J 99:522, 1968. Bourgeois G, Olson L, Comer D, et al: Encephalopathy and fatty degeneration of the viscera: A clinicopathologic analysis of 110 cases, Am J Clin Pathol 56:558, 1971. Sherlock S: The liver in circulatory failure, in Schiff L, editor: Diseases of the liver, Philadelphia, 1969, JB Lippincott Company, pp 815-834. Reid WD, and Krishna G: Centrolobular hepatic necrosis related to covalent binding of metabolites of helogenated aromatic hydrocarbons, Exp Mol Pathol 18:80, 1973. Reid WD, Krishna G, Gillette R, et al: Biochemical mechanism of hepatic necrosis induced by aromatic hydrocarbons, Pharmacology 10:193, 1973. Elias H, and Sherrick JD: Morphology of the liver, New York, 1969, Academic Press~ Inc., pp 319. Beckert W: Zentrilobulare parenchymnekrosen der leber. Beitrag zur Kenntnis arzneimittelbedingter Leberschaden, Zentralbl Allg Pathol 117:219, 1973. Child PL, MacKenzie RB, Valverde LR, et al: Bolivian hemorrhagic fever, Arch Pathol 83:434, 1967. Partin JC, Schubert WK, and Partin JS: Mitochondrial ultrastructure in Reye's syndrome. Encephalopathy and fatty degeneration of the viscera, N Engl J Med 285:1339, 1971. Schaffner F: Oxygen supply and the hepatocyte, Ann NY Acad Sci i70:67, 1970. Boler RK, and Bibighaus AJ: Ultrastructural alterations of d o g livers during endotoxin shock, Lab Invest 17:537, 1967. Haddow JE, Sher N, Gall DG, and Green D: Streptococcal wound infection with evidence of widespread tissue involvement, Pediatrics 48:458, 1971.
869
Acute liver disease and encephalopathy mimicking Reye syndrome A report of three cases
Three patients are described whose clinical presentation suggested Reye syndrome, and in whom the initial laboratory investigations supported the diagnosis. The subsequent clinical and biochemical evolution of the illness differed from that of Reye syndrome. The liver biopsy of each patient revealed changes in centrilobular hepatocytes rather than the diffuse small droplet fatty change characteristic of Reye syndrome. In each of them normal liver functions were regained The findings in these patients suggest that a firm diagnosis of Reye syndrome cannot be made without histologic examination of the liver.
D. G r a n t Gall, M . D . , * E r n e s t C u t z , M . D . , Toronto, Ont., Canada, H. J u h l i n g M e C l n n g , M . D . , C o l u m b u s , Ohio, a n d M a r k L. G r e e n b e r g , M . D . , Toronto, Ont., C a n a d a
SINCE REYE AND CO-AUTHORS ~ first described acute encephalopathy associated with fatty change of the viscera several authors 2' 3 have suggested that the syndrome can be diagnosed by history and routine laboratory data without confirmation of fatty degeneration of the liver. In fact, Samaha and associates 3 state that routine liver biopsy is contraindicated. Our recent experience suggests that a diagnosis of Reye syndrome based on clinical and biochemical grotmds alone may be unreliable. Between December, 1973, and September, 1974, when we saw ten patients with histologically confirmed Reye syndrome, we encountered three other children initially suspected of having this condition who had, on further examination, what we believe to be a u n i q u e combination of clinical, biochemical, and histologic findings. The three cases form. the basis for this report.
From the Departments of Paediatrics and Pathology, University of Toronto and The Research Institute, The Hospital For Sick Children. *Reprint address: The Hospital For Sick Children, 555 University Ave., Toronto M5G 1X8, Ont., Canada.
CASE REPORTS
Table 1 compares the early clinical and laboratory data and hepatic histologic changes in these patients to those of Reye syndrome.
See related articles, pp. 867 through 887.
Abbreviations used PR: pulse rate RR: respiratory rate CSF: cerebrospinal fluid BUN: blood urea nitrogen SGOT: serum glutamic oxaloacetic transaminase EEG: electroencephalogram IQ: intelligence quotient Case 1. A 6-year-old boy was admitted to a local hospital after being found unconscious in bed. Three days earlier he had developed an upper respiratory infection and had appeared to be recovering. He had received a single 250 mg dose of erythromycin. No history of toxic exposure or trauma was elicited. On transfer to our care two days later he was in Stage III
Vol. 87, No. 6, part 1, pp. 869-874
870
Gall et al.
Table I.
The Journal of Pediatrics December 1975
Comparison
o f cases r e p o r t e d
with
Reye
syndrome
Cases Reye syndrome Early clinical findings" Prodrome Vomiting Seizures Palpable liver Coma grade Decerebrate posturing Tone Deep tendon reflexes Plantar reflexes
+ + _+ + II-IV + * or ~ ~ or ~
+
~
lII +
+ + + III +
+ + + + II +
+ ~
)~
4
)t~
)t~
~
Early laboratory data WBC/mm ~ Prothrombin time ( < 14 see)* SGOT ( < 40 IU)* NH3 ( < 100/~g/ dl)* Bilirubin serum total ( < 1.0 mg/ dl)* fi-l-C ( > 120 mg/ dl) Urinalysis Protein Hemoglobin RBC/HPF BUN ( < 20 mg/ dl) Creatinine (<0.8 mg/dl)
Variable
25,700 22,300 10,700 16 15 22
§ § N or slightly §
-
_+ 0 0 N or ~' N
3,202 142 1.0
850 14 0.5
8J0 56 1.5
66
84
<50
0 0 0 47
2+ 3+ 5-10 67
4+ 3+ 5-10 62
--
4.9
4.2
Hepatic histopathology Diffuse small droplet fatty change of hepatocytes
Centrilobular necrosis
Central hepatocyte nuclei
Minimal fatty change, confined to injured hepatocytes Early signs of liver regeneration No inflammation Normal portal areas
No necrosis
No inflammation Normal portal areas "~Normal values.
coma, 4 with generalized hypertonicity and hyperreflexia; intermittent decerebrate posturing, and extensor plantar responses. Temperature was 39 ~ C, PR 130, RR 60, and BP 130/80 mm Hg. Pupils were dilated and reacted slowly to light. Corneal reflexes
and fundi were normal. He had bilateral otitis media. No hepatomegaly was found. Opening CSF pressure was 228 mm of H20 and no cells were found. Abnormal laboratory studies included elevated white blood cell count with 98% neutrophils and 2% lymphocytes, elevated BUN, SGOT, and blood ammonia levels, prolonged prothrombin time, and depressed fi-l-C globulin (Table I). Blood gas values were consistent with a respiratory alkalosis. Coagulation abnormalities were corrected and a liver biopsy was performed 24 hours after admission. Normal laboratory values included an initial urinalysis, hemoglobin concentration, platelet count, CSF protein and sugar, serum alkaline phosphatase, serum bilirubin, toxicology screen, partial thromboplastin time, and blood sugar. Lipoprotein electrophoresis was normal and demonstrated the presence of a pre-beta fraction. The serum ASO titer was 100 Todd units. Bacterial cultures of blood, CSF, urine, stool, and tracheal aspiration and viral cultures of liver tissue and tracheal aspiration were all negative. Serologic studies for influenza A and B, hepatitis B, cytomegalovirus, Herpes simplex, and EB virus were also negative. The EEG was diffusely abnormal with a generalized excess of slow wave activity but without focal features. Brain scan demonstrated irregular increased cortical uptake bilaterally. On the fourth hospital day rectal bleeding and hematuria occurred. Urinalysis revealed 2 + protein, numerous red blood cells, and granular casts. These abnormalities resolved by day 12 and no evidence of renal failure evolved. Concentration of blood ammonia was normal by the second day and by the third week white blood cell count, BUN, SGOT, a n d / ? - I - C globulin levels had returned to normal. During the second week in hospital the boy gradually regained consciousness. By the time of discharge, on the twenty-second day, he still had symmetrically increased tone and hyperreflexia in all limbs, extensor plantar responses, and cortical blindness. Four months later there was a persistent small defect in the right visual field and a partial right hemiparesis. Repeat laboratory studies were normal. The EEG had improved but continued to show excess slow wave activity, especially on the left. Liver biopsy was repeated. Psychologic assessment eight months after the illness demonstrated severe impairment of visomotor skills with a verbal IQ of 80 and performance IQ o f 53. Assessment prior to his illness had revealed a boy o f above average intelligence. Case 2. A 4-year-old girl seemed to be recovering from an uncomplicated upper respiratory infection o f four days duration when she was found unconscious and convulsing in bed and was taken to the local hospital. She had received phenylephrinehydrocodone compound for two days prior to admission. Seizures were controlled with diazepam and she was transferred to The Hospital For Sick Children. On admission Stage IlI coma was present and temperature was 38.5 ~ C, RR 48, PR 80, BP 110/60 m m Hg. Pupils were dilated and reacted slowly. Corneal reflexes and fundi were normal. She had generalized hypertonicity and hyperreflexia, intermittent decerebrate posturing and extensor plantar responses. Rfiles were heard over the right upper lobe. The liver edge was palpable 2 cm below the right costal margin. Lumbar puncture yielded no abnormal findings. Initial laboratory data are presented in Table
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Liver disease and encephalopathy mimicking Reye syndrome
871
Fig. 1. Case 2. The well-demarcated, pale areas represent zones of centrilobular necrosis of hepatocytes (cv, central vein). Lack of staining is due to loss of glycogen from injured hepatocytes. The portal areas (pa) and rest of the liver parenchyma appear normal. (Periodic acid-Schiffstain; x 60.)
Fig. 2. Case 1. Hepatic tissue in the acute phase of the illness. Higher magnification of the centrilobular area depicts the zone of necrosis with eosinophilic bodies, congestion, and proliferation of Kupffer cells. The adjacent surviving hepatocytes show mild swelling and increase in mitosis. (Hematoxylin-eosin; x 400.)
I. Investigations listed as normal in Case 1 were also normal in this patient. In addition concentration of serum amylase was 3,246 Symogyi units; no evidence of mumps infection was found on examination of acute and convalescent sera. Chest roentgenograms demonstrated a right upper lobe pneumonia consistent with aspiration. Brain scan and EEG findings were identical to those described for Case I. Liver biopsy was performed on the first hospital day. Laboratory evidence of renal failure progressed with peak values of BUN, 140 mg/dl, and serum creatinine, 5.5 mg/dl occurring on the fourth.hospital day. Examination at discharge after 32 hospital days demonstrated cortical blindness and spastic quadraplegia. The renal and hepati c dysfunction had resolved and serum amylase and fl-l-C globulin levels were normal. At re-examination six months later vision was normal, but persistent spastic diplegia of lower limbs was noted and her IQ was 85. Laboratory investigations, of renal and hepatic function were normal. Brain scan and EEG had improved but were still abnormal Case 3. Eight days after the onset of an upper respiratory infection, treated with tetracycline, this 23-month-boy was found convulsing in bed. In his local hospital seizures were controlled with diazepam, but he remained comatose, and vomited coffeeground material several times over the next two days which prompted transfer to our hospital. Past history revealed a convulsive disorder, which developed at six months of age following pneumococcal meningitis and had been well controlled with diphenylhydantoin. He was mildly dehydrated and in Stage II coma with generalized hypertonicity and hyperreflexia and extensor plantar responses. Temperature was 37 ~ C, RR 26, PR 120, and BP 120/ 80 mm Hg. Pupillary and corneal reflexes and fundi were normal. The only other positive physical findings were gum hypertrophy and a liver edge palpable 4 cm below the costal margin. Laboratory data in addition to that presented in Table I included concentration of CSF sugar 40 mg/dl, blood sugar 46 mg/dl, partial thromboplastin time 46 seconds, and bleeding time 18 minutes. Serum amylase concentration was normal as were other
studies listed as normal for Cases 1 and 2. Serum diphenylhydantoin level was within the therapeutic range. Brain scan and EEG revealed findings identical to those seen in the previous two cases. Brain scans prior to this illness had been normal and EEGs had demonstrated seizure activity in the left temporofrontal region. He gradually became anuric during the first week and required peritoneal dialysis for two days. Renal and hepatic function were normal at the time of discharge four weeks later and his mental status had returned to his preillness level. Liver biopsy was performed seven days after admission at which time his SCOT value had decreased to 61 IU and his serum bilirubin and/?-I-C globulin levels had returned to normal. HISTOPATHOLOGY
Materials and methods. N e e d l e biopsies o f liver f r o m all three patients were processed for light ( L M ) a n d electron microscopy ( E M ) by s t a n d a r d procedures. ,The stains for L M in addition to routine staining i n c l u d e d fat stain on frozen sections. Samples for E M were fixed in 1% O,O4 a n d portions o f the same samples in 3% glutaraldehyde followed b y 1% OsO~. Light microscopy. T h e L M histologic changes in C a s e s 1 a n d 2 were similar, b u t differed in severity. T h e r e was extensive coagulative h e p a t o c e l l u l a r necrosis, involving the centrilobular areas o f the liver p a r e n c h y m a . In some lobules, necrosis involved o n e - t h i r d to o n e - h a l f o f the liver cells. These necrotic areas were p r o m i n e n t in sections stained with periodic acid Schiff because of loss of glycogen from the d a m a g e d cells (Fig. 1). Sections stained for fat showed small droplet fatty change, b u t only in hepatocytes s u r r o u n d i n g the necrotic areas. T h e rest o f the p a r e n c h y m a was free o f fat. The degree o f centrilobular h e p a t o c e l l u l a r necrosis was greatest in Case 1 (Fig. 2). T h e hepatocytes a p p e a r e d shrunken, showed m a r k e d cytoplasmic eosinophilia, a n d
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contained pyknotic nuclei. In some areas, congestion and extravasation of red blood cells were present. Occasional foci of inflammatory cells and hyperplastic Kupffer cells were seen. Hepatocytes from the marginal zone between necrotic and normal areas showed numerous mitoses. In Case 2 the changes were milder and there were fewer necrotic areas. The centrilobular hepatocytes appeared swollen and had uniformly eosinophilic cytoplasm, but the nuclei appeared intact. Loss of glycogen from these cells, as well as mild. small droplet fatty change in hepatocytes at the margins, outlined the injured areas in a fashion similar to that seen in Case 1. Portal areas in both cases were intact, with no evidence of inflammation. cholestasis, or other lesions. The repeat liver biopsy from Case 1 taken four months later revealed normal histology. The biopsy of liver from Case 3 was taken ten days after the onset of encephalopathy and therefore is not entirely comparable to the other two eases. The hepatocellular changes were less well demarcated but were primarily confined to the centrilobular areas. The hepatocytes appeared swollen, pleomorphic, and. in some areas. formed pseudoacinar structures. Occasional acidophilic bodies and liver cell mitoses were seen. Foci of intracellular and intracanalicular cholestasis were found. predominantiy around the central veins. Stains for fat revealed small and medium-sized droplet fatty change with centrilobular distribution. As in Cases I and 2. the portal areas were normal. Elecwon microscopy. The most striking ultrastructural alterations in Cases 1 and 2 were confined to centrilobular hepatocytes. The periportal and, in some areas, midzonal hepatocytes were essentially normal. In the most severely affected areas, particularly in Case 1, the hepatocytes had disintegra!ed and adjacent Kupffer cells contained phagocytosed cellular-debris. The less involved hepatoeytes showed profound cytoplasmic alterations (Fig. 3). The conspicuous absence of glycogen was accompanied by an increase in smooth endoplasmic reticulum which, in some areas, formed whorllike structures. The rough endoplasmic reticulum showed focal loss of ribosomes and slight dilatation of dsternae. Mitochondria varied in size and were moderately swolle n. There was loss of mitochondrial cristae and dense bodies. The pale and finely granular mitochondrial matrix contained occasional dense floccular deposits. The number of peroxysomes was increased above normal and numerous autophagic vacuoles were scattered in the cytoplasm. Small- and medium-sized fatty droplets were also seen. The nuclei showed rarification of the nucleoplasm. The cell membranes and bile canaliculi were normal. No viral particles were seen. When the biopsy was repeated in
The Journal of Pediatrics December 1975
Case 1, the ultrastructure of hepatocytes had returned to normal. In Case 3 the ultrastructural alterations of hepatocytes differed from those discussed i n Cases 1 and 2 and probably represent the early stages of recovery. The smooth endop!asmic reticulum was prominent but glycogen particles were present. The mitoch0ndria varied slightly in size; but showed normal morphology. PeroxYsomes and autophagic vacuoles, however, were still prominent. The bile canaliculi were dilated and contained occasional bile plugs. The nuclei were normal. DISCUSSION The onset, }ypical history, clinical, and biochemical data in the three patients suggested a diagnosis of Reye syndrome. All had a virallike prodrome with apparent improyement followed by acute encephalopathy and laboratory evidence of liver dysfunction. Case 1 fulfilled all the clinical and biochemical criteria for a nonhistologic diagnosis of Reye syndrome including elevated concentration of blood ammonia. 2, 3 Without benefit of liver histology these patients would have been labeled as having Reye syndrome. Findings unusual for Reye syndrome were lack of vomiting prior to the onset of encephalopathy, sudden onset of coma without preceding delirium, Slow recovery of consciousness with severe neurologic sequel a occurring in two of the children, se.vere renal impairment, normal pre-beta fraction on lipoprotein electrophoresis, 5 decreased levels Of/?-I-C globulin, and normal blood ammonia levels in two patients. The light microscopic histol0gic changes in liver biopsies from these patients differed in manY aspects from those described in Reye syndromer -" In early stages of Reye syndrome, liver histology is characterized by diffuse small droplet fatty change Of hepatocytes without necrosis or associated inflammatory lesions. In our patients the main insult affected the centrilobular hepatocytes which showed eoagulative necrosis. Unlike Reye syndrome, the fatty change was focal and confined to the injured hepatocytes surrounding the necrotic areas, suggesting a degenerative rather than a primary phenomenon. Histopathologic findings similar to Reye syndrome were lack of portal inflammation and return to normal within a short time after the acute insult as shown by th e l%llow-up biopsy in Case 1. In spite of extensive investigations the etiology of acute liver disease in our patients ha s not been established. The central areas of the liver lobule (Zone II! of Rappaport) are considered to be more sensitive to injury than peripheral areas, because of lower oxygen tension in the blood supplying the centrilobular hepatocytes than tl~at supplying the peripheral hepat0cytesY Centrilobuiar necrosis of
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Liver disease and encephalopathy mimicking Reye syndrome
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Fig. 3. Case 2. Electron m!crograph of a portionof cytoplasm from an injured hepatocyte. There is complete dep!etion of glycogen particles. The mitochondria (mi) are swollen and show loss of cristae and dense bodies. There is proliferation of smooth endoplasmic reticulum which forms membranous structures (arrow). Numbers of lysozomes (ly) and peroxysomes (pc) are increased. Fat droplet (fd.) and portion of a nucleus (nu) are seen at upper left. (OsO4fixation; x 30,000.)
liver is a nonspecific lesion and has been described in various conditions such as circulatory failure, carbon tetrachloride poisoning, exposure to various toxins, or drugs and some infectious diseases. 9-14 Recently described Ultrastructural changes in liver biopsies from patients With Reye syndrome were considered characteristic. 1~The most severe changes affected the mitochondria suggesting a disturbance in their oxidative function. Alterations in the fine structure of mitochondria, in our caseS, were confined only to hepatocytes in the injured areas but bore some resemblance to those described in Reye syndrome, where they are diffuse. The complete depletion of glycogen from injured hepatocytes in our patients contrasts with the only moderate char~ges in hepatic glycogen Of patients with Reye syndrome. The ultrastrUctural changes seen in our patients are probably not Specific since similar changes have been described in hypoxia, shock, and in various experimental conditions.16. 17
in our patients there was no history of toxic exposure or clinical evidence of shock. The medications prescribed prior to the onset Of the encephalopathy differed in each case so that drug toxicity seems unlikely; ' There was a prodrome suggestive of viral infection, but cultures and Serologic evaluation at the time of the encephalopathy provided no evidence of a specific viral agent. Group A beta hemolytic streptococcal infections have been assodated with widespread tissue involvement and encephalopathy, '8 but bacterial cultures were negative and serum ASO titers were not indicative of recent infection. The low fi-l-C globulin levels suggested an immunologic process with increased consumption of complement by antigenantibody complexes, and this could also have accounted for the associated renal dysfunction. An alternative possibility for the decreased levels of fi-l-C g l o b u l i n is decreased production, as a result of the hepatocellular damage. We believe these patients suffered from a previously
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unrecognized disorder with multiple organ involvement, including brain, liver, kidneys, and possibly pancreas. The clinical and biochemical features could easily be confused with Reye syndrome, a possibility which makes histologic examination of the liver imperative. In the absence o f rigid diagnostic criteria a diagnosis of Reye syndrome should be reserved for children who have typical clinical, biochemical, and histologic features. Our findings suggest that previous studies of Reye syndrome which have not relied on histologic confirmation may include inappropriate cases similar to ours or possibly other disease entities and thus bias evaluation of therapy and prognosis. We wish to thank Dr. J. B. J. McKendry and Dr. D. A. McGreal for permitting us to study their patients and Dr. D. L. Gilday for interpretation of the brain scans. REFERENCES
1. Reye RDK, Morgan G, and Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood, Lancet 2:749, 1963. 2. Glasgow AM, Cotton RB, and Dhiensire K: Reye's Syndrome: I. Blood ammonia and consideration of the nonhistologic diagnosis, Am J Dis Child 124:827, 1972. 3. Samaha EF, Glau E, and Berardinelli JL: Reye's syndrome: Clinical diagnosis and treatment with peritoneal dialysis, Pediatrics 53:336, 1974. 4. Huttenlocher PR: Reye's syndrome: Relation of outcome to therapy, J PEI~IA'rR80:845, 1972. 5. Brown RE, Madge GE, Trauner RB, et al: Lipid and lipoprotein studies in Reye's syndrome, Va Med Mon 99:622, 1972. 6. Schubert WK, Partin JC, and Partin JS: Encephalopathy and fatty liver, in Dopper H, and Schaffner F, editors:
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Progress in liver disease, New York, 1972, Grune & Stratton, pp 489-510. Norman MG: Encephalopathy and fatty degeneration of the viscera in childhood: I. Review of cases at The Hospital For Sick Children, Toronto (1954-56), Canad Med Assoc J 99:522, 1968. Bourgeois G, Olson L, Comer D, et al: Encephalopathy and fatty degeneration of the viscera: A clinicopathologic analysis of 110 cases, Am J Clin Pathol 56:558, 1971. Sherlock S: The liver in circulatory failure, in Schiff L, editor: Diseases of the liver, Philadelphia, 1969, JB Lippincott Company, pp 815-834. Reid WD, and Krishna G: Centrolobular hepatic necrosis related to covalent binding of metabolites of helogenated aromatic hydrocarbons, Exp Mol Pathol 18:80, 1973. Reid WD, Krishna G, Gillette R, et al: Biochemical mechanism of hepatic necrosis induced by aromatic hydrocarbons, Pharmacology 10:193, 1973. Elias H, and Sherrick JD: Morphology of the liver, New York, 1969, Academic Press~ Inc., pp 319. Beckert W: Zentrilobulare parenchymnekrosen der leber. Beitrag zur Kenntnis arzneimittelbedingter Leberschaden, Zentralbl Allg Pathol 117:219, 1973. Child PL, MacKenzie RB, Valverde LR, et al: Bolivian hemorrhagic fever, Arch Pathol 83:434, 1967. Partin JC, Schubert WK, and Partin JS: Mitochondrial ultrastructure in Reye's syndrome. Encephalopathy and fatty degeneration of the viscera, N Engl J Med 285:1339, 1971. Schaffner F: Oxygen supply and the hepatocyte, Ann NY Acad Sci i70:67, 1970. Boler RK, and Bibighaus AJ: Ultrastructural alterations of d o g livers during endotoxin shock, Lab Invest 17:537, 1967. Haddow JE, Sher N, Gall DG, and Green D: Streptococcal wound infection with evidence of widespread tissue involvement, Pediatrics 48:458, 1971.