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Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis.

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Official Journal of The American Rheumatism Association
Section of The Arthritis Foundation
Salicylate Hepatotoxicity in Patients with
Juvenile Rheumatoid Arthritis
Robert R. Rich and John S. Johnson
Salicylates were administered to 6 patients with juvenile rheumatoid arthritis in doses sufficient to produce a serum salicylate level in excess of
25 mg/100 ml. All 6 patients developed elevations of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase. In addition, 4 patients had other evidence of hepatic dysfunction. Abnormalities
were dose-related and were reversible upon lowering the salicylate dose.
Liver biopsies performed in 2 patients revealed a mononuclear cell infiltrate of portal triads in both and scattered single cell necrosis in the
parenchyma in 1case.
After decades of use, chronic salicylate therapy remains of central importance in the care of
patients with arthritis. This is due, in substantial measure, to the relative infrequency with
which such therapy has been associated with
serious adverse side-effects. Nonetheless, certain pathophysiologic processes-eg, alterations
From the Laboratory of Clinical Investigation, National
Institute of Allergy and Infectious Diseases, The National
Institutes of Health, Bethesda, Md.
ROBERT R . RICH, MD: Department of Pathology, Harvard
Medical School, Boston, Mass; JOHN s. JOHNSON, MU:
Scripps Clinic and Research Foundation, La Jolla, Calif.
Reprint requests should be addressed to: Dr. Rich or Dr.
Johnson. National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Building 1011N232, Bethnda, Md 20014.
Submitted for publication April 4, 1972; accepted October 10.1972.
in platelet function ( l ) , prolongation of bleeding time (2,3) and erosion of gastric mucosa (4), are now recognized as frequent concomitants of aspirin ingestion. Manso and
colleagues (5), in 1956, reported elevations of
serum glutamic oxaloacetic transaminase
(SGOT) and serum glutamic pyruvic transaminase (SGPT) activities in children at Irvington House receiving sustained salicylate therapy in daily doses of 0.6 to 1 g/15 lb of body
weight. More than half of the patients studied,
both patients with possible rheumatic fever and
those without evidence of rheumatic disease, developed elevations of one or both enzymes. Recently Russell et al (6) reported transient elevations of serum transaminase levels in 8 of 32
juvenile patients suffering from chronic poly-
Arthritis and Rheumatism, Vol. 16, No. 1(January-February1973)
arthritis and in 1 patient with dermatomyositis.
These abnormalities were reversibly associated
with salicylate therapy; the serum salicylate
level was greater than 35 mg/100 ml in all cases
except one. Two of these patients also had elevations of serum alkaline phosphatase. The significance of these reports is uncertain, however,
since other parameters of liver function were not
systematically studied, clinical hepatitis was
apparently not observed and liver biopsies were
not performed. It is, in fact, generally thought
that salicylates, even in large dosage, do not
damage the hepatic parenchyma, as indicated
by usual tests of liver function (7). The present
investigation followed observation of abnormal
liver function in several patients with juvenile
rheumatoid arthritis (JRA) coincident with salicylate therapy.
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APfl 19 JUN9
Six patients with JRA were treated in The National Institutes of Health (NIH) Clinical Center with large sustained doses of salicylates, sufficient to result in serum
salicylate levels in excess of 25 mg/100 ml. Salicylate therapy was administered as aspirin, choline salicylate or sodium salicylate. To facilitate comparison, doses of choline
and sodium salicylate are expressed as equivalent milligram
salicylate doses of aspirin. Each drug was administered
daily in 6 equally divided doses, given at 4-hour intervals.
Serum salicylate levels were measured 4 hours after the
most recent dose.
Although only 3 patients were in the juvenile age group
when studied, the diagnosis of JRA was regarded as well established, according to the criteria of Ansell and Bywat e n (8),in all except Case 3, a 19-year-old man with a
poorly understood constitutional illness who had an identical twin with typical JRA. Bentonite flocculation test for
rheumatoid factor was consistently negative in all patients.
Renal function of all patients was normal.
All laboratory studies were performed in the routine clinical laboratories of the Clinical Center. Normal values and
methods in these laboratories include the following: SGOT
8 to 40 Karmen units(9); SGPT 5 to 35 Karmen
units (10); serum lactic dehydrogenase (LDH) males: 200
to 600 units, and females: 200 to 500 units (1 1); total serum
bilirubin up to 1.2 mg/100 ml (12); serum alkaline
phosphatase adults: 0 to 78 IU, children: 75 to 115 IU (13);
and brornsulfalein retention (BSP) less than 5% at 45 minutes (14). Serum salicylate levels were determined by the
method of Keller (15). Addition of choline salicylate to nor-
Fig 1. Correlation of serum salicylate level during
aspirin therapy with hepatic dysfunction in Case 1
(Patient BP). SGOT (o---o); SGPT (A- . -A); serum
alkaline phosphatase (0-0);
serum lactic dehydrogenase (m-m); (*) denotes development of bilirubinuria.
ma1 serum in vitro to yield a serum salicylate level of 30
mg/100 rnl had no effect on SGOT or SGPT determination.
Case 1
BP, a 2 1-year-old male, developed a migratory polyarthritis at age 12. This was followed, 2 to 3 years later, by a severe deforming arthritis involving all major joints of the extremities, the temporomandibular joint and the cervical
spine. Spiking fevers, weakness, muscle wasting and general
debilitation were particularly notable for several months
preceding N I H admission. The patient had never been
treated with sustained high-dose salicylate therapy. There
was no history of liver disease; there was no hepatomegaly.
He received several blood transfusions at age 16 for chronic
anemia but none since that time. He was taking no medications at the time of admission.
During his hospitalization the patient was treated with
aspirin in doses of 100 to 150 mg/kg/day. A dose of 100
mg/kg/day was inadequate on three occasions to control
active arthritis. Two courses of aspirin, 150 mg/kg/day,
were accompanied by elevation of serum salicylate level to
greater than 30 mg/100 mi and concomitant deterioration
Arthritis and Rheumatism, Vol. 16, No. 1(January-February 1973)
Case 2
CA, a 13-year-old female, entered with a history of
polyanicular rheumatoid arthritis and iridocyclitis since
age 4. The patient had not received chronic salicylate therapy in high doses. There was no history of liver disease or
blood transfusion. Her liver was not enlarged.
The patient received no systemic drugs except aspirin
during her hospitalization. Aspirin dose ranged from 45 to
75 mg/kg/day. Good symptomatic relief of joint symptoms
was obtained with doses in excess of 50 mg/kg/day; at
lower doses serum salicylate level fell below 15 mg/lOO ml
and symptomatic relapse occurred. Two courses of therapy
with aspirin at 75 mg/kg/day were associated with serum
salicylate levels above 25 mg/100 ml, and with elevations of
SGOT and SGPT (Figure 2). On Day 40, at the time of the
second rise in hepatic enzymes, the patient complained of
abdominal pain, food intolerance and anorexia. Eosinophil
count was 94/cu mm on admission and rose to 440/cu mm
before the second enzyme elevation. Australia antigen, antinuclear antibody titer, bilirubin, L D H and alkaline
phosphatase remained normal or negative throughout.
Case 3
SF, a 19-year-old male, was well until age 17 when he
Fig 2. Elevations of SGOT (0---0) and SGPT
(A- . -A) with aspirin therapy in Case 2 (Patient
of liver function (Figure 1). Each of these courses was also
associated with nausea, vomiting and anorexia for several
days. During the final 50 days of hospitalization the patient
was maintained on a constant aspirin dose of 125 mg/kg/
day. At this level the patient’s arthritis was well controlled,
serum salicylate levels varied from 23 to 28 mg/100 ml and
hepatic function remained normal. Except for aspirin, the
patient received no medications during his hospitalization
but occasional doses of propoxyphene or meperidine.
Hematocrit was 27% on admission and rose to 38% prior
to discharge. White blood cell count was 5,300 to 14,2OO/cu
mm. Eosinophil count was 90/cu mm on admission and
rose to 735/cu mm on aspirin therapy. Antinuclear antibody titer was less than 1:lO; lupus erythematosus cell
preparations were negative and Australia antigen was not
detected. Serum bilirubin was consistently normal, but rose
from 0.5 mg/lOO ml on admission to 1.0 mg/100 ml on Day
26. at the time of the enzyme peak and concomitant with the
development of bilirubinuria. An oral cholecystogram was
normal. Rectal biopsy, with stains for amyloid, was unremarkable. Permission to perform percutaneous liver biopsy
was denied.
- 500 g
- 250
29 JULY9
29 AUG8
Fig 3. Deterioration of liver function with high
serum salicylate levels during aspirin therapy in
Case 3 (Patient SF). SGOT (0-0); SGPT (A- . -A):
serum alkaline phosphatase (0-0);
serum lactic
dehydrogenase (W-W).
Arthritis and Rheumatism. Vol. 16, No. 1(January-February1973)
developed intermittent fever and myalgias associated with
left upper quadrant abdominal pain and splenomegaly. His
only articular complaints were modest joint stiffness and occasional transient pain in the knees. There was no history
of liver disease or transfusion. He had an identical twin
with typical JRA. The patient's spleen was palpable 5 cm
below the left costal margin; the liver was not enlarged.
There was bilateral axillary lymphadenopathy. Neither
joint abnormalities nor evidence of muscle disease were observed.
The patient was treated with aspirin during his hospitalization, with doses ranging from 0 to 90 mg/kg/day.
Each of two courses of 90 mg/kg/day was associated with
serum salicylate levels in excess of 30 mg/lOO ml and on
each occasion the patient reported malaise, anorexia, nausea and loss of taste for cigarettes. Substantial elevations of
S C O T and SGPT and smaller increments of LDH and alkaline phosphatase were concomitants of high serum salicylate levels (Figure 3). Serum bilirubin remained within
normal limits. Eosinophil count was 70/cu m m on admission and 924/cu mm at discharge. During the final 16 days
of hospitalization an aspirin dose of 60 mg/kg/day adequately controlled symptoms while tests of liver function
remained normal and serum salicylate level varied about
15 mg/100 ml.
Other laboratory studies that were normal or negative included lupus erythematosus cell preparation, antinuclear
antibody titer, serum test for Australia antigen and serum
proteins. Liver biopsy, when liver function was abnormal,
was precluded by prolongation of partial thromboplastin
Fig4. SGOT (0---0) and SGPT (A- . -A) during
therapy with choline salicylate and sodium salicylate in Case 4 (Patient NT).
2800 to 4400/cu mm. Antinurlear antibody was not detected.
Case 4
NT, a 48-year-old female, suffered recurrent febrile illness with frequent anhralgias throughout childhood. These
were associated with growth retardation and development
of micrognathia. After the second decade she was well until
age 43, when she developed severe polyarticular seronegative rheumatoid arthritis. Moderate control was achieved
with salicylates and prednisone. Nine months prior to admission the patient had begun therapy with cyclophosphamide, 75 mg/day. There was no history of liver disease or
blood transfusion; there was no hepatomegaly.
Therapy during hospitalization included both choline
and sodium salicylate in doses equivalent to 60 to 90 mg/
kg/day of aspirin. Cyclophosphamide was reduced from 75
mg/day to 50 mg/day on Day 16 and maintained at that
dose thereafter.
Bilirubin, LDH and alkaline phosphatase remained normal throughout hospitalization. Modest elevations of
SGOT and SCPT (Figure 4) were not accompanied by
symptoms suggestive of hepatitis. Eosinophil count was
310/cu m m on admission and rose to 570/cu m m just prior
to the peak in hepatic enzymes. White blood cell count was
Case 5
SC, a 4-year-old female, was admitted with generalized
lymphadenopathy, hepatosplenomegaly, a macular rash,
and a 1-year history of periodic high fever and polyarthritis.
There was no history of liver disease or blood transfusion.
The patient had been receiving chronic salicylate therapy
prior to admission and at the time of initial evaluation
SCOT was 100 units, SGPT 19 units and LDH 1180 units.
She was treated with choline salicylate during her hospitalization, usually at a dose of 130 mg/kg/day, but with
several brief trials at 160 mg/kg/day. Lower doses were entirely unsuccessful in control of either arthritis or constitutional illness. Other medications included only ferrous
gluconate and multiple vitamins.
Liver function remained abnormal throughout the treatment period (Figure 5). Serum alkaline phosphatase rose
from 75 to 146 IU on therapy. Bilirubin remained normal.
Hematocrit was 28 to 36% and white blood cell count
11,000 to 37,00O/cu mm.Eosinophil count was 400/cu m m
Arthritis and Rheumatism, Vol. 16, No. 1(January-February1973)
at the time of admission, rose to 4900/cu mm on Day 10,
was 2350/cu mm on Day 43, and thereafter fell slowly to 0.
Antinuclear antibody was not detected, lupus erythematows cell preparations were negative and Australia antigen
was not present.
On Day 94 the patient underwent percutaneous liver
biopsy. At this time salicylate level was 12 mg/lOO ml,
SGOT 158 units, LDH 2000 units, eosinophil count 0 and
BSP retention 0% at 45 minutes. Biopsy demonstrated minimal infiltration of portal triads with mononuclear inflammatory cells. No parenchymal necrosis was observed.
Case 6
2010 -
Fig 5. Hepatic dysfunction correlated with choline salicylate administration in Case 5 (Patient SC).
SGOT (0---0);serum lactic dehydrogenase(-.-).
GS, a 12-year-old male, was admitted to the Clinical
Center several months after the onset of an illness characterized by a macular rash, spiking fevers, conjunctivitis,
lymphadenopathy, splenomegaly and polyarthritis. There
was no history of liver disease or transfusion. Hepatomegaly was not observed.
T h e patient had received high-dose salicylate therapy
prior to admission, and liver function was abnormal at the
time of initial N I H evaluation (Figure 6). Prior to initiation
of therapy 2 months previously, however, SGOT was 32
units, S G P T 11 units and LDH 609 units.
The patient was treated with choline salicylate in a dose
equivalent to 125 mg/kg/day of aspirin. His only additional medication was ferrous gluconate. Arthritis was adequately controlled on this regimen but he developed clinical
hepatitis. In addition to the abnormal liver function studies
illustrated in Figure 6, BSP retention was 29% at 45 min-
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FEE3 MAR13 23
Arthritis and Rheumatism, Vol. 16, No. 1(JanuaryFebruary 1973)
Fig 6. Abnormal liver function during two separate courses
of salicylates in Case 6 (Patient
GS). Choline salicylate was administered during t h e first
course, aspirin during the second. Arrows denote percutaneous liver biopsies: (*) indicates
development of bil'irubinuria;
SGOT (o---o); SGPT (A- . -A);
serum lactic dehydrogenase
Fig7. Liver biopsy during second course of salicylate therapy i n Case 6 (Patient GS). Infiltra.
tion of periportal tissue with mononuclear inflammatory cells is observed (H & E. x 100).
utes and serum alkaline phosphatase rose from 98 to 133
IU. Lupus erythematosus cell preparations, negative on
three occasions early in the hospital course, became positive
on Day 25. Antinuclear antibody titer, originally less than
1 :lo, rose to 1 :320 on Day 26. Serum test for Australia antigen was consistently negative.
Percutaneous liver biopsy was performed on Day 13 and
revealed moderate numbers of mononuclear inflammatory
cells in portal areas with scattered single cell necrosis in the
parenchyma. There was no vasculitis.
On Day 25 the patient developed unexplained agranulocytosis and salicylate therapy was consequently discontinued. The abrupt fall in serum salicylate levels coincided
with a prompt return of hepatic enzymes to normal values.
Serum bilirubin rose briefly to 2.3 mg/100 ml and then also
reverted to normal. Lupus erythematosus cell preparations
reverted to negative in 3 weeks and antinuclear antibody titer again fell to less than 1:lO. After a 10-day period of
profound agranulocytosis, the patient’s bone marrow gradually recovered and peripheral granulocyte count returned
slowly to normal.
The patient was restudied 2 years later when, at age 14,
his arthritis was in spontaneous remission. Aspirin, rather
than choline salicylate, was administered. The dose was
gradually increased during the first 15 days of therapy from
10 to 100 mg/kg/day. Liver function studies remained normal during this period, with serum salicylate level never exceeding 17 mg/100 ml. After 5 days of aspirin at 100 mg/
kg/day, SGOT and SGPT again became abnormal; serum
salicylate peak was 21 mg/100 ml (Figure 6). On this occasion, LDH, bilirubin and alkaline phosphatase remained
within normal limits, lupus erythematosus cell preparation
remained negative and antinuclear antibody titer was consistently less than 1 :lo. Percutaneous liver biopsy was performed on Day 23 and again revealed moderate infiltration
of portal triads with mononuclear inflammatory cells (Figure 7). however necrosis of parenchymal cells was not again
observed. Scattered mast cells were seen in the parenchyma
and portal areas with toluidine blue stain. Aspirin was then
discontinued and SGOT and SGPT returned rapidly to
normal. Eosinophil count was 175/cu mm on admission,
rose to 485/cu mm with aspirin administration, fell to 125,’
cu mm at the time of hepatic enzyme peak and was 280/cu
mm at discharge.
Arthritis and Rheumatism,Vol. 16, No. 1(January-February1973)
Six patients with JRA were treated with
salicylates in dosages sufficient to raise serum
salicylate levels to above 25 mg/100 ml. All
developed hepatic dysfunction evinced by
disturbances in routine liver function studies.
Elevation of SGOT and SGPT activities was
most consistent and striking and was regularly
associated with peaks in serum salicylate concentration. Additionally, 4 patients had elevated
L D H levels, 4 had elevated alkaline phosphatase, 1 had excessive BSP retention, 1 had elevation of serum bilirubin and 2 had bilirubinuria, in every case concomitant with S G O T
and SGPT elevations. At the time of hepatic
dysfunction 4 of the 6 patients had symptomatic
complaints typical of clinical hepatitis. No
patient had a history of nor evidence of liver disease antedating salicylate therapy, and in no
case was Australia antigen present in the serum. Finally, all patients also developed significant eosinophilia at some time during the
course of salicylate therapy. In 4 of the 6 cases
onset of eosinophilia preceded liver enzyme
rises. Maximal disturbance in hepatic function,
however, was consistently associated with a fall
in eosinophil count.
Changes in hepatic function are not generally
thought to be associated with chronic salicylate
ingestion, even in large doses (7, 16). The
present investigation suggests, to the contrary,
that disturbances of liver function occur regularly in patients with JRA treated with salicylates in doses sufficient to raise serum levels
above 25 mg/100 ml. These data confirm and
extend the observations of Manso et aZ(5) that
a majority of patients, with or without evidence
of acute rheumatic fever, developed elevations of
SGOT and SGPT 6 to 32 days after beginning
a course of salicylates, and the report of Russell
et a1 (6) of elevated serum transaminase levels
in juvenile patients with chronic polyarthritis
and high serum salicylate levels.
Comparison of the data from these studies
permits broader interpretation of their significance. Salicylate hepatotoxicity was observed
only among children by Manso and in only 1
patient, with preexisting liver disease, of 18
adults studied by Russell. However, duration or
dose of therapy or both were lower in adults
than children treated by these investigators.
Half of the patients in the present series were
adults. Consequently, although children may be
more susceptible they are not uniquely predisposed to this entity. In no study was hepatotoxicity a property of a specific salicylate preparation. Aspirin and sodium and choline salicylates
all regularly produced liver dysfunction in similar doses.
A difference in patient populations, JRA in
the reports of Russell (6) and ourselves, individuals with or without rheumatic fever in the
study of Manso (5), suggests that these effects
are not peculiarities of a particular disease but,
rather, a general consequence of salicylate therapy in high doses. T h e hepatic involvement reported in 5 cases of JRA by Schaller et al (17)
appears unlike that observed in conjunction
with salicylate therapy. These patients all had
massive hepatomegaly and profound systemic
manifestations of JRA. In no case could abnormal hepatic function be related to therapy, although all patients were thought to have received salicylates sporadically. It was correlated
instead with the magnitude of hepatomegaly
and severity of other systemic manifestations.
Conversely, among our patients hepatomegaly
was observed in only 1 of 6 patients. Moreover,
abnormal liver function was clearly related to
high-dose salicylate therapy. Hepatotoxicity
was maximal at times when arthritis was under
good control with salicylates and remitted when
therapy was reduced or discontinued and
exacerbations of arthritis were permitted. Nevertheless, because of the occasional association
of JRA and liver disease, some predisposition of
patients with JRA to the development of salicylate hepatotoxicity must be considered until
larger studies clarify the relationship of these
apparently separable entities.
Manso (5) reported no consistent relation of
serum salicylate levels to serum enzyme activi-
Arthritis and Rheumatism, Vol. 16, No. 1(January-February 1973)
ties. Conversely, abnormalities were usually observed by Russell (6) only with serum salicylate
concentrations above 35 mg/100 ml, although
specific correlations are presented for only 1
patient. In the present study maximal hepatic
dysfunction was well correlated with serum
salicylate peaks. As previously noted, every
patient on chronic therapy who developed a serum salicylate level greater than 25 mg/100 ml
evinced hepatotoxicity. Furthermore, in only
one instance did abnormal liver function develop below that level. It was, in general, possible to carefully titrate salicylate dosage to
achieve symptomatic control of arthritis at a
dose below that causing deterioration of liver
function. T h e therapeutic index was often, however, strikingly narrow.
It is clearly more difficult to sustain high serum salicylate levels in an out-patient population than in our unusual setting of long-term
hospital care. This may partially explain the
general failure to previously recognize salicylate
hepatotoxicity. If so, it suggest that therapy
usually regarded as somewhat suboptimal for
control of arthritis may be preferable in the
chronic management of these patients.
Both Manso (5) and Russell (6) considered
the possibility of a direct effect of salicylates
upon the rate of the transamination reaction or
upon the optimal density of the reaction mixture. However, the in vitro addition of aspirin
or sodium salicylate to the test solutions had no
effect on either variable. O u r observations following addition of choline salicylate to normal
serum in vitro confirm this conclusion. S G O T
values in our investigation were all determined
by a modification of the specific enzyme method
of Karmen (9), thereby mitigating against colorimetric interference (18). Moreover, the
present study provides more convincing evidence of significant hepatic dysfunction. Not
only were S G O T and S G P T activities elevated,
but L D H , alkaline phosphatase, serum or urine
bilirubin, or BSP retention were abnormal in
some patients. Moreover, 4 of the 6 patients had
a clinical illness compatible with acute hepatitis
at the time of maximal serum salicylate levels
and maximal liver dysfunction.
Histologic confirmation of active liver disease
was obtained on two different occasions in 1
patient, with single cell parenchymal necrosis
and infiltration of portal triads with mononuclear inflammatory cells and mast cells. One
cannot generalize regarding the histology of the
hepatotoxic reaction from this single case, since
this patient (Case 6) also uniquely developed, at
the time of the first biopsy, transiently positive
lupus erythematosus cell preparations, elevated
antinuclear antibody titers and agranulocytosis.
These features did not recur with aspirin challenge, and hepatic dysfunction and liver biopsy,
2 years later. It is nonetheless possible that in
this case both toxic and hypersensitivity mechanisms were of pathogenetic significance. Liver
biopsy of a second patient (Case 5) revealed
only minimal portral infiltration with mononuclear cells, without evidence of parenchymal
disease. This biopsy was performed at a time
when S G O T was returning rapidly to normal,
23 days after peak activity, and it is possible
that partial healing of a histologic lesion had occurred in the interval. These biopsy findings are
obviously relatively nonspecific. Histologic examination of patients with JRA and hepatomegaly by Schaller et a1 (17) also revealed periportal infiltration with chronic inflammatory
cells, although parenchymal necroses were not
Several important questions remain unanswered by this investigation. First, the report of
Manso (5) notwithstanding, the effect of highdose chronic salicylate therapy on ,liver function
of normal individuals remains uncertain. Salicylate hepatotoxicity was observed in all
patients in our treatment group, however, administration of aspirin to control subjects in
similar doses and regimens was felt unwarranted. Second, the histology of the hepatotoxic
reaction will require further delineation. Finally, it is not clear from these data whether or
not the liver eventually becomes tolerant of
chronically administered salicylates in large
Arthritis and Rheumatism, Vol. 16, No. 1(January-February 1973)
doses. It is apparent that hepatic dysfunction
can persist for weeks on salicylate therapy and,
also, that discontinuation of the d r u g or lowering the dose results in prompt improvement in
function. Previous failure to recognize this entity, however, suggests that chronic liver disease
does not commonly develop in this population.
It is possible, instead, that after weeks or
months of sustained therapy at hepatotoxic
doses, liver function spontaneously returns to
normal by some process of metabolic accommodation. T h i s difficult but important question
also remains for further study. Until these questions a r e resolved, we urge the regular determination of routine liver function studies a n d serum salicylate levels in patients receiving
chronic high-dose salicylate therapy.
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Arthritis and Rheumatism, Vol. 16, No. 1(January-February 1973)
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patients, hepatotoxicity, arthritis, juvenile, rheumatoid, salicylates
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