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Histopathologic findings in the liver of rheumatoid arthritis patients treated with long-term bolus methotrexate.

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Arthritis & Rheumatism
Official Journal of t h e American Rheumatism Association
HISTOPATHOLOGIC FINDINGS IN THE LIVER OF
RHEUMATOID ARTHRITIS PATIENTS TREATED WITH
LONG-TERM BOLUS METHOTREXATE
JULIO APONTE and MARY PETRELLI
Twenty-three patients with severe rheumatoid
arthritis were treated with oral methotrexate (MTX) for
more than 10 years. MTX was given as a bolus of 5-15
mg/week; the total cumulative dose ranged from 4,690
mg to 10,230 mg. Liver biopsies were performed on 21
of the patients to assess possible fibrosis and cirrhosis.
Grade I histopathologic changes were found in 13 of the
21 biopsy samples, grade I1 changes were found in 3,
and grade IIIA changes (mild fibrosis) were found in 5
specimens. None of the biopsy samples showed cirrhosis.
Repeat biopsies were performed on the 5 patients with
grade IIIA changes while they were still taking MTX.
No progression of the fibrosis was noted. Two of the 5
samples, however, were graded IIIB because of portal
and perilobular inflammation. Our findings support the
premise that prolonged administration of oral MTX,
when given as a weekly bolus at a low dose, does not
cause cirrhosis or severe fibrosis in the rheumatoid
arthritis patient who does not abuse alcohol.
From the Departments of Medicine and Pathology, Cleveland
Metropolitan General Hospital at Case Western Reserve University.
and the Department of Medicine. Fairview General Hospital. Cleveland, Ohio.
Julio Aponte, MD. FACP: Department of Medicine, Cleveland Metropolitan General Hospital at Case Western Reserve University and Fairview General Hospital: Mary Petrelli, MB, BS, FRCPath:
Department of Pathology, Cleveland Metropolitan General Hospital at
Case Western Reserve University.
Address reprint requests to Julio Aponte, MD, FACP.
Fairview General Hospital, 18101 Lorain Avenue, Cleveland, OH
44111.
Submitted for publication February 23, 1988: accepted in
revised form July 14, 1988.
The use of methotrexate (MTX) in the treatment of nonmalignant diseases has been debated since
it became evident that the drug had significant antiinflammatory effects (1-3). The largest qnd longest
experience with the use of MTX in treating benign
diseases has been in the treatment of psoriasis ( 4 3 .
Soon after the first reports of positive results in
MTX-treated patients with psoriasis, a number of
investigators found that significant hepatotoxicity,
with progression to cirrhosis, developed in patients
taking this medication (6-18).
In rheumatoid arthritis (RA) patients, however,
the number and degree of liver abnormalities associated with MTX treatment have been lower (19-26).
Results of open studies of MTX therapy in RA patients
have been encouraging. A good risk:benefit ratio has
been found (27-341, and in 6 double-blind studies, the
drug has been shown to be effective (35-40). In our
experience with RA patients, use of a once-a-week,
low-dose bolus of oral MTX has been associated with
few toxic effects, and this regimen has been well
tolerated and effective over prolonged periods of therapy (41).
The inconsistent correlation between findings
from liver function tests and from histopathologic
examinations of the liver are well known. Therefore,
the only reliable tests for evaluating chronic hepatotoxicity is liver biopsy. Because the effects of longterm exposure to MTX in RA patients are not known,
and because we considered a I0-year period sufficient
for any possible histopathologic changes to appear, we
conducted a histopathologic investigation of changes
Arthritis and Rheumatism, Vol. 31, No. 12 (December 1988)
1457
APONTE AND PETRELLI
Table 1. Clinical characteristics of 23 patients with rheumatoid arthritis undergoing long-term treatment with methotrexate (MTX)*
Patient
Total
History
cumulaof
Duration Duration
tive
History elevated
of
of
dose of
RheumaAlcohol
of
liver
Age1 disease treatment MTX
toid
Disease CRP consump- Sjogren's
macro- enzyme
sex
(years) (years)
(mg) RF nodules activity (mgldl)
tion
syndrome Obesity cytosis levels
1
601M
14
12
7,380
2
3
4
5
6
7
8
9
10
14
41
23
26
18
20
13
13
20
12
11
10
25
20
12
23
16
24
16
16
11
19
13
14
20
11
14
12
13
14
1.5
16
17
18
19
20
21
591F
70lF
71lF
81/F
68lM
69lM
53lM
63lF
73lM
731F
60lF
56lF
40lM
65lF
62lF
56lM
68lM
60lM
801F
711F
19
5,265
6,760
7,800
4,690
7,370
5,100
4,750
5,600
5,460
5,150
5,200
5,740
6,370
6, I60
5.650
5,200
7.800
5,320
5.070
10,230
22
23
60lF
60lF
16
13
12
12
4,950
5,070
11
I5
10
10
10
12
13
13
10
10
15
10
13
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
1+
2.2
2+
2+
2+
2+
2+
2+
2+
I+
15.3
7.3
1.9
45.3
5.6
4.0
12.5
3.2
30.2
4.3
3.6
16.7
I .3
12.7
7.7
36.0
25.7
0.0
15.0
4.0
0
0
9.2
4.6
I+
2+
2+
3+
2+
0
0
0
2+
2+
0
2+
Before
MTX
Very rare
Frequent
Rare
No
Very rare
No
Very rare
Very rare
Frequent
Very rare
Very rare
Occasional
Occasional
Occasional
Occasional
No
Very rare
Occasional
No
Occasional
to often
No
No
~~~
NSAID
No
No
Yes
No
Sulindac
Yes
No
Yes
No
Yes
Yes
No
Yes
No
No
Yes
No
No
Yes
No
No
No
No
No
Yes
No
No
No
No
No
Yes
Yes
No
No
No
No
No
Yes
No
Yes
No
No
Yes
No
No
No
Yes
Yes
No
No
No
Yes
No
Yes
No
No
Yes
Yes
No
No
No
No
No
No
No
No
Yes
Yes
No
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
Yes
No
No
No
Yes
Naproxen
Naproxen
Aspirin
Aspirin
Naproxen
Naproxen
Naproxen
Naproxen
Naproxen
Naproxen
Naproxen
Naproxen
Aspirin
Aspirin
Naproxen
Naproxen
Aspirin
Naproxen
Sulindac
Naproxen
No
No
No
No
No
No
No
No
Naproxen
Naproxen
~~
~~
* MTX was given as a weekly oral bolus of 5-15
RF
=
mg (mean 10.1, mode 7.5). Disease activity was graded on a scale of 0 (inactive) to 3 + (severe).
rheumatoid factor; CRP = C-reactive protein, NSAlD = nonsteroidal antiinflammatory drug.
in the liver of RA patients w h o had been treated for
more than 10 years with a weekly oral bolus of MTX.
PATIENTS AND METHODS
The study group consisted of 23 white patients with
severe RA (9 men and 14 women) who had been treated with
MTX for more than 10 years (range 10-20 years, mean 12.6
years). At the time of the first liver biopsy, the total
cumulative dose ranged from 4,690 mg to 10,230 mg (mean
8,828) (41). All patients fulfilled the American Rheumatism
Association criteria for classic RA (42).These 23 patients are
among the cohort of 123 patients with severe RA who were
treated with a 5-15-mg bolus of MTX each week for more
than 1 year (mean weekly dose 10.1 mg, mode 7.5 mg), as
described elsewhere (41).
Pertinent clinical data are summarized in Table 1. In
addition to the medical conditions shown in the table,
patients I , 3, 4, 11, 17, 18, and 20 had arteriosclerotic
cardiovascular disease; patients 4, 5, 14, 15, 16, and 20 had
hypertension; and patients 6, 7, 9, 12, 16, 21, and 22 had
peptic ulcer disease. There was no clinical evidence of liver
disease in any of these patients, and their liver enzyme levels
at the time of liver biopsy were normal, except in patient 21.
There were no contraindications for liver biopsy. Two
patients refused to undergo liver biopsy. Both patients were
Women, were not obese, did not abuse alcohol, and did not
differ from the other RA patients in disease severity, disease
duration, and total cumulative dose and duration of MTX
treatment.
Each patient was admitted to Fairview General Hospital, and a clinical evaluation and the following laboratory
tests were done: complete blood cell count, serum protein,
albumin, prothrombin time, partial thromboplastin time,
C-reactive protein, and serum liver enzyme determinations,
including lactate dehydrogenase, serum glutamic oxaloacetic
transaminase (SCOT), serum glutamic pyruvic transaminase
(SGPT), alkaline phosphatase, and gamma glutarnyl transpeptidase (GGTP).
Liver biopsies were performed by one of us (JA),
with the patient under local anesthesia with 2% lidocaine.
The technique described by Menghini (43) was used for all
biopsies. The liver biopsy specimens were fixed in 10%
buffered formalin, processed, and embedded in paraffin.
Sections (5p) were stained with hematoxylin and eosin and
Masson trichrome. Staining for iron was performed on
selected samples.
The biopsy specimens were identified only by code
number, were included among other liver biopsy samples
LIVER STUDIES OF MTX-TREATED RA PATIENTS
1459
obtained in a clinical setting, and were examined by 2
pathologists who had no knowledge of the clinical history of
the patient from whom the material was obtained. One of the
pathologists (MP) has a specific interest and expertise in
hepatic pathology. The histopathologic findings were classified and graded according to established guidelines for
MTX-treated patients, as revised by Roenigk et a1 (8). The
hepatic changes were graded from I to IV, in progressive
order of severity. In this revised classification scheme, grade
I11 is divided into A and B to denote the degree of inflammation and portal and septal fibrosis. Grade IIIB denotes the
more extensive changes, but without cirrhosis.
RESULTS
A total of 26 liver biopsies were performed on
21 patients. The 5 patients with grade IIIA changes
underwent a second biopsy 12-44 months after the first
biopsy, while still receiving MTX treatment. There
was no evidence of cirrhosis in any of the samples.
Biopsy samples from 2 patients were normal; the other
24 samples showed abnormalities of varying degrees.
Table 2. System used to grade abnormalities noted in liver
biopsy specimens obtained from rheumatoid arthritis patients
undergoing long-term treatment with methowexate*
Grade, appearance
Grade I
Normal; fatty changes, anisonucleosis,
and/or mild portal inflammation
Grade I1
Fatty changes, anisonucleosis, portal
inflammation, and
moderate-to-severe, spotty,
hepatocellular necrosis of lobules
Grade IIIA
Grade I or grade 11 abnormalities,
with mild portal fibrosis and with or
without short septa extending into
the lobule
Grade IllB
Grade IIIA changes, with piecemeal
necrosis or moderate-to-severe
portal septal fibrosis, with portal-toportal or central-to-portal bridging;
no cirrhosis
Grade 1V
Cirrhosis; fibrosis, loss of
architecture, and nodular
regeneration
No. at
initial
biopsy
(n = 21)
No. at
second
biopsy
(n = 5 )
13
0
3
I
5
2
0
2
0
0
* Classification and grading according to Roenigk et al (8). Two
patients (patients 22 and 23) refused to undergo liver biopsy. Initial
biopsy material from 5 patients was graded IIIA; those patients
underwent a second biopsy 1 2 4 4 months later.
Figure 1. Liver biopsy specimen obtained from patient 6, showing
macrovesicular steatosis and moderate anisonucleosis (hematoxylin
and eosin stained, original magnification x 500).
The overall histopathologic changes are summarized
in Table 2 and are described below.
Among the initial biopsies, anisonucleosis was
noted in samples from 19 of the patients. These
changes were classified as mild in 13 patients and
moderate in 6 patients. Variable numbers of glycogenated nuclei were seen (Figure I).
Hepatic steatosis (fatty changes in the hepatocytes) of macrovesicular type was also noted in
some of these samples. The degree of accumulation of
fat was determined in a semiquantitative manner by
one of us (MP), as follows: <25% = involvement of
scattered hepatocytes throughout the biopsy specimen, and 50% involvement of hepatocytes in at least 2
lobules; 25-50% = involvement of <50% of all hepatocytes in 25-50% of the lobules; >50% = involvement of >50% of all hepatocytes in all lobules. Fat
accumulation in 4 samples was graded <25%, in 2
samples it was graded 25-50%, and in 1 sample it was
graded >50%.
Portal and lobular inflammation was more pronounced in the biopsy samples with grade IIIA
changes. The inflammatory infiltrate predominantly
consisted of lymphocytes and was confined within the
portal areas. The bile ducts were normal. Spotty
hepatocellular lobular necrosis with inflammation was
an infrequent finding. When present, it was of a mild
APONTE AND PETRELLI
1460
Figure 2. Second (“repeat”) biopsy specimen obtained from patient 21, showing mild portal fibrosis, with short septa, portal
inflammation, and steatosis. The lobular architecture is normal
(Masson trichrome stained, original magnification X 75).
degree, except in 1 sample that showed moderate
inflammation. KupEer cell hyperplasia was seen occasionally.
Mild portal fibrosis, with infrequent short septa
and minimal patchy sinusoidal centrilobular fibrosis
(zone 3 of the Rappaport lobule), was present in 5 of
the initial 21 biopsy samples. There was no loss of the
normal architecture, no complete septa1 formation,
and no nodular regeneration.
Other histologic changes in these initial biopsy
specimens included cholestasis in 1 sample, epithelioid
cell granulomas with inflammation in 2 samples, and
lipogranulomas in 1 sample. Three biopsy specimens
had various degrees of sinusoidal dilatation and congestion, with mild focal sinusoidal fibrosis.
Among the 5 patients who underwent repeat
biopsies because of grade IIIA changes in the initial
samples taken, there was no increase in fibrosis and no
cirrhosis in the sections obtained from 4 of the patients. In l patient, repeat biopsy showed no fibrosis,
and the findings were downgraded to 11. Lipogranulomas were present in samples from 2 patients. This
finding had been noted in the initial biopsy samples
Figure 3. Higher magnification of the biopsy specimen shown in Figure 2, showing portal and
periportal inflammation and focal erosion of the limiting plate, with liver cell degeneration and
lymphocytic infiltration. Note degenerated bile duct (arrow) (hematoxylin and eosin stained, original
magnification x 310).
LIVER STUDIES OF MTX-TREATED RA PATIENTS
1461
Figure 4. Higher magnification of the portal area in Figure 3, showing focal perilobular hepatitis and
septa1 fibrosis (hernatoxylin and eosin stained, original magnification x 500).
from 1 of these patients, but the other patient’s initial
biopsy specimen showed only epithelioid granulomas.
The repeat biopsies in patients 3 and 21 showed
increased inflammation, with focal disruption of the
limiting plate, mild piecemeal necrosis, and perilobular
inflammation. Because of the perilobular inflammation, these specimens were graded IIIB (Figure 2).
Both biopsies of patient 21 showed >50% accumulation of fat, moderate lymphoplasmacytic portal inflammation with eosinophils and polymorphonuclear cells,
and inflammation involving one duct (Figures 3 and 4).
In all cases, the repeat biopsies were performed while
the patients were still receiving MTX therapy ( 1 2 4 4
months after the first biopsies).
DISCUSSION
The histopathologic changes of methotrexateinduced hepatotoxicity are well recognized, but the
pathogenetic mechanism of liver cell damage and
fibrosis is not known. This detailed study of the
hepatotoxic effects of long-term MTX therapy (10
years) failed to show progression to severe fibrosis and
cirrhosis. In most of our patients’ biopsy material, the
pathologic findings varied from normal changes to mild
changes. Grade I1 changes were based on inflammation and the degree of steatosis. The second pathologist, a hepatopathologist, assigned higher scores to all
changes noted in the biopsy samples, and those are the
grades reported here.
Anisonucleosis was the most common change,
and in most biopsy specimens, it was mild. Anisonucleosis may indicate a direct interference of MTX in cell
division and nuclear maturation. The degree of anisonucleosis, however, did not exceed the degree of
change that we have found in liver biopsy material
from older patients, nor did it differ from the anisonucleosis Mackenzie (23) described in liver biopsies of
25 RA patients performed before initiation of MTX
treatment.
It has been stated that the variation in the size
of hepatocyte nuclei may be correlated to macrocytosis of peripheral red blood cells and megaloblastic
changes in bone marrow. The degree of hepatic aniso-
1462
nucleosis in our patients did not correlate with the
presence of macrocytosis. While on the MTX regimen,
5 patients had anemia secondary to loss of blood. In 3
patients, blood loss was due to peptic ulcer disease,
and in 2, it was related to surgery. There was no
thrombocytopenia or leukopenia in our patients. Folate levels were not measured, but there was no
clinical evidence of overt folic acid deficiency. There
are no data to indicate that long-term folk acid supplementation will decrease the toxicity of MTX (44).
Therefore, we do not routinely give folic acid supplements to our patients receiving MTX therapy.
The hepatotoxic effects of MTX that are of
concern are the severe fibrosis and cirrhosis. To detect
any degree of fibrosis, particularly mild fibrosis, we
believe that connective tissue staining must be done on
every liver biopsy. In our patients, despite the prolonged (up to 20 years) therapy, there was no severe
fibrosis or cirrhosis. In the biopsy specimens graded
IIIA and IIIB, the fibrosis was mild. In 3 patients,
sinusoidal fibrosis and congestion in zone 3 of the
Rappaport lobule correlated with congestive heart
failure. Samples from the repeat biopsies of patients 3
and 21 were classified as IIIB because of localized
piecemeal necrosis, rather than bridging fibrosis. The
change from grade IIIA to grade I1 abnormalities in the
repeat biopsy of patient 15 was attributed to the fact
that the initial biopsy specimen was small and fragmented, and most probably, it was “overread.” The
patient continued taking MTX after the initial biopsy
and was not abusing alcohol; it is therefore unlikely
that the fibrosis had regressed. It is well recognized
that sampling errors in liver biopsies, particularly in
areas with localized changes, occur. Because the
repeat biopsy sample was larger than the initial one,
we consider it to be more representative of the patient’s liver.
The severity of MTX-induced hepatotoxicity
has been lower in RA patients than in patients with
psoriasis (20,21,23-25,27). It has been proposed that
this difference may be attributable to the way the
psoriasis patient’s liver responds to MTX and the
possible additive effect of other chemicals (e.g., arsenic and alcohol) (6-18). One of the most important
factors that influences the severity of MTX-induced
hepatotoxicity in psoriasis pdtients is the frequency of
administration. Cirrhosis is rare when MTX is given as
a once-weekly bolus (16,17).
In patients 3 and 21, in whom the degree of
hepatic inflammation was greater in the second biopsy,
it is possible that a synergistic hepatotoxic effect of
APONTE AND PETRELLI
alcohol and MTX had occurred. After the second
biopsy, the families of both patients informed us that
the patient had abused alcohol. Only patient 3 admitted that she had done so. Only patient 21 had elevated
values on liver function studies at the time of both
biopsies. MTX therapy was discontinued in both patients after the second biopsy. After 3 months, MTX
therapy was resumed in patient 3 because of a severe
exacerbation of the RA, which had resulted in her
being unable to get out of bed. During a family
conference, it was decided that both her alcohol and
drug intake should be supervised. Thirty months later,
she is doing well. This additive effect is now a wellrecognized phenomenon (12,13,24), and in the absence
of alcohol abuse, MTX probably does not lead to
cirrhosis in RA patients when it is administered as a
weekly bolus.
The portal inflammation with ductal involvement in patient 21, although rare, has been reported
(25). In a patient with RA, ductal degeneration always
raises the possibility of primary biliary cirrhosis. Tests
for antimitochondrial antibody gave negative results,
and this patient did not have any of the clinical or
biochemical features of primary biliary cirrhosis. The
pathogenetic mechanism and the significance of the
perilobular hepatitis and duct inflammation are unclear. This patient was concurrently taking naproxen,
fenoprofen, trimethoprim/sulfamethoxazole, acetaminophen with codeine, and diazepam. These medications had been prescribed by other doctors, and we
did not know that she was taking them. These drugs
might have contributed to the pathologic changes and
the abnormal liver function test results; the latter
improved during hospitalization, after discontinuation
of these additional drugs.
In 2 of the patients (patients 12 and 16), the liver
biopsy showed epithelioid cell granulomas. In initial
samples obtained from patient 12, the granulomas
were associated with fibrosis and inflammation. The
repeat biopsy showed mild fibrosis, with less inflammation, and lipogranulomas; no epithelioid cell granulomas were detected. Granulomatous hepatitis has
not been a reported feature of MTX toxicity, and in
our patients, we presume this was caused by a drug
other than MTX. However, granulomas were seen in 1
of Mackenzie’s patients (23) and in 1 of Nyfors and
Poulsen’s patients (13). In the case reported by Mackenzie (23), the granulomas were not observed on
repeat liver biopsy a year later, while the patient was
still taking MTX. Hepatic lipogranulomas, presumably
caused by mineral oil rather than steatosis, are well
LIVER STUDIES OF MTX-TREATED RA PATIENTS
recognized and have been described in the literature
(45).
In summary, despite the large cumulative dose
of MTX, the advanced age of our patients, and the
many associated diseases, this study of the hepatotoxicity associated with long-term MTX therapy in RA
has shown that severe liver disease and cirrhosis are
rare. Moreover, liver biopsies are not routinely required for the monitoring of these patients as long as
the bolus method of MTX administration is used
(taking all the tablets at one time once a week) so that
the time of exposure of the liver cell to the drug is
decreased. A liver biopsy is indicated if there is a
history of alcohol abuse, if any clinical evidence of
liver disease is present, or if the following biochemical
abnormalities are noted: elevation of SGOT and SGPT
levels to twice normal and elevation of the GGTP
value to 1 M times normal at 2 consecutive determinations 2 weeks apart. We suggest that followup biopsies
be performed on patients with grade IIIA liver changes
during MTX therapy, and we suggest the drug be
discontinued when grade IIIB changes are observed.
MTX should not be prescribed for alcoholics or for
patients prone to abuse of alcoholic beverages, because of the risk of additive effects and because these
patients cannot be relied upon to comply with the
protocol.
ACKNOWLEDGMENTS
We thank Dr. Harlan R. Peterjohn (Fairview General
Hospital) for encouragement and support, Sophie Deseran
and Willa Destouet for technical assistance, Jana Meditz and
Vicki Kasmin for preparation of the manuscript, and Drs. M.
Asim Khan and Arthur J. McCullough for critical review of
the manuscript.
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