Methotrexate and liver function_

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					                                                                                                                             JEADV ISSN 1468-3083



ORIGINAL ARTICLE
Blackwell Publishing Ltd




Methotrexate and liver function: a study of 13 psoriasis cases
treated with different cumulative dosages
SC Carneiro,† FF Cássia,† F Lamy,† VLA Chagas,‡ M Ramos-e-Silva*†
†Sector of Dermatology and Post Graduation Course and ‡Department of Pathology, HUCFF/UFRJ and School of Medicine, Federal University of Rio de
Janeiro, Rio de Janeiro, Brazil




Keywords                                               Abstract
liver, methotrexate, needle biopsy, psoriasis,
psoriatic arthritis                                    Background The need and frequency of hepatic biopsies during methotrexate
                                                       (MTX) therapy are still controversial.
*Corresponding author, Sector of Dermatology           Objectives The purpose of this investigation is to assess MTX liver toxicity
and Post Graduation Course, HUCFF/UFRJ and             in patients with psoriasis through percutaneous liver biopsy, and compare liver
School of Medicine, Federal University of
                                                       morphology changes with increasing cumulative dosages (1, 2, 3 and 4 g) of
Rio de Janeiro, Rio de Janeiro, Brazil,
                                                       MTX.
tel. +55 21 22864632; fax +55 21 22864632;
E-mail: ramos.e.silva@dermato.med.br                   Results Cumulative dosages of 1 to 2 g MTX did not cause significant liver
                                                       toxicity. From a cumulative dosage of 3 to 4 g, there is fibrosis formation,
Received: 1 November 2006,                             inflammation enhancement in the portal area and fibrous septa, configuring
accepted 28 March 2007                                 regenerative nodes.
                                                       Conclusion In patients with no risk factors for liver disease, with normal
DOI: 10.1111/j.1468-3083.2007.02322.x
                                                       physical examination and liver tests, biopsy can be done after a cumulative
                                                       MTX dosage of approximately 1 to 1.5 g and repeated for each gram. In patients
                                                       with risk factors, liver biopsy should be done before use of MTX, or within
                                                       the first 2 months of treatment at the most, and repeated for each gram of
                                                       cumulative dosage.




                                                                                    liver toxicity, such as age, gender, use of drugs, alcoho-
Introduction                                                                        lism, obesity and diabetes mellitus and severity of the
Methotrexate (MTX), a folic acid antagonist, is the first                            disease. The recommendations regarding the need and
effective systemic therapy for psoriasis, and even today                            frequency of hepatic biopsies are controversial, in spite of
it is considered to be the standard systemic therapy,                               the existence of consensus, guidelines and their periodic
particularly for disseminated cases or those with extra-                            reviews.4–6
cutaneous compromise. The binding of MTX to folic acid                                 The purpose of this investigation is to assess MTX liver
reductase blocks DNA synthesis, thus decreasing cell                                toxicity in patients with psoriasis, through percutaneous
division. In accordance with the new perspective on                                 liver biopsy, and compare liver morphology changes with
psoriasis pathogenesis, MTX would act on changes                                    increasing cumulative dosages (1, 2, 3 and 4 g) of MTX.
secondary to the stimulation mediated by T lymphocytes,                             Non-invasive techniques have not been taken into con-
such as the hyperproliferation of keratinocytes. It seems,                          sideration in this study.
however, that MTX may also affect the inflammatory
component of psoriasis, leading to a decrease of T CD8+
lymphocytes, and other T-cell functions, and the suppres-                           Methodology
sion of neutrophilic chemotaxis. The potential for the
                                                                                    Patients
development of liver abnormalities, such as hepatic fibrosis
and cirrhosis, with a long-term treatment, imposes attention                        All eligible patients, either with or without arthritic disease,
with its use.1–3 Other factors may also contribute to MTX                           had the diagnosis of psoriasis established by histopathology.


© 2007 The Authors                                                                                                                               25
JEADV 2008, 22, 25– 29 Journal compilation © 2007 European Academy of Dermatology and Venereology
Methotrexate and liver function in psoriasis                                                                                           Carneiro et al.


Inclusion criteria were patients of both genders, from 18               • Grade I: normal; mild to moderate steatosis; mild portal
to 70 years old, with psoriasis vulgaris (affecting over 20%              inflammation and nuclear variability
of the body surface), erythroderma, pustular or arthropatic             • Grade II: moderate to severe inflammation and portal
forms. Exclusion criteria were history of excessive alcohol               fibrosis; moderate to severe necrosis, nuclear variability
intake; bone marrow suppression (severe anaemia, leuco-                   and steatosis
penia or thrombocytopenia); liver fibrosis or cirrhosis;                 • Grade IIIA: portal fibrosis with formation of fibrous
active peptic ulcer; kidney or liver impairment; active                   septa
infection; active or recent hepatitis; positive antibodies              • Grade IIIB: marked septal fibrosis
tests for human immunodeficiency virus (HIV); hepatitis                  • Grade IV: cirrhosis
A, B, and/or C; pregnancy or nursing; or raised levels of
liver enzymes.
   All patients signed a written informed consent approved              Results
by the ethics committee of the hospital, and the present
                                                                        Data from the sample
study was conducted in accordance to the Declaration of
Helsinki and its amendments.                                            Thirteen patients were included in the study, according to
                                                                        the inclusion and exclusion criteria. There were 7 (54%)
                                                                        females and 6 (46%) males. Mean age was 46 years (range
Methods
                                                                        29–69 years). Seven patients presented psoriatic arthro-
                                                                        pathy; three with the erythrodermal type; two with local-
Assessment previous to and during treatment
                                                                        ized pustular; and one patient presented vulgar psoriasis
Patients were assessed prior to the use of MTX by their                 affecting more than 20% of the body surface.
medical history, physical examination, and laboratorial
tests, which included complete blood count (CBC); platelet
                                                                        Previous liver biopsy
count; urine test; serum creatinine and creatinine clearance;
transaminase oxalacetic and piruvic (TGO and TGP); alka-                The liver specimen collected during biopsy prior to MTX
line phosphatase; bilirubin; antibodies tests for HIV; hepatitis        treatment revealed hepatocyte tumefaction and nuclear
A, B, and/or C; prothrombin activity and time (TAP); gamma              variation in 13 biopsies, liver steatosis in 6, and regenerative
GT; chest X-ray and liver biopsy.                                       aspect and perisinusoidal fibrosis in 10 (fig. 1). Moreover,
   Laboratorial tests during follow-up included CBC and
platelet count on a weekly basis in the two initial months
of treatment; urine test, alkaline phosphatase, TGO, TGP
and TAP every 3 to 4 months; creatinine clearance and
chest X-ray were done on an annual basis.


Therapeutic regimen
Patients would take oral doses of MTX thrice a week, with
an initial weekly dose of 7.5 mg, which was gradually
increased in 2.5 mg increments until the maximum weekly
dose of 15 mg. Maximum dosage was kept until the patient
was properly stabilized, and then it was gradually reduced.


Liver biopsy
Pre-treatment percutaneous liver biopsies were done
and then after cumulative doses of 1 to 4 mg MTX.
Liver specimen were examined under optical microscopy
[haematoxylin and eosin (H & E), PAS after digestion with
diastase, Masson’s trichrome, and reticulin, the two latter
to detect fibrosis] and analysed morphologically and com-
paratively according to the cumulative dosage of MTX.
   Histopathology abnormalities of the liver specimen were              fig. 1 Hepatic biopsy before MTX administration: swollen hepatocytes,
classified according to Roenigk et al. (1988)6 as:                       mild perisinusoidal fibrosis (H & E ×100).



26                                                                                                                                  © 2007 The Authors
                                                     JEADV 2008, 22, 25– 29 Journal compilation © 2007 European Academy of Dermatology and Venereology
Carneiro et al.                                                                                                                                                           Methotrexate and liver function in psoriasis


there was an accumulation of intracytoplasmic biliary




                                                                                                                                                     hyperplasia
pigment in 6, focal hepatocyte necrosis in 10, and sinus




                                                                                                                                                     Cellular
congestion and dilation in 8. Sinusoidal cell hyperplasia




                                                                                                                                                                          Y*




                                                                                                                                                                          Y*
was observed in nine biopsies, and of these, two were




                                                                                                                                                                          N

                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
associated to polymorphonuclear cells (Table 1).




                                                                                                                                                           Dilation




                                                                                                                                                                          N
                                                                                                                                                                          N

                                                                                                                                                                          N



                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y



                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y
Post-MTX liver biopsy




                                                                                                                                                           Congestion
Liver biopsies carried out after cumulative dosages of MTX
1 g (10 patients), 2 g (8 patients), 3 g (6 patients), and 4 g
(4 patients) were classified according to Roenigk et al.6




                                                                                                                                                                          N



                                                                                                                                                                          N

                                                                                                                                                                          N



                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y

                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y
   Roenigk’s grade I histopathology changes were seen in




                                                                                                                                      Sinusoids



                                                                                                                                                           Fibrosis
biopsies of patients with cumulative dosages of MTX 1g
(6 patients) and 2g (4 patients). A pattern between grades




                                                                                                                                                                          N




                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
I and II was observed in biopsies of two patients with




                                                                                                                                                     necrosis
cumulative MTX dosage of 1 g, two with 2 g and 2 with 3 g.




                                                                                                                                                     Focal
Nine biopsies were classified as grade II, with cumulative




                                                                                                                                                                          N




                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
dosages of 1g (2 patients), 2g (2 patients), 3g (3 patients)




                                                                                                                                                     variable
                                                                                                                                                     Nuclear
and 4g (2 patients). Grade III was observed in one biopsy of
cumulative dosage of 3 g, whereas grade IV was observed




                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
in two of 4 g (Table 2).




                                                                                                                                                           Regeneration
   In our study, we have observed that perisinusoidal fibrosis
and the hepatocitary regenerative aspect characterized by
multiplicity of nuclei, voluminous nuclei and prominent
nucleoli did not change with cumulative dosages between



                                                                                                                                                                          N




                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
1 g compared with pre-MTX biopsies (figs 2 and 3). How-                                                                                                     Steatosis
ever, after a cumulative dosage of 2 g, three biopsies with
marked perisinusoidal fibrosis and regenerative aspect
                                                                                                                                                                          N



                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N




                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y




                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                     pigment
                                                                                                                                                     Billiary




                                                                                                                                                                          N



                                                                                                                                                                          N



                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y

                                                                                                                                                                          Y
                                                                                                                                                                          Y




                                                                                                                                                                                                                  N, absent; Y, present; Y*, present in association with polymorphonuclear cells.
                                                                                                                                      Hepatocytes



                                                                                                                                                           Tumefaction

                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                                          Y
                                                                                                                                                           Septa

                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                           Inflammation
                                                                                   Table 1 Histological changes in pre-MTX biopsies

                                                                                                                                      Portal space




                                                                                                                                                                          N

                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N

                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y




                                                                                                                                                                          Y
                                                                                                                                                           Fibrosis

                                                                                                                                                                          N

                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          N
                                                                                                                                                                          Y
                                                                                                                                                           Age

                                                                                                                                                                          57
                                                                                                                                                                          36
                                                                                                                                                                          58
                                                                                                                                                                          45
                                                                                                                                                                          66
                                                                                                                                                                          59
                                                                                                                                                                          65
                                                                                                                                                                          55
                                                                                                                                                                          33
                                                                                                                                                                          51
                                                                                                                                                                          53
                                                                                                                                                                          46
                                                                                                                                                                          35
                                                                                                                                                           Sex



                                                                                                                                                                          M



                                                                                                                                                                          M

                                                                                                                                                                          M
                                                                                                                                                                          M

                                                                                                                                                                          M



                                                                                                                                                                          M
                                                                                                                                                                          F

                                                                                                                                                                          F
                                                                                                                                                                          F

                                                                                                                                                                          F



                                                                                                                                                                          F

                                                                                                                                                                          F
                                                                                                                                                                          F
                                                                                                                                                           Case#




fig. 2 MTX 1 g: more accentuated perisinusoidal fibrosis (reticulin ×100).
                                                                                                                                                                          10
                                                                                                                                                                          11
                                                                                                                                                                          12
                                                                                                                                                                          13
                                                                                                                                                                          1
                                                                                                                                                                          2
                                                                                                                                                                          3
                                                                                                                                                                          4
                                                                                                                                                                          5
                                                                                                                                                                          6
                                                                                                                                                                          7
                                                                                                                                                                          8
                                                                                                                                                                          9




© 2007 The Authors                                                                                                                                                                                                            27
JEADV 2008, 22, 25– 29 Journal compilation © 2007 European Academy of Dermatology and Venereology
Methotrexate and liver function in psoriasis                                                                                                           Carneiro et al.




fig. 3 MTX 1.5 g: swollen hepatocytes and mild regenerative activity (H & E ×200).     fig. 5 MTX 3 g: swollen steatosis and regenerative pattern of hepatocytes
                                                                                      (H & E ×400).




fig. 4 MTX 2 g: swollen hepatocytes, pronounced perisinusoidal fibrosis
                                                                                      fig. 6 MTX 4 g: perisinusoidal fibrosis with regenerative nodules (reticulin ×200).
(reticulin ×200).

were seen (fig. 4). Six patients were given 3 g and four                               Alterations, such as sinusoidal dilation and congestion,
patients with 4 g; three evolved with portal fibrosis and                              were not directly related to increase of MTX dosage; there
fibrous septa around groups of hepatocytes (fig. 5); the                                was, however, a decrease in sinusoidal and inflammatory
others presented Roenigk II-type abnormalities (fig. 6),                               cells in most investigated cases.


28                                                                                                                                                © 2007 The Authors
                                                                   JEADV 2008, 22, 25– 29 Journal compilation © 2007 European Academy of Dermatology and Venereology
Carneiro et al.                                                                                              Methotrexate and liver function in psoriasis


Table 2 Roenigk grades versus the cumulative dosage of MTX                          unknown pathophysiological mechanisms, which lead to
                                                                                    the development of psoriasis, could explain such difference.
                   No. of patients

                   1 g MTX         2 g MTX         3 g MTX          4 g MTX         Conclusions
Roenigk I          6               4                                                We have concluded that cumulative dosages of 1 to 2 g MTX
Roenigk I/II       2               2               2                                apparently foster a regenerative, reactional hepatocyte
Roenigk II         2               2               3                2               response, and a marked enhancement of the perisinusoidal
Roenigk III                                        1
                                                                                    fibrosis detected in biopsies prior to treatment. These
Roenigk IV                                                          2
                                                                                    dosages did not cause significant liver toxicity. From a
                                                                                    cumulative dosage of 3 to 4 g, there is fibrosis formation,
                                                                                    inflammation enhancement in the portal area, and fibrous
Discussion                                                                          septa, configuring regenerative nodes.
It is unknown why one develops MTX-related liver toxicity.7
The patients under investigation presented liver lesions prior
to the use of MTX. Could they be related to psoriasis?                              Recommendations
    It is known that the transforming growth factor has a                           In patients with no risk factors for liver disease, such as
similar structure to the epidermal growth factor and to the                         alcohol intake, viral hepatitis, diabetes, and obesity, with
synovial growth factor; it plays a role in angiogenesis and                         normal physical examination and liver tests, biopsy can be
stimulates proliferation of keratinocytes, synoviocytes                             done after a cumulative MTX dosage of approximately 1
and fibroblasts, all increased in psoriasis.8 There are also                         to 1.5 g and repeated for each gram. In patients with risk
changes in the GMPc/AMPc ratio, which regulates cell                                factors, liver biopsy should be done before use of MTX, or
growth and differentiation. The proteases, which play an                            within the first 2 months of treatment at the most, and
important role in the regulation of cell proliferation and                          repeated for each gram of cumulative dosage.
are capable of generating inflammatory mediators via cas-
cade of the complement, are also increased in psoriasis.
    Cytokines released in the T-lymphocyte-mediated self-                           References
reactive inflammatory response act on synovial fibroblasts,                            1 Zachariae H, Kragballe K, Sogaard H. Methotrexate induced
monocytes and other musculoskeletal system cells, similarly                            liver cirrhosis. Studies including serial liver biopsies during
to what happens in the psoriatic plaque.                                               continued treatment. Br J Dermatol 1980; 102: 407–412.
    It is, therefore, possible that similar changes take place                       2 Zachariae H, Sogaard H. Methotrexate-induced liver
in fibroblast of various organs, such as the liver, which                               cirrhosis: a follow-up. Dermatologica 1987; 175: 178–182.
may contribute to primary liver abnormalities in psoriasis.                          3 Zachariae H, Sogaard H, Heickendorff L. Methotrexate-induced
Concurrently, histological exams in humans suggest that                                liver cirrhosis. Clinical, histological and serological studies –
an alteration in the liver ultrastructure mediated by                                  a further 10 year follow up. Dermatology 1996; 192: 343–346.
hyperplasia and proliferation of stellate cells, a myo-                              4 Roenigk HH Jr, Maibach HI, Weinstein GD. Guidelines on
fibroblast present in the liver, is responsible for the toxic                           methotrexate therapy for psoriasis. Arch Dermatol 1972; 105:
lesion caused by MTX.9 This could explain why the incid-                               363–365.
                                                                                     5 Roenigk HH Jr, Maibach HI, Weinstein GD. Methotrexate
ence of cirrhosis in psoriatic patients treated with MTX is
                                                                                       therapy for psoriasis: guidelines revisions. Arch Dermatol
higher than in patients with rheumatoid arthritis.
                                                                                       1973; 108: 35–38.
    On the other hand, because psoriasis is a chronic disease,
                                                                                     6 Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD.
patients typically use a number of different drugs prior to
                                                                                       Methotrexate guidelines – revised. J Am Acad Dermatol 1988;
the use of MTX, and these drugs could contribute to liver
                                                                                       6: 145–155.
toxicity. There are also other possible causes of liver cells
                                                                                     7 Orion E, Matz H, Wolf R. The life-threatening complications
injury, such as alcohol intake and virus infections, among                             of dermatologic therapies. Clin Dermatol 2005; 23: 182–192.
others. Rheumatologists do prescribe MTX for rheumatic                               8 Sack KE, Fye KH. Rheumatic diseases. In: Stites DP, Ten AJ,
arthritis (RA) and do not routinely do liver biopsies in their                         Parslow TG, eds. Medical Immunology, 9th edn. Appleton &
patients. A review of the literature of patients with psoriasis                        Lange, Stemford, 1997: 456–479.
and RA shows that cirrhosis is more frequent in patients                             9 Horvath E, Saibil FH, Kovacs K, Kerenyi NA, Ross RC Fine
with psoriasis.10 The concurrent use of nonsteroidal anti-                             structural changes in the liver of methotrexate-treated
inflammatory drugs and lower doses of MTX for RA may                                    psoriatics. Digestion 1978; 17: 488–493.
contribute for this fact. Another factor could be the higher                        10 Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic
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© 2007 The Authors                                                                                                                                    29
JEADV 2008, 22, 25– 29 Journal compilation © 2007 European Academy of Dermatology and Venereology