463485

2012
MSJ19910.1177/1352458512463485Multiple Sclerosis JournalMartínez-Lapiscina et al.

MULTIPLE
SCLEROSIS MSJ
Letter to the Editor JOURNAL

Multiple Sclerosis Journal

19(9) 1234­–1235
© The Author(s) 2012
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DOI: 10.1177/1352458512463485
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Natalizumab-induced autoimmune
hepatitis in a patient with multiple sclerosis

Dear Sir,

An increased frequency of additional autoimmune disor-

ders (ADs) has been described among multiple sclerosis
(MS) patients. Autoimmune hepatitis has been reported
in untreated patients1 and patients treated with interferon
beta2 (INFB) and glatiramer acetate.3 However, drug-
induced liver injury is a rare complication of
natalizumab.4
We report the case of a 51-year-old woman diagnosed
with relapsing–remitting MS who was admitted to our hos-
pital for acute liver failure. She was treated with INFB-1b
for 13 years without hepatotoxicity. In 2009, INFB-1b was
stopped owing to disease progression and natalizumab was Figure 1a. Interface hepatitis.
Interface hepatitis assessed by hematoxylin and eosin (HE) staining.
started. After the 33rd dose, she presented fatigue, hipo- Original magnification × 10.
rexia, jaundice and dark urine. Concomitant drugs included
alfuzosin, baclofen and escitalopram. She rarely consumes
alcohol and had no drug allergies. She did not have any
history of liver disease, and liver function tests (LFTs)
were normal before her last dose of natalizumab.
Laboratory tests revealed aspartate aminotransferase level
of 1201 U/l (normal: 0–31), alanine aminotransferase level
of 1324 U/l (normal: 0–31), total bilirubin level of 3.4 mg/
dl (normal: 0–1.1) with direct bilirubin level of 2.59 mg/dl
(normal: 0–0.4), alkaline phosphatase level of 215 U/l
(normal: 35–104) and gamma-glutamyl transpeptidase
level of 114 U/l (normal: 5–36) and 61% prothrombin
activity (normal: 70–120). There was no evidence of acute
viral infection (hepatitis B and C, herpesvirus 1–4). Anti-
nuclear, anti-mitochondrial and anti-liver and kidney
microsome antibodies were negative. Anti-smooth muscle
antibodies (ASMAs) were negative at an initial test and
turned out to be positive in a second one 20 days later.
Liver biopsy showed interface hepatitis (Figure 1a) with a Figure 1b. Inflammatory infiltrate.
predominantly lymphoplasmacytic inflammatory infiltrate A lymphoplasmacytic inflammatory infiltrate extends across the
limiting plate assessed by hematoxylin and eosin (HE) staining. Original
extending across the limiting plate (Figure 1b), occasional magnification × 40.
pyknotic hepatocytes and porto-portal bridging fibrosis
(Figure 1c). Natalizumab was stopped and she was suc-
cessfully treated with methylprednisolone for three diagnosis of natalizumab-induced autoimmune hepatitis.
months. A positive shift of ASMA, histopathological find- The patient gave written consent for publication. We
ings and optimal response to corticosteroids supported the reported this case to BIOGEN Laboratory.

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Martínez-Lapiscina et al.
Figure 1c. Porto-portal bridging fibrosis.
Porto-portal bridging fibrosis assessed by Masson’s trichrome (MT)
staining. Original magnification × 4.
Natalizumab-induced liver injury can be explained by
different mechanisms. First, we may consider chronic or
atypical infectious agents causing liver injury in patients on
immunosuppressive therapy.5 However, serologies were
negative. Second, we should take into account a hypersen-
sitivity effect. Hypersensitivity is usually associated with
urticaria, fever and eosinophilia and commonly appears
early. Our patient did not show these symptoms, and liver
dysfunction started after the 33rd dose of natalizumab.
Third, we may consider hepatotoxicity. Although natali-
zumab did not undergo hepatic metabolism and liver injury
was not described as a side effect during the premarketing
trials, infrequent cases of hepatic injury have been described
through post-marketing.4 Finally, a heightened activity
against self-antigens due to natalizumab-induced immu-
nomodulatory deregulation should be taken into account.
ASMA positivitation may suggest this change.
Histopathological findings and optimal response to corti-
costeroids also argue for autoimmune hepatitis. However,
we cannot distinguish if it was a type of hepatotoxicity that
only implies autoimmune immunological effects or if natal-
izumab unmasked a genetic predisposition to autoimmune
hepatitis because of its immunomodulatory properties.
In conclusion, LFT and autoantibody screening should
be performed before starting natalizumab to rule out undi-
agnosed autoimmune hepatitis, and they may be repeated
on treatment monitoring to detect natalizumab-induced
autoimmune hepatitis.
Conflict of interest
Dr E.H. Martínez-Lapiscina receives travel and accommodation
expenses for national meetings and international congresses
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1235
(European Committee for Treatment and Research in Multiple
Sclerosis (ECTRIMS)) from Teva and Bayer.
Dr F. Lacruz-Bescós receives travel and accommoda-
tion expenses for national meetings and international congress
(ECTRIMS) from Novartis, Biogen, Merck Serono. He par-
ticipates in clinical trials of Novartis (fingolimod) and Biogen
(natalizumab).
Dr F. Bolado-Concejo reports no disclosures.
Dr I. Rodriguez-Perez reports no disclosures.
Dr T Ayuso-Blanco receives payment for development of
educational presentations from Biogen, Teva, Bayer and Merck
Serono. She receives travel and accommodation expenses for
national meetings and international congress (ECTRIMS) from
Biogen, Teva-Sanofi, Bayer and Merck Serono. She participates in
clinical trials of Novartis (fingolimod) and Biogen (natalizumab).
Dr M. Garaigorta de Dios reports no disclosures.
Dr J. Urman Fernández reports no disclosures.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
References
1. Núñez O, de Andrés C, Alvarez E, et al. Autoimmune
hepatitis in patients with a diagnosis of multiple sclerosis.
Gastroenterol Hepatol 2004; 27: 521–524.
2. Pulicken M, Koteish A, DeBusk K, et al. Unmasking of auto-
immune hepatitis in a patient with MS following interferon
beta therapy. Neurology 2006; 66: 1954–1955.
3. Neumann H, Csepregi A, Sailer M, et al. Glatiramer ace-
tate induced acute exacerbation of autoimmune hepatitis
in a patient with multiple sclerosis. J Neurol 2007; 254:
816–817.
4. Bezabeh S, Flowers CM, Kortepeter C, et al. Clinically
significant liver injury in patients treated with natalizumab.
Aliment Pharmacol Ther 2010; 31: 1028–1035.
5. Esteve M, Saro C, González-Huix F, et al. Chronic hepatitis B reac-
tivation following infliximab therapy in Crohn’s disease patients:
Need for primary prophylaxis. Gut 2004; 53: 1363–1365.
EH Martínez-Lapiscina1, F Lacruz1, F Bolado-Concejo2,
I Rodríguez-Pérez3, T Ayuso1, M Garaigorta2
and JM Urman2
1Neurology Service Complejo Hospitalario de Navarra,
Spain.
2Gastroenterology Service, Complejo Hospitalario de
Navarra, Spain.
3Pathology Service, Complejo Hospitalario
de Navarra, Spain.
Corresponding author:
EH Martínez-Lapiscina, Neurology, Complejo
Hospitalario de Navarra, Irunlarrea Street 3, 31011
Pamplona, Spain.
Email: elenahmlapiscina@gmail.com