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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: June 18, 2015.



Natalizumab is a monoclonal antibody to human alpha-4 integrin which has potent immune suppressive activity and is used in the therapy of severe inflammatory bowel disease and relapsing multiple sclerosis. Natalizumab has been linked to rare instances of idiosyncratic acute liver injury and may be a rare cause of reactivation of hepatitis B.


Natalizumab (na" ta liz' ue mab) is a humanized monoclonal antibody to alpha-4 integrin, which binds avidly to the cellular adhesion molecule found on leukocytes which blocks their ability to migrate to inflammatory foci. Inhibition of alpha-4 integrin activity leads to modulation of inflammatory pathways that are activated in autoimmune disorders. Natalizumab was shown to improve vision and motor function in patients with multiple sclerosis and to decrease inflammation, symptoms and relapses in patients with Crohn disease. Natalizumab was approved for use in the United States in 2005 and indications included severe Crohn disease and relapsing multiple sclerosis. However, after its general availability, natalizumab was linked to several instances of progressive multifocal leukoencephalopathy (PML), a severe neurological condition which is believed to be due to reactivation of the JC virus in neural cells. Because of this severe complication (which is often fatal), natalizumab has been restricted in use and is available only by a special program that requires thorough assessment of risks and careful monitoring and reporting. Natalizumab is available in 15 mL vials of 300 mg under the brand name Tysabri. The recommended dose is 300 mg intravenously every 4 weeks. Common side effects include headache, fatigue and infusion reactions. Natalizumab is also capable of causing immune suppression, resulting in an increased susceptibility to severe viral and bacterial infections.


In large clinical trials, serum aminotransferase elevations occurred in an average of 5% of patients on natalizumab therapy and in a slightly lower, although similar proportion (~3%) of those who received placebo. While there were no individual case reports of liver injury attributed to natalizumab therapy, at least 59 instances of hepatic injury were reported to the Adverse Event Reporting System maintained by the FDA. In a report summarizing six clinically apparent cases of liver injury attributable to natalizumab, all were associated with jaundice. The onset of injury followed the initial infusion of natalizumab in 4 patients, and after 5 and 12 courses of treatment in the other two reported cases. The pattern of liver injury was hepatocellular in 5 cases and cholestatic in one. Several cases were accompanied by autoantibodies and were treated with corticosteroids (Case 1), but autoimmune features were not prominent and immunoallergic features (fever, rash, eosinophilia) were not reported. The clinical cases were moderate in severity and no patient developed acute liver failure or progressed to chronic liver injury or vanishing bile duct syndrome. Natalizumab can cause immune suppression and has been linked to bacterial and viral infections, but interestingly has not been reported to cause reactivation of tuberculosis or hepatitis B. Nevertheless, because of its mechanism of action, it should be considered as a potential cause of reactivation.

Mechanism of Injury

The mechanism of liver injury caused by natalizumab is probably immunologically mediated, perhaps as a result of its effects on leukocyte function. It is a monoclonal antibody and like other proteins it is taken up by cells by endocytosis and is metabolized into amino acids.

Outcome and Management

The hepatotoxicity of natalizumab is usually moderate in severity and reversible with discontinuation of infusions. Recurrence of injury with a shorter latency and more severe course has been reported. There is no information about cross sensitivity to liver injury with other monoclonal antibodies or immune modulating agents, but at least one reported case had a history of liver injury due to interferon beta therapy of multiple sclerosis. Other immunomodulatory monoclonal antibodies used to treat autoimmune diseases include adalimumab, certolizumab, and infliximab.

Drug Class: Gastrointestinal Agents, Inflammatory Bowel Disease Agents; Monoclonal Antibodies, Multiple Sclerosis Agents


Case 1. Acute hepatocellular injury due to natalizumab.

[Modified from: Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther 2010; 31: 1028-35. PubMed Citation]

A 43 year old man with multiple sclerosis developed fatigue, fever and back pain 8 days after the fifth monthly dose of natalizumab. On hospital admission, he was found to have elevations in serum enzymes but was not jaundiced. Serum ALT was 410 U/L, AST 134 U/L, INR 1.17 and bilirubin 0.4 mg/dL. Over the next several days, his liver tests worsened, serum bilirubin peaking at 3.0 mg/dL. A liver biopsy showed acute lobular and portal hepatitis with mild fibrosis. Recovery was slow and prednisone was given. Natalizumab was not continued. Over the next 6 months liver tests returned to normal, whereupon natalizumab was restarted. After the second monthly infusion, however, he redeveloped fatigue and jaundice and liver tests were again abnormal: ALT 3494 U/L, AST 1259 U/L and bilirubin 13.4 mg/dL. The antinuclear antibody, which was negative during the first episode, was positive in titers >1:320. Natalizumab was again stopped and prednisone was given with subsequent improvement.

Key Points

Medication:Natalizumab (300 mg infusions monthly for 5 months)
Pattern:Hepatocellular (R=21.5)
Severity:3+ (jaundice, hospitalization)
Latency:11 days after 5th monthly infusion initially; shortly after second monthly infusion on rechallenge 6 months later
Recovery:6 months initially, unknown upon rechallenge
Other medications:Spirulina (food supplement), multivitamins, prednisone


This patient developed clinically apparent acute hepatocellular injury within 2 weeks of receiving his fifth monthly infusion of natalizumab for relapsing multiple sclerosis. The injury was moderate in severity, but slow to resolve. Liver histological features suggested an element of autoimmunity, and he was treated with prednisone but tolerated its withdrawal and had normal liver tests six months later. Upon reexposure, he redeveloped the liver injury with a shorter latency and with a more severe course. At this point, he was found to have high titers of ANA and prednisone was restarted. Although compatible with spontaneous autoimmune hepatitis (which has been reported in patients with multiple sclerosis), the timing of onset and recurrence of similar injury upon reexposure is reasonably convincing evidence that it was due to natalizumab, perhaps an autoimmune hepatitis that was triggered by the immunomodulatory therapy. This example was case 2 from the six case series reported by the FDA, which were based upon review of spontaneous adverse event reports during the first 4 years of general availability of natalizumab. The six cases were selected as the clinically apparent examples among a total of 59 separate reports of liver injury. The authors estimated the frequency of idiosyncratic clinically apparent liver injury from natalizumab to be 17 per 100,000 exposed patients. Events occurring at this low rate are unlikely to be detected in premarketing studies.



Natalizumab – Tysabri®


Gastrointestinal Agents; Multiple Sclerosis Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Natalizumab189261-10-7Monoclonal AntibodyNot Available


References updated: 18 June 2015

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    (Expert review of hepatotoxicity published in 1999, well before the availability of most antibody therapies).
  • Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.
    (Review of hepatotoxicity of immunosuppressive agents mentions the report of six cases of severe liver injury attributed to natalizumab report to the FDA Adverse Event Reporting System database).
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    (Summary of 6 clinically apparent hepatic adverse events reported to the FDA over a 4 year period included 1 man and 5 women, ages 26 to 59 years, arising after the first to 11th dose [bilirubin 4.5 to 16.1 mg/dL, ALT 753-3494 U/L, Alk P 46-1043 U/L], all resolving, all were icteric and symptomatic and 5 were hepatocellular; 3 had autoantibodies but immune features were not prominent: Case 1).
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    (29 year old man with multiple sclerosis developed generalized rash 30 days after starting natalizumab with abnormal liver tests [bilirubin not given, ALT 185 U/L, GGT 320 U/L, eosinophils 2150 cells/L], resolving within 3 weeks).
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    (Among 27 patients with multiple sclerosis treated with natalizumab, 6 had a reactive tuberculin test, but none had clinical evidence of reactivation during an average of 19 months of therapy; furthermore, worldwide at least 88,100 patients have been treated with natalizumab, but there have been no reports of tuberculosis associated with treatment in the literature).
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    (31 year old woman developed ALT elevations after a first injection of natalizumab and jaundice after a second [bilirubin 23.1 mg/dL, ALT > 50 times ULN, "mild elevation" in Alk P, INR 2.6, ANA 1:160], with response to corticosteroid therapy and no recurrence on long term azathioprine).
  • O'Connor P, Goodman A, Kappos L, Lublin F, Polman C, Rudick RA, Hauswirth K, et al. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. Neurology 2014; 83: 78-86. [PMC free article: PMC4114173] [PubMed: 24898925]
    (Among 1094 patients with multiple sclerosis formerly enrolled in clinical trials of natalizumab and continued on therapy [300 mg every 4 weeks] for up to 5 years, 171 [16%] had at least one serious adverse event including 7 listed as "hepatobiliary" [without specific details] and 8 confirmed cases of PML).
  • Butzkueven H, Kappos L, Pellegrini F, Trojano M, Wiendl H, Patel RN, Zhang A, et al.; TYSABRI Observational Program (TOP) Investigators. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014; 85: 1190-7. [PMC free article: PMC4215289] [PubMed: 24532785]
    (Among 4821 patients with multiple sclerosis being treated with natalizumab enrolled in a prospective observational program, 3599 continued on treatment, among whom there were 465 serious adverse events including 7 were abnormal liver tests [0.1% yearly], 18 cases of PML [0.4%] and 9 deaths, but none due to liver disease).


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