Mycophenolate mofetil-induced liver injury in a patient with aquaporin-4 antibody positive transverse myelitis
- Arun Iyer ,
- Madeleine Frank ,
- Susan Davies and
- William T Gelson
- Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Correspondence to Dr Madeleine Frank; madeleinefrank@doctors.org.uk
Abstract
We present a case of a 49-year-old woman diagnosed with aquaporin-4 antibody-positive transverse myelitis, who developed a significant transaminitis 2 months after commencing mycophenolate mofetil (MMF) as a steroid-sparing agent. No other risk factors were identified, a blood liver panel was negative and liver biopsy showed features compatible with drug-induced liver injury (DILI). MMF was stopped with a corresponding normalisation of serum alanine aminotransferase over the next 2 months. This case highlights MMF as a rare cause of DILI and provides justification for monitoring of liver biochemistry on therapy.
Background
Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated spectrum of disease of the central nervous system which may involve long segments of myelitis, and/or severe optic neuritis.1 Approximately 75% of patients have antibodies against aquaporin-4, a water channel expressed on astrocytes.1 Transverse myelitis is a classic presentation of the disease characterised by inflammation across a discrete spinal cord segment.2 Symptoms may include weakness, pain, spasticity, sensory alterations and bowel and bladder dysfunction.3 These develop over a period of hours or days then may worsen over days or weeks, with up to two-thirds of patients experiencing a moderate-to-severe degree of disability.3 The incidence of transverse myelitis ranges from 1.3 to 4.6 cases per million, increasing to 24.6 cases per million, if neuromyelitis optica and multiple sclerosis are included.3–5 There is no definitive cure but treatments include corticosteroids, plasma exchange and steroid-sparing agents.6
Mycophenolate mofetil (MMF) was first introduced in 1995 and is an immunosuppressant medication which acts by inhibiting the de novo pathway of guanosine nucleotide synthesis.7 It has been widely used for solid organ transplantation and in the management of autoimmune diseases.8 MMF has been successfully used in treating NMOSD including acute transverse myelitis.9 10 MMF is generally well tolerated, however it may be associated with gastrointestinal side effects such as pain, nausea and diarrhoea.8 9 Although rare, hepatotoxicity has also been reported with its use.8 9 11 12
Case presentation
A 49-year-old woman presented with a progressive transaminitis on a background of aquaporin-4 antibody-positive transverse myelitis. Two months prior, MMF had been started as a steroid-sparing agent at a dose of 500 mg two times per day. She was undergoing regular blood tests according to Trust protocol for patients recently started on MMF. Other than general malaise since commencing MMF, there were no specific symptoms. Her other blood results were unremarkable, and the full blood count remained normal throughout. Medical history included morphea since childhood, infrequent migraines and three pregnancies, two of which were complicated by pre-eclampsia. There was no significant alcohol intake or any other risk factors for liver disease.
Investigations
Alanine aminotransferase (ALT) at presentation was 399 IU/L with a pre-MMF treatment baseline of 67 IU/L 2 months earlier (figure 1). Other liver biochemistry was within normal limits (alkaline phosphatase 93; bilirubin 9). A blood screen for autoimmune and viral aetiologies (hepatitis A, B, C, E, Epstein-Barr virus and Cytomegalovirus) was negative other than antinuclear antibody positivity (speckled pattern at 1:160). Liver ultrasound with portal and hepatic venous Doppler studies revealed mild liver heterogeneity but was otherwise unremarkable. As the ALT continued to rise for several weeks after discontinuing the MMF and to exclude other liver conditions such as autoimmune hepatitis, percutaneous liver biopsy was undertaken.
Graph showing biochemical parameters in relation to time from instituting MMF. ALT, alanine aminotransferase; MMF, mycophenolate mofetil.
A liver biopsy showed preserved architecture without evidence of chronic liver disease and a focal mild portal chronic inflammatory cell infiltrate, predominantly lymphocytic and with a few eosinophils. The lobules showed prominent hepatocyte injury with confluent cell loss around terminal hepatic venules, with prominent ceroid-laden macrophages, lymphocytes and rare eosinophils. There were adjacent acidophil bodies but little hepatocyte damage elsewhere and no bilirubinostasis (figure 2A–C). These hepatocytic features were considered to be likely due to drug-induced liver injury (DILI).
(A) Slight inflammatory cell infiltrate in the portal tract (fine arrow) and focus of necro-inflammation around the terminal hepatic venule (broad arrow), with little intervening abnormality (H&E, ×100). (B) More prominent inflammatory infiltrate and perivenular focus of hepatocyte injury (H&E, ×200). (C) A focus of perivenular hepatocyte loss with lymphocytic infiltrate and acidophilic body formation (fine arrow, H&E, ×400). THV, terminal hepatic venule.
Differential diagnosis
All working diagnoses need to be substantiated.
Treatment
MMF was discontinued. Oral prednisolone was started at 40 mg/day as a replacement for MMF and later tapered (20 mg/day). She was also prescribed a proton-pump inhibitor (lansoprazole 30 mg). ALT levels gradually normalised over a period of 2 months and malaise resolved.
Outcome and follow-up
Follow-up blood tests at 2 months revealed normal transaminases. She was started on Rituximab and remains in clinical remission from NMSOD.
Discussion
MMF is a broadly safe and well-tolerated immunosuppressant that is widely used in solid organ transplantation and autoimmune diseases.13 Common side effects include diarrhoea, nausea, headache, fatigue and dizziness.13 Table 1 summarises the adverse events encountered by patients receiving MMF for treatment of NMOSD in a paper by Huang et al.9 MMF-induced liver injury has infrequently been reported.8 9 11 12 14 15 It usually causes liver biochemical abnormalities (transaminase and/or alkaline phosphatase elevation) which respond well to drug cessation,13 and a histological picture of hepatocellular injury with inflammatory cell infiltrates has been described.15 A study investigating hepatotoxicity with MMF after renal transplantation found that 13.9% of patients had transaminitis which regressed after withdrawal or dose reduction, with no other cause for liver function abnormality found.8 The significance of the ALT elevation was not documented and no other studies corroborate such a high prevalence in the transplant field. A study investigating side effects of MMF in the treatment of NMOSD found an incidence of mild liver enzyme derangement of 20%.9 The remainder of the studies are single case reports which document significant transaminitis.11 12 14 15 None of the cases of MMF-induced liver injury resulted in acute hepatic failure.13 The degree of transaminitis experienced by the patient in our report was within the range of liver enzyme abnormalities reported in the other studies.
Reported adverse events after MMF treatment in 90 patients with NMOSD9
Our case demonstrated a significant transaminitis following institution of MMF for management of aquaporin-4 positive transverse myelitis. There was a temporal relationship of transaminitis with institution of MMF, histology was compatible with DILI and ALT normalised on cessation of MMF, together providing good evidence of MMF being the culprit. The mild elevation of ALT preinstitution of MMF remains unexplained. It may have been secondary to the transverse myelitis disease process or to another medication such as prednisolone.
Mycophenolic acid (MPA) is the active compound of MMF and is often used for therapeutic drug monitoring in patients with solid organ transplants.16 MPA is a major immunosuppressive agent frequently used in autoimmune conditions as a steroid-sparing agent, in order to avoid steroid-related adverse effects.16 Its principal complications are gastrointestinal side effects and myelosuppression.16 In clinical practice for patients with autoimmune conditions, MMF is frequently started at a low dose such as 500 mg two times per day and titrated upwards with regular biochemical and blood count monitoring.17 The British Society for Rheumatology recommends 2 weekly blood monitoring until a stable dose is reached for 6 weeks, then monthly for 3 months.18 By adhering to this guidance, the patient’s transaminitis was promptly identified and the MMF was discontinued while alternative causes were sought and excluded.
This case highlights the importance of blood test monitoring when commencing MMF therapy, as MMF-induced liver injury is a rare but important complication.
Learning points
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Hepatotoxicity is a rare complication of mycophenolate mofetil (MMF) therapy usually presenting with abnormal serum liver enzymes.
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Liver biochemistry usually improve spontaneously following withdrawal of MMF.
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Monitoring liver biochemistry is recommended before and during MMF therapy.
Footnotes
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Contributors MF and AI planned and wrote the case report. SD provided the images included in the report. WG treated the patient and edited the case report.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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