Cyclophosphamide-induced liver injury during treatment of interstitial lung disease in juvenile dermatomyositis
- 1 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- 2 Pediatric Rheumatology, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
- Correspondence to Dr Christopher Costin; ccostin@luriechildrens.org
Abstract
A middle-childhood aged girl with recently diagnosed MDA5+ juvenile dermatomyositis complicated by interstitial lung disease presented with diffuse abdominal pain and scleral icterus following the initiation of cyclophosphamide therapy. A laboratory workup revealed elevated liver enzymes and hyperbilirubinaemia. She was admitted for worsening liver function, and all medications were held with concern for drug-induced liver injury. A workup for infectious and autoimmune causes of transaminitis was negative. A liver biopsy revealed diffuse apoptotic cells without evidence of portal obstruction. A diagnosis of cyclophosphamide-induced liver injury was made. She was initiated on intravenous methylprednisolone with a steroid taper, leading to recovery. Cyclophosphamide was replaced by tofacitinib and abatacept for control of interstitial lung disease, which was well tolerated. Although cyclophosphamide in high doses may cause sinusoidal obstruction syndrome, hepatocellular liver injury is rare. Here to our knowledge, we present the first case report of hepatocellular injury caused by intravenous cyclophosphamide in a paediatric patient with a rheumatic condition.
Background
Cyclophosphamide is an alkylating agent used to treat cancer and autoimmune diseases, including juvenile dermatomyositis. Doses given in myeloablative therapy can cause acute sinusoidal obstruction syndrome, characterised by damage to small hepatic vessels and typically presenting with hepatomegaly, ascites and hyperbilirubinaemia. Cyclophosphamide may be associated with transient transaminitis; however, acute liver injury is rare. Nonetheless, it is essential to keep drug-induced liver injury in the differential of transaminitis.
Case presentation
A middle childhood aged girl initially presented to the rheumatology clinic with polyarticular joint pain, muscle weakness, rash and fatigue. She was admitted and ultimately found to have juvenile dermatomyositis based on clinical weakness, elevated muscle enzymes, reverse Gottron papules, and an MRI showing diffuse myositis. Myositis-specific antigen testing returned positive for MDA-5. A chest CT was performed, and the findings were unique for interstitial lung disease. She received a 5-day course of high-dose intravenous methylprednisolone and was given one dose of 500 mg/m2 of cyclophosphamide and mesna. She was discharged home on daily oral steroids, prophylactic trimethoprim-sulfamethoxazole (TMP-SMX), and weekly pulse steroids. At follow-up 2 weeks later, her weakness and rash improved, but she was noted to have scleral icterus and diffuse abdominal pain. An initial laboratory workup revealed transaminitis and indirect hyperbilirubinaemia. She was directed to the emergency department, where a liver ultrasound revealed no abnormalities. She was discharged home with close rheumatology follow-up. One week after discharge, a repeat laboratory evaluation showed worsening hyperbilirubinaemia, and she was admitted to the rheumatology service.
Investigations
During her admission, her transaminases, ferritin, gamma glutamyl transferase, and bilirubin were trended and found to be elevated (table 1). Other studies included negative Epstein-Barr virus PCR and titers, cytomegalovirus PCR and titers, enterovirus PCR, hepatitis A, B and C panel, and hepatitis E PCR and antibody. An autoimmune hepatitis evaluation, including total IgG, antinuclear antibody, anti-smooth muscle antibody and anti-LKM1, was ultimately negative. A T cell hepatitis evaluation, including a soluble interleukin two receptor level and neopterin level, was obtained and negative with normal natural killer cell function and mildly elevated soluble IL-2 receptor in proportion to her juvenile dermatomyositis disease activity. A screening for alpha-1-antitrypsin deficiency and Wilson’s disease was negative. Faecal calprotectin and stool ova and parasite studies were unremarkable. An ultrasound liver with Doppler was performed to evaluate anatomy and vasculature and was ultimately normal. A liver biopsy was performed, and findings were unique for hepatocellular swelling and apoptosis, suggestive of drug-induced liver injury. No eosinophils were noted. There was no evidence of sinusoidal obstructive syndrome.
Admission laboratory results
| Haemoglobin | 109 g/L |
| White cell count | 5.6x10∧3/µL |
| Absolute neutrophils | 4.050x10∧3µL |
| Platelets | 263x10∧3/µL |
| Aspartate aminotransferase | 2423 IU/L |
| Alanine aminotransferase | 692 IU/L |
| Total bilirubin | 3.2 mg/dL |
| Alkaline phosphatase | 312 IU/L |
| Gamma glutamyl transferase | 437 IU/L |
| C reactive protein | <0.3 mg/dL |
| Erythrocyte sedimentation rate | 43 |
| Lactate dehydrogenase | 548 IU/L |
| Aldolase | 19.4 U/L |
| Creatine kinase | 57 IU/L |
| Faecal calprotectin | 388 µg/g |
| Ferritin | 1520 ng/mL |
| Triglycerides | 427 mg/dL |
| Soluble IL-2 receptor | 1814 pg/mL |
| Neopterin (normal: 0–10) | 26.3 nmol/L |
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Abnormal values compared with reference values are highlighted in red.
Differential diagnosis
The clinical pattern of scleral icterus accompanied by elevated liver enzymes is concerning for hepatic injury. The differential diagnosis of acute liver injury in this patient was broad. An initial investigation ruling out underlying infectious and autoimmune causes is important for any liver injury in the setting of rheumatic disease.1 A study of the aetiologies of liver injuries showed drug-induced liver injury as the most common cause; others include fatty liver, viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, and the collagen diseases.2 Liver injury with elevations of transaminases to the thousands may be seen in juvenile dermatomyositis, but it is usually seen as frank autoimmune hepatitis or a feature of thrombosis, both of which were unlikely given her laboratory evaluation, imaging and biopsy results. Notably, a study of liver injury in patients with adult dermatomyositis found that patients with positive MDA5 antibody have significantly increased incidence of liver injury, although this was in part due to fatty liver disease.3 Liver involvement in MDA5 dermatomyositis is well-documented and may pose an increased risk of haemophagocytic lymphohistiocytosis.4 Her systemic inflammation and hyperferritinaemia may suggest a differential of macrophage activation syndrome/haemophagocytic lymphohistiocytosis with associated liver injury. Her biopsy was overall reassuring against this. While there are no diagnostic criteria for macrophage activation syndrome in juvenile dermatomyositis, she did not meet the 2004 hemophagocytic lymphohistiocytosis diagnostic criteria, and her mild hyperferritinaemia was attributed to her liver injury.5 Infectious causes such as hepatitis viruses, Epstein-Barr virus, cytomegalovirus, or human immunodeficiency virus were unlikely, given her negative studies.
A toxic/metabolic condition was high in the differential, with drug-induced causes being most likely. Of highest suspicion was cyclophosphamide, given the liver injury presentation occurring with the peak of cyclophosphamide activity. Other considerations included liver injury associated with TMP-SMX; however, her few prophylactic doses and lack of drug hypersensitivity symptoms made this less likely. While TMP-SMX has rarely been associated with hepatocellular injury, patients typically have recovery in 2–4 weeks.6 In this patient, her transaminitis lingered for months after medication withdrawal, further arguing in favour of cyclophosphamide as the offending agent. Cyclophosphamide as the cause of her liver is bolstered by another case of long but ultimately reversible hepatocellular injury was seen in a case of oral cyclophosphamide-induced hepatocellular injury in patient with nephrotic syndrome.7
Treatment
On admission, the potentially offending medications were discontinued. She was initiated on intravenous methylprednisolone. The liver enzymes subsequently improved without further intervention. At a follow-up appointment, she was started on tofacitinib, intravenous immunoglobulin (IVIG), and abatacept to manage her interstitial lung disease and underlying juvenile dermatomyositis.
Outcome and follow-up
The patient followed up with rheumatology, pulmonology and hepatology for drug-induced liver injury in the setting of juvenile dermatomyositis complicated by interstitial lung disease. Her monthly cyclophosphamide was stopped and replaced with tofacitinib and abatacept, and her TMP-SMX was replaced with pentamidine. Her liver injury had slowly improved and had completely resolved 10 weeks after her admission (figures 1–2). She is clinically doing well. Her juvenile dermatomyositis and interstitial lung disease improved to remission with tofacitinib, IVIG and abatacept therapy. After 1 year of therapy, we have weaned both the abatacept and IVIG off. She continues to do well without progression of her interstitial lung disease on tofacitinib monotherapy.
The patient’s serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) from admission through follow-up in their respective colours.
The patient’s indirect bilirubin from admission through follow-up.
Discussion
Cyclophosphamide has previously been reported as a rare cause of hepatocellular liver injury without sinusoidal obstructive syndrome.8–10 To our knowledge, here we have described the first known paediatric case of cyclophosphamide-induced liver injury through direct hepatocellular injury in a paediatric rheumatology patient. Although somewhat novel, it has been reported previously that cyclophosphamide may cause this effect in the paediatric population. In particular, Milford et al reported a case of hepatocellular injury occurring from oral cyclophosphamide in nephrotic syndrome. 7 , 11 Oral cyclophosphamide may have a higher side effect profile than intravenous cyclophosphamide.12 The finding that our patient with juvenile dermatomyositis developed hepatic dysfunction with only one dose of intravenous cyclophosphamide as opposed to months of oral cyclophosphamide is novel and represents a unique safety signal in the MDA5+ JDM population although further studies are needed.
The diagnosis of cyclophosphamide-induced liver injury remains challenging. In this patient, the diagnosis was characterised by association of the liver injury with the peak effect of cyclophosphamide and a supportive biopsy result. The differential of liver injury is broad and includes thrombotic, infectious, immune-mediated and drug-induced causes as was considered in this case. Additionally, treatment for ILD remains varied with many different approaches. This case shows that tofacitinib and abatacept either separately or combined may have an emerging role in treating ILD in JDM although more studies are needed.
Learning points
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Cyclophosphamide is an uncommon but not exceedingly rare cause of liver injury, although this is usually by sinusoidal obstructive syndrome.
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Cyclophosphamide may cause acute liver injury in a hepatocellular pattern, as seen in this patient.
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There may be an evolving role for the use of abatacept and tofacitinib either independently or in combination for the treatment of connective tissue disease-associated ILD, but especially MDA5 JDM-associated ILD.
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The differential of liver injury in patients with autoimmune disease is broad and includes both the manifestations of their underlying disease, and the medications needed to control their disease.
Ethics statements
Patient consent for publication
Footnotes
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Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: CC and YZ. The following authors gave final approval of the manuscript: CC and YZ.
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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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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
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