Rheumatology Advance Access originally published online on December 6, 2007
Rheumatology 2008 47(2):226-227; doi:10.1093/rheumatology/kem316
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An unusual cause of abnormal liver function in a patient with rheumatoid arthritis
Royal Hallamshire Hospital, Glossop Road, Sheffield, UK.
Correspondence to: J. G. Boulton. E-mail: jgboulton{at}btinternet.com
SIR, A 70-yr-old male with long-standing seropositive rheumatoid arthritis (RA) was seen as part of his routine follow-up. His disease had been difficult to control, requiring numerous joint replacements, and over the last several years he had been managed with a combination of i.m. gold and methotrexate. Three months prior to review these were stopped and he had been commenced on adalimumab.
On review, his joints were quiescent, but he complained of vague abdominal discomfort. Routine bloods revealed CRP 87, Alk P 359, ALT 253, AST 175, GGT 362 and bilirubin 32. He was reviewed again a few days later and described himself as being well, denying any recent infection, alcohol use or weight loss. Examination revealed 2 cm of tender hepatomegaly.
Further investigation revealed an elevated Epstein–Barr virus (EBV) immunoglobulin (Ig)M suggesting recent EBV infection. His ultrasound abdomen revealed numerous echo-poor lesions throughout the liver, which were suspicious for metastatic deposits. CT imaging revealed no evidence of a primary neoplasm and no lymphadenopathy. The lesions were poorly visualized, and CT appearances were not typical for metastases. Therefore, other causes such as hepatic abscess were considered.
While an inpatient, he was noted to have a swinging pyrexia. A blood culture grew coagulase-negative Staphylococcus that was considered to be a contaminant. However, on the advice of Infectious Diseases Department, he was commenced on i.v. flucloxacillin and co-amoxiclav. His pyrexia remained despite antibiotic therapy. Further cultures were negative.
After initial reluctance by the Radiology Department, he underwent an ultrasound-guided liver biopsy. Histology revealed infiltration by tumour cells. Immunohistochemical staining was positive for CD45, CD20 and BCL-6. Proliferation rate was >95%. This was consistent with high-grade non-Hodgkin's lymphoma (NHL) of diffuse large B-cell subtype. A bone marrow examination did not reveal any evidence of infiltration. The antibiotics were stopped and he was treated with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab) therapy. His liver function tests normalized within 2 weeks of induction. At present, he is currently maintained in remission, with his arthritis also much improved as a result of his chemotherapy.
RA is thought to develop as a result of immuno-incompetence, with evidence of contraction of T-cell diversity and premature ageing of the immune system. Immune failure, especially impairment of T-cell function is thought to be the main risk factor for the development of NHL [1]. EBV replication may be associated with impairment of T-cell function and a high EBV load is frequently implicated in the pathogenesis of lymphoma [2]. This may explain a mechanism for the increased incidence of lymphoma in RA. While essentially a disease related to T-cell dysfunction, lymphomas occurring in RA are predominantly NHL, and more specifically of diffuse large B-cell subtypes. Chronic B-cell stimulation, at the germinal centre stage of development, results from T-cell-dependent antigen exposure. Mutations in the variable region Ig genes occur, causing B-cell proliferation and lymphomagenesis. Furthermore, increased resistance to apoptosis that occurs in many autoimmune conditions may enhance the carcinogenic effects of chronic B-cell proliferation [3].
In the past, a number of disease-modifying drugs have been implicated in the development of lymphoma. Although epidemiological studies have not found any association between methotrexate use and the development of lymphoma, there are reports of individuals developing lymphoma while taking methotrexate. A significant proportion of these are EBV positive and NHL often regresses following cessation of methotrexate [4, 5]. Anti-tumour necrosis factor (TNF) therapies have revolutionized the management of RA. Recent studies suggest that the risk of lymphoma may not be increased beyond that of the general population of RA patients [6].
Primary hepatic lymphoma (PHL) is rare; accounting for <1% of all extra-nodal lymphomas. Patients classically present complaining of abdominal pain and nausea [7], with B symptoms (fevers, night sweats and weight loss) present in 37–86% of the cases. Hepatomegaly and abnormal liver function tests are found in the majority. PHL may present as a solitary mass or multiple lesions, the pattern being of little or no prognostic value [8]. Diagnosis of PHL can often be complex. Ultrasonographic appearance may mimic metastases, abscess formation and liver cirrhosis, and CT scanning does not provide better results for similar reasons [9, 10]. Tissue diagnosis is therefore of paramount importance.
Although a rare cause of abnormal liver function, this case highlights the need for adequate investigation. PHL often presents with non-specific features and mimics a number of other conditions. Abnormal liver function in RA patients may not always be related to drugs. Tissue sampling is essential in the investigation and management of patients whose differential diagnosis lies between infection, malignancy and adverse drug reaction.
Disclosure statement: The authors have declared no conflicts of interest.
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 Top References |
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- Weyand CM, Goronzy JJ, Kurtin PJ. Lymphoma in rheumatoid arthritis: an immune system set up for failure. Arthritis Rheum (2006) 54:685–9.[CrossRef][Web of Science][Medline]
- Knowles DM. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol (1999) 12:200–17.[Web of Science][Medline]
- Ekstr
m SK, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-hodgkin lymphoma by subtype. J Natl Cancer Inst (2006) 98:51–60.[Abstract/Free Full Text] - Georgescu L, Quinn GC, Schwartzmann S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with disease state or Methotrexate treatment. Semin Arthritis Rheum (1997) 14:1943–9.
- Dawson TM, Starkebaum G, Wood BL, Willkens RF, Gown AM. Epstein-Barr virus, methotrexate and lymphoma in patients with rheumatoid arthritis and primary Sjgren's syndrome: case series. J Rheumatol (2001) 28:47–53.
[Abstract/Free Full Text] - Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis (2005) 64:1421–6.
[Abstract/Free Full Text] - Lei K. Primary non-Hodgkin's lymphoma of the liver. Leuk Lymphoma (1998) 29:293–9.[Web of Science][Medline]
- Page RD, Romangura JE, Osborne B, et al. Primary hepatic lymphoma. Favorable outcome after combination chemotherapy. Cancer (2001) 92:2023–9.[CrossRef][Web of Science][Medline]
- Ginaldi S, Bernardino ME, et al. Ultrasonographic patterns of hepatic lymphoma. Radiology (1980) 136:427–31.
[Abstract/Free Full Text] - Zornoza J, Ginaldi S. Computed tomography in hepatic lymphoma. Radiology (1981) 138:405–10.
[Abstract/Free Full Text]
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