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Pyrexia, Massive Hepatomegaly, and Extreme Hyperferritinemia
CLINICAL COMMUNICATION TO THE EDITOR
Pyrexia, Massive Hepatomegaly, and Extreme Hyperferritinemia To the Editor: A 39-year-old woman presented with pyrexia. Extensive investigations showed negative results. On referral, she was febrile (41 C) and jaundiced, with a massive hepatomegaly to the pelvis.
CLINICAL SUMMARY Investigations showed a hemoglobin level of 9.3 g/dL, leukocyte level of 2.3109/L, platelet level of 162109/L, bilirubin level of 76 (4-23) mmol/L, alanine aminotransferase level of 94 (7-36) IU/mL, aspartate aminotransferase level of 94 (14-30) IU/mL, and alkaline phosphatase level of 824 (32-93) IU/mL. Serologic markers for autoimmune diseases were negative. Serum ferritin, measured by a 2-site chemiluminometric assay with the World Health Organization standard 80/578, was elevated to 883,100 (25-275) pmol/L. Bone marrow examination showed hemophagocytosis (Figure 1A, B) and 10% atypical lymphoid cells. Polymerase chain reaction for T-cell receptor alpha, beta, and gamma genes showed polyclonal bands, excluding a T-cell lymphoma. Positron emission tomography and computed tomography showed eumetabolic massive hepatomegaly (Figure 1C, D). Liver biopsy showed moderate mixed macrovesicular and microvesicular steatosis (Figure 1E, F). Two months after presentation, hepatic failure developed, and liver allografting was considered. However, there was improvement after prednisolone (1 mg/kg) therapy. One month later, a salmon-pink rash developed on the patient’s face and trunk. Adult-onset Still’s disease was diagnosed. She was treated with intravenous tocilizumab (8 mg/kg), resulting in defervescence within 1 day, liver decreasing to 10 cm within 1 week, and ferritin decreasing to 42,505 pmol/L. Her blood counts normalized after the second dose of tocilizumab. The addition of cyclosporin with tocilizumab (8 mg/kg every 4 weeks) ultimately led to complete Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Yok-Lam Kwong, MD, Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
remission. At the latest follow-up 22 months afterward, she was entirely asymptomatic.
DISCUSSION Adult-onset Still’s disease is diagnosed by Yamaguchi et al’s1 definition (2 major criteria: fever, arthralgia, typical rash, and leukocytosis; and other minor criteria: sore throat, lymphadenopathy or splenomegaly, liver dysfunction, absence of rheumatoid factor, and antinuclear antibody).1 Our case did not initially qualify, but the typical rash appeared 3 months after presentation, providing enough diagnostic criteria. Two findings have not been described in adult-onset Still’s disease: massive hepatomegaly due to steatohepatitis and extreme hyperferritinemia (elevated >3200 times). These disparate features might be linked by an underlying macrophage activation syndrome. Clinical features of macrophage activation syndrome, in descending prevalence, are thrombocytopenia, hyperferritinemia, marrow hemophagocytosis, impaired liver function, leukopenia, persistent fever 38 C, decreasing erythrocyte sedimentation rate, hypofibrinogenemia, and hypertriglyceridemia.2 Many of these conditions occurred in our case. The pathogenesis of macrophage activation syndrome is related to massive release of cytokines due to systemic inflammation. Our case might have evolved through the following steps. Because of the initial atypical features, the undiagnosed adult-onset Still’s disease led to a protracted state of hypercytokinemia, especially involving tumor necrosis factor-a and interleukin-6.3 Of note, tumor necrosis factor-a and interleukin-6 also are cytokines involved in the pathogenesis of nonalcoholic steatohepatitis.4 Thus, prolonged exposure of our patient to these cytokines resulted in severe steatosis and massive hepatomegaly. Furthermore, macrophages were stimulated by these cytokines, leading to hemophagocytosis. Because serum ferritin is secreted by macrophages, unchecked macrophage activation led to the extreme hyperferritinemia. The excellent response to the anti-interleukin-6 antibody tocilizumab, with subsidence of systemic symptoms, normalization of investigations, and resolution of the massive hepatomegaly and the extreme hyperferritinemia, was another validation of our proposition.
CONCLUSIONS The importance of recognizing this constellation of observations is first to distinguish it from a malignant lymphoid disease. Second and more important, targeting the
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The American Journal of Medicine, Vol 127, No 6, June 2014
Figure 1 Macrophage activation syndrome leading to massive hepatomegaly due to steatohepatitis and extreme hyperferritinemia in adult-onset Still’s disease. (A), Marrow hemophagocytosis, showing macrophage ingestion of red blood cells (arrow). (B), Macrophage ingestion of leukocytes (arrow). (C), Massive hepatomegaly down to the pelvic brim. (D), Massive hepatosplenomegaly, with the liver showing minimal fluorodeoxyglucose uptake. (E), Liver biopsy showing mixed microvesicular and macrovesicular steatosis. (F), Immunohistochemical staining for CD3, showing that the scanty small lymphoid cells were mainly T cells, most likely to be reactive.
interleukin-6 pathway provides efficacious control of the disease and its potentially fatal complications. a
Gerry Kwok, MB, BS Amanda Kan, MB, ChBb Rock Y.Y. Leung, MB,BSb Sidney Tam, MB, BSc Chak-Sing Lau, MDa Yok-Lam Kwong, MDa a
Department of Medicine, Queen Mary Hospital Hong Kong b Department of Pathology, Queen Mary Hospital Hong Kong c Department of Clinical Biochemistry, Queen Mary Hospital Hong Kong
http://dx.doi.org/10.1016/j.amjmed.2014.01.015
References 1. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992;19: 424-430. 2. Davì S, Consolaro A, Guseinova D, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011;38: 764-768. 3. Chen DY, Lan JL, Lin FJ, Hsieh TY. Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still’s disease. J Rheumatol. 2004;31:2189-2198. 4. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52: 1836-1846.
Pyrexia, Massive Hepatomegaly, and Extreme Hyperferritinemia To the Editor: A 39-year-old woman presented with pyrexia. Extensive investigations showed negative results. On referral, she was febrile (41 C) and jaundiced, with a massive hepatomegaly to the pelvis.
CLINICAL SUMMARY Investigations showed a hemoglobin level of 9.3 g/dL, leukocyte level of 2.3109/L, platelet level of 162109/L, bilirubin level of 76 (4-23) mmol/L, alanine aminotransferase level of 94 (7-36) IU/mL, aspartate aminotransferase level of 94 (14-30) IU/mL, and alkaline phosphatase level of 824 (32-93) IU/mL. Serologic markers for autoimmune diseases were negative. Serum ferritin, measured by a 2-site chemiluminometric assay with the World Health Organization standard 80/578, was elevated to 883,100 (25-275) pmol/L. Bone marrow examination showed hemophagocytosis (Figure 1A, B) and 10% atypical lymphoid cells. Polymerase chain reaction for T-cell receptor alpha, beta, and gamma genes showed polyclonal bands, excluding a T-cell lymphoma. Positron emission tomography and computed tomography showed eumetabolic massive hepatomegaly (Figure 1C, D). Liver biopsy showed moderate mixed macrovesicular and microvesicular steatosis (Figure 1E, F). Two months after presentation, hepatic failure developed, and liver allografting was considered. However, there was improvement after prednisolone (1 mg/kg) therapy. One month later, a salmon-pink rash developed on the patient’s face and trunk. Adult-onset Still’s disease was diagnosed. She was treated with intravenous tocilizumab (8 mg/kg), resulting in defervescence within 1 day, liver decreasing to 10 cm within 1 week, and ferritin decreasing to 42,505 pmol/L. Her blood counts normalized after the second dose of tocilizumab. The addition of cyclosporin with tocilizumab (8 mg/kg every 4 weeks) ultimately led to complete Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Yok-Lam Kwong, MD, Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
remission. At the latest follow-up 22 months afterward, she was entirely asymptomatic.
DISCUSSION Adult-onset Still’s disease is diagnosed by Yamaguchi et al’s1 definition (2 major criteria: fever, arthralgia, typical rash, and leukocytosis; and other minor criteria: sore throat, lymphadenopathy or splenomegaly, liver dysfunction, absence of rheumatoid factor, and antinuclear antibody).1 Our case did not initially qualify, but the typical rash appeared 3 months after presentation, providing enough diagnostic criteria. Two findings have not been described in adult-onset Still’s disease: massive hepatomegaly due to steatohepatitis and extreme hyperferritinemia (elevated >3200 times). These disparate features might be linked by an underlying macrophage activation syndrome. Clinical features of macrophage activation syndrome, in descending prevalence, are thrombocytopenia, hyperferritinemia, marrow hemophagocytosis, impaired liver function, leukopenia, persistent fever 38 C, decreasing erythrocyte sedimentation rate, hypofibrinogenemia, and hypertriglyceridemia.2 Many of these conditions occurred in our case. The pathogenesis of macrophage activation syndrome is related to massive release of cytokines due to systemic inflammation. Our case might have evolved through the following steps. Because of the initial atypical features, the undiagnosed adult-onset Still’s disease led to a protracted state of hypercytokinemia, especially involving tumor necrosis factor-a and interleukin-6.3 Of note, tumor necrosis factor-a and interleukin-6 also are cytokines involved in the pathogenesis of nonalcoholic steatohepatitis.4 Thus, prolonged exposure of our patient to these cytokines resulted in severe steatosis and massive hepatomegaly. Furthermore, macrophages were stimulated by these cytokines, leading to hemophagocytosis. Because serum ferritin is secreted by macrophages, unchecked macrophage activation led to the extreme hyperferritinemia. The excellent response to the anti-interleukin-6 antibody tocilizumab, with subsidence of systemic symptoms, normalization of investigations, and resolution of the massive hepatomegaly and the extreme hyperferritinemia, was another validation of our proposition.
CONCLUSIONS The importance of recognizing this constellation of observations is first to distinguish it from a malignant lymphoid disease. Second and more important, targeting the
e14
The American Journal of Medicine, Vol 127, No 6, June 2014
Figure 1 Macrophage activation syndrome leading to massive hepatomegaly due to steatohepatitis and extreme hyperferritinemia in adult-onset Still’s disease. (A), Marrow hemophagocytosis, showing macrophage ingestion of red blood cells (arrow). (B), Macrophage ingestion of leukocytes (arrow). (C), Massive hepatomegaly down to the pelvic brim. (D), Massive hepatosplenomegaly, with the liver showing minimal fluorodeoxyglucose uptake. (E), Liver biopsy showing mixed microvesicular and macrovesicular steatosis. (F), Immunohistochemical staining for CD3, showing that the scanty small lymphoid cells were mainly T cells, most likely to be reactive.
interleukin-6 pathway provides efficacious control of the disease and its potentially fatal complications. a
Gerry Kwok, MB, BS Amanda Kan, MB, ChBb Rock Y.Y. Leung, MB,BSb Sidney Tam, MB, BSc Chak-Sing Lau, MDa Yok-Lam Kwong, MDa a
Department of Medicine, Queen Mary Hospital Hong Kong b Department of Pathology, Queen Mary Hospital Hong Kong c Department of Clinical Biochemistry, Queen Mary Hospital Hong Kong
http://dx.doi.org/10.1016/j.amjmed.2014.01.015
References 1. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992;19: 424-430. 2. Davì S, Consolaro A, Guseinova D, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011;38: 764-768. 3. Chen DY, Lan JL, Lin FJ, Hsieh TY. Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still’s disease. J Rheumatol. 2004;31:2189-2198. 4. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52: 1836-1846.