Successful Treatment With Cyclosporine in a Caseof Hemophagocytic Syndrome Manifesting as Severe Liver Dysfunction

Successful Treatment With Cyclosporine in a Case of Hemophagocytic Syndrome Manifesting as Severe Liver Dysfunction KATSUHISA OMAGARI, MD,* RYUICHI ASHIDA, MD,* HIDEO OH-I, MD,* YASUSHI MINAMINO, MD,* OSAMU SASAKI, MD,* YOSHIYUKI OZONO, MD,* TAKAHIRO MAEDA, MD,t NAOKI SADAMORI, MD,t MASAO TOMONAGA, MD,t SHIGERU KOHNO, MD*

ABSTRACT: Forms of hemophagocytic syndrome, which affects mainly children, vary from mild to very severe and often fatal. We describe an adult patient with hemophagocytic syndrome in whom severe liver dysfunction developed. The condition continued to deteriorate despite treatment with plasma exchange, high-dose gamma globulin, and corticosteroid therapy. Treatment with cyclosporine (2.3 mg/ kg/day) dramatically improved the condition and normalized liver function. Cyclosporine reduced the serum levels of ferritin, interferon-T, interleukin-6, and soluble interleukin-2 receptor. These findings suggest that hemophagocytic syndrome accompanied with severe liver dysfunction results from hypercytokinemia, and cyclosporine is useful in preventing a fatal outcome during the acute phase. KEY INDEXING TERMS: Hemaphagocytic syndrome; Cyclosporine; Liver dysfunction. [Am J Med Sci 1997;314(6):403-407.]

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emophagocytic syndrome (HPS) is a rare disorder characterized by a group of clinical and histopathologic features, such as fever, pancytopenia, hepatosplenomegaly, liver dysfunction, hypertriglyceridemia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. 1 - 3 Although its clinical features are well described, the precise etiologic and pathophysiologic mechanisms of HPS reFrom the *Second Department of Internal Medicine and tthe Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan. Submitted May 23, 1997; accepted in revised form July 16, 1997. Correspondence: Katsuhisa Omagari, MD, Second Department of Internal Medicine, Nagasaki University School of Medicine, 17-1 Sakamoto, Nagasaki 852, Japan. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

main unknown. It has been suggested that uncontrolled T cells producing excessive amounts of interferon (lFN)-T and other cytokines may play a key role in the development of hemophagocytosis. 4 In the present report, we describe an adult patient with HPS manifesting as severe liver dysfunction who was successfully treated with cyclosporine (esA), which selectively suppresses the cytokine production of helper T cells. 5 •s We also reported changes in serum levels of ferritin, IFN-T, interleukin (lL)-6 and soluble IL-2 receptor (sIL-2R) before and after treatment. Case Report A 26-year-old woman was referred to Nagasaki University Hospital, Japan, in June 1996 for investigation of fever and liver dysfunction. Persistent high fever developed 2 weeks after her second normal delivery of a neonate in May 1996, and subsequently she was found to have liver dysfunction based on abnormal liver enzymes. History was negative for any liver disease, and she had never received a blood transfusion. There was no family history of liver diseases. Physical examination at admission showed a fever of 39.1 °C, jaundice, and marked hepatosplenomegaly. The serum level of total bilirubin was 9.2 mg/dL (normal value, < 1.0 mg/dL), aspartate aminotransferase level was 842 lUlL, alanine aminotransferase level was 326 lUlL, lactate dehydrogenase level was 7,130 lUlL, ammonia level was 89 tLg/dL and serum ferritin level was 10,000 ng/mL. Serum level of endotoxin was within normal range. Red blood cell count was 4.32 x 1012IL, hemoglobin level was 10.9 g/dL, white blood cell count was 4.7 X 109IL (lymphocyte count 0.8 X 109IL), and platelet count was 76 X 109IL. Prothrombin time was 19.3 seconds (30%). All test for serum markers for hepatitis B virus infection, antibodies to hepatitis C virus (second-generation enzyme-linked immunosorbent assay), hepatitis B virus-DNA, hepatitis C virus-RNA and hepatitis GB virus CRNA by polymerase chain reaction test, immunoglobulin M antibody to hepatitis A virus and human Tcell leukemia virus type I antibodies, were all negative. Her serum was also negative for autoantibodies, including antinuclear antibodies, anti-smooth muscle antibodies and antimitochondrial antibodies by indirect immunofluorescence. In addition, results of serologic tests for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, parainfluenza virus, parvovirus B19, and human herpesvirus-6 were negative. Computed tomography of the abdomen revealed marked hepatosplenomegaly with a fatty liver and

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HPS Treated With CsA

Figure 1. Histolopathologic examination ofthe liver biopsy specimen obtained in June 1996 showing necroinflammatory changes in the parenchyma and moderate macrovesicular steatosis. The presence of histiocytosis in the portal tracts is uncertain. (Hematoxylin-eosin stain, magnification X 33)

minimal ascites. Examination of a liver biopsy specimen showed necroinflammatory changes in the parenchyma and moderate macrovesicular steatosis (Figure 1). Bone marrow aspirate revealed marked proliferation of mature histiocytes, including hemophagocytes (Figure 2). A diagnosis of HPS was made based on these clinical and laboratory findings. The patient was treated using plasma exchange, two courses of high-dose intravenous gamma globulin therapy (20 g/day for 5 days) and two courses of pulse therapy of methylprednisolone (2 g/day intravenously for 3 days). However, treatment

was ineffective, and her condition gradually deteriorated; liver dysfunction worsened, serum total bilirubin increased to 26.9 mgt dL, and she had a persistent high fever. Subsequent bone marrow smears still showed hemophagocytosis. Therefore, CsA was administered in August 1996 at a dosage of 2.3 mg/kg/day intravenously for 5 weeks and was continued orally at a dosage to maintain serum levels within the therapeutic range of 200 ng/mL to 250 ng/mL. During the next 2 weeks, platelet count returned to within normal range, and bone marrow aspirate in October 1996 showed no evidence of hemophagocytosis. Within 3 months, se-

Figure 2. Photomicrograph of a bone marrow specimen showing marked proliferation of mature histiocytes, including hemophagocytes. (May-Giemsa stain, magnification x 1,000)

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Figure 3. Histopathologic examination ofthe liver biopsy specimen obtained after treatment with cyclosporine showing fibrous portal expansion accompanied with mild necroinflammatory reaction and mild macrovesicular steatosis. (Hematoxylin-eosin stain, magnification X 25)

rum total bilirubin gradually returned to within normal limits and CsA administration was tapered. Computed tomography of the abdomen in November 1996 showed hepatosplenomegaly but no fatty liver. A liver biopsy specimen obtained during the same month showed fibrous portal expansion with mild necroinflammatory reaction and mild macrovesicular steatosis (Figure 3). Serum levels of ferritin, IFN-T, IL-6, and sIL-2R, measured in July 1996, showed a marked improvement when tests were repeated after CsA treatment (December 1996). The serum ferritin level decreased from 18,285 ng/mL to 20.9 ng/mL (normal range, 20 ng/mL to 70 ng/mL), the IFN-T level decreased from 5.6 lUI mL to 0.6 IU/mL (normal value, < 0.5 IU/mL), the IL-6 level decreased from 31.4 pg/mL to 1.6 pg/mL (normal value, < 54.9 pg/mL), and the level of sIL-2R decreased from 5,170 U/mL to 200 U/mL (normal range, 145 U/mL to 519 U/mL) (Figure 4). The patient remains well and results of liver function tests were normal at the latest follow-up in May 1997.

Discussion

Hemophagocytic syndrome has been described in association with a various infections, neoplasms, administration of drugs, or other disorders. 1- 3,7 In this young woman in the postpartum period, an autoimmune cause can be suspected for the HPS that is not attributable to the presence of neoplasm or a recognized infection. 7,8 Moreover, autoimmune diseases (eg, systemic lupus erythematosus) may respond to the administration of CsA; however, there was no evidence of such disorders in this patient. Several recent studies have reported elevated serum concentrations of cytokines in HPS, including IFN-T, sIL-2R, IL-1, IL-6, and tumor necrosis factora. 9 - 12 It has been suggested that uncontrolled T cells producing excessive amounts ofIFN-T and other cytokines may playa major role in the development of HPS. 4 Fujiwara et al. 12 reported that the presence THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

of high serum concentrations of IL-6 (> 300 nglL), IFN-T (> 30 U/mL) , and sIL-2R (> 10,000 U/mL) could be markers of poor prognosis in HPS patients. Therefore, anticytokine therapy could be effective in preventing a fatal outcome, at least during the acute phase of HPS. Several forms of treatment, including splenectomy, corticosteroid administration, plasma exchange, high-dose gamma globulin therapy,t3 and etoposide administration,2 have been used for HPS, producing limited success. 14 Based on the identification that hypercytokinemia, caused by uncontrolled T -cell activation, may playa major role in HPS, recent studies reported a successful treatment of HPS using CsA, which inhibits the production of various cytokines using helper T cells. 4,15,16 In the present report, we described an adult patient who was successfully treated with CsA, and reported serial changes in serum levels of a number of cytokines to provide further evidence for this mechanism and effectiveness of CsA in HPS. Administration of CsA suppressed the high serum levels of ferritin, IFN-T, IL-6, and sIL-2R, although the serum concentrations before treatment were not at the criticallevels. 12 The present case showed severe liver dysfunction with marked and persistent elevation of serum total bilirubin. Abnormalities of liver function tests frequently accompany HPS,t7 and thus, the condition may be mistaken for primary hepatocellular disease, despite initial extensive clinical evaluation. Liver dysfunction in HPS may be caused by the causal viruses (eg, human herpesvirus-6,18-19 hepatic

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HPS Treated With CsA

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Figure 4. Clinical course. Administration of cyc1osporine (CsA) decreased serum ferritin, interferon-T, interleukin-6, and soluble IL2 receptor. Platelet (PLT) count, total bilirubin (T. Bil) levels, and alanine aminotransferase (ALT) levels returned to normal levels after the administration of CsA therapy.

lymphoma,20 or inappropriate activation of Kupffer cells}. Histologic findings in the liver of patients with HPS include Kupffer cell hyperplasia accompanied with hemophagocytosis. Beaugrand et a1. 21 postulated that jaundice and hepatic abnormalities in malignant histiocytosis were consequences of Kupffer cell dysfunction because activation of Kupffer cells may reduce the clearance of endotoxins. Arai et aJ.2 2 also reported that activated Kupffer cells and hepatic macrophages may contribute to the development of liver injury and hepatocyte necrosis. The cause of liver dysfunction in this case is unclear because the serum level of endotoxin was normal, and the liver biopsy specimen did not show evidence of these abnormalities. Hemophagocytic syndrome should be considered when liver dysfunction is accompanied with high fever and progressive cytopenia. The present case suggests that HPS accompanied with severe liver dysfunction results from hypercytokinemia and that

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CsA administration is useful in preventing the potentially serious consequences of this disease. References 1. Henter J-I, Elinder G, Ost A. Diagnostic guidelines for

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ohistiocytosis: Experience at two U.K. centres. Br J Haematol. 1994;88:731-9. 15. Imashuku S, Hibi S. Cytokines in haemophagocytic syndrome. Br J Haematol. 1991;77:438-40. 16. Watson HG, Goulden NJ, Manson LM, McDermid G, Gray JA, Parker AC. Virus-associated haemophagocytic syndrome: Further evidence for a T-cell mediated disorder. Br J Haematol. 1994;86:213-5. 17. Reiner AP, Spivak JL. Hematophagic histiocytosis: A report of 23 new patients and a review of the literature. Medicine. 1988;67:369-88. 18. Huang L-M, Lee CoY, Lin K-H, Chuu W-M, Lee P-I, Chen R- L, et al. Human herpesvirus-6 associated with fatal haemophagocytic syndrome. Lancet. 1990;336:60-1. 19. Asano Y, Yoshikawa T, Suga S, Yazaki T, Kondo K, Yamanishi K. Fatal fulminant hepatitis in an infant with human herpesvirus-6 infection. Lancet. 1990;335:862-3. 20. King PD, Diaz-Arias AA, Birkby WF, Loy TS. Reactive hemophagocytic syndrome simulating acute hepatitis. A case due to hepatic peripheral T-cell lymphoma. J Clin Gastroenterol. 1994; 19:234-7. 21. Beaugrand M, Trinchet JC, Callard P, Ferrier JP. Malignant histiocytosis presenting as a fulminant hepatic disease. Gastroenterology. 1983;84:447-8. 22. Arai M, Mochida S, Ohno A, Ogata I, Fujiwara K. Sinusoidal endothelial cell damage by activated macrophages in rat liver necrosis. Gastroenterology. 1993; 104:1466-71.

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