Digestive Diseases and Sciences, Vol. 50, No. 2 (February 2005), pp. 314–316 ( C  2005) DOI: 10.1007/s10620-005-1601-5 CASE REPORT Nodular Regenerative Hyperplasia of the Liver and Castleman’s Disease: Potential Role of Interleukin-6 AYAKO KIYUNA, MD, TAKASHI SUNAGAWA, MD, AKIRA HOKAMA, MD, MASATO TOUYAMA, MD, RYOSAKU TOMIYAMA, MD, HIROSHI SAKUGAWA, MD, FUKUNORI KINJO, MD, and ATSUSHI SAITO, MD KEY WORDS: nodular regenerative hyperplasia; Castleman’s disease; interleukin-6. Nodular regenerative hyperplasia (NRH) of the liver is a rare disorder that is often associated with collagen diseases and hematological diseases. We herein describe a case of NRH associated with Castleman’s disease. We discuss the potential role of interleukin-6 (IL-6) in the pathogenesis of NRH. CASE REPORT A 45-year-old man presented in September 1999, with a 9-year history of weakness, fatigue, intermittent fever, and liver dysfunction. He had had muscle atrophy of the right arm due to cervical spondylosis. On examination, he was afebrile and had nontender cervical lymphadenopathy and splenomegaly. Laboratory evaluation revealed an increased erythrocyte sedi- mentation rate (91 mm/hr) and C-reactive protein (73.4 mg/L), with a normal white blood cell count (6.4 × 10 9 /L). Other val- ues were as follows—hemoglobin, 11.8 g/dL; platelet count, 17.9 × 10 9 /L; alkaline phosphatase, 1020 IU/L (normal value [NV], 80–260); γ -glutamyl transpeptidase, 102 IU/L (NV, 10– 65)—and the rest of the liver function tests were normal. He had hyperglobulinemia: total protein was 82 g/L (NV, 67–83), of which 35 g/L was albumin, and the serum immunoglobu- lin showed an excess of polyclonal IgG at 29.9 g/L (NV, 8.7– 17), IgM at 2.1 g/L (NV, 0.3–1.9), and IgA at 7.36 g/L (NV, 1.1–4.1). Serum markers of viral, autoimmune, and metabolic causes of liver dysfunction were negative. A liver biopsy was performed, which showed the nodular formation displacing the normal liver parenchyma and fibrous expansion of the portal tract with chronic inflammatory infiltrate (Figure 1). These find- ings were consistent with NRH of the liver. Infectious diseases Manuscript received July 18, 2004; accepted July 23, 2004. From the First Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan. Address for reprint requests: Dr. Akira Hokama, First Department of Internal Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan; hokama-a@med.u-ryukyu.ac.jp. and multiple myeloma were excluded; however, the patient’s puzzling abnormalities were unexplained. Over the next 3 years his condition remained unchanged. In June 2002, he admitted to our hospital with long-standing weakness and acute-onset diarrhea. The known laboratory abnormalities remained, and, in addition, serum IL-6 was elevated (30.5 pg/ml; NV, <4.0). CT confirmed a 3-cm, well-circumscribed lymphadenopathy in the right cardiophrenic region (Figure 2) and multiple enlarged lymph nodes of the paraoesophageal and paraceliac artery re- gion. As the lymphadenopathy was suspected to relate to his long-lasting disorder, the cardiophrenic node was removed with video-assisted thoracoscopic surgery. The lymph node was com- posed of germinal follicles surrounded by an “onion skin” ar- rangement of lymphocytes (Figure 3). Flow cytometry analysis of the lymphocytes from the specimen showed no monoclonal population, and large quantities of IL-6 without any significant production of other cytokines were detected in the supernatant of cultured lymph nodes. The histopathological diagnosis was multicentric Castleman’s disease of plasma cell type. We treated the patient with predonisolone, which dramatically improved his long-standing clinical and laboratory abnormalities. He has re- mained well for 2 years. DISCUSSION Castleman’s disease (angiofollicular lymph node hy- perplasia), first described in 1956 (1), is an uncommon polyclonal lymphproliferative disorder characterized by enlarged hyperplastic lymph nodes with marked vascu- lar proliferation. It has been classified into two sub- types: the hyaline–vascular and plasma cell types. The latter is frequently associated with systemic manifesta- tions. The precise pathogenesis of this disease remains unknown; however, dysregulated overproduction of IL- 6 from affected lymph nodes has been postulated to be responsible for lymphoproliferation and plasma cell dif- ferentiation, leading to the systemic manifestations (2). 314 Digestive Diseases and Sciences, Vol. 50, No. 2 (February 2005) 0163-2116/05/0200-0314/0 C  2005 Springer Science+Business Media, Inc.