Received for Publication: August 7, 2006

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1 447 Case Report St. Marianna Med. J. Vol. 34, pp , 2006 Analysis of Interleukin 2 Receptor IL-2R and Type III Procollagen-N-peptide P-III-P in a Case of Retroperitoneal Fibrosis Haruyuki Takama 1, Naoko Shirai 1, Rieko Koganei 1, Ryusei Obi 1, Akihiko Kondo 1, Takuyuki Katabami 1, Yasushi Tanaka 1, and Nobuhiko Saito 2 Received for Publication: August 7, 2006 Abstract A case of retroperitoneal fibrosis is described along with serological findings during the therapeutic course. An 81-year-old man with diabetes mellitus treated by insulin therapy was admitted because of bilateral pretibial edema. Abdominal computed tomography demonstrated tumorous lesions around the abdominal aorta and the hilum of the spleen. Open biopsy specimens showed excessive production of fibrous tissue and chronic inflammatory cells. We therefore diagnosed this case as retroperitoneal fibrosis and administered prednisolone. Serological abnormalities included the elevation of C-reactive protein, interleukin 2 receptor IL-2R and type III procollagen-n-peptide P-III-P before the start of therapy. These levels improved simultaneously with the reduction of the tumorous lesions around the abdominal aorta and the hilum of the spleen. We considered IL-2R to be a marker indicating activation of retroperitoneal fibrosis, and P-III-P demonstrated the excessive production of collagen fibers in this disease. Key Words Retroperitoneal fibrosis, Interleukin 2 receptor, Type III procollagen-n-peptide Introduction Retroperitoneal fibrosis is considered a chronic inflammatory disease that occurs by an autoimmune process 1 3. Although, there have been many reports, few cases have described serological abnormalities. We report here a case of retroperitoneal fibrosis with analysis of interleukin 2 receptor IL-2 R and type III procollagen-n-peptide P-III-P. IL-2R reflects the T-cell activity, and is elevated in malignant lymphoma or autoimmune disease. P- III-P reflects excessive production of collagen fibers. Case Report An 81-year-old man was admitted to our hospital because of pretibial edema in November He had been diagnosed as having diabetes mellitus and was being treated by insulin therapy. The pretibial edema had initially occurred in August 2004 and despite repeated episodes of improvement, had become worse. Physical examination on admission demonstrated splenomegaly and pretibial edema. The right side of the extremities showed brown pigmentation, and sclerotic changes such as elephantiasis were found. Laboratory data on admission demonstrated normocytic normochromic anemia and the erythrocyte sedimentation rate was 154 mm in an hour, but there was no abnormality in leukocytes. The serum levels of g-globulin, blood urea nitrogen, creatinine, C-reactive protein CRP, and IL-2R were elevated. On the other hand, serum iron level and total iron binding capacity were decreased Table 1. Abdominal computed tomography CT demonstrated a tumorous lesion extend- 1 Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 2 International University of Health and Welfare, Mita Hospital, Tokyo. 235

2 448 Takama H Shirai N et al Table 1. Laboratory Data on Admission Fig. 1. CT findings on admission A: Abdominal CT demonstrated that a tumorous lesion existed around the bifurcation of the abdominal aorta arrows. B: A tumorous lesion was also detected in the hilum of the spleen and splenomegaly was seen arrows. ing from around the abdominal aorta to the bilateral iliac artery. The tumorous lesion was also present in the hilum of the spleen and around the splenic artery. Splenomegaly was noted Fig. 1. Gallium-67 scintigraphy demonstrated abnormal accumulation in the lower abdomen and on the left side of the abdomen in association with the tumorous lesions of CT Fig. 2. Open biopsy specimens obtained by laparotomy showed excessive production of fibrous tissue, and lymphocytosis indicating chronic inflammation Fig. 3. Thus, the diagnosis was retroperitoneal fibrosis with bilateral pretibial edema in the extremities due to compression of the inferior vena cava. Splenomegaly occurred because of compression of the splenic vein, in resulting anemia associated with the chronic inflammatory process. The etiology of retroperitoneal fibrosis was investigated in relation to immunological disorder and malignant tumor. As a result, antinuclear antibody was positive and anti ds-dna IgG was slightly elevated, but there were no symptoms suggesting collagen disease Table 2. Chest X-ray did not show any abnormalities, and chest CT revealed a ground glass opacity lesion. Gastrointestinal fiberscopy showed atrophic gastritis, but colon fiberscopy results were normal. Therefore, we diagnosed this patient as having idiopathic retroperitoneal fibrosis. 236

3 IL-2R and P-III-P in retroperitoneal fibrosis 449 Discussion Fig. 2. Gallium-67 scintigraphy on admission demonstrated abnormal accumulation arrows in association with the tumorous lesions of abdominal CT Prednisolone was administered, and it was very e#ective. Two days after the start of 30mg per day of prednisolone, pretibial edema subsided, and the dose of diuretics was decreased. Twelve days later, abdominal CT demonstrated that the tumorous lesions around the abdominal aorta and hilum of the spleen had decreased in size. Three weeks after the start of prednisolone, the serum IL-2R level had decreased from 3500IU L to 856IU L with a decrease in the CRP level simultaneously. Thereafter, IL-2R and CRP levels decreased over time despite tapering of the prednisolone dose IL-2R was 553 IU L and CRP was 0.16 mg dl on 10 May. The P-III-P level measured before the start of treatment was 6.1U ml, and was 0.8U ml in the three months later after the start of prednisolone Fig. 4. The tumorous lesions subsided, and the area traced at the level of the bifurcation of the abdominal aorta showed a reduction of about 90 after forty days Fig. 5. Gallium-67 scintigraphy did not show any abnormal accumulation compared with that before treatment Fig. 6. Tumorous lesions around the aorta and hilum of the spleen and splenomegaly did not worsen after tapering of the prednisolone dose, the symptoms of pretibial edema were not recurrent and improved anemia. Retroperitoneal fibrosis is considered a chronic inflammatory disease due to an autoimmune response to plaque on the arteries. Parums et al. speculated that the etiology is an immnoreaction to lipoprotein in the plaques, and found elevated antibodies to ceroid and oxyidized low-density lipoprotein 4. However, the course of the development of this disease is not yet clearly known. Retroperitoneal fibrosis occurs secondary to various diseases such as collagen disease or malignant tumor 1 3. Furthermore, the condition can be induced by some drugs, for example, pergolide those administered in the treatment of Parkison s disease 5. In our patient, there was no neoplasm detected by various examinations, and there was no history of medication known to cause this disease. Although antinuclear antibody was positive and the anti ds-dna IgG level was slightly elevated, we considered that this case was idiopathic retroperitoneal fibrosis because the symptoms were unclear. Retroperitoneal fibrosis caused obstruction of the retroperitoneal structures, notably the ureters. In a few reported cases, fibrosis was complicated in the mediastinum, thyroid, and bile duct, but the frequency of the occurrence around the spleen is unknown 6. Many references were published by urologists and surgeons, but there were few reports describing the serological findings. It was previously reported that hyper-g-globulinemia and gallium-67 scintigraphy can be markers demonstrating activation because this disease is a chronic inflammatory condition like sarcoidosis 6, 7. Concerning the various laboratory findings in this case during the course of therapy, the serum level of CRP elevation and hyperproteinemia due to hyper-g-globulinemia were seen because of the chronic inflammatory process. We also found normocytic normochromic anemia due to iron deficiency and hyersplenism. The occlusion of the bilateral ureter tracts by retroperitoneal fibrosis induced renal dysfunction. Indeed, IL-2R was measured because we strongly suspected malignant lymphoma. Therefore, we selected open biopsy for further examination and did not carry out immunological staining for Interleukin 2 IL-2. After prednisolone was started, the CRP and IL-2R levels also decreased. In the same way, abdominal CT showed that the size of the tumorous lesions and splenomegaly improved with the IL-2R level simultaneously. IL-2 is secreted 237

4 450 Takama H Shirai N et al Fig. 3. A: The tissue obtained from the tumor around the abdominal aorta by laparotomy shows excessive fibrosis and infiltration of lymphocytes. ῌHEῐ400 B: The tissue obtained from the tumor around the abdominal aorta shows excessive fibrosis and lymphocytic infiltration ῌarrows with peritoneal fatty tissue ῌarrow heads. HE ῐ200 C: Lymphocytes are positive for immunostaining of CD3. D: Lymphocytes are positive for immunostaining of CD20. Table 2. Laboratory Data on Admission 238

5 IL-2R and P-III-P in retroperitoneal fibrosis 451 Fig. 4. Clinical course After the start of 30mg per day prednisolone, pretibial edma was improved. IL-2R level decreased with the CRP level simultaneously despite tapering of the prednisolone dose. P-III-P was 6.1U ml, and normalized three months later after the start of prednisolone. Fig. 5. CT findings during treatment A: Abdominal CT demonstrated decreased size of the tumorous lesion around the bifurcation of the abdominal aorta. B: The tumorous lesion in the hilum of the spleen and splenomegaly were improved during treatment. 239

6 452 Takama H Shirai N et al CD3 and CD20 but they are not specific for any disease. Thus, the discussion of a specific lymphocyte marker in retroperitoneal fibrosis is very important. Reference Fig. 6. Gallium-67 scintigraphy during treatment demonstrated no abnormal accumulation from T-cells, and is a growth factor. IL-2R increases with the secretion of IL-2 8 Namely, activation of the autoimmune process leads to the elevation of IL-2 and IL-2R. On the other hand, P-III-P level in our case normalized three months later after the start of treatment. P-III-P is a marker indicating production of collagen fibers, but does not indicate accumulation. Therefore, we considered that IL-2R indicates the activity of retroperitoneal fibrosis, whereas P-III-P is a marker of excessive production of collagen fibers in this disease. Immunological staining of the open biopsy tissue was positive for 1 van Bommel EF. Retroperitoneal fibrosis. Neth J Med 2002; 12: Vaglio A and Buzio C. Chronic peraortits: a spectrum of disease. Curr Opin Rheumatol 2005; 17: Monev S. Idiopathic retroperitoneal fibrosis: prompt diagnosis preserves organ function. Cleve Clin J Med 2002; 69: Parums DV. Serum antibodies to oxidized lowdensity lipoprotein and ceroid in chronic periaortitis. Arch Pathol Lab Med 1990; 114: Bilici A, Karadag B, Doventas A, Erdincler DS, Cetinkaya S, Ogut G, Tezcan V, and Beger T. Retroperitoneal fibrosis caused by pergolide in a patient with Parkinson s disease. Neth J Med 2004; 62: Tada Y and Nagasawa K. Retroperitoneal fibrosis. Nippon Naika Gakkai Zasshi J Jpn Soc Intern Med 2001; 90: Ohteki T Tomida C, Goto M, Usui J, Muro K, Yamagata K and Koyama A. Recurrent retroperitoneal fibrosis associated with hyperglobulinemia. Nippon Naika Gakkai Zasshi J Jpn Soc Intern Med 2000; 89: in Japanese 8 Rubin LA, and Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med 1990; 113:

7 IL-2R and P-III-P in retroperitoneal fibrosis III -N CT 30 mg 2 interleukin-2 receptor: IL-2R 3500U ml, III -N- type III procollagen-n-peptide: P-III-P 6.1U ml, CRP 1.3 mg dl IL-2R P-III-P